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[ "Cryptococcus is a ubiquitous fungus and is known for causing meningitis and cutaneous infections in immunocompromised individuals. Disseminated cryptococcal infection is very rare and almost always found to occur in immunocompromised individuals especially in persons infected with HIV. This is particularly attributed to its capsulated spores. But there are few reported cases in which it has been found to cause disseminated infections even in immunocompetent individuals. We report a similar case of disseminated cryptococcal infection in an immunocompetent host. Early detection and treatment of disseminated cryptococcosis is essential to reduce morbidity and for better outcome.", "Dysphoric Milk Ejection Reflex (D-MER) is an abrupt emotional \"drop\" that occurs in some women just before milk release and continues for not more than a few minutes. The brief negative feelings range in severity from wistfulness to self-loathing, and appear to have a physiological cause. The authors suggest that an abrupt drop in dopamine may occur when milk release is triggered, resulting in a real or relative brief dopamine deficit for affected women. Clinicians can support women with D-MER in several ways; often, simply knowing that it is a recognized phenomenon makes the condition tolerable. Further study is needed.", "Severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome is a recently recognized syndrome caused by mutations in the desmoglein 1 (DSG1) and desmoplakin (DSP) genes. Only two cases of SAM-DSP have been reported. We report on a 2-year-old girl presenting with pustular lakes within areas of erythema and large accumulations of intraepidermal neutrophils, which initially led to our misdiagnosis of generalized pustular psoriasis. No mutation was found in either the IL36RN or CARD14 genes by Sanger sequencing. The distinctive manifestations of erythroderma with severe itching, hypotrichosis, enamel defects, onychodystrophy, palmoplantar keratoderma and the crucial result of de novo missense mutation in exon 14 of the DSP gene (c.1828T>C, p.S610P) discovered by next-generation sequencing finally confirmed the diagnosis of SAM syndrome. The eruptions significantly improved after a 4-week treatment with oral acitretin and topical pimecrolimus. Oral gabapentin was prescribed simultaneously for 4 months, relieving her skin pruritus and suggesting that early treatment with pimecrolimus, acitretin and gabapentin for SAM-DSP syndrome is effective. It may even inhibit multiple allergies induced by skin barrier injury. In this work we also review the clinical features, differential diagnoses and pathological manifestations of SAM-DSP syndrome.", "IMPORTANCE: Genetic testing of hereditary cancer using comprehensive gene panels can identify patients with more than one pathogenic mutation in high and/or moderate-risk-associated cancer genes. This phenomenon is known as multilocus inherited neoplasia alleles syndrome (MINAS), which has been potentially linked to more severe clinical manifestations.OBJECTIVE: To determine the prevalence and clinical features of MINAS in a large cohort of adult patients with hereditary cancer homogeneously tested with the same gene panel.PATIENTS AND METHODS: A cohort of 1023 unrelated patients with suspicion of hereditary cancer was screened using a validated panel including up to 135 genes associated with hereditary cancer and phakomatoses.RESULTS: Thirteen (1.37%) patients harbouring two pathogenic mutations in dominant cancer-predisposing genes were identified, representing 5.7% (13/226) of patients with pathogenic mutations. Most (10/13) of these cases presented clinical manifestations associated with only one of the mutations identified. One case showed mutations in MEN1 and MLH1 and developed tumours associated with both cancer syndromes. Interestingly, three of the double mutants had a young age of onset or severe breast cancer phenotype and carried mutations in moderate to low-risk DNA damage repair-associated genes; two of them presented biallelic inactivation of CHEK2. We included these two patients for the sake of their clinical interest although we are aware that they do not exactly fulfil the definition of MINAS since both mutations are in the same gene.CONCLUSIONS AND RELEVANCE: Genetic analysis of a broad cancer gene panel identified the largest series of patients with MINAS described in a single study. Overall, our data do not support the existence of more severe manifestations in double mutants at the time of diagnosis although they do confirm previous evidence of severe phenotype in biallelic CHEK2 and other DNA repair cancer-predisposing genes.", "PCSK9 (proprotein convertase subtilisin/kexin type 9) binds to the LDLR (low-density lipoprotein receptor) at the cell surface and disrupts recycling of the LDLR. However, PCSK9 also interacts with the LDLR in the ER (endoplasmic reticulum). In the present study we have investigated the role of PCSK9 for the transport of the LDLR from the ER to the cell membrane. A truncated LDLR consisting of the ectodomain (ED-LDLR) was used for these studies to avoid PCSK9-mediated degradation of the LDLR. The amount of secreted ED-LDLR was used as a measure of the amount of ED-LDLR transported from the ER. From co-transfection experiments of various PCSK9 and ED-LDLR plasmids, PCSK9 increased the amount of WT (wild-type) ED-LDLR in the medium, but not of an ED-LDLR lacking the EGF (epidermal growth factor)-A repeat or of a Class 2a mutant ED-LDLR which fails to exit the ER. Mutant PCSK9s which failed to undergo autocatalytic cleavage or failed to exit the ER, failed to increase the amount of WT-ED-LDLR in the medium. These mutants also reduced the amount of WT-ED-LDLR intracellularly, which could partly be prevented by the proteasome inhibitor lactacystine. WT-ED-LDLR promoted autocatalytic cleavage of pro-PCSK9. The findings of the present study indicate that the binding of WT-ED-LDLR to pro-PCSK9 in the ER promotes autocatalytic cleavage of PCSK9, and autocatalytically cleaved PCSK9 acts as a chaperone to promote the exit of WT-ED-LDLR from the ER.", "The authors report a male patient, a seller with no detected immunosuppression, with an extensive ulcerated skin lesion localized on the left forearm, caused by Cryptococcus neoformans var. gattii serotype B. Oral treatment with fluconazole was successful. A review of the literature showed the rarity of this localization in HIV-negative patients. In contrast, skin lesions frequently occurs in HIV-positive patients, with Cryptococcus neoformans var. neoformans serotype A predominating as the etiological agent. In this paper, the pathogenicity of C. neoformans to skin lesions in patients immunocompromised or not, is discussed, showing the efficacy of fluconazole for the treatment of these processes.", "The advent of molecular targeted therapies offers the hope of therapeutic advance in the fight against cancer. However, this hope is tempered by recent findings that certain targeted therapies may have unique side effects. The Hedgehog (HH) pathway is a potential target for treatment of several cancers, including basal cell carcinoma and a subset of medulloblastoma. Recent clinical trials in adults have shown responses to HH pathway inhibition in both basal cell carcinoma and medulloblastoma. However, concerns have been raised about the use of HH pathway inhibitors in children because of the role the HH pathway plays in development. Indeed, young mice treated with the HH pathway inhibitor HhAntag developed severe bone defects, including premature differentiation of chondrocytes, thinning of cortical bone, and fusion of the growth plate. In an effort to lessen the severity of bone defects caused by HhAntag, we treated young mice simultaneously with HhAntag and parathyroid hormone-related protein (PTHrP), which functions downstream of Indian Hedgehog to maintain chondrocytes in a proliferative state. The results show that whereas treatment with PTHrP causes a significant increase in trabecular bone, it does not prevent fusion of the growth plate induced by HhAntag.", "In many genomic studies, one works with genome-position-dependent data, e.g. ChIP-chip or ChIP-Seq scores. Using conventional tools, it can be difficult to get a good feel for the data, especially the distribution of features. This article argues that the so-called Hilbert curve visualization can complement genome browsers and help to get further insights into the structure of one's data. This is demonstrated with examples from different use cases. An open-source application, called HilbertVis, is presented that allows the user to produce and interactively explore such plots.AVAILABILITY: http://www.ebi.ac.uk/huber-srv/hilbert/.", "Cryptococcus neoformans is an encapsulated yeast that can cause primary pulmonary infections or disseminate and cause infections of the central nervous system, meninges, skin, and bone in the immunocompromised host. We present here an unusual case of an immunocompetent patient who had laryngitis due to C. neoformans that mimicked a laryngeal carcinoma on clinical examination and imaging studies.", "Deletions on chromosome 22q11.2 are a strong genetic risk factor for development of schizophrenia and cognitive dysfunction. We employed shotgun liquid chromatography-mass spectrometry (LC-MS) proteomic and metabonomic profiling approaches on prefrontal cortex (PFC) and hippocampal (HPC) tissue from Df(16)A+/- mice, a model of the 22q11.2 deletion syndrome. Proteomic results were compared with previous transcriptomic profiling studies of the same brain regions. The aim was to investigate how the combined effect of the 22q11.2 deletion and the corresponding miRNA dysregulation affects the cell biology at the systems level. The proteomic brain profiling analysis revealed PFC and HPC changes in various molecular pathways associated with chromatin remodelling and RNA transcription, indicative of an epigenetic component of the 22q11.2DS. Further, alterations in glycolysis/gluconeogenesis, mitochondrial function and lipid biosynthesis were identified. Metabonomic profiling substantiated the proteomic findings by identifying changes in 22q11.2 deletion syndrome (22q11.2DS)-related pathways, such as changes in ceramide phosphoethanolamines, sphingomyelin, carnitines, tyrosine derivates and panthothenic acid. The proteomic findings were confirmed using selected reaction monitoring mass spectrometry, validating decreased levels of several proteins encoded on 22q11.2, increased levels of the computationally predicted putative miR-185 targets UDP-N-acetylglucosamine-peptide N-acetylglucosaminyltransferase 110 kDa subunit (OGT1) and kinesin heavy chain isoform 5A and alterations in the non-miR-185 targets serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform, neurofilament light chain and vesicular glutamate transporter 1. Furthermore, alterations in the proteins associated with mammalian target of rapamycin signalling were detected in the PFC and with glutamatergic signalling in the hippocampus. Based on the proteomic and metabonomic findings, we were able to develop a schematic model summarizing the most prominent molecular network findings in the Df(16)A+/- mouse. Interestingly, the implicated pathways can be linked to one of the most consistent and strongest proteomic candidates, (OGT1), which is a predicted miR-185 target. Our results provide novel insights into system-biological mechanisms associated with the 22q11DS, which may be linked to cognitive dysfunction and an increased risk to develop schizophrenia. Further investigation of these pathways could help to identify novel drug targets for the treatment of schizophrenia.", "BACKGROUND: Rapid antigen detection testing (RADT) is often performed for diagnosis of group A beta-hemolytic streptococcal (GABHS) pharyngitis among children. Among adults, the sensitivity of this test varies on the basis of disease severity (spectrum bias). A similar phenomenon may occur when this test is used in a pediatric population, which may affect the need for culture confirmation of all negative RADT results.OBJECTIVES: To assess the performance of a clinical scoring system and to determine whether RADT spectrum bias is present among children who are evaluated for GABHS pharyngitis.METHODS: Laboratory and clinical records for a consecutive series of pediatric patients who underwent RADT at the Marshfield Clinic between January 2002 and March 2002 were reviewed retrospectively. Patients were stratified according to the number of clinical features present by using modified Centor criteria, ie, history of fever, absence of cough, presence of pharyngeal exudates, and cervical lymphadenopathy. The sensitivity of the RADT was defined as the number of patients with positive RADT results divided by the number of patients with either positive RADT results or negative RADT results but positive throat culture results.RESULTS: RADT results were positive for 117 of 561 children (21%), and culture results were positive for 35 of 444 children (8%) with negative RADT results. The overall prevalence of GABHS pharyngitis was 27% (95% confidence interval: 23-31%). The prevalence of GABHS pharyngitis was 18% among patients with 0 Centor criteria, 16% among those with 1 criterion, 32% among those with 2 criteria, and 50% among those with 3 or 4 criteria. Spectrum bias was present, inasmuch as RADT sensitivity increased with Centor scores, ie, 47% sensitivity among children with 0 Centor criteria, 65% among those with 1 criterion, 82% among those with 2 criteria, and 90% among those with 3 or 4 criteria.CONCLUSIONS: The sensitivity of RADT for GABHS pharyngitis is not a fixed value but varies with the severity of disease. However, even among pediatric patients with > or =3 Centor criteria for GABHS pharyngitis, the sensitivity of RADT is still too low to support the use of RADT without culture confirmation of negative results.", "Uptake rates for the combined measles, mumps and rubella (MMR) vaccine have been below the required 95% in the UK since a retracted and discredited article linking the MMR vaccine with autism and inflammatory bowel disease was released in 1998. This study undertook semi-structured telephone interviews among parents or carers of 47 unvaccinated measles cases who were aged between 13 months and 9 years, during a large measles outbreak in Merseyside. Results showed that concerns over the specific links with autism remain an important cause of refusal to vaccinate, with over half of respondents stating this as a reason. A quarter stated child illness during scheduled vaccination time, while other reasons included general safety concerns and access issues. Over half of respondents felt that more information or a discussion with a health professional would help the decision-making process, while a third stated improved access. There was clear support for vaccination among respondents when asked about current opinions regarding MMR vaccine. The findings support the hypothesis that safety concerns remain a major barrier to MMR vaccination, and also support previous evidence that experience of measles is an important determinant in the decision to vaccinate.", "Farnesoid X receptor (FXR) is a bile acid nuclear receptor described through mouse knockout studies as a tumor suppressor for the development of colon adenocarcinomas. This study investigates the regulation of FXR in the development of human colon cancer. We used immunohistochemistry of FXR in normal tissue (n = 238), polyps (n = 32), and adenocarcinomas, staged I-IV (n = 43, 39, 68, and 9), of the colon; RT-quantitative PCR, reverse-phase protein array, and Western blot analysis in 15 colon cancer cell lines; NR1H4 promoter methylation and mRNA expression in colon cancer samples from The Cancer Genome Atlas; DNA methyltransferase inhibition; methyl-DNA immunoprecipitation (MeDIP); bisulfite sequencing; and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) knockdown assessment to investigate FXR regulation in colon cancer development. Immunohistochemistry and quantitative RT-PCR revealed that expression and function of FXR was reduced in precancerous lesions and silenced in a majority of stage I-IV tumors. FXR expression negatively correlated with phosphatidylinositol-4, 5-bisphosphate 3 kinase signaling and the epithelial-to-mesenchymal transition. The NR1H4 promoter is methylated in ~12% colon cancer The Cancer Genome Atlas samples, and methylation patterns segregate with tumor subtypes. Inhibition of DNA methylation and KRAS silencing both increased FXR expression. FXR expression is decreased early in human colon cancer progression, and both DNA methylation and KRAS signaling may be contributing factors to FXR silencing. FXR potentially suppresses epithelial-to-mesenchymal transition and other oncogenic signaling cascades, and restoration of FXR activity, by blocking silencing mechanisms or increasing residual FXR activity, represents promising therapeutic options for the treatment of colon cancer.", "Neurotrophic factors are among the most promising treatments aiming at slowing or stopping and even reversing Parkinson's disease (PD). However, in most cases, they cannot readily cross the human blood-brain-barrier (BBB). Herein, we propose as a therapeutic for PD the small molecule 17-beta-spiro-[5-androsten-17,2'-oxiran]-3beta-ol (BNN-20), a synthetic analogue of DHEA, which crosses the BBB and is deprived of endocrine side-effects. Using the \"weaver\" mouse, a genetic model of PD, which exhibits progressive dopaminergic neurodegeneration in the Substantia Nigra (SN), we have shown that long-term administration (P1-P21) of BNN-20 almost fully protected the dopaminergic neurons and their terminals, via i) a strong anti-apoptotic effect, probably mediated through the Tropomyosin receptor kinase B (TrkB) neurotrophin receptor's PI3K-Akt-NF-κB signaling pathway, ii) by exerting an efficient antioxidant effect, iii) by inducing significant anti-inflammatory activity and iv) by restoring Brain-Derived Neurotrophic Factor (BDNF) levels. By intercrossing \"weaver\" with NGL mice (dual GFP/luciferase-NF-κΒ reporter mice, NF-κΒ.GFP.Luc), we obtained Weaver/NGL mice that express the NF-κB reporter in all somatic cells. Acute BNN-20 administration to Weaver/NGL mice induced a strong NF-κB-dependent transcriptional response in the brain as detected by bioluminescence imaging, which was abolished by co-administration of the TrkB inhibitor ANA-12. This indicates that BNN-20 exerts its beneficial action (at least in part) through the TrkB-PI3K-Akt-NF-κB signaling pathway. These results could be of clinical relevance, as they suggest BNN-20 as an important neuroprotective agent acting through the TrkB neurotrophin receptor pathway, mimicking the action of the endogenous neurotrophin BDNF. Thus BNN-20 could be proposed for treatment of PD.", "AIM: This study aimed to investigate the mechanism of reversal of multidrug resistance mediated by ABC transporters with tivozanib (AV-951 and KRN-951). Tivozanib is a potent inhibitor of VEGF-1, -2 and -3 receptors.MATERIALS & METHODS: ABCB1- and ABCG2-overexpressing cell lines were treated with respective substrate antineoplastic agents in the presence or absence of tivozanib.RESULTS: The results indicate that tivozanib can significantly reverse ABCB1-mediated resistance to paclitaxel, vinblastine and colchicine, as well as ABCG2-mediated resistance to mitoxantrone, SN-38 and doxorubicin. Drug efflux assays showed that tivozanib increased the intracellular accumulation of substrates by inhibiting the ABCB1 and ABCG2 efflux activity. Furthermore, at a higher concentration, tivozanib inhibited the ATPase activity of both ABCB1 and ABCG2 and inhibited the photolabeling of ABCB1 or ABCG2.CONCLUSION: We conclude that tivozanib at noncytotoxic concentrations has the previously unknown activity of reversing multidrug resistance mediated by ABCB1 and ABCG2 transporters.", "OBJECTIVE: Cryptococcus is an opportunistic yeast with a worldwide distribution that primarily causes significant infections in immunocompromised individuals, generally by affecting the respiratory tract. But primary cutaneous cryptococcosis (PCC) without systemic infection is rare. We report a case of PCC in a patient with nephrotic syndrome.METHODS: The 23-year-old man developed severe necrotising cellulitis on both the anterior and posterior of his trunk following a massage. He had been treated with systemic corticosteroids over 20 months for nephrotic syndrome. A skin biopsy of the wound area revealed cutaneous vasculitis and chronic inflammation with yeast-like organisms. Periodic acid-Schiff (PAS) staining indicated that the structures were consistent with Cryptococcus. A Cryptococcus neoformans infection was confirmed by culture. Azole therapy was begun, and the skin ulcers gradually stopped disseminating. However, the patient died following continuous capillary haemorrhage on the 22 day since admission.CONCLUSION: Cryptococcus is crucial to be considered in the differential diagnosis of subcutaneous necrosis in any patient on immunosuppressive therapy." ]

[ "Cardiac stem cell therapy to promote engraftment of de novo beating cardiac muscle cells in cardiomyopathies could potentially improve clinical outcomes for many patients with congestive heart failure. Clinical trials carried out over the last decade for cardiac regeneration have revealed inadequacy of current approaches in cell therapy. Chief among them is the choice of stem cells to achieve the desired outcomes. Initial enthusiasm of adult bone marrow stems cells for myocyte regeneration has largely been relegated to paracrine-driven, donor cell-independent, endogenous cardiac repair. However, true functional restoration in heart failure is likely to require considerable myocyte replacement. In order to match stem cell application to various clinical scenarios, we review the necessity to preprime stem cells towards cardiac fate before myocardial transplantation and if these differentiated stem cells could confer added advantage over current choice of undifferentiated stem cells. We explore differentiation ability of various stem cells to cardiac progenitors/cardiomyocytes and compare their applicability in providing targeted recovery in light of current clinical challenges of cell therapy.", "OBJECTIVE: To assess the accuracy of obtaining body temperatures in dogs with a noncontact infrared thermometer (NCIT) on the cornea compared with a rectal digital thermometer (RDT).DESIGN: Prospective single center study.SETTING: University teaching hospital.ANIMALS: Three hundred dogs presented with low, normal, or high body temperatures.INTERVENTIONS: Three body temperature readings were measured by an RDT and by an NCIT on the cornea of the left eye by 2 investigators (experienced and inexperienced). Results obtained by the 2 methods were compared.MEASUREMENTS AND MAIN RESULTS: Median body temperature measured by the experienced investigator with the RDT and the NCIT were 38.3°C (range 35.5°C-41.1°C; 95% CI: 38.2-38.4°C) and 37.7°C (35.9°C-40.1°C; 95% CI: 37.7°C-37.9°C), respectively. Measurement of RDT as well as of NCIT correlated well between both investigators (rRDT = 0.94; rNCIT = 0.82; respectively, P < 0.001 for both methods). Mean RDT and NCIT-temperature correlated poorly (r = 0.43; P < 0.001) when taken by the experienced investigator and even less by the nonexperienced investigator (r = 0.38; P < 0.001). Repeatability of the NCIT revealed an unsatisfactory value (0.24°C) compared to RDT measurement (0.12°C). Agreement between both devices in measuring low, normal, and high values, calculated by Cohens-Kappa, was unsatisfactory (к = 0.201; P < 0.001). Calculating the receiver operating characteristic curve to determine the best threshold for fever (defined as RDT temperature >39.0°C) showed an area under the curve of 0.76. Mean discomfort score was significantly lower using NCIT compared to RDT measurement (P < 0.001).CONCLUSIONS: There was poor agreement between body temperatures obtained by RDT and NCIT. The corneal NCIT measurement tends to underrecognize hypothermic and hyperthermic conditions. Although the use of the NCIT yields faster results and is significantly more comfortable for the dog than the RDT measurement, it cannot be recommended in dogs at this time.", "Supravalvular aortic stenosis (SVAS) may occur as an isolated autosomal dominant trait or as a feature of Williams syndrome. It has been suggested that a defect in calcitonin function may play a role in Williams syndrome. We have excluded calcitonin as a candidate gene for SVAS using a gene specific probe.", "Familial pituitary adenomas occurr in the classical syndromes of MEN1 and Carney Complex as well as in Familial Isolated Pituitary Adenomas (FIPA), an autosomal dominant disease with incomplete penetrance. In some families and also rarely in sporadic tumours germline mutations of a gene located on chromosome 11q13 known as the aryl hydrocarbon receptor interacting protein have been found. This article discusses the AIP mutations in these groups and the different molecular interactions of AIP that may play a role in pituitary tumour formation.", "Here, we describe an in-house built ultra-high pressure liquid chromatography (UHPLC) system, with little complexity in design and high separation power combined with convenience in operation. This system enables the use of long columns of 40 cm packed with 1.8 μm particles generating pressures below 1000 bar. Furthermore, the system could be operated at flow rates between 50 and 200 nL min(-1) while maintaining its separation power. Several gradients were optimized ranging from 23 to 458 minutes. With the longest gradient we identified over 4500 protein groups and more than 26,000 unique peptides from 1 μg of a human cancer cell lysate in a single run using an Orbitrap Velos - a level of performance often seen solely using multidimensional separation strategies. Further experiments using a mass spectrometer with faster sequencing speeds, like the TripleTOF 5600, enabled us to identify over 1400 protein groups in a 23 min gradient. The TripleTOF 5600 performed especially well, compared to the Orbitrap Velos, for the shorter gradients used. Our data demonstrate that the combination of UHPLC with high resolution mass spectrometry at increased sequencing speeds enables extensive proteome analysis in single runs.", "BACKGROUND: Trastuzumab, a HER2 monoclonal antibody, has transformed the prognosis of patients with the aggressive HER2-positive breast cancer type. Trastuzumab augments the cardiotoxic effects of anthracyclines, but its effect is thought to be at least partially reversible. The objective of this study was to examine the time trends of left ventricular (LV) size and function in a cohort of women treated with anthracyclines and trastuzumab.METHODS: Twenty-nine patients >18 years of age with first-time breast cancer treated with anthracyclines and trastuzumab were monitored using echocardiography before, at the completion of, and at a median follow-up of 24.7 months (interquartile range, 15.9-34 months) after the end of their cancer treatment. LV volume, LV ejection fraction, and global peak systolic longitudinal strain and strain rate were measured in the apical four- and two-chamber views. Left ventricular ejection fraction was measured using a modified Simpson's biplane method.RESULTS: LV end-diastolic and end-systolic volumes increased at the end of treatment compared with baseline and did not recover during follow-up. Left ventricular ejection fraction, strain, and strain rate decreased at the end of treatment compared with baseline (from 64 ± 6% to 59 ± 8%, from -20.0 ± 2.5% to -17.6 ± 2.6%, and from -1.26 ± 0.23 to -1.13 ± 0.16 sec(-1), respectively; P < .05 for all parameters) and remained decreased at follow-up.CONCLUSIONS: LV dilation and subclinical impairment in cardiac function persists >2 years after the end of anthracycline and trastuzumab treatment, without significant recovery after trastuzumab cessation, suggestive of long-term underlying cardiac damage and remodeling.", "Author information:(1)Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich 8093, Switzerland.(2)Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.(3)Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.(4)RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan.(5)RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan Telethon Kids Institute, The University of Western Australia, Subiaco, Western Australia 6008, Australia.(6)RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama 351-0198, Japan.(7)RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan Cancer and Cell Biology Division, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, Western Australia 6009, Australia.(8)Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich 8093, Switzerland michael.detmar@pharma.ethz.ch." ]

[ "Taliglucerase alfa is an enzyme replacement therapy approved for treatment of Gaucher disease (GD) in children and adults in several countries. This multicenter extension study assessed the efficacy and safety of taliglucerase alfa in pediatric patients with GD who were treatment-naïve (n=10) or switched from imiglucerase (n=5). Patients received taliglucerase alfa 30 or 60U/kg (treatment-naïve) or the same dose as previously treated with imiglucerase every other week. In treatment-naïve patients, taliglucerase alfa 30 and 60U/kg, respectively, reduced mean spleen volume (-18.6 multiples of normal [MN] and -26.0MN), liver volume (-0.8MN and -0.9MN), and chitotriosidase activity (-72.7% and -84.4%), and increased mean Hb concentration (+2.0g/dL and +2.3g/dL) and mean platelet count (+38,200/mm3 and +138,250/mm3) from baseline through 36 total months of treatment. In patients previously treated with imiglucerase, these disease parameters remained stable through 33 total months of treatment with taliglucerase alfa. Most adverse events were mild/moderate; treatment was well tolerated. These findings extend the taliglucerase alfa safety and efficacy profile and demonstrate long-term clinical improvement in treatment-naïve children receiving taliglucerase alfa and maintenance of disease stability in children switched to taliglucerase alfa. Treatment was well-tolerated, with no new safety signals. This study is registered at www.clinicaltrials.gov as NCT01411228.", "Interest in the role of thyroid hormones (TH) in heart failure is steadily increasing due to evidence for a physiological, homeostatic role of TH and the effects of altered TH metabolism on the cardiovascular system, particularly in presence of heart failure. Experimental studies have shown that altered TH metabolism modifies cardiovascular homeostasis by inducing alterations of cardiac histology, cardiomyocyte morphology and gene expression and consequently, of diastolic and systolic myocardial function. Clinical studies have shown that mild forms of thyroid dysfunction, both primary (subclinical hypothyroidism and subclinical hyperthyroidism) and secondary (low T(3) syndrome) have negative prognostic impact in patients with heart failure. In these patients, the administration of synthetic triiodothyronine (T(3)) was well tolerated and induced significant improvement in cardiac function without increased heart rate and metabolic demand. Large multicenter, placebo-controlled prospective studies are necessary to evaluate the safety and prognostic effects of chronic treatment with TH replacement therapy in patients with heart failure. The article also discusses recent patents in this field.", "Much has been learned about thrombotic thrombocytopenic purpura (TTP) and heparin-induced thrombocytopenia (HIT) and much remains a diagnostic and management challenge. While the pentad of thrombocytopenia, microangiopathic hemolytic anemia, fever, and renal and neurologic abnormalities characterize the clinical presentation of TTP, few patients present with all signs and symptoms. Worse yet, the pentad and its components are seen in other so-called thrombotic microangiopathies that demand different treatment approaches. HIT is another systemic disorder presenting with thrombocytopenia and/or thrombosis with potential devastating consequences whose diagnosis is difficult and management is still evolving. Highlights of the conditions and clinical and laboratory hints that allow physicians to diagnose TTP and HIT efficiently and offer patients the best available therapeutic interventions are presented.", "Phosphoinositide-3-kinase (PI3K) is an enzyme group, known to regulate key survival pathways in acute myeloid leukaemia (AML). It generates phosphatidylinositol-3,4,5-triphosphate, which provides a membrane docking site for protein kinaseB activation. PI3K catalytic p110 subunits are divided into 4 isoforms; α,β,δ and γ. The PI3Kδ isoform is always expressed in AML cells, whereas the frequency of PI3Kγ expression is highly variable. The functions of these individual catalytic enzymes have not been fully resolved in AML, therefore using the PI3K p110δ and p110γ-targeted inhibitor IPI-145 (duvelisib) and specific p110δ and p110γ shRNA, we analysed the role of these two p110 subunits in human AML blast survival. The results show that PI3Kδ and PI3Kγ inhibition with IPI-145 has anti-proliferative activity in primary AML cells by inhibiting the activity of AKT and MAPK. Pre-treatment of AML cells with IPI-145 inhibits both adhesion and migration of AML blasts to bone marrow stromal cells. Using shRNA targeted to the individual isoforms we demonstrated that p110δ-knockdown had a more significant anti-proliferative effect on AML cells, whereas targeting p110γ-knockdown significantly inhibited AML migration. The results demonstrate that targeting both PI3Kδ and PI3Kγ to inhibit AML-BMSC interactions provides a biologic rationale for the pre-clinical evaluation of IPI-145 in AML.", "Promoters have diverse regulatory architectures and thus activate genes differently. For example, some have a TATA-box, many others do not. Even the ones with it can differ in its position relative to the transcription start site (TSS). No Promoter Left Behind (NPLB) is an efficient, organism-independent method for characterizing such diverse architectures directly from experimentally identified genome-wide TSSs, without relying on known promoter elements. As a test case, we show its application in identifying novel architectures in the fly genome.AVAILABILITY AND IMPLEMENTATION: Web-server at http://nplb.ncl.res.in Standalone also at https://github.com/computationalBiology/NPLB/ (Mac OSX/Linux).CONTACT: l.narlikar@ncl.res.inSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "INTRODUCTION: Alterations in the CDK4/6-RB signaling pathway are common causes of cell cycle dysregulation in many cancers, including glioblastoma. Palbociclib is an oral inhibitor of CDK4/6, which leads to phosphorylation of RB1 and cell-cycle arrest. We conducted a two-arm study evaluating efficacy and tissue pharmacokinetics/pharmacodynamics of palbociclib in patients with recurrent glioblastoma.METHODS: Eligibility criteria included confirmation of RB1 proficiency by IHC; ≤ 3 relapses; KPS ≥ 60; no limit on prior treatments. Arm 1 received palbociclib for 7 days prior to indicated resection followed by adjuvant palbociclib. Arm 2 received palbociclib without resection. Primary objective was PFS6; secondary included toxicity, OS, and ORR. Exploratory aims included biomarker assessment and pharmacokinetic/pharmacodynamic effects in surgical patients.RESULTS: Total of 22 patients were enrolled; 6 on Arm 1 and 16 on Arm 2. Trial was stopped early secondary to lack of efficacy, with 95% of evaluable patients progressing within 6 months. Median PFS was 5.14 weeks (range 5 days-142 weeks) and median OS was 15.4 weeks (range 2-274 weeks). Two patients (10%) had related grade ≥ 3 AEs. In Arm 1, 5 patients had tissue concentrations of palbociclib felt to be sufficient for biological effect and paired samples available for RB1 IHC. There were no consistent changes in RB1 expression or cell proliferation in the paired tissue.CONCLUSION: In this trial, despite adequate tissue PK, palbociclib monotherapy was not an effective treatment for recurrent glioblastoma. However, these were heavily pretreated patients and targeting the CDK4/6 pathway may still deserve further exploration.", "INTRODUCTION: Osteopenia and osteoporosis because of hyperprolactinaemia caused by prolactinoma may be followed by an increased risk of fracture. There are no data on the bone effects of functional hyperprolactinaemia. The aim was to assess the influence of hyperprolactinaemia of various origins on bone turnover and density in different skeletal sites.MATERIAL AND METHODS: The study was carried out in 75 women (aged 30.53 +/- 7.8): Group I--32 women with prolactinoma and Group II--43 women with functional hyperprolactinaemia. Both groups of patients were subdivided into those with hypogonadism and those with normal gonadal function. The control group consisted of 29 healthy women aged (33.59 +/- 4.7). In all subjects PRL and bone turnover markers (BAP, OC, ICTP) were studied. BMD measurements (lumbar spine, forearm, proximal femur and total body) were carried out using DXA.RESULTS: Higher PRL concentrations were observed in patients than in controls. The values of bone turnover markers (BAP, ICTP) were shown to be higher in patient groups and subgroups than in controls. In patients with prolactinoma lumbar spine BMD was lower than in patients with functional hyperprolactinaemia and controls. Total body BMD was also lower, albeit to a lesser extent.CONCLUSIONS: Hyperprolactinaemia caused by prolactinoma in women influences bone metabolism unfavourably, more by the impact on the activity of bone turnover markers than on BMD. This provides an opportunity for earlier assessment of bone metabolism disturbances before the BMD changes can be observed. Functional hyperprolactinaemia does not determine such a harmful effect on bone metabolism as hyperprolactinemia due to prolactinoma." ]

[ "Due to next-generation sequencing (NGS) technology, genome sequencing is able to process much more data at low cost. In NGS data analysis, the mapping of sequences into a reference genome takes the largest amount of time to process. Although the Burrows-Wheeler Aligner (BWA) tool is one of the most widely used open-source software tools to align read sequences, it is still limited in that it does not fully support multi-thread mechanisms during the alignment steps. In this paper, we propose a BWA-MT tool, evolved from BWA but supporting multi-thread computation, designed to fully utilize the underlying multi-core architecture of computing resources. By using multi-thread computation, BWA-MT can significantly shorten the time needed to generate an alignment for single-end read sequences. Meanwhile, it generates an identical Sequence Alignment Map (SAM) result file as BWA. To evaluate BWA-MT, we use an evaluation system equipped with twelve cores and 32 GB memory. As a workload, we used the hg19 human genome reference sequence and various numbers of read sequences from 1M to 40M. In our evaluation, BWA-MT displays up to 3.7 times faster performance and generates an identical SAM result file to BWA. Although the increased speed might be dependent on computing resources, we confirm that BWA-MT is highly efficient and effective.", "Isocitrate dehydrogenase (IDH) is a key enzyme involved in the conversion of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid (TCA) cycle. IDH mutation produces a neomorphic enzyme, which can lead to the abnormal accumulation of R-2-HG and promotes leukemogenesis. IDH mutation occurs in 20% of acute myeloid leukemia (AML) patients, mainly including IDH1 R132, IDH2 R140, and IDH2 R172. Different mutant isoforms have different prognostic values. In recent years, IDH inhibitors have shown good clinical response in AML patients. Hence, enasidenib and ivosidenib, the IDH2 and IDH1 inhibitors developed by Agios Pharmaceuticals, have been approved by the Food and Drug Administration on 1 August 2017 and 20 July 2018 for the treatment of adult relapsed or refractory (R/R) AML with IDH2 and IDH1 mutations, respectively. IDH inhibitor monotherapy for R/R AML is efficacious and safe; however, there are problems, such as primary or acquired resistance. Clinical trials of IDH inhibitors combined with hypomethylating agents or standard chemotherapy for the treatment of R/R AML or newly diagnosed AML, as well as in post hematopoietic stem cell transplantation as maintenance therapy, are ongoing. This article summarizes the use of IDH inhibitors in AML with IDH mutations.", "This review summarises the evolution of recent major advances in cancer immunotherapy, using metastatic melanoma as a model. The first true clinical progress with immunotherapy developed from the application of recombinant DNA technology for the large scale production of immunostimulant cytokines. Clinical trials demonstrated that the systemic administration of recombinant high-dose bolus intravenous interleukin-2 (IL-2; 720 000 IU/kg every 8 hours) mediated objective tumour progression in 20% of patients with metastatic renal cancer and in 17% of patients with metastatic melanoma, with complete responses of 9% and 7%, respectively. The use of adoptive immunotherapy (the transfer of immune cells with anti-tumour activity to the tumour-bearing host) focused interest on T lymphocyte-mediated tumour recognition. Clinical trials described the systemic administration of lymphokine activated killer (LAK) cells and subsequently tumour infiltrating lymphocytes (TIL) to patients with advanced cancer. Although able to kill tumour targets in vitro, LAK cells did not prove useful for the treatment of patients with metastatic melanoma and renal cancer. A randomised trial, in which IL-2 was administered alone or with LAK cells, failed to show a difference in response rate or survival. In contrast, the treatment of 86 patients with metastatic melanoma using TIL plus IL-2 resulted in a 34% objective response rate, which included patients who had previously failed treatment with high-dose IL-2 alone. The focus on cellular immune responses, combined with rapid biotechnological advances, resulted in the identification of tumour specific antigens, such as MART-1 and gp100, that could be recognised by autologous TIL. This provided fundamental evidence of the existence of melanoma-associated antigens that were recognised in vivo by effector cells of the immune system. In vitro studies demonstrated immunodominant epitopes from MART-1 and gp100 that could induce in vitro-specific cytotoxic T lymphocyte reactivity. To enhance in vitro immunogenicity, single amino acid substitutions were made to identify peptides with higher affinity for HLA-A*0201. Modified peptides from gp100 were compared with the parental peptide for increased immunogenicity based on their ability to induce anti-tumour lymphocytes in vitro. From these studies, a candidate peptide was identified (G9-209-2M) which had increased immunogenic reactivity in vitro. Clinical trials demonstrated that the modified G9-209-2M peptide was more effective. Unfortunately, objective tumour regression was still low. However, when high-dose IL-2 was combined with G9-209-2M objective clinical responses increased to 42%. Efforts to find better ways to immunise against self antigens are ongoing and involve further peptide immunisations, as well as recombinant viral vectors, adjuvant cytokine therapy and cellular adjuvants such as dendritic cells.", "We previously demonstrated, by limited mutagenesis, that conserved sequence elements within the 5' end of influenza virus virion RNA (vRNA) are required for the polyadenylation of mRNA in vitro. To further characterize the nucleotide residues at the 5' end of vRNA which might be involved in polyadenylation, a complete set of short and long model vRNA-like templates with mutations at nucleotides 1' to 13' (prime notation denotes numbering from the 5' end) of vRNA were synthesized and transcribed in vitro. The products were assayed for mRNA production with both reverse transcription-PCR and [alpha-32P]ATP incorporation assays. Results from these independent assays showed that vRNA templates with point mutations at positions 2', 3', 7' to 9', and 11' to 13' synthesized polyadenylated transcripts inefficiently compared with those with mutations at positions 1', 4' to 6', and 10'. Positions 2', 3', 7' to 9', and 11' are known to be involved in RNA polymerase binding. Furthermore, residues at positions 11' to 13' are known to be involved in base pairing between the 3' and 5' ends of vRNA. These findings demonstrate that the RNA polymerase has to bind to the 5' end of the template vRNA, which must then interact with the 3' end of the same template for polyadenylation to occur. These results support a model in which a cis-acting RNA polymerase is required for the polyadenylation of influenza virus.", "CD4 T(h) are critical for orchestrating adaptive immune responses. The expression of the transcription factor GATA3 (GATA-binding protein 3) is up-regulated or down-regulated during T(h)2 or T(h)1 cell differentiation, respectively. Furthermore, GATA3 is responsible for induction of T(h)2 differentiation and represses T(h)1 differentiation. In this review, we present an updated view on the molecular mechanisms through which GATA3 regulates T(h)1/T(h)2 differentiation. During T(h)2 cell differentiation, GATA3 directly binds to the T(h)2 cytokine gene locus at several regions and regulates expression. On the other hand, GATA3 inhibits T(h)1 cell differentiation by preventing up-regulation of IL-12 receptor β2 and STAT4 (signal transducer and activator of transcription 4) and neutralization of Runx3 (runt-related transcription factor 3) function through protein-protein interaction. GATA3 may also directly act on the Ifng gene. In summary, GATA3 serves as a transcriptional activator or repressor through direct action on transcriptional machinery and/or affecting chromatin remodeling at many critical loci encoding cytokines, cytokine receptors, signaling molecules as well as transcription factors that are involved in the regulation of T(h)1 and T(h)2 differentiation.", "BACKGROUND: The sodium-glucose cotransporter 2 (SGLT2) inhibitors, which include canagliflozin, dapagliflozin, and empagliflozin, represent a new class of antihyperglycemic agents. Few studies have assessed their cost per response, with \"cost per response\" being the total cost of a select drug, divided by the resulting change in glycated hemoglobin (HbA1c) levels.OBJECTIVE: To examine the drug cost of SGLT2 inhibitors per a reduction in placebo-adjusted 1% HbA1c in patients with type 2 diabetes mellitus who received treatment during 26 weeks with canagliflozin, dapagliflozin, or empagliflozin.METHODS: The drug cost per response for each of the 3 agents individually was assessed based on data from a subset of clinical trials discussed in the prescribing information for each drug that were all placebo-controlled studies evaluating each drug as monotherapy, dual therapy (combined with metformin), and triple therapy (combined with metformin and a sulfonylurea) in patients with uncontrolled, type 2 diabetes mellitus. The US 2015 wholesale acquisition cost for each drug was used to calculate each drug's treatment costs over 26 weeks. The average cost per response for each drug was defined as the prescription drug cost of each SGLT2 inhibitor, divided by the average, placebo-adjusted HbA1c reduction at 26 weeks.RESULTS: The drug cost per unit dose was the same for canagliflozin (100 mg or 300 mg), dapagliflozin (5 mg or 10 mg), and empagliflozin (10 mg or 25 mg), at $11.43. The drug cost per placebo-adjusted 1% HbA1c reduction varied by agent and by dose, as a result of the differences in the treatment responses for each of the 3 drugs. The costs per response for canagliflozin 100 mg as monotherapy, dual therapy, and triple therapy regimens ranged from $2286 to $3355, and for canagliflozin 300 mg, from $1793 to $2702. The costs per response for dapagliflozin 5 mg as monotherapy and dual therapy (triple therapy was not available at the time of the study) ranged from $4161 to $5201; the cost for dapagliflozin 10 mg ranged from $2972 to $4161. The costs per response for empagliflozin 10 mg ranged from $2972 to $3467 across the monotherapy, dual therapy, and triple therapy regimens; the cost for empagliflozin 25 mg ranged from $2311 to $3467.CONCLUSION: Simple analyses, such as the drug cost per placebo-adjusted 1% reduction in HbA1c, may be useful when considering the addition of antihyperglycemic agents to the health plan's formulary.", "PURPOSE: Retrospective study of patients treated for high-grade glioma, with or without biodegradable carmustine wafers and according to the Stupp protocol.METHODS AND MATERIALS: Between May 2007 and June 2008, 65 patients underwent surgery for high-grade glioma, 28 had implantation of Gliadel and 37 patients did not. Patients received radiotherapy with concomitant temozolomide followed by 5 consecutive days of temozolomide every month for 6 months.RESULTS: Overall median follow-up was 17.1 months; the median relapse-free survival (RFS) was 14 months with a RFS of 54% at 12 months, and 38% at 24 months. For patient with and without Gliadel, median and 1-year RFS were 12.9 months and 52% vs. 14 months and 42%, respectively (p = 0.89). According to pathology, Gliadel did not influence RFS of patients with Grade III or glioblastoma. However, for all patients, in multivariate analysis, non-methylated methylguanine methyltransferase (MGMT) was the only unfavorable prognostic factor of RFS (p = 0.017; HR 2.8; CI [1.2-7]). Median overall survival (OS) was 20.8 months; the OS rate at 12 months was 78.5%, and at 24 months 35.4%. For patients treated with and without Gliadel, median and 1-year OS were 20.6 months and 78.6% vs. 20.8 months and 78.4%, respectively. According to pathology, Gliadel did not influence OS of patients with Grade III or glioblastoma. For all patients, in multivariate analysis, unfavorable prognosticators for OS were non-methylated MGMT (p = 0.001; HR: 6.5; CI [2-20]) and irradiation dose <60 Gy (p = 0.02; HR: 6.3; CI [2-20]). With carmustine wafers, before irradiation, median gross tumor volume plus edema was 84 mL (27-229), whereas it was 68 mL (10-362) without carmustine (p = nonsignificant). Four cases of Grade 3 thrombopenia occurred, all in the carmustine wafer group.CONCLUSION: In patients with high-grade gliomas, adding Gliadel before performing a Stupp protocol did not improve survival.", "A comprehensive, unbiased inventory of synuclein forms present in Lewy bodies from patients with dementia with Lewy bodies was carried out using two-dimensional immunoblot analysis, novel sandwich enzyme-linked immunosorbent assays with modification-specific synuclein antibodies, and mass spectroscopy. The predominant modification of alpha-synuclein in Lewy bodies is a single phosphorylation at Ser-129. In addition, there is a set of characteristic modifications that are present to a lesser extent, including ubiquitination at Lys residues 12, 21, and 23 and specific truncations at Asp-115, Asp-119, Asn-122, Tyr-133, and Asp-135. No other modifications are detectable by tandem mass spectrometry mapping, except for a ubiquitous N-terminal acetylation. Small amounts of Ser-129 phosphorylated and Asp-119-truncated alpha-synuclein are present in the soluble fraction of both normal and disease brains, suggesting that these Lewy body-associated forms are produced during normal metabolism of alpha-synuclein. In contrast, ubiquitination is only detected in Lewy bodies and is primarily present on phosphorylated synuclein; it therefore likely occurs after phosphorylated synuclein has deposited into Lewy bodies. This invariant pattern of specific phosphorylation, truncation, and ubiquitination is also present in the detergent-insoluble fraction of brain from patients with familial Parkinson's disease (synuclein A53T mutation) as well as multiple system atrophy, suggesting a common pathogenic pathway for both genetic and sporadic Lewy body diseases. These observations are most consistent with a model in which preferential accumulation of normally produced Ser-129 phosphorylated alpha-synuclein is the key event responsible for the formation of Lewy bodies in various Lewy body diseases.", "Bronchiolo-alveolar carcinoma has been described in man and in several animal species, including cattle, dogs, opossums, goats and sheep. In sheep, a bronchiolo-alveolar carcinoma, known as ovine pulmonary carcinoma (OPC), is caused by jaagsiekte sheep retrovirus (JSRV), an exogenous type D retrovirus. In the mid-1980s, a severe outbreak of a disease resembling OPC was described in captive Sardinian moufflon (Ovis musimon). In the present study, the use of polymerase chain reaction (PCR) amplification of nucleic acids extracted from archival material established that JSRV was associated with OPC in affected moufflon. JSRV was detected in the lungs and mediastinal lymph nodes. Immunohistochemical and in-situ PCR demonstrated that in the lungs, JSRV proviral DNA was localized in transformed and untransformed type II pneumocytes and in the alveolar macrophages. In the mediastinal lymph nodes, JSRV DNA was mainly located in the cortical follicles and paracortex. These data suggest that JSRV is the cause of OPC in Sardinian moufflon, as it is in Sardinian sheep.", "Understanding the factors governing host species barriers to virus transmission has added significantly to our appreciation of virus pathogenesis. Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary adenocarcinoma (OPA), a transmissible lung cancer of sheep that has rarely been found in goats. In this study, in order to further clarify the pathogenesis of OPA, we investigated whether goats are resistant to JSRV replication and carcinogenesis. We found that JSRV induces lung tumors in goats with macroscopic and histopathological features that dramatically differ from those in sheep. However, the origins of the tumor cells in the two species are identical. Interestingly, in experimentally infected lambs and goat kids, we revealed major differences in the number of virus-infected cells at early stages of infection. These differences were not related to the number of available target cells for virus infection and cell transformation or the presence of a host-specific immune response toward JSRV. Indeed, we also found that goats possess transcriptionally active endogenous retroviruses (enJSRVs) that likely influence the host immune response toward the exogenous JSRV. Overall, these results suggest that goat cells, or at least those cells targeted for viral carcinogenesis, are not permissive to virus replication but can be transformed by JSRV.", "Breast cancer is the most common malignancy in women continuing to rise worldwide. Breast cancer emerges through a multi-step process, encompassing progressive changes from a normal cell to hyperplasia (with and without atypia), carcinoma in situ, invasive carcinoma, and metastasis. In the current study, we analyzed the morphological changes and alterations of DNA methylation, histone methylation and microRNA expression during estradiol-17beta (E(2))-induced mammary carcinogenesis in female August Copenhagen Irish (ACI) rats. E(2)-induced breast carcinogenesis in ACI rats provides a physiologically relevant and genetically defined animal model for studying human sporadic breast cancer. The pattern of morphological changes in mammary glands during E(2)-induced carcinogenesis was characterized by transition from normal appearing alveolar and ductular hyperplasia to focal hyperplastic areas of atypical glands and ducts accompanied by a rapid and sustained loss of global DNA methylation, LINE-1 hypomethylation, loss of histone H3 lysine 9 and histone H4 lysine 20 trimethylation, and altered microRNAs expression. More importantly, these alterations in the mammary tissue occurred after six weeks of E(2)-treatment, whereas the atypical hyperplasia, which represents a putative precursor lesion to mammary carcinoma in this model, was detected only after twelve weeks of exposure, demonstrating clearly that these events are directly associated with the effects of E(2) and are not a consequence of the preexisting preneoplastic lesions. The results of this study show that deregulation of cellular epigenetic processes plays a crucial role in the mechanism of E(2)-induced mammary carcinogenesis in ACI rats, especially in the tumor initiation process.", "OBJECTIVES: Pulmonary hypertension (PHT) is associated with tricuspid annular dilatation, but the effect of acute increase of pulmonary pressure on three-dimensional (3D) tricuspid annular dynamics and shape is unknown. Better understanding of tricuspid annular dynamics may lead to improved and more durable surgical reparative techniques.METHODS: In nine open-chest anaesthetized sheep nine sonomicrometry crystals were implanted on the right ventricle while on cardiopulmonary bypass. Additional nine crystals were implanted around the tricuspid annulus (TA) with one crystal at each commissure defining three separate annular regions: anterior, posterior and septal. Two additional equidistant crystals were implanted between each commissure, creating three segments for every region. Pressure transducers were placed in the left ventricular (LV), right ventricular (RV) and right atrium. PHT was induced by acute pulmonary artery constriction with a pneumatic occluder. Sonomicrometry and echocardiographic data were collected before and after induction of PHT. TA area, regional and total perimeter, and 3D annular geometry were calculated from 3D crystal coordinates. Regional annular contraction was defined as the percentage difference between maximal and minimal region length during the cardiac cycle.RESULTS: PHT increased RV pressure from 31 ± 9 mmHg to 46 ± 13 mmHg (P = 0.001) and decreased left ventricular (LV) pressure from 111 ± 24 mmHg to 78 ± 36 mmHg (P = 0.018). There was no significant tricuspid regurgitation observed with PHT. During PHT, the TA area increased by 12 ± 13% from 641 ± 139 mm(2) to 721 ± 177 mm(2) (P = 0.037). The total perimeter increased from 103 ± 11 mm to 109 ± 13 mm (P = 0.02). All annular regions dilated significantly with PHT with 8 ± 10, 5 ± 5 and 5 ± 5% increase in anterior, posterior and septal annular length, respectively (P < 0.05). PHT reduced regional annular contraction in the anterior region only (17 ± 7 vs 14 ± 8%; P = 0.02). The TA had a complex 3D saddle geometry and the shape of the annulus was altered during PHT only in the antero-posterior region.CONCLUSIONS: The changes in tricuspid annular conformation, contractility and its 3D geometry observed during acute ovine PHT may help in the design of new pathology-specific tricuspid annular rings." ]

[ "Thyroid-associated ophthalmopathy (TAO) is a complex disease process presumed to emerge from autoimmunity occurring in the thyroid gland, most frequently in Graves disease (GD). It is disfiguring and potentially blinding, culminating in orbital tissue remodeling and disruption of function of structures adjacent to the eye. There are currently no medical therapies proven capable of altering the clinical outcome of TAO in randomized, placebo-controlled multicenter trials. The orbital fibroblast represents the central target for immune reactivity. Recent identification of fibroblasts that putatively originate in the bone marrow as monocyte progenitors provides a plausible explanation for why antigens, the expressions of which were once considered restricted to the thyroid, are detected in the TAO orbit. These cells, known as fibrocytes, express relatively high levels of functional TSH receptor (TSHR) through which they can be activated by TSH and the GD-specific pathogenic antibodies that underpin thyroid overactivity. Fibrocytes also express insulin-like growth factor I receptor (IGF-IR) with which TSHR forms a physical and functional signaling complex. Notably, inhibition of IGF-IR activity results in the attenuation of signaling initiated at either receptor. Some studies suggest that IGF-IR-activating antibodies are generated in GD, whereas others refute this concept. These observations served as the rationale for implementing a recently completed therapeutic trial of teprotumumab, a monoclonal inhibitory antibody targeting IGF-IR in TAO. Results of that trial in active, moderate to severe disease revealed dramatic and rapid reductions in disease activity and severity. The targeting of IGF-IR with specific biologic agents may represent a paradigm shift in the therapy of TAO.", "Author information:(1)Department of Systems Medicine, University of Rome \"Tor Vergata\", Rome, Italy; Unit of Neuro-Oncohematology, Santa Lucia Foundation-I.R.C.C.S., Rome, Italy. Electronic address: faraoni@med.uniroma2.it.(2)Unit of Neuro-Oncohematology, Santa Lucia Foundation-I.R.C.C.S., Rome, Italy. Electronic address: mircocomp@gmail.com.(3)Unit of Neuro-Oncohematology, Santa Lucia Foundation-I.R.C.C.S., Rome, Italy; Department of Biomedicine and Prevention, University of Rome \"Tor Vergata\", Rome, Italy. Electronic address: serena.lavorgna@hotmail.it.(4)Unit of Neuroimmunology, Santa Lucia Foundation-I.R.C.C.S., Rome, Italy. Electronic address: df.angelini@gmail.com.(5)Unit of Neuroimmunology, Santa Lucia Foundation-I.R.C.C.S., Rome, Italy. Electronic address: mt.cencioni@hsantalucia.it.(6)Unit of Neuroimmunology, Santa Lucia Foundation-I.R.C.C.S., Rome, Italy. Electronic address: e.piras@hsantalucia.it.(7)Unit of Neuro-Oncohematology, Santa Lucia Foundation-I.R.C.C.S., Rome, Italy; Department of Biomedicine and Prevention, University of Rome \"Tor Vergata\", Rome, Italy. Electronic address: paolapanetta@yahoo.it.(8)Unit of Neuro-Oncohematology, Santa Lucia Foundation-I.R.C.C.S., Rome, Italy; Department of Biomedicine and Prevention, University of Rome \"Tor Vergata\", Rome, Italy. Electronic address: tizianaottone@hotmail.com.(9)Department of Biomedicine and Prevention, University of Rome \"Tor Vergata\", Rome, Italy. Electronic address: dolci@uniroma2.it.(10)Department of Biomedicine and Prevention, University of Rome \"Tor Vergata\", Rome, Italy. Electronic address: adriano.venditti@uniroma2.it.(11)Department of Systems Medicine, University of Rome \"Tor Vergata\", Rome, Italy. Electronic address: graziani@uniroma2.it.(12)Unit of Neuro-Oncohematology, Santa Lucia Foundation-I.R.C.C.S., Rome, Italy; Department of Biomedicine and Prevention, University of Rome \"Tor Vergata\", Rome, Italy. Electronic address: francesco.lo.coco@uniroma2.it.", "A cytosine DNA methyltransferase containing a chromodomain, Zea methyltransferase2 (Zmet2), was cloned from maize. The sequence of ZMET2 is similar to that of the Arabidopsis chromomethylases CMT1 and CMT3, with C-terminal motifs characteristic of eukaryotic and prokaryotic DNA methyltransferases. We used a reverse genetics approach to determine the function of the Zmet2 gene. Plants homozygous for a Mutator transposable element insertion into motif IX had a 13% reduction in methylated cytosines. DNA gel blot analysis of these plants with methylation-sensitive restriction enzymes and bisulfite sequencing of a 180-bp knob sequence showed reduced methylation only at CpNpG sites. No reductions in methylation were observed at CpG or asymmetric sites in heterozygous or homozygous mutant plants. Our research shows that chromomethylase Zmet2 is required for in vivo methylation of CpNpG sequences.", "Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.", "In the great majority of patients with chronic myelogenous leukemia (CML) the reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34;q11), resulting in the Philadelphia (Ph) chromosome produces fusion DNA sequences consisting of the 5' part of the major breakpoint cluster region-1 (M-BCR-1) and the ABL protooncogene which encodes for the P210BCR-ABL phosphoprotein with tyrosine kinase activity implicated in the pathogenesis of CML. Molecular analysis was performed on 25 patients with Ph-positive CML using 2 breakpoint cluster region (bcr) probes within the M-BCR-1 DNA sequences, and two of them did not contain either detectable rearranged DNA homologous to the 5' side bcr probe or ABL-related fusion mRNA. The chromosomal in situ hybridization technique revealed that these two Ph-positive CML cases did not carry DNAs homologous to the 5' bcr or ABL probes on the Ph chromosome. Furthermore, one of the two Ph-positive CML cases did not show either rearranged DNA or regions homologous to the 3' bcr probe on a 9q+ chromosome, while the other CML case showed a rearrangement detected by the 3' bcr probe and transposition of the 3' bcr homologous to the 9q+ chromosome. Thus, the possibility is raised that the BCR/ABL fusion DNA has been deleted in rare CML cases, and that the deletion possibly occurred in a stepwise manner following the formation of the Ph chromosome at any stage of the disease.", "Narcolepsy is a chronic sleep disorder characterized by a pentad of excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and disturbed nocturnal sleep. While non-pharmacological treatments are sometimes helpful, more than 90% of narcoleptic patients require a pharmacological treatment. Areas covered: The present review is based on an extensive Internet and PubMed search from 1994 to 2017. It is focused on drugs currently in development for the treatment of narcolepsy. Expert opinion: Currently there is no cure for narcolepsy, with treatment focusing on symptoms control. However, these symptomatic treatments are often unsatisfactory. The research is leading to a better understanding of narcolepsy and its symptoms. New classes of compounds with possible applications in the development of novel stimulant/anticataplectic medications are described. H3 receptor antagonists represent a new therapeutic option for EDS in narcolepsy. JZP-110, with its distinct mechanism of action, would be a new therapeutic option for the treatment of EDS in the coming years. In the future, hypocretin-based therapies and immune-based therapies, could modify the clinical course of the disease. However, more information would be necessary to completely understand the autoimmune process and also how this process can be altered for therapeutic benefits.", "Mutations in the hematopoietic transcription factor GATA-1 alter the proliferation/differentiation of hemopoietic progenitors. Mutations in exon 2 interfere with the synthesis of the full-length isoform of GATA-1 and lead to the production of a shortened isoform, GATA-1s. These mutations have been found in patients with Diamond-Blackfan anemia (DBA), a congenital erythroid aplasia typically caused by mutations in genes encoding ribosomal proteins. We sequenced GATA-1 in 23 patients that were negative for mutations in the most frequently mutated DBA genes. One patient showed a c.2T > C mutation in the initiation codon leading to the loss of the full-length GATA-1 isoform.", "BACKGROUND: Mutations in the ribosomal protein S19 gene (RPS19) have been found in 25% of patients with Diamond-Blackfan anemia, a rare syndrome of congenital bone marrow failure characterized by erythroblastopenia and various malformations. Mechanistic understanding of the role of RPS19 in normal erythropoiesis and in the Diamond-Blackfan anemia defect is still poor. However, defective ribosome biogenesis and, in particular, impaired 18S ribosomal RNA maturation have been documented in association with various identified RPS19 mutations. Recently, new genes, all encoding ribosomal proteins, have been found to be mutated in Diamond-Blackfan anemia, adding further support to the concept that ribosome biogenesis plays an important role in regulating erythropoiesis. We previously showed variability in the levels of expression and subcellular localization of a subset of RPS19 mutant proteins.DESIGN AND METHODS: To define the mechanistic basis for this variability better, we studied a large number of mutant proteins and characterized both RPS19 expression level using a specific antibody against RPS19 and RPS19 subcellular localization after transfection of Cos-7 cells with various green fluorescent protein-RPS19 mutants. To investigate the role of the proteasome in RPS19 degradation, we examined the effect of various proteasome inhibitors, namely lactacystin, MG132, and bortezomib on RPS19 expression and subcellular localizationRESULTS: We found two distinct classes of RPS19 protein defects in Diamond-Blackfan anemia based on the stability of the mutant proteins: (i) slightly decreased to normal levels of expression and normal nucleolar localization and (ii) markedly deficient expression and failure to localize to the nucleolus. All the proteasome inhibitors tested were able to restore the expression levels and normal subcellular localization of several unstable mutant proteins.CONCLUSIONS: Our findings demonstrate an important role for the proteasomal degradation pathway in regulating the expression levels and nucleolar localization of certain mutant RPS19 proteins in Diamond-Blackfan anemia.", "We have cloned and sequenced the genes encoding cytochrome b (cob) and cytochrome c oxidase subunit I (cox1) from Rickettsia prowazekii, a member of the alpha-proteobacteria. The phylogenetic analysis supports the hypothesis that mitochondria are derived from the alpha-proteobacteria and more specifically from within the Rickettsiaceae. We have estimated that the common ancestor of mitochondria and Rickettsiaceae dates back to more than 1500 million years ago.", "The balanced growth of a cell requires the integration of major systems such as DNA replication, membrane biosynthesis, and ribosome formation. An example of such integration is evident from our recent finding that, in Saccharomyces cerevisiae, any failure in the secretory pathway leads to severe repression of transcription of both rRNA and ribosomal protein genes. We have attempted to determine the regulatory circuit(s) that connects the secretory pathway with the transcription of ribosomal genes. Experiments show that repression does not occur through the circuit that responds to misfolded proteins in the endoplasmic reticulum, nor does it occur through circuits known to regulate ribosome synthesis, e.g. the stringent response, or the cAMP pathway. Rather, it appears to depend on a stress response at the plasma membrane that is transduced through protein kinase C (PKC). Deletion of PKC1 relieves the repression of both ribosomal protein and rRNA genes that occurs in response to a defect in the secretory pathway. We propose that failure of the secretory pathway prevents the synthesis of new plasma membrane. As protein synthesis continues, stress develops in the plasma membrane. This stress is monitored by Pkc1p, which initiates a signal transduction pathway that leads to repression of transcription of the rRNA and ribosomal protein genes. The importance of the transcription of the 137 ribosomal protein genes to the economy of the cell is apparent from the existence of at least three distinct pathways that can effect the repression of this set of genes.", "BACKGROUND: The Ribosomal protein S19 gene locus (RPS19) has been linked to two kinds of red cell aplasia, Diamond-Blackfan Anemia (DBA) and Transient Erythroblastopenia in Childhood (TEC). Mutations in RPS19 coding sequences have been found in 25% of DBA patients, but not in TEC patients. It has been suggested that non-coding RPS19 sequence variants contribute to the considerable clinical variability in red cell aplasia. We therefore aimed at identifying non-coding variations associated with DBA or TEC phenotypes.METHODOLOGY/PRINCIPAL FINDINGS: We targeted a region of 19'980 bp encompassing the RPS19 gene in a cohort of 89 DBA and TEC patients for resequencing. We provide here a catalog of the considerable, previously unrecognized degree of variation in this region. We identified 73 variations (65 SNPs, 8 indels) that all are located outside of the RPS19 open reading frame, and of which 67.1% are classified as novel. We hypothesize that specific alleles in non-coding regions of RPS19 could alter the binding of regulatory proteins or transcription factors. Therefore, we carried out an extensive analysis to identify transcription factor binding sites (TFBS). A series of putative interaction sites coincide with detected variants. Sixteen of the corresponding transcription factors are of particular interest, as they are housekeeping genes or show a direct link to hematopoiesis, tumorigenesis or leukemia (e.g. GATA-1/2, PU.1, MZF-1).CONCLUSIONS: Specific alleles at predicted TFBSs may alter the expression of RPS19, modify an important interaction between transcription factors with overlapping TFBS or remove an important stimulus for hematopoiesis. We suggest that the detected interactions are of importance for hematopoiesis and could provide new insights into individual response to treatment.", "Powassan virus (POWV) is a rare tick-borne agent of encephalitis in North America. Historically, confirmed cases occurred mainly in the northeastern United States. Since 2008, confirmed cases in Minnesota and Wisconsin have increased. We report a fatal case of POWV encephalitis in Minnesota. POWV infection should be suspected in tick-exposed patients with viral encephalitis." ]

[ "Single nucleotide polymorphisms (SNPs) in TMEM106B encoding the lysosomal type II transmembrane protein 106B increase the risk for frontotemporal lobar degeneration (FTLD) of GRN (progranulin gene) mutation carriers. Currently, it is unclear if progranulin (PGRN) and TMEM106B are synergistically linked and if a gain or a loss of function of TMEM106B is responsible for the increased disease risk of patients with GRN haploinsufficiency. We therefore compare behavioral abnormalities, gene expression patterns, lysosomal activity, and TDP-43 pathology in single and double knockout animals. Grn-/- /Tmem106b-/- mice show a strongly reduced life span and massive motor deficits. Gene expression analysis reveals an upregulation of molecular signature characteristic for disease-associated microglia and autophagy. Dysregulation of maturation of lysosomal proteins as well as an accumulation of ubiquitinated proteins and widespread p62 deposition suggest that proteostasis is impaired. Moreover, while single Grn-/- knockouts only occasionally show TDP-43 pathology, the double knockout mice exhibit deposition of phosphorylated TDP-43. Thus, a loss of function of TMEM106B may enhance the risk for GRN-associated FTLD by reduced protein turnover in the lysosomal/autophagic system.", "BACKGROUND: Chromatin immunoprecipitation (ChIP) followed by high-throughput sequencing (ChIP-seq) or ChIP followed by genome tiling array analysis (ChIP-chip) have become standard technologies for genome-wide identification of DNA-binding protein target sites. A number of algorithms have been developed in parallel that allow identification of binding sites from ChIP-seq or ChIP-chip datasets and subsequent visualization in the University of California Santa Cruz (UCSC) Genome Browser as custom annotation tracks. However, summarizing these tracks can be a daunting task, particularly if there are a large number of binding sites or the binding sites are distributed widely across the genome.RESULTS: We have developed ChIPpeakAnno as a Bioconductor package within the statistical programming environment R to facilitate batch annotation of enriched peaks identified from ChIP-seq, ChIP-chip, cap analysis of gene expression (CAGE) or any experiments resulting in a large number of enriched genomic regions. The binding sites annotated with ChIPpeakAnno can be viewed easily as a table, a pie chart or plotted in histogram form, i.e., the distribution of distances to the nearest genes for each set of peaks. In addition, we have implemented functionalities for determining the significance of overlap between replicates or binding sites among transcription factors within a complex, and for drawing Venn diagrams to visualize the extent of the overlap between replicates. Furthermore, the package includes functionalities to retrieve sequences flanking putative binding sites for PCR amplification, cloning, or motif discovery, and to identify Gene Ontology (GO) terms associated with adjacent genes.CONCLUSIONS: ChIPpeakAnno enables batch annotation of the binding sites identified from ChIP-seq, ChIP-chip, CAGE or any technology that results in a large number of enriched genomic regions within the statistical programming environment R. Allowing users to pass their own annotation data such as a different Chromatin immunoprecipitation (ChIP) preparation and a dataset from literature, or existing annotation packages, such as GenomicFeatures and BSgenome, provides flexibility. Tight integration to the biomaRt package enables up-to-date annotation retrieval from the BioMart database.", "AIM: To evaluate the efficacy and safety of Denosumab (Prolia), a first-line osteoporosis (OP) medication that is a fully human monoclonal antibody to the receptor activator of nuclear factor xB ligand (RANKL), within an open-label observational study.SUBJECTS AND METHODS: Patients aged 50 years or older with postmenopausal OP, who were treated with Prolia in clinical practice, were examined. The concentrations of the bone resorption (BR) marker of C-terminal telopeptide and other laboratory indicators (total serum calcium, total alkaline phosphatase, and creatinine) were measured following 3 months. Adverse drug reactions were recorded.RESULTS: Three months after initiation of the investigation, there was a significant decrease in the BR marker C-terminal telopeptide (by 89%; p<0.0001). There were rare adverse reactions: hypocalcemia in 3 (5.9%) patients, arthralgias in 2 (3.9%), and eczema in 1 (1.9%). There were neither serious adverse events nor study withdrawal cases.CONCLUSION: The preliminary results of the open-label study of Prolia in postmenopausal OP suggest that the significantly lower BR activity determines the efficacy of this drug and its high safety.", "Duane retraction syndrome has been reported in association with structural abnormalities of the eye, including epibulbar dermoid, keratoconus, iris dysplasia, heterochromia iridis, persistent fetal vasculature, cataract, choroidal coloboma, microphthalmia, and optic nerve dysplasia. A novel association, that of bilateral Duane syndrome with bilateral aniridia, is the subject of this report.", "Ohtahara syndrome or Early Infantile Epileptic Encephalopathy (EIEE) with Suppression-Burst, is the most severe and the earliest developing age-related epileptic encephalopathy. Clinically, the syndrome is characterized by early onset tonic spasms associated with a severe and continuous pattern of burst activity. It is a debilitating and early progressive neurological disorder, resulting in intractable seizures and severe mental retardation. Specific mutations in at least four genes (whose protein products are essential in lower brain's neuronal and interneuronal functions, including mitochondrial respiratory chains have been identified in unrelated individuals with EIEE and include: (a) the ARX (aristaless-related) homeobox gene at Xp22.13 (EIEE-1 variant); (b) the CDKL5 (SYK9) gene at Xp22 (EIEE-2 variant); (c) the SLC25A22 (GC1) gene at 11p15.5 (EIEE-3 variant); and (d) the Stxbp1 (MUNC18-1) gene at 9q34-1 (EIEE-4 variant). A yet unresolved issue involves the relationship between early myoclonic encephalopathy (EME-ErbB4 mutations) versus the EIEE spectrum of disorders.", "This study was to evaluate the efficacy and safety of early application of citicoline in the treatment of patients with acute stroke by meta-analysis. Randomized controlled trials published until May 2015 were electronically searched in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, WHO International Clinical Trial Registration Platform, Clinical Trial.gov, and China Biology Medicine disc. Two reviewers independently screened the articles and extracted the data based on the inclusion and exclusion criteria. The quality of included articles was evaluated by using Revman5.0, and meta-analysis was performed. The results showed that 1027 articles were obtained in initial retrieval, and finally 7 articles, involving a total of 4039 cases, were included for analysis. The meta-analysis showed that no significant differences were found in the long-term mortality (OR=0.91, 95% CI 0.07 to 1.09, P=0.30), the rate of dependency (OR=1.02, 95% CI 0.87 to 1.24, P=0.85), and the effective rate (OR=0.98, 95% CI 0.84 to 1.14, P=0.82) between citicoline group and control group. The overall rate of adverse events in citicoline group was not significantly different from that in control group (P=0.30). The quality of included articles reached moderate-low level. In conclusion, citicolne cannot reduce long-term mortality and dependence rate in the treatment of acute stroke, and the effective rate of citivoline may be not better than that of controls but with reliable safety.", "BACKGROUND: Conventional smallpox vaccines based on replicating vaccinia virus (VV) strains (e.g. Lister Elstree, NYCBOH) are associated with a high incidence of myo-/pericarditis, a severe inflammatory cardiac complication. A new smallpox vaccine candidate based on a non-replicating Modified Vaccinia Ankara (MVA) poxvirus has been assessed for cardiac safety in a large placebo-controlled clinical trial.METHODS: Cardiac safety of one and two doses of MVA compared to placebo was assessed in 745 healthy subjects. Vaccinia-naïve subjects received either one dose of MVA and one dose of placebo, two doses of MVA, or two doses of placebo by subcutaneous injection four weeks apart; vaccinia-experienced subjects received a single dose of MVA. Solicited and unsolicited adverse events (AE) and cardiac safety parameters (recorded as Adverse Events of Special Interest, AESI) were monitored after each injection.RESULTS: A total of 5 possibly related AESI (3 cases of palpitations, 2 of tachycardia) were reported during the study. No case of myo- or pericarditis occurred. One possibly related serious AE (SAE) was reported during the 6-month follow-up period (sarcoidosis). The most frequently observed AEs were injection site reactions.CONCLUSIONS: Vaccination with MVA was safe and well tolerated and did not increase the risk for development of myo-/pericarditis.TRIAL REGISTRATION: ClinicalTrials.gov NCT00316524." ]

[ "Although pain was previously not considered an important element of multiple sclerosis (MS), recent evidence indicates that over 50% of MS patients suffer from chronic pain. In the present study, we utilized the Theiler's murine encephalomyelitis virus (TMEV) model of MS to examine whether changes in nociception occur during disease progression and to investigate whether sex influences the development of nociception or disease-associated neurological symptoms. Using the rotarod assay, TMEV infected male mice displayed increased neurological deficits when compared to TMEV infected female mice, which mimics what is observed in human MS. While both male and female TMEV infected mice exhibited thermal hyperalgesia and mechanical allodynia, female mice developed mechanical allodynia at a faster rate and displayed significantly more mechanical allodynia than male mice. Since neuropathic symptoms have been described in MS patients, we quantified sensory nerve fibers in the epidermis of TMEV-infected and non-infected mice to determine if there were alterations in epidermal nerve density. There was a significantly higher density of PGP9.5 and CGRP-immunoreactive axons in the epidermis of TMEV-infected mice versus controls. Collectively these results indicate that the TMEV model is well suited to study the mechanisms of MS-induced nociception and suggest that alterations in peripheral nerve innervation may contribute to MS pain.", "Clathrin-mediated endocytosis is a central and well-studied trafficking process in eukaryotic cells. How this process is initiated is likely to be a critical point in regulating endocytic activity spatially and temporally, but the underlying mechanisms are poorly understood. During the early stages of endocytosis three components-adaptor and accessory proteins, cargo, and lipids-come together at the plasma membrane to begin the formation of clathrin-coated vesicles. Although different models have been proposed, there is still no clear picture of how these three components cooperate to initiate endocytosis, which may indicate that there is some flexibility underlying this important event.", "BACKGROUND: Tpr is a large coiled-coil protein located in the nuclear basket of the nuclear pore complex for which many different functions were proposed from yeast to human.METHODOLOGY/PRINCIPAL FINDINGS: Here we show that depletion of Tpr by RNA interference triggers G0-G1 arrest and ultimately induces a senescent-like phenotype dependent on the presence of p53. We also found that Tpr depletion impairs the NES [nuclear export sequence]-dependent nuclear export of proteins and causes partial co-depletion of Nup153. In addition Tpr depletion impacts on level and function of the SUMO-protease SENP2 thus affecting SUMOylation regulation at the nuclear pore and overall SUMOylation in the cell.CONCLUSIONS: Our data for the first time provide evidence that a nuclear pore component plays a role in controlling cellular senescence. Our findings also point to new roles for Tpr in the regulation of SUMO-1 conjugation at the nuclear pore and directly confirm Tpr involvement in the nuclear export of NES-proteins.", "BACKGROUND: The apolipoprotein E (APOE) ε4 allele has been implicated in a range of neuropsychiatric conditions. The present research examined if the ε4 allele of the APOE gene moderated the effect of combat exposure on posttraumatic stress disorder (PTSD) among Iraq/Afghanistan-era veterans.METHOD: Participants included 765 non-Hispanic White (NHW) and 859 non-Hispanic Black (NHB) Iraq/Afghanistan-era veterans. A structured interview established psychiatric diagnoses. Combat exposure and PTSD symptom severity were assessed via self-report.RESULTS: The most common lifetime diagnoses were depression (39.2%), PTSD (38.4%), and alcohol dependence (24.38%). After correcting for multiple comparisons, no significant effects were observed on any of the outcomes among the NHW sample; however, within the NHB sample, significant gene × environment (G × E) interactions were observed for lifetime PTSD (P = .0029) and PTSD symptom severity (P = .0009). In each case, the APOE ε4 allele had no effect on the outcomes when combat exposure was low; however, when combat exposure was high, an additive effect was observed such that ε4 homozygotes exposed to high levels of combat reported the highest rates of PTSD (92%) and the worst symptom severity scores on the Davidson Trauma Scale (M = 79.5).CONCLUSIONS: Although preliminary, these findings suggest that the APOE ε4 allele, in conjunction with exposure to high levels of combat exposure, may increase veterans' risk for developing PTSD.", "It has become amply clear that mitochondrial function defined by quality, quantity, dynamics, homeostasis, and regulated by mitophagy and mitochondrial biogenesis is a critical metric of human aging and disease. As a consequence, therapeutic interventions that can improve mitochondrial function can have a profound impact on human health and longevity. Kisspeptins are neuropeptides belonging to the family of metastasis suppressors that are known to regulate functions like fertility, reproduction, and metabolism. Using SKNSH cell line, hippocampus explant cultures and hippocampus of aging Wistar rat models, we show that Kisspeptin-10 (Kp) induces autophagy and mitophagy via calcium, Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ), AMP-activated protein kinase (AMPK), and Unc-51 like autophagy activating kinase (ULK1) signaling pathway that is independent of mammalian target of rapamycin (mTOR). Intriguingly, Kp administration in vivo also results in the enhancement of mitochondrial number, complex I activity, and Adenosine Triphosphate (ATP) levels. This study uncovers potential effects of Kp in protecting mitochondrial health and as a possible therapeutic intervention to hippocampus associated impairments such as memory, cognitive aging, and other diseases linked to mitochondrial dysfunction.", "Centrally administered thyrotropin-releasing hormone exerts a well documented hypertensive effect. In this study, the possible physiological role of thyrotropin-releasing hormone in the central cardiovascular regulation was evaluated in spontaneously hypertensive rats receiving long-term (8-14 days) intracerebroventricular infusion of a heterologous antiserum to thyrotropin-releasing hormone. The effect of this passive immunization on the blood pressure was monitored from conscious animals by the tail-cuff method. Thyrotropin-releasing hormone antiserum significantly decreased the systolic arterial pressure in adult rats with established hypertension. No alterations in serum thyroid hormone status were observed indicating that the antihypertensive effect of immunological blockade of thyrotropin-releasing hormone was not due to changes in the serum thyroid hormone levels. These results provide evidence for a role of endogenous brain thyrotropin-releasing hormone in the maintenance of hypertension in spontaneously hypertensive rats.", "BACKGROUND: Cytosine arabinoside-based chemotherapy coupled with anthracycline is currently the first-line treatment for acute myeloid leukaemia (AML), but diverse responses to the regimen constitute obstacles to successful treatment. Therefore, outcome prediction to chemotherapy at diagnosis is believed to be a critical consideration.METHODS: The mRNA expression of 12 genes closely involved in the actions of cytosine arabinoside and anthracycline was evaluated by real-time reverse transcriptase PCR (RT-PCR), in 54 diagnostic bone marrow specimens of M2-subtype AML.RESULTS: Low expression levels of ribonucleotide reductase M2 (RRM2) and high expression levels of topoisomerase 2 beta (TOP2B) were correlated with longer survival in a univariate analysis. Another interesting finding is that high ratios of TOP2B/RRM2 and TOP2B/TOP2 alpha (TOP2A) in a combined analysis were also shown to have a prognostic impact for longer survival with improved accuracy. Among the four markers, when adjusted for the influence of other clinical factors in multivariate analysis, the TOP2B/TOP2A ratio was significantly correlated with treatment outcomes; patients with high ratios trended toward longer disease-free survival (HR, 0.24; P=0.002) and overall survival (HR, 0.29; P=0.005).CONCLUSION: Genes with distinct expression profiles such as TOP2B/TOP2A expression ratio at diagnosis can be employed for outcome prediction after the treatment with standard regimens in AML patients with M2 subtype." ]

[ "Kleefstra syndrome (KS) is an autosomal dominant disorder caused by a chromosomal deletion at 9q34.3 resulting in pathogenic variants of the gene that codes for the enzyme, euchromatin histone methyltransferase 1 (EHMT1). KS is a rare, yet clinically relevant congenital disorder for anesthesiologists because of its potential for cardiac and craniofacial involvement. We present a 3-month-old patient with KS who required anesthetic care for diagnostic laryngoscopy and rigid bronchoscopy. The end-organ effects of KS are reviewed and our anesthetic care presented.", "The serotonergic system, serotonin (5HT), serotonin transporter (SERT), and serotonin receptors (5HT-x), is an evolutionarily ancient system that has clear physiological advantages to all life forms from bacteria to humans. This review focuses on the role of platelet/plasma serotonin and the cardiovascular system with minor references to its significant neurotransmitter function. Platelets transport and store virtually all plasma serotonin in dense granules. Stored serotonin is released from activated platelets and can bind to serotonin receptors on platelets and cellular components of the vascular wall to augment aggregation and induce vasoconstriction or vasodilation. The vascular endothelium is critical to the maintenance of cardiovascular homeostasis. While there are numerous ligands, neurological components, and baroreceptors that effect vascular tone it is proposed that serotonin and nitric oxide (an endothelium relaxing factor) are major players in the regulation of systemic blood pressure. Signals not fully defined, to date, that direct serotonin binding to one of the 15 identified 5HT receptors versus the transporter, and the role platelet/plasma serotonin plays in regulating hypertension within the cardiovascular system remain important issues to better understand many diseases and to develop new drugs. Also, expanded research of these pathways in lower life-forms may serve as important model systems to further our understanding of the evolution and mechanisms of action of serotonin.", "The cytoskeleton is a complex of detergent-insoluble components of the cytoplasm playing critical roles in cell motility, shape generation, and mechanical properties of a cell. Fibrillar polymers-actin filaments, microtubules, and intermediate filaments-are major constituents of the cytoskeleton, which constantly change their organization during cellular activities. The actin cytoskeleton is especially polymorphic, as actin filaments can form multiple higher order assemblies performing different functions. Structural information about cytoskeleton organization is critical for understanding its functions and mechanisms underlying various forms of cellular activity. Because of the nanometer-scale thickness of cytoskeletal fibers, electron microscopy (EM) is a key tool to determine the structure of the cytoskeleton. This article describes application of rotary shadowing (or metal replica) EM for visualization of the cytoskeleton. The procedure is applicable to thin cultured cells growing on glass coverslips and consists of detergent extraction of cells to expose their cytoskeleton, chemical fixation to provide stability, ethanol dehydration and critical point drying to preserve three-dimensionality, rotary shadowing with platinum to create contrast, and carbon coating to stabilize replicas. This technique provides easily interpretable three-dimensional images, in which individual cytoskeletal fibers are clearly resolved, and individual proteins can be identified by immunogold labeling. More importantly, replica EM is easily compatible with live cell imaging, so that one can correlate the dynamics of a cell or its components, e.g., expressed fluorescent proteins, with high resolution structural organization of the cytoskeleton in the same cell.", "Endothelin receptor antagonists and phosphodiesterase type 5 inhibitors are used to treat pulmonary arterial hypertension. We tested the hypothesis that a selective endothelin type A receptor antagonist (ambrisentan) and a phosphodiesterase type 5 inhibitor (tadalafil) may act synergistically to relax endothelin-constricted pulmonary arteries. Rat isolated intrapulmonary arterial rings contracted with 8 nmol/L endothelin-1 were relaxed by 10 nmol/L ambrisentan and 30 nmol/L tadalafil alone by 26±3% and 21±1%, respectively, whereas both drugs in combination acted synergistically to relax arterial rings by 83±6%. The nonselective endothelin type A and B receptor antagonists bosentan (100 nmol/L) and macitentan (30 nmol/L) alone relaxed endothelin-contracted rings by 30±5% and 24±3%, respectively. Combinations of 30 nmol/L tadalafil with 100 nmol/L bosentan or 30 nmol/L macitentan relaxed endothelin-contracted rings by 53±5% or 46±7%, respectively; these values are similar to the calculated sums of the individual effects of these compounds. Denudation of endothelium from pulmonary arterial rings abolished the vasodilator response to 30 nmol/L tadalafil and the synergistic vasorelaxant effect of tadalafil with ambrisentan. In the presence of 1 μmol/L BQ-788, a selective endothelin type B receptor antagonist, the vasorelaxant effects of 10 nmol/L ambrisentan and 30 nmol/L tadalafil were additive but not synergistic. These data can be interpreted to suggest that ambrisentan and tadalafil synergistically inhibit endothelin-1-induced constriction of rat intrapulmonary arteries and that endothelin type B receptors in endothelium are necessary to enable a synergistic vasorelaxant effect of the drug combination.", "In this review, we describe the current knowledge of the biology of the JAKs. The JAK family comprises the four nonreceptor tyrosine kinases JAK1, JAK2, JAK3, and Tyk2, all key players in the signal transduction from cytokine receptors to transcription factor activation. We also review the progresses made towards the optimization of JAK inhibitors and the importance of their selectivity profile. Indeed, the full array of many medicinal chemistry enabling tools (HTS, X-ray crystallography, scaffold morphing, etc.) has been deployed to successfully design molecules that discriminate among JAK family and other kinases. While the first JAK inhibitor was launched in 2011, this review also summarizes the status of several other small-molecule JAK inhibitors currently in development to treat arthritis, psoriasis, organ rejection, and multiple cancer types.", "mDia proteins are mammalian homologues of Drosophila diaphanous and belong to the formin family proteins that catalyze actin nucleation and polymerization. Although formin family proteins of nonmammalian species such as Drosophila diaphanous are essential in cytokinesis, whether and how mDia proteins function in cytokinesis remain unknown. Here we depleted each of the three mDia isoforms in NIH 3T3 cells by RNA interference and examined this issue. Depletion of mDia2 selectively increased the number of binucleate cells, which was corrected by coexpression of RNAi-resistant full-length mDia2. mDia2 accumulates in the cleavage furrow during anaphase to telophase, and concentrates in the midbody at the end of cytokinesis. Depletion of mDia2 induced contraction at aberrant sites of dividing cells, where contractile ring components such as RhoA, myosin, anillin, and phosphorylated ERM accumulated. Treatment with blebbistatin suppressed abnormal contraction, corrected localization of the above components, and revealed that the amount of F-actin at the equatorial region during anaphase/telophase was significantly decreased with mDia2 RNAi. These results demonstrate that mDia2 is essential in mammalian cell cytokinesis and that mDia2-induced F-actin forms a scaffold for the contractile ring and maintains its position in the middle of a dividing cell.", "Expansion of a tandem repeat tract is responsible for the Repeat Expansion diseases, a group of more than 20 human genetic disorders that includes those like Fragile X (FX) syndrome that result from repeat expansion in the FMR1 gene. We have previously shown that the ATM and Rad3-related (ATR) checkpoint kinase protects the genome against one type of repeat expansion in a FX premutation mouse model. By crossing the FX premutation mice to Ataxia Telangiectasia-Mutated (Atm) mutant mice, we show here that ATM also prevents repeat expansion. However, our data suggest that the ATM-sensitive mechanism is different from the ATR-sensitive one. Specifically, the effect of the ATM deficiency is more marked when the premutation allele is paternally transmitted and expansions occur more frequently in male offspring regardless of the Atm genotype of the offspring. The gender effect is most consistent with a repair event occurring in the early embryo that is more efficient in females, perhaps as a result of the action of an X-linked DNA repair gene. Our data thus support the hypothesis that two different mechanisms of FX repeat expansion exist, an ATR-sensitive mechanism seen on maternal transmission and an ATM-sensitive mechanism that shows a male expansion bias." ]

[ "HTLV-I is associated with a broad spectrum of manifestations, including tropical spastic paraparesis and adult T-cell leukemia/lymphoma. Arnold Chiari syndrome is a condition characterized by herniation of the cerebellar tonsils through the foramen magnum. This condition should be suspected in all patients with headache and impaired motor coordination. Syringomyelia is a developmental anomaly that leads to the formation of an intramedullary cavity. Its clinical presentation is classically characterized by syringomyelic dissociation of sensation, with suspended distribution in the proximal portion of the trunk and upper limbs and preservation in other regions. We report here a case of association of the three diseases, which is rare in clinical practice, illustrating the difficulty in the diagnosis and therapeutic management of these conditions.", "Cholesteryl ester storage disease (CESD) and Wolman disease (WD) are both autosomal recessive disorders associated with reduced activity and genetic defects of lysosomal acid lipase (LAL). The strikingly more severe course of WD is caused by genetic defects of LAL that leave no residual enzymatic activity. Mutations at the exon 8/intron 8 transition of the LAL gene have been identified in several CESD and WD patients and are responsible for the manifestation of the disease. We have determined the genetic defect in a 3-month-old boy of African origin affected by WD. No enzymatic activity of the lysosomal acid lipase was detectable in white blood cells and cultured fibroblasts. Analysis of his LAL cDNA and genomic DNA revealed that he was homozygous for a mutation at position -3 of the exon 8 splice donor site. A C-->T transition leads to a nonsense codon and to a premature termination of the LAL protein at amino acid 277. Due to this mutation, a shorter LAL mRNA species was also generated that lacked exon 8 and was deficient of the nonsense codon. As a consequence, the protein synthesis proceeded to the natural termination codon, but the enzyme generated had an internal deletion of 24 amino acids (254-277) and was also inactive. These findings, together with our previous observations when analyzing the mutations in WD and CESD patients lead to the conclusion that the more severe WD is due to mutations that absolutely abolish lysosomal acid lipase (LAL) enzyme activity and the cholesteryl ester storage disease phenotype is due to mutations that allow some residual LAL activity to be manifested.", "Disturbance of intracellular trafficking plays a major role in several neurodegenerative disorders including Alzheimer or Parkinson's disease. The Chediak-Higashi syndrome (CHS), a life-threatening autosomal recessive disease with frequent mutations in the LYST gene, and its animal model, the beige mouse, are both characterized by lysosomal defects with accumulation of giant lysosomes. Clinically they manifest as hypopigmentation, abnormal bleeding and increased susceptibility to infection with various degrees of involvement of the nervous system. In the course of a recessive N-ethyl-N-nitrosurea (ENU) mutagenesis screen, we identified the first murine missense mutation in the lysosomal trafficking regulator gene (Lyst(Ing3618)) located at a highly conserved position in the WD40 protein domain. Nearly all described human Lyst alleles lead to protein truncation and fatal childhood CHS. Only four different missense mutations have been reported in patients with adolescent or adult forms of CHS involving the nervous system. Interestingly, the Lyst(Ing3618) model presents with a predominant neurodegenerative phenotype with progressive degeneration and loss of Purkinje cells and lacks severe impairment of the immune system. Therefore, the Lyst(Ing3618 )allele could represent a new model for adult CHS with neurological impairment. It could also provide an important tool to elucidate the role of neuronal lysosomal trafficking in the pathophysiology of neurodegeneration.", "Restless legs syndrome (RLS)/Willis-Ekbom disease (WED) is a common disorder, occurring at least twice a week and causing at least moderate distress in 1.5% to 2.7% of the population. It is important for primary care physicians to be familiar with this disorder and its management. Much has changed in its management since our previous algorithm was published in 2004, including the availability of several new drugs. This revised algorithm was written by members of the Medical Advisory Board of the Willis-Ekbom Disease Syndrome Foundation based on scientific evidence and expert opinion. It considers the management of RLS/WED under intermittent RLS/WED, chronic persistent RLS/WED, and refractory RLS/WED. Nonpharmacological approaches, including mental alerting activities, avoiding substances or medications that may exacerbate RLS, and the role of iron supplementation, are outlined. Chronic persistent RLS/WED should be treated with either a nonergot dopamine agonist or a calcium channel α-2-δ ligand. We discuss the available drugs, the factors determining which to use, and their adverse effects. We define refractory RLS/WED and describe management approaches, including combination therapy and the use of high-potency opioids.", "DNA replication is a primary mechanism for maintaining genome integrity, but it serves this purpose best by cooperating with other proteins involved in DNA repair and recombination. Unlike leading strand synthesis, lagging strand synthesis has a greater risk of faulty replication for several reasons: First, a significant part of DNA is synthesized by polymerase alpha, which lacks a proofreading function. Second, a great number of Okazaki fragments are synthesized, processed and ligated per cell division. Third, the principal mechanism of Okazaki fragment processing is via generation of flaps, which have the potential to form a variety of structures in their sequence context. Finally, many proteins for the lagging strand interact with factors involved in repair and recombination. Thus, lagging strand DNA synthesis could be the best example of a converging place of both replication and repair proteins. To achieve the risky task with extraordinary fidelity, Okazaki fragment processing may depend on multiple layers of redundant, but connected pathways. An essential Dna2 endonuclease/helicase plays a pivotal role in processing common structural intermediates that occur during diverse DNA metabolisms (e.g. lagging strand synthesis and telomere maintenance). Many roles of Dna2 suggest that the preemptive removal of long or structured flaps ultimately contributes to genome maintenance in eukaryotes. In this review, we describe the function of Dna2 in Okazaki fragment processing, and discuss its role in the maintenance of genome integrity with an emphasis on its functional interactions with other factors required for genome maintenance.", "Author information:(1)Unit of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. A.V. Zhirmunsky Institute of Marine Biology of the Far Eastern Branch of the Russian Academy of Sciences, Vladivostok, Russia.(2)Unit of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.(3)Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden.(4)Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.(5)Division of Molecular Neurobiology, Medical Research Council (MRC) National Institute for Medical Research, London, UK.(6)Department of Neuroscience, The Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany.(7)Unit of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. igor.adameyko@ki.se patrik.ernfors@ki.se.(8)Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. igor.adameyko@ki.se patrik.ernfors@ki.se.", "Mal de debarquement (MdD) is a subjective perception of self-motion after exposure to passive motion, in most cases sea travel, hence the name. Mal de debarquement occurs quite frequently in otherwise healthy individuals for a short period of time (several hours). However, in some people symptoms remain for a longer period of time or even persist and this is then called mal de debarquement syndrome (MdDS). The underlying pathogenesis is poorly understood and therefore, treatment options are limited. In general, limited studies have focused on the topic, but the past few years more and more interest has been attributed to MdDS and its facets, which is reflected by an increasing number of papers. Till date, some interesting reviews on the topic have been published, but a systematic review of the literature is lacking and could help to address the shortcomings and flaws of the current literature. We here present a systematic review of MdD(S) based on a systematic search of medical databases employing predefined criteria, using the terms \"mal de debarquement\" and \"sea legs\". Based on this, we suggest a list of criteria that could aid healthcare professionals in the diagnosis of MdDS. Further research needs to address the blank gaps by addressing how prevalent MdD(S) really is, by digging deeper into the underlying pathophysiology and setting up prospective, randomized placebo-controlled studies to evaluate the effectiveness of possible treatment strategies." ]

[ "Pharmaceutical companies and the NIH have invested heavily in a variety of potential disease-modifying therapies for Alzheimer's disease (AD) but unfortunately all double-blind placebo-controlled Phase III studies of these drugs have failed to show statistically significant results supporting their clinical efficacy on cognitive measures. These negative results are surprising as most of these medications have the capability to impact the biomarkers which are associated with progression of Alzheimer's disease. Areas covered: This contradiction prompted us to review all study phases of Intravenous Immunoglobulin (IVIG), Bapineuzumab, Solanezumab, Avagacestat and Dimebolin to shed more light on these recent failures. We critically analyzed these studies, recommending seven lessons from these failures which should not be overlooked. Expert commentary: We suggest a new methodology for future treatment research in Alzheimer's disease considering early intervention with more focus on cognitive decline as a screening tool, more sophisticated exclusion criteria with more reliance on biomarkers, stratification of subjects based on the rate of cognitive decline aiming less heterogeneity, and a longer study duration with periodic assessment of cognition and activities of daily living during the study and also after a washout period.", "A search for candidates for a functional homologue of Escherichia coli MutT in yeast Saccharomyces cerevisiae was made in the NCBI-BLAST database using the Nudix box, a short amino acid sequence conserved among E.coli MutT, Pseudomonoas vulgaris MutT, and human, rat and mouse MTH1. Among five candidates, we focused on the open reading frame YLR151c, because it had a region with approximately 76% similarity to the N-terminal half of MutT including the Nudix box. We thus evaluated the ability of YLR151c as a functional homologue of E.coli MutT in S.cerevisiae. Expression of YLR151c was able to suppress the transversion from A:T to C:G caused by misincorporation of the oxidized nucleotide 8-oxo-dGTP in the E.coli mutT-deficient strain. The disruption of the YLR151c in yeast strain caused approximately 14-fold increase in the frequency of spontaneous mutation compared to the wild type. Additionally, biochemical analysis indicated that GST-YLR151c fusion protein possessed pyrophosphatase activity for both 7,8-dihydro-8-oxo-2'-deoxyguanosine triphosphate (8-oxo-dGTP) and 1,2-dihydro-2-hydroxy-2'-deoxyadenosine triphosphate (2-OH-dATP). The specific activity of GST-YLR151c for 8-oxo-dGTP was 5.6 x 10(-3) microM(-1) s(-1), which was similar to that of RibA, a backup enzyme for MutT in E.coli, but was 150-fold lower than that of hMTH1. From these results, we conclude that YLR151c has an ability to prevent spontaneous mutagenesis via sanitization of oxidized nucleotides, and that it may be the functional homologue of E.coli MutT in S.cerevisiae.", "Telomerase is the enzyme that extends the chromosome ends, thereby contributing to eukaryotic cell genome stability. Telomerase is expressed in the majority of cells that have an unlimited proliferation such as stem cells and cancer cells. The increased interest in telomerase in cancer research, challenged by the low cellular abundance of the enzyme, has led to the development of a reliable and at the same time very sensitive approach to detect telomerase activity. The telomeric repeat amplification protocol (TRAP) represents an easy and rapid method for detection of telomerase activity in cells. A non-telomeric TS primer is extended by telomerase in the first step followed by the PCR amplification of the products. The PCR step renders this protocol very sensitive to detect telomerase activity at the single cell level making it compatible with the analysis of tumor samples. When run on a polyacrylamide gel, the PCR product is a characteristic ladder of bands due to the repetitive nature of telomeric DNA sequence. The densitometric analysis of the ladder allows the TRAP assay to be used for comparative quantification of telomerase activity in different samples.", "BACKGROUND: The Ottawa Ankle Rules, Ottawa Knee Rule, and Canadian C-Spine Rule-together known as The Ottawa Rules-are a set of internationally validated clinical decision rules developed to decrease unnecessary diagnostic imaging in the emergency department. In this study, we sought to develop and evaluate the use of a mobile app version of The Ottawa Rules.OBJECTIVE: The primary objective of this study was to determine acceptability of The Ottawa Rules app among emergency department clinicians. The secondary objective was to evaluate the effect of publicity efforts on uptake of The Ottawa Rules app.METHODS: The Ottawa Rules app was developed and publicly released for free on iOS and Android operating systems in April 2016. Local and national news and academic media coverage coincided with app release. This study was conducted at a large tertiary trauma care center in Ottawa, Canada. The study was advertised through posters and electronically by email. Emergency department clinicians were approached in person to enroll via in-app consent for a 1-month study during which time they were encouraged to use the app when evaluating patients with suspected knee, foot, or neck injuries. A 23-question survey was administered at the end of the study period via email to determine self-reported frequency, perceived ease of use of the app, and participant Technology Readiness Index scores.RESULTS: A total of 108 emergency department clinicians completed the study including 42 nurses, 33 residents, 20 attending physicians, and 13 medical students completing emergency department rotations. The median Technology Readiness Index for this group was 3.56, indicating a moderate degree of openness for technological adoption. The majority of survey respondents indicated favorable receptivity to the app including finding it helpful to applying the rules (73/108, 67.6%), that they would recommend the app to colleagues (81/108, 75.0%), and that they would continue using the app (73/108, 67.6%). Feedback from study participants highlighted a desire for access to more clinical decision rules and a higher degree of interactivity of the app. Between April 21, 2016, and June 1, 2017, The Ottawa Rules app was downloaded approximately 4000 times across 89 countries.CONCLUSIONS: We have found The Ottawa Rules app to be an effective means to disseminate the Ottawa Ankle Rules, Ottawa Knee Rule, and Canadian C-Spine Rule among all levels of emergency department clinicians. We have been successful in monitoring uptake and access of the rules in the app as a result of our publicity efforts. Mobile technology can be leveraged to improve the accessibility of clinical decision tools to health professionals.", "During the past ten years, microRNAs (miRNAs) have been shown to play a more significant role in the formation and progression of cancer diseases than previously thought. With an increase in reports about the dysregulation of miRNAs in diverse tumor types, it becomes more obvious that classic tumor-suppressive molecules enter deep into the world of miRNAs. Recently, it has been demonstrated that a typical tumor suppressor p53, known as the guardian of the genome, regulates some kinds of miRNAs to contribute to tumor suppression by the induction of cell-cycle arrest and apoptosis. Meanwhile, miRNAs directly/indirectly control the expression level and activity of p53 to fine-tune its functions or to render p53 inactive, indicating that the interplay between p53 and miRNA is overly complicated. The findings, along with current studies, will underline the continuing importance of understanding this interlocking control system for future therapeutic strategies in cancer treatment and prevention.", "Hox genes are essential regulators of embryonic development. Their step-wise transcriptional activation follows their genomic topology and the various states of activation are subsequently memorized into domains of progressively overlapping gene products. We have analyzed the 3D chromatin organization of Hox clusters during their early activation in vivo, using high-resolution circular chromosome conformation capture. Initially, Hox clusters are organized as single chromatin compartments containing all genes and bivalent chromatin marks. Transcriptional activation is associated with a dynamic bi-modal 3D organization, whereby the genes switch autonomously from an inactive to an active compartment. These local 3D dynamics occur within a framework of constitutive interactions within the surrounding Topological Associated Domains, indicating that this regulation process is mostly cluster intrinsic. The step-wise progression in time is fixed at various body levels and thus can account for the chromatin architectures previously described at a later stage for different anterior to posterior levels.DOI: http://dx.doi.org/10.7554/eLife.02557.001.", "Diet may represent a modifiable prostate cancer risk factor, but a vegetable-based prostate-healthy diet is a major change for most men. We used a ratio of animal to vegetable proteins (A:V) to evaluate whether a comprehensive dietary change was self-sustaining following completion of 11 weekly dietary and cooking classes that integrated mindfulness training. Thirty-six men with recurring prostate cancer were randomized to the intervention or wait-list control. Assessments were at baseline, 3 months, and 6 months. Of 17 men randomized to the intervention, 14 completed the requirements. Nineteen were randomized to control and 17 completed requirements. Compared with controls, a significant postintervention (3 months) decrease in A:V in the intervention group (P=0.01) was self-maintained 3 months postintervention (P=0.049). At each assessment, A:V was correlated with lycopene, fiber, saturated fat, and dietary cholesterol, four dietary components linked to clinically relevant outcomes in prostate cancer. Change in A:V was also significantly correlated with changes in fiber, saturated fat, and dietary cholesterol intake. Participants reported regular mindfulness training practice, and there was a significant correlation between mindfulness training practice and changes in both initiation and maintenance of the change in A:V. These pilot results provide encouraging evidence for the feasibility of a dietary program that includes mindfulness training in supporting dietary change for men with recurrent prostate cancer and invite further study to explore the possible role of mindfulness training as a means of supporting both initiation of dietary changes and maintenance of those changes over time." ]

[ "The major tumour suppressor protein, p53, is one of the most well-studied proteins in cell biology. Often referred to as the Guardian of the Genome, the list of known functions of p53 include regulatory roles in cell cycle arrest, apoptosis, angiogenesis, DNA repair and cell senescence. More recently, p53 has been implicated as a key molecular player regulating substrate metabolism and exercise-induced mitochondrial biogenesis in skeletal muscle. In this context, the study of p53 therefore has obvious implications for both human health and performance, given that impaired mitochondrial content and function is associated with the pathology of many metabolic disorders such as ageing, type 2 diabetes, obesity and cancer, as well as reduced exercise performance. Studies on p53 knockout (KO) mice collectively demonstrate that ablation of p53 content reduces intermyofibrillar (IMF) and subsarcolemmal (SS) mitochondrial yield, reduces cytochrome c oxidase (COX) activity and peroxisome proliferator-activated receptor gamma co-activator 1-α protein content whilst also reducing mitochondrial respiration and increasing reactive oxygen species production during state 3 respiration in IMF mitochondria. Additionally, p53 KO mice exhibit marked reductions in exercise capacity (in the magnitude of 50 %) during fatiguing swimming, treadmill running and electrical stimulation protocols. p53 may regulate contractile-induced increases in mitochondrial content via modulating mitochondrial transcription factor A (Tfam) content and/or activity, given that p53 KO mice display reduced skeletal muscle mitochondrial DNA, Tfam messenger RNA and protein levels. Furthermore, upon muscle contraction, p53 is phosphorylated on serine 15 and subsequently translocates to the mitochondria where it forms a complex with Tfam to modulate expression of mitochondrial-encoded subunits of the COX complex. In human skeletal muscle, the exercise-induced phosphorylation of p53(Ser15) is enhanced in conditions of reduced carbohydrate availability in association with enhanced upstream signalling through 5'adenosine monophosphate-activated protein kinase but not p38 mitogen-activated protein kinase. In this way, undertaking regular exercise in carbohydrate restricted states may therefore be a practical approach to achieve the physiological benefits of consistent p53 signalling. Although our knowledge of p53 in exercise metabolism has advanced considerably, much of our current understanding of p53 regulation and associated targets is derived from various non-muscle cells and tissues. As such, many fundamental questions remain unanswered in contracting skeletal muscle. Detailed studies concerning the time-course of p53 activation (including additional post-translational modifications and subsequent subcellular translocation), as well as the effects of exercise modality (endurance versus resistance), intensity, duration, fibre type, age, training status and nutrient availability, must now be performed so that we can optimise exercise prescription guidelines to strategically target p53 signalling. The emerging role of p53 in skeletal muscle metabolism therefore represents a novel and exciting research area for exercise and muscle physiologists.", "Mining of the genome for lipid genes has since the early 1970s helped to shape our understanding of how triglycerides are packaged (in chylomicrons), repackaged (in very low density lipoproteins; VLDL), and hydrolyzed, and also how remnant and low-density lipoproteins (LDL) are cleared from the circulation. Gene discoveries have also provided insights into high-density lipoprotein (HDL) biogenesis and remodeling. Interestingly, at least half of these key molecular genetic studies were initiated with the benefit of prior knowledge of relevant proteins. In addition, multiple important findings originated from studies in mouse, and from other types of non-genetic approaches. Although it appears by now that the main lipid pathways have been uncovered, and that only modulators or adaptor proteins such as those encoded by LDLRAP1, APOA5, ANGPLT3/4, and PCSK9 are currently being discovered, genome wide association studies (GWAS) in particular have implicated many new loci based on statistical analyses; these may prove to have equally large impacts on lipoprotein traits as gene products that are already known. On the other hand, since 2004 - and particularly since 2010 when massively parallel sequencing has become de rigeur - no major new insights into genes governing lipid metabolism have been reported. This is probably because the etiologies of true Mendelian lipid disorders with overt clinical complications have been largely resolved. In the meantime, it has become clear that proving the importance of new candidate genes is challenging. This could be due to very low frequencies of large impact variants in the population. It must further be emphasized that functional genetic studies, while necessary, are often difficult to accomplish, making it hazardous to upgrade a variant that is simply associated to being definitively causative. Also, it is clear that applying a monogenic approach to dissect complex lipid traits that are mostly of polygenic origin is the wrong way to proceed. The hope is that large-scale data acquisition combined with sophisticated computerized analyses will help to prioritize and select the most promising candidate genes for future research. We suggest that at this point in time, investment in sequence technology driven candidate gene discovery could be recalibrated by refocusing efforts on direct functional analysis of the genes that have already been discovered. This article is part of a Special Issue entitled: From Genome to Function.", "The identification of Zika virus as a significant teratogen has raised international concern, causing the World Health Organization to declare a Public Health Emergency of International Concern. This has allowed a global mobilization of experts in tropical infectious diseases, obstetrics, pediatrics, virology, public health policy, reproductive health, bioethics, and germ cell research to name just a few. This worldwide crisis has also raised awareness of health care disparities and concerns regarding the ability of families and societies to shoulder the long-term financial burden that the follow-up of affected children will require. There is now strong biologic evidence of causality between Zika virus and microcephaly and other neurologic abnormalities identified. Multiple national and international organizations have collaborated to develop guidelines for the management of pregnant women who reside in or who are exposed to Zika virus, whether from travel to affected areas or via sexual contact with an infected individual. These guidelines are updated frequently as data are made available. Testing algorithms are available and though testing is fraught with interpretation issues, the development of better diagnostic tests is ongoing.", "Apoptosis, or programmed cell death, is a physiological form of cell death that plays a critical role in the development and maintenance of multicellular organisms. Apoptosis is characterized based on morphological and biochemical criteria. Morphological characteristics include cell shrinkage, cytoplasmic condensation, chromatin segregation and condensation, membrane blebbing, and the formation of membrane-bound apoptotic bodies, whereas the biochemical hallmark of apoptosis is internucleosomal DNA cleavage into oligonucleosome-length fragments. A great deal of research is aimed at defining the molecular mechanisms that play a role in apoptosis. As one of the common end points of experiments related to apoptosis is in fact the death of the cell, it has become important to develop reliable assays to measure cell death that may be compared among the various systems being investigated. This chapter reviews many of the current methods used to measure apoptotic cell death and points out strengths and weaknesses of each approach with respect to the system being examined and the questions being asked. Traditional cell-based methods, including light and electron microscopy, vital dyes, and nuclear stains, are described. Biochemical methods such as DNA laddering, lactate dehydrogenase enzyme release, and MTT/XTT enzyme activity are described as well. Additionally, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling of DNA fragments (TUNEL) and in situ end labeling (ISEL) techniques are reviewed, which when used in conjunction with standard flow cytometric staining methods may yield informative data relating cell death to various cellular parameters, including cell cycle and cell phenotype. The use of one or more of the methods described in this chapter for measuring cell death should enable investigators to accurately assess apoptosis in the context of the various models being examined and help define causal relationships between the mechanisms that regulate apoptosis and the cell death event itself.", "BACKGROUND: Angiopoietin-like protein 3 (ANGPTL3) affects lipid metabolism by inhibiting the activity of lipoprotein and endothelial lipases. Angptl3 knockout mice have marked hypolipidemia, and heterozygous carriers of ANGPLT3, loss-of-function mutations were found among individuals in the lowest quartile of plasma triglycerides in population studies. Recently, 4 related individuals with primary hypolipidemia were found to be compound heterozygotes for ANGPTL3 loss-of-function mutations.METHODS AND RESULTS: We resequenced ANGPTL3 in 4 members of 3 kindreds originally identified for very low levels of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (0.97±0.16 and 0.56±0.20 mmol/L, respectively) in whom no mutations of known candidate genes for monogenic hypobetalipoproteinemia and hypoalphalipoproteinemia had been detected. These subjects were found to be homozygous or compound heterozygous for ANGPTL3 loss-of-function mutations (p.G400VfsX5, p.I19LfsX22/p.N147X) associated with the absence of ANGPTL3 in plasma. They had reduced plasma levels of triglyceride-containing lipoproteins and of HDL particles that contained only apolipoprotein A-I and pre-β-high-density lipoprotein. In addition, their apolipoprotein B-depleted sera had a reduced capacity to promote cell cholesterol efflux through the various pathways (ABCA1-, SR-BI-, and ABCG1-mediated efflux); however, these subjects had no clinical evidence of accelerated atherosclerosis. Heterozygous carriers of the ANGPTL3 mutations had low plasma ANGPTL3 and moderately reduced low-density lipoprotein cholesterol (2.52±0.38 mmol/L) but normal plasma high-density lipoprotein cholesterol.CONCLUSIONS: Complete ANGPTL3 deficiency caused by loss-of-function mutations of ANGPTL3 is associated with a recessive hypolipidemia characterized by a reduction of apolipoprotein B and apolipoprotein A-I-containing lipoproteins, changes in subclasses of high-density lipoprotein, and reduced cholesterol efflux potential of serum. Partial ANGPTL3 deficiency is associated only with a moderate reduction of low-density lipoprotein.", "Fat-specific protein (FSP)27/Cidec is most highly expressed in white and brown adipose tissues and increases in abundance by over 50-fold during adipogenesis. However, its function in adipocytes has remained elusive since its discovery over 15 years ago. Here we demonstrate that FSP27/Cidec localizes to lipid droplets in cultured adipocytes and functions to promote lipid accumulation. Ectopically expressed FSP27-GFP surrounds lipid droplets in 3T3-L1 adipocytes and colocalizes with the known lipid droplet protein perilipin. Immunostaining of endogenous FSP27 in 3T3-L1 adipocytes also confirmed its presence on lipid droplets. FSP27-GFP expression also markedly increases lipid droplet size and enhances accumulation of total neutral lipids in 3T3-L1 preadipocytes as well as other cell types such as COS cells. Conversely, RNA interference-based FSP27/Cidec depletion in mature adipocytes significantly stimulates lipolysis and reduces the size of lipid droplets. These data reveal FSP27/Cidec as a novel adipocyte lipid droplet protein that negatively regulates lipolysis and promotes triglyceride accumulation.", "PURPOSE: With three available chemotherapy drugs for advanced colorectal cancer (CRC), response rate (RR) and survival outcomes have improved with associated morbidity, accentuating the need for tools to select optimal individualized treatment. Pharmacogenetics identifies the likelihood of adverse events or response based on variants in genes involved in drug transport, metabolism, and cellular targets.PATIENTS AND METHODS: Germline DNA was extracted from 520 patients on the North American Gastrointestinal Intergroup N9741 study. Three study arms were evaluated: IFL (fluorouracil [FU] + irinotecan [IRN]), FOLFOX (FU + oxaliplatin), and IROX (IRN + oxaliplatin). Information on adverse events, response, and disease-free survival was available. Thirty-four variants in 15 candidate genes for analysis based on previous associations with adverse events or outcome were assessed. Genotyping was performed using pyrosequencing.RESULTS: All variants were polymorphic. The homozygous UGT1A1*28 allele observed in 9% of patients was associated with risk of grade 4 neutropenia in patients on IROX (55% v 15%; P = .002). Deletion in GSTM1 was associated with grade 4 neutropenia after FOLFOX (28% v 16%; P = .02). Patients with a homozygous variant genotype for GSTP1 were more likely to discontinue FOLFOX because of neurotoxicity (24% v 10%; P = .01). The presence of a CYP3A5 variant was significantly associated with RR on IFL (29% v 60%; P = .0074). Most previously published genotype-toxicity or -efficacy relationships were not validated in this study.CONCLUSION: This study provides a platform to evaluate pharmacogenetic predictors of response or severe adverse events in advanced CRC. Pharmacogenetic studies can be conducted in multicenter trials, and our findings demonstrate that with continued research, clinical application is practical.", "The iliac hemophilic pseudotumor is a rare complication of hemophilia occurring in 1-2% of patients with Factor VIII or Factor IX deficiency. It is frequently disabling and life threatening. This report presents a comparative study of postoperative results of two cases of hemophilic pseudotumor of ilium. One patient undergoing partial resection showed a favorable postoperative course, whereas the patient with complete resection of the pseudotumor died of postoperative bleeding and sepsis. Studies on the postoperative results of these two cases indicate that careful preoperative consideration of tumor size and degree of infiltration is of the utmost importance in operative management. Early excision of tumors eliminates the possibility of endogenous infection. Even partial resection of huge tumors, leaving the lateral wall intact for compression, can promote recovery of functions." ]

[ "Gene expression assays that are used in daily clinical practice for treating early breast cancer patients have been introduced in the clinic only recently. This review discusses the development of these arrays, summarizes the validation of those that are commercially available and indicates how the information provided by these assays can help in the care of patients. The review also provides an extensive overview of commercially available assays focusing on MammaPrint, the first and only assay for breast cancer management that has been cleared by the FDA.", "One-and-a-half syndrome is a syndrome characterized by horizontal movement disorders of the eyeballs, which was first reported and named by Fisher in 1967. It presents a combination of ipsilateral conjugate horizontal gaze palsy (one) and ipsilateral internuclear ophthalmoplegia (INO) (a half). On the basis of the one-and-a-half syndrome, there are a series of related rare syndromes called the one-and-a-half syndrome spectrum disorders. This article reviews rare cases of one-and-a-half syndrome spectrum disorder, describes the clinical and pathological features of different syndromes, and summarizes their nomenclature.", "OBJECTIVE: Since 1983, hemin has been FDA-approved for acute intermittent porphyria (AIP) attacks. In 2019, FDA approved givosiran for the treatment of adults with acute hepatic porphyria. The objective of this research was to estimate and compare the total cost of AIP-related healthcare for patients treated with hemin or givosiran.METHODS: A microsimulation cost model was developed to estimate the annual economic impact of hemin versus givosiran treatment for patients with AIP from the U.S. healthcare payer perspective. Hemin treatment costs were calculated from the Hemin Shipment Data in which patients were defined as receiving acute attack treatment or prophylaxis treatment based on shipment patterns. Three separate hemin subpopulations were considered: one attack per year, multiple attacks per year, and hemin prophylaxis. Treatment costs for givosiran (with hemin for acute attacks) were simulated based on Phase III trial efficacy results applied to individual treatment histories in the Hemin Shipment Data. Other healthcare utilization was also considered. Outcomes were annualized and expenditures inflated to 2019.RESULTS: For all patients with AIP, the average annual total cost of care with hemin was 78% lower (difference = $482,113; 95% CI=$373,638-$594,778) than the average annual total cost of care with givosiran. Average annual total cost of care with hemin was between 46% and 92% lower than givosiran for the three hemin subpopulations: one attack per year (difference = $545,219; 95% CI=$436,584-$657,239), multiple attacks per year (difference = $459,366; 95% CI=$350,291-$574,403), and hemin prophylaxis (difference = $311,950; 95% CI=$191,898-$435,893). Cost savings with hemin were robust to one-way and probabilistic sensitivity as well as scenario analyses.CONCLUSIONS: Hemin is expected to provide cost savings compared to givosiran for all AIP patients and subpopulations. Lower annual total costs of care with hemin range from $311,950 to $545,219 less depending on whether the patient uses hemin prophylactically or for acute treatment attacks.", "Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients. However, a significant subset of patients does not respond to anti-TNF agents, for reasons that are still unknown. The aim of this study was to validate five single nucleotide polymorphisms (SNPs) of PTPRC, CD226, AFF3, MyD88 and CHUK gene loci that have previously been reported to predict anti-TNF outcome. In addition, two markers of RA susceptibility, namely TRAF1/C5 and STAT4 were assessed, in a cohort of anti-TNF-treated RA patients, from the homogeneous Greek island of Crete, Greece. The RA patient cohort consisted of 183 patients treated with either of 3 anti-TNF biologic agents (infliximab, adalimumab and etanercept) from the Clinic of Rheumatology of the University Hospital of Crete. The SNPs were genotyped by TaqMan assays or following the Restriction Fragments Length Polymorphisms (RFLPs) approach. Disease activity score in 28 joints (DAS28) at baseline and after 6 months were available for all patients and analysis of good versus poor response at 6 months was performed for each SNP. None of the 7 genetic markers correlated with treatment response. We conclude that the gene polymorphisms under investigation are not strongly predictive of anti-TNF response in RA patients from Greece.", "PURPOSE: To describe the genotype-phenotype relationship of a cohort of consecutive patients with isolated ectopia lentis (EL) secondary to ADAMTSL4 and FBN1 mutations.METHODS: Patients underwent detailed ocular, cardiovascular, and skeletal examination. This was correlated with Sanger sequencing of ADAMTSL4 and FBN1 genes.RESULTS: Seventeen patients were examined, including one with ectopia lentis et pupillae. Echocardiography and skeletal examination revealed no sign of systemic disorders associated with EL, in particular Marfan syndrome (MFS). Nine patients (52.9%) were found to have mutations in ADAMTSL4, including four novel nonsense mutations. Four patients (25%) were found to have novel FBN1 mutations, not previously reported as causing classical Marfan syndrome. One additional patient was found to have an FBN1 mutation previously reported in classical MFS. Four patients (25%) were found to have no mutations in either gene. Median age of diagnosis of EL was 35 years in patients with FBN1 mutations and 2 years in patients with ADAMTSL4 mutations (P < 0.01). Mean axial length was 22.74 mm (95% confidence interval [CI]: 21.3-24.2) (FBN1) and 27.54 mm (95% CI: 24.2-30.9) (ADAMTSL4) (P < 0.01). Other ophthalmic features, including corneal thickness and power, foveal thickness, visual acuity, and direction of lens displacement, were similar for both groups.CONCLUSIONS: ADAMTSL4 is the most important known causative gene in isolated EL. Mutations in ADAMTSL4 appear to cause earlier manifestation of EL and are associated with increased axial length as compared to FBN1. We suggest that ADAMTSL4 be screened in all patients with isolated EL and that physicians be vigilant for the more severe ocular phenotype associated with mutations in this gene.", "Epigenetic regulation of gene expression is important in maintaining self-renewal of embryonic stem (ES) and trophoblast stem (TS) cells. Histone deacetylases (HDACs) negatively control histone acetylation by removing covalent acetylation marks from histone tails. Because histone acetylation is a known mark for active transcription, HDACs presumably associate with inactive genes. Here, we used genome-wide chromatin immunoprecipitation to investigate targets of HDAC1 in ES and TS cells. Through evaluation of genes associated with acetylated histone H3 marks, and global expression analysis of Hdac1 knockout ES and trichostatin A-treated ES and TS cells, we found that HDAC1 occupies mainly active genes, including important regulators of ES and TS cells self-renewal. We also observed occupancy of methyl-CpG binding domain protein 3 (MBD3), a subunit of the nucleosome remodeling and histone deacetylation (NuRD) complex, at a subset of HDAC1-occupied sequences in ES cells, including the pluripotency regulators Oct4, Nanog and Kfl4. By mapping HDAC1 targets on a global scale, our results describe further insight into epigenetic mechanisms of ES and TS cells self-renewal.", "The introduction of anti-TNF therapy has dramatically improved the outlook for patients suffering from a number of inflammatory conditions including rheumatoid arthritis and inflammatory bowel disease. Despite this, a substantial proportion of patients (approximately 30-40%) fail to respond to these potentially toxic and expensive therapies. Treatment response is likely to be multifactorial; however, variation in genes or their expression may identify those most likely to respond. By targeted testing of variants within candidate genes, potential predictors of anti-TNF response have been reported; however, very few markers have replicated consistently between studies. Emerging genome-wide association studies suggest that there may be a number of genes with modest effects on treatment response rather than a few genes of large effect. Other potential serum biomarkers of response have also been explored including cytokines and autoantibodies, with antibodies developing to the anti-TNF drugs themselves being correlated with treatment failure.", "PURPOSE: The purpose of this study was to verify the value of computed tomography (CT) in the diagnosis of the \"crowned dens\" syndrome, not only in crystal deposition diseases, but also in other rheumatic or nonrheumatic conditions.MATERIALS AND METHODS: Thirty-eight patients (15 men and 23 women; mean age 55 years; age range 35-79) with neck pain were examined and divided into two groups: (1) patients already identified as rheumatic and referred for further investigation of the atlantoaxial region; (2) patients with symptoms confined to the cervical spine, with inconclusive radiographic findings. Unenhanced CT of the cervical spine (Tomoscan SR 7000 Philips, Eindhoven, Netherlands) was performed in all patients. There were 11 cases of rheumatoid arthritis (ten women and one man), two calcium pyrophosphate dihydrate crystal deposition disease (both women), one of systemic sclerosis (a woman), one of osteoarthritis (a man), one of seronegative arthritis (a man), four of neoplasm (one woman and three men) with suspected cervical involvement, one (a man) of haematological disease (lymphoma), one (a woman) of menopausal osteoporosis, ten (five men and five women) of recent or previous trauma with suspected involvement of the skull base and first cervical vertebrae and six of unknown painful cervical dysfunction (three men and three women).RESULTS: CT demonstrated calcific deposits around the dens in 12 patients (three men and nine women), in the transverse and alar ligaments, and in the anterior atlantooccipital membrane. CT revealed horseshoe- or crown-like calcification surrounding the odontoid process. In our series, other rheumatic diseases, especially rheumatoid arthritis, showed similar irregular calcifications of the atlantoaxial joint. Discussion. In calcium pyrophosphate dihydrate (CPPD) crystal deposition disease, the spine may be the only site of involvement, generally asymptomatic. Crystals located in the transverse ligament of the atlas give rise to the crowned dens syndrome, usually in patients affected by severe degenerative lesions of the atlantoaxial joint and peripheral chondrocalcinosis. Symptoms may be absent, or a neurological compressive syndrome may develop. Symptoms tend to worsen with age. The diagnosis is not always easy, as the symptoms are similar to those of other diseases, such as meningitis, cervicobrachial pain, occipitotemporal headache, calcific tendinitis of the longus colli muscle, spondylodiscitis and retropharyngeal abscess.CONCLUSION: CT is the gold standard in identifying crowned dens syndrome, as it is able to depict the shape and site of calcification and any bone erosions. Radiography of other joints (wrist, knee, pubic symphysis) may help to ascertain whether the disease is due to calcium pyrophosphate dihydrate or hydroxyapatite crystals, and is therefore recommended for routine patient management. Magnetic resonance imaging (MRI) is indicated for the study of neurological complications." ]

[ "Author information:(1)Groupe Francophone de Cytogénétique Hématologique (GFCH).(2)Laboratoire de Cytogénétique Hématologique, Centre Hospitalier Universitaire (CHU) de Marseille, Aix-Marseille University, Marseille, France.(3)Centre de Recherches en Cancérologie de Toulouse (CRCT), Team 16, Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France.(4)Groupe Francophone d'Hématologie Cellulaire (GFHC) and.(5)Laboratoire d'hématologie, CHU de Guadeloupe, Inserm Unité Mixte de Recherche 1134, Pointe à Pitre, France.(6)Laboratoire d'Hématologie, Institut Universitaire de Cancérologie de Toulouse, CHU Toulouse, France.(7)Department of Hematology, University Toulouse III, Toulouse, France.(8)Centre de Recherches en Cancérologie de Toulouse (CRCT), Team 8, Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France.(9)Gene Editing, Wellcome Sanger Institute, Hinxton, Cambridge, UK.(10)Stem Cell Genetics, Wellcome Sanger Institute, Hinxton, Cambridge, UK.(11)Wellcome Sanger Institute, Hinxton, UK.(12)Department of Haematology, Cambridge University Hospitals National Health Service Trust, Cambridge, UK.(13)Wellcome-Medical Research Council Stem Cell Institute, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.(14)Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.(15)Institute of Medical Informatics, University of Münster, Münster, Germany.(16)Institut Cochin, Université de Paris, Inserm U1016, Centre National de la Recherche Scientifique UMR8104, Paris, France.(17)Belgium Cancer Registry, Brussels, Belgium.(18)Department of Human Genetics, Katholieke Universiteit Leuven and Universitair Ziekenhuis, Leuven, Belgium.(19)Laboratoire de Cytogénétique, CHU de Tours, France.(20)Laboratoire d'Hématologie, CHU de Bordeaux, Bordeaux, France.(21)Laboratoire de Cytogénétique, CHU de Besançon, Besançon, France.(22)Laboratoire de Cytogénétique, CHU de Strasbourg, Strasbourg, France.(23)Département de Biopathologie, Institut Paoli-Calmettes, Marseille, France.(24)Laboratoire de Cytogénétique, CHU de Grenoble, Grenoble, France.(25)Laboratoire de Cytogénétique, CHU de Reims, Reims, France.(26)Laboratoire de Cytogénétique, CHU de Saint-Etienne, Saint-Etienne, France.(27)Laboratoire de Cytogénétique, CHU de Paris-Necker, Paris, France.(28)Laboratoire d'Hématologie, CHU d'Angers, Angers, France.(29)Laboratoire de Cytogénétique, CHU de Nantes, Nantes, France.(30)Laboratoire de Cytogénétique, CH de Versailles, Le Chesnay, France.(31)Laboratoire de Cytogénétique, CHU de Lyon, Lyon, France.(32)Laboratoire de Cytogénétique, Centre Henri-Becquerel, Rouen, France.(33)Laboratoire d'Hématologie, CHU Avicenne, Bobigny, France.(34)Groupe Francophone des Myélodysplasies (GFM); and.(35)Laboratoire d'hématologie, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris, Paris, France.", "The ErbB network is dysregulated in many solid tumors. To exploit this, we have developed a chimeric Ag receptor (CAR) named T1E28z that targets several pathogenetically relevant ErbB dimers. T1E28z is coexpressed with a chimeric cytokine receptor named 4αβ (combination termed T4), enabling the selective expansion of engineered T cells using IL-4. Human T4(+) T cells exhibit antitumor activity against several ErbB(+) cancer types. However, ErbB receptors are also expressed in several healthy tissues, raising concerns about toxic potential. In this study, we have evaluated safety of T4 immunotherapy in vivo using a SCID beige mouse model. We show that the human T1E28z CAR efficiently recognizes mouse ErbB(+) cells, rendering this species suitable to evaluate preclinical toxicity. Administration of T4(+) T cells using the i.v. or intratumoral routes achieves partial tumor regression without clinical or histopathologic toxicity. In contrast, when delivered i.p., tumor reduction is accompanied by dose-dependent side effects. Toxicity mediated by T4(+) T cells results from target recognition in both tumor and healthy tissues, leading to release of both human (IL-2/IFN-γ) and murine (IL-6) cytokines. In extreme cases, outcome is lethal. Both toxicity and IL-6 release can be ameliorated by prior macrophage depletion, consistent with clinical data that implicate IL-6 in this pathogenic event. These data demonstrate that CAR-induced cytokine release syndrome can be modeled in mice that express target Ag in an appropriate distribution. Furthermore, our findings argue that ErbB-retargeted T cells can achieve therapeutic benefit in the absence of unacceptable toxicity, providing that route of administration and dose are carefully optimized.", "Posttranslational histone modifications and histone variants form a unique epigenetic landscape on mammalian chromosomes where the principal epigenetic heterochromatin markers, trimethylated histone H3(K9) and the histone H2A.Z, are inversely localized in relation to each other. Trimethylated H3(K9) marks pericentromeric constitutive heterochromatin and the male Y chromosome, while H2A.Z is dramatically reduced at these chromosomal locations. Inactivation of a lysosomal and nuclear protease, cathepsin L, causes a global redistribution of epigenetic markers. In cathepsin L knockout cells, the levels of trimethylated H3(K9) decrease dramatically, concomitant with its relocation away from heterochromatin, and H2A.Z becomes enriched at pericentromeric heterochromatin and the Y chromosome. This change is also associated with global relocation of heterochromatin protein HP1 and histone H3 methyltransferase Suv39h1 away from constitutive heterochromatin; however, it does not affect DNA methylation or chromosome segregation, phenotypes commonly associated with impaired histone H3(K9) methylation. Therefore, the key constitutive heterochromatin determinants can dynamically redistribute depending on physiological context but still maintain the essential function(s) of chromosomes. Thus, our data show that cathepsin L stabilizes epigenetic heterochromatin markers on pericentromeric heterochromatin and the Y chromosome through a novel mechanism that does not involve DNA methylation or affect heterochromatin structure and operates on both somatic and sex chromosomes.", "Atherosclerosis and related cardiovascular diseases pose severe threats to human health worldwide. There is evidence to suggest that at least 50% of foam cells in atheromas are derived from vascular smooth muscle cells (VSMCs); the first step in this process involves migration to human atherosclerotic lesions. Long non‑coding RNAs (lncRNAs) have been found to play significant roles in diverse biological processes. The present study aimed to investigate the role of lncRNAs in VSMCs. The expression of lncRNAs or mRNAs was detected using reverse transcription‑quantitative polymerase chain reaction. The Gene Expression Omnibus datasets in the NCBI portal were searched using the key words 'Atherosclerosis AND tissue AND Homo sapiens' and the GSE12288 dataset. Gene expression in circulating leukocytes was measured to identify patients with coronary artery disease (CAD) or controls, and used to analyze the correlation coefficient and expression profiles. The protein level of ATP‑binding cassette sub‑family G member 1 (ABCG1) and matrix metalloproteinase (MMP)3 was determined using immunohistochemistry and western blot analysis. The analysis of mouse aortic roots was performed using Masson's and Oil Red O staining. The expression of lncRNA AL355711, ABCG1 and MMP3 was found to be higher in human atherosclerotic plaques or in patients with atherosclerotic CAD. The correlation analysis revealed that ABCG1 may be involved in the regulation between lncRNA AL355711 and MMP3 in atherosclerotic CAD. The knockdown of lncRNA AL355711 inhibited ABCG1 transcription and smooth muscle cell migration. In addition, lncRNA AL355711 was found to regulate MMP3 expression through the ABCG1 pathway. The expression of ABCG1 and MMP3 was found to be high in an animal model of atherosclerosis. The results indicated that lncRNA AL355711 promoted VSMC migration and atherosclerosis partly via the ABCG1/MMP3 pathway. On the whole, the present study demonstrates that the inhibition of lncRNA AL355711 may serve as a novel therapeutic target for atherosclerosis. lncRNA AL355711 in circulating leukocytes may be a novel biomarker for atherosclerotic CAD.", "Bacteriophage T4 initiates DNA replication from specialized structures that form in its genome. Immediately after infection, RNA-DNA hybrids (R-loops) occur on (at least some) replication origins, with the annealed RNA serving as a primer for leading-strand synthesis in one direction. As the infection progresses, replication initiation becomes dependent on recombination proteins in a process called recombination-dependent replication (RDR). RDR occurs when the replication machinery is assembled onto D-loop recombination intermediates, and in this case, the invading 3' DNA end is used as a primer for leading strand synthesis. Over the last 15 years, these two modes of T4 DNA replication initiation have been studied in vivo using a variety of approaches, including replication of plasmids with segments of the T4 genome, analysis of replication intermediates by two-dimensional gel electrophoresis, and genomic approaches that measure DNA copy number as the infection progresses. In addition, biochemical approaches have reconstituted replication from origin R-loop structures and have clarified some detailed roles of both replication and recombination proteins in the process of RDR and related pathways. We will also discuss the parallels between T4 DNA replication modes and similar events in cellular and eukaryotic organelle DNA replication, and close with some current questions of interest concerning the mechanisms of replication, recombination and repair in phage T4.", "Pagetoid spread of primary esophageal melanomas and several cases of pagetoid esophageal squamous cell carcinoma are known. However, true esophageal Paget disease (intraepithelial growth of neoplastic cells with glandular differentiation) has only rarely been reported. We encountered 3 endoscopic biopsy specimens containing Paget cells in squamous epithelium associated with adenocarcinomas in Barrett esophagus (BE) and in the esophagogastric junction. To determine the prevalence of Paget cells in the esophagus, we studied 81 endoscopic mucosal resections and 27 esophagectomies from patients with invasive or intramucosal adenocarcinoma, and compared the findings to a control group of 47 endoscopic mucosal resections and 25 esophagectomies from patients with high-grade dysplasia in BE. Paget cells were present in squamous epithelium overlying 5 (4.9%) of 108 adenocarcinomas but in none (0%) of 72 BE with high-grade dysplasia (P=0.16). A computerized search for primary Paget disease using the terms \"Paget's and esophagus\" or \"pagetoid and esophagus\" from 1994 to 2007 did not yield any additional cases. Among the 8 patients with Paget cells (including the 2 index biopsies) there were no differences in either sex distribution (7M:1F) or age (mean 62.4 y) as compared with 103 adenocarcinomas without Paget cells (93M:10F, P=0.58; mean age 69.2 y, P=0.78). Morphologically, all adenocarcinomas with Paget cells contained at least a component of diffuse, poorly differentiated adenocarcinoma, and 1 was a signet ring cell carcinoma. Paget cells involved only squamous epithelium directly above the poorly differentiated tumor foci. Histochemistry for periodic acid-Schiff with diastase (PAS-D) and mucicarmine, and immunohistochemistry for CK7, CK20, p53, and E-cadherin, were performed on 7 Paget cases with the following results: PAS-D+ (7 of 7, 100%), mucicarmine+ (6 of 7, 86%), CK7+ (7 of 7, 100%), CK20+ (5 of 7, 71%), p53 overexpression (3 of 7, 43%), and E-cadherin loss (complete loss in 1 and faint expression in 3, 57%). Overall, PAS-D was the most efficacious stain for highlighting Paget cells. A control group of 19 adenocarcinomas without Paget cells were also stained for E-cadherin; only 1 showed faint expression (5%) and none showed complete loss (P=0.01). These results demonstrate a low but significant prevalence (4.9%) of Paget cells in esophageal and esophagogastric junction adenocarcinomas. Unlike previously described cases of mammary, vulvar, and perianal Paget disease, esophageal Paget cells are almost universally associated with underlying adenocarcinoma and not with high grade dysplasia (\"in situ\" disease) or primary Paget disease. A commonality among cases with Paget cells is the presence of focal or diffuse, poorly differentiated adenocarcinoma with discohesive cells. E-cadherin alterations seem to play a less significant role.", "Transcription termination by RNA polymerase II is coupled to transcript 3' end formation. A large cleavage and polyadenylation complex containing the major poly(A) polymerase Pap1 produces mRNA 3' ends, whereas those of nonpolyadenylated snoRNAs in yeast are formed either by endonucleolytic cleavage or by termination, followed by trimming by the nuclear exosome. We show that synthesis of independently transcribed snoRNAs involves default polyadenylation of two classes of precursors derived from termination at a main Nrd1/Nab3-dependent site or a \"fail-safe\" mRNA-like signal. Poly(A) tails are added by Pap1 to both forms, whereas the alternative poly(A) polymerase Tfr4 adenylates major precursors and processing intermediates to facilitate further polyadenylation by Pap1 and maturation by the exosome/Rrp6. A more important role of Trf4/TRAMP, however, is to enhance Nrd1 association with snoRNA genes. We propose a model in which polyadenylation of pre-snoRNAs is a key event linking their transcription termination, 3' end processing, and degradation.", "We describe the cloning and characterization of a human homolog of the yeast transcription/RNA-processing factor Ssu72, following a yeast two-hybrid screen for pRb-binding factors in the prostate gland. Interaction between hSsu72 and pRb was observed in transfected mammalian cells and involved multiple domains in pRb; however, so far, mutual effects of these two factors could not be demonstrated. Like the yeast counterpart, mammalian Ssu72 associates with TFIIB and the yeast cleavage/polyadenylation factor Pta1, and exhibits intrinsic phosphatase activity. Mammals contain a single ssu72 gene and a few pseudogenes. During mouse embryogenesis, ssu72 was highly expressed in the nervous system and intestine; high expression in the nervous system persisted in adult mice and was also readily observed in multiple human tumor cell lines. Both endogenous and ectopically expressed mammalian Ssu72 proteins resided primarily in the cytoplasm and only partly in the nucleus. Interestingly, fusion to a strong nuclear localization signal conferred nuclear localization only in a fraction of transfected cells, suggesting active tethering in the cytoplasm. Suppression of ssu72 expression in mammalian cells by siRNA did not reduce proliferation/survival, and its over-expression did not affect transcription of candidate genes in transient reporter assays. Despite high conservation, hssu72 was unable to rescue an ssu72 lethal mutation in yeast. Together, our results highlight conserved and mammalian specific characteristics of mammalian ssu72.", "Blepharospasm (BSP) is a rather distressing form of focal dystonia. Although many aspects of its pathophysiological mechanisms are already known, we lack fundamental evidence on etiology, prevention, and treatment. To advance in our knowledge, we need to review what is already known in various aspects of the disorder and use these bases to find future lines of interest. Some of the signs observed in BSP are cause, while others are consequence of the disorder. Non-motor symptoms and signs may be a cue for understanding better the disease. Various cerebral sites have been shown to be functionally abnormal in BSP, including the basal ganglia, the cortex, and the cerebellum. However, we still do not know if the dysfunction or structural change affecting these brain regions is cause or consequence of BSP. Further advances in neurophysiology and neuroimaging may eventually clarify the pathophysiological mechanisms implicated. In this manuscript, we aim to update what is known regarding epidemiology, clinical aspects, and pathophysiology of the disorder and speculate on the directions of research worth pursuing in the near future.", "In Saccharomyces cerevisiae, short noncoding RNA (ncRNA) generated by RNA polymerase II (Pol II) are terminated by the NRD complex consisting of Nrd1, Nab3, and Sen1. We now show that Pcf11, a component of the cleavage and polyadenylation complex (CPAC), is also generally required for NRD-dependent transcription termination through the action of its C-terminal domain (CTD)-interacting domain (CID). Pcf11 localizes downstream from Nrd1 on NRD terminators, and its recruitment depends on Nrd1. Furthermore, mutation of the Pcf11 CID results in Nrd1 retention on chromatin, delayed degradation of ncRNA, and restricted Pol II CTD Ser2 phosphorylation and Sen1-Pol II interaction. Finally, the pcf11-13 and sen1-1 mutant phenotypes are very similar, as both accumulate RNA:DNA hybrids and display Pol II pausing downstream from NRD terminators. We predict a mechanism by which the exchange of Nrd1 and Pcf11 on chromatin facilitates Pol II pausing and CTD Ser2-P phosphorylation. This in turn promotes Sen1 activity that is required for NRD-dependent transcription termination in vivo.", "Cohesin is a chromosome-bound, multisubunit adenosine triphosphatase complex. After loading onto chromosomes, it generates loops to regulate chromosome functions. It has been suggested that cohesin organizes the genome through loop extrusion, but direct evidence is lacking. Here, we used single-molecule imaging to show that the recombinant human cohesin-NIPBL complex compacts both naked and nucleosome-bound DNA by extruding DNA loops. DNA compaction by cohesin requires adenosine triphosphate (ATP) hydrolysis and is force sensitive. This compaction is processive over tens of kilobases at an average rate of 0.5 kilobases per second. Compaction of double-tethered DNA suggests that a cohesin dimer extrudes DNA loops bidirectionally. Our results establish cohesin-NIPBL as an ATP-driven molecular machine capable of loop extrusion.", "Author information:(1)Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain; Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.(2)Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.(3)Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.(4)Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain.(5)Genotyping Unit (CeGen), Spanish National Cancer Centre (CNIO), Madrid, Spain.(6)IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.(7)Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain.(8)Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain.(9)Institute of Biology and Molecular Genetics, Universidad de Valladolid (IBGM-UVA), Valladolid, Spain.(10)Oncogenetics Laboratory, University Hospital Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Institut de Recerca (VHIR), and Universitat Autonoma de Barcelona, Barcelona, Spain.(11)Oncology Service, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.(12)Molecular Diagnostics Laboratory IRRP, National Centre for Scientific Research Demokritos Aghia Paraskevi Attikis, Athens, Greece.(13)Molecular Genetics Laboratory (Department of Biochemistry), Cruces Hospital Barakaldo, Bizkaia, Spain.(14)Medical Oncology Service, Hospital Clínico Lozano Blesa, San Juan Bosco, Zaragoza, Spain.(15)Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Canada.(16)Department of Oncology, Lund University, Lund, Sweden.(17)Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.(18)Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.(19)Department of Oncology, Lund University Hospital, Lund, Sweden.(20)Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.(21)Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois, United States of America.(22)Departments of Medicine, Epidemiology, and Biostatistics, University of California, San Francisco, San Francisco, California, United States of America.(23)Abramson Cancer Center and Department of Medicine, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.(24)Abramson Cancer Center and Center for Clinical Epidemiology and Biostatistics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.(25)University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.(26)Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.(27)Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, United States of America.(28)Department of Health Research & Policy, Stanford University School of Medicine, Stanford, California, United States of America.(29)Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.(30)Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Australia.(31)Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Victoria, Australia.(32)Department of Epidemiology, Columbia University, New York, New York, United States of America.(33)Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.(34)Vilnius University Hospital Santariskiu Clinics, Hematology, oncology and transfusion medicine center, Department of Molecular and Regenerative Medicine, Vilnius, Lithuania.(35)Department of Genetics, University of Pretoria, Pretoria, South Africa.(36)Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, United States of America.(37)Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.(38)Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.(39)Department of Clinical Genetics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.(40)Clinical Cancer Genetics, City of Hope, Duarte, California, United States of America.(41)Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy.(42)Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.(43)IFOM, Fondazione Istituto FIRC di Oncologia Molecolare and Cogentech Cancer Genetic Test Laboratory, Milan, Italy.(44)Division of Experimental Oncology 1, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.(45)Unit of Hereditary Cancer, Department of Epidemiology, Prevention and Special Functions, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.(46)Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.(47)Department of Molecular Medicine, \"Sapienza\" University, Rome, Italy.(48)UO Anatomia Patologica, Ospedale di Circolo-Università dell'Insubria, Varese, Italy.(49)Unit of Molecular bases of genetic risk and genetic testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy.(50)Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.(51)Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.(52)South East Thames Regional Genetics Service, Guy's Hospital London, United Kingdom.(53)Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, United Kingdom.(54)Yorkshire Regional Genetics Service, Leeds, United Kingdom.(55)Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, United Kingdom.(56)West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, United Kingdom.(57)Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom.(58)Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, United Kingdom.(59)Clinical Genetics Department, St Georges Hospital, University of London, London, United Kingdom.(60)Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, United Kingdom.(61)Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge, United Kingdom.(62)Institute of Human Genetics, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom.(63)South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, United Kingdom.(64)North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom.(65)Oxford Regional Genetics Service, Churchill Hospital, Oxford, United Kingdom.(66)Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, United Kingdom.(67)South West Regional Genetics Service, Bristol, United Kingdom.(68)Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin and St James's Hospital, Dublin, Eire.(69)Cheshire & Merseyside Clinical Genetics Service, Liverpool Women's NHS Foundation Trust, Liverpool, United Kingdom.(70)Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, United States of America.(71)Centre of Familial Breast and Ovarian Cancer and Centre for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany.(72)Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.(73)Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.(74)Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.(75)Institute of Human Genetics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.(76)Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.(77)Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.(78)Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.(79)Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.(80)Institute of Human Genetics, University of Münster, Münster, Germany.(81)Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.(82)Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Berlin, Germany.(83)Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Würzburg, Germany.(84)Institut Curie, Department of Tumour Biology, Paris, France; Institut Curie, INSERM U830, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.(85)Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, Lyon, France; INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France.(86)INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France.(87)Center for Medical Genetics, Ghent University, Ghent, Belgium.(88)Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, New York, United States of America.(89)Prince of Wales Hospital. Sydney, Australia.(90)Ohio State University, Columbus Cancer Council, Columbus, Ohio, United States of America.(91)Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, Illinois, United States of America.(92)Division of Gynecologic Oncology, NorthShore University HealthSystem, Chicago, Illinois, United States of America.(93)For Tufts Medical Center, Boston, Massachusetts, United States of America.(94)Yale University School of Medicine, New Haven, Connecticut, United States of America.(95)Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.(96)Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands.(97)Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.(98)Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands.(99)Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands.(100)University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.(101)Department of Clinical Genetics, Leiden University Medical Center Leiden, Leiden, The Netherlands.(102)Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands.(103)Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.(104)Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands.(105)Department of Pathology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands.(106)Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.(107)Department of Human Genetics & Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.(108)The Hereditary Breast and Ovarian Cancer Research Group, Netherlands Cancer Institute, Amsterdam, The Netherlands.(109)Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.(110)Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain.(111)Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.(112)Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland; Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland.(113)Department of Oncology, Landspitali University Hospital and BMC, Faculty of Medicine, University of Iceland, Reykjavik Iceland.(114)Laboratoire de Diagnostic Génétique et Service d'Onco-hématologie, Hopitaux Universitaire de Strasbourg, CHRU Nouvel Hôpital Civil, Strasbourg, France.(115)Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.(116)Department of Genetics, Portuguese Oncology Institute, Porto, and Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal.(117)Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia.(118)Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Peter MacCallum Cancer Center, Melbourne, Australia.(119)Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America.(120)Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.(121)Center for Individualized Medicine, Mayo Clinic, Scottsdale, Arizona, United States of America.(122)Center for Translational Cancer Research, Department of Biological Sciences, University of Delaware, Newark, Delaware, United States of America.(123)Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.(124)Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.(125)Diagnostic Molecular Genetics Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.(126)Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.(127)Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States of America.(128)Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America.(129)Clalit National Israeli Cancer Control Center, Haifa, Israel.(130)Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, and Cancer Care Ontario, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.(131)Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.(132)Ontario Cancer Genetics Network: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.(133)Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.(134)Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark.(135)Section of Molecular Diagnostics, Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark.(136)Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.(137)Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.(138)Sheba Medical Center, Tel Aviv, Israel.(139)Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Canada.(140)Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.(141)Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain; Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain; Genotyping Unit (CeGen), Spanish National Cancer Centre (CNIO), Madrid, Spain.", "Obesity/metabolic syndrome are common risk factors for overactive bladder. This study aimed to investigate the functional and molecular changes of detrusor smooth muscle (DSM) in high-fat insulin resistant obese mice, focusing on the role of protein kinase C (PKC) and Ca(v)1.2 in causing bladder dysfunction. Male C57BL/6 mice were fed with high-fat diet for 10 weeks. In vitro functional responses and cystometry, as well as PKC and Ca(v)1.2 expression in bladder were evaluated. Obese mice exhibited higher body weight, epididymal fat mass, fasting glucose and insulin resistance. Carbachol (0.001-100 µM), α,β-methylene ATP (1-10 µM), KCl (1-300 mM), extracellular Ca(2+) (0.01-100 mM) and phorbol-12,13-dibutyrate (PDBu; 0.001-3 µM) all produced greater DSM contractions in obese mice, which were fully reversed by the Ca(v)1.2 blocker amlodipine. Cystometry evidenced augmented frequency, non-void contractions and post-void pressure in obese mice that were also prevented by amlodipine. Metformin treatment improved the insulin sensitivity, and normalized the in vitro bladder hypercontractility and cystometric dysfunction in obese mice. The PKC inhibitor GF109203X (1 µM) also reduced the carbachol induced contractions. PKC protein expression was markedly higher in bladder tissues from obese mice, which was normalized by metformin treatment. The Ca(v)1.2 channel protein expression was not modified in any experimental group. Our findings show that Ca(v)1.2 blockade and improvement of insulin sensitization restores the enhanced PKC protein expression in bladder tissues and normalizes the overactive detrusor. It is likely that insulin resistance importantly contributes for the pathophysiology of this urological disorder in obese mice.", "Harlequin syndrome is characterized by the sudden onset of unilateral facial flushing and sweating, often preceded by exercise, excessive heat, or, rarely, regional anesthesia. Although the exact mechanism remains unclear, it is often referred to as transient or permanent interruption of the sympathetic nervous system. We present a case of Harlequin syndrome without Horner syndrome in a patient with unilateral right-sided facial flushing that started shortly after a left-sided thoracic paravertebral nerve block for a mastectomy. We discuss the interruption of the sympathetic and parasympathetic nervous system and the levels of spinal nerve block associated with a thoracic paravertebral nerve block.", "Author information:(1)Clinical Assistant Professor, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA", "The general transcription factor TFIIB plays a central role in preinitiation complex (PIC) assembly and the recruitment of RNA polymerase II (RNA pol II) to the promoter. Recent studies have revealed that TFIIB engages in contact with the transcription termination region and also with complexes that are involved in 3' end processing and/or termination. Here we report that TFIIB can be phosphorylated within the N terminus at serine 65 in vivo and that the phosphorylated form of TFIIB is present within (PICs). Surprisingly, TFIIB serine 65 phosphorylation is required after the phosphorylation of serine 5 of RNA pol II C-terminal domain (CTD) has occurred, but before productive transcription initiation begins. We show that phosphorylation of TFIIB at serine 65 regulates the interaction between TFIIB and the CstF-64 component of the CstF 3' cleavage and polyadenylation complex. This directs the recruitment of CstF (cleavage stimulatory factor) to the terminator and also the recruitment of the CstF and CPSF (cleavage and polyadenylation specific factor) complexes to the promoter. Our results reveal that phosphorylation of TFIIB is a critical event in transcription that links the gene promoter and terminator and triggers initiation by RNA pol II.", "Gene loops have been described in different organisms from yeast to human and form through interaction between components of the transcription pre-initiation complex and Ssu72, a member of the 3' end cleavage and polyadenylation complex. A recent study by Tan-Wong et al. reports a new role for gene loops in promoting ORF transcription directionality from otherwise bidirectional promoters.", "The mouse Grg gene encodes a 197 amino acid nuclear protein homologous to the amino-terminal domain of the product of the groucho (gro) gene of the Drosophila Enhancer of split complex. Recent work has suggested that the gro protein functions as a transcriptional corepressor during Drosophila development. We therefore examined possible roles of the mouse Grg protein in DNA binding and in vitro transcription. No sequence-specific DNA binding activity was detected by polymerase chain reaction-DNA binding site selection nor was the glutamine-rich Grg protein capable of acting as an activation domain in an in vivo transactivation assay. However, depletion of Grg protein from HeLa nuclear extracts inhibited the in vitro transcription activity of the extracts. We suggest that Grg protein may interact with components of the basal transcription machinery.", "About one-third of the US population will develop herpes zoster (HZ, commonly known as shingles) over a lifetime, while two-thirds will not. It is not clear exactly why certain people are susceptible to HZ; however, we may be coming closer to an answer. In this issue of the JCI, a study by Levin et al. provides important details concerning pathogenesis of and protection from HZ. The authors characterized differences in the immunologic responses induced by two HZ vaccines, the live attenuated zoster vaccine (ZV) and the more recently developed adjuvanted varicella-zoster virus (VZV) glycoprotein E (gE) subunit herpes zoster vaccine (HZ/su), in vaccine-naive subjects and those previously vaccinated with HZ. The observed differences in responses paralleled the observed clinical protection of the two zoster vaccines, with HZ/su being superior to HZ. Together, these results seem to explain immunologically why the new subunit vaccine outperforms the live vaccine. These differences may also provide clues as to why HZ develops in the first place.", "Induced pluripotent stem (iPS) cells were originally generated from mouse fibroblasts by enforced expression of Yamanaka factors (Oct3/4, Sox2, Klf4, and c-Myc). The technique was quickly reproduced with human fibroblasts or mesenchymal stem cells. Although having been showed therapeutic potential in animal models of sickle cell anemia and Parkinson's disease, iPS cells generated by viral methods do not suit all the clinical applications. Various non-viral methods have appeared in recent years for application of iPS cells in cell transplantation therapy. These methods mainly include DNA vector-based approaches, transfection of mRNA, and transduction of reprogramming proteins. This review summarized these non-viral methods and compare the advantages, disadvantages, efficiency, and safety of these methods.", "Publisher: TITLE: Revision de las novedades del XXXI Congreso ECTRIMS 2015, presentadas en la VIII Reunion Post-ECTRIMS.Reconocidos especialistas nacionales en esclerosis multiple (EM) se han reunido, por octavo año consecutivo, para exponer lo mas novedoso que se presento en la ultima edicion del congreso ECTRIMS 2015 y que recoge esta revision. En esta edicion ha destacado la nueva clasificacion de los fenotipos de la EM. Tambien se revisaron los criterios diagnosticos del espectro de la neuromielitis optica y los problemas en el diagnostico diferencial derivados de la falta de definicion del espectro radiologico. La microbiota adquiere protagonismo como posible factor determinante de la enfermedad, junto con factores extrinsecos como el tabaco, la ingesta de sal o el deficit de vitamina D. Los avances en inmunomodulacion impulsan el progreso en el tratamiento de la EM. El ocrelizumab es el primer tratamiento con resultados positivos en las formas primariamente progresivas, y el tocilizumab, un farmaco para la artritis reumatoide, destaca como candidato potencial para el tratamiento de la neuromielitis optica. Ciertos antibioticos y vitaminas tambien podrian tener un papel en el tratamiento de la EM. En esta edicion se presto especial atencion a la terapia personalizada. Actualmente disponemos de 11 farmacos aprobados en Europa. Se necesitan algoritmos terapeuticos que nos ayuden a elegir el mejor tratamiento para cada paciente. Asimismo, necesitamos poder identificar en los estadios precoces de la enfermedad el riesgo de desarrollar discapacidad, para diseñar estrategias terapeuticas, para lo que se precisan biomarcadores moleculares y otras herramientas pronosticas. Los problemas aun existentes en la tecnologia del software en resonancia magnetica dificultan su traslacion a la practica clinica diaria.", "In the endopterygote Drosophila melanogaster, Zelda is an activator of the zygotic genome during the maternal-to-zygotic transition (MZT). Zelda binds cis-regulatory elements (TAGteam heptamers), making chromatin accessible for gene transcription. Zelda has been studied in other endopterygotes: Apis mellifera and Tribolium castaneum, and the paraneopteran Rhodnius prolixus. We studied Zelda in the cockroach Blattella germanica, a hemimetabolan, short germ-band, and polyneopteran species. B. germanica Zelda has the complete set of functional domains, which is typical of species displaying ancestral features concerning embryogenesis. Interestingly, we found D. melanogaster TAGteam heptamers in the B. germanica genome. The canonical one, CAGGTAG, is present at a similar proportion in the genome of these two species and in the genome of other insects, suggesting that the genome admits as many CAGGTAG motifs as its length allows. Zelda-depleted embryos of B. germanica show defects involving blastoderm formation and abdomen development, and genes contributing to these processes are down-regulated. We conclude that in B. germanica, Zelda strictly activates the zygotic genome, within the MZT, a role conserved in more derived endopterygote insects. In B. germanica, zelda is expressed during MZT, whereas in D. melanogaster and T. castaneum it is expressed beyond this transition. In these species and A. mellifera, Zelda has functions even in postembryonic development. The expansion of zelda expression beyond the MZT in endopterygotes might be related with the evolutionary innovation of holometabolan metamorphosis. DATABASES: The RNA-seq datasets of B. germanica, D. melanogaster, and T. castaneum are accessible at the GEO databases GSE99785, GSE18068, GSE63770, and GSE84253. In addition, the RNA-seq library from T. castaneum adult females is available at SRA: SRX021963. The B. germanica reference genome is available as BioProject PRJNA203136.", "Eukaryotic RNA polymerase II transcribes precursors of mRNAs and of non-protein-coding RNAs such as snRNAs and snoRNAs. These RNAs have to be processed at their 3' ends to be functional. mRNAs are matured by cleavage and polyadenylation that require a well-characterized protein complex. Small RNAs are also subject to 3' end cleavage but are not polyadenylated. Here we show that two newly identified proteins, Pti1p and Ref2p, although they were found associated with the pre-mRNA 3' end processing complex, are essential for yeast snoRNA 3' end maturation. We also provide evidence that Pti1p probably acts by uncoupling cleavage and polyadenylation, and functions in coordination with the Nrd1p-dependent pathway for 3' end formation of non-polyadenylated transcripts.", "Vanishing lung syndrome (VLS) is a rare and distinct clinical syndrome that usually affects young men. VLS leads to severe progressive dyspnea and is characterized by extensive, asymmetric, peripheral, and predominantly upper lobe giant lung bullae. Case reports have suggested an additive role of marijuana use in the development of this disease in young male tobacco smokers. We herein report a case of a 65-year-old Hispanic male previously diagnosed with severe emphysema and acquired immune deficiency syndrome (AIDS), with a history of intravenous heroin use and active marijuana smoking who presents to the emergency department with severe progressive shortness of breath he was found to have multiple large subpleural bullae occupying more than one-third of the hemithorax on chest computerized tomography (CT), characteristic of vanishing lung syndrome. The patient was mechanically ventilated and later developed a pneumothorax requiring chest tube placement and referral for surgical bullectomy. Surgical bullectomy has shown high success rates in alleviating the debilitating symptoms and preventing the life threatening complications of this rare syndrome. This case further emphasizes the importance of recognizing VLS in patients with severe emphysema and heavy marijuana smoking.", "DAPID is a database of domain-annotated protein interactions inferred from three-dimensional (3D) interacting domains of protein complexes in the Protein Data Bank (PDB). The DAPID data model allows users to visualize 3D interacting domains, contact residues, and molecular details of any predicted protein-protein interactions. Our model derives these interactions by utilizing a new concept, called the ''3D-domain interologs'' which is similar to ''interologs''. In S. cerevisiae, there is 18.6% overlap between our predicted protein-protein interactions and ones in the DIP database. The mean correlation coefficient of the gene expression profiles of our predicted interactions is significantly higher than that for random pairs in S. cerevisiae. In addition, we find several novel interactions which are consistent with the functions of the proteins. The DAPID currently holds 1008 3D-interacting domain pairs and 101511 predicted 3D-domain annotated protein-protein interactions. It is available online at http://gemdock.life.nctu.edu.tw/dapid.", "Over the past 20 years, there has been a concerted effort to expand our understanding of the neural circuitry involved in the pathogenesis of psychiatric disorders. Distinct neuronal circuits and networks have been implicated in obsessive compulsive disorder (OCD) and major depressive disorder (MDD) involving feedback loops between the cortex, striatum, and thalamus. When neurosurgery is used as a therapeutic tool in severe OCD and MDD, the goal is to modulate specific targets or nodes within these networks in an effort to produce symptom relief.Currently, four lesioning neurosurgical procedures are utilized for treatment refractory OCD and MDD: cingulotomy, capsulotomy, subcaudate tractotomy, and limbic leucotomy. Deep brain stimulation (DBS) is a novel neurosurgical approach that has some distinct advantages over lesioning procedures. With DBS, the desired clinical effect can be achieved by reversible, high frequency stimulation in a nucleus or at a node in the circuit without the need to produce an irreversible lesion. Recent trials of deep brain stimulation in both OCD and MDD at several neuroanatomical targets have reported promising early results in highly refractory patients and with a good safety profile. Future definitive trials in MDD and OCD are envisaged.", "Parkinson disease psychosis (PDP) is a common phenomenon in Parkinson disease (PD) patients treated with dopaminergic drugs, and is associated with high morbidity and mortality. It also correlates with depression and dementia, and can contribute to considerable caregiver stress and burnout. While symptoms can be relieved by decreasing doses or number of anti-PD medications, this may lead to an unacceptable worsening of motor function. When general medical or psychiatric conditions have been ruled out, and decreasing dopaminergic agents is not effective in treating psychosis, therapies include atypical antipsychotics, primarily clozapine and quetiapine. Of these, clozapine is effective but is associated with a poor side-effect profile and the necessity for frequent blood draws. Clinicians prefer quetiapine for its theoretically better safety profile, although there is no evidence for efficacy in treating psychosis. All atypical antipsychotics are associated with increased mortality in this patient population. Cholinesterase inhibitors can ameliorate psychosis symptoms. The serotonin 5-HT2A receptor inverse agonist pimavanserin was recently approved by the US FDA for the treatment of PDP and may prove to be a more targeted therapy without the downsides of atypical antipsychotics.", "To discover antifungal treatments that possess the desired characteristics of broad spectrum activity, a strong safety profile, and oral bioavailability, new discovery strategies must be implemented to identify structural classes of molecules capable of combating these microorganisms. One such technique that has been implemented is the Candida albicans Fitness Test, a whole cell screening platform capable of delineating the mechanism of action of compounds that demonstrate activity against the clinically relevant pathogenic fungus, C. albicans. Screening crude natural product extracts with this technology has resulted in the identification of a novel family of antifungal natural products, named the parnafungins, which inhibit the enzyme polyadenosine polymerase (PAP), a key component of the mRNA cleavage and polyadenylation complex. Owing to the rapid interconversion of the structural and stereoisomers of the parnafungins at neutral pH, the determination of the structural isomer with the highest affinity for PAP with standard biochemical assays has not been possible. Herein, we present an application of affinity-selection/mass spectrometry (AS-MS) to determine that the \"straight\" parnafungin structural isomer (parnafungin A) binds preferentially to PAP compared to the \"bent\" structural isomer (parnafungin B)." ]

[ "BACKGROUND: Shone's complex is a rare lesion affecting the mitral valve (MV) and left ventricular outflow tract (LVOT). The objective of this study is to report the outcomes after Shone's complex repair, the growth of mitral and aortic valve and LVOT, and long-term survival.METHODS: This retrospective study included all patients diagnosed with Shone's complex, who underwent biventricular repair. Data including patients' characteristics, type of the MV lesion and the associated lesions were collected. Patients were followed up regularly with echocardiography, and the changes in mitral and aortic valve z-score and LVOT z-score were recorded.RESULTS: Thirty-seven patients were included in the study, the median age was 3.4 months, and 11 patients (30.6%) had pulmonary hypertension. The main procedure performed during the first surgical intervention was coarctation repair in 26 patients (70%). Twelve patients had MV repair, and five had MV replacement. Operative mortality occurred in 1 patient (2.7%), median follow up was 52 (25-75th percentile: 22-84) months. Survival at 1, 5, and 10 years was 94.4%, 90%, and 76.9%, respectively. Reoperation was required in 13 patients, mainly for LVOT repair (n = 8). Reoperation was significantly associated with associated aortic valve lesion (p = .044). The growth of the MV z-score was 0.35 per year; p < .001, aortic valve z-score 0.086 per year; p = 0.422, and the LVOT z-score was 0.53 per year; p = .01.CONCLUSION: Biventricular repair of Shone's complex has good outcomes. Reoperation is frequently encountered, especially with low aortic valve z-score. The MV and LVOT have significant growth following Shone's complex repair.", "Corneal diseases exhibit a high prevalence and are prone to cause blindness; furthermore, maintaining the morphology and ionic transporter expression in corneal endothelial cells (CECs) is crucial for treatment of these diseases. This study aimed to investigate the effects of the novel Rho associated coiled-coil containing protein kinase (ROCK) inhibitor, thiazovivin (2,4‑disubstituted thiazole, TZV), on human corneal endothelial‑to‑mesenchymal transition/epithelial‑to‑mesenchymal transition (EndMT/EMT), cell morphology, junction proteins and ionic transporter expression in human CECs (HCECs) in vitro and then to clarify the mechanisms of action of TZV. In the present study, primary HCECs were cultured in vitro and passaged. The expression levels of adhesion proteins (E‑cadherin and N‑cadherin), the EndMT/EMT marker, α smooth muscle  actin (α‑SMA), the tight junction protein, Zonula occludens-1 (ZO‑1), and the ionic transporter, Na+/K+‑ATPase, were detected by immunofluorescence. The proliferative ability of the HCECs was determined by CCK-8 assay. The mRNA expression of the EndMT/EMT‑inducing gene, Snail, was examined by RT‑PCR. The protein expression levels of ROCK1/2 were evaluated by western blot analysis. The HCECs were cultured with TZV at various concentrations (2, 4, or 6 µM) for different periods of time (24 or 48 h). We found that the the cell states of the HCECs co‑cultured with 4 µM TZV for 48 h reached the optimum, and corneal EndMT/EMT was inhibited, as evidenced by the significantly upregulated expression of ZO‑1 and E‑cadherin, and the markedly downregulated expression of N‑cadherin and α‑SMA. Furthermore, the cells exhibited a normal, tightly connected hexagonal or pentagonal morphology. Additionally, the protein expression of ROCK1/2 and the mRNA expression of Snail were significantly decreased. However, there was no significant difference between the TZV‑treated and the control groups as regards HCEC proliferative ability. These findings suggested that the ROCK inhibitor, TZV (4 µM), was effective in improving the morphology, cell junctions and ionic transporter expression of HCECs by inhibiting EndMT/EMT, but had no effect on HCEC proliferation.", "The IkappaB-Kinase (IKK) complex is a multisubunit protein complex crucial for signal-induced phosphorylation of the IkappaB proteins and thus controls the activity of the transcription factor NF-kappaB. Besides the two kinases IKKalpha and IKKbeta, the IKK complex contains NEMO/IKKgamma, an additional subunit with regulatory and adaptor functions. NEMO not only confers structural stability to the IKK complex but also participates in the activation process of the IKK complex by linking the IKK subunits to upstream activators. In this study we analyze the IKKbeta-mediated phosphorylation of the IKK-binding domain of NEMO. In vitro, IKKbeta phosphorylates three serine residues in the domain of NEMO at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the IKK-binding domain plays an essential role for the formation and the function of the IKK complex. Thus, Ser(68) phosphorylation attenuates the amino-terminal dimerization of NEMO as well as the IKKbeta-NEMO interaction. In contrast, the NEMO-IKKalpha interaction was only mildly affected by the phosphorylation of Ser(68). However, functional analysis revealed that Ser(68) phosphorylation primarily affects the activity of IKKalpha. Furthermore, in complementation experiments of NEMO-deficient murine embryonic fibroblasts, a S68A-NEMO mutant enhanced, whereas a S68E mutant decreased, TNF-alpha-induced NF-kappaB activity, thus emphasizing the inhibitory role of the Ser(68) phosphorylation on the signal-induced NF-kappaB activity. Finally, we provide evidence that the protein phosphatase PP2A is involved in the regulation of the Ser(68)-based mechanism. In summary, we provide evidence for a signal-induced phosphorylation-dependent alteration of the IKK complex emphasizing the dynamic nature of this multisubunit kinase complex.", "BACKGROUND: Several antidiabetic drugs (i.e., sulfonylureas; SU, rosiglitazone) have been reported to be associated with increased risks of cardiovascular diseases (CVD) in patients with type 2 diabetes mellitus (T2DM). Dipeptidyl peptidase-4 inhibitors (DPP4i) are newly available antidiabetic drugs. Most studies only compared DPP4i with a placebo or SU, or targeted a specific CVD event of interest (i.e., heart failure; HF). Comparative research of CVD risks of DPP4i with other antidiabetic drugs (i.e., metformin, thiazolidinediones, meglitinides, acarbose, and insulin) remains scarce. This study was aimed to assess comparative risks of CVD, including ischemic stroke, myocardial infarction (MI) and HF, and hypoglycemia of DPP4i with other antidiabetic drugs.METHODS: We utilized Taiwan's National Health Insurance Research Database. A total of 123,050 T2DM patients newly prescribed oral antidiabetic treatments were identified in 2009-2010 and followed until 2013. Outcome endpoints included a composite of CVD events: hospitalizations for ischemic stroke, MI and HF, and hypoglycemia. Time-varying Cox proportional hazards regression was applied to assess the time to event hazards of various antidiabetic drugs, adjusted for patients' demographics, comorbidity, diabetic complications, and co-medications. Additional analyses were performed for the patients with and without CVD history, respectively.RESULTS: DPP4i users had significantly lower CVD risks as compared to that of non-DPP4i users (adjusted hazard ratio [aHR]: 0.83, 95 % confidence interval [CI]: 0.76-0.91). Compared to DPP4i users, meglitinides (aHR 1.3, 95 % CI 1.20-1.43) and insulin users (aHR 3.73, 95 % CI 3.35, 4.14) had significantly higher risks for composite CVD, as well as those for stroke, MI, HF, and hypoglycemia. Additionally, metformin users had significantly lower risks for composite CVD risk (aHR 0.87, 95 % CI 0.79-0.94), as well as those for MI, HF, and hypoglycemia, as compared to those of DPP4i users. Although there was a trend toward low CVD risks in pioglitazone users, the role of potential confounding by indication cannot be excluded.CONCLUSIONS: DPP4i-treated T2DM patients had lower risks for CVD as compared to those for non-DPP4i users, except metformin users.", "Plasmodium falciparum is the causative agent of malaria, a disease that kills almost one million persons each year, mainly in sub-Saharan Africa. P. falciparum is transmitted to the human host by the bite of an Anopheles female mosquito, and Anopheles gambiae sensus stricto is the most tremendous malaria vector in Africa, widespread throughout the afro-tropical belt. An. gambiae s.s. is subdivided into two distinct molecular forms, namely M and S forms. The two molecular forms are morphologically identical but they are distinct genetically, and differ by their distribution and their ecological preferences. The epidemiological importance of the two molecular forms in malaria transmission has been poorly investigated so far and gave distinct results in different areas. We have developed a real-time quantitative PCR (qPCR) assay, and used it to detect P. falciparum at the oocyst stage in wild An. gambiae s.s. mosquitoes experimentally infected with natural isolates of parasites. Mosquitoes were collected at immature stages in sympatric and allopatric breeding sites and further infected at the adult stage. We next measured the infection prevalence and intensity in female mosquitoes using the qPCR assay and correlated the infection success with the mosquito molecular forms. Our results revealed different prevalence of infection between the M and S molecular forms of An. gambiae s.s. in Cameroon, for both sympatric and allopatric populations of mosquitoes. However, no difference in the infection intensity was observed. Thus, the distribution of the molecular forms of An. gambiae s.s. may impact on the malaria epidemiology, and it will be important to monitor the efficiency of malaria control interventions on the two M and S forms.", "The beta-thalassemia syndromes are a heterogeneous group of genetic disorders characterized by reduced or absent expression of the beta-globin gene. To date, over 300 beta-thalassemia alleles have been characterized in or around the beta-globin region. Thalassemia major is severe anemia necessitating chronic blood transfusions, splenectomy, iron chelation therapy, and bone marrow transplantation. Usually thalassemia major results from homozygosity or compound heterozygosity for severe betaO- and/or beta+-thalassemia mutations. Thalassemia intermedia is a clinical diagnosis that describes a symptomatic but less severe condition than beta-thalassemia major. beta-thalassemia intermedia may arise from several different combinations of alpha- and/or beta-thalassemia mutations. Heterozygous beta-thalassemia is typically characterized by a mild microcytic hypochromic anemia without any significant clinical implications. In this report, we describe a 63-year-old Africian American woman with asymptomatic homozygous beta-thalassemia, who seems to carry 2 copies of the -29 mutation in the promoter region of the beta-globin gene. Her elevated hemoglobin F level of 83% was associated with heterozygosity for the Xmn I polymorphism upstream of the Ggamma-globin gene. Southern blot analysis at the alpha-globin locus did not show any deletion that would account for the mildness of her phenotype. Therefore, homozygosity for the -29 mutation along with the Xmn I polymorphism appears to confer an extremely mild beta-thalassemia phenotype. This observation has important implications in the prenatal diagnosis and genetic counseling of families segregating this type of genetic defect.", "Beta-thalassemia, one of the most common single-gene disorders, is the result of reduced or absent production of β-globin chains. Patients with β-thalassemia show weak genotype-phenotype correlations. Mitochondrial DNA polymorphisms are a potential source for different physiological and pathological characteristics and have been found to be associated as genetic modifiers with various pathophysiologies, including cancers and neurodegenerative diseases. A group of 35 patients with β-thalassemia was investigated for the presence of mtDNA D-loop polymorphisms in comparison with 504 normal controls. We found four mtDNA D-loop polymorphisms at nucleotides 16,069C > T, 16,189T > C, 16,319G > A, and 16,519T > C that showed significant differences between patients and normal subjects. There is no strong proof for the association of these polymorphisms with β-thalassemia. It is hypothesized that iron overload or its effects on sequestration of calcium or zinc can lead to oxidative stress and ROS production inside the mitochondria. Therefore, possible accompanying of mtDNA polymorphisms with β-thalassemia disease may complicate the genotype-phenotype correlation and could affect the clinical outcomes in the patients.", "Two double-blind, randomized, placebo-controlled feasibility trials of minocycline in ALS were conducted. In Trial 1, 19 subjects received 200 mg/day or placebo for 6 months; there were no significant differences in adverse events (AE). In Trial 2, 23 subjects received up to 400 mg/day in an 8-month crossover trial. The mean tolerated dose was 387 mg/day, there was a trend toward more gastrointestinal AE (p = 0.057), and blood urea nitrogen and liver enzymes became elevated (p < 0.05). Using these data, the authors have designed and launched a phase III trial." ]

[ "MOTIVATION: Single-molecule, real-time sequencing (SMRT) developed by Pacific BioSciences produces longer reads than secondary generation sequencing technologies such as Illumina. The long read length enables PacBio sequencing to close gaps in genome assembly, reveal structural variations, and identify gene isoforms with higher accuracy in transcriptomic sequencing. However, PacBio data has high sequencing error rate and most of the errors are insertion or deletion errors. During alignment-based homology search, insertion or deletion errors in genes will cause frameshifts and may only lead to marginal alignment scores and short alignments. As a result, it is hard to distinguish true alignments from random alignments and the ambiguity will incur errors in structural and functional annotation. Existing frameshift correction tools are designed for data with much lower error rate and are not optimized for PacBio data. As an increasing number of groups are using SMRT, there is an urgent need for dedicated homology search tools for PacBio data.RESULTS: In this work, we introduce Frame-Pro, a profile homology search tool for PacBio reads. Our tool corrects sequencing errors and also outputs the profile alignments of the corrected sequences against characterized protein families. We applied our tool to both simulated and real PacBio data. The results showed that our method enables more sensitive homology search, especially for PacBio data sets of low sequencing coverage. In addition, we can correct more errors when comparing with a popular error correction tool that does not rely on hybrid sequencing.AVAILABILITY AND IMPLEMENTATION: The source code is freely available at https://sourceforge.net/projects/frame-pro/CONTACT: yannisun@msu.edu.", "OBJECTIVE: To investigate the predictive value of baseline depression/anxiety on the likelihood of achieving joint remission in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) as well as the associations between baseline depression/anxiety and the components of the remission criteria at follow-up.METHODS: We included 1326 patients with RA and 728 patients with PsA from the prospective observational NOR-DMARD study starting first-time tumour necrosis factor inhibitors or methotrexate. The predictive value of depression/anxiety on remission was explored in prespecified logistic regression models and the associations between baseline depression/anxiety and the components of the remission criteria in prespecified multiple linear regression models.RESULTS: Baseline depression/anxiety according to EuroQoL-5D-3L, Short Form-36 (SF-36) Mental Health subscale ≤56 and SF-36 Mental Component Summary ≤38 negatively predicted 28-joint Disease Activity Score <2.6, Simplified Disease Activity Index ≤3.3, Clinical Disease Activity Index ≤2.8, ACR/EULAR Boolean and Disease Activity Index for Psoriatic Arthritis ≤4 remission after 3 and 6 months treatment in RA (p≤0.008) and partly in PsA (p from 0.001 to 0.73). Baseline depression/anxiety was associated with increased patient's and evaluator's global assessment, tender joint count and joint pain in RA at follow-up, but not with swollen joint count and acute phase reactants.CONCLUSION: Depression and anxiety may reduce likelihood of joint remission based on composite scores in RA and PsA and should be taken into account in individual patients when making a shared decision on a treatment target.", "The development of technologies that allow the stable delivery of large genomic DNA fragments in mammalian systems is important for genetic studies as well as for applications in gene therapy. DNA transposons have emerged as flexible and efficient molecular vehicles to mediate stable cargo transfer. However, the ability to carry DNA fragments >10 kb is limited in most DNA transposons. Here, we show that the DNA transposon piggyBac can mobilize 100-kb DNA fragments in mouse embryonic stem (ES) cells, making it the only known transposon with such a large cargo capacity. The integrity of the cargo is maintained during transposition, the copy number can be controlled and the inserted giant transposons express the genomic cargo. Furthermore, these 100-kb transposons can also be excised from the genome without leaving a footprint. The development of piggyBac as a large cargo vector will facilitate a wider range of genetic and genomic applications.", "BACKGROUND: Plasmodium falciparum the main causative agent of malaria is an important public health vector. With the use of PCR, its genetic diversity has been extensively studied with dearth information from Nigeria.METHODS: In this study, 100 P. falciparum strains merozoite surface protein 1(msp-1), merozoite surface protein 2 (msp-2) and Glutamate rich protein (Glurp) from Ogun State General Hospitals were characterized. The genetic diversity of P. falciparum isolates was analyzed by restriction fragment length polymorphism following gel electrophoresis of DNA products from nested polymerase chain reactions (PCR) of their respective allelic families KI, MAD 20, RO33 (MSP-1);FC27, 3D7 (MSP-2) and Glutamate rich protein respectively.RESULTS: Majority of the patients showed monoclonal infections while multiplicity of the infection for msp-1 and msp-2 were 1.1 and 1.2 respectively. The estimated number of genotypes was 8 msp-1 (4 KI; 3 MAD; 1 RO33) and 6 msp-2 (3 FC27; 3 3D7). 80% of the isolates coded for Glurp with allelic size ranged between 700 and 900 bp.CONCLUSION: The allelic distributions however were similar to those previously reported in other endemic malaria countries. Future studies will be designed to include other malaria endemic regions of Nigeria such as the oil exploration regions.", "Circadian clock genes regulate 10-15% of the transcriptome, and might function as tumor suppressor genes. Relatively little is known about the circadian clock in tumors and its effect on surrounding healthy tissues. Therefore, we compared the 24-hr expression levels of key circadian clock genes in liver and kidney of healthy control mice with those of mice bearing C26 colorectal tumor metastases in the liver. Metastases were induced by injection of C26 colorectal carcinoma cells into the spleen. Subsequently, tumor, liver and kidney tissue was collected around the clock to compare circadian rhythmicity. Expression levels of five clock genes (Rev-Erbα, Per1, Per2, Bmal1 and Cry1) and three clock-controlled genes (CCGs; Dbp, p21 and Wee1) were determined by qRT-PCR. Liver and kidney tissue of healthy control mice showed normal 24-hr oscillations of all clock genes and CCGs, consistent with normal circadian rhythmicity. In colorectal liver metastases, however, 24-hr oscillations were completely absent for all clock genes and CCGs except Cry1. Liver and kidney tissue of tumor-bearing mice showed a shift in clock periodicity relative to control mice. In the liver we observed a phase advance, whereas in the kidney the phase was delayed. These data show that hepatic metastases of C26 colon carcinoma with a disrupted circadian rhythm phase shift liver and kidney tissue clocks, which strongly suggests a systemic effect on peripheral clocks. The possibility that tumors may modify peripheral clocks to escape from ordinary circadian rhythms and in this way contribute to fatigue and sleep disorders in cancer patients is discussed.", "De novo sequencing of complex genomes is one of the main challenges for researchers seeking high-quality reference sequences. Many de novo assemblies are based on short reads, producing fragmented genome sequences. Third-generation sequencing, with read lengths >10 kb, will improve the assembly of complex genomes, but these techniques require high-molecular-weight genomic DNA (gDNA), and gDNA extraction protocols used for obtaining smaller fragments for short-read sequencing are not suitable for this purpose. Methods of preparing gDNA for bacterial artificial chromosome (BAC) libraries could be adapted, but these approaches are time-consuming, and commercial kits for these methods are expensive. Here, we present a protocol for rapid, inexpensive extraction of high-molecular-weight gDNA from bacteria, plants, and animals. Our technique was validated using sunflower leaf samples, producing a mean read length of 12.6 kb and a maximum read length of 80 kb.", "OBJECTIVE: Despite improved perioperative management, atrial fibrillation (AF) after coronary artery bypass grafting (CABG) remains a relevant clinical problem, whose pathogenetic mechanisms remain incompletely explained. A reduced incidence of postoperative AF has been described in CABG patients receiving IV tri-iodothyronine (T3). This study was designed to define the role of thyroid metabolism on the genesis of postoperative AF.METHODS AND RESULTS: Free T3 (fT3), free thyroxine (fT4), and thyroid stimulating hormone were assayed at admission in 107 consecutive patients undergoing isolated CABG surgery. Patients with thyroid disease or taking drugs known to interfere with thyroid function were excluded. A preoperative rhythm other than sinus rhythm was considered an exclusion criterion. Thirty-three patients (30.8%) had postoperative AF. An older age (P=0.03), no therapy with beta-blockers (P=0.08), chronic obstructive pulmonary disease (P=0.08), lower left ventricle ejection fraction (P=0.09) and lower fT3 concentration (P=0.001), were univariate predictors of postoperative AF. On multivariate analysis, low fT3 concentration and lack of beta-blocking therapy were independently related with the development of postoperative AF (odds ratio, OR, 4.425; 95% confidence interval, CI, 1.745-11.235; P=0.001 and OR 3.107; 95% CI 1.087-8.875; P=0.03, respectively). Postoperative AF significantly prolonged postoperative hospital stay (P=0.002).CONCLUSIONS: Low basal fT3 concentration can reliably predict the occurrence of postoperative AF in CABG patients.", "The cardioprotective effects of SEA0400, a novel Na(+)-Ca(2+) exchanger inhibitor, were examined in isolated guinea pig myocardial tissue and ventricular myocytes. In a coronary-perfused right ventricular tissue preparation, SEA0400 had no cardiosuppressive effect during normoxia and experimental ischemia, but enhanced the recovery of contractile force during reperfusion. SEA0400 had no effect on tissue ATP content during normoxia, but attenuated its decrease during ischemia. Treatment of ventricular myocytes with an ischemia mimetic solution (high K(+), glucose free, pH 6.0, gassed with N(2)) resulted in the depolarization of the mitochondrial membrane potential and an increase in cytoplasmic and mitochondrial Ca(2+) concentration, which had a similar time course. SEA0400 significantly delayed these changes. These results suggest that SEA0400 maintains mitochondrial function and tissue ATP content during ischemia through the inhibition of cytoplasmic and mitochondrial Ca(2+) overload.", "During the past decade, DNA sequencing output has been mostly dominated by the second generation sequencing platforms which are characterized by low cost, high throughput and shorter read lengths for example, Illumina. The emergence and development of so called third generation sequencing platforms such as PacBio has permitted exceptionally long reads (over 20 kb) to be generated. Due to read length increases, algorithm improvements and hybrid assembly approaches, the concept of one chromosome, one contig and automated finishing of microbial genomes is now a realistic and achievable task for many microbial laboratories. In this paper, we describe high quality sequence datasets which span three generations of sequencing technologies, containing six types of data from four NGS platforms and originating from a single microorganism, Clostridium autoethanogenum. The dataset reported here will be useful for the scientific community to evaluate upcoming NGS platforms, enabling comparison of existing and novel bioinformatics approaches and will encourage interest in the development of innovative experimental and computational methods for NGS data.", "Although it has been known for almost half a century that migratory birds can detect the direction of the Earth's magnetic field, the primary sensory mechanism behind this remarkable feat is still unclear. The leading hypothesis centers on radical pairs-magnetically sensitive chemical intermediates formed by photoexcitation of cryptochrome proteins in the retina. Our primary aim here is to explain the chemical and physical aspects of the radical-pair mechanism to biologists and the biological and chemical aspects to physicists. In doing so, we review the current state of knowledge on magnetoreception mechanisms. We dare to hope that this tutorial will stimulate new interdisciplinary experimental and theoretical work that will shed much-needed additional light on this fascinating problem in sensory biology.", "The mechanisms that regulate mammalian organ size are poorly understood. It is unclear whether the pathways that control organ size also impinge on stem/progenitor cells. A highly expressed gene in stem cells is YAP1, the ortholog of Drosophila Yorkie, a downstream component of the Hippo pathway. Mutations in components of this pathway produce tissue overgrowth phenotypes in the fly whereas mammalian orthologs, like salvador, merlin, LATS, and YAP1, have been implicated in tumorigenesis. We report here that YAP1 increases organ size and causes aberrant tissue expansion in mice. YAP1 activation reversibly increases liver size more than 4-fold. In the intestine, expression of endogenous YAP1 is restricted to the progenitor/stem cell compartment, and activation of YAP1 expands multipotent undifferentiated progenitor cells, which differentiate upon cessation of YAP1 expression. YAP1 stimulates Notch signaling, and administration of gamma-secretase inhibitors suppressed the intestinal dysplasia caused by YAP1. Human colorectal cancers expressing higher levels of YAP1 share molecular aspects with YAP1-induced dysplastic growth in the mouse. Our data show that the Hippo signaling pathway regulates organ size in mammals and can act on stem cell compartments, indicating a potential link between stem/progenitor cells, organ size, and cancer.", "Gene duplication with subsequent divergence plays a central role in the acquisition of genes with novel function and complexity during the course of evolution. With reduced functional constraints or through positive selection, these duplicated genes may experience accelerated evolution. Under the model of subfunctionalization, loss of subfunctions leads to complementary acceleration at sites with two copies, and the difference in average rate between the sequences may not be obvious. On the other hand, the classical model of neofunctionalization predicts that the evolutionary rate in one of the two duplicates is accelerated. However, the classical model does not tell which of the duplicates experiences the acceleration in evolutionary rate. Here, we present evidence from the Saccharomyces cerevisiae genome that a duplicate located in a genomic region with a low-recombination rate is likely to evolve faster than a duplicate in an area of high recombination. This observation is consistent with population genetics theory that predicts that purifying selection is less effective in genomic regions of low recombination (Hill-Robertson effect). Together with previous studies, our results suggest the genomic background (e.g., local recombination rate) as a potential force to drive the divergence between nontandemly duplicated genes. This implies the importance of structure and complexity of genomes in the diversification of organisms via gene duplications." ]

[ "PANTHER-PSEP is a new software tool for predicting non-synonymous genetic variants that may play a causal role in human disease. Several previous variant pathogenicity prediction methods have been proposed that quantify evolutionary conservation among homologous proteins from different organisms. PANTHER-PSEP employs a related but distinct metric based on 'evolutionary preservation': homologous proteins are used to reconstruct the likely sequences of ancestral proteins at nodes in a phylogenetic tree, and the history of each amino acid can be traced back in time from its current state to estimate how long that state has been preserved in its ancestors. Here, we describe the PSEP tool, and assess its performance on standard benchmarks for distinguishing disease-associated from neutral variation in humans. On these benchmarks, PSEP outperforms not only previous tools that utilize evolutionary conservation, but also several highly used tools that include multiple other sources of information as well. For predicting pathogenic human variants, the trace back of course starts with a human 'reference' protein sequence, but the PSEP tool can also be applied to predicting deleterious or pathogenic variants in reference proteins from any of the ∼100 other species in the PANTHER database.AVAILABILITY AND IMPLEMENTATION: PANTHER-PSEP is freely available on the web at http://pantherdb.org/tools/csnpScoreForm.jsp Users can also download the command-line based tool at ftp://ftp.pantherdb.org/cSNP_analysis/PSEP/ CONTACT: pdthomas@usc.eduSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "The regions bound by sequence-specific transcription factors can be highly variable across different cell types despite the static nature of the underlying genome sequence. This has been partly attributed to changes in chromatin accessibility, but a systematic picture has been hindered by the lack of large-scale data sets. Here, we use 456 binding experiments for 119 regulators and 84 chromatin maps generated by the ENCODE in six human cell types, and relate those to a global map of regulatory motif instances for these factors. We find specific and robust chromatin state preferences for each regulator beyond the previously reported open-chromatin association, suggesting a much richer chromatin landscape beyond simple accessibility. The preferentially bound chromatin states of regulators were enriched for sequence motifs of regulators relative to all states, suggesting that these preferences are at least partly encoded by the genomic sequence. Relative to all regions bound by a regulator, however, regulatory motifs were surprisingly depleted in the regulator's preferentially bound states, suggesting additional non-sequence-specific binding beyond the level predicted by the regulatory motifs. Such permissive binding was largely restricted to open-chromatin regions showing histone modification marks characteristic of active enhancer and promoter regions, whereas open-chromatin regions lacking such marks did not show permissive binding. Lastly, the vast majority of cobinding of regulator pairs is predicted by the chromatin state preferences of individual regulators. Overall, our results suggest a joint role of sequence motifs and specific chromatin states beyond mere accessibility in mediating regulator binding dynamics across different cell types.", "Proteomics has revealed differential protein expression and glycosylation in membrane proteins from premature aging Hutchinson-Gilford progeria syndrome fibroblasts (progeria). Progeria is a rare autosomal dominant genetic disorder of premature aging characterized by marked growth retardation and specific, progressive, premature senescent changes of the skin and other tissues. Affected children live to an average age of 13 years. The 1q20-24 region of chromosome 1 which codes for one of these proteins, lamin A/C, has previously been implicated by Brown et al. (1990) who described identical twins with progeria, where cytogenetic analysis showed an inverted insertion in the long arm of the chromosome in 70% of cells. Luengo et al. (2002) similarly reported an interstitial deletion of chromosome 1q23, in a 9-year-old patient with a classic clinical picture of progeria.", "Chest injuries in children are part of polytrauma resulting from high-energy violence, most often caused by traffic accidents. Blunt chest injuries (95%) are significantly more frequent than penetrating injuries (5%). Lung contusion, rib fracture, pneumothorax or haemothorax, are the more common injuries, but tracheobronchial rupture, cardiac or diaphragmatic injuries may also occur. The anterior X-ray image remains the basic examination method for isolated chest injuries. CT trauma scan with a contrast medium is done in polytraumatized children. Blunt injuries of intra-thoracic organs in haemodynamically stable children are treated mostly conservatively (85%) under full monitoring at the ICU. Surgical treatment is necessary in a minority of patients. Mortality and morbidity of patients with chest injury depend on the actual combination of multiple body systems injury. The severity of total injury can be predicted using objective scoring systems (Abbreviated Injury Scale=AIS; Injury Severity Score=ISS). Overall mortality ranges from 6 to 20%. Mortality is high but this is mainly due to associated head injuries.Key words: multiple trauma thoracic trauma - paediatric lung contusion Injury Severity Score=ISS.", "As part of personalised medicine emerging from the human genomics revolution, many websites now offer direct-to-consumer genetic testing. Here, we examine three personal genomics companies--Navigenics, deCODEme and 23andMe--each of which represents contrasting registers of 'personalisation'. We identify three distinctive registers in these websites: a paternalistic (medical) register; a translational (scientific) register and a democratic (consumerist) register. We explore in detail the rhetorical and discourse devices employed in these websites to assess how personalised healthcare is promised to the public. Promising information that will empower prevention of common complex diseases and ensure better quality of life is conflated with promising greater access to personal information. The presence and absence of scientific legitimacy is related to concerns about accuracy and validity on the one side, and fears of paternalism and elitism on the other. Nevertheless, a common strategy uniting these different styles of personalisation is consumer empowerment. Finally, we consider the tension between the drive of translational medicine to make human genomic research practically relevant, and the intrinsic uncertainties of scientific research and show how, in the commercial domain, future risks are transformed into discourses of promise by concealing these uncertainties.", "Essentials Emicizumab mimics factor (F)VIIIa cofactor function, augments the intrinsic tenase activity. We assessed the emicizumab-driven hemostatic function in FXI-deficient plasmas. Emicizumab improved the coagulation potentials in severe FXI-deficient plasma. Emicizumab may provide a possibility for clinical application in patients with FXI deficiency. SUMMARY: Background Patients with factor (F)XI deficiency commonly present with markedly prolonged activated partial thromboplastin times (APTT), although bleeding phenotypes are heterogeneous. Emicizumab, a bispecific monoclonal antibody to FIX/FIXa and FX/FXa, mimics FVIIIa cofactor function on phospholipid (PL) surfaces. Antibody reactions were designed, therefore, to augment mechanisms during the propagation phase of blood coagulation. Aim To assess emicizumab-driven hemostatic function in FXI-deficient plasmas. Methods and Results Standard ellagic acid (Elg)/PL-based APTTs of different FXI-deficient plasmas (n = 13; FXI activity, < 1 IU dl-1 ) were markedly shortened dose dependently by the presence of emicizumab. To further analyze the effects of emicizumab, clot waveform analysis (CWA) in FXI-deficient plasmas with emicizumab, triggered by tissue factor (TF)/Elg demonstrated improvements in both clot times, reflecting the initiation phase, and coagulation velocity, which represents the propagation phase. Emicizumab also enhanced the TF/Elg-triggered thrombin generation in FXI-deficient plasmas dose-dependently although the degree of enhancement varied in individual cases. Thrombin generation with either FVII-deficient plasma or FIX-deficient plasma treated with anti-FXI antibody showed little or no increase by the co-presence of emicizumab, suggesting that the accelerated thrombin generation in FXI-deficient plasmas by emicizumab should depend on the FIXa-involved coagulation propagation initially triggered by FVIIa/TF. The ex vivo addition of emicizumab to whole blood from three patients with severe FXI deficiency demonstrated modest, dose-dependent improvements in Ca2+ -triggered thromboelastograms (NATEM mode). Conclusion Emicizumab appeared to improve coagulation function in severe FXI-deficient plasma, and might provide possibilities for clinical application in patients with FXI deficiency.", "We describe the imaging findings of the HELLP (haemolysis, elevated liver enzymes and low platelets) syndrome in a gravid 36-year-old-woman who presented at 19.5 weeks gestation with severe right upper quadrant pain. Ultrasound findings suggested a focal hyperechoic liver lesion suggesting pregnancy-related hepatopathy prior to development of biochemical signs of HELLP syndrome. Within 3 days, the patient developed characteristic clinical and laboratory evidence of the HELLP syndrome. MR imaging at this time demonstrated localized hepatic ischaemia, further strengthening the diagnosis of HELLP syndrome." ]

[ "OBJECTIVES: South Asians exhibit extensive variation in skin melanin index (MI) which is observed across the broader region of South Asia as well as within restricted geographic regions. However, the genetic variants associated with variation in the skin pigmentation phenotype are poorly understood in these populations. The present study examines the association between MI measures and genetic variants from 5 candidate pigmentation genes among 533 individuals representing 6 populations of West Maharashtra.METHODS: Associations between five single nucleotide polymorphisms (SNPs) known to play a role in pigmentation (rs1426654-SLC24A5, rs1042602-TYR, rs16891982-SLC45A2, rs6058017-ASIP, and rs642742-KITLG) and MI measures were tested using standard one-way analysis of variance (ANOVA) within each population. Multiple linear regression was used to test the effects of these SNPs in the full West Maharashtra sample using sex, age, and population or social group as covariates.RESULTS: rs1426654 showed significant association with MI in all six study populations (P < 0.01). Association tests using sex, age, and population as covariates showed rs1426654 and rs1042602 to be significantly (P < 0.01) associated with lighter skin pigmentation in West Maharashtra as a whole. By contrast, when social group was added as a covariate instead of population, rs1426654, rs1042602, and rs16891982 were significantly (P < 0.01) associated with lighter skin pigmentation.CONCLUSIONS: Only rs1426654 is significantly associated with MI in each individual population; however, rs1426654, rs1042602, and rs16891982 are significantly associated with pigmentation in the broader West Maharashtra region after controlling for population and social group, with rs1426654 (SLC24A5) explaining the majority of the observed variation. Am. J. Hum. Biol. 28:610-618, 2016. © 2016 Wiley Periodicals, Inc.", "Multiple endocrine neoplasia type 2 (MEN2) is an inherited, autosomal-dominant disorder caused by deleterious mutations within the RET protooncogene. MEN2 RET mutations are mainly heterozygous, missense sequence changes found in RET exons 10, 11, and 13-16. Our group has developed the publicly available, searchable MEN2 RET database to aid in genotype/phenotype correlations, using Human Genome Variation Society recommendations for sequence variation nomenclature and database content. The MEN2 RET database catalogs all RET sequence variation relevant to the MEN2 syndromes, with associated clinical information. Each database entry lists a RET sequence variation's location within the RET gene, genotype, pathogenicity classification, MEN2 phenotype, first literature reference, and comments (which may contain information on other clinical features, complex genotypes, and additional literature references). The MEN2 phenotype definitions were derived from the International RET Mutation Consortium guidelines for classification of MEN2 disease phenotypes. Although nearly all of the 132 RET sequence variation entries initially cataloged in the database were from literature reports, novel sequence variation and updated phenotypic information for any existing database entry can be submitted electronically on the database website. The database website also contains links to selected MEN2 literature reviews, gene and protein information, and RET reference sequences. The MEN2 RET database (www.arup.utah.edu/database/MEN2/MEN2_welcome.php) will serve as a repository for MEN2-associated RET sequence variation and reference for RET genotype/MEN2 phenotype correlations.", "The precise relationship between endometriosis and infertility is debated. Surgery is considered to play a role within the framework of the therapeutic options to cure infertile women with the disease even though its effectiveness is generally modest. In fact, there is unquestionably the need to improve surgical techniques in this area. Specifically, two main aspects require optimization: 1) preventing the injury to the follicular reserve that follows surgical excision of ovarian endometriomas and 2) preventing post-surgical formation and re-formation of adhesions. The comparison between the excision/stripping and the vaporization/coagulation techniques represents the main point of debate on what is the best procedure to remove ovarian endometrioma. Randomized controlled trials showed that the excision technique is associated with a higher pregnancy rate and a lower rate of recurrence although it may determine severe injury to the ovarian reserve. Improvements to this latter aspect may be represented by a combined excisional-vaporization technique or by replacing diathermy coagulation with surgical ovarian suture. Barrier agents reduce but not eliminate the post-surgical adhesion formation in women with endometriosis. Encouraging evidence has been reported with Interceed, Oxiplex/AP gel and Adept solution. However, available studies are mainly based on II look laparoscopies performed few weeks after the intervention and data on fertility is lacking. Clinical trials including pregnancy rate as a specific outcome are warranted.", "The recent feasibility of genome-wide studies of adaptation in human populations has provided novel insights into biological pathways that have been affected by adaptive pressures. However, only a few African populations have been investigated using these genome-wide approaches. Here, we performed a genome-wide analysis for evidence of recent positive selection in a sample of 120 individuals of Wolaita ethnicity belonging to Omotic-speaking people who have inhabited the mid- and high-land areas of southern Ethiopia for millennia. Using the 11 HapMap populations as the comparison group, we found Wolaita-specific signals of recent positive selection in several human leukocyte antigen (HLA) loci. Notably, the selected loci overlapped with HLA regions that we previously reported to be associated with podoconiosis-a geochemical lymphedema of the lower legs common in the Wolaita area. We found selection signals in PPARA, a gene involved in energy metabolism during prolonged food deficiency. This finding is consistent with the dietary use of enset, a crop with high-carbohydrate and low-fat and -protein contents domesticated in Ethiopia subsequent to food deprivation 10 000 years ago, and with metabolic adaptation to high-altitude hypoxia. We observed novel selection signals in CDKAL1 and NEGR1, well-known diabetes and obesity susceptibility genes. Finally, the SLC24A5 gene locus known to be associated with skin pigmentation was in the top selection signals in the Wolaita, and the alleles of single-nucleotide polymorphisms rs1426654 and rs1834640 (SLC24A5) associated with light skin pigmentation in Eurasian populations were of high frequency (47.9%) in this Omotic-speaking indigenous Ethiopian population.", "INTRODUCTION: Conventional markers of acute kidney injury (AKI) lack diagnostic accuracy and are expressed only late after cardiac surgery with cardiopulmonary bypass (CPB). Recently, interest has focused on hepcidin, a regulator of iron homeostasis, as a unique renal biomarker.METHODS: We studied 100 adult patients in the control arm of a randomized, controlled trial http://www.clinicaltrials.gov/NCT00672334 who were identified as being at increased risk of AKI after cardiac surgery with CPB. AKI was defined according to the Risk, Injury, Failure, Loss, End-stage renal disease classification of AKI classification stage. Samples of plasma and urine were obtained simultaneously (1) before CPB (2) six hours after the start of CPB and (3) twenty-four hours after CPB. Plasma and urine hepcidin 25-isoforms were quantified by competitive enzyme-linked immunoassay.RESULTS: In AKI-free patients (N = 91), urine hepcidin concentrations had largely increased at six and twenty-four hours after CPB, and they were three to seven times higher compared to patients with subsequent AKI (N = 9) in whom postoperative urine hepcidin remained at preoperative levels (P = 0.004, P = 0.002). Furthermore, higher urine hepcidin and, even more so, urine hepcidin adjusted to urine creatinine at six hours after CPB discriminated patients who did not develop AKI (area under the curve (AUC) receiver operating characteristic curve 0.80 [95% confidence interval (95% CI) 0.71 to 0.87] and 0.88 [95% CI 0.78 to 0.97]) or did not need renal replacement therapy initiation (AUC 0.81 [95% CI 0.72 to 0.88] 0.88 [95% CI 0.70 to 0.99]) from those who did. At six hours, urine hepcidin adjusted to urine creatinine was an independent predictor of ruling out AKI (P = 0.011). Plasma hepcidin did not predict no development of AKI. The study findings remained essentially unchanged after excluding patients with preoperative chronic kidney disease.CONCLUSIONS: Our findings suggest that urine hepcidin is an early predictive biomarker of ruling out AKI after CPB, thereby contributing to early patient risk stratification.", "Methylsulfonylmethane (MSM) is a popular dietary supplement used in a variety of conditions including pain, inflammation, allergies, arthritis, parasitic infections and the maintenance of normal keratin levels in hair, skin and nails. Despite its popularity, there is little published toxicology data on MSM. The objective of this study was to evaluate the acute and subchronic toxicity of MSM in rats at a dose five to seven times the maximum recommended dose in humans. MSM administered in a single gavage dose of 2 g/kg resulted in no adverse events or mortality. MSM administered as a daily dose of 1.5 g/kg for 90 days by gavage resulted in no adverse events or mortality. Necropsy did not reveal any gross pathological lesions or changes in organ weights. Renal histology of treated animals was normal. It is concluded that MSM is well tolerated in rats at an acute dose of 2 g/kg and at a subacute chronic dose of 1.5 g/kg.", "Phospholamban (PLN) is the endogenous inhibitor of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), the integral membrane enzyme responsible for 70 % of the removal of Ca(2+) from the cytosol, inducing cardiac muscle relaxation in humans. Dysfunctions in SERCA:PLN interactions have been implicated as having a critical role in cardiac disease, and targeting Ca(2+) transport has been demonstrated to be a promising avenue in treating conditions of heart failure. Here, we designed a series of new mutants able to tune SERCA function, targeting the loop sequence that connects the transmembrane and cytoplasmic helices of PLN. We found that a variable degree of loss of inhibition mutants is attainable by engineering glycine mutations along PLN's loop domain. Remarkably, a double glycine mutation results in a complete loss-of-function mutant, fully mimicking the phosphorylated state of PLN. Using nuclear magnetic resonance spectroscopy, we rationalized the effects of these mutations in terms of entropic control on PLN function, whose inhibitory function can be modulated by increasing its conformational dynamics. However, if PLN mutations go past a threshold set by the phosphorylated state, they break the structural coupling between the transmembrane and cytoplasmic domains, resulting in a species that behaves as the inhibitory transmembrane domain alone. These studies provide new potential candidates for gene therapy to reverse the effects of heart failure.", "To achieve the 90-90-90 goals set by UNAIDS, the number of new HIV infections needs to decrease to approximately 500,000 by 2020. One of the 'five pillars' to achieve this goal is pre-exposure prophylaxis (PrEP). Truvada (emtricitabine-tenofovir) is currently the only medication approved for PrEP. Despite its advantages, Truvada is costly and requires individuals to adhere to the once-daily regimen. To improve PrEP, many next-generation regimen, including long-acting formulations, are currently investigated. However, pre-clinical testing may not guide candidate selection, since it often fails to translate into clinical efficacy. On the other hand, quantifying prophylactic efficacy in the clinic is ethically problematic and requires to conduct long (years) and large (N>1000 individuals) trials, precluding systematic evaluation of candidates and deployment strategies. To prioritize- and help design PrEP regimen, tools are urgently needed that integrate pharmacological-, viral- and host factors determining prophylactic efficacy. Integrating the aforementioned factors, we developed an efficient and exact stochastic simulation approach to predict prophylactic efficacy, as an example for dolutegravir (DTG). Combining the population pharmacokinetics of DTG with the stochastic framework, we predicted that plasma concentrations of 145.18 and 722.23nM prevent 50- and 90% sexual transmissions respectively. We then predicted the reduction in HIV infection when DTG was used in PrEP, PrEP 'on demand' and post-exposure prophylaxis (PEP) before/after virus exposure. Once daily PrEP with 50mg oral DTG prevented 99-100% infections, and 85% of infections when 50% of dosing events were missed. PrEP 'on demand' prevented 79-84% infections and PEP >80% when initiated within 6 hours after virus exposure and continued for as long as possible. While the simulation framework can easily be adapted to other PrEP candidates, our simulations indicated that oral 50mg DTG is non-inferior to Truvada. Moreover, the predicted 90% preventive concentrations can guide release kinetics of currently developed DTG nano-formulations." ]

[ "IMPORTANCE OF THE FIELD: Rho GDP dissociation inhibitor 2 (RhoGDI2) has been identified as a regulator of Rho GTPases that play important roles in the development of numerous aspects of the malignant phenotype, including cell cycle progression, resistance to apoptotic stimuli, neovascularization, tumor cell motility, invasiveness, and metastasis. Although RhoGDI2 has been known to be expressed only in hematopoietic tissues, recent studies suggest that this protein is also aberrantly expressed in several human cancers and contributes to aggressive phenotypes, such as invasion and metastasis. Hence, RhoGDI2 appears to be a target of interest for therapeutic manipulation.AREAS COVERED IN THIS REVIEW: Here, we summarize the role of RhoGDI2 in human cancers, specifically metastasis-related processes, and discuss its potential as a therapeutic target.WHAT THE READER WILL GAIN: RhoGDI2 modulates the invasiveness and metastatic ability of cancer cells through regulation of Rac1 activity.TAKE HOME MESSAGE: RhoGDI2 may be a useful marker for tumor progression in human cancers, and interruption of the RhoGDI2-mediated cancer cell invasion and metastasis by an interfacial inhibitor may be a powerful therapeutic approach to cancer.", "Protein domains are the common currency of protein structure and function. Over 10,000 such protein families have now been collected in the Pfam database. Using these data along with animal gene phylogenies from TreeFam allowed us to investigate the gain and loss of protein domains. Most gains and losses of domains occur at protein termini. We show that the nature of changes is similar after speciation or duplication events. However, changes in domain architecture happen at a higher frequency after gene duplication. We suggest that the bias towards protein termini is largely because insertion and deletion of domains at most positions in a protein are likely to disrupt the structure of existing domains. We can also use Pfam to trace the evolution of specific families. For example, the immunoglobulin superfamily can be traced over 500 million years during its expansion into one of the largest families in the human genome. It can be shown that this protein family has its origins in basic animals such as the poriferan sponges where it is found in cell-surface-receptor proteins. We can trace how the structure and sequence of this family diverged during vertebrate evolution into constant and variable domains that are found in the antibodies of our immune system as well as in neural and muscle proteins.", "Many insects rely on bacterial symbionts with tiny genomes specialized for provisioning nutrients lacking in host diets. Xylem sap and phloem sap are both deficient as insect diets, but differ dramatically in nutrient content, potentially affecting symbiont genome evolution. For sap-feeding insects, sequenced symbiont genomes are available only for phloem-feeding examples from the suborder Sternorrhyncha and xylem-feeding examples from the suborder Auchenorrhyncha, confounding comparisons. We sequenced genomes of the obligate symbionts, Sulcia muelleri and Nasuia deltocephalinicola, of the phloem-feeding pest insect, Macrosteles quadrilineatus (Auchenorrhyncha: Cicadellidae). Our results reveal that Nasuia-ALF has the smallest bacterial genome yet sequenced (112 kb), and that the Sulcia-ALF genome (190 kb) is smaller than that of Sulcia in other insect lineages. Together, these symbionts retain the capability to synthesize the 10 essential amino acids, as observed for several symbiont pairs from xylem-feeding Auchenorrhyncha. Nasuia retains genes enabling synthesis of two amino acids, DNA replication, transcription, and translation. Both symbionts have lost genes underlying ATP synthesis through oxidative phosphorylation, possibly as a consequence of the enriched sugar content of phloem. Shared genomic features, including reassignment of the UGA codon from Stop to tryptophan, and phylogenetic results suggest that Nasuia-ALF is most closely related to Zinderia, the betaproteobacterial symbiont of spittlebugs. Thus, Nasuia/Zinderia and Sulcia likely represent ancient associates that have co-resided in hosts since the divergence of leafhoppers and spittlebugs >200 Ma, and possibly since the origin of the Auchenorrhyncha, >260 Ma.", "Efficient synthesis of many small abundant RNAs is achieved by the proficient recycling of RNA polymerase (pol) III and stable transcription complexes. Cellular Alu and related retroposons represent unusual pol III genes that are normally repressed but are activated by viral infection and other conditions. The core sequences of these elements contain pol III promoters but must rely on fortuitous downstream oligo(dT) tracts for terminator function. We show that a B1-Alu gene differs markedly from a classical pol III gene (tRNAiMet) in terminator sequence requirements. B1-Alu genes that differ only in terminator sequence context direct differential RNA 3' end formation. These genes are assembled into stable transcription complexes but differ in their ability to be recycled in the presence of the La transcription termination factor. La binds to the nascent RNA 3' UUUOH end motif that is generated by transcriptional termination within the pol III termination signal, oligo(dT). We found that the recycling efficiency of the B1-Alu genes is correlated with the ability of La to access the 3' end of the nascent transcript and protect it from 3'-5' exonucleolytic processing. These results illuminate a relationship between RNA 3' end formation and transcription termination, and La-mediated reinitiation by pol III.", "OBJECTIVE: Activation of extracellular signal-regulated kinase-(ERK)-1/2 by cytokines in adipocytes is involved in the alterations of adipose tissue functions participating in insulin resistance. This study aims at identifying proteins regulating ERK1/2 activity, specifically in response to inflammatory cytokines, to provide new insights into mechanisms leading to abnormal adipose tissue function.RESEARCH DESIGN AND METHODS: Kinase activities were inhibited with pharmacological inhibitors or siRNA. Lipolysis was monitored through glycerol production. Gene expression in adipocytes and adipose tissue of obese mice and subjects was measured by real-time PCR.RESULTS: IkappaB kinase-(IKK)-beta inhibition prevented mitogen-activated protein (MAP) kinase kinase (MEK)/ERK1/2 activation in response to interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha but not insulin in 3T3-L1 and human adipocytes, suggesting that IKKbeta regulated a MAP kinase kinase kinase (MAP3K) involved in ERK1/2 activation induced by inflammatory cytokines. We show that the MAP3K8 called Tpl2 was expressed in adipocytes and that IL-1beta and TNF-alpha activated Tpl2 and regulated its expression through an IKKbeta pathway. Pharmacological inhibition or silencing of Tpl2 prevented MEK/ERK1/2 activation by these cytokines but not by insulin, demonstrating its involvement in ERK1/2 activation specifically in response to inflammatory stimuli. Importantly, Tpl2 was implicated in cytokine-induced lipolysis and in insulin receptor substrate-1 serine phosphorylation. Tpl2 mRNA expression was upregulated in adipose tissue of obese mice and patients and correlated with TNF-alpha expression.CONCLUSIONS: Tpl2 is selectively involved in inflammatory cytokine-induced ERK1/2 activation in adipocytes and is implicated in their deleterious effects on adipocyte functions. The deregulated expression of Tpl2 in adipose tissue suggests that Tpl2 may be a new actor in adipose tissue dysfunction in obesity.", "OBJECTIVE: To review the immunogenicity, efficacy, and safety of the 13-valent pneumococcal conjugate vaccine (PCV13) for use in pediatric patients.DATA SOURCES: A MEDLINE search (2000-September 2011) was conducted using the key words Streptococcus pneumoniae and pneumococcal conjugate vaccine for clinical trials, limited to studies conducted in humans and published in English.STUDY SELECTION AND DATA EXTRACTION: Randomized, controlled, multicenter trials were reviewed and included to evaluate the safety and efficacy of PCV13. Literature on the epidemiology and pathology of pneumococcal infections and recommendations from the Advisory Committee on Immunization Practices (ACIP) were also reviewed.DATA SYNTHESIS: PCV13 is approved for routine vaccination of all infants as a 4-dose series at age 2, 4, 6, and 12-15 months for children who previously received 1 or more doses of the 7-valent pneumococcal conjugate vaccine (PCV7), and for children with underlying medical conditions that increase their risk for pneumococcal disease or its complications. PCV13 has comparable immunogenicity to the serotypes common with PCV7 and also provides protection against 6 additional pneumococcal serotypes. PCV13 has also been shown to have a comparable adverse reaction profile to PCV7.CONCLUSIONS: Based on published immunogenicity and safety data, as well as the recent recommendations by the ACIP for routine use in infants and indications for high-risk pediatric patients, PCV13 is a revised formulation of pneumococcal vaccine that should be included on pharmacy formularies.", "The recount2 resource is composed of over 70,000 uniformly processed human RNA-seq samples spanning TCGA and SRA, including GTEx. The processed data can be accessed via the recount2 website and the recount Bioconductor package. This workflow explains in detail how to use the recount package and how to integrate it with other Bioconductor packages for several analyses that can be carried out with the recount2 resource. In particular, we describe how the coverage count matrices were computed in recount2 as well as different ways of obtaining public metadata, which can facilitate downstream analyses. Step-by-step directions show how to do a gene-level differential expression analysis, visualize base-level genome coverage data, and perform an analyses at multiple feature levels. This workflow thus provides further information to understand the data in recount2 and a compendium of R code to use the data." ]

[ "Telomere length is regulated around an equilibrium set point. Telomeres shorten during replication and are lengthened by telomerase. Disruption of the length equilibrium leads to disease; thus, it is important to understand the mechanisms that regulate length at the molecular level. The prevailing protein-counting model for regulating telomerase access to elongate the telomere does not explain accumulating evidence of a role of DNA replication in telomere length regulation. Here I present an alternative model: the replication fork model that can explain how passage of a replication fork and regulation of origin firing affect telomere length.", "Angiotensin-converting enzyme inhibitors (ACEI) are commonly prescribed for blood pressure control and renal protection. ACEI angioedema is a common problem in patients who are taking ACEI, although, in most cases, the disorder is self-limited, and spontaneous episodes of apparently unprovoked angioedema stop with the discontinuation of the medication. In a subset of patients, hospitalization and even intubation are required for airway protection. The diagnosis is made clinically. There are no laboratory studies that establish the diagnosis. However, such investigations help exclude alternative diagnoses as the cause for the patient's presentation. Conventional treatment with regimens used to control allergic angioedema is ineffective in this condition. The mechanism of ACEI-induced angioedema is thought to be related to its effect on the kallikrein-kinin system. Kallikrein is a protease that converts high-molecular-weight kininogens into kinins, primarily bradykinin. Medications recently developed, primarily icatibant and ecallantide, to control hereditary angioedema, a disorder also associated with kallikrein-kinin activation, have been used to treat ACEI angioedema with some success. The efficacy of these agents and their optimal use remains to be established by randomized and placebo controlled trials.", "Ziconotide (SNX-111), a selective blocker of neuronal N-type voltage-sensitive calcium channels, is antinociceptive when it is administered intrathecally. It is currently under clinical investigation for the treatment of malignant and non-malignant pain syndromes. The present study was undertaken to compare and contrast antinociceptive properties of ziconotide, morphine and clonidine in a rat model of post-operative pain. Post-operative pain was produced by making a longitudinal incision through the skin, fascia, and muscle of the plantar aspect of the left hindpaw. This procedure produced immediate (0.5 h after surgery) and long-lasting (4-7 days post-surgery) heat hyperalgesia and mechanical allodynia in the injured hindpaw. Pain thresholds in the contralateral hindpaw were unaffected. Administered one day after incisional surgery, intrathecal ziconotide blocked established heat hyperalgesia in the injured hindpaw in a dose-dependent manner yielding an ED(50)4 h) but reversible (<24 h) blockade of established mechanical allodynia. Administered one day after surgery, intrathecal bolus injection of morphine dose-dependently blocked heat hyperalgesia in the injured hindpaw with an ED(50) of 1.6 microg (2.1 nmol) and heat nociceptive responses in the normal hindpaw with an ED(50) of 2.7 microg (3.6 nmol). The effects were immediate and short-lasting (</=1 h). Intravenous bolus injection of 3 mg/kg (1.1 micromol/kg) ziconotide, administered either before or after incisional surgery, had no effect on thermal pain thresholds measured in either the injured or normal hindpaw. In contrast, intraperitoneal injections of 2 mg/kg (2.6 micromol/kg) morphine and 2.5 mg/kg (9.4 micromol/kg) clonidine blocked heat hyperalgesia in the injured hindpaw; morphine, but not clonidine, also elevated thermal (heat) nociceptive response thresholds in the normal hindpaw. The results of this study show that intrathecal ziconotide is antinociceptive in a rat incisional model of post-operative pain and is more potent, longer acting, and more specific in its actions than intrathecal morphine.", "The discovery of microRNAs (miRNAs) has opened an entire new avenue for drug development. These short (15-22 nucleotides) noncoding RNAs, which function in RNA silencing and posttranscriptional regulation of gene expression, have been shown to critically affect numerous pathways in both development and disease progression. Current miRNA drug development focuses on either reintroducing the miRNA into cells through the use of a miRNA mimic or inhibiting its function via use of a synthetic antagomir. Although these methods have shown some success as therapeutics, they face challenges particularly with regard to cellular uptake and for use as systemic reagents. We recently presented a novel mechanism of inhibiting miR-544 by directed inhibition of miRNA biogenesis. We found that inhibition of DICER processing of miR-544 through the use of a small molecule abolished miR-544 function in regulating adaptation of breast cancer cells to hypoxic stress. Herein, we describe a protocol that utilizes bioinformatics to first identify lead small molecules that bind to DICER cleavage sites in pre-miRNAs and then employ an efficient, high-throughput fluorescent-based screening system to determine the inhibitory potential of the lead compounds and their derivatives.", "In addition to the typical manifestations of thrombotic-thrombocytopenic purpura like thrombocytopenia, haemolysis, fever, coma and renal failure, signs of a beginning DIC could be seen in a patient after abdominal surgery. Haemostatic, cardiovascular and respiratory data are presented. Pulmonary angiography by using a Swan-Ganz-catheter revealed multiple filling defects reversible with therapy. Treatment with fresh whole blood aggravated thrombocytopenia. Daily infusions of fresh frozen plasma combined with heparinisation and antithrombin III because of DIC, induced haematologic remission. Renal failure and cerebral symptoms could not be influenced. Diagnosis, monitoring and therapy are discussed.", "Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. It is known that MTHFR deficiency may result in hyperhomocysteinemia, but MTHFR deficiency-induced schizophrenia has been rarely reported. Here we present the clinical course, biochemical and genetic characteristics of schizophrenia resulted from MTHFR deficiency in a school-age boy. He was 13 years old. He was admitted with a two-year history of fear, auditory hallucination, learning difficulty, sleeping problems, irascibility, drowsing and giggling. At admission, he had significantly elevated plasma and urine levels of total homocysteine, significantly decreased levels of folate in serum and cerebrospinal fluid, and a normal blood concentration of methionine. Further DNA sequencing analysis showed 665C>T homozygous mutations in the MTHFR gene. The patient was diagnosed with MTHFR deficiency-associated schizophrenia and treatment with calcium folinate, vitamin B12, vitamin B6, and betaine was initiated. After the treatment for 1 week, his plasma and urine levels of homocysteine were decreased to a normal range and the clinical symptoms were significantly improved. After 3 months of treatment, the patient returned to school. He is now living with normal school life. In summary, children with late-onset MTHFR deficiency and secondary cerebral folate deficiency may lead to schizophrenia. This rare condition can be early diagnosed through analyses of blood and urine total homocysteine, amino acids in blood and folate in blood and cerebral fluid and successfully treated with folinic acid, vitamin B6, vitamin B12 and betaine.", "Diabetes is generally associated with vasculopathy, which contains both microvascular and macrovascular complications, associated with high morbidity and mortality. Currently, despite interventional therapy, the overall prognosis for patients with diabetic vasculopathy remains unsatisfactory. Angiogenesis and vascular injury and repair are associated with a variety of cells. However, the molecular mechanisms of the cells that are involved in pathogenesis of diabetic vasculopathy remain largely unknown. As novel molecules, microRNAs (miRs) take part in regulating protein-coding gene expression at the post-transcriptional level, and contribute to the pathogenesis of various types of chronic metabolism disease, especially diabetic vasculopathy. This allows miRs to have a direct function in regulation of various cellular events. Additionally, circulating miRs have been proposed as biomarkers for a wide range of cardiovascular diseases. This review elucidates miR-mediated regulatory mechanisms in diabetic vasculopathy. Furthermore, we discuss the current understanding of miRs in diabetic vasculopathy. Finally, we summarize the development of novel diagnostic and therapeutic strategies for diabetic vasculopathy related to miRs.", "RNA-dependent RNA polymerase from healthy tomato plant tissue accepts potato spindle tuber viroid (PSTV) RNA as a template for the in vitro synthesis of full-length RNA copies of the PSTV genome. Viroid transcription requires the presence of Mn2+ and /or Mg2+ ions and is not inhibited by concentrations of 10(-5) M alpha-amanitin. This is the first report of a well-defined product synthesized in vitro by an RNA-dependent RNA polymerase from healthy plants.", "Homozygous or compound heterozygous mutations in the phosphatase and tensin homolog-induced putative kinase 1 (PINK1) gene are causative of autosomal recessive, early onset Parkinson's disease. Single heterozygous mutations have been detected repeatedly both in a subset of patients and in unaffected individuals, and the significance of these mutations has long been debated. Several neurophysiological studies from non-manifesting PINK1 heterozygotes have demonstrated the existence of neural plasticity abnormalities, indicating the presence of specific endophenotypic traits in the heterozygous state. We performed a functional analysis of corticostriatal synaptic plasticity in heterozygous PINK1 knockout (PINK1(+/-) ) mice using a multidisciplinary approach and observed that, despite normal motor behavior, repetitive activation of cortical inputs to striatal neurons failed to induce long-term potentiation (LTP), whereas long-term depression was normal. Although nigral dopaminergic neurons exhibited normal morphological and electrophysiological properties with normal responses to dopamine receptor activation, a significantly lower dopamine release was measured in the striatum of PINK1(+/-) mice compared with control mice, suggesting that a decrease in stimulus-evoked dopamine overflow acts as a major determinant for the LTP deficit. Accordingly, pharmacological agents capable of increasing the availability of dopamine in the synaptic cleft restored normal LTP in heterozygous mice. Moreover, monoamine oxidase B inhibitors rescued physiological LTP and normal dopamine release. Our results provide novel evidence for striatal plasticity abnormalities, even in the heterozygous disease state. These alterations might be considered an endophenotype to this monogenic form of Parkinson's disease and a valid tool with which to characterize early disease stage and design possible disease-modifying therapies.", "On June 7, 2021, the US Food and Drug Administration (FDA) approved aducanumab, a monoclonal amyloid targeting β-amyloid, for the treatment for Alzheimer's disease (AD). This decision was achieved through the Accelerated Approval Pathway and was essentially motivated by the evidence that aducanumab reduces brain amyloid plaques. This news is causing a heated debate in the scientific community. On the one hand, aducanumab is the first drug to be approved for the treatment of the disease since 2003 and is the first drug to act on the alleged pathophysiological mechanisms of AD. At the same time, the evidence of clinical benefit coming from two phase 3 clinical trials is contradictory and still inconclusive. The aim of the present editorial is to provide some points to consider that can help understand the peculiarities and implications of this approval and feed the scientific debate underway.", "BACKGROUND: Duchenne muscular dystrophy (DMD) is a fatal progressive muscle-wasting disease caused by mutations in the DMD gene. Dilated cardiomyopathy is the leading cause of death in DMD; therefore, further understanding of this complication is essential to reduce morbidity and mortality.METHODS: A common null variant (R577X) in the ACTN3 gene, which encodes α-actinin-3, has been studied in association with muscle function in healthy individuals; however it has not yet been examined in relationship to the cardiac phenotype in DMD. In this study, we determined the ACTN3 genotype in 163 patients with DMD and examined the correlation between ACTN3 genotypes and echocardiographic findings in 77 of the 163 patients.RESULTS: The genotypes 577RR(RR), 577RX(RX) and 577XX(XX) were identified in 13 (17%), 44 (57%) and 20 (26%) of 77 patients, respectively. We estimated cardiac involvement-free survival rate analyses using Kaplan-Meier curves. Remarkably, the left ventricular dilation (> 55 mm)-free survival rate was significantly lower in patients with the XX null genotype (P < 0.01). The XX null genotype showed a higher risk for LV dilation (hazard ratio 9.04).CONCLUSIONS: This study revealed that the ACTN3 XX null genotype was associated with a lower left ventricular dilation-free survival rate in patients with DMD. These results suggest that the ACTN3 genotype should be determined at the time of diagnosis of DMD to improve patients' cardiac outcomes.", "The prevailing view of the RNA polymerase II (RNAP II) transcription cycle is that RNAP II is recruited to the promoter, transcribes a linear DNA template, then terminates transcription and dissociates from the template. Subsequent rounds of transcription are thought to require de novo recruitment of RNAP II to the promoter. Several recent findings, including physical interaction of 3'-end processing factors with both promoter and terminator regions, challenge this concept. Here we report a physical association of promoter and terminator regions of the yeast BUD3 and SEN1 genes. These interactions are transcription-dependent, require the Ssu72 and Pta1 components of the CPF 3'-end processing complex, and require the phosphatase activity of Ssu72. We propose a model for RNAP II transcription in which promoter and terminator regions are juxtaposed, and that the resulting gene loops facilitate transcription reinitiation by the same molecule of RNAP II in a manner dependent upon Ssu72-mediated CTD dephosphorylation.", "Liver fibrosis occurs during chronic injury and represents, in large part, an exaggerated matrigenic output by hepatic stellate cells (HSCs) which become activated as a result of injury-induced signaling pathways in parenchymal and inflammatory cells (hepatocytes, macrophages, etc.). The molecular components in these pathways (e.g., CCN proteins) are modulated by transcription factors as well as by factors such as microRNAs (miRs) that act posttranscriptionally. MiRs are small (~23 nt) noncoding RNAs that regulate gene expression by specifically interacting with the 3' untranslated region (UTR) of target gene mRNA to repress translation or enhance mRNA cleavage. As well as acting in their cells of production, miRs (and other cellular constituents such as mRNAs and proteins) can be liberated from their cells of origin in nanovesicular membrane exosomes, which traverse the intercellular spaces, and can be delivered to neighboring cells into which they release their molecular payload, causing alterations in gene expression in the target cells. Here we summarize some of the experimental approaches for studying miR action and exosomal trafficking between hepatic cells. Insights into the mechanisms involved will yield new information about how hepatic fibrosis is regulated and, further, may identify new points of therapeutic intervention.", "Bladder cancer (BC) is generally divided into non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC). The standard treatment protocol for MIBC patients is radical cystectomy preceded by neoadjuvant chemotherapy (NAC). About one-half of the MIBC patients show a priori resistance to chemotherapy, and are therefore exposed to the risks of disease progression and toxicity from ineffective NAC. The discovery of microRNA (miRNA) regulation in tumorigenesis has provided new directions for the development of a new type of BC biomarkers. In this review, we describe the emerging miRNAs as BC biomarkers for different purposes, including diagnosis, prognosis and therapeutic response. miRNA expression profile changes with alteration of the tissue phenotype. This phenomenon is utilized to predict tumor diagnosis, cancer subclass, disease stage, prognosis and therapeutic response. We classified the miRNAs which are involved in bladder cancer according to malignant potential, chemoresistance, discrimination between normal to cancerous and clinical outcome. Focusing on the major obstacle regarding MIBC patient's NAC response, we summarized the miRNAs that are deregulated and have the potential to identify the patients resistant to NAC, such as miR-34, miR-100, miR-146b and miR-9 and miR-193a-3p. In conclusion, miRNAs expression profile of bladder cancer patient is a promising tool that can serve as biomarker for different aims. Based on this profile we propose upfront radical cystectomy instead of standard NAC to those MIBC patients who are at higher risk for chemoresistance and poor response.", "BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited cardiac disorder caused by mutations predominantly in the ryanodine receptor (RyR2) gene. We sought to identify mutations in genes affecting cardiac calcium cycling in patients with CPVT and in less typical familial exercise-related ventricular arrhythmias.METHODS AND RESULTS: We recruited 33 consecutive patients with frequent ventricular premature complexes (VPCs) without structural heart disease and often history of syncope or sudden death in family. Sixteen of the patients featured a phenotype typical of CPVT. In 17 patients, VPCs emerged also at rest. Exercise stress test and echocardiography were performed to each patient and 232 family members. Familial background was evident in 42% of cases (n = 14). We sequenced all the coding exons of the RyR2, FKBP1B, ATP2A2 and SLC8A1 genes from the index patients. Single channel recordings of a mutant RyR2 were performed in planar lipid bilayers. Two novel RyR2 missense mutations (R1051P and S616L) and two RyR2 exon 3 deletions were identified, explaining 25% of the CPVT phenotypes. A rare variant (N3308S) with open probabilities similar to the wild type channels in vitro, was evident in a patient with resting VPCs. No disease-causing variants were detectable in the FKBP1B, ATP2A2 or SLC8A1 genes.CONCLUSION: We report two novel CPVT-causing RyR2 mutations and a novel RyR2 variant of uncertain clinical significance in a patient with abundant resting VPCs. Our data also strengthen the previous assumption that exon 3 deletions of RyR2 should screened for in CPVT and related phenotypes.", "The combined use of electrospray ionization run in so-called \"native mode\" with top-down mass spectrometry (nTDMS) is enhancing both structural biology and discovery proteomics by providing three levels of information in a single experiment: the intact mass of a protein or complex, the masses of its subunits and non-covalent cofactors, and fragment ion masses from direct dissociation of subunits that capture the primary sequence and combinations of diverse post-translational modifications (PTMs). While intact mass data are readily deconvoluted using well-known software options, the analysis of fragmentation data that result from a tandem MS experiment - essential for proteoform characterization - is not yet standardized. In this tutorial, we offer a decision-tree for the analysis of nTDMS experiments on protein complexes and diverse bioassemblies. We include an overview of strategies to navigate this type of analysis, provide example data sets, and highlight software for the hypothesis-driven interrogation of fragment ions for localization of PTMs, metals, and cofactors on native proteoforms. Throughout we have emphasized the key features (deconvolution, search mode, validation, other) that the reader can consider when deciding upon their specific experimental and data processing design using both open-access and commercial software." ]

[ "Staphylococcal bi-component pore-forming toxins, also known as leukocidins, target and lyse human phagocytes in a receptor-dependent manner. S-components of the leukocidins Panton-Valentine leukocidin (PVL), γ-haemolysin AB (HlgAB) and CB (HlgCB), and leukocidin ED (LukED) specifically employ receptors that belong to the class of G-protein coupled receptors (GPCRs). Although these receptors share a common structural architecture, little is known about the conserved characteristics of the interaction between leukocidins and GPCRs. In this study, we investigated host cellular pathways contributing to susceptibility towards S. aureus leukocidin cytotoxicity. We performed a genome-wide CRISPR/Cas9 library screen for toxin-resistance in U937 cells sensitized to leukocidins by ectopic expression of different GPCRs. Our screen identifies post-translational modification (PTM) pathways involved in the sulfation and sialylation of the leukocidin-receptors. Subsequent validation experiments show differences in the impact of PTM moieties on leukocidin toxicity, highlighting an additional layer of refinement and divergence in the staphylococcal host-pathogen interface. Leukocidin receptors may serve as targets for anti-staphylococcal interventions and understanding toxin-receptor interactions will facilitate the development of innovative therapeutics. Variations in the genes encoding PTM pathways could provide insight into observed differences in susceptibility of humans to infections with S. aureus.", "Autophagy is a highly conserved process by which cells can recycle organelles and proteins by degrading them in the lysosomes. Although autophagy is considered a dynamic system responsible for cellular renovation and homeostasis under physiological conditions, it is increasingly clear that autophagy is directly relevant to clinical disease. During disease progression, autophagy not only serves as a cellular protective mechanism but also can represent a harmful event under certain conditions. In addition, although autophagy can act as a nonselective bulk degradation process, recent research shows that autophagy can selectively degrade specific proteins, organelles, and invading bacteria, in processes termed \"selective autophagy.\" Selective autophagy has drawn the attention of researchers because of its potential importance in clinical diseases. In this article, we outline the most recent studies implicating autophagy and selective autophagy in human lung diseases, including chronic obstructive pulmonary disease, pulmonary hypertension, idiopathic pulmonary fibrosis, and sepsis. We also discuss the relationship between autophagy and other molecular mechanisms related to disease progression, including programmed necrosis (necroptosis) and the inflammasome, an inflammatory signaling platform that regulates the secretion of IL-1β and IL-18. Finally, we examine the dual nature of autophagy and selective autophagy in the lung, which have both protective and injurious effects for human lung disease.", "Autophagy, a programmed process in which cell contents are delivered to lysosomes for degradation, appears to have both tumor-suppressive and tumor-promoting functions; both stimulation and inhibition of autophagy have been reported to induce cancer cell death, and particular genes and proteins have been associated both positively and negatively with autophagy. To provide a basis for incisive analysis of those complexities and ambiguities and to guide development of new autophagy-targeted treatments for cancer, we have compiled a comprehensive, curated inventory of autophagy modulators by integrating information from published siRNA screens, multiple pathway analysis algorithms, and extensive, manually curated text-mining of the literature. The resulting inventory includes 739 proteins and 385 chemicals (including drugs, small molecules, and metabolites). Because autophagy is still at an early stage of investigation, we provide extensive analysis of our sources of information and their complex relationships with each other. We conclude with a discussion of novel strategies that could potentially be used to target autophagy for cancer therapy.", "Organophosphate-induced delayed polyneuropathy (OPIDP) is a rare toxicity resulting from exposure to certain organophosphorus (OP) esters. It is characterised by distal degeneration of some axons of both the peripheral and central nervous systems occurring 1-4 weeks after single or short-term exposures. Cramping muscle pain in the lower limbs, distal numbness and paraesthesiae occur, followed by progressive weakness, depression of deep tendon reflexes in the lower limbs and, in severe cases, in the upper limbs. Signs include high-stepping gait associated with bilateral foot drop and, in severe cases, quadriplegia with foot and wrist drop as well as pyramidal signs. In time, there might be significant recovery of the peripheral nerve function but, depending on the degree of pyramidal involvement, spastic ataxia may be a permanent outcome of severe OPIDP. Human and experimental data indicate that recovery is usually complete in the young. At onset, the electrophysiological changes include reduced amplitude of the compound muscle potential, increased distal latencies and normal or slightly reduced nerve conduction velocities. The progression of the disease, usually over a few days, may lead to non-excitability of the nerve with electromyographical signs of denervation. Nerve biopsies have been performed in a few cases and showed axonal degeneration with secondary demyelination. Neuropathy target esterase (NTE) is thought to be the target of OPIDP initiation. The ratio of inhibitory powers for acetylcholinesterase and NTE represents the crucial guideline for the aetiological attribution of OP-induced peripheral neuropathy. In fact, pre-marketing toxicity testing in animals selects OP insecticides with cholinergic toxicity potential much higher than that to result in OPIDP. Therefore, OPIDP may develop only after very large exposures to insecticides, causing severe cholinergic toxicity. However, this was not the case with certain triaryl phosphates that were not used as insecticides but as hydraulic fluids, lubricants and plasticisers and do not result in cholinergic toxicity. Several thousand cases of OPIDP as a result of exposure to tri-ortho-cresyl phosphate have been reported, whereas the number of cases of OPIDP as a result of OP insecticide poisoning is much lower. In this article, we mainly discuss OP pesticide poisoning, particularly when caused by chlorpyrifos, dichlorvos, isofenphos, methamidophos, mipafox, trichlorfon, trichlornat, phosphamidon/mevinphos and by certain carbamates. We also discuss case reports where neuropathies were not convincingly attributed to fenthion, malathion, omethoate/dimethoate, parathion and merphos. Finally, several observational studies on long-term, low-level exposures to OPs that sometimes reported mild, inconsistent and unexplained changes of unclear significance in peripheral nerves are briefly discussed.", "OBJECTIVES: The purpose of this work was to assess the long-term outcome of adolescents with chronic fatigue syndrome who received cognitive behavioral therapy and to determine the predictive value of fatigue severity and physical impairments of the adolescent and the fatigue severity of the mother at baseline for the outcome of the treatment at follow-up.PATIENTS AND METHODS: Sixty-six adolescent patients with chronic fatigue syndrome who previously participated in a randomized, controlled trial that showed that cognitive behavioral therapy was more effective than a waiting-list condition in reducing fatigue and improving physical functioning were contacted for a follow-up assessment. Fifty participants of the follow-up study had received cognitive behavioral therapy for chronic fatigue syndrome (32 formed the cognitive behavioral therapy group in the original trial, and 18 patients received cognitive behavioral therapy after the waiting period). The remaining 16 patients had refused cognitive behavioral therapy after the waiting period. The main outcome measures were fatigue severity (Checklist Individual Strength), physical functioning (Short-Form General Health Survey), and school attendance.RESULTS: Data were complete for 61 patients at follow-up (cognitive behavioral therapy group: 47 patients; no-treatment group: 14 patients). The mean follow-up time was 2.1 years. There was no significant change in fatigue severity between posttreatment and follow-up in the cognitive behavioral therapy group. There was a significant further increase in physical functioning and school attendance (10% increase). The adolescents in the cognitive behavioral therapy group were significantly less fatigued and significantly less functionally impaired and had higher school attendance at follow-up than those in the no-treatment group. Fatigue severity of the mother was a significant predictor of treatment outcome.CONCLUSIONS: The positive effects of cognitive behavioral therapy in adolescents with chronic fatigue syndrome are sustained after cognitive behavioral therapy. Higher fatigue severity of the mother predicts lower treatment outcome in adolescent patients.", "Autophagy and the effects of its inhibition or induction were investigated during the entire infectious cycle of varicella-zoster virus (VZV), a human herpesvirus. As a baseline, we first enumerated the number of autophagosomes per cell after VZV infection compared with the number after induction of autophagy following serum starvation or treatment with tunicamycin or trehalose. Punctum induction by VZV was similar in degree to punctum induction by trehalose in uninfected cells. Treatment of infected cells with the autophagy inhibitor 3-methyladenine (3-MA) markedly reduced the viral titer, as determined by assays measuring both cell-free virus and infectious foci (P < 0.0001). We next examined a virion-enriched band purified by density gradient sedimentation and observed that treatment with 3-MA decreased the amount of VZV gE, while treatment with trehalose increased the amount of gE in the same band. Because VZV gE is the most abundant glycoprotein, we selected gE as a representative viral glycoprotein. To further investigate the role of autophagy in VZV glycoprotein biosynthesis as well as confirm the results obtained with 3-MA inhibition, we transfected cells with ATG5 small interfering RNA to block autophagosome formation. VZV-induced syncytium formation was markedly reduced by ATG5 knockdown (P < 0.0001). Further, we found that both expression and glycan processing of VZV gE were decreased after ATG5 knockdown, while expression of the nonglycosylated IE62 tegument protein was unchanged. Taken together, our cumulative results not only documented abundant autophagy within VZV-infected cells throughout the infectious cycle but also demonstrated that VZV-induced autophagy facilitated VZV glycoprotein biosynthesis and processing.", "Histatins are a group of small, cationic, antifungal peptides present in human saliva. A previous molecular modeling analysis suggested structural similarity between the Phe14-His15 and His18-His19 dipeptide sequences in histatin-5 (Hsn-5; a 24-amino-acid polypeptide) and the sequence of miconazole (one of the azole-based antifungal therapeutic agents), implying that the mechanisms of killing of Candida albicans by these two molecules may be similar. To further elaborate on this observation, we have produced two variants of Hsn-5 in which Phe14-His15 or His18-His19 dipeptide sequences were replaced by Ala-Ala (F14A/H15A and H18A/H19A) to eliminate the phenyl and imidazole rings of the side chains and assessed their candidacidal activities against C. albicans. In addition, we tested azole-resistant C. albicans and Candida glabrata strains for their susceptibilities to Hsn-5. Analysis of the purified recombinant proteins for their candidacidal activities indicated that both variants were significantly less effective (the molar concentrations required to kill half of the maximum number of cells [ED50s], approximately 67 and approximately 149 microM for F14A/H15A and H18A/H19A, respectively) than the unaltered Hsn-5 (ED50, approximately 8 microM) at killing C. albicans, suggesting that the two dipeptide sequences are important for the candidacidal activity of Hsn-5. Assessment of the candidacidal activity of Hsn-5 with the well-characterized azole-resistant strains of C. albicans and C. glabrata, however, suggested that the mode of action of histatins against Candida is distinct from that of azole-based antifungal agents because Hsn-5 kills both azole-sensitive and azole-resistant strains equally well.", "Chibby (Cby) is an evolutionarily conserved antagonist of beta-catenin, a central player of the canonical Wnt signaling pathway, which acts as a transcriptional coactivator. Cby physically interacts with the C-terminal activation domain of beta-catenin and blocks its transcriptional activation potential through competition with DNA-binding Tcf/Lef transcription factors. Our recent study revealed a second mechanism for Cby-mediated beta-catenin inhibition in which Cby cooperates with 14-3-3 adaptor proteins to facilitate nuclear export of beta-catenin, following phosphorylation of Cby by Akt kinase. Therefore, our findings unravel a novel molecular mechanism regulating the dynamic nucleo-cytoplasmic trafficking of beta-catenin and provide new insights into the cross-talk between the Wnt and Akt signaling pathways. Here, we review recent literature concerning Cby function and discuss our current understanding of the relationship between Wnt and Akt signaling.", "Cariprazine is an oral antipsychotic approved in the US and EU for the treatment of schizophrenia. Cariprazine differs from other antipsychotics in that it is a dopamine D3- and D2-receptor partial agonist, with tenfold higher affinity for D3 receptors than for D2 receptors. Cariprazine is metabolized in two steps by CYP3A4 to didesmethyl-cariprazine (DDCAR). DDCAR has a long half-life of 1-3 weeks and is the predominant circulating active moiety. Efficacy and safety in persons with acute schizophrenia were assessed in four similarly designed, short-term, randomized, placebo-controlled clinical trials in nonelderly adults, with three studies considered positive and yielding a number needed to treat vs placebo for response (change from baseline ≥30% in Positive and Negative Syndrome Scale total score) of ten for the approved dose range of cariprazine 1.5-6 mg/day. The most common adverse reactions were extrapyramidal symptoms (15% and 19% for 1.5-3 and 4.5-6 mg/day, respectively, vs 8% for placebo) and akathisia (9% and 12.5% for 1.5-3 and 4.5-6 mg/day, respectively, vs 4% for placebo). For the approved dose range, rates of discontinuation because of an adverse event were lower overall for patients receiving cariprazine vs placebo (9% vs 12%). Weight and metabolic profile appear favorable. Cariprazine does not increase prolactin levels or prolong the electrocardiographic QT interval. Cariprazine has also been found to be effective for the maintenance treatment of schizophrenia by delaying time to relapse when compared with placebo (HR 0.45). A 26-week randomized clinical trial evidenced superiority of cariprazine over risperidone for the treatment of predominantly negative symptoms in patients with schizophrenia. Cariprazine is also approved in the US for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults and is being studied for the treatment of bipolar I depression and major depressive disorder.", "The severe acute respiratory syndrome coronavirus (SARS-CoV) genome is predicted to encode 14 functional open reading frames, leading to the expression of up to 30 structural and non-structural protein products. The functions of a large number of viral ORFs are poorly understood or unknown. In order to gain more insight into functions and modes of action and interaction of the different proteins, we cloned the viral ORFeome and performed a genome-wide analysis for intraviral protein interactions and for intracellular localization. 900 pairwise interactions were tested by yeast-two-hybrid matrix analysis, and more than 65 positive non-redundant interactions, including six self interactions, were identified. About 38% of interactions were subsequently confirmed by CoIP in mammalian cells. Nsp2, nsp8 and ORF9b showed a wide range of interactions with other viral proteins. Nsp8 interacts with replicase proteins nsp2, nsp5, nsp6, nsp7, nsp8, nsp9, nsp12, nsp13 and nsp14, indicating a crucial role as a major player within the replication complex machinery. It was shown by others that nsp8 is essential for viral replication in vitro, whereas nsp2 is not. We show that also accessory protein ORF9b does not play a pivotal role for viral replication, as it can be deleted from the virus displaying normal plaque sizes and growth characteristics in Vero cells. However, it can be expected to be important for the virus-host interplay and for pathogenicity, due to its large number of interactions, by enhancing the global stability of the SARS proteome network, or play some unrealized role in regulating protein-protein interactions. The interactions identified provide valuable material for future studies.", "Anthracycline-based chemotherapy is the cornerstone of modern curative regimens for aggressive lymphomas; however, these drugs cannot be safely administered in the setting of severe hepatic dysfunction. Alternative regimens for this setting are required. We describe 2 patients with newly diagnosed advanced aggressive lymphoma (diffuse large B-cell lymphoma [DLBCL] and classic Hodgkin lymphoma [HL]) presenting with severe hepatic dysfunction with hyperbilirubinemia (4.3-13.2 mg/dL). Because of the inability to safely administer unattenuated doses of anthracycline-based regimens, dexamethasone, high-dose cytarabine, and cisplatin (DHAP) was used at full doses (along with rituximab for the DLBCL patient) until hepatic function normalized (1-5 cycles). The treatment was then converted to R-CHOP (rituximab/cyclophosphamide/ doxorubicin/vincristine/prednisone) and ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) for the DLBCL and HL patient, respectively, to complete therapy. The patients had a partial remission and complete remission, respectively. These data suggest that DHAP is a safe and effective regimen that can be used without dose modification as part of initial therapy in the setting of aggressive lymphoma and hepatic failure. The literature on the use of treatment regimens for aggressive lymphoma in the setting of hepatic dysfunction is reviewed.", "Exacerbations of chronic obstructive pulmonary disease (COPD) are an important cause of morbidity and healthcare expenditure. In hospitalized patients, antibiotics decrease treatment failure and reduce mortality. There is also evidence for the effectiveness of antibiotics in treating COPD exacerbations in the community, but this is most convincing in patients with severe airflow obstruction and there is uncertainty regarding the value of antibiotics in patients with mild airflow obstruction. Treatment with antibiotics is usually recommended for patients who have an increase in sputum volume, sputum purulence and breathlessness, but the most important determinant of bacterial infection appears to be purulence. There is some evidence to suggest that the decision to use antibiotics can be guided by the use of procalcitonin, although this needs to be confirmed in further studies. Newer broad-spectrum antibiotics may be more effective than older antibiotics but, because of concerns regarding antibiotic resistance, it may be appropriate to reserve them for patients at highest risk of treatment failure. A number of studies suggest that antibiotic courses of 5 days in duration may be as effective as those for 7 days or more in patients with mild-to-moderate exacerbations of COPD. Guidelines do not recommend the use of prophylactic antibiotics in COPD but there is preliminary evidence to suggest that they may reduce the number of exacerbations. Until the full results of these studies are published, it will not be clear if they should be used.", "Mutations in NOTCH3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary angiopathy causing stroke and vascular dementia. All CADASIL mutations identified so far result in the loss or gain of one cysteine residue within epidermal growth factor (EGF)-like repeat domains. Here an in-frame deletion causing a loss of three cysteine residues within EGF repeat 6 is reported. These data are consistent with the hypothesis that the change toward an odd number of cysteine residues within a given EGF repeat and therefore an unpaired, reactive cysteine residue is the common and critical molecular event in CADASIL.", "Autophagy (macroautophagy) is a dynamic process for degradation of cytosolic components. Autophagy has intracellular anti-viral and anti-bacterial functions, and plays a role in the initiation of innate and adaptive immune system responses to viral and bacterial infections. Some viruses encode virulence factors for blocking autophagy, whereas others utilize some autophagy components for their intracellular growth or cellular budding. The \"core\" autophagy-related (Atg) complexes in mammals are ULK1 protein kinase, Atg9-WIPI-1 and Vps34-beclin1 class III PI3-kinase complexes, and the Atg12 and LC3 conjugation systems. In addition, PI(3)-binding proteins, PI3-phosphatases, and Rab proteins contribute to autophagy. The autophagy process consists of continuous dynamic membrane formation and fusion. In this review, the relationships between these Atg complexes and each process are described. Finally, the critical points for monitoring autophagy, including the use of GFP-LC3 and GFP-Atg5, are discussed.", "AIM: To investigate the effects of mammalian target of rapamycin (mTOR) inhibition on liver regeneration and autophagy in a surgical resection model.METHODS: C57BL/6 mice were subjected to a 70% partial hepatectomy (PH) and treated intraperitoneally every 24 h with a combination of the mTOR inhibitor rapamycin (2.5 mg/kg per day) and the steroid dexamethasone (2.0 mg/kg per day) in phosphate buffered saline (PBS) or with PBS alone as vehicle control. In the immunosuppressant group, part of the group was treated subcutaneously 4 h prior to and 24 h after PH with a combination of human recombinant interleukin 6 (IL-6; 500 μg/kg per day) and hepatocyte growth factor (HGF; 100 μg/kg per day) in PBS. Animals were sacrificed 2, 3 or 5 d after PH and liver tissue and blood were collected for further analysis. Immunohistochemical staining for 5-Bromo-2'-deoxyuridine (BrdU) was used to quantify hepatocyte proliferation. Western blotting was used to detect hepatic microtubule-associated protein 1 light chain 3 (LC3)-II protein expression as a marker for autophagy. Hepatic gene expression levels of proliferation-, inflammation- and angiogenesis-related genes were examined by real-time reverse transcription-polymerase chain reaction and serum bilirubin and transaminase levels were analyzed at the clinical chemical core facility of the Erasmus MC-University Medical Center.RESULTS: mTOR inhibition significantly suppressed regeneration, shown by decreased hepatocyte proliferation (2% vs 12% BrdU positive hepatocyte nuclei at day 2, P < 0.01; 0.8% vs 1.4% at day 5, P = 0.02) and liver weight reconstitution (63% vs 76% of initial total liver weight at day 3, P = 0.04), and furthermore increased serum transaminase levels (aspartate aminotransferase 641 U/L vs 185 U/L at day 2, P = 0.02). Expression of the autophagy marker LC3-II, which was reduced during normal liver regeneration, increased after mTOR inhibition (46% increase at day 2, P = 0.04). Hepatic gene expression showed an increased inflammation-related response [tumor necrosis factor (TNF)-α 3.2-fold upregulation at day 2, P = 0.03; IL-1Ra 6.0-fold upregulation at day 2 and 42.3-fold upregulation at day 5, P < 0.01] and a reduced expression of cell cycle progression and angiogenesis-related factors (HGF 40% reduction at day 2; vascular endothelial growth factor receptor 2 50% reduction at days 2 and 5; angiopoietin 1 60% reduction at day 2, all P ≤ 0.01). Treatment with the regeneration stimulating cytokine IL-6 and growth factor HGF could overcome the inhibitory effect on liver weight (75% of initial total liver weight at day 3, P = 0.02 vs immunosuppression alone and P = 0.90 vs controls) and partially reversed gene expression changes caused by rapamycin (TNF-α and IL-1Ra levels at day 2 were restored to control levels). However, no significant changes in hepatocyte proliferation, serum injury markers or autophagy were found.CONCLUSION: mTOR inhibition severely impairs liver regeneration and increases autophagy after PH. These effects are partly reversed by stimulation of the IL-6 and HGF pathways.", "Autophagy is a lysosome-mediated catabolic process involving the degradation of intracellular contents (e.g., proteins and organelles) as well as invading microbes (e.g., parasites, bacteria and viruses). Multiple forms of cellular stress can stimulate this pathway, including nutritional imbalances, oxygen deprivation, immunological response, genetic defects, chromosomal anomalies and cytotoxic stress. Damage-associated molecular pattern molecules (DAMPs) are released by stressed cells undergoing autophagy or injury, and act as endogenous danger signals to regulate the subsequent inflammatory and immune response. A complex relationship exists between DAMPs and autophagy in cellular adaption to injury and unscheduled cell death. Since both autophagy and DAMPs are important for pathogenesis of human disease, it is crucial to understand how they interplay to sustain homeostasis in stressful or dangerous environments.", "Oncogene-induced senescence (OIS) is a highly dynamic process, involving several different effector mechanisms, the multitude and combination of which likely determines the quality of the phenotype (Pérez-Mancera et al., Nat Rev Cancer 14:547-558, 2014). Autophagy, a cellular degradation process, has been proposed to be one of these senescence effectors, although its functional relevance seems highly context dependent (Hoare et al., Semin Cancer Biol 21:397-404, 2011). A number of methods for monitoring autophagy are available, and several excellent protocols have been published in this journal (Klionsky et al., Autophagy 8:445-544, 2012; Tooze et al., Methods Mol Biol 1270:155-165, 2015; Tabata et al., Methods Mol Biol 931:449-466, 2013; Young and Tooze, Methods Mol Biol 445:147-157, 2008). The same principles apply to models of OIS in culture. Thus, in this chapter, we describe how to generate OIS cells using human diploid fibroblasts (HDFs), the best-characterized cell model of OIS, and how to detect autophagy, particularly focusing on immunofluorescence methods.", "OBJECTIVE: Cerebral vasospasm is a major source of morbidity and mortality following aneurysmal subarachnoid hemorrhage (SAH). A variety of therapies have been utilized to prevent or treat vasospasm. Despite the large number of clinical trials, few randomized controlled trials (RCTs) of sufficient quality have been published. We review the RCTs and meta-analyses in the literature regarding the treatment and prevention of cerebral vasospasm following aneurysmal SAH.METHODS: A literature search of MEDLINE, the Cochrane Controlled Trials Registry, and the National Institutes of Health/National Library of Medicine clinical trials registry was performed in January 2010 using predefined search terms. These trials were critically reviewed and categorized based on therapeutic modality.RESULTS: Forty-four RCTs and 9 meta-analyses met the search criteria. Significant findings from these trials were analyzed. The results of this study were as follows: nimodipine demonstrated benefit following aneurysmal SAH; other calcium channel blockers, including nicardipine, do not provide unequivocal benefit; triple-H therapy, fasudil, transluminal balloon angioplasty, thrombolytics, endothelin receptor antagonists, magnesium, statins, and miscellaneous therapies such as free radical scavengers and antifibrinolytics require additional study. Tirilazad is ineffective.CONCLUSIONS: There are many possible successful treatment options for preventing vasospasm, delayed ischemic neurologic deficits, and poor neurologic outcome following aneurysmal subarachnoid hemorrhage; however, further multicenter RCTs need to be performed to determine if there is a significant benefit from their use. Nimodipine is the only treatment that provided a significant benefit across multiple studies.", "BACKGROUND: B-cell prolymphocytic leukemias or T-cell prolymphocytic leukemias are aggressive variants of chronic lymphoid leukemias. The small studies conducted to date have shown median survival durations of approximately 3 years for patients who have B-cell prolymphocytic leukemia and 7.5 months for those who have T-cell prolymphocytic leukemia, compared with about 8 years for patients who have chronic lymphocytic leukemia. In chronic lymphocytic leukemia, chemotherapy consisting of alkylating agents such as cyclophosphamide and chlorambucil combined with prednisone has achieved overall response rates of 50% to 70%, but this regimen has resulted in response rates of less than 25% in prolymphocytic leukemia. Pentostatin (2'-deoxycoformycin; DCF) is a purine analogue that has shown activity in treatment of chronic lymphoid malignancies.PURPOSE: This prospective phase II trial by the Leukemia Cooperative Group of the European Organization for Research and Treatment of Cancer was performed to assess the activity and toxicity of DCF in prolymphocytic leukemia.METHODS: Twenty patients with B-cell or T-cell prolymphocytic leukemia were given DCF at a dosage of 4 mg/m2 intravenously once a week for 3 weeks, then every other week for three doses. Patients who had at least partial response received maintenance therapy once a month for a maximum of 6 months. Fourteen patients had B-cell prolymphocytic leukemia, and six had T-cell prolymphocytic leukemia, as evidenced by morphologic and immunologic criteria; three were previously untreated, eight had been given one or two chemotherapeutic regimens, and nine had been given more than two.RESULTS: One patient died of an unknown cause during the first 6 weeks of treatment, and one died of disseminated toxoplasmosis during the period of maintenance therapy, 5 months after achieving partial remission. Nine (45% response rate) of the 20 patients achieved partial remission, including seven (50%) of 14 with B-cell prolymphocytic leukemia and two (33%) of six with T-cell prolymphocytic leukemia. The median duration of response was 9 months (range, 2-30 months); for patients with B-cell prolymphocytic leukemia, the median remission duration was 12 months. No complete remission was observed. Toxic effects included nausea and vomiting (30%), infections (30%), and transient increase in liver enzymes (35%) and in creatinine (20%) levels. Eight patients experienced thrombocytopenia, the major hematologic toxic effect; four had grade 3 or 4 toxic effects.CONCLUSION: DCF is active in prolymphocytic leukemia, even as salvage therapy in patients who had received multiple prior chemotherapeutic regimens.IMPLICATIONS: Trials using DCF or other purine analogues alone or in combination with standard chemotherapeutic agents in front-line or salvage therapy are warranted to improve the prognosis of patients with prolymphocytic leukemia.", "Rett syndrome (RTT) is a neurodevelopmental disorder, which almost exclusively affects girls, who, after an initial period of apparently normal development, display gradual loss of speech and purposeful hand use, gait abnormalities and stereotypical hand movements. In the year 2000, mutations in the gene for the methyl CpG binding protein 2, MECP2, have been identified in 35-80% of the patients in three different studies. We have identified 15 different MECP2 mutations in 26 of 30 Danish RTT patients. The mutations included five novel mutations (one point mutation, three smaller deletions involving identical regions in the gene, and one duplication). In contrast to the point mutations and the duplication, which all affect the methyl binding domain or the transcriptional repressing domain, the three overlapping deletions are clustered in the 3' end of the gene. We found no consistent correlation between the type of mutation and the clinical presentation of the patient or the X-inactivation pattern in peripheral blood. Our high mutation detection rate, compared to two of the previous studies, underscores the importance of the inclusion criteria of the patients and supports that MECP2 is the most important, if not the only, gene responsible for RTT.", "The large majority of mitochondrial DNA (mtDNA) deletions analyzed from mitochondrial myopathies and aging humans have been found to be flanked by direct repeats, a finding which has led to the slip-replication hypothesis of deletion formation. In this study, we have characterized 13 mtDNA deletion breakpoints from skeletal muscle harvested from 9- to 27-year-old rhesus monkeys. Seven of the deletions, five of which were unique to a particular animal, did not have direct repeats at the deletion breakpoints. In contrast, two of the three deletions common to several animals had direct repeats flanking the breakpoints. It appears, therefore, that at least two different mechanisms exist by which mtDNA deletions are formed during aging, one requiring and one independent of flanking direct repeats. Furthermore, the species in which mtDNA deletions are detected may determine which mechanism predominates.", "Southern tick-associated rash illness is a Lyme-like syndrome that occurs in the southern states. Borrelia lonestari, which has been suggested as a possible causative agent of southern tick-associated rash illness, naturally infects white-tailed deer (WTD; Odocoileus virginianus) and is transmitted by the lone star tick (Amblyomma americanum). To better understand the prevalence and distribution of Borrelia exposure among WTD, we tested WTD from 21 eastern states for antibodies reactive to B. lonestari using an indirect immunofluorescent antibody assay and Borrelia burgdorferi using the IDEXX SNAP 4Dx test. A total of 107/714 (15%) had antibodies reactive to B. lonestari, and prevalence of antibodies was higher in deer from southern states (17.5%) than in deer from northern states (9.2%). Using the SNAP 4DX test, we found that 73/723 (10%) were positive for B. burgdorferi, and significantly more northern deer (23.9%) were positive compared with southern deer (3.8%). Our data demonstrate that WTD are exposed to both Borrelia species, but antibody prevalence for exposure to the two species differs regionally and distributions correlate with the presence of Ixodes scapularis and A. americanum ticks.", "MOTIVATION: New sequencing technologies generate larger amount of short reads data at decreasing cost. De novo sequence assembly is the problem of combining these reads back to the original genome sequence, without relying on a reference genome. This presents algorithmic and computational challenges, especially for long and repetitive genome sequences. Most existing approaches to the assembly problem operate in the framework of de Bruijn graphs. Yet, a number of recent works use the paradigm of string graph, using a variety of methods for storing and processing suffixes and prefixes, like suffix arrays, the Burrows-Wheeler transform or the FM index. Our work is motivated by a search for new approaches to constructing the string graph, using alternative yet simple data structures and algorithmic concepts.RESULTS: We introduce a novel hash-based method for constructing the string graph. We use incremental hashing, and specifically a modification of the Karp-Rabin fingerprint, and Bloom filters. Using these probabilistic methods might create false-positive and false-negative edges during the algorithm's execution, but these are all detected and corrected. The advantages of the proposed approach over existing methods are its simplicity and the incorporation of established probabilistic techniques in the context of de novo genome sequencing. Our preliminary implementation is favorably comparable with the first string graph construction of Simpson and Durbin (2010) (but not with subsequent improvements). Further research and optimizations will hopefully enable the algorithm to be incorporated, with noticeable performance improvement, in state-of-the-art string graph-based assemblers.", "Autophagy, an intracellular degradation process highly conserved from yeast to humans, is viewed as an important defence mechanism to clear intracellular bacteria. However, recent work has shown that autophagy may have different roles during different bacterial infections that restrict bacterial replication (antibacterial autophagy), act in cell autonomous signalling (non-bacterial autophagy) or support bacterial replication (pro-bacterial autophagy). This review will focus on newfound interactions of autophagy and pathogenic bacteria, highlighting that, in addition to delivering bacteria to the lysosome, autophagy responding to bacterial invasion may have a much broader role in mediating disease outcome.", "The viral infectivity factor (Vif) is essential for the productive infection and dissemination of HIV-1 in non-permissive cells that involve most natural HIV-1 target cells. Vif counteracts the packaging of two cellular cytidine deaminases named APOBEC3G (A3G) and A3F by diverse mechanisms including the recruitment of an E3 ubiquitin ligase complex and the proteasomal degradation of A3G/A3F, the inhibition of A3G mRNA translation or by a direct competition mechanism. In addition, Vif appears to be an active partner of the late steps of viral replication by participating in virus assembly and Gag processing, thus regulating the final stage of virion formation notably genomic RNA dimerization and by inhibiting the initiation of reverse transcription. Vif is a small pleiotropic protein with multiple domains, and recent studies highlighted the importance of Vif conformation and flexibility in counteracting A3G and in binding RNA. In this review, we will focus on the oligomerization and RNA chaperone properties of Vif and show that the intrinsic disordered nature of some Vif domains could play an important role in virus assembly and replication. Experimental evidence demonstrating the RNA chaperone activity of Vif will be presented.", "Autophagy, a form of lysosomal degradation capable of eliminating dysfunctional proteins and organelles, is a cellular process associated with homeostasis. Autophagy functions in cell survival by breaking down proteins and organelles and recycling them to meet metabolic demands. However, aberrant up regulation of autophagy can function as an alternative to apoptosis. The duality of autophagy, and its regulation over cell survival/death, intimately links it with human disease. Non-coding RNAs regulate mRNA levels and elicit diverse effects on mammalian protein expression. The most studied non-coding RNAs to-date are microRNAs (miRNA). MicroRNAs function in post-transcriptional regulation, causing profound changes in protein levels, and affect many biological processes and diseases. The role and regulation of autophagy, whether it is beneficial or harmful, is a controversial topic in cardiovascular disease. A number of recent studies have identified miRNAs that target autophagy-related proteins and influence the development, progression, or treatment of cardiovascular disease. Understanding the mechanisms by which these miRNAs work can provide promising insight and potential progress towards the development of therapeutic treatments in cardiovascular disease.", "The landscape of systemic treatment for metastatic renal cell carcinoma (RCC) has dramatically changed with the introduction of targeted agents including vascular endothelial growth factor (VEGF) inhibitors. Recently, multiple new agents including growth factor receptor antagonists and a checkpoint inhibitor were approved for the treatment of refractory metastatic RCC based on encouraging benefit shown in clinical trials. Areas covered: The background and biological rationale of existing treatment options including a brief discussion of clinical trials which led to their approval, is presented. This is followed by reviewing the limitations of these therapeutic options, medical need to develop new treatments and major goals of ongoing research. We then discuss two recently approved growth factor receptor antagonists i.e. cabozantinib and lenvatinib, and a recently approved checkpoint inhibitor, nivolumab, and issues pertaining to drug development, and future directions in treatment of metastatic RCC. Expert opinion: Recently approved growth factor receptor antagonists have shown encouraging survival benefit but associated drug toxicity is a major issue. Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, has similarly shown survival benefit and is well tolerated. With multiple options now available in this patient population, the right sequence of these agents remains to be determined.", "BACKGROUND: Heated, humidified, high-flow nasal cannula oxygen therapy (HHHFNC) has been used to improve ventilation in preterm infants. There are no data on airway pressures generated and efficacy in bronchiolitis.OBJECTIVE: The objective of this study was to determine nasopharyngeal (NP) pressures generated with HHHFNC therapy in bronchiolitis.METHODS: We conducted a prospective, observational study to measure NP pressures at varying flow rates of HHHFNC therapy in moderate to severe bronchiolitis. Vital signs, bronchiolitis severity scores, and oxygen saturation were also noted.RESULTS: Twenty-five patients were enrolled (mean, 78.1 [SD, 30.9] days; weight, 5.3 [SD, 1.1] kg). Nasopharyngeal pressures increased linearly with flow rates up to 6 L/min. Beyond 6 L/min, pressure increase was linear but less accelerated. On average, NP pressure increased by 0.45 cm H2O for each 1-L/min increase in flow rate. There were significant differences between pressures in open- and closed-mouth states for flow rates up to 6 L/min. At 6 L/min, the pressure in open-mouth state was 2.47 cm H2O and that in closed-mouth state was 2.74 cm H2O (P < 0.001). Linear regression analysis revealed that only flow (not weight or gender) had an effect on generated pressure. Bronchiolitis severity scores improved significantly with HHHFNC therapy (pre: 14.5 [SD, 1.4], post: 10.4 [SD, 1.2]; P < 0.001).CONCLUSIONS: Increasing flow rates of HHHFNC therapy are associated with linear increases in NP pressures in bronchiolitis patients. Larger studies are needed to assess the clinical efficacy of HHHFNC therapy in bronchiolitis.", "Hepatic mesenchymal hamartoma is a rare benign tumour in children. It is often large and centrally located in the liver at diagnosis, making surgical resection difficult; thus non-radical resection has been proposed in the past as acceptable management. However, a literature survey and a case with recurrence associated with cytogenetic anomalies suggest that radical liver surgery (resection with a margin of normal liver parenchyma, as for malignant tumour) should be recommended for mesenchymal hamartoma.", "Autophagy is a cellular process that targets proteins, lipids and organelles to lysosomes for degradation, but it has also been shown to combat infection with various pathogenic bacteria. In turn, bacteria have developed diverse strategies to avoid autophagy by interfering with autophagy signalling or the autophagy machinery and, in some cases, they even exploit autophagy for their growth. In this Review, we discuss canonical and non-canonical autophagy pathways and our current knowledge of antibacterial autophagy, with a focus on the interplay between bacterial factors and autophagy components.", "BACKGROUND: Due to its overarching role in genome function, sequence-dependent DNA curvature continues to attract great attention. The DNA double helix is not a rigid cylinder, but presents both curvature and flexibility in different regions, depending on the sequence. More in depth knowledge of the various orders of complexity of genomic DNA structure has allowed the design of sophisticated bioinformatics tools for its analysis and manipulation, which, in turn, have yielded a better understanding of the genome itself. Curved DNA is involved in many biologically important processes, such as transcription initiation and termination, recombination, DNA replication, and nucleosome positioning. CpG islands and tandem repeats also play significant roles in the dynamics and evolution of genomes.RESULTS: In this study, we analyzed the relationship between these three structural features within rice (Oryza sativa) and Arabidopsis (Arabidopsis thaliana) genomes. A genome-scale prediction of curvature distribution in rice and Arabidopsis indicated that most of the chromosomes of both genomes have maximal chromosomal DNA curvature adjacent to the centromeric region. By analyzing tandem repeats across the genome, we found that frequencies of repeats are higher in regions adjacent to those with high curvature value. Further analysis of CpG islands shows a clear interdependence between curvature value, repeat frequencies and CpG islands. Each CpG island appears in a local minimal curvature region, and CpG islands usually do not appear in the centromere or regions with high repeat frequency. A statistical evaluation demonstrates the significance and non-randomness of these features.CONCLUSIONS: This study represents the first systematic genome-scale analysis of DNA curvature, CpG islands and tandem repeats at the DNA sequence level in plant genomes, and finds that not all of the chromosomes in plants follow the same rules common to other eukaryote organisms, suggesting that some of these genomic properties might be considered as specific to plants.", "Melioidosis, an infectious disease caused by the Gram-negative bacterium Burkholderia pseudomallei, is now recognized as an important public health problem in Southeast Asia and tropical northern Australia. Although B. pseudomallei has been detected in various water and soil samples in southeast China, the enviromental distribution of B. pseudomallei in China is unclear. In the winter months of 2007, 154 and 130 soil and water samples, respectively, were collected from several locations in Guangxi, China. The samples were screened for B. pseudomallei by bacterial culture and identification and confirmed by PCR for species-specific 16S rDNA and flagellin genes. B. pseudomallei was detected in 8.4% of the soil samples but in none of the water samples. All positive samples were confined to a single low-lying region from rice paddy fields. Counts of B. pseudomallei ranged from 23 to 521 c.f.u./g soil. This is the first geographical distribution survey of B. pseudomallei in soil in Guangxi, China, and the data are of importance for further evaluating the impact of this pathogen on melioidosis in this region.", "Steroid 5-alpha-reductase 2 deficiency is a rare disorder leading to male pseudohermaphroditism, a condition characterized by incomplete differentiation of male genitalia in 46,XY patients. Here, we report a case of a 21-year-old woman from Ardabil who presented with primary amenorrhea, ambiguous genitalia, and lack of breast development. All of the serum hormone profiles were normal except for raised serum total testosterone. Testosterone to DHT ratio (T/DHT) was elevated before (15.72) and further increased after hCG stimulation (32.46). A chromosomal study revealed a 46,XY karyotype. A bilateral gonadectomy, recessive cliteroplasty, urethroplasty, and vaginoplasty were performed and hormonal replacement therapy using estrogen was started. In conclusion, the diagnosis of 5-alpha-reductase 2 deficiency may be suspected in infants with ambiguous genitalia or in adolescents or young adults with the characteristic phenotype and serum hormone profiles.", "Publisher: El déficit de vitamina B12 es una de las complicaciones más importantes que puede producir el vegetarianismo. Los lactantes hijos de madres vegetarianas tienen riesgo aumentado de deficiencia y de presentar compromiso neurológico irreversible si esta no se identifica y corrige adecuadamente. Se describe el caso de un lactante de un mes y veinte días que consultó por episodios paroxísticos de mecanismo epileptógeno, en el cual los estudios complementarios permitieron identificar un déficit de vitamina B12 como causa de estos. Tras la confirmación diagnóstica, se instauró el tratamiento con vitamina B12 intramuscular, con remisión completa de los síntomas, buena evolución posterior y desarrollo psicomotor sin alteraciones. Teniendo en cuenta las tendencias alimentarias actuales, es necesario incorporar, en la práctica clínica habitual, la anamnesis nutricional materna detallada para detectar precozmente el riesgo de déficit de esta vitamina y prevenirlo.", "BACKGROUND: Long noncoding RNAs (lncRNAs) are more than 200 nucleotides in length and lack transcriptional ability. The biological function of lncRNAs in oral squamous cell carcinoma (OSCC) remains unclear. The aim of this study was to identify the dysfunction of lncRNA in OSCC.RESULTS: We analyzed the transcriptome profiles of human OSCC tissues and paired adjacent normal tissues from two patients through a next-generation sequencing approach. A total of 14 lncRNAs were upregulated (fold change ≥3) and 13 were downregulated (fold change ≤-3) in OSCC tissues compared with the adjacent normal tissues. SOX21-AS1 was subjected to further analysis, revealing that the expression levels of SOX21-AS1 significantly decreased in OSCC compared with the adjacent normal tissue. The promoter activity of SOX21-AS1 was obviously suppressed by in vitro methylation. The DNA methylation status of the SOX21-AS1 promoter was analyzed using combined bisulfite restriction analysis, revealing that the aberrant promoter hypermethylation of SOX21-AS1 was observed frequently in OSCC tissues. The effects of SOX21-AS1 on cell proliferation and invasion were examined through transient transfection. Our data showed that SOX21-AS1 could significantly suppress oral cancer cell growth and invasion. Furthermore, the low expression level of SOX21-AS1 was significantly correlated with an advanced stage (P = 0.047), large tumor size (P = 0.033), and poor disease-specific survival in OSCC patients (P = 0.002).CONCLUSIONS: SOX21-AS1 was identified as susceptible dysfunction correlated with promoter hypermethylation in OSCC. Low SOX21-AS1 expression may be an adverse prognostic biomarker for OSCC.", "Stress signals elicit a wide variety of cellular responses, many of which converge on the phosphorylation of JNK and p38 kinases, the activation of which has been well-characterized. How these kinases are switched off by dephosphorylation is not well understood. Here we describe how diverse cellular stresses affect differently the stability and activity of a JNK-inactivating dual-specificity threonine-tyrosine phosphatase M3/6. Both anisomycin and arsenite activate the JNK pathway and, in addition, inactivate the M3/6 phosphatase. However, while anisomycin treatment of cells leads to M3/6 protein degradation, arsenite appears to inactivate M3/6 directly. These results might have implications for the mechanism of tumour promotion by arsenic.", "Japanese encephalitis virus (JEV), an enveloped Flavivirus with a positive-sense RNA genome, causes acute encephalitis with high mortality in humans. We used a virulent (RP-9) and an attenuated (RP-2ms) JEV strain to assess the role of autophagy in JEV infection. By monitoring the levels of lipidated LC3, we found that autophagy was induced in human NT-2 cells infected with RP-2ms, especially at the late stage, and to a lesser extent with RP-9. The induction of autophagy by rapamycin increased viral production, whereas the inhibition of autophagy by 3-methyladenine reduced viral yields for both RP-9 and RP-2ms. The viral replication of RP-9 and RP-2ms was also reduced in cells with downregulated ATG5 or Beclin 1 expression, suggesting a proviral role of autophagy in JEV replication. To determine the step of JEV life cycle affected by autophagy, we used an mCherry-LC3 fusion protein as the autophagosome marker. Little of no colocalization of LC3 puncta with dsRNA was noted, whereas the input JEV particles were targeted to autophagosomes stained positive for early endosome marker. Overall, we show for the first time that the cellular autophagy process is involved in JEV infection and the inoculated viral particles traffic to autophagosomes for subsequent steps of viral infection.", "Early secretory and endoplasmic reticulum (ER)-localized proteins that are terminally misfolded or misassembled are degraded by a ubiquitin- and proteasome-mediated process known as ER-associated degradation (ERAD). Protozoan pathogens, including the causative agents of malaria, toxoplasmosis, trypanosomiasis, and leishmaniasis, contain a minimal ERAD network relative to higher eukaryotic cells, and, because of this, we observe that the malaria parasite Plasmodium falciparum is highly sensitive to the inhibition of components of this protein quality control system. Inhibitors that specifically target a putative protease component of ERAD, signal peptide peptidase (SPP), have high selectivity and potency for P. falciparum. By using a variety of methodologies, we validate that SPP inhibitors target P. falciparum SPP in parasites, disrupt the protein's ability to facilitate degradation of unstable proteins, and inhibit its proteolytic activity. These compounds also show low nanomolar activity against liver-stage malaria parasites and are also equipotent against a panel of pathogenic protozoan parasites. Collectively, these data suggest ER quality control as a vulnerability of protozoan parasites, and that SPP inhibition may represent a suitable transmission blocking antimalarial strategy and potential pan-protozoan drug target.", "BACKGROUND: The mechanism of reflex pupillary dilation was investigated in eight patients who were declared brain dead after rupture of intracranial vascular malformations and in eight awake volunteers. The authors hypothesized that the reflex was primarily a spinal sympathetic reflex that would be blocked by topical application of the alpha1-adrenergic blocking agent dapiprazole and that it would be present in organ donors with intact spinal reflexes and no history of hypoxia.METHODS: In volunteers, pupil size was measured with an infrared pupillometer while brief painful electric stimuli were delivered to the finger. Pain was assessed with a visual analog scale and adjusted with each volunteer to equal 3 on a visual analog scale of 0-10. Subjects were studied before and after topical application of the alpha1-adrenergic antagonist dapiprazole. In organ donors, the authors measured pupil size after high-intensity tetanic electric stimulation and in dapiprazole-blocked and -unblocked pupils after surgically induced nociception.RESULTS: In volunteers, the pupil dilated 0.43 +/- 0.23 mm after nociceptive stimuli. Dapiprazole eyedrops blocked this dilation, confirming that the reflex in awake humans is primarily a sympathetic reflex. Baseline diameters were 5.7 +/- 0.5 mm before dapiprazole and 4.1 +/- 0.9 mm after dapiprazole. In organ donors, a tetanic electric current failed to dilate the pupil, whereas the skin incision dilated the pupil 0.4 +/- 0.4 mm, but this dilation was not blocked by dapiprazole.CONCLUSION: The authors conclude that pupillary reflex dilation, as it is clinically performed in awake subjects by stimulating somatic nociceptors, is a sympathetic reflex. Because it is not present in organ donors, the neural pathway must require a supraspinal component for completion.", "Zinc finger proteins are a massive, diverse family of proteins that serve a wide variety of biological functions. However, the roles of them during meiosis are not yet clearly defined. Here, we report that Zfp207 localizes at the kinetochores during mouse oocyte meiotic maturation. Depletion of Zfp207 leads to a significantly higher proportion of impaired spindle organization and misaligned chromosomes in oocytes. This is coupled with the defective kinetochore-microtubule attachments, and resultantly increasing incidence of aneuploid metaphase II eggs. The precocious polar body extrusion and escape of metaphase I arrest induced by nocodazole treatment in Zfp207-depleted oocytes indicates that Zfp207 is essential for activation of SAC (Spindle Assembly Checkpoint) activity. Notably, we find that Zfp207 binds to Bub3 to form a complex and maintains its protein level in oocytes, and that overexpression of Bub3 is able to partially rescue the occurrence of aneuploid eggs in Zfp207-depleted oocytes. Collectively, we identify Zfp207 as a novel Bub3 binding protein in oocytes which plays an important role in controlling meiotic chromosome alignment and SAC function." ]

[ "With the avalanche of biological sequences generated in the post-genomic age, one of the most challenging problems in computational biology is how to effectively formulate the sequence of a biological sample (such as DNA, RNA or protein) with a discrete model or a vector that can effectively reflect its sequence pattern information or capture its key features concerned. Although several web servers and stand-alone tools were developed to address this problem, all these tools, however, can only handle one type of samples. Furthermore, the number of their built-in properties is limited, and hence it is often difficult for users to formulate the biological sequences according to their desired features or properties. In this article, with a much larger number of built-in properties, we are to propose a much more flexible web server called Pse-in-One (http://bioinformatics.hitsz.edu.cn/Pse-in-One/), which can, through its 28 different modes, generate nearly all the possible feature vectors for DNA, RNA and protein sequences. Particularly, it can also generate those feature vectors with the properties defined by users themselves. These feature vectors can be easily combined with machine-learning algorithms to develop computational predictors and analysis methods for various tasks in bioinformatics and system biology. It is anticipated that the Pse-in-One web server will become a very useful tool in computational proteomics, genomics, as well as biological sequence analysis. Moreover, to maximize users' convenience, its stand-alone version can also be downloaded from http://bioinformatics.hitsz.edu.cn/Pse-in-One/download/, and directly run on Windows, Linux, Unix and Mac OS.", "The glandular kallikrein family is composed of structurally related serine proteases. Studies show that the mouse family encompasses at least 14 highly conserved functional genes, but of these only the tissue kallikarein has a human ortholog. In man, the tissue kallikrein display high sequence similarity with prostate specific antigen and human glandular kallikrein 2, suggesting that they evolved after the separation of primates and rodents. A phylogenetic study of the genes encoding glandular kallikreins in species evolutionarily located between rodents and man may reveal interesting details on how the gene family evolved, which in turn could yield information about the function of the proteins. Therefore, we have initiated a study of the glandular kallikreins of the cotton-top tamarin (Saguinus oedipus), a New World Monkey. Here, we report the cloning and nucleotide sequence of one of these, the tissue kallikrein gene. The gene of 4.4 kb is composed of five exons, and the structure is 90% similar to that of the orthologous human gene. It gives rise to a polypeptide of 261 amino acids, including a signal peptide of 17 residues, a pro-piece of 7 residues, and the mature protein of 237 residues with an estimated molecular mass of 26.3 kD. The similarity to the human prostate specific antigen and human glandular kallikrein 2 genes is 73% and 72%, respectively, including introns and flanking regions. The lower similarity to these genes compared with the human tissue kallikrein gene indicates that they, or a progenitor to them, arose in primates prior to the separation of New and Old World monkeys. Genomic Southern blots also show that the cotton-top tamarin genome encompasses at least one more glandular kallikrein gene.", "The Morel-Lavallée lesion (MLL) is a posttraumatic close degloving injury, which is often underdiagnosed at first. Patients with MLLs usually present with tender and enlarging soft tissue swelling with fluctuation, decreased skin sensation, ecchymosis, or even skin necrosis hours to days after the inciting injury. The lesion can lead to intractable morbidity if it remains untreated. There is no consensus regarding the treatment for MLL at present. Here, we report an MLL in the pretibial region of a 43-year-old woman who experienced a low-energy contusion in a motorbike accident. The pretibial lesion was diagnosed using sonography and fine-needle aspiration. We successfully treated the patient by performing percutaneous debridement via a small incision and injections of fibrin after conservative treatment failed. The method we herein propose achieved the goal of open surgical debridement, providing faster recovery and a high degree of patient comfort. We reviewed the available pertinent literature and propose our own treatment protocol with the aim to establish common therapies ofMLL.", "The rat is the preferred animal model in many areas of biomedical research and drug development. Genetic manipulation in rats has lagged behind that in mice due to the lack of efficient gene targeting tools. Previously, we generated a knockout rat via conventional homologous recombination in rat embryonic stem (ES) cells. Here, we show that efficient gene targeting in rat ES cells can be achieved quickly through transcription activator-like effector nuclease (TALEN)-mediated DNA double-strand breaks. Using the Golden Gate cloning technique, we constructed a pair of TALEN targeting vectors for the gene of interest in 5 days. After gene transfection, the targeted rat ES cell colonies were isolated, screened, and confirmed by PCR without the need of drug selection. Our results suggest that TALEN-mediated gene targeting is a superior means of establishing genetically modified rat ES cell lines with high efficiency and short turnaround time.", "Birds, particularly passerines, can be parasitized by Ixodid ticks, which may be infected with tick-borne pathogens, like Borrelia spp., Babesia spp., Anaplasma, Rickettsia/Coxiella, and tick-borne encephalitis virus. The prevalence of ticks on birds varies over years, season, locality and different bird species. The prevalence of ticks on different species depends mainly on the degree of feeding on the ground. In Europe, the Turdus spp., especially the blackbird, Turdus merula, appears to be most important for harboring ticks. Birds can easily cross barriers, like fences, mountains, glaciers, desserts and oceans, which would stop mammals, and they can move much faster than the wingless hosts. Birds can potentially transport tick-borne pathogens by transporting infected ticks, by being infected with tick-borne pathogens and transmit the pathogens to the ticks, and possibly act as hosts for transfer of pathogens between ticks through co-feeding. Knowledge of the bird migration routes and of the spatial distribution of tick species and tick-borne pathogens is crucial for understanding the possible impact of birds as spreaders of ticks and tick-borne pathogens. Successful colonization of new tick species or introduction of new tick-borne pathogens will depend on suitable climate, vegetation and hosts. Although it has never been demonstrated that a new tick species, or a new tick pathogen, actually has been established in a new locality after being seeded there by birds, evidence strongly suggests that this could occur.", "Dendritic cells (DCs) constantly sample peripheral tissues for antigens, which are subsequently ingested to derive peptides for presentation to T cells in lymph nodes. To do so, DCs have to traverse many different tissues with varying oxygen tensions. Additionally, DCs are often exposed to low oxygen tensions in tumors, where vascularization is lacking, as well as in inflammatory foci, where oxygen is rapidly consumed by inflammatory cells during the respiratory burst. DCs respond to oxygen levels to tailor immune responses to such low-oxygen environments. In the present study, we identified a mechanism of hypoxia-mediated potentiation of release of tumor necrosis factor α (TNF-α), a pro-inflammatory cytokine with important roles in both anti-cancer immunity and autoimmune disease. We show in human monocyte-derived DCs (moDCs) that this potentiation is controlled exclusively via the p38/mitogen-activated protein kinase (MAPK) pathway. We identified MAPK kinase kinase 8 (MAP3K8) as a target gene of hypoxia-induced factor (HIF), a transcription factor controlled by oxygen tension, upstream of the p38/MAPK pathway. Hypoxia increased expression of MAP3K8 concomitant with the potentiation of TNF-α secretion. This potentiation was no longer observed upon siRNA silencing of MAP3K8 or with a small molecule inhibitor of this kinase, and this also decreased p38/MAPK phosphorylation. However, expression of DC maturation markers CD83, CD86, and HLA-DR were not changed by hypoxia. Since DCs play an important role in controlling T-cell activation and differentiation, our results provide novel insight in understanding T-cell responses in inflammation, cancer, autoimmune disease and other diseases where hypoxia is involved.", "In this study, we analyse the evolutionary dynamics and phylogenetic implications of gene order rearrangements in five newly sequenced mitochondrial (mt) genomes and four published mt genomes of isopod crustaceans. The sequence coverage is nearly complete for four of the five newly sequenced species, with only the control region and some tRNA genes missing, while in Janira maculosa only two thirds of the genome could be determined. Mitochondrial gene order in isopods seems to be more plastic than that in other crustacean lineages, making all nine known mt gene orders different. Especially the asellote Janira is characterized by many autapomorphies. The following inferred ancestral isopod mt gene order exists slightly modified in modern isopods: nad1, tnrL1, rrnS, control region, trnS1, cob, trnT, nad5, trnF. We consider the inferred gene translocation events leading to gene rearrangements as valuable characters in phylogenetic analyses. In this first study covering major isopod lineages, potential apomorphies were identified, e.g., a shared relative position of trnR in Valvifera. We also report one of the first findings of homoplasy in mitochondrial gene order, namely a shared relative position of trnV in unrelated isopod lineages. In addition to increased taxon sampling secondary structure, modification in tRNAs and GC-skew inversion may be potentially fruitful subjects for future mt genome studies in a phylogenetic context." ]

[ "STUDY DESIGN: A retrospective case report.OBJECTIVE: The objective of this article is to report an unusual complication of dry needling.SUMMARY OF BACKGROUND DATA: Epidural hematomas after dry needling are quite unusual and only a few cases of epidural hematoma after acupuncture have been reported in the literature. We are presenting the first report of acute cervical epidural hematoma after dry needling.METHODS: A 58-year-old woman presented with quadriparesis and neck pain. Magnetic resonance imaging of the spine revealed a hyperintense mass in the T2-weighted magnetic resonance image at the C2-T2 level, which proved to be an epidural hematoma.RESULTS: Symptoms related to the epidural hematoma resolved after decompression.CONCLUSION: Though rare, epidural hematomas are a possible complication when applying needling therapies. Therapists need to have precise knowledge of human anatomy, especially in the region where he or she will puncture. Continuous attention must be paid throughout the whole procedure.", "In eukaryotes transcriptional regulation often involves multiple long-range elements and is influenced by the genomic environment. A prime example of this concerns the mouse X-inactivation centre (Xic), which orchestrates the initiation of X-chromosome inactivation (XCI) by controlling the expression of the non-protein-coding Xist transcript. The extent of Xic sequences required for the proper regulation of Xist remains unknown. Here we use chromosome conformation capture carbon-copy (5C) and super-resolution microscopy to analyse the spatial organization of a 4.5-megabases (Mb) region including Xist. We discover a series of discrete 200-kilobase to 1 Mb topologically associating domains (TADs), present both before and after cell differentiation and on the active and inactive X. TADs align with, but do not rely on, several domain-wide features of the epigenome, such as H3K27me3 or H3K9me2 blocks and lamina-associated domains. TADs also align with coordinately regulated gene clusters. Disruption of a TAD boundary causes ectopic chromosomal contacts and long-range transcriptional misregulation. The Xist/Tsix sense/antisense unit illustrates how TADs enable the spatial segregation of oppositely regulated chromosomal neighbourhoods, with the respective promoters of Xist and Tsix lying in adjacent TADs, each containing their known positive regulators. We identify a novel distal regulatory region of Tsix within its TAD, which produces a long intervening RNA, Linx. In addition to uncovering a new principle of cis-regulatory architecture of mammalian chromosomes, our study sets the stage for the full genetic dissection of the X-inactivation centre.", "Mast cells are widely distributed throughout the body, predominantly near blood vessels and nerves, and express effector functions in allergic reactions, inflammatory diseases, and host defense. The activation of mast cells results in secretion of the preformed chemical mediators in their granules by a regulated process of exocytosis and leads to synthesis and secretion of lipid mediators and cytokines. Their soluble factors contribute to allergic inflammation. Mast cells are associated with hypersensitivity reactions, not only in the classical immunoglobulin E (IgE)-dependent mechanism but also in an IgE-independent manner. In particular, investigations of potential anatomical and functional interactions between mast cells and the nervous system have recently attracted great interest. To understand these molecular mechanisms in mast cell activation, the ability to visualize, track, and quantify molecules and events in living mast cells is an essential and powerful tool. Recent dramatic advances in imaging technology and labeling techniques have enabled us to carry out these tasks with high spatiotemporal resolution using confocal laser scanning microscopes, green fluorescent protein and its derivatives, and image analysis systems. Here we review our investigations of the dynamic processes of intracellular signaling molecules, cellular structure, and interactions with neurons in mast cells to provide basic and valuable information for allergy and clinical immunology using these new imaging methods.", "Abstract Background: Studies investigating the molecular basis of psoriasis have established the central roles of TNFα, interleukin (IL)-12, IL-22 and IL-23 and there is increasing evidence that IL-17 plays a critical role in the complex pathophysiology. Preclinical studies suggest that IL-17 is a desirable therapeutic target for psoriasis treatment.METHODS: We reviewed the results of the phase II clinical trials for the anti-IL-17 agents secukinumab, ixekizumab and brodalumab in order to assess the efficacy and safety profile of each agent.RESULTS: By week 12, the proportion of patients reaching Psoriasis Area and Severity Index (PASI 75) was comparable among the most efficacious dosage between the different agents (secukinumab 82%, ixekizumab 83% and brodalumab 82%; p<0.001 compared to placebo for all agents). The safety profiles of the agents were similar with the most frequently reported adverse events of nasopharyngitis, upper respiratory infections and injection site reaction. A small percentage of patients experienced low-grade neutropenia that was predominantly transient and asymptomatic.CONCLUSION: The anti-IL-17 agents demonstrated a rapid and robust clinical improvement accompanied by a favorable short-term safety profile. The results of the phase II trials support the theory that the IL-17 pathway is an essential target in psoriasis treatment.", "Circular RNAs (circRNAs) are highly stable forms of non-coding RNAs with diverse biological functions. They are implicated in modulation of gene expression thus affecting various cellular and disease processes. Based on existing bioinformatics approaches, we developed a comprehensive workflow called Circ-Seq to identify and report expressed circRNAs. Circ-Seq also provides informative genomic annotation along circRNA fused junctions thus allowing prioritization of circRNA candidates. We applied Circ-Seq first to RNA-sequence data from breast cancer cell lines and validated one of the large circRNAs identified. Circ-Seq was then applied to a larger cohort of breast cancer samples (n = 885) provided by The Cancer Genome Atlas (TCGA), including tumors and normal-adjacent tissue samples. Notably, circRNA results reveal that normal-adjacent tissues in estrogen receptor positive (ER+) subtype have relatively higher numbers of circRNAs than tumor samples in TCGA. Similar phenomenon of high circRNA numbers were observed in normal breast-mammary tissues from the Genotype-Tissue Expression (GTEx) project. Finally, we observed that number of circRNAs in normal-adjacent samples of ER+ subtype is inversely correlated to the risk-of-relapse proliferation (ROR-P) score for proliferating genes, suggesting that circRNA frequency may be a marker for cell proliferation in breast cancer. The Circ-Seq workflow will function for both single and multi-threaded compute environments. We believe that Circ-Seq will be a valuable tool to identify circRNAs useful in the diagnosis and treatment of other cancers and complex diseases.", "Author information:(1)Max Planck Institute for Molecular Genetics, RG Development & Disease, 14195 Berlin, Germany; Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.(2)Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.(3)Medical Genetics Unit, Policlinico Tor Vergata University Hospital, 00133 Rome, Italy.(4)Institute of Human Genetics Biozentrum, Julius Maximilian University of Würzburg, 97070 Würzburg, Germany.(5)Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, 34093 Istanbul, Turkey.(6)Department of Pediatrics, School of Medicine, University of Utah, Salt Lake City, UT 84108, USA.(7)Instituto de Genética Médica y Molecular (INGEMM), IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, Spain; U753 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28046 Madrid, Spain.(8)Service de Génétique, C.H.U. de Poitiers, 86021 Poitiers, France.(9)Department Developmental Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.(10)Max Planck Institute for Molecular Genetics, RG Development & Disease, 14195 Berlin, Germany.(11)Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.(12)Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.(13)Max Planck Institute for Molecular Genetics, Sequencing Core Facility, 14195 Berlin, Germany.(14)Max Planck Institute for Molecular Genetics, RG Development & Disease, 14195 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.(15)Max Planck Institute for Molecular Genetics, RG Development & Disease, 14195 Berlin, Germany; Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.(16)Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA; School of Natural Sciences, University of California, Merced, CA 95343, USA.(17)Max Planck Institute for Molecular Genetics, RG Development & Disease, 14195 Berlin, Germany; Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany. Electronic address: mundlos@molgen.mpg.de.", "The purpose of this study was to review the use of lithium in pregnancy and its effects on the neonate. This was a case study and review of the published literature. Lithium is commonly used in the treatment of psychiatric disorders, specifically bipolar depression. Bipolar disorders that require treatment with lithium demand special consideration when the woman becomes pregnant. Reported neonatal problems with maternal lithium therapy include Ebstein's anomaly, poor respiratory effort and cyanosis, rhythm disturbances, nephrogenic diabetes insipidus, thyroid dysfunction, hypoglycemia, hypotonia and lethargy, hyperbilirubinemia, and large-for-gestational-age infants. Lithium can have adverse effects on the fetus and newborn infant, but data suggest normal behavioral patterns in childhood.", "Infection by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes COVID-19 disease. Therapeutic antibodies are being developed that interact with the viral spike proteins to limit viral infection of epithelium. We have applied a method to dramatically improve the performance of anti-SARS-CoV-2 antibodies by enhancing avidity through multimerization using simple engineering to yield tetrameric antibodies. We have re-engineered six anti-SARS-CoV-2 antibodies using the human p53 tetramerization domain, including three clinical trials antibodies casirivimab, imdevimab and etesevimab. The method yields tetrameric antibodies, termed quads, that retain efficient binding to the SARS-CoV-2 spike protein, show up to two orders of magnitude enhancement in neutralization of pseudovirus infection and retain potent interaction with virus variant of concern spike proteins. The tetramerization method is simple, general and its application is a powerful methodological development for SARS-CoV-2 antibodies that are currently in pre-clinical and clinical investigation." ]

[ "Triple-negative breast cancers (TNBCs) are defined by a lack of expression of estrogen, progesterone, and HER2 receptors. Because of the absence of identified targets and targeted therapies, and due to a heterogeneous molecular presentation, treatment guidelines for patients with TNBC include only conventional chemotherapy. Such treatment, while effective for some, leaves others with high rates of early relapse and is not curative for any patient with metastatic disease. Here, we demonstrate that these tumors are sensitive to the heat shock protein 90 (Hsp90) inhibitor PU-H71. Potent and durable anti-tumor effects in TNBC xenografts, including complete response and tumor regression, without toxicity to the host are achieved with this agent. Notably, TNBC tumors respond to retreatment with PU-H71 for several cycles extending for over 5 months without evidence of resistance or toxicity. Through a proteomics approach, we show that multiple oncoproteins involved in tumor proliferation, survival, and invasive potential are in complex with PU-H71-bound Hsp90 in TNBC. PU-H71 induces efficient and sustained downregulation and inactivation, both in vitro and in vivo, of these proteins. Among them, we identify downregulation of components of the Ras/Raf/MAPK pathway and G(2)-M phase to contribute to its anti-proliferative effect, degradation of activated Akt and Bcl-xL to induce apoptosis, and inhibition of activated NF-kappaB, Akt, ERK2, Tyk2, and PKC to reduce TNBC invasive potential. The results identify Hsp90 as a critical and multimodal target in this most difficult to treat breast cancer subtype and support the use of the Hsp90 inhibitor PU-H71 for clinical trials involving patients with TNBC.", "Allgrove (Triple A) syndrome is a rare autosomal recessive disorder characterized by cardinal features of adrenal insufficiency due to adrenocorticotropic hormone (ACTH) resistance, achalasia, and alacrimia. It is frequently associated with neurological manifestations like polyneuropathy. Since its first description by Allgrove in 1978, approximately 100 cases have been reported in the literature. Here we report an 18-year-old boy diagnosed as having Allgrove syndrome, with ACTH resistant adrenal insufficiency, achalasia, alacrimia, and severe motor polyneuropathy. Alacrimia was the earliest feature evident at the age of 8 years. He presented with achalasia and adrenal insufficiency at 12 and 18 years respectively and developed neurological symptoms in the form of severe muscle wasting at the age of 15 years. Patients with Allgrove syndrome usually manifest adrenal insufficiency and achalasia during first decade of life. Our patient manifested adrenal insufficiency and achalasia in the second decade and manifested neurological dysfunction before adrenal dysfunction.", "A unique Pro250Arg point mutation in fibroblast growth factor receptor 3 (FGFR3) was initially reported by Bellus et al. [1996: Nat Genet 14:174-176] and the phenotype subsequently by Muenke et al. [1997: Am J Hum Genet 60:555-564], Reardon et al. [1997: J Med Genet 34:632-636], and Graham et al. [1998: Am J Med Genet 77:322-329]. These authors emphasized the pleiotropic nature of this form of coronal craniosynostosis, including brachydactyly with carpal and/or tarsal coalitions, with other anomalies at lower frequency. We report on a family with autosomal dominant coronal synostosis, segmentation and fusion anomalies of the vertebra and ribs, and Sprengel shoulder due to the Pro250Arg mutation. We also report a single case with an identical phenotype without the mutation.", "Phase II studies using ifosfamide both alone and combined with vindesine and cisplatin have shown the effectiveness of this drug in patients with Ewing's sarcoma (ES) who had relapsed during VAC (vincristine, actinomycin, cyclosphosphamide)/VAd (vincristine, Adriamycin) therapy. In November 1984, these results led the SFOP to adopt a protocol consisting of (1) initial chemotherapy with three cycles of IVA (ifosfamide, 3 g/m2 on days 1 and 2; actinomycin D, 750 mg/m2 on days 1-3; vincristine, 1.5 mg/m2 on day 1) alternating every 3 weeks with IVAd (vincristine on day 22; ifosfamide on days 21-23; Adriamycin, 60 mg/m2 on day 22); (2) radical surgery if possible; (3) local radiotherapy (RT); and (4) maintenance chemotherapy with alternating IVA and VAd (vincristine, Adriamycin) for up to 9 months. In May 1987, 87 patients with previously untreated ES entered the study; 61 had localized ES. To date, 54 patients with localized disease and 22 with metastatic disease have finished initial chemotherapy; 40 patients with localized disease have been evaluated. In all, 28 patients (70%) were in complete remission (17 patients) or had a tumor regression of greater than 50% 11 patients) and were considered to be good responders; 12 patients were considered to be poor responders. After local radiotherapy in all but 7 patients and surgical resection in 29, 52 of 54 were considered to be in clinical remission. A total of 13 patients with metastatic disease were good responders at the completion of the initial chemotherapy. These results confirm the efficacy of primary chemotherapy using ifosfamide for the treatment of ES.", "BACKGROUND: The ACVR1 gene encodes a type I receptor for bone morphogenetic proteins (BMPs). Mutations in the ACVR1 gene are associated with Fibrodysplasia Ossificans Progressiva (FOP), a rare and extremely disabling disorder characterized by congenital malformation of the great toes and progressive heterotopic endochondral ossification in muscles and other non-skeletal tissues. Several aspects of FOP pathophysiology are still poorly understood, including mechanisms regulating ACVR1 expression. This work aimed to identify regulatory elements that control ACVR1 gene transcription.METHODS AND RESULTS: We first characterized the structure and composition of human ACVR1 gene transcripts by identifying the transcription start site, and then characterized a 2.9 kb upstream region. This region showed strong activating activity when tested by reporter gene assays in transfected cells. We identified specific elements within the 2.9 kb region that are important for transcription factor binding using deletion constructs, co-transfection experiments with plasmids expressing selected transcription factors, site-directed mutagenesis of consensus binding-site sequences, and by protein/DNA binding assays. We also characterized a GC-rich minimal promoter region containing binding sites for the Sp1 transcription factor.CONCLUSIONS: Our results showed that several transcription factors such as Egr-1, Egr-2, ZBTB7A/LRF, and Hey1, regulate the ACVR1 promoter by binding to the -762/-308 region, which is essential to confer maximal transcriptional activity. The Sp1 transcription factor acts at the most proximal promoter segment upstream of the transcription start site. We observed significant differences in different cell types suggesting tissue specificity of transcriptional regulation. These findings provide novel insights into the molecular mechanisms that regulate expression of the ACVR1 gene and that could be targets of new strategies for future therapeutic treatments.", "Isolated ventricular non-compaction is a rare congenital cardiomyopathy, manifested morphologically as prominent myocardial trabeculations and deep inter-trabecular recesses that communicate with the ventricular cavity. Heart failure is the most common presenting condition. Other manifestations include arrhythmia and cardioembolic events. This report is illustrative of isolated ventricular non-compaction in a 78-year-old woman. The diagnosis was made when she presented with ventricular tachycardia many years after a stroke. She subsequently underwent implantation of a cardioverter-defibrillator. This report documents an uncommon presentation of this disease entity in the oldest patient at presentation as yet reported in the literature.", "Genomic datasets are often interpreted in the context of large-scale reference databases. One approach is to identify significantly overlapping gene sets, which works well for gene-centric data. However, many types of high-throughput data are based on genomic regions. Locus Overlap Analysis (LOLA) provides easy and automatable enrichment analysis for genomic region sets, thus facilitating the interpretation of functional genomics and epigenomics data.AVAILABILITY AND IMPLEMENTATION: R package available in Bioconductor and on the following website: http://lola.computational-epigenetics.org." ]

[ "Eliciting effective antitumor immune responses in patients who fail checkpoint inhibitor therapy is a critical challenge in cancer immunotherapy, and in such patients, tumor-associated myeloid cells and macrophages (TAMs) are promising therapeutic targets. We demonstrate in an autochthonous, poorly immunogenic mouse model of melanoma that combination therapy with an agonistic anti-CD40 mAb and CSF-1R inhibitor potently suppressed tumor growth. Microwell assays to measure multiplex protein secretion by single cells identified that untreated tumors have distinct TAM subpopulations secreting MMP9 or cosecreting CCL17/22, characteristic of an M2-like state. Combination therapy reduced the frequency of these subsets, while simultaneously inducing a separate polyfunctional inflammatory TAM subset cosecreting TNF-α, IL-6, and IL-12. Tumor suppression by this combined therapy was partially dependent on T cells, and on TNF-α and IFN-γ. Together, this study demonstrates the potential for targeting TAMs to convert a \"cold\" into an \"inflamed\" tumor microenvironment capable of eliciting protective T cell responses.", "By identifying genomic sequence regions conserved among several species, comparative genomics offers opportunities to discover putatively functional elements without any prior knowledge of what these functions might be. Comparative analyses across mammals estimated 4-5% of the human genome to be functionally constrained, a much larger fraction than the 1-2% occupied by annotated protein-coding or RNA genes. Such functionally constrained yet unannotated regions have been referred to as conserved non-coding sequences (CNCs) or ultra-conserved elements (UCEs), which remain largely uncharacterized but probably form a highly heterogeneous group of elements including enhancers, promoters, motifs, and others. To facilitate the study of such CNCs/UCEs, we present our resource of Conserved Elements from Genomic Alignments (CEGA), accessible from http://cega.ezlab.org. Harnessing the power of multiple species comparisons to detect genomic elements under purifying selection, CEGA provides a comprehensive set of CNCs identified at different radiations along the vertebrate lineage. Evolutionary constraint is identified using threshold-free phylogenetic modeling of unbiased and sensitive global alignments of genomic synteny blocks identified using protein orthology. We identified CNCs independently for five vertebrate clades, each referring to a different last common ancestor and therefore to an overlapping but varying set of CNCs with 24 488 in vertebrates, 241 575 in amniotes, 709 743 in Eutheria, 642 701 in Boreoeutheria and 612 364 in Euarchontoglires, spanning from 6 Mbp in vertebrates to 119 Mbp in Euarchontoglires. The dynamic CEGA web interface displays alignments, genomic locations, as well as biologically relevant data to help prioritize and select CNCs of interest for further functional investigations.", "AIMS: Short-QT syndrome (SQTS) is a recently recognized disorder associated with atrial fibrillation (AF) and sudden death due to ventricular arrhythmias. Mutations in several ion channel genes have been linked to SQTS; however, the mechanism remains unclear. This study describes a novel heterozygous gain-of-function mutation in the inward rectifier potassium channel gene, KCNJ2, identified in SQTS.METHODS AND RESULTS: We studied an 8-year-old girl with a markedly short-QT interval (QT = 172 ms, QTc = 194 ms) who suffered from paroxysmal AF. Mutational analysis identified a novel heterozygous KCNJ2 mutation, M301K. Functional assays displayed no Kir2.1 currents when M301K channels were expressed alone. However, co-expression of wild-type (WT) with M301K resulted in larger outward currents than the WT at more than -30 mV. These results suggest a gain-of-function type modulation due to decreased inward rectification. Furthermore, we analysed the functional significance of the amino acid charge at M301 (neutral) by changing the residue. As with M301K, in M301R (positive), the homozygous channels were non-functional, whereas the heterozygous channels demonstrated decreased inward rectification. Meanwhile, the currents recorded in M301A (neutral) showed normal inward rectification under both homo- and heterozygous conditions. Heterozygous overexpression of WT and M301K in neonatal rat ventricular myocytes exhibited markedly shorter action potential durations than the WT alone.CONCLUSION: In this study, we identified a novel KCNJ2 gain-of-function mutation, M301K, associated with SQTS. Functional assays revealed no functional currents in the homozygous channels, whereas impaired inward rectification demonstrated under the heterozygous condition resulted in larger outward currents, which is a novel mechanism predisposing SQTS.", "Craniosynostosis is a complex condition, characterized by the premature fusion of one of more of the cranial sutures. They can be seen individually or as part of multisystem syndromes. This review uses computed tomography (CT) with three-dimensional reconstructions to help describe some of the types and classifications of craniosynostosis, as well as describing some of the associations and the management of craniosynostosis.", "Dermatitis herpetiformis (DH) is a relatively rare skin disorder with an estimated incidence of 1:10,000 in the UK. It is characterized by urticarial plaques and blisters on the elbows, buttocks, and knees, although other sites may also be involved. The eruption tends to be persistent: only 10-15% of patients have spontaneous remission over a 25-year study period. The disease is characterized by the presence of IgA deposits in the upper dermis of uninvolved skin and the diagnosis should not be made in the absence of these deposits. Two-thirds of patients have a small intestinal enteropathy with villous atrophy as seen in coeliac disease (CD). However, the remaining third also show evidence of a gluten sensitivity in the intestine, as judged by increased lymphocytic infiltration of the epithelium. Villous atrophy also ensues after gluten challenge in those patients with previous normal villous architecture. The initial treatment of the rash is with one of the following three drugs, dapsone, sulphapyridine or sulphamethoxypyridazine. However, the rash also clears with gluten withdrawal. It must be stressed, however, that the average time to achieve significant reduction in drug requirements is 6 months and it can be over 2 years before drugs are no longer required. On re-introduction of gluten the eruption recurs. Patients with DH have a high incidence of auto-immune disorders, thyroid disease, pernicious anaemia, and insulin-dependent diabetes, and should be screened for those diseases on a yearly basis. As with coeliac disease there is also an increased incidence of lymphoma and a gluten-free diet appears to protect patients from this complication. The mechanism by which gluten causes the skin lesions has still to be elucidated, but current investigations implicate lymphocytes and cytokines in the pathogenesis. The original hypothesis of an antigen-antibody reaction in the skin with complement activation causing the skin lesions, may not be correct.", "BACKGROUND: Target of rapamycin inhibitors (TOR-I) have a novel mode of action but uncertain clinical role. We performed a systematic review of randomized trials where immunosuppressive regimens containing TOR-I were compared with other regimens as initial therapy for kidney transplant recipients.METHODS: Databases (inception, June 2005) and conference proceedings (1996-2005) were searched. Two independent reviewers assessed trials for eligibility and quality. Results at 1 year, are expressed as relative risk (RR), where values<1 favor TOR-I, or lower dose of TOR-I, and for continuous outcomes are expressed as weighted mean difference (WMD), both expressed with 95% confidence intervals (CI).RESULTS: Thirty-three trials (142 reports) were included (27 trials of sirolimus, 5 of everolimus, and 1 of head-to-head comparison). When TOR-I replaced calcineurin inhibitors (CNI) (8 trials with 750 participants), there was no difference in acute rejection (RR, 1.03; 95% CI, 0.74-1.44), but serum creatinine was lower (WMD, -18.31 micromol/L; 95% CI, -30.96 to -5.67) and bone marrow more suppressed (leukopenia: RR 2.02; 95% CI, 1.12-3.66; thrombocytopenia: RR, 6.97; 95% CI, 2.97-16.36; and anaemia: RR, 1.67; 95% CI, 1.27-2.20). When TOR-I replaced antimetabolites (11 trials with 3966 participants), acute rejection and cytomegalovirus infection (CMV) were reduced (RR, 0.84; 95% CI, 0.71-0.99; RR, 0.49; 95% CI, 0.37-0.65, respectively), but hypercholesterolemia was increased (RR, 1.65; 95% CI, 1.32-2.06). When low- was compared with high-dose TOR-I, with equal CNI dose (10 trials with 3,175 participants), rejection was increased (RR, 1.23; 95% CI, 1.06-1.43) but calculated glomerular filtration rate (GFR) higher (WMD, 4.27 mL/min; 95% CI, 1.12-7.41), and when lower-dose TOR-I and standard-dose CNI were compared with higher-dose TOR-I and reduced CNI, acute rejection was reduced (RR, 0.67; 95% CI, 0.52-0.88), but calculated GFR was also reduced (WMD, -9.46 mL/min; 95% CI, -12.16 to -6.76). There was no significant difference in mortality, graft loss, or malignancy risk for TOR-I in any comparison.CONCLUSIONS: TOR-I have been evaluated in four different primary immunosuppressive algorithms: as replacement for CNI and antimetabolites, in combination with CNI at low and high doses, and with a variable dose of CNI. Generally, surrogate endpoints for graft survival favor TOR-I (lower risk of acute rejection and higher GFR), and surrogate endpoints for patient outcomes are worsened by TOR-I (bone marrow suppression and lipid disturbance). Long-term hard-endpoint data from methodologically robust randomized trials are still required.", "Heerfordt's syndrome is a rare manifestation of sarcoidosis characterized by the presence of facial nerve palsy, parotid gland enlargement, anterior uveitis, and low grade fever. Two cases of Heerfordt's syndrome and a literature review are presented. Case  1. A 53-year-old man presented with swelling of his right eyelid, right facial nerve palsy, and swelling of his right parotid gland. A biopsy specimen from the swollen eyelid indicated sarcoidosis and he was diagnosed with incomplete Heerfordt's syndrome based on the absence of uveitis. His symptoms were improved by corticosteroid therapy. Case  2. A 55-year-old woman presented with left facial nerve palsy, bilateral hearing loss, and swelling of her bilateral parotid glands. She had been previously diagnosed with uveitis and bilateral hilar lymphadenopathy. Although no histological confirmation was performed, she was diagnosed with complete Heerfordt's syndrome on the basis of her clinical symptoms. Swelling of the bilateral parotid glands and left facial nerve palsy were improved immediately by corticosteroid therapy. Sarcoidosis is a relatively uncommon disease for the otolaryngologist. However, the otolaryngologist may encounter Heerfordt's syndrome as this syndrome presents with facial nerve palsy and swelling of the parotid gland. Therefore, we otolaryngologists should diagnose and treat Heerfordt's syndrome appropriately in cooperation with pneumologists and ophthalmologists." ]

[ "Author information:(1)1] Department of Medical Genetics, University of Cambridge, Cambridge, UK. [2] Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.(2)Department of Orthopaedics, Medical University Vienna, Vienna, Austria.(3)Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo, Japan.(4)Friedrich-Baur-Institute, Ludwig Maximilians University Munich, Munich, Germany.(5)1] Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. [2] Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.(6)1] Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. [2] Institute of Human Genetics, Technische Universität München, Munich, Germany.(7)Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.(8)Disease Mechanism Research Core, RIKEN Brain Science Institute, Saitama, Japan.(9)Neusentis Research Unit, Pfizer, Cambridge, UK.(10)1] Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. [2] School of Health and Rehabilitation Sciences, The University of Queensland, St. Lucia, Australia.(11)Department of Neurology, Istanbul University, Istanbul, Turkey.(12)Ambulantes Gesundheitszentrum der Charité Campus Virchow (Humangenetik), Universitätsmedizin Berlin, Berlin, Germany.(13)1] Praxis für Humangenetik Cottbus, Cottbus, Germany. [2] Institut für Humangenetik, Universitätsklinikum Leipzig, Leipzig, Germany.(14)1] Institut für Humangenetik, Universitätsklinikum Leipzig, Leipzig, Germany. [2] Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.(15)Department of Dermatology, Our Lady's Children's Hospital, Dublin, Ireland.(16)Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.(17)Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.(18)Neuropädiatrische Ambulanz, Krankenhaus der Barmherzigen Schwestern Linz, Linz, Austria.(19)Neurogenetics Unit, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.(20)Departamento de Cirugía Plástica, Hospital Infantil Universitario de San José, Bogotá, Colombia.(21)Unidad de Genética, Universidad del Rosario, Bogotá, Colombia.(22)Institut für Neuropathologie, Uniklinik RWTH Aachen, Aachen, Germany.(23)1] Friedrich-Baur-Institute, Ludwig Maximilians University Munich, Munich, Germany. [2] German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.(24)Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.(25)Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK.(26)SPZ Neuropädiatrie Charité, Universitätsmedizin Berlin, Berlin, Germany.(27)CharitéCentrum für Zahn-, Mund- und Kieferheilkunde, Arbeitsbereich Kinderzahnmedizin, Universitätsmedizin Berlin, Berlin, Germany.(28)GENDIA (GENetic DIAgnostic Network), Antwerp, Belgium.(29)Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.(30)Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK.(31)1] Department of Neurology, University of California San Francisco, San Francisco, California, USA. [2] Department of Neuroscience, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.(32)Department of Neurology and Neurophysiology, Our Lady's Children's Hospital, Dublin, Ireland.(33)1] Department of Neurology, Adelaide &Meath Hospital, Dublin, Ireland. [2] Academic Unit of Neurology, Trinity College, Dublin, Ireland.(34)1] Department of Dermatology, Our Lady's Children's Hospital, Dublin, Ireland. [2] Clinical Medicine, Trinity College, Dublin, Ireland.(35)Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.(36)1] Center for Human Genetics, Bioscientia, Ingelheim, Germany. [2] Department of Medicine, Renal Division, Freiburg University Medical Center, Freiburg, Germany. [3] Center for Clinical Research, Freiburg University Medical Center, Freiburg, Germany.(37)1] Friedrich-Baur-Institute, Ludwig Maximilians University Munich, Munich, Germany. [2] Medizinisch Genetisches Zentrum, Munich, Germany.(38)1] Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium. [2] Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. [3] Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.(39)MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, National Hospital for Neurology, London, UK.(40)Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany.(41)Institute of Human Genetics, Jena University Hospital, Jena, Germany.(42)1] Institute of Human Genetics, Technische Universität München, Munich, Germany. [2] Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. [3] Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.(43)Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.", "DNA ends get exposed in cells upon either normal or dysfunctional cellular processes or molecular events. Telomeres need to be protected by the shelterin complex to avoid junctions occurring between chromosomes while failing topoisomerases or clustered DNA damage processing may produce double-strand breaks, thus requiring swift repair to avoid cell death. The rigorous study of the great many proteins involved in the maintenance of DNA integrity is a challenging task because of the innumerous unspecific electrostatic and/or hydrophobic DNA-protein interactions that arise due to the chemical nature of DNA. We devised a technique that discriminates the proteins recruited specifically at DNA ends from those that bind to DNA because of a generic affinity for the double helix. Our study shows that the DNA ends proteome comprises proteins of an unexpectedly wide functional spectrum, ranging from DNA repair to ribosome biogenesis and cytoskeleton, including novel proteins of undocumented function. A global mapping of the identified proteome on published DNA repair protein networks demonstrated the excellent specificity and functional coverage of our purification technique. Finally, the native nucleoproteic complexes that assembled specifically onto DNA ends were shown to be endowed with a highly efficient DNA repair activity.", "Muscle problems and other adverse symptoms associated with statin use are frequent reasons for non-adherence and discontinuation of statin therapy, which results in inadequate control of hyperlipidemia and increased cardiovascular risk. However, most patients who experience adverse symptoms during statin use are able to tolerate at least some degree of statin therapy. Given the profound cardiovascular benefits derived from statins, an adequate practical approach to statin intolerance is, therefore, of great clinical importance. Statin intolerance can be defined as the occurrence of myalgia or other adverse symptoms that are attributed to statin therapy and that lead to its discontinuation. In reality, these symptoms are actually unrelated to statin use in many patients, especially in those with atypical presentations following long periods of treatment. Thus, the first step in approaching patients with adverse symptoms during the course of statin therapy is identification of those patients for whom true statin intolerance is unlikely, since most of these patients would probably be capable of tolerating adequate statin therapy. In patients with statin intolerance, an altered dosing regimen of very low doses of statins should be attempted and, if tolerated, should gradually be increased to achieve the highest tolerable doses. In addition, other lipid-lowering drugs may be needed, either in combination with statins, or alone, if statins are not tolerated at all. Stringent control of other risk factors can aid in reducing cardiovascular risk if attaining lipid treatment goals proves difficult.", "Since the first unequivocal description of RNA interference (RNAi) in 1998, it has remained one of the hottest topics under investigation, culminating in the award of a Nobel Prize to its discoverers in 2006. Excitement over this technique derives from the ease with which it can be used to switch-off a specific gene in almost any organism, thereby allowing the role of that gene to be identified. More importantly, it offers the potential to treat certain diseases by switching-off the causative genes. Key to the RNAi pathway are the small-interfering RNAs (siRNAs), which at 21-23 nucleotides in length are very amenable to analogue development by chemists. However in comparison to the use of oligonucleotides as antisense agents, an area where many chemists first developed an interest in nucleic acids, the RNAi pathway is exceedingly complex. The literature is also complicated by the fact that the phenomenon has been studied in a wide range of organisms. In this tutorial review we have presented the subject from a more chemical perspective, incorporating a glossary to give a clear explanation of the specialist terms. However, the coverage of the biology remains sufficiently detailed to give the reader the necessary insight that we believe will be essential for the successful design of chemically modified siRNA.", "PR homology domain-containing member 12 (PRDM12) belongs to a family of conserved transcription factors implicated in cell fate decisions. Here we show that PRDM12 is a key regulator of sensory neuronal specification in Xenopus. Modeling of human PRDM12 mutations that cause hereditary sensory and autonomic neuropathy (HSAN) revealed remarkable conservation of the mutated residues in evolution. Expression of wild-type human PRDM12 in Xenopus induced the expression of sensory neuronal markers, which was reduced using various human PRDM12 mutants. In Drosophila, we identified Hamlet as the functional PRDM12 homolog that controls nociceptive behavior in sensory neurons. Furthermore, expression analysis of human patient fibroblasts with PRDM12 mutations uncovered possible downstream target genes. Knockdown of several of these target genes including thyrotropin-releasing hormone degrading enzyme (TRHDE) in Drosophila sensory neurons resulted in altered cellular morphology and impaired nociception. These data show that PRDM12 and its functional fly homolog Hamlet are evolutionary conserved master regulators of sensory neuronal specification and play a critical role in pain perception. Our data also uncover novel pathways in multiple species that regulate evolutionary conserved nociception.", "The mycobiotic component of the microbiota comprises an integral, yet under-researched, part of the gastrointestinal tract. Here, we present a preliminary study of the possible contribution of gut mycobiota to sub-clinical atherosclerosis in a well-characterised group of obese and non-obese subjects in association with the Framingham Risk Score (FRS) and carotid intima-media thickness (cIMT). From all taxa identified, the relative abundance of the phylum Zygomycota, comprising the family Mucoraceae and genus Mucor, was negatively associated with cIMT and this association remained significant after controlling for false discovery rate. Obese subjects with detectable Mucor spp. had a similar cardiovascular risk profile as non-obese subjects. Interestingly, the relative abundance of Mucor racemosus was negatively associated both with FRS and cIMT. Partial least square discriminant analyses modelling, evaluating the potential relevance of gut mycobiota in patients stratified by mean values of cIMT, showed that even a 1 component model had a high accuracy (0.789), with a high R2 value (0.51). Variable importance in projection scores showed that M. racemosus abundance had the same impact in the model as waist-to-hip ratio, high-density lipoprotein-cholesterol, fasting triglycerides or fasting glucose, suggesting that M. racemosus relative abundance in the gut may be a relevant biomarker for cardiovascular risk.", "Les troubles du spectre autistique font référence à des syndromes de gravité diverse, caractérisés par une perturbation des interactions sociales, des retards sur le plan de la communication, ainsi que des comportements et des intérêts limités et répétés. La prévalence des troubles du spectre autistique est en hausse, tandis que leur étiologie reste imprécise et fort probablement multifactorielle. Plusieurs rapports ont avancé l’hypothèse d’un lien entre l’autisme et certains symptômes gastro-intestinaux chroniques. Des études endoscopiques ont notamment montré une prévalence plus élevée de colite non spécifique, d’hyperplasie lymphoïde et de gastrite en foyers chez des sujets malades comparativement à des témoins. Parmi les mécanismes potentiellement en cause, on retrouve : réponse immunitaire aberrante à certaines protéines alimentaires, perméabilité intestinale anormale et microflore intestinale inappropriée. On décrit ici le cas de deux patients atteints de troubles du spectre autistique qui présentaient des symptômes intestinaux chroniques et des anomalies endoscopiques, le tout est suivi d’une revue sur ce sujet controversé.", "Cellular reprogramming consists of the conversion of differentiated cells into pluripotent cells; the so-called induced Pluripotent Stem Cells. iPSC are amenable to in vitro manipulation and, in theory, direct production of any differentiated cell type. Furthermore, iPSC can be obtained from sick individuals and subsequently used for disease modeling, drug discovery and regenerative treatments. iPSC production was first achieved by transducing, with the use of retroviral vectors, four specific transcription factors: Oct4, Klf4, Sox2 and c-Myc (OKSM), into primary cells in culture Takahashi and Yamanaka, (Cell 126(4):663-676, 2006). Many alternative protocols have since been proposed: repeated transfections of expression plasmids containing the four pluripotency-associated genes Okita et al. (Science 322(5903):949-953, 2008), lentiviral delivery of the four factors Sommer et al. (Stem Cells 27(3):543-549, 2009), Sendai virus delivery Fusaki et al. (Proceedings of the Japan Academy. Series B, Physical and Biological Sciences 85(8):348-362, 2009), removal of the reprogramming vectors by 'piggyBac' transposition Woltjen et al. (Nature 458(7239):766-770, 2009); Kaji et al. (Nature 458(7239):771-775, 2009), Cre-recombinase excisable viruses Soldner et al. (Cell 136(5):964-977, 2009), episomal vectors Yu et al. (Science 324(5928):797-801, 2009), cell-penetrating reprogramming proteins Zhou et al. (Stem Cells 4(5):381-384, 2009), mammalian artificial chromosomes Hiratsuka et al. (PLoS One 6(10):e25961, 2011) synthetically modified mRNAs Warren et al. (Scientific Reports 2:657, 2012), miRNA Anokye-Danso et al. (Cell Stem Cell 8(4):376-388, 2009); however, although some of these methods are commercially available, in general they still need to attain the reproducibility and reprogramming efficiency required for routine applications Mochiduki and Okita (Biotechnol Journal 7(6):789-797, 2012). Herein we explain, in four detailed protocols, the isolation of mouse and human somatic cells and their reprogramming into iPSC. All-encompassing instructions, not previously published in a single document, are provided for mouse and human iPSC colony isolation and derivation. Although mouse and human iPSC share similarities in the cellular reprogramming process and culture, both cell types need to be handled differently.", "Apolipoprotein E (apoE) is associated with plasma lipoproteins and is important in modulating the catabolism of remnants of triglyceride-rich lipoproteins. ApoE is a polymorphic protein, and homozygosity for the E2 allele is associated with type III hyperlipoproteinemia. A variant of apoE, apoEBethesda, was found that migrates in the E1 position on isoelectric focusing. Evaluation of the proband and her family showed that both individuals with apoEBethesda had type III hyperlipoproteinemia, and the analysis was consistent with the concept that apoEBethesda was coded by a new E allele and that this allele was expressed in a codominant fashion. The discovery of apoEBethesda and its association with type III hyperlipoproteinemia provides additional evidence for the genetic heterogeneity of the E allele and suggests that a number of different structural mutations of the E apolipoprotein may be associated with the type III phenotype.", "Erroneous activation of the pain-sensing system, as in chronic or neuropathic pain, represents a major health burden with insufficient treatment options. However, the study of genetic disorders rendering individuals completely unable to feel pain offers hope. All causes of congenital painlessness affect nociceptors, evolutionarily conserved specialist neurons able to sense all type of tissue damage. The discovery of new genes essential for sensing pain (SCN11A, PRDM12, and CLTCL1) has provided unexpected insights into the biological mechanisms that drive distinct stages of nociception. Drugs targeting two previously discovered painlessness genes, NGF and SCN9A, are currently in late-stage clinical trials; thus, characterization of these new painlessness genes has significant potential for the generation of new classes of analgesics.", "BACKGROUND: The CYP2C19*2 or *3 loss-of-function (LOF) allele is associated with high platelet reactivity (HPR) on clopidogrel treatment. East Asians may benefit from a lower dose of prasugrel due to their more potent platelet inhibitory response. The impact of LOF alleles on the pharmacodynamic response to half-dose prasugrel in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI) is unknown.METHODS: Seventy patients with the LOF alleles were assigned to half-dose prasugrel (n = 35, 30-mg load followed by 5 mg daily) or clopidogrel (n = 35, 600-mg load followed by 75 mg daily). The primary endpoint was the rate of HPR, defined as VerifyNow-P2Y12 reaction unit (PRU) >235, at 24 h post loading.RESULTS: Prasugrel achieved a lower PRU compared to clopidogrel after loading (119 [56-175] vs. 245 [189-299]), at 24 h (34 [8-58] vs. 196 [122-244]), and at 30 days (134 [98-189] vs. 203 [144-248]). Prasugrel had a lower rate of HPR after loading (5.7% vs. 57.1%, p <0.001), at 24 h (2.9% vs. 28.6%, p=0.006), and at 30 days (11.4% vs. 34.3%, p=0.004). Prasugrel had a similar rate of optimal platelet reactivity at 30 days (71.4% vs. 60.0%, p=0.450). There was no significant difference in the occurrence of periprocedural myonecrosis within 48 h after PCI with clopidogrel and prasugrel (22.9% vs. 17.1%, p>0.960).CONCLUSIONS: Half-dose prasugrel provided potent platelet inhibition in NSTE-ACS patients that were carriers of the CYP2C19*2 or *3 allele, with a lower rate of HPR. Periprocedural myonecrosis was not significantly different in the 2 groups.", "A 32-year-old woman is described as having the following characteristics of Emery-Dreifuss muscular dystrophy: humeroperoneal muscular atrophy and weakness, neck and elbow contractures with sinus bradycardia, first-degree atrioventricular block, and dilated cardiomyopathy. The biopsy specimen of skeletal muscle showed dystrophic character; a cardiac endomyocardial biopsy specimen showed adipose tissue infiltration and deposition of antihuman IgG. Emery-Dreifuss muscular dystrophy is an X-linked recessive myopathy. The patient had no familial background of the disease. This patient might have a sporadic inheritance pattern with severe cardiac involvement." ]

[ "Reactive oxygen species (ROS), by-products of aerobic respiration, promote genetic instability and contribute to the malignant transformation of cells. Among the genes related to ROS metabolism, Bach1 is a repressor of the oxidative stress response, and a negative regulator of ROS-induced cellular senescence directed by p53 in higher eukaryotes. While ROS are intimately involved in carcinogenesis, it is not clear whether Bach1 is involved in this process. We found that senescent Bach1-deficient mouse embryonic fibroblasts (MEFs) underwent spontaneous immortalization the same as did the wild-type cells. When transduced with constitutively active Ras (H-Ras(V12)), the proliferation and colony formation of these cells in vitro were markedly reduced. When transplanted into athymic nude mice, the growth and vascularization of tumors derived from Bach1-deficient cells were also decreased. Gene expression profiling of the MEFs revealed a new H-Ras(V12) signature, which was distinct from the previously reported signatures in epithelial tumors, and was partly dependent on Bach1. The Bach1-deficient cells showed diminished phosphorylation of MEK and ERK1/2 in response to H-Ras(V12), which was consistent with the alterations in the gene expression profile, including phosphatase genes. Finally, Bach1-deficient mice were less susceptible to 4-nitroquinoline-1-oxidide (4-NQO)-induced tongue carcinoma than wild-type mice. Our data provide evidence for a critical role of Bach1 in cell transformation and tumor growth induced by activated H-Ras(V12).", "Background Exploding head syndrome (EHS) is characterized by loud noises or a sense of explosion in the head during sleep transitions. Though relatively common, little is known about its characteristic symptoms or associated features. Methods A cross-sectional study of 49 undergraduates with EHS was performed. A clinical interview established diagnosis. Results The most common accompanying symptoms were tachycardia, fear, and muscle jerks/twitches with the most severe associated with respiration difficulties. Visual phenomena were more common than expected (27%). EHS episodes were perceived as having a random course, but were most likely to occur during wake-sleep transitions and when sleeping in a supine position. Only 11% reported EHS to a professional, and 8% of those with recurrent EHS attempted to prevent episodes. Conclusions EHS episodes are complex (Mean (M) = 4.5 additional symptoms), often multisensorial, and usually associated with clinically-significant fear. They are rarely reported to professionals and treatment approaches are limited.", "The promoter activity of yeast genes can depend on lysine 56 (K56) acetylation of histone H3. This modification of H3 is performed by lysine acetylase Rtt109 acting in concert with histone chaperone Asf1. We have examined the contributions of Rtt109, Asf1, and H3 K56 acetylation to nutrient regulation of a well-studied metabolic gene, ARG1. As expected, Rtt109, Asf1, and H3 K56 acetylation are required for maximal transcription of ARG1 under inducing conditions. However, Rtt109 and Asf1 also inhibit ARG1 under repressing conditions. This inhibition requires Asf1 binding to H3-H4 and Rtt109 KAT activity, but not tail acetylation of H3-H4 or K56 acetylation of H3. These observations suggest the existence of a unique mechanism of transcriptional regulation by Rtt109. Indeed, chromatin immunoprecipitation and genetic interaction studies support a model in which promoter-targeted Rtt109 represses ARG1 by silencing a pathway of transcriptional activation that depends on ASF1. Collectively, our results show that ARG1 transcription intensity at its induced and repressed set points is controlled by different mechanisms of functional interplay between Rtt109 and Asf1.", "The fortuitously discovered antiaging membrane protein αKlotho (Klotho) is highly expressed in the kidney, and deletion of the Klotho gene in mice causes a phenotype strikingly similar to that of chronic kidney disease (CKD). Klotho functions as a co-receptor for fibroblast growth factor 23 (FGF23) signaling, whereas its shed extracellular domain, soluble Klotho (sKlotho), carrying glycosidase activity, is a humoral factor that regulates renal health. Low sKlotho in CKD is associated with disease progression, and sKlotho supplementation has emerged as a potential therapeutic strategy for managing CKD. Here, we explored the structure-function relationship and post-translational modifications of sKlotho variants to guide the future design of sKlotho-based therapeutics. Chinese hamster ovary (CHO)- and human embryonic kidney (HEK)-derived WT sKlotho proteins had varied activities in FGF23 co-receptor and β-glucuronidase assays in vitro and distinct properties in vivo Sialidase treatment of heavily sialylated CHO-sKlotho increased its co-receptor activity 3-fold, yet it remained less active than hyposialylated HEK-sKlotho. MS and glycopeptide-mapping analyses revealed that HEK-sKlotho is uniquely modified with an unusual N-glycan structure consisting of N,N'-di-N-acetyllactose diamine at multiple N-linked sites, one of which at Asn-126 was adjacent to a putative GalNAc transfer motif. Site-directed mutagenesis and structural modeling analyses directly implicated N-glycans in Klotho's protein folding and function. Moreover, the introduction of two catalytic glutamate residues conserved across glycosidases into sKlotho enhanced its glucuronidase activity but decreased its FGF23 co-receptor activity, suggesting that these two functions might be structurally divergent. These findings open up opportunities for rational engineering of pharmacologically enhanced sKlotho therapeutics for managing kidney disease.", "Programmed death 1 (PD-1, CD279) and programmed death ligand 1 (PD-L1, CD274) are involved in generating tumor-associated immunosuppression by suppression of T-cell proliferation and interleukin 2 (IL-2) production and immune checkpoint inhibitors targeting these molecules are showing compelling activity against a variety of human cancers. PD-L1 expression has shown a positive association with response to PD-1 inhibition in noncentral nervous system (CNS) tumors, e.g., melanoma or non-small cell lung cancer, and is discussed as a potential predictive biomarker for patient selection in these tumor types. This review summarizes current knowledge and potential clinical implications of PD-L1 expression in glioblastoma. At present, the following conclusions are drawn: (a) functional data support a role for PD-1/PD-L1 in tumor-associated immunosuppression in glioblastoma; (b) the incidence of PD-L1-expressing glioblastomas seems to be relatively high in comparison to other tumor types, however, the reported rates of glioblastomas with PD-L1 protein expression vary and range from 61 to 88%; (c) there is considerable variability in the methodology of PD-L1 assessment in glioblastoma across studies with heterogeneity in utilized antibodies, tissue sampling strategies, immunohistochemical staining protocols, cut-off definitions, and evaluated staining patterns; (d) there are conflicting data on the prognostic role and so far no data on the predictive role of PD-L1 gene and protein expression in glioblastoma. In summary, the ongoing clinical studies evaluating the activity of PD-1/PD-L1 inhibitors in glioblastoma need to be complemented with well designed and stringently executed studies to understand the influence of PD-1/PD-L1 expression on therapy response or failure and to develop robust means of PD-L1 assessment for meaningful biomarker development.", "AFP-producing adenocarcinoma is a variant of adenocarcinoma with high malignancy. Production of AFP suggests enteroblastic or hepatoid differentiation of cancer cells. GATA4 is a key molecule involved in the prenatal development of the stomach and liver. GATA4 is epigenetically silenced by hypermethylation of primer region in many types of cancers including gastric cancer. The aim of this study is to investigate the expression and epigenetic regulation of GATA4 in AFP-producing adenocarcinoma. Immunohistochemical analysis revealed that GATA4 was positive in 3/8 cases of AFP-producing gastric adenocarcinomas and in 28/30 cases of common type adenocarcinomas. Epigenetic modification of GATA4 promoter region was investigated with 3 AFP-producing and 4 common-type gastric cancer cell lines. GATA4 mRNA was detected in 1/3 of AFP-producing and 2/4 of common-type gastric cancer cell lines by RT-PCR. Methylation-specific PCR revealed no GATA4 methylation in any of the AFP-producing gastric cancers, whereas methylation was consistent with GATA4 expression in the common-type gastric cancers. Chromatin immunoprecipitation assay for AFP-producing gastric cancers revealed that histones H3 and H4 were hypoacetylated in the GATA4-negative cells, while they were hyperacetylated in the GATA4-positive cells. Treatment with trichostain A, an inhibitor for histone deacetylase, induced acetylation of histones H3 and H4, and tri-methylation of lysine 4 of histone H3, which was associated with the active transcription of GATA4 in GATA4-negative AFP-producing cells. These results indicated that histone deacetylation is a silencing mechanism for GATA4 expression in AFP-producing gastric cancer cells. Differences between AFP-producing gastric cancer and common-type gastric cancer in terms of the mechanism of GATA4 regulation may be reflected in the phenotypic deviation of AFP-producing gastric cancer from common-type gastric cancer.", "Replisome assembly at eukaryotic replication forks connects the DNA helicase to DNA polymerases and many other factors. The helicase binds the leading-strand polymerase directly, but is connected to the Pol α lagging-strand polymerase by the trimeric adaptor Ctf4. Here, we identify new Ctf4 partners in addition to Pol α and helicase, all of which contain a \"Ctf4-interacting-peptide\" or CIP-box. Crystallographic analysis classifies CIP-boxes into two related groups that target different sites on Ctf4. Mutations in the CIP-box motifs of the Dna2 nuclease or the rDNA-associated protein Tof2 do not perturb DNA synthesis genome-wide, but instead lead to a dramatic shortening of chromosome 12 that contains the large array of rDNA repeats. Our data reveal unexpected complexity of Ctf4 function, as a hub that connects multiple accessory factors to the replisome. Most strikingly, Ctf4-dependent recruitment of CIP-box proteins couples other processes to DNA synthesis, including rDNA copy-number regulation." ]

[ "In Italy until sec. XIX, the beginning of vaccination duty allows to obtain some weighty aims in Public Health, like small pox eradication, polio and diphtheria elimination, or like the great reduction of tetanus and hepatitis B incidence. At the some, however, the vaccination duty doesn't allow to develop a \"vaccination conscience\" to do to accept the vaccines like the most important instrument, for effectiveness and utility, in the infectious diseases prevention. So, if from a side it's necessary to leave the vaccination duty from the another side it's necessary to make e leaded way of health education in the people and it's necessary to make a share of resources and aims in the sanitary world.", "MicroRNAs are a recently discovered class of small noncoding functional RNAs. These molecules mediate post-transcriptional regulation of gene expression in a sequence specific manner. MicroRNAs are now known to be key players in a variety of biological processes and have been shown to be deregulated in a number of cancers. The discovery of viral encoded microRNAs, especially from a family of oncogenic viruses, has attracted immense attention towards the possibility of microRNAs as critical modulators of viral oncogenesis. The host-virus crosstalk mediated by microRNAs, messenger RNAs and proteins, is complex and involves the different cellular regulatory layers. In this commentary, we describe models of microRNA mediated viral oncogenesis.", "BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is one of the main contributors to the death of prostate cancer patients. To date, the detailed molecular mechanisms underlying mCRPC are unclear. Given the crucial role of epithelial-mesenchymal transition (EMT) in cancer metastasis, we aimed to analyse the expression and function of Transforming growth factor-beta (TGF-β) signal-associated protein named Sox5 in mCRPC.METHODS: The protein expression levels were analysed by western blot, immunohistochemistry and immunofluorescence. Luciferase reporter assays and chromatin immunoprecipitation were employed to validate the target of Sox5. The effect of Smad3/Sox5/Twist1 on PCa progression was investigated in vitro and in vivo.RESULTS: Here, we found that TGF-β-induced EMT was accompanied by increased Sox5 expression. Interestingly, knockdown of Sox5 expression attenuated EMT induced by TGF-β signalling. Furthermore, we demonstrated that Smad3 could bind to the promoter of Sox5 and regulate its expression. Mechanistically, Sox5 could bind to Twist1 promoter and active Twist1, which initiated EMT. Importantly, knockdown of Sox5 in prostate cancer cells resulted in less of the mesenchymal phenotype and cell migration ability. Furthermore, targeting Sox5 could inhibit prostate cancer progression in a xenograft mouse model. In clinic, patients with high Sox5 expression were more likely to suffer from metastases, and high Sox5 expression also has a lower progression-free survival and cancer specific-survival in clinic database.CONCLUSIONS: Therefore, we propose a new mechanism in which Smad3/Sox5/Twist1 promotes EMT and contributes to PCa progression.", "Bluetongue virus (BTV) genome contains ten double-stranded RNA segments. The sequence of the plus strand of each of the BTV genomic double-stranded RNAs is the same as that of its mRNA, which encodes for a single viral protein, except the smallest S4 segment which can encode for two nonstructural proteins, primarily for the release assistance of the viral progeny. The separation and isolation of each BTV dsRNA segment and viral protein have provided extensive data related to its viral infection, pathology, suppression of host cellular functions, and eventual apoptosis of the infected host cells. This cytoplasmic virus is also an animal killer that costs the U.S. livestock industry at least $125 million yearly. However, this virus has no known effect on humans. Thus, it is very safe to carry out investigation with the virus, preferably in a BSL-2 laboratory.", "Tumor-associated macrophages (TAMs) of M2 phenotype have mediated the immunosuppression in a tumor microenvironment, facilitating the escape of tumor cells from immunosurveillance. Reprograming the immunosuppressive M2 TAMs to immunostimulatory M1 phenotype can activate the antitumor immune responses for cancer immunotherapy. Herein, hollow iron oxide (Fe3O4) nanoparticles (NPs) were employed to reprogram M2 TAMs toward M1 TAMs, aiming to release proinflammatory cytokines and recruit T cells to kill tumor cells. After loaded with l-arginine (l-Arg) and sealed with poly(acrylic acid) (PAA), hollow Fe3O4 NPs were fabricated into LPFe3O4 NPs, which could release l-Arg based on pH-responsive PAA and produce nitric oxide (NO) with the help of nitric oxide synthase (iNOS) overexpressed by M1 TAMs, as a result of additional tumor elimination for gas therapy. In vitro and in vivo studies demonstrate that LPFe3O4 NPs could effectively reprogram M2 to M1 macrophages, activating T cells, releasing TNF-α, and producing high levels of NO, leading to synergistic tumor therapy.", "BACKGROUND: Non-motor symptoms (NMSs) are a real burden in Parkinson's disease (PD). They may appear in early pre-symptomatic stage as well as throughout the disease course. However, their relationship with the deterioration of the patient's quality of life (QoL) is still under debate. This study aimed to investigate the prevalence of NMSs and their impact on the QoL in a cohort of Moroccan patients.METHODS: We carried out a cross-transactional study, where a total of 117 patients were submitted to a structured clinical interview and examination investigating motor and NMSs based on common and conventional scales. Motor symptoms were assessed by the UPDRS I-VI during ON condition. The NMSs were evaluated with common scales and their relationship with the QoL was investigated.RESULTS: The mean patient's age was 60.77 ± 11.36 years old, and the median disease duration was 6 years [2.5-9.5]. Motor's phenotype subtypes were the mixed form in 40.2% of patients, akinetic-rigid in 20.5% and a tremor-dominant form in 39.3%. The median Hoehn and Yahr staging was 2 [1-2.5]. Regarding NMSs, the most common were urinary dysfunctions (82.6%), sleep (80.6%), and gastrointestinal (80%) disorders. Other autonomic dysfunctions were also frequent: thermoregulatory dysfunctions 58.6%, cardiovascular troubles 50.9%, and sexual dysfunctions 47.9%. Depression was present in 47.9% and fatigue symptoms in 23.1%. The median score of SCOPA-AUT was 14 [7.75-21.80]. The median PD questionnaire 39-score index (PDQ39-SI) was 23.22% and the most affected dimension was \"mobility.\" Univariate and multivariate analyses showed that the SCOPA-AUT score impacted the QoL (p = 0.001), especially the gastrointestinal (p = 0.007), and cardiovascular (p = 0.049) dimensions.CONCLUSION: Our data show that all patients have presented at least one NMS. Autonomic and sleep disorders were the most frequent, and in contrast to other studies, digestive and cardiovascular disorders were rather the factors influencing negatively the QoL of patients. Understanding the pathophysiology of these NMSs should be placed at the forefront in order to develop new therapeutic approaches by improving the QoL of PD patients.", "Intravenous alemtuzumab is an effective and well-tolerated treatment for T-cell prolymphocytic leukemia (T-PLL). Alemtuzumab given intravenously as first-line treatment in 32 patients resulted in an overall response rate of 91% with 81% complete responses. Studies in B-cell chronic lymphocytic leukemia have shown subcutaneous alemtuzumab to be equally as effective as intravenous alemtuzumab. The UKCLL05 pilot study examined the efficacy and toxicity of this more convenient method of administration in 9 previously untreated patients with T-PLL. Only 3 of 9 patients (33%) responded to treatment. Furthermore, 2 of 9 patients (22%) died while on treatment. Recruitment was terminated because of these poor results. After rescue therapy with intravenous alemtuzumab and/or pentostatin, median progression-free survival and overall survival were similar to the intravenous group. Alemtuzumab delivered intravenously, but not subcutaneously, remains the treatment of choice for previously untreated T-PLL." ]

[ "From an otological standpoint, Lyme disease can manifest itself as Ménière's disease both clinically and electrophysiologically. The aim of this study was to describe the findings of routine clinical, auditory and vestibular tests in patients with Ménière's and Lyme disease and to use electrocochleography (ECoG) to assess the presence of endolymphatic hydrops (EH) in both diseases. Transtympanic ECoG was performed in 91 patients with Ménière's disease and in 11 patients with confirmed Lyme disease. In both diseases the majority of patients had more than one complaint. There was one case with isolated hearing loss in the Lyme disease group. Typical clinical manifestations of Ménière's disease (vertigo, sensorineural hearing loss and tinnitus) were found in 6/11 patients (54.5%) in the Lyme disease group. The ECoG results indicated that there were 65/91 patients (71.4%) with Ménière's disease and 5 patients (45.5%) with Lyme disease who presented with EH. No statistically significant difference was found between the incidence of different symptoms of Ménière's and Lyme disease. On the basis of these results, patients with Lyme disease should undergo careful examination and investigation, especially in endemic regions. The presence of EH does not exclude the presence of infection with borreliosis as a cause of Ménière's disease-like symptoms.", "Collaborators: Achiron A, Achtnichts L, Agan K, Akman-Demir G, Allen AB, Antel JP, Antiguedad AR, Apperson M, Applebee AM, Ayuso GI, Baba M, Bajenaru O, Balasa R, Balci BP, Barnett M, Bass A, Becker VU, Bejinariu M, Bergh FT, Bergmann A, Bernitsas E, Berthele A, Bhan V, Bischof F, Bjork RJ, Blevins G, Boehringer M, Boerner T, Bonek R, Bowen JD, Bowling A, Boyko AN, Boz C, Bracknies V, Braune S, Brescia Morra V, Brochet B, Brola W, Brownstone PK, Brozman M, Brunet D, Buraga I, Burnett M, Buttmann M, Butzkueven H, Cahill J, Calkwood JC, Camu W, Cascione M, Castelnovo G, Centonze D, Cerqueira J, Chan A, Cimprichova A, Cohan S, Comi G, Conway J, Cooper JA, Corboy J, Correale J, Costell B, Cottrell DA, Coyle PK, Craner M, Cui L, Cunha L, Czlonkowska A, da Silva AM, de Sa J, de Seze J, Debouverie M, Debruyne J, Decoo D, Defer G, Derfuss T, Deri NH, Dihenia B, Dioszeghy P, Donath V, Dubois B, Duddy M, Duquette P, Edan G, Efendi H, Elias S, Emrich PJ, Estruch BC, Evdoshenko EP, Faiss J, Fedyanin AS, Feneberg W, Fermont J, Fernandez OF, Ferrer FC, Fink K, Ford H, Ford C, Francia A, Freedman M, Frishberg B, Galgani S, Garmany GP, Gehring K, Gitt J, Gobbi C, Goldstick LP, Gonzalez RA, Grandmaison F, Grigoriadis N, Grigorova O, Grimaldi LME, Gross J, Gross-Paju K, Gudesblatt M, Guillaume D, Haas J, Hancinova V, Hancu A, Hardiman O, Harmjanz A, Heidenreich FR, Hengstman GJD, Herbert J, Herring M, Hodgkinson S, Hoffmann OM, Hofmann WE, Honeycutt WD, Hua LH, Huang D, Huang Y, Huang D, Hupperts R, Imre P, Jacobs AK, Jakab G, Jasinska E, Kaida K, Kalnina J, Kaprelyan A, Karelis G, Karussis D, Katz A, Khabirov FA, Khatri B, Kimura T, Kister I, Kizlaitiene R, Klimova E, Koehler J, Komatineni A, Kornhuber A, Kovacs K, Koves A, Kozubski W, Krastev G, Krupp LB, Kurca E, Lassek C, Laureys G, Lee L, Lensch E, Leutmezer F, Li H, Linker RA, Linnebank M, Liskova P, Llanera C, Lu J, Lutterotti A, Lycke J, Macdonell R, Maciejowski M, Maeurer M, Magzhanov RV, Maida EM, Malciene L, Mao-Draayer Y, Marfia GA, Markowitz C, Mastorodimos V, Matyas K, Meca-Lallana J, Merino JAG, Mihetiu IG, Milanov I, Miller AE, Millers A, Mirabella M, Mizuno M, Montalban X, Montoya L, Mori M, Mueller S, Nakahara J, Nakatsuji Y, Newsome S, Nicholas R, Nielsen AS, Nikfekr E, Nocentini U, Nohara C, Nomura K, Odinak MM, Olsson T, van Oosten BW, Oreja-Guevara C, Oschmann P, Overell J, Pachner A, Panczel G, Pandolfo M, Papeix C, Patrucco L, Pelletier J, Piedrabuena R, Pless M, Polzer U, Pozsegovits K, Rastenyte D, Rauer S, Reifschneider G, Rey R, Rizvi SA, Robertson D, Rodriguez JM, Rog D, Roshanisefat H, Rowe V, Rozsa C, Rubin S, Rusek S, Saccà F, Saida T, Salgado AV, Sanchez VEF, Sanders K, Satori M, Sazonov DV, Scarpini EA, Schlegel E, Schluep M, Schmidt S, Scholz E, Schrijver HM, Schwab M, Schwartz R, Scott J, Selmaj K, Shafer S, Sharrack B, Shchukin IA, Shimizu Y, Shotekov P, Siever A, Sigel KO, Silliman S, Simo M, Simu M, Sinay V, Siquier AE, Siva A, Skoda O, Solomon A, Stangel M, Stefoski D, Steingo B, Stolyarov ID, Stourac P, Strassburger-Krogias K, Strauss E, Stuve O, Tarnev I, Tavernarakis A, Tello CR, Terzi M, Ticha V, Ticmeanu M, Tiel-Wilck K, Toomsoo T, Tubridy N, Tullman MJ, Tumani H, Turcani P, Turner B, Uccelli A, Urtaza FJO, Vachova M, Valikovics A, Walter S, Van Wijmeersch B, Vanopdenbosch L, Weber JR, Weiss S, Weissert R, Vermersch P, West T, Wiendl H, Wiertlewski S, Wildemann B, Willekens B, Visser LH, Vorobeychik G, Xu X, Yamamura T, Yang YN, Yelamos SM, Yeung M, Zacharias A, Zelkowitz M, Zettl U, Zhang M, Zhou H, Zieman U, Ziemssen T.", "To combat neglected diseases, the Novartis Institute of Tropical Diseases (NITD) was founded in 2002 through private-public funding from Novartis and the Singapore Economic Development Board. One of NITD's missions is to develop antivirals for dengue virus (DENV), the most prevalent mosquito-borne viral pathogen. Neither vaccine nor antiviral is currently available for DENV. Here we review the progress in dengue drug discovery made at NITD as well as the major discoveries made by academia and other companies. Four strategies have been pursued to identify inhibitors of DENV through targeting both viral and host proteins: (i) HTS (high-throughput screening) using virus replication assays; (ii) HTS using viral enzyme assays; (iii) structure-based in silico docking and rational design; (iv) repurposing hepatitis C virus inhibitors for DENV. Along the developmental process from hit finding to clinical candidate, many inhibitors did not advance beyond the stage of hit-to-lead optimization, due to their poor selectivity, physiochemical or pharmacokinetic properties. Only a few compounds showed efficacy in the AG129 DENV mouse model. Two nucleoside analogs, NITD-008 and Balapiravir, entered preclinical animal safety study and clinic trial, but both were terminated due to toxicity and lack of potency, respectively. Celgosivir, a host alpha-glucosidase inhibitor, is currently under clinical trial; its clinical efficacy remains to be determined. The knowledge accumulated during the past decade has provided a better rationale for ongoing dengue drug discovery. Though challenging, we are optimistic that this continuous, concerted effort will lead to an effective dengue therapy.", "Replicative DNA helicases expose the two strands of the double helix to the replication apparatus, but accessory helicases are often needed to help forks move past naturally occurring hard-to-replicate sites, such as tightly bound proteins, RNA/DNA hybrids, and DNA secondary structures. Although the Schizosaccharomyces pombe 5'-to-3' DNA helicase Pfh1 is known to promote fork progression, its genomic targets, dynamics, and mechanisms of action are largely unknown. Here we address these questions by integrating genome-wide identification of Pfh1 binding sites, comprehensive analysis of the effects of Pfh1 depletion on replication and DNA damage, and proteomic analysis of Pfh1 interaction partners by immunoaffinity purification mass spectrometry. Of the 621 high confidence Pfh1-binding sites in wild type cells, about 40% were sites of fork slowing (as marked by high DNA polymerase occupancy) and/or DNA damage (as marked by high levels of phosphorylated H2A). The replication and integrity of tRNA and 5S rRNA genes, highly transcribed RNA polymerase II genes, and nucleosome depleted regions were particularly Pfh1-dependent. The association of Pfh1 with genomic integrity at highly transcribed genes was S phase dependent, and thus unlikely to be an artifact of high transcription rates. Although Pfh1 affected replication and suppressed DNA damage at discrete sites throughout the genome, Pfh1 and the replicative DNA polymerase bound to similar extents to both Pfh1-dependent and independent sites, suggesting that Pfh1 is proximal to the replication machinery during S phase. Consistent with this interpretation, Pfh1 co-purified with many key replisome components, including the hexameric MCM helicase, replicative DNA polymerases, RPA, and the processivity clamp PCNA in an S phase dependent manner. Thus, we conclude that Pfh1 is an accessory DNA helicase that interacts with the replisome and promotes replication and suppresses DNA damage at hard-to-replicate sites. These data provide insight into mechanisms by which this evolutionarily conserved helicase helps preserve genome integrity.", "Previous studies showed that a Bacillus subtilis strain deficient in mismatch repair (MMR; encoded by the mutSL operon) promoted the production of stationary-phase-induced mutations. However, overexpression of the mutSL operon did not completely suppress this process, suggesting that additional DNA repair mechanisms are involved in the generation of stationary-phase-associated mutants in this bacterium. In agreement with this hypothesis, the results presented in this work revealed that starved B. subtilis cells lacking a functional error prevention GO (8-oxo-G) system (composed of YtkD, MutM, and YfhQ) had a dramatic propensity to increase the number of stationary-phase-induced revertants. These results strongly suggest that the occurrence of mutations is exacerbated by reactive oxygen species in nondividing cells of B. subtilis having an inactive GO system. Interestingly, overexpression of the MMR system significantly diminished the accumulation of mutations in cells deficient in the GO repair system during stationary phase. These results suggest that the MMR system plays a general role in correcting base mispairing induced by oxidative stress during stationary phase. Thus, the absence or depression of both the MMR and GO systems contributes to the production of stationary-phase mutants in B. subtilis. In conclusion, our results support the idea that oxidative stress is a mechanism that generates genetic diversity in starved cells of B. subtilis, promoting stationary-phase-induced mutagenesis in this soil microorganism.", "In 29 adults with attention deficit hyperactivity disorder (ADHD) striatal dopamine transporter (DAT) availability was assessed by [(99m)Tc]TRODAT-1 SPECT and correlated with 3' VNTR polymorphism of the DAT gene on chromosome 5p15.3. Seventeen patients showed homozygosity for the 10-repeat allele, two homozygosity of the 9 allele and 10 were heterozygous (9-10). No statistically significant difference in DAT availability was found between patients with 10-10 carriers (DAT 1.28 +/- 0.34) and with at least one 9 allele (DAT 1.31 +/- 0.27); when smokers were excluded, DAT availability was 1.38 +/- 0.28 in the 10-10 carriers (n = 12) and 1.42 +/- 0.19 in the 9-10 and 9-9 carriers (n = 7). In conclusion, no higher striatal DAT was found in patients with homozygosity of the 10 allele of the DAT gene in this study. These results differ from a study in 11 Korean children with ADHD, in which 10-10 carriers showed higher DAT availability in [(123)I]IPT SPECT. Discrepancies may be explained by differences in patient's age, ethnical differences, different imaging techniques or the limited number of patients included in both studies.", "Replication forks encounter impediments as they move through the genome, including natural barriers due to stable protein complexes and highly transcribed genes. Unlike lesions generated by exogenous damage, natural barriers are encountered in every S phase. Like humans, Schizosaccharomyces pombe encodes a single Pif1 family DNA helicase, Pfh1. Here, we show that Pfh1 is required for efficient fork movement in the ribosomal DNA, the mating type locus, tRNA, 5S ribosomal RNA genes, and genes that are highly transcribed by RNA polymerase II. In addition, converged replication forks accumulated at all of these sites in the absence of Pfh1. The effects of Pfh1 on DNA replication are likely direct, as it had high binding to sites whose replication was impaired in its absence. Replication in the absence of Pfh1 resulted in DNA damage specifically at those sites that bound high levels of Pfh1 in wild-type cells and whose replication was slowed in its absence. Cells depleted of Pfh1 were inviable if they also lacked the human TIMELESS homolog Swi1, a replisome component that stabilizes stalled forks. Thus, Pfh1 promotes DNA replication and separation of converged replication forks and suppresses DNA damage at hard-to-replicate sites.", "BACKGROUND: In infants, nonshivering thermogenesis from brown adipose tissue provides an important source of heat for thermoregulation. Infants are known to have a high susceptibility to hypothermia during anesthesia. To investigate whether this could be due to an inhibition of nonshivering thermogenesis by anesthetics, the effect of preincubation with volatile anesthetics on the norepinephrine-induced heat production of brown adipocytes was investigated.METHODS: Brown adipocytes from hamsters were isolated with a collagenase digestion method and preincubated with volatile anesthetics. The cells were stimulated with norepinephrine, and heat production, measured as oxygen consumption, was monitored polarographically.RESULTS: Norepinephrine addition led to a 20-fold increase in the rate of oxygen consumption (thermogenesis). However, preincubation of cells with 3% halothane reduced the response to norepinephrine by more than 70%. The potency of norepinephrine (the median effective concentration) was not affected by halothane. Full effect of halothane was reached quickly, and after halothane withdrawal, the thermogenic response recovered, although rather slowly. Halothane, isoflurane, and enflurane were approximately equipotent inhibitors of thermogenesis, with concentrations of approximately 0.7% resulting in 50% inhibition. The inhibitory effect of 1% halothane was unaffected by the presence of 74% nitrous oxide, but nitrous oxide alone also reduced thermogenesis.CONCLUSIONS: Volatile anesthetics severely attenuated the thermogenic response to norepinephrine of isolated brown-fat cells. It is inferred that brown-adipose-tissue heat production is reduced during (and probably also some time after) anesthesia. Because infants are dependent on brown-fat-derived nonshivering thermogenesis for thermal balance, the inhibition by volatile anesthetic agents of brown-adipocyte heat production may at least partly explain the susceptibility of infants to hypothermia during and after anesthesia." ]

[ "Bioconjugate vaccines, consisting of polysaccharides attached to carrier proteins, are enzymatically generated using prokaryotic glycosylation systems in a process termed bioconjugation. Key to bioconjugation are a group of enzymes known as oligosaccharyltransferases (OTases) that transfer polysaccharides to engineered carrier proteins containing conserved amino acid sequences known as sequons. The most recently discovered OTase, PglS, has been shown to have the broadest substrate scope, transferring many different types of bacterial glycans including those with glucose at the reducing end. However, PglS is currently the least understood in terms of the sequon it recognizes. PglS is a pilin-specific O-linking OTase that naturally glycosylates a single protein, ComP. In addition to ComP, we previously demonstrated that an engineered carrier protein containing a large fragment of ComP is also glycosylated by PglS. Here we sought to identify the minimal ComP sequon sufficient for PglS glycosylation. We tested >100 different ComP fragments individually fused to Pseudomonas aeruginosa exotoxin A (EPA), leading to the identification of an 11-amino acid sequence sufficient for robust glycosylation by PglS. We also demonstrate that the placement of the ComP sequon on the carrier protein is critical for stability and subsequent glycosylation. Moreover, we identify novel sites on the surface of EPA that are amenable to ComP sequon insertion and find that Cross-Reactive Material 197 fused to a ComP fragment is also glycosylated. These results represent a significant expansion of the glycoengineering toolbox as well as our understanding of bacterial O-linking sequons.", "Galactocerebrosidase (GALC) is the lysosomal enzyme deficient in human and certain animal species with globoid cell leukodystrophy (GLD) or Krabbe disease. It catalyzes the hydrolysis of specific galactolipids including galactosylceramide and psychosine. The GALC protein is found in very low amounts in all tissues, which delayed its purification and the subsequent cloning of its cDNA and gene. We previously published the exon-intron organization of the human gene, but did not functionally analyze the 5' flanking region. We now provide a description of this GC-rich region which includes one potential YY1 element and one potential SP1 binding site. There are 13 GGC trinucleotides within the first 150 bp preceding the initiation codon. The 5' end of intron 1 contains six potential Sp1 binding sites, one AP1 binding site, and eight AP2 binding sites. A construct containing nucleotides -176 to -24 had the strongest promoter activity using a vector containing the chloramphenicol acetyltransferase reporter gene. We also provide evidence for the presence of inhibitory sequences located immediately upstream of the promoter region, and within the first 234 nucleotides of intron 1. These elements together with a suboptimal nucleotide at position +4 may explain the low level of GALC protein in all cell types.", "Plant-made or \"biofarmed\" viral vaccines are some of the earliest products of the technology of plant molecular farming, and remain some of the brightest prospects for the success of this field. Proofs of principle and of efficacy exist for many candidate viral veterinary vaccines; the use of plant-made viral antigens and of monoclonal antibodies for therapy of animal and even human viral disease is also well established. This review explores some of the more prominent recent advances in the biofarming of viral vaccines and therapies, including the recent use of ZMapp for Ebolavirus infection, and explores some possible future applications of the technology.", "BACKGROUND: Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). Varenicline was developed as a nicotine receptor partial agonist from cytisine, a drug widely used in central and eastern Europe for smoking cessation. The first trial reports of varenicline were released in 2006, and further trials have now been published or are currently are underway.OBJECTIVES: The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation.SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('varenicline' or 'cytisine' or 'Tabex' or 'nicotine receptor partial agonist') and 'smoking' in the title or abstract, or as keywords. We also searched MEDLINE, EMBASE, PsycINFO and CINAHL using MeSH terms and free text, and we contacted authors of trial reports for additional information where necessary. The latest search was in March 2008.SELECTION CRITERIA: We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment.DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow up. The main outcome measured was abstinence from smoking after at least six months from the beginning of treatment. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we performed meta-analysis to produce a risk ratio, using the Mantel-Haenszel fixed-effect model.MAIN RESULTS: We found seven trials of varenicline compared with placebo for smoking cessation; three of these also included a bupropion experimental arm. We found one relapse prevention trial, comparing varenicline with placebo. We also found one open-label trial comparing varenicline with nicotine replacement therapy. The nine trials covered 7267 participants, 4744 of whom used varenicline. We identified one trial of cytisine (Tabex) for inclusion. The pooled risk ratio (RR) for continuous abstinence at six months or longer for varenicline versus placebo was 2.33 (95% confidence interval [CI] 1.95 to 2.80). The pooled RR for varenicline versus bupropion at one year was 1.52 (95% CI 1.22 to 1.88). The RR for varenicline versus NRT at one year was 1.31 (95% CI 1.01 to 1.71). The two trials which tested the use of varenicline beyond the 12-week standard regimen found the drug to be well-tolerated during long-term use. The main adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. Post-marketing safety data suggest that varenicline may be associated with depressed mood, agitation, and suicidal behaviour or ideation. The labelling of varenicline has been amended, and the FDA is conducting a safety review. The one cytisine trial included in this review found that more participants taking cytisine stopped smoking compared with placebo at two-year follow up, with an RR of 1.61 (95% CI 1.24 to 2.08).AUTHORS' CONCLUSIONS: Varenicline increased the chances of successful long-term smoking cessation between two- and threefold compared with pharmacologically unassisted quit attempts. More participants quit successfully with varenicline than with bupropion. One open-label trial of varenicline versus nicotine replacement therapy demonstrated a modest benefit of varenicline. The effectiveness of varenicline as an aid to relapse prevention has not been clearly established. The main adverse effect of varenicline is nausea, but mostly at mild to moderate levels and tending to subside over time. Possible links with serious adverse events, including depressed mood, agitation and suicidal thoughts, are currently under review. There is a need for independent community-based trials of varenicline, to test its efficacy and safety in smokers with varying co-morbidities and risk patterns. There is a need for further trials of the efficacy of treatment extended beyond 12 weeks. Cytisine may also increase the chances of quitting, but the evidence at present is inconclusive.", "Proper development of the immune system is an intricate process dependent on many factors, including an intact DNA damage response. The DNA double-strand break signaling kinase ATM and its cofactor NBS1 are required during T cell development and for the maintenance of genomic stability. The role of a second ATM cofactor, ATMIN (also known as ASCIZ) in T cells is much less clear, and whether ATMIN and NBS1 function in synergy in T cells is unknown. Here, we investigate the roles of ATMIN and NBS1, either alone or in combination, using murine models. We show loss of NBS1 led to a developmental block at the double-positive stage of T cell development, as well as reduced TCRα recombination, that was unexpectedly neither exacerbated nor alleviated by concomitant loss of ATMIN. In contrast, loss of both ATMIN and NBS1 enhanced DNA damage that drove spontaneous peripheral T cell hyperactivation, proliferation as well as excessive production of proinflammatory cytokines and chemokines, leading to a highly inflammatory environment. Intriguingly, the disease causing T cells were largely proficient for both ATMIN and NBS1. In vivo this resulted in severe intestinal inflammation, colitis and premature death. Our findings reveal a novel model for an intestinal bowel disease phenotype that occurs upon combined loss of the DNA repair cofactors ATMIN and NBS1.", "BACKGROUND: Mutations in BRCA1/2 genes confer ovarian, alongside breast, cancer risk. We examined the risk of developing ovarian cancer in BRCA1/2-positive families and if this risk is extended to BRCA negative families.PATIENTS AND METHODS: A prospective study involving women seen at a single family history clinic in Manchester, UK. Patients were excluded if they had ovarian cancer or oophorectomy prior to clinic. Follow-up was censored at the latest date of: 31/12/2010; ovarian cancer diagnosis; oophorectomy; or death. We used person-years at risk to assess ovarian cancer rates in the study population, subdivided by genetic status (BRCA1, BRCA2, BRCA negative, BRCA untested) compared with the general population.RESULTS: We studied 8005 women from 895 families. Women from BRCA2 mutation families showed a 17-fold increased risk of invasive ovarian cancer (relative risk (RR) 16.67; 95% CI 5.41 to 38.89). This risk increased to 50-fold in women from families with BRCA1 mutations (RR 50.00; 95% CI 26.62 to 85.50). No association was found for women in families tested negative for BRCA1/2, where there was 1 observed invasive ovarian cancer in 1613 women when 2.74 were expected (RR 0.37; 95% CI 0.01 to 2.03). There was no association with ovarian cancer in families untested for BRCA1/2 (RR 0.99; 95% CI 0.45 to 1.88).DISCUSSION: This study showed no increased risk of ovarian cancer in families that tested negative for BRCA1/2 or were untested. These data help counselling women from BRCA1/2 negative families with breast cancer that their risk of invasive ovarian cancer is not higher than the general population.", "CpG islands (CGIs) are commonly used as genomic markers to study the patterns and regulatory consequences of DNA methylation. Interestingly, recent studies reveal a substantial diversity among CGIs: long and short CGIs, for example, exhibit contrasting patterns of gene expression complexity and nucleosome occupancy. Evolutionary origins of CGIs are also highly heterogeneous. In order to systematically evaluate potential diversities among CGIs and ultimately to illuminate the link between diversity of CGIs and their epigenetic variation, we analyzed the nucleotide-resolution DNA methylation maps (methylomes) of multiple cellular origins. We discover novel 'clusters' of CGIs according to their patterns of DNA methylation; the stably hypomethylated CGI cluster (cluster I), sperm-hypomethylated CGI cluster (cluster II), and variably methylated CGI cluster (cluster III). These epigenomic CGI clusters are strikingly distinct at multiple biological features including genomic, evolutionary, and functional characteristics. At the genomic level, the stably hypomethylated CGI cluster tends to be longer and harbors many more CpG dinucleotides than those in other clusters. They are also frequently associated with promoters, while CGI clusters II and III mostly reside in intragenic or intergenic regions and exhibit highly tissue-specific DNA methylation. Functional ontology terms and transcriptional profiles co-vary with CGI clusters, indicating that the regulatory functions of CGIs are tightly linked to their heterogeneity. Finally, CGIs associated with distinctive biological processes, such as diseases, aging, and imprinting, occur disproportionately across CGI clusters. These new findings provide an effective means to combine existing knowledge on CGIs into a genomic context while bringing new insights that elucidate the significance of DNA methylation across different biological conditions and demography." ]

[ "Acute necrotizing encephalopathy (ANE) is a rapidly progressing neurologic disorder that occurs in children after common viral infections of the respiratory or gastrointestinal systems. This disease is commonly seen in East Asia. Normal healthy infants and children can get affected. The condition carries a poor prognosis with high morbidity and mortality rates. We report here a case of a 23-year-old female with ANE and describe its neuroimaging findings. Magnetic resonance imaging examination performed showed symmetric lesions involving the thalami, brainstem, and cerebellum.", "BACKGROUND: Intramural hematomas (IMHs) are reported to dynamically evolve into different clinical outcomes ranging from regression to aortic rupture, but no practice guidelines are available in China.OBJECTIVE: To determine the evolution of IMHs after long-term follow-up and to identify the predictive factors of IMH outcomes in the Chinese population.METHODS: A total of 123 IMH patients with clinical and imaging follow-up data were retrospectively studied. The primary endpoints were aortic disease-related death, aortic dissection, penetrating aortic ulcer (PAU), thickening of the aortic hematoma and aortic complications requiring surgical or endovascular treatment.RESULTS: All 123 IMH patients were monitored clinically. The follow-up duration ranged from 1.4 to 107 months (median, 20 months). Thirty-nine patients had type A IMH, and 84 had type B. The multivariate analysis showed that a baseline MAD ≥ 44.75 mm (2.9% vs 61.4%, P < 0.001) and acute PAUs (2.9% vs 34.1%, P = 0.008) were independent predictors of aorta-related events.CONCLUSIONS: Medication and short-term imaging are recommended for Chinese IMH patients with a hematoma thickness < 10.45 mm and a baseline MAD < 44.75 mm. Rigorous medical observation should also be performed during the acute phase of IMH.", "Measles, mumps, rubella (MMR) vaccine is a live vaccine preparation containing attenuated strains of all 3 viruses. MMR vaccine is widely used throughout the world, with the US having the widest experience with the vaccine. In countries where the vaccine has been introduced successfully, significant reductions in all 3 diseases for which it is protective have occurred. The vaccine has been shown to be highly immunogenic, with seroconversion rates of 95 to 100% being achieved for each of the 3 component vaccines. This immunity appears to be long-lasting and may even be lifelong. Minor adverse effects may occur approximately 1 week after immunisation. Rarely, mumps vaccine-induced meningitis (milder than that associated with wild mumps virus) may occur, its frequency varying with the strain of attenuated mumps virus contained in any particular vaccine. Clinically, the vaccine is indicated for infants aged between 12 and 15 months, and should be administered by intramuscular or deep subcutaneous injection. A few specific contraindications exist, including a genuine hypersensitivity to eggs, and to the aminoglycoside antibiotics kanamycin and neomycin. An increasing number of countries are now adopting a 2-stage MMR policy in an attempt to prevent epidemics among those who remain unprotected, and to move towards eventual disease eradication.", "BACKGROUND: Migraine is associated with activation of the trigeminovascular system, release of calcitonin gene-related peptide (CGRP) and dilation of dural arteries. Novel treatments target calcitonin gene-related peptide or its receptor, which are present in all vascular beds, raising cardiovascular concerns. Erenumab is a human CGRP-receptor antibody approved for the prophylactic treatment of migraine.METHODS: We characterised the relaxant responses to CGRP in the absence and presence of erenumab (1 μM) in isolated human middle meningeal, internal mammary and (proximal and distal) coronary arteries. Furthermore, in human internal mammary arteries from cardiovascularly-compromised patients, we assessed the pharmacological specificity of erenumab by investigating whether the vasodilatory responses to acetylcholine, sodium nitroprusside, pituitary adenylate cyclase activating polypeptide-38 (PACAP), vasoactive intestinal peptide and nicardipine, along with the vasoconstrictor responses to dihydroergotamine, were modified by erenumab.RESULTS: Calcitonin gene-related peptide induced concentration-dependent vasodilatory responses in all vessels studied that were significantly antagonised by erenumab. In human internal mammary arteries from cardiovascularly-compromised patients, the responses to acetylcholine, sodium nitroprusside, PACAP, vasoactive intestinal peptide, nicardipine and dihydroergotamine were unaffected by erenumab.CONCLUSION: Erenumab inhibits calcitonin gene-related peptide-induced vasodilatory responses in human middle meningeal arteries, human internal mammary arteries and human coronary arteries. Moreover, erenumab shows functional specificity as no interaction was observed with the relaxant responses to several vasodilators, nor the dihydroergotamine-dependent vasoconstrictor responses.", "Uptake rates for the combined measles, mumps and rubella (MMR) vaccine have been below the required 95% in the UK since a retracted and discredited article linking the MMR vaccine with autism and inflammatory bowel disease was released in 1998. This study undertook semi-structured telephone interviews among parents or carers of 47 unvaccinated measles cases who were aged between 13 months and 9 years, during a large measles outbreak in Merseyside. Results showed that concerns over the specific links with autism remain an important cause of refusal to vaccinate, with over half of respondents stating this as a reason. A quarter stated child illness during scheduled vaccination time, while other reasons included general safety concerns and access issues. Over half of respondents felt that more information or a discussion with a health professional would help the decision-making process, while a third stated improved access. There was clear support for vaccination among respondents when asked about current opinions regarding MMR vaccine. The findings support the hypothesis that safety concerns remain a major barrier to MMR vaccination, and also support previous evidence that experience of measles is an important determinant in the decision to vaccinate.", "Intrinsic termination signals for multisubunit bacterial RNA polymerases (RNAPs) encode a GC-rich stem-loop structure followed by a polyuridine [poly(U)] tract, and it has been proposed that steric clash of the stem-loop with the exit pore of the RNAP imposes a shearing force on the RNA in the downstream RNA:DNA hybrid, resulting in misalignment of the active site. The structurally unrelated T7 RNAP terminates at a similar type of signal (TΦ), suggesting a common mechanism for termination. In the absence of a hairpin (passive conditions), T7 RNAP slips efficiently in both homopolymeric A and U tracts, and we have found that replacement of the U tract in TΦ with a slippage-prone A tract still allows efficient termination. Under passive conditions, incorporation of a single G residue following a poly(U) tract (which is the situation during termination at TΦ) results in a \"locked\" complex that is unable to extend the transcript. Our results support a model in which transmission of the shearing force generated by steric clash of the hairpin with the exit pore is promoted by the presence of a slippery tracts downstream, resulting in alterations in the active site and the formation of a locked complex that represents an early step in the termination pathway.", "OBJECTIVES: Isradipine is a dihydropyridine calcium channel inhibitor that has demonstrated concentration-dependent neuroprotective effects in animal models of Parkinson's disease (PD) but failed to show efficacy in a phase 3 clinical trial. The objectives of this study were to model the plasma pharmacokinetics of isradipine in study participants from the phase 3 trial; and, to investigate associations between drug exposure and longitudinal clinical outcome measures of PD progression.METHODS: Plasma samples from nearly all study participants randomized to immediate-release isradipine 5-mg twice daily (166 of 170) were collected for population pharmacokinetic modeling. Estimates of isradipine exposure included apparent oral clearance and area under the concentration-time curve. Isradipine exposure parameters were tested for correlations with 36-month changes in disease severity clinical assessment scores, and time-to-event analyses for initiation of antiparkinson therapy.RESULTS: Isradipine exposures did not correlate with the primary clinical outcome, changes in the antiparkinson therapy-adjusted Unified Parkinson's Disease Rating Scale parts I-III score over 36 months (Spearman rank correlation coefficient, rs : 0.09, P = 0.23). Cumulative levodopa equivalent dose at month 36 was weakly correlated with isradipine plasma clearance (rs : 0.18, P = 0.035). This correlation was sex dependent and significant in males, but not females. Those with higher isradipine exposure had decreased risk of needing antiparkinson treatment over 36 months compared with placebo (hazard ratio: 0.87, 95% CI: 0.78-0.98, P = 0.02).INTERPRETATION: In this clinical trial, higher isradipine plasma exposure did not affect clinical assessment measures of PD severity but modestly decreased cumulative levodopa equivalent dose and the time needed for antiparkinson treatment initiation.TRIAL REGISTRATION: ClinicalTrials.gov NCT02168842.", "BACKGROUND: Retinochoroiditis is the most common ocular manifestation of congenital toxoplasmosis, but other associated ophthalmological pathologies can also occur. The aim of this study was to determine the nature of the latter in treated cases of the disease and to assess their impact on visual function.METHODS: Four hundred and thirty consecutive children with serologically confirmed congenital toxoplasmosis were included in this study. Data were prospectively collected using standardized ophthalmological assessment forms. The presence of retinochoroiditis and of associated pathologies was ascertained, and their impact on visual function was assessed.RESULTS: After a median follow-up of 12 years [range 0.6-26 years], 130 children manifested retinochoroiditis. We detected 22 foci of retinochoroiditis at birth and 264 additional ones during the follow-up period. Of these, 48 (17%) were active when first diagnosed. Twenty-five of the 130 children (19%) had other associated ocular pathologies. Of these, 21 (16%) had a strabismus, which was due to macular lesions in 86% of the cases; 7 (5.4%) presented with unilateral microphthalmia, and 4 (3%) with cataracts. Most of these events were detected after the onset of retinochoroiditis. None of the children presented with ocular involvement in the absence of chorioretinal lesions. Macular lesions occurred more frequently in children with associated pathologies (p<0.0001), and associated pathologies were likewise more common in individuals with macular lesions (p=0.0003). Visual impairment occurred in 31/130 cases, and in all but 3 of these eyes it was due not to an associated pathology but to macular retinochoroiditis.CONCLUSIONS: At the end of the follow-up period, ocular involvement existed in 30% of the treated children with congenital toxoplasmosis. Associated eye pathologies were manifested less frequently than anticipated. They may occur later in life and are an indirect marker of the severity of congenital toxoplasmosis, but they do not have a direct impact on visual acuity. The overall functional prognosis of congenital toxoplasmosis is better than would be expected on the basis of literature findings, with only 2 of the 130 children suffering bilateral visual impairment." ]

[ "The complex language of eukaryotic gene expression remains incompletely understood. Despite the importance suggested by many noncoding variants statistically associated with human disease, nearly all such variants have unknown mechanisms. Here, we address this challenge using an approach based on a recent machine learning advance-deep convolutional neural networks (CNNs). We introduce the open source package Basset to apply CNNs to learn the functional activity of DNA sequences from genomics data. We trained Basset on a compendium of accessible genomic sites mapped in 164 cell types by DNase-seq, and demonstrate greater predictive accuracy than previous methods. Basset predictions for the change in accessibility between variant alleles were far greater for Genome-wide association study (GWAS) SNPs that are likely to be causal relative to nearby SNPs in linkage disequilibrium with them. With Basset, a researcher can perform a single sequencing assay in their cell type of interest and simultaneously learn that cell's chromatin accessibility code and annotate every mutation in the genome with its influence on present accessibility and latent potential for accessibility. Thus, Basset offers a powerful computational approach to annotate and interpret the noncoding genome.", "BACKGROUND: Calcific uraemic arteriolopathy (CUA, calciphylaxis) is a rare disease predominantly in dialysis patients and associated with high mortality. Painful skin ulcerations and calcification of cutaneous arterioles characterize calciphylaxis.METHODS: We established an observational, Internet-based registry allowing online notification for all German CUA cases. The registry recorded data about patient characteristics, biochemistry and therapies. Blood samples were stored in a central biobank.RESULTS: Between 2006 and 2015, 253 CUA patients were recorded: median age 70 [interquartile range (IQR) 61-76] years, 60% females and 86% ( n = 207) dialysis patients, translating into an estimated annual incidence rate of 0.04% in German dialysis patients. Fifty-two per cent received vitamin K antagonists (VKAs) prior to CUA. Skin lesions were localized in 71% on the legs or gluteal region. In dialysis CUA patients median total serum calcium was 2.20 (IQR 2.06-2.37) mmol/L, phosphorus 1.67 (IQR 1.35-2.03) mmol/L, intact parathyroid hormone 147 (IQR 72-276) pg/mL and fetuin-A 0.21 (IQR 0.16-0.26) g/L (normal range 0.35-0.95). Median sclerostin, osteoprotegerin, TRAP5b, bone-specific alkaline phosphatase and c-terminal FGF23 levels were all elevated. The most frequently recorded therapeutic procedures in dialysis CUA patients were as follows: wound debridement (29% of cases), stopping VKA (25%), lowering calcium supply (24%), sodium thiosulphate (22%), application of vitamin K (18%), increase of dialysis duration/frequency (17%) and stoping active vitamin D (16%).CONCLUSIONS: Approximately 50% of CUA patients used VKA. Our data suggest that uncontrolled hyperparathyroidism is not the key determinant of calciphylaxis. Therapeutic strategies were heterogeneous. The experience of the German registry will help substantially to initiate a large-scale multinational CUA registry.", "Herein we review our progress on the development of phosphopeptide-based prodrugs targeting the SH2 domain of STAT3 to prevent recruitment to cytokine and growth factor receptors, activation, nuclear translocation and transcription of genes involved in cancer. We developed high affinity phosphopeptides (K I = 46-200 nM). Corresponding prodrugs inhibited constitutive and IL-6 induced Tyr705 phosphorylation at 0.5-1 μM in a variety of human cancer cell lines. They were not cytotoxic at 5 μM in vitro but they inhibited tumor growth in a human xenograft breast cancer model in mice, accompanied by reduced VEGF expression and angiogenesis.", "La toxocarose humaine est une zoonose parasitaire cosmopolite causée par Toxocara canis et Toxocara catisqui sont des ascarides des chiens et des chats. C’est une affection le plus souvent bénigne. Nous rapportons un cas de pancréatite aigue dans le décours une toxocarose.", "BACKGROUND: Burning mouth syndrome is a disorder usually associated with an unexplained, prolonged sensation of burning inside the oral cavity. Although the etiology is unknown, neural and psychologic factors and cytokines may be implicated in the pathogenesis of burning mouth syndrome. The aim of this study was to investigate the relationship between serum cytokine and T regulatory cell levels in patients with burning mouth syndrome with regard to depression and anxiety.METHODS: Thirty patients with burning mouth syndrome and 30 matched controls participated in the study. Serum cytokine levels were measured with cytometric bead array and T regulatory cells were defined as CD4(+)CD25(+)Foxp-3(+) cells by flow cytometry. The level of anxiety and depression were analyzed by means of the Speilberger State-Trait Anxiety Inventory and Zung Self-Rating Depression Scale. Visual analogue scale was used in the quantification of burning levels of patients.RESULTS: Serum IL-2 and TNF-alpha levels were significantly decreased in patients with burning mouth syndrome compared with controls [mean 16.79 +/- 8.70 vs. 37.73 +/- 41.05 pg / ml (P < 0.05) and mean 39.09 +/- 29.40 vs. 70.83 +/- 42.44 pg / ml (P < 0.01) respectively].CONCLUSIONS: IL-2 and TNF-alpha might play a role in burning mouth syndrome. Burning mouth syndrome may occur as a sign of predisposition to autoimmunity. Presence of low levels of CD28(+) supports the provision that BMS might be a pre-autoimmune disease.", "The conceptual shift of our understanding of migraine from a vascular disorder to a brain disorder has dramatically altered the approach to the development of new medicines in the field. Current pharmacologic treatments of acute migraine consist of nonspecific and relatively specific agents. Migraine-specific drugs comprise two classes, the ergot alkaloid derivatives and the triptans, serotonin 5-HT(1B/1D) receptor agonists. The ergots, consisting of ergotamine and dihydroergotamine (DHE), are the oldest specific antimigraine drugs available and are considered relatively safe and effective. Ergotamine has been used less extensively because of its adverse effects; DHE is better tolerated. The triptan era, beginning in the 1990s, was a period of considerable change, although these medicines retained vasoconstrictor actions. New methods of delivering older drugs include orally inhaled DHE and the transdermal formulation of sumatriptan, both currently under study. Novel medicines being developed are targeted at neural sites of action. Serotonin 5-HT(1F) receptor agonists have proven effective in phase II studies and have no vascular actions. Calcitonin gene-related peptide (CGRP) receptor antagonists are another promising nonvasoconstrictor approach to treating acute migraine. Olcegepant (BIBN4096BS) and telcagepant (MK-0974) have been shown to be safe and effective in phase I, II, and (for telcagepant) phase III clinical trials. Other targets under investigation include glutamate (AMPA/kainate), TRPV1, prostanoid EP4, and nitric oxide synthase. With new neural targets and the potential for therapeutic advances, the next era of antimigraine medications is near.", "Long non-coding RNAs (lncRNAs) are transcripts longer than ~200 nucleotides with little or no protein-coding capacity. Growing evidence shows that lncRNAs present important function in development and are associated with many human diseases such as cancers, Alzheimer disease, and heart diseases. Transcribed ultraconserved region (T-UCR) transcripts are a novel class of lncRNAs transcribed from ultraconserved regions (UCRs). UCRs are absolutely conserved (100%) between the orthologous regions of the human, rat, and mouse genomes. The UCRs are frequently located at fragile sites and at genomic regions involved in cancers. Recent data suggest that T-UCRs are altered at the transcriptional level in human tumorigenesis and the aberrant T-UCRs expression profiles can be used to differentiate human cancer types. The profound understanding of T-UCRs can throw new light on the pathogenesis of human cancers." ]

[ "Administration of artrofoon in combination with SCENAR therapy to patients with localized suppurative peritonitis in the postoperative period considerably reduced plasma MDA level, stabilized ceruloplasmin activity, and increased catalase activity in erythrocytes compared to the corresponding parameters in patients receiving standard treatment in combination with SCENAR therapy.", "Resistance training of healthy young men typically results in muscle hypertrophy and a shift in vastus lateralis composition away from type IIx fibers to an increase in IIa fiber content. Our previous studies of 8 wk of resistance training found that many metabolic syndrome men and women paradoxically increased IIx fibers with a decrease in IIa fibers. To confirm the hypothesis that obese subjects might have muscle remodeling after resistance training very different from healthy lean subjects, we subjected a group of nine obese male volunteers to progressive resistance training for a total of 16 wk. In these studies, weight loss was discouraged so that muscle changes would be attributed to the training alone. Detailed assessments included comparisons of histological examinations of needle biopsies of vastus lateralis muscle pretraining and at 8 and 16 wk. Prolonging the training from 8 to 16 wk resulted in increased strength, improved body composition, and more muscle fiber hypertrophy, but euglycemic clamp-quantified insulin responsiveness did not improve. Similar to prior studies, muscle fiber composition shifted toward more fast-twitch type IIx fibers (23 to 42%). Eight weeks of resistance training increased the muscle expression of phosphorylated Akt2 and mTOR. Muscle GLUT4 expression increased, although insulin receptor and IRS-1 expression did not change. We conclude that resistance training of prediabetic obese subjects is effective at changing muscle, resulting in fiber hypertrophy and increased type IIx fiber content, and these changes continue up to 16 wk of training.NEW & NOTEWORTHY Obese, insulin-resistant men responded to 16 wk of progressive resistance training with muscle hypertrophy and increased strength and a shift in muscle fiber composition toward fast-twitch, type IIx fibers. Activation of muscle mTOR was increased by 8 wk but did not increase further at 16 wk despite continued augmentation of peak power and rate of force generation.", "In the absence of DNA, purified yeast RNA polymerase II can bind RNA to form a binary complex. RNA in such RNA-RNA polymerase complexes undergoes reactions previously thought to be unique to nascent RNA in ternary complexes with DNA, including TFIIS-dependent cleavage and elongation by 3'-terminal addition of NMP from NTP. Both of these reactions are inhibited by alpha-amanitin. Hence, by several criteria the RNA in binary complexes is bound to the polymerase in a manner quite similar to that in ternary complexes in which the catalytic site for nucleotide addition is positioned at or near the 3'-OH terminus of the RNA. These findings are consistent with a model for the RNA polymerase ternary complex in which the RNA is bound at the 3' terminus through two protein-binding sites located up to 10 nt apart.", "The marine cyanobacterium Prochlorococcus is the numerically dominant photosynthetic organism in the oligotrophic oceans, and a model system in marine microbial ecology. Here we report 27 new whole genome sequences (2 complete and closed; 25 of draft quality) of cultured isolates, representing five major phylogenetic clades of Prochlorococcus. The sequenced strains were isolated from diverse regions of the oceans, facilitating studies of the drivers of microbial diversity-both in the lab and in the field. To improve the utility of these genomes for comparative genomics, we also define pre-computed clusters of orthologous groups of proteins (COGs), indicating how genes are distributed among these and other publicly available Prochlorococcus genomes. These data represent a significant expansion of Prochlorococcus reference genomes that are useful for numerous applications in microbial ecology, evolution and oceanography.", "The marine cyanobacterium Prochlorococcus is the smallest and most abundant photosynthetic organism on Earth. In this Review, we summarize our understanding of the diversity of this remarkable phototroph and describe its role in ocean ecosystems. We discuss the importance of interactions of Prochlorococcus with the physical environment, with phages and with heterotrophs in shaping the ecology and evolution of this group. In light of recent studies, we have come to view Prochlorococcus as a 'federation' of diverse cells that sustains its broad distribution, stability and abundance in the oceans via extensive genomic and phenotypic diversity. Thus, it is proving to be a useful model system for elucidating the forces that shape microbial populations and ecosystems.", "AIM: Charcot neuroarthropathy is a very rare form of diabetic foot syndrome occurring among others in patients with diabetes mellitus. Charcot neuroarthropathy leads to bone tissue destruction and may result in foot amputation. The aim of the study was to identify risk factors of Charcot neuroarthropathy occurrence in patients with diabetic foot and type 2 diabetes.MATERIALS: The study included 144 patients with type 2 diabetes; 33 with Charcot neuroarthropathy and 111 with diabetic foot of neuropathic origin without neuroarthropathy. The study was perform in Gastroenterology and Metabolic Diseases Department, Medical University of Warsaw, Poland.RESULTS: The regression analysis showed that Charcot neuroarthropathy occurrence risk factors were: male gender (OR=4.94, 95% CI:1.63-15.03, p=0.003), age (OR=0.92, 95% CI:0.87-0.96, p=0.0001), diabetic foot duration (OR=1.19, 95% CI:1.08-1.32, p=0.00002) and height (OR=1.078, 95% CI:1.019-1.140, p=0.007). A positive effect on Charcot neuroarthropathy presence was exerted by body weight (OR=1.027, 95% CI:1.003-1.051, p=0.03) and hips circumference (OR=1.034, 95% CI:0.997-1.072, p=0.04).CONCLUSIONS: The existence of the specific factors influencing Charcot neuroarthropathy development may result in earlier identification of patients at risk of its development. There is a necessity to take special care for patients prone to develop Charcot neuroarthropathy in order to prevent its occurrence and severe complications.", "Recent progress in biological clock research has facilitated genetic analysis of circadian rhythm sleep disorders, such as delayed sleep phase syndrome (DSPS) and non-24-h sleep-wake syndrome (N-24). We analyzed the human period3 (hPer3) gene, one of the human homologs of the Drosophila clock-gene period (Per), as a possible candidate for rhythm disorder susceptibility. All of the coding exons in the hPer3 gene were screened for polymorphisms by a PCR-based strategy using genomic DNA samples from sleep disorder patients and control subjects. We identified six sequence variations with amino acid changes, of which five were common and predicted four haplotypes of the hPer3 gene. One of the haplotypes was significantly associated with DSPS (Bonferroni's corrected P = 0.037; odds ratio = 7.79; 95% CI 1.59-38.3) in our study population. Our results suggest that structural polymorphisms in the hPer3 gene may be implicated in the pathogenesis of DSPS.", "BACKGROUND: Overexpression of the HER-2/neu oncoprotein has been reported to occur in </= 60% of patients with prostate carcinoma and to correlate with shortened survival. Trastuzumab is a humanized monoclonal antibody to the HER-2 receptor and has activity against HER-2-positive breast carcinoma, more so when combined with a taxane. The authors screened for HER-2 overexpression in patients developing hormone-refractory prostate carcinoma (HRPC) and conducted a Phase II trial of trastuzumab plus docetaxel in HER-2-positive patients.METHODS: Paraffin-embedded tumor specimens from potentially eligible patients were screened for HER-2 expression by immunohistochemistry (IHC) and/or amplification by fluorescent in situ hybridization (FISH). Shed HER-2 was also assessed by enzyme-linked immunoradsorbent assay (ELISA). Patients with HER-2-positive tumor specimens (IHC 2+ or 3+ or FISH ratio > 2) were initially randomized to receive either single-agent trastuzumab or docetaxel. After two treatment cycles, nonresponding patients received the trastuzumab/docetaxel combination. Treatment was comprised of 30 mg/m(2) of docetaxel weekly for 6 weeks followed by a 2-week break and 4 mg/kg of trastuzumab intravenously during Week 1 then 2 mg/kg per week thereafter. The cycle length was 8 weeks.RESULTS: One hundred patients with HPRC were screened. IHC results were as follows: 3+ (n = 1), 2+ (n = 6), 1+ (n = 26), 0 (n = 39), and insufficient tissue specimen/not tested (n = 28). Only 3 of 37 patients had elevated shed HER-2 by ELISA (> 15 mg/mL). None overexpressed HER-2 by IHC. FISH amplification was found in 0 of 34 tissue samples. Of seven patients with IHC 3+ or 2+, four were tested by ELISA and two by FISH. None were abnormal. Age and Gleason score did not correlate with IHC status. Of the seven patients eligible for the Phase II study, only four agreed to participate. The trial was thus closed for nonfeasibility (the overall HER-2 positivity rate was < 20%). No patient responded to trastuzumab alone. The median survival was not reached and the median progression-free survival was 7 months.CONCLUSIONS: HER-2 overexpression by IHC in archival prostate carcinoma specimens was infrequent. There was no apparent correlation among IHC, ELISA, and FISH, although the sample size was limited. Conclusions regarding the predictive value of HER-2 status on outcome after trastuzumab-based therapy were not reached and were only drawn after larger-scale screening efforts. The authors estimated that 1000 patients need to be screened to complete accrual to a 40-patient efficacy trial.", "The marine cyanobacterium Prochlorococcus is the most abundant photosynthetic organism in oligotrophic regions of the oceans. The inability to assimilate nitrate is considered an important factor underlying the distribution of Prochlorococcus, and thought to explain, in part, low abundance of Prochlorococcus in coastal, temperate, and upwelling zones. Here, we describe the widespread occurrence of a genomic island containing nitrite and nitrate assimilation genes in uncultured Prochlorococcus cells from marine surface waters. These genes are characterized by low GC content, form a separate phylogenetic clade most closely related to marine Synechococcus, and are located in a different genomic region compared with an orthologous cluster found in marine Synechococcus strains. This sequence distinction suggests that these genes were not transferred recently from Synechococcus. We demonstrate that the nitrogen assimilation genes encode functional proteins and are expressed in the ocean. Also, we find that their relative occurrence is higher in the Caribbean Sea and Indian Ocean compared with the Sargasso Sea and Eastern Pacific Ocean, which may be related to the nitrogen availability in each region. Our data suggest that the ability to assimilate nitrite and nitrate is associated with microdiverse lineages within high- and low-light (LL) adapted Prochlorococcus ecotypes. It challenges 2 long-held assumptions that (i) Prochlorococcus cannot assimilate nitrate, and (ii) only LL adapted ecotypes can use nitrite. The potential for previously unrecognized productivity by Prochlorococcus in the presence of oxidized nitrogen species has implications for understanding the biogeography of Prochlorococcus and its role in the oceanic carbon and nitrogen cycles.", "In earlier work, we demonstrated that 5'-CG-3' methylation inhibits the transcriptional activity of human Alu elements associated with the alpha 1-globin and the angiogenin genes in a cell-free transcription system from HeLa nuclear extracts. These studies have been extended to different Alu sequences and to investigations on the mechanism involved in transcriptional silencing by methylation. By comparing the results of DNase I and dimethyl sulfate (DMS) in vitro footprinting on a consensus sequence in the RNA polymerase III promoter control B region between the unmethylated and the 5'-CG-3' methylated B box, evidence has been adduced for effects of 5'-CG-3' methylation on the interaction of specific nuclear proteins with DNA sequences in the B control region of the Alu elements. These results are consistent with the interpretation that the 5'-CG-3' methylation interferes with the binding of proteins that are essential for the function of the B control region in these RNA polymerase III-transcribed elements, and that promoter methylation thus inhibits transcription.", "The components of the replisome that preserve genomic stability by controlling the progression of eukaryotic DNA replication forks are poorly understood. Here, we show that the GINS (go ichi ni san) complex allows the MCM (minichromosome maintenance) helicase to interact with key regulatory proteins in large replisome progression complexes (RPCs) that are assembled during initiation and disassembled at the end of S phase. RPC components include the essential initiation and elongation factor, Cdc45, the checkpoint mediator Mrc1, the Tof1-Csm3 complex that allows replication forks to pause at protein-DNA barriers, the histone chaperone FACT (facilitates chromatin transcription) and Ctf4, which helps to establish sister chromatid cohesion. RPCs also interact with Mcm10 and topoisomerase I. During initiation, GINS is essential for a specific subset of RPC proteins to interact with MCM. GINS is also important for the normal progression of DNA replication forks, and we show that it is required after initiation to maintain the association between MCM and Cdc45 within RPCs.", "A number of DNaseI-hypersensitive (DH) sites have been mapped within a regulatory region situated upstream of the human apolipoprotein B (apoB) promoter (-5262 to -899) that is required for high level expression of human apoB transgenes in the livers of mice. These DH sites were observed in nuclei from transcriptionally active liver-derived HepG2 cells, but were absent from transcriptionally inactive HeLa cell nuclei. Several nuclear protein binding sites were detected in the DNaseI-hypersensitive region by DNaseI footprinting with HepG2 nuclear extracts, representing putative binding sites for the liver-specific activators. The locations of binding sites for these transcription factors were revealed via computer analysis of the DNA sequence of this region against a transcription factor database. Many micrococcal nuclease hypersensitive (MH) sites were also observed in nuclei from HepG2 cells but not in HeLa cell nuclei, implying that in hepatic cells, nucleosomes are either absent or have been displaced from this region by the liver-specific transcriptional activators, as inferred by the correspondence between the DH sites, the MH sites and the footprints.", "PURPOSE OF REVIEW: We aim to illustrate the potential viability of MCTD as an underlying aetiology of Melkersson-Rosenthal syndrome. The case is probably the first description available in the literature of the Melkersson-Rosenthal as an early manifestation of mixed connective tissue disease.RECENT FINDINGS: The Melkersson-Rosenthal syndrome consists of a triad of recurrent lip and/or face swelling, fissured tongue, and intermittent facial palsy. Mixed connective tissue disease is a multisystemic disorder with overlapping features of systemic lupus erythematosus, scleroderma, and polymyositis, and is differentiated from them by a high titer of antibodies to ribonucleoprotein. The paper presents a case report of Melkersson-Rosenthal syndrome with an onset in childhood that derived from vasculitis that turned out to be an early manifestation of mixed connective tissue disease. We used MRI to evaluate patient's brain structure and Immunoblot Ena Profil 1 test to test serum autoantibodies level. The patient has a typical for Melkersson-Rosenthal syndrome triad of symptoms: bilateral facial nerve palsy, lingua plicata and facial oedema. Both TC and MRI of the head show no changes as well as laboratory tests except Anti-SS-A (Anti-Ro) and Anti-RNP autoantibody serum level that was highly positive. Neurological involvement of the MCTD usually includes, according to the frequency of the occurrence, trigeminal neuralgia, headaches, sensorineural hearing, cerebral haemorrhage, transverse myelitis, cauda equina syndrome, retinal vasculitis, progressive multifocal encephalopathy, and demyelinating neuropathy. For clinical practice it is important to remember that Melkersson-Rosenthal syndrome can also be the neurological manifestation of MCTD, especially when accompanied by other systemic symptoms.", "The oceanic picoplankton Prochlorococcus - probably the most abundant photosynthetic organism on our planet - can grow at great depths where light intensity is very low. We have found that the chlorophyll-binding proteins in a deep-living strain of this oxyphotobacterium form a ring around a trimer of the photosystem I (PS I) photosynthetic reaction centre, a clever arrangement that maximizes the capture of light energy in such dim conditions.", "OBJECTIVE: Influenza outbreaks have revealed that elderly persons are a great risk of death and serious complications after infection. The administration of oseltamivir, a neuramidase inhibitor, is effective for prophylaxis of influenza and to reduce disease duration and severity in healthy adults with naturally acquired febrile influenza. To clarify the usefulness of oseltamivir in the elderly we administered oseltamivir to all residents when an influenza A outbreak occurred in a nursing home.PATIENTS: Sixty-eight residents in the nursing home were investigated in which the influenza A outbreak occurred; 32 residents had fever and 28 residents were positive for influenza A with direct enzyme immunoassay.METHODS: Oseltamivir was administered at 75 mg twice daily for 5 days to all residents.RESULTS: Oseltamivir almost inhibited symptom onset in the influenza A-positive afebrile group. Initiation at 0 hour (22 cases), 1-12 hours (4 cases), 13-24 hours (5 cases) or 72 hours (1 case) from onset of symptoms was associated with mean fever durations of 26+/-18 hours, 38+/-21 hours, 54+/-12 hours and 120 hours, respectively, indicating that earlier initiation of therapy was associated with faster resolution of fever in elderly patients. Oseltamivir may be effective for household prophylaxis in the elderly persons. Oseltamivir administration was well tolerated in elderly persons.CONCLUSION: Oseltamivir is effective for the reduction or prophylaxis of influenza A infection in elderly persons.", "Giant cell arteritis (GCA) is a systemic inflammatory vasculitis affecting medium and large vessels with potentially sight and life-threatening complications. Early diagnosis and prompt treatment are imperative in order to prevent vision loss and progression of the disease. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are inflammatory markers which are elevated in the majority of patients and support the diagnosis of GCA among patients who present with typical symptoms. GCA is confirmed with superficial temporal artery biopsy which demonstrates characteristic pathological findings. Treatment of suspected ophthalmic involvement must be initiated urgently, even when diagnostic studies are pending. High dose corticosteroid therapy is the mainstay of treatment and is administered either intravenously or orally to prevent further vision loss and treat systemic vasculitis. Oral corticosteroid therapy is required for months to years with careful follow-up and periodic laboratory evaluations with ESR and CRP. Corticosteroids are tapered gradually over months and may be associated with complications such as hypertension, diabetes mellitus, osteoporosis, psychosis, peptic ulcer disease, and infection. Supplementation with calcium, vitamin D, bisphosphonate therapy, antimicrobial prophylaxis, and initiation of a proton pump inhibitor or Histamine H2-receptor antagonist should be considered. Recurrence of inflammation is common in GCA and necessitates an escalation of corticosteroid dose. Adjunctive immunomodulatory therapy may be considered in patients experiencing relapsing inflammation despite high doses of corticosteroids or those with corticosteroid-induced complications. Emerging evidence for adjunctive therapy with tocilizumab, methotrexate, aspirin, angiotensin receptor blockers, and statins is encouraging and may lead to a more mainstream role for these therapies among patients with GCA." ]

[ "The majority of existing computational tools rely on sequence homology and/or structural similarity to identify novel microRNA (miRNA) genes. Recently supervised algorithms are utilized to address this problem, taking into account sequence, structure and comparative genomics information. In most of these studies miRNA gene predictions are rarely supported by experimental evidence and prediction accuracy remains uncertain. In this work we present a new computational tool (SSCprofiler) utilizing a probabilistic method based on Profile Hidden Markov Models to predict novel miRNA precursors. Via the simultaneous integration of biological features such as sequence, structure and conservation, SSCprofiler achieves a performance accuracy of 88.95% sensitivity and 84.16% specificity on a large set of human miRNA genes. The trained classifier is used to identify novel miRNA gene candidates located within cancer-associated genomic regions and rank the resulting predictions using expression information from a full genome tiling array. Finally, four of the top scoring predictions are verified experimentally using northern blot analysis. Our work combines both analytical and experimental techniques to show that SSCprofiler is a highly accurate tool which can be used to identify novel miRNA gene candidates in the human genome. SSCprofiler is freely available as a web service at http://www.imbb.forth.gr/SSCprofiler.html.", "Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Majority of PD are sporadic, for which genetic causes remain largely unknown. Alpha-synuclein, the main component of Lewy bodies, plays a central role in the PD pathogenesis. Macroautophagy is a highly conserved cellular process that digests dysfunctional macromolecules and damaged organelles. Accumulating evidence indicates that macroautophagy (hereafter referred to as autophagy) is involved in alpha-synuclein degradation. Dysregulation of autophagy has been observed in the brain tissues from PD patients and animal models. We hypothesized that change expression levels of autophagy-related genes (ATG), including ATG5, may contribute to PD. In this study, we genetically and functionally analyzed the ATG5 gene promoter in groups of sporadic PD patients and ethnic-matched healthy controls. A novel heterozygous variant, 106774459T>A, was identified in one female patient, but in none of controls, which significantly enhanced transcriptional activities of the ATG5 gene promoter. Furthermore, ATG5 gene expression level in the PD patient was significantly elevated than that in controls. Four novel heterozygous variants, 106774423C>A, 106774418C>A, 106774382C>A and 106774206G>A, were only found in controls. The variant, 106774464C>T, and SNP-106774030A>G (rs510432) were found in PD patients and controls with similar frequencies. Collectively, the variant identified in PD patient may change ATG5 protein levels and alter autophagy activities, contributing to PD onset as a risk factor.", "PURPOSE: Von Hippel-Lindau (VHL) disease is an inherited syndrome caused by germline mutations in the VHL tumor suppressor gene, predisposing to a variety of neoplasms including pancreatic neuroendocrine tumors (PanNET). In VHL disease, PanNET probably progress according to a specific pathway of carcinogenesis. Our aim was to characterize by molecular quantitative analysis a panel of molecules implicated in the VHL pathway and in tumor progression in the PanNET of patients with VHL.EXPERIMENTAL DESIGN: The expression of 52 genes was studied by quantitative reverse transcriptase PCR in 18 patients with VHL operated on for PanNET and compared with 16 non-VHL PanNET. The VHL and non-VHL tumors were matched according to their size and cell proliferation. For some genes, we looked for differences in the protein expression in VHL PanNET (n = 31), microadenomas (n = 22), and non-VHL PanNET (n = 16), included in tissue microarray blocks.RESULTS: Nineteen (36%) genes were significantly upregulated and three (6%) downregulated in VHL PanNET. The upregulated genes were related to (i) hypoxia-inducible factor (HIF) molecules (CA9, HIF2A, and GLUT1), (ii) angiogenesis (CDH5, VEGFR1, EDNRA, ANGPT2, CD34, VEGFR2, VEGFA, and ANGPT1), (iii) the processes of epithelial-mesenchymal transition (VIM) and/or metastasis (LAMA4 and CXCR4), (iv) growth factors and receptors (PDGFB, IRS1, and ERBB1), or (v) cell cycle (CCND1 and CDKN2A). The downregulated genes were related to (i) EMT (OCLN) and (ii) signaling pathways (RPS6KB1 and GADD45B).CONCLUSION: This study shows that the progression of PanNET in patients with VHL tumors follows a specific pathway and supports that targeting molecules specifically involved may be of therapeutic importance.", "Histatins are a group of small, cationic, antifungal peptides present in human saliva. A previous molecular modeling analysis suggested structural similarity between the Phe14-His15 and His18-His19 dipeptide sequences in histatin-5 (Hsn-5; a 24-amino-acid polypeptide) and the sequence of miconazole (one of the azole-based antifungal therapeutic agents), implying that the mechanisms of killing of Candida albicans by these two molecules may be similar. To further elaborate on this observation, we have produced two variants of Hsn-5 in which Phe14-His15 or His18-His19 dipeptide sequences were replaced by Ala-Ala (F14A/H15A and H18A/H19A) to eliminate the phenyl and imidazole rings of the side chains and assessed their candidacidal activities against C. albicans. In addition, we tested azole-resistant C. albicans and Candida glabrata strains for their susceptibilities to Hsn-5. Analysis of the purified recombinant proteins for their candidacidal activities indicated that both variants were significantly less effective (the molar concentrations required to kill half of the maximum number of cells [ED50s], approximately 67 and approximately 149 microM for F14A/H15A and H18A/H19A, respectively) than the unaltered Hsn-5 (ED50, approximately 8 microM) at killing C. albicans, suggesting that the two dipeptide sequences are important for the candidacidal activity of Hsn-5. Assessment of the candidacidal activity of Hsn-5 with the well-characterized azole-resistant strains of C. albicans and C. glabrata, however, suggested that the mode of action of histatins against Candida is distinct from that of azole-based antifungal agents because Hsn-5 kills both azole-sensitive and azole-resistant strains equally well.", "BACKGROUND: Celiac disease (CD) is a frequent inflammatory intestinal disease, with a genetic background, caused by gliadin-containing food. Some gliadin peptides are not digested by intestinal proteases and can have different biological effects. Gliadin peptides can induce innate and adaptive T cell-mediated immune responses. The major mediator of the stress and innate immune response to gliadin peptides (i.e., peptides 31-43 and 31-55) is the cytokine interleukin-15 (IL-15). Other peptides such as the 33 mer containing the P57-68 sequence, after tissue transglutaminase deamidation, are well presented to T cell in the intestine and can induce an adaptive immune response.FINDINGS: In this paper, we review the recent studies on the digestion of gliadin and the peptides released by the digestion process. We will also discuss the mechanisms responsible for the internalization and transcytosis of indigested gliadin peptides in the intestinal epithelium.CONCLUSIONS: Gliadin is not completely digested by the intestinal proteases producing bioactive peptides that have different biological effects. These peptides are internalized in the cells by an active process of endocytosis and can traverse the intestinal mucosa with different kinetics and immunological effects. In vivo findings will also be discussed.", "Base J, β-d-glucosyl-hydroxymethyluracil, is an epigenetic modification of thymine in the nuclear DNA of flagellated protozoa of the order Kinetoplastida. J is enriched at sites involved in RNA polymerase (RNAP) II initiation and termination. Reduction of J in Leishmania tarentolae via growth in BrdU resulted in cell death and indicated a role of J in the regulation of RNAP II termination. To further explore J function in RNAP II termination among kinetoplastids and avoid indirect effects associated with BrdU toxicity and genetic deletions, we inhibited J synthesis in Leishmania major and Trypanosoma brucei using DMOG. Reduction of J in L. major resulted in genome-wide defects in transcription termination at the end of polycistronic gene clusters and the generation of antisense RNAs, without cell death. In contrast, loss of J in T. brucei did not lead to genome-wide termination defects; however, the loss of J at specific sites within polycistronic gene clusters led to altered transcription termination and increased expression of downstream genes. Thus, J regulation of RNAP II transcription termination genome-wide is restricted to Leishmania spp., while in T. brucei it regulates termination and gene expression at specific sites within polycistronic gene clusters.", "The phosphorylation-induced mobility shift of the high molecular weight form of phospholamban (24,500 daltons) in the cardiac sarcoplasmic reticulum produced on 3',5'-cyclic AMP (cAMP)-dependent phosphorylation with 5 mM ATP was resolved into five clear steps on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and on Ca2+-calmodulin-dependent phosphorylation into ten steps. The mobility shift of the low molecular weight form of phospholamban (less than 14,400 daltons) in these reactions occurred in one step and two steps, respectively. With the two protein kinase activities, the electrophoretic pattern of the mobility shifts of the high and low molecular weight forms of phospholamban was similar to that obtained with Ca2+-calmodulin-dependent protein kinase alone. The results of pulse-chase experiments involving the centrifuge column method suggested that the site(s) of phosphorylation by cAMP- and Ca2+-calmodulin-dependent protein kinase activities are on the same phospholamban molecule. Two-dimensional tryptic peptide maps of phosphorylated phospholamban indicated that cAMP-dependent protein kinase phosphorylates at a single site, A, and Ca2+-calmodulin-dependent protein kinase phosphorylates at sites C1 and C2 in the low molecular weight form, where A is different from C1 but may be the same as C2. The high molecular weight form of phospholamban is suggested to be a pentamer of identical monomers (low molecular weight form) having one phosphorylation site for cAMP-dependent protein kinase and two for Ca2+-calmodulin-dependent protein kinase." ]

[ "BACKGROUND: Metagenomics is a powerful methodology to study microbial communities, but it is highly dependent on nucleotide sequence similarity searching against sequence databases. Metagenomic analyses with next-generation sequencing technologies produce enormous numbers of reads from microbial communities, and many reads are derived from microbes whose genomes have not yet been sequenced, limiting the usefulness of existing sequence similarity search tools. Therefore, there is a clear need for a sequence similarity search tool that can rapidly detect weak similarity in large datasets.RESULTS: We developed a tool, which we named CLAST (CUDA implemented large-scale alignment search tool), that enables analyses of millions of reads and thousands of reference genome sequences, and runs on NVIDIA Fermi architecture graphics processing units. CLAST has four main advantages over existing alignment tools. First, CLAST was capable of identifying sequence similarities ~80.8 times faster than BLAST and 9.6 times faster than BLAT. Second, CLAST executes global alignment as the default (local alignment is also an option), enabling CLAST to assign reads to taxonomic and functional groups based on evolutionarily distant nucleotide sequences with high accuracy. Third, CLAST does not need a preprocessed sequence database like Burrows-Wheeler Transform-based tools, and this enables CLAST to incorporate large, frequently updated sequence databases. Fourth, CLAST requires <2 GB of main memory, making it possible to run CLAST on a standard desktop computer or server node.CONCLUSIONS: CLAST achieved very high speed (similar to the Burrows-Wheeler Transform-based Bowtie 2 for long reads) and sensitivity (equal to BLAST, BLAT, and FR-HIT) without the need for extensive database preprocessing or a specialized computing platform. Our results demonstrate that CLAST has the potential to be one of the most powerful and realistic approaches to analyze the massive amount of sequence data from next-generation sequencing technologies.", "Induced pluripotent stem (iPS) cells are derived by epigenetic reprogramming, but their DNA methylation patterns have not yet been analyzed on a genome-wide scale. Here, we find substantial hypermethylation and hypomethylation of cytosine-phosphate-guanine (CpG) island shores in nine human iPS cell lines as compared to their parental fibroblasts. The differentially methylated regions (DMRs) in the reprogrammed cells (denoted R-DMRs) were significantly enriched in tissue-specific (T-DMRs; 2.6-fold, P < 10(-4)) and cancer-specific DMRs (C-DMRs; 3.6-fold, P < 10(-4)). Notably, even though the iPS cells are derived from fibroblasts, their R-DMRs can distinguish between normal brain, liver and spleen cells and between colon cancer and normal colon cells. Thus, many DMRs are broadly involved in tissue differentiation, epigenetic reprogramming and cancer. We observed colocalization of hypomethylated R-DMRs with hypermethylated C-DMRs and bivalent chromatin marks, and colocalization of hypermethylated R-DMRs with hypomethylated C-DMRs and the absence of bivalent marks, suggesting two mechanisms for epigenetic reprogramming in iPS cells and cancer.", "BACKGROUND: Oral immunization has numerous advantages over parenteral administrations. In addition to ease administration, more effective pathogen elimination on the mucosa before spreading into the blood circulation, constitutes the main benefit. This is particularly true for pathogens that enter the body through the oral route. On the other hand, it is the most challenging administration route for peptides, proteins and recombinant antigens due to gastrointestinal (GI) tract, numerous barriers including the harsh environment and the inherent weak immunogenicity. In addition to the adjuvant properties, polymeric particles arise as the most promising strategy to overcome poor antigen bioavailability/ stability upon oral administration. The Peyer's patches have been considered an important structure of the gut associate lymphoid tissue (GALT) for the initiation of the immune response towards particulate oral antigens.OBJECTIVE: The transport mechanism of both, nano and microparticles across intestinal mucosa, particularly throughout Peyer's patches, is discussed in this review.CONCLUSION: We provide a short and concise update (last decade) focused on the importance of particle physicochemical properties, M-cell ligands and size-dependent transport and intracellular fate concerning Peyer's patches targeted oral vaccination.", "Stroke is a major cause of mortality and morbidity, and thrombolysis has served as a catalyst for major changes in the management of acute ischaemic stroke. Intravenous alteplase (recombinant tissue plasminogen activator) is the only approved thrombolytic agent at present indicated for acute ischaemic stoke. While the licensed time window extends to 3h from symptom onset, recent data suggest that the trial window can be extended up to 4.5 h with overall benefit. Nonetheless, 'time is brain' and every effort must be made to reduce the time delay to thrombolysis. Intracranial haemorrhage is the major complication associated with thrombolysis, and key factors increasing risk of haemorrhage include increasing age, high blood pressure, diabetes and stroke severity. Currently, there is no direct evidence to support thrombolysis in patients >80 years of age, with a few case series indicating no overt harm. Identification of viable penumbra based on computed tomography/magnetic resonance imaging may allow future extension of the time window. Adjuvant transcranial Doppler ultrasound has the potential to improve reperfusion rates. While intra-arterial thrombolysis has been in vogue for a few decades, there is no clear advantage over intravenous thrombolysis. The evidence base for thrombolysis in specific situations (e.g. dissection, pregnancy) is inadequate, and individualized decisions are needed, with a clear indication to the patient/carer about the lack of direct evidence, and the risk-benefit balance. Patient-friendly information leaflets may facilitate the process of consent for thrombolysis. This article summarizes the recent advances in thrombolysis for acute ischaemic stroke. Key questions faced by clinicians during the decision-making process are answered based on the evidence available.", "alpha-neurotoxins from elapid snake venoms and alpha-conotoxins from marine snails bind specifically and with high affinity to nicotinic cholinoceptors. Although both types of toxin are polypeptides, there is more than a fourfold difference in size between the two and no clear sequence homology is evident. A systematic computer search of the three-dimensional structure of erabutoxin b (an alpha-neurotoxin from the false sea snake Laticauda semifasciata) was performed to identify the locality that most closely matched the amino acid compositions of the smaller alpha-conotoxins (from the marine snails Conus magus and Conus geographus). The area of greatest similarity centered on residue position 25 of erabutoxin b, a locale that is conserved throughout the snake alpha-neurotoxins and their homologues. Six proteins unrelated to erabutoxin b were compared to the alpha-conotoxins to show that the extent of the erabutoxin b/alpha-conotoxin match was too high to be coincidental. Homologues of erabutoxin b, namely alpha-cobratoxin from Naja naja siamensis and cytotoxin VII4 from Naja mossambica mossambica, were also analyzed. The extent of the matching with the alpha-conotoxins decreased in the series erabutoxin b greater than alpha-cobratoxin greater than cytotoxin VII4, and this also relates the order of similarity to the pharmacological properties of the alpha-conotoxins. The alpha-conotoxin-like area of the snake alpha-neurotoxins is peripheral to the site previously considered important for binding to the cholinoceptor, even though it seems to represent the focus of evolutionary convergence between the two types of neurotoxin. The area of resemblance does, however, have strong associations with the conformational behavior of the snake toxins. Hence, the outcome of this study has important consequences for the current ideas on snake alpha-neurotoxin structure/activity relationships and the evolutionary origins of neurotoxicity.", "The pattern recognition molecules Nod1 and Nod2 play important roles in intestinal homeostasis; however, how these proteins impact on the development of inflammation during bacterial colitis has not been examined. In the streptomycin-treated mouse model of Salmonella colitis, we found that mice deficient for both Nod1 and Nod2 had attenuated inflammatory pathology, reduced levels of inflammatory cytokines, and increased colonization of the mucosal tissue. Nod1 and Nod2 from both hematopoietic and nonhematopoietic sources contributed to the pathology, and all phenotypes were recapitulated in mice deficient for the signaling adaptor protein Rip2. However, the influence of Rip2 was strictly dependent on infection conditions that favored expression of the Salmonella pathogenicity island 2 (SPI-2) type III secretion system (TTSS), as Rip2 was dispensable for inflammation when mice were infected with bacteria grown under conditions that promoted expression of the SPI-1 TTSS. Thus, Nod1 and Nod2 can modulate inflammation and mediate efficient clearance of bacteria from the mucosal tissue during Salmonella colitis, but their role is dependent on the expression of the SPI-2 TTSS.", "Because of high stability and slow unfolding rates of G-quadruplexes (G4), cells have evolved specialized helicases that disrupt these non-canonical DNA and RNA structures in an ATP-dependent manner. One example is DHX36, a DEAH-box helicase, which participates in gene expression and replication by recognizing and unwinding parallel G4s. Here, we studied the molecular basis for the high affinity and specificity of DHX36 for parallel-type G4s using all-atom molecular dynamics simulations. By computing binding free energies, we found that the two main G4-interacting subdomains of DHX36, DSM and OB, separately exhibit high G4 affinity but they act cooperatively to recognize two distinctive features of parallel G4s: the exposed planar face of a guanine tetrad and the unique backbone conformation of a continuous guanine tract, respectively. Our results also show that DSM-mediated interactions are the main contributor to the binding free energy and rely on making extensive van der Waals contacts between the GXXXG motifs and hydrophobic residues of DSM and a flat guanine plane. Accordingly, the sterically more accessible 5'-G-tetrad allows for more favorable van der Waals and hydrophobic interactions which leads to the preferential binding of DSM to the 5'-side. In contrast to DSM, OB binds to G4 mostly through polar interactions by flexibly adapting to the 5'-terminal guanine tract to form a number of strong hydrogen bonds with the backbone phosphate groups. We also identified a third DHX36/G4 interaction site formed by the flexible loop missing in the crystal structure." ]

[ "BACKGROUND: The monoamine oxidase-A (MAOA) gene plays a vital role in the metabolism of neurotransmitters, e.g, serotonin, norepinephrine, and dopamine. A polymorphism in the promoter region (MAOA-uVNTR) affects transcriptional efficiency. Allelic variation in MAOA-uVNTR has been associated with body mass index (BMI). We extended previous work by examining relations among this polymorphism and serum lipid levels.MATERIAL/METHODS: The sample consisted of 74 males enrolled in a study of caregivers for relatives with dementia. Regression models, adjusted for age, race, group status (caregiver/control), and cholesterol lowering medication (yes/no), were used to examine associations between high verses low MAOA-uVNTR activity alleles and total cholesterol, HDL, LDL, VLDL, LDL/HDL ratio, triglycerides, and BMI.RESULTS: Higher total cholesterol (p<0.03), LDL/HDL ratio (p<0.01), triglycerides (p<0.02), and VLDL (p<0.02) were associated with low activity MAOA-uVNTR alleles. HDL and LDL were modestly related to MAOA-uVNTR activity, however, they did not reach the conventional significance level (p<0.07 and p<0.10, respectively). BMI (p<0.74) was unrelated to MAOA-uVNTR transcription.CONCLUSIONS: The present findings suggest that MAOA-uVNTR may influence lipid levels and individuals with less active alleles are at increased health risk.", "Aberrant expression of different family members of the Eph/ephrin system, which comprises the Eph receptors (Ephs) and their ligands (ephrins), has been implicated in various malignancies including breast cancer. The latter presents as a heterogeneous disease with diverse molecular, morphologic and clinical behavior signatures. This review reflects the existing Eph/ephrin literature while focusing on breast cancer heterogeneity. Hormone positive, HER2 positive and triple negative breast cancer (TNBC) cell lines, xenografts/mutant animal models and patient samples are examined separately as, in humans, they represent entities with differences in prognosis and treatment. EphA2, EphB4 and EphB6 are the members most extensively studied in breast cancer. Existing research points to the potential use of various Eph/ephrin members as biomarkers for assessing prognosis and selecting the most suitable therapeutic strategies in variable clinical scenarios, also for overcoming drug resistance, in the era of breast cancer heterogeneity.", "Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders.", "Author information:(1)Assistance Publique-Hôpitaux de Marseille (AP-HM), Pharmacie Usage Intérieur, Hôpital Nord, 13015 Marseille, France.(2)Assistance Publique-Hôpitaux de Marseille (AP-HM), Pharmacie Usage Intérieur, Hôpital de la Conception, 13005 Marseille, France.(3)Assistance Publique-Hôpitaux de Marseille (AP-HM), Oncopharma, 13005 Marseille, France; Aix-Marseille Université, CNRS, Institut de Chimie Radicalaire ICR, UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, 13005 Marseille, France.(4)Aix-Marseille Université, CNRS, Institut de Chimie Radicalaire ICR, UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, 13005 Marseille, France; Assistance Publique-Hôpitaux de Marseille (AP-HM), Service Central de la Qualité et de l'Information Pharmaceutiques (SCQIP), 13005 Marseille, France.(5)Aix-Marseille Université, CNRS, Institut de Chimie Radicalaire ICR, UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, 13005 Marseille, France; Assistance Publique-Hôpitaux de Marseille (AP-HM), Service Central de la Qualité et de l'Information Pharmaceutiques (SCQIP), 13005 Marseille, France. Electronic address: patrice.vanelle@univ-amu.fr.", "The androgen receptor gene (AR) contains a domain which includes a variable number of CAG sequences and alleles with low numbers of CAG repeats show high transactivation activity when complexed with testosterone. The ratio of 2nd and 4th digit length (2D:4D) is negatively correlated with phenotypic effects of testosterone. Low numbers of CAG repeats and low 2D:4D are both associated with high sperm numbers and protection against breast cancer. This suggests that CAG number and 2D:4D are correlated i.e. low CAG number and low 2D:4D indicate high activation of androgen-responsive genes. Findings from AR studies predict that low 2D:4D will be associated with prostate and hepatocellular cancer, urolithiasis, ADHD, ankylosing spondylitis, spontaneous abortion, and polycystic ovaries, while high 2D:4D will be associated with motor neuron diseases and endometrial cancer. Findings from 2D:4D studies predict that short CAG length will be common in autism and Asperger's syndrome, while high numbers of CAG repeats will be found in men who are prone to early myocardial infarction.", "CircRNAs are novel members of the non-coding RNA family. For several decades circRNAs have been known to exist, however only recently the widespread abundance has become appreciated. Annotation of circRNAs depends on sequencing reads spanning the backsplice junction and therefore map as non-linear reads in the genome. Several pipelines have been developed to specifically identify these non-linear reads and consequently predict the landscape of circRNAs based on deep sequencing datasets. Here, we use common RNAseq datasets to scrutinize and compare the output from five different algorithms; circRNA_finder, find_circ, CIRCexplorer, CIRI, and MapSplice and evaluate the levels of bona fide and false positive circRNAs based on RNase R resistance. By this approach, we observe surprisingly dramatic differences between the algorithms specifically regarding the highly expressed circRNAs and the circRNAs derived from proximal splice sites. Collectively, this study emphasizes that circRNA annotation should be handled with care and that several algorithms should ideally be combined to achieve reliable predictions.", "Large-scale RNAseq has substantially changed the transcriptomics field, as it enables an unprecedented amount of high resolution data to be acquired. However, the analysis of these data still poses a challenge to the research community. Many tools have been developed to overcome this problem, and to facilitate the study of miRNA expression profiles and those of their target genes. While a few of these enable both kinds of analysis to be performed, they also present certain limitations in terms of their requirements and/or the restrictions on data uploading. To avoid these restraints, we have developed a suite that offers the identification of miRNA, mRNA and circRNAs that can be applied to any sequenced organism. Additionally, it enables differential expression, miRNA-mRNA target prediction and/or functional analysis. The miARma-Seq pipeline is presented as a stand-alone tool that is both easy to install and flexible in terms of its use, and that brings together well-established software in a single bundle. Our suite can analyze a large number of samples due to its multithread design. By testing miARma-Seq in validated datasets, we demonstrate here the benefits that can be gained from this tool by making it readily accessible to the research community.", "Telomerase, a ribonucleoprotein, is responsible for maintaining the telomere length and therefore promoting genomic integrity, proliferation, and lifespan. In addition, telomerase protects the mitochondria from oxidative stress and confers resistance to apoptosis, suggesting its possible importance for the surviving of non-mitotic, highly active cells such as neurons. We previously demonstrated the ability of novel telomerase activators to increase telomerase activity and expression in the various mouse brain regions and to protect motor neurons cells from oxidative stress. These results strengthen the notion that telomerase is involved in the protection of neurons from various lesions. To underline the role of telomerase in the brain, we here compare the activity of telomerase in male and female mouse brain and its dependence on age. TRAP assay is a standard method for detecting telomerase activity in various tissues or cell lines. Here we demonstrate the analysis of telomerase activity in three regions of the mouse brain by non-denaturing protein extraction using CHAPS lysis buffer followed by modification of the standard TRAP assay. In this 2-step assay, endogenous telomerase elongates a specific telomerase substrate (TS primer) by adding TTAGGG 6 bp repeats (telomerase reaction). The telomerase reaction products are amplified by PCR reaction creating a DNA ladder of 6 bp increments. The analysis of the DNA ladder is made by 4.5% high resolution agarose gel electrophoresis followed by staining with highly sensitive nucleic acid stain. Compared to the traditional TRAP assay that utilize (32)P labeled radioactive dCTP's for DNA detection and polyacrylamide gel electrophoresis for resolving the DNA ladder, this protocol offers a non-toxic time saving TRAP assay for evaluating telomerase activity in the mouse brain, demonstrating the ability to detect differences in telomerase activity in the various female and male mouse brain region." ]

[ "A Thai woman, who was affected with neurofibromatosis type 1, was followed up and re-evaluated at ages 45, 61, and 67 years. Her mother and her three brothers were also affected. The proposita was very severely affected. She was born blind with underdeveloped eyeglobes and had large plexiform neurofibromas on her face. Her eyelids were gigantic and tears drained from the orifice between them. Cutaneous neurofibromas were observed all over her body. A novel mutation c.4821delA was identified in NF1 gene, which predicted truncation of neurofibromin (p.Leu1607fs).", "Heterozygous mutations of the gene encoding neutrophil elastase (ELA2) have been associated with cyclic neutropenia (CN) and severe congenital neutropenia (SCN). To date, 30 different mutations have been reported, but no correlation has been found with the degree of neutropenia. To address this issue, we analyzed the clinical, hematologic, and molecular characteristics of 81 unrelated patients with SCN (n = 54) or CN (n = 27). We identified mutations in 31 patients, two thirds of whom had sporadic forms. Familial cases were consistent with dominant inheritance. Seventeen novel mutations were identified, showing that the mutational spectrum encompasses not only the region encoding the mature enzyme but also the prodomains and promoter region. Genotype-phenotype analysis strongly suggested that ELA2 mutations correlate with more severe expression of neutropenia, specifically in patients diagnosed with SCN. This study underlines the importance of ELA2 molecular screening to identify patients who may be at particular risk of severe bacterial infections and/or acute myeloid leukemia/myelodysplasia. By phenotypic analysis of affected relatives and carriers of the same ELA2 mutations, we showed that the expression of neutropenia in CN and SCN may be either homogeneous or variable according to the type of mutations, suggesting different pathogenetic mechanisms.", "Zieve's syndrome consists of transient haemolytic anaemic, jaundice, hyperlipidaemia and alcohol-induced liver disease. It is rare with less than 75 cases reported in a Medicine literature search from 1966. It can present acutely with abdominal pain.", "Ehlers-Danlos syndrome denotes a group of inherited connective tissue diseases comprising nine types. Type IV Ehlers-Danlos syndrome is the most life-threatening form. It is characterized by a type III collagen deficiency resulting in arterial fragility and death from vascular rupture or bowel perforation. This disease involves a col 3A1 gene mutation. We report the case of a 44 year-old woman with type IV Ehlers-Danlos syndrome. The medical history of our patient included bowel necrosis and two vascular ruptures. We indicate data required to establish Ehlers-Danlos syndrome diagnosis and guidelines for patient management.", "Structure/function relationships of acid beta-glucosidase, the enzyme deficient in Gaucher disease, were evaluated by characterizing the proteins expressed from cDNAs encoding normal and mutant enzymes. Twenty-two Gaucher disease mutations or created mutations were expressed in Spodoptera frugiperda (Sf9) cells and analyzed for catalytic properties, stability, inhibitor binding, and modifier interactions. Many Gaucher disease mutations encoded highly disruptive amino acid substitutions (e.g. P289L and D409V) and produced severely compromised proteins with very reduced activity (kcat < 1% of normal) and/or stability. Six mutant enzymes had sufficient catalytic activity (kcat approximately 5-30% of normal) for extensive studies. The highly conservative substitutions, i.e. F216Y or S364T and V394L, led to severe, but selective, abnormalities of enzyme stability or large decreases in catalytic activity, respectively. The T323I, N370S, and V394L enzymes interacted abnormally with active site-directed inhibitors and localized these residues to the glycon binding region. Selected mutant enzymes were poorly activated by phosphatidylserine (V394L, L444P, and R463C) or by saposin C (L444P and T323I), indicating that the enzyme sites for interaction with these activators were within the carboxyl one-third of the enzyme. Substitutions of Ser, Glu, and/or Gly at residues Asp-443 and/or Asp-445 demonstrated important steric roles for these residues in the active site, but neither is the catalytic nucleophile. Together with previous studies, the present analyses provide an insight into the pathogenesis of Gaucher disease and the functional organization of acid beta-glucosidase.", "OBJECTIVE: Previous experimental studies have provided evidence showing that changes in thyroid hormone signaling correspond to alterations in myocardial function in animal models of heart failure. The present study further explores whether thyroid hormone alterations are correlated with the functional status of the myocardium in patients with heart failure.METHODS: In this study, 37 patients with mean ejection fraction (EF%) of 26.2 (8.2) were included. Myocardial performance was assessed by echocardiography and cardiopulmonary exercise testing. Total tri-iodothyronine (T3), thyroxine, and TSH levels were measured in plasma.RESULTS: Total T3 was strongly correlated with VO2max (r = 0.78, P = 2 x 10(-8)). Furthermore, multivariate analysis revealed that total T3 was an independent predictor of VO2max (P = 0.000 005). A weaker but significant correlation was also found between total T3 and EF% (r = 0.56, P = 0.0004), systolic (r = 0.43, P = 0.009) and diastolic (r = 0.46, P = 0.004) blood pressure.CONCLUSIONS: changes in thyroid hormone were closely correlated to myocardial functional status in patients with heart failure. These data probably indicate a possible role of thyroid hormone in the pathophysiology of heart failure and confirm previous experimental reports.", "In cancer research, background models for mutation rates have been extensively calibrated in coding regions, leading to the identification of many driver genes, recurrently mutated more than expected. Noncoding regions are also associated with disease; however, background models for them have not been investigated in as much detail. This is partially due to limited noncoding functional annotation. Also, great mutation heterogeneity and potential correlations between neighboring sites give rise to substantial overdispersion in mutation count, resulting in problematic background rate estimation. Here, we address these issues with a new computational framework called LARVA. It integrates variants with a comprehensive set of noncoding functional elements, modeling the mutation counts of the elements with a β-binomial distribution to handle overdispersion. LARVA, moreover, uses regional genomic features such as replication timing to better estimate local mutation rates and mutational hotspots. We demonstrate LARVA's effectiveness on 760 whole-genome tumor sequences, showing that it identifies well-known noncoding drivers, such as mutations in the TERT promoter. Furthermore, LARVA highlights several novel highly mutated regulatory sites that could potentially be noncoding drivers. We make LARVA available as a software tool and release our highly mutated annotations as an online resource (larva.gersteinlab.org)." ]

[ "Chronic stable angina pectoris (CSAP) is the most common manifestation of coronary artery disease (CAD). Angina pectoris occurs as a result of an imbalance between myocardial perfusion and the demands of the myocardium. Elevated heart rate (HR) is an important pathophysiological variable that increases myocardial oxygen demand, and also limits tissue perfusion by reducing the duration of diastole during which most myocardial perfusion occurs. Elevated resting HR represents a significant predictor of all-cause and cardiovascular mortality in the general population and patients with cardiovascular disease (CVD) because it assists the progression of CVD through the development of atherosclerosis, plaque destabilization, and initiation of arrhythmias. Since β-blockers have been found to reduce HR, therefore, they are currently viewed as the first line therapy for CSAP and are associated with an improved prognosis after acute myocardial infarction (AMI) or congestive heart failure (CHF). The classical treatments for HR reduction have shown negative aspects, such as β-blockers therapy which exerts negative effects on regional myocardial blood flow and function when HR reduction is eliminated by atrial pacing. Calcium channel antagonists functionally antagonize coronary vasoconstriction mediated through α-adrenoreceptors, and are thus devoid of this undesired effect, but the compounds are nevertheless negative inotrope. Ivabradine (IVA), a pure HR lowering drug, reduces the demand of myocardial oxygen during exercise, contributes to the restoration of oxygen balance and is therefore beneficial in chronic CVD. No relevant negative effects have been observed on cardiac conduction, contractility, relaxation, repolarization or blood pressure (BP). Beneficial effects of IVA have been noticed in CSAP and CHF, with optimal tolerability profile due to selective interaction with I(f) channel of sino atrial node cells. More recently, IVA has been highly recommended to be used in patients with CAD in association with β-blockers. This review highlights the importance of IVA in the treatment of ischemic heart disease.", "Epoxyeicosatrienoic acids (EETs) are potent lipid mediators formed by cytochrome P450 epoxygenases from arachidonic acid. They consist of four regioisomers of cis-epoxyeicosatrienoic acids: 5,6-, 8,9-, 11,12- and 14,15-EET. Here we investigated whether these triene epoxides are electrophilic enough to form covalent adducts with DNA in vitro. Using the thin-layer chromatography (TLC) (32)P-postlabelling method for adduct detection we studied the reaction of individual deoxynucleoside 3'-monophosphates and calf thymus DNA with the four racemic EETs. Under physiological conditions (pH 7.4) only ±11,12-EET11,12-EET formed adducts with DNA in a dose dependent manner detectable by the (32)P-postlabelling method. However, when pre-incubated at pH 4 all four racemic EETs were capable to bind to DNA forming several adducts. Under these conditions highest DNA adduct levels were found with ±11,12-EET followed by ±5,6-EET, ±8,9-EET, and ±14,15-EET, all of them two orders of magnitude higher (between 3 and 1 adducts per 10(5) normal nucleotides) than those obtained with ±11,12-EET at pH 7.4. Similar DNA adduct patterns consisting of up to seven spots were observed with all four racemic EETs the most abundant adducts being derived from the reaction with deoxyguanosine and deoxyadenosine. In summary, when analysed by the (32)P-postlabelling method all four racemic EETs formed multiple DNA adducts after activation by acidic pH, only ±11,12-EET produced DNA adducts in aqueous solution at neutral pH. Therefore, we conclude from our in vitro studies that EETs might be endogenous genotoxic compounds.", "Ataxia with vitamin E deficiency is an autosomal recessive condition associated with a defect in the a-tocopherol transfer protein. Clinically it manifests as a progressive ataxia with a phenotype resembling that of Friedreich's ataxia. There is some evidence that progression of neurological symptoms is prevented by vitamin E therapy. A patient is described who was given a clinical diagnosis of Friedreich's ataxia. Molecular genetic analysis showed the absence of the frataxin gene expansion. Subsequent vitamin E assay showed deficiency and a diagnosis of ataxia with vitamin E deficiency was made. It is recommended that all patients with ataxia of unknown cause should have vitamin E deficiency excluded. When a diagnosis of Friedreich's ataxia is considered patients should have frataxin analysis in addition. Further, neurologists should be aware that ataxia with vitamin E deficiency may present as \"mutation negative\" Friedreich's ataxia.", "The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms.", "The G-protein-coupled receptor, CXCR4, is highly expressed on a number of cell types, and together with its ligand, CXCL12, plays an important role in immune development and trafficking of cells. CXCR4 promotes tumor growth, angiogenesis and metastasis, and is a prognostic marker in a number of different types of tumors. Additionally, CXCR4 is utilized, together with CD4, for entry of T-tropic HIV viruses. Ethnic differences in incidence and mortality of various cancers, and in the response to highly active antiretroviral treatment (HAART) of HIV-1 infected individuals have been reported. The aim of this study was to establish if differences in the CXCR4-CXCL12 axis exist between ethnically divergent uninfected South Africans. CXCR4 density was significantly higher on CD4(+) and CD8(+) T cells, B cells and CD56(dim) NK cells, and CXCL12 levels lower in Black compared with Caucasian individuals. Furthermore, an inverse correlation was observed between CXCR4 density on CD56(+) and CD3(+) cells and age, only in Black individuals. CXCL12-3'A heterozygosity (AG) found in 28% of Caucasians did not explain the higher plasma levels of CXCL12 compared to Black individuals who were all GG genotypes, suggesting that other factors influence homeostatic levels of CXCL12. In conclusion, this study demonstrates that ethnically divergent populations show clear differences in both CXCR4 density and CXCL12 plasma levels which may influence the course of cancer and HIV-1 infection.", "Prevention is an important treatment strategy for diminishing prostate cancer morbidity and mortality and is applicable to both early- and late-stage disease. There are three basic classifications of cancer prevention: primary (prevention of incident disease), secondary (identification and treatment of preclinical disease), and tertiary (prevention of progression or recurrence). Based on level I evidence, 5-alpha reductase inhibitors (5-ARIs) should be considered in selected men to prevent incident prostate cancer. Level I evidence also supports the consideration of dutasteride, a 5-ARI, for tertiary prevention in active surveillance and biochemical recurrence patients. Vitamins and supplements, including selenium or vitamin E, have not been proven in clinical trials to prevent prostate cancer and in the case of Vitamin E has been found to increase the risk of incident prostate cancer. Ongoing and future trials may further elucidate the role of diet and immunotherapy for prevention of prostate cancer.", "BACKGROUND: Data extraction and integration methods are becoming essential to effectively access and take advantage of the huge amounts of heterogeneous genomics and clinical data increasingly available. In this work, we focus on The Cancer Genome Atlas, a comprehensive archive of tumoral data containing the results of high-throughout experiments, mainly Next Generation Sequencing, for more than 30 cancer types.RESULTS: We propose TCGA2BED a software tool to search and retrieve TCGA data, and convert them in the structured BED format for their seamless use and integration. Additionally, it supports the conversion in CSV, GTF, JSON, and XML standard formats. Furthermore, TCGA2BED extends TCGA data with information extracted from other genomic databases (i.e., NCBI Entrez Gene, HGNC, UCSC, and miRBase). We also provide and maintain an automatically updated data repository with publicly available Copy Number Variation, DNA-methylation, DNA-seq, miRNA-seq, and RNA-seq (V1,V2) experimental data of TCGA converted into the BED format, and their associated clinical and biospecimen meta data in attribute-value text format.CONCLUSIONS: The availability of the valuable TCGA data in BED format reduces the time spent in taking advantage of them: it is possible to efficiently and effectively deal with huge amounts of cancer genomic data integratively, and to search, retrieve and extend them with additional information. The BED format facilitates the investigators allowing several knowledge discovery analyses on all tumor types in TCGA with the final aim of understanding pathological mechanisms and aiding cancer treatments.", "BACKGROUND: TGF-β1 regulates bone metabolism and mediates bone turnover during postmenopause. Sclerostin negatively regulates Wnt signaling pathway and also has an important role in postmenopausal bone loss. Little is known about the relationship between serum TGF-β1 and sclerostin during menopause.METHODS: We compared serum levels of TGF-β1 and sclerostin in pre- and postmenopausal women and assessed the potential correlations of these levels with each other and with serum levels of bone turnover markers and bone mineral density.RESULTS: A total of 176 women (58 premenopausal, 62 early postmenopausal, and 56 late postmenopausal) were included in this study. Serum TGF-β1 level was significantly higher in early postmenopausal women compared with premenopausal (32.0±7.19 vs. 26.55±6.67 ng/ml, p=0.01) and late postmenopausal (32.0±7.19 vs. 28.65±7.70 pg/ml, p=0.031) women, and no significant differences in serum sclerostin levels were observed among the 3 groups. There was a significant negative correlation between TGF-β1 and sclerostin in early postmenopausal women, but not in other groups of women. Based on multiple regression analysis, only TGF-β1 (β=-0.362; p=0.007) was an independent predictor of sclerostin during early postmenopause.CONCLUSIONS: Our findings suggest that serum TGF-β1 level increases during postmenopause and declines in old age. Sclerostin production is inhibited by TGF-β1 during early postmenopause.", "BACKGROUND: Autophagy is a ubiquitous cellular process responsible for the bulk degradation of cytoplasmic components through the autophagosomal-lysosomal pathway. In skeletal muscle, autophagy has been regarded as a key regulator for muscle mass maintenance, and its imbalance leads to sarcopenia. However, the underlying mechanism is poorly understood.RESULTS: In this study, we demonstrate that ceMTM3, a FYVE-domain containing myotubalarin family phosphatase, is required for the maintenance of muscle fibers by preventing excessive autophagy in Caenorhabditis elegans. Knockdown of ceMTM3 by using feeding-based RNA interference caused loss of muscle fibers accompanied by shortening of muscle cell and body size in aged C. elegans worms. This was preceded by the occurrence of excessive autophagy in the muscle and other tissues, which subsequently resulted in increased lysosomal activity and necrotic cell death. However, knockdown of ceMTM3 did not aggravate the abnormalities of muscle wasting in autophagy-deficient atg-18 mutant worms.CONCLUSIONS: Our data suggest an important role of ceMTM3 in regulating autophagy and maintaining muscle fibers. This study may have clinical implications for prevention and treatment of sarcopenia.", "There are several studies that relate oxidative damage as possible mechanism for many cancers. Many studies have also shown that anti-oxidants like selenium and vitamin E decrease the risk for prostate cancer. The main objective of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) study was to look for the benefits of selenium and vitamin E supplementation on prostate cancer. The study had a large sample size, stringent experimental conditions, very long duration, standardized laboratories for biochemical analyses and other factors that contribute to high external validity. The SELECT study failed to show any significant risk reduction for prostate cancers ascribable to selenium and vitamin E supplementations. Because of these conflicting results, many researchers argue about the methods used, supplementations administered (selenium and vitamin E) and indicators used for assessing levels of supplementations. We reviewed many epidemiological studies, clinical trials, and pre-clinical studies. With corroborative evidences we justify that SELECT study has a sound methodology and rationale. In lieu of the contrary results of the select study, researchers should focus on the probable mechanisms for these contrary findings and continue their search for newer and effective agents for prevention of prostate cancer.", "Drug plasma monitoring has emerged as an important tool to obtain optimal levels of a particular drug among individual patients. Plasma monitoring of imatinib levels would appear to be practical in cases where there is lack of response, heightened toxicity, or evidence of poor adherence to therapy. However, the potential role of monitoring plasma drug concentrations in guiding treatment decisions and optimizing patient therapy has yet to be established. Currently, there are no clinical recommendations regarding how to incorporate imatinib drug plasma monitoring in patients with either chronic myeloid leukemia or gastrointestinal stromal tumors, indications for which imatinib is approved. Here, the latest research and evidence regarding imatinib drug plasma monitoring is discussed. Three cases are presented to illustrate the most common examples where monitoring imatinib plasma concentrations may help to guide treatment decisions. These cases include a suboptimal response to imatinib treatment, lack of patient adherence to imatinib, and imatinib-related toxicity. By understanding the potential role of monitoring plasma imatinib concentrations in patients with chronic myeloid leukemia or gastrointestinal stromal tumors, physicians can identify patients who may benefit from drug plasma monitoring and consider incorporating the data in order to improve patient outcomes.", "In 29 adults with attention deficit hyperactivity disorder (ADHD) striatal dopamine transporter (DAT) availability was assessed by [(99m)Tc]TRODAT-1 SPECT and correlated with 3' VNTR polymorphism of the DAT gene on chromosome 5p15.3. Seventeen patients showed homozygosity for the 10-repeat allele, two homozygosity of the 9 allele and 10 were heterozygous (9-10). No statistically significant difference in DAT availability was found between patients with 10-10 carriers (DAT 1.28 +/- 0.34) and with at least one 9 allele (DAT 1.31 +/- 0.27); when smokers were excluded, DAT availability was 1.38 +/- 0.28 in the 10-10 carriers (n = 12) and 1.42 +/- 0.19 in the 9-10 and 9-9 carriers (n = 7). In conclusion, no higher striatal DAT was found in patients with homozygosity of the 10 allele of the DAT gene in this study. These results differ from a study in 11 Korean children with ADHD, in which 10-10 carriers showed higher DAT availability in [(123)I]IPT SPECT. Discrepancies may be explained by differences in patient's age, ethnical differences, different imaging techniques or the limited number of patients included in both studies.", "BACKGROUND/OBJECTIVES: Selenium was thought to have a role in cardiovascular disease (CVD) owing to its antioxidant properties; however, evidence from observational studies and randomized controlled trials (RCTs) has been inconsistent and controversial. We thus conducted a meta-analysis to assess the discrepancies between observational and randomized trial evidence.SUBJECTS/METHODS: We searched MEDLINE and EMBASE for eligible prospective studies regarding the relationship between selenium and CVD up to 15 December 2013 and finally included 16 prospective observational studies and 16 RCTs. Random effects model was used to estimate the pooled relative risk (RR). Generalized least-squares trend test and restricted cubic spline model were performed to assess a linear and a nonlinear dose-response relationship.RESULTS: Our meta-analysis of prospective studies showed a nonlinear relationship of CVD risk with blood selenium concentrations across a range of 30-165 μg/l and a significant benefit of CVD within a narrow selenium range of 55-145 μg/l. Our meta-analyses of RCTs showed that oral selenium supplements (median dose: 200 μg/day) for 2 weeks to 144 months significantly raised the blood selenium concentrations by 56.4 μg/l (95% confidence interval (CI): 40.9, 72.0 μg/l), whereas oral selenium supplements (median: 100 μg/day) for 6 to 114 months caused no effect on CVD (RR=0.91; 95% CI: 0.74, 1.10).CONCLUSIONS: Our meta-analysis in prospective studies demonstrated a significant inverse association between selenium status and CVD risk within a narrow selenium range and a null effect of selenium supplementation on CVD was observed in RCTs. These findings indicate the importance of considering selenium status, dose and safety in health assessment and future study design.", "To understand how commitment to cell division in late G1 phase (Start) is controlled by growth and nutrients in budding yeast, we determined the absolute concentrations of the G1/S transcription factors SBF (composed of Swi4 and Swi6) and MBF (composed of Mbp1 and Swi6), the transcriptional repressor Whi5, and the G1 cyclins, Cln1 and Cln2, in single live yeast cells using scanning number and brightness (sN&B) microscopy. In rich medium, Whi5, Mbp1, and Swi6 concentrations were independent of cell size, whereas Swi4 concentration doubled in G1 phase, leading to a size-dependent decrease in the Whi5/Swi4 ratio. In small cells, SBF and MBF copy numbers were insufficient to saturate target G1/S promoters, but this restriction diminished as cells grew in size. In poor medium, SBF and MBF subunits, as well as Cln1, were elevated, consistent with a smaller cell size at Start. A mathematical model constrained by sN&B data suggested that size- and nutrient-dependent occupancy of G1/S promoters by SBF/MBF helps set the cell size threshold for Start activation.", "BACKGROUND: Few studies have evaluated the relation between selenium supplementation after diagnosis and prostate cancer outcomes.METHODS: We prospectively followed 4459 men initially diagnosed with nonmetastatic prostate cancer in the Health Professionals Follow-Up Study from 1988 through 2010 and examined whether selenium supplement use (from selenium-specific supplements and multivitamins) after diagnosis was associated with risk of biochemical recurrence, prostate cancer mortality, and, secondarily, cardiovascular disease mortality and overall mortality, using Cox proportional hazards models. All P values were from two-sided tests.RESULTS: We documented 965 deaths, 226 (23.4%) because of prostate cancer and 267 (27.7%) because of cardiovascular disease, during a median follow-up of 8.9 years. In the biochemical recurrence analysis, we documented 762 recurrences during a median follow-up of 7.8 years. Crude rates per 1000 person-years for prostate cancer death were 5.6 among selenium nonusers and 10.5 among men who consumed 140 or more μg/day. Crude rates per 1000 person-years were 28.2 vs 23.5 for all-cause mortality and 28.4 vs 29.3 for biochemical recurrence, for nonuse vs highest-dose categories, respectively. In multivariable analyses, men who consumed 1 to 24 μg/day, 25 to 139 μg/day, and 140 or more μg/day of supplemental selenium had a 1.18 (95% confidence interval [CI] = 0.73 to 1.91), 1.33 (95% CI = 0.77 to 2.30), and 2.60-fold (95% CI = 1.44 to 4.70) greater risk of prostate cancer mortality compared with nonusers, respectively, P trend = .001. There was no statistically significant association between selenium supplement use and biochemical recurrence, cardiovascular disease mortality, or overall mortality.CONCLUSION: Selenium supplementation of 140 or more μg/day after diagnosis of nonmetastatic prostate cancer may increase risk of prostate cancer mortality. Caution is warranted regarding usage of such supplements among men with prostate cancer.", "POEMS syndrome is a paraneoplastic manifestation associated with hematopoietic disorders such as multiple myeloma and Castleman disease. POEMS is an acronym for the main clinical features of the syndrome, namely, Polyneuropathy, Organomegaly, Endocrinopathy, M protein, and Skin abnormalities. Glomeruloid hemangiomas are considered to be a specific clinical marker of POEMS syndrome. However, while they are not pathognomonic, their presence should raise suspicion of this syndrome or alert clinicians to its possible future development, as these lesions can appear years before the onset of the syndrome. We report the cases of 2 women with plasma cell dyscrasias and sudden onset of lesions with a vascular appearance and histologic findings consistent with glomeruloid hemangioma. Recognition of this vascular tumor is important for the early diagnosis of POEMS syndrome." ]

[ "Bardet-Biedl syndrome (BBS) is a multisystem disorder caused by ciliary defects. To date, mutations in 15 genes have been associated with the disease and BBS1 is most frequently affected in patients with BBS. The use of homozygosity mapping in a large consanguineous family allowed us to identify the splice donor site (SD) mutation c.479G>A in exon 5 of BBS1. Clinically affected family members show symptoms of retinitis pigmentosa (RP) but lack other primary features that would clearly support the diagnosis of BBS. In agreement with this exceptionally mild BBS1-associated phenotype, we did not detect obvious ciliary defects in patient-derived cells. SDs are bound by the U1 small nuclear RNA (U1), a process that initiates exon recognition during splicing. The mutation described herein interferes with U1 binding and induces aberrant splicing of BBS1. For a gene therapeutic approach, we have adapted the sequence of U1 to increase its complementarity to the mutated SD. Lentiviral treatment of patient-derived fibroblasts with the adapted U1 partially corrected aberrant splicing of endogenously expressed BBS1 transcripts. This therapeutic effect was dose-dependent. Our results show that the adaptation of U1 can correct pathogenic effects of splice donor site mutations and suggest a high potential for gene therapy.", "Wilson's disease is an inherited disorder leading to accumulation of copper in tissues, mainly in the liver and brain. Genetic defect is in the gene coding ATPase type P (ATP7B). The inheritance is autosomal recessive. Up to now, more then 500 mutations causing Wilson's disease were described. The most frequent mutation in Central Europe is mutation H1069Q. The manifestation of Wilson's disease is usually hepatic or neurologic. Hepatic form is manifested by acute or chronic hepatitis, steatosis or cirrhosis. Neurologic involvement is manifested usually after 20 year of age by motor disturbances (tremor, disturbed speech, problems with writing), which could progress into severe extrapyramidal syndrome with tremor, rigidity, dysartria, dysfagia and muscle contracture. Diagnosis is based on clinical and laboratory examinations (neurologic symptoms, liver disease, low serum ceruloplasmin levels, elevated free copper concentration in serum, high urine copper excretion, and presence of Kayser-Fleischer rings). Confirmation of diagnosis is done by hepatic copper concentration in liver biopsy or by genetic examination. Untreated disease leads to the death of a patient. Treatment is based on chelating agents decreasing the copper content by excretion into urine (D-penicillamine, trientine) or on agents preventing absorption of copper from food (zinc, ammonium-tetrahiomolybdene). Patients with asymptomatic Wilson's disease have to be treated as well. In Czech Republic either penicillamine or zinc are used. Liver transplantation is indicated in patients with fulminant liver failure or decompensated cirrhosis. Screening in families of affected patients (all siblings) is obvious.", "Werner syndrome, also called adult progeria, is a heritable autosomal recessive human disorder characterized by the premature onset of numerous age-related diseases including juvenile cataracts, dyslipidemia, diabetes mellitus (DM), osteoporosis, atherosclerosis, and cancer. Werner syndrome is a segmental progeroid syndrome whose presentation resembles accelerated aging. The most common causes of death for WS patients are atherosclerosis and cancer. A 40-year-old female presented with short stature, bird-like facies, canities with alopecia, scleroderma-like skin changes, and non-healing foot ulcers. The patient reported a history of delayed puberty, abortion, hypertriglyceridemia, and juvenile cataracts. A clinical diagnosis of WS was made and subsequently confirmed. We discovered two WRN gene mutations in the patient, Variant 1 was the most common WRN mutation, nonsense mutation (c.1105C>T:p.R369Ter) in exon 9, which caused a premature termination codon (PTC) at position 369. Variant 2 was a frameshift mutation (c.1134delA:p.E379KfsTer5) in exon 9, which caused a PTC at position 383 and has no published reports describing. Patients with WS can show a wide variety of clinical and biological manifestations in endocrine-metabolic systems (DM, thyroid dysfunction, and hyperlipidemia). Doctors must be cognizant of early manifestations of WS and treatment options.", "We describe the clinical, hematological and histomorphological features in children of primary myelodysplastic syndrome (MDS) seen at the All India Institute of Medical Sciences over three years (Jan 2001-Jan 2004). Twenty-one patients of primary MDS aged 17 year or less were classified using the latest proposed WHO classification for Pediatric MDS. The median age was 9 years with male predominance (80%). Pallor was present in all the cases while fever and bleeding diathesis was present in more than 50% of the cases. Morphological assessment of the peripheral blood showed macrocytosis in 50%, pancytopenia in 15% and blast cells in 45% of cases. A complete analysis of clinical features in conjunction with the bone marrow profile revealed 8 cases of refractory cytopenia (RC), 3 cases of refractory anemia with excess blasts (RAEB), 5 cases of refractory anemia with excess blasts in transformation (RAEB-T), 4 cases of Juvenile myelomonocytic leukemia (JMML) and a solitary cases of acute myeloid leukemia (AML) in Downs syndrome. These children were followed up from 1-36 months (mean 15 months). Three patients of RAEB-T progressed to AML within 3-4 months. RC had the best prognosis and all are alive and under regular follow up. The solitary case of AML of Downs syndrome died 1.5 months after initial diagnosis. All 3 cases of RAEB are under regular follow-up and doing well. Three cases of RAEB-T died (all had progressed to AML); the remaining 2 cases were lost to follow up. Of the 4 cases of JMML 1 died within 6 months of diagnosis; the other 3 cases are under regular follow up of whom 1 has a progressively increasing blast count. We conclude that the latest proposed WHO classification for Pediatric MDS can be successfully applied to all cases of primary MDS.", "The association of Down's syndrome and leukemia has been documented for over 50 years. Multiple studies have established the incidence of leukemia in Down's syndrome patients to be 10- to 20-fold higher than that in the general population. The age of onset for leukemia in these children is bimodal, peaking first in the newborn period and again at 3-6 years. This increased risk extends into adulthood. All cytogenetic types of Down's syndrome apparently predispose to leukemia. The proportion of acute lymphoblastic leukemia and acute nonlymphoblastic leukemia in patients with Down's syndrome is similar to non-Down's syndrome leukemia patients matched for age. There are case reports in which leukemia, Down's syndrome, and other chromosomal aberrations cluster within a family. In these kindreds, there may be a familial tendency toward nondisjunction. Congenital leukemia also occurs with increased frequency in Down's syndrome patients, and is characterized by a preponderance of acute nonlymphoblastic leukemia (similar to non-Down's syndrome patients). Transient leukemoid reactions have been observed in Down's syndrome patients, as well as in phenotypically normal children with constitutional trisomy 21 mosaicism. The transient leukemoid reactions are characterized by a high spontaneous remission rate. However, in some Downs syndrome patients with apparent transient leukemoid reaction, leukemia relapse following periods of spontaneous remission have been reported. Cytogenetic studies of leukemic cells in Down's syndrome patients show a tendency toward hyperdiploidy. Besides trisomy 21, there is no other specific cytogenetic abnormality that is characteristic of the leukemia cells in Down's syndrome patients. The possible mechanisms for leukemogenesis in Down's syndrome patients may involve factors at the levels of the organism, the organ/system, the cell, the chromosomes or the DNA.", "A new born with a mongoloid slant, brachycephaly and low-set ears presented at birth with a total leucocyte count of 57 x 10(3)/microL and the differential leucocyte count revealed 70% of these to be blasts. The morphology of the blasts was not characteristic of myeloid and lymphoid lineage. Cytochemistry showed myeloperoxidase (MPO), Sudan Black B (SBB), periodic acid-Schiff (PAS) and non-specific esterase (NSE) negativity. Flowcytometry showed blasts that were positive for CD-33, CD-34 and CD-7. On second follow-up on the 10th day, the same picture persisted on morphology. On subsequent follow-up, the blasts disappeared. This was thus confirmed to be a case with transient leukemia with Downs syndrome.", "CONTEXT: Low-T(3) syndrome is a predictor of poor outcome in patients with cardiac dysfunction. The study aimed to assess the short-term effects of synthetic L-T(3) replacement therapy in patients with low-T(3) syndrome and ischemic or nonischemic dilated cardiomyopathy (DC).DESIGN: A total of 20 clinically stable patients with ischemic (n = 12) or nonischemic (n = 8) DC were enrolled. There were 10 patients (average age 72 yr, range 66-77; median, 25-75th percentile) who underwent 3-d synthetic L-T(3) infusion (study group); the other 10 patients (average age 68 yr, range 64-71) underwent placebo infusion (control group). Clinical examination, electrocardiography, cardiac magnetic resonance, and bio-humoral profile (free thyroid hormones, TSH, plasma renin activity, aldosterone, noradrenaline, N-terminal-pro-B-Type natriuretic peptide, and IL-6) were assessed at baseline and after 3-d synthetic L-T(3) (initial dose: 20 microg/m(2) body surface.d) or placebo infusion.RESULTS: After T(3) administration, free T(3) concentrations increased until reaching a plateau at 24-48 h (3.43, 3.20-3.84 vs. 1.74, 1.62-1.93 pg/ml; P = 0.03) without side effects. Heart rate decreased significantly after T(3) infusion (63, 60-66 vs. 69, 60-76 beats per minute; P = 0.008). Plasma noradrenaline (347; 270-740 vs. 717, 413-808 pg/ml; P = 0.009), N-terminal pro-B-Type natriuretic peptide (3000, 438-4005 vs. 3940, 528-5628 pg/ml; P = 0.02), and aldosterone (175, 152-229 vs. 231, 154-324 pg/ml; P = 0.047) significantly decreased after T(3) administration. Neurohormonal profile did not change after placebo infusion in the control group. After synthetic L-T(3) administration, left-ventricular end-diastolic volume (142, 132-161 vs. 133, 114-158 ml/m(2) body surface; P = 0.02) and stroke volume (40, 34-44 vs. 35, 28-39 ml/m(2) body surface; P = 0.01) increased, whereas external and intracardiac workload did not change.CONCLUSIONS: In DC patients, short-term synthetic L-T(3) replacement therapy significantly improved neuroendocrine profile and ventricular performance. These data encourage further controlled trials with more patients and longer periods of synthetic L-T(3) administration.", "Single or double-level compression of the lumbosacral nerve roots located in the dural sac results in a polyradicular symptomatology clinically diagnosed as cauda equina syndrome. The cauda equina nerve roots provide the sensory and motor innervation of most of the lower extremities, the pelvic floor and the sphincters. Therefore, in a fully developed cauda equina syndrome, multiple signs of sensory disorders may appear. These disorders include low-back pain, saddle anesthesia, bilateral sciatica, then motor weakness of the lower extremities or chronic paraplegia and, bladder dysfunction. Multiple etiologies can cause the cauda equina syndrome. Among them, non-neoplastic compressive etiologies such as herniated lumbosacral discs and spinal stenosis and spinal neoplasms play a significant role in the development of the cauda equina syndrome. Non-compressive etiologies of the cauda equina syndrome include ischemic insults, inflammatory conditions, spinal arachnoiditis and other infectious etiologies. The use of canine, porcine and rat models mimicking the cauda equina syndrome enabled discovery of the effects of the compression on nerve root neural and vascular anatomy, the impairment of impulse propagation and the changes of the neurotransmitters in the spinal cord after compression of cauda equina. The involvement of intrinsic spinal cord neurons in the compression-induced cauda equina syndrome includes anterograde, retrograde and transneuronal degeneration in the lumbosacral segments. Prominent changes of NADPH diaphorase exhibiting, Fos-like immunoreactive and heat shock protein HSP72 were detected in the lumbosacral segments in a short-and long-lasting compression of the cauda equina in the dog. Developments in the diagnosis and treatment of patients with back pain, sciatica and with a herniated lumbar disc are mentioned, including many treatment options available.", "Human glioblastomas often develop resistance to radiation therapy. The molecular details of this phenomenon are not completely understood. Recent studies have suggested that deficiency in DNA repair pathways may alter the resistance to ionizing radiation in gliobastomas. The human glioma cell line M059J is deficient in DNA-dependent protein kinase (DNA-PK), whereas cell line M059K, isolated from the same malignant tumor, has normal DNA-PK activity. DNA-PK plays a central role in the repair of ionizing-radiation-induced double-strand break repair, and its deficiency has been correlated with ionizing radiation sensitivity in these glioblastoma cells. We argued that other cellular pathways could also play a role in the resistance to radiation therapy in gliomas. We hypothesized that micro-RNAs (miRNAs) are differentially modulated in M059J and M059K cells exposed to ionizing radiation and that the miRNA modulation contributes to the resistance to ionizing radiation. miRNAs are small nonprotein coding single-stranded RNA molecules, which are crucial posttranscriptional regulators of gene expression. Numerous studies have documented the participation of miRNAs in a wide range of biological processes. The contribution of miRNAs in mediating resistance of glioblastoma cell to ionizing radiation treatment has not been elucidated. To test this hypothesis, we examined the expression patterns of a number of miRNAs involved in carcinogenesis in irradiated M059J and M059K cells. The relative expression level as determined by real-time quantitative PCR for miRNAs belonging to the let-7 family indicated an upregulation in irradiated M059K cells. On the contrary, the analysis of irradiated M059J cells for the modulation of let-7 family of miRNAs revealed an overall downregulation. The miR-17-3p, miR-17-5p, miR-19a, miR-19b, miR-142-3p, and miR-142-5p were upregulated in both M059K and M059J cells. The miR-15a, miR-16, miR-143, miR-155, and miR-21 were upregulated in M059K, and the modulation of these miRNAs fluctuated in M059J cells in a time-dependent manner. These results indicate the involvement of miRNAs in the differential response of glioblastoma cells to ionizing radiation treatment.", "BACKGROUND: ERBB2 is a proto-oncogene of multiple cancers including breast and gastric cancers with HER2 protein overexpression or gene amplification and has been proven clinically as a valid target for these cancers. HER2-targeting agents such as Herceptin®, Kadcyla® and ENHERTU® have been approved by the FDA for the treatment of breast cancer, but these drugs still face the challenge of acquired resistance and/or severe adverse reactions in clinical use. Therefore, there is significant unmet medical need for developing new agents that are more effective and safer for patients with advanced HER2-positive solid tumors including breast and gastric cancers.METHODS: We report here the making of MRG002, a novel HER2-targeted antibody drug conjugate (ADC), and preclinical characterization including pharmacology, pharmacodynamics and toxicology and discuss its potential as a novel agent for treating patients with HER2-positive solid tumors.RESULTS: MRG002 exhibited similar antigen binding affinity but much reduced antibody-dependent cellular cytotoxicity (ADCC) activity compared to trastuzumab. In addition to potent in vitro cytotoxicity, MRG002 showed tumor regression in both high- and medium-to-low HER2 expressing in vivo xenograft models. Furthermore, MRG002 showed enhanced antitumor activity when used in combination with an anti-PD-1 antibody. Main findings from toxicology studies are related to the payload and are consistent with literature report of other ADCs with monomethyl auristatinE.CONCLUSION: MRG002 has demonstrated a favorable toxicity profile and potent antitumor activities in the breast and gastric PDX models with varying levels of HER2 expression, and/or resistance to trastuzumab or T-DM1. A phase I clinical study of MRG002 in patients with HER2-positive solid tumors is ongoing (CTR20181778).", "BACKGROUND & AIMS: Idiopathic achalasia is a motility disorder of the esophagus characterized by incomplete relaxation of the lower esophageal sphincter and a loss of normal peristaltic activity in the body of the esophagus. The loss of inhibitory neurons in the distal esophagus, as well as abnormalities in the vagus nerve, dorsal motor nucleus of the vagus nerve, and autonomic nervous system, have been described in achalasia. Although the underlying cause of idiopathic achalasia is unknown, the diffuse neuronal effects found suggest a possible viral or neurodegenerative mechanism. By use of serological methods, a significant association between the HLA-DQ1 phenotype and idiopathic achalasia has been found, suggesting a possible immunogenetic mechanism. To further define immunogenetics in the pathogenesis of idiopathic achalasia, we performed tissue typing in patients with achalasia to determine their specific HLA phenotypes.METHODS: We prospectively studied 32 patients (23 white and 9 black) with idiopathic achalasia. Peripheral blood was collected, and HLA-DR and -DQ typing by polymerase chain reaction with sequence-specific primers was performed. Results were compared with those from 268 racially matched local controls.RESULTS: Idiopathic achalasia and the broad HLA-DQ1 allele were not significantly associated in either population, although a trend was found in white subjects (odds ratio [OR], 2.16; chi2 = 5.36, P corrected [Pc] = 0.0824). Further subtyping in white subjects revealed a significant association between idiopathic achalasia and the DQB1*0602 allele (OR, 3.10; chi2 = 7.32, Pc = 0.0408). A strong trend was also found with the DRB1*15 allele (OR, 2.83; chi2 = 8.11, Pc = 0.0572). In the black population, there was no association between idiopathic achalasia and DQB1*0602 or DRB1*15, but a trend was found with DRB1*12 (OR, 6. 19; chi2 = 5.19, P = 0.0227 uncorrected, Pc = 0.295).CONCLUSIONS: Idiopathic achalasia is associated with HLA alleles in a race-specific manner. These results support an immunogenetic mechanism in the pathogenesis of idiopathic achalasia.", "Congenital leukemia is a rare but a well-documented disease in which leukemic process is detected at birth or very shortly thereafter (Philip McCoy and Roy Overton, Commun Clin Cytom 22:85-88, 1995). These leukemias represent approximately 0.8 % of all childhood leukemias. We present a case of congenital acute myeloid leukemia manifesting from the very first day of birth. Diagnosis of acute myeloid leukemia was suspected by the presence of blasts in the peripheral blood smear and was confirmed on bone marrow by flowcytometry. Karyotyping revealed Trisomy 21.", "BACKGROUND AND OBJECTIVES: Finerenone is a selective, non-steroidal mineralocorticoid receptor antagonist. In vivo and in vitro studies were performed to assess absolute bioavailability of finerenone, the effect of metabolic enzyme inhibitors on the pharmacokinetics of finerenone and its metabolites, the quantitative contribution of the involved enzymes cytochrome P450 (CYP) 3A4 and CYP2C8 and the relevance of gut wall versus liver metabolism.METHODS: The pharmacokinetics, safety and tolerability of finerenone (1.25-10 mg orally or 0.25-1.0 mg intravenously) were evaluated in healthy male volunteers in four crossover studies. Absolute bioavailability was assessed in volunteers receiving finerenone orally and by intravenous infusion (n = 15) and the effects of erythromycin (n = 15), verapamil (n = 13) and gemfibrozil (n = 16) on finerenone pharmacokinetics were investigated. Finerenone was also incubated with cryopreserved human hepatocytes in vitro in the presence of erythromycin, verapamil or gemfibrozil.RESULTS: Finerenone absolute bioavailability was 43.5% due to first-pass metabolism in the gut wall and liver. The geometric mean AUC0-∞ ratios of finerenone (drug + inhibitor/drug alone) were 3.48, 2.70 and 1.10 with erythromycin, verapamil and gemfibrozil, respectively. The contribution ratio of CYP3A4 to the metabolic clearance of finerenone derived from these values was 0.88-0.89 and was consistent with estimations based on in vitro data, with the remaining metabolic clearance due to CYP2C8 involvement.CONCLUSION: Finerenone is predominantly metabolized by CYP3A4 in the gut wall and liver. Increases in systemic exposure upon concomitant administration of inhibitors of this isoenzyme are predictable and consistent with in vitro data. Inhibition of CYP2C8, the second involved metabolic enzyme, has no relevant effect on finerenone in vivo.", "BACKGROUND: Everolimus, an orally administered rapamycin analogue, inhibits the mammalian target of rapamycin (mTOR), a highly conserved intracellular serine-threonine kinase that is a central node in a network of signaling pathways controlling cellular metabolism, growth, survival, proliferation, angiogenesis, and immune function. Everolimus has demonstrated substantial clinical benefit in randomized, controlled, phase III studies leading to approval for the treatment of advanced renal cell carcinoma, advanced neuroendocrine tumors of pancreatic origin, renal angiomyolipoma and subependymal giant-cell astrocytoma associated with tuberous sclerosis complex, as well as advanced hormone-receptor-positive (HR(+)) and human epidermal growth factor receptor-2-negative advanced breast cancer.MATERIALS AND METHODS: We discuss clinically relevant everolimus-related adverse events from the phase III studies, including stomatitis, noninfectious pneumonitis, rash, selected metabolic abnormalities, and infections, with focus on appropriate clinical management of these events and specific considerations in patients with breast cancer.RESULTS: The majority of adverse events experienced during everolimus therapy are of mild to moderate severity. The safety profile and protocols for toxicity management are well established. The class-effect adverse event profile observed with everolimus plus endocrine therapy in breast cancer is (as expected) distinct from that of endocrine therapy alone, but is similar to that observed with everolimus in other solid tumors. Information gained from the experience in other carcinomas on prompt diagnosis and treatments to optimize drug exposure, treatment outcomes, and patients' quality of life also applies to the patient population with advanced breast cancer.CONCLUSIONS: As with all orally administered agents, education of both physicians and patients in the management of adverse events for patients receiving everolimus is critical to achieving optimal exposure and clinical benefit. Active monitoring for early identification of everolimus-related adverse events combined with aggressive and appropriate intervention should lead to a reduction in the severity and duration of the event.", "Macitentan (Opsumit(®)) is an orally active, dual endothelin receptor antagonist (ERA) with tissue targeting properties. Macitentan was approved recently in the EU (as monotherapy or combination therapy) for the long-term treatment of pulmonary arterial hypertension (PAH) in adults of WHO functional class II or III, and in the USA for the treatment of PAH (WHO group I) to delay disease progression and reduce hospitalization for PAH. This article reviews the pharmacological properties, efficacy and tolerability data relevant to the use of macitentan in this indication. Treatment with macitentan 10 mg once daily significantly reduced the risk for the primary composite endpoint of morbidity and mortality in patients with PAH (mostly WHO functional class II or III) in the large, randomized, placebo-controlled SERAPHIN study. Other efficacy outcomes, including exercise capacity, haemodynamic parameters and health-related quality of life also improved significantly with macitentan relative to placebo. Macitentan was generally well tolerated in this study. As with other ERAs, haemoglobin levels decreased with macitentan therapy; however, these were not progressive and stabilized following longer-term treatment. Although comparative studies are needed to definitively position macitentan with respect to other approved agents, current evidence suggests that macitentan is a useful treatment option for initial therapy in patients with WHO functional class II or III PAH, which has the potential advantage of once-daily administration.", "Ion channels underlie the electrical activity of cells. Calcium channels have a unique functional role, because not only do they participate in this activity, they form the means by which electrical signals are converted to responses within the cell. Calcium channels play an integral role in excitation in the heart and shaping the cardiac action potential. In addition, calcium influx through calcium channels is responsible for initiating contraction. Abnormalities in calcium homeostasis underlie cardiac arrhythmia, contractile dysfunction and cardiac remodelling. Reactive oxygen species participate in the development of pathology by altering the redox state of regulatory proteins. There is now good evidence that reactive oxygen species regulate the function of calcium channels. In this mini-review, the evidence for regulation of calcium channels by reactive oxygen species and implications with respect to pathology are presented. Calcium channels may represent a target for intervention during hypoxic trigger of arrhythmia or chronic pathological remodelling." ]

[ "Romosozumab (Romo), a humanized sclerostin antibody, is a bone-forming agent under development for treatment of osteoporosis. To examine the effects of Romo on bone quality, mature cynomolgus monkeys (cynos) were treated 4 months post- ovariectomy (OVX) with vehicle, 3 mg/kg, or 30 mg/kg Romo for 12 months, or with 30 mg/kg Romo for 6 months followed by vehicle for 6 months (30/0). Serum bone formation markers were increased by Romo during the first 6 months, corresponding to increased cancellous, endocortical, and periosteal bone formation in rib and iliac biopsies at months 3 and 6. Dual-energy X-ray absorptiometry (DXA) bone mineral density (BMD) was increased by 14% to 26% at the lumbar spine and proximal femur at month 12, corresponding to significant increases in bone strength at 3 and 30 mg/kg in lumbar vertebral bodies and cancellous cores, and at 30 mg/kg in the femur diaphysis and neck. Bone mass remained positively correlated with strength at these sites, with no changes in calculated material properties at cortical sites. These bone-quality measures were also maintained in the 30/0 group, despite a gradual loss of accrued bone mass. Normal bone mineralization was confirmed by histomorphometry and ash analyses. At the radial diaphysis, a transient, reversible 2% reduction in cortical BMD was observed with Romo at month 6, despite relative improvements in bone mineral content (BMC). High-resolution pQCT confirmed this decline in cortical BMD at the radial diaphysis and metaphysis in a second set of OVX cynos administered 3 mg/kg Romo for 6 months. Radial diaphyseal strength was maintained and metaphyseal strength improved with Romo as estimated by finite element modeling. Decreased radial cortical BMD was a consequence of increased intracortical remodeling, with no increase in cortical porosity. Romo resulted in marked improvements in bone mass, architecture, and bone strength, while maintaining bone quality in OVX cynos, supporting its bone efficacy and safety profile. © 2016 American Society for Bone and Mineral Research.", "The 50th annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held in Boston, included topics covering new therapeutic developments in the field of infectious disease. This conference report highlights selected presentations on research with novel antimicrobial agents. Investigational drugs discussed include the chitin synthase inhibitor nikkomycin Z (Valley Fever Solutions/University of Arizona), the glycosylphosphatidylinositol biosynthesis inhibitor E-1210 (Eisai), the β-1,3-d-glucan synthesis inhibitor MK-3118 (Merck & Co/SCYNEXIS), the metalloenzyme inhibitors VT-1129 and VT-1161 (both Viamet Pharmaceuticals), and the anti-inflammatory nanoemulsion NB-003 (NanoBio).", "MOTIVATION: Nowadays, knowledge extraction methods from Next Generation Sequencing data are highly requested. In this work, we focus on RNA-seq gene expression analysis and specifically on case-control studies with rule-based supervised classification algorithms that build a model able to discriminate cases from controls. State of the art algorithms compute a single classification model that contains few features (genes). On the contrary, our goal is to elicit a higher amount of knowledge by computing many classification models, and therefore to identify most of the genes related to the predicted class.RESULTS: We propose CAMUR, a new method that extracts multiple and equivalent classification models. CAMUR iteratively computes a rule-based classification model, calculates the power set of the genes present in the rules, iteratively eliminates those combinations from the data set, and performs again the classification procedure until a stopping criterion is verified. CAMUR includes an ad-hoc knowledge repository (database) and a querying tool.We analyze three different types of RNA-seq data sets (Breast, Head and Neck, and Stomach Cancer) from The Cancer Genome Atlas (TCGA) and we validate CAMUR and its models also on non-TCGA data. Our experimental results show the efficacy of CAMUR: we obtain several reliable equivalent classification models, from which the most frequent genes, their relationships, and the relation with a particular cancer are deduced.AVAILABILITY AND IMPLEMENTATION: dmb.iasi.cnr.it/camur.phpCONTACT: emanuel@iasi.cnr.itSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "BACKGROUND: The involvement of muscle triacylglycerol (TAG) storage in the onset of insulin resistance is questioned and the attention has shifted towards inhibition of insulin signalling by the lipid intermediate diacylglycerol (DAG). The enzyme 1,2-acylCoA:diacylglyceroltransferase-1 (DGAT1) esterifies a fatty acyl-CoA on DAG to form TAG. Therefore, the aim of the present study was to investigate if unilateral overexpression of DGAT1 in adult rat Tibialis anterior (TA) muscle will increase conversion of the lipid intermediate DAG into TAG, thereby improving muscle insulin sensitivity.METHODOLOGY/PRINCIPAL FINDINGS: The DGAT1 gene construct was injected in the left TA muscle of male rats on chow or high-fat (45% kcal) diet for three weeks, followed by application of one 800 V/cm and four 80 V/cm pulses, using the contralateral leg as sham-electroporated control. Seven days after electroporation, muscle specific insulin sensitivity was assessed with a hyperinsulinemic euglycemic clamp using 2-deoxy-[3H]glucose. Here, we provide evidence that unilateral overexpression of DGAT1 in TA muscle of male rats is associated with an increased rather than decreased DAG content. Strikingly, this increase in DAG content was accompanied by improved muscle insulin sensitivity. Interestingly, markers of muscle lipolysis and mitochondrial function were also increased in DGAT1 overexpressing muscle.CONCLUSIONS/SIGNIFICANCE: We conclude that unilateral DGAT1 overexpression can rescue insulin sensitivity, possibly by increasing DAG and TAG turnover in skeletal muscle. In case of a proper balance between the supply and oxidation of fatty acids in skeletal muscle, the lipid intermediate DAG may not exert harmful effects on insulin signalling.", "Detailed characterization of the amino acid (aa) compositions of recombinant histone H3 (Xenopus laevis) and its Lys-9 mono-, di-, and trimethylated isoforms was carried out by ESI/FT-ICR-MS. The measured molecular masses of these four proteins did not agree with those predicted from the published wild-type histone H3 sequence. Using MS/MS with both collision-activated dissociation and electron capture dissociation, three aa substitutions (Gly102Ala, Cys110Ala, and Gly111Ala) were unambiguously identified in each protein by protein database searching and de novo peptide tag sequencing. In addition, it was determined through accurate mass measurement and elemental composition generation that Lys-9, to which the methyl groups are attached, is not in fact a lysine. Instead, it was identified as a chemical analog of lysine--aminoethylcysteine--in the methylated proteins. After incorporation of these three aa substitutions and the aminoethylcysteine into the protein sequences, the re-calculated molecular masses of four proteins were completely consistent with the measured values within 1 ppm. This work demonstrates the power of top-down MS for a detailed structural confirmation of recombinant proteins, even without prior information on aa substitutions or modifications.", "CYLD is a lysine 63-deubiquitinating enzyme that inhibits NF-κB and JNK signaling. Here, we show that CYLD knock-out mice have markedly increased numbers of regulatory T cells (Tregs) in peripheral lymphoid organs but not in the thymus. In vitro stimulation of CYLD-deficient naive T cells with anti-CD3/28 in the presence of TGF-β led to a marked increase in the number of Foxp3-expressing T cells when compared with stimulated naive control CD4(+) cells. Under endogenous conditions, CYLD formed a complex with Smad7 that facilitated CYLD deubiquitination of Smad7 at lysine 360 and 374 residues. Moreover, this site-specific ubiquitination of Smad7 was required for activation of TAK1 and p38 kinases. Finally, knockdown of Smad7 or inhibition of p38 activity in primary T cells impaired Treg differentiation. Together, our results show that CYLD regulates TGF-β signaling function in T cells and the development of Tregs through deubiquitination of Smad7.", "Recent phase 1-2 trials reported manageable safety profiles and promising antitumor activities of anti-PD-1 drugs (pembrolizumab, nivolumab, camrelizumab and JS001) with/without chemotherapy in recurrent/metastatic nasopharyngeal carcinoma (RM-NPC), however head-to-head comparison among these regimens is lacking. We aimed to comprehensively compare the efficacy and safety of different anti-PD-1 drugs, standard chemotherapy, and their combination therapy in RM-NPC. Adverse event (AE) and objective response rate (ORR) were assessed. The pooled incidence rates of grade 1-5/3-5 AEs were 74.1%/29.6, 54.2%/17.4, 92.3%/24.5, 96.8%/16.1, 91.2%/42.8, and 100%/87.9% for pembrolizumab, nivolumab, JS001, camrelizumab, chemotherapy and camrelizumab+chemotherapy, respectively, which suggested that nivolumab and pembrolizumab exhibited the optimal safety regarding grade 1-5 AEs whereas camrelizumab and nivolumab regarding grade 3-5 AEs. As second- or later-line therapy, ORR was higher with camrelizumab (34.1%), followed by pembrolizumab (26.3%), JS001 (23.3%), and nivolumab (19.0%); whereas ORR with first-line nivolumab reached 40%. Additionally, first-line camrelizumab+chemotherapy achieved a dramatically higher ORR than that with chemotherapy alone (90.9% vs. 64.1%). Pooled ORR was 28.4 and 17.4% for PD-L1-positive and PD-L1-negative patients, respectively (P = 0.11). Here, we represent preliminary evidence for the comparative safety and efficacy of existing anti-PD-1 agents with/without chemotherapy in RM-NPC, which indicated that camrelizumab has the least toxicity profile and merits future investigation. Our findings might provide insights into the future design of immunotherapy trials in RM-NPC." ]

[ "BACKGROUND: The 2021 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium represents an unmissable event for oncologists who deal with renal cell carcinoma (RCC).AIM AND RESULTS: This article describes the main acquisitions of RCC management, including the advent of a new combo (pembrolizumab+lenvatinib) as first-line therapy, the confirmation of an OS advantage of ICI plus VEGFR-TKI combinations over sunitinib at longer follow-up, the persistent benefit from these combinations in particular subgroups (clear cell mRCC tumors with sarcomatoid differentiation), and possible new approaches in subsequent lines of therapy (including the HIF-2α inhibitor belzutifan).CONCLUSIONS: This 2021 ASCO Genitourinary Cancer Symposium laid the foundations for further knowledge development necessary for an increasingly personalized management of mRCC.", "A major challenge in chromatin biology is to understand the mechanisms by which chromatin is remodeled into active or inactive states as required during development and cell differentiation. One complex implicated in these processes is the nucleosome remodeling and histone deacetylase (NuRD) complex, which contains both histone deacetylase and nucleosome remodeling activities and has been implicated in the silencing of subsets of genes involved in various stages of cellular development. Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a core component of the NuRD complex and contains a nucleosome remodeling ATPase domain along with two chromodomains and two plant homeodomain (PHD) fingers. We have previously demonstrated that the second PHD finger of CHD4 binds peptides corresponding to the N terminus of histone H3 methylated at Lys(9). Here, we determine the solution structure of PHD2 in complex with H3K9me3, revealing the molecular basis of histone recognition, including a cation-π recognition mechanism for methylated Lys(9). Additionally, we demonstrate that the first PHD finger also exhibits binding to the N terminus of H3, and we establish the histone-binding surface of this domain. This is the first instance where histone binding ability has been demonstrated for two separate PHD modules within the one protein. These findings suggest that CHD4 could bind to two H3 N-terminal tails on the same nucleosome or on two separate nucleosomes simultaneously, presenting exciting implications for the mechanism by which CHD4 and the NuRD complex could direct chromatin remodeling.", "INTRODUCTION: Wellens Syndrome (WS) is a condition characterized by typical changes in ECG, which are biphasic T-wave inversions (less common) or symmetric and deeply inverted T waves (including 75%) in lead V2-V3 chest derivations. WS is considered important because it has not only diagnostic value but also prognostic value.CASE REPORT: A 52-year-old male patient without cardiovascular disease or risk factors was admitted to the emergency department (ED) suffering with chest pain and syncope, just after having been involved in a discussion at work. Chest pain was radiating to the left arm and was not precipitated by exertion. Shortness of breath was not accompanied by angina. The patient underwent cardiac catheterization at Department of Cardiology. Stents were positioned in both LADA and a severe lesion in the left main coronary artery. The patient was discharged two days following catheterization, due to no chest pain and hemodynamic instability during the hospitalization. The patient has approved the inform consent for to be used for this case report.", "Hot water epilepsy is a reflex epilepsy. Seizures are provoked by hot water, and result from the association of both cutaneous and heat stimuli. Described mainly in India and Japan, the condition seems to be rare in Europe, where it occurs in young children. We report five infants aged from 6 months to 2 years. They had brief seizures during bathing with activity arrest, hypotonia, and vasoactive modification; clonic movements were observed. A simple treatment-decreasing the bath temperature-can be sufficient. Sometimes an antiepileptic drug is required. Seizure course and psychomotor development are favorable. Hot water epilepsy is a benign form of epilepsy. Its incidence could be underestimated because of confusion with febrile convulsions, vagal fits, or aquagenic urticaria.", "Replisome disassembly is the final step of DNA replication in eukaryotes, involving the ubiquitylation and CDC48-dependent dissolution of the CMG helicase (CDC45-MCM-GINS). Using Caenorhabditis elegans early embryos and Xenopus laevis egg extracts, we show that the E3 ligase CUL-2LRR-1 associates with the replisome and drives ubiquitylation and disassembly of CMG, together with the CDC-48 cofactors UFD-1 and NPL-4. Removal of CMG from chromatin in frog egg extracts requires CUL2 neddylation, and our data identify chromatin recruitment of CUL2LRR1 as a key regulated step during DNA replication termination. Interestingly, however, CMG persists on chromatin until prophase in worms that lack CUL-2LRR-1, but is then removed by a mitotic pathway that requires the CDC-48 cofactor UBXN-3, orthologous to the human tumour suppressor FAF1. Partial inactivation of lrr-1 and ubxn-3 leads to synthetic lethality, suggesting future approaches by which a deeper understanding of CMG disassembly in metazoa could be exploited therapeutically.", "INTRODUCTION: The objective is to analyse our experience with the new intranasal formulation of zolmitriptan 5 mg in the symptomatic treatment of cluster headache in daily clinical practice.PATIENTS AND METHODS: We collected a total of 18 patients with cluster headache and experience with intranasal zolmitriptan; 17 had used subcutaneous sumatriptan and 8 oral triptans. The main reasons for trying intranasal zolmitriptan were: poor tolerability in 12 patients and insufficient efficacy in 6.RESULTS: Among the 17 patients experienced in subcutaneous sumatriptan, 12 (71 %) preferred nasal zolmitriptan, 2 (18 %) subcutaneous sumatriptan and 2 (12 %) did not express any preference. The reasons for preferring intranasal zolmitriptan were: higher convenience (n = 6), better tolerability (n = 5), lower price (n = 2) and higher efficacy (n = 1). Seven out of the 8 patients who had taken oral triptans preferred nasal zolmitriptan, in all cases due to higher subjective efficacy. A total of 11 patients showed efficacy within 30 minutes. Only 3 patients referred to adverse events, always mild.CONCLUSIONS: The 5 mg nasal formulation of zolmitriptan is a potential new option for the symptomatic treatment of cluster headache. This formulation should be considered in patients with poor tolerability to subcutaneous sumatriptan and in those attacks where quick access to inhaled oxygen is not possible. These results suggest that a controlled trial with nasal zolmitriptan in this indication would be worthwhile.", "Human enteric α-defensins (HD5 and HD6), major antimicrobial peptides produced by Paneth cells in the intestine, play important roles in intestinal innate immunity. Since their expression is decreased in Crohn's disease (CD), with decreased expression being more pronounced in the presence of NOD2 mutations, it would be extremely interesting to investigate the mechanism by which NOD2 may regulate expression of human enteric α-defensins. Here we show that although NOD2 by itself can slightly up-regulate expression of enteric α-defensins mainly through activation of the NF-κB pathway, it can strongly down-regulates their expression during differentiation of the Paneth cell lineage mainly by inhibiting activation of the MAPK pathway. Since NOD2 is over-expressed in CD and mutant NOD2 cannot result in NF-κB activity, our finding can provide an explanation of the previous observation showing decreased expression of human enteric α-defensin in CD and even more so in the presence of NOD2 mutations. In addition, this finding provides a new view on the function of NOD2 in regulating intestinal innate immunity." ]

[ "BACKGROUND: Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disorder characterised by loss of motor neurons leading to severe weakness and death from respiratory failure within 3-5 years. Riluzole prolongs survival in ALS. A published report has suggested a dramatic effect of lithium carbonate on survival. 44 patients were studied, with 16 randomly selected to take LiCO3 and riluzole and 28 allocated to take riluzole alone. In the group treated with lithium, no patients had died (i.e., 100% survival) at the end of the study (15 months from entry), compared to 71% surviving in the riluzole-only group. Although the trial can be criticised on several grounds, there is a substantial rationale from other laboratory studies that lithium is worth investigating therapeutically in amyotrophic lateral sclerosis.METHODS/DESIGN: LiCALS is a multi-centre double-blind randomised parallel group controlled trial of the efficacy, safety, and tolerability of lithium carbonate (LiCO3) at doses to achieve stable 'therapeutic' plasma levels (0.4-0.8 mmol/L), plus standard treatment, versus matched placebo plus standard treatment, in patients with amyotrophic lateral sclerosis. The study will be based in the UK, in partnership with the MND Association and DeNDRoN (the Dementias and Neurodegnerative Diseases Clinical Research Network). 220 patients will be recruited. All patients will be on the standard treatment for ALS of riluzole 100 mg daily. The primary outcome measure will be death from any cause at 18 months defined from the date of randomisation. Secondary outcome measures will be changes in three functional rating scales, the ALS Functional Rating Scale-Revised, The EuroQOL (EQ-5D), and the Hospital Anxiety and Depression Scale.Eligible patients will have El Escorial Possible, Laboratory-supported Probable, Probable or Definite amyotrophic lateral sclerosis with disease duration between 6 months and 36 months (inclusive), vital capacity ≥ 60% of predicted within 1 month prior to randomisation and age at least18 years.DISCUSSION: Patient recruitment began in June 2009 and the last patient is expected to complete the trial protocol in November 2011.TRIAL REGISTRATION: Current controlled trials ISRCTN83178718.", "IMGT, the international ImMunoGeneTics information system http://imgt.cines.fr, was created in 1989 by the Laboratoire d'ImmunoGénétique Moléculaire (LIGM) (Université Montpellier II and CNRS) at Montpellier, France. IMGT is a high quality integrated knowledge resource specialized in immunoglobulins (IG), T cell receptors (TR), major histocompatibility complex (MHC) of human and other vertebrates, and related proteins of the immune system (RPI) of any species which belong to the immunoglobulin superfamily (IgSF) and to the MHC superfamily (MhcSF). IMGT consists of five databases, ten on-line tools and more than 8,000 HTML pages of Web resources. IMGT provides a common access to standardized data from genome, genetics, proteome and three-dimensional structures. The accuracy and the consistency of IMGT data are based on IMGT-ONTOLOGY, a semantic specification of terms to be used in immunogenetics and immunoinformatics. IMGT-ONTOLOGY comprises six main concepts: IDENTIFICATION, CLASSIFICATION, DESCRIPTION, NUMEROTATION, ORIENTATION and OBTENTION. Based on these concepts, the controlled vocabulary and the annotation rules necessary for the immunogenetics data identification, classification, description and numbering and for the management of IMGT knowledge are defined in the IMGT Scientific chart. IMGT is the international reference in immunogenetics and immunoinformatics for medical research (repertoire analysis of the IG antibody sites and of the TR recognition sites in autoimmune and infectious diseases, AIDS, leukemias, lymphomas, myelomas), veterinary research (IG and TR repertoires in farm and wild life species), genome diversity and genome evolution studies of the adaptive immune responses, biotechnology related to antibody engineering (single chain Fragment variable (scFv), phage displays, combinatorial libraries, chimeric, humanized and human antibodies), diagnostics (detection and follow up of residual diseases) and therapeutical approaches (grafts, immunotherapy, vaccinology). IMGT is freely available at http://imgt.cines.fr.", "In 2012, Fiji introduced rotavirus vaccine (Rotarix, GSK) into the national immunisation schedule. We describe the intussusception epidemiology prior to rotavirus vaccine, temporal association of intussusception cases to administration of rotavirus vaccine, and estimate the additional number of intussusception cases that may be associated with rotavirus vaccine. A retrospective review of intussusception cases for children aged <24 months old was undertaken between January 2007 and October 2012 pre-vaccine. All admissions and deaths with a discharge diagnosis of intussusception, bowel obstruction, paralytic ileus, or intussusception ICD10-AM codes were extracted from national databases and hospital records. Nationwide active intussusception surveillance was established for three years post-vaccine (2013-2015). There were 24 definite intussusception cases in the pre-rotavirus vaccine period, 96% were confirmed by surgery. The median age was 6.5 months. The incidence rate was 22.2 (95% CI: 13.9-33.7) per 100,000 infants. There were no deaths. Active surveillance identified 25 definite intussusception cases, 96% of which were among children who were age-eligible for rotavirus vaccine. None were potentially vaccine related. We estimated one to five additional  cases of intussusception every five years. The incidence of intussusception pre-rotavirus vaccine in Fiji is low. Intussusception associated with rotavirus vaccine is likely a rare event in Fiji.", "Three-dimensional (3D) chromatin structure is an emerging paradigm for understanding gene regulation mechanisms. Hi-C (high-throughput chromatin conformation capture), a method to detect long-range chromatin interactions, allows extensive genome-wide investigation of 3D chromatin structure. However, broad application of Hi-C data have been hindered by the level of complexity in processing Hi-C data and the large size of raw sequencing data. In order to overcome these limitations, we constructed a database named 3DIV (a 3D-genome Interaction Viewer and database) that provides a list of long-range chromatin interaction partners for the queried locus with genomic and epigenomic annotations. 3DIV is the first of its kind to collect all publicly available human Hi-C data to provide 66 billion uniformly processed raw Hi-C read pairs obtained from 80 different human cell/tissue types. In contrast to other databases, 3DIV uniquely provides normalized chromatin interaction frequencies against genomic distance dependent background signals and a dynamic browsing visualization tool for the listed interactions, which could greatly advance the interpretation of chromatin interactions. '3DIV' is available at http://kobic.kr/3div.", "Fragile X-related disorders (FXDs), also known as FMR1 disorders, are examples of repeat expansion diseases (REDs), clinical conditions that arise from an increase in the number of repeats in a disease-specific microsatellite. In the case of FXDs, the repeat unit is CGG/CCG and the repeat tract is located in the 5' UTR of the X-linked FMR1 gene. Expansion can result in neurodegeneration, ovarian dysfunction, or intellectual disability depending on the number of repeats in the expanded allele. A growing body of evidence suggests that the mutational mechanisms responsible for many REDs share several common features. It is also increasingly apparent that in some of these diseases the pathologic consequences of expansion may arise in similar ways. It has long been known that many of the disease-associated repeats form unusual DNA and RNA structures. This review will focus on what is known about these structures, the proteins with which they interact, and how they may be related to the causative mutation and disease pathology in the FMR1 disorders.", "Angiogenin, a potent angiogenic factor, was cloned and expressed by Escherichia coli and then purified with gel filtration chromatography. Approximately 90% pure angiogenin was obtained to generate a monoclonal antibody. Using western immunoblotting and ELISA, we confirmed that monoclonal antibody C46 secreted from hybridoma cells stably and specifically binds to angiogenin. The fused protein angiogenin-EGF was then expressed in HUVECs, and the subcellular localization of the recombinant protein was determined by confocal microscopy and TEM assay. Recombinant angiogenin was found to mainly concentrate in the pars granulosa of the nucleus, where the protein accumulates to form ribonucleoprotein particles.", "H4K20 monomethylation maintains genome integrity by regulating proper mitotic condensation, DNA damage response, and replication licensing. Here, we show that, in non-dividing hepatic cells, H4K20Me1 is specifically enriched in active gene bodies and dynamically regulated by the antagonistic action of Kmt5a methylase and Kdm7b demethylase. In liver-specific Kmt5a-deficient mice, reduced levels of H4K20Me1 correlated with reduced RNA Pol II release from promoter-proximal regions. Genes regulating glucose and fatty acid metabolism were most sensitive to impairment of RNA Pol II release. Downregulation of glycolytic genes resulted in an energy starvation condition partially compensated by AMP-activated protein kinase (AMPK) activation and increased mitochondrial activity. This metabolic reprogramming generated a highly sensitized state that, upon different metabolic stress conditions, quickly aggravated into a senescent phenotype due to ROS overproduction-mediated oxidative DNA damage. The results illustrate how defects in the general process of RNA Pol II transition into a productive elongation phase can trigger specific metabolic changes and genome instability." ]

[ "Histone lysine methylation is a critical marker for controlling gene expression. The position and extent of methylation (mono-, di-, or tri-) controls the binding of effector proteins that determine whether the associated DNA is expressed or not. Dysregulation of histone protein methylation has been associated with a number of types of cancer, and development of inhibitors for the effector proteins is becoming an active area of research. For this reason, understanding the mechanism by which effector proteins obtain selectivity for the different methylation states of lysine is of great interest. To this end, we have performed mutation studies on the Drosophila HP1α chromodomain, which binds H3K9Me(2) and H3K9Me(3) with approximately equal affinities. The selectivity of HP1α chromodomain for H3K9Me(3) over H3K9Me(2) was investigated by mutating E52 to remove or weaken the hydrogen bond to K9Me(2) while maintaining affinity for K9Me(3,) including E52F, E52I, E52V, E52D, an E52Q. The E52Q mutant exhibited the greatest degree of selectivity for KMe3, with 3.5-fold weaker binding to the dimethylated peptide (K(D) =52 μM) compared to the trimethylated peptide (K(D) =15 μM). These studies provide insight into the role of electrostatic interactions and hydrogen bonding in the differentiation of methylation states and have implications regarding the evolutionary pressure for selectivity in this protein-protein interaction. Moreover, the information from this study may help guide inhibitor development for this class of proteins.", "Chronic myeloproliferative neoplasms (MPN) comprise a spectrum of clonal neoplastic disorders characterized by overproduction of terminally differentiated cells of the myeloid lineage. A common genetic basis for the BCR-ABL-negative MPN disorders was elucidated in 2005 with the identification of the JAK2V617F mutation in the majority of MPN patients. The discovery of JAK2V617F had a dramatic impact on the diagnosis and treatment of MPN. Testing for JAK2 mutations is now included in the World Health Organization (WHO) criteria for the diagnosis of MPN, and in 2011 the oral JAK2 kinase inhibitor ruxolitinib became the first Food and Drug Administration (FDA)-approved drug for the treatment of myelofibrosis. The drug is now also approved in Europe and Canada.", "Filifactor alocis, a gram-positive, obligate anaerobic rod, is an emerging periodontal pathogen that is frequently isolated from patients with periodontitis, peri-implantitis, and apical periodontitis. Recent studies have shown that extracellular vesicles (EVs) from gram-negative periodontal pathogens, so-called outer membrane vesicles (OMVs), harbor various effector molecules responsible for inducing host inflammatory responses. However, there are no reports of EVs from F. alocis. In this study, we purified and characterized the protein profiles of EVs from F. alocis and investigated their immunostimulatory activity on human monocytic THP-1 and human oral keratinocyte HOK-16B cell lines. Highly pure EVs were obtained from F. alocis using density gradient ultracentrifugation. Nanoparticle tracking analysis and transmission electron microscopy showed that F. alocis EVs were between 50 and 270 nm in diameter. Proteome analysis identified 28 proteins, including lipoproteins, autolysins, F. alocis complement inhibitor (FACIN), transporter-related proteins, metabolism-related proteins, and ribosomal proteins. Human cytokine array analysis showed that F. alocis EVs remarkably induced the expression of CCL1, CCL2, MIP-1, CCL5, CXCL1, CXCL10, ICAM-1, IL-1β, IL-1ra, IL-6, IL-8, MIF, SerpinE, and TNF-α in THP-1 cells and CXCL1, G-CSF, GM-CSF, IL-6, and IL-8 in HOK-16B cells. The immunostimulatory activity of F. alocis EVs was similar to that of the whole bacterial cells. Our findings provide new insight into the role of EVs from gram-positive oral bacteria in periodontal diseases.", "OBJECTIVE: The purpose of this study is to investigate the injury patterns of noncatastrophic accidents by individual age groups.METHODS: Data were collected from the Korean In-Depth Accident Study database based on actual accident investigation. The noncatastrophic criteria were classified according to U.S. experts from the Centers for Disease Control and Prevention's recommendations for field triage guidelines of high-risk automobile crash criteria by vehicle intrusions more than 12 in. on occupant sites (including the roof) and more than 18 in. on any site. The Abbreviated Injury Scale (AIS) was used to determine injury patterns for each body region. Severely injured patients were classified as Maximum Abbreviated Injury Scale (MAIS) 3 or higher.RESULTS: In this study, the most significant injury regions were the head and neck, extremities, and thorax. In addition, the incidence of severe injury among elderly patients was nearly 1.6 times higher than that of non-elderly patients. According to age group, injured body regions among the elderly were the thorax, head and neck, and extremities, in that order. For the non-elderly groups, these were head and neck, extremities, and thorax. Severe injury rates were slightly different for the elderly group (head and neck, abdomen) and non-elderly group (thorax, head and neck).CONCLUSIONS: In both age groups, the rate of severe injury is proportional to an increase in crush extent zone. Front airbag deployment may have a relatively significant relationship to severe injuries.", "OBJECTIVE: A retrospective case series published in 2012 concluded that miconazole and nystatin used as topical antifungal drugs appear to interact equally strongly with warfarin. If confirmed, this finding has significant implications for clinical practice. This study evaluates the evidence.MATERIALS AND METHODS: Evidence from the pharmacology literature, the medical literature and the 'yellow card' adverse drug reaction surveillance reports was analysed regarding possible interactions of nystatin and miconazole with warfarin.RESULTS: There is strong evidence to support the derangement of warfarin anticoagulation by miconazole oral gel in all areas of evidence studied. No postulated mechanism of interaction, no additional published reported cases and no supportive data from adverse drug reports were identified which would corroborate the case for a significant interaction between nystatin and warfarin.CONCLUSION: Miconazole and nystatin used as topical antifungal drugs do not interact equally strongly with warfarin. Miconazole oral gel can clearly interact with warfarin to cause derangement of anticoagulation. Nystatin appears unlikely to interact with warfarin.", "Author information:(1)Sorbonne Universités, UPMC Univ Paris 06, Institut Pierre Louis d'Epidémiologie et de Santé Publique, GRC-UPMC 08 (EEMOIS), Paris, France Department of rheumatology, AP-HP, Pitié Salpêtrière Hospital, Paris, France.(2)Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria Second Department of Medicine, Hietzing Hospital, Vienna, Austria.(3)Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.(4)EULAR, representing People with Arthritis/Rheumatism in Europe (PARE), London, UK.(5)Research Laboratory and Clinical Division of Rheumatology, Department of Internal Medicine, University of Genova, Viale Benedetto, Italy.(6)Medicine Faculty, Paris Descartes University, Paris, France Rheumatology B Department, APHP, Cochin Hospital, Paris, France.(7)Leeds NIHR Musculoskeletal Biomedical Research Unit, LTHT, Leeds, UK Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.(8)Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology Center, Amsterdam, The Netherlands Atrium Medical Center, Heerlen, The Netherlands.(9)North Devon, UK.(10)Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria.(11)Rheumazentrum Ruhrgebiet, Herne and Ruhr-Universität Bochum, Herne, Germany.(12)Department of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Germany.(13)Arthritis Unit, Department of Rheumatology, Hospital Clínic and IDIBAPS, Barcelona, Spain.(14)Belgrade University School of Medicine, Belgrade, Serbia.(15)Department of Rheumatology, St. Vincent's University Hospital and Conway Institute, University College Dublin, Dublin, Ireland.(16)Section of Rheumatology, Department of Clinical Sciences, Lund University, Lund, Sweden Sweden and School of Business, Engineering and Science, Halmstad University, Halmstad, Sweden.(17)Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.(18)Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.(19)Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven, Belgium Division of Rheumatology, University Hospitals Leuven, Leuven, Belgium.(20)Department of Dermatology, University Hospital Münster, Münster, Germany.(21)A.DI.PSO. (Associazione per la Difesa degli Psoriasici)-PE.Pso.POF (Pan European Psoriasis Patients' Organization Forum), Rome, Italy.(22)Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.(23)Rheumatology Department of Lucania, San Carlo Hospital of Potenza and Madonna delle Grazie Hospital of Matera, Potenza, Italy.(24)Institute and Clinic of Rheumatology Charles University Prague, Czech Republic.(25)Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.(26)Department of Rheumatology, Campus Benjamin Franklin, Charité, Berlin, Germany.(27)Ghent University Hospital, Ghent, Belgium.(28)Centre for Arthritis and Rheumatic Disease, Dublin Academic Medical Centre, St. Vincent's University Hospital, Dublin, Ireland.(29)Schoen Klinik Hamburg, Rheumatology and Clinical Immunology, Hamburg, Germany.(30)Department of Rheumatology and Clinical Immunology, German Rheumatism Research Centre Berlin, Charité-University Medicine Berlin, Germany.", "p73, a member of the p53 family, exhibits activities similar to those of p53, including the ability to induce growth arrest and apoptosis. p73 influences chemotherapeutic responses in human cancer patients, in association with p53. Alternative splicing of the TP73 gene produces many p73 C- and N-terminal isoforms, which vary in their transcriptional activity towards p53-responsive promoters. In this paper, we show that the C-terminal spliced isoforms of the p73 protein differ in their DNA-binding capacity, but this is not an accurate predictor of transcriptional activity. In different p53-null cell lines, p73beta induces either mitochondrial-associated or death receptor-mediated apoptosis, and these differences are reflected in different gene expression profiles. In addition, p73 induces cell cycle arrest and p21(WAF1) expression in H1299 cells, but not in Saos-2. This data shows that TAp73 isoforms act differently depending on the tumour cell background, and have important implications for p73-mediated therapeutic responses in individual human cancer patients." ]

[ "The recent report of positive results from a Phase IIa clinical trial of PBT2, a novel drug that targets amyloid-beta-metal interactions, underscores the value of abnormal transition metal metabolism as a potential therapeutic target in Alzheimer's disease. The Metals Hypothesis of Alzheimer's disease is based upon observations of the precipitation of amyloid-beta by zinc and its radicalization by copper. Both metals are markedly enriched in plaques. The Hypothesis involves the perturbance of these endogenous brain metals, and it does not consider toxicological exposure part of pathogenesis. Recent descriptions of the release of ionic zinc and copper in the cortical glutamatergic synapse, modulating the response of the NMDA receptor, may explain the vulnerability of amyloid-beta to abnormal interaction with these metal ions in the synaptic region leading to aggregation and fostering toxicity. Increasingly sophisticated medicinal chemistry approaches are being tested which correct the abnormalities without causing systemic disturbance of these essential minerals. PBT2, clioquinol and related compounds are ionophores rather than chelators. PBT2 is a once per day, orally bioavailable, second generation 8-OH quinoline derivative of clioquinol. It has performed very satisfactorily in toxicology and Phase I clinical trials and is advancing as a disease-modifying candidate drug for Alzheimer's disease.", "BACKGROUND: Exploding head syndrome (EHS) is characterized by attacks of a sudden noise or explosive feeling experienced in the head occurring during the transition from wake to sleep or from sleep to wake.METHODS: We present six new cases extending the clinical experience with the syndrome. We also reviewed all available cases from the scientific literature and evaluated the typical features of EHS.RESULTS: The female to male ratio is 1.5 to 1. The median age at onset is 54. In average, one attack per day to one attack per week occurs. Some patients suffer from several attacks per night. In about half of all patients, a chronic time course can be observed but episodic or sporadic occurrence is also common. The most frequent accompanying symptoms beside the noise are fear and flashes of light. Polysomnographic studies do not reveal any specific sleep pattern associated with EHS. Tricyclic antidepressants are helpful in some patients. However, most patients do not need treatment because of the benign nature of the syndrome.CONCLUSION: EHS is a well-defined disease entity with a benign nature.", "BACKGROUND: Since the ATP-binding cassette transporter ABCG2 plays a physiologically significant role of porphyrin efflux from living cells, the expression of ABCG2 may influences the efficacy of photodynamic therapy (PDT). In this study, we evaluated the effect of gefitinib, a potent ABCG2 inhibitor, on 5-aminolevulinic acid (5-ALA)-PDT in brain tumor cell lines in vitro.MATERIALS AND METHODS: Four human glioma cell lines (U87MG, U118MG, A172, and T98G) and a malignant meningioma cell line (IOMM-Lee) were incubated with gefitinib (0.01-1.0μM) before incubation with 5-ALA (1mM). The effects gefitinib on intracellular protoporphyrin IX (PpIX), mRNA and protein expression of ABCG2, and PDT were evaluated, in vitro.RESULTS: At concentrations of 0.1μM or higher, gefitinib enhanced intracellular levels of PpIX in a dose-dependent manner in all those cell lines. Gefitinib decreased mRNA and plasma membrane protein expression of ABCG2, and efficiently enhanced the effect of 5-ALA-PDT in malignant brain tumor cells.CONCLUSION: Gefitinib can inhibit ABCG2-mediated PpIX efflux from malignant brain tumor cells to increase the intracellular PpIX and thereby enhance the PDT effect.", "Though Deflazacort and prednisone improve clinical endpoints in Duchenne muscular dystrophy (DMD) patients, Deflazacort produces fewer side effects. As mechanisms of improvement and side effect differences remain unknown, we evaluated effects of corticosteroid administration on gene expression in blood of DMD patients. Whole blood was obtained from 14 children and adolescents with DMD treated with corticosteroids (DMD-STEROID) and 20 DMD children and adolescents naïve to corticosteroids (DMD). The DMD-STEROID group was further subdivided into Deflazacort and prednisone groups. Affymetrix U133 Plus 2.0 expression microarrays were used to evaluate mRNA expression. Expression of 524 probes changed with corticosteroids, including genes in iron trafficking and the chondroitin sulfate biosynthesis pathway. Deflazacort compared with prednisone yielded 508 regulated probes, including many involved in adipose metabolism. These genes and pathways help explain mechanisms of efficacy and side effects of corticosteroids, and could provide new treatment targets for DMD and other neuromuscular disorders.", "Acid sphingomyelinase deficiency (ASMD; Niemann-Pick disease type A and B) is a lysosomal storage disorder characterized by abnormal intracellular sphingomyelin (SM) accumulation. Prominent liver involvement results in hepatomegaly, fibrosis/cirrhosis, abnormal liver chemistries, and a proatherogenic lipid profile. Olipudase alfa (recombinant human ASM) is in clinical development as an investigational enzyme replacement therapy for the non-neurological manifestations of ASMD. In a phase 1b study conducted to evaluate the safety and tolerability of within-patient dose escalation with olipudase alfa, measurement of SM levels in liver biopsies was used as a pharmacodynamic biomarker of substrate burden. Five adult patients with non neuronopathic ASMD received escalating doses of olipudase alfa every 2 weeks for 26 weeks. Liver biopsies obtained at baseline and 26 weeks after treatment were evaluated for SM storage by histomorphometric analysis, biochemistry, and electron microscopy. Biopsies were also assessed for inflammation and fibrosis, and for the association of SM levels with liver volume, liver function tests, and lipid profiles. At baseline, SM storage present in Kupffer cells and hepatocytes ranged from 9.8% to 53.8% of the microscopic field. After 26 weeks of treatment, statistically significant reductions in SM (P<0.0001) measured by morphometry were seen in 4 patients with evaluable liver biopsies. The 26-week biopsy of the fifth patient was insufficient for morphometric quantitation. Posttreatment SM levels ranged from 1.2% to 9.5% of the microscopic field, corresponding to an 84% to 92% relative reduction from baseline. Improvements in liver volume, liver function tests, and lipid profiles were also observed. This study illustrates the utility of SM assessment by liver biopsy as a pharmacodynamic biomarker of disease burden in these patients.", "INTRODUCTION: Interleukin (IL)-17 is critical in the pathogenesis of psoriasis and psoriatic arthritis (PsA) with most data suggesting that IL-17A alone was the key cytokine. However, in vitro and in vivo studies have suggested dual blockade of IL-17A and IL-17 F may be more effective than IL-17 A blockade alone. Bimekizumab is the first human monoclonal antibody to exert simultaneous specific inhibition of IL-17A and IL-17 F, and has been studied in several phase II/III trials for psoriasis and PsA.AREAS COVERED: Bimekizumab is not currently licensed for use. A literature search identified clinical trials examining the efficacy and safety of bimekizumab for psoriasis and PsA, and these were critically appraised.EXPERT OPINION: Clinical trials of bimekizumab have been promising, demonstrating a rapid onset of response and superior efficacy compared to three currently licensed biologics: secukinumab, ustekinumab, and adalimumab. Bimekizumab maintains a high level of efficacy with maintenance dosing intervals of 8 weeks, compared with 4 weeks for currently licensed IL-17A antagonists. No unexpected adverse events have been identified, although mild-to-moderate fungal infections occur in approximately 10%. Studies over longer time periods involving additional active comparators would be valuable in further defining the role of bimekizumab amongst currently available treatments.", "The coincidence of aortic valve stenosis and cryptogenic gastrointestinal bleeding usually from angiodysplasia of the cecum and ascending colon has been called Heyde syndrome. The pathophysiologic link between both remains unclear and may be due to subtle changes in plasmatic coagulation. There are some statistic and numerous casuistic reports, and recently the existence of the syndrome has been questioned. We describe two cases of aortic valve stenosis and cryogenic gastrointestinal bleeding in which bleeding subsided after replacement with a bioprosthesis. We give an overview of the current literature." ]

[ "Author information:(1)Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92034;(2)Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92034;Department of Information and Computer Science, Aalto University School of Science, FI-00076 Aalto, Finland;(3)Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92034;Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037;(4)Howard Hughes Medical Institute,Department of Molecular, Cell, and Developmental Biology, andEli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095; and.(5)Department of Information and Computer Science, Aalto University School of Science, FI-00076 Aalto, Finland;(6)Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92034;Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037;Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093 arao@liai.org.", "The relevance of the non-coding genome to human disease has mainly been studied in the context of the widespread disruption of microRNA (miRNA) expression and function that is seen in human cancer. However, we are only beginning to understand the nature and extent of the involvement of non-coding RNAs (ncRNAs) in disease. Other ncRNAs, such as PIWI-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), transcribed ultraconserved regions (T-UCRs) and large intergenic non-coding RNAs (lincRNAs) are emerging as key elements of cellular homeostasis. Along with microRNAs, dysregulation of these ncRNAs is being found to have relevance not only to tumorigenesis, but also to neurological, cardiovascular, developmental and other diseases. There is great interest in therapeutic strategies to counteract these perturbations of ncRNAs.", "Author information:(1)Centre for Personalized Medicine, Department of Pediatrics, Faculty of Medicine, Linköping University, 581 85 Linköping, Sweden. Electronic address: colm.nestor@liu.se.(2)Centre for Personalized Medicine, Department of Pediatrics, Faculty of Medicine, Linköping University, 581 85 Linköping, Sweden.(3)Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, 581 83 Linköping, Sweden.(4)MD Anderson Cancer Center, Houston, TX 77030, USA.(5)MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.(6)Genomatix Software GmbH, 80335 Munich, Germany.(7)Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany.(8)Else Kröner-Fresenius-Center for Nutritional Medicine, Chair of Nutritional Medicine, MRI and ZIEL, Technische Universität München, 85354 Freising-Weihenstephan, Germany; German Center for Diabetes Research (DZD), Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes at the Helmholtz Zentrum München, 85764 Neuherberg, Germany; Technische Universität München, 85354 Freising-Weihenstephan, Germany.(9)Centre for Personalized Medicine, Department of Pediatrics, Faculty of Medicine, Linköping University, 581 85 Linköping, Sweden. Electronic address: mikael.benson@liu.se.", "α7 Nicotinic acetylcholine receptor (α7 nAChR) has been found in several non-neuronal cells and is described as an important regulator of cellular function. Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) are essential for the active suppression of autoimmunity. The present study investigated whether naturally occurring Tregs expressed α7 nAChR and investigated the functionary role of this receptor in controlling suppressive activity of these cells. We found that CD4(+)CD25(+) Tregs from naive C57BL/6J mice positively expressed α7 nAChR, and its activation by nicotine enhanced the suppressive capacity of Tregs. Nicotine stimulation up-regulated the expression of cytotoxic T-lymphocyte-associated antigen (CTLA)-4 and forkhead/winged helix transcription factor p3 (Foxp3) on Tregs but had no effect on the production of interleukin (IL)-10 and transforming growth factor-β1 by Tregs. In the supernatants of CD4(+)CD25(+) Tregs/CD4(+)CD25(-) T-cell cocultures, we observed a decrease in the concentration of IL-2 in nicotine-stimulated groups, but nicotine stimulation had no effect on the ratio of IL-4/interferon (IFN)-γ, which partially represented T-cell polarization. The above-mentioned effects of nicotine were reversed by a selective α7 nAChR antagonist, α-bungarotoxin. In addition, the ratio of IL-4/IFN-γ was increased by treatment with α-bungarotoxin. We conclude that nicotine might increase Treg-mediated immune suppression of lymphocytes via α7 nAChR. The effect is related to the up-regulation of CTLA-4 as well as Foxp3 expression and decreased IL-2 secretion in CD4(+)CD25(+) Tregs/CD4(+)CD25(-) T-cell coculture supernatants. α7 nAChR seems to be a critical regulator for immunosuppressive function of CD4(+)CD25(+) Tregs.", "BACKGROUND: Previous studies have found a strong correlation between internet search and public health surveillance data. Less is known about how search data respond to public health interventions, such as vaccination, and the consistency of responses in different countries. In this study, we aimed to study the correlation between internet searches for \"rotavirus\" and rotavirus disease activity in the United States, United Kingdom, and Mexico before and after introduction of rotavirus vaccine.METHODS: We compared time series of internet searches for \"rotavirus\" from Google Trends with rotavirus laboratory reports from the United States and United Kingdom and with hospitalizations for acute gastroenteritis in the United States and Mexico. Using time and location parameters, Google quantifies an internet query share (IQS) to measure the relative search volume for specific terms. We analyzed the correlation between IQS and laboratory and hospitalization data before and after national vaccine introductions.RESULTS: There was a strong positive correlation between the rotavirus IQS and laboratory reports in the United States (R2 = 0.79) and United Kingdom (R2 = 0.60) and between the rotavirus IQS and acute gastroenteritis hospitalizations in the United States (R2 = 0.87) and Mexico (R2 = 0.69) (P < .0001 for all correlations). The correlations were stronger in the prevaccine period than in the postvaccine period. After vaccine introduction, the mean rotavirus IQS decreased by 40% (95% confidence interval [CI], 25%-55%) in the United States and by 70% (95% CI, 55%-86%) in Mexico. In the United Kingdom, there was a loss of seasonal variation after vaccine introduction.CONCLUSIONS: Rotavirus internet search data trends mirrored national rotavirus laboratory trends in the United States and United Kingdom and gastroenteritis-hospitalization data in the United States and Mexico; lower correlations were found after rotavirus vaccine introduction.", "Fifty patients suffering from the \"exploding head syndrome\" are described. This hitherto unreported syndrome is characterised by a sense of an explosive noise in the head usually in the twilight stage of sleep. The associated symptoms are varied, but the benign nature of the condition is emphasised and neither extensive investigation nor treatment are indicated.", "Plasma levels of atrial natriuretic peptide (ANP), arginine vasopressin (AVP), renin activity (PRA), aldosterone (PA), catecholamines and urinary prostaglandins (PG), as well as renal function were measured in children in the edematous state of the nephrotic syndrome before and after infusion of human serum albumin. Before albumin infusion, plasma levels of AVP, PRA, PA and noradrenaline (NA) and urinary excretion of PGE2, PGE-Met, PGF2 alpha were elevated. The mean value of plasma ANP was in the normal range. Albumin infusion produced a 36% increase in the calculated plasma volume. It was associated with a fivefold rise in the plasma level of ANP (31.6 +/- 22.6 vs. 151.4 +/- 52 fmol/ml mean, SD), and a significant fall in the levels of PRA, AVP, PA, and NA. Similarly, urinary concentration of PGE2, PGE-Met and PGF2 alpha fell. Urine flow, GFR, UNaV, FENa, and COsm increased significantly, while CH2O remained unchanged. The diuresis, natriuresis and GFR correlated with the level of plasma ANP, while urinary sodium excretion did not correlate with PA or NA levels. These findings suggest that ANP plays an important role in albumin induced natriuresis in children with nephrotic syndrome.", "Thyroid hormone (TH) is critical in cardiac cell differentiation (regulating contractile proteins and cell geometry) and this effect could be potentially exploited therapeutically in reversing the process of de-differentiation which underlies postischemic cardiac remodeling. Acute myocardial infarction was induced in male Wistar rats by ligating left coronary artery (AMI, n=8), while sham operated animals served as control (SHAM, n=8). 13 weeks after AMI, TH was administered in a group of animals for 4 weeks (AMI-THYR, n=9). TH significantly increased beta-MHC and decreased alpha-MHC expression in the myocardium. This response was accompanied by changes in cardiac geometry: sphericity index, (SI, long to short axis ratio) was found to be 1.95 (SEM, 0.02) in SHAM, 1.51(0.03) in AMI and 1.64(0.03) in AMI-THYR, p<0.05. As a consequence, cardiac function was significantly improved: left ventricular ejection fraction (EF%) was 74.5% (SEM, 2.8) in SHAM vs 29.5% (2.1) in AMI, and 40.0% in AMI-THYR, p<0.05. Furthermore, +dp/dt and -dp/dt were 4250 (127) and 2278 (55) in SHAM vs 2737(233) and 1508 (95) in AMI vs 3866 (310) and 2137(111) in AMI -THYR, respectively, p<0.05. TH treatment partially reverses cardiac dysfunction in rats with old myocardial infarction by favorably changing cardiac chamber geometry and expression of myosin isoforms. Thyroid hormone, unlike current treatments, appears to be a paradigm of therapeutic intervention which aims at restoring cardiac geometry and may prove new effective treatment for heart failure." ]

[ "MOTIVATION: In the evolution of species, a kind of special sequences, termed ultraconserved sequences (UCSs), have been inherited without any change, which strongly suggests those sequences should be crucial for the species to survive or adapt to the environment. However, the UCSs are still regarded as mysterious genetic sequences so far. Here, we present a systematic study of ultraconserved genomic regions in the budding yeast based on the publicly available genome sequences, in order to reveal their relationship with the adaptability or fitness advantages of the budding yeast.RESULTS: Our results indicate that, in addition to some fundamental biological functions, the UCSs play an important role in the adaptation of Saccharomyces cerevisiae to the acidic environment, which is backed up by the previous observation. Besides that, we also find the highly unchanged genes are enriched in some other pathways, such as the nutrient-sensitive signaling pathway. To facilitate the investigation of unique UCSs, the UCSC Genome Browser was utilized to visualize the chromosomal position and related annotations of UCSs in S.cerevisiae genome.AVAILABILITY AND IMPLEMENTATION: For more details on UCSs, please refer to the Supplementary information online, and the custom code is available on request.CONTACT: fgao@tju.edu.cn.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "Modafinil improves working memory in healthy subjects and individuals diagnosed with schizophrenia and Attention Deficit/Hyperactivity Disorder, though the effects of modafinil have not been evaluated on working memory in methamphetamine-dependent subjects. This double-blind, placebo-controlled study evaluated whether a daily dose of 400 mg of modafinil, administered over three consecutive days, would enhance performance on a measure of working memory relative to test performance at baseline and following 3 days of placebo administration in 11 methamphetamine addicted, nontreatment-seeking volunteers. The results revealed that participants demonstrating relatively poor performance on the third day of a 3-day washout period (ie, at baseline), showed significant improvement on measures of working memory, but not on measures of episodic memory or information processing speed. In contrast, for participants demonstrating relatively high performance at baseline, modafinil administration did not affect test scores. The findings provide an initial indication that modafinil can reverse methamphetamine-associated impairments in working memory.", "Dyskeratosis congenita is a group of rare genetic bone marrow failure syndromes. Revesz syndrome, a variant disorder, is characterized by retinopathy, aplastic anemia, nail dystrophy, and cerebellar hypoplasia. We report the case of an 11-month-old boy with bilateral cicatricial retinal detachments associated with fibrovascular proliferation. Genetic testing ultimately confirmed a diagnosis of Revesz syndrome, which can mimic cicatricial retinopathy of prematurity. Prompt referral to a hematologist expedites diagnosis and treatment.", "The present study provides a survey of the immunolocalization of ionotropic glutamate receptor subunits throughout the rat and cat cerebellar cortex, with emphasis on the unipolar brush cell (UBC), a hitherto neglected cerebellar cell that is densely concentrated in the granular layer of the vestibulocerebellum and that forms giant synapses with mossy fibers. An array of nine previously characterized antibodies has been used, each of which stained a characteristic profile of cerebellar cells. The UBCs of both rat and cat were strongly immunostained by an antibody against the alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) receptor subunits, GluR2 and GluR3; were moderately immunostained by a monoclonal antibody to kainate receptor subunits, GluR5/6/7; were weakly immunostained by antibodies to NR1 subunits; and were not stained by antibodies to GluR1, GluR4, GluR6/7, KA-2, and NR2A/B. Postsynaptic densities of the giant mossy fiber-UBC synapses were GluR2/3, GluR5/6/7, and NR1 immunoreactive. The other cerebellar neurons were all immunolabeled to some extent with the GluR2/3 and NR1 antibodies. In addition, Purkinje cells were immunopositive for GluR1 and GluR5/6/7; granule cells were immunopositive for GluR5/6/7, GluR6/7, KA-2, and NR2A/B. The Golgi-Bergmann glia was densely stained by GluR1 and GluR4 antibodies, whereas astrocytes of the granular layer were stained by the GluR4 antiserum. Data provided herein may guide further electrophysiological and pharmacological studies of cerebellar cells in general and the UBCs in particular.", "BACKGROUND: Immune checkpoint inhibitor (ICI)-related cardiotoxicity (iRC) is uncommon but can be fatal. There have been few reports of iRC from a rural cancer population and few data for iRC and inflammatory biomarkers.OBJECTIVES: The purpose of this study was to characterize major adverse cardiac events (MACE) in ICI-treated lung cancer patients based in a rural setting and to assess the utility of C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) in the diagnosis of iRC.METHODS: Patients with lung cancer treated with ICIs at Vidant Medical Center/East Carolina University (VMC/ECU) between 2015 and 2018 were retrospectively identified. MACE included myocarditis, non-ST-segment elevated myocardial infarction (NSTEMI), supraventricular tachycardia (SVT), and pericardial disorders. Medical history, laboratory values, pre-ICI electrocardiography (ECG), and echocardiography results were compared in patients with and without MACE.RESULTS: Among 196 ICI-treated patients, 23 patients (11%) developed MACE at a median of 46 days from the first ICI infusion (interquartile range [IQR]: 17 to 83 days). Patients who developed MACE experienced myocarditis (n = 9), NSTEMI (n = 3), SVT (n = 7), and pericardial disorders (n = 4). Ejection fraction was not significantly different at the time of MACE compared to that at baseline (p = 0.495). Compared to baseline values, NLR (10.9 ± 8.3 vs. 20.7 ± 4.2, respectively; p = 0.032) and CRP (42.1 ± 10.1 mg/l vs. 109.9 ± 15.6 mg/l, respectively; p = 0.010) were significantly elevated at the time of MACE.CONCLUSIONS: NLR and CRP were significantly elevated at the time of MACE compared to baseline values in ICI-treated patients. Larger datasets are needed to validate these findings and identify predictors of MACE that can be used in the diagnosis and management of ICI-related iRC.", "Farnesyl protein transferase inhibitors (FTIs) have demonstrated clinical activity in certain solid tumors and hematological malignancies. Little is known about mechanisms of resistance to these agents. To provide a basis for better understanding FTI resistance, the colorectal carcinoma cell line HCT 116 was selected by stepwise exposure to increasing 4-(2-(4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo-(5,6)-cyclohepta(1,2-b)-pyridin-11(R)-yl)-1-piperidinyl)-2-oxo-ethyl)-1-piperidinecarboxamide (SCH66336) concentrations. The resulting line, HCT 116R, was 100-fold resistant to SCH66336 and other FTIs, including methyl {N-[2-phenyl-4-N[2(R)-amino-3-mercaptopropylamino] benzoyl]}-methionate (FTI-277), but was less than 2-fold resistant to the standard agents gemcitabine, cisplatin, and paclitaxel. Accumulation of the unfarnesylated forms of prelamin A and HDJ-2, two substrates that reflect farnesyl transferase inhibition, was similar in FTI-treated parental and HCT 116R cells, indicating that alterations in drug uptake or inhibition of farnesyl protein transferase is not the mechanism of resistance. Changes in signal-transduction pathways that might account for this resistance were examined by immunoblotting and confirmed pharmacologically. There was no difference in activation of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase pathway or sensitivity to the MEK1/2 inhibitor 2'-amino-3'-methoxyflavone (PD98059) in HCT 116R cells. In contrast, increased phosphorylation of the molecular target of rapamycin (mTOR) and its downstream target p70 S6 kinase and increased levels of Akt1 and Akt2 were demonstrated in HCT 116R cells. Further experiments demonstrated that the mTOR inhibitor rapamycin selectively sensitized HCT 116R cells to SCH66336 but not to gemcitabine, cisplatin, or paclitaxel. These findings provide evidence that alterations in the phosphatidylinositol-3 kinase/Akt pathway can contribute to FTI resistance and suggest a potential strategy for overcoming this resistance.", "The emergence of femtosecond diffractive imaging with X-ray lasers has enabled pioneering structural studies of isolated particles, such as viruses, at nanometer length scales. However, the issue of missing low frequency data significantly limits the potential of X-ray lasers to reveal sub-nanometer details of micrometer-sized samples. We have developed a new technique of dark-field coherent diffractive imaging to simultaneously overcome the missing data issue and enable us to harness the unique contrast mechanisms available in dark-field microscopy. Images of airborne particulate matter (soot) up to two microns in length were obtained using single-shot diffraction patterns obtained at the Linac Coherent Light Source, four times the size of objects previously imaged in similar experiments. This technique opens the door to femtosecond diffractive imaging of a wide range of micrometer-sized materials that exhibit irreproducible complexity down to the nanoscale, including airborne particulate matter, small cells, bacteria and gold-labeled biological samples." ]

[ "BACKGROUND: Growth differentiation factor 15 (GDF-15) is expressed and secreted in response to inflammation, oxidative stress, hypoxia, telomere erosion, and oncogene activation. Cardiovascular (CV) disease is a major driver of GDF-15 production. GDF-15 has favorable preanalytic characteristics and can be measured in serum and plasma by immunoassay.CONTENT: In community-dwelling individuals higher concentrations of GDF-15 are associated with increased risks of developing CV disease, chronic kidney disease, and cancer, independent of traditional CV risk factors, renal function, and other biomarkers (C-reactive protein, B-type natriuretic peptide, cardiac troponin). Low concentrations of GDF-15 are closely associated with longevity. GDF-15 is as an independent marker of all-cause mortality and CV events in patients with coronary artery disease, and may help select patients with non-ST-elevation acute coronary syndrome for early revascularization and more intensive medical therapies. GDF-15 is independently associated with mortality and nonfatal events in atrial fibrillation and heart failure (HF) with preserved or reduced ejection fraction. GDF-15 reflects chronic disease burden and acute perturbations in HF and responds to improvements in hemodynamic status. GDF-15 is independently associated with major bleeding in patients receiving antithrombotic therapies and has been included in a new bleeding risk score, which may become useful for decision support.SUMMARY: GDF-15 captures distinct aspects of CV disease development, progression, and prognosis, which are not represented by clinical risk predictors and other biomarkers. The usefulness of GDF-15 to guide management decisions and discover new treatment targets should be further explored.", "An X chromosome specific nucleic acid probe was used to study the positions of the X chromosomes in leukocyte nuclei by in situ hybridization to smears of peripheral blood. This autoradiographic approach allowed the first direct demonstration of the presence of X chromosomal material in the drumstick-like structures of female polymorphonuclear leukocytes.", "Apoptosis is dependent upon caspase activation leading to substrate cleavage and, ultimately, cell death. Although required for the apoptotic phenotype, it has become apparent that cells frequently die even when caspase function is blocked. This process, termed caspase-independent cell death (CICD), occurs in response to most intrinsic apoptotic cues, provided that mitochondrial outer membrane permeabilization has occurred. Death receptor ligation can also trigger a form of CICD termed necroptosis. In this review, we will examine the molecular mechanisms governing CICD, highlight recent findings demonstrating recovery from conditions of CICD and discuss potential pathophysiological functions of these processes.", "Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of tau protein aggregates in the basal ganglia, brainstem and cerebral cortex leading to rapid disease progression and death. The neurofibrillary tangles that define the neuropathology of PSP are comprised of aggregated 4R tau and show a well-defined distribution. Classically, PSP is diagnosed by symptoms that include progressive gait disturbance, early falls, vertical ophthalmoparesis, akinetic-rigid features, prominent bulbar dysfunction and fronto-subcortical dementia. There are currently no effective therapies for the treatment of this rapidly degenerating and debilitating disease. Davunetide is a novel neuroprotective peptide that is thought to impact neuronal integrity and cell survival through the stabilization of microtubules. Preclinical activity in models of tauopathy has been translated to clinical studies, demonstrating pharmacologic activity that has supported further development. Davunetide's efficacy and tolerability are being tested in a placebo-controlled study in PSP patients, making it the most advanced drug candidate in this indication. This review examines the disease characteristics of PSP, the rationale for treating PSP with davunetide and assesses some of the challenges of clinical trials in this patient population.", "The spatial organization of the genome is intimately linked to its biological function, yet our understanding of higher order genomic structure is coarse, fragmented and incomplete. In the nucleus of eukaryotic cells, interphase chromosomes occupy distinct chromosome territories, and numerous models have been proposed for how chromosomes fold within chromosome territories. These models, however, provide only few mechanistic details about the relationship between higher order chromatin structure and genome function. Recent advances in genomic technologies have led to rapid advances in the study of three-dimensional genome organization. In particular, Hi-C has been introduced as a method for identifying higher order chromatin interactions genome wide. Here we investigate the three-dimensional organization of the human and mouse genomes in embryonic stem cells and terminally differentiated cell types at unprecedented resolution. We identify large, megabase-sized local chromatin interaction domains, which we term 'topological domains', as a pervasive structural feature of the genome organization. These domains correlate with regions of the genome that constrain the spread of heterochromatin. The domains are stable across different cell types and highly conserved across species, indicating that topological domains are an inherent property of mammalian genomes. Finally, we find that the boundaries of topological domains are enriched for the insulator binding protein CTCF, housekeeping genes, transfer RNAs and short interspersed element (SINE) retrotransposons, indicating that these factors may have a role in establishing the topological domain structure of the genome.", "We investigated whether single nucleotide polymorphisms within ultraconserved elements (UCEs) are associated with susceptibility to overall colorectal cancer (CRC) and susceptibility to tumor site-specific CRC. The study included 787 CRC patients and 551 healthy controls. The study comprised of a training set (520 cases and 341 controls) and a replication set (267 cases and 210 controls). We observed associations in rs7849 and rs1399685 with CRC risk. For example, a dose-dependent trend (per-allele odds ratio (OR), 0.78; 95% confidence interval (CI), 0.63-1.00; P for trend = 0.05) associated with the variant allele of rs7849 in the training set. The significant trend toward a decrease in CRC risk was confirmed in the replication set (per-allele OR, 0.72; 95% CI, 0.52-0.99; P for trend = 0.044). When stratified by tumor location, for left-sided CRC (LCRC) risk, significant association was observed for the variant-containing genotypes of rs1399685 (OR, 1.77; 95% CI, 1.02-3.06) and the risk was replicated in the replication population (OR, 2.04; 95% CI, 1.02-4.07). The variant genotypes of rs9784100 and rs7849 conferred decreased risk but the associations were not replicated. Three right-sided CRC (RCRC) susceptibility loci were identified in rs6124509, rs4243289 and rs12218935 but none of the loci was replicated. Joint effects and potential higher order gene-gene interactions among significant variants further categorized patients into different risk groups. Our results strongly suggest that several genetic variants in the UCEs may contribute to CRC susceptibility, individually and jointly, and that different genetic etiology may be involved in RCRC and LCRC.", "Several studies have reported the occurrence of sensory neuropathy with exposure to chlorpyrifos and other organophosphorus insecticides, at levels not associated with overt toxicity. We evaluated 113 chemical workers, including 53 of 66 (80%) eligible chlorpyrifos workers and 60 of 74 (81%) randomly selected referent workers, to identify evidence of sensory neuropathy or subclinical neuropathy. Compared to referents, chlorpyrifos subjects had significantly longer duration of work in chlorpyrifos-exposed areas (9.72 vs. 0.01 years; P < 0.0001), greater cumulative chlorpyrifos exposure (64.16 vs. 0.69 mg/m(3). day; P < 0.0001), higher urine 3,5,6-trichloro-2-pyridinol (TCP) excretion (108.6 vs. 4.3 microg/g creatinine; P < 0.0001), and lower plasma butyrylcholinesterase (BuChE) activity (7281 vs. 8176 mU/ml; P = 0.003). Despite exposures among chlorpyrifos subjects to levels at which well-described physiological effects on B-esterases exist, the frequency of symptoms or signs of neuropathy did not differ significantly between groups, and the only 2 subjects fulfilling criteria for confirmed neuropathy were both in the referent group. Mean nerve conduction study results were comparable to established control values and did not differ significantly between groups. We found no evidence of sensory neuropathy or isolated peripheral abnormalities among subjects with long-term chlorpyrifos exposure at levels known to be associated with the manufacturing process." ]

[ "Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of both upper and lower motor neurons (MNs). The main clinical features of ALS are motor function impairment, progressive muscle weakness, muscle atrophy and, ultimately, paralysis. Intrinsic skeletal muscle deterioration plays a crucial role in the disease and contributes to ALS progression. Currently, there are no effective treatments for ALS, highlighting the need to obtain a deeper understanding of the molecular events underlying degeneration of both MNs and muscle tissue, with the aim of developing successful therapies. Muscle tissue is enriched in a group of microRNAs called myomiRs, which are effective regulators of muscle homeostasis, plasticity and myogenesis in both physiological and pathological conditions. After providing an overview of ALS pathophysiology, with a focus on the role of skeletal muscle, we review the current literature on myomiR network dysregulation as a contributing factor to myogenic perturbations and muscle atrophy in ALS. We argue that, in view of their critical regulatory function at the interface between MNs and skeletal muscle fiber, myomiRs are worthy of further investigation as potential molecular targets of therapeutic strategies to improve ALS symptoms and counteract disease progression.", "Mitosis is orchestrated by several protein kinases including Cdks, Plks and Aurora kinases. Despite considerable progress toward understanding the individual function of these protein kinases, how their activity is coordinated in space and time during mitosis is less well understood. In a recent article published in the Journal of Cell Biology, we show that CDK-1 regulates PLK-1 activity during mitosis in C. elegans embryos through multisite phosphorylation of the PLK-1 activator SPAT-1 (Aurora Borealis, Bora in human). SPAT-1 variants mutated on CDK-1 phosphorylation sites results in severe delays in mitotic entry, mimicking embryos lacking spat-1 or plk-1 function. We further show that SPAT-1 phosphorylation by CDK-1 promotes its binding to PLK-1 and stimulates PLK-1 phosphorylation on its activator T-loop by Aurora A kinase in vitro. Likewise, we find that phosphorylation of Bora by Cdk1 promotes phosphorylation of human Plk1 by Aurora A suggesting that this mechanism is conserved in humans. These results indicate that Cdk1 regulates Plk1 by boosting its kinase activity. Here we discuss these recent findings and open questions regarding the regulation of Plk1/PLK-1 by Cdk1/CDK-1 and Bora/SPAT-1.", "Tumor suppressor protein p53 plays a crucial role in maintaining genomic integrity in response to DNA damage. Regulation of translation of p53 mRNA is a major mode of regulation of p53 expression under genotoxic stress. The AU/U-rich element-binding protein HuR has been shown to bind to p53 mRNA 3'UTR and enhance translation in response to DNA-damaging UVC radiation. On the other hand, the microRNA miR-125b is reported to repress p53 expression and stress-induced apoptosis. Here, we show that UVC radiation causes an increase in miR-125b level in a biphasic manner, as well as nuclear cytoplasmic translocation of HuR. Binding of HuR to the p53 mRNA 3'UTR, especially at a site adjacent to the miR-125b target site, causes dissociation of the p53 mRNA from the RNA-induced silencing complex (RISC) and inhibits the miR-125b-mediated translation repression of p53. HuR prevents the oncogenic effect of miR-125b by reversing the decrease in apoptosis and increase in cell proliferation caused by the overexpression of miR-125b. The antagonistic interplay between miR-125b and HuR might play an important role in fine-tuning p53 gene expression at the post-transcriptional level, and thereby regulate the cellular response to genotoxic stress.", "BACKGROUND: The cytogenetic characteristic of Chronic Myeloid Leukemia (CML) is the formation of the Philadelphia chromosome gene product, BCR-ABL. Given that BCR-ABL is the specific target of Gleevec in CML treatment, we investigated the regulation of the catalytic component of telomerase, hTERT, by BCR-ABL at multiple levels in K562 cells.METHODS: Molecular techniques such as over expression, knockdown, real-time PCR, immunoprecipitation, western blotting, reporter assay, confocal microscopy, telomerase assays and microarray were used to suggest that hTERT expression and activity is modulated by BCR-ABL at multiple levels.RESULTS: Our results suggest that BCR-ABL plays an important role in regulating hTERT in K562 (BCR-ABL positive human leukemia) cells. When Gleevec inhibited the tyrosine kinase activity of BCR-ABL, phosphorylation of hTERT was downregulated, therefore suggesting a positive correlation between BCR-ABL and hTERT. Gleevec treatment inhibited hTERT at mRNA level and significantly reduced telomerase activity (TA) in K562 cells, but not in HL60 or Jurkat cells (BCR-ABL negative cells). We also demonstrated that the transcription factor STAT5a plays a critical role in hTERT gene regulation in K562 cells. Knockdown of STAT5a, but not STAT5b, resulted in a marked downregulation of hTERT mRNA level, TA and hTERT protein level in K562 cells. Furthermore, translocation of hTERT from nucleoli to nucleoplasm was observed in K562 cells induced by Gleevec.CONCLUSIONS: Our data reveal that BCR-ABL can regulate TA at multiple levels, including transcription, post-translational level, and proper localization. Thus, suppression of cell growth and induction of apoptosis by Gleevec treatment may be partially due to TA inhibition. Additionally, we have identified STAT5a as critical mediator of the hTERT gene expression in BCR-ABL positive CML cells, suggesting that targeting STAT5a may be a promising therapeutic strategy for BCR-ABL positive CML patients.", "Antisense long non-coding (aslnc)RNAs represent a substantial part of eukaryotic transcriptomes that are, in yeast, controlled by the Xrn1 exonuclease. Nonsense-Mediated Decay (NMD) destabilizes the Xrn1-sensitive aslncRNAs (XUT), but what determines their sensitivity remains unclear. We report that 3' single-stranded (3'-ss) extension mediates XUTs degradation by NMD, assisted by the Mtr4 and Dbp2 helicases. Single-gene investigation, genome-wide RNA analyses, and double-stranded (ds)RNA mapping revealed that 3'-ss extensions discriminate the NMD-targeted XUTs from stable lncRNAs. Ribosome profiling showed that XUT are translated, locking them for NMD activity. Interestingly, mutants of the Mtr4 and Dbp2 helicases accumulated XUTs, suggesting that dsRNA unwinding is a critical step for degradation. Indeed, expression of anticomplementary transcripts protects cryptic intergenic lncRNAs from NMD. Our results indicate that aslncRNAs form dsRNA that are only translated and targeted to NMD if dissociated by Mtr4 and Dbp2. We propose that NMD buffers genome expression by discarding pervasive regulatory transcripts.", "Non-coding (nc)RNAs are key players in numerous biological processes such as gene regulation, chromatin domain formation and genome stability. Large ncRNAs interact with histone modifiers and are involved in cancer development, X-chromosome inactivation and autosomal gene imprinting. However, despite recent evidence showing that pervasive transcription is more widespread than previously thought, only a few examples mediating gene regulation in eukaryotes have been described. In Saccharomyces cerevisiae, the bona-fide regulatory ncRNAs are destabilized by the Xrn1 5'-3' RNA exonuclease (also known as Kem1), but the genome-wide characterization of the entire regulatory ncRNA family remains elusive. Here, using strand-specific RNA sequencing (RNA-seq), we identify a novel class of 1,658 Xrn1-sensitive unstable transcripts (XUTs) in which 66% are antisense to open reading frames. These transcripts are polyadenylated and RNA polymerase II (RNAPII)-dependent. The majority of XUTs strongly accumulate in lithium-containing media, indicating that they might have a role in adaptive responses to changes in growth conditions. Notably, RNAPII chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) analysis of Xrn1-deficient strains revealed a significant decrease of RNAPII occupancy over 273 genes with antisense XUTs. These genes show an unusual bias for H3K4me3 marks and require the Set1 histone H3 lysine 4 methyl-transferase for silencing. Furthermore, abolishing H3K4me3 triggers the silencing of other genes with antisense XUTs, supporting a model in which H3K4me3 antagonizes antisense ncRNA repressive activity. Our results demonstrate that antisense ncRNA-mediated regulation is a general regulatory pathway for gene expression in S. cerevisiae.", "Antisense transcription can regulate sense gene expression. However, previous annotations of antisense transcription units have been based on detection of mature antisense long noncoding (aslnc)RNAs by RNA-seq and/or microarrays, only giving a partial view of the antisense transcription landscape and incomplete molecular bases for antisense-mediated regulation. Here, we used native elongating transcript sequencing to map genome-wide nascent antisense transcription in fission yeast. Strikingly, antisense transcription was detected for most protein-coding genes, correlating with low sense transcription, especially when overlapping the mRNA start site. RNA profiling revealed that the resulting aslncRNAs mainly correspond to cryptic Xrn1/Exo2-sensitive transcripts (XUTs). ChIP-seq analyses showed that antisense (as)XUT's expression is associated with specific histone modification patterns. Finally, we showed that asXUTs are controlled by the histone chaperone Spt6 and respond to meiosis induction, in both cases anti-correlating with levels of the paired-sense mRNAs, supporting physiological significance to antisense-mediated gene attenuation. Our work highlights that antisense transcription is much more extended than anticipated and might constitute an additional nonpromoter determinant of gene regulation complexity.", "Andersen's syndrome is a rare disorder that has been defined with a triad: periodic paralysis, cardiac arrhythmia, and development anomalies. Muscle weakness has been reported in two-thirds of the patients. KCNJ2 remains the only gene linked to Andersen's syndrome; this gene encodes for the alpha-subunit of the strong inward-rectifier K+ channel Kir2.1. Several studies have shown that Andersen's syndrome mutations lead to a loss of function of the K+ channel activity in vitro. However, ex vivo studies on isolated patient muscle tissue have not been reported. We have performed muscle biopsies of controls and patients presenting with clinically and genetically defined Andersen's syndrome disorder. Myoblasts were cultured and characterized morphologically and functionally using the whole cell patch-clamp technique. No morphological difference was observed between Andersen's syndrome and control myoblasts at each passage of the cell culture. Cellular proliferation and viability were quantified in parallel with direct cell counts and showed no difference between control and Andersen's syndrome patients. Moreover, our data show no significant difference in myoblast fusion index among Andersen's syndrome and control patients. Current recordings carried out on myotubes revealed the absence of an inwardly rectifying Ba2+-sensitive current in affected patient cells. One consequence of the Ik1 current loss in Andersen's syndrome myotubes is a shift of the resting membrane potential toward depolarizing potentials. Our data describe for the first time the functional consequences of Andersen's syndrome mutations ex vivo and provide clues to the K+ channel pathophysiology in skeletal muscle.", "Background We evaluated the effect of erenumab, a fully human monoclonal antibody that inhibits the canonical calcitonin gene-related peptide receptor, on migraine-related disability, impact, and health-related quality of life among patients with episodic migraine. Methods Patients enrolled in a phase 3, 6-month, double-blind, placebo-controlled study of once-monthly erenumab 70 and 140 mg for migraine prevention (STRIVE) used an eDiary during the baseline and double-blind treatment phases to complete validated, specific questionnaires, including the modified (monthly) Migraine Disability Assessment Questionnaire; Headache Impact Test; and Migraine-Specific Quality of Life Questionnaire-role function-restrictive (MSQ-RFR), -role function-preventive (MSQ-RFP), and -emotional function (MSQ-EF). Results A total of 955 patients were randomized to receive erenumab 70 mg (n = 317), erenumab 140 mg (n = 319), or placebo (n = 319). Erenumab versus placebo resulted in significantly greater improvements in all patient-reported outcomes; changes from baseline were numerically higher with 140 mg erenumab. Improvements occurred rapidly and were maintained over 6 months of treatment. Between-group differences from placebo over months 4-6 for the 70- and 140-mg dose groups were, respectively, -2.1 and -2.8 for modified (monthly) Migraine Disability Assessment Questionnaire, -2.1 and -2.3 for Headache Impact Test, 5.1 and 6.5 for MSQ-RFR, 4.2 and 5.4 for MSQ-RFP, and 5.2 and 6.7 for MSQ-EF ( p < 0.001 for all). Erenumab also significantly reduced the proportion of patients with severe and very severe migraine-related disability and increased the proportion of patients with clinically meaningful improvements in migraine-related impact and health-related quality of life. Conclusion Erenumab reduced migraine disability and impact and improved patients' health-related quality of life, reinforcing its role as a promising new therapy for migraine prevention.", "Patients with cholestasis-lymphedema syndrome (CLS) suffer severe neonatal cholestasis that usually lessens during early childhood and becomes episodic; they also develop chronic severe lymphedema. The genetic cause of CLS is unknown. We performed a genome screen, using DNA from eight Norwegian patients with CLS and from seven unaffected relatives, all from an extended pedigree. Regions potentially shared identical by descent in patients were further characterized in a larger set of Norwegian patients. The patients manifest extensive allele and haplotype sharing over the 6.6-cM D15S979-D15S652 region: 30 (83.3%) of 36 chromosomes of affected individuals carry a six-marker haplotype not found on any of the 32 nontransmitted parental chromosomes. All Norwegian patients with CLS are likely homozygous for the same disease mutation, inherited from a shared ancestor.", "BACKGROUND: Aleglitazar, a dual PPAR-α/γ agonist, combines the lipid benefits of fibrates and the insulin-sensitizing benefits of thiazolidinediones.OBJECTIVE: To investigate the pharmacokinetic effects of co-administration of atorvastatin or rosuvastatin with aleglitazar.RESEARCH DESIGN AND METHODS: In a two-cohort, open-label, randomised, three-period crossover study, 44 healthy subjects received once-daily oral doses of aleglitazar 300 μg, statin (atorvastatin 80 mg or rosuvastatin 40 mg) and aleglitazar co-administered with each statin for 7 days. Plasma concentrations of each drug were measured and pharmacokinetic parameters determined on day 7 in each period.MAIN OUTCOME MEASURES: Peak observed plasma concentration (C(max)) and total exposures (AUC(0 - 24)) of aleglitazar, atorvastatin and rosuvastatin.RESULTS: C(max) and AUC(0 - 24) to aleglitazar were similar, whether administered alone or in combination with a statin. Total exposure to either statin was unaffected by co-administration with aleglitazar. C(max) treatment ratios for both statins exceeded the conventional no-effect boundary (1.25) when administered with aleglitazar.CONCLUSIONS: Co-administration of aleglitazar with a statin does not alter the pharmacokinetic profile of either drug.", "Author information:(1)Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Via Venezian 1, 20133, Milano, Italy. maura.massimino@istitutotumori.mi.it.(2)Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Via Venezian 1, 20133, Milano, Italy.(3)Medical Statistics, Biometry and Bioinformatics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Via Venezian 1, 20133, Milano, Italy.(4)Department of Neuroradiology, University of Würzburg, Josef-Schneider-Str.11, 97080, Wurzburg, Germany.(5)Genetics Unit, Pathology Department, Ospedale S. Anna, San Fermo della Battaglia, 22100, Como, Italy.(6)Radiotherapy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Via Venezian 1, 20133, Milano, Italy.(7)Radiological and Oncological Sciences Department, Universita` Sapienza, Viale del Policlinico, 00151, Roma, Italy.(8)Pathology Department, Universita` Sapienza, Viale del Policlinico, 00151, Roma, Italy.(9)Radiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Via Venezian 1, 20133, Milano, Italy.(10)Neuropathology Unit, IRCCS Istituto Neurologico Carlo Besta, Via Celoria, 20133, Milano, Italy.(11)Human Tumor Immunobiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Via Venezian 1, 20133, Milano, Italy.(12)Physiopathology Department, State Medical School, Via Festa del Perdono, 20100, Milano, Italy.(13)Neuro-Oncology Unit, Ospedale Meyer, Viale Pieraccini 24, 50139, Firenze, Italy.(14)Molecular Therapies Unit, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Via Venezian 1, 20133, Milano, Italy.(15)Department of Pediatric Hematology/Oncology, University of Bonn Medical School, Bonn, Germany.(16)Oncoscience AG, Hafenstraße 32, 22880, Wedel, Germany." ]

[ "We investigated DNA sequence diversity for loci on chromosomes 1 and 2 in six natural populations of Arabidopsis lyrata and tested for the role of natural selection in structuring genomewide patterns of variability, specifically examining the effects of recombination rate on levels of silent polymorphism. In contrast with theoretical predictions from models of genetic hitchhiking, maximum-likelihood-based analyses of diversity and divergence do not suggest reduction of diversity in the region of suppressed recombination near the centromere of chromosome 1, except in a single population from Russia, in which the pericentromeric region may have undergone a local selective sweep or demographic process that reduced variability. We discuss various possibilities that might explain why nucleotide diversity in most A. lyrata populations is not related to recombination rate, including genic recombination hotspots, and low gene density in the low recombination rate region.", "Activation of large conductance Ca(2+)-activated potassium (BK) channels hastens action potential repolarisation and generates the fast afterhyperpolarisation in hippocampal pyramidal neurons. A rapid coupling of Ca(2+) entry with BK channel activation is necessary for this to occur, which might result from an identified coupling of Ca(2+) entry through N-type Ca(2+) channels to BK channel activation. This selective coupling was extremely rapid and resistant to intracellular BAPTA, suggesting that the two channel types are close. Using reciprocal co-immunoprecipitation, we found that N-type channels were more abundantly associated with BK channels than L-type channels (Ca(V)1.2) in rat brain. Expression of only the pore-forming alpha-subunits of the N-type (Ca(V)2.2) and BK (Slo(27)) channels in a non-neuronal cell-line gave robust macroscopic currents and reproduced the interaction. Co-expression of Ca(V)2.2/Ca(V)beta(3) subunits with Slo(27) channels revealed rapid functional coupling. By contrast, extremely rare examples of rapid functional coupling were observed with co-expression of Ca(V)1.2/Ca(V)beta(3) and Slo(27) channels. Action potential repolarisation in hippocampal pyramidal neurons was slowed by the N-type channel blocker omega-conotoxin GVIA, but not by the L-type channel blocker isradipine. These data showed that selective functional coupling between N-type Ca(2+) and BK channels provided rapid activation of BK channels in central neurons.", "We performed a post hoc analysis of the Belimumab International Study in Lupus Nephritis (BLISS-LN), a Phase 3, multinational, double-blind, 104-week trial, in which 448 patients with lupus nephritis were randomized to receive intravenous belimumab 10 mg/kg or placebo with standard therapy (cyclophosphamide/azathioprine or mycophenolate mofetil). Add-on belimumab was found to be most effective in improving the primary efficacy kidney response and complete kidney response in patients with proliferative lupus nephritis and a baseline urine protein/creatinine ratio under 3 g/g. However, there was no observed improvement in the kidney response with belimumab treatment in patients with lupus nephritis and sub-epithelial deposits or with a baseline protein/creatinine ratio of 3 g/g or more. Belimumab significantly reduced the risk of kidney-related events or death and lupus nephritis flare in the overall population. Belimumab reduced the risk of a sustained 30% or 40% decline in estimated glomerular filtration rate (eGFR) versus standard treatment alone and attenuated the annual rate of eGFR decline in patients who remained on-study. Thus, our data suggest that the addition of belimumab to standard therapy could attenuate the risk of lupus nephritis flare and eGFR decline in a broad spectrum of patients with lupus nephritis.", "Upon oxygen shift-down, Mycobacterium tuberculosis complex bacteria can induce a genetic program characterized by halted duplication, which is called Non-replicating persistence (NRP). During this phase, at least 48 genes, collectively named Dormancy survival regulator (DosR) regulon, are important for the long-term survival of bacilli under a non-respiring state, a condition that bacilli encounter inside granulomatous lesions. It remains unclear whether expression of NRP genes occurs within the tissue of Mycobacterium bovis naturally infected cattle. In order to start dissecting this question, total RNA from bovine lymph node tissues of sacrificed tuberculin reacting animals was isolated and transcription of genes required for in vivo duplication (esxB and fbpB) and in vitro NRP (hspX, pfkB, and mb2660c) were analyzed by RT-PCR approaches. Detection of transcripts was positive in bovine tissue samples for genes hspX, pfkB, and mb2660c in 84, 32, and 21%, respectively. NRP genes were upregulated even in animals with a negative IFN-γ in vitro test, and the expression of NRP genes occurred more often than expression of the esxB gene.", "A case of a nine year and eight months old child with Kartagener's syndrome (triad) is described: chronic maxillary sinusitis, bronchiectasis and \"situs inversus totalis\". Literature is reviewed. It is important to understand genetical and etiology aspects of bronchiectasis. Diagnosis was considered on the basis of physical and radiographic examination.", "Transcript elongation by RNA polymerase II (RNAPII) is accompanied by conserved patterns of histone modification. Whereas histone modifications have established roles in transcription initiation, their functions during elongation are not understood. Mono-ubiquitylation of histone H2B (H2Bub1) plays a key role in coordinating co-transcriptional histone modification by promoting site-specific methylation of histone H3. H2Bub1 also regulates gene expression through an unidentified, methylation-independent mechanism. Here we reveal bidirectional communication between H2Bub1 and Cdk9, the ortholog of metazoan positive transcription elongation factor b (P-TEFb), in the fission yeast Schizosaccharomyces pombe. Chemical and classical genetic analyses indicate that lowering Cdk9 activity or preventing phosphorylation of its substrate, the transcription processivity factor Spt5, reduces H2Bub1 in vivo. Conversely, mutations in the H2Bub1 pathway impair Cdk9 recruitment to chromatin and decrease Spt5 phosphorylation. Moreover, an Spt5 phosphorylation-site mutation, combined with deletion of the histone H3 Lys4 methyltransferase Set1, phenocopies morphologic and growth defects due to H2Bub1 loss, suggesting independent, partially redundant roles for Cdk9 and Set1 downstream of H2Bub1. Surprisingly, mutation of the histone H2B ubiquitin-acceptor residue relaxes the Cdk9 activity requirement in vivo, and cdk9 mutations suppress cell-morphology defects in H2Bub1-deficient strains. Genome-wide analyses by chromatin immunoprecipitation also demonstrate opposing effects of Cdk9 and H2Bub1 on distribution of transcribing RNAPII. Therefore, whereas mutual dependence of H2Bub1 and Spt5 phosphorylation indicates positive feedback, mutual suppression by cdk9 and H2Bub1-pathway mutations suggests antagonistic functions that must be kept in balance to regulate elongation. Loss of H2Bub1 disrupts that balance and leads to deranged gene expression and aberrant cell morphologies, revealing a novel function of a conserved, co-transcriptional histone modification.", "BACKGROUND: Low oxygen availability has been shown previously to stimulate M. tuberculosis to establish non-replicative persistence in vitro. The two component sensor/regulator dosRS is a major mediator in the transcriptional response of M. tuberculosis to hypoxia and controls a regulon of approximately 50 genes that are induced under this condition. The aim of this study was to determine whether the induction of the entire DosR regulon is triggered as a synchronous event or if induction can unfold as a cascade of events as the differential expression of subsets of genes is stimulated by different oxygen availabilities.RESULTS: A novel aspect of our work is the use of chemostat cultures of M. tuberculosis which allowed us to control environmental conditions very tightly. We exposed M. tuberculosis to a sudden drop in oxygen availability in chemostat culture and studied the transcriptional response of the organism during the transition from a high oxygen level (10% dissolved oxygen tension or DOT) to a low oxygen level (0.2% DOT) using DNA microarrays. We developed a Bayesian change point analysis method that enabled us to detect subtle shifts in the timing of gene induction. It results in probabilities of a change in gene expression at certain time points. A computational analysis of potential binding sites upstream of the DosR-controlled genes shows how the transcriptional responses of these genes are influenced by the affinity of these binding sites to DosR. Our study also indicates that a subgroup of DosR-controlled genes is regulated indirectly.CONCLUSION: The majority of the dosR-dependent genes were up-regulated at 0.2% DOT, which confirms previous findings that these genes are triggered by hypoxic environments. However, our change point analysis also highlights genes which were up-regulated earlier at levels of about 8% DOT indicating that they respond to small fluctuations in oxygen availability. Our analysis shows that there are pairs of divergent genes where one gene in the pair is up-regulated before the other, presumably for a flexible response to a constantly changing environment in the host.", "OBJECTIVE: To evaluate the pharmacokinetics of amantadine in children with impaired consciousness from acquired brain injury.DESIGN: Randomized, double-blind, placebo-controlled, crossover study with sparse sampling for pharmacokinetics.SETTING: Tertiary care pediatric hospital.PARTICIPANTS: Children, ages 6-18 years, with impaired consciousness 5-10 weeks after acquired brain injury.METHODS: Subjects received amantadine for 3 weeks. Subjects were randomized to placebo or amantadine 4 mg/kg/day for 7 days followed by 6 mg/kg/day for 14 days. Crossover was after a 7-day washout period.MAIN OUTCOME MEASURES: The Coma/Near-Coma Scale and Coma Recovery Scale-Revised were done 3 times per week to evaluate arousal and consciousness. Plasma concentrations of amantadine were determined for pharmacokinetic parameter estimation and evaluation of the exposure-response relationship. Adverse events were monitored.RESULTS: Nine subjects met the final inclusion and exclusion criteria, 7 of whom agreed to participate. Five subjects completed both arms of the study. Amantadine total body clearance was 0.17 L/h/kg with a half-life of 13.9 hours. Higher exposure of amantadine (average concentration of amantadine during 6 mg/kg/day > 1.5 mg/L) may be associated with better recovery of consciousness.CONCLUSIONS: Amantadine was well-tolerated in children with acquired brain injury and demonstrates pharmacokinetics similar to those reported for healthy young adults. Based on the preliminary data, higher dosing may be considered in the setting of brain injury.", "The PTEN tumor suppressor protein inhibits phosphatidylinositol 3-kinase (PI3K)/Akt signaling that promotes translocation of Mdm2 into the nucleus. When restricted to the cytoplasm, Mdm2 is degraded. The ability of PTEN to inhibit the nuclear entry of Mdm2 increases the cellular content and transactivation of the p53 tumor suppressor protein. Retroviral transduction of PTEN into U87MG (PTEN null) glioblastoma cells increases p53 activity and expression of p53 target genes and induces cell cycle arrest. U87MG/PTEN glioblastoma cells are more sensitive than U87MG/PTEN null cells to death induced by etoposide, a chemotherapeutic agent that induces DNA damage. Previously, tumor suppressor proteins have been supposed to act individually to suppress cancers. Our results establish a direct connection between the activities of two major tumor suppressors and show that they act together to respond to stresses and malignancies. PTEN protects p53 from survival signals, permitting p53 to function as a guardian of the genome. By virtue of its capacity to protect p53, PTEN can sensitize tumor cells to chemotherapy that relies on p53 activity. p53 induces PTEN gene expression, and here it is shown that PTEN protects p53, indicating that a positive feedback loop may amplify the cellular response to stress, damage, and cancer.", "Cell states in hematopoiesis are controlled by master regulators and by complex circuits of a growing family of RNA species impacting cell phenotype maintenance and plasticity. Circular RNAs (circRNAs) are rapidly gaining the status of particularly stable transcriptome members with distinctive qualities. RNA-seq identified thousands of circRNAs with developmental stage- and tissue-specific expression corroborating earlier suggestions that circular isoforms are a natural feature of the cell expression program. CircRNAs are abundantly expressed also in the hematopoietic compartment. There are a number of studies on circRNAs in blood cells, a specific overview is however lacking. In this review we first present current insight in circRNA biogenesis discussing the relevance for hematopoiesis of the highly interleaved processes of splicing and circRNA biogenesis. Regarding molecular functions circRNAs modulate host gene expression, but also compete for binding of microRNAs, RNA-binding proteins or translation initiation and participate in regulatory circuits. We examine circRNA expression in the hematopoietic compartment and in hematologic malignancies and review the recent breakthrough study that identified pathogenic circRNAs derived from leukemia fusion genes. CircRNA high and regulated expression in blood cell types indicate that further studies are warranted to inform the position of these regulators in normal and malignant hematopoiesis.", "Increasing knowledge about DosR regulon-encoded proteins has led us to produce novel Mycobacterium tuberculosis antigens for immunogenicity testing in human populations in three countries in Africa to which tuberculosis (TB) is endemic. A total of 131 tuberculin skin test-positive and/or ESAT-6/CFP10-positive, human immunodeficiency virus-negative adult household contacts of active pulmonary TB cases from South Africa (n = 56), The Gambia (n = 26), and Uganda (n = 49) were tested for gamma interferon responses to 7 classical and 51 DosR regulon-encoded M. tuberculosis recombinant protein antigens. ESAT-6/CFP10 fusion protein evoked responses in >75% of study participants in all three countries. Of the DosR regulon-encoded antigens tested, Rv1733c was the most commonly recognized by participants from both South Africa and Uganda and the third most commonly recognized antigen in The Gambia. The four most frequently recognized DosR regulon-encoded antigens in Uganda (Rv1733c, Rv0081, Rv1735c, and Rv1737c) included the three most immunogenic antigens in South Africa. In contrast, Rv3131 induced the highest percentage of responders in Gambian contacts (38%), compared to only 3.4% of Ugandan contacts and no South African contacts. Appreciable percentages of TB contacts with a high likelihood of latent M. tuberculosis infection responded to several novel DosR regulon-encoded M. tuberculosis proteins. In addition to significant similarities in antigen recognition profiles between the three African population groups, there were also disparities, which may stem from genetic differences between both pathogen and host populations. Our findings have implications for the selection of potential TB vaccine candidates and for determining biosignatures of latent M. tuberculosis infection, active TB disease, and protective immunity.", "The transcription factor gene MYC is important in breast cancer, and its mRNA is maintained at a high level even in the absence of gene amplification. The mechanism(s) underlying increased MYC mRNA expression is unknown. Here, we demonstrate that MYC mRNA was stabilized upon estrogen stimulation of estrogen receptor-positive breast cancer cells via SRC-dependent effects on a recently described RNA-binding protein, IMP1 with an N-terminal deletion (ΔN-IMP1). We also show that loss of the tumor suppressor p53 increased MYC mRNA levels even in the absence of estrogen stimulation. However, in cells with wild-type p53, SRC acted to overcome p53-mediated inhibition of estrogen-stimulated cell cycle entry and progression. SRC thus promotes cell proliferation in two ways: by stabilizing MYC mRNA and by inhibiting p53 function. Since estrogen receptor-positive breast cancers typically express wild-type p53, these studies establish a rationale for p53 status to be predictive for effective SRC inhibitor treatment in this subtype of breast cancer.", "Dasatinib, a dual tyrosine kinase inhibitor, is known to modulate or suppress T-cell activation and proliferation. We report a series of 8 patients who developed chronic peripheral lymphocytosis, identified as natural killer cells or natural killer/T-cells based on their large granular lymphocyte morphologies and CD16(+), CD56(+), CD3(-) or CD3(+) immunophenotypic profiles, out of 18 patients receiving dasatinib therapy. All cases that developed large granular lymphocyte lymphocytosis achieved optimal molecular response (8/8 in large granular lymphocyte(+) patients vs. 3/10 in large granular lymphocyte(-) patients, p=0.002). A (51)Cr release assay demonstrated that natural killer cell cytotoxicity has been enhanced in a case of large granular lymphocyte lymphocytosis compared to normal healthy donors, and that natural killer cell cytotoxicity in dasatinib-responders was superior to that in non-responders. In summary, the present study suggests that natural killer or natural killer/T cell lineage large granular lymphocyte lymphocytosis develops in association with dasatinib therapy and that large granular lymphocyte might have a therapeutic effect on Ph(+) leukemic cells.", "The use of cardiovascular magnetic resonance in patients with hypertrophic cardiomyopathy over the last decade has helped elucidate the diagnosis, prognosis, pathophysiology, and management of this disease. Studies have shown that the use of magnetic resonance imaging in a patient with a permanent pacemaker and implantable cardioverter defibrillator is safe.", "One of the challenges faced by Mycobacterium tuberculosis (M. tuberculosis) in dormancy is hypoxia. DosR/DevR of M. tuberculosis is a two component dormancy survival response regulator which induces the expression of 48 genes. In this study, we have used DosR regulon proteins of M. tuberculosis H37Rv as the query set and performed a comprehensive homology search against the non-redundant database. Homologs were found in environmental mycobacteria, environmental bacteria and archaebacteria. Analysis of genomic context of DosR regulon revealed that they are distributed as nine blocks in the genome of M. tuberculosis with many transposases and integrases in their vicinity. Further, we classified DosR regulon proteins into eight functional categories. One of the hypothetical proteins Rv1998c could probably be a methylisocitrate lyase or a phosphonomutase. Another hypothetical protein, Rv0572 was found only in mycobacteria. Insights gained in this study can potentially aid in the development of novel therapeutic interventions.", "Bruxism is a pathological activity of the stomatognathic system that involves tooth grinding and clenching during parafunctional jaw movements. Clinical signs of bruxism are mostly related to dental wear and muscular and joint discomforts, but a large number of etiological factors can be listed, as local, systemic, psychological and hereditary factors. The association between bruxism, feeding and smoking habits and digestive disorders may lead to serious consequences to dental and related structures, involving dental alterations (wear, fractures and cracks), periodontal signs (gingival recession and tooth mobility) and muscle-joint sensitivity, demanding a multidisciplinary treatment plan. This paper presents a case report in which bruxism associated with acid feeding, smoking habit and episodes of gastric reflow caused severe tooth wear and great muscular discomfort with daily headache episodes. From the diagnosis, a multidisciplinary treatment plan was established. The initial treatment approach consisted of medical follow up with counseling on diet and smoking habits and management of the gastric disorders. This was followed by the installation of an interocclusal acrylic device in centric relation of occlusion (CRO) for reestablishment of the occlusal stability, vertical dimension of occlusion, anterior guides and return to normal muscle activity (90-day use approximately). After remission of initial symptoms, oral rehabilitation was implemented in CRO by means of full resin composite restorations and new interocclusal device for protection of restorations. Satisfactory esthetics, improved function and occlusal stability were obtained after oral rehabilitation. The patient has attended annual follow-ups for the past 2 years. The multidisciplinary treatment seems to be the key for a successful rehabilitation of severe cases of dental wear involving the association of different health disorders.", "Leukemic cells of a patient diagnosed with chronic myeloid leukemia (CML) showed a complex BCR-ABL1 rearrangement hidden within a normal appearing karyotype. Previous molecular studies had established that the 3' BCR had recombined at a novel site within the variable region of the immunoglobulin lambda locus ( IGL). A segment of DNA mapping very close to the site of the IGL/3' BCR recombination recognized a previously undescribed insertion polymorphism. A combination of molecular hybridization studies and long-range polymerase chain reaction was used to isolate a 6-kb full-length long interspersed nuclear element (LINE or L1), here designated L1(IGL), which occupies 19% of alleles in the general population. Although unclonable, DNA sequence analysis by a primer walking approach established that L1(IGL) has features characteristic of an actively retrotransposing element. The L1(IGL) element has a 5' untranslated region, two open reading frames (ORF-1 and ORF-2), a 3' untranslated region and terminates in a poly-A tail. We compared the DNA sequence and the predicted amino acid sequence of L1(IGL) with a consensus sequence compiled from seven reported active L1 elements. This analysis indicated that L1(IGL) has high potential for involvement in as yet undetermined somatically and constitutionally acquired disease, not only through recombination mechanisms, but also through retrotransposition events. This full-length L1 element maps close within the IGLlocus to L1.2, one of only nine active L1 elements that have been reported so far. L1(IGL) and L1.2 map within a wider and well-recognized region of genomic instability on chromosome 22.", "The presence of thyrotropin receptors (TSHR) has been reported in some extrathyroidal tissues but its physio-pathological role still remains unclear. TSH (seems to) affects the human erythrocytes Na(+)/K(+)-ATPase in vitro, however receptors on erythrocytes have not yet been described. In this work the effect of recombinant human TSH (rhTSH) on sites number and activity of erythrocyte Na(+)/K(+)-ATPase was investigated in a group of thyroidectomized patient enrolled for rhTSH test. As detected by (3)H-ouabain binding, rhTSH administration induced a significant increase in the number of sites (p=0.005) and in the Kd (p=0.006) of Na(+)/K(+)-ATPase. rhTSH did not induce significant difference in Na(+)/K(+)-ATPase activity measured by (86)Rb uptake. (125)I-TSH binding studies and Western blotting data showed the existence of TSHR in the erythrocytes of healthy donors. In conclusion The TSH action on Na(+)/K(+)-ATPase of human erythrocytes can be explained by the presence of TSHR.", "1. The toxic principles in the venom of the sea-snake Laticauda semifasciata were separated into two components by CM-cellulose chromatography and obtained in crystalline forms. They were named ;erabutoxins a and b'. 2. The homogeneity of each toxin was shown by rechromatography, by disk electrophoresis, by ultracentrifuging, by toxicity measurements before and after repeated crystallizations and by N-terminal analysis. 3. They had molecular weights of about 7000. Both of them contained 61 (or 62) amino acid residues/molecule. The only difference between erabutoxins a and b was that one of the aspartic acid (or asparagine) residues in erabutoxin a was replaced by a histidine residue in erabutoxin b. 4. Both of the toxins had LD(50) values of 0.15mug./g. body wt. for mice and 0.07mug./g. for rats. It was shown with frog-muscle preparations that they acted on postsynaptic membrane to block neuromuscular transmission.", "Hallervorden-Spatz syndrome (HSS) is a rare autosomal recessive disorder clinically characterized by extrapyramidal signs and progressive dementia. In a typical case, the clinical symptoms become apparent during late childhood, and usually the course is protracted over a decade or more. We recently had an opportunity to study the brains of two cases of HSS with a clinical course of over 30 years. Case 1 was a 44-year-old female and case 2 was a 37-year-old male. Grossly, the brains showed severe fronto-temporal lobar atrophy with abundant spheroids and mild iron deposits in the globus pallidus, associated with features of motor neuron disease. In addition, there was diffuse sponginess in the atrophic cortex as well as widespread Alzheimer's neurofibrillary tangles (NFTs) and Lewy bodies (LBs) in the cortical and subcortical regions, including the spinal cord. Ultrastructurally, NFTs were composed of paired helical filaments, and LBs of central dense cores with radiating fibrils. Discrete immunostaining was demonstrated in NFTs and neuropil threads with various antibodies against phosphorylated tau, and in LBs with antibody against alpha-synuclein. In addition, diffuse, overlapping immunoreactivity of alpha-synuclein and phosphorylated tau was seen within the cytoplasm of many neurons. However, when LBs and NFTs coexisted within the same neurons, they were clearly segregated. The findings of our present cases as well as those reported in the literature may indicate that simultaneous and extensive occurrence of abnormal phosphorylation of tau and accumulation of alpha-synuclein may constitute cardinal pathological features of HSS with protracted clinical course.", "In early 1992, U.S. troops returning from the Gulf War began reporting a variety of nonspecific symptoms such as fatigue, skin rash, headache, muscle and joint pain, and loss of memory. These reports marked the beginning of what was to be identified as the Gulf War Syndrome (GWS). In the years since the war, as many as 100,000 troops have claimed they suffer from this mysterious disease. In our culture, the existence of disease as a specific entity is fundamental to ensuring the validity of that disease. The legitimacy of GWS has been repeatedly called into question because no specific physiological etiology has been confirmed, and it is becoming more and more likely that the origin of GWS will never be clearly delineated. The purpose of this paper is to illustrate the complicated process of defining GWS as a legitimate illness in the absence of etiological evidence and to suggest a method of treatment for individuals who still suffer from its sequelae.", "Bronchial and head and neck (HN) cancers share similarities especially regarding the HER pathway. Therapeutic progresses targeting the HER pathway are based on monoclonal antibodies, especially cetuximab, and tyrosine kinase (TK) inhibitors, targeting HER only, as gefitinib and erlotinib, or HER and other receptor(s), as VEGFR for the ZD6474. The results obtained already led to the registration of cetuximab (combined with radiotherapy) for management of locally advanced HN cancers, and the registration of erlotinib (and gefitinib in some countries) for management of non-small-cell lung cancer (NSCLC) in the second or third line setting. Therefore, these first successes led to the development of several drugs including monoclonal antibodies (trastuzumab, panitumumab, matuzumab), TK inhibitors targeting one receptor as well as TK pan-inhibitors (lapatinib, HKI 272, PKI 166, EKB-569, AEE-788), currently assessed through clinical trials worldwide. In the same time, progresses regarding the HER pathway also focused on a better selection of patients who clearly beneficiate from these drugs (EGFR gene mutations, EGFR gene amplification by FISH) allowing the first steps in tailoring anticancer treatments in lung cancer. In conclusion, therapeutic progresses targeting the HER pathway have improve management of HN and NSCLC patients and rise hopes for the future.", "The eukaryotic DNA recombination repair protein BRCA2 is functional in the parasitic protozoan Trypanosoma brucei. The mechanism of the involvement of BRCA2 in homologous recombination includes its interaction with the DNA recombinase proteins of the RAD51 family. BRCA2 is known to interact with RAD51 through its unique and essential BRC sequence motifs. T. brucei BRCA2 homolog (TbBRCA2) has fifteen repeating BRC motifs as compared to mammalian BRCA2 that has only eight. We report here our yeast 2-hybrid analysis studies on the interactions of TbBRCA2 BRC motifs with five different RAD51 paralogues of T. brucei. Our study revealed that a single BRC motif is sufficient to bind to these RAD51 paralogues. To test the possibility whether a single 44 amino acid long repeating unit of the TbBRCA2 BRC motif may be exploited as an inhibitor of T. brucei growth, we ectopically expressed this peptide segment in the procyclic form of the parasite and evaluated its effects on cell survival as well as the sensitivity of these cells to the DNA damaging agent methyl methane sulfonate (MMS). Expression of a single BRC motif led to MMS sensitivity and inhibited cellular proliferation in T. brucei.", "Mycobacterium bovis BCG is widely used as a vaccine against tuberculosis (TB), despite its variable protective efficacy. Relatively little is known about the immune response profiles following BCG vaccination in relation to protection against TB. Here we tested whether BCG vaccination results in immune responses to DosR (Rv3133c) regulon-encoded proteins. These so-called TB latency antigens are targeted by the immune system during persistent Mycobacterium tuberculosis infection and have been associated with immunity against latent M. tuberculosis infection. In silico analysis of the DosR regulon in BCG and M. tuberculosis showed at least 97% amino acid sequence homology, with 41 out of 48 genes being identical. Transcriptional profiling of 14 different BCG strains, under hypoxia and nitric oxide exposure in vitro, revealed a functional DosR regulon similar to that observed in M. tuberculosis. Next, we assessed human immune responses to a series of immunodominant TB latency antigens and found that BCG vaccination fails to induce significant responses to latency antigens. Similar results were obtained with BCG-vaccinated BALB/c mice. In contrast, responses to latency antigens were observed in individuals with suspected exposure to TB (as indicated by positive gamma interferon responses to TB-specific antigens ESAT-6 and CFP-10) and in mice vaccinated with plasmid DNA encoding selected latency antigens. Since immune responses to TB latency antigens have been associated with control of latent M. tuberculosis infection, our findings support the development of vaccination strategies incorporating DosR regulon antigens to complement and improve the current BCG vaccine.", "Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), which claims approximately two million people annually, remains a global health concern. The non-replicating or dormancy like state of this pathogen which is impervious to anti-tuberculosis drugs is widely recognized as the culprit for this scenario. The dormancy survival regulator (DosR) regulon, composed of 48 co-regulated genes, is held as essential for Mtb persistence. The DosR regulon is regulated by a two-component regulatory system consisting of two sensor kinases-DosS (Rv3132c) and DosT (Rv2027c), and a response regulator DosR (Rv3133c). The underlying regulatory mechanism of DosR regulon expression is very complex. Many factors are involved, particularly the oxygen tension. The DosR regulon enables the pathogen to persist during lengthy hypoxia. Comparative genomic analysis demonstrated that the DosR regulon is widely distributed among the mycobacterial genomes, ranging from the pathogenic strains to the environmental strains. In-depth studies on the DosR response should provide insights into its role in TB latency in vivo and shape new measures to combat this exceeding recalcitrant pathogen.", "BACKGROUND: Increased knowledge of the molecular regulatory mechanisms that contribute to the pathogenesis of psoriasis and other inflammatory diseases has created new opportunities for the development of targeted drug therapy for inflammatory conditions. Two new oral medications, apremilast and tofacitinib, have been developed for their immunomodulatory properties, and their potential efficacy in treating psoriasis is being evaluated.METHODS: We reviewed phase III randomized, placebo-controlled clinical trial results for apremilast and tofacitinib for efficacy and safety in psoriasis.RESULTS: Psoriasis Area and Severity Index (PASI) 75 after 16 weeks for apremilast was between 28.8% and 33.1%. PASI 75 was 39.5% after 12 weeks on tofacitinib 5 mg, and 63.6% after 12 weeks on tofacitinib 10 mg. Common side effects for both drugs included nasopharyngitis and upper respiratory tract infections. Gastrointestinal disturbance was common for apremilast. Dyslipidemia and infections were more common with tofacitinib than placebo.CONCLUSION: Both new oral medications, apremilast and tofacitinib, appear to be effective in treating psoriasis", "DevR regulon function is believed to be crucial for the survival of Mycobacterium tuberculosis during dormancy. In this study, we undertook a comprehensive analysis of the DevR regulon. All the regulon promoters were assigned to four classes based on the number of DevR binding sites (Dev boxes). A minimum of two boxes are essential for complete interaction and their tandem arrangement is an architectural hallmark at all promoters. Initial interaction of DevR with the conserved box is essential for its cooperative binding to adjacent sites bearing low to very poor sequence conservation and is the universal mechanism underlying DevR-mediated transcriptional induction. The functional importance of tandem arrangement was established by analyzing promoter variants harboring Dev boxes with altered spacing. Conserved sequence logos were generated from 47 binding sequences which included 24 newly discovered Dev boxes. In each half site of an 18-bp binding motif, G(5) and C(7) are essential for DevR binding. Finally, we show that DevR regulon induction occurs in a temporal manner and genes that are induced early are also usually powerfully induced. The information theory-based approach along with binding and temporal expression studies provide us with comprehensive insights into the complex pattern of DevR regulon activation.", "The neuropeptide calcitonin gene-related peptide is well established as a key player in the pathogenesis of migraine. Clinical studies show calcitonin gene-related peptide levels correlate with migraine attacks, and decreases in this neuropeptide can indicate antimigraine therapy effectiveness. Research has revealed a wide distribution of expression sites for calcitonin gene-related peptide in the central and peripheral nervous system. Of these, the calcitonin gene-related peptide receptor, which binds calcitonin gene-related peptide with high affinity, has attracted growing interest as a viable target for antimigraine therapies. An incentive to pursue such research is the continuing unmet medical need of patients. Triptans have offered some clinical benefit, but many patients do not respond and these drugs have important safety considerations. Initial calcitonin gene-related peptide-focused research led to development of the \"gepant\" small-molecule calcitonin gene-related peptide receptor blockers. Positive efficacy reports concerning the gepants have been tempered by safety findings which led to the discontinuation of some of these agents. Currently, there is considerable excitement regarding monoclonal antibodies against calcitonin gene-related peptide (eptinezumab, galcanezumab, fremanezumab) and the calcitonin gene-related peptide receptor (erenumab). To date, these monoclonal antibodies have shown promising efficacy in clinical trials, with no major safety concerns. If ongoing long-term studies show that their efficacy can be maintained, this may herald a new era for effective antimigraine therapies." ]

[ "Author information:(1)The University of Toledo College of Medicine & Life Sciences, Toledo, OH 43606, USA.(2)ProMedica Health System, Toledo, OH 43606, USA.(3)West German Cancer Center, Deparment of Medical Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.(4)Centre Léon Bérard, Unicancer, LYRICAN and Université Claude Bernard Lyon 1, Lyon, France.(5)Leiden University Medical Center, Leiden, The Netherlands.(6)Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.(7)University Hospitals Leuven, Department of General Medical Oncology, Leuven Cancer Institute, Leuven, Belgium.(8)Fox Chase Cancer Center, Philadelphia, PA 19111, USA.(9)Department of Epidemiology & Preventive Medicine, School of Public Health & Preventive Medicine, Monash University & Department of Medical Oncology Alfred Health, Melbourne, Australia.(10)Deciphera Pharmaceuticals, LLC, Waltham, MA 02451, USA.(11)Portland VA Health Care System & OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.", "Apert syndrome, characterised by craniosynostosis, craniofacial anomalies, and symmetrical syndactyly of the digits (cutaneous and bony fusion), has been associated with two canonical mutations in the FGFR2 gene (S252W, P253R) in the great majority of cases. Since these two alterations have been observed exclusively among these patients, it has been suggested that the S252W and P253R changes may play an important role in the occurrence of syndactyly. In order to verify whether the mutations S252W and P253R could also cause a milder phenotype, without involvement of the limbs, we have screened 22 patients with clinical characteristics compatible with Crouzon or Pfeiffer syndrome for these two particular changes. Surprisingly, we identified a Pfeiffer-like patient with the mutation S252W, and therefore we have shown for the first time the occurrence of one of the canonical Apert mutations without severe abnormalities of the upper and lower extremities.", "PURPOSE OF REVIEW: Aortitis is the inflammation of the aorta due to various causes. Clinical presentations vary as well as the imaging findings. Exact pathogenetic mechanisms or triggering factors, as well as the best diagnostic and monitoring modalities and treatment strategies, are yet to be elucidated. We reviewed recent studies in aortitis and associated diseases.RECENT FINDINGS: Multiple cohort studies reporting long-term outcomes in patients with noninfectious aortitis were recently published. Comparative features of isolated aortitis were described. Six angiographic clusters for giant cell arteritis and Takayasu have been identified. New classification criteria have been proposed for IgG4-related disease by a data-driven method. The ultrasonographic slope sign and a halo score were described as specific imaging parameters in giant cell arteritis. The promising role of PET-computed tomography, not only in the diagnosis of aortitis but also in monitoring disease activity, has been noted. Results of in-vitro studies on Janus kinase (JAK)/signal transducers and activators of transcription and mammalian target of rapamycin (mTOR) pathways, comparative studies with leflunomide as an induction therapy, and a long-term follow-up study with tocilizumab may contribute to the management of Takayasu arteritis.SUMMARY: An impressive number of studies have addressed aortitis in recent years. However, there still is a lack of robust data on causes, monitoring disease activity by imaging and biomarkers, and drugs providing steroid-free remission in noninfectious aortitis.", "Diacylglycerol-O-acyltransferase (DGAT1) gene encodes the rate-limiting enzyme of triglyceride synthesis. A polymorphism in this gene, DGAT1 K232A, has been associated with milk production and composition in taurine breeds. However, this polymorphism is not a good tool for ascertaining the effects of this QTL in Bos indicus (Zebu), since the frequency of the DGAT1 232A allele is too low in these breeds. We sequenced the 3'-untranslated region of DGAT1 gene in a sample of bulls of the breeds Guzerá (Bos indicus) and Holstein (Bos taurus) and, using in silico analysis, we searched for genetic variation, evolutionary conservation, regulatory elements, and possible substitution effects. Six single nucleotide (SNPs) and one insertion-deletion (INDEL) polymorphisms were found in the Guzerá bulls. Additionally, we developed a preliminary association study, using this INDEL polymorphism as a genetic marker. A significant association was detected (P ≤ 0.05) between the INDEL (DGAT1 3'UTR INDEL) and the breeding values (BV) for protein, fat, and milk yields over a 305-day lactation period. The DGAT1 3' UTR INDEL genotype I/I (I, for insertion) was associated with lower BVs (-38.77 kg for milk, -1.86 kg for fat, and -1.48 kg for protein yields), when compared to the genotype I/D (D, for deletion). I/D genotype was lower D/D genotype (-34.98 kg milk, -1.73 kg fat, and -1.09 kg protein yields). This study reports the first polymorphism of DGAT1 3'UTR in the Guzerá breed, as well as its association with BV for milk protein, fat, and milk yields.", "High-glucose-induced cardiomyocyte injury is the major cause of diabetic cardiomyopathy, but its regulatory mechanisms are not fully understood. Here, we report that a circadian clock gene, brain and muscle Arnt-like 1 (Bmal1), increases autophagy in high-glucose-induced cardiomyocyte injury. We constructed a hyperglycemia model with cultured cardiomyocytes from neonatal rats. High-glucose-induced inhibition of autophagy and cardiomyocyte injury were attenuated by Bmal1 overexpression and aggravated by its knockdown. Furthermore, autophagy stabilization by 3-methyladenine or rapamycin partially suppressed the effects of altered Bmal1 expression on cardiomyocyte survival. Mechanistically, Bmal1 mediated resistance to high-glucose-induced inhibition of autophagy at least partly by inhibiting mTOR signaling activity. Collectively, our findings suggest that the clock gene Bmal1 is a positive regulator of autophagy through the mTOR signaling pathway and protects cardiomyocytes against high-glucose toxicity.", "One-and-a-half syndrome is a syndrome characterized by horizontal movement disorders of the eyeballs, which was first reported and named by Fisher in 1967. It presents a combination of ipsilateral conjugate horizontal gaze palsy (one) and ipsilateral internuclear ophthalmoplegia (INO) (a half). On the basis of the one-and-a-half syndrome, there are a series of related rare syndromes called the one-and-a-half syndrome spectrum disorders. This article reviews rare cases of one-and-a-half syndrome spectrum disorder, describes the clinical and pathological features of different syndromes, and summarizes their nomenclature.", "Intravesical Bacillus Calmette-Guerin (BCG) is the best treatment modality for progression of non-muscle invasive bladder cancer. We aimed to monitor changes at the proteome level to identify putative protein biomarkers associated with the response of urothelial precancerous lesions to intravesical BCG treatment. The rats were divided into three groups (n = 10/group): control, non-treated, and BCG-treated groups. The non-treated and BCG-treated groups received N-methyl-N-nitrosourea intravesically. BCG Tice-strain was instilled into bladder in BCG-treated group. At the endpoint of experiment, all surviving rat bladders were collected and equally divided into two portions vertically from dome to neck. Half of each bladder was assessed immunohistopathologically and the other half was used for 2D-based comparative proteomic analysis. Differentially expressed proteins were validated by Western blot analysis. Precancerous lesions of bladder cancer were more common in non-treated group (77.8%) than in BCG-treated group (50%) and the control group (0%). Greater than twofold changes occurred in the expression of a number of proteins. Among them, Rab-GDIβ, aldehyde dehydrogenase 2 (ALDH2) and 14-3-3 zeta/delta were important since they were previously reported to be associated with cancer and their expression levels were found to be lower in BCG-treated group in comparison to the non-treated group. ALDH2 and 14-3-3 zeta/delta were also found to be highly expressed in the non-treated group compared to the control group. The down-regulation of these proteins and Rab-GDIβ was achieved with BCG; this result indicates that they may be used as putative biomarkers for monitoring changes in bladder carcinogenesis in response to BCG immunotherapy.", "BACKGROUND: DNA methylation of CpG islands within the promoters of specific genes may play roles in tumor initiation and progression. It has been suggested such events may serve as critical check points.METHODS: The present study analyzed the methylation status of CpG islands within the promoters of secreted frizzled-related proteins (SFRPs) in 87 acute leukemia (AL) patients, 20 normal controls, and four AL cell lines. 5-aza-2'- deoxycytidine (5-Aza-CdR), an inhibitor of DNA methylation, was employed to determine its effect on SFRP expression.RESULT: Methylation of at least one SFRP promoter was observed in 69% of the AL patients analyzed. In addition, methylation of all four SFRP promoters was observed in Molt-4, Jurkat, HL60 and NB4 cells. In Jurkat cells, methylation levels of four SFRP promoters decreased in a dose-dependent manner upon treatment with 5-Aza-CdR, which coincided with increased mRNA expression. With increasing 5-Aza-CdR concentrations, the expression of DNA methyltransferases, DNMT3A and DNMT3B, significantly decreased in a dose-dependent manner.CONCLUSION: The present study demonstrated that SFRP gene methylation may be involved in AL progression, with a possible epigenetic mechanism influencing Wnt signaling.", "Autophagy is a highly conserved intracellular degradation system, and recently was shown to display circadian rhythms in mice. The mechanisms underlying circadian regulation of autophagy, however, are still unclear. Here, we observed that numbers of autophagosomes and autolysosomes exhibit daily rhythms in the zebrafish liver, and cebpb/(c/ebpβ) and various autophagy genes are rhythmically expressed in zebrafish larvae but significantly upregulated in per1b and TALEN-generated nr1d1/rev-erbα mutant fish, indicating that both Per1b and Nr1d1 play critical roles in autophagy rhythms. Luciferase reporter and ChIP assays show that the circadian clock directly regulates autophagy genes through Nr1d1, and also regulates transcription of cebpb through Per1b. We also found that fasting leads to altered expression of both circadian clock genes and autophagy genes in zebrafish adult peripheral organs. Further, transcriptome analysis reveals multiple functions of Nr1d1 in zebrafish. Taken together, these findings provide evidence for how the circadian clock regulates autophagy, imply that nutritional signaling affects both circadian regulation and autophagy activities in peripheral organs, and shed light on how circadian gene mutations act through autophagy to contribute to common metabolic diseases such as obesity.", "Between 2009-2010, a group of 259 patients suspected of contracting Lyme disease were examined in the Provincial Sanitary-Epidemiological Station in Olsztyn for the presence of IgM and IgG against specific Borrelia burgdorferi sensu lato (s.l.) genospecies antigens by immunoblot. A total of 27.4% and 29.0% of the blood serum samples showed positive and uncertain results for IgM and IgG antibodies. The majority of positive and uncertain results were found in patients aged 30-40 years (30%) for IgM, and people aged 50 and over (35.8%) for IgG. Significantly more positive results for IgG were found in males (40.2%) then females (19.7%). In both groups, similar proportions of positive results for IgM anti-Borrelia were recorded (26.1% of females and 29% of males. In 71.5% of patients, IgM against flagellin protein (p41) of B. burgdorferi sensu stricto (s.s.) was found. For IgG, the most frequently detected antibodies were found against the p41 protein of B. burgdorferi s.s. (64.8%) and the recombinant variable surface antigens (VlsE) (49%). Among all the analysed antigens those of B. burgdorferi s.s. were the most frequent cause of immunological reaction, followed by antigens of B. afzelii and B. garinii. Reaction to antigens of B. spielmanii was rarely detected.", "Abnormal autophagy regulation affects the chemoresistance of ovarian cancer, during which the circadian gene clock may play a major role. In this study, RNA interference plasmid pSUPER-Clock and overexpression plasmid pcDNA3.1-Clock of CLOCK were used to stably transfect the SKOV3/DDP cells by lipofection. Upon screening, the in vitro transfected cell lines with pSUPER-Clock, the autophagy level, and G0/G1 phase cells were significantly reduced, and the expression levels of Clock, LC3, P-gp, and MRP2 were inhibited. In contrast, the autophagy level and G0/G1 phase cells in cell lines transfected with pcDNA3.1-Clock were significantly increased, and the expressions of Clock, LC3, P-gp, and MRP2 were enhanced. In comparison with the untransfected control group showed the percentage of apoptotic cells in SKOV3/DDP cell lines of Clock interfering expression group after cisplatin treatment was significantly increased while the survival was substantially reduced. These results indicated that inhibiting the circadian gene Clock expression can reverse the cisplatin resistance of ovarian cancer SKOV3/DDP cell lines by affecting the protein expression of drug resistance genes during which autophagy plays an important role. The CLOCK gene may be designated as a novel candidate for targeted gene therapy in drug-resistant ovarian cancer.", "The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A2 beta enzyme that selectively hydrolyses glycerophospholipids to release free fatty acids. Mutations in PLA2G6 have been associated with disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome. More recently, PLA2G6 was identified as the causative gene in a subgroup of patients with autosomal recessive early-onset dystonia-parkinsonism. Neuropathological examination revealed widespread Lewy body pathology and the accumulation of hyperphosphorylated tau, supporting a link between PLA2G6 mutations and parkinsonian disorders. Here we show that knockout of the Drosophila homologue of the PLA2G6 gene, iPLA2-VIA, results in reduced survival, locomotor deficits and organismal hypersensitivity to oxidative stress. Furthermore, we demonstrate that loss of iPLA2-VIA function leads to a number of mitochondrial abnormalities, including mitochondrial respiratory chain dysfunction, reduced ATP synthesis and abnormal mitochondrial morphology. Moreover, we show that loss of iPLA2-VIA is strongly associated with increased lipid peroxidation levels. We confirmed our findings using cultured fibroblasts taken from two patients with mutations in the PLA2G6 gene. Similar abnormalities were seen including elevated mitochondrial lipid peroxidation and mitochondrial membrane defects, as well as raised levels of cytoplasmic and mitochondrial reactive oxygen species. Finally, we demonstrated that deuterated polyunsaturated fatty acids, which inhibit lipid peroxidation, were able to partially rescue the locomotor abnormalities seen in aged flies lacking iPLA2-VIA gene function, and restore mitochondrial membrane potential in fibroblasts from patients with PLA2G6 mutations. Taken together, our findings demonstrate that loss of normal PLA2G6 gene activity leads to lipid peroxidation, mitochondrial dysfunction and subsequent mitochondrial membrane abnormalities. Furthermore we show that the iPLA2-VIA knockout fly model provides a useful platform for the further study of PLA2G6-associated neurodegeneration.", "Drosophila melanogaster is a common model used to study circadian rhythms in behavior and circadian clocks. However, numerous circadian rhythms have also been detected in non-clock neurons, especially in the first optic neuropil (lamina) of the fly's visual system. Such rhythms have been observed in the number of synapses and in the structure of interneurons, which exhibit changes in size and shape in a circadian manner. Although the patterns of these changes are known, the mechanism remains unclear. In the present study, we investigated the role of the TOR signaling pathway and autophagy in regulating circadian rhythms based on the behavior and structural plasticity of the lamina L2 monopolar cell dendritic trees. In addition, we examined the cyclic expression of the TOR signaling pathway (Tor, Pi3K class 1, Akt1) and autophagy (Atg5 and Atg7) genes in the fly's brain. We observed that Tor, Atg5 and Atg7 exhibit rhythmic expressions in the brain of wild-type flies in day/night conditions (LD 12:12) that are abolished in per01 clock mutants. The silencing of Tor in per expressing cells shortens a period of the locomotor activity rhythm of flies. In addition, silencing of the Tor and Atg5 genes in L2 cells disrupts the circadian plasticity of the L2 cell dendritic trees measured in the distal lamina. In turn, silencing of the Atg7 gene in L2 cells changes the pattern of this rhythm. Our results indicate that the TOR signaling pathway and autophagy are involved in the regulation of circadian rhythms in the behavior and plasticity of neurons in the brain of adult flies.", "The molecular clockwork drives rhythmic oscillations of signaling pathways managing intermediate metabolism; the circadian timing system synchronizes behavioral cycles and anabolic/catabolic processes with environmental cues, mainly represented by light/darkness alternation. Metabolic pathways, bile acid synthesis, and autophagic and immune/inflammatory processes are driven by the biological clock. Proper timing of hormone secretion, metabolism, bile acid turnover, autophagy, and inflammation with behavioral cycles is necessary to avoid dysmetabolism. Disruption of the biological clock and mistiming of body rhythmicity with respect to environmental cues provoke loss of internal synchronization and metabolic derangements, causing liver steatosis, obesity, metabolic syndrome, and diabetes mellitus.", "Pancreatic ductal adenocarcinoma (PDAC) remains a major unsolved health problem. As conventional treatments have shown only a modest impact on disease course, development of new therapeutic strategies based on the molecular biology of PDAC must be a high priority. The identification of relevant predictive and prognostic biomarkers which can be used to select patient subgroups that may benefit from conventional treatments and new targeted agents will be of considerable interest. We have demonstrated the ability of the metabolizing gemcitabine protein (the human Equilibrative nucleoside transporter 1 and the deoxycytidine kinase) in predicting the benefit of adjuvant gemcitabine-based therapy in resected PDAC patients. Beside these predictive biomarkers, we have evaluated different molecular factors that may impact on the likely course of this cancer. The chemokine receptor CXCR4 that has been shown to be implicated in PDAC tumorigenicity and aggressiveness could serve as a prognostic marker for survival after a curative-intent surgery and was associated with the pattern of tumour recurrence (distant versus local relapse). Our findings were validated in an independent cohort of patients. Overall our results suggested that (i) the benefit of an adjuvant gemcitabine-based therapy can be predicted based on the tumour expression of hENT1 and dCK, (ii) CXCR4 is an independent negative prognostic factor and an independent predictor of distant relapse suggesting that anti-CXCR4 targeting therapies can be a promising treatment in combination with cytotoxic chemotherapy in the adjuvant setting. These data open new perspectives for designing trials based on a molecular driven strategy.", "Mutations in fused in sarcoma (FUS), a DNA/RNA binding protein, have been associated with familial amyotrophic lateral sclerosis (fALS), which is a fatal neurodegenerative disease that causes progressive muscular weakness and has overlapping clinical and pathologic characteristics with frontotemporal lobar degeneration. However, the role of autophagy in regulation of FUS-positive stress granules (SGs) and aggregates remains unclear. We found that the ALS-linked FUS(R521C) mutation causes accumulation of FUS-positive SGs under oxidative stress, leading to a disruption in the release of FUS from SGs in cultured neurons. Autophagy controls the quality of proteins or organelles; therefore, we checked whether autophagy regulates FUS(R521C)-positive SGs. Interestingly, FUS(R521C)-positive SGs were colocalized to RFP-LC3-positive autophagosomes. Furthermore, FUS-positive SGs accumulated in atg5(-/-) mouse embryonic fibroblasts (MEFs) and in autophagy-deficient neurons. However, FUS(R521C) expression did not significantly impair autophagic degradation. Moreover, autophagy activation with rapamycin reduced the accumulation of FUS-positive SGs in an autophagy-dependent manner. Rapamycin further reduced neurite fragmentation and cell death in neurons expressing mutant FUS under oxidative stress. Overall, we provide a novel pathogenic mechanism of ALS associated with a FUS mutation under oxidative stress, as well as therapeutic insight regarding FUS pathology associated with excessive SGs.", "BACKGROUND AND AIM: Peyer's patches (PPs) play a major role in intestinal mucosal immunity; however, their role in ulcerative colitis (UC) is not well investigated. We evaluated endoscopic features of PPs on narrow-band imaging with magnifying endoscopy (NBI-ME) and investigated their association with clinical factors.METHODS: We prospectively recruited 105 patients with UC, 18 with Crohn's disease, 16 with disease control, and 33 healthy control subjects at three institutions from 2014 to 2017. NBI-ME images of the villi of PPs were evaluated according to the Villi Index, and patients were divided into the Villi Index low (L) and high (H) types. The 1-year sustained clinical remission rate was evaluated between L-type and H-type PPs in patients with UC.RESULTS: The proportions of patients with H-type PPs were significantly higher among UC, Crohn's disease, and disease control patients than among healthy control patients (P = 0.0125, 0.018, 0.0007). In UC, age, gender, endoscopic score, and extent of disease involvement were not significantly different between L-type and H-type PPs, whereas the sustained clinical remission rate was significantly higher in L-type PPs than in H-type PPs (88% [57/65] vs 65% [17/26], P = 0.019). Multivariate analysis revealed that the L type of PPs was a significant factor for sustained clinical remission (odds ratio 3.8, 95% confidence interval 1.1-12.9, P = 0.033).CONCLUSIONS: Patients with UC showed endoscopic alterations in PPs on NBI-ME, and highly altered appearance of PPs can be associated with a high risk of clinical relapse in patients with UC.", "BACKGROUND: Mechanical ventilation can induce or aggravate lung injury, which is termed ventilator-induced lung injury (VILI). Piezo1 is a key element of the mechanotransduction process and can transduce mechanical signals into biological signals by mediating Ca2+ influx, which in turn regulates cytoskeletal remodeling and stress alterations. We hypothesized that it plays an important role in the occurrence of VILI, and investigated the underlying mechanisms.METHODS: High tidal volume mechanical ventilation and high magnitude cyclic stretch were performed on Sprague-Dawley rats, and A549 and human pulmonary microvascular endothelial cells, respectively, to establish VILI models. Immunohistochemical staining, flow cytometry, histological examination, enzyme-linked immunosorbent assay, western blotting, quantitative real-time polymerase chain reaction and survival curves were used to assess the effect of Piezo1 on induction of lung injury, as well as the signaling pathways involved.RESULTS: We observed that Piezo1 expression increased in the lungs after high tidal volume mechanical ventilation and in cyclic stretch-treated cells. Mechanistically, we observed the enhanced expression of RhoA/ROCK1 in both cyclic stretch and Yoda1-treated cells, while the deficiency or inhibition of Piezo1 dramatically antagonized RhoA/ROCK1 expression. Furthermore, blockade of RhoA/ROCK1 signaling using an inhibitor did not affect Piezo1 expression. GSMTx4 was used to inhibit Piezo1, which alleviated VILI-induced pathologic changes, water content and protein leakage in the lungs, and the induction of systemic inflammatory mediators, and improved the 7-day mortality rate in the model rats.CONCLUSIONS: These findings indicate that Piezo1 affects the development and progression of VILI through promotion of RhoA/ROCK1 signaling.", "The blood serum TSH and PRL levels were studied in 12 ALS patients after TRH stimulation. The TSH test was repeated after 4-weeks TRH treatment. The results were compared with the data obtained in the control group. It was shown that after TRH stimulation the TSH responses did not reveal greater abnormalities, but PRL responses were significantly diminished. The results could confirm our previous observations concerning the dysregulation of dopamine metabolism in ALS patients.", "INTRODUCTION: Studies have shown that opioid antagonists like naltrexone are efficient in reducing heavy drinking. The neurobiological mechanism by which opioid modulators affect drinking behavior is based on the strong connection between the endogenous opioid system, the dopamine system and the influence of the CNS stress response.AREAS COVERED: This review provides an overview of the pathophysiological role of the opioid system in alcohol dependence and the neurobiological mechanisms of possible pharmacological interventions. An extensive Medline and Internet research was performed to retrieve information on existing and currently investigated opioid modulators. The findings were assessed critically and interpreted with regard to an individualized therapy for alcohol dependence.EXPERT OPINION: The opioid system is of crucial importance in the genesis and maintenance of alcohol dependence. Naltrexone- and to a lesser extent nalmefene- is an agent that modulates opioidergic transmission in the CNS and it shows a limited but well-studied efficacy in treating alcohol dependence. Several agents (LY2196044, ALKS-29, ALKS-33) that are currently undergoing Phase II and Phase III studies are of interest but first their efficacy must be proved in clinical practice.", "Severe congenital neutropenia (SCN) is a BM failure syndrome with a high risk of progression to acute myeloid leukemia (AML). The underlying genetic changes involved in SCN evolution to AML are largely unknown. We obtained serial hematopoietic samples from an SCN patient who developed AML 17 years after the initiation of G-CSF treatment. Next- generation sequencing was performed to identify mutations during disease progression. In the AML phase, we found 12 acquired nonsynonymous mutations. Three of these, in CSF3R, LLGL2, and ZC3H18, co-occurred in a subpopulation of progenitor cells already in the early SCN phase. This population expanded over time, whereas clones harboring only CSF3R mutations disappeared from the BM. The other 9 mutations were only apparent in the AML cells and affected known AML-associated genes (RUNX1 and ASXL1) and chromatin remodelers (SUZ12 and EP300). In addition, a novel CSF3R mutation that conferred autonomous proliferation to myeloid progenitors was found. We conclude that progression from SCN to AML is a multistep process, with distinct mutations arising early during the SCN phase and others later in AML development. The sequential gain of 2 CSF3R mutations implicates abnormal G-CSF signaling as a driver of leukemic transformation in this case of SCN.", "We investigated structural and functional aspects of the first mutation in TNNC1, coding for the calcium-binding subunit (cTnC) of cardiac troponin, which was detected in a patient with hypertrophic cardiomyopathy [ Hoffmann B, Schmidt-Traub H, Perrot A, Osterziel KJ & Gessner R (2001) Hum Mut17, 524]. This mutation leads to a leucine-glutamine exchange at position 29 in the nonfunctional calcium-binding site of cTnC. Interestingly, the mutation is located in a putative interaction site for the nonphosphorylated N-terminal arm of cardiac troponin I (cTnI) [ Finley NL, Abbott MB, Abusamhadneh E, Gaponenko V, Dong W, Seabrook G, Howarth JW, Rana M, Solaro RJ, Cheung HC et al. (1999) EJB Lett453, 107-112]. According to peptide array experiments, the nonphosphorylated cTnI arm interacts with cTnC around L29. This interaction is almost abolished by L29Q, as observed upon protein kinase A-dependent phosphorylation of cTnI at serine 22 and serine 23 in wild-type troponin. With CD spectroscopy, minor changes are observed in the backbone of Ca2+-free and Ca2+-saturated cTnC upon the L29Q replacement. A small, but significant, reduction in calcium sensitivity was detected upon measuring the Ca2+-dependent actomyosin subfragment 1 (actoS1)-ATPase activity and the sliding velocity of thin filaments. The maximum actoS1-ATPase activity, but not the maximum sliding velocity, was significantly enhanced. In addition, we performed our investigations at different levels of protein kinase A-dependent phosphorylation of cTnI. The in vitro assays mainly showed that the Ca2+ sensitivity of the actoS1-ATPase activity, and the mean sliding velocity of thin filaments, were no longer affected by protein kinase A-dependent phosphorylation of cTnI owing to the L29Q exchange in cTnC. The findings imply a hindered transduction of the phosphorylation signal from cTnI to cTnC.", "BACKGROUND: The mammalian circadian clock and its associated clock genes are increasingly been recognized as critical components for a number of physiological and disease processes that extend beyond hormone release, thermal regulation, and sleep-wake cycles. New evidence suggests that clinical behavior disruptions that involve prolonged shift work and even space travel may negatively impact circadian rhythm and lead to multi-system disease.METHODS: In light of the significant role circadian rhythm can hold over the body's normal physiology as well as disease processes, we examined and discussed the impact circadian rhythm and clock genes hold over lifespan, neurodegenerative disorders, and tumorigenesis.RESULTS: In experimental models, lifespan is significantly reduced with the introduction of arrhythmic mutants and leads to an increase in oxidative stress exposure. Interestingly, patients with Alzheimer's disease and Parkinson's disease may suffer disease onset or progression as a result of alterations in the DNA methylation of clock genes as well as prolonged pharmacological treatment for these disorders that may lead to impairment of circadian rhythm function. Tumorigenesis also can occur with the loss of a maintained circadian rhythm and lead to an increased risk for nasopharyngeal carcinoma, breast cancer, and metastatic colorectal cancer. Interestingly, the circadian clock system relies upon the regulation of the critical pathways of autophagy, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) as well as proliferative mechanisms that involve the wingless pathway of Wnt/β-catenin pathway to foster cell survival during injury and block tumor cell growth.CONCLUSION: Future targeting of the pathways of autophagy, mTOR, SIRT1, and Wnt that control mammalian circadian rhythm may hold the key for the development of novel and effective therapies against aging- related disorders, neurodegenerative disease, and tumorigenesis.", "The paired-class homeobox-containing gene, Cart1, is expressed in forebrain mesenchyme, branchial arches, limb buds and cartilages during embryogenesis. Here, we show that Cart1-homozygous mutant mice are born alive with acrania and meroanencephaly but die soon after birth-a phenotype that strikingly resembles a corresponding human syndrome caused by a neural tube closure defect. Developmental studies suggest that Cart1 is required for forebrain mesenchyme survival and that its absence disrupts cranial neural tube morphogenesis by blocking the initiation of closure in the midbrain region that ultimately leads to the generation of lethal craniofacial defects. Prenatal treatment of Cart1 homozygous mutants with folic acid suppresses the development of the acrania/meroanencephaly phenotype." ]

[ "Mycobacterium tuberculosis is a major human pathogen that has evolved survival mechanisms to persist in an immune-competent host under a dormant condition. The regulation of M. tuberculosis metabolism during latent infection is not clearly known. The dormancy survival regulon (DosR regulon) is chiefly responsible for encoding dormancy related functions of M. tuberculosis. We describe functional characterization of an important gene of DosR regulon, Rv0079, which appears to be involved in the regulation of translation through the interaction of its product with bacterial ribosomal subunits. The protein encoded by Rv0079, possibly, has an inhibitory role with respect to protein synthesis, as revealed by our experiments. We performed computational modelling and docking simulation studies involving the protein encoded by Rv0079 followed by in vitro translation and growth curve analysis experiments, involving recombinant E. coli and Bacille Calmette Guérin (BCG) strains that overexpressed Rv0079. Our observations concerning the interaction of the protein with the ribosomes are supportive of its role in regulation/inhibition of translation. We propose that the protein encoded by locus Rv0079 is a 'dormancy associated translation inhibitor' or DATIN.", "Anesthesia-resistant memory (ARM) was described decades ago, but the mechanisms that underlie this protein synthesis-independent form of consolidated memory in Drosophila remain poorly understood. Whether the several signaling molecules, receptors, and synaptic proteins currently implicated in ARM operate in one or more pathways and how they function in the process remain unclear. We present evidence that Drk, the Drosophila ortholog of the adaptor protein Grb2, is essential for ARM within adult mushroom body neurons. Significantly, Drk signals engage the Rho kinase Drok, implicating dynamic cytoskeletal changes in ARM, and this is supported by reduced F-actin in the mutants and after pharmacological inhibition of Drok. Interestingly, Drk-Drok signaling appears independent of the function of Radish (Rsh), a protein long implicated in ARM, suggesting that the process involves at least two distinct molecular pathways. Based on these results, we propose that signaling pathways involved in structural plasticity likely underlie this form of translation-independent memory.", "The posterior HoxA and HoxD genes are essential in appendicular development. Studies have demonstrated that a \"distal limb enhancer,\" remotely located upstream of the HoxD complex, is required to drive embryonic autopod expression of the posterior Hox genes as well as the two additional non-Hox genes in the region: Evx2 and Lnp. Our work demonstrates a similar mode of regulation for Hoxa13 and four upstream genes: Evx1, Hibadh, Tax1bp, and Jaz1. These genes all show embryonic (E11.5-E13.5) distal limb and genital bud expression, suggesting the existence of a nearby enhancer influencing the expression of a domain of genes. Comparative sequence analysis between homologous human and mouse genomic sequence upstream of Hoxa13 revealed a remote 2.25-kb conserved noncoding sequence (mmA13CNS) within the fourth intron of the Hibadh gene. mmA13CNS shares a common 131-bp core identity within a conserved noncoding sequence upstream of Hoxd13, which is located within the previously identified distal limb enhancer critical region. To test the function of this conserved sequence, we created mmA13CNS-Hsp86-lacZ transgenic mice. mmA13CNS directed a wide range of tissue expression, including the central nervous system, developing olfactory tissue, limb, and genital bud. Limb and genital bud expression directed by mmA13CNS is not identical to the patterns exhibited by Hoxa13/Evx1/Hibadh/Tax1bp1/Jaz1, suggesting that mmA13CNS is not sufficient to fully recapitulate their expression in those tissues. The Evx1- and Evx2-like central nervous system expression observed in these mice suggests that the long-range regulatory element(s) for the Hox cluster existed before the cluster duplication.", "We report a patient with multiple trichoepitheliomas whose biopsy material also demonstrated a range of other neoplasms with follicular differentiation, including small nodular trichoblastoma, small nodular basal cell carcinoma (BCC), and areas resembling infundibulocystic BCC/basaloid follicular hamartoma. These were all intimately associated with otherwise typical trichoepitheliomas that dominated the microscopic appearances. Peripheral blood and tumor tissues of the patient and his 2 daughters, who apparently had a milder phenotype, were studied for alterations in the CYLD and PTCH genes, but mutations or loss of heterozygosity was not found in either gene. The occurrence of multiple follicular neoplasms within a single lesion adds evidence that, although in most cases BCC and trichoblastoma are distinct lesions, the 2 neoplasms do encompass a morphological spectrum of follicular differentiation, which is probably more overtly expressed in syndromic patients.", "Macropinocytosis defines a series of events initiated by extensive plasma membrane reorganization or ruffling to form an external macropinocytic structure that is then enclosed and internalized. The process is constitutive in some organisms and cell types but in others it is only pronounced after growth factor stimulation. Internalized macropinosomes share many features with phagosomes and both are distinguished from other forms of pinocytic vesicles by their large size, morphological heterogeneity and lack of coat structures. A paucity of information is available on other distinguishing features for macropinocytosis such as specific marker proteins and drugs that interfere with its mechanism over other endocytic processes. This has hampered efforts to characterize the dynamics of this pathway and to identify regulatory proteins that are expressed in order to allow it to proceed. Upon internalization, macropinosomes acquire regulatory proteins common to other endocytic pathways, suggesting that their identities as unique structures are short-lived. There is however less consensus regarding the overall fate of the macropinosome cargo or its limiting membrane and processes such as fusion, tubulation, recycling and regulated exocytosis have all been implicated in shaping the macropinosome and directing cargo traffic. Macropinocytosis has also been implicated in the internalization of cell penetrating peptides that are of significant interest to researchers aiming to utilize their translocation abilities to deliver therapeutic entities such as genes and proteins into cells. This review focuses on recent findings on the regulation of macropinocytosis, the intracellular fate of the macropinosome and discusses evidence for the role of this pathway as a mechanism of entry for cell penetrating peptides.", "Nerve growth factor (NGF) antagonism has long been proposed as a chronic pain treatment. In 2010, the FDA suspended clinical trials using tanezumab, a humanized monoclonal anti-NGF antibody, to treat osteoarthritis due to worsening joint damage in 16 patients. Increased physical activity in the absence of acute pain which normally prevents self-harm was purported as a potential cause. Such an adverse effect is consistent with an extension of tanezumab's primary mechanism of action by decreasing pain sensitivity below baseline levels. In animal inflammatory pain models, NGF antagonism decreases intraepidermal nerve fiber (IENF) density and attenuates increases in expression of nociception-related proteins, such as calcitonin gene-related peptide (CGRP) and substance P (SP). Little is known of the effects of NGF antagonism in noninflamed animals and the hypoalgesia that ensues. In the current study, we immunized rats with NGF or cytochrome C (cytC) and examined (1) nocifensive behaviors with thermal latencies, mechanical thresholds, the hot plate test, and the tail flick test, (2) IENF density, and (3) expression of CGRP, SP, voltage-gated sodium channel 1.8 (Nav1.8), and glutaminase in subpopulations of dorsal root ganglion (DRG) neurons separated by size and isolectin B4 (IB4) labeling. Rats with high anti-NGF titers had delayed responses on the hot plate test but no other behavioral abnormalities. Delayed hot plate responses correlated with lower IENF density. CGRP and SP expression was decreased principally in medium (400-800 μm(2)) and small neurons (<400 μm(2)), respectively, regardless of IB4 labeling. Expression of Nav1.8 was only decreased in small and medium IB4 negative neurons. NGF immunization appears to result in a more profound antagonism of NGF than tanezumab therapy, but we hypothesize that decreases in IENF density and nociception-related protein expression are potential mechanisms for tanezumab-induced hypoalgesia.", "Studying the cognitive and immunological changes that occur in old age as well as genetic function have been considered an important subject to differentiate between normal brain aging and early dementia especially Alzheimer's disease. The aim of this study is to stress on age-related neuropsychological and electrophysiological (P(300)) changes in normal Egyptian subjects, to throw light on the value of genetic (Apo-E(4) genotype) and immunological markers [interleukin-6 (IL-6) and intercellular adhesion molecules (ICAM-1) in the serum] as tools used in early detection of cognitive decline in cerebral aging. Ninety-four normal Egyptian subjects (below and above 60 years) were submitted to the following: (1) neuropsychological tests for testing memory, perception, psychomotor performance and attention, (2) Eysenck Personality Questionnaire (EPQ) for personality traits, (3) event-related potential study (P(300), latency and amplitude), (4) genetic test for detection of Apolipoprotein E genotype and (5) immunological studies including detection of the level of IL-6 and ICAM-1 in serum. There was a significant impairment of memory, psychomotor performance and perception in elderly subjects particularly males and subjects with low level of education. Regarding personality, significantly high scores were obtained in neuroticism scale of EPQ in elderly subjects. Apo-E(3)/E(3) was the most common genotype encountered in Egyptian subjects (49.1%). It was found that subjects with Apo-E(4) genotype did significantly worse in scores of intentional memory test (sensory memory) when compared with other genotypes. Statistically significant impairment in attention and sensory memory was found in subjects with high IL-6 level. This could not be detected in subjects with high ICAM-1 level. In conclusion, advancing age and lower levels of education are considered risk factors for cognitive decline in normal brain aging. Neuropsychological tests remain as the highly sensitive tools for detection of early cognitive impairment. Neurotic traits are more encountered in old age. Apo-E(4) genotype is associated with significant sensory (intentional) memory impairment. High IL-6 level in the serum is accompanied by significant impairment in attention and sensory (intentional) memory." ]

[ "Diagnosis of paroxysmal events in epilepsy patients is often made through video-telemetry electroencephalography in the epilepsy monitoring unit. This case report describes the first-ever diagnosis of exploding head syndrome in a patient with longstanding epilepsy and novel nocturnal events. In this report, we describe the presentation of exploding head syndrome and its prevalence and risk factors. In addition, the prevalence of newly diagnosed sleep disorders through video-telemetry electroencephalography in the epilepsy monitoring unit is briefly reviewed. This report also illustrates the novel use of clobazam for the treatment of exploding head syndrome.", "There is no effective treatment for recurrent glioblastoma (GBM) after bevacizumab failure. Putative mechanisms of resistance to bevacizumab include increased pericyte coverage, mediated partly by platelet-derived growth factor receptor (PDGFR) signaling, and an infiltrative tumor growth pattern potentially dependent on SRC. We explored the efficacy of dasatinib, a SRC, BCR-ABL, c-KIT, EPHA2, and PDGFRβ inhibitor, in patients with recurrent GBM after bevacizumab failure. Adult patients with histologically confirmed GBM who failed bevacizumab therapy were treated with dasatinib 70-100 mg twice daily in combination with bevacizumab (n = 14), until tumor progression or unacceptable toxicity. Fourteen patients were treated. Median age was 55 years (range 32-66) and median KPS was 80 (range 50-90). All patients (100%) had glioblastomas. The median number of prior regimens was 4 (range from 2 to 6). Of the thirteen evaluable patients, none had a complete or partial response. Only one patient had stable disease after an 8 week interval. Median progression-free survival (PFS) was 28 days (95% confidence interval [CI] 26-35 days). Six month progression-free survival (PFS6) was 0%. Median overall survival (OS) was 78 days (95% CI 41-137 days). Treatment was moderately well-tolerated, although one patient sustained a grade 4 intracerebral hemorrhage. Dasatinib in conjunction with bevacizumab does not appear to have activity in patients with recurrent, heavily pretreated GBM.", "Forward motility stimulating factor (FMSF), a glycoprotein isolated from buffalo serum, binds to the surface of the mature sperm cells to promote their progressive motility. This article reports the mode of signal transduction of this extracellular factor in goat sperm. The mechanism was investigated by assaying intracellular second messenger level and forward motility in presence of different pharmacological modulators. Mg++-dependent Forskolin responsive form of transmembrane adenylyl cyclase (tmAC) of goat spermatozoa was probed for its involvement in FMSF action. Dideoxyadenosine, a selective inhibitor of tmACs, was used to identify the role of this enzyme in the scheme of FMSF-signaling. Involvement of the α-subunit of G-protein in this regard has been inspected using GTPγS. Participation of protein kinase A (PKA) and tyrosine kinase was checked using IP20 and genistein, respectively. FMSF promotes tmAC activity in a dose-dependent manner through receptor/G-protein activation to enhance intracellular cAMP and forward motility. Motility boosting effects of this glycoprotein are almost lost in presence of dideoxyadenosine. But, FMSF displayed substantial motility promoting activity when movement of spermatozoa was inhibited with KH7, the specific inhibitor of soluble adenylyl cyclase indicating tmAC to be the primary target of FMSF action. Involvement of cAMP in mediating FMSF action was confirmed by the application of dibutyryl cAMP. Observed motility regulatory effects with IP20 and genistein indicate contribution of PKA and tyrosine kinase in FMSF activity; enhanced phosphorylation of a tyrosine containing ≈50 kDa protein was detected in this regard. FMSF initiates a novel signaling cascade to stimulate tmAC activity that augments intracellular cAMP, which through downstream crosstalk of phosphokinases leads to enhanced forward motility in mature spermatozoa. Thus, this article for the first time describes conventional tmAC-dependent profound activation of progressive motility by a physiologic extracellular factor in a mammalian species.", "Mulibrey nanism is a rare growth disorder of prenatal onset caused by mutations in the TRIM37 gene, which encodes a RING-B-box-coiled-coil protein. The pathogenetic mechanisms of mulibrey nanism are unknown. We have used transiently transfected cells and antibodies raised against the predicted TRIM37 protein to characterize the TRIM37 gene product and to determine its intracellular localization. We show that the human TRIM37 cDNA encodes a peroxisomal protein with an apparent molecular weight of 130 kD. Peroxisomal localization is compromised in mutant protein representing the major Finnish TRIM37 mutation but is retained in the protein representing the minor Finnish mutation. Colocalization of endogenous TRIM37 with peroxisomal markers was observed by double immunofluorescence staining in HepG2 and human intestinal smooth muscle cell lines. In human tissue sections, TRIM37 shows a granular cytoplasmic pattern. Endogenous TRIM37 is not imported into peroxisomes in peroxin 1 (PEX1(-/-)) and peroxin 5 (PEX5(-/-)) mutant fibroblasts but is imported normally in peroxin 7 (PEX7(-/-)) deficient fibroblasts, giving further evidence for a peroxisomal localization of TRIM37. Fibroblasts derived from patients with mulibrey nanism lack C-terminal TRIM37 immunoreactivity but stain normally for both peroxisomal matrix and membrane markers, suggesting apparently normal peroxisome biogenesis in patient fibroblasts. Taken together, this molecular evidence unequivocally indicates that TRIM37 is located in the peroxisomes, and Mulibrey nanism thus can be classified as a new peroxisomal disorder.", "BACKGROUND: glioblastomas are highly vascularized tumors and various antiangiogenic drugs have been investigated in clinical trials showing unclear results. We performed a systematic review and a meta-analysis to clarify and evaluate their effectiveness in glioblastoma patients.PATIENTS AND METHODS: we searched relevant published and unpublished randomized clinical trials analyzing antiangiogenic drugs versus chemotherapy in glioblastoma patients from January 2006 to January 2016 in MEDLINE, WEB of SCIENCE, ASCO, ESMO and SNO databases.RESULTS: fourteen randomized clinical trials were identified (7 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) including 4330 patients. Antiangiogenic drugs showed no improvement in overall survival with a pooled HR of 1.00, a trend for an inferior outcome, in terms of overall survival, was observed in the group of patients receiving antiangiogenic drug alone compared to cytotoxic drug alone (HR=1.24, p=0.056). Bevacizumab did not improve overall survival. Twelve trials (4113 patients) were analyzed for progression-free survival. Among antiangiogenic drugs, only bevacizumab demonstrated an improvement of progression-free survival (HR=0.63, p<0.001), both alone (HR=0.60, p=0.003) or in combination to chemotherapy (HR=0.63; p<0.001), both as first-line treatment (HR=0.70, p<0.001) or in recurrent disease (HR=0.52, p<0.001).CONCLUSIONS: antiangiogenic drugs did not improve overall survival in glioblastoma patients, either as first or second-line treatment, and either as single agent or in combination with chemotherapy. Among antiangiogenic drugs, only bevacizumab improved progression-free survival regardless of treatment line, both as single agent or in combination with chemotherapy.", "Embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass of blastocysts. Self-renewal of mouse ES cells depends on activation of Stat3 by leukaemia inhibitory factor (LIF) in collaboration with bone morphogenetic protein signalling. The transcription factor Nanog is essential in maintaining pluripotency but the mechanisms involved are poorly understood. Here we examine the functional interactions of Nanog with the Stat3 and NFkappaB pathways. Nanog and Stat3 were found to bind to and synergistically activate Stat3-dependent promoters. We also found that Nanog binds to NFkappaB proteins; however, Nanog binding inhibited transcriptional activity of NFkappaB proteins. Endogenous NFkappaB activity and target-gene expression increased during differentiation of ES cells. Overexpression of NFkappaB proteins promoted differentiation, whereas inhibition of NFkappaB signalling, either by genetic ablation of the Ikbkg gene or overexpression of the IkappaBalpha super-repressor, increased expression of pluripotency markers. We conclude that Nanog represses the pro-differentiation activities of NFkappaB and cooperates with Stat3 to maintain pluripotency.", "Author information:(1)Department of Nephrology, Medical School, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. ute.scholl@charite.de.(2)Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin Institute of Health, Berlin, Germany. ute.scholl@charite.de.(3)Institute of Complex Systems, Zelluläre Biophysik (ICS-4), Forschungszentrum Jülich, Jülich, Germany.(4)Department of Nephrology, Medical School, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.(5)Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.(6)Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.(7)Yale Center for Mendelian Genomics, New Haven, CT, USA.(8)Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.(9)Endocrine Hypertension Research Center, University of Queensland Diamantina Institute, Greenslopes and Princess Alexandra Hospitals, Brisbane, Queensland, Australia.(10)Proteomics Platform, Max Delbrück Center for Molecular Medicine in the Helmholtz Society and Core Unit of Proteomics, Berlin Institute of Health, Berlin, Germany.(11)Nephrology, Le Bonheur Children's Hospital, Memphis, TN, USA.(12)Cooper Clinic, PA, Fort Smith, AR, USA.(13)Peyton Manning Children's Hospital at St. Vincent, Indianapolis, IN, USA.(14)Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI, USA.(15)Division of Nephrology and Hypertension, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA.(16)Olin Teague Veterans Administration Hospital, Temple, TX, USA.(17)Division of Endocrinology, Nemours Children's Specialty Care, Jacksonville, FL, USA.(18)Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.(#)Contributed equally", "The human cofactor complexes ARC (activator-recruited cofactor) and CRSP (cofactor required for Sp1 activation) mediate activator-dependent transcription in vitro. Although these complexes share several common subunits, their structural and functional relationships remain unknown. Here, we report that affinity-purified ARC consists of two distinct multisubunit complexes: a larger complex, denoted ARC-L, and a smaller coactivator, CRSP. Reconstituted in vitro transcription with biochemically separated ARC-L and CRSP reveals differential cofactor functions. The ARC-L complex is transcriptionally inactive, whereas the CRSP complex is highly active. Structural determination by electron microscopy (EM) and three-dimensional reconstruction indicate substantial differences in size and shape between ARC-L and CRSP. Moreover, EM analysis of independently derived CRSP complexes reveals distinct conformations induced by different activators. These results suggest that CRSP may potentiate transcription via specific activator-induced conformational changes.", "We report the development and application of photoactivatable Green Cherry (G(PA)C), the first genetically encoded \"continuously red-photoactivatable green\" two-color probe for live cell imaging. G(PA)C is unique in that it enables real-time tracking of selected subpopulations of proteins and organelles in the cell or of cells within tissues and whole organisms, with constant reference to the entire population of the probe. Using G(PA)C-zyxin as proof of utility, we obtained new insights into the dynamic movement of the cytoskeletal protein zyxin. We show that zyxin is continuously and rapidly recruited from the cytosol into established focal adhesions. It can also move rapidly within a given focal adhesion and \"hop\" between adjacent focal adhesions, emphasizing the dynamic nature of proteins within these structures. The in vivo utility of G(PA)C is exemplified by tracking hemocyte movements using a versatile transgenic Drosophila model engineered to express G(PA)C in tissues and cells of interest under the control of the GAL4-inducible promoter.", "Social stressors, like other stressors, are powerful activators of the sympathoadrenomedullary system. Differential housing (single vs. group) and social defeat of rats is known to alter the activity of catecholamine-synthesizing enzymes in the medulla. The present studies examined the effect of 70 days of triad (3 rats per large cage) and individual housing of male rats on adrenal mRNA levels of tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH) and phenylethanolamine-N-methyltransferase (PNMT) and on TH protein levels. Behavioral ratings carried out at the triad formation indicated that dominant rats exhibited mostly offensive aggressive behaviors. By contrast, subordinate rats expressed primarily defensive behaviors, while the subdominant rats displayed intermediate levels of these behaviors. Overall, compared with single housing, triad housing resulted in lower gene expression for TH, DBH and PNMT and lower TH protein in the adrenals. Within triads, gene expression for these enzymes and TH protein concentration were higher in subordinate compared with dominant and subdominant rats. The dominant rats tended to have the lowest gene expression of these enzymes. These data indicate that in rodents, individual housing and a subject's social rank have a differential impact on the regulation of catecholamine biosynthesis already during the process of gene expression of catecholamine biosynthetic enzymes in the adrenals.", "BACKGROUND: We conducted a phase II trial to evaluate the efficacy of dasatinib, a multitargeted tyrosine kinase inhibitor, for adults with recurrent glioblastoma (GBM).METHODS: Eligibility requirements were Karnofsky performance status ≥ 60%; no concurrent hepatic enzyme-inducing anticonvulsants; prior treatment with surgery, radiotherapy, and temozolomide exclusively; and activation or overexpression of ≥ 2 putative dasatinib targets in GBM (ie, SRC, c-KIT, EPHA2, and PDGFR). Using a 2-stage design, 77 eligible participants (27 in stage 1, if favorable, and then 50 in stage 2) were needed to detect an absolute improvement in the proportion of patients either alive and progression-free patients at 6 months (6mPFS) or responding (any duration) from a historical 11% to 25%.RESULTS: A high rate of ineligibility (27%) to stage 1 precluded a powered assessment of efficacy, but there was also infrequent treatment-related toxicity at 100 mg twice daily. Therefore, the study was redesigned to allow intrapatient escalation by 50 mg daily every cycle as tolerated (stage 1B) before determining whether to proceed to stage 2. Escalation was tolerable in 10 of 17 (59%) participants evaluable for that endpoint; however, among all eligible patients (stages 1 and 1B, n = 50), there were no radiographic responses, median overall survival was 7.9 months, median PFS was 1.7 months, and the 6mPFS rate was 6%. The clinical benefit was insufficient to correlate tested biomarkers with efficacy. The trial was closed without proceeding to stage 2.CONCLUSIONS: Intraparticipant dose escalation was feasible, but dasatinib was ineffective in recurrent GBM. Clinical trials.gov identified. NCT00423735 (available at http://clinicaltrials.gov/ct2/show/NCT00423735).", "The pivotal role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology was identified over 30 years ago, but the successful clinical development of targeted therapies has only recently been realized. This Perspective traces the decades long evolution of medicinal chemistry required to advance small molecule CGRP receptor antagonists, also called gepants, including the current clinical agents rimegepant, vazegepant, ubrogepant, and atogepant. Providing clinically effective blockade of CGRP signaling required surmounting multiple challenging hurdles, including defeating a sizable ligand with subnanomolar affinity for its receptor, designing antagonists with an extended confirmation and multiple pharmacophores while retaining solubility and oral bioavailability, and achieving circulating free plasma levels that provided near maximal CGRP receptor coverage. The clinical efficacy of oral and intranasal gepants and the injectable CGRP monoclonal antibodies (mAbs) are described, as are recent synthetic developments that have benefited from new structural biology data. The first oral gepant was recently approved and heralds a new era in the treatment of migraine.", "The treatment of patients with recurrent glioblastoma remains a major oncologic problem, with median survival after progression of 7-9 months. To determine the maximum tolerated dose and dose-limiting toxicity (DLT), the combination of dasatinib and cyclonexyl-chloroethyl-nitrosourea (CCNU) was investigated in this setting. The study was designed as multicenter, randomized phase II trial, preceded by a lead-in safety phase. The safety component reported here, which also investigated pharmacokinetics and preliminary clinical activity, required expansion and is therefore considered a phase I part to establish a recommended dosing regimen of the combination of CCNU (90-110 mg/m(2)) and dasatinib (100-200 mg daily). Overall, 28 patients were screened, and 26 patients were enrolled. Five dose levels were explored. DLTs, mainly myelosuppression, occurred in 10 patients. Grade 3 or 4 neutropenia was recorded in 7 patients (26.9%) and thrombocytopenia in 11 patients (42.3%). No significant effect of CCNU coadministration on dasatinib pharmacokinetics was found. Median progression-free survival (PFS) was 1.35 months (95% confidence interval: 1.2-1.4) and 6-month PFS was 7.7%. In this phase I study of recurrent glioblastoma patients, the combination of CCNU and dasatinib showed significant hematological toxicities and led to suboptimal exposure to both agents.", "OBJECTIVE: Both modest screening performance and declining patient and physician acceptance have stimulated interest in alternative markers to the triple screen for the detection of Down syndrome. Our purpose was to compare the concentration of a single urinary analyte, hyperglycosylated human chorionic gonadotropin, with the serum triple screen (alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol concentrations combined with age) for second-trimester Down syndrome detection.STUDY DESIGN: Urine and blood were obtained from pregnant women in the second trimester undergoing genetic amniocentesis. Urinary hyperglycosylated human chorionic gonadotropin concentration and serum triple-screen values were measured. Individuals undergoing amniocentesis because of abnormal triple-screen results were excluded. Individual Down syndrome risks on the basis of urinary hyperglycosylated human chorionic gonadotropin concentration plus maternal age and on the basis of the triple-screen results were calculated. For each algorithm the sensitivity and false-positive rate for Down syndrome detection at different risk thresholds were determined. From these values receiver operating characteristic curves were constructed, and the area under the curve was determined for each algorithm. Finally, the performance of a new combination in which urinary hyperglycosylated human chorionic gonadotropin concentration replaced serum human chorionic gonadotropin concentration in the triple screen was ascertained.RESULTS: We studied 24 pregnancies complicated by Down syndrome and 500 unaffected pregnancies between 14 and 22 weeks' gestation in a mostly white (93.5%) population undergoing amniocentesis primarily because of advanced maternal age. The sensitivity and false-positive rate for urinary hyperglycosylated human chorionic gonadotropin concentration were 75. 0% and 5.6%, respectively, whereas those for the triple screen were 75.0% and 33.2%, respectively. Urinary hyperglycosylated human chorionic gonadotropin concentration was superior to the triple screen (area under the curve, 0.9337 vs 0.7887; P =.02). The substitution of urinary hyperglycosylated human chorionic gonadotropin concentration for serum human chorionic gonadotropin concentration in the triple screen resulted in a 91.7% sensitivity at a 10.0% false-positive rate, versus a 54.2% sensitivity for the traditional triple screen at the same false-positive rate.CONCLUSION: The performance of urinary hyperglycosylated human chorionic gonadotropin concentration was statistically superior to that of the serum triple screen in a high-risk population. The use of urinary hyperglycosylated human chorionic gonadotropin concentration as an alternative test or substitution of this measurement for serum human chorionic gonadotropin concentration in the triple screen would improve diagnostic accuracy and address many current concerns related to the triple screen.", "BACKGROUND: Galcanezumab is a calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) indicated for the preventive treatment of migraine. While galcanezumab has demonstrated efficacy in patients who did not respond to prior preventive medications in general, its efficacy in patients who did not benefit from individual, commonly prescribed preventive treatments due to inadequate efficacy or safety/tolerability remains unknown.METHODS: CONQUER was a 3-month, randomized, double-blind, placebo-controlled, phase 3b study that enrolled patients with episodic or chronic migraine who had 2 to 4 migraine preventive medication category failures in the past 10 years. Patients were randomly assigned 1:1 to receive placebo (N = 230) or galcanezumab 120 mg/month (240 mg loading dose; N = 232). Post hoc analyses were conducted to determine the efficacy of galcanezumab in patients who had not benefited from six of the most commonly prescribed migraine preventive medications. The mean change from baseline in monthly migraine headache days and ≥ 50 % response rates were assessed over months 1-3. Improvement in Migraine-Specific Questionnaire Role Function-Restrictive (MSQ-RFR) scores were assessed at month 3. The endpoints were estimated via mixed model with repeated measures.RESULTS: The most common treatment failures due to inadequate efficacy or safety/tolerability, which at least 20 % of patients reported trying without benefit, included topiramate, amitriptyline, propranolol, valproate or divalproex, onabotulinum toxin A, and metoprolol. Patients who had not previously benefited from these treatments had a greater mean reduction in monthly migraine headache days across months 1-3 in the galcanezumab group compared to placebo (all p < 0.01). More patients treated with galcanezumab experienced a ≥ 50 % reduction from baseline in monthly migraine headache days across months 1-3 compared to placebo (all p < 0.05). Galcanezumab-treated patients had a greater improvement in mean MSQ-RFR scores at month 3 compared to placebo (all p < 0.01).CONCLUSIONS: In this population, galcanezumab was effective in reducing monthly migraine headache days, improving response rates, and enhancing quality of life in patients who had not previously benefited from topiramate, amitriptyline, propranolol, valproate or divalproex, onabotulinum toxin A, and/or metoprolol due to inadequate efficacy or safety/tolerability.TRIAL REGISTRATION: ClinicalTrials.gov NCT03559257 (CONQUER).", "Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown evidence of single-agent activity in glioblastoma (GBM), and in preclinical studies, we have demonstrated significant synergistic cytotoxicity between HDAC inhibitors and proteasome inhibitors in GBM cell lines. We therefore conducted a phase II trial to evaluate the efficacy of vorinostat in combination with the proteasome inhibitor bortezomib in patients with recurrent GBM. Vorinostat was administered at a dose of 400 mg daily for 14 days of a 21-day cycle, and bortezomib was administered at a dose of 1.3 mg/m(2) intravenously on days 1, 4, 8, and 11 of the cycle. A total of 37 patients were treated, and treatment was well tolerated: grade 3, 4 nonhematologic toxicity occurred in 30% of patients and consisted mainly of fatigue (14%) and neuropathy (5%); grade 3, 4 hematologic toxicity occurred in 37% of patients and consisted of thrombocytopenia (30%), lymphopenia (4%), and neutropenia (4%). The trial was closed at the predetermined interim analysis, with 0 of 34 patients being progression-free at 6 months. One patient achieved a partial response according to the Macdonald criteria. The median time to progression for all patients was 1.5 months (range, 0.5-5.6 months), and median overall survival (OS) was 3.2 months. Patients who had received prior bevacizumab therapy had a shorter time to progression and OS, compared with those who had not. On the basis of the results of this phase II study, further evaluation of the vorinostat-bortezomib combination in GBM patients in this dose and schedule is not recommended." ]

[ "Deregulation of imprinted genes has been observed in a number of human diseases such as Beckwith-Wiedemann syndrome, Prader-Willi/Angelman syndromes and cancer. Imprinting diseases are characterised by complex patterns of mutations and associated phenotypes affecting pre- and postnatal growth and neurological functions. Regulation of imprinted gene expression is mediated by allele-specific epigenetic modifications of DNA and chromatin. These modifications preferentially affect central regulatory elements that control in cis over long distances allele-specific expression of several neighbouring genes. Investigations of imprinting diseases have a strong impact on biomedical research and provide interesting models for function and mechanisms of epigenetic gene control.", "Delayed cerebral ischemia (DCI) is an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). We studied differences in incidence and impact of DCI as defined clinically after coiling and after clipping in the International Subarachnoid Aneurysm Trial. We calculated odds ratios (OR) for DCI for clipping versus coiling with logistic regression analysis. With coiled patients without DCI as the reference group, we calculated ORs for poor outcome at 2 months and 1 year for coiled patients with DCI and for clipped patients without, and with DCI. With these ORs, we calculated relative excess risk due to Interaction (RERI). Clipping increased the risk of DCI compared to coiling in the 2,143 patients OR 1.24, 95% confidence interval (95% CI 1.01-1.51). Coiled patients with DCI, clipped patients without DCI, and clipped patients with DCI all had higher risks of poor outcome than coiled patients without DCI. Clipping and DCI showed no interaction for poor outcome at 2 months: RERI 0.12 (95% CI -1.16 to 1.40) or 1 year: RERI -0.48 (95% CI -1.69 to 0.74). Only for patients treated within 4 days, coiling and DCI was associated with a poorer outcome at 1 year than clipping and DCI (RERI -2.02, 95% CI -3.97 to -0.08). DCI was more common after clipping than after coiling in SAH patients in ISAT. Impact of DCI on poor outcome did not differ between clipped and coiled patients, except for patients treated within 4 days, in whom DCI resulted more often in poor outcome after coiling than after clipping.", "PURPOSE OF REVIEW: Familial chilblain lupus belongs to the group of type I interferonopathies and is characterized by typical skin manifestations and acral ischaemia. This review aims to give an overview of clinical signs and the pathophysiological mechanisms.RECENT FINDINGS: There are several mutations that can lead to this autosomal dominant disease. Most frequent is a mutation of the gene for TREX-1. However, as well cases of families with mutations in the SAMHD1 gene and, recently, with one for the gene that codes for the protein stimulator of interferon genes have been described. These genes are involved in the process of the detection of intracellular DNA, and their mutation results in an increased production of type I interferons and their gene products, resulting in auto-inflammation and auto-immunity. JAK inhibitors have been successfully used to treat this disorder. Familial chilblain is a rare disorder with very distinct clinical signs. Its pathophysiological mechanism gives insight into the process of interferon-induced inflammation in auto-immune diseases.", "In phase I/II KRYSTAL-1 trial, the KRASG12C inhibitor adagrasib demonstrated encouraging clinical activity against metastatic colorectal cancer, both as a monotherapy and when combined with the EGFR inhibitor cetuximab. In patients who received adagrasib alone, the disease control rate was 87% and progression-free survival was 5.6 months. Among patients who received the drug combination, the disease control rate was 100%; data on progression-free survival were immature. The findings, along with data on the KRASG12C inhibitor sotorasib, were presented at the 2021 European Society for Medical Oncology Congress.", "Type I interferon is a potent substance. As such, the induction, transmission, and resolution of the type I interferon-mediated immune response are tightly regulated. As defined, the type I interferonopathies represent discrete examples of a disturbance of the homeostatic control of this system caused by Mendelian mutations. Considering the complexity of the interferon response, the identification of further monogenic diseases belonging to this disease grouping seems likely, with the recognition of type I interferonopathies becoming of increasing clinical importance as treatment options are developed based on an understanding of disease pathology and innate immune signaling. Definition of the type I interferonopathies indicates that autoinflammation can be both interferon and noninterferon related, and that a primary disturbance of the innate immune system can \"spill over\" into autoimmunity in some cases. Indeed, that several non-Mendelian disorders, most particularly systemic lupus erythematosus and dermatomyositis, are also characterized by an up-regulation of type I interferon signaling suggests the possibility that insights derived from this work will have relevance to a broader field of clinical medicine.", "BACKGROUND: Liver hepatocellular carcinoma (LIHC) is a lethal cancer. This study aimed to identify the N6 -methyladenosine (m6 A)-targeted long non-coding RNA (lncRNA) related to LIHC prognosis and to develop an m6 A-targeted lncRNA model for prognosis prediction in LIHC.METHODS: The expression matrix of mRNA and lncRNA was obtained, and differentially expressed (DE) mRNAs and lncRNAs between tumor and normal samples were identified. Univariate Cox and pathway enrichment analyses were performed on the m6 A-targeted lncRNAs and the LIHC prognosis-related m6 A-targeted lncRNAs. Prognostic analysis, immune infiltration, and gene DE analyses were performed on LIHC subgroups, which were obtained from unsupervised clustering analysis. Additionally, a multi-factor Cox analysis was used to construct a prognostic risk model based on the lncRNAs from the LASSO Cox model. Univariate and multivariate Cox analyses were used to assess prognostic independence.RESULTS: A total of 5031 significant DEmRNAs and 292 significant DElncRNAs were screened, and 72 LIHC-specific m6 A-targeted binding lncRNAs were screened. Moreover, a total of 29 LIHC prognosis-related m6 A-targeted lncRNAs were obtained and enriched in cytoskeletal, spliceosome, and cell cycle pathways. An 11-m6 A-lncRNA prognostic model was constructed and verified; the top 10 lncRNAs included LINC00152, RP6-65G23.3, RP11-620J15.3, RP11-290F5.1, RP11-147L13.13, RP11-923I11.6, AC092171.4, KB-1460A1.5, LINC00339, and RP11-119D9.1. Additionally, the two LIHC subgroups, Cluster 1 and Cluster 2, showed significant differences in the immune microenvironment, m6 A enzyme genes, and prognosis of LIHC.CONCLUSION: The m6 A-lncRNA prognostic model accurately and effectively predicted the prognostic survival of LIHC. Immune cells, immune checkpoints (ICs), and m6 A enzyme genes could act as novel therapeutic targets for LIHC.", "BACKGROUND: Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity in a 1:1 molar ratio. We investigated the safety, tolerability, and efficacy of increasing doses of idarucizumab for the reversal of anticoagulant effects of dabigatran in a two-part phase 1 study (rising-dose assessment and dose-finding, proof-of-concept investigation). Here we present the results of the proof-of-concept part of the study.METHODS: In this randomised, placebo-controlled, double-blind, proof-of-concept phase 1 study, we enrolled healthy volunteers (aged 18-45 years) with a body-mass index of 18·5-29·9 kg/m(2) into one of four dose groups at SGS Life Sciences Clinical Research Services, Belgium. Participants were randomly assigned within groups in a 3:1 ratio to idarucizumab or placebo using a pseudorandom number generator and a supplied seed number. Participants and care providers were masked to treatment assignment. All participants received oral dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab (1 g, 2 g, or 4 g 5-min infusion, or 5 g plus 2·5 g in two 5-min infusions given 1 h apart) was administered about 2 h after the final dabigatran etexilate dose. The primary endpoint was incidence of drug-related adverse events, analysed in all randomly assigned participants who received at least one dose of dabigatran etexilate. Reversal of diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were secondary endpoints assessed by measuring the area under the effect curve from 2 h to 12 h (AUEC2-12) after dabigatran etexilate ingestion on days 3 and 4. This trial is registered with ClinicalTrials.gov, number NCT01688830.FINDINGS: Between Feb 23, and Nov 29, 2013, 47 men completed this part of the study. 12 were enrolled into each of the 1 g, 2 g, or 5 g plus 2·5 g idarucizumab groups (nine to idarucizumab and three to placebo in each group), and 11 were enrolled into the 4 g idarucizumab group (eight to idarucizumab and three to placebo). Drug-related adverse events were all of mild intensity and reported in seven participants: one in the 1 g idarucizumab group (infusion site erythema and hot flushes), one in the 5 g plus 2·5 g idarucizumab group (epistaxis); one receiving placebo (infusion site haematoma), and four during dabigatran etexilate pretreatment (three haematuria and one epistaxis). Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner; the mean ratio of day 4 AUEC2-12 to day 3 AUEC2-12 for dTT was 1·01 with placebo, 0·26 with 1 g idarucizumab (74% reduction), 0·06 with 2 g idarucizumab (94% reduction), 0·02 with 4 g idarucizumab (98% reduction), and 0·01 with 5 g plus 2·5 g idarucizumab (99% reduction). No serious or severe adverse events were reported, no adverse event led to discontinuation of treatment, and no clinically relevant difference in incidence of adverse events was noted between treatment groups.INTERPRETATION: These phase 1 results show that idarucizumab was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy men, and was well tolerated with no unexpected or clinically relevant safety concerns, supporting further testing. Further clinical studies are in progress.FUNDING: Boehringer Ingelheim Pharma GmbH & Co KG.", "Transcription coupled nucleotide excision repair (TC-NER) is involved in correcting UV-induced damage and other road-blocks encountered in the transcribed strand. Mutation frequency decline (Mfd) is a transcription repair coupling factor, involved in repair of template strand during transcription. Mfd from M. tuberculosis (MtbMfd) is 1234 amino-acids long harboring characteristic modules for different activities. Mtbmfd complemented Escherichia coli mfd (Ecomfd) deficient strain, enhanced survival of UV irradiated cells and increased the road-block repression in vivo. The protein exhibited ATPase activity, which was stimulated ∼1.5-fold in the presence of DNA. While the C-terminal domain (CTD) comprising amino acids 630 to 1234 showed ∼2-fold elevated ATPase activity than MtbMfd, the N-terminal domain (NTD) containing the first 433 amino acid residues was able to bind ATP but deficient in hydrolysis. Overexpression of NTD of MtbMfd led to growth defect and hypersensitivity to UV light. Deletion of 184 amino acids from the C-terminal end of MtbMfd (MfdΔC) increased the ATPase activity by ∼10-fold and correspondingly exhibited efficient translocation along DNA as compared to the MtbMfd and CTD. Surprisingly, MtbMfd was found to be distributed in monomer and hexamer forms both in vivo and in vitro and the monomer showed increased susceptibility to proteases compared to the hexamer. MfdΔC, on the other hand, was predominantly monomeric in solution implicating the extreme C-terminal region in oligomerization of the protein. Thus, although the MtbMfd resembles EcoMfd in many of its reaction characteristics, some of its hitherto unknown distinct properties hint at its species specific role in mycobacteria during transcription-coupled repair.", "Proteolytic processing of the p105 precursor (NF-kappa B1) generates the p50 subunit of NF-kappa B. To address the function of p105 precursor, we have generated embryonic stem (ES) cells which lack the C-terminal inhibiting ankyrin-containing domain of p105 (I kappa B gamma) but contain a functional p50 by homologous recombination. Two forms of p50 were found in ES cells lacking p105. While one was a p50 molecule with the expected size of 415 amino acids, the other was an isoform of 358 amino acids generated by alternative splicing. This isoform lacked the C-terminal 62 amino acids of p50 including the putative nuclear localization signal (NLS), but included five unrelated amino acids. This p50 molecule lacking the NLS behaved similar to wild type p50. Importantly, the p50 isoform-RelA complex interacted efficiently with I kappa B alpha, implying that the NLS of p50 is not essential for these functions. Also, p50 isoform dimers were present in the nucleus. Loss of p105 and the augment of total p50 produced an increase in the nuclear kappa B-binding activity of p50-RelA and p50 dimers. In wild type ES cells, a significant proportion of total p50 is associated with p105. Therefore, the mutation introduced in NF-kappa B1 eliminates both the processing to generate p50 and the trapping of p50 by p105. In contrast to p50, only a small fraction of RelA is associated with p105. These findings indicate that p105 plays a unique role in controlling p50 dimer activity.", "We describe an 18-month-old male infant suffering from the ichthyosis follicularis, atrichia, and photophobia (IFAP) syndrome and further delineate the clinical phenotype. Severe retardation of growth and psychomotor development, chill-like seizures, bronchial asthma, urticaria, a proneness to skin infections and transient nail dystrophy observed in our patient are non-obligatory manifestations of this disorder. Histological examination of the atrichia revealed poorly developed, shortened hair follicles and a complete absence of sebaceous glands. The sex ratio of published cases suggests an X-linked recessive inheritance. The marked clinical variability of the IFAP syndrome might be the expression of a contiguous gene defect.", "Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder; however, it remains underdiagnosed and undertreated. Although screening tools such as the Berlin questionnaire (BQ), STOP-BANG questionnaire (SBQ), STOP questionnaire (STOP), and Epworth sleepiness scale (ESS) are widely used for OSA, the findings regarding their diagnostic accuracy are controversial. Therefore, this meta-analysis investigated and compared the summary sensitivity, specificity, and diagnostic odds ratio (DOR) among the BQ, SBQ, STOP, and ESS according to the severity of OSA. Electronic databases, namely the Embase, PubMed, PsycINFO, ProQuest dissertations and theses A&I databases, and China knowledge resource integrated database, were searched from their inception to July 15, 2016. We included studies examining the sensitivity and specificity of the BQ, SBQ, STOP, and ESS against the apnea-hypopnea index (AHI) or respiratory disturbance index (RDI). The revised quality assessment of diagnostic accuracy studies was used to evaluate the methodological quality of studies. A random-effects bivariate model was used to estimate the summary sensitivity, specificity, and DOR of the tools. We identified 108 studies including a total of 47 989 participants. The summary estimates were calculated for the BQ, SBQ, STOP, and ESS in detecting mild (AHI/RDI ≥ 5 events/h), moderate (AHI/RDI ≥ 15 events/h), and severe OSA (AHI/RDI ≥ 30 events/h). The performance levels of the BQ, SBQ, STOP, and ESS in detecting OSA of various severity levels are outlined as follows: for mild OSA, the pooled sensitivity levels were 76%, 88%, 87%, and 54%; pooled specificity levels were 59%, 42%, 42%, and 65%; and pooled DORs were 4.30, 5.13, 4.85, and 2.18, respectively. For moderate OSA, the pooled sensitivity levels were 77%, 90%, 89%, and 47%; pooled specificity levels were 44%, 36%, 32%, and 621%; and pooled DORs were 2.68, 5.05, 3.71, and 1.45, respectively. For severe OSA, the pooled sensitivity levels were 84%, 93%, 90%, and 58%; pooled specificity levels were 38%, 35%, 28%, and 60%; and pooled DORs were 3.10, 6.51, 3.37, and 2.10, respectively. Therefore, for mild, moderate, and severe OSA, the pooled sensitivity and DOR of the SBQ were significantly higher than those of other screening tools (P < .05); however, the specificity of the SBQ was lower than that of the ESS (P < .05). Moreover, age, sex, body mass index, study sample size, study populations, presence of comorbidities, PSG or portable monitoring performance, and risk of bias in the domains of the index test and reference standard were significant moderators of sensitivity and specificity (P < .05). Compared with the BQ, STOP, and ESS, the SBQ is a more accurate tool for detecting mild, moderate, and severe OSA. Sleep specialists should use the SBQ to conduct patient interviews for the early diagnosis of OSA in clinical settings, particularly in resource-poor countries and sleep clinics where PSG is unavailable.", "The field of heart transplantation was built upon the discoveries of immunity and tolerance by Landsteiner, Medawar, Burnet, and others, as well as technical advancements in surgical technique by Carrel. Since the first successful human heart transplant performed by Christiaan Barnard in 1967, there has been substantial progress in the field of heart transplantation, especially over the last several decades. With advances in immunosuppression and surgical techniques, the rates of acute rejection and infection leading to graft failure have declined. However, the detection of acute and chronic allograft rejection remains one of the most important yet unsettled matters. As such, many new horizons exist for further advancement of the field of heart transplantation and for improving the outcomes of the patients we serve.", "Author information:(1)Department of Physiology, School of Medicine, Taipei Medical University, 110301 Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, 115201 Taipei, Taiwan.(2)Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.(3)Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany; Department of Otolaryngology - Head and Neck Surgery, Eberhard Karls University, 72076 Tübingen, Germany.(4)NIHR Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, UK.(5)Genetics and Molecular Cell Sciences Research Centre, St George's University of London, Cranmer Terrace, SW17 0RE London, UK.(6)Centogene AG, 18055 Rostock, Germany.(7)Department of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.(8)Department of Paediatric Endocrinology, Emma Children's Hospital, Amsterdam University Medical Center, 1105 AZ Amsterdam, the Netherlands.(9)Department of Cell and Molecular Biology & Microbiology, University of Isfahan, 8174673441 Isfahan, Iran.(10)Confocal Microscopy Core Facility, Research Laboratories, IRCCS Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.(11)Department of Genetics, King Faisal Specialist Hospital and Research Center, 11211 Riyadh, Saudi Arabia; Qatar Biomedical Research Institute, Hamad Bin Khalifa University, 34110 Doha, Qatar.(12)Pediatric Endocrinology Unit, Ruth Rappaport Children's Hospital, Rambam Healthcare Campus, 352540 Haifa, Israel; Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, 352540 Haifa, Israel.(13)Pediatric Endocrinology Unit, Ruth Rappaport Children's Hospital, Rambam Healthcare Campus, 352540 Haifa, Israel.(14)Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621 Tel-Hashomer, Israel; The Sackler Faculty of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel.(15)Department of Pediatric Endocrinology, Gaziantep Cengiz Gökcek Maternity & Children's Hospital, 27010 Gaziantep, Turkey.(16)Department of Pediatrics, Leiden University Medical Center, 2333ZA Leiden, the Netherlands.(17)Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany; Institute of Bioinformatics, Julius Maximilians University, 97070 Würzburg, Germany.(18)Unidade de Endocrinologia Genética, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo, 01246903 Sao Paulo, Brazil.(19)Unidade de Genética do Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo, 05403000 Sao Paulo, Brazil.(20)Sheba Cancer Research Center, Sheba Medical Center, 52621 Tel-Hashomer, Israel; Wohl Institute for Translational Medicine, Sheba Medical Center, 52621 Tel-Hashomer, Israel.(21)Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, SE1 9RT London, UK; Birmingham Women's and Children's NHS Foundation Trust, University of Birmingham, B4 6NH Birmingham, UK.(22)Department of Paediatrics, Sheikh Khalifa Medical City, 51900 Abu Dhabi, United Arab Emirates.(23)Johns Hopkins Aramco Healthcare, 34465 Dhahran, Saudi Arabia.(24)Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, SE1 9RT London, UK.(25)Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621 Tel-Hashomer, Israel; The Sackler Faculty of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel; Wohl Institute for Translational Medicine, Sheba Medical Center, 52621 Tel-Hashomer, Israel.(26)Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India.(27)Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany.(28)Department of Genetics, King Faisal Specialist Hospital and Research Center, 11211 Riyadh, Saudi Arabia.(29)Institute of Biomedical Sciences, Academia Sinica, 115201 Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, 110301 Taipei, Taiwan; Institute of Pharmacology, School of Medicine, National Yang-Ming University, 112304, Taipei, Taiwan. Electronic address: rbyang@ibms.sinica.edu.tw.(30)Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address: marco.tartaglia@opbg.net.", "Recent studies of patients with systemic lupus erythematosus, together with data from lupus-prone mice, suggest that inappropriate activation of type I interferon might have a role in disease pathogenesis. Serum levels of IFN-alpha are elevated in SLE patients, and gene expression profiling of peripheral blood cells shows that most lupus cases demonstrate an upregulation of IFN-responsive genes. Of interest, the IFN gene 'signature' correlates with more severe disease. The available data support a model whereby chromatin-containing immune complexes circulating in the blood of lupus patients stimulate leukocytes to produce IFN, which perpetuates disease. These emerging insights into the connection between IFN and lupus provide a host of new diagnostic and therapeutic opportunities.", "BACKGROUND: The ABCD2 score (Age, Blood pressure, Clinical features, Duration of symptoms and Diabetes) is used to identify patients having a transient ischemic attack who are at high risk for imminent stroke. However, despite its widespread implementation, the ABCD2 score has not yet been prospectively validated. We assessed the accuracy of the ABCD2 score for predicting stroke at 7 (primary outcome) and 90 days.METHODS: This prospective cohort study enrolled adults from eight Canadian emergency departments who had received a diagnosis of transient ischemic attack. Physicians completed data forms with the ABCD2 score before disposition. The outcome criterion, stroke, was established by a treating neurologist or by an Adjudication Committee. We calculated the sensitivity and specificity for predicting stroke 7 and 90 days after visiting the emergency department using the original \"high-risk\" cutpoint of an ABCD2 score of more than 5, and the American Heart Association recommendation of a score of more than 2.RESULTS: We enrolled 2056 patients (mean age 68.0 yr, 1046 (50.9%) women) who had a rate of stroke of 1.8% at 7 days and 3.2% at 90 days. An ABCD2 score of more than 5 had a sensitivity of 31.6% (95% confidence interval [CI] 19.1-47.5) for stroke at 7 days and 29.2% (95% CI 19.6-41.2) for stroke at 90 days. An ABCD2 score of more than 2 resulted in sensitivity of 94.7% (95% CI 82.7-98.5) for stroke at 7 days with a specificity of 12.5% (95% CI 11.2-14.1). The accuracy of the ABCD2 score as calculated by either the enrolling physician (area under the curve 0.56; 95% CI 0.47-0.65) or the coordinating centre (area under the curve 0.65; 95% CI 0.57-0.73) was poor.INTERPRETATION: This multicentre prospective study involving patients in emergency departments with transient ischemic attack found the ABCD2 score to be inaccurate, at any cut-point, as a predictor of imminent stroke. Furthermore, the ABCD2 score of more than 2 that is recommended by the American Heart Association is nonspecific.", "Autoinflammatory disorders are sterile inflammatory conditions characterized by episodes of early-onset fever and disease-specific patterns of organ inflammation. Recently, the discoveries of monogenic disorders with strong type I interferon (IFN) signatures caused by mutations in proteasome degradation and cytoplasmic RNA and DNA sensing pathways suggest a pathogenic role of IFNs in causing autoinflammatory phenotypes. The IFN response gene signature (IGS) has been associated with systemic lupus erythematosus (SLE) and other autoimmune diseases. In this review, we compare the clinical presentations and pathogenesis of two IFN-mediated autoinflammatory diseases, CANDLE and SAVI, with Aicardi Goutières syndrome (AGS) and monogenic forms of SLE (monoSLE) caused by loss-of-function mutations in complement 1 (C1q) or the DNA nucleases, DNASE1 and DNASE1L3. We outline differences in intracellular signaling pathways that fuel a pathologic type I IFN amplification cycle. While IFN amplification is caused by predominantly innate immune cell dysfunction in SAVI, CANDLE, and AGS, autoantibodies to modified RNA and DNA antigens interact with tissues and immune cells including neutrophils and contribute to IFN upregulation in some SLE patients including monoSLE, thus justifying a grouping of \"autoinflammatory\" and \"autoimmune\" interferonopathies. Understanding of the differences in the cellular sources and signaling pathways will guide new drug development and the use of emerging targeted therapies.", "INTRODUCTION: : On Guadeloupe, atypical parkinsonism is abnormally frequent, and represents 75% of progressive parkinsonism while Parkinson's disease (PD) accounts for only 25%, which is an inversed percentage in comparison with Europe. Herbal tea made with Annonaceae leaves (containing benzyltetrahydroisoquinolines (Be-TIQ), tetrahydroprotoberberines (THPB) and acetogenins (potent mitochondrial complex I inhibitors) are commonly used on Guadeloupe.CLINICAL STUDY: : Of 265 patients studied on Guadeloupe, 66 (25%) had PD, and 199 (75%) had atypical parkinsonism. This latter group includes 58 patients (29%) with progressive supranuclear palsy (PSP), and 100 patients (50%) with unclassifiable parkinsonism (UP). This focus resembles the parkinsonism-dementia complex (PDC) described on Guam, where a very high prevalence of atypical parkinsonism has been reported since the second World War, including one-third of PSP. A preliminary case-control study on Guadeloupe showed a significant higher consumption of fruits and herbal tea of Annonaceae in atypical parkinsonian cases (PSP and unclassifiable parkinsonism, UP), compared to hospital controls and to idiopathic PD.DISCUSSION: : The overrepresentation of atypical parkinsonism on Guadeloupe and Guam could be related to the consumption of plants containing (simultaneously) isoquinoline derivates which are toxic for dopaminergic neurons and inhibitors of the mitochondrial respiratory chain such as acetogenins. This hypothesis is in keeping with epidemiologic data and experimental studies showing neuronal loss after exposure to isoquinolines or acetogenins.", "OBJECTIVES: Valproic acid (VPA) and trichostatin A (TSA) exert antitumor activity as histone deacetylase inhibitors, whereas ellipticine action is based mainly on DNA intercalation, inhibition of topoisomerase II and formation of cytochrome P450 (CYP)- and peroxidase-mediated covalent DNA adducts. This is the first report on the molecular mechanism of combined treatment of human neuroblastoma UKF-NB-3 and UKF-NB-4 cells with these compounds.METHODS: HPLC with UV detection was employed for the separation and characterization of ellipticine metabolites formed by microsomes and peroxidases. Covalent DNA modifications by ellipticine in neuroblastoma cells and in incubations with microsomes and peroxidases were detected by 32P-postlabeling. Expression of CYP enzymes, peroxidases and cytochrome b5 was examined by Western blot.RESULTS: The cytotoxicity of ellipticine to neuroblastomas was increased by pre-treating these cells with VPA or TSA. A higher sensitivity of cells to ellipticine correlated with an increase in formation of covalent ellipticine-derived DNA adducts in these cells. To evaluate the mechanisms of this finding, we investigated the modulation by VPA and TSA of CYP- and peroxidase-mediated ellipticine-derived DNA adduct formation in vitro. The effects of ellipticine in the presence of VPA and TSA on expression of CYPs and peroxidases relevant for ellipticine activation and levels of cytochrome b5 and P-glycoprotein in neuroblastoma cells were also investigated. Based on these studies, we attribute most of the enhancing effects of VPA and TSA on ellipticine cytotoxicity to enhanced ellipticine-DNA adduct formation caused by an increase in levels of cytochrome b5, CYP3A4 and CYP1A1 in neuroblastoma cells. A lower sensitivity of UKF-NB-4 cells to combined effects of ellipticine with VPA and TSA than of UKF-NB-3 cells is also attributable to high levels of P-glycoprotein expressed in this cell line.CONCLUSION: The results found here warrant further studies and may help in the design of new protocols geared to the treatment of high risk neuroblastomas.", "The linear ubiquitin (Ub) chain assembly complex (LUBAC) is an E3 ligase that specifically assembles Met1-linked (also known as linear) Ub chains that regulate nuclear factor κB (NF-κB) signaling. Deubiquitinases (DUBs) are key regulators of Ub signaling, but a dedicated DUB for Met1 linkages has not been identified. Here, we reveal a previously unannotated human DUB, OTULIN (also known as FAM105B), which is exquisitely specific for Met1 linkages. Crystal structures of the OTULIN catalytic domain in complex with diubiquitin reveal Met1-specific Ub-binding sites and a mechanism of substrate-assisted catalysis in which the proximal Ub activates the catalytic triad of the protease. Mutation of Ub Glu16 inhibits OTULIN activity by reducing kcat 240-fold. OTULIN overexpression or knockdown affects NF-κB responses to LUBAC, TNFα, and poly(I:C) and sensitizes cells to TNFα-induced cell death. We show that OTULIN binds LUBAC and that overexpression of OTULIN prevents TNFα-induced NEMO association with ubiquitinated RIPK1. Our data suggest that OTULIN regulates Met1-polyUb signaling.", "Pannexins (Panx) are proteins with a similar membrane topology to connexins, the integral membrane protein of gap junctions. Panx1 channels are generally of major importance in a large number of system and cellular processes and their function has been thoroughly characterized. In contrast, little is known about channel structure and subcellular distribution. We therefore determine the subcellular localization of Panx1 channels in cultured cells and aim at the identification of channel morphology in vitro. Using freeze-fracture replica immunolabeling on EYFP-Panx1-overexpressing HEK 293 cells, large particles were identified in plasma membranes, which were immunogold-labeled using either GFP or Panx1 antibodies. There was no labeling or particles in the nuclear membranes of these cells, pointing to plasma membrane localization of Panx1-EYFP channels. The assembly of particles was irregular, this being in contrast to the regular pattern of gap junctions. The fact that no counterparts were identified on apposing cells, which would have been indicative of intercellular signaling, supported the idea of Panx1 channels within one membrane. Control cells (transfected with EYFP only, non-transfected) were devoid of both particles and immunogold labeling. Altogether, this study provides the first demonstration of Panx1 channel morphology and assembly in intact cells. The identification of Panx1 channels as large particles within the plasma membrane provides the knowledge required to enable recognition of Panx1 channels in tissues in future studies. Thus, these results open up new avenues for the detailed analysis of the subcellular localization of Panx1 and of its nearest neighbors such as purinergic receptors in vivo.", "OBJECTIVE: Type I interferon (IFN) is implicated in the pathogenesis of systemic lupus erythematosus (SLE) and interferonopathies such as Aicardi-Goutières syndrome. A recently discovered DNA-activated type I IFN pathway, cyclic GMP-AMP synthase (cGAS), has been linked to Aicardi-Goutières syndrome and mouse models of lupus. The aim of this study was to determine whether the cGAS pathway contributes to type I IFN production in patients with SLE.METHODS: SLE disease activity was measured by the Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index. Expression of messenger RNA for cGAS and IFN-stimulated genes (ISGs) was determined by quantitative polymerase chain reaction analysis. Cyclic GMP-AMP (cGAMP) levels were examined by multiple reaction monitoring with ultra-performance liquid chromatography tandem mass spectrometry.RESULTS: Expression of cGAS in peripheral blood mononuclear cells (PBMCs) was significantly higher in SLE patients than in normal controls (n = 51 and n = 20 respectively; P < 0.01). There was a positive correlation between cGAS expression and the IFN score (P < 0.001). The expression of cGAS in PBMCs showed a dose response to type I IFN stimulation in vitro, consistent with it being an ISG. Targeted measurement of cGAMP by tandem mass spectrometry detected cGAMP in 15% of the SLE patients (7 of 48) but none of the normal (0 of 19) or rheumatoid arthritis (0 of 22) controls. Disease activity was higher in SLE patients with cGAMP versus those without cGAMP.CONCLUSION: Increased cGAS expression and cGAMP in a proportion of SLE patients indicates that the cGAS pathway should be considered as a contributor to type I IFN production. Whereas higher cGAS expression may be a consequence of exposure to type I IFN, detection of cGAMP in patients with increased disease activity indicates potential involvement of this pathway in disease expression.", "PURPOSE OF REVIEW: We give an update on the etiology and potential treatment options of rare inherited monogenic disorders associated with arterial calcification and calcific cardiac valve disease.RECENT FINDINGS: Genetic studies of rare inherited syndromes have identified key regulators of ectopic calcification. Based on the pathogenic principles causing the diseases, these can be classified into three groups: (1) disorders of an increased extracellular inorganic phosphate/inorganic pyrophosphate ratio (generalized arterial calcification of infancy, pseudoxanthoma elasticum, arterial calcification and distal joint calcification, progeria, idiopathic basal ganglia calcification, and hyperphosphatemic familial tumoral calcinosis; (2) interferonopathies (Singleton-Merten syndrome); and (3) others, including Keutel syndrome and Gaucher disease type IIIC. Although some of the identified causative mechanisms are not easy to target for treatment, it has become clear that a disturbed serum phosphate/pyrophosphate ratio is a major force triggering arterial and cardiac valve calcification. Further studies will focus on targeting the phosphate/pyrophosphate ratio to effectively prevent and treat these calcific disease phenotypes.", "Oncotype DX, PAM50, and MammaPrint are multigene tests that are being used clinically for early-stage breast cancer to predict recurrence risk and guide adjuvant chemotherapy decisions. These tests have been validated in multiple retrospective studies, and prospective clinical trials are in progress. The TAILORx trial uses the Oncotype DX recurrence score to assign estrogen receptor-positive (ER+), node-negative patients to chemotherapy plus hormonal therapy versus hormonal therapy alone. The RxPONDER (SWOG S1007) trial uses Oncotype DX in a similar approach but on node-positive patients, and it includes the PAM50 test as a secondary analysis. The MINDACT trial uses Mamma-Print and Adjuvant! Online for treatment arm assignments. MINDACT has very broad eligibility criteria and 2 secondary randomizations for selecting chemotherapy and hormonal therapy regimens. This article discusses how the latest results on cancer genome sequencing apply to early-stage breast cancer. Several hundred breast cancers have already undergone genome sequencing, and the somatic DNA changes found in the tumor, compared with the patient's normal DNA, have been identified. Higher rates of point mutations and chromosomal translocations are found in aromatase inhibitor-resistant ER+ cancers and in the basal-like and HER2-enriched breast cancer subtypes. Correlations of somatic mutations with neoadjuvant aromatase inhibitor response are discussed. Genome sequencing can potentially identify the molecular abnormalities that underlie the poor risk identified by multigene tests and provide potential new targets for therapy, but more clinical trials correlating clinical outcome and somatic DNA changes are needed.", "The RET proto-oncogene (REarranged during Transfection; RET) plays an important role in the causation of many thyroid tumours. Germline RET proto-oncogene missense mutations have been clearly linked to medullary thyroid carcinoma (MTC) and the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2A, MEN2B).METHODS: We investigated a cohort of MEN2-related patients referred to Tygerberg Hospital, W Cape (2003-2009). The study cohort was divided into three groups based on pathology (viz. MEN/MTC, phaeochromocytoma, and a miscellaneous group of MEN pathologies). Families with identified high-risk factors were recalled. Serum calcitonin levels were monitored where indicated. DNA was extracted from whole blood by standard techniques and polymerase chain reaction (PCR) products screened for RET gene variations by heteroduplex single-strand duplication techniques (heteroduplex single-strand conformation polymorphism analysis) being validated with automated sequencing techniques showing conformational variants in acrylamide gel.RESULTS: We screened 40 persons, male/female ratio 1:1.5. Three ethnic groups were represented (white (12), black (11) and mixed race (17)). Nine were index MTC cases, 5 phaeochromocytoma, 3 Hirschsprung's disease-MEN associations and 2 miscellaneous (1 neuroblastoma, 1 intestinal neuronal dysplasia), while 1 fell into the MEN2B category. The remaining 19 were unaffected relatives screened for carrier status, among whom afamilial recurrence was observed in 7. On genetic testing, an RET point mutation at the high-risk 634 cysteine allele was identified in 11 cases. A further cysteine radical mutation at the 620 position was related to MEN2 in 3 families plus 1 other family referred from elsewhere. Other less-recognised gene variations were detected throughout the RET gene in 70% of cases and included the 691 position on codon 11 (11 cases); the 432 position (4 cases, 1 homozygous) intronic mutations on exon 4 (1 case); and an IVS19-37G/C and a D1017N variation in exon 19 in 2 MEN families. Fifteen MTC patients have had thyroidectomies, of which 2 were prophylactic (C-cell hyperplasia; early occult MTC). A further 3 are awaiting prophylactic surgery.CONCLUSION: RET gene mutation carries a risk of MEN2 and MTC in all ethnic groups in South Africa. Prophylactic surgery may prevent MTC, so genetic screening is important to identify and treat high-risk patients.", "PURPOSE OF REVIEW: In recent years, immunosuppressive therapy, as an alternative to corticosteroids, has been proposed as novel agents which target the various antigens involved in the pathogenesis of Graves' ophthalmopathy. Although the lack of randomized and controlled studies suggests caution in generalizing results, some data show interesting results.RECENT FINDINGS: Potential targets for immune therapy in Graves' ophthalmopathy are the antigens expressed on the target organ of inflammation, namely the receptor and the insulin growth factor -1 receptor on fibroblasts, inflammatory cytokines, and B and T cells. The most promising results are observed with small thyroid stimulating hormone receptor molecules interacting with the receptor on thyrocytes and fibroblasts and with the anti-IGF-1 receptor antibody teprotumumab. A recent open study with tocilizumab, an anti-soluble interleukin-6 receptor, has shown inactivation of Graves' ophthalmopathy. Consistent reports on the efficacy of rituximab will have to be confirmed by randomized controlled trials, which are now in progress.SUMMARY: Current clinical practice for Graves' ophthalmopathy will greatly benefit from the availability of immunosuppressors that act as disease-modifying drugs, as compared to steroids, the current standard treatment for Graves' ophthalmopathy. Rituximab seems to be a good candidate, as preliminary results from ongoing randomized trials suggest good efficacy with a relative well tolerated profile.", "The field of immuno-oncology has witnessed unprecedented success in recent years, with several PD=1 and PD-L1 inhibitors obtaining US FDA registration and breakthrough drug therapy designation in multiple tumor types. Despite its clear efficacy in certain cancers, treatment with these agents carries a risk of immune-related toxicities and substantial financial burden. It is, therefore, critical to identify patients likely to benefit from such immunotherapies and develop strategies to differentiate responders from nonresponders early during treatment. Here we discuss the development of predictive and treatment response biomarkers for immune checkpoint inhibitors. We first examine the role of PD-L1 expression, the most extensively studied predictive biomarker of response, and further discuss emerging putative predictive biomarkers. We also detail challenges faced in the development of response assessments for immunotherapeutics and propose other biomarkers that may be useful as surrogate intermediate end points of response.", "Type I interferons (IFNs), IFN-α and IFN-β, represent the major effector cytokines of the host immune response against viruses and other intracellular pathogens. These cytokines are produced via activation of numerous pattern recognition receptors, including the Toll-like receptor signaling network, retinoic acid-inducible gene-1 (RIG-1), melanoma differentiation-associated protein-5 (MDA-5) and interferon gamma-inducible protein-16 (IFI-16). Whilst the contribution of type I IFNs to peripheral immunity is well documented, they can also be produced by almost every cell in the central nervous system (CNS). Furthermore, IFNs can reach the CNS from the periphery to modulate the function of not only microglia and astrocytes, but also neurons and oligodendrocytes, with major consequences for cognition and behavior. Given the pleiotropic nature of type I IFNs, it is critical to determine their exact cellular impact. Inappropriate upregulation of type I IFN signaling and interferon-stimulated gene expression have been linked to several CNS diseases termed \"interferonopathies\" including Aicardi-Goutieres syndrome and ubiquitin specific peptidase 18 (USP18)-deficiency. In contrast, in the CNS of mice with virus-induced neuroinflammation, type I IFNs can limit production of other cytokines to prevent potential damage associated with chronic cytokine expression. This capacity of type I IFNs could also explain the therapeutic benefits of exogenous type I IFN in chronic CNS autoimmune diseases such as multiple sclerosis. In this review we will highlight the importance of a well-balanced level of type I IFNs for healthy brain physiology, and to what extent dysregulation of this cytokine system can result in brain 'interferonopathies'.", "BACKGROUND: At present, colorectal cancer is routinely treated with adjuvant radiotherapy and chemotherapy postoperatively. The adverse effects (AEs) of chemotherapy usually interrupt the treatment of chemotherapy. Traditional Chinese medicine (TCM) has demonstrated great potential in improving patients' clinical symptoms, regulating the immune function, improving the life quality, and reducing the AEs of chemotherapy.AIM: To observe the clinical efficacy of Yiqi Jianpi anti-cancer prescription combined with chemotherapy in patients with colorectal cancer after operation.METHODS: Data from patients diagnosed with colorectal cancer between January 2019 and February 2021 were collected from Liaoning Cancer Hospital and Institute and the Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine. Patients receiving the chemotherapy regimen of capecitabine plus oxaliplatin (CAPOX) after radical resection of colorectal cancer were prospectively collected and randomly divided into an experimental group and a control group. The experimental group was given Yiqi Jianpi anti-cancer prescription combined with the CAPOX regimen, while the control group was given the CAPOX regimen alone. After six cycles of chemotherapy, the scores of TCM symptoms, Karnofsky performance scale (KPS) score, levels of T-cell subsets, and AEs after chemotherapy of the two groups were compared.RESULTS: A total of 70 patients were randomly divided into either an experimental group (n = 35, no dropout) or a control group (n = 33, with 2 dropouts). Compared with the control group, the experimental group improved significantly (P < 0.05) in scores of TCM symptoms, KPS score, levels of T-cell subsets, and AEs of chemotherapy.CONCLUSION: Yiqi Jianpi anti-cancer prescription can effectively improve spleen deficiency, regulate the immune function, and alleviate the AEs of chemotherapy, so as to improve the life quality of patients with good therapeutic effects and application prospect in clinical practice.", "Purpose We report the first-in-human phase Ia study to our knowledge ( ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor. Patients and Methods In the dose-escalation phase, patients with PIK3CA-altered advanced solid tumors received once-daily or twice-daily oral alpelisib on a continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered solid tumors and PIK3CA-wild-type, estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer received alpelisib 400 mg once daily. Results One hundred thirty-four patients received treatment. Alpelisib maximum tolerated doses were established as 400 mg once daily and 150 mg twice daily. Nine patients (13.2%) in the dose-escalation phase had dose-limiting toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and hypophosphatemia (n = 1). Frequent all-grade, treatment-related adverse events included hyperglycemia (51.5%), nausea (50.0%), decreased appetite (41.8%), diarrhea (40.3%), and vomiting (31.3%). Alpelisib was rapidly absorbed; half-life was 7.6 hours at 400 mg once daily with minimal accumulation. Objective tumor responses were observed at doses ≥ 270 mg once daily; overall response rate was 6.0% (n = 8; one patient with endometrial cancer had a complete response, and seven patients with cervical, breast, endometrial, colon, and rectal cancers had partial responses). Stable disease was achieved in 70 (52.2%) patients and was maintained > 24 weeks in 13 (9.7%) patients; disease control rate (complete and partial responses and stable disease) was 58.2%. In patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, median progression-free survival was 5.5 months. Frequently mutated genes (≥ 10% tumors) included TP53 (51.3%), APC (23.7%), KRAS (22.4%), ARID1A (13.2%), and FBXW7 (10.5%). Conclusion Alpelisib demonstrated a tolerable safety profile and encouraging preliminary activity in patients with PIK3CA-altered solid tumors, supporting the rationale for selective PI3Kα inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors.", "The knowledge on systemic autoinflammatory disorders (SAID) is expanding rapidly and new signalling pathways are being decrypted. The concept of autoinflammation has been proposed since 1999, to define a group of diseases with abnormal innate immunity activation. Since then, more than 30 monogenic SAID have been described. In this review, we first describe inflammasomopathies and SAID related to the interleukin-1 pathway. Recent insights into the pathogenesis of familial Mediterranean fever and the function of Pyrin are detailed. In addition, complex or polygenic SAID, such as Still's disease or PFAPA syndrome, are also discussed. Then, major players driving autoinflammation, such as type-1 interferonopathies (including the recently described haploinsuffiency in A20 and otulipenia), TNF-associated periodic syndromes, defects in ubiquitination, and SAID with overlapping features of autoimmunity or immunodeficiency. Discoveries of the pathogenic role of mosaicism, intronic defects coupled to the likelihood to identify digenic or polygenic diseases are providing new challenges for physicians and geneticists. This comprehensive review depicts the various SAID, presenting them according to their predominant pathophysiological mechanism, with a particular emphasis on recent findings. Epidemiologic data are also presented. Finally, we propose a practical diagnostic approach to the most common monogenic SAID, based on the most characteristic clinical presentation of these disorders.", "Aicardi-Goutières syndrome (AGS) is an inflammatory disorder belonging to the recently characterized group of type I interferonopathies. The most consistently affected tissues in AGS are the central nervous system and skin, but various organ systems and tissues have been reported to be affected, pointing to the systemic nature of the disease. Here we describe a patient with AGS due to a homozygous p.Arg114His mutation in the TREX1 gene. The histologically proven inflammatory myopathy in our patient expands the range of clinical features of AGS. Histological signs of muscle biopsies in the proband, and in two other AGS patients described earlier, are similar to those seen in various autoimmune myositises and could be ascribed to inapproapriate IFN I activation. In view of signs of possible mitochondrial damage in AGS, we propose that mitochondrial DNA could be a trigger of autoimmune responses in AGS.", "We recently showed that diencephalic TRH may mediate the central leptin-induced pressor effect. Here, to study the role of TRH in obesity-induced hypertension (OIH), we used a model of OIH produced by a high-fat diet (HFD, 45 days) in male Wistar rats. After 4 wk, body weight and systolic arterial blood pressure (SABP) increased in HFD animals. Plasma leptin was correlated with peritoneal adipose tissue. Then, we treated OIH animals with an antisense oligodeoxynucleotide and small interfering (si)RNA against the prepro-TRH. Antisense significantly decreased diencephalic TRH content and SABP at 24 and 48 h posttreatment. Similar effects were observed with siRNA against prepro-TRH but for up to 4 wk. Conversely, vehicle, an inverted antisense sequence and siRNA against green fluorescence protein, produced no changes. SABP decrease seems to be owing to an inhibition of the obesity-enhanced sympathetic outflow but not to an alteration in thyroid status. Using a simple OIH model we demonstrated, for the first time, that central TRH participates in the hypertension induced by body weight gain probably through its well-known action on sympathetic activity. Thus the TRH-leptin interaction may contribute to the strong association between hypertension and obesity." ]

[ "Author information:(1)Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University, Shanghai 200433, China.(2)Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.(3)Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.(4)Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.(5)MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic & Systems Biology, TNLIST; Department of Automation, Tsinghua University, Beijing 100084, China.(6)Department of Biochemistry, University at Buffalo, Buffalo, NY 14214, USA.(7)Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.(8)Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA cliff@jimmy.harvard.edu.(9)Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University, Shanghai 200433, China xsliu@jimmy.harvard.edu.", "CCN1 is a matricellular protein and a member of the CCN family of growth factors. CCN1 is associated with the development of various cancers including pancreatic ductal adenocarcinoma (PDAC). Our recent studies found that CCN1 plays a critical role in pancreatic carcinogenesis through the induction of EMT and stemness. CCN1 mRNA and protein were detected in the early precursor lesions, and their expression intensified with disease progression. However, biochemical activity and the molecular targets of CCN1 in pancreatic cancer cells are unknown. Here we show that CCN1 regulates the Sonic Hedgehog (SHh) signaling pathway, which is associated with the PDAC progression and poor prognosis. SHh regulation by CCN1 in pancreatic cancer cells is mediated through the active Notch-1. Notably, active Notch-1is recruited by CCN1 in these cells via the inhibition of proteasomal degradation results in stabilization of the receptor. We find that CCN1-induced activation of SHh signaling might be necessary for CCN1-dependent in vitro pancreatic cancer cell migration and tumorigenicity of the side population of pancreatic cancer cells (cancer stem cells) in a xenograft in nude mice. Moreover, the functional role of CCN1 could be mediated through the interaction with the αvβ3 integrin receptor. These extensive studies propose that targeting CCN1 can provide a new treatment option for patients with pancreatic cancer since blocking CCN1 simultaneously blocks two critical pathways (i.e. SHh and Notch1) associated with the development of the disease as well as drug resistance.", "We identified and characterized a CYP9 family gene, CrCYP9AT2, from Chironomus riparius, an eco-toxicologically important model organism. The 1978 base pair (bp) length CrCYP9AT2 cDNA has an open reading frame of 1587 bp encoding a putative 528 amino acid protein. There was 267 bp 5' and 123 bp 3' untranslated region with a polyadenylation signal site (AATAAA). The putative heme-binding cysteine at position 471 and the typical p450 signature sequence of 463-FGIGPRNCIG-473 were also present. The CrCYP9AT2 transcript was present in all life stages with the highest expression in larvae. The modulation of CrCYP9AT2 was studied using real-time polymerase chain reaction after 24h exposure to cadmium chloride, benzo(a)pyrene; bisphenol A; nonylphenol; chlorpyrifos and ethinylestradiol. Significant up-regulation of CrCYP9AT2 gene was observed after exposure to Cd, B(a)P and CP. However, CrCYP9AT2 was significantly down-regulated after exposure to BPA, NP and EE.", "BACKGROUND: Autophagy induction can increase or decrease anticancer drug efficacy. Anticancer drug-induced autophagy induction is poorly characterized in osteosarcoma (OS). In this study, we investigated the impact of autophagy inhibition on camptothecin (CPT)-induced cytotoxicity in OS.METHODS: Autophagy-inhibited DLM8 and K7M3 metastatic murine OS cell lines were generated by infection with lentiviral shRNA directed against the essential autophagy protein ATG5. Knockdown of ATG5 protein expression and inhibition of autophagy was confirmed by immunoblot of ATG5 and LC3II proteins, respectively. Metabolic activity was determined by MTT assay and cell viability was determined by trypan blue exclusion. Acridine orange staining and immunoblotting for LC3II protein expression were used to determine autophagy induction. Oxidative stress was assessed by staining cells with HE and DCFH-DA followed by flow cytometry analysis. Mitochondrial membrane potential was determined by staining cells with TMRE followed by flow cytometry analysis. Immunoblotting was used to detect caspase activation, Parp cleavage and p53 phosphorylation.RESULTS: Autophagy inhibition caused a greater deficit in metabolic activity and cell growth in K7M3 cells compared to DLM8 cells. K7M3 cells exhibited higher basal autophagy levels than DLM8 cells and non-transformed murine MCT3 osteoblasts. Autophagy inhibition did not affect CPT-induced DNA damage. Autophagy inhibition decreased CPT-induced cell death in DLM8 cells while increasing CPT-induced cell death in K7M3 cells. Autophagy inhibition reduced CPT-induced mitochondrial damage and CPT-induced caspase activation in DLM8 cells. Buthionine sulfoximine (BSO)-induced cell death was greater in autophagy-competent DLM8 cells and was reversed by antioxidant pretreatment. Camptothecin-induced and BSO-induced autophagy induction was also reversed by antioxidant pretreatment. Significantly, autophagy inhibition not only reduced CPT-induced oxidative stress but also reduced basal oxidative stress.CONCLUSIONS: The results of this study indicate that autophagy inhibition can have an opposing effect on CPT-induced cytotoxicity within OS. The cytoprotective mechanism of autophagy inhibition observed in DLM8 cells involves reduced CPT-induced oxidative stress and not reduced DNA damage. Our results also reveal the novel finding that knockdown of ATG5 protein reduces both basal oxidative stress and drug-induced oxidative stress.", "Cytarabine is a potent anticancer drug that interferes with elongation of the lagging strand at the replication fork during DNA synthesis. The effects of cytarabine substitution on the structural and thermodynamic properties of a model Okazaki fragment were investigated using UV hyperchromicity and 1H NMR spectroscopy to determine how cytarabine alters the physicochemical properties of Okazaki fragments that are intermediates during DNA replication. Two model Okazaki fragments were prepared corresponding to a primary initiation site for DNA replication in the SV40 viral genome. One model Okazaki fragment consisted of five ribo- and seven deoxyribonucleotides on the hybrid strand, together with its complementary (DNA) strand. The second model Okazaki fragment was identical to the first with the exception of cytarabine substitution for deoxycytidine at the third DNA nucleotide of the hybrid strand. Thermodynamic parameters for the duplex to single strand transition for each model Okazaki fragment were calculated from the concentration dependence of the T m at 260 nm. Cytarabine significantly decreased the stability of this model Okazaki fragment, decreasing the melting temperature from 46.8 to 42.4 degrees C at a concentration of 1.33 x 10(-5) M. The free energy for the duplex to single strand transition was 1.2 kcal/mol less favorable for the cytarabine-substituted Okazaki fragment relative to the control at 37 degrees C. Analysis of the temperature dependence of the imino1H resonances for the two duplexes demonstrated that cytarabine specifically destabilized the DNA:DNA duplex portion of the model Okazaki fragment. These results are consistent with inhibition of lagging strand DNA synthesis by cytarabine substitution resulting from destabilization of the DNA:DNA duplex portion of Okazaki fragments in vivo .", "Disassembly of the Cdc45-MCM-GINS (CMG) DNA helicase is the key regulated step during DNA replication termination in eukaryotes, involving ubiquitylation of the Mcm7 helicase subunit, leading to a disassembly process that requires the Cdc48 \"segregase\". Here, we employ a screen to identify partners of budding yeast Cdc48 that are important for disassembly of ubiquitylated CMG helicase at the end of chromosome replication. We demonstrate that the ubiquitin-binding Ufd1-Npl4 complex recruits Cdc48 to ubiquitylated CMG. Ubiquitylation of CMG in yeast cell extracts is dependent upon lysine 29 of Mcm7, which is the only detectable site of ubiquitylation both in vitro and in vivo (though in vivo other sites can be modified when K29 is mutated). Mutation of K29 abrogates in vitro recruitment of Ufd1-Npl4-Cdc48 to the CMG helicase, supporting a model whereby Ufd1-Npl4 recruits Cdc48 to ubiquitylated CMG at the end of chromosome replication, thereby driving the disassembly reaction.", "Etizolam is a thienodiazepine that although licensed for clinical usage in Japan, India and South Korea is commonly abused and detected in post-mortem cases around the world. To date, there are limited data in the literature to allow for the interpretation of blood concentrations of etizolam in post-mortem cases. A liquid chromatography with tandem mass spectrometry method was used to quantitate etizolam concentrations in 28 post-mortem cases where etizolam was detected. The median concentration of etizolam in femoral blood was 8.5 ng/mL (range 1.0-172.0 ng/mL; n = 24); in antemortem plasma, the etizolam concentration range was 4-44 ng/mL (n = 4). The mean age of the individuals abusing etizolam was 38.5 ± 8.4 years (median 39 years), with the majority being male (86%). In all of the cases, multiple drugs were detected, with the most common being pregabalin (61%) followed by morphine/heroin (54%), diazepam (54%) and benzoylecgonine (21%), illustrating the increasing problem of poly-substance use in drug abusers. The cause of death in the cases in which etizolam was detected was multi-drug toxicity in 87.5% of the cases, with 12.5% unrelated to drug use (hangings and blunt-force trauma). These data will further help forensic practitioners with the interpretation of post-mortem etizolam concentrations." ]

[ "The first human-to-human heart transplant was performed 50 years ago in 1967. Heart transplantation has now entered an era of tremendous growth and innovation. The future of heart transplantation is bright with the advent of newer immunosuppressive medications and strategies that may even result in tolerance. Much of this progress in heart transplant medicine is predicated on a better understanding of acute and chronic rejection pathways through basic science studies. The future will also include personalized medicine where genomics and molecular science will dictate customized treatment for optimal outcomes. The introduction of mechanical circulatory support (MCS) devices has changed the landscape for patients with severe heart failure to stabilize the most ill patient and make them better candidates for heart transplant. As ex vivo preservation takes hold, we may witness an expansion of the donor pool through the use of donation after cardiac death (DCD) donors. In addition, further geographical donor heart sharing through ex vivo preservation may further decrease waitlist mortality by enabling longer distance donor hearts to be allocated for the sickest waitlist patient. It is no doubt an exciting time to be involved in the field of heart transplantation. In this perspective, we will summarize the present state of heart transplantation and discuss various innovations that are being pursued.", "PURPOSE: Brain tumors are associated with neurological sequelae and poor survival, contributing to distress in patients and their families. Our institution has conducted separate support groups for brain tumor patients and caregivers since 1999. This retrospective cohort study aimed to identify characteristics of brain tumor group participants in relation to attendance frequency, and compare themes of discussion in patient and caregiver groups.METHODS: Demographic and medical characteristics were obtained from patient and caregiver group registration sheets and medical chart review. We quantified discussion topics recorded by group facilitators between 1999 and 2006, extracted themes, and examined similarities and differences in the way these themes were expressed.RESULTS: A total of 137 patients and 238 caregivers attended the groups; about half attended more than one session. The chart review of a randomly selected subset of patient participants revealed that 57.5 % were married, 58.8 % had high-grade gliomas, and 55 % attended their first group within 3 months of diagnosis or at tumor progression. Both groups discussed physical and cognitive consequences, emotional reactions, relationships, coping, end of life, and practical issues. Caregivers discussed difficulties achieving self-care and caregiver burden.CONCLUSIONS: Brain tumor support group facilitators can expect to encounter a range of medical and psychosocial issues in accommodating patients' and caregivers' diverse concerns. Separate brain tumor patient and caregiver groups may allow participants to explore those concerns without worrying about effects on their friends or family. It remains to be seen whether the groups meet the needs of attendees, and whether those who do not attend the groups have unmet needs.", "Clostridium difficile is a gram-positive intestine bacterium that causes a severe diarrhea and could eventually be lethal. The main virulence factor is related to the release of two major exotoxins, toxin A (TcdA) and toxin B (TcdB). Recent C. difficile-associated disease (CDAD) outbreaks have been caused by hypervirulent strains which secrete an additional binary toxin (CDTa/CDTb). Vaccination against these toxins is considered the best way to combat the CDAD. Recently, a novel tetravalent C. difficile vaccine candidate containing all four toxins produced from a baculovirus expression system has been developed. A dose assay to release this tetravalent C. difficile vaccine was developed using tandem ion-exchange HPLC chromatography. A sequential weak cation exchange (carboxyl group) and weak anion exchange (tertiary amine group) columns were employed. The four C. difficile vaccine antigen pIs range from 4.4 to 8.6. The final optimized separation employs salt gradient elution at two different pHs. The standard analytical parameters such as LOD, LOQ, linearity, accuracy, precision and repeatability were evaluated for this method and it was deemed acceptable as a quantitative assay for vaccine release. Furthermore, the developed method was utilized for monitoring the stability of the tetravalent C. difficile vaccine in final container.", "Circularized oligonucleotides, or coligos, were previously found to serve as RNA polymerase III (Pol III) templates in vitro and in human tissue culture cells. Here we randomized the 12-nucleotide larger loop (L-loop) of a well characterized coligo and found unexpectedly that in vitro transcription by FLAG-Pol III was not significantly affected. This observation allowed us to test the variable of coligo L-loop size separately from the variable of its sequence. Transcription efficiency increased with L-loop size from 3 to 12 nucleotides of randomized sequence, and the smallest loop forced initiation to move into the stem region. To test further the need for any specific sequence we compared seven nucleotide L-loops composed of random, abasic and abasic-acyclic nucleotides, and all supported transcription by Pol III. Transcription of a series of coligos containing twelve contiguous randomized nucleotides placed at different locations within the coligo structure provided further evidence that the stem-loop junction structure is important for precise initiation. Nearly the same transcript pattern was formed in vitro by Pol III from yeast and human cells. Overall, these experiments support structure, rather than L-loop sequence, as the major determinant of coligo transcription initiation by Pol III.", "The rapid accumulation of whole-genome data has renewed interest in the study of genomic rearrangements. Comparative genomics, evolutionary biology, and cancer research all require models and algorithms to elucidate the mechanisms, history, and consequences of these rearrangements. However, even simple models lead to NP-hard problems, particularly in the area of phylogenetic analysis. Current approaches are limited to small collections of genomes and low-resolution data (typically a few hundred syntenic blocks). Moreover, whereas phylogenetic analyses from sequence data are deemed incomplete unless bootstrapping scores (a measure of confidence) are given for each tree edge, no equivalent to bootstrapping exists for rearrangement-based phylogenetic analysis. We describe a fast and accurate algorithm for rearrangement analysis that scales up, in both time and accuracy, to modern high-resolution genomic data. We also describe a novel approach to estimate the robustness of results-an equivalent to the bootstrapping analysis used in sequence-based phylogenetic reconstruction. We present the results of extensive testing on both simulated and real data showing that our algorithm returns very accurate results, while scaling linearly with the size of the genomes and cubically with their number. We also present extensive experimental results showing that our approach to robustness testing provides excellent estimates of confidence, which, moreover, can be tuned to trade off thresholds between false positives and false negatives. Together, these two novel approaches enable us to attack heretofore intractable problems, such as phylogenetic inference for high-resolution vertebrate genomes, as we demonstrate on a set of six vertebrate genomes with 8,380 syntenic blocks. A copy of the software is available on demand.", "Chemically synthesized DNA can carry small RNA sequence information but converting that information into small RNA is generally thought to require large double-stranded promoters in the context of plasmids, viruses and genes. We previously found evidence that circularized oligodeoxynucleotides (coligos) containing certain sequences and secondary structures can template the synthesis of small RNA by RNA polymerase III in vitro and in human cells. By using immunoprecipitated RNA polymerase III we now report corroborating evidence that this enzyme is the sole polymerase responsible for coligo transcription. The immobilized polymerase enabled experiments showing that coligo transcripts can be formed through transcription termination without subsequent 3' end trimming. To better define the determinants of productive transcription, a structure-activity relationship study was performed using over 20 new coligos. The results show that unpaired nucleotides in the coligo stem facilitate circumtranscription, but also that internal loops and bulges should be kept small to avoid secondary transcription initiation sites. A polymerase termination sequence embedded in the double-stranded region of a hairpin-encoding coligo stem can antagonize transcription. Using lessons learned from new and old coligos, we demonstrate how to convert poorly transcribed coligos into productive templates. Our findings support the possibility that coligos may prove useful as chemically synthesized vectors for the ectopic expression of small RNA in human cells.", "Brooke-Spiegler syndrome (BSS) is an autosomal dominant disease characterized by cylindromas, trichoepitheliomas and occasionally spiradenomas. The disease gene was mapped to 16q12-13, and mutations in the CYLD gene were identified in families with BSS. In the present report, we describe a large consanguineous Chinese family with BSS showing an intra-family phenotypic variability. Clinically, some affected individuals only revealed discrete small skin-coloured tumors whereas the proband showed an expansion of multiple large tumors on the back of nose and numerous dome-shaped papules on her scalp. Histologically, both trichoepitheliomas and cylindromas were found in the affected individuals. By sequence analysis, we identified a recurrent mutation 2272C>T (R758X) of the CYLD gene in the affected individuals of this family, which was previously identified in other ethnic families with familial cylindromatosis. Our result provided additional information for phenotype-genotype correlation in BSS.", "Cross-linking and immunoprecipitation (CLIP) is increasingly used to map transcriptome-wide binding sites of RNA-binding proteins. We developed a method for CLIP data analysis, and applied it to compare CLIP with photoactivatable ribonucleoside-enhanced CLIP (PAR-CLIP) and to uncover how differences in cross-linking and ribonuclease digestion affect the identified sites. We found only small differences in accuracies of these methods in identifying binding sites of HuR, which binds low-complexity sequences, and Argonaute 2, which has a complex binding specificity. We found that cross-link-induced mutations led to single-nucleotide resolution for both PAR-CLIP and CLIP. Our results confirm the expectation from original CLIP publications that RNA-binding proteins do not protect their binding sites sufficiently under the denaturing conditions used during the CLIP procedure, and we show that extensive digestion with sequence-specific RNases strongly biases the recovered binding sites. This bias can be substantially reduced by milder nuclease digestion conditions." ]

[ "Effects of thyroid gland hormones on cardiovascular system have been known for many years. Thyroid gland hormones deficiency is connected with a range of metabolic and hemodynamic changes which can contribute to a genesis of heart failure. Recent works refer to an importance of connection of thyroid gland hormones metabolism with heart insufficiency pathophysiology. That is especially a syndrome of a low trijodthyronin level marked as euthyroid sick syndrome which is significantly more frequent in patients with chronic heart failure compared to a population of healthy individuals. Recent clinical works proved that treatment administration of thyroid gland hormones to patients with heart failure is connected with favourable hemodynamic changes and increased working capacity if the treatment is well tolerated.", "Stress granules aid cell survival in response to environmental stressors by acting as sites of translational repression. We report an unanticipated link between stress granules and the serine/threonine kinase RSK2. In stressed breast cells, endogenous RSK2 colocalizes in granules with TIA-1 and poly(A)-binding protein 1, and the sequestration of RSK2 and TIA-1 exhibits codependency. The RSK2 N-terminal kinase domain controls the direct interaction with the prion-related domain of TIA-1. Silencing RSK2 decreases cell survival in response to stress. Mitogen releases RSK2 from the stress granules and permits its nuclear import via a nucleocytoplasmic shuttling sequence in the C-terminal domain. Nuclear accumulation is dependent on TIA-1. Surprisingly, nuclear localization of RSK2 is sufficient to enhance proliferation through induction of cyclin D1, in the absence of other active signaling pathways. Hence, RSK2 is a pivotal factor linking the stress response to survival and proliferation.", "OBJECTIVES: This study sought to evaluate the effect of macitentan on hospitalization of patients with symptomatic pulmonary arterial hypertension (PAH).BACKGROUND: PAH is a progressive, life-threatening disease often requiring hospitalization.METHODS: In the multicenter, double-blind, randomized, event-driven, phase III SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome) trial, patients with symptomatic PAH were randomized (1:1:1) to receive placebo or 3 mg or 10 mg of macitentan. Effects of macitentan on the risk, rate, and number of hospital days for all-cause and PAH-related hospitalizations were compared with those for placebo. Risk and causes of hospitalizations unrelated to PAH were investigated.RESULTS: Of 742 randomized patients, 250 received placebo, 250 received 3 mg of macitentan, and 242 received 10 mg of macitentan; the overall median duration of treatment was 115 weeks. Risk of all-cause hospitalization was reduced by 18.9% (p = 0.1208) and 32.3% (p = 0.0051) in the macitentan 3-mg and 10-mg arm, respectively. Rates of all-cause hospitalizations and numbers of hospital days were reduced by 20.5% (p = 0.0378) and 30.6% (p = 0.0278), respectively, with 3 mg of macitentan and by 33.1% (p = 0.0005) and 31.0% (p = 0.0336), respectively, with 10 mg of macitentan. Risk of PAH-related hospitalizations were reduced by 42.7% (p = 0.0015) and 51.6% (p < 0.0001) in the macitentan 3-mg and 10-mg arms, respectively. Rate of PAH-related hospitalizations and numbers of hospital days were reduced by 44.5% (p = 0.0004) and 53.3% (p = 0.0001), respectively, with 3 mg of macitentan, and reduced by 49.8% (p < 0.0001) and 52.3% (p = 0.0003), respectively, with 10 mg of macitentan. Risk of non-PAH-related hospitalization was similar between treatment arms.CONCLUSIONS: Macitentan 10 mg significantly reduced the risk and rate of all-cause hospitalization, which was driven by reductions in the risk and rate of PAH-related hospitalization. (Study of Macitentan [ACT-064992] on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension; NCT00660179).", "A substantial proportion of patients with type 2 diabetes mellitus do not reach glycemic targets, despite treatment with oral anti-diabetic drugs and basal insulin therapy. Several options exist for treatment intensification beyond basal insulin, and the treatment paradigm is complex. In this review, the options for treatment intensification will be explored, focusing on drug classes that act via the incretin system and paying particular attention to the short-acting glucagon-like peptide-1 receptor agonists exenatide and lixisenatide. Current treatment guidelines will be summarized and discussed. © 2016 The Authors. Diabetes/Metabolism Research and Reviews Published by John Wiley & Sons Ltd.", "Pentalogy of Fallot is a rare cyanotic congenital heart disease characterized by biventricular origin of the aorta above a large ventricular septal defect, obstruction of the pulmonary outflow, right ventricular hypertrophy (tetralogy of Fallot), and an atrial septal defect. Mortality due to syncope, arrhythmia or congestive heart failure is about 75% by the age of 10 years and 97% by the age of 40. We report a 69-year old female with uncorrected pentalogy of Fallot who suffered from recurrent syncope during classic cyanotic spells. Treatment with bisoprolol is recommended in symptomatic children and also improved symptoms in our patient. We conclude that single patients with pentalogy of Fallot reach the seventh decade and that cyanotic congenital heart disease is a rare cause of syncope in the elderly.", "BACKGROUND: Hemophilic pseudotumor (HPT) is a rare disease with many challenges. Only a few reports on surgical treatment for HPT have been published.METHODS: The cases of 23 patients with HPT who had surgical treatment from July 1996 to December 2014 were retrospectively reviewed. Demographic data, blood loss and transfusion during surgery, outcomes, and complications after surgery were analyzed.RESULTS: Eleven patients underwent HPT resection; 4 underwent HPT excision, allograft transplantation, and absorbable screw fixation; 3 had HPT resection and metallic internal fixation; 2 had HPT resection, autogenous fibular grafting, and absorbable screw fixation; 2 underwent curettage and bone-grafting; and 1 patient received above-the-knee amputation. The average age (and standard deviation) of the patients at the time of surgery was 31.9 ± 12.8 years (range, 6 to 54 years) with an average follow-up of 5.3 ± 4.7 years (range, 1.1 to 19.6 years). The median duration of the surgery was 157 minutes (range, 90 to 315 minutes). The median amount of blood loss during surgery was 800 mL (range, 100 to 4,000 mL). Three patients (13%) had a postoperative infection, 2 (8.7%) had recurrence of HPT, and another 2 patients had fracture nonunion.CONCLUSIONS: Surgical treatment of HPT with a modified protocol of coagulation factor replacement is safe and effective. It should be recommended for patients with HPT who have progressive enlargement of the mass, recurrent and massive bleeding, spontaneous perforation, bone erosion, or compression of surrounding tissues or who have had failure of conservative treatment.LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.", "Cyclic-AMP response element-binding protein (CREB) signaling has a critical role in the formation of memories. CREB signaling is dysfunctional in the brains of mouse models of Alzheimer's disease (AD), and evidence suggests that CREB signaling may be disrupted in human AD brains as well. Here, we show that both CREB and its activated form pCREB-Ser(133) (pCREB) are reduced in the prefrontal cortex of AD patients. Similarly, the transcription cofactors CREB-binding protein (CBP) and p300 are reduced in the prefrontal cortex of AD patients, indicating additional dysfunction of CREB signaling in AD. Importantly, we show that pCREB expression is reduced in peripheral blood mononuclear cells (PBMC) of AD subjects. In addition, pCREB levels in PBMC positively correlated with pCREB expression in the postmortem brain of persons with AD. These results suggest that pCREB expression in PBMC may be indicative of its expression in the brain, and thus offers the intriguing possibility of pCREB as a biomarker of cognitive function and disease progression in AD.", "The ability to adequately measure the phosphorylation state of a protein has major biological as well as clinical relevance. Due to its variable nature, reversible protein phosphorylations are sensitive to changes in the tissue environment. StabilizorTM T1 is a system for rapid inactivation of enzymatic activity in biological samples. Enzyme inactivation is accomplished using thermal denaturation in a rapid, homogeneous, and reproducible fashion without the need of added chemical inhibitors. Using pCREB(Ser133) as a model system, the applicability of the Stabilizor system to preserve a rapidly lost phosphorylation is shown." ]

[ "Growth differentiation factor 15 (GDF15), a distant member of the transforming growth factor (TGF)-β family, is a secreted protein that circulates as a 25-kDa dimer. In humans, elevated GDF15 correlates with weight loss, and the administration of GDF15 to mice with obesity reduces body weight, at least in part, by decreasing food intake. The mechanisms through which GDF15 reduces body weight remain poorly understood, because the cognate receptor for GDF15 is unknown. Here we show that recombinant GDF15 induces weight loss in mice fed a high-fat diet and in nonhuman primates with spontaneous obesity. Furthermore, we find that GDF15 binds with high affinity to GDNF family receptor α-like (GFRAL), a distant relative of receptors for a distinct class of the TGF-β superfamily ligands. Gfral is expressed in neurons of the area postrema and nucleus of the solitary tract in mice and humans, and genetic deletion of the receptor abrogates the ability of GDF15 to decrease food intake and body weight in mice. In addition, diet-induced obesity and insulin resistance are exacerbated in GFRAL-deficient mice, suggesting a homeostatic role for this receptor in metabolism. Finally, we demonstrate that GDF15-induced cell signaling requires the interaction of GFRAL with the coreceptor RET. Our data identify GFRAL as a new regulator of body weight and as the bona fide receptor mediating the metabolic effects of GDF15, enabling a more comprehensive assessment of GDF15 as a potential pharmacotherapy for the treatment of obesity.", "Aberrant DNA methylation of CpG islands, CpG island shores and first exons is known to play a key role in the altered gene expression patterns in all human cancers. To date, a systematic study on the effect of DNA methylation on gene expression using high resolution data has not been reported. In this study, we conducted an integrated analysis of MethylCap-sequencing data and Affymetrix gene expression microarray data for 30 breast cancer cell lines representing different breast tumor phenotypes. As well-developed methods for the integrated analysis do not currently exist, we created a series of four different analysis methods. On the computational side, our goal is to develop methylome data analysis protocols for the integrated analysis of DNA methylation and gene expression data on the genome scale. On the cancer biology side, we present comprehensive genome-wide methylome analysis results for differentially methylated regions and their potential effect on gene expression in 30 breast cancer cell lines representing three molecular phenotypes, luminal, basal A and basal B. Our integrated analysis demonstrates that methylation status of different genomic regions may play a key role in establishing transcriptional patterns in molecular subtypes of human breast cancer.", "Thyroid cancer is the most common cancer of the endocrine system and is responsible for the majority of deaths from endocrine malignancies. Although a large proportion of thyroid cancers belong to well differentiated histologic subtypes, which in general show a good prognosis after surgery and radioiodine ablation, the treatment of radio-resistant papillary-type, of undifferentiated anaplastic, and of medullary-type thyroid cancers remains unsatisfactory. Autophagy is a vesicular process for the lysosomal degradation of protein aggregates and of damaged or redundant organelles. Autophagy plays an important role in cell homeostasis, and there is evidence that this process is dysregulated in cancer cells. Recent in vitro preclinical studies have indicated that autophagy is involved in the cytotoxic response to chemotherapeutics in thyroid cancer cells. Indeed, several oncogenes and oncosuppressor genes implicated in thyroid carcinogenesis also play a role in the regulation of autophagy. In addition, some epigenetic modulators involved in thyroid carcinogenesis also influence autophagy. In this review, we highlight the genetic and epigenetic factors that mechanistically link thyroid carcinogenesis and autophagy, thus substantiating the rationale for an autophagy-targeted therapy of aggressive and radio-chemo-resistant thyroid cancers.", "The congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome (OMIM 604168) is a recently described autosomal recessive developmental disorder. It is almost completely restricted to an endogamous group of the European Vlax Roma population, called the Rudari. The CCFDN syndrome is a complex phenotype involving multiple systems, characterized by facial dysmorphism, congenital cataracts, microcorneae, delayed early motor and intellectual development, hypogonadotrop hypogonadism, hypomyelination of the peripheral nervous system, and serious complications related to general anaesthesia. This disorder is caused by a homozygous mutation of the carboxy-terminal domain phosphatase 1 (CTDP1) gene, localized to the 18q23 region. Authors present one genetically identified case in a large Roma family. The case documents that the CCFDN mutation is present also in the Hungarian Roma population. Underlie of antropomorphological data the authors presume that the CCFDN mutation reached Hungary as a result of emigration of Vlax Gypsies in the 18th century. The paper calls attention to the fact that molecular genetic diagnostics can replace invasive methods and makes possible the identification of heterozygotes without clinical symptoms. The introduction of the genetic screening enables us to perform genetic counselling and prevention in this high-risk population.", "In Escherichia coli and related bacteria, the very-short-patch (VSP) repair pathway uses an endonuclease, Vsr, to correct T-G mismatches that result from the deamination of 5-methylcytosines in DNA to C-G. The products of mutS and mutL, which are required for adenine methylation-directed mismatch repair (MMR), enhance VSP repair. Multicopy plasmids carrying mutS alleles that are dominant negative for MMR were tested for their effects on VSP repair. Some mutS mutations (class I) did not lower VSP repair in a mutS(+) background, and most class I mutations increased VSP repair in mutS cells more than plasmids containing mutS(+). Other plasmid-borne mutS mutations (class II) and mutS(+) decreased VSP repair in the mutS(+) background. Thus, MutS protein lacking functions required for MMR can still participate in VSP repair, and our results are consistent with a model in which MutS binds transiently to the mispair and then translocates away from the mispair to create a specialized structure that enhances the binding of Vsr.", "Clinical trials for new therapeutic strategies are now being planned for Duchenne and Becker muscular dystrophies (DMD/BMD); however, many challenges exist in the planning and conduction of a clinical trial for rare diseases. The epidemiological data, total number of patients, natural history, and clinical outcome measures are unclear. Adequate numbers of patients are needed to achieve significant results in clinical trials. As solutions to these problems, patient registries are an important infrastructure worldwide, especially in the case of rare diseases such as DMD/BMD. In Europe, TREAT-NMD, a clinical research network for neuromuscular disorders, developeda global database for dystrophinopathy patients. We developed a national registry of Japanese DMD/BMD patients in collaboration with TREAT-NMD. The database includes clinical and molecular genetic data as well as all required items for the TREAT-NMD global patient registry. As of July 2011, 750 patients were registered in the database. The purpose of this registry is the effective recruitment of eligible patients for clinical trials, and it may also provide timely information to individual patients about upcoming trials. This registry data also provides more detailed knowledge about natural history, epidemiology, and clinical care. In recent years, drug development has become dramatically globalized, and global clinical trials (GCTs) are being conducted in Japan. It is appropriate, particularly with regard to orphan diseases, to include Japanese patients in GCTs to increase evidence for evaluation, because such large-scale trials would be difficult to conduct solely within Japan. GCTs enable the synchronization of clinical drug development in Japan with that in Western countries, minimizing drug approval delays.", "The varied spectrum of presentation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is intriguing. Multisystem inflammatory syndrome in children (MIS-C) is a well described and documented condition that is associated with the active or recent COVID-19 infection. A similar presentation in adults is termed as Multisystem inflammatory syndrome in Adults (MIS-A). With only very limited cases reported from the west, MIS-A is considered a rare and serious complication of COVID-19. However, it is not as uncommon as we think. Many cases go undiagnosed for lack of COVID -19 like symptoms and unawareness among treating clinicians about this newer clinical entity. Further, antibody testing and inflammatory markers are not easily available in many of the Indian hospitals especially in rural India where the second wave had been intense, thereby making it difficult for the diagnosis of MIS-A. Also, there is no clear treatment guideline for MIS-A unlike MIS-C where the treatment protocol is well laid out. Awareness about MIS-A among treating clinicians can thus help in further evaluation and increased identification of the syndrome at the early stages thereby helping in the early institution of treatment. Our tertiary COVID care hospital in South India which has handled about 5200 cases of COVID-19 is been able to identify 04 cases of MIS-A proving that this clinical entity is not as rare as it is thought but lacks reporting and prompt identification. Here we describe 04 cases of MIS-A and strive to bring in the various aspects of it, including the clinical presentation, laboratory markers, diagnostic criteria and treatment considerations in this post second wave of the COVID-19 pandemic in India." ]

[ "Tanezumab, an antibody to nerve growth factor, was administered to pregnant cynomolgus monkeys at 0, 0.5, 4, and 30 mg/kg weekly, beginning gestation day (GD) 20 through parturition (∼GD165). Maternal tanezumab administration appeared to increase stillbirths and infant mortality, but no consistent pattern of gross and/or microscopic change was detected to explain the mortality. Offspring exposed in utero were evaluated at 12 months of age using light microscopy (all tissues), stereology (basal forebrain cholinergic and dorsal root ganglia neurons), and morphometry (sural nerve). Light microscopy revealed decreased number of neurons in sympathetic ganglia (superior mesenteric, cervicothoracic, and ganglia in the thoracic sympathetic trunk). Stereologic assessment indicated an overall decrease in dorsal root ganglion (thoracic) volume and number of neurons in animals exposed to tanezumab 4 mg/kg (n = 9) and 30 mg/kg (n = 1). At all tanezumab doses, the sural nerve was small due to decreases in myelinated and unmyelinated axons. Existing axons/myelin sheaths appeared normal when viewed with light and transmission electron microscopy. There was no indication of tanezumab-related, active neuron/nerve fiber degeneration/necrosis in any tissue, indicating decreased sensory/sympathetic neurons and axonal changes were due to hypoplasia or atrophy. These changes in the sensory and sympathetic portions of the peripheral nervous system suggest some degree of developmental neurotoxicity, although what effect, if any, the changes had on normal function and survival was not apparent. Overall, these changes were consistent with published data from rodent studies.", "OBJECTIVE: To explore the involvement of M-type potassium channels KCNQ2, Q3, and Q5 in the pathogenesis of common idiopathic epilepsies.METHODS: Sequence analysis of the KCNQ2, Q3, and Q5 coding regions was performed in a screening sample consisting of 58 nuclear families with rolandic epilepsy. Subsequently, an association study was conducted for all discovered variants in a case-control sample comprising 459 German patients with idiopathic generalized epilepsy (IGE) and 462 population controls.RESULTS: An in-frame deletion of codon 116 in KCNQ2 (p.Lys116del) and a missense mutation in KCNQ3 (p.Glu299Lys) were detected in two index cases exhibiting rolandic epilepsy and benign neonatal convulsions. Both mutations resulted in reduced potassium current amplitude in Xenopus oocytes. Mutation analysis of families with rolandic epilepsy without neonatal seizures discovered three novel missense variations (KCNQ2 p.Ile592Met, KCNQ3 p.Ala381Val, KCNQ3 p.Pro574Ser). The KCNQ2 p.Ile592Met variant displayed a significant reduction of potassium current amplitude in Xenopus oocytes and was present only once in 552 controls. Both missense variants identified in KCNQ3 (p.Ala381Val and p.Pro574Ser) were present in all affected family members and did not occur in controls, but did not show obvious functional abnormalities. The KCNQ3 missense variant p.Pro574Ser was also detected in 8 of 455 IGE patients but not in 454 controls (p = 0.008). In KCNQ2, a silent single nucleotide polymorphism (rs1801545) was found overrepresented in both epilepsy samples (IGE, p = 0.004).CONCLUSION: Sequence variations of the KCNQ2 and KCNQ3 genes may contribute to the etiology of common idiopathic epilepsy syndromes.", "Niemann-Pick type C1 (NPC) disease is an autosomal recessive neurodegenerative disorder. One feature of the mouse model of NPC1 is it's infertility. We have made transgenic mice which express the Npc1 protein exclusively in fibrillary astrocytes, using the glial fibrillary acidic protein (GFAP) promoter. This selective expression of Npc1 corrects sterility in GFAP-Npc1(-/-), Npc1(-/-) mice. Counts of acidophils in the pituitary of GFAP-Npc1E, Npc1(-/-) mice, as compared Npc1(-/-) mice, and measurements of dopamine D2 receptor (DRD2) mRNA in the pituitary, suggest mechanisms for fertility enhancement. We conclude that the correction of sterility in GFAP-Npc1E, Npc1(-/-) mice is a result of restoring hypothalamic control of the pituitary.", "We report on the function of the human ortholog of Saccharomyces cerevisiae Rif1 (Rap1-interacting factor 1). Yeast Rif1 associates with telomeres and regulates their length. In contrast, human Rif1 did not accumulate at functional telomeres, but localized to dysfunctional telomeres and to telomeric DNA clusters in ALT cells, a pattern of telomere association typical of DNA-damage-response factors. After induction of double-strand breaks (DSBs), Rif1 formed foci that colocalized with other DNA-damage-response factors. This response was strictly dependent on ATM (ataxia telangiectasia mutated) and 53BP1, but not affected by diminished function of ATR (ATM- and Rad3-related kinase), BRCA1, Chk2, Nbs1, and Mre11. Rif1 inhibition resulted in radiosensitivity and a defect in the intra-S-phase checkpoint. The S-phase checkpoint phenotype was independent of Nbs1 status, arguing that Rif1 and Nbs1 act in different pathways to inhibit DNA replication after DNA damage. These data reveal that human Rif1 contributes to the ATM-mediated protection against DNA damage and point to a remarkable difference in the primary function of this protein in yeast and mammals.", "Huntington's disease (HD) is an autosomal disease caused by a CAG repeat expansion in the huntingtin (HTT) gene. The resultant mutant HTT protein (mHTT) forms aggregates in various types of cells, including neurons and glial cells and preferentially affects brain function. We found that two HD mouse models (Hdh(150Q) and R6/2) were more susceptible than wild-type (WT) mice to lipopolysaccharide-evoked systemic inflammation and produced more proinflammatory cytokines in the brain. Such an enhanced inflammatory response in the brain was not observed in N171- 82Q mice that express mHTT only in neurons, but not in glial cells. Thus, HD glia might play an important role in chronic inflammation that accelerates disease progression in HD mice. Intriguingly, enhanced activation of nuclear factor (NF)-κB-p65 (p65), a transcriptional mediator of inflammatory responses, was observed in astrocytes of patients and mice with HD. Results obtained using primary R6/2 astrocytes suggest that these cells exhibited higher IκB kinase (IKK) activity that caused prolongation of NF-κB activation, thus upregulating proinflammatory factors during inflammation. R6/2 astrocytes also produced a more-damaging effect on primary R6/2 neurons than did WT astrocytes during inflammation. Blockage of IKK reduced the neuronal toxicity caused by R6/2 astrocytes and ameliorated several HD symptoms of R6/2 mice (e.g. decreased neuronal density, impaired motor coordination and poor cognitive function). Collectively, our results indicate that enhancement of the p65-mediated inflammatory response in astrocytes contributes to HD pathogenesis. Therapeutic interventions aimed at preventing neuronal inflammation may be an important strategy for treating HD.", "The \"hygiene hypothesis\" is a theory try to explain the dramatic increases in the prevalence of autoimmune and allergic diseases over the past two to three decades in developed countries. According to this theory, reduced exposure to parasites and microorganisms in childhood is the main cause for the increased incidences of both T helper 1 (Th1)-mediated autoimmunity and Th2-mediated allergy. In this study, we investigated the impact of Schistosoma japonicum infection on the allergic airway inflammation induced by repeated intracheal inoculations of house dust mites (HDM), which is a Th17 and neutrophils dominant murine asthma model, mimicking severe asthma. We found that S. japonicum infection downregulated airway hyperresponsiveness. The infiltrating cells, Th17 and Th2 effector cytokines in the bronchoalveolar lavage (BAL) fluids and lungs were significantly reduced in the infected mice. Our findings indicated that S. japonicum infection was able to effectively inhibit host's allergic airway inflammation, which may be related to the upregulated Treg cells upon infection. To our knowledge, it is the first study to reveal the impact of S. japonicum infection on house dust mite induced severe asthma. More in depth investigation is need to elucidate the underlying mechanisms.", "BACKGROUND & OBJECTIVE: Usually pituitary adenomas are histological benign and grow slowly, but a proportion of them will become locally aggressive, and develop into invasive pituitary adenomas. The reasons for these differences in tumor behavior are poorly understood. Pituitary adenomas are abounding blood vessels. Angiogenesis and tumor invasion both require degradation of the extracellular matrix components to allow cell migration. The matrix metalloproteinases (MMPs) and their nature inhibitors-the tissue inhibitors of metalloproteinases (TIMPs) may play a central role in these processes. The aggressive mechanism of pituitary adenomas was studied through investigating the expression of MMP-9, MMP-2, TIMP-1, and TIMP-2 in both invasive and non-invasive adenomas.METHODS: Sixty-one surgical removed pituitary adenomas (forty-nine cases invasive and twelve non-invasive adenomas) were investigated. Immunohistochemistry staining (SP method) was used to detect the expression of MMP-9, MMP-2, TIMP-1, and TIMP-2 in two groups. The results were treated with semi-quantitative method and analyzed by using non-parameter rank sum test.RESULTS: Immunohistochemical staining of tumor cells for MMP-9, TIMP-1, MMP-2, and TIMP-2 were noted 95.9% (47/49), 57.1% (28/49), 75.5% (37/49) and 89.8% (44/49) in invasive adenomas, and 100% (12/12), 91.7% (11/12), 66.7% (8/12), and 91.7% (11/12) in non-invasive adenomas, respectively. Invasive tumors were significantly less expressing TIMP-1 and TIMP-2 (P < 0.05). There was no significant difference for MMP-9 or MMP-2 between invasive and non-invasive groups (P > 0.05).CONCLUSIONS: TIMP-1 and TIMP-2 may play a key role in invasive pituitary adenomas to biological behavior.", "The role of RNA polymerase (Pol) III in eukaryotic transcription is commonly thought of as being restricted to a small set of highly expressed, housekeeping non-protein-coding (nc)RNA genes. Recent studies, however, have remarkably expanded the set of known Pol III-synthesized ncRNAs, suggesting that gene-specific Pol III regulation is more common than previously appreciated. Newly identified Pol III transcripts include small nucleolar RNAs, microRNAs, short interspersed nuclear element-encoded or tRNA-derived RNAs and novel classes of ncRNA that can display significant sequence complementarity to protein-coding genes and might thus regulate their expression. The extent of the Pol III transcriptome, the complexity of its regulation and its influence on cell physiology, development and disease are emerging as new areas for future research.", "RNA polymerase III (Pol III) transcribes small untranslated RNAs, such as tRNAs. To define the Pol III transcriptome in Saccharomyces cerevisiae, we performed genome-wide chromatin immunoprecipitation using subunits of Pol III, TFIIIB and TFIIIC. Virtually all of the predicted targets of Pol III, as well as several novel candidates, were occupied by Pol III machinery. Interestingly, TATA box-binding protein occupancy was greater at Pol III targets than virtually all Pol II targets, and the highly occupied Pol II targets are generally strongly transcribed. The temporal relationships between factor occupancy and gene activity were then investigated at selected targets. Nutrient deprivation rapidly reduced both Pol III transcription and Pol III occupancy of both a tRNA gene and RPR1. In contrast, TFIIIB remained bound, suggesting that TFIIIB release is not a critical aspect of the onset of repression. Remarkably, TFIIIC occupancy increased dramatically during repression. Nutrient addition generally reestablished transcription and initial occupancy levels. Our results are consistent with active Pol III displacing TFIIIC, and with inactivation/release of Pol III enabling TFIIIC to bind, marking targets for later activation. These studies reveal new aspects of the kinetics, dynamics, and targets of the Pol III system.", "RNA polymerase III (Pol III) transcribes a limited set of short genes in eukaryotes producing abundant small RNAs, mostly tRNA. The originally defined yeast Pol III transcriptome appears to be expanding owing to the application of new methods. Also, several factors required for assembly and nuclear import of Pol III complex have been identified recently. Models of Pol III based on cryo-electron microscopy reconstructions of distinct Pol III conformations reveal unique features distinguishing Pol III from other polymerases. Novel concepts concerning Pol III functioning involve recruitment of general Pol III-specific transcription factors and distinctive mechanisms of transcription initiation, elongation and termination. Despite the short length of Pol III transcription units, mapping of transcriptionally active Pol III with nucleotide resolution has revealed strikingly uneven polymerase distribution along all genes. This may be related, at least in part, to the transcription factors bound at the internal promoter regions. Pol III uses also a specific negative regulator, Maf1, which binds to polymerase under stress conditions; however, a subset of Pol III genes is not controlled by Maf1. Among other RNA polymerases, Pol III machinery represents unique features related to a short transcript length and high transcription efficiency.", "Balloon cells are histopathological hallmarks of various cortical malformations, i.e., focal cortical dysplasia (Taylor's type, FCD IIb), hemimegalencephaly (HME) or cortical tubers (tuberous sclerosis, TSC). Whether this intriguing cell type results from similar pathogenetic pathways remains to be shown. Here, we analyzed the immunohistochemical distribution pattern of the CD34 epitope in surgical specimens from 34 patients with FCD IIb, compared to that of 6 patients with TSC and 3 patients with HME. In normal brain, CD34 occurs only transiently during neurulation, but cannot be detected in mature neuroectodermal cell progenies. In contrast, 58% of our patients showed CD34 immunoreactivity within a subpopulation of balloon cells. Interestingly, CD34-positive balloon cells were confined to the white matter, but never observed in neocortical layers. Furthermore, balloon cells expressing neurofilament protein were also restricted to white matter, whereas GFAP-positive balloon cells were observed either in white or gray matter location. Clinical characteristics did not significantly differ between patients with CD34-positive versus CD34-negative lesions. No significant correlation was found between CD34 expression and genetic alterations of the TSC1 gene, which is affected in many FCD and TSC patients and which plays a role in the regulation of cell size. Further studies are warranted to clarify the restricted expression of CD34 in balloon cells of the white matter.", "Messenger RNAs (mRNAs) that contain premature translation termination codons (PTCs) are targeted for rapid degradation in all eukaryotes tested. The mechanisms of nonsense-mediated mRNA decay (NMD) have been described in considerable detail, but the biological roles of NMD in wild-type organisms are poorly understood. mRNAs of wild-type organisms known to be degraded by NMD (\"natural targets\" of NMD) include by-products of regulated alternative splicing, out-of-frame mRNAs derived from unproductive gene rearrangements, cytoplasmic pre-mRNAs, endogenous retroviral and transposon RNAs, and mRNAs having upstream open reading frames or other unusual sequence features. NMD may function to eliminate aberrant PTC-containing mRNAs in order to protect cells from expression of potentially deleterious truncated proteins. Pseudogenes are nonfunctional genes or gene fragments that accumulate mutations through genetic drift. Such mutations will often introduce shifts of reading frame and/or PTCs, and mRNAs of expressed pseudogenes may thus be substrates of NMD. We demonstrate that mRNAs expressed from C. elegans pseudogenes are degraded by NMD and discuss possible implications for both mRNA surveillance and protein evolution. We describe an expressed pseudogene that encodes a small nucleolar RNA (snoRNA) within an intron and suggest this represents an evolutionary intermediate between snoRNA-encoding host genes that do or do not encode proteins." ]

[ "Fanconi anemia is an autosomal recessive syndrome characterized by diverse clinical symptoms, hypersensitivity to DNA crosslinking agents, chromosomal instability and susceptibility to cancer. Fanconi anemia has at least 11 complementation groups (A, B, C, D1, D2, E, F, G, I, J, L); the genes mutated in 8 of these have been identified. The gene BRCA2 was suggested to underlie complementation group B, but the evidence is inconclusive. Here we show that the protein defective in individuals with Fanconi anemia belonging to complementation group B is an essential component of the nuclear protein 'core complex' responsible for monoubiquitination of FANCD2, a key event in the DNA-damage response pathway associated with Fanconi anemia and BRCA. Unexpectedly, the gene encoding this protein, FANCB, is localized at Xp22.31 and subject to X-chromosome inactivation. X-linked inheritance has important consequences for genetic counseling of families with Fanconi anemia belonging to complementation group B. Its presence as a single active copy and essentiality for a functional Fanconi anemia-BRCA pathway make FANCB a potentially vulnerable component of the cellular machinery that maintains genomic integrity.", "RNA editing, a post-transcriptional process, allows the diversification of proteomes beyond the genomic blueprint; however it is infrequently used among animals for this purpose. Recent reports suggesting increased levels of RNA editing in squids thus raise the question of the nature and effects of these events. We here show that RNA editing is particularly common in behaviorally sophisticated coleoid cephalopods, with tens of thousands of evolutionarily conserved sites. Editing is enriched in the nervous system, affecting molecules pertinent for excitability and neuronal morphology. The genomic sequence flanking editing sites is highly conserved, suggesting that the process confers a selective advantage. Due to the large number of sites, the surrounding conservation greatly reduces the number of mutations and genomic polymorphisms in protein-coding regions. This trade-off between genome evolution and transcriptome plasticity highlights the importance of RNA recoding as a strategy for diversifying proteins, particularly those associated with neural function. PAPERCLIP.", "Two inherited disorders of connective tissue have major cardiovascular complications, Marfan syndrome and Ehlers-Danlos syndrome type IV. Major progress has been made toward understanding both the genetic defect and the molecular pathogenesis of these two disorders. Marfan syndrome results from mutations in the FBN1 gene, which encodes fibrillin-1, an extracellular matrix component found in structures called microfibrils. Histologic characterization of the effect of FBN1 mutations on fibrillin-1 cellular processing and microfibril formation has provided insights into fibrillin-1 function. Ehlers-Danlos syndrome type IV results from mutations in the COL3A1 gene, which encodes the polypeptides in type III collagen. Despite advances in the molecular genetics of these two disorders, there is not a molecular diagnostic test for these syndromes based on the identification of gene mutations. Marfan syndrome remains primarily a clinical diagnosis. Biochemical analysis of the amount of type III collagen produced by dermal fibroblasts has proven to be a powerful diagnostic test for Ehlers-Danlos syndrome type IV.", "Genome editing using engineered nucleases such as transcription activator-like effector nucleases (TALENs) has become a powerful technology for reverse genetics. In this study, we have described efficient detection methods for TALEN-induced mutations at endogenous loci and presented guidelines of TALEN design for efficient targeted mutagenesis in medaka, Oryzias latipes. We performed a heteroduplex mobility assay (HMA) using an automated microchip electrophoresis system, which is a simple and high-throughput method for evaluation of in vivo activity of TALENs and for genotyping mutant fish of F1 or later generations. We found that a specific pattern of mutations is dominant for TALENs harboring several base pairs of homologous sequences in target sequence. Furthermore, we found that a 5' T, upstream of each TALEN-binding sequence, is not essential for genomic DNA cleavage. Our findings provide information that expands the potential of TALENs and other engineered nucleases as tools for targeted genome editing in a wide range of organisms, including medaka.", "In addition to RNA synthesis, multisubunit RNA polymerases (msRNAPs) support enzymatic reactions such as intrinsic transcript cleavage. msRNAP active sites from different species appear to exhibit differential intrinsic transcript cleavage efficiency and have likely evolved to allow fine-tuning of the transcription process. Here we show that a single amino-acid substitution in the trigger loop (TL) of Saccharomyces RNAP II, Rpb1 H1085Y, engenders a gain of intrinsic cleavage activity where the substituted tyrosine appears to participate in acid-base chemistry at alkaline pH for both intrinsic cleavage and nucleotidyl transfer. We extensively characterize this TL substitution for each of these reactions by examining the responses RNAP II enzymes to catalytic metals, altered pH, and factor inputs. We demonstrate that TFIIF stimulation of the first phosphodiester bond formation by RNAP II requires wild type TL function and that H1085Y substitution within the TL compromises or alters RNAP II responsiveness to both TFIIB and TFIIF. Finally, Mn(2+) stimulation of H1085Y RNAP II reveals possible allosteric effects of TFIIB on the active center and cooperation between TFIIB and TFIIF.", "BACKGROUND: There are virtually no controlled data suggesting that concomitant psychotropic medications (CPMs) improve outcome in schizophrenia after the acute phase. Despite that, polypharmacy (with all of its disadvantages) is far more common than monotherapy. To our knowledge, there have been no published reports of prospective systematic investigations of the efficacy of unrestricted CPM use in nonacute schizophrenia.METHOD: This was a naturalistic, systematic study using a sample of 53 stabilized patients with DSM-IV-TR schizophrenia from 1 clinical practice setting including both private patients and patients from controlled research studies of the effectiveness of antipsychotics. Since there are meager controlled or systematic data on the effectiveness of CPM use with antipsychotics in nonacute schizophrenia, we tested the clinical strategy of CPM use by gradually tapering all CPMs (except antianxiety agents). The aim was to determine if the CPM improved outcome, had no effect, or worsened outcome using the Clinical Global Impressions-Improvement scale before and after taper, over at least 3 months and in some cases up to 18 months after discontinuation. Data were gathered from July 2002 to June 2005.RESULTS: For 21 patients undergoing 22 antidepressant tapers, no change was noted in 18 of 22 tapers, while in 3 improvement was noted and in 1 worsening was noted. For the 12 patients on treatment with mood stabilizers, no change was noted in 10 of 13 discontinuations, while in 3 mild worsening was noted. One patient was on treatment with both modafinil and trazodone and reported no change after tapering each in separate discontinuation trials, while another 3 patients were taking sleeping medications and also noted no change after discontinuation.CONCLUSION: For most stabilized, chronic patients with schizophrenia, tapering adjunctive medications did not change outcome. This naturalistic study further defines the limits of efficacy of some concomitant classes of medications in patients with chronic schizophrenia who are already receiving adequate antipsychotic therapy.", "OBJECTIVE: Use of wearable ECG devices for arrhythmia screening is limited due to poor signal quality, small number of leads and short records, leading to incorrect recognition of pathological events. This paper introduces a novel approach to classification (normal/'N', atrial fibrillation/'A', other/'O', and noisy/'P') of short single-lead ECGs recorded by wearable devices.APPROACH: Various rhythm and morphology features are derived from the separate beats ('local' features) as well as the entire ECGs ('global' features) to represent short-term events and general trends respectively. Various types of atrial and ventricular activity, heart beats and, finally, ECG records are then recognised by a multi-level approach combining a support vector machine (SVM), decision tree and threshold-based rules.MAIN RESULTS: The proposed features are suitable for the recognition of 'A'. The method is robust due to the noise estimation involved. A combination of radial and linear SVMs ensures both high predictive performance and effective generalisation. Cost-sensitive learning, genetic algorithm feature selection and thresholding improve overall performance. The generalisation ability and reliability of this approach are high, as verified by cross-validation on a training set and by blind testing, with only a slight decrease of overall F1-measure, from 0.84 on training to 0.81 on the tested dataset. 'O' recognition seems to be the most difficult (test F1-measures: 0.90/'N', 0.81/'A' and 0.72/'O') due to high inter-patient variability and similarity with 'N'.SIGNIFICANCE: These study results contribute to multidisciplinary areas, focusing on creation of robust and reliable cardiac monitoring systems in order to improve diagnosis, reduce unnecessary time-consuming expert ECG scoring and, consequently, ensure timely and effective treatment.", "Austrian syndrome is a rare triad of endocarditis, meningitis, and pneumonia caused by Streptococcus pneumonia described by Robert Austrian in 1956. The incidence has reduced since the introduction of beta-lactam therapy in the early 1940s. Additionally, the introduction of the pneumococcal vaccination in 1977 further decreased the incidence of infection. Streptococcal endocarditis could potentially be very aggressive and life threatening despite appropriate therapy. It has a high mortality rate nearing 30 % even after proper antibiotics and surgical intervention. Therefore, an early recognition is crucial for early intervention and mortality reduction. We present a patient with Austrian syndrome who had a poor outcome despite proper management that is attributed to late presentation and delayed treatment.", "Atopic dermatitis is a common, chronic, immune-mediated disease associated with several comorbidities. Elevated levels of T helper (Th)2, Th22, and also some Th1 and Th17 cytokines are found in atopic dermatitis skin lesions. Similar to psoriasis, there is a tendency towards increased use of more targeted therapies. However, there are still several unmet needs in the treatment of atopic dermatitis concerning long-term efficacy, tolerability, safety, route of administration, and cost. The increased knowledge of atopic dermatitis pathogenesis and the role of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways has allowed the development of new compounds to inhibit this intracellular signaling pathway implicated in atopic dermatitis-related immune responses. Currently, JAK inhibitors are an important focus of therapeutic research for atopic dermatitis. Upadacitinib and abrocitinib are oral small molecules that inhibit the JAK/STAT pathway by selectively blocking JAK1. Data from phase II and III trials are encouraging, revealing that JAK1 inhibitors are effective and well-tolerated agents for moderate-to-severe atopic dermatitis. Selective JAK1 inhibitors may represent an important therapeutic option to be included in the treatment algorithm of atopic dermatitis, owing to oral administration and a favorable safety and tolerability profile. In this article, we review the current evidence on the efficacy and safety of oral selective JAK1 inhibitors for the treatment of atopic dermatitis.", "The response of cells to ionizing radiation-induced DNA double-strand breaks (DSB) is determined by the activation of multiple pathways aimed at repairing the injury and maintaining genomic integrity. Densely ionizing radiation induces complex damage consisting of different types of DNA lesions in close proximity that are difficult to repair and may promote carcinogenesis. Little is known about the dynamic behavior of repair proteins on complex lesions. In this study we use live-cell imaging for the spatio-temporal characterization of early protein interactions at damage sites of increasing complexity. Beamline microscopy was used to image living cells expressing fluorescently-tagged proteins during and immediately after charged particle irradiation to reveal protein accumulation at damaged sites in real time. Information on the mobility and binding rates of the recruited proteins was obtained from fluorescence recovery after photobleaching (FRAP). Recruitment of the DNA damage sensor protein NBS1 accelerates with increasing lesion density and saturates at very high damage levels. FRAP measurements revealed two different binding modalities of NBS1 to damage sites and a direct impact of lesion complexity on the binding. Faster recruitment with increasing lesion complexity was also observed for the mediator MDC1, but mobility was limited at very high damage densities due to nuclear-wide binding. We constructed a minimal computer model of the initial response to DSB based on known protein interactions only. By fitting all measured data using the same set of parameters, we can reproduce the experimentally characterized steps of the DNA damage response over a wide range of damage densities. The model suggests that the influence of increasing lesion density accelerating NBS1 recruitment is only dependent on the different binding modes of NBS1, directly to DSB and to the surrounding chromatin via MDC1. This elucidates an impact of damage clustering on repair without the need of invoking extra processing steps.", "Coleoid cephalopods (octopus, squid and cuttlefish) are active, resourceful predators with a rich behavioural repertoire. They have the largest nervous systems among the invertebrates and present other striking morphological innovations including camera-like eyes, prehensile arms, a highly derived early embryogenesis and a remarkably sophisticated adaptive colouration system. To investigate the molecular bases of cephalopod brain and body innovations, we sequenced the genome and multiple transcriptomes of the California two-spot octopus, Octopus bimaculoides. We found no evidence for hypothesized whole-genome duplications in the octopus lineage. The core developmental and neuronal gene repertoire of the octopus is broadly similar to that found across invertebrate bilaterians, except for massive expansions in two gene families previously thought to be uniquely enlarged in vertebrates: the protocadherins, which regulate neuronal development, and the C2H2 superfamily of zinc-finger transcription factors. Extensive messenger RNA editing generates transcript and protein diversity in genes involved in neural excitability, as previously described, as well as in genes participating in a broad range of other cellular functions. We identified hundreds of cephalopod-specific genes, many of which showed elevated expression levels in such specialized structures as the skin, the suckers and the nervous system. Finally, we found evidence for large-scale genomic rearrangements that are closely associated with transposable element expansions. Our analysis suggests that substantial expansion of a handful of gene families, along with extensive remodelling of genome linkage and repetitive content, played a critical role in the evolution of cephalopod morphological innovations, including their large and complex nervous systems.", "Genetic screens in the fruit fly Drosophila melanogaster have identified a class of neoplastic tumor suppressor genes (endocytic nTSGs), which encode proteins that localize to endosomes and facilitate the trafficking of membrane-bound receptors and adhesion molecules into the degradative lysosome. Loss of endocytic nTSGs transforms imaginal disc epithelia into highly proliferative, invasive tissues that fail to differentiate and display defects in cellular apicobasal polarity, adhesion and tissue architecture. As vertebrate homologs of some Drosophila nTSGs are linked to tumor formation, identifying molecular changes in signaling associated with nTSG loss could inform understanding of neoplastic transformation in vertebrates. Here we show that mutations in genes that act at multiple steps of the endolysosomal pathway lead to autonomous activation of the Sav/Wts/Hpo (SWH) transcriptional effector Yki (YAP/TAZ in vertebrates) and the Jun N-terminal kinase (JNK), which is known to promote Yki activity in cells with disrupted polarity. Yki and JNK activity are elevated by mutations at multiple steps in the endolysosomal pathway including mutations in the AP-2σ gene, which encodes a component of the AP-2 adaptor complex that recruits cargoes into clathrin-coated pits for subsequent internalization. Moreover, reduction of JNK activity can decrease elevated Yki-signaling caused by altered endocytosis. These studies reveal a broad requirement for components of the endocytic pathway in regulating SWH and JNK outputs, and place Drosophila endocytic nTSGs into a network that involving two major signaling pathways implicated in oncogenesis.", "Recently, deletions encompassing the nuclear receptor binding SET-Domain 1 (NSD1) gene have been described as the major cause of Japanese patients with the Sotos syndrome, whereas point mutations have been identified in the majority of European Sotos syndrome patients. In order to investigate a possible phenotype-genotype correlation and to further define the predictive value of NSD1 mutations, we performed mutational analysis of the NSD1 gene in 20 patients and one familial case with Sotos syndrome, five patients with Weaver syndrome, six patients with unclassified overgrowth/mental retardation, and six patients with macrocephaly/mental retardation. We were able to identify mutations within the NSD1 gene in 18 patients and the familial case with Sotos syndrome (90%). The mutations (six nonsense, eight frame shifts, three splice site, one missense, one in-frame deletion) are expected to result in an impairment of NSD1 function. The best correlation between clinical assessment and molecular results was obtained for the Sotos facial gestalt in conjunction with overgrowth, macrocephaly, and developmental delay. In contrast to the high mutation detection rate in Sotos syndrome, none of the patients with Weaver syndrome, unclassified overgrowth/mental retardation and macrocephaly/mental retardation, harbored NSD1 mutations. We tested for large deletions by FISH analysis but were not able to identify any deletion cases. The results indicate that the great majority of patients with Sotos syndrome are caused by mutations in NSD1. Deletions covering the NSD1 locus were not found in the patients analyzed here.", "BACKGROUND: Activating mutations in one allele of an oncogene (heterozygous mutations) are widely believed to be sufficient for tumorigenesis. However, mutant allele specific imbalance (MASI) has been observed in tumors and cell lines harboring mutations of oncogenes.METHODOLOGY/PRINCIPAL FINDINGS: We determined 1) mutational status, 2) copy number gains (CNGs) and 3) relative ratio between mutant and wild type alleles of KRAS, BRAF, PIK3CA and EGFR genes by direct sequencing and quantitative PCR assay in over 400 human tumors, cell lines, and xenografts of lung, colorectal, and pancreatic cancers. Examination of a public database indicated that homozygous mutations of five oncogenes were frequent (20%) in 833 cell lines of 12 tumor types. Our data indicated two major forms of MASI: 1) MASI with CNG, either complete or partial; and 2) MASI without CNG (uniparental disomy; UPD), due to complete loss of wild type allele. MASI was a frequent event in mutant EGFR (75%) and was due mainly to CNGs, while MASI, also frequent in mutant KRAS (58%), was mainly due to UPD. Mutant: wild type allelic ratios at the genomic level were precisely maintained after transcription. KRAS mutations or CNGs were significantly associated with increased ras GTPase activity, as measured by ELISA, and the two molecular changes were synergistic. Of 237 lung adenocarcinoma tumors, the small number with both KRAS mutation and CNG were associated with shortened survival.CONCLUSIONS: MASI is frequently present in mutant EGFR and KRAS tumor cells, and is associated with increased mutant allele transcription and gene activity. The frequent finding of mutations, CNGs and MASI occurring together in tumor cells indicates that these three genetic alterations, acting together, may have a greater role in the development or maintenance of the malignant phenotype than any individual alteration.", "PURPOSE OF REVIEW: New treatment options have been studied over the last several years, with a recent approval, a first for Behçet syndrome, in the United States. New management guidelines have also been published, helping with this nowadays more commonly recognized condition's management. The goal of this review is to summarize the most important and potentially clinically relevant recent developments and discuss their impact in the management of patients with Behçet syndrome.RECENT FINDINGS: Apremilast is now approved for the treatment of oral ulcer of Behçet syndrome in the United States. It's possible benefits in controlling nonoral ulcer features of the syndrome are awaited. Long-term use of tumor necrosis factor inhibitors for the treatment of especially eye disease in Behçet syndrome seems to be safe and efficacious. New treatment options such as ustekinumab, secukinumab, tocilizumab and others have early promising data but more studies are needed to better clarify their role in Behçet management.SUMMARY: The last 2 years have not only seen the approval of the first drug specifically labeled for the treatment of Behçet syndrome in the case of apremilast, many groups have also presented and published their findings on promising new therapeutic agents, which may soon be added to our tools in treating this condition. We also know more about other drugs, such as tumor necrosis factor inhibitors as many patients have been on these for long periods of time, and long-term follow-up data seem to confirm their role in Behçet treatment. Lack of placebo controlled, randomized trials, for the most part, are still outstanding issues.", "The spinal cord of two tetraodontiform fishes, the Japanese file fish (Navodon modestus) and the panther puffer (Takifugu pardalis), are unusual among vertebrates in having a markedly abbreviated spinal cord with a long and flattened filum terminale. Only the rostral short part of the cord of both species is cylindrical; the greater part of the cord is markedly flat. The majority of the spinal nerve roots leave the short cylindrical part. The flattened part of the cord contains the central canal, myelinated nerve fibers, and a few motoneurons surrounding the cauda equina, and it is histologically similar to the filum terminale of amphibians and mammals. The spinal cords of other teleosts, the sun-fish and angler, also are abbreviated and possess a filum terminale and cauda equina. These orders possess an enormous head and short trunk. However, the correlation between this body form and an abbreviated cord is not causal, since the tetraodontiform species described here show ordinary body proportions. The spinal cord may be abbreviated in tetraodontiform fishes in general.", "Collaborators: Stein JL, Medland SE, Arias Vasquez A, Hibar DP, Senstad RE, Winkler AM, Toro R, Appel K, Bartecek R, Bergmann Ø, Bernard M, Brown AA, Cannon DM, Chakravarty M, Christoforou A, Domin M, Grimm O, Hollinshead M, Holmes AJ, Homuth G, Hottenga JJ, Langan C, Lopez LM, Hansell NK, Hwang KS, Kim S, Laje G, Lee PH, Liu X, Loth E, Lourdusamy A, Maniega SM, Mattingsdal M, Mohnke S, Nho K, Nugent AC, O'Brien C, Papmeyer M, Pütz B, Ramasamy A, Rasmussen J, Rijpkema M, Risacher SL, Roddey JC, Rose EJ, Ryten M, Shen L, Sprooten E, Strengman E, Teumer A, Trabzuni D, Turner J, van Eijk K, van Erp TG, van Tol MJ, Wittfeld K, Wolf C, Woudstra S, Aleman A, Alhusaini S, Almasy L, Binder EB, Brohawn DG, Cantor RM, Carless MA, Corvin A, Czisch M, Curran JE, Davies G, de Almeida MA, Delanty N, Depondt C, Duggirala R, Dyer TD, Erk S, Fagerness J, Fox PT, Freimer NB, Gill M, Göring HH, Hagler DJ, Hoehn D, Holsboer F, Hoogman M, Hosten N, Jahanshad N, Johnson MP, Kasperaviciute D, Kent JW Jr, Kochunov P, Lancaster JL, Lawrie SM, Liewald DC, Mandl R, Matarin M, Mattheisen M, Meisenzahl E, Melle I, Moses EK, Mühleisen TW, Nauck M, Nöthen MM, Olvera RL, Pandolfo M, Pike GB, Puls R, Reinvang I, Rentería ME, Rietschel M, Roffman JL, Royle NA, Rujescu D, Savitz J, Schnack HG, Schnell K, Seiferth N, Smith C, Steen VM, Valdés Hernández MC, Van den Heuvel M, van der Wee NJ, Van Haren NE, Veltman JA, Völzke H, Walker R, Westlye LT, Whelan CD, Agartz I, Boomsma DI, Cavalleri GL, Dale AM, Djurovic S, Drevets WC, Hagoort P, Hall J, Heinz A, Jack CR Jr, Foroud TM, Le Hellard S, Macciardi F, Montgomery GW, Poline JB, Porteous DJ, Sisodiya SM, Starr JM, Sussmann J, Toga AW, Veltman DJ, Walter H, Weiner MW, Andreassen OA, Apostolova LG, Bastin ME, Blangero J, Brunner HG, Buckner RL, Cichon S, Coppola G, de Zubicaray GI, Deary IJ, Donohoe G, de Geus EJ, Espeseth T, Fernández G, Glahn DC, Grabe HJ, Hardy J, Hulshoff Pol HE, Jenkinson M, Kahn RS, McDonald C, McIntosh AM, McMahon FJ, McMahon KL, Meyer-Lindenberg A, Morris DW, Müller-Myhsok B, Nichols TE, Ophoff RA, Paus T, Pausova Z, Penninx BW, Potkin SG, Sämann PG, Saykin AJ, Schumann G, Smoller JW, Wardlaw JM, Weale ME, Martin NG, Franke B, Wright MJ, Thompson PM.", "RNA editing can yield protein products that differ from those directly encoded by genomic DNA. This process is pervasive in the mitochondria of many eukaryotes, where it predominantly results in the restoration of ancestral protein sequences. Nuclear mRNAs in metazoans also undergo editing (adenosine-to-inosine or 'A-to-I' substitutions), and most of these edits appear to be nonadaptive 'misfirings' of adenosine deaminases. However, recent analysis of cephalopod transcriptomes found that many editing sites are shared by anciently divergent lineages within this group, suggesting they play some adaptive role. Recent discoveries have also revealed that some fungi have an independently evolved A-to-I editing mechanism, resulting in extensive recoding of their nuclear mRNAs. Here, phylogenetic comparisons were used to determine whether RNA editing generally restores ancestral protein sequences or creates derived variants. Unlike in mitochondrial systems, RNA editing in metazoan and fungal nuclear transcripts overwhelmingly leads to novel sequences not found in inferred ancestral proteins. Even for the subset of RNA editing sites shared by deeply divergent cephalopod lineages, the primary effect of nuclear editing is an increase-not a decrease-in protein divergence. These findings suggest fundamental differences in the forces responsible for the evolution of RNA editing in nuclear versus mitochondrial systems.", "The adenosine-to-inosine (A-to-I) RNA editomes have been systematically characterized in various metazoan species, and many editing sites were found in clusters. However, it remains unclear whether the clustered editing sites tend to be linked in the same RNA molecules or not. By adopting a method originally designed to detect linkage disequilibrium of DNA mutations, we examined the editomes of ten metazoan species and detected extensive linkage of editing in Drosophila and cephalopods. The prevalent linkages of editing in these two clades, many of which are conserved between closely related species and might be associated with the adaptive proteomic recoding, are maintained by natural selection at the cost of genome evolution. Nevertheless, in worms and humans, we only detected modest proportions of linked editing events, the majority of which were not conserved. Furthermore, the linkage of editing in coding regions of worms and humans might be overall deleterious, which drives the evolution of DNA sites to escape promiscuous editing. Altogether, our results suggest that the linkage landscape of A-to-I editing has evolved during metazoan evolution. This present study also suggests that linkage of editing should be considered in elucidating the functional consequences of RNA editing.", "In the mutualistic relationship between the squid Euprymna tasmanica and the bioluminescent bacterium Vibrio fischeri, several host factors, including immune-related proteins, are known to interact and respond specifically and exclusively to the presence of the symbiont. In squid and octopus, the white body is considered to be an immune organ mainly due to the fact that blood cells, or hemocytes, are known to be present in high numbers and in different developmental stages. Hence, the white body has been described as the site of hematopoiesis in cephalopods. However, to our knowledge, there are no studies showing any molecular evidence of such functions. In this study, we performed a transcriptomic analysis of white body tissue of the Southern dumpling squid, E. tasmanica. Our primary goal was to gain insights into the functions of this tissue and to test for the presence of gene transcripts associated with hematopoietic and immune processes. Several hematopoiesis genes including CPSF1, GATA 2, TFIID, and FGFR2 were found to be expressed in the white body. In addition, transcripts associated with immune-related signal transduction pathways, such as the toll-like receptor/NF-κβ, and MAPK pathways were also found, as well as other immune genes previously identified in E. tasmanica's sister species, E. scolopes. This study is the first to analyze an immune organ within cephalopods, and to provide gene expression data supporting the white body as a hematopoietic tissue.", "Botulinum neurotoxins (BoNTs) are proteases that cleave specific cellular proteins essential for neurotransmitter release. Seven BoNT serotypes (A-G) exist; 4 usually cause human botulism (A, B, E, and F). We developed a rapid, mass spectrometry-based method (Endopep-MS) to detect and differentiate active BoNTs A, B, E, and F. This method uses the highly specific protease activity of the toxins with target peptides specific for each toxin serotype. The product peptides derived from the endopeptidase activities of BoNTs are detected by matrix-assisted laser-desorption ionization time-of-flight mass spectrometry. In buffer, this method can detect toxin equivalents of as little as 0.01 mouse lethal dose (MLD)50 and concentrations as low as 0.62 MLD50/mL. A high-performance liquid chromatography-tandem mass spectrometry method for quantifying active toxin, where the amount of toxin can be correlated to the amount of product peptides, is also described.", "Histone H3-lysine(9) (H3K9) trimethyltransferase gene Su(var) 3-9 was cloned and identified in three Spodoptera insects, Spodopterafrugiperda (S. frugiperda), S. exigua and S. litura. Sequence analysis showed that Spodoptera Su(var) 3-9 is highly conserved evolutionarily. Su(var) 3-9 protein was found to be localized in the nucleus in Sf9 cells, and interact with histone H3, and the heterochromatin protein 1a (HP1a) and HP1b. A dose-dependent enzymatic activity was found at both 27 °C and 37 °C in vitro, with higher activity at 27 °C. Addition of specific inhibitor chaetocin resulted in decreased histone methylation level and host chromatin relaxation. In contrast, overexpression of Su(var) 3-9 caused increased histone methylation level and cellular genome compaction. In AcMNV-infected Sf9 cells, the transcription of Su(var) 3-9 increased at late time of infection, although the mRNA levels of most cellular genes decreased. Pre-treatment of Sf9 cells with chaetocin speeded up viral DNA replication, and increased the transcription level of a variety of virus genes, whereas in Sf9 cells pre-transformed with Su(var) 3-9 expression vector, viral DNA replication slow down slightly. These findings suggest that Su(var) 3-9 might participate in the viral genes expression an genome replication repression during AcMNPV infection. It provided a new insight for the understanding virus-host interaction mechanism.", "Li-Fraumeni syndrome (LFS) is a highly penetrant, autosomal dominant, human familial cancer predisposition. Although a key role for the tumor suppressor p53 has been implicated in LFS, the genetic and cellular mechanisms underpinning this disease remain unknown. Therefore, modeling LFS in a vertebrate system that is accessible to both large-scale genetic screens and in vivo cell biological studies will facilitate the in vivo dissection of disease mechanisms, help identify candidate genes, and spur the discovery of therapeutic compounds. Here, we describe a forward genetic screen in zebrafish embryos that was used to identify LFS candidate genes, which yielded a p53 mutant (p53(I166T)) that as an adult develops tumors, predominantly sarcomas, with 100% penetrance. As in humans with LFS, tumors arise in heterozygotes and display loss of heterozygosity (LOH). This report of LOH indicates that Knudson's two-hit hypothesis, a hallmark of human autosomal dominant cancer syndromes, can be modeled in zebrafish. Furthermore, as with some LFS mutations, the zebrafish p53(I166T) allele is a loss-of-function allele with dominant-negative activity in vivo. Additionally, we demonstrate that the p53 regulatory pathway, including Mdm2 regulation, is evolutionarily conserved in zebrafish, providing a bona fide biological context in which to systematically uncover novel modifier genes and therapeutic agents for human LFS.", "Coleoid cephalopods like squids have a camera-type eye similar to vertebrates. On the other hand, Nautilus (Nautiloids) has a pinhole eye that lacks lens and cornea. Since pygmy squid and Nautilus are closely related species they are excellent model organisms to study eye evolution. Having being able to collect Nautilus embryos, we employed next-generation RNA sequencing using Nautilus and pygmy squid developing eyes. Their transcriptomes were compared and analyzed. Enrichment analysis of Gene Ontology revealed that contigs related to nucleic acid binding were largely up-regulated in squid, while the ones related to metabolic processes and extracellular matrix-related genes were up-regulated in Nautilus. These differences are most likely correlated with the complexity of tissue organization in these species. Moreover, when the analysis focused on the eye-related contigs several interesting patterns emerged. First, contigs from both species related to eye tissue differentiation and morphogenesis as well as to cilia showed best hits with their Human counterparts, while contigs related to rabdomeric photoreceptors showed the best hit with their Drosophila counterparts. This bolsters the idea that eye morphogenesis genes have been generally conserved in evolution, and compliments other studies showing that genes involved in photoreceptor differentiation clearly follow the diversification of invertebrate (rabdomeric) and vertebrate (ciliated) photoreceptors. Interestingly some contigs showed as good a hit with Drosophila and Human homologues in Nautilus and squid samples. One of them, capt/CAP1, is known to be preferentially expressed in Drosophila developing eye and in vertebrate lens. Importantly our analysis also provided evidence of gene duplication and diversification of their function in both species. One of these genes is the Neurofibromatosis 1 (NF1/Nf1), which in mice has been implicated in lens formation, suggesting a hitherto unsuspected role in the evolution of the lens in molluscs." ]

[ "Hodgkin's lymphoma is one of the curable cancers and the standard treatment regimen involves combination chemotherapy involving bleomycin. One of the fatal side effect of bleomycin is pulmonary toxicity. Here we present three cases of Hodgkin's lymphoma treated with ABVD chemotherapy who had pulmonary toxicity. All three developed bleomycin induced pulmonary toxicity in the form of pulmonary fibrosis during treatment of the disease. Mode of treatment, severity of the condition and the treatment outcome varied among the three. Two recovered following treatment and one patient died due to irreversible pulmonary damage. Causality assessment using Naranjo's scale gave a score of 7 for case one and three and a score of 6 for case two, both indicating the adverse drug reaction to be a probable bleomycin induced Lung fibrosis.", "BACKGROUND: Patisiran is an investigational RNA interference (RNAi) therapeutic in development for the treatment of hereditary ATTR (hATTR) amyloidosis, a progressive disease associated with significant disability, morbidity, and mortality.METHODS: Here we describe the rationale and design of the Phase 3 APOLLO study, a randomized, double-blind, placebo-controlled, global study to evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy. Eligible patients are 18-85 years old with hATTR amyloidosis, investigator-estimated survival of ≥2 years, Neuropathy Impairment Score (NIS) of 5-130, and polyneuropathy disability score ≤IIIb. Patients are randomized 2:1 to receive either intravenous patisiran 0.3 mg/kg or placebo once every 3 weeks. The primary objective is to determine the efficacy of patisiran at 18 months based on the difference in the change in modified NIS+7 (a composite measure of motor strength, sensation, reflexes, nerve conduction, and autonomic function) between the patisiran and placebo groups. Secondary objectives are to evaluate the effect of patisiran on Norfolk-Diabetic Neuropathy quality of life questionnaire score, nutritional status (as evaluated by modified body mass index), motor function (as measured by NIS-weakness and timed 10-m walk test), and autonomic symptoms (as measured by the Composite Autonomic Symptom Score-31 questionnaire). Exploratory objectives include assessment of cardiac function and pathologic evaluation to assess nerve fiber innervation and amyloid burden. Safety of patisiran will be assessed throughout the study.DISCUSSION: APOLLO represents the largest randomized, Phase 3 study to date in patients with hATTR amyloidosis, with endpoints that capture the multisystemic nature of this disease.TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov ( NCT01960348 ); October 9, 2013.", "BACKGROUND & AIMS: Regulatory assessments of drug risks do not routinely consider patient preferences, despite evidence that some patients are willing to accept increased side-effect risk in exchange for therapeutic benefits. The aim of this study is to estimate the willingness of Crohn's disease (CD) patients to accept life-threatening adverse event risks in exchange for CD symptom relief.METHODS: Patients with CD completed choice-format conjoint trade-off tasks involving hypothetical treatments with varying efficacy and risk levels. The treatment features included daily symptoms and activity limitations, serious complications (fistulas, abscesses, bowel obstructions), time between flare-ups, oral steroid use and risk of 3 serious adverse events (SAEs) known to be associated with CD treatment (progressive multifocal leukoencephalopathy (PML), serious infections, and lymphoma). The mean maximum acceptable annual risk (MAR) for each of the SAEs was calculated for various levels of clinical benefit.RESULTS: Daily symptom severity was the most important factor in treatment preferences. Higher MAR was observed for trade-off tasks involving higher levels of clinical benefit. The MAR was similar across the 3 SAEs. For improvements from severe daily symptoms to remission and from moderate daily symptoms to remission, the MARs ranged from 0.69% to 0.81% and from 0.39% to 0.55%, respectively.CONCLUSIONS: Patients with CD have well-defined preferences among treatment attributes and are willing to accept tradeoffs among attributes. The patients indicated they are willing to accept elevated SAE risks in exchange for clinical efficacy. The perspective of the patients on the benefit versus risk balance can assist in making treatment and regulatory decisions.", "There is a need for novel and effective prophylactic treatments and radioprotective materials to protect civilians and military personnel from ionizing radiation in contaminated environments. Melanin, a naturally occurring, ubiquitous pigment, has been shown to confer radioresistance, acting as a potential radioprotective agent. We have demonstrated that melanized Cryptococcus neoformans (CN) cells had improved survival post ionizing irradiation than non-melanized ones. The goal of this study was to identify morphological changes in melanized and non-melanized CN cells following irradiation with densely-ionizing deuterons and alpha particles relative to sparsely-ionizing gamma radiation. We observed significant differences between the melanized and non-melanized CN cellular ultrastructure following irradiation. Melanized CN cells were relatively resistant to mid and max-dose levels of alpha particles and deuterons irradiation. Following irradiation the capsule was stripped, but the cell wall was intact and structural integrity was maintained. At the maximum dose, cytoplasmic vacuolization, and mitochondrial swelling started to occur. In contrast, the non-melanized CN strain was sensitive to the mid-dose radiation. Non-melanized cells presented two morphologies: small condensed, and swollen, lacking structural integrity. This morphological investigation provides the first direct evidence of the radioprotective properties of melanin in CN cells subjected to high RBE and high LET ionizing radiation.", "The proximal tubule's sodium-glucose linked transporter-2 (SGLT2) accounts for the vast majority of glucose reabsorption by the kidney. Its selective inhibition, accordingly, leads to substantial glycosuria, lowering blood glucose, and facilitating weight loss in individuals with diabetes. During the past year, two SGLT2 inhibitors, canagliflozin and dapagliflozin, have been approved for the treatment of type 2 diabetes. Beyond their anti-hyperglycemic properties, however, this new class of drugs has several other attributes that provide a theoretical basis for kidney protection. Like agents that block the renin-angiotensin system, SGLT2 inhibitors also reduce single-nephron glomerular filtration rate (SNGFR) in the chronically diseased kidney, though by quite different mechanisms. Additional potentially beneficial effects of SGLT2 inhibition include modest reductions in blood pressure and plasma uric acid. Finally, cell culture studies indicate that glucose uptake from the tubular lumen, as well as from the basolateral compartment, can contribute to proximal tubular production of extracellular matrix proteins. Whether such attributes will translate into reducing the progression of chronic kidney disease will require the undertaking of long-term, dedicated studies.", "Pim-1 proto-oncogene, serine/threonine kinase (PIM-1) phosphorylates a series of substrates to exert its oncogenic function in numerous malignancies. The present study investigated the clinical significance of the PIM-1 protein, apoptosis status and apoptosis-associated proteins, including forkhead box O3a (FOXO3a), B cell lymphoma-2 (BCL-2) and BCL-2-associted agonist of cell death (BAD), were investigated in salivary gland adenoid cystic carcinoma (ACC) tissues. PIM-1 expression levels in 4 pairs of ACC tissues and corresponding normal salivary gland tissues were determined by western blot analysis. PIM-1, FOXO3a, BAD and BCL-2 expression levels in 60 ACC tissues were evaluated by immunohistochemistry (IHC). A terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling assay was performed to detect the apoptosis status of ACC tissues. PIM-1 was revealed to be highly expressed in ACC tissues compared with adjacent normal tissues. IHC staining results demonstrated high expression ratios of PIM-1, FOXO3a, BCL-2 and BAD [33.33% (20/60), 51.67% (31/60), 51.67% (31/60) and 55% (33/60)], respectively, and significant correlations between the expression of PIM-1 and FOXO3a and BCL-2 (P<0.05). Apoptotic rates were significantly associated with PIM-1, FOXO3a, BCL-2 and BAD expression levels (P<0.05). PIM-1 expression levels were significantly associated with tumor size, lymph node involvement, nerve invasion, distant metastasis and weakly associated with tumor node metastasis stage. Kaplan-Meier survival curves revealed that PIM-1 expression level was significantly associated with disease-free survival of patients with ACC (P=0.009). Cox regression multivariate analysis results revealed that histotype, distant metastasis and apoptotic rate were independent prognosis factors for ACC. Assessment of PIM-1 may be useful in investigating the malignant behaviors of ACC and predicting the outcome of patients with ACC.", "One of the more often used measures of multiple injuries is the injury severity score (ISS). Determination of the ISS is based on the abbreviated injury scale (AIS). This paper suggests a new algorithm to sort the AISs for each case and calculate ISS. The program uses unsorted abbreviated injury scale (AIS) levels for each case and rearranges them in descending order. The first three sorted AISs representing the three most severe injuries of a person are then used to calculate injury severity score (ISS). This algorithm should be useful for analyses of clusters of injuries especially when more patients have multiple injuries." ]

[ "Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative condition with a rapid disease course and a mortality rate of 100%. Several forms of the disease have been described, and the most common is the sporadic type. The most challenging aspect of this disease is its diagnosis-the gold standard for definitive diagnosis is considered to be histopathological confirmation-but newer tests are providing means for an antemortem diagnosis in ways less invasive than brain biopsy. Imaging studies, electroencephalography, and biomarkers are used in conjunction with the clinical picture to try to make the diagnosis of CJD without brain tissue samples, and all of these are reviewed in this article. The current diagnostic criteria are limited; test sensitivity and specificity varies with the genetics of the disease as well as the clinical stage. Physicians may be unsure of all diagnostic testing available, and may order outdated tests or prematurely request a brain biopsy when the diagnostic workup is incomplete. The authors review CJD, discuss the role of brain biopsy in this patient population, provide a diagnostic pathway for the patient presenting with rapidly progressive dementia, and propose newer diagnostic criteria.", "Wernicke's encephalopathy is an acute neurological syndrome due to thiamine deficiency, which is characterized by a typical triad of mental status changes, oculomotor dysfunction and ataxia. Despite the fact that Wernicke's encephalopathy, in developed countries, is frequently associated with chronic alcoholism, there have been a number of published cases associating this encephalopathy with parenteral feeding without vitamin supplementation. Diagnosis is primarily a clinical one, and can be supported by laboratory tests and imaging studies; treatment should start as soon as possible, for the morbidity and mortality (almost 20%) associated with this syndrome is high. Thiamine supplementation, along with other vitamins, is recommended for patients in risk of developing this syndrome.", "We have investigated a family in which three siblings with the autosomal dominant disorder tuberous sclerosis had unaffected parents. The family were typed for polymorphic markers spanning the two genes known to cause tuberous sclerosis located at 9q34 (TSC1) and 16p13.3 (TSC2). TSC1 markers showed different maternal and paternal haplotypes in affected children, excluding a mutation in TSC1 as the cause of the disease. For the TSC2 markers all the affected children had the same maternal and paternal haplotypes, as did three of their unaffected siblings. Mutation screening by RT-PCR and direct sequencing of the TSC2 gene identified a 4 bp insertion TACT following nucleotide 2077 in exon 18 which was present in the three affected children but not in five unaffected siblings or the parents. This mutation would cause a frameshift and premature termination at codon 703. Absence of the mutation in lymphocyte DNA from the parents was consistent with germline mosaicism and this was confirmed by our finding of identical chromosome 16 haplotypes in affected and unaffected siblings, providing unequivocal evidence of two different cell lines in the gametes. Molecular analysis of the TSC2 alleles present in the affected subjects showed that the mutation had been inherited from the mother. This is the first case of germline mosaicism in tuberous sclerosis proven by molecular genetic analysis and also the first example of female germline mosaicism for a characterized autosomal dominant gene mutation apparently not associated with somatic mosaicism.", "MOTIVATION: The vast majority of introns in protein-coding genes of higher eukaryotes have a GT dinucleotide at their 5'-terminus and an AG dinucleotide at their 3' end. About 1-2% of introns are non-canonical, with the most abundant subtype of non-canonical introns being characterized by GC and AG dinucleotides at their 5'- and 3'-termini, respectively. Most current gene prediction software, whether based on ab initio or spliced alignment approaches, does not include explicit models for non-canonical introns or may exclude their prediction altogether. With present amounts of genome and transcript data, it is now possible to apply statistical methodology to non-canonical splice site prediction. We pursued one such approach and describe the training and implementation of GC-donor splice site models for Arabidopsis and rice, with the goal of exploring whether specific modeling of non-canonical introns can enhance gene structure prediction accuracy.RESULTS: Our results indicate that the incorporation of non-canonical splice site models yields dramatic improvements in annotating genes containing GC-AG and AT-AC non-canonical introns. Comparison of models shows differences between monocot and dicot species, but also suggests GC intron-specific biases independent of taxonomic clade. We also present evidence that GC-AG introns occur preferentially in genes with atypically high exon counts.AVAILABILITY: Source code for the updated versions of GeneSeqer and SplicePredictor (distributed with the GeneSeqer code) isavailable at http://bioinformatics.iastate.edu/bioinformatics2go/gs/download.html. Web servers for Arabidopsis, rice and other plant species are accessible at http://www.plantgdb.org/PlantGDB-cgi/GeneSeqer/AtGDBgs.cgi, http://www.plantgdb.org/PlantGDB-cgi/GeneSeqer/OsGDBgs.cgi and http://www.plantgdb.org/PlantGDB-cgi/GeneSeqer/PlantGDBgs.cgi, respectively. A SplicePredictor web server is available at http://bioinformatics.iastate.edu/cgi-bin/sp.cgi. Software to generate training data and parameterizations for Bayesian splice site models is available at http://gremlin1.gdcb.iastate.edu/~volker/SB05B/BSSM4GSQ/", "Growth differentiation factor 15 (GDF15; also known as MIC-1) is a divergent member of the TGF-β superfamily and is associated with body-weight regulation in humans and rodents. However, the cognate receptor of GDF15 is unknown. Here we show that GDF15 binds specifically to GDNF family receptor α-like (GFRAL) with high affinity, and that GFRAL requires association with the coreceptor RET to elicit intracellular signaling in response to GDF15 stimulation. We also found that GDF15-mediated reductions in food intake and body weight of mice with obesity were abolished in GFRAL-knockout mice. We further found that GFRAL expression was limited to hindbrain neurons and not present in peripheral tissues, which suggests that GDF15-GFRAL-mediated regulation of food intake is by a central mechanism. Lastly, given that GDF15 did not increase energy expenditure in treated mice with obesity, the anti-obesity actions of the cytokine are likely driven primarily by a reduction in food intake.", "We genotyped 370 subjects with primary myelofibrosis (PMF) and 148 with postpolycythemia vera/postessential thrombocythemia (PPV/PET) MF for mutations of EZH2. Mutational status at diagnosis was correlated with hematologic parameters, clinical manifestations, and outcome. A total of 25 different EZH2 mutations were detected in 5.9% of PMF, 1.2% of PPV-MF, and 9.4% of PET-MF patients; most were exonic heterozygous missense changes. EZH2 mutation coexisted with JAK2V617F or ASXL1 mutation in 12 of 29 (41.4%) and 6 of 27 (22.2%) evaluated patients; TET2 and CBL mutations were found in 2 and 1 patients, respectively. EZH2-mutated PMF patients had significantly higher leukocyte counts, blast-cell counts, and larger spleens at diagnosis, and most of them (52.6%) were in the high-risk International Prognostic Score System (IPSS) category. After a median follow-up of 39 months, 128 patients (25.9%) died, 81 (63.3%) because of leukemia. Leukemia-free survival (LFS) and overall survival (OS) were significantly reduced in EZH2-mutated PMF patients (P = .028 and P < .001, respectively); no such impact was seen for PPV/PET-MF patients, possibly due to the low number of mutated cases. In multivariate analysis, survival of PMF patients was predicted by IPSS high-risk category, a < 25% JAK2V617F allele burden, and EZH2 mutation status. We conclude that EZH2 mutations are independently associated with shorter survival in patients with PMF.", "The activation of the extracellular signal-regulated kinases (ERKs) by tumour necrosis factor-alpha (TNF) receptors (TNFRs) is an integral part of the cytokine's pleiotropic cellular responses. Here we report differences in the caspase sensitivity and TNFR subtype activation of members of the ERK family. Inhibition in HeLa cells of caspase function by pharmacological inhibitors or the expression of CrmA (cytokine response modifier A), a viral modifier protein, blocks TNF-induced apoptosis or caspase-dependent protein kinase Cdelta and poly(ADP-ribose) polymerase protein degradation. TNFR1- or TNFR2-stimulated c-Jun N-terminal kinase (JNK) activity was attenuated in cells in which caspase activity was inhibited either by pharmacological blockers or CrmA expression. Both TNFR1- and TNFR2-stimulated JNK activity was caspase-sensitive; however, only TNFR1 was capable of stimulating p42/44 mitogen-activated protein kinase (MAPK) and p38 MAPK activities. TNFR1-stimulated p42/44 MAPK and p38 MAPK activities were insensitive to pharmacological caspase inhibition or CrmA. These findings were supported when measuring TNF-induced cytosolic phospholipase A(2) activation, which is a downstream target for MAPK and p38 MAPK. Profiling caspase enzymes activated by TNF in HeLa cells showed sequential caspase-8, -3, -7, -6 and -9 activation, with their inhibition characteristics suggesting a role for caspase-3 and/or caspase-6 in modulating JNK activity. Taken together these results show delineated ERK-activation pathways employed by TNFR subtypes." ]

[ "Oculocutaneous albinism type 1 (OCA1) is an autosomal recessive disease resulting from mutations of the tyrosinase gene (TYR). To elucidate the molecular basis of OCA1 phenotypes, we analysed the early processing and maturation of several different types of mutant tyrosinase with various degrees of structural abnormalities (i.e. two large deletion mutants, two missense mutants that completely destroy catalytic function and three missense mutants that have a temperature-sensitive phenotype). When expressed in COS7 cells, all mutant tyrosinases were sensitive to endoglycosidase H digestion, and immunostaining showed their localization in the endoplasmic reticulum (ER) and their failure to be sorted further to their target organelles. Pulse-chase experiments showed that all mutant tyrosinases were retained by calnexin in the ER and that they were degraded at similarly rapid rates, which coincided with their dissociation from calnexin. Temperature-sensitive mutant enzymes were sorted more efficiently at 31 degrees C than at 37 degrees C, and their degradation was accelerated at 37 degrees C compared with 31 degrees C. Thus in contrast to the current concept that mutant tyrosinases are transported to melanosomes but are functionally inactive there, our results suggest that mutant tyrosinases may not be transported to melanosomes in the first place. We conclude that a significant component of mutant tyrosinase malfunction in OCA1 results from their retention and degradation in the ER compartment. This quality-control process is highly sensitive to minimal changes in protein folding, and so even relatively minor mutations in peripheral sequences of the enzyme not involved with catalytic activity may result in a significant reduction of functional enzyme in melanosomes.", "Psoriatic arthritis (PsA) is a heterogeneous disease that can involve a variety of distinct anatomical sites including a patient's peripheral and axial joints, entheses, skin and nails. Appropriate management of PsA requires early diagnosis, monitoring of disease activity, and utilization of cutting edge therapies. To accomplish the former there are a variety of PsA-specific tools available to screen, diagnose, and assess patients. This review will outline the recently developed PsA screening tools, including the Toronto Psoriatic Arthritis Screening Questionnaire (TOPAS), the Psoriasis Epidemiology Screening Tool (PEST), the Psoriatic Arthritis Screening and Evaluation (PASE), and the Psoriasis and Arthritis Screening Questionnaire (PASQ). We will also review the Classification Criteria for Psoriatic Arthritis (CASPAR) and current PsA disease severity measures, such as the Disease Activity index for Psoriatic Arthritis (DAPSA), the Psoriatic Arthritis Joint Activity Index (PsAJAI) and the Composite Psoriatic Disease Activity Index (CPDAI). As is the case for PsA screening and assessment tools, there are also a variety of new therapies available for PsA. Historically, patients with PsA were treated with NSAIDS and traditional disease-modifying anti-rheumatic drugs (DMARDs). However, the ability of these medications to slow down the radiographic progression of joint disease has not been demonstrated. In contrast, anti-TNF agents, such as etanercept, infliximab, adalimumab, golimumab and certolizumab, are effective in this regard. Emerging PsA treatments include an oral phosphodiesterase 4 inhibitor, apremilast; a Janus kinase (JAK) inhibitor, tofacitinib; and several new biologics that target the IL-23/IL-17 pathway including secukinumab, brodalumab, ixekizumab, and ustekinumab. Herein we will review the mechanisms of action of these drugs, their results in clinical trials, and guidelines for administration. Lastly, treatment recommendations from the European League Against Rheumatism (EULAR) and The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) will be discussed.", "Arsenic is a clinically effective treatment for acute promyelocytic leukaemia (APL) in which the promyelocytic leukaemia (PML) protein is fused to retinoic receptor alpha (RARα). PML-RARα is degraded by the proteasome by a SUMO-dependent, ubiquitin-mediated pathway in response to arsenic treatment, curing the disease. Six major PML isoforms are expressed as a result of alternative splicing, each of which encodes a unique C-terminal region. Using a system in which only a single EYFP-linked PML isoform is expressed, we demonstrate that PMLI, PMLII and PMLVI accumulate in the cytoplasm following arsenic treatment, whereas PMLIII, PMLIV and PMLV do not. 3D structured illumination was used to obtain super-resolution images of PML bodies, revealing spherical shells of PML along with associated SUMO. Arsenic treatment results in dramatic isoform-specific changes to PML body ultrastructure. After extended arsenic treatment most PML isoforms are degraded, leaving SUMO at the core of the nuclear bodies. A high-content imaging assay identifies PMLV as the isoform most readily degraded following arsenic treatment, and PMLIV as relatively resistant to degradation. Immunoprecipitation analysis demonstrates that all PML isoforms are modified by SUMO and ubiquitin after arsenic treatment, and by using siRNA, we demonstrate that arsenic-induced degradation of all PML isoforms is dependent on the ubiquitin E3 ligase RNF4. Intriguingly, depletion of RNF4 results in marked accumulation of PMLV, suggesting that this isoform is an optimal substrate for RNF4. Thus the variable C-terminal domain influences the rate and location of degradation of PML isoforms following arsenic treatment.", "To maintain genomic integrity, DNA repair enzymes continually remove damaged bases and lesions resulting from endogenous and exogenous processes. These repair enzymes must distinguish damaged bases from normal bases to prevent the inadvertent removal of normal bases, which would promote genomic instability. The mechanisms by which this high level of specificity is accomplished are as yet unresolved. One member of the uracil-DNA glycosylase family of repair enzymes, Escherichia coli mismatch-specific uracil-DNA glycosylase (Mug), is reported to distinguish U:G mispairs from U:A base pairs based upon specific contacts with the mispaired guanine after flipping the target uracil out of the duplex. However, recent studies suggest other mechanisms for base selection, including local duplex stability. In this study, we used the modified base N6-methyladenine to probe the effect of local helix perturbation on Mug recognition of uracil. N6-Methyladenine is found in E. coli as part of both the mismatch repair and restriction-modification systems. In its cis isomer, N6-methyladenine destabilizes hydrogen bonding by interfering with pseudo-Watson-Crick base pairing. It is observed that the selection of uracil by Mug is sequence dependent and that uracil residues in sequences of reduced thermostability are preferentially removed. The replacement of adenine by N6-methyladenine increases the frequency of removal of the uracil residue paired opposite the modified adenine. These results are in accord with suggestions that local helix stability is an important determinant of base recognition by some DNA repair enzymes and provide a potential strategy for identifying the sequence location of modified bases in DNA.", "Both sarcolipin (SLN) and phospholamban (PLN) lower the apparent affinity of either SERCA1a or SERCA2a for Ca(2+). Since SLN and PLN are coexpressed in the heart, interactions among these three proteins were investigated. When SERCA1a or SERCA2a were coexpressed in HEK-293 cells with both SLN and PLN, superinhibition resulted. The ability of SLN to elevate the content of PLN monomers accounts, at least in part, for the superinhibitory effects of SLN in the presence of PLN. To evaluate the role of SLN in skeletal muscle, SLN cDNA was injected directly into rat soleus muscle and force characteristics were analyzed. Overexpression of SLN resulted in significant reductions in both twitch and tetanic peak force amplitude and maximal rates of contraction and relaxation and increased fatigability with repeated electrical stimulation. Ca(2+) uptake in muscle homogenates was impaired, suggesting that overexpression of SLN may reduce the sarcoplasmic reticulum Ca(2+) store. SLN and PLN appear to bind to the same regulatory site in SERCA. However, in a ternary complex, PLN occupies the regulatory site and SLN binds to the exposed side of PLN and to SERCA.", "The small nuclear structures known as ND10 or PML nuclear bodies have been implicated in a variety of cellular processes including response to stress and interferons, oncogenesis, and viral infection, but little is known about their biochemical properties. Recently, a ubiquitin-specific protease enzyme (named HAUSP) and a ubiquitin-homology family protein (PIC1) have been found associated with ND10. HAUSP binds strongly to Vmw110, a herpesvirus regulatory protein which has the ability to disrupt ND10, while PIC1 was identified as a protein which interacts with PML, the prototype ND10 protein. We have investigated the role of ubiquitin-related pathways in the mechanism of ND10 disruption by Vmw110 and the effect of virus infection on PML stability. The results show that the disruption of ND10 during virus infection correlates with the loss of several PML isoforms and this process is dependent on active proteasomes. The PML isoforms that are most sensitive to virus infection correspond closely to those which have recently been identified as being covalently conjugated to PIC1. In addition, a large number of PIC1-protein conjugates can be detected following transfection of a PIC1 expression plasmid, and many of these are also eliminated in a Vmw110-dependent manner during virus infection. These observations provide a biochemical mechanism to explain the observed effects of Vmw110 on ND10 and suggest a simple yet powerful mechanism by which Vmw110 might function during virus infection.", "In the last decade, SUMOylation has emerged as an essential post-translational modification in eukaryotes. In plants, the biological role of SUMO (small ubiquitin-related modifier) has been studied through genetic approaches that together with recent biochemical studies suggest that the plant SUMOylation system has a high degree of complexity. The present review summarizes our current knowledge on the SUMOylation system in Arabidopsis, focusing on the mechanistic properties of the machinery components identified.", "Amyloid β (Aβ) accumulation is considered the main culprit in the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that decreasing Aβ production at very early stages of AD could be a promising strategy to slow down disease progression. Serotonin 5-HT4 receptor activation stimulates α-cleavage of the amyloid precursor protein (APP), leading to the release of the soluble and neurotrophic sAPPα fragment and thus precluding Aβ formation. Using the 5XFAD mouse model of AD that shows accelerated Aβ deposition, we investigated the effect of chronic treatments (treatment onset at different ages and different durations) with the 5-HT4 receptor agonist RS 67333 during the asymptomatic phase of the disease. Chronic administration of RS 67333 decreased concomitantly the number of amyloid plaques and the level of Aβ species. Reduction of Aβ levels was accompanied by a striking decrease in hippocampal astrogliosis and microgliosis. RS 67333 also transiently increased sAPPα concentration in the cerebrospinal fluid and brain. Moreover, a specific 5-HT4 receptor antagonist (RS 39604) prevented the RS 67333-mediated reduction of the amyloid pathology. Finally, the novel object recognition test deficits of 5XFAD mice were reversed by chronic treatment with RS 67333. Collectively, these results strongly highlight this 5-HT4 receptor agonist as a promising disease modifying-agent for AD." ]

[ "Many outer membrane proteins (OMPs) in Gram-negative bacteria possess known beta-barrel three-dimensional (3D) structures. These proteins, including channel-forming transmembrane porins, are diverse in sequence but exhibit common structural features. We here report computational analyses of six outer membrane proteins of known 3D structures with respect to (1) secondary structure, (2) hydropathy, and (3) amphipathicity. Using these characteristics, as well as the presence of an N-terminal targeting sequence, a program was developed allowing prediction of integral membrane beta-barrel proteins encoded within any completely sequenced prokaryotic genome. This program, termed the beta-barrel finder (BBF) program, was used to analyze the proteins encoded within the Escherichia coli genome. Out of 4290 sequences examined, 118 (2.8%) were retrieved. Of these, almost all known outer membrane proteins with established beta-barrel structures as well as many probable outer membrane proteins were identified. This program should be useful for predicting the occurrence of outer membrane proteins in bacteria with completely sequenced genomes.", "On a model pair Aedes aegypti--Plasmodium gallinaceum in has been shown that changes in the conditions of larvae development caused by the addition into the water medium of the live culture of Synochocystis sp. cyanobacteria or green seaweeds Chlorella vulgaris, acetone extracts from the live culture precipitate or Chlorella powder, as well as nitrogen-containing fertilizer--ammonium chloride did not lower the sensitivity of the imago flying to malaria parasites. The results of the experiments assessing the effect of biologically active compounds introduced into the larvae habitation medium on the ability to change sensitivity of the survived mosquito females to malaria agent have been summed up. The data obtained are indicative of the high level of mutual adaptation between mosquito-carriers and malaria parasites.", "Ascomycetes develop four major types of fruiting bodies that share a common ancestor, and a set of common core genes most likely controls this process. One way to identify such genes is to search for conserved expression patterns. We analysed microarray data of Fusarium graminearum and Sordaria macrospora, identifying 78 genes with similar expression patterns during fruiting body development. One of these genes was asf1 (anti-silencing function 1), encoding a predicted histone chaperone. asf1 expression is also upregulated during development in the distantly related ascomycete Pyronema confluens. To test whether asf1 plays a role in fungal development, we generated an S. macrospora asf1 deletion mutant. The mutant is sterile and can be complemented to fertility by transformation with the wild-type asf1 and its P. confluens homologue. An ASF1-EGFP fusion protein localizes to the nucleus. By tandem-affinity purification/mass spectrometry as well as yeast two-hybrid analysis, we identified histones H3 and H4 as ASF1 interaction partners. Several developmental genes are dependent on asf1 for correct transcriptional expression. Deletion of the histone chaperone genes rtt106 and cac2 did not cause any developmental phenotypes. These data indicate that asf1 of S. macrospora encodes a conserved histone chaperone that is required for fruiting body development.", "OBJECTIVE: To examine the function of the novel mutation E82K in LMNA gene identified in a Chinese family infected by dilated cardiomyopathy.METHODS: (1) One Chinese family infected by dilated cardiomyopathy was chosen for the study. Exons 1-12 of the LMNA gene were screened with both PCR method and the cycle sequencing of the PCR products. (2) cDNA of the E82K mutation or wild type of LMNA gene was transfected into HEK293 cells and the apoptosis of the cells was detected after treatment with 0.8 mmol/L H2O2.RESULTS: (1) A new mutation E82K in LMNA gene was identified in this dilated cardiomyopathy family. (2) Apoptosis was more in the HEK293 cells transfected with E82K mutation than those with empty vector or wild type LMNA gene.CONCLUSIONS: The missense mutation E82K in LMNA gene changed the polar of the amino acid. It showed a malignant phenotype of severe clinical symptoms, early onset, poor survival prognosis and might be associated with atrioventricular conduction block (II degrees-III degrees), suggesting that the E82K mutation in LMNA gene may be a candidate for nosogenesis of dilated cardiomyopathy.", "BACKGROUND: We investigated the effect of corn-derived biodiesel glycerol on microRNAs (miRNAs) and mRNAs, which play a central role in regulating cell survival, apoptosis and carcinogenesis.MATERIALS AND METHODS: Inbred Balb/c mice were treated with purified glycerol from biodiesel for 24 hours. After administration, we determined the expressions of miR-21, miR-27a, miR-34a, miR-93, miR-143, miR-146a, miR-148a, miR-155, miR-196a, miR-203, miR-205, miR-221 and nuclear factor kappa-light-chain enhancer of activated B-cells-1 (Nfκb1), mitogen-activated protein kinase-8 (Mapk8) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-ras) genes in the liver of mice.RESULTS: We found a parallel altered expression of miRNAs and mRNAs in animals consuming biodiesel glycerol that compared to control mice; these alterations reached significant levels only in few cases.CONCLUSION: Biodiesel glycerol presents no higher risk for carcinogenicity or toxicity.", "To evaluate the use of general-purpose graphics processing units (GPGPUs) to improve the performance of MODFLOW, an unstructured preconditioned conjugate gradient (UPCG) solver has been developed. The UPCG solver uses a compressed sparse row storage scheme and includes Jacobi, zero fill-in incomplete, and modified-incomplete lower-upper (LU) factorization, and generalized least-squares polynomial preconditioners. The UPCG solver also includes options for sequential and parallel solution on the central processing unit (CPU) using OpenMP. For simulations utilizing the GPGPU, all basic linear algebra operations are performed on the GPGPU; memory copies between the central processing unit CPU and GPCPU occur prior to the first iteration of the UPCG solver and after satisfying head and flow criteria or exceeding a maximum number of iterations. The efficiency of the UPCG solver for GPGPU and CPU solutions is benchmarked using simulations of a synthetic, heterogeneous unconfined aquifer with tens of thousands to millions of active grid cells. Testing indicates GPGPU speedups on the order of 2 to 8, relative to the standard MODFLOW preconditioned conjugate gradient (PCG) solver, can be achieved when (1) memory copies between the CPU and GPGPU are optimized, (2) the percentage of time performing memory copies between the CPU and GPGPU is small relative to the calculation time, (3) high-performance GPGPU cards are utilized, and (4) CPU-GPGPU combinations are used to execute sequential operations that are difficult to parallelize. Furthermore, UPCG solver testing indicates GPGPU speedups exceed parallel CPU speedups achieved using OpenMP on multicore CPUs for preconditioners that can be easily parallelized.", "Many of the studies conducted to examine the developmental and reproductive toxicity potential of candidate pharmaceuticals use the Sprague-Dawley rat as the animal model. This is due in part to the large database for this outbred rat available for comparison of litter data, and the low incidence of fetal malformations and variations. The following study was conducted to generate information on potential embryo-fetal developmental defects and litter data in another outbred stock of rat, the Wistar Hannover. One hundred fifty pregnant female Wistar Hannover rats (Tac:Glx:WIfBR) were dosed orally once per day with distilled water from Gestation Days (GD) 6 through 17 covering the time from implantation to closure of the hard palate (GD0 = day of insemination). Caesarean sections were performed on Day 20 of gestation. All fetuses were examined for external, visceral and skeletal malformations and variations. Macroscopic and histomorphologic examinations were also completed for the F0 females at termination. The percent pregnant (88%) and litter size (average 10.6) were found to be lower than that commonly reported for the Sprague-Dawley rat (Crl:CD (SD)BR; 95.4% and 14.6, respectively). Pre-implantation loss (14.1%), post-implantation loss (7.4%) and percent resorptions (7.2%) occurred at a higher incidence than typically seen in the Sprague-Dawley rat (5.9, 5.6 and 5.1%, respectively). The average fetal body weights for both the female and male rats were lower than those typically seen in the Sprague-Dawley rat. External, visceral and skeletal examination of the F1 fetuses revealed numerous malformations and variations which also occurred at higher incidences than those reported for the Sprague-Dawley rat. Routine macroscopic and histomorphologic examination showed there were no changes that would be interpreted to have impaired mating performance, fertility or gestation. Thus, this study provides information on the reproductive effects and the background incidence of embryo-fetal development defects that could be used for comparison to those identified when using this outbred rat for developmental and reproductive toxicity studies, as well as for comparison to the more commonly used rat stock, the Sprague-Dawley rat. For the parameters evaluated, the Wistar Hannover rat had greater variability and an increased incidence of spontaneous malformations as compared to the Crl:CD (SD)BR Sprague-Dawley rat. These findings should be considered if this stock of rat is selected in the conduct of developmental and reproductive toxicity studies.", "DeQuervain tenosynovitis, which involves the abductor pollicis longus and extensor pollicis brevis tendons, is much more common in women than men and is due to repetitive movements of the hand such as grasping and twisting. Housewives and persons involved in manual occupations using the hands and wrists account for most cases in previous series. In this series, six of 24 female patients (25%) were pregnant or postpartum at the time of onset. In five of the six, activities of infant care aggravated symptoms. Both pregnancy, per se, and mechanical factors appear to play a role in causing this condition.", "BACKGROUND: Six known steps are required for the circulating thyroid hormone (TH) to exert its action on target tissues. For three of these steps, human mutations and distinct phenotypes have been identified.SCOPE OF REVIEW: The clinical, laboratory, genetic and molecular characteristics of these three defects of TH action are the subject of this review. The first defect, recognized 45years ago, produces resistance to TH and carries the acronym, RTH. In the majority of cases it is caused by TH receptor β gene mutations. It has been found in over 3000 individuals belonging to approximately 1000 families. Two relatively novel syndromes presenting reduced sensitivity to TH involve membrane transport and metabolism of TH. One of them, caused by mutations in the TH cell-membrane transporter MCT8, produces severe psychomotor defects. It has been identified in more than 170 males from 90 families. A defect of the intracellular metabolism of TH in 10 individuals from 8 families is caused by mutations in the SECISBP2 gene required for the synthesis of selenoproteins, including TH deiodinases.MAJOR CONCLUSIONS: Defects at different steps along the pathway leading to TH action at cellular level can manifest as reduced sensitivity to TH.GENERAL SIGNIFICANCE: Knowledge of the molecular mechanisms involved in TH action allows the recognition of the phenotypes caused by defects of TH action. Once previously known defects have been ruled out, new molecular defects could be sought, thus opening the avenue for novel insights in thyroid physiology. This article is part of a Special Issue entitled Thyroid hormone signaling.", "DeQuervain's tenosynovitis is a common cause of radial-sided wrist pain. Symptoms result from a narrow first dorsal compartment and associated tendinosis of the enclosed extensor pollicis brevis and/or abductor pollicis longus (APL). Surgical intervention, offered when conservative measures fail to adequately relieve symptoms, requires a detailed understanding of potentially aberrant anatomy in order to avoid persistence or recurrence of symptoms. We describe a case whereby the patient presented with complaints of thumb triggering in extension and associated disabling first dorsal compartment tendinosis. Intraoperatively, after supernumerary tendons were identified and addressed, the APL was at risk for subluxation over a prominent fibroosseous ridge. Routine first dorsal compartment release alone may have failed to address all of this patient's pathology.", "Recent trends in neurodegeneration research have been aimed at developing new amyloid ligands for the neuroimaging of dementia. Among the positron emission tomography (PET) radiotracers, fluorodeoxyglucose F 18 ((18)F-FDG) is the compound most widely used in the diagnosis of neurodegenerative dementias. However, this compound shows a level of specificity and sensitivity for early Alzheimer's disease detection that is lower than that provided by high-affinity ligands for β-amyloid (Aβ). Among the new widely available fluorine 18 ((18)F)-labeled Aβ ligands, florbetapir F 18 ((18))F-AV-45; Amyvid™) showed clear qualitative and quantitative correlations between in vivo PET imaging and postmortem histopathologic analysis of Aβ. Florbetapir F 18 stands out for its high Aβ affinity and its pharmacokinetic properties that allow 10-minute PET scan imaging within 90 minutes after administration (dose = 370 MBq). Importantly, no safety concerns for florbetapir F 18 were found in preclinical studies. In 2012, the U.S. Food and Drug Administration (FDA) approved Amyvid as a radiotracer helpful for excluding the presence of Aβ in the brain. It was then approved earlier this year by the European Medicines Agency (EMA).", "DeQuervain's disease of the first dorsal compartment of the wrist, is a common wrist pathology, pain results from resisted gliding of the abductor pollicis longus and the extensor pollicis brevis tendon in the fibroosseous canal. Management of resistant cases of DeQuervain's disease with failed conservative treatment treated by surgical decompression yield satisfactory outcomes. A large number of patients being dissatisfied with the medical treatment, still present with persistent pain and positive clinical finding. Surgical decompression is an effective method for the treatment of resistant cases of DeQuervain's disease. Outcome variables were measured by Scheller, Forget and Macey evaluation criteria. Most of our patients were female 28(93.3%), housewife 17(56.7%) with mean age of 41.57 years, ranging from 25-60 years. Right sided involvement was 20(66.7%) and Left sided involvement was 10(33.3%). Restricted movement of thumb in 30(100%) were the predominant symptoms. One (3.3%) patient develop chronic tenosynovitis, 1(3.3%) patient develop hypertrophic scar. There was no wound infection in the follow-up period of 3-18 months. Satisfactory results were found in 29(96.7%)." ]

[ "BACKGROUND: The overall analysis of the rivaroxaban versus warfarin in Japanese patients with atrial fibrillation (J-ROCKET AF) trial revealed that rivaroxaban was not inferior to warfarin with respect to the primary safety outcome. In addition, there was a strong trend for a reduction in the rate of stroke/systemic embolism with rivaroxaban compared with warfarin.METHODS: In this subanalysis of the J-ROCKET AF trial, we investigated the consistency of safety and efficacy profile of rivaroxaban versus warfarin among the subgroups of patients with previous stroke, transient ischemic attack, or non-central nervous system systemic embolism (secondary prevention group) and those without (primary prevention group).RESULTS: Patients in the secondary prevention group were 63.6% of the overall population of J-ROCKET AF. In the secondary prevention group, the rate of the principal safety outcome (% per year) was 17.02 in rivaroxaban-treated patients and 18.26 in warfarin-treated patients (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.70-1.29), while the rate of the primary efficacy endpoint was 1.66 in rivaroxaban-treated patients and 3.25 in warfarin-treated patients (HR 0.51; 95% CI 0.23-1.14). There were no significant interactions in the principal safety and the primary efficacy endpoints of rivaroxaban compared to warfarin between the primary and secondary prevention groups (P=.090 and .776 for both interactions, respectively).CONCLUSIONS: The safety and efficacy profile of rivaroxaban compared with warfarin was consistent among patients in the primary prevention group and those in the secondary prevention group.", "The Japanese Committee for the National Registry of Subacute Sclerosing Panencephalitis (SSPE) confirmed that 215 cases of SSPE occurred in the 20 years from 1966 to 1985, as discovered in the 10-year surveillance from April 1976 through March 1986. The annual incidence in recent years has been between 10 and 23 cases. Among cases with a certain history of measles illness or measles vaccination, 184 (90.2%) had a history of measles illness without receiving measles vaccine. There were 11 probable measles vaccine-associated cases (5.4%), three (1.5%) being vaccinated with a combined use of killed and live vaccine and eight (3.9%) with further attenuated live vaccine. There were nine cases (4.4%) without a history of either measles illness or measles vaccination. Intervals between measles illness and the onset of SSPE varied from 1 to 16 years (mean, 7.0 years). The periods following measles vaccination with further attenuated live vaccine were 2 to 11 years (mean, 4.6 years). Annual incidence rates of SSPE per million cases of measles ranged between 6.1 and 40.9 (mean, 16.1) in the 10 measles epidemic years 1968-1977, and those following vaccination with further attenuated live vaccine were zero in most years and at the highest 3.08 (mean, 0.9) per million doses of distributed vaccine.", "Profilin is a conserved actin-monomer-binding protein which is found in all eukaryotes, including yeast. Although amino acid sequence analysis and RNase protection analysis suggest a single profilin isoform in mammalian cells, Southern blot analysis of human and somatic cell hybrid DNA indicates several loci in the human genome which hybridize with the profilin cDNA. We therefore isolated human genomic clones to analyze these genetic loci in detail. Only one of the cloned loci has typical features of a functional gene, including upstream transcriptional elements and typical exon-intron structure. Four other isolated loci are all diverged, intronless pseudogenes and are likely to be nonfunctional. The functional gene was localized to human chromosome band 17p13 by analysis of somatic cell hybrids and by in situ chromosomal localization. The Miller-Dieker syndrome (MDS), a rare congenital disorder manifested by characteristic facial abnormalities and lissencephaly (smooth brain), is associated with microdeletions of the distal 17p region. RFLP analysis of a patient with MDS, and analysis of somatic cell hybrids containing partially deleted chromosomes 17 from patients with MDS, using the profilin gene probe, indicate that profilin is localized to chromosome subband 17p13.3. These results also indicate that profilin is the first identified cloned gene which is part of the genetic material deleted in some patients with MDS but that other patients have smaller deletions not affecting the profilin locus. Thus, single allelic deletion of the profilin locus may contribute to the clinical phenotype of the MDS in some patients but does not play a major role in the essential phenotype.", "Enhancers have been defined operationally as cis-regulatory sequences that can stimulate transcription of RNA polymerase-II-transcribed genes over large distances and even when located downstream of the gene. Recently, it has become evident that enhancers can also stimulate transcription in trans if they are brought into close proximity to the promoter/gene. These reports provide clues to the mechanism of remote enhancer action. In addition, the findings, together with genetic studies in Drosophila, strongly suggest that enhancer action in trans could underlie phenomena such as 'transvection', where one chromosome affects gene expression in the paired homolog.", "RNA interference has tremendous yet unrealized potential to treat a wide range of illnesses. Innovative solutions are needed to protect and selectively deliver small interfering RNA (siRNA) cargo to and within a target cell to fully exploit siRNA as a therapeutic tool in vivo. Herein, we describe ammonium-functionalized carbon nanotube (fCNT)-mediated transport of siRNA selectively and with high efficiency to renal proximal tubule cells in animal models of acute kidney injury (AKI). fCNT enhanced siRNA delivery to tubule cells compared to siRNA alone and effectively knocked down the expression of several target genes, includingTrp53,Mep1b,Ctr1, andEGFP A clinically relevant cisplatin-induced murine model of AKI was used to evaluate the therapeutic potential of fCNT-targeted siRNA to effectively halt the pathogenesis of renal injury. Prophylactic treatment with a combination of fCNT/siMep1band fCNT/siTrp53significantly improved progression-free survival compared to controls via a mechanism that required concurrent reduction of meprin-1β and p53 expression. The fCNT/siRNA was well tolerated, and no toxicological consequences were observed in murine models. Toward clinical application of this platform, fCNTs were evaluated for the first time in nonhuman primates. The rapid and kidney-specific pharmacokinetic profile of fCNT in primates was comparable to what was observed in mice and suggests that this approach is amenable for use in humans. The nanocarbon-mediated delivery of siRNA provides a therapeutic means for the prevention of AKI to safely overcome the persistent barrier of nephrotoxicity during medical intervention.", "Orexin A and B, orexigenic peptides produced primarily by the lateral hypothalamus that signal through two G protein-coupled receptors, orexin receptors 1/2, have been implicated in the regulation of several physiological processes in mammals. In avian (nonmammalian vertebrates) species; however, the physiological roles of orexin are not well defined. Here, we provide novel evidence that not only is orexin and its related receptors 1/2 (ORXR1/2) expressed in chicken muscle tissue and quail muscle (QM7) cell line, orexin appears to be a secretory protein in QM7 cells. In vitro administration of recombinant orexin A and B (rORX-A and B) differentially regulated prepro-orexin expression in a dose-dependent manner with up-regulation for rORX-A (P < 0.05) and downregulation for rORX-B (P < 0.05) in QM7 cells. While both peptides upregulated ORXR1 expression, only a high dose of rORX-B decreased the expression of ORXR2 (P < 0.05). The presence of orexin and its related receptors and the regulation of its own system in avian muscle cells indicate that orexin may have autocrine, paracrine, and/or endocrine roles. rORXs differentially regulated mitochondrial dynamics network. While rORX-A significantly induced the expression of mitochondrial fission-related genes (DNM1, MTFP1, MTFR1), rORX-B increased the expression of mitofusin 2, OPA1, and OMA1 genes that are involved in mitochondrial fusion. Concomitant with these changes, rORXs differentially regulated the expression of several mitochondrial metabolic genes (av-UCP, av-ANT, Ski, and NRF-1) and their related transcriptional regulators (PPARγ, PPARα, PGC-1α, PGC-1β, and FoxO-1) without affecting ATP synthesis. Taken together, our data represent the first evidence of the presence and secretion of orexin system in the muscle of nonmammalian species and its role in mitochondrial fusion and fission, probably through mitochondrial-related genes and their related transcription factors.", "DNA replication depends critically upon chromatin structure. Little is known about how the replication complex overcomes the nucleosome packages in chromatin during DNA replication. To address this question, we investigate factors that interact in vivo with the principal initiation DNA polymerase, DNA polymerase alpha (Polalpha). The catalytic subunit of budding yeast Polalpha (Pol1p) has been shown to associate in vitro with the Spt16p-Pob3p complex, a component of the nucleosome reorganization system required for both replication and transcription, and with a sister chromatid cohesion factor, Ctf4p. Here, we show that an N-terminal region of Polalpha (Pol1p) that is evolutionarily conserved among different species interacts with Spt16p-Pob3p and Ctf4p in vivo. A mutation in a glycine residue in this N-terminal region of POL1 compromises the ability of Pol1p to associate with Spt16p and alters the temporal ordered association of Ctf4p with Pol1p. The compromised association between the chromatin-reorganizing factor Spt16p and the initiating DNA polymerase Pol1p delays the Pol1p assembling onto and disassembling from the late-replicating origins and causes a slowdown of S-phase progression. Our results thus suggest that a coordinated temporal and spatial interplay between the conserved N-terminal region of the Polalpha protein and factors that are involved in reorganization of nucleosomes and promoting establishment of sister chromatin cohesion is required to facilitate S-phase progression." ]

[ "As the most common subtype of Leber congenital amaurosis (LCA), LCA10 is a severe retinal dystrophy caused by mutations in the CEP290 gene. The most frequent mutation found in patients with LCA10 is a deep intronic mutation in CEP290 that generates a cryptic splice donor site. The large size of the CEP290 gene prevents its use in adeno-associated virus (AAV)-mediated gene augmentation therapy. Here, we show that targeted genomic deletion using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system represents a promising therapeutic approach for the treatment of patients with LCA10 bearing the CEP290 splice mutation. We generated a cellular model of LCA10 by introducing the CEP290 splice mutation into 293FT cells and we showed that guide RNA pairs coupled with SpCas9 were highly efficient at removing the intronic splice mutation and restoring the expression of wild-type CEP290. In addition, we demonstrated that a dual AAV system could effectively delete an intronic fragment of the Cep290 gene in the mouse retina. To minimize the immune response to prolonged expression of SpCas9, we developed a self-limiting CRISPR/Cas9 system that minimizes the duration of SpCas9 expression. These results support further studies to determine the therapeutic potential of CRISPR/Cas9-based strategies for the treatment of patients with LCA10.", "Rho GTPases play central roles in a wide variety of cellular processes, including cytoskeletal dynamics, cell adhesion and cell polarity. RhoU and RhoV are Rho GTPases that have some atypical properties compared with classical Rho family members, such as the presence of N- and C-terminal extension regions, unusual GDP/GTP cycling and post-translational modification by palmitoylation but not prenylation. Their activity and localization is regulated by the N-terminal and C-terminal regions, and so far no GEFs or GAPs have been identified for them. Similar to Rac and Cdc42, they interact with PAK serine/threonine kinases, and in the case of PAK4, this interaction leads to RhoU protein stabilization. In cells, RhoU and RhoV alter cell shape and cell adhesion, which probably underlies some of the phenotypes reported for these proteins in vivo, for example in heart development and epithelial morphogenesis. However, the molecular basis for these functions of RhoU and RhoV remains to be characterized.", "The unipolar brush cell (UBC) is a novel type of small neuron that is characterized by sets of morphological and chemical phenotypes. UBCs occur in the granular layer of the mammalian cerebellar cortex, particularly in folia of the vestibulocerebellum, and in the granule cell domains of the dorsal cochlear nucleus. The UBC is characterized by a single dendrite that terminates with a brush-like tip of dendrioles. The soma, the dendritic stem, and especially the dendrioles emit short, non-synaptic appendages. The dendrioles represent the main synaptic apparatus of the UBC and articulate tightly with a single mossy fiber rosette forming a glomerular array characterized by an extraordinarily extensive synaptic contact. Electron microscopic and electrophysiological observations indicate that the unusual synaptic ultrastructure may produce entrapment of neurotransmitter in the synaptic cleft. While ionotropic glutamate receptors are enriched in correspondence of the postsynaptic density, metabotropic glutamate receptors are situated extrasynaptically and are particularly enriched at the appendages, which usually do not bear synaptic junctions. Some of the UBCs receive their input from choline acetyltransferase-positive mossy rosettes originating from the vestibular nuclei, suggesting that ACh and glutamate are co-released at these synapses. The UBC brush occupies a glomerulus where granule cell dendrites are intermixed with the UBC dendrioles, both of which receive synapses from the same mossy fiber rosette and portions of the Golgi axonal plexus. In addition, the dendrioles are presynaptic to granule cell dendrites, forming dendrodendritic contacts that display features of excitatory synapses. Branches of the UBC axon in the granular layer bear large endings resembling mossy fibers. The UBCs may represent an extraordinary device for feedforward, excitatory links along the mossy fiber pathways of cerebellum and dorsal cochlear nucleus.", "IMPORTANCE: The US Preventive Services Task Force recently recommended the use of aspirin to prevent colorectal cancer and cardiovascular disease among many US adults. However, the association of aspirin use with the risk for other cancer types and the potential population-wide effect of aspirin use on cancer, particularly within the context of screening, remain uncertain.OBJECTIVES: To examine the potential benefits of aspirin use for overall and subtype-specific cancer prevention at a range of doses and durations of use and to estimate the absolute benefit of aspirin in the context of screening.DESIGN, SETTING, AND PARTICIPANTS: Two large US prospective cohort studies, the Nurses' Health Study (1980-2010) and Health Professionals Follow-up Study (1986-2012), followed up 135 965 health care professionals (88 084 women and 47 881 men, respectively) who reported on aspirin use biennially. The women were aged 30 to 55 years at enrollment in 1976; the men, aged 40 to 75 years in 1986. Final follow-up was completed on June 30, 2012, for the Nurses' Health Study cohort and January 31, 2010, for the Health Professionals Follow-up Study cohort, and data were accessed from September 15, 2014, to December 17, 2015.MAIN OUTCOMES AND MEASURES: Relative risks (RRs) for incident cancers and population-attributable risk (PAR).RESULTS: Among the 88 084 women and 47 881 men who underwent follow-up for as long as 32 years, 20 414 cancers among women and 7571 cancers among men were documented. Compared with nonregular use, regular aspirin use was associated with a lower risk for overall cancer (RR, 0.97; 95% CI, 0.94-0.99), which was primarily owing to a lower incidence of gastrointestinal tract cancers (RR, 0.85; 95% CI, 0.80-0.91), especially colorectal cancers (RR, 0.81; 95% CI, 0.75-0.88). The benefit of aspirin on gastrointestinal tract cancers appeared evident with the use of at least 0.5 to 1.5 standard aspirin tablets per week; the minimum duration of regular use associated with a lower risk was 6 years. Among individuals older than 50 years, regular aspirin use could prevent 33 colorectal cancers per 100 000 person-years (PAR, 17.0%) among those who had not undergone a lower endoscopy and 18 colorectal cancers per 100 000 person-years (PAR, 8.5%) among those who had. Regular aspirin use was not associated with the risk for breast, advanced prostate, or lung cancer.CONCLUSIONS AND RELEVANCE: Long-term aspirin use was associated with a modest but significantly reduced risk for overall cancer, especially gastrointestinal tract tumors. Regular aspirin use may prevent a substantial proportion of colorectal cancers and complement the benefits of screening.", "BACKGROUND: Depression after acute coronary syndromes (ACS) is an important risk factor for further coronary events; but the influence of anhedonia, the decreased capacity to experience pleasure, has received little attention. The aim of the study was to investigate the effects of anhedonia on prognosis at 3-year follow-up in patients hospitalized for ACS.METHOD: Consecutively admitted ACS patients (n = 291) completed the Chapman Physical Anhedonia Scale (PAS) and the Hospital Anxiety and Depression Scale depression subscale (HAD-D) at baseline (1-4 days after their admission). Two definitions of anhedonia were taken into account: dimensional definition using PAS score as well as categorical definition using several cutoff scores (hedonics: PAS less than 23 or 29; anhedonics: PAS equal to or greater than 23 or 29). Patients were followed during 3 years for adverse clinical events divided into severe cardiac events (mortality or myocardial infarction [MI]) and clinical events (mortality, MI, recurrence of ACS, hospital readmission, and onset or deterioration of heart failure).RESULTS: At follow-up, there were 176 clinical events (36 deaths, 8 MIs, 58 ACS, 55 hospital readmissions, 19 heart failures). Dimensional anhedonia and depression were associated with poor prognosis, but anhedonia was the only predictor of severe cardiac events and clinical events after adjusting for demographic and clinical variables. Contrary to depression, categorical anhedonia (PAS >23) was an independent and significant predictor of severe cardiac events after adjusting for clinical variables. The incidence of death/MI in hedonics vs anhedonics was 11.1% vs 22.1% (hazard ratio = 2.18; 95% confidence interval, 1.11-4.26).CONCLUSIONS: Dimensional and categorical anhedonias predicted independently severe cardiac events and clinical events after ACS.", "Despite having caused one of the greatest medical catastrophies of the last century through its teratogenic side-effects, thalidomide continues to be an important agent in the treatment of leprosy and cancer. The protein cereblon, which forms an E3 ubiquitin ligase compex together with damaged DNA-binding protein 1 (DDB1) and cullin 4A, has been recently indentified as a primary target of thalidomide and its C-terminal part as responsible for binding thalidomide within a domain carrying several invariant cysteine and tryptophan residues. This domain, which we name CULT (cereblon domain of unknown activity, binding cellular ligands and thalidomide), is also found in a family of secreted proteins from animals and in a family of bacterial proteins occurring primarily in δ-proteobacteria. Its nearest relatives are yippee, a highly conserved eukaryotic protein of unknown function, and Mis18, a protein involved in the priming of centromeres for recruitment of CENP-A. Searches for distant homologs point to an evolutionary relationship of CULT, yippee, and Mis18 to proteins sharing a common fold, which consists of two four-stranded β-meanders packing at a roughly right angle and coordinating a zinc ion at their apex. A β-hairpin inserted into the first β-meander extends across the bottom of the structure towards the C-terminal edge of the second β-meander, with which it forms a cradle-shaped binding site that is topologically conserved in all members of this fold. We name this the β-tent fold for the striking arrangement of its constituent β-sheets. The fold has internal pseudosymmetry, raising the possibility that it arose by duplication of a subdomain-sized fragment.", "BACKGROUND: Little is known concerning the degree to which initiation of sildenafil for pulmonary arterial hypertension (PAH) impacts patterns of healthcare utilization and costs.METHODS: Using a large US health insurance claims database, we identified all patients with evidence of PAH (ICD-9-CM diagnosis codes 416.0, 416.8) who received sildenafil between 1/1/2005 and 9/30/2008. Date of the first-noted prescription for sildenafil was designated the \"index date,\" and claims data were compiled for all study subjects for 6 months prior to their index date (\"pretreatment\") and 6 months thereafter (\"follow-up\"); patients with incomplete data during either of these periods were excluded. Healthcare utilization and costs were then compared between pretreatment and follow-up for all study subjects.RESULTS: A total of 567 PAH patients were identified who began therapy with sildenafil and met all other study entry criteria. Mean (SD) age was 52 (10) years; 73% were women. Healthcare utilization was largely unchanged between pretreatment and follow-up, the only exceptions being decreases in the mean number of emergency department visits (from 0.7 to 0.5 per patient; p<0.01) and the percentage of patients hospitalized (from 35% to 29%; p=0.01). The mean cost of all PAH-related medication was $7139 during pretreatment and $14,095 during follow-up (sildenafil cost during follow-up= $5236); exclusive of PAH-related medications, however, total healthcare costs decreased modestly (from $30,104 to $27,605) (p<0.01 for all comparisons).CONCLUSIONS: The cost of sildenafil therapy may be partially offset by reductions in other healthcare costs." ]

[ "Growth factor independent 1 (Gfi1) is a transcriptional repressor originally identified as a gene activated in T-cell leukemias induced by Moloney-murine-leukemia virus infection. Notch1 is a transmembrane receptor that is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL). Gfi1 is an important factor in the initiation and maintenance of lymphoid leukemias and its deficiency significantly impedes Notch dependent initiation of T-ALL in animal models. Here, we show that immature hematopoietic cells require Gfi1 to competently integrate Notch-activated signaling. Notch1 activation coupled with Gfi1 deficiency early in T-lineage specification leads to a dramatic loss of T-cells, whereas activation in later stages leaves development unaffected. In Gfi1 deficient multipotent precursors, Notch activation induces lethality and is cell autonomous. Further, without Gfi1, multipotent progenitors do not maintain Notch1-activated global expression profiles typical for T-lineage precursors. In agreement with this, we find that both lymphoid-primed multipotent progenitors (LMPP) and early T lineage progenitors (ETP) do not properly form or function in Gfi1(-/-) mice. These defects correlate with an inability of Gfi1(-/-) progenitors to activate lymphoid genes, including IL7R, Rag1, Flt3 and Notch1. Our data indicate that Gfi1 is required for hematopoietic precursors to withstand Notch1 activation and to maintain Notch1 dependent transcriptional programming to determine early T-lymphoid lineage identity.", "Technological advances in DNA sequencing have made gene testing fast and more affordable. Evidence of effectiveness and cost-effectiveness of genetic service models is essential for the successful translation of sequencing improvements for patient benefit, but remain sparse in the genetics literature. In particular, there is a lack of detailed cost data related to genetic services. A detailed micro-costing of 28 possible pathways relating to breast and/or ovarian cancer and BRCA testing was carried out by defining service activities and establishing associated costs. These data were combined with patient-level data from a Royal Marsden Cancer Genetics Service audit over a 6-month period during which BRCA testing was offered to individuals at ≥10 % risk of having a mutation, in line with current NICE guidance. The average cost across all patient pathways was £2227.39 (range £376.51 to £13,553.10). The average cost per pathway for an affected person was £1897.75 compared to £2410.53 for an unaffected person. Of the women seen in the Cancer Genetics Service during the audit, 38 % were affected with breast and/or ovarian cancer, and 62 % were unaffected but concerned about their family history. The most efficient service strategy is to identify unaffected relatives from an affected individual with an identified BRCA mutation. Implementation of this strategy would require more comprehensive testing of all eligible cancer patients, which could be achieved by integrating BRCA testing into oncology services. Such integration would be also more time-efficient and deliver greater equity of access to BRCA testing than the standard service model.", "BACKGROUND: Armodafinil (Nuvigil(®), Cephalon, Inc., Frazer, PA, USA), the longer-lasting isomer of racemic modafinil, is a nonamphetamine, wakefulness-promoting medication. In patients with excessive sleepiness associated with shift work disorder, treated obstructive sleep apnoea, or narcolepsy, armodafinil has been found to improve wakefulness throughout the shift or day. In addition, while not approved for this indication, armodafinil has been found to improve excessive sleepiness associated with jet-lag disorder.OBJECTIVE: This study evaluated systemic exposure to armodafinil and its two major circulating metabolites, R-modafinil acid and modafinil sulfone, and assessed the tolerability profile of armodafinil in elderly and young subjects.METHODS: The pharmacokinetics and tolerability of armodafinil were assessed in an open-label, multiple-dose, parallel-group study in two groups (n = 25 in each group) of healthy men (elderly group aged ≥65 years and young group aged 18-45 years) who received armodafinil 50 mg on day 1, 100 mg on day 2 and 150 mg once daily on days 3 through 7. Plasma concentrations of armodafinil and its metabolites were quantified over 72 hours following the last dose on day 7. Pharmacokinetic parameters, including area under the plasma drug concentration-versus-time curve during a dosing interval (AUC(τ)) and maximum observed plasma drug concentration (C(max)), and tolerability were assessed.RESULTS: All 50 subjects enrolled in the study were evaluable for tolerability and 49 were included in the pharmacokinetic analysis. One elderly subject was excluded from the pharmacokinetic analyses because of apparent noncompliance with armodafinil dosing. Systemic exposure following administration of armodafinil, as measured by steady-state AUC(τ) and C(max) values, was approximately 15% greater in elderly subjects compared with young subjects. Geometric mean ratios for AUC(τ) and C(max) in the two groups were 1.14 (95% CI 1.03, 1.25; p = 0.0086) and 1.15 (95% CI 1.08, 1.24; p = 0.0002), respectively. When data were analysed for elderly subgroups, systemic exposure in the old-elderly group (age ≥75 years; n = 7) was 27% greater than in young subjects, as compared with 10% greater in the young-elderly group (age 65-74 years; n = 17). Although steady-state exposure to the metabolite R-modafinil acid was also higher in elderly than in young subjects (geometric mean ratios for AUC(τ) and C(max) were 1.73 and 1.61, respectively; p < 0.0001), there were no significant differences in systemic exposure to modafinil sulfone. Armodafinil was generally well tolerated by both groups. Headache (four subjects in each group), nausea (one in the elderly group and four in the young group), insomnia (two in the elderly group and one in the young group), and dizziness (two in the young group) were the most common adverse events.CONCLUSIONS: Systemic exposure following administration of armodafinil is increased in the elderly in comparison with younger subjects, particularly in those aged ≥75 years. Although the increase in plasma armodafinil concentration in elderly subjects does not appear to result in more adverse events compared with young subjects, consideration should be given to the use of lower dosages of armodafinil for the management of excessive sleepiness in older patients, particularly the very elderly.", "Since DNA topoisomerase II (EC 5.99.1.3) is an essential enzyme in yeast, heterologous topoisomerase II gene expression in yeast cells can provide a system for analyzing the structure and function of topoisomerase II genes from other species. A series of yeast expression plasmids was constructed in which segments of the cDNA sequences encoding Drosophila DNA topoisomerase II were inserted under the transcriptional control of yeast GAL1 promoter. Expression of the functional form of Drosophila topoisomerase II cDNA can complement conditionally lethal, temperature-sensitive mutations in the yeast topoisomerase II gene (TOP2), as well as mutations in which the TOP2 locus was disrupted. The survival of these yeast cells depends upon the continuous expression of Drosophila topoisomerase II. Repression of Drosophila gene expression by glucose causes these yeast cells to cease dividing after a few generations. In addition to these genetic complementation data, the expression of the Drosophila topoisomerase II gene in yeast cells with a disruption in TOP2 can also be detected by immunochemical methods with an antibody specific for Drosophila topoisomerase II.", "The gene TOP2 encoding yeast topoisomerase II has been cloned by immunological screening of a yeast genomic library constructed in the phage lambda expression vector, lambda gt11. The ends of the message encoded by the cloned DNA fragment were delimited by the Berk and Sharp procedure (S1 nuclease mapping) for the 5' end and mapping of the polyA tail portion of a cDNA fragment for the 3' end. The predicted size of the message agrees with the length of the message as determined by Northern blot hybridization analysis. The identity of the gene was confirmed by expressing the gene in E. coli from the E. coli promoter lac UV5 to give catalytically active yeast DNA topoisomerase II. Disruption of one copy of the gene in a diploid yeast creates a recessive lethal mutation, indicating that the single DNA topoisomerase II gene of yeast has an essential function.", "The gene encoding topoisomerase II in yeast is unique and essential, required for both mitotic and meiotic proliferation. The use of temperature-sensitive mutants in topoisomerase II have demonstrated roles in the relaxation of tortional stress, reduction of recombination rates, and in the separation of sister chromatids after replication. In vertebrate cells, topoisomerase II was shown to be the most abundant component of the metaphase chromosomal scaffold, and has been shown to play a role in chromosome condensation in vitro. The cell cycle control of chromosome condensation may well require phosphorylation of topoisomerase II, since the enzyme is more highly phosphorylated in metaphase than in G1. Recent studies have identified casein kinase II as the major enzyme phosphorylating topoisomerase II in intact yeast cells. The target sites of CKII are exclusively in the C-terminal 400 amino acids of topoisomerase II, the region that is most divergent among the eukaryotic type II enzymes and which is absent in the bacterial gyrase homologues.", "Mutations in the lysosomal acid beta-galactosidase (EC 3.2.1.23) underlie two different disorders: GM1 gangliosidosis, which involves the nervous system and visceral organs to varying extents, and Morquio's syndrome type B (Morquio B disease), which is a skeletal-connective tissue disease without any CNS symptoms. This article shows that transduction of human GM1 gangliosidosis fibroblasts with retrovirus vectors encoding the human acid beta-galactosidase cDNA leads to complete correction of the enzymatic deficiency. The newly synthesized enzyme is correctly processed and targeted to the lysosomes in transduced cells. Cross-correction experiments using retrovirus-modified cells as enzyme donors showed, however, that the human enzyme is transferred at low efficiencies. Experiments using a different retrovirus vector carrying the human cDNA confirmed this observation. Transduction of human GM1 fibroblasts and mouse NIH 3T3 cells with a retrovirus vector encoding the mouse beta-galactosidase cDNA resulted in high levels of enzymatic activity. Furthermore, the mouse enzyme was found to be transferred to human cells at high efficiency. Enzyme activity measurements in medium conditioned by genetically modified cells suggest that the human beta-galactosidase enzyme is less efficiently released to the extracellular space than its mouse counterpart. This study suggests that lysosomal enzymes, contrary to the generalized perception in the field of gene therapy, may differ significantly in their properties and provides insights for design of future gene therapy interventions in acid beta-galactosidase deficiency.", "The decatenation activity of DNA topoisomerase II is essential for viability as eukaryotic cells traverse mitosis. Phosphorylation has been shown to stimulate topoisomerase II activity in vitro. Here we show that topoisomerase II is a phosphoprotein in yeast and that the level of incorporated phosphate is significantly higher at mitosis than in G1. Comparison of tryptic phosphopeptide maps reveals that the major phosphorylation sites in vivo are targets for casein kinase II. Incorporation of phosphate into topoisomerase II is nearly undetectable at the non-permissive temperature in a conditional casein kinase II mutant. The sites modified by casein kinase II are located in the extreme C-terminal domain of topoisomerase II. This domain is absent in prokaryotic and highly divergent among eukaryotic type II topoisomerases, and may serve to regulate functions of topoisomerase II that are unique to eukaryotic cells.", "Many advances have occurred in the field of Barth Syndrome biology in the 26 years since it was first described as an X-linked cardiomyopathy. Barth Syndrome is the first human disease recognized in which the primary causative factor is an alteration in cardiolipin remodeling. Cardiolipin is required for the optimal function of many proteins within the mitochondria, particularly in the respiratory chain and is involved in the mitochondrial-mediated apoptotic process. The appropriate content of cardiolipin appears to be critical for these functions. Cardiolipin is synthesized de novo in mitochondria and is rapidly remodeled to produce CL enriched in linoleic acid. The Barth Syndrome gene TAZ has been identified and expression of the gene yields proteins known as tafazzins. Mutations in TAZ result in a decrease in tetra-linoleoyl species of cardiolipin and an accumulation of monolysocardiolipin within cells from Barth Syndrome patients. Although the protein product of the TAZ gene shows sequence homology to the glycerolipid acyltransferase family of enzymes, its precise biochemical function remains to be elucidated. In this review we highlight some of the recent literature on cardiolipin metabolism and Barth Syndrome.", "Antimicrobial resistance continues to rise on a global scale, affecting the environment, humans, animals and food systems. Use of natural antimicrobials has been favoured over synthetic molecules in food preservation owing to concerns over the adverse health effects of synthetic chemicals. The continuing need for novel natural antimicrobial compounds has spurred research to investigate natural sources, such as bacteria, for antimicrobials. The antimicrobial-producing potential of bacteria has been investigated in numerous studies. However, the discovery of antimicrobials has been biased towards aerobes and facultative anaerobes, and strict anaerobes such as Clostridium spp. have been largely neglected. In recent years, genomic studies have indicated the genetic potential of strict anaerobes to produce putative bioactive molecules and this has encouraged the exploration of Clostridium spp. for their antimicrobial production. So far, only a limited number of antimicrobial compounds have been isolated, identified and characterised from the genus Clostridium. This review discusses our current knowledge and understanding of clostridial antimicrobial compounds as well as recent genome mining studies of Clostridium spp. focused at identification of putative gene clusters encoding bacterial secondary metabolite groups and peptides reported to possess antimicrobial properties. Furthermore, opportunities and challenges in the identification of antimicrobials from Clostridium spp. using genomic-guided approaches are discussed. The limited studies conducted so far have identified the genus Clostridium as a viable source of antimicrobial compounds for future investigations.", "Mutations in the transcriptional regulator, Aire, cause APECED, a polyglandular autoimmune disease with monogenic transmission. Animal models of APECED have revealed that Aire plays an important role in T cell tolerance induction in the thymus, mainly by promoting ectopic expression of a large repertoire of transcripts encoding proteins normally restricted to differentiated organs residing in the periphery. The absence of Aire results in impaired clonal deletion of self-reactive thymocytes, which escape into the periphery and attack a variety of organs. In addition, Aire is a proapoptotic factor, expressed at the final maturation stage of thymic medullary epithelial cells, a function that may promote cross-presentation of the antigens encoded by Aire-induced transcripts in these cells. Transcriptional regulation by Aire is unusual in being very broad, context-dependent, probabilistic, and noisy. Structure/function analyses and identification of its interaction partners suggest that Aire may impact transcription at several levels, including nucleosome displacement during elongation and transcript splicing or other aspects of maturation.", "Smoking is a risk factor for complications during and after surgery, but most smokers are unable to quit before elective surgery. We tested the efficacy of bupropion in improving smoking cessation rates in this setting by enrolling 47 patients from the elective surgery waiting list in a double-blind randomised controlled trial. Patients receiving bupropion had a lower daily cigarette consumption at the time of hospital admission, median (IQR) cigarettes per day: 6 (2-7) vs. 15 (9-20), p = 0.046. They also had a reduction in end-expired carbon monoxide (p = 0.004), a known contaminant of cigarette smoke, and increased arterial oxygen saturation on pulse oximetry (p = 0.011). They were more likely to have stopped smoking at the 3-week visit (p = 0.036), but not at the 6-week visit (p = 0.25) or at the time of hospital admission for surgery (p > 0.99). This study found that smokers waiting for elective surgery are more likely to reduce or stop smoking when treated with bupropion.", "Amyloid imaging with (18)F-labeled radiotracers will allow widespread use, facilitating research, diagnosis, and therapeutic development for Alzheimer disease. The purpose of the study program was to compare cortical amyloid deposition using (18)F-florbetaben and PET in controls and subjects with mild cognitive impairment (MCI), frontotemporal lobar degeneration (FTLD), dementia with Lewy bodies (DLB), vascular dementia (VaD), Parkinson disease (PD), and Alzheimer disease (AD).METHODS: One hundred nine subjects in 3 clinical studies at Austin Health were reviewed: 32 controls, 20 subjects with MCI, and 30 patients with AD, 11 with FTLD, 7 with DLB, 5 with PD, and 4 with VaD underwent PET after intravenous injection of 300 MBq of (18)F-florbetaben. Standardized uptake value ratios (SUVR) using the cerebellar cortex as a reference region were calculated between 90 and 110 min after injection.RESULTS: When compared with the other groups, AD patients demonstrated significantly higher SUVRs (P < 0.0001) in neocortical areas. Most AD patients (96%) and 60% of MCI subjects showed diffuse cortical (18)F-florbetaben retention. In contrast, only 9% of FTLD, 25% of VaD, 29% of DLB, and no PD patients and 16% of controls showed cortical binding. Although there was a correlation between Mini Mental State Examination and β-amyloid burden in the MCI group, no correlation was observed in controls, FTLD or AD.CONCLUSION: (18)F-florbetaben had high sensitivity for AD, clearly distinguished patients with FTLD from AD, and provided results comparable to those reported with (11)C-Pittsburgh Compound B in a variety of neurodegenerative diseases.", "The burden of depression as a severe illness with high suicidality and prevalence is immense. Despite substantial advancement in psychopharmacology and psychotherapy over the last decades a residual group of very ill patients with a chronic disease and high suicidal risk remains. Modern theories about the pathophysiology of depression are derived from studies examining the mechanism of antidepressants influencing the serotonergic (5-HT) and noradrenergic (NE) systems. Serotonergic fibers originate from the dorsal raphe nuclei (DRN), noradrenergic fibers from the locus coeruleus (LC). Both nuclei represent relatively small brain regions and both are controlled to some extent by the habenular complex. We propose the hypothesis of an overactivation of the habenula in human major depressive episodes (MDE's). Increased activation of the lateral habenular nucleus leads to the down regulation of the serotonergic, noradrenergic, dopaminergic systems and stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Functional inhibition of the lateral habenula via deep brain stimulation (DBS) has antidepressive properties. The hypothesis is based on the findings of a clinical imaging study examining the habenular after tryptophan depletion and on several animal studies which are discussed. Providing that our hypothesis will be validated by an analogous tyrosine depletion study and additional preclinical studies, the next logical step would be to directly test our hypothesis in patients. Possible criteria for patient selection, ethical issues and locus of DBS are carefully discussed.", "Protein homeostasis, proteostasis, is essential to understand cell function. Protein degradation is a crucial component of the proteostatic mechanisms of the cell. Experiments on protein degradation are nowadays present in many investigations in the field of molecular and cell biology. In the present paper, we focus on the different experimental approaches to study protein degradation and present a critical appraisal of the results derived from steady-state and kinetic experiments using detection of unlabelled and labelled protein methodologies with a proteostatic perspective. This perspective allows pinpointing the limitations in interpretation of results and the need of further experiments and/or controls to establish \"definitive evidence\" for the role of protein degradation in the proteostasis of a given protein or the entire proteome. We also provide a spreadsheet for simple calculations of mRNA and protein decays for mimicking different experimental conditions and a checklist for the analysis of experiments dealing with protein degradation studies that may be useful for researchers interested in the area of protein turnover.", "The causes of sudden and unexpected death in 29 highly conditioned, competitive athletes, ages 13-30 years, are summarized. Sudden death occurred during or just after severe exertion on the athletic field in 22 of the 29 athletes. Structural cardiovascular abnormalities were identified at necropsy in 28 of the 29 athletes (97%), and in 22 (76%) were almost certainly the cause of death. The most common cause of death in this series was hypertrophic cardiomyopathy, which was present in 14 athletes. Other cardiovascular abnormalities that occurred in more than one athlete were anomalous origin of the left coronary artery from the right (anterior) sinus of Valsalva, idiopathic concentric left ventricular hypertrophy, coronary heart disease and ruptured aorta. Cardiac disease was suspected during life in only seven of the 29 patients, and in only two of the seven was the correct diagnosis made clinically. Hence, in this series of young athletes, sudden death was usually due to structural cardiovascular disease, and hypertrophic cardiomyopathy was a frequent cause of sudden death; atherosclerotic coronary heart disease was relatively uncommon.", "The cause for the neurofibrillary tangles and plaques in Alzheimer disease likely relates to an abnormal accumulation of their key components, which include β-amyloid and hyperphosphorylated tau protein. We segregated Alzheimer brain sections from people with end-stage disease into those with abundant hyperphosphorylated tau protein and those without and compared each to normal brains for global microRNA patterns. A significant reduced expression of several microRNAs, including miR-512, was evident in the Alzheimer brain sections with abundant hyperphosphorylated tau. Immunohistochemistry documented that 2 known targets of microRNA-512, cFLIP and MCL1, were significantly over expressed and each colocalized to neurons with the abnormal tau protein. Analysis for apoptosis including activated caspase-3, increased caspase-4 and caspase-8, apoptosis initiating factor, APAF-1 activity, and the TUNEL assay was negative in the areas where neurons showed hyperphosphorylated tau. MCM2 expression, a marker of neuroprogenitor cells, was significantly reduced in the Alzheimer sections that contained the hyperphosphorylated tau. These results suggest that a basic defect in Alzheimer disease may be the reduced microRNA-driven increased expression of proteins that may alter the apoptotic/antiapoptotic balance of neurons. This, in turn, could lead to the accumulation of key Alzheimer proteins such as hyperphosphorylated tau that ultimately prevent normal neuronal function and lead to disease symptomatology.", "HbVar (http://globin.bx.psu.edu/hbvar) is a locus-specific database (LSDB) developed in 2001 by a multi-center academic effort to provide timely information on the genomic sequence changes leading to hemoglobin variants and all types of thalassemia and hemoglobinopathies. Database records include extensive phenotypic descriptions, biochemical and hematological effects, associated pathology, and ethnic occurrence, accompanied by mutation frequencies and references. In addition to the regular updates to entries, we report significant advances and updates, which can be useful not only for HbVar users but also for other LSDB development and curation in general. The query page provides more functionality but in a simpler, more user-friendly format and known single nucleotide polymorphisms in the human alpha- and beta-globin loci are provided automatically. Population-specific beta-thalassemia mutation frequencies for 31 population groups have been added and/or modified and the previously reported delta- and alpha-thalassemia mutation frequency data from 10 population groups have also been incorporated. In addition, an independent flat-file database, named XPRbase (http://www.goldenhelix.org/xprbase), has been developed and linked to the main HbVar web page to provide a succinct listing of 51 experimental protocols available for globin gene mutation screening. These updates significantly augment the database profile and quality of information provided, which should increase the already high impact of the HbVar database, while its combination with the UCSC powerful genome browser and the ITHANET web portal paves the way for drawing connections of clinical importance, that is from genome to function to phenotype.", "PURPOSE: To investigate pregnancy, delivery, and child outcome in an unselected population of women with both treated and untreated epilepsy.METHODS: In the compulsory Medical Birth Registry of Norway, all 2,861 deliveries by women with epilepsy recorded from 1999-2005 were compared to all 369,267 nonepilepsy deliveries in the same period.RESULTS: The majority (66%, n = 1900) in the epilepsy group did not use antiepileptic drugs (AEDs) during pregnancy. A total of 961 epilepsy-pregnancies were exposed to AEDs. Compared to nonepilepsy controls, AED-exposed infants were more often preterm (p = 0.01), and more often had birth weight <2,500 g (p < 0.001), head circumference <2.5 percentile (p < 0.001), and low Apgar score (p = 0.03). Small-for-gestational-age (SGA) infants (<10 percentile) occurred more frequently in both AED-exposed (p = 0.05) and unexposed (p = 0.02) epilepsy-pregnancies. Frequency of major congenital malformations (MCMs) was 2.8% (n = 81) in the epilepsy group versus 2.5% in controls (p = 0.3). Increased risk for MCMs could be demonstrated only for exposure to valproate (5.6%, p = 0.005) and AED polytherapy (6.1%, p = 0.02). Neonatal spina bifida was not significantly increased, but was a major indication for elective pregnancy termination among women with epilepsy. Cesarean section was performed more often in maternal epilepsy, regardless of AED-exposure (p < 0.001).DISCUSSION: Adverse pregnancy and birth outcome in women with epilepsy is mainly confined to AED-exposed pregnancies, although some risks are associated also with untreated epilepsy. The risk for congenital malformations was lower than previously reported. This could be due to a shift in AED selection, folic acid supplement, or possibly reflect the true risks in an unselected epilepsy population.", "To examine the RNA polymerase (EC 2.7.7.6) specificity of RNA maturation/utilization and transcriptional enhancement, we constructed a chimeric plasmid (pPolI-CAT) in which a promoter for mouse rRNA gene transcription was placed adjacent the coding sequences for chloramphenicol acetyltransferase (CAT; EC 2.3.1.28). A number of other constructs, including plasmids also containing a murine sarcoma virus enhancer or lacking any natural eukaryotic promoter sequences, were also prepared. In apparent agreement with earlier conclusions that an RNA polymerase I transcript can act as a messenger RNA, transient transfection of mouse L cells with pPolI-CAT yielded both high levels of transcription from the RNA polymerase I promoter and enzymatically active CAT protein. However, further examination revealed that CAT protein is not translated from RNA that begins at the normal rRNA transcription initiation site. Polysomal RNA is devoid of such RNA and instead consists of CAT-encoding transcripts that begin elsewhere in the mouse ribosomal DNA (rDNA) region. Since transcription of these aberrant RNAs is stimulated by the addition of a murine sarcoma virus enhancer segment, they are probably transcribed by RNA polymerase II. Transcripts that map to the authentic rRNA start site are not similarly enhanced. Moreover, unlike the RNAs deriving from the rRNA initiation site, these aberrant RNAs are more stable and the level of translatable CAT transcripts is suppressed by inclusion of larger segments of the rDNA promoter regions. Fortuitously initiated mRNAs are also formed in the absence of any natural eukaryotic promoter sequence. From these data we conclude that there is no evidence that normal RNA polymerase I transcription yields functional mRNA and that transcriptional enhancement appears to be RNA polymerase specific.", "We have isolated mutants defective in DNA topoisomerases and an endonuclease from the fission yeast Schizosaccharomyces pombe by screening individual extracts of mutagenized cells. Two type I topoisomerase mutants (top1) and three endonuclease mutants (end1) were all viable. The double mutant top1 end1 was also viable and, in its extract, Mg2+- and ATP- dependent type II activity could be detected. Three temperature-sensitive (ts-) mutants having heat-sensitive (hs-) type II enzymes were isolated, and the ts- marker cosegregated with the hs- type II activity. All the ts- mutations fell in one gene (top2) tightly linked to leul in chromosome II. The nuclear division of single top2 mutants was blocked at the restrictive temperature, but the formation of a septum was not inhibited so that the nucleus was cut across with the cell plate. In contrast, the double top1 top2 mutants were rapidly arrested at various stages of the cell cycle, showing a strikingly altered nuclear chromatin region. The type II topoisomerase may have an essential role in the compaction and/or segregation of chromosomes during the nuclear division but also complement the defect of the type I enzyme whose major function is the maintenance of chromatin organization throughout the cell cycle.", "Studies with yeast DNA topoisomerase mutants indicate that neither topoisomerase I nor II appears to be essential for transcription by RNA polymerase II. However, plasmids carrying transcriptionally active genes are found to be extremely negatively supercoiled when isolated from mutants lacking topoisomerase I. Supercoiling occurs during transcriptional elongation rather than during transcriptional activation. It takes place in the absence of topoisomerase I and does not seem to be dependent on topoisomerase II since it can occur at the nonpermissive temperature in a top1-top2 ts mutant. Whether this change in linking number is due to an unusual form of topoisomerase II or whether it is due to a new enzyme has yet to be determined. The results suggest that topoisomerase I is normally required to relax transcriptionally induced supercoils. A model is discussed which considers the role of topoisomerases in the movement of RNA polymerase along the DNA template.", "Topoisomerase II (Topo II) performs topological modifications on double-stranded DNA molecules that are essential for chromosome condensation, resolution, and segregation. In mammals, G2 and metaphase cell cycle delays induced by Topo II poisons have been proposed to be the result of checkpoint activation in response to the catenation state of DNA. However, the apparent lack of such controls in model organisms has excluded genetic proof that Topo II checkpoints exist and are separable from the conventional DNA damage checkpoint controls. But here, we define a Topo II-dependent G2/M checkpoint in a genetically amenable eukaryote, budding yeast, and demonstrate that this checkpoint enhances cell survival. Conversely, a lack of the checkpoint results in aneuploidy. Neither DNA damage-responsive pathways nor Pds1/securin are needed for this checkpoint. Unusually, spindle assembly checkpoint components are required for the Topo II checkpoint, but checkpoint activation is not the result of failed chromosome biorientation or a lack of spindle tension. Thus, compromised Topo II function activates a yeast checkpoint system that operates by a novel mechanism.", "OBJECTIVE: To confirm if using a neutral density filter (NDF) affects eyes with strabismic amblyopia differently compared to fellow non-amblyopic eyes, and to determine if a similar effect could be observed when using a NDF during peripheral visual field testing.DESIGN: Prospective controlled case series.PARTICIPANTS: 19 subjects with strabismic amblyopia with visual acuities between 20/400 and 20/40 in their affected eyes were recruited to the study. Fellow non-amblyopic eyes served as the control group.METHODS: Visual acuity in both eyes was assessed using a projected Snellen eye chart with two NDFs (0.4 and 3.0 densities). Visual fields were assessed using a Humphrey perimeter using one NDF (0.4 density). Best corrected visual acuity and visual fields were also recorded.RESULTS: When using a 3.0 NDF, visual acuity was reduced in all eyes (p < 0.0001). When using a 0.4 NDF, visual acuity was significantly improved in eyes with strabismic amblyopia compared to unfiltered conditions (p = 0.0011). There was no significant effect by NDFs on visual field testing in eyes with strabismic amblyopia or fellow non-amblyopic eyes.CONCLUSIONS: Neutral density filters affect eyes with strabismic amblyopia differently than they do non-amblyopic eyes. A significant improvement in visual acuity of eyes with strabismic amblyopia was observed when using a 0.4 NDF compared to non-amblyopic eyes. Visual acuity was reduced in amblyopic as well as non-amblyopic eyes when viewing through a 3.0 NDF. No significant change in visual fields was observed when using a 0.4 NDF in amblyopic or non-amblyopic eyes.", "Eukaryotic DNA topoisomerase II is an abundant nuclear enzyme that is essential for cell proliferation. This homodimeric enzyme catalyzes the cleavage and re-ligation of double-stranded DNA required to separate replicated sister chromatids. Both biochemical and genetic studies show that its catalytic activity is required for chromosome condensation and segregation, and that its decatenation activity can be stimulated by a variety of protein kinases in vitro. In budding yeast, topoisomerase II is most highly phosphorylated in metaphase, and casein kinase II (CKII) was shown to be the major kinase modifying topoisomerase II. We have investigated the effects of phosphorylation of yeast topoisomerase II by CKII in vitro, by means of gel-retardation and filter binding assays. The phosphorylation of the C terminus of topoisomerase II by CKII appears to increase the stability of the complex formed with linear DNA fragments, while dephosphorylation has the opposite effect. Rephosphorylation of phosphatase-treated topoisomerase II by chicken casein kinase II restores a stable protein-DNA complex using a linear DNA fragment. The enhanced stability of the topoisomerase II-DNA complex is also observed with relaxed circular DNA, but not with supercoiled minicircles, in agreement with published results using topoisomerase II from Drosophila. Limited proteolysis and probing with domain-specific antibodies shows that, with the exception of a weakly modified residue between amino acid residues 660 and 1250, all residues modified by casein kinase II are in the last 180 amino acid residues of yeast topoisomerase II.", "Diphtheria, an acute infectious condition caused by Corynebacterium diphtheriae, was once a major killer of children. Although the mortality rates dropped dramatically in the mid-twentieth century, due to a combination of improved standards of living and immunization programs, outbreaks are still occurring. Two children, aged four and five years respectively, are reported to demonstrate characteristic features of lethal cases. Death in case 1 was due to an extensive upper airway pseudomembrane causing acute respiratory failure. The diagnosis of diphtheria was only made at postmortem. Death in case 2 was due to acute cardiac failure with heart block complicating diphtheria. Other mechanisms in fatal cases involve disseminated intravascular coagulation, renal and endocrine failure. Declining levels of immunity among adults has resulted in a change in the epidemiological pattern of the disease with an older age of victims in recent outbreaks. As a result of population shifts and failure to immunize children it is likely that forensic pathologists may see more cases of diphtheria in the future. Due to the rarity of cases in Western communities and atypical presentations, the diagnosis may only be established at autopsy.", "Eukaryotic topoisomerase II (topo II) is the essential decatenase of newly replicated chromosomes and the main relaxase of nucleosomal DNA. Apart from these general tasks, topo II participates in more specialized functions. In mammals, topo IIα interacts with specific RNA polymerases and chromatin-remodeling complexes, whereas topo IIβ regulates developmental genes in conjunction with chromatin remodeling and heterochromatin transitions. Here we show that in budding yeast, topo II regulates the expression of specific gene subsets. To uncover this, we carried out a genomic transcription run-on shortly after the thermal inactivation of topo II. We identified a modest number of genes not involved in the general stress response but strictly dependent on topo II. These genes present distinctive functional and structural traits in comparison with the genome average. Yeast topo II is a positive regulator of genes with well-defined promoter architecture that associates to chromatin remodeling complexes; it is a negative regulator of genes extremely hypo-acetylated with complex promoters and undefined nucleosome positioning, many of which are involved in polyamine transport. These findings indicate that yeast topo II operates on singular chromatin architectures to activate or repress DNA transcription and that this activity produces functional responses to ensure chromatin stability.", "Topoisomerase II is a ubiquitous enzyme that removes knots and tangles from the genetic material by generating transient double-strand DNA breaks. While the enzyme cannot perform its essential cellular functions without cleaving DNA, this scission activity is inherently dangerous to chromosomal integrity. In fact, etoposide and other clinically important anticancer drugs kill cells by increasing levels of topoisomerase II-mediated DNA breaks. Cells rely heavily on recombination to repair double-strand DNA breaks, but the specific pathways used to repair topoisomerase II-generated DNA damage have not been defined. Therefore, Saccharomyces cerevisiae was used as a model system to delineate the recombination pathways that repair DNA breaks generated by topoisomerase II. Yeast cells that expressed wild-type or a drug-hypersensitive mutant topoisomerase II or overexpressed the wild-type enzyme were examined. Based on cytotoxicity and recombination induced by etoposide in different repair-deficient genetic backgrounds, double-strand DNA breaks generated by topoisomerase II appear to be repaired primarily by the single-strand invasion pathway of homologous recombination. Non-homologous end joining also was triggered by etoposide treatment, but this pathway was considerably less active than single-strand invasion and did not contribute significantly to cell survival in S.cerevisiae.", "PURPOSE: Histamine H3 receptor ligands may have antidepressant and anxiolytic effects. They can also compensate for metabolic disorders, which affect glucose or triglyceride levels. In previous studies, we have shown that pitolisant, a histamine H3 receptor antagonist/inverse agonist and σ1 receptor agonist, prevented the development of certain metabolic and depressive-like disorders in mice that have been treated chronically with olanzapine.METHODS: As a continuation of our previous experiments, this study aimed to investigate the antidepressant- and anxiolytic-like activity of pitolisant in mice using the corticosterone-induced depression model. The forced swim and the elevated plus maze tests were used as behavioral endpoints. We also studied the effect pitolisant had on the level of acetoacetic acid in the urine as well as the glucose tolerance and body weight of the mice that had been administered corticosterone.RESULTS: Pitolisant (10 mg/kg b.w.) did not prevent depressive-like behavior in mice during the chronic corticosterone administration but did counteract anxiety-like behavior, whilst fluoxetine (10 mg/kg) was shown to protect the mice from both of these behaviors. None of the treatments that were used in the study showed an effect on the locomotor activity of the mice. Pitolisant did not prevent an increase in acetoacetic acid levels in the urine, nor did it improve glucose tolerance in the tested mice.CONCLUSION: Although literature data indicates that there is significant potential for finding an antidepressant and anti-diabetic drug among the histamine H3 and σ1 receptor ligands, in our study, pitolisant was shown to only slightly compensate for corticosterone-induced abnormalities. However, further research will be required to study pitolisant's anxiolytic-like activity.", "Glutamic acid is an alpha-amino acid used by all living beings in protein biosynthesis. One of the important glutamic acid modifications is post-translationally modified 4-carboxyglutamate. It has a significant role in blood coagulation. 4-carboxyglumates are required for the binding of calcium ions. On the contrary, this modification can also cause different diseases such as bone resorption, osteoporosis, papilloma, and plaque atherosclerosis. Considering its importance, it is necessary to predict the occurrence of glutamic acid carboxylation in amino acid stretches. As there is no computational based prediction model available to identify 4-carboxyglutamate modification, this study is, therefore, designed to predict 4-carboxyglutamate sites with a less computational cost. A machine learning model is devised with a Multilayered Perceptron (MLP) classifier using Chou's 5-step rule. It may help in learning statistical moments and based on this learning, the prediction is to be made accurately either it is 4-carboxyglutamate residue site or detected residue site having no 4-carboxyglutamate. Prediction accuracy of the proposed model is 94% using an independent set test, while obtained prediction accuracy is 99% by self-consistency tests.", "Rheumatoid arthritis (RA) is the most prevalent immune-mediated chronic rheumatic disease and is associated with joint destruction and disability. Therapeutic strategies, including biological disease-modifying antirheumatic drugs (bDMARDs) have improved the prognosis and quality of life of RA patients. Tocilizumab (TCZ) is a humanized monoclonal antibody against IL-6 receptor licensed in 2009 that has demonstrated clinical efficacy in various adult RA populations. RA management guidelines and recommendations consider TCZ as one of the bDMARDS indicated after methotrexate or other conventional synthetic DMARDs and/or TNF inhibitors failure in adult RA. Of particular interest is the demonstration of its effectiveness in monotherapy in comparison with other bDMARDs. Recent observational studies have shown good results for the safety profile of TCZ with no new alert signals.", "High-performance MS instrumentation coupled with improved protein extraction techniques enables metaproteomics to identify active members of soil and groundwater microbial communities. Metaproteomics workflows were applied to study the initial responses (i.e. 4 days post treatment) of the indigenous aquifer microbiota to biostimulation with emulsified vegetable oil (EVO) at a uranium-contaminated site. Members of the Betaproteobacteria (i.e. Dechloromonas, Ralstonia, Rhodoferax, Polaromonas, Delftia, Chromobacterium) and the Firmicutes dominated the biostimulated aquifer community. Proteome characterization revealed distinct differences between the microbial biomass collected from groundwater influenced by biostimulation and groundwater collected upgradient of the EVO injection points. In particular, proteins involved in ammonium assimilation, EVO degradation, and polyhydroxybutyrate granule formation were prominent following biostimulation. Interestingly, the atypical NosZ of Dechloromonas spp. was highly abundant, suggesting active nitrous oxide (N2 O) respiration. c-Type cytochromes were barely detected, as was citrate synthase, a biomarker for hexavalent uranium reduction activity, suggesting that uranium reduction has not commenced 4 days post EVO amendment. Environmental metaproteomics identified microbial community responses to biostimulation and elucidated active pathways demonstrating the value of this technique as a monitoring tool and for complementing nucleic acid-based approaches.", "Sirtuins are NAD-dependent lysine deacylases that play critical roles in cellular regulation and are implicated in human diseases. Modulators of sirtuins are needed as tools for investigating their biological functions and possible therapeutic applications. However, the discovery of sirtuin modulators is hampered by the lack of efficient sirtuin assays. Here we report an improved fluorogenic assay for SIRT1, SIRT2, and SIRT3 using a new substrate, a myristoyl peptide with a C-terminal aminocoumarin. The new assay has several advantages, including significantly lower substrate concentration needed, increased signal-to-background ratio, and improved Z'-factor. The novel assay thus will expedite high-throughput screening of SIRT1, SIRT2, and SIRT3 modulators.", "Little is known about the natural history of children with pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). This study prospectively followed 33 children with PANDAS for up to 4.8 years (mean 3.3 ± 0.7 years) after enrollment in a 24-week randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin (IVIG) (N = 35). Fourteen of eighteen children randomized to placebo received open label IVIG 6 weeks after the blinded infusion, so follow-up results reported below largely reflect outcomes in a population of children who received at least one dose of IVIG. Telephone interviews with the parents of participants found that at the time of phone follow-up, 29 (88%) were not experiencing clinically significant obsessive-compulsive symptoms. During the interim period (6-57 months after entering the clinical trial), 24 (72%) had experienced at least one exacerbation of PANDAS symptoms, with a median of one exacerbation per child (range 1-12; interquartile range 0-3). A variety of treatment modalities, including antibiotics, IVIG, psychiatric medications, cognitive behavioral therapy, and others, were used to treat these exacerbations, and were often used in combination. The outcomes of this cohort are better than those previously reported for childhood-onset OCD, which may support conceptualization of PANDAS as a subacute illness similar to Sydenham chorea. However, some children developed a chronic course of illness, highlighting the need for research that identifies specific symptoms or biomarkers that can be used to predict the longitudinal course of symptoms in PANDAS.", "Zinc-finger nucleases (ZFNs) are a powerful tool that can be used to edit the human genome ad libitum. The technology has experienced remarkable development in the last few years with regard to both the target site specificity and the engineering platforms used to generate zinc-finger proteins. As a result, two phase I clinical trials aimed at knocking out the CCR5 receptor in T cells isolated from HIV patients to protect these lymphocytes from infection with the virus have been initiated. Moreover, ZFNs have been successfully employed to knockout or correct disease-related genes in human stem cells, including hematopoietic precursor cells and induced pluripotent stem cells. Targeted genome engineering approaches in multipotent and pluripotent stem cells hold great promise for future strategies geared toward correcting inborn mutations for personalized cell replacement therapies. This review describes how ZFNs have been applied to models of gene therapy, discusses the opportunities and the risks associated with this novel technology, and suggests future directions for their safe application in therapeutic genome engineering.", "Splicing and alternative splicing are involved in the expression of most human genes, playing key roles in differentiation, cell cycle progression, and development. Misregulation of splicing is frequently associated to disease, which imposes a better understanding of the mechanisms underlying splicing regulation. Accumulated evidence suggests that multiple trans-acting factors and cis-regulatory elements act together to determine tissue-specific splicing patterns. Besides, as splicing is often cotranscriptional, a complex picture emerges in which splicing regulation not only depends on the balance of splicing factor binding to their pre-mRNA target sites but also on transcription-associated features such as protein recruitment to the transcribing machinery and elongation kinetics. Adding more complexity to the splicing regulation network, recent evidence shows that chromatin structure is another layer of regulation that may act through various mechanisms. These span from regulation of RNA polymerase II elongation, which ultimately determines splicing decisions, to splicing factor recruitment by specific histone marks. Chromatin may not only be involved in alternative splicing regulation but in constitutive exon recognition as well. Moreover, splicing was found to be necessary for the proper 'writing' of particular chromatin signatures, giving further mechanistic support to functional interconnections between splicing, transcription and chromatin structure. These links between chromatin configuration and splicing raise the intriguing possibility of the existence of a memory for splicing patterns to be inherited through epigenetic modifications.", "A 62-year-old woman with Sjogren syndrome was admitted for computed tomographic (CT) evaluation of a thickened trachea and parotid tumor. She had been given a diagnosis of mucosa-associated lymphoid tissue (MALT) lymphoma 6 years previously, and had undergone surgical resection of the parotid tumor. Endoscopic examination revealed an annular tumor that had formed a stricture in the mid-trachea. Pathologic specimens were obtained by surgical resection of the parotid tumor and bronchoscopic biopsy of the tracheal tumor. Both histological examinations revealed MALT-type marginal zone B-cell lymphoma. Because CD20 immunostaining was positive, the patient received 6 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) without any signs of major toxicity. All lesions disappeared after treatment, and this patient remained disease-free for 40 months.", "DNA topoisomerases are specialized nuclear enzymes that perform topological modifications on double-stranded DNA (dsDNA) and hence are essential for DNA metabolism such as replication, transcription, recombination, condensation and segregation. In a genetic screen, we identified a temperature-sensitive mutant allele of topoisomerase 2 that exhibits conditional synthetic lethality with a chk1 knockout strain. The mutant allele of topoisomerase 2 is defective in chromosome segregation at a non-permissive temperature and there was increase in chromosome segregation defects in the double mutant of top2-10 and chk1 delete at a non-permissive temperature. More importantly, topoisomearse 2 mutant cells mildly delay the mitotic progression at non-permissive temperature that is mediated by checkpoint protein kinase Chk1. Additionally, top2-10 mutant cells also activate the Chk1 at a non-permissive temperature and this activation of Chk1 takes place at the time of mitosis. Interestingly, top2-10 mutant cells retain their viability at a non-permissive temperature if the cells are not allowed to enter into mitosis. Taking together our results, we speculate that in the top2-10 mutant, the segregation of entangled chromatids during mitosis could result in delaying the mitotic progression through the activation of Chk1 kinase.", "Type II topoisomerases are essential for resolving topologically entwined double-stranded DNA. Although anti-topoisomerase 2 (Top2) drugs are clinically important antibiotics and chemotherapies, to our knowledge, the mechanisms of cell killing by Top2 depletion and inactivation have never been directly compared. We show that depletion of Top2 protein from budding yeast cells prevents DNA decatenation during S phase. Cells complete DNA replication and enter the ensuing mitosis on schedule, suffering extensive chromosome missegregation. Cytokinesis through incompletely segregated chromosomes causes lethal DNA damage. By contrast, expression of catalytically inactive Top2 causes a stable G2 arrest requiring an intact DNA damage checkpoint. Checkpoint activation correlates with an inability to complete DNA replication, resulting in hypercatenated, gapped daughter DNA molecules. Thus, Top2 depletion and inactivation kill cells by different mechanisms, which has implications for understanding the nature of the catenation checkpoint, how DNA replication terminates, how anti-Top2 drugs work, and how new drugs might be designed.", "PURPOSE OF REVIEW: This review summarizes recent insights into the pathogenesis and therapeutic options for patients with MOG- or AQP4-antibodies.RECENT FINDINGS: Although AQP4-IgG are linked to NMOSD, MOG-IgG-associated diseases (MOGAD) include a broader clinical spectrum of autoimmune diseases of the central nervous system (CNS). Details of membrane assembly of AQP4-IgG required for complement activation have been uncovered. Affinity-purified MOG-IgG from patients were shown to be pathogenic by induction of demyelination when the blood--brain barrier (BBB) was breached and by enhancement of activation of cognate T cells. A high-affinity AQP4-IgG, given peripherally, could induce NMOSD-like lesions in rats in the absence of BBB breach. Circulating AQP4-specific and MOG-specific B cells were identified and suggest differences in origin of MOG-antibodies or AQP4-antibodies. Patients with MOG-IgG show a dichotomy concerning circulating MOG-specific B cells; whether this is related to differences in clinical response of anti-CD20 therapy remains to be analyzed. Clinical trials of AQP4-IgG-positive NMOSD patients showed success with eculizumab (preventing cleavage of complement factor C5, thereby blocking formation of chemotactic C5a and membrane attack complex C9neo), inebilizumab (depleting CD19 + B cells), and satralizumab (anti-IL-6R blocking IL-6 actions).SUMMARY: New insights into pathological mechanisms and therapeutic responses argue to consider NMOSD with AQP4-IgG and MOGAD as separate disease entities.", "Members of the 2-aminobenzamide class of histone deacetylase (HDAC) inhibitors show promise as therapeutics for the neurodegenerative diseases Friedreich's ataxia (FRDA) and Huntington's disease (HD). While it is clear that HDAC3 is one of the important targets of the 2-aminobenzamide HDAC inhibitors, inhibition of other class I HDACs (HDACs 1 and 2) may also be involved in the beneficial effects of these compounds in FRDA and HD, and other HDAC interacting proteins may be impacted by the compound. To this end, we synthesized activity-based profiling probe (ABPP) versions of one of our HDAC inhibitors (compound 106), and in the present study we used a quantitative proteomic method coupled with multidimensional protein identification technology (MudPIT) to identify the proteins captured by the ABPP 106 probe. Nuclear proteins were extracted from FRDA patient iPSC-derived neural stem cells, and then were reacted with control and ABPP 106 probe. After reaction, the bound proteins were digested on the beads, and the peptides were modified using stable isotope-labeled formaldehyde to form dimethyl amine. The selectively bound proteins determined by mass spectrometry were subjected to functional and pathway analysis. Our findings suggest that the targets of compound 106 are involved not only in transcriptional regulation but also in posttranscriptional processing of mRNA.", "Taraxasterol is an effective component of dandelion that has anti-inflammatory effects in vivo and in vitro. The present study was performed to explore whether taraxasterol exhibits a protective effect against rheumatoid arthritis through the modulation of inflammatory responses in mice. Eight-week-old CCR9-deficient mice were injected with a collagen II monoclonal antibody cocktail to create a rheumatoid arthritis model. In the experimental group, arthritic model mice were treated with 10 mg/kg taraxasterol once per day for 5 days. Treatment with taraxasterol significantly increased the pain thresholds and reduced the clinical arthritic scores of the mice in the experimental group compared with those of the model group. Furthermore, treatment with taraxasterol significantly suppressed tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and nuclear factor-κB protein expression levels compared with those in the rheumatoid arthritis model mice. Taraxasterol treatment also significantly reduced nitric oxide, prostaglandin E2 and cyclooxygenase-2 levels compared with those in the rheumatoid arthritis model group. These observations indicate that the protective effect of taraxasterol against rheumatoid arthritis is mediated via the modulation of inflammatory responses in mice.", "BACKGROUND: Sudden death due to low-energy blunt trauma to the precordium (commotio cordis) has been described with a variety of sporting objects. However, the risk of ventricular fibrillation (VF) relative to the shape of the impact object is not known.OBJECTIVE: The objective of the current experiment is to test whether the impact object shape is a clinical variable that affects the risk for commotio cordis.METHODS: In a juvenile swine model, impacts were given in random order with two different spherical shapes (72 mm diameter, equivalent to a baseball; 42 mm diameter, equivalent to a golf ball) and a flat round object 72 mm in diameter. Objects were equal in weight (150 g), thrown at 30 mph, and gated to the vulnerable portion of the cardiac cycle.RESULTS: Sixteen swine received 144 impacts. The flat object did not cause VF (P = .01 compared with the two spherical objects), nonsustained VF, ST elevation, or bundle branch block. The smaller diameter sphere caused VF in nine of 48 impacts (19%), and the larger diameter sphere caused VF in five of 48 impacts (10%; P = .25). The smaller diameter sphere was associated with a greater increase in left ventricular pressure (P <.0001 and P = .001 compared with larger sphere only) and a higher likelihood of ST segment elevations (P <.001 and P = .08 compared with larger sphere only) and bundle branch block (Fisher's exact P = .008, and Fisher's exact P = .18 compared with larger sphere only).CONCLUSION: The shape of the projectile markedly influences the risk of VF from chest wall impact. This effect is likely mediated via a greater increase in left ventricular pressure with smaller diameter objects. Spreading the impact force over a larger area may decrease the risk of sudden death and has implications for the design of protective athletic equipment.", "Ivabradine is an I(f) current inhibitor, that has documented antianginal efficacy. The BEAUTIFUL trial tested ivabradine against placebo in a large population of 10,917 patients in sinus rhythm, with coronary artery disease and left ventricular dysfunction, defined as left ventricular ejection fraction < or =35%. Overall, there was no impact of ivabradine on the primary end-point of the trial (cardiovascular mortality, hospitalisation for myocardial infarction, new onset or worsening heart failure). In the placebo arm of the trial, baseline heart rate > or = 70 bpm was associated with an increased risk of cardiovascular mortality, myocardial infarction, heart failure and coronary revascularisation. In the subgroup of patients with a baseline heart rate > or =70 bpm, treatment with ivabradine resulted in a significant, 36% reduction in the risk of myocardial infarction and a 20% reduction in the need for coronary revascularisation. Ivabradine was well tolerated, with an increased rate of treatment discontinuation, mainly due to bradycardia, compared with placebo. Because of its safety and efficacy to control angina, ivabradine should be considered first-line antianginal treatment in coronary artery disease patients with left ventricular dysfunction and increased heart rate, already receiving beta-blocker therapy or in whom these medications are not tolerated.", "There is considerable experimental evidence that hyperactive Ras proteins promote breast cancer growth and development including invasiveness, despite the low frequency of mutated forms of Ras in breast cancer. We have previously shown that H-Ras, but not N-Ras, induces an invasive phenotype mediated by small GTPase Rac1 in MCF10A human breast epithelial cells. Epidermal growth factor (EGF) plays an important role in aberrant growth and metastasis formation of many tumor types including breast cancer. The present study aims to investigate the correlation between EGF-induced invasiveness and Ras activation in four widely used breast cancer cell lines. Upon EGF stimulation, invasive abilities and H-Ras activation were significantly increased in Hs578T and MDA-MB-231 cell lines, but not in MDA-MB-453 and T47D cell lines. Using small interfering RNA (siRNA) to target H-Ras, we showed a crucial role of H-Ras in the invasive phenotype induced by EGF in Hs578T and MDA-MB-231 cells. Moreover, siRNA-knockdown of Rac1 significantly inhibited the EGF-induced invasiveness in these cells. Taken together, this study characterized human breast cancer cell lines with regard to the relationship between H-Ras activation and the invasive phenotype induced by EGF. Our data demonstrate that the activation of H-Ras and the downstream molecule Rac1 correlates with EGF-induced breast cancer cell invasion, providing important information on the regulation of malignant progression in mammary carcinoma cells.", "Eosinophils are major pro-inflammatory cells that make a major contribution to diseases that affect the upper and lower airways, skin and gastrointestinal tract. Interleukin (IL)-5 is central to their maturation and release from the bone marrow together with their subsequent accumulation and activation in the tissues. Mepolizumab is a humanized monoclonal antibody (mAb) with potent IL-5 neutralizing effects that represents a potential treatment for eosinophilic diseases. Several clinical trials with mepolizumab reported that treatment of patients with mild to severe asthma resulted in a substantial reduction in blood and sputum eosinophil numbers. However, clinical outcomes were disappointing as there were no significant effects on airway hyper-reactivity or the late asthmatic reaction to inhaled allergen challenge. More recently two studies, one in in patients with refractory eosinophilic asthma with a history of recurrent severe exacerbations and the other in patients with persistent sputum eosinophilia and symptoms despite systemic treatment with prednisone treatment, reported that monthly intravenous mepolizumab reduced sputum/blood eosinophilia, asthma exacerbations together with improvments in quality of life. Mepolizumab also appears to be an effective therapy for hypereosinophilic syndrome while other trials have shown efficacy of mepolizumab therapy in eosinophilic esophagitis. This review will consider the current status of the clinical development of mepolizumab for diseases with a significant eosinophilic component to their pathology.", "Cone snails (Conidae) are marine predators with some extraordinary features. Their venom contains a hundred or more peptides that target numerous ion channels and receptors in mammals, including several that are involved in disease. omega-Conotoxins from fish hunting snails are 24-27 residue peptides with a rigid 4-loop cysteine framework that target the N-type voltage-gated calcium channel (VGCC). Two omega-conotoxins, MVIIA and CVID are currently in clinical development for chronic pain management (Ziconotide or Prialt, and AM336, respectively). In an attempt to develop small molecule equivalents of CVID, we defined the Calpha-Cbeta vectors of the residues believed to be important for binding to the N-type VGCC. Using these vectors, we undertook a virtual screening of virtual libraries approach to identify compounds that matched the pharmacophore. Cyclic pentapeptides containing residues of loop 2 of CVID, with one or more being a D-amino acid were designed and synthesised and were found to be active at the N-type VGCC (IC50 approximately 20 microM). Agreeing with the specificity profile of CVID, molecules were inactive at the P/Q-type VGCC.", "BACKGROUND AND OBJECTIVES: PDT has been used in the treatment of malignant brain tumors. This communication updates our series of unselected malignant gliomas treated with Photofrin-PDT.STUDY DESIGN AND METHODS: We examined the records of 112 patients with malignant gliomas, metastatic brain tumors and meningiomas treated with Photofrin-PDT at St. Michael's Hospital, Toronto. These patients were treated prior to the onset of ongoing randomized trials in Photofrin PDT or had pathology that excluded them from such trials.RESULTS: The overall post-PDT survival of 96 patients with supratentorial gliomas was 42 weeks, with a 40 and 22% 1- and 2-year survival, respectively. The greater the degree of oligodendroglial involvement the longer was the survival. Seventy-five percent of patients had no significant post-operative complications.CONCLUSIONS: Photofrin-PDT was safe. However, higher light doses than were used in these patients may be required for improved responses." ]

[ "Annexins are a highly conserved protein family that bind to phospholipids in a calcium (Ca2+) - dependent manner. Studies with purified annexins, as well as overexpression and knockdown approaches identified multiple functions predominantly linked to their dynamic and reversible membrane binding behavior. However, most annexins are found at multiple locations and interact with numerous proteins. Furthermore, similar membrane binding characteristics, overlapping localizations and shared interaction partners have complicated identification of their precise functions. To gain insight into annexin function in vivo, mouse models deficient of annexin A1 (AnxA1), A2, A4, A5, A6 and A7 have been generated. Interestingly, with the exception of one study, all mice strains lacking one or even two annexins are viable and develop normally. This suggested redundancy within annexins, but examining these knockout (KO) strains under stress conditions revealed striking phenotypes, identifying underlying mechanisms specific for individual annexins, often supporting Ca2+ homeostasis and membrane transport as central for annexin biology. Conversely, mice lacking AnxA1 or A2 show extracellular functions relevant in health and disease that appear independent of membrane trafficking or Ca2+ signaling. This review will summarize the mechanistic insights gained from studies utilizing mouse models lacking members of the annexin family.", "BACKGROUND AND PURPOSE: Stroke subtypes and prognosis differ among older black patients compared with whites; however, few data are available regarding stroke among young black patients.METHODS: To determine the risk factors for stroke, stroke subtype, and prognosis among young black patients, we retrospectively reviewed the medical records of all 15- to 44-year-old patients admitted with stroke to a university-affiliated public hospital from January 1990 through June 1994.RESULTS: Of the 248 eligible patients admitted with stroke, 219 were blacks. Hypertension was more frequently associated with stroke in young black than in non-black patients (55% versus 24%, P = .003). Cocaine abuse was frequent among both black and non-black patients (27% versus 38%, P = NS). Hypertensive intracerebral hemorrhage (64%) was the most common subtype of intracerebral hemorrhage (n = 67), and lacunar infarction (21%) was the most common subtype of cerebral infarction (n = 112) in young black patients. Outcome in black patients with stroke at discharge was 69% independent, 8% dependent, and 23% dead.CONCLUSIONS: The high frequency of hypertension, hypertensive intracerebral hemorrhage, and lacunar infarction among young black patients with stroke suggests accelerated hypertensive arteriolar damage, possibly due to poor control of hypertension.", "Amyloid fibril formation is associated with a range of neurodegenerative diseases in humans, including Alzheimer's, Parkinson's, and prion diseases. In yeast, amyloid underlies several non-Mendelian phenotypes referred to as yeast prions. Mechanism of amyloid formation is critical for a complete understanding of the yeast prion phenomenon and human amyloid-related diseases. Ure2 protein is the basis of yeast prion [URE3]. The Ure2p prion domain is largely disordered. Residual structures, if any, in the disordered region may play an important role in the aggregation process. Studies of Ure2p prion domain are complicated by its high aggregation propensity, which results in a mixture of monomer and aggregates in solution. Previously we have developed a solid-support electron paramagnetic resonance (EPR) approach to address this problem and have identified a structured state for the Alzheimer's amyloid-β monomer. Here we use solid-support EPR to study the structure of Ure2p prion domain. EPR spectra of Ure2p prion domain with spin labels at every fifth residue from position 10 to position 75 show similar residue mobility profile for denaturing and native buffers after accounting for the effect of solution viscosity. These results suggest that Ure2p prion domain adopts a completely disordered structure in the native buffer. A completely disordered Ure2p prion domain implies that the amyloid formation of Ure2p, and likely other Q/N-rich yeast prion proteins, is primarily driven by inter-molecular interactions.", "Primary mucosal melanoma of the oral cavity is an exceedingly rare neoplasm which is estimated to comprise 1-2% of all oral malignancies. In contrast to cutaneous melanomas, the risk factors and pathogenesis are poorly understood. The predominate localization of primary oral melanoma is hard palate and maxillary alveolus. Dermoscopy may be utilized as an adjunctive tool in the clinical differential diagnosis of oral mucosal melanoma whenever the lesion is accessible with a dermoscope. Surgery is the mainstay of treatment, but it may be challenging depending on the location of the tumor within the oral cavity and its size. Adjuvant therapy with dacarbazine, platinum analogs, nitrosoureas and interleukin-2 have been utilized with low response rates. Imatinib may be effective for patients with with c-Kit gene mutations. Sunitinib and dasatinib have been reported effective in selected cases. Vemurafenib and dabrafenib are targeted agents for patients with BRAF mutation-positive melanoma. Ipilimumab, an anti-cytotoxic T-lymphocyte antigen 4 antibody and pembrolizumab, a monoclonal antibody targeting programmed death 1 receptor may be a feasible treatment option in patients with metastatic mucosal melanoma.", "Neurofibromatosis type 1 (NF1) is a dominant genetic disorder that causes tumors of the peripheral nervous system. In addition, >40% of afflicted children have learning difficulties. The NF1 protein contains a highly conserved GTPase-activating protein domain that inhibits Ras activity, and the C-terminal region regulates cAMP levels via G-protein-dependent activation of adenylyl cyclase. Behavioral analysis indicates that learning is disrupted in both Drosophila and mouse NF1 models. Our previous work has shown that defective cAMP signaling leads to the learning phenotype in Drosophila Nf1 mutants. In the present report, our experiments showed that in addition to learning, long-term memory was also abolished in Nf1 mutants. However, altered NF1-regulated Ras activity is responsible for this defect rather than altered cAMP levels. Furthermore, by expressing clinically relevant human NF1 mutations and deletions in Drosophila Nf1-null mutants, we demonstrated that the GAP-related domain of NF1 was necessary and sufficient for long-term memory, whereas the C-terminal domain of NF1 was essential for immediate memory. Thus, we show that two separate functional domains of the same protein can participate independently in the formation of two distinct memory components.", "The COP9 signalosome (CSN) is an essential regulator of cullin-RING-ubiquitin (Ub) ligases (CRLs), which ubiquitinate important cellular regulators and target them for degradation by the Ub proteasome system (UPS). The CSN exhibits deneddylating activity localized on subunit CSN5, which removes the ubiquitin-like protein Nedd8 from the cullins of CRLs. CSN-mediated deneddylation is an important step in the process of CRL remodeling, in which new substrate recognition units are incorporated into Ub ligases to meet changed requirements for proteolysis in cells. For instance, extensive CRL remodeling occurs during adipogenic differentiation when new CRL3s are formed. Diversification of CSN complexes during evolution is most likely another adaptation to meet different cellular requirements. Best known CSN variants are formed by different CSN subunit isoforms. For instance, in plant cells, isoforms have been identified for the MPN-domain subunits CSN5 (CSN5A and CSN5B) and CSN6 (CSN6A and CSN6B) which form four distinct CSN variants. In mammalian cells CSNCSN7A and CSNCSN7B variants are generated by CSN7 isoforms. We demonstrate that the two variants coexist in human LiSa-2 cells and in mouse embryonic fibroblasts. During adipogenic differentiation of LiSa-2 cells CSN7B increases in parallel with an elevation of the total CSN complex. Permanent overexpression of Flag-CSN7B but not of Flag-CSN7A accelerates adipogenesis in LiSa-2 cells indicating a specific function of the CSNCSN7B variant in stimulating adipogenesis. Silencing of CSN7A as well as of CSN7B in LiSa-2 cells and in mouse embryonic fibroblasts (MEFs) reduces adipogenic differentiation demonstrating that both CSNCSN7A and CSNCSN7B variants are involved in the process.", "Neurofibromatosis 1 (NF1) is a common single-gene disorder that causes learning impairments in patients. Neurofibromin encoded by the NF1 causal gene regulates Ras/MAPK and cAMP signaling pathways. These signaling pathways play critical roles in controlling gene transcription during synaptic plasticity and memory formation. We hypothesized that NF1 mutations disturb the expression of genes important for memory formation. To test this hypothesis, we performed DNA microarray analysis on the hippocampus of NF1(+/-) mice, the mouse model for NF1 learning disabilities. Our results indicated that genes involved in a wide spectrum of biological processes are dysregulated in the NF1(+/-) hippocampus. Many of the NF1-affected genes play critical roles in synaptic plasticity, such as Rabs, synaptotagmins, NMDAR1, CaMKII, and CREB1. Because NF1-associated learning disabilities can be reversed by lovastatin, we also determined the effect of lovastatin treatment on genome-wide expression patterns of the NF1(+/-) hippocampus. We found that lovastatin altered the expression of a large number of genes, including those disturbed by NF1 mutations. Our results reveal a genome-wide overview of the molecular abnormalities in the NF1(+/-) hippocampus and should be useful for further identifying the novel molecular pathways that cause NF1 learning deficits.", "Author information:(1)Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, PR China.(2)Department of Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, PR China.(3)Department of Neurosurgery, General Hospital of Jinan Military Command, Jinan 250031, PR China.(4)Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China. Electronic address: xcju@ion.ac.cn.(5)Department of Gynecology Oncology, The Tumor Hospital, Harbin Medical University, Harbin, 150086, PR China. Electronic address: louge@ems.hrbmu.edu.cn.(6)Institute of Nano Biomedicine and Engineering, Shanghai Engineering Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai 200240, PR China; National Center for Translational Medicine, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, Shanghai 200240, PR China; Shaanxi Key Laboratory of Brain Disorders and School of Basic Medical Sciences, Xi'an Medical University, Xi'an 710021, PR China. Electronic address: weilinjin@yahoo.com." ]

[ "The gene coding for the metabolically stable 6S RNA of Escherichia coli has been cloned, sequenced, and partially characterized in expression analyses. The DNA sequence results confirm the accuracy of the previously established RNA sequence and, with genomic hybridization data, reveal that there is only one copy of the 6S DNA in the chromosome. Consistent with its relaxed mode of expression, the promoter region of the 6S RNA gene was found to lack the hypothetical GC-rich discriminator domain common to other stable RNA genes under stringent control. The sequence results also revealed the occurrence of a 540-base-pair open reading frame immediately downstream from the 6S RNA coding region. Results from the expression analyses show that the protein and RNA coding regions are cotranscribed in vitro and that the open reading frame is translated in vivo.", "Thyrotropin-releasing hormone (TRH) plays an important role in central cardiovascular regulation. Recently, we described that the TRH precursor gene overexpression induces hypertension in the normal rat. In addition, we published that spontaneously hypertensive rats (SHR) have central extrahypothalamic TRH hyperactivity with increased TRH synthesis and release and an elevated TRH receptor number. In the present study, we report that intracerebroventricular antisense (AS) treatment with a phosphorothioate oligonucleotide against the TRH precursor gene significantly diminished up to 72 hours and in a dose-dependent manner the increased diencephalic TRH content, whereas normalized systolic blood pressure (SABP) was present in the SHR compared with Wistar-Kyoto (WKY) rats. Although basal thyrotropin was higher in SHR compared with WKY rats and this difference disappeared after antisense treatment, no differences were observed in plasma T4 or T3 between strains with or without AS treatment, indicating that the effect of the AS on SABP was independent of the thyroid status. Because the encephalic renin-angiotensin system seems to be crucial in the development and/or maintenance of hypertension in SHR, we investigated the effect of antisense inhibition of TRH on that system and found that TRH antisense treatment significantly diminished the elevated diencephalic angiotensin II (Ang II) content in the SHR without any effect in control animals, suggesting that the Ang II system is involved in the TRH cardiovascular effects. To summarize, the central TRH system seems to be involved in the etiopathogenesis of hypertension in this model of essential hypertension.", "The complex language of eukaryotic gene expression remains incompletely understood. Despite the importance suggested by many noncoding variants statistically associated with human disease, nearly all such variants have unknown mechanisms. Here, we address this challenge using an approach based on a recent machine learning advance-deep convolutional neural networks (CNNs). We introduce the open source package Basset to apply CNNs to learn the functional activity of DNA sequences from genomics data. We trained Basset on a compendium of accessible genomic sites mapped in 164 cell types by DNase-seq, and demonstrate greater predictive accuracy than previous methods. Basset predictions for the change in accessibility between variant alleles were far greater for Genome-wide association study (GWAS) SNPs that are likely to be causal relative to nearby SNPs in linkage disequilibrium with them. With Basset, a researcher can perform a single sequencing assay in their cell type of interest and simultaneously learn that cell's chromatin accessibility code and annotate every mutation in the genome with its influence on present accessibility and latent potential for accessibility. Thus, Basset offers a powerful computational approach to annotate and interpret the noncoding genome.", "Author information:(1)Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.(2)Department of Biology, University of Miami, Miami, FL 33146, USA.(3)Department of Otology and Laryngology, Harvard Medical School and Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston 02114, USA; Department of Otology and Skull Base Surgery, Eye, Ear, Nose and Throat Hospital, Shanghai Medical College, Fudan University, Shanghai, China.(4)Department of Otology and Laryngology, Harvard Medical School and Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston 02114, USA; Department of Otolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.(5)Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan, China.(6)Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital Central South University, Changsha, Hunan, China.(7)Department of Otolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.(8)Department of Otolaryngology-Head and Neck Surgery, Chinese PLA General Hospital, Beijing, China.(9)Department of Otology and Laryngology, Harvard Medical School and Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston 02114, USA. Electronic address: zheng-yi_chen@meei.harvard.edu.(10)Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital Central South University, Changsha, Hunan, China; Department of Otolaryngology-Head and Neck Surgery, Chinese PLA General Hospital, Beijing, China. Electronic address: xliu@med.miami.edu.", "BACKGROUND: Among men with high-risk non-metastatic castrate-resistant prostate cancer (nmCRPC), we used network meta-analysis to compare non-steroidal anti-androgens (NSAAs) and stratified class-level meta-analysis to identify subgroups with particular benefit from NSAAs with androgen deprivation therapy versus androgen deprivation therapy alone.MATERIALS AND METHODS: We performed a systematic review of phase III parallel-group randomized controlled trials in adult men with nmCRPC. Primary outcome was metastasis-free survival (MFS). Secondary outcomes included overall survival (OS), prostate-specific antigen (PSA) progression-free survival (PFS), and rates of grade 3 to 4 adverse events (AEs). We assessed class-level effects using random effects models; effect modification owing to subgroup effects using random-effects models to pool study-level differences; and comparative outcomes between agents using fixed-effect network models in a Bayesian framework.RESULTS: Three randomized controlled trials were identified. Pooled MFS, PSA-PFS, and OS were significantly greater with NSAA versus placebo (hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.25-0.41; HR, 0.08; 95% CI, 0.05-0.13; and HR, 0.74; 95% CI, 0.61-0.90, respectively). Subgroup analysis demonstrated a greater benefit with NSAAs in men with Eastern Cooperative Oncology Group performance status 0 (HR, 0.30; 95% CI, 0.24-0.38) versus 1 (HR, 0.45; 95% CI, 0.36-0.56; P = .005), but no difference owing to PSA doubling time (P = .43) or use of osteoclast targeting therapy (P = .77). Bayesian analysis showed apalutamide and enzalutamide had a 56% and 44% likelihood of maximizing MFS, respectively, with subgroup analysis demonstrating these agents were preferred regardless of PSA doubling time and performance status. There was a 44%, 41%, and 15% likelihood that apalutamide, darolutamide and enzalutamide offered the greatest OS benefit, respectively. Grade 3 to 4 AEs were more common with NSAAs (odds ratio [OR], 1.47; 95% CI, 1.27-1.71) and there was a 61% chance that darolutamide was preferred.CONCLUSIONS: NSAAs improve survival in high-risk nmCRPC. Apalutamide and enzalutamide may result in improved oncologic outcomes. Darolutamide may result in fewer AEs. Phase IV data are needed to validate these findings.", "A 45 year-old male with a butterfly glioma received stereotactic biopsy for histologic confirmation of the clinical diagnosis. Microscopically, the results were controversial since some biopsy specimens showed distinct inflammatory changes, while others displayed typical features of a malignant glioma. The patient died four days after the stereotactic approach due to therapy-resistant intracranial pressure rise. In addition to a large butterfly glioblastoma originating from the frontal part of the corpus callosum, neuropathologic examination revealed a mycotic encephalitis with formation of numerous fungi-containing inflammatory foci in all parts of the brain and in the glioma. General autopsy disclosed pulmonary aspergillosis as the source of the inflammatory spread. A previous steroid medication over several weeks for treatment of increased intracranial pressure may be considered as an important factor in the origin of the pulmonary aspergillosis complicating the butterfly glioma.", "CONTEXT: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown.OBJECTIVE: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA).DESIGN: This was a multicenter, international, collaborative study.SETTING: The study was conducted in 34 university endocrinology and genetics departments in nine countries.PATIENTS: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis.MAIN OUTCOME MEASURES: Presence/absence and description of AIP gene mutations were the main outcome measures.INTERVENTION: There was no intervention.RESULTS: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations.CONCLUSIONS: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.", "BACKGROUND: Nuclease-based technologies have been developed that enable targeting of specific DNA sequences directly in the zygote. These approaches provide an opportunity to modify the genomes of inbred mice, and allow the removal of strain-specific mutations that confound phenotypic assessment. One such mutation is the Cdh23 (ahl) allele, present in several commonly used inbred mouse strains, which predisposes to age-related progressive hearing loss.RESULTS: We have used targeted CRISPR/Cas9-mediated homology directed repair (HDR) to correct the Cdh23 (ahl) allele directly in C57BL/6NTac zygotes. Employing offset-nicking Cas9 (D10A) nickase with paired RNA guides and a single-stranded oligonucleotide donor template we show that allele repair was successfully achieved. To investigate potential Cas9-mediated 'off-target' mutations in our corrected mouse, we undertook whole-genome sequencing and assessed the 'off-target' sites predicted for the guide RNAs (≤4 nucleotide mis-matches). No induced sequence changes were identified at any of these sites. Correction of the progressive hearing loss phenotype was demonstrated using auditory-evoked brainstem response testing of mice at 24 and 36 weeks of age, and rescue of the progressive loss of sensory hair cell stereocilia bundles was confirmed using scanning electron microscopy of dissected cochleae from 36-week-old mice.CONCLUSIONS: CRISPR/Cas9-mediated HDR has been successfully utilised to efficiently correct the Cdh23 (ahl) allele in C57BL/6NTac mice, and rescue the associated auditory phenotype. The corrected mice described in this report will allow age-related auditory phenotyping studies to be undertaken using C57BL/6NTac-derived models, such as those generated by the International Mouse Phenotyping Consortium (IMPC) programme.", "Castleman's disease is a rare disorder, yet a rarer newly described syndrome called TAFRO syndrome was discovered to accompany it. TAFRO represents the constellation of symptoms (Thrombocytopenia, Anasarca, MyeloFibrosis, Renal failure, Organomegaly). Most cases were described in Japan. We present the first case of TAFRO syndrome in Syria. A 58-year-old Caucasian male with no relevant history presented with fatigue, oliguria, decreased platelets, increased creatinine level, hepatosplenomegaly, ascites, pitting edema and lymph node enlargement. Possible differential diagnoses were excluded by laboratory, radiologic and cytologic tests including TB, malignancy and autoimmune diseases. A biopsy of a supraclavicular lymph node confirmed Castleman disease. Our patient had Catleman's disease, and presented with only four diagnostic criteria for TAFRO syndrome (Myelofibrosis was absent) in addition to other minor characteristics (microcytic anemia, negative HIV and HHV-8 infections.) which make the presentation consistent with TAFRO syndrome described in the Japanese cases. The criteria for diagnosing TAFRO syndrome are still changing, and the pathophysiology behind it is unclear. We recommend further research to understand this syndrome taking into account that its prevalence might be worldwide.", "Gemcitabine is indicated in combination with cisplatin as first-line therapy for solid tumours including non-small cell lung cancer (NSCLC), bladder cancer and mesothelioma. Gemcitabine is an analogue of pyrimidine cytosine and functions as an anti-metabolite. Structurally, however, gemcitabine has similarities to 5-aza-2-deoxycytidine (decitabine/Dacogen®), a DNA methyltransferase inhibitor (DNMTi). NSCLC, mesothelioma and prostate cancer cell lines were treated with decitabine and gemcitabine. Reactivation of epigenetically silenced genes was examined by RT-PCR/qPCR. DNA methyltransferase activity in nuclear extracts and recombinant proteins was measured using a DNA methyl-transferase assay, and alterations in DNA methylation status were examined using methylation-specific PCR (MS-PCR) and pyrosequencing. We observe a reactivation of several epigenetically silenced genes including GSTP1, IGFBP3 and RASSF1A. Gemcitabine functionally inhibited DNA methyltransferase activity in both nuclear extracts and recombinant proteins. Gemcitabine dramatically destabilised DNMT1 protein. However, DNA CpG methylation was for the most part unaffected by gemcitabine. In conclusion, gemcitabine both inhibits and destabilises DNA methyltransferases and reactivates epigenetically silenced genes having activity equivalent to decitabine at concentrations significantly lower than those achieved in the treatment of patients with solid tumours. This property may contribute to the anticancer activity of gemcitabine.", "The genetic correction of induced pluripotent stem cells (iPSCs) induced from somatic cells of patients with sensorineural hearing loss (caused by hereditary factors) is a promising method for its treatment. The correction of gene mutations in iPSCs could restore the normal function of cells and provide a rich source of cells for transplantation. In the present study, iPSCs were generated from a deaf patient with compound heterozygous MYO7A mutations (c.1184G>A and c.4118C>T; P-iPSCs), the asymptomatic father of the patient (MYO7A c.1184G>A mutation; CF-iPSCs), and a normal donor (MYO7A(WT/WT); C-iPSCs). One of MYO7A mutation sites (c.4118C>T) in the P-iPSCs was corrected using CRISPR/Cas9. The corrected iPSCs (CP-iPSCs) retained cell pluripotency and normal karyotypes. Hair cell-like cells induced from CP-iPSCs showed restored organization of stereocilia-like protrusions; moreover, the electrophysiological function of these cells was similar to that of cells induced from C-iPSCs and CF-iPSCs. These results might facilitate the development of iPSC-based gene therapy for genetic disorders.SIGNIFICANCE: Induced pluripotent stem cells (iPSCs) were generated from a deaf patient with compound heterozygous MYO7A mutations (c.1184G>A and c.4118C>T). One of the MYO7A mutation sites (c.4118C>T) in the iPSCs was corrected using CRISPR/Cas9. The genetic correction of MYO7A mutation resulted in morphologic and functional recovery of hair cell-like cells derived from iPSCs. These findings confirm the hypothesis that MYO7A plays an important role in the assembly of stereocilia into stereociliary bundles. Thus, the present study might provide further insight into the pathogenesis of sensorineural hearing loss and facilitate the development of therapeutic strategies against monogenic disease through the genetic repair of patient-specific iPSCs.", "Prevention and correction of oxidative DNA lesions in Pseudomonas aeruginosa is ensured by the DNA oxidative repair system (GO). Single inactivation of mutT, mutY and mutM involved in GO led to elevated mutation rates (MRs) that correlated to increased development of resistance to antibiotics. In this study, we constructed a double mutant in mutY and mutM (PAOMY-Mgm) and characterized the phenotype and the gene expression profile using microarray and RT-PCR. PAOMY-Mgm presented 28-fold increases in MR compared with wild-type reference strain PAO1. In comparison, the PAOMYgm (mutY) single mutant showed only a fivefold increase, whereas the single mutant PAOMMgm (mutM) showed a nonsignificant increase in MR compared with PAO1 and the single mutants. Mutations in the regulator nfxB leading to hyperexpression of MexCD-OprJ efflux pump were found as the mechanism of resistance to ciprofloxacin in the double mutant. A better fitness of the mutator compared with PAO1 was found in growth competition experiments in the presence of ciprofloxacin at concentrations just below minimal inhibitory concentration. Up-regulation of the antimutator gene pfpI, that has been shown to provide protection to oxidative stress, was found in PAOMY-Mgm compared with PAO1. In conclusion, we showed that MutY and MutM are cooperating in the GO of P. aeruginosa, and that oxidative DNA lesions might represent an oxidative stress for the bacteria.", "Mitochondria are essential and dynamic organelles in eukaryotes. Cardiolipin (CL) is a key phospholipid in mitochondrial membranes, playing important roles in maintaining the functional integrity and dynamics of mitochondria in animals and yeasts. However, CL's role in plants is just beginning to be elucidated. In this study, we used Arabidopsis thaliana to examine the subcellular distribution of CL and CARDIOLIPIN SYNTHASE (CLS) and analyzed loss-of-function cls mutants for defects in mitochondrial morphogenesis and stress response. We show that CL localizes to mitochondria and is enriched at specific domains, and CLS targets to the inner membrane of mitochondria with its C terminus in the intermembrane space. Furthermore, cls mutants exhibit significantly impaired growth as well as altered structural integrity and morphogenesis of mitochondria. In contrast to animals and yeasts, in which CL's effect on mitochondrial fusion is more profound, Arabidopsis CL plays a dominant role in mitochondrial fission and exerts this function, at least in part, through stabilizing the protein complex of the major mitochondrial fission factor, DYNAMIN-RELATED PROTEIN3. CL also plays a role in plant responses to heat and extended darkness, stresses that induce programmed cell death. Our study has uncovered conserved and plant-specific aspects of CL biology in mitochondrial dynamics and the organism response to environmental stresses.", "Trastuzumab (Herceptin®), a monoclonal antibody against the ErbB2 (HER2) receptor, has significantly improved clinical outcomes for HER2+ breast cancer patients. However, the drug also has known cardiotoxic side effects through mechanisms that are not fully understood. Here we utilized human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) to model trastuzumab-related cardiotoxicity in vitro. We demonstrate that cardiotoxic effects of ErbB2 inhibition by trastuzumab can be recapitulated only when the cardioprotective effects of ErbB2/4 signaling is observed. We observed no cardioprotective effects of ErbB2/4 signaling without cellular stress (doxorubicin exposure in this study). In addition to neuregulin-1 (NRG-1), we show that heparin-binding epidermal growth factor-like growth factor (HB-EGF) also provides cardioprotective effects for iPS-CMs. Finally, we demonstrate a simple, high-throughput co-culture platform utilizing iPS-CMs and endothelial cells that is capable of detecting trastuzumab-related cardiotoxicity. We conclude that iPS-CMs can recapitulate trastuzumab-related cardiotoxicity, and may be used to elucidate additional modes of toxicity of trastuzumab and related compounds.", "Deafness or hearing loss is a major issue in human health. Inner ear hair cells are the main sensory receptors responsible for hearing. Defects in hair cells are one of the major causes of deafness. A combination of induced pluripotent stem cell (iPSC) technology with genome-editing technology may provide an attractive cell-based strategy to regenerate hair cells and treat hereditary deafness in humans. Here, we report the generation of iPSCs from members of a Chinese family carrying MYO15A c.4642G>A and c.8374G>A mutations and the induction of hair cell-like cells from those iPSCs. The compound heterozygous MYO15A mutations resulted in abnormal morphology and dysfunction of the derived hair cell-like cells. We used a CRISPR/Cas9 approach to genetically correct the MYO15A mutation in the iPSCs and rescued the morphology and function of the derived hair cell-like cells. Our data demonstrate the feasibility of generating inner ear hair cells from human iPSCs and the functional rescue of gene mutation-based deafness by using genetic correction.", "CCN1 is a matricellular protein and a member of the CCN family of growth factors. CCN1 is associated with the development of various cancers including pancreatic ductal adenocarcinoma (PDAC). Our recent studies found that CCN1 plays a critical role in pancreatic carcinogenesis through the induction of EMT and stemness. CCN1 mRNA and protein were detected in the early precursor lesions, and their expression intensified with disease progression. However, biochemical activity and the molecular targets of CCN1 in pancreatic cancer cells are unknown. Here we show that CCN1 regulates the Sonic Hedgehog (SHh) signaling pathway, which is associated with the PDAC progression and poor prognosis. SHh regulation by CCN1 in pancreatic cancer cells is mediated through the active Notch-1. Notably, active Notch-1is recruited by CCN1 in these cells via the inhibition of proteasomal degradation results in stabilization of the receptor. We find that CCN1-induced activation of SHh signaling might be necessary for CCN1-dependent in vitro pancreatic cancer cell migration and tumorigenicity of the side population of pancreatic cancer cells (cancer stem cells) in a xenograft in nude mice. Moreover, the functional role of CCN1 could be mediated through the interaction with the αvβ3 integrin receptor. These extensive studies propose that targeting CCN1 can provide a new treatment option for patients with pancreatic cancer since blocking CCN1 simultaneously blocks two critical pathways (i.e. SHh and Notch1) associated with the development of the disease as well as drug resistance." ]

[ "BACKGROUND: The rapid publication of important research in the biomedical literature makes it increasingly difficult for researchers to keep current with significant work in their area of interest.RESULTS: This paper reports a scalable method for the discovery of protein-protein interactions in Medline abstracts, using a combination of text analytics, statistical and graphical analysis, and a set of easily implemented rules. Applying these techniques to 12,300 abstracts, a precision of 0.61 and a recall of 0.97 were obtained, (f = 0.74) and when allowing for two-hop and three-hop relations discovered by graphical analysis, the precision was 0.74 (f = 0.83).CONCLUSION: This combination of linguistic and statistical approaches appears to provide the highest precision and recall thus far reported in detecting protein-protein relations using text analytic approaches.", "Author information:(1)Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, & Sense Organs, University of Bari Aldo Moro, Bari, Italy.(2)Department of Clinical Research in Neurology, University of Bari Aldo Moro, 'Pia Fondazione Cardinale G. Panico,' Tricase, Lecce, Italy.(3)Geriatric Unit & Laboratory of Gerontology & Geriatrics, Department of Medical Sciences, IRCCS 'Casa Sollievo della Sofferenza,' San Giovanni Rotondo, Foggia, Italy.(4)Geriatric Medicine-Memory Unit & Rare Disease Centre, University of Bari Aldo Moro, Bari, Italy.(5)Research & Development Department, Chiesi Farmaceutici, Parma, Italy.(6)Physical Medicine & Rehabilitation Section, 'OORR' Hospital, University of Foggia, Foggia, Italy.(7)Psychiatric Unit, Department of Basic Medicine, Neuroscience, & Sense Organs, University of Bari Aldo Moro, Bari, Italy.(8)Department of OrthoGeriatrics, Rehabilitation & Stabilization, Frailty Area, E.O. Galliera NR-HS Hospital, Genova, Italy.(9)Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy.", "Understanding how silent genes can be competent for activation provides insight into development as well as cellular reprogramming and pathogenesis. We performed genomic location analysis of the pioneer transcription factor FoxA in the adult mouse liver and found that about one-third of the FoxA bound sites are near silent genes, including genes without detectable RNA polymerase II. Virtually all of the FoxA-bound silent sites are within conserved sequences, suggesting possible function. Such sites are enriched in motifs for transcriptional repressors, including for Rfx1 and type II nuclear hormone receptors. We found one such target site at a cryptic \"shadow\" enhancer 7 kilobases (kb) downstream of the Cdx2 gene, where Rfx1 restricts transcriptional activation by FoxA. The Cdx2 shadow enhancer exhibits a subset of regulatory properties of the upstream Cdx2 promoter region. While Cdx2 is ectopically induced in the early metaplastic condition of Barrett's esophagus, its expression is not necessarily present in progressive Barrett's with dysplasia or adenocarcinoma. By contrast, we find that Rfx1 expression in the esophageal epithelium becomes gradually extinguished during progression to cancer, i.e, expression of Rfx1 decreased markedly in dysplasia and adenocarcinoma. We propose that this decreased expression of Rfx1 could be an indicator of progression from Barrett's esophagus to adenocarcinoma and that similar analyses of other transcription factors bound to silent genes can reveal unanticipated regulatory insights into oncogenic progression and cellular reprogramming.", "AIM: Mutations in the SLC16A2 gene have been implicated in Allan-Herndon-Dudley syndrome (AHDS), an X-linked learning disability* syndrome associated with thyroid function test (TFT) abnormalities. Delayed myelination is a non-specific finding in individuals with learning disability whose genetic basis is often uncertain. The aim of this study was to describe neuroimaging findings and neurological features in males with SLC16A2 gene mutations.METHOD: We reviewed brain magnetic resonance imaging (MRI) findings and neurological features in a cohort of five males aged between 1 year 6 months and 6 years (median 4y) from four families harbouring SLC16A2 gene mutations.RESULTS: The participants presented aged between 4 and 9 months with initial hypotonia and subsequent spastic paraparesis with dystonic posturing and superimposed paroxysmal dyskinesias. Dystonic cerebral palsy was the most common initial clinical diagnosis, and AHDS was suspected only retrospectively, considering the characteristically abnormal thyroid function tests, with high serum tri-iodothyronine (T(3)), as the most consistent finding. Brain MRI showed absent or markedly delayed myelination in all five participants, prompting the suspicion of Pelizaeus-Merzbacher disease in one patient.INTERPRETATION: Our findings indicate a consistent association between defective neuronal T(3) uptake and delayed myelination. SLC16A2 involvement should be considered in males with learning disability, an associated motor or movement disorder, and evidence of delayed myelination on brain MRI. Although dysmorphic features suggestive of AHDS are not always present, T(3) measurement is a reliable screening test.", "PURPOSE: The phenotypic manifestations of cerebral cavernous malformation disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase-mediated hyperpermeability, a potential therapeutic target, has not been established.METHODS: We analyzed PDCD10 small interfering RNA-treated endothelial cells for stress fibers, Rho kinase activity, and permeability. Rho kinase activity was assessed in cerebral cavernous malformation lesions. Brain permeability and cerebral cavernous malformation lesion burden were quantified, and clinical manifestations were assessed in prospectively enrolled subjects with PDCD10 mutations.RESULTS: We determined that PDCD10 protein suppresses endothelial stress fibers, Rho kinase activity, and permeability in vitro. Pdcd10 heterozygous mice have greater lesion burden than other Ccm genotypes. We demonstrated robust Rho kinase activity in murine and human cerebral cavernous malformation vasculature and increased brain vascular permeability in humans with PDCD10 mutation. Clinical phenotype is exceptionally aggressive compared with the more common KRIT1 and CCM2 familial and sporadic cerebral cavernous malformation, with greater lesion burden and more frequent hemorrhages earlier in life. We first report other phenotypic features, including scoliosis, cognitive disability, and skin lesions, unrelated to lesion burden or bleeding.CONCLUSION: These findings define a unique cerebral cavernous malformation disease with exceptional aggressiveness, and they inform preclinical therapeutic testing, clinical counseling, and the design of trials.Genet Med 17 3, 188-196.", "BACKGROUND: Lbx/ladybird genes originated as part of the metazoan cluster of Nk homeobox genes. In all animals investigated so far, both the protostome genes and the vertebrate Lbx1 genes were found to play crucial roles in neural and muscle development. Recently however, additional Lbx genes with divergent expression patterns were discovered in amniotes. Early in the evolution of vertebrates, two rounds of whole genome duplication are thought to have occurred, during which 4 Lbx genes were generated. Which of these genes were maintained in extant vertebrates, and how these genes and their functions evolved, is not known.RESULTS: Here we searched vertebrate genomes for Lbx genes and discovered novel members of this gene family. We also identified signature genes linked to particular Lbx loci and traced the remnants of 4 Lbx paralogons (two of which retain Lbx genes) in amniotes. In teleosts, that have undergone an additional genome duplication, 8 Lbx paralogons (three of which retain Lbx genes) were found. Phylogenetic analyses of Lbx and Lbx-associated genes show that in extant, bony vertebrates only Lbx1- and Lbx2-type genes are maintained. Of these, some Lbx2 sequences evolved faster and were probably subject to neofunctionalisation, while Lbx1 genes may have retained more features of the ancestral Lbx gene. Genes at Lbx1 and former Lbx4 loci are more closely related, as are genes at Lbx2 and former Lbx3 loci. This suggests that during the second vertebrate genome duplication, Lbx1/4 and Lbx2/3 paralogons were generated from the duplicated Lbx loci created during the first duplication event.CONCLUSION: Our study establishes for the first time the evolutionary history of Lbx genes in bony vertebrates, including the order of gene duplication events, gene loss and phylogenetic relationships. Moreover, we identified genetic hallmarks for each of the Lbx paralogons that can be used to trace Lbx genes as other vertebrate genomes become available. Significantly, we show that bony vertebrates only retained copies of Lbx1 and Lbx2 genes, with some Lbx2 genes being highly divergent. Thus, we have established a base on which the evolution of Lbx gene function in vertebrate development can be evaluated.", "The mechanism of RNA degradation in Escherichia coli involves endonucleolytic cleavage, polyadenylation of the cleavage product by poly(A) polymerase, and exonucleolytic degradation by the exoribonucleases, polynucleotide phosphorylase (PNPase) and RNase II. The poly(A) tails are homogenous, containing only adenosines in most of the growth conditions. In the chloroplast, however, the same enzyme, PNPase, polyadenylates and degrades the RNA molecule; there is no equivalent for the E. coli poly(A) polymerase enzyme. Because cyanobacteria is a prokaryote believed to be related to the evolutionary ancestor of the chloroplast, we asked whether the molecular mechanism of RNA polyadenylation in the Synechocystis PCC6803 cyanobacteria is similar to that in E. coli or the chloroplast. We found that RNA polyadenylation in Synechocystis is similar to that in the chloroplast but different from E. coli. No poly(A) polymerase enzyme exists, and polyadenylation is performed by PNPase, resulting in heterogeneous poly(A)-rich tails. These heterogeneous tails were found in the amino acid coding region, the 5' and 3' untranslated regions of mRNAs, as well as in rRNA and the single intron located at the tRNA(fmet). Furthermore, unlike E. coli, the inactivation of PNPase or RNase II genes caused lethality. Together, our results show that the RNA polyadenylation and degradation mechanisms in cyanobacteria and chloroplast are very similar to each other but different from E. coli." ]

[ "Cytokines, growth factors, and other chemical messengers rely on a class of intracellular nonreceptor tyrosine kinases known as Janus kinases (JAKs) to rapidly transduce intracellular signals. A number of these cytokines are critical for lymphocyte development and mediating immune responses. JAK3 is of particular interest due to its importance in immune function and its expression, which is largely confined to lymphocytes, thus limiting the potential impact of JAK3 inhibition on nonimmune physiology. The aim of this study was to evaluate the potency and selectivity of the investigational JAK3 inhibitor VX-509 (decernotinib) [(R)-2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide] against JAK3 kinase activity and inhibition of JAK3-mediated signaling in vitro and JAK3-dependent physiologic processes in vivo. These results demonstrate that VX-509 potently inhibits JAK3 in enzyme assays (Ki = 2.5 nM + 0.7 nM) and cellular assays dependent on JAK3 activity (IC50 range, 50-170 nM), with limited or no measurable potency against other JAK isotypes or non-JAK kinases. VX-509 also showed activity in two animal models of aberrant immune function. VX-509 treatment resulted in dose-dependent reduction in ankle swelling and paw weight and improved paw histopathology scores in the rat collagen-induced arthritis model. In a mouse model of oxazolone-induced delayed-type hypersensitivity, VX-509 reduced the T cell-mediated inflammatory response in skin. These findings demonstrate that VX-509 is a selective and potent inhibitor of JAK3 in vitro and modulates proinflammatory response in models of immune-mediated diseases, such as collagen-induced arthritis and delayed-type hypersensitivity. The data support evaluation of VX-509 for treatment of patients with autoimmune and inflammatory diseases such as rheumatoid arthritis.", "IMPORTANCE: Dysregulation of the mesenchymal-epithelial transition (MET) signaling pathway is associated with poor prognosis in gastroesophageal adenocarcinoma (GEC). We report results of METGastric, a phase 3 trial of the MET inhibitor onartuzumab plus standard first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative, MET-positive, advanced GEC.OBJECTIVE: To determine whether the addition of onartuzumab to first-line fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) improves efficacy compared with mFOLFOX6 plus placebo in HER2-negative, MET-positive GEC.DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, multicenter trial conducted from November 2012 to March 2014. Patients were 18 years or older with an adenocarcinoma of the stomach or gastroesophageal junction with metastatic disease not amenable for curative therapy. Tumor samples were centrally tested for MET expression using Ventana anti-Total c-MET (SP44) rabbit monoclonal antibody, HER2 status, and Lauren histologic subtype. MET-positive tumors were defined as at least 50% of tumor cells showing weak, moderate, and/or strong staining intensity (MET 1+/2+/3+, respectively) by immunohistochemistry.INTERVENTIONS: Patients with HER2-negative, MET-positive GEC were enrolled and randomized 1:1 to receive mFOLFOX6 with or without onartuzumab (10 mg/kg).MAIN OUTCOMES AND MEASURES: Co-primary end points: overall survival in the intent-to-treat (ITT) population and in patients with MET 2+/3+ GEC. Secondary end points: progression-free survival (PFS), overall response rate (ORR), and safety.RESULTS: Enrollment was stopped early due to sponsor decision, which was agreed with an independent data monitoring committee. At the data cutoff (April 25, 2014) there were 562 patients in the ITT population (n = 283 placebo plus mFOLFOX6 [median age, 58 y; 65% male]; n = 279 onartuzumab plus mFOLFOX6 [median age, 60 y; 67% male]); 109 (38.5%) and 105 (37.6%) of the ITT population were MET 2+/3+, respectively. Addition of onartuzumab to mFOLFOX6 did not significantly improve OS, PFS, or ORR vs placebo plus mFOLFOX6 in the ITT (OS hazard ratio [HR], 0.82; 95% CI, 0.59-1.15; P = .24; PFS HR, 0.90; 95% CI, 0.71-1.16; P = .43; ORR, 46.1% vs 40.6%) or MET 2+/3+ populations (OS HR, 0.64; 95% CI, 0.40-1.03; P = .06; PFS HR, 0.79; 95% CI, 0.54-1.15; P = .22; ORR, 53.8% vs 44.6%). Safety was as expected for onartuzumab.CONCLUSIONS AND RELEVANCE: Addition of onartuzumab to first-line mFOLFOX6 did not significantly improve clinical benefits in the ITT or MET 2+/3+ populations.TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01662869.", "Huntington's disease (HD) is an incurable, fatal neurodegenerative disorder that is caused by a polyglutamine expansion in the huntingtin (Htt) protein. Neuronal death in the striatum-the most obvious manifestation of the disease-is likely to result from widespread dysregulation of gene expression in various brain regions. To date, several potential mechanisms for this have been discovered, including one involving REST (RE1-Silencing Transcription Factor), a master regulator of neuronal genes. Recently, independent studies have demonstrated that post-transcriptional gene regulation by microRNAs is also disrupted in HD. Expression of key neuronal microRNAs-including mir-9/9*, mir-124 and mir-132-is repressed in the brains of human HD patients and mouse models. These changes occur downstream of REST, and are likely to result in major disruption of mRNA regulation and neuronal function. In this study we will discuss these findings and their implications for our understanding of HD. Using updated bioinformatic analysis, we predict 21 new candidate microRNAs in HD. We propose future strategies for unifying large-scale transcriptional and microRNA datasets with the aim of explaining HD aetiology. By way of example, we show how available genomic datasets can be integrated to provide independent, analytical validation for dysregulation of REST and microRNA mir-124 in HD. As a consequence, gene ontology analysis indicates that HD is characterised by a broad-based depression of neural genes in the caudate and motor cortex. Thus, we propose that a combination of REST, microRNAs and possibly other non-coding RNAs profoundly affect the neuronal transcriptome in HD.", "Liver-type fatty acid binding protein (L-FABP) is a 14kDa protein found in the cytoplasm of human renal proximal tubules. Fatty acids are bound with L-FABP and transported to the mitochondria or peroxisomes, where fatty acids are beta-oxidized, and this may play a role in fatty acid homeostasis. Moreover, L-FABP has high affinity and capacity to bind long-chain fatty acid oxidation products, and may be an effective endogenous antioxidant. Renal L-FABP is rarely expressed in the kidneys of rodents. In order to evaluate the pathological dynamics of renal L-FABP in kidney disease, human L-FABP chromosomal transgenic mice were generated. Various stress, such as massive proteinuria, hyperglycemia, hypertension, and toxins overloaded in the proximal tubules were revealed to up-regulate the gene expression of renal L-FABP and increase the excretion of L-FABP derived from the proximal tubules into urine. In clinical studies of chronic kidney disease (CKD), urinary L-FABP accurately reflected the degree of tubulointerstitial damage and correlated with the rate of CKD progression. Furthermore, a multicenter trial has shown that urinary L-FABP is more sensitive than urinary protein in predicting the progression of CKD. With respect to diabetic nephropathy and acute kidney disease (AKI), urinary L-FABP is an early diagnostic of kidney disease or a predictive marker for renal prognosis. After many clinical studies, urinary L-FABP was approved as a new tubular biomarker promulgated by the Ministry of Health, Labour and Welfare in Japan.", "Pseudomelanosis duodeni is a rare incidental finding seen on endoscopy and has the characteristic appearance of flat, black-speckled pigmented mucosa. We present the case of an 83-year-old woman who presented with gastrointestinal bleeding and was found to have pseudomelanosis duodeni. The finding has no diagnostic or prognostic significance. Therapeutic chelation or endoscopic follow-up is not recommended.", "Autosomal recessive osteogenesis imperfecta (AR-OI) is an inherited condition which in recent years has been shown with increasing genetic and clinical heterogeneity. In this article, we performed clinical assessment and sought mutations in patients from 10 unrelated families with AR-OI, one of whom was presented with the additional features of Bruck syndrome (BS). Pathogenic changes were identified in five different genes: three families had mutations in FKBP10, three in SERPINF1, two in LEPRE1, one in CRTAP, and one in PPIB. With the exception of a FKBP10 mutation in the BS case, all changes are novel. Of note, insertion of an AluYb8 repetitive element was detected in exon 6 of SERPINF1. Since the studied patients had variable manifestations and some distinctive features, genotype/phenotype correlations are suggested.", "Glycidaldehyde is an industrial chemical which has been shown to be genotoxic in in vitro experiments and carcinogenic in rodent studies. It is a bifunctional alkylating agent capable of reacting with DNA to form exocyclic hydroxymethyl-substituted ethenobases. In this work, 8-(hydroxymethyl)-3,N4-etheno-2'-deoxycytidine (8-HM-epsilondC), a potential nucleoside derivative of glycidaldehyde, was synthesized using phosphoramidite chemistry and site-specifically incorporated into a defined 25-mer oligodeoxynucleotide. The 8-HM-epsilonC adduct is structurally related to 3,N4-ethenocytosine (epsilonC), a product of reaction with vinyl chloride or through lipid peroxidation. In Escherichia coli, epsilonC has been shown previously to be a primary substrate for the mismatch uracil-DNA glycosylase (Mug). In this study, we report that the same glycosylase also acts on 8-HM-epsilonC in an oligonucleotide duplex. The enzyme binds to the 8-HM-epsilonC-oligonucleotide to a similar extent as the epsilonC-oligonucleotide. The Mug excision activity toward 8-HM-epsilonC is approximately 2.5-fold lower than that toward the epsilonC substrate. Both activities can be stimulated up to approximately 2-fold higher by the addition of E. coli endonuclease IV. These two adducts, when mispaired with normal bases, were all excised from DNA by Mug with similar efficiencies. Structural studies using molecular simulations showed similar adjustment and hydrogen bonding pattern for both 8-HM-epsilonC*G and epsilonC*G pairs in oligomer duplexes. We believe that these findings may have biological and structural implications in defining the role of 8-HM-epsilonC in glycosylase recognition/repair." ]

[ "Sonic hedgehog (Shh) is necessary for sustaining the proliferation of neural stem cells (NSCs), yet little is known about its mechanisms. Whereas Gli1, Gli2, and Gli3, the primary mediators of Shh signaling, were all expressed in hippocampal neural progenitors, Shh treatment of NSCs induced only Gli1 expression. Acute depletion of Gli1 in postnatal NSCs by short-hairpin RNA decreased proliferation, whereas germline deletion of Gli1 did not affect NSC proliferation, suggesting a difference in mechanisms of Gli1 compensation that may be developmentally dependent. To determine whether Gli1 was sufficient to enhance NSC proliferation, we overexpressed this mitogen and were surprised to find that Gli1 resulted in decreased proliferation, accumulation of NSCs in the G2/M phase of cell cycle, and apoptosis. In contrast, Gli1-expressing lineage-restricted neural precursors demonstrated a 4.5-fold proliferation enhancement. Expression analyses of Gli1-expressing NSCs identified significant induction of Gadd45a and decreased cyclin A2 and Stag1 mRNA, genes involved in the G2-M transition and apoptosis. Furthermore, Gadd45a overexpression was sufficient to partially recapitulate the Gli1-induced G2/M accumulation and cell death of NSCs. In contrast to normal stem cells, tumor-derived stem cells had markedly higher basal Gli1 expression and did not undergo apoptosis with further elevation of Gli1. Our data suggest that Gli1-induced apoptosis may serve as a protective mechanism against premature mitosis and may give insight into mechanisms by which nonmalignant stem cells restrain hyperproliferation in the context of potentially transforming mitogenic signals. Tumor-derived stem cells apparently lack these mechanisms, which may contribute to their unrestrained proliferation and malignant potential.", "Babesiosis is a tick-borne disease caused by eukaryotic Babesia parasites which are morphologically similar to Plasmodium falciparum, the causative agent of malaria in humans. Like Plasmodium, different species of Babesia are tuned to infect different mammalian hosts, including rats, dogs, horses and cattle. Most species of Plasmodium and Babesia possess an essential bifunctional enzyme for nucleotide synthesis and folate metabolism: dihydrofolate reductase-thymidylate synthase. Although thymidylate synthase is highly conserved across organisms, the bifunctional form of this enzyme is relatively uncommon in nature. The structural characterization of dihydrofolate reductase-thymidylate synthase in Babesia bovis, the causative agent of babesiosis in livestock cattle, is reported here. The apo state is compared with structures that contain dUMP, NADP and two different antifolate inhibitors: pemetrexed and raltitrexed. The complexes reveal modes of binding similar to that seen in drug-resistant malaria strains and point to the utility of applying structural studies with proven cancer chemotherapies towards infectious disease research.", "Pitolisant (Wakix®), an orally available, first-in-class antagonist/inverse agonist of the histamine 3 receptor, is approved in the EU (as of March 2016) for the treatment of narcolepsy with or without cataplexy in adults and in the USA (as of August 2019) for the treatment of excessive daytime sleepiness (EDS) in adults with narcolepsy. Pitolisant was demonstrated to have minimal risk of abuse in preclinical and clinical studies, and is the only anti-narcoleptic drug not scheduled as a controlled substance in the USA. The totality of evidence from pivotal and supportive phase III trials suggests that pitolisant administered at up to the recommended maximum dose of 36 mg once daily reduces EDS and cataplexy in adults with narcolepsy relative to placebo. Noninferiority of pitolisant to modafinil in the management of EDS was not demonstrated. Pitolisant was generally well tolerated in clinical trials. Consistent with its mechanism of action, the most common treatment-emergent adverse events included headache, insomnia and anxiety. With minimal abuse potential and offering the convenience of oral, once-daily administration, pitolisant extends the range of approved treatment options available to adult patients with narcolepsy with or without cataplexy.", "Beneficial health effects have recently been claimed for pomegranate juice. In vitro and in vivo studies have demonstrated its anti-atherosclerotic capacity, chemoprevention and chemotherapy of prostate cancer, and antiproliferative, apoptotic, and antioxidant activity, among others. On the other hand, there is a complex interplay between tumor initiation, promotion, and progression and xenobiotic biotranformation. This led us to investigate the effect of pomegranate juice consumption on cytochrome P450 (CYP) activity and expression. For this purpose, male mice consumed this fruit juice for 4 weeks, and pentobarbital-induced sleeping time and total hepatic CYP content, activity, and expression were evaluated. Moreover, the activity of CYP isoform 2E1 and expression of the main CYP isoforms, namely, CYP1A1/2, CYP2E1, and CYP3A, were also assessed. It was found that pomegranate juice consumption decreased total hepatic CYP content as well as the expression of CYP1A2 and CYP3A. Prevention of procarcinogen activation through CYP activity/expression inhibition may be involved in pomegranate juice's effect on tumor initiation, promotion, and progression.", "Multiple familial trichoepithelioma (MFT) and familial cylindromatosis are two clinically distinct cancer syndromes. MFT patients developed mostly trichoepithelioma in the face while cylindromatosis patients developed cylindromas predominantly (approximately 90%) on the head and neck. However, multiple familial trichoepithelioma is occasionally associated with familial cylindromatosis while cylindromatosis patients can also develop trichoepithelioma. This has led to the speculation that the 2 types of dermatoses may be caused by dysfunction of a common pathway. Previously, a candidate MTF locus has been mapped to 9p21 while disease gene for familial cylindromatosis, the CYLD gene located on 16q21-13 has been identified. Here, we show that mutations in the CYLD gene are also the genetic basis for three different Chinese families with MFT. Sequence analysis reveal a single nucleotide deletion, c.1462delA (P.Ile488fsX9) in exon 9, a nonsense mutation, c.2128C>T (p. Gln710X) in exon 17, and a missense mutation, c.2822A>T (p. Asp941Val) in exon 21 in each of the three families respectively. This provides direct evidence that the mutations in CYLD can cause two clinically distinct cancer syndromes.", "Klotho interacts with various membrane proteins such as receptors for transforming growth factor-β (TGF-β) and insulin-like growth factor (IGF). Renal expression of klotho is diminished in polycystic kidney disease (PKD). In the present study, the effects of klotho supplementation on PKD were assessed. Recombinant human klotho protein (10 μg·kg-1·day-1) or a vehicle was administered daily by subcutaneous injection to 6-wk-old mice with PKD (DBA/2-pcy). Blood pressure was measured using tail-cuff methods. After 2 mo, mice were killed, and the kidneys were harvested for analysis. Exogenous klotho protein supplementation reduced kidney weight, cystic area, systolic blood pressure, renal angiotensin II levels, and 8-epi-PGF2α excretion (P < 0.05). Klotho protein supplementation enhanced glomerular filtration rate, renal expression of superoxide dismutase, and klotho itself (P < 0.05). Klotho supplementation attenuated renal expressions of TGF-β and collagen type I and diminished renal abundance of Twist, phosphorylated Akt, and mammalian target of rapamycin (P < 0.05). Pathological examination revealed that klotho decreased the fibrosis index and nuclear staining of Smad in PKD kidneys (P < 0.05). Our data indicate that klotho protein supplementation ameliorates the renin-angiotensin system, reducing blood pressure in PKD mice. Furthermore, the present results implicate klotho supplementation in the suppression of Akt/mammalian target of rapamycin signaling, slowing cystic expansion. Finally, our findings suggest that klotho protein supplementation attenuated fibrosis at least partly by inhibiting epithelial mesenchymal transition in PKD.", "Genome-wide association studies (GWAS) have emerged as a powerful tool to uncover the genetic basis of human common diseases, which often show a complex, polygenic and multi-factorial aetiology. These studies have revealed that 70-90% of all single nucleotide polymorphisms (SNPs) associated with common complex diseases do not occur within genes (i.e. they are non-coding), making the discovery of disease-causative genetic variants and the elucidation of the underlying pathological mechanisms far from straightforward. Based on emerging evidences suggesting that disease-associated SNPs are frequently found within cell type-specific regulatory sequences, here we present GARLIC (GWAS-based Prediction Toolkit for Connecting Diseases and Cell Types), a user-friendly, multi-purpose software with an associated database and online viewer that, using global maps of cis-regulatory elements, can aetiologically connect human diseases with relevant cell types. Additionally, GARLIC can be used to retrieve potential disease-causative genetic variants overlapping regulatory sequences of interest. Overall, GARLIC can satisfy several important needs within the field of medical genetics, thus potentially assisting in the ultimate goal of uncovering the elusive and complex genetic basis of common human disorders." ]

[ "BACKGROUND & OBJECTIVES: Chemotherapy combined with other therapeutic modalities is the main option for advanced and metastatic soft tissue sarcoma(STS). So far there is no standard regimen for STS yet. Adrimycin, ifosfamide, and dacarbazine are the most effective agents at present. The purpose of this clinical trial was to evaluate the efficacy and toxicity of MAID regimen (mesna/ifosfamide + Adriamycin + dacarbazine) in the treatment of advanced soft tissue sarcoma.METHODS: Twenty-two patients with advanced STS were treated by MAID(Adriamycin 60 mg/m2, ifosfamide 6,000 mg/m2, and dacarbazine 1,000 mg/m2). These drugs were administered as continuous intravenous infusion for 72 hours while mesna was infused continuously for 96 hours.RESULTS: Partial response rate was 36.4% without complete remission. The duration of response ranged from 2-10 months with median of 4.6 months. Main toxicities were myelosuppression, gastrointestinal toxicity and alopecia. Percentage of leucopenia, nausea/vomiting, and alopecia in WHO grade III and IV were 63.6%, 27.3%, and 50%, respectively.CONCLUSIONS: The response rate of MAID for advanced STS was not satisfactory with evident myelosuppression. Further study on new anti-cancer agents and regimen are needed.", "The cellular response to genotoxic stress is mediated by a well-characterized network of DNA surveillance pathways. The contribution of post-transcriptional gene regulatory networks to the DNA damage response (DDR) has not been extensively studied. Here, we systematically identified RNA-binding proteins differentially interacting with polyadenylated transcripts upon exposure of human breast carcinoma cells to ionizing radiation (IR). Interestingly, more than 260 proteins, including many nucleolar proteins, showed increased binding to poly(A)+ RNA in IR-exposed cells. The functional analysis of DDX54, a candidate genotoxic stress responsive RNA helicase, revealed that this protein is an immediate-to-early DDR regulator required for the splicing efficacy of its target IR-induced pre-mRNAs. Upon IR exposure, DDX54 acts by increased interaction with a well-defined class of pre-mRNAs that harbor introns with weak acceptor splice sites, as well as by protein-protein contacts within components of U2 snRNP and spliceosomal B complex, resulting in lower intron retention and higher processing rates of its target transcripts. Because DDX54 promotes survival after exposure to IR, its expression and/or mutation rate may impact DDR-related pathologies. Our work indicates the relevance of many uncharacterized RBPs potentially involved in the DDR.", "Checkpoint kinase 2 (CHEK2, Chk2) emerges as an important signal transducer of cellular responses to DNA damage and a candidate tumor suppressor whose defects contribute to molecular pathogenesis of diverse types of human malignancies, both sporadic and hereditary. Here, we briefly outline the molecular properties, regulation and physiological role of CHEK2, and review in more detail its defects that predispose to tumors, with particular emphasis on familial breast cancer. The frequency, penetrance and epidemiological as well as clinical significance of the two most studied breast cancer-predisposing variants of the CHEK2 gene, 1100delC and I157T, are highlighted in more depth, and additional CHEK2 mutations and their cancer relevance are discussed as well. These recent findings are considered also from a broader perspective of CHEK2 as the integral component of the ataxia telangiectasia-mutated-CHEK2-p53 pathway within the genome integrity maintenance system and a barrier against tumor progression. Finally, the potential value of information about the CHEK2 status in family counseling and optimizition of individualized cancer treatment is discussed.", "MicroRNAs are a recently discovered class of small noncoding functional RNAs. These molecules mediate post-transcriptional regulation of gene expression in a sequence specific manner. MicroRNAs are now known to be key players in a variety of biological processes and have been shown to be deregulated in a number of cancers. The discovery of viral encoded microRNAs, especially from a family of oncogenic viruses, has attracted immense attention towards the possibility of microRNAs as critical modulators of viral oncogenesis. The host-virus crosstalk mediated by microRNAs, messenger RNAs and proteins, is complex and involves the different cellular regulatory layers. In this commentary, we describe models of microRNA mediated viral oncogenesis.", "Alzheimer's disease (AD) is a common, chronic expensive debilitating neurodegenerative disease with no current treatments to prevent the physical deterioration of the brain and the consequent cognitive deficits. The current pathophysiology of Alzheimer's disease is the accumulation of neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein and amyloid-beta (Aβ) plaques. Antibody therapy of Tau and Amyloid beta, vaccines and other methods to decrease Tau and or Amyloid have not been successful after considerable pharmaceutical and biotech efforts. For example, Eli Lilly announced a major change to its closely watched clinical trial for the Alzheimer's drug solanezumab which failed to reach statistical significance. Recently, a report on animal models using photomodulation with near infrared light to treat AD pathology in K369I tau transgenic model (K3) l engineered to develop neurofibrillary tangles, and the APPs/PSEN1dE9 transgenic model (APP/PS1) to develop amyloid plaques. Mice were treated with NIR 20 times over a four-week period and NIR treatment (600-1000 nm) was associated with a reduction in the size and number of amyloid-β plaques in the neocortex and hippocampus. We now report a small pilot double blind, placebo-controlled trial (n=11) 6 active, 3 controls and 2 dropouts assessing the effect of 28 consecutive, sixminute transcranial sessions of near infrared (NIR) stimulation using 1060-1080 nm light emitting diodes. Subjects were independently diagnosed with dementia conducted in an outpatient behavioral healthcare clinic. IRB approval was obtained through the Quietmind Foundation's institutional review Board (IRB). Results showed changes in executive functioning; clock drawing, immediate recall, praxis memory, visual attention and task switching (Trails A&B) as well as a trend of improved EEG amplitude and connectivity measures. Neuroplasticity has also been reported with NIR light stimulation and mitochondrial enhancement.", "The IFAP syndrome is characterized by the congenital onset of ichthyosis follicularis, absence of hair, and photophobia. A limited number of patients with the disorder have been described, and X-linked recessive inheritance has been proposed. Two unrelated female patients with a complete IFAP syndrome are reported. Both patients show a diffuse distribution of the disorder without linear arrangement. Because the suggested X-linked recessive pattern of inheritance is unlikely in these patients, a different way of transmission or, alternatively, genetic heterogeneity of the disorder has to be considered.", "Tumor suppressor p53 plays a central role in tumor suppression. As a transcription factor, p53 mainly exerts its tumor suppressive function through transcriptional regulation of many target genes. To maintain the proper function of p53, p53 protein level and activity are exquisitely controlled by a group of positive and negative regulators in cells. Thus, p53, its regulators, and regulated genes form a complicated p53 signaling network. microRNAs (miRNAs) are a group of endogenous small non-coding RNA molecules. miRNAs play an important role in regulation of gene expression by blocking translational protein synthesis and/or degrading target mRNAs. Recent studies have demonstrated that p53 and its network are regulated by miRNAs at multiple levels. Some miRNAs regulate the level and function of p53 through directly targeting p53, whereas some other miRNAs target regulators of p53, such as MDM2 and MDM4, to indirectly regulate the activity and function of p53. On the other hand, p53 also regulates the transcriptional expression and the biogenesis of a group of miRNAs, which contributes to the tumor suppressive function of p53. p53 is the most frequently mutated gene in human cancer. Many tumor-associated mutant p53, which have \"gain-of-function\" activities in tumorigenesis independently of wild type p53, can regulate the expression of different miRNAs and modulate the biogenesis of specific miRNAs to promote tumorigenesis. These findings have demonstrated that miRNAs are important regulators and mediators of p53 and its signaling pathway, which highlights a pivotal role of miRNAs in the p53 network and cancer. J. Cell. Biochem. 118: 7-14, 2017. © 2016 Wiley Periodicals, Inc." ]

[ "Conflict of interest statement: Declaration of interests SR’s institution has received grants from Spark Therapeutics and he has provided presentations on behalf of Spark Therapeutics. DC and AD have received grants from Spark Therapeutics. JB has received grants from the Foundation Fighting Blindness, the National Institutes of Health, and Spark Therapeutics; non-financial support from the Center for Advanced Retinal and Ocular Therapeutics, University of Pennsylvania, and the FM Kirby Foundation; has a provisional patent pending and a US patent licensed to Spark Therapeutics for which she has waived financial interest; and is a coauthor on a copyrighted visual function questionnaire used in the present study. JAW is an employee of and has equity/options in Spark Therapeutics; has received grants from the National Institutes of Health (specifically for Clinical and Translational Research Centre services); and has a patent pending pertaining to the primary endpoint measure licensed to Spark Therapeutics. DCC is an employee of Spark Therapeutics and has a patent pending pertaining to the primary endpoint measure licensed to Spark Therapeutics. Z-FY, AT, and JWi are employees of Statistics Collaborative, which provides statistical and regulatory consulting to Spark Therapeutics. JP is an employee of Westat, which was contracted by Spark Therapeutics. SM is a clinical coordinator of a study sponsored by Spark Therapeutics, receives salary support from the Center for Cellular and Molecular Therapeutics (CCMT) at The Children’s Hospital of Philadelphia, and has a patent pending licensed to Spark Therapeutics. KAM is a clinical coordinator of a study sponsored by Spark Therapeutics and received salary support from CCMT at Children’s Hospital of Philadelphia. JWa, TLK, and MD have received salary support from Spark Therapeutics and grants from the Carver Center for Macular Degeneration and Children’s Hospital of Philadelphia; TLK has received travel support from Spark Therapeutics. JAH has received consulting fees from Merck and Kalvista, grants from ThromboGenics, and serves on boards for Janssen and Celgene. ES’s institution has received grants from Children’s Hospital of Philadelphia and Spark Therapeutics. EHS has received grants from Oxford Biomedica. KW is an employee of and has equity/options with Spark Therapeutics and has received grants from the National Institutes of Health. FS has received grants from Regione Campania and serves on boards for Sanofi, Dompe Farmaceutici, and Spark Therapeutics. JFW has a patent and a patent pending, both licensed to Spark Therapeutics. KAH is an employee of Spark Therapeutics and has a patent pending pertaining to the primary endpoint measure. AMM has received grants from Spark Therapeutics, the National Institutes of Health, and the Foundation Fighting Blindness; non-financial support from the Center for Advanced Retinal and Ocular Therapeutics, University of Pennsylvania, and the FM Kirby Foundation; and has a provisional patent pending and a US patent licensed to Spark Therapeutics for which he has waived financial interest. OE, HR, LR, LAG, FPH, LD, XZ, VBM, WP, MW, CJ, DG, and BPL declare no competing interests.", "The outer hair cell (OHC) membrane harbors a voltage-dependent protein, prestin (SLC26a5), in high density, whose charge movement is evidenced as a nonlinear capacitance (NLC). NLC is bell-shaped, with its peak occurring at a voltage, Vh, where sensor charge is equally distributed across the plasma membrane. Thus, Vh provides information on the conformational state of prestin. Vh is sensitive to membrane tension, shifting to positive voltage as tension increases and is the basis for considering prestin piezoelectric (PZE). NLC can be deconstructed into real and imaginary components that report on charge movements in phase or 90 degrees out of phase with AC voltage. Here we show in membrane macro-patches of the OHC that there is a partial trade-off in the magnitude of real and imaginary components as interrogation frequency increases, as predicted by a recent PZE model (Rabbitt in Proc Natl Acad Sci USA 17:21880-21888, 2020). However, we find similar behavior in a simple 2-state voltage-dependent kinetic model of prestin that lacks piezoelectric coupling. At a particular frequency, Fis, the complex component magnitudes intersect. Using this metric, Fis, which depends on the frequency response of each complex component, we find that initial Vh influences Fis; thus, by categorizing patches into groups of different Vh, (above and below - 30 mV) we find that Fis is lower for the negative Vh group. We also find that the effect of membrane tension on complex NLC is dependent, but differentially so, on initial Vh. Whereas the negative group exhibits shifts to higher frequencies for increasing tension, the opposite occurs for the positive group. Despite complex component trade-offs, the low-pass roll-off in absolute magnitude of NLC, which varies little with our perturbations and is indicative of diminishing total charge movement, poses a challenge for a role of voltage-driven prestin in cochlear amplification at very high frequencies.", "Intoxications due to organophosphate insecticides are common in our country, since agriculture has an important place. Besides the well known acute cholinergic toxicity, these compounds may cause late-onset distal polyneuropathy occurring two to three weeks after the acute exposure. An eight-year-old boy and a 13-year-old girl admitted to the hospital with gait disturbances. Beginning 15 and 20 days, respectively, after organophosphate ingestion. Neurologic examination revealed bilateral dropped foot, absent Achilles tendon reflexes and peripheral sensory loss. Electromyography demonstrated motor weighed sensory-motor polyneuropathy with axonal degeneration significant in the distal parts of bilateral lower extremities. Biochemical, radiological findings and magnetic resonance imagings were normal. The two cases were taken under a physiotherapy program. The two cases are presented here since organophosphate poisonings are common in our country, and since late-onset polyneuropathy is not a well known clinical presentation as acute toxicity.", "Purpose: Neuroblastoma is treated with aggressive multimodal therapy, yet more than 50% of patients experience relapse. We recently showed that relapsed neuroblastomas frequently harbor mutations leading to hyperactivated ERK signaling and sensitivity to MEK inhibition therapy. Here we sought to define a synergistic therapeutic partner to potentiate MEK inhibition.Experimental Design: We first surveyed 22 genetically annotated human neuroblastoma-derived cell lines (from 20 unique patients) for sensitivity to the MEK inhibitor binimetinib. After noting an inverse correlation with sensitivity to ribociclib (CDK4/6 inhibitor), we studied the combinatorial effect of these two agents using proliferation assays, cell-cycle analysis, Ki67 immunostaining, time-lapse microscopy, and xenograft studies.Results: Sensitivity to binimetinib and ribociclib was inversely related (r = -0.58, P = 0.009). MYCN amplification status and expression were associated with ribociclib sensitivity and binimetinib resistance, whereas increased MAPK signaling was the main determinant of binimetinib sensitivity and ribociclib resistance. Treatment with both compounds resulted in synergistic or additive cellular growth inhibition in all lines tested and significant inhibition of tumor growth in three of four xenograft models of neuroblastoma. The augmented growth inhibition was attributed to diminished cell-cycle progression that was reversible upon removal of drugs.Conclusions: Here we demonstrate that combined binimetinib and ribociclib treatment shows therapeutic synergy across a broad panel of high-risk neuroblastoma preclinical models. These data support testing this combination therapy in relapsed high-risk neuroblastoma patients, with focus on cases with hyperactivated RAS-MAPK signaling. Clin Cancer Res; 23(7); 1785-96. ©2016 AACR.", "BACKGROUND: In the last years, the biotechnological production of platform chemicals for fuel components has become a major focus of interest. Although ligno-cellulosic material is considered as suitable feedstock, the almost inevitable pretreatment of this recalcitrant material may interfere with the subsequent fermentation steps. In this study, the fungus Ustilago maydis was used to produce itaconic acid as platform chemical for the synthesis of potential biofuels such as 3-methyltetrahydrofuran. No studies, however, have investigated how pretreatment of ligno-cellulosic biomass precisely influences the subsequent fermentation by U. maydis. Thus, this current study aims to first characterize U. maydis in shake flasks and then to evaluate the influence of three exemplary pretreatment methods on the cultivation and itaconic acid production of this fungus. Cellulose enzymatically hydrolysed in seawater and salt-assisted organic-acid catalysed cellulose were investigated as substrates. Lastly, hydrolysed hemicellulose from fractionated beech wood was applied as substrate.RESULTS: U. maydis was characterized on shake flask level regarding its itaconic acid production on glucose. Nitrogen limitation was shown to be a crucial condition for the production of itaconic acid. For itaconic acid concentrations above 25 g/L, a significant product inhibition was observed. Performing experiments that simulated influences of possible pretreatment methods, U. maydis was only slightly affected by high osmolarities up to 3.5 osmol/L as well as of 0.1 M oxalic acid. The production of itaconic acid was achieved on pretreated cellulose in seawater and on the hydrolysed hemicellulosic fraction of pretreated beech wood.CONCLUSION: The fungus U. maydis is a promising producer of itaconic acid, since it grows as single cells (yeast-like) in submerged cultivations and it is extremely robust in high osmotic media and real seawater. Moreover, U. maydis can grow on the hemicellulosic fraction of pretreated beech wood. Thereby, this fungus combines important advantages of yeasts and filamentous fungi. Nevertheless, the biomass pretreatment does indeed affect the subsequent itaconic acid production. Although U. maydis is insusceptible to most possible impurities from pretreatment, high amounts of salts or residues of organic acids can slow microbial growth and decrease the production. Consequently, the pretreatment step needs to fit the prerequisites defined by the actual microorganisms applied for fermentation.", "The original and modified Ottawa Ankle Rules (OARs) were developed as clinical decision rules for use in emergency departments. However, the OARs have not been evaluated as an acute clinical evaluation tool.OBJECTIVE: To evaluate the measures of diagnostic accuracy of the OARs in the acute setting.METHODS: The OARs were applied to all appropriate ankle injuries at 2 colleges (athletics and club sports) and 21 high schools. The outcomes of OARs, diagnosis, and decision for referral were collected by the athletic trainers (ATs) at each of the locations. Contingency tables were created for evaluations completed within 1 h for which radiographs were obtained. From these data the sensitivity, specificity, positive and negative likelihood ratios, and positive and negative predictive values were calculated.RESULTS: The OARs met the criteria for radiographs in 100 of the 124 cases, of which 38 were actually referred for imaging. Based on radiographic findings in an acute setting, the OARs (n = 38) had a high sensitivity (.88) and are good predictors to rule out the presence of a fracture. Low specificity (0.00) results led to a high number of false positives and low positive predictive values (.18).CONCLUSION: When applied during the first hour after injury the OARs significantly overestimate the need for radiographs. However, a negative finding rules out the need to obtain radiographs. It appears the AT's decision making based on the totality of the examination findings is the best filter in determining referral for radiographs.", "BACKGROUND: In obesity, increased tumor necrosis factor (TNF)-alpha level is involved in the development of insulin resistance. Toll-like receptor (TLR)-4 and TLR2 are expressed in adipose tissue, and polymorphisms of these receptors may influence TNF-alpha secretion from adipocytes. In our study, TNF-alpha, soluble TNF receptor 1 (sTNFR1), and soluble TNF receptor 2 (sTNFR2) levels were determined, and any association between polymorphisms of TLR4 (D299G, T399I), TLR2 (R753Q, R677W), and cytokine levels was assessed in obese children and non-obese control subjects.MATERIAL/METHODS: In a cross-sectional study, 79 obese children and 42 matched non-obese control children were investigated. Cytokine levels were measured by enzyme amplified sensitivity immunoassay. TLR4 and TLR2 polymorphisms were determined using polymerase chain reaction - restriction fragment length polymorphism technique.RESULTS: TNF-alpha and sTNFR2 levels in obese children were significantly (P<.01) higher than controls. Significant (P<.05), positive, linear correlations were observed between TNF-alpha, sTNFR2 levels, and BMI. Patients carrying the mutant alleles of TLR4 (299G and 399I) had lower TNF-alpha and sTNFR2 levels compared to patients carrying wild-type alleles (299D and 399T) (TNF-alpha 4.4+/-0.7 pg/mL vs 5.5+/-0.9 pg/mL; sTNFR2 2.9+/-1.2 ng/mL vs 4.4+/-1.1 ng/mL; P<.001). The R753Q polymorphism of TLR2 was not associated with altered cytokine levels, and the R677W polymorphism was not detected in the sample population.CONCLUSIONS: Serum levels of TNF-alpha and its soluble receptors are elevated and associated with increasing BMI values in obese children. Serum cytokine levels, as modifying factors of insulin resistance, may be affected by TLR4 polymorphisms in obese children." ]

[ "ETHNOPHARMACOLOGICAL RELEVANCE: The antibacterial activities of 18 plants from 10 different families were investigated for their antimicrobial efficacy, based on the traditional uses of these species by Bakola pygmies living in Central Africa, especially along the Ngoyang area in Cameroon for the treatment of respiratory and tuberculosis-related symptoms. The aim of the study is to test the antimicrobial efficacy of these plants against some pathogens associated with respiratory disease and to determine if there is any validation for the traditional use against Mycobacterium species.MATERIALS AND METHODS: Medium polar extracts were prepared in MeOH/DCM (1:1, v/v) from the plant parts of each species used traditionally and were assayed against pathogens associated with respiratory tract ailments [Staphylococcus aureus (ATCC 25923), Klebsiella pneumoniae (ATCC 13883) and Morexella cattarhalis (ATCC 14468)] using the minimum inhibitory concentration (MIC) method. Two additional faster growing Mycobacterium strains [Mycobacterium smegmatis (ATCC 23246) and Mycobacterium aurum (NCTC 10437)] were included in the assay as predictive test organisms for the more pathogenic strain Mycobacterium tuberculosis.RESULTS: Some plant species, such as Alchornea floribunda, Musanga cecropioides (both leaves and stem bark), Tetracera potatoria and Xylopia aethiopica (stem bark), were effective in inhibiting Morexella cattarhalis, having MIC values between 65 and 250 μg/mL. Some noteworthy antimycobacterial inhibition (MIC≤200 μg/mL and as low as MIC 6.5 µg/mL) for 54% of the extracts were observed.CONCLUSION: While moderate activity was shown for pathogens causing respiratory tract infections, these plant species seems to be selectively targeting Mycobacteria spp. suggesting that the traditional use for treating tuberculosis related symptoms may be indeed be accurate.", "Netherton syndrome (NTS) is a rare genetic skin disease caused by mutations in the serine protease inhibitor Kazal-type 5 gene, which encodes the lympho-epithelial Kazal-type-related inhibitor. NTS patients have profoundly impaired skin barrier function. As stratum corneum (SC) lipids have a crucial role in the skin barrier function, we investigated the SC lipid composition and organization in NTS patients. We studied the SC lipid composition by means of mass spectrometry, and the lipid organization was examined by infrared spectroscopy and X-ray diffraction. Decreased free fatty acid (FFA) chain length and increased levels of monounsaturated FFAs were observed in the SC of NTS patients compared with controls. Furthermore, the level of short-chain ceramides (CERs) was enhanced in NTS patients and a strong reduction in long-chain CER levels was seen in several patients. The changes in lipid composition modified the lipid organization leading to an increased disordering of the lipids compared with the controls. In addition, in a subgroup of patients the organization of the lipid layers changed dramatically. The altered FFA and CER profiles in NTS patients corresponded to changes in the expression of enzymes involved in SC lipid processing. The observed changes in lipid composition, lipid organization, and enzyme expression are likely to contribute to the barrier dysfunction in NTS.", "The efficacy and safety of oral ofloxacin, 400 mg once daily, for the treatment of patients with lower respiratory tract infections were studied. The most common species recovered from the sputum specimens of these patients were Haemophilus influenzae, followed by Streptococcus pneumoniae (S. pneumoniae), Staphylococcus aureus (S. aureus), Gram positive cocci unidentified, Pseudomonas aeruginosa (P. aeruginosa), Morexella catarrhalis, Streptococcus epidermidis, and another Haemophilus species in this order. All these bacteria were susceptible to ofloxacin except for one strain of methicillin resistant S. aureus. A satisfactory clinical outcome was achieved in 34 of 40 patients (85%). It is concluded that ofloxacin, 400 mg once daily, is useful for patients with respiratory tract infections.", "The genetic syndrome Fanconi anemia (FA) is characterized by aplastic anemia, cancer predisposition and hypersensitivity to DNA interstrand crosslinks (ICLs). FA proteins (FANCs) are thought to work in pathway(s) essential for dealing with crosslinked DNA. FANCs interact with other proteins involved in both DNA repair and S-phase checkpoint such as BRCA1, ATM and the RAD50/MRE11/NBS1 (RMN) complex. We deciphered the previously undefined pathway(s) leading to the ICLs-induced S-phase checkpoint and the role of FANCs in this process. We found that ICLs activate a branched pathway downstream of the ATR kinase: one branch depending on CHK1 activity and the other on the FANCs-RMN complex. The transient slow-down of DNA synthesis was abolished in cells lacking ATR, whereas CHK1-siRNA-treated cells, NBS1 or FA cells showed partial S-phase arrest. CHK1 RNAi in NBS1 or FA cells abolished the S-phase checkpoint, suggesting that CHK1 and FANCs/NBS1 proteins work on parallel pathways. Furthermore, we found that ICLs trigger ATR-dependent FANCD2 phosphorylation and FANCD2/ATR colocalization. This study demonstrates a novel relationship between the FA pathway(s) and the ATR kinase.", "Thrombospondin-1 (TSP-1) is a matricellular protein that participates in numerous normal and pathological tissue processes and is rapidly modulated by different stimuli. The presence of 8 highly-conserved AU rich elements (AREs) within the 3'-untranslated region (3'UTR) of the TSP-1 mRNA suggests that post-transcriptional regulation is likely to represent one mechanism by which TSP-1 gene expression is regulated. We investigated the roles of these AREs, and proteins which bind to them, in the control of TSP-1 mRNA stability. The endogenous TSP-1 mRNA half-life is approximately 2.0 hours in HEK293 cells. Luciferase reporter mRNAs containing the TSP-1 3'UTR show a similar rate of decay, suggesting that the 3'UTR influences the decay rate. Site-directed mutagenesis of individual and adjacent AREs prolonged reporter mRNA halflife to between 2.2 and 4.4 hours. Mutation of all AREs increased mRNA half life to 8.8 hours, suggesting that all AREs have some effect, but that specific AREs may have key roles in stability regulation. A labeled RNA oligonucleotide derived from the most influential ARE was utilized to purify TSP-1 ARE-binding proteins. The AU-binding protein AUF1 was shown to associate with this motif. These studies reveal that AREs in the 3'UTR control TSP-1 mRNA stability and that the RNA binding protein AUF1 participates in this control. These studies suggest that ARE-dependent control of TSP-1 mRNA stability may represent an important component in the control of TSP-1 gene expression.", "BACKGROUND: Most patients with locally advanced, unresectable, non-small-cell lung cancer (NSCLC) have disease progression despite definitive chemoradiotherapy (chemotherapy plus concurrent radiation therapy). This phase 3 study compared the anti-programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy.METHODS: We randomly assigned patients, in a 2:1 ratio, to receive durvalumab (at a dose of 10 mg per kilogram of body weight intravenously) or placebo every 2 weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy. The coprimary end points were progression-free survival (as assessed by means of blinded independent central review) and overall survival (unplanned for the interim analysis). Secondary end points included 12-month and 18-month progression-free survival rates, the objective response rate, the duration of response, the time to death or distant metastasis, and safety.RESULTS: Of 713 patients who underwent randomization, 709 received consolidation therapy (473 received durvalumab and 236 received placebo). The median progression-free survival from randomization was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; P<0.001); the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events.CONCLUSIONS: Progression-free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).", "We report a case of a 68-year-old man diagnosed with pulmonary pleomorphic carcinoma who showed partial response after a single treatment with camrelizumab (PD1 monoclonal antibody). The patient's tumor was positive for programmed cell death ligand 1 (PD-L1) and progressed rapidly after a course of chemotherapy. Fortunately, the tumors dramatically shrank after one cycle of camrelizumab, an anti-programmed cell death-1 (PD-1) antibody developed by Chinese Hengrui Medicine. In conclusion, camrelizumab may be a good treatment option, especially in tumors that express PD-L1.", "PURPOSE: Depressed employees are vulnerable to adverse work outcomes. We hypothesized that work performance is impaired by depression and is worsened by exposure to psychosocial work stressors.DESIGN: Longitudinal cohort study with surveys administered at baseline, 6, 12, and 18 months.SETTING: Recruitment in primary care offices.SUBJECTS: A total of 14,268 were screened; 286 depressed, employed adults (18-62 years) and 193 controls were enrolled.MEASURES: At-work limitations (presenteeism) and absenteeism were measured with the Work Limitations Questionnaire (WLQ) and WLQ Work Absence Module, respectively. Work stressors were assessed using a modified version of the Job Content Questionnaire.ANALYSIS: Univariate and multivariate tests assessed the degree to which at-work limitations were related to depression and/or stressful work.RESULTS: Presenteeism and absenteeism were significantly worse for the depression group at each time point (p < or = .001). In cross-sectional models, presenteeism was associated with more severe depression symptoms, poorer general physical health, psychologically demanding work, the interaction ofpsychologically demanding work with depression, and less job control (r2 range = .33-.54). Absences were explained by depression symptom severity and poorer general physical health but not work stressors (r2 = .19). Because of minimal change in the work stressors, their longitudinal effects on outcomes were mostly nonsignificant.CONCLUSION: This study found that depression symptoms are related to work absences and impaired work performance, and results partly confirmed that work stressors add to this impact. Results suggest that workers with depression may benefit from care involving medical and vocational interventions." ]

[ "BACKGROUND: Management of nonalcoholic steatohepatitis (NASH) is an unmet clinical need. Lanifibranor is a pan-PPAR (peroxisome proliferator-activated receptor) agonist that modulates key metabolic, inflammatory, and fibrogenic pathways in the pathogenesis of NASH.METHODS: In this phase 2b, double-blind, randomized, placebo-controlled trial, patients with noncirrhotic, highly active NASH were randomly assigned in a 1:1:1 ratio to receive 1200 mg or 800 mg of lanifibranor or placebo once daily for 24 weeks. The primary end point was a decrease of at least 2 points in the SAF-A score (the activity part of the Steatosis, Activity, Fibrosis [SAF] scoring system that incorporates scores for ballooning and inflammation) without worsening of fibrosis; SAF-A scores range from 0 to 4, with higher scores indicating more-severe disease activity. Secondary end points included resolution of NASH and regression of fibrosis.RESULTS: A total of 247 patients underwent randomization, of whom 103 (42%) had type 2 diabetes mellitus and 188 (76%) had significant (moderate) or advanced fibrosis. The percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher among those who received the 1200-mg dose, but not among those who received the 800-mg dose, of lanifibranor than among those who received placebo (1200-mg dose vs. placebo, 55% vs. 33%, P = 0.007; 800-mg dose vs. placebo, 48% vs. 33%, P = 0.07). The results favored both the 1200-mg and 800-mg doses of lanifibranor over placebo for resolution of NASH without worsening of fibrosis (49% and 39%, respectively, vs. 22%), improvement in fibrosis stage of at least 1 without worsening of NASH (48% and 34%, respectively, vs. 29%), and resolution of NASH plus improvement in fibrosis stage of at least 1 (35% and 25%, respectively, vs. 9%). Liver enzyme levels decreased and the levels of the majority of lipid, inflammatory, and fibrosis biomarkers improved in the lanifibranor groups. The dropout rate for adverse events was less than 5% and was similar across the trial groups. Diarrhea, nausea, peripheral edema, anemia, and weight gain occurred more frequently with lanifibranor than with placebo.CONCLUSIONS: In this phase 2b trial involving patients with active NASH, the percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher with the 1200-mg dose of lanifibranor than with placebo. These findings support further assessment of lanifibranor in phase 3 trials. (Funded by Inventiva Pharma; NATIVE ClinicalTrials.gov number, NCT03008070.).", "Cell type-specific gene expression in humans involves complex interactions between regulatory factors and DNA at enhancers and promoters. Mapping studies for expression quantitative trait loci (eQTLs), transcription factors (TFs) and chromatin markers have become widely used tools for identifying gene regulatory elements, but prediction of target genes remains a major challenge. Here, we integrate genome-wide data on TF-binding sites, chromatin markers and functional annotations to predict genes associated with human eQTLs. Using the random forest classifier, we found that genomic proximity plus five TF and chromatin features are able to predict >90% of target genes within 1 megabase of eQTLs. Despite being regularly used to map target genes, proximity is not a good indicator of eQTL targets for genes 150 kilobases away, but insulators, TF co-occurrence, open chromatin and functional similarities between TFs and genes are better indicators. Using all six features in the classifier achieved an area under the specificity and sensitivity curve of 0.91, much better compared with at most 0.75 for using any single feature. We hope this study will not only provide validation of eQTL-mapping studies, but also provide insight into the molecular mechanisms explaining how genetic variation can influence gene expression.", "Interleukin-10 (IL-10) modulates inflammatory responses elicited in vitro and in vivo by Borrelia burgdorferi, the Lyme disease spirochete. How IL-10 modulates these inflammatory responses still remains elusive. We hypothesize that IL-10 inhibits effector functions of multiple genes induced by B. burgdorferi in macrophages to control concomitantly elicited inflammation. Because macrophages are essential in the initiation of inflammation, we used mouse J774 macrophages and live B. burgdorferi spirochetes as the model target cell and stimulant, respectively. First, we employed transcriptome profiling to identify genes that were induced by stimulation of cells with live spirochetes and that were perturbed by addition of IL-10 to spirochete cultures. Spirochetes significantly induced upregulation of 347 genes at both the 4-h and 24-h time points. IL-10 inhibited the expression levels, respectively, of 53 and 65 of the 4-h and 24-h genes, and potentiated, respectively, at 4 h and 24 h, 65 and 50 genes. Prominent among the novel identified IL-10-inhibited genes also validated by quantitative real-time PCR (qRT-PCR) were Toll-like receptor 1 (TLR1), TLR2, IRAK3, TRAF1, IRG1, PTGS2, MMP9, IFI44, IFIT1, and CD40. Proteome analysis using a multiplex enzyme-linked immunosorbent assay (ELISA) revealed the IL-10 modulation/and or potentiation of RANTES/CCL5, macrophage inflammatory protein 2 (MIP-2)/CXCL2, IP-10/CXCL10, MIP-1α/CCL3, granulocyte colony-stimulating factor (G-CSF)/CSF3, CXCL1, CXCL5, CCL2, CCL4, IL-6, tumor necrosis factor alpha (TNF-α), IL-1α, IL-1β, gamma interferon (IFN-γ), and IL-9. Similar results were obtained using sonicated spirochetes or lipoprotein as stimulants. Our data show that IL-10 alters effectors induced by B. burgdorferi in macrophages to control concomitantly elicited inflammatory responses. Moreover, for the first time, this study provides global insight into potential mechanisms used by IL-10 to control Lyme disease inflammation.", "Statins remain the cornerstone of hypolipidaemic drug treatment. The recent American College of Cardiology (ACC)/American Heart Association (AHA) lipid guidelines suggest using percent reductions of low density lipoprotein cholesterol (LDL-C), according to cardiovascular disease (CVD) risk, rather than specific LDL-C targets. These guidelines raised concerns and other Societies (US, International, European) have not endorsed them. The implementation of previous guidelines in clinical practice is suboptimal due to attitudes of physicians and restrictions in health care systems. Monoclonal antibodies that inhibit proprotein convertase subtilisin/ kexin type 9 (PCSK9), which degrades the LDL receptor, like alirocumab and evolocumab, are in phase 3 trials. These drugs are suitable for statin intolerant or resistant patients, heterozygous familial hypercholesterolaemia (HeFH) and some forms of homozygous FH (HoFH). Mipomersen (antisense oligonucleotide against apolipoprotein B) and lomitapide (microsomal triglyceride transfer protein blocker) have already been approved for HoFH. Eventually, silencing micro-RNA oligonucleotides may also become available. The repair or silencing of genes implicated in hyperlipidaemia and/or atherosclerosis is also on the horizon. If the new therapeutic options mentioned above prove to be effective and safe then by combining them with statins and/or ezetimibe we should be able to effectively control acquired or hereditary dyslipidaemias and substantially further reduce CVD morbidity and mortality.", "Novel treatment approaches are desperately needed for malignant rhabdoid tumor (MRT). Telomerase is an attractive therapeutic target because it is specific to cancer and critical for cancer cell immortality. We evaluated the effect of the telomerase inhibitor imetelstat in preclinical models of MRT. Three MRT cell lines, BT-12, G401, and RT-peri, were treated with the telomerase inhibitor imetelstat. The effects of imetelstat on telomere length, DNA damage response, and cell proliferation were assessed. The efficacy of imetelstat in vivo was evaluated in subcutaneous xenografts derived from each of the cell lines. Treatment with imetelstat resulted in inhibition of telomerase activity, marked telomere shortening, and activation of the DNA damage response pathway, as measured by formation of γ-H2AX nuclear foci, phosphorylation of ATM, and phosphorylation of TP53. Imetelstat-treated G401 cells underwent complete growth arrest after 16 passages. The other two cell lines exhibited growth inhibition. Imetelstat resulted in 40-50% growth inhibition compared to placebo-treated controls in all three xenograft models. The activity of imetelstat as a single agent suggests that further studies of telomerase inhibitors in combination with other agents may be warranted.", "Epigenetic changes in pediatric neuroblastoma may contribute to the aggressive pathophysiology of this disease, but little is known about the basis for such changes. In this study, we examined a role for the DNA methyltransferase DNMT3B, in particular, the truncated isoform DNMT3B7, which is generated frequently in cancer. To investigate if aberrant DNMT3B transcripts alter DNA methylation, gene expression, and phenotypic character in neuroblastoma, we measured DNMT3B expression in primary tumors. Higher levels of DNMT3B7 were detected in differentiated ganglioneuroblastomas compared to undifferentiated neuroblastomas, suggesting that expression of DNMT3B7 may induce a less aggressive clinical phenotype. To test this hypothesis, we investigated the effects of enforced DNMT3B7 expression in neuroblastoma cells, finding a significant inhibition of cell proliferation in vitro and angiogenesis and tumor growth in vivo. DNMT3B7-positive cells had higher levels of total genomic methylation and a dramatic decrease in expression of the FOS and JUN family members that comprise AP1 transcription factors. Consistent with an established antagonistic relationship between AP1 expression and retinoic acid receptor activity, increased differentiation was seen in the DNMT3B7-expressing neuroblastoma cells following treatment with all-trans retinoic acid (ATRA) compared to controls. Our results indicate that DNMT3B7 modifies the epigenome in neuroblastoma cells to induce changes in gene expression, inhibit tumor growth, and increase sensitivity to ATRA.", "Trypanosomatid parasites infect over 21 million people worldwide, with a range of disease phenotypes. Trypanosoma cruzi causes American trypanosomiasis, wherein 30-40% of infected individuals develop disease manifestations, most commonly cardiomyopathy but also digestive megasyndromes. In the case of Trypanosoma brucei, the etiological agent of African trypanosomiasis, disease progression can be rapid or slow, with early or late central nervous system involvement. Finally, Leishmania species cause leishmaniasis, a disease that ranges from self-healing but scarring cutaneous lesions to fatal visceral leishmaniasis in which parasites disseminate to the liver, spleen, and bone marrow. This review highlights parasite factors involved in disease phenotype in all three trypanosomatid diseases, with a particular focus on recent advances using large-scale 'omics' techniques." ]

[ "TANK-binding kinase 1 (TBK1) is a multifunctional kinase with an essential role in mitophagy, the selective clearance of damaged mitochondria. More than 90 distinct mutations in TBK1 are linked to amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia, including missense mutations that disrupt the abilities of TBK1 to dimerize, associate with the mitophagy receptor optineurin (OPTN), autoactivate, or catalyze phosphorylation. We investigated how ALS-associated mutations in TBK1 affect Parkin-dependent mitophagy using imaging to dissect the molecular mechanisms involved in clearing damaged mitochondria. Some mutations cause severe dysregulation of the pathway, while others induce limited disruption. Mutations that abolish either TBK1 dimerization or kinase activity were insufficient to fully inhibit mitophagy, while mutations that reduced both dimerization and kinase activity were more disruptive. Ultimately, both TBK1 recruitment and OPTN phosphorylation at S177 are necessary for engulfment of damaged mitochondra by autophagosomal membranes. Surprisingly, we find that ULK1 activity contributes to the phosphorylation of OPTN in the presence of either wild-type or kinase-inactive TBK1. In primary neurons, TBK1 mutants induce mitochondrial stress under basal conditions; network stress is exacerbated with further mitochondrial insult. Our study further refines the model for TBK1 function in mitophagy, demonstrating that some ALS-linked mutations likely contribute to disease pathogenesis by inducing mitochondrial stress or inhibiting mitophagic flux. Other TBK1 mutations exhibited much less impact on mitophagy in our assays, suggesting that cell-type-specific effects, cumulative damage, or alternative TBK1-dependent pathways such as innate immunity and inflammation also factor into the development of ALS in affected individuals.", "Several nuclear pore-associated factors, including the SUMO-protease Ulp1, have been proposed to prevent the export of intron-containing messenger ribonucleoparticles (mRNPs) in yeast. However, the molecular mechanisms of this nuclear pore-dependent mRNA quality control, including the sumoylated targets of Ulp1, have remained unidentified. Here, we demonstrate that the apparent 'pre-mRNA leakage' phenotype arising upon ULP1 inactivation is shared by sumoylation mutants of the THO complex, an early mRNP biogenesis factor. Importantly, we establish that alteration of THO complex activity differentially impairs the expression of intronless and intron-containing reporter genes, rather than triggering bona fide 'pre-mRNA leakage'. Indeed, we show that the presence of introns within THO target genes attenuates the effect of THO inactivation on their transcription. Epistasis analyses further clarify that different nuclear pore components influence intron-containing gene expression at distinct stages. Ulp1, whose maintenance at nuclear pores depends on the Nup84 complex, impacts on THO-dependent gene expression, whereas the nuclear basket-associated Mlp1/Pml39 proteins prevent pre-mRNA export at a later stage, contributing to mRNA quality control. Our study thus highlights the multiplicity of mechanisms by which nuclear pores contribute to gene expression, and further provides the first evidence that intronic sequences can alleviate early mRNP biogenesis defects.", "Nuclear pore complexes (NPCs) span the 2 membranes of the nuclear envelope (NE) and facilitate nucleocytoplasmic exchange of macromolecules. NPCs have a roughly tripartite structural organization with the so-called nuclear basket emanating from the NPC scaffold into the nucleoplasm. The nuclear basket is composed of the 3 nucleoporins Nup153, Nup50, and Tpr, but their specific role for the structural organization of this NPC substructure is, however, not well established. In this study, we have used thin-section transmission electron microscopy to determine the structural consequences of altering the expression of Nup153 in human cells. We show that the assembly and integrity of the nuclear basket is not affected by Nup153 depletion, whereas its integrity is perturbed in cells expressing high concentrations of the zinc-finger domain of Nup153. Moreover, even mild over-expression of Nup153 is coinciding with massive changes in nuclear organization and it is the excess of the zinc-finger domain of Nup153 that is sufficient to induce these rearrangements. Our data indicate a central function of Nup153 in the organization of the nucleus, not only at the periphery, but throughout the entire nuclear interior.", "Genomes are organized into three-dimensional structures, adopting higher-order conformations inside the micron-sized nuclear spaces (7, 2, 12). Such architectures are not random and involve interactions between gene promoters and regulatory elements (13). The binding of transcription factors to specific regulatory sequences brings about a network of transcription regulation and coordination (1, 14). Chromatin Interaction Analysis by Paired-End Tag Sequencing (ChIA-PET) was developed to identify these higher-order chromatin structures (5,6). Cells are fixed and interacting loci are captured by covalent DNA-protein cross-links. To minimize non-specific noise and reduce complexity, as well as to increase the specificity of the chromatin interaction analysis, chromatin immunoprecipitation (ChIP) is used against specific protein factors to enrich chromatin fragments of interest before proximity ligation. Ligation involving half-linkers subsequently forms covalent links between pairs of DNA fragments tethered together within individual chromatin complexes. The flanking MmeI restriction enzyme sites in the half-linkers allow extraction of paired end tag-linker-tag constructs (PETs) upon MmeI digestion. As the half-linkers are biotinylated, these PET constructs are purified using streptavidin-magnetic beads. The purified PETs are ligated with next-generation sequencing adaptors and a catalog of interacting fragments is generated via next-generation sequencers such as the Illumina Genome Analyzer. Mapping and bioinformatics analysis is then performed to identify ChIP-enriched binding sites and ChIP-enriched chromatin interactions (8). We have produced a video to demonstrate critical aspects of the ChIA-PET protocol, especially the preparation of ChIP as the quality of ChIP plays a major role in the outcome of a ChIA-PET library. As the protocols are very long, only the critical steps are shown in the video.", "BACKGROUND: In bioanalysis, phospholipids may affect the precision and accuracy of LC-MS/MS methods and compromise the quality of the results, especially when samples in complex biomatrices are extracted by protein precipitation techniques.RESULTS: It was found that the retentive behavior of both common pharmaceuticals and physiologically relevant phospholipids under bare silica hydrophilic-interaction LC (HILIC) is more predictable than under reversed-phase conditions. In particular, the retention time of phospholipids was not significantly affected by varying the salt and acid modifiers in the mobile phases, but common pharmaceuticals can be shifted away from these phospholipid interferences through mobile phase modifiers. Several mass spectrometric techniques were applied to confirm this finding.CONCLUSION: HILIC chromatography is a valued tool in the development of robust bioanalytical assays with minimal and predictable phospholipid interferences. Furthermore, addition of a small amount of ion-pairing additives can reliably move pharmaceutical compounds away from these suppressive regions.", "BACKGROUND: Patisiran is an investigational RNA interference (RNAi) therapeutic in development for the treatment of hereditary ATTR (hATTR) amyloidosis, a progressive disease associated with significant disability, morbidity, and mortality.METHODS: Here we describe the rationale and design of the Phase 3 APOLLO study, a randomized, double-blind, placebo-controlled, global study to evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy. Eligible patients are 18-85 years old with hATTR amyloidosis, investigator-estimated survival of ≥2 years, Neuropathy Impairment Score (NIS) of 5-130, and polyneuropathy disability score ≤IIIb. Patients are randomized 2:1 to receive either intravenous patisiran 0.3 mg/kg or placebo once every 3 weeks. The primary objective is to determine the efficacy of patisiran at 18 months based on the difference in the change in modified NIS+7 (a composite measure of motor strength, sensation, reflexes, nerve conduction, and autonomic function) between the patisiran and placebo groups. Secondary objectives are to evaluate the effect of patisiran on Norfolk-Diabetic Neuropathy quality of life questionnaire score, nutritional status (as evaluated by modified body mass index), motor function (as measured by NIS-weakness and timed 10-m walk test), and autonomic symptoms (as measured by the Composite Autonomic Symptom Score-31 questionnaire). Exploratory objectives include assessment of cardiac function and pathologic evaluation to assess nerve fiber innervation and amyloid burden. Safety of patisiran will be assessed throughout the study.DISCUSSION: APOLLO represents the largest randomized, Phase 3 study to date in patients with hATTR amyloidosis, with endpoints that capture the multisystemic nature of this disease.TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov ( NCT01960348 ); October 9, 2013.", "The legal systems of the Germanic tribes in the early Middle Ages elaborated detailed catalogs of forfeits in compensation for certain physical injuries. The perpetrator had to pay the forfeit to the injured person, or in case of manslaughter, to the tribe of the dead. By doing so he could avert the feud which otherwise faced him. These catalogs of forfeits exactly reflect the relative value that was appointed to certain parts of the body and to sensory functions. The catalog of the Lex Saxonum (c. 802), in which physical injuries are listed, ranging from loss of single phalanges, differentiated between thumb, forefinger, small finger, and the other fingers, to death, is compared with modern grades of disability. There are surprising parallels and interesting contrasts. Bilateral deafness is put on a level with bilateral blindness, the loss of both hands, both feet, both testicles, and death." ]

[ "Heart failure became a leading cause of mortality in the past few decades with a progressively increasing prevalence. Its current therapy is restricted largely to the suppression of the sympathetic activity and the renin-angiotensin system in combination with diuretics. This restrictive strategy is due to the potential long-term adverse effects of inotropic agents despite their effective influence on cardiac function when employed for short durations. Positive inotropes include inhibitors of the Na+/K+ pump, β-receptor agonists, and phosphodiesterase inhibitors. Theoretically, Ca2+ sensitizers may also increase cardiac contractility without resulting in Ca2+ overload; nevertheless, their mechanism of action is frequently complicated by other pleiotropic effects. Recently, a new positive inotropic agent, the myosin activator omecamtiv mecarbil, has been developed. Omecamtiv mecarbil binds directly to β-myosin heavy chain and enhances cardiac contractility by increasing the number of the active force-generating cross-bridges, presumably without major off-target effects. This review focuses on recent in vivo and in vitro results obtained with omecamtiv mecarbil, and discusses its mechanism of action at a molecular level. Based on clinical data, omecamtiv mecarbil is a promising new tool in the treatment of systolic heart failure.", "Mutations in the Dynamin 2 gene (DNM2) cause autosomal dominant centronuclear myopathy or autosomal dominant (AD) Charcot-Marie-Tooth (CMT) disease. Here the authors report one large Czech family with 15 members affected with an AD CMT phenotype of extraordinary variability. Genetic linkage analysis using SNP arrays revealed a locus of about 9.6 Mb on chromosome 19p13.1-13.2. In this critical interval, 373 genes were located. The only gene herein known to be associated with an intermediate type of CMT was Dynamin 2 (DNM2). Subsequent sequence analysis of the DNM2 gene in the index patient revealed a novel missense mutation p.Met580Thr. This missense mutation segregated with the neuropathy, indicating the causal character of this mutation. The phenotype of CMT in this family shows mild to moderate impairment with relatively preserved upper limbs and a very broad range of the onset of clinical symptoms from an early onset around the age of 12 to the late onset during the fifth decade. Electrophysiology showed an intermediate type of peripheral neuropathy. The motor median nerve conduction velocity varied from 36 m/s to normal values with signs of asymmetrical affection of peripheral nerves. No additional symptoms such as cranial nerve involvement, cataract, and signs of neutropenia or myopathy syndrome were observed in any member of the family yet. The progression was slow with no loss of ambulation. The authors suggest that the characterization of clinical variability in a single family may help to direct the genetic analysis directly to the rarely observed DNM2 mutations.", "The isoflavonoid conjugates medicarpin-3-O-glucoside-6''-O-malonate (MGM), afrormosin-7-O-glucoside (AG), and afrormosin-7-O-glucoside-6''-O-malonate (AGM) were isolated and characterized from cell suspension cultures of alfalfa (Medicago sativa L.), where they were the major constitutive secondary metabolites. They were also found in alfalfa roots but not in other parts of the plant. The phytoalexin medicarpin accumulated rapidly in suspension cultured cells treated with elicitor from Colletotrichum lindemuthianum, and this was subsequently accompanied by an increase in the levels of MGM. In contrast, net accumulation of afrormosin conjugates was not affected by elicitor treatment. Labeling studies with [(14)C]phenylalanine indicated that afrormosin conjugates were the major de novo synthesized isoflavonoid products in unelicited cells. During elicitation, [(14)C]phenylalanine was incorporated predominantly into medicarpin, although a significant proportion of the newly synthesized medicarpin was also conjugated. Treatment of (14)C-labeled, elicited cells with l-alpha-aminooxy-beta-phenylpropionic acid, a potent inhibitor of PAL activity in vivo, resulted in the initial appearance of labeled medicarpin of very low specific activity, suggesting that the phytoalexin could be released from a preformed conjugate under these conditions. Our data draw attention to the involvement of isoflavone hydroxylases during the constitutive and elicitor-induced accumulation of isoflavonoids and their conjugates in alfalfa cell cultures.", "Melkersson-Rosenthal syndrome (MRS) is an uncommon granulomatous condition characterized by persistent or recurrent orofacial oedema, relapsing facial paralysis and fissured tongue. We report here a case of MRS with the classical triad of signs accompanied by unilateral anterior uveitis. A 35-year-old man with a fissured tongue, recurrent facial palsy and orofacial oedema presented with a 3-month history of conjunctival redness and decreased vision in the right eye. On evaluation of visual acuity, the patient was only able to count fingers. Slit lamp examination revealed severe conjunctival injection, cells and flare, posterior synechiae and keratic precipitates. Examination of the left eye revealed no evidence of inflammation. Examination of the other systems was normal. The patient was treated with topical corticosteroids and cycloplegics and the visual acuity improved to 7/10. To our knowledge, there are no previous reports of an association between uveitis and MRS.", ": We describe Manta, a method to discover structural variants and indels from next generation sequencing data. Manta is optimized for rapid germline and somatic analysis, calling structural variants, medium-sized indels and large insertions on standard compute hardware in less than a tenth of the time that comparable methods require to identify only subsets of these variant types: for example NA12878 at 50× genomic coverage is analyzed in less than 20 min. Manta can discover and score variants based on supporting paired and split-read evidence, with scoring models optimized for germline analysis of diploid individuals and somatic analysis of tumor-normal sample pairs. Call quality is similar to or better than comparable methods, as determined by pedigree consistency of germline calls and comparison of somatic calls to COSMIC database variants. Manta consistently assembles a higher fraction of its calls to base-pair resolution, allowing for improved downstream annotation and analysis of clinical significance. We provide Manta as a community resource to facilitate practical and routine structural variant analysis in clinical and research sequencing scenarios.AVAILABILITY AND IMPLEMENTATION: Manta is released under the open-source GPLv3 license. Source code, documentation and Linux binaries are available from https://github.com/Illumina/manta.CONTACT: csaunders@illumina.comSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "The calcium-sensing receptor (CaSR) plays a pivotal role in systemic calcium metabolism by regulating parathyroid hormone secretion and urinary calcium excretion. The CaSR is ubiquitously expressed, implying a wide range of functions regulated by this receptor. Abnormal CaSR function affects the development of both calciotropic disorders such as hyperparathyroidism, and non-calciotropic disorders such as cardiovascular disease and cancer, which are the leading causes of mortality worldwide. The CaSR is able to bind a plethora of ligands; it interacts with multiple G protein subtypes, and regulates highly divergent downstream signalling pathways, depending on the cellular context. The CaSR is a key regulator for such diverse processes as hormone secretion, gene expression, inflammation, proliferation, differentiation, and apoptosis. Due to this pleiotropy, the CaSR is able to regulate cell fate and is implicated in the development of many types of benign or malignant tumours of the breast, prostate, parathyroid, and colon. In cancer, the CaSR appears to have paradoxical roles, and depending on the tissue involved, it is able to prevent or promote tumour growth. In tissues like the parathyroid or colon, the CaSR inhibits proliferation and induces terminal differentiation of the cells. Therefore, loss of the receptor, as seen in colorectal or parathyroid tumours, confers malignant potential, suggestive of a tumour suppressor role. In contrast, in prostate and breast tumours the expression of the CaSR is increased and it seems that it favours metastasis to the bone, acting as an oncogene. Deciphering the molecular mechanism driving the CaSR in the different tissues could lead to development of new allosteric drug compounds that selectively target the CaSR and have therapeutic potential for cancer. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.", "The United States Food and Drug Administration issued a Black Box warning in October 2004 after placebo-controlled trials of antidepressant medications found an increased risk of suicidal thoughts and behaviors among children and adolescents taking antidepressant medications relative to placebo. Subsequently, some researchers have concluded that the Black Box warning caused severe unintended consequences; specifically, they have argued that the warning led to reduced use of antidepressants among youth, which led to more suicides. In this paper, we critically examine research regarding the Black Box warning's alleged deleterious consequences. One study claimed that controlled trials did not actually find an increased risk of suicidality among youth taking fluoxetine relative to those taking placebo, but its measure of suicidality is likely invalid. We found that ecological time series studies claiming that decreasing antidepressant prescriptions are linked to higher rates of suicide attempts or actual suicides among youth were methodologically weak. These studies exhibited shortcomings including: selective use of time points, use of only a short-term time series, lack of performing statistical analysis, not examining level of severity/impairment among participants, inability to control confounding variables, and/or use of questionable measures of suicide attempts. Further, while some time-series studies claim that increased antidepressant prescriptions are related to fewer youth suicides, more recent data suggests that increasing antidepressant prescriptions are related to more youth suicide attempts and more completed suicides among American children and adolescents. We also note that case-control studies show increased risk of suicide attempts and suicide among youth taking antidepressants, even after controlling for some relevant confounds. As clinical trials have the greatest ability to control relevant confounds, it is important to remember such trials demonstrated increased risk of suicidality adverse events among youth taking antidepressants. The Black Box warning is firmly rooted in solid data whereas attempts to claim the warning has caused harm are based on quite weak evidence." ]

[ "BACKGROUND: Puffy hand syndrome is a complication of intravenous drug abuse, which has no current available treatment. Arm and forearm edema are voluminous and cause functional and aesthetic disturbances. We report two cases successfully treated by low-stretch bandages.OBSERVATIONS: A 40-year-old man and a 34-year-old woman, both intravenous drug users, with puffy hand syndrome were hospitalized for 11 days. Treatment included daily multilayer bandaging. Lymphedema volumes calculated by utilizing the formula for a truncated cone decreased by 16% on the left side and 12% on the right side for the first patient and 31 and 17% for the second. Hand circumference decreased 4.3 cm on the left side and 3.2 cm on the right side in case 1, and 2.5 cm and 1.9 cm respectively for case 2. The patients were taught self-bandaging techniques during their hospital stays. Elastic gloves were fitted at the end of treatment. Reduction of lymphedema volume remained stable after 18 months in one patient while for the second patient further treatment and hospitalization were required due to poor compliance.DISCUSSION: The pathogenesis of this edema is probably multifactorial: venous, lymphatic insufficiency and the direct toxicity of injected drugs. Lymphedema treatment currently consists of low-stretch bandaging and wearing elastic garments, which is effective in decreasing the volume of puffy hand syndrome.", "Narcotic addiction may induce systemic and local complications. Intravenous injections of drugs can cause venous thrombosis, and septic or embolic complications. The puffy hand sign is a more uncommon complication of hard-core injection addicts. Three long-term intravenous drug users, two males, one female, mean age 30.6 years (26-37) presented puffy hands. These patients had been drug addicts for four to twelve years (mean duration 7.3 years) and had stopped heroin injections for 3-5 years (mean 4.6), participating in a buprenorphine substitution program. The edema appeared several years after drug cessation (1.5-5, mean 2.3). Typically the puffiness was bilateral, the hands swollen from the proximal segments of the fingers to the wrist. In one patient, the edema was localized both in the hands and in the feet. The edema was not pitting and unaffected by elevation. Duplex ultrasound examination of the extremities was normal. Lymphangiography performed in one patient was consistent with deep lymphatic destruction. Puffy hand syndrome appears to be the end result of lymphatic obstruction. Repeated injections of drugs in or outside the veins destroy the lymphatics. Buprenorphine may play an important role in the puffy hand sign. Although it is supposed to be administered orally, many drug addicts use it as an i.v. solution. Because buprenorphine is poorly soluble, it causes lymphatic obstruction. This type of hand for which no therapy exists must be differentiated from deep palmar space infection with dorsal edema which requires incision and drainage.", "Intravenous drug addiction is responsible for many complications, especially cutaneous and infectious. There is a syndrome, rarely observed in rheumatology, resulting in \"puffy hands\": the puffy hand syndrome. We report two cases of this condition from our rheumatologic consultation. Our two patients had intravenous drug addiction. They presented with an edema of the hands, bilateral, painless, no pitting, occurring in one of our patient during heroin intoxication, and in the other 2 years after stopping injections. In our two patients, additional investigations (biological, radiological, ultrasound) were unremarkable, which helped us, in the context, to put the diagnosis of puffy hand syndrome. The pathophysiology, still unclear, is based in part on a lymphatic toxicity of drugs and their excipients. There is no etiological treatment but elastic compression by night has improved edema of the hands in one of our patients.", "The new oral anticoagulants directly inhibit either thrombin (Dabigatran, Pradaxa®,) or activated Factor X (rivaroxaban, Xarelto®, and apixaban, Eliquis®) and have been approved for thromboprophylaxis after hip and knee replacement surgery and stroke prevention in non-valvular atrial fibrillation. Moreover, rivaroxaban has been approved for the treatment of deep venous thrombosis, prevention of pulmonary embolism and anticoagulation after acute myocardial infarction. The direct FXa-inhibitor edoxaban (Lixiana®) expects approval for the prevention of stroke in atrial fibrillation in Germany in 2014. The half lives of all direct anticoagulants range between 8 and 17 hours. Dabigatran (Pradaxa®) and rivaroxaban (Xarelto®) are mainly excreted by the kidneys, apixaban (Eliquis®) by the liver (75%) and edoxaban (Lixiana®) by the kidneys (40%) and the faeces in 60%. Prior to surgery a shorter cessation is expected compared to the vitamin k antagonists phenprocoumon (Marcumar®, Falithrom®) and warfarin (Coumadin®). For acute bleedings caused by the direct thrombin inhibitor dabigatran (Pradaxa®) hemodialysis is recommended to eliminate the drug from the plasma. Due to the high protein binding the direkt FXa-inhibitors rivaroxaban (Xarelto®) and apixaban (Eliquis®) can not be hemodialysed. For edoxaban (Lixiana®) no data on elimination by renal replacement therapy are available. In case of life-threatening bleeding the replacement of a prothrombin complex preparation (PCC) containing the factors II, VII, IX and X and, second line, activated factor concentrates as recombinant factor VIIa or activated prothrombin complex preparations are recommended.", "The purpose of this study was to determine the isolation rates of Mycoplasma hominis and Ureaplasma urealyticum from three populations of women and also to relate the presence of these microorganisms with some indicators of nonspecific vaginitis. Three hundred vaginal swabs were taken from delivery, pregnant and control (not pregnant) women. Cultures were done in E broth supplemented with arginine or urea. M. hominis was isolated in 5% at delivery, 12% from pregnant and 5% from control women and U. urealyticum was isolated in 21%, 31% and 28% respectively. There was statistical difference in the isolation rate of M. hominis in pregnant women respect to the other groups. Both microorganisms were more frequently isolated in women with acid vaginal pH, amine-like odor in KOH test, clue cells and leucorrhea. M. hominis was isolated in 17% and U. urealyticum in 52% from women with nonspecific vaginitis. M. hominis was isolated in 2% and U. urealyticum in 13% from women without nonspecific vaginitis. Although the presence of clue cells and amine-like odor in KOH test have relationship with Gardnerella vaginalis, these tests could also suggest the presence of these mycoplasmas.", "In a previous study, we demonstrated that apoptosis increased according to gestational age, accounting partly for the presence of free fetal DNA in maternal plasma and serum. Using simultaneous TUNEL assay and FISH analysis, we identified the fetal origin of part of the apoptotic cell population, but very few TUNEL-positive cells showed hybridization signals since they were in a late apoptosis stage and nuclei were destroyed. In the present study, the apoptotic cell population was identified immunocytochemically using Annexin V, a marker of cells in an early stage of apoptosis. The mean apoptosis rate in mononuclear cells isolated from the peripheral blood of 20 pregnant women in the 16th to 19th week of pregnancy with Annexin V was 6.8 +/- 0.5% (range: 4.2-8.1%) compared to 6.14 +/- 0.5% (range: 3.7-6.9%) obtained with ethidium bromide staining. FISH using X and Y chromosome-specific probes was applied in 11 cases known to be carrying male fetuses. Eighty percent of Annexin V+ cells showed hybridization signals, while the proportion of apoptotic cells showing X/Y signals was 7.8% (range: 5-12%). Although our results are still preliminary, it seems that use of Annexin V antibody to detect the apoptotic cell population improves FISH analysis and allows a more accurate estimate of the proportion of fetal cells among the apoptotic cell population.", "BACKGROUND: Genome sciences have experienced an increasing demand for efficient text-processing tools that can extract biologically relevant information from the growing amount of published literature. In response, a range of text-mining and information-extraction tools have recently been developed specifically for the biological domain. Such tools are only useful if they are designed to meet real-life tasks and if their performance can be estimated and compared. The BioCreative challenge (Critical Assessment of Information Extraction in Biology) consists of a collaborative initiative to provide a common evaluation framework for monitoring and assessing the state-of-the-art of text-mining systems applied to biologically relevant problems.RESULTS: The Second BioCreative assessment (2006 to 2007) attracted 44 teams from 13 countries worldwide, with the aim of evaluating current information-extraction/text-mining technologies developed for one or more of the three tasks defined for this challenge evaluation. These tasks included the recognition of gene mentions in abstracts (gene mention task); the extraction of a list of unique identifiers for human genes mentioned in abstracts (gene normalization task); and finally the extraction of physical protein-protein interaction annotation-relevant information (protein-protein interaction task). The 'gold standard' data used for evaluating submissions for the third task was provided by the interaction databases MINT (Molecular Interaction Database) and IntAct.CONCLUSION: The Second BioCreative assessment almost doubled the number of participants for each individual task when compared with the first BioCreative assessment. An overall improvement in terms of balanced precision and recall was observed for the best submissions for the gene mention (F score 0.87); for the gene normalization task, the best results were comparable (F score 0.81) compared with results obtained for similar tasks posed at the first BioCreative challenge. In case of the protein-protein interaction task, the importance and difficulties of experimentally confirmed annotation extraction from full-text articles were explored, yielding different results depending on the step of the annotation extraction workflow. A common characteristic observed in all three tasks was that the combination of system outputs could yield better results than any single system. Finally, the development of the first text-mining meta-server was promoted within the context of this community challenge.", "OBJECTIVES: The goal of this study was to examine rates of psychotropic medication use and identify associated child and family characteristics among children and adolescents with autism spectrum disorder (ASD) enrolled in an autism registry maintained by the Autism Treatment Network (ATN).METHODS: The sample, derived from the ATN registry, consists of 2853 children aged 2 to 17 years with diagnoses of ASD supported by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and the Autism Diagnostic Observation Schedule with available data on medication use. As part of initial enrollment in the registry, parents completed questionnaires on current psychotropic medication use, psychiatric and medical conditions, and demographics.RESULTS: Of the 2853 children, 763 (27%) were taking ≥ 1 psychotropic medication; 15% were prescribed 1 medication, 7.4% received 2 medications, and 4.5% received ≥ 3. Among children aged 3 to 5 years, 11% were taking ≥ 1 psychotropic medication; among 6- to 11-year-old children, 46%; and 66% of adolescents aged 12 to 17 years were taking at ≥ 1 psychotropic medication. A parent report of comorbid diagnosis of attention-deficit/hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, depression, or anxiety was associated with a high rate of use, with 80% receiving ≥ 1 psychotropic medication. Only 15% of children with no comorbid psychiatric disorder were taking psychotropic medication. Psychotropic medication use was also related to sleep and gastrointestinal problems.CONCLUSIONS: The prescription of psychotropic medications in this registry sample is highly related to comorbid psychiatric disorder. Other factors associated with use include medical comorbidities, race, ethnicity, and older age.", "Melkersson-Rosenthal syndrome (MRS) is a rare idiopathic non-caseating granulomatous condition. It is rarely described in otorhinolaryngology-related journals, although facial palsy, lip-swelling, and lingua plicata, are its most common presenting features. This classical triad however is not always present in MRS. Other forms of orofacial swelling exist. This paper describes a patient with a variant of MRS, treated by us with intra-lesional steroid injection. We also discuss the other differential diagnoses that may mimic MRS.", "Puffy hand syndrome develops after long-term intravenous drug addiction. It is characterized by a nonpitting edema, affecting the dorsal side of fingers and hands with puffy aspect. Frequency and severity of the complications of this syndrome are rarely reported. Local infectious complications such as cellulitis can be severe and can enable the diagnosis. Herein, we report the case of a 41-year-old man who went to the emergency department for abdominal pain, fever, and bullous lesions of legs and arms with edema. Bacteriologic examination of a closed bullous lesion evidenced a methicillin sensitive Staphylococcus aureus. The abdomen computed tomography excluded deep infections and peritoneal effusion. The patient was successfully treated by intravenous oxacillin and clindamycin. He had a previous history of intravenous heroin addiction. We retained the diagnosis of puffy hand syndrome revealed by a severe staphylococcal infection with toxic involvement mimicking a four limbs cellulitis. Puffy hand syndrome, apart from the chronic lymphedema treatment, has no specific medication available. Prophylactic measures against skin infections are essential.", "Prions are self-templating protein conformers that are naturally transmitted between individuals and promote phenotypic change. In yeast, prion-encoded phenotypes can be beneficial, neutral or deleterious depending upon genetic background and environmental conditions. A distinctive and portable 'prion domain' enriched in asparagine, glutamine, tyrosine and glycine residues unifies the majority of yeast prion proteins. Deletion of this domain precludes prionogenesis and appending this domain to reporter proteins can confer prionogenicity. An algorithm designed to detect prion domains has successfully identified 19 domains that can confer prion behavior. Scouring the human genome with this algorithm enriches a select group of RNA-binding proteins harboring a canonical RNA recognition motif (RRM) and a putative prion domain. Indeed, of 210 human RRM-bearing proteins, 29 have a putative prion domain, and 12 of these are in the top 60 prion candidates in the entire genome. Startlingly, these RNA-binding prion candidates are inexorably emerging, one by one, in the pathology and genetics of devastating neurodegenerative disorders, including: amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), Alzheimer's disease and Huntington's disease. For example, FUS and TDP-43, which rank 1st and 10th among RRM-bearing prion candidates, form cytoplasmic inclusions in the degenerating motor neurons of ALS patients and mutations in TDP-43 and FUS cause familial ALS. Recently, perturbed RNA-binding proteostasis of TAF15, which is the 2nd ranked RRM-bearing prion candidate, has been connected with ALS and FTLD-U. We strongly suspect that we have now merely reached the tip of the iceberg. We predict that additional RNA-binding prion candidates identified by our algorithm will soon surface as genetic modifiers or causes of diverse neurodegenerative conditions. Indeed, simple prion-like transfer mechanisms involving the prion domains of RNA-binding proteins could underlie the classical non-cell-autonomous emanation of neurodegenerative pathology from originating epicenters to neighboring portions of the nervous system. This article is part of a Special Issue entitled RNA-Binding Proteins.", "Hemochromatosis (iron storage disease) has been reported in diverse mammals including bottlenose dolphins (Tursiops truncatus). The primary cause of excessive iron storage in humans is hereditary hemochromatosis. Most human hereditary hemochromatosis cases (up to 90%) are caused by a point mutation in the hfe gene, resulting in a C282Y substitution leading to iron accumulation. To evaluate the possibility of a hereditary hemochromatosis-like genetic predisposition in dolphins, we sequenced the bottlenose dolphin hfe gene, using reverse transcriptase-PCR and hfe primers designed from the dolphin genome, from liver of affected and healthy control dolphins. Sample size included two case animals and five control animals. Although isotype diversity was evident, no coding differences were identified in the hfe gene between any of the animals examined. Because our sample size was small, we cannot exclude the possibility that hemochromatosis in dolphins is due to a coding mutation in the hfe gene. Other potential causes of hemochromatosis, including mutations in different genes, diet, primary liver disease, and insulin resistance, should be evaluated.", "OBJECTIVE: To investigate the effect of a novel LMNA gene mutation E82K found in a Chinese family with dilated cardiomyopathy on cell cycle of HEK293 cells.METHODS: (1) Human wild type full-length LMNA gene cDNA was subcloned into eukaryotic expression vector pTracer-CMV and point mutation was introduced into the cDNA. LMNA gene wild type and mutant E82K LMNA gene were transfected into HEK293 cells respectively and stable cell lines resistant to antibiotic were obtained 4 weeks later. (2) Cell cycle changes were analyzed by flow cytometry in HEK293 cells transfected with wild type and mutant E82K LMNA gene and empty vector in the presence of 0.8 mmol/L H(2)O(2).RESULTS: Cell circle was arrested at G0/G1 phase in the cells transfected with mutated E82K LMNA gene and at G2/M phase in other cell groups in the presence of H(2)O(2).CONCLUSION: Cell circle was arrested at G0/G1 phase in the cells transfected with E82K LMNA gene in the presence of H(2)O(2) in HEK293 cells.", "Our objective was to mine Reddit to discover long-COVID symptoms self-reported by users, compare symptom distributions across studies, and create a symptom lexicon. We retrieved posts from the /r/covidlonghaulers subreddit and extracted symptoms via approximate matching using an expanded meta-lexicon. We mapped the extracted symptoms to standard concept IDs, compared their distributions with those reported in recent literature and analyzed their distributions over time. From 42 995 posts by 4249 users, we identified 1744 users who expressed at least 1 symptom. The most frequently reported long-COVID symptoms were mental health-related symptoms (55.2%), fatigue (51.2%), general ache/pain (48.4%), brain fog/confusion (32.8%), and dyspnea (28.9%) among users reporting at least 1 symptom. Comparison with recent literature revealed a large variance in reported symptoms across studies. Temporal analysis showed several persistent symptoms up to 15 months after infection. The spectrum of symptoms identified from Reddit may provide early insights about long-COVID.", "Cell surface heparan sulfate (HS) proteoglycans are carbohydrate-rich regulators of cell migratory, mitogenic, secretory, and inflammatory activity that bind and present soluble heparin-binding growth factors (e.g., fibroblast growth factor, Wnt, Hh, transforming growth factor beta, amphiregulin, and hepatocyte growth factor) to their respective signaling receptors. We demonstrate that the deglycanated core protein of syndecan-1 (SDC1) and not HS chains nor SDC2 or -4, appears to target the epithelial selective prosecretory mitogen lacritin. An important and novel step in this mechanism is that binding necessitates prior partial or complete removal of HS chains by endogenous heparanase. This limits lacritin activity to sites where heparanase appears to predominate, such as sites of exocrine cell migration, secretion, renewal, and inflammation. Binding is mutually specified by lacritin's C-terminal mitogenic domain and SDC1's N terminus. Heparanase modification of the latter transforms a widely expressed HS proteoglycan into a highly selective surface-binding protein. This novel example of cell specification through extracellular modification of an HS proteoglycan has broad implications in development, homeostasis, and disease.", "There are several candidate neuroprotective agents that have been shown in preclinical testing to improve outcomes following traumatic brain injury (TBI). Xiao and colleagues have performed an in hospital, double blind, randomized, controlled clinical trial utilizing progesterone in the treatment of patients sustaining TBI evaluating safety and long term clinical outcomes. These data, combined with the results of the previously published ProTECT trial, show progesterone to be safe and potentially efficacious in the treatment of TBI. Larger phase III trials will be necessary to verify results prior to clinical implementation. Clinical trials networks devoted to the study of TBI are vital to the timely clinical testing of these candidate agents and need to be supported.", "Inulin is a carbohydrate composed of linear chains of β-2,1-linked D-fructofuranose molecules terminated by a glucose residue through a sucrose-type linkage at the reducing end. Jerusalem artichoke (JA) is one of the most interesting materials among unconventional and renewable raw materials, with levels of inulin reaching 50-80% of dry matter. Inulin or inulin-rich materials can be actively hydrolyzed by microbial inulinases to produce glucose and fructose syrups that can be used in bioprocesses. In this study, several microbial strains were isolated and their ability to inulinase biosynthesis was evaluated. The novel yeast strain Talf1, identified as Zygosaccharomyces bailii, was the best inulinase producer, attaining 8.67 U/ml of inulinase activity when JA juice was used as the inducer substrate. Z. bailii strain Talf1 and/or its enzymatic crude extract were further applied for bioethanol production and biodesulfurization (BDS) processes, using inulin and JA juice as carbon source. In a consolidated bioprocessing for ethanol production from 200 g/l inulin, Z. bailii strain Talf1 was able to produce 67 g/l of ethanol. This ethanol yield was improved in a simultaneous saccharification and fermentation (SSF) process, with the ethanologenic yeast Saccharomyces cerevisiae CCMI 885 and the Talf1 inulinases, achieving a production of 78 g/l ethanol. However, the highest ethanol yield (∼48%) was obtained in a SSF process from JA juice (∼130 g/l fermentable sugars), where the S. cerevisiae produced 63 g/l ethanol. Relatively to the dibenzothiophene BDS tests, the Gordonia alkanivorans strain 1B achieved a desulfurization rate of 4.8 μM/h within a SSF process using Talf1 inulinases and JA juice, highlighting the potential of JA as a less expensive alternative carbon source. These results showed the high potential of Z. bailii strain Talf1 inulinases as a versatile tool for bioprocesses using inulin-rich materials.", "X-ray crystallography provides the vast majority of macromolecular structures, but the success of the method relies on growing crystals of sufficient size. In conventional measurements, the necessary increase in X-ray dose to record data from crystals that are too small leads to extensive damage before a diffraction signal can be recorded. It is particularly challenging to obtain large, well-diffracting crystals of membrane proteins, for which fewer than 300 unique structures have been determined despite their importance in all living cells. Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes. More than 3,000,000 diffraction patterns were collected in this study, and a three-dimensional data set was assembled from individual photosystem I nanocrystals (∼200 nm to 2 μm in size). We mitigate the problem of radiation damage in crystallography by using pulses briefer than the timescale of most damage processes. This offers a new approach to structure determination of macromolecules that do not yield crystals of sufficient size for studies using conventional radiation sources or are particularly sensitive to radiation damage.", "Recent evidence suggests that many members of the human kallikrein gene family are differentially regulated in breast cancer and other endocrine-related malignancies. In this study, we utilised the serial analysis of gene expression (SAGE) and expressed sequence tag (EST) databases of the Cancer Genome Anatomy Project (CGAP) to perform in silico analyses of the expression pattern of the 15 human kallikrein genes in normal and cancerous breast tissues and cell lines using different analytical tools such as Virtual Northern blotting, Digital Differential Display and X-profiler. Our results indicate that at least four kallikrein genes (KLK5, 6, 8, 10) are downregulated in breast cancer. Probing eight normal and 24 breast cancer SAGE libraries with gene-specific tags for each of the above kallikreins indicated moderate-to-high expression densities in normal breast (27-319 tags per million; tpm, in two to five out of eight libraries), compared to no or low expression (0 - 34 tpm in zero to two libraries out of 24) in breast cancer. These data were verified by screening the EST databases, where all mRNA clones isolated for these genes, except for one in each, were from normal breast libraries, with no clones detected from breast cancer tissues or cell lines (with the exception of KLK8). X-profiler comparison of two pools of normal and breast cancer libraries further verified the presence of significant downregulation of expression levels of 4 of the kallikreins genes (KLK5, 6, 10, 12). We experimentally verified the downregulation of these four kallikreins (KLK5, 6, 8, 10 and 12) by RT - PCR analysis.", "Puffy hand syndrome is an unrecognized complication of intravenous drug abuse. This painless syndrome appears during or after a long period of drug addiction. It involves the hands and sometimes the forearms, and may cause functional, aesthetic and social disturbances when the hand volume is important. Physiopathological mechanisms of the puffy hand syndrome are unclear and include venous and lymphatic insufficiencies, infectious complications and direct toxicity of injected drugs and their adulterants. Low-stretch bandage and elastic garment, usually used in lymphedema treatment, are proposed to treat the puffy hand syndrome.", "In the present study the hypothesis was tested that N-bromoacetyl-3,3',5-[125I]triiodothyronine (BrAc[125I]T3) is a useful affinity label for both type I and type III iodothyronine deiodinases (ID-I and ID-III). Therefore, the microsomal fractions of various rat tissues were tested for ID-I and ID-III activities, and microsomal proteins were labeled with BrAc[125I]T3 and analyzed by SDS-PAGE. In agreement with previous observations, high ID-I activities were found in liver, kidney and thyroid, and high ID-III activities in brain, in particular fetal brain, and placenta. SDS-PAGE of BrAc[125I]T3-labeled microsomes showed a prominent radioactive approximately 27 kDa protein (p27) in liver, kidney and thyroid, which was previously identified as ID-I, and a approximately 32 kDa protein (p32) in brain, in particular fetal brain, and placenta. A good correlation was found between the affinity labeling of p32 and the inactivation of ID-III by BrAcT3, suggesting that p32 represents ID-III or a subunit thereof. After treatment of microsomes with 0.05% deoxycholate or carbonate buffer (pH 11.5) p32 was still labeled by BrAc[125I]T3, indicating that p32 is a transmembrane protein. Although 3,3',5'-triiodothyronine (rT3) is not a substrate for ID-III, p32 was readily labeled with BrAc[125I]rT3. Labeling of p32 in rat brain microsomes by BrAc[125I]rT3 was not affected by addition of 100 microM unlabeled thyroxine (T4) or T3, whereas deiodination of [125I]T3 by ID-III was inhibited by 91 and 96% in the presence of 1 microM T4 and T3, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)", "β-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the transmembrane aspartyl protease that catalyzes the first cleavage step in the proteolysis of the APP to the amyloid β-protein (Aβ), a process involved in the pathogenesis of Alzheimer disease. BACE1 pre-mRNA undergoes complex alternative splicing, the regulation of which is not well understood. We identified a G-rich sequence within exon 3 of BACE1 involved in controlling splice site selection. Mutation of the G-rich sequence decreased use of the normal 5' splice site of exon 3, which leads to full-length and proteolytically active BACE1, and increased use of an alternative splice site, which leads to a shorter, essentially inactive isoform. Nuclease protection assays, nuclear magnetic resonance, and circular dichroism spectroscopy revealed that this sequence folds into a G-quadruplex structure. Several proteins were identified as capable of binding to the G-rich sequence, and one of these, heterogeneous nuclear ribonucleoprotein H, was found to regulate BACE1 exon 3 alternative splicing and in a manner dependent on the G-rich sequence. Knockdown of heterogeneous nuclear ribonucleoprotein H led to a decrease in the full-length BACE1 mRNA isoform as well as a decrease in Aβ production from APP, suggesting new possibilities for therapeutic approaches to Alzheimer's disease.", "The tularemia-causing bacterium Francisella tularensis is a facultative intracellular organism with a complex intracellular lifecycle that ensures its survival and proliferation in a variety of mammalian cell types, including professional phagocytes. Because this cycle is essential to Francisella pathogenesis and virulence, much research has focused on deciphering the mechanisms of its intracellular survival and replication and characterizing both bacterial and host determinants of the bacterium's intracellular cycle. Studies of various strains and host cell models have led to the consensual paradigm of Francisella as a cytosolic pathogen, but also to some controversy about its intracellular cycle. In this review, we will detail major findings that have advanced our knowledge of Francisella intracellular survival strategies and also attempt to reconcile discrepancies that exist in our molecular understanding of the Francisella-phagocyte interactions.", "Author information:(1)Sorbonne Universités, UPMC Univ Paris 06, Institut Pierre Louis d'Epidémiologie et de Santé Publique, GRC-UPMC 08 (EEMOIS), Paris, France Department of rheumatology, AP-HP, Pitié Salpêtrière Hospital, Paris, France.(2)Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria Second Department of Medicine, Hietzing Hospital, Vienna, Austria.(3)Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.(4)EULAR, representing People with Arthritis/Rheumatism in Europe (PARE), London, UK.(5)Research Laboratory and Clinical Division of Rheumatology, Department of Internal Medicine, University of Genova, Viale Benedetto, Italy.(6)Medicine Faculty, Paris Descartes University, Paris, France Rheumatology B Department, APHP, Cochin Hospital, Paris, France.(7)Leeds NIHR Musculoskeletal Biomedical Research Unit, LTHT, Leeds, UK Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.(8)Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology Center, Amsterdam, The Netherlands Atrium Medical Center, Heerlen, The Netherlands.(9)North Devon, UK.(10)Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria.(11)Rheumazentrum Ruhrgebiet, Herne and Ruhr-Universität Bochum, Herne, Germany.(12)Department of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Germany.(13)Arthritis Unit, Department of Rheumatology, Hospital Clínic and IDIBAPS, Barcelona, Spain.(14)Belgrade University School of Medicine, Belgrade, Serbia.(15)Department of Rheumatology, St. Vincent's University Hospital and Conway Institute, University College Dublin, Dublin, Ireland.(16)Section of Rheumatology, Department of Clinical Sciences, Lund University, Lund, Sweden Sweden and School of Business, Engineering and Science, Halmstad University, Halmstad, Sweden.(17)Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.(18)Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.(19)Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven, Belgium Division of Rheumatology, University Hospitals Leuven, Leuven, Belgium.(20)Department of Dermatology, University Hospital Münster, Münster, Germany.(21)A.DI.PSO. (Associazione per la Difesa degli Psoriasici)-PE.Pso.POF (Pan European Psoriasis Patients' Organization Forum), Rome, Italy.(22)Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.(23)Rheumatology Department of Lucania, San Carlo Hospital of Potenza and Madonna delle Grazie Hospital of Matera, Potenza, Italy.(24)Institute and Clinic of Rheumatology Charles University Prague, Czech Republic.(25)Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.(26)Department of Rheumatology, Campus Benjamin Franklin, Charité, Berlin, Germany.(27)Ghent University Hospital, Ghent, Belgium.(28)Centre for Arthritis and Rheumatic Disease, Dublin Academic Medical Centre, St. Vincent's University Hospital, Dublin, Ireland.(29)Schoen Klinik Hamburg, Rheumatology and Clinical Immunology, Hamburg, Germany.(30)Department of Rheumatology and Clinical Immunology, German Rheumatism Research Centre Berlin, Charité-University Medicine Berlin, Germany.", "Fanconi anemia (FA) is a multisystem disease, characterized by the triad of physical abnormalities, bone marrow failure, and increased risk for malignancy. In the past few years, data has accumulated regarding fertility issues in FA patients, mostly due to gonadal dysfunction, which is prevalent in FA patients reaching puberty. It seems that attenuated FA phenotype lacking the classical manifestations often is presented with POI or azoospermia. Searching the literature, we summarized data regarding FA patients presenting as suffering from sub/infertility due to gonadal dysfunction, with or without other FA symptoms. We present a summary of the patients having biallelic pathogenic variants in FA genes FANCA, FANCM, BRCA2, and XRCC2 that presented with gonadal dysfunction with or without other phenotypic features of FA. Some were in mosaic, while some are considered hypomorphic, enabling residual protein function. There are also a few descriptions of POI associated with monoallelic pathogenic variants in FANCA, BRCA2, and FANCL. We conclude that the diagnosis of FA in gonadal dysfunction patients is of utmost importance due to its actionability. Follow-up strategies in FA patients are designed to discover early stages of leukemias and solid tumors and thus save lives. The feasibility of next-generation sequencing (NGS) can now ease this diagnostic procedure. An open question is the justification of performing NGS for all isolated azoospermia/POI patients.", "AMP-activated protein kinase (AMPK) is a key sensor of cellular energy. The activation of AMPK by metformin prevents cardiac remodeling after myocardial infarction (MI). Besides, the innate immune response through TLRs is activated during MI. In the present study, the effects of short-term treatment with metformin on TLRs activity and its relation with AMPK in isoproterenol-induced MI were assessed in rats. To induce MI, a subcutaneous injection of isoproterenol was given to Wistar rats for two consecutive days. Metformin (25, 50, and 100mg/kg) was orally administered to rats twice daily for two days. Interstitial fibrosis was dose-dependently attenuated in the treated groups in comparison to the MI group (score: 1.25 ± 0.28 with 100 mg/kg metformin versus 3.5 ± 0.28; P<0.001). Further, metformin reduced TLR-dependent inflammatory cytokines as indexed by reduced myocardial levels of TNFα (maximum 68%; P<0.001) and IL6 (maximum 84%; P<0.001) as well as by reduced myocardial MPO activity (25%; P<0.01). It was found that the level of phosphorylated AMPK was significantly upregulated by 165% (P<0.001) when treated with 100 mg/kg of metformin, but not with 25 and 50mg/kg. This was associated with a remarkable suppression of TLR4 expression and reduction of protein level of TLRs adapter protein, MyD88 (P<0.01) in the infarcted myocardium. These results suggest that AMPK activation by metformin and the subsequent suppression of TLRs activity could be considered as a target in protecting the infarcted heart, which may indicate a link between AMPK and TLRs.", "The authors report an original clinical presentation of factitious disorders of the upper extremity in an ex-drug-addict patient with puffy hand syndrome. Chronic self-inflicted ulcerations appeared with sequential manner. The patient confessed deliberate self-harm and transfer of anxiety on his hands, the aspect of which had become intolerable. Association of puffy hand syndrome with comorbid psychosis and major depression explained immediate recurrence of ulcerations despite fitted medication and long-term psychotherapy.", "T-cell prolymphocytic leukemia (T-PLL) is a chemotherapy-resistant malignancy with a median survival of 7.5 months. Preliminary results indicated a high remission induction rate with the human CD52 antibody, CAMPATH-1H. This study reports results in 39 patients with T-PLL treated with CAMPATH-1H between March 1993 and May 2000. All but 2 patients had received prior therapy with a variety of agents, including 30 with pentostatin; none achieved complete remission (CR). CAMPATH-1H (30 mg) was administered intravenously 3 times weekly until maximal response. The overall response rate was 76% with 60% CR and 16% partial remission (PR). These responses were durable with a median disease-free interval of 7 months (range, 4-45 months). Survival was significantly prolonged in patients achieving CR compared to PR or no response (NR), including one patient who survived 54 months. Nine patients remain alive up to 29 months after completing therapy. Seven patients received high-dose therapy with autologous stem cell support, 3 of whom remain alive in CR 5, 7, and 15 months after autograft. Stem cell harvests in these patients were uncontaminated with T-PLL cells as demonstrated by dual-color flow cytometry and polymerase chain reaction. Four patients had allogeneic stem cell transplants, 3 from siblings and 1 from a matched unrelated donor. Two had nonmyeloablative conditioning. Three are alive in CR up to 24 months after allograft. The conclusion is that CAMPATH-1H is an effective therapy in T-PLL, producing remissions in more than two thirds of patients. The use of stem cell transplantation to consolidate responses merits further study.", "AIM: We studied the pathogenesis of puffy hand syndrome of intravenous drug use. We hypothesized that injections of high-dose sublingual buprenorphine, instead of the recommended sublingual administration, could play an important role in lymphatic obstruction and destruction.DESIGN AND PARTICIPANTS: We set up a case-control study in substitution centres, recruiting intravenous drug addicts with and without puffy hands, respectively. The subjects were asked to answer anonymously a questionnaire of 40 items comprising social and demographic status, history of illicit drugs use, buprenorphine misuse and injection practices.FINDINGS: We included 33 cases and 33 controls, mean age of 34 years. They were past heroin users, mainly methadone-substituted. In multivariate analysis, sex (women) (OR = 8.9, P = 0.03), injections in the hands (OR = 5.9, P = 0.03), injections in the feet (OR = 6.5, P = 0.01) and the absence of tourniquet (OR = 7.0, p = 0.02) were significant risk factors for puffy hand syndrome. In 69.7% of the cases and 59.4% of the controls, respectively, there was a high-dose sublingual buprenorphine misuse, although it appeared not to be a significant risk factor for puffy hand syndrome.CONCLUSIONS: Injection practices are likely to cause puffy hands syndrome, but buprenorphine misuse should not be considered as a significant risk factor. However, intravenous drug users must still be warned of local and systemic complications of intravenous drug misuse.", "BACKGROUND: The nonsense-mediated mRNA decay (NMD) pathway promotes the rapid degradation of mRNAs containing premature termination codons (PTCs). In yeast Saccharomyces cerevisiae, the activity of the NMD pathway depends on the recognition of the PTC by the translational machinery. Translation termination factors eRF1 (Sup45) and eRF3 (Sup35) participate not only in the last step of protein synthesis but also in mRNA degradation and translation initiation via interaction with such proteins as Pab1, Upf1, Upf2 and Upf3.RESULTS: In this work we have used previously isolated sup45 mutants of S. cerevisiae to characterize degradation of aberrant mRNA in conditions when translation termination is impaired. We have sequenced his7-1, lys9-A21 and trp1-289 alleles which are frequently used for analysis of nonsense suppression. We have established that sup45 nonsense and missense mutations lead to accumulation of his7-1 mRNA and CYH2 pre-mRNA. Remarkably, deletion of the UPF1 gene suppresses some sup45 phenotypes. In particular, sup45-n upf1Delta double mutants were less temperature sensitive, and more resistant to paromomycin than sup45 single mutants. In addition, deletion of either UPF2 or UPF3 restored viability of sup45-n double mutants.CONCLUSION: This is the first demonstration that sup45 mutations do not only change translation fidelity but also acts by causing a change in mRNA stability.", "From the cells of an Escherichia coli K-12 strain, a 22,000-dalton protein which has an affinity for the superhelical DNA molecule was purified to apparent homogeneity by monitoring the DNA-binding activity using the filter binding assay. In the sedimentation analysis of the DNA-protein complex, the protein has an affinity for the superhelical or single-stranded DNA molecule but neither for the open-circular nor for the linear DNA molecule. The amino acid composition of the protein resembled those of the other prokaryotic histone-like proteins and also to eukaryotic histones H2A and H2B. The protein precipitated upon heating, which is in contrast to the heat-stable feature of the other histone-like proteins. Furthermore, DNA and RNA syntheses in vitro were not affected by the presence of the protein. In view of these characteristics, this protein may play a role in maintaining the bacterial nucleoid structure.", "The incidence of vascular complications due to drug abuse is at present increasing due to new types of drugs and to the different ways of intake of such substances. The vascular complications related to drug abuse may affect venous, arterious and lymphatic districts and in particular: ischemia following intra-arterial injections, arterious and venous pseudoaneurysm, vasculitis, aneurysms, aortic dissections, abscesses complicated by erosions of vessels, arteriovenous fistulas, compartment syndrome, superficial and deep venous thrombosis, septic trombophlebitis, puffy hand syndrome. The scientific knowledge in this matter is incomplete because of the new pathological cases and the lack of information regarding the efficacy of different treatments. The authors report four patients affected by vascular pathologies due to drug abuse. In one case, a heroin addict has undergone multiple fasciotomies for compartimental syndrome arising because the patient maintained an innatural posture for several hours during an overdose coma. In a second case, a segmental right subclavear deep venous thrombosis has been treated by pharmacological therapy with satisfactory functional recovery of the arm. A third patient has been successfully submitted to intra-arterial pharmacological vasodilatation for generalised lower limbs vasospasm caused by drug abuse. In the last case, the voluntary swallowing of a great dose of cocaine caused the patient's death after multiple ischemic and hemorrhagic cerebral episodes. After the description of these cases, a review of the recent literature and some observations on this topic are presented. A better knowledge of vascular complications due to drug abuse should improve the therapeutical approach of these patients.", "Essential blepharospasm is an idiopathic disorder that consists of spontaneous, spasmodic, and involuntary eyelid closure in the absence of ocular disease. Some patients develop an inability to open their eyelids in the absence of orbicularis spasms. These patients have essential blepharospasm combined with apraxia of eyelid opening. Botulinum toxin injections are the treatment of choice for blepharospasm but results may be insufficient, especially in cases associated with apraxia. Apraxia can be treated surgically by levator aponeurosis advancement, frontalis suspension, and upper myectomy. The authors report the first browlift using polypropylene suture to manage eyelid apraxia associated with blepharospasm as an alternative and minimally invasive procedure.", "Infections generally occur in intravenous drug abuse (IVDA) patients, most commonly affecting the spine and proximal joints. Numerous serious musculoskeletal complications of IVDA may involve the upper extremity, however. Soft-tissue complications in the upper extremity of IVDA patients include cellulitis, ulceration, abscess, pyomyositis, septic bursitis, tenosynovitis, and necrotizing fasciitis. Foreign bodies in soft tissue due to needle fragments are common findings. Primary bone and joint IVDA complications include osteomyelitis (acute and chronic) and septic arthritis. Other IVDA complications in the upper extremity affecting blood vessels and lymphatics include hematoma, arterial aneurysm and pseudoaneurysm, thrombosis, thrombophlebitis, \"puffy hand\" syndrome, and lymphadenopathy. These complications usually present as urgent issues requiring prompt and accurate evaluation in the acute setting. Diagnostic imaging not only aids in making the correct diagnosis but also permits precise definition of the location and extent of these abnormalities. We review the imaging findings and illustrate a wide range of disabling and even life-threatening complications affecting the upper extremity of IVDA patients that require early diagnosis for optimal outcome.", "PURPOSE OF REVIEW: The results of phase 2 randomized controlled trials for the prevention of episodic and chronic migraine demonstrating the efficacy and safety of four mAbs targeting the calcitonin gene-related peptide (CGRP) pathway [ALD403 (eptinezumab), AMG334 (erenumab), LY2951742 (galcanezumab) and TEV48125 (fremanezumab)] have been published recently, and phase 3 trials are in process. This development will change headache management fundamentally. We aim to summarize and compare the phase 2 data.RECENT FINDINGS: The change from baseline in the number of migraine days at the end of treatment in high-frequency episodic migraine was -1 (at weeks 5-8), -1.1 (at weeks 9-12), -1.2 (at weeks 9-12) and -2.6 (at weeks 9-12) days for ALD403, AMG344, LY2951742 and TEV48125 (225 mg), respectively. Number needed to treats for responders and odds ratio for any adverse event were 4.7, 6.2, 4.0 and 4.0 and 1.09, 0.96, 1.07 and 1.05, respectively.SUMMARY: All four CGRP antibodies display comparable efficacy that does not differ significantly from that of the currently available oral antimigraine drugs. However, their safety and tolerability profiles as well as low frequency of administration looks promising but remains to be verified in long-term and large-scale trials. Considerations related to pregnancy, risk for cardiovascular effects and cost are subject for further evaluation.", "Yamanaka factors (Oct3/4, Sox2, Klf4, c-Myc) are highly expressed in embryonic stem (ES) cells, and their over-expression can induce pluripotency in both mouse and human somatic cells, indicating that these factors regulate the developmental signaling network necessary for ES cell pluripotency. However, systemic analysis of the signaling pathways regulated by Yamanaka factors has not yet been fully described. In this study, we identified the target promoters of endogenous Yamanaka factors on a whole genome scale using ChIP (chromatin immunoprecipitation)-on-chip in E14.1 mouse ES cells, and we found that these four factors co-occupied 58 promoters. Interestingly, when Oct4 and Sox2 were analyzed as core factors, Klf4 functioned to enhance the core factors for development regulation, whereas c-Myc seemed to play a distinct role in regulating metabolism. The pathway analysis revealed that Yamanaka factors collectively regulate a developmental signaling network composed of 16 developmental signaling pathways, nine of which represent earlier unknown pathways in ES cells, including apoptosis and cell-cycle pathways. We further analyzed data from a recent study examining Yamanaka factors in mouse ES cells. Interestingly, this analysis also revealed 16 developmental signaling pathways, of which 14 pathways overlap with the ones revealed by this study, despite that the target genes and the signaling pathways regulated by each individual Yamanaka factor differ significantly between these two datasets. We suggest that Yamanaka factors critically regulate a developmental signaling network composed of approximately a dozen crucial developmental signaling pathways to maintain the pluripotency of ES cells and probably also to induce pluripotent stem cells." ]

[ "The past decade has brought tremendous progress in unraveling the pathophysiology of Alzheimer's disease (AD). While increasingly sophisticated immunotherapy targeting soluble and aggregated brain amyloid-beta (Aβ) continues to dominate clinical research in AD, a deeper understanding of Aβ physiology has led to the recognition of distinct neuronal signaling pathways linking Aβ to synaptotoxicity and neurodegeneration and to new targets for therapeutic intervention. Identifying specific signaling pathways involving Aβ has allowed for the development of more precise therapeutic interventions targeting the most relevant molecular mechanisms leading to AD. In this review, I highlight the discovery of cellular prion protein as a high-affinity receptor for Aβ oligomers, and the downstream signaling pathway elucidated to date, converging on nonreceptor tyrosine kinase Fyn. I discuss preclinical studies targeting Fyn as a therapeutic intervention in AD and our recent experience with the safety, tolerability, and cerebrospinal fluid penetration of the Src family kinase inhibitor saracatinib in patients with AD. Fyn is an attractive target for AD therapeutics, not only based on its activation by Aβ via cellular prion protein but also due to its known interaction with tau, uniquely linking the two key pathologies in AD. Fyn is also a challenging target, with broad expression throughout the body and significant homology with other members of the Src family kinases, which may lead to unintended off-target effects. A phase 2a proof-of-concept clinical trial in patients with AD is currently under way, providing critical first data on the potential effectiveness of targeting Fyn in AD.", "This article summarizes the results of 30 y of follow-up of cancer and noncancer effects in Ukrainian cleanup workers after the Chornobyl accident. The number of power plant employees and first responders with acute radiation syndrome under follow-up by the National Research Center for Radiation Medicine decreased from 179 in 1986-1991 to 105 in 2011-2015. Cancers and leukemia (19) and cardiovascular diseases (21) were the main causes of deaths among acute radiation syndrome survivors (54) during the postaccident period. Increased radiation risks of leukemia in the Ukrainian cohort of 110,645 cleanup workers exposed to low doses are comparable to those among survivors of the atomic bomb explosions in Japan in 1945. Additionally, an excess of chronic lymphocytic leukemia was demonstrated in the cleanup workers cohort for 26 y after the exposure. A significant excess of multiple myeloma incidence [standardized incidence rate (SIR) 1.61 %, 95% confidence interval (CI) 1.01-2.21], thyroid cancer (SIR 4.18, 95% CI 3.76-4.59), female breast cancer (SIR 1.57 CI 1.40-1.73), and all cancers combined (SIR 1.07; 95% CI 1.05-1.09) was registered. High prevalence was demonstrated for cardio- and cerebrovascular diseases and mental health changes. However, the reasons for the increases require further investigation. To monitor other possible late effects of radiation exposure in Chornobyl cleanup workers, analytical cohort and case-control studies need to include cardiovascular pathology, specifically types of potentially radiogenic cancers using a molecular epidemiology approach. Possible effects for further study include increased rates of thyroid, breast, and lung cancers and multiple myeloma; reduction of radiation risks of leukemia to population levels; and increased morbidity and mortality of cleanup workers from cardio- and cerebrovascular pathology.", "The hepatic stellate cell (HSC) is the predominant cell type responsible for excess collagen deposition during liver fibrosis. Both transforming growth factor-beta (TGF-beta), the most potent fibrogenic cytokine for HSCs, which classically activates Smad signaling, and p38 MAPK signaling have been shown to influence collagen gene expression; however, the relative contribution and mechanisms that these two signaling pathways have in regulating collagen gene expression have not been investigated. The aim of this study was to investigate the relative roles and mechanisms of both Smad and p38 MAPK signaling in alpha1(I) collagen gene expression in HSCs. Inhibiting either p38 MAPK or Smad signaling reduced alpha1(I) collagen mRNA expression in untreated or TGF-beta-treated HSCs, and when both signaling pathways were simultaneously inhibited, alpha1(I) collagen gene expression was essentially blocked. Both signaling pathways were found to independently and additively increase alpha1(I) collagen gene expression by transcriptional mechanisms. TGF-beta treatment increased alpha1(I) collagen mRNA half-life, mediated by increased stability of alpha1(I) collagen mRNA through p38 MAPK signaling but not through Smad signaling. In conclusion, both p38 MAPK and Smad signaling independently and additively regulate alpha1(I) collagen gene expression by transcriptional activation, whereas p38 MAPK and not Smad signaling increased alpha1(I) collagen mRNA stability.", "We conducted a review of patient medical records to assess treatment response patterns and prognostic indicators of response among chronic myeloid leukemia (CML) patients in the United States, the United Kingdom, Germany, and Japan. All 1,063 patients selected met the following inclusion criteria: aged 18 or older and in chronic phase at the time of diagnosis, Philadelphia chromosome and/or BCR-ABL positive, received first-line treatment with imatinib, and not enrolled in a randomized clinical trial during the period of retrospective review. Multivariable logistic regression models were used to evaluate prognostic indicators of complete hematological response (CHR), complete cytogenetic response (CCyR), and complete or major molecular response (C/MMR). Among patients treated with first-line imatinib, CHR at three months, CCyR at 12 months, and C/MMR at 18 months were observed in 53, 53.1, and 57.8 % of patients, respectively. Among patients treated with second-line dasatinib or nilotinib, CHR was achieved at three months in 49 and 42 %, CCyR at 12 months in 32 and 23 %, and MMR at 18 months in 30.5 and 26.1 % of patients, respectively. Prognostic indicators of first-line response included age, race, and Sokal score. For second-line treatment, duration of first-line hematological response and choice of drug used were also significant.", "Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare arrhythmogenic disorder characterized by syncopal events and sudden cardiac death at a young age during physical stress or emotion, in the absence of structural heart disease. We report the first nonsense mutations in the cardiac calsequestrin gene, CASQ2, in three CPVT families. The three mutations, a nonsense R33X, a splicing 532+1 G>A, and a 1-bp deletion, 62delA, are thought to induce premature stop codons. Two patients who experienced syncopes before the age of 7 years were homozygous carriers, suggesting a complete absence of calsequestrin 2. One patient was heterozygous for the stop codon and experienced syncopes from the age of 11 years. Despite the different mutations, there is little phenotypic variation of CPVT for the CASQ2 mutations. Of the 16 heterozygous carriers of these various mutations, 14 were devoid of clinical symptoms or ECG anomalies, whereas 2 of them had ventricular arrhythmias at ECG on exercise tests. In line with this, the diagnosis of the probands was difficult because of the absence of a positive family history. In conclusion, these additional three CASQ2 CPVT families suggest that CASQ2 mutations are more common than previously thought and produce a severe form of CPVT. The full text of this article is available at http://www.circresaha.org.", "The sequence of the tyrosinase (Tyr) gene coding tracts has been obtained for the gorilla (Gorilla gorilla gorilla). The five exons of the gene were sequenced in three gorillas and in a normally pigmented human. The tyrosinase gene has been found to be a very conserved locus with a very low substitution rate. Some nucleotide and amino acid differences were found between the gorilla and human tyrosinase coding sequences. One of the gorillas included in the study is the only known case of albinism in a gorilla ('Snowflake'). Mutations of the TYR gene lead to Oculocutaneous Albinism type 1 (OCA1), the most common type of albinism in humans (OMIM accession number 203100). The TYR gene encodes the tyrosinase enzyme (E.C. 1.14.18.1), whose activity was found to be completely lacking in 'Snowflake', indicating that a mutation in the Tyr gene is the likely cause of his albinism. Nonetheless, no nucleotide changes were detected that could account for the lack of Tyr product or tyrosinase activity in Snowflake, and explanations of these findings are discussed.", "BACKGROUND: Past and repeated self-harm are long-term risks to completed suicide. A brief rating scale to assess repetition risk of self-harm is important for high-risk identification and early interventions in suicide prevention. The study aimed to examine the validity of the Chinese SAD PERSONS Scale (CSPS) and to evaluate its feasibility in clinical settings.METHODS: One hundred and forty-seven patients with self-harm were recruited from the Emergency Department and assessed at baseline and the sixth month. The controls, 284 people without self-harm from the Family Medicine Department in the same hospital were recruited and assessed concurrently. The psychometric properties of the CSPS were examined using baseline and follow-up measurements that assessed a variety of suicide risk factors. Clinical feasibility and applicability of the CSPS were further evaluated by a group of general nurses who used case vignette approach in CSPS risk assessment in clinical settings. An open-ended question inquiring their opinions of scale adaptation to hospital inpatient assessment for suicide risks were also analyzed using content analysis.RESULTS: The CSPS was significantly correlated with other scales measuring depression, hopelessness and suicide ideation. A cut-off point of the scale was at 4/5 in predicting 6-month self-harm repetition with the sensitivity and specificity being 65.4% and 58.1%, respectively. Based on the areas under the Receiver Operating Characteristic curves, the predictive validity of the scale showed a better performance than the other scales. Fifty-four nurses, evaluating the scale using case vignette found it a useful tool to raise the awareness of suicide risk and a considerable tool to be adopted into nursing care.CONCLUSIONS: The Chinese SAD PERSONS Scale is a brief instrument with acceptable psychometric properties for self-harm prediction. However, cautions should be paid to level of therapeutic relationships during assessment, staff workload and adequate training for wider clinical applications." ]

[ "Systemic lupus erythematosus (SLE) is a generalized autoimmune disease characterized by abnormal B cell activation and the occurrence of increased frequencies of circulating plasma cells (PC). The molecular characteristics and nature of circulating PC and B cells in SLE have not been completely characterized. Microarray analysis of gene expression was used to characterize circulating PC in subjects with active SLE. Flow cytometry was used to sort PC and comparator B cell populations from active SLE blood, normal blood and normal tonsil. The gene expression profiles of the sorted B cell populations were then compared. SLE PC exhibited a similar gene expression signature as tonsil PC. The differences in gene expression between SLE PC and normal tonsil PC and tonsil plasmablasts (PB) suggest a mature Ig secreting cell phenotype in the former population. Despite this, SLE PC differed in expression of about half the genes from previously published gene expression profiles of normal bone marrow PC, indicating that these cells had not achieved a fully mature status. Abnormal expression of several genes, including CXCR4 and S1P(1), suggests a mechanism for the persistence of SLE PC in the circulation. All SLE B cell populations revealed an interferon (IFN) gene signature previously only reported in unseparated SLE peripheral blood mononuclear cells. These data indicate that SLE PC are a unique population of Ig secreting cells with a gene expression profile indicative of a mature, but not fully differentiated phenotype.", "Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized clinically by the triad of abnormal nails, reticular skin pigmentation, and oral leukoplakia, and is associated with high risk of developing aplastic anemia, myelodysplastic syndrome, leukemia, and solid tumors. Patients have very short germline telomeres, and approximately half have mutations in one of six genes encoding proteins that maintain telomere function. Accurate diagnosis of DC is critical to ensure proper clinical management, because patients who have DC and bone marrow failure do not respond to immunosuppressive therapy and may have increased morbidity and mortality associated with hematopoietic stem cell transplantation.", "Over the last decade, it has become increasingly clear that the cardiovascular and renal systems are interdependent. Primary disorders of either system have been shown to disturb the other system. As a result, a class of cardiorenal syndrome (CRS) has been identified where in a vicious cycle is established in which acute/chronic dysfunction of either the kidney or the heart exacerbates the loss of function in the other organ. The ADQI organization has proposed a classification derived from a consensus conference held in 2008. CRS is classified as a disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other. The general definition has been expanded into five subtypes: CRS type 1 = acute worsening of heart function (acute heart failure-acute coronary syndrome) leading to kidney injury and/or dysfunction; CRS type 2 = chronic abnormalities in heart function (chronic heart failure-chronic heart disease) leading to kidney injury or dysfunction; CRS type 3 = acute worsening of kidney function (acute kidney injury) leading to heart injury and/or dysfunction; CRS type 4 = chronic kidney disease (chronic kidney disease) leading to heart injury, disease and/or dysfunction; and CRS type 5 = systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney. A major problem with previous terminology was that it did not allow for identification of pathophysiological interactions occurring in the different types of combined heart/kidney disorders. The subdivision into different subtypes seems to provide a better approach to this syndrome.", "Proanthocyanidin is commonly used for inhibiting urinary tract infection (UTI) of sensitive strains of Escherichia coli. The aim of this study was to investigate the effect of proanthocyanidin on adherence of uropathogenic multi-drug resistant E. coli to uroepithelial cells, which has not yet been investigated so far. Extracts of the purified proanthocyanidin were prepared from dried cranberry juice. Purity and structural assignment of proanthocyanidin was assessed using high performance liquid chromatography and (13)C nuclear magnetic resonance spectroscopy, respectively. Subsequently, its affect on multi-drug resistant bacteria as well as quantification of anti-adherence bioactivity on human vaginal and bladder epithelial cells was appraised. Inhibition of adherence to an extent of about 70% with multi-drug resistant E. coli strains was observed on uroepithelial cell. The anti-adherence bioactivity of the proanthocyanidin was detected at concentrations of 10-50 µg/ml with significant bacteriuria. Probable proanthocyanidin through A-type linkages either combines to P-fimbriae of bacterial cells or modifies the structural entity of P-fimbriae and inhibits bacterial adherence to uroepithelial cells. The proanthocyanidin exhibited anti-adherence property with multi-drug resistant strains of uropathogenic P-fimbriated E. coli with in vitro study. Hence proanthocyanidin may be considered as an inhibitory agent for multi-drug resistant strains of E. coli adherence to uroepithelial cells.", "Lennox-Gastaut syndrome (LGS) is a severe pediatric epilepsy syndrome characterized by mixed seizures, cognitive decline, and generalized slow (<3 Hz) spike wave discharges on electroencephalography. Atonic seizures result in dangerous drop attacks with risks of injury and impairment of the quality of life. The seizures are frequently resistant to multiple antiepileptic (AED) drugs. Newer AEDs, such as rufinamide, are now available. When multiple AED trials fail, non-pharmacological treatments such as the ketogenic diet, vagus nerve stimulation, and epilepsy surgery, should be considered. The aim of this review is to present an updated outline of LGS and the available treatments. Although the prognosis for complete seizure control remains poor, the addition of newer therapies provides an improved hope for some of these patients and their families. Further long term randomized controlled trials are required to compare different therapeutic interventions in terms of efficacy and tolerability.", "Dravet syndrome is an epileptic encephalopathy characterized by multiple types of seizures. We report the first case of musicogenic reflex seizures in a 7-year-old male with a mutation in the SCN1A gene causing Dravet syndrome. Reflex seizures have been reported in patients with Dravet syndrome provoked by body temperature elevation, looking at visual patterns, or under intermittent photic stimulation. The case we report widens the spectrum of reflex seizures recorded in patients with Dravet syndrome. Cortical hyperexcitability of genetic origin could explain the tendency of these patients to experience reflex seizures.", "Developmental genes in metazoan genomes are surrounded by dense clusters of conserved noncoding elements (CNEs). CNEs exhibit unexplained extreme levels of sequence conservation, with many acting as developmental long-range enhancers. Clusters of CNEs define the span of regulatory inputs for many important developmental regulators and have been described previously as genomic regulatory blocks (GRBs). Their function and distribution around important regulatory genes raises the question of how they relate to 3D conformation of these loci. Here, we show that clusters of CNEs strongly coincide with topological organisation, predicting the boundaries of hundreds of topologically associating domains (TADs) in human and Drosophila. The set of TADs that are associated with high levels of noncoding conservation exhibit distinct properties compared to TADs devoid of extreme noncoding conservation. The close correspondence between extreme noncoding conservation and TADs suggests that these TADs are ancient, revealing a regulatory architecture conserved over hundreds of millions of years.Metazoan genomes contain many clusters of conserved noncoding elements. Here, the authors provide evidence that these clusters coincide with distinct topologically associating domains in humans and Drosophila, revealing a conserved regulatory genomic architecture." ]

[ "The Wnt/β-catenin pathway plays a crucial role in the pathogenesis of various human cancers. In multiple myeloma (MM), aberrant auto-and/or paracrine activation of canonical Wnt signaling promotes proliferation and dissemination, while overexpression of the Wnt inhibitor Dickkopf1 (DKK1) by MM cells contributes to osteolytic bone disease by inhibiting osteoblast differentiation. Since DKK1 itself is a target of TCF/β-catenin mediated transcription, these findings suggest that DKK1 is part of a negative feedback loop in MM and may act as a tumor suppressor. In line with this hypothesis, we show here that DKK1 expression is low or undetectable in a subset of patients with advanced MM as well as in MM cell lines. This absence of DKK1 is correlated with enhanced Wnt pathway activation, evidenced by nuclear accumulation of β-catenin, which in turn can be antagonized by restoring DKK1 expression. Analysis of the DKK1 promoter revealed CpG island methylation in several MM cell lines as well as in MM cells from patients with advanced MM. Moreover, demethylation of the DKK1 promoter restores DKK1 expression, which results in inhibition of β-catenin/TCF-mediated gene transcription in MM lines. Taken together, our data identify aberrant methylation of the DKK1 promoter as a cause of DKK1 silencing in advanced stage MM, which may play an important role in the progression of MM by unleashing Wnt signaling.", "Endogenous metabolites have gained increasing interest over the past 5 years largely for their implications in diagnostic and pharmaceutical biomarker discovery. METLIN (http://metlin.scripps.edu), a freely accessible web-based data repository, has been developed to assist in a broad array of metabolite research and to facilitate metabolite identification through mass analysis. METLINincludes an annotated list of known metabolite structural information that is easily cross-correlated with its catalogue of high-resolution Fourier transform mass spectrometry (FTMS) spectra, tandem mass spectrometry (MS/MS) spectra, and LC/MS data.", "Disappearance of TAR-DNA-binding protein 43 kDa (TDP-43) from the nucleus contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS), but the nuclear function of TDP-43 is not yet fully understood. TDP-43 associates with nuclear bodies including Gemini of coiled bodies (GEMs). GEMs contribute to the biogenesis of uridine-rich small nuclear RNA (U snRNA), a component of splicing machinery. The number of GEMs and a subset of U snRNAs decrease in spinal muscular atrophy, a lower motor neuron disease, suggesting that alteration of U snRNAs may also underlie the molecular pathogenesis of ALS. Here, we investigated the number of GEMs and U11/12-type small nuclear ribonucleoproteins (snRNP) by immunohistochemistry and the level of U snRNAs using real-time quantitative RT-PCR in ALS tissues. GEMs decreased in both TDP-43-depleted HeLa cells and spinal motor neurons in ALS patients. Levels of several U snRNAs decreased in TDP-43-depleted SH-SY5Y and U87-MG cells. The level of U12 snRNA was decreased in tissues affected by ALS (spinal cord, motor cortex and thalamus) but not in tissues unaffected by ALS (cerebellum, kidney and muscle). Immunohistochemical analysis revealed the decrease in U11/12-type snRNP in spinal motor neurons of ALS patients. These findings suggest that loss of TDP-43 function decreases the number of GEMs, which is followed by a disturbance of pre-mRNA splicing by the U11/U12 spliceosome in tissues affected by ALS.", "Insulators are sequences that uncouple adjacent chromosome domains. Here we have shown that Saccharomyces cerevisiae Rap1p and Abf1p proteins are endowed with a potent insulating capacity. Insulating domains in Rap1p coincide with previously described transcription activation domains, whereas four adjacent subdomains spanning the whole of the Abf1p C terminus (440-731) were found to display autonomous insulating capacity. That both Rap1p and Abf1p silencing domains either contain or largely overlap with an insulating domain suggests that insulation conveys some undefined chromosome organization capacity that also contributes a function in silencing. Together with Reb1p and Tbf1p, previously involved in the activity of Saccharomyces cerevisiae subtelomeric insulators, insulating potential emerges as a supplementary common property of General Regulatory Factors (GRFs). Thus GRFs, which bind to sites scattered throughout the genome within promoters, would not only play a key role in regulating gene expression but also partition the genome in functionally independent domains.", "We report a 73-year-old Japanese woman with familial Parkinson's disease. The patient was well until her 67 years of the age, when she noted rest tremor in her right hand. Soon after her gait became short stepped. She visited our clinic on October 6, 1992 when she was 68 years old. She was alert and well oriented without dementia. She showed masked face, small voice, small stepped gait, retropulsion, resting tremor in her right hand, rigidity in the neck, and bradykinesia. She was treated with 400 mg/day of levodopa-carbidopa, which improved her symptoms, however, she developed wearing off phenomenon 3 years after the initiation of levodopa treatment. On August 26, 1998, she developed abdominal pain, diarrhea, and vomiting. She was admitted to another hospital, where abdominal plain x-ray revealed an evidence of intestinal obstruction (ileus). She was treated with nasogastric suction and intravenous fluid. Her condition did not improve and she was transferred to our hospital on August 29, 1998. Her family history revealed no consanguineous marriage. She had two elder brothers and three elder sisters. One of her brothers had been diagnosed as Parkinson's disease. Her husband also suffered from Parkinson's disease, however, her parents apparently did not have Parkinson's disease. On admission, she appeared to be drowsy. Her blood pressure was 102/70 mmHg, body temperature 36.2 degrees C. The lungs were clear and no cardiac murmur was present. Abdomen was flat and bowel sound was audible. No abnormal mass was palpable. Neurologic examination revealed mild consciousness disturbance, masked face, and small voice. No motor paralysis was noted. Muscle tone was hypotonic. No abnormal involuntary movement was noted. Abnormal laboratory findings on admission were as follows; WBC 11,300/microliter, amylase 1,373 IU/l, CK 446 IU/l, BUN 50 mg/dl, creatinine 1.17 mg/dl, CRP 22.7 mg/ dl, Na 134 mEq/l, K 3.1 mEq/l, and Cl 81 mEq/l. A chest x-ray film revealed pneumonic shadows in both lower lung fields. She was treated by nasointestinal suction, intravenous fluids, and chemotherapy for her infection. Her BP started to drop on September 2 and she developed cardiac arrest on the same day. She was discussed in a neurological CPC. The chief discussant arrived at the conclusion that the patient had a form of autosomal dominant familial Parkinson's disease. As parents did not have Parkinson's disease, some of the participants raised the possibility of autosomal recessive inheritance. But the age of onset was too late for autosomal recessive inheritance. Majority thought that the mode of inheritance was autosomal dominant with low penetrance. alpha-Synuclein mutation causes an autosomal dominant familial Parkinson's disease, but this type is very rare in non-Greek populations and the penetrance is high. Chromosome 2-linked autosomal dominant familial Parkinson's disease shows low penetrance. There are many other autosomal dominant forms of familial Parkinson's disease linked to yet unknown chromosome loci. Majority thought that this patient also had a form of Lewy-body positive autosomal dominant familial Parkinson's disease of unknown chromosome locus. Post mortem examination revealed ischemic intestinal lesion with strangulation. This was thought to be the cause of her death. In the central nervous system, the brain appeared to be normal by inspection. In the coronal sections, the substantia nigra and the locus coeruleus showed marked depigmentation. Histologic examination revealed marked neuronal loss and Lewy body formation in the remaining neurons. Pathologic examination was consistent with Parkinson's disease. Mutational analysis for the parkin gene was negative.", "INTRODUCTION: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung carcinoma (NSCLC), which characterized by insensitive to conventional radiotherapy and chemotherapy and poor prognosis. Except MET exon 14 alterations and other oncogene mutations, PSC commonly harbor high tumor mutational burden (TMB) and high level of PD-L1, which provide new therapeutic opportunities. Toripalimab (JS001) is IgG4 monoclonal antibody targeting PD-1, which has been approved for treatment of patients with metastatic melanoma after previous systemic therapy. PD-1 combined with radiotherapy has been tried in several cancer types.CASE PRESENTATION: We reported a case of a PSC patient with PD-L1 overexpression responding to toripalimab and after progression the patients also benefits from toripalimab combined with local radiotherapy, which provides a promising option for PSC patients.CONCLUSION: This case provides the evidence of the effective role of toripalimab and PD-1 combined with local radiotherapy in PSC patients, which was the first application as far as we know.", "The evolution of drug resistance in HIV occurs by the fixation of specific, well-known, drug-resistance mutations, but the underlying population genetic processes are not well understood. By analyzing within-patient longitudinal sequence data, we make four observations that shed a light on the underlying processes and allow us to infer the short-term effective population size of the viral population in a patient. Our first observation is that the evolution of drug resistance usually occurs by the fixation of one drug-resistance mutation at a time, as opposed to several changes simultaneously. Second, we find that these fixation events are accompanied by a reduction in genetic diversity in the region surrounding the fixed drug-resistance mutation, due to the hitchhiking effect. Third, we observe that the fixation of drug-resistance mutations involves both hard and soft selective sweeps. In a hard sweep, a resistance mutation arises in a single viral particle and drives all linked mutations with it when it spreads in the viral population, which dramatically reduces genetic diversity. On the other hand, in a soft sweep, a resistance mutation occurs multiple times on different genetic backgrounds, and the reduction of diversity is weak. Using the frequency of occurrence of hard and soft sweeps we estimate the effective population size of HIV to be 1.5 x 10(5) (95% confidence interval [0.8 x 10(5),4.8 x 10(5)]). This number is much lower than the actual number of infected cells, but much larger than previous population size estimates based on synonymous diversity. We propose several explanations for the observed discrepancies. Finally, our fourth observation is that genetic diversity at non-synonymous sites recovers to its pre-fixation value within 18 months, whereas diversity at synonymous sites remains depressed after this time period. These results improve our understanding of HIV evolution and have potential implications for treatment strategies." ]

[ "BACKGROUND: Invasion and metastasis are two important hallmarks of malignant tumors caused by complex genetic and epigenetic alterations. The present study investigated the contribution of aberrant methylation profiles of cancer related genes, APC, BIN1, BMP6, BRCA1, CST6, ESR-b, GSTP1, P14 (ARF), P16 (CDKN2A), P21 (CDKN1A), PTEN, and TIMP3, in the matched axillary lymph node metastasis in comparison to the primary tumor tissue and the adjacent normal tissue from the same breast cancer patients to identify the potential of candidate genes methylation as metastatic markers.METHODS: The quantitative methylation analysis was performed using the SEQUENOM's EpiTYPER™ assay which relies on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS).RESULTS: The quantitative DNA methylation analysis of the candidate genes showed higher methylation proportion in the primary tumor tissue than that of the matched normal tissue and the differences were significant for the APC, BIN1, BMP6, BRCA1, CST6, ESR-b, P16, PTEN and TIMP3 promoter regions (P<0.05). Among those candidate methylated genes, APC, BMP6, BRCA1 and P16 displayed higher methylation proportion in the matched lymph node metastasis than that found in the normal tissue (P<0.05). The pathway analysis revealed that BMP6, BRCA1 and P16 have a role in prevention of neoplasm metastasis.CONCLUSIONS: The results of the present study showed methylation heterogeneity between primary tumors and metastatic lesion. The contribution of aberrant methylation alterations of BMP6, BRCA1 and P16 genes in lymph node metastasis might provide a further clue to establish useful biomarkers for screening metastasis.", "HF2 is a haloarchaeal virus infecting two Halorubrum species (Family Halobacteriaceae). It is lytic, has a head-and-tail morphology and belongs to the Myoviridae (contractile tails). The linear double-stranded DNA genome was sequenced and found to be 77 670 bp in length, with a mol% G+C of 55.8. A total of 121 likely open reading frames (ORFs) were identified, of which 37 overlapped at start and stop codons. The predicted proteins were usually acidic (average pI of 4.8), and less than about 12% of them had homologues in the sequence databases. Four complete tRNA-like sequences (tRNA-Arg, -Asx, -Pro and -Tyr) and an incomplete tRNA-Thr were detected. A transcription map showed that most of the genome was transcribed and that the synthesis of transcripts occurred in a highly organized and reproducible pattern over a 5 h infection cycle. Transcripts often spanned multiple ORFs, suggesting that viral genes were organized into operons. The predicted ORF and observed transcript directions matched well and showed that transcription is mainly directed inwards from the genome termini, meeting at about 45-48 kb, and this was also a turning point in a cumulative GC-skew plot. The low point in cumulative GC-skew, near the left end, was a region rich in short repeats and lacking ORFs, which is likely to be an origin of replication. The HF2 genome is a mosaic of components from widely different sources, demonstrating clearly that viruses of haloarchaea, like their bacteriophage counterparts, are vectors for the exchange and transmission of genetic material between wide taxonomic distances, even across domains.", "Telomerase is activated in human papillomavirus (HPV) positive cervical cancer and targeting telomeres offers a novel anticancer therapeutic strategy. In this study, the telomere targeting properties, the cytotoxic as well as the pro-apoptotic effects of hexane (IV-HE) and dichloromethane (IV-DF) fractions from Inula viscosa L. extracts were investigated on human cervical HeLa and SiHa cancer cells. Our data demonstrate that IV-HE and IV-DF extracts were able to inhibit cell growth in HeLa and SiHa cells in a dose-dependent manner and studied resistant cell lines exhibited a resistance factor less than 2 when treated with the extracts. IV-HE and IV-DF extracts were able to inhibit telomerase activity and to induce telomere shortening as shown by telomeric repeat amplification protocol and TTAGGG telomere length assay, respectively. The sensitivity of fibroblasts to the extracts was increased when telomerase was expressed. Finally, IV-HE and IV-DF were able to induce apoptosis as evidenced by an increase in annexin-V labeling and caspase-3 activity. This study provides the first evidence that the IV-HE and IV-DF extracts from Inula viscosa L. target telomeres induce apoptosis and overcome drug resistance in tumor cells. Future studies will focus on the identification of the molecules involved in the anticancer activity.", "In our monoclonal antibody (MAb) stocks prepared against the BHK-21 cell antigens, two (#11875 and 28276) recognized a 21-kDa polypeptide (referred to as VAP21) which is efficiently incorporated into the rabies virion. By using these MAbs, we isolated the cDNA clones that encoded a polypeptide of 144 amino acids from our BHK-21 cell cDNA library. Based on the following evidence, the cDNA was assumed to encode a full-length sequence of VAP21 antigen: i) expression of the cDNA in animal cells resulted in the production of a polypeptide recognized by the two MAbs, and its electrophoretic mobility was the same as that of authentic VAP21 antigen; and ii) immunization with the products from the cDNA-transformed E. coli cells raised specific antibodies in rabbits that recognized a 21-kDa polypeptide in the virion. From the deduced amino acid sequence, it is suggested that the VAP21 antigen has a molecular structure of type-I transmembrane protein containing characteristic proline-rich and glycine-rich regions in its ectodomain. Homology searches resulted in finding homologous sequences (totally about 40% homology) in the human MIC2 gene product (CD99; 32-kDa) of T lymphocytes. These results suggest that the VAP21 antigen in the rabies virion is a cellular CD99-related transmembrane protein.", "Alzheimer's disease (AD) is a chronic neurodegenerative disease associated with intracerebral accumulation of aggregated amyloid-beta (Aβ) and tau proteins, as well as neuroinflammation. Human intravenous immunoglobulin (IVIG) is a mixture of polyclonal IgG antibodies isolated and pooled from thousands of healthy human donors. The scientific rationale for testing IVIG as a potential AD treatment include its natural anti-Aβ antibody activity, its favorable safety profile and inherent anti-inflammatory/immunomodulatory properties. Over the past decade, several clinical and pre-clinical experimental findings, advanced our knowledge about biological and therapeutic properties of IVIG that are relevant to AD therapy. Anti-amyloid antibodies in IVIG show significantly higher binding avidity for amyloid oligomers and fibrils than for Aβ monomers. In a double transgenic murine model of AD, intracerebral injection of IVIG causes suppression of Aβ fibril pathology whereas long term peripheral IVIG treatments causes elevation of total brain Aβ levels with no measurable impact on Aβ deposits or tendency for inducing cerebral microhemmorhage. Furthermore, chronic IVIG treatment suppressed neuroinflammation and fostered adult hippocampal neurogenesis. In clinical studies with AD patients, IVIG showed an acceptable safety profile and has not been reported to increase the incidence of amyloid related imaging abnormalities. Preliminary studies on small number of patients reported clinical benefits in mild to moderate stage AD patients. However, double blind, placebo controlled studies later did not replicate those initial findings. Interestingly though, in APOE4 carriers and in moderate disease stage subgroups, positive cognitive signals were reported. Nevertheless, both clinical and experimental (mouse) studies show that antibodies in IVIG can accumulate in CNS and its biological activities include neutralization of Aβ oligomers, suppression of neuroinflammation and immunomodulation. Identifying mediators of IVIG's effects at the cellular and molecular level is warranted. In light of its favourable safety profile and aforementioned biological properties, IVIG is still an enigmatic experimental candidate with enormous potential for being an AD therapeutic.", "BACKGROUND AND AIM: Extremely poor prognosis in hepatocellular carcinoma (HCC) patients with progressing disease was denoted by vascular invasion. Cytokeratin 18 (CK18) has been shown to be overexpressed in hepatocellular carcinoma so it is a valuable tumor marker; however, its role in vascular invasion is still unclear. This study aimed to predict CK18 as a predictive marker for macrovascular malignant invasion.METHODS: The present study was conducted on three groups of patients: group I included 91 HCC patients without macrovascular invasion, group II included 34 HCC patients with radiological evidence of vascular invasion, and group III included 110 control individuals subdivided into IIIA as healthy blood donors and IIIB as post-HCV cirrhotic patients without HCC.RESULTS: ROC curve of M30 fragments of CK18 was constructed for discrimination between HCC with and without macrovascular invasion. Optimum cutoff value was 304.5 ng/mL (AUC = 0.997, P < 0.001), sensitivity (100%) and specificity (98.8%). Regression analysis was conducted for prediction of macrovascular invasion within HCC patients. The following variables: higher levels of AST, M30, bilirubin, and AFP, lower levels of serum albumin, larger tumor size, child B score, and multiple lesions were associated with vascular invasion in univariate analysis. While in multivariate analysis, higher levels of AST and bilirubin and elevated levels of M30 and AFP serum were considered independent predictors for macrovascular invasion in HCC patients.CONCLUSION: The present study suggests that increased M30 fragments of CK18 levels may be useful as a possible marker of early tumor invasiveness.", "Ewing sarcoma family tumors (ESFT) are highly aggressive and highly metastatic tumors caused by a chromosomal fusion between the Ewing sarcoma protein (EWS) with the transcription factor FLI-1. However, expression of the EWS/FLI-1 chimeric oncogene by itself is insufficient for carcinogenesis, suggesting that additional events are required. Here, we report the identification of the Akt substrate PRAS40 as an EWS target gene. EWS negatively regulates PRAS40 expression by binding the 3' untranslated region in PRAS40 mRNA. ESFT cell proliferation was suppressed by treatment with an Akt inhibitor, and ESFT cell proliferation and metastatic growth were suppressed by siRNA-mediated PRAS40 knockdown. Furthermore, PRAS40 knockdown was sufficient to reverse an increased cell proliferation elicited by EWS knockdown. In support of a pathologic role for PRAS40 elevation in EFST, we documented inverse protein levels of EWS and PRAS40 in ESFT cells. Together, our findings suggest that PRAS40 promotes the development of ESFT and might therefore represent a novel therapeutic target in this aggressive disease." ]

[ "Leisure-time physical activity is associated with better health and a reduced risk of all-cause mortality. It is unclear if this association is also present with a high level of physical activity as it is found in professional athletes. In a population-based retrospective cohort study, we compared the survival experience of all soccer players participating for Germany in international matches between 1908 and 2006 to that of the general population. To summarize survival experience, we calculated cumulative relative survival ratios (RSRs) from a life table. We included data of 812 international players, of which 428 (=52.7%) died during follow-up. In all 13 intervals, cumulative observed survival was smaller than cumulative expected survival, resulting in cumulative RSRs being <1. The cumulative RSRs are statistically significantly different from 1 in all but the last interval. This impaired survival experience of the internationals translates into a loss of median residual lifetime of 1.9 years [95% confidence interval: 0.6, 3.2] years at the entry time into the cohort. This loss is mainly driven by the mortality of internationals from the earlier half of the observation period. Reasons for this might be poorer medical care in former times, internationals being killed in action during World War II, and a changing distribution of causes of death during the 20th century.", "The molecular mechanisms underlying chordoma pathogenesis are unknown. We therefore sought to identify novel mutations to better understand chordoma biology and to potentially identify therapeutic targets. Given the relatively high costs of whole genome sequencing, we performed a focused genetic analysis using matrix-assisted laser desorption/ionization-time of flight mass spectrometer (Sequenom iPLEX genotyping). We tested 865 hotspot mutations in 111 oncogenes and selected tumor suppressor genes (OncoMap v. 3.0) of 45 human chordoma tumor samples. Of the analyzed samples, seven were identified with at least one mutation. Six of these were from fresh frozen samples, and one was from a paraffin embedded sample. These observations were validated using an independent platform using homogeneous mass extend MALDI-TOF (Sequenom hME Genotyping). These genetic alterations include: ALK (A877S), CTNNB1 (T41A), NRAS (Q61R), PIK3CA (E545K), PTEN (R130), CDKN2A (R58*), and SMARCB1 (R40*). This study reports on the largest comprehensive mutational analysis of chordomas performed to date. To focus on mutations that have the greatest chance of clinical relevance, we tested only oncogenes and tumor suppressor genes that have been previously implicated in the tumorigenesis of more common malignancies. We identified rare genetic changes that may have functional significance to the underlying biology and potential therapeutics for chordomas. Mutations in CDKN2A and PTEN occurred in areas of chromosomal copy loss. When this data is paired with the studies showing 18 of 21 chordoma samples displaying copy loss at the locus for CDKN2A, 17 of 21 chordoma samples displaying copy loss at PTEN, and 3 of 4 chordoma samples displaying deletion at the SMARCB1 locus, we can infer that a loss of heterozygosity at these three loci may play a significant role in chordoma pathogenesis.", "Here, we review the recent literature on molecular discoveries in ependymomas and pediatric diffuse gliomas. Ependymomas can now be categorized into three location-related subgroups according to their biological profile: posterior fossa ependymomas, group A (PFA) and B (PFB), and supratentorial ependymomas. Although no recurrently mutated genes were found throughout these groups of ependymomas, PFA exhibited a CpG island methylator phenotype, PFB was associated with extensive chromosomal aberrations, and the C11orf95-RELA fusion gene was frequently observed in supratentorial ependymomas. Meanwhile, it has now become apparent that pediatric diffuse gliomas have a distinct genetic status from their adult counterparts, even though they share an indistinguishable histology. In pediatric low-grade diffuse gliomas, an intragenic duplication of the portion of FGFR1 encoding the tyrosine kinase domain (TKD) and rearrangements of MYB/MYBL1 were found recurrently and mutually exclusively. As for non-brainstem high-grade tumors, in addition to H3F3A, TP53, and ATRX mutations, which were frequently observed in older children, recurrent fusions involving NTRK1, NTRK2, and NTRK3 were reported in infants younger than 3 years of age. Moreover, in diffuse intrinsic pontine gliomas (DIPG), recurrent somatic mutations of ACVR1 were found in association with HIST1H3B mutations.", "Author information:(1)Service de réanimation médicale, hôpital Saint-Louis, AP-HP, 1, avenue Claude-Vellefaux, 75010 Paris, France. Electronic address: dumas.guillaume1@gmail.com.(2)Service de réanimation médicale, hôpital Saint-Louis, AP-HP, 1, avenue Claude-Vellefaux, 75010 Paris, France. Electronic address: sybille07@gmail.com.(3)Service de réanimation médicale, hôpital Saint-Louis, AP-HP, 1, avenue Claude-Vellefaux, 75010 Paris, France. Electronic address: larazafrani@hotmail.com.(4)Service de réanimation médicale, hôpital Saint-Louis, AP-HP, 1, avenue Claude-Vellefaux, 75010 Paris, France. Electronic address: emmanuel.canet@sls.aphp.fr.(5)Service de réanimation médicale, hôpital Saint-Louis, AP-HP, 1, avenue Claude-Vellefaux, 75010 Paris, France. Electronic address: virginie.lemiale@sls.aphp.fr.(6)Service de réanimation médicale, CHU d'Angers, 4, rue Larrey, 49100 Angers, France. Electronic address: ackouatchet@chu-angers.fr.(7)Service de réanimation médicale, hôpital Saint-Louis, AP-HP, 1, avenue Claude-Vellefaux, 75010 Paris, France. Electronic address: elie.azoulay@sls.aphp.fr.", "Prader-Willi syndrome is characterized by severe infantile hypotonia with poor suck and failure to thrive; hypogonadism causing genital hypoplasia and pubertal insufficiency; characteristic facial features; early-childhood onset obesity and hyperphagia; developmental delay/mild intellectual disability; short stature; and a distinctive behavioral phenotype. Sleep abnormalities and scoliosis are common. Growth hormone insufficiency is frequent, and replacement therapy provides improvement in growth, body composition, and physical attributes. Management is otherwise largely supportive. Consensus clinical diagnostic criteria exist, but diagnosis should be confirmed through genetic testing. Prader-Willi syndrome is due to absence of paternally expressed imprinted genes at 15q11.2-q13 through paternal deletion of this region (65-75% of individuals), maternal uniparental disomy 15 (20-30%), or an imprinting defect (1-3%). Parent-specific DNA methylation analysis will detect >99% of individuals. However, additional genetic studies are necessary to identify the molecular class. There are multiple imprinted genes in this region, the loss of which contribute to the complete phenotype of Prader-Willi syndrome. However, absence of a small nucleolar organizing RNA gene, SNORD116, seems to reproduce many of the clinical features. Sibling recurrence risk is typically <1%, but higher risks may pertain in certain cases. Prenatal diagnosis is available.", "BACKGROUND: Exhaled NO (FE(NO)) is a useful biomarker for the monitoring of asthma control and response to therapy. However, there is a lack of data on FE(NO) levels and their interpretation in Primary Care asthma population depending on their treatment and smoking habit. Besides, the majority of current FE(NO) tests have been done by stationary chemiluminescence analysers whose use is limited to research laboratories.METHODS: FE(NO) measurements by the novel hand-held NO monitoring device (NIOX MINO) were made in 96 asthma patients (32 males, mean age 53+/-12) at five local General Practices during their scheduled 15-20 min visits for lung function assessment.RESULTS: Success rate was 78% and the intra-subject coefficient of variation was 8.7%. Inhaled corticosteroid treatment had an overall reducing effect on the FE(NO) value (30.5 [19.8-49.8]) vs. patients not on the ICS (26.5 [19-94]) (p<0.044). FE(NO) levels in the ICS treated current or ex-smokers group of patients were still significantly above the normal values (p<0.0001). FE(NO) levels were similar in patients receiving ICS whether there were current, ex-smokers or non-smokers. The highest FE(NO) levels (94 [15.8-151]) were found in asthmatic current smokers and not receiving treatment with ICS. The most \"normalised\" FE(NO) levels (35.3 [13.5-35.3]) were seen in ex-smokers.CONCLUSIONS: FE(NO) measurements performed with a new hand-held monitoring device are reproducible and feasible in General Practice in the majority of patients of different ages and asthma severities. A high percentage of patients with different severities of asthma and regardless of their treatment with ICS and current smoking habit (current and/or ex-smokers) had highly elevated FE(NO) values, suggesting that their current therapy was possibly insufficient to control the underlying degree of airway inflammation and asthma symptoms.", "BACKGROUND: The exponential growth of available biological data has caused bioinformatics to be rapidly moving towards a data-intensive, computational science. As a result, the computational power needed by bioinformatics applications is growing exponentially as well. The recent emergence of accelerator technologies has made it possible to achieve an excellent improvement in execution time for many bioinformatics applications, compared to current general-purpose platforms. In this paper, we demonstrate how the PlayStation 3, powered by the Cell Broadband Engine, can be used as a computational platform to accelerate the Smith-Waterman algorithm.RESULTS: For large datasets, our implementation on the PlayStation 3 provides a significant improvement in running time compared to other implementations such as SSEARCH, Striped Smith-Waterman and CUDA. Our implementation achieves a peak performance of up to 3,646 MCUPS.CONCLUSION: The results from our experiments demonstrate that the PlayStation 3 console can be used as an efficient low cost computational platform for high performance sequence alignment applications.", "Author information:(1)1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada [3] Division of Neurosurgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada [4].(2)1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [3] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [4].(3)1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.(4)1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.(5)Department of Molecular Genetics, Banting and Best Department of Medical Research, The Donnelly Centre, University of Toronto, Toronto, Ontario M4N 1X8, Canada.(6)1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Genome Biology, European Molecular Biology, Laboratory Meyerhofstr. 1, Heidelberg 69117, Germany.(7)1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.(8)Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada.(9)Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.(10)1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK), Heidelberg 69120, Germany.(11)1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Division of Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.(12)Department of Neurology, Harvard Medical School, Children's Hospital Boston, MIT, Boston, Massachusetts 02115, USA.(13)Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.(14)1] Ontario Cancer Institute, Princess Margaret Cancer Centre-University Health Network, Toronto, Ontario M5G 1L7, Canada [2] Ontario Institute for Cancer Research, Toronto, Ontario M5G 1L7, Canada.(15)Cancer Epigenetics Discovery Performance Unit, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426, USA.(16)Department of Oncogenomics, Academic Medical Center, Amsterdam 1105, The Netherlands.(17)1] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [2] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [3] CCU Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.(18)1] Centre for High-Throughput Biology, Department of Microbiology & Immunology, University of British Columbia, Vancouver, V6T 1Z4 British Columbia, Canada [2] Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.(19)1] Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada.(20)Department of Pediatrics and National Capital Consortium, Uniformed Services University, Bethesda, Maryland 20814, USA.(21)Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.(22)Pediatric Neurosurgery, Catholic University Medical School, Gemelli Hospital, Rome 00168, Italy.(23)Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.(24)Department of Pediatrics, Virginia Commonwealth, Richmond, Virginia 23298-0646, USA.(25)Department of Pathology, University of Warsaw, Children's Memorial Health Institute University of Warsaw, Warsaw 04-730, Poland.(26)Division of Anatomical Pathology, Department of Pathology and Molecular Medicine, McMaster University, Hamilton General Hospital, Hamilton, Ontario L8S 4K1, Canada.(27)1] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [2] German Cancer Consortium (DKTK), Heidelberg 69120, Germany.(28)1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Department of Neuropathology Ruprecht-Karls-University Heidelberg, Institute of Pathology, Heidelberg 69120, Germany.(29)1] University of Michigan Cell and Developmental Biology, Ann Arbor, Michigan 48109-2200, USA [2] Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.(30)Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.(31)Department of Neurosurgery, University of California San Francisco, San Francisco, California 94143-0112, USA.(32)Departments of Neurology, Pediatrics, and Neurosurgery, University of California, San Francisco, The Helen Diller Family Cancer Research Building, San Francisco, California 94158, USA.(33)1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Department of Neuro-oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.(34)Department of Haematology and Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.(35)1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada [3] Division of Neurosurgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada.(36)Departments of Pediatrics and Human Genetics, McGill University and the McGill University Health Center Research Institute, Montreal, Quebec H3Z 2Z3, Canada.(37)Department of Neuro-oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.(38)Genome Biology, European Molecular Biology, Laboratory Meyerhofstr. 1, Heidelberg 69117, Germany.(39)1] Ontario Cancer Institute, Princess Margaret Cancer Centre-University Health Network, Toronto, Ontario M5G 1L7, Canada [2] Ontario Institute for Cancer Research, Toronto, Ontario M5G 1L7, Canada [3] Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1X8, Canada.(40)1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada [3] Division of Neurosurgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada [4] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.(41)1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [3] German Cancer Consortium (DKTK), Heidelberg 69120, Germany.(42)1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] University of Michigan Cell and Developmental Biology, Ann Arbor, Michigan 48109-2200, USA [3] CCU Neuropathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.", "OBJECTIVE: To investigate the influence of occupational stress on salivary cortisol concentration in employees.METHODS: In September 2014, occupational stress evaluation was performed for 186 employees in a solar photovoltaic company, and enzyme-linked immunosorbent assay was used to measure the salivary cortisol concentration.RESULTS: The salivary cortisol concentration showed no significant differences between groups with different demographic features(P>0.05). The group with a high score of job control had a significantly lower salivary cortisol concentration than that with a low score(74.62±15.34 μg/L vs 79.95±12.99 μg/L, P<0.05). The groups with high scores of job danger and job responsibility and burden had significantly higher salivary cortisol concentrations than those with low scores(80.29±9.45 μg/L vs 75.60±16.41, P<0.05; 80.94±10.87 μg/L vs 74.05±16.35 μg/L, P<0.05). The salivary cortisol concentration was positively correlated with the scores of job danger and job responsibility and burden(r=0.176 and 0.252, P<0.05) and negatively correlated with the score of job control(r=-0.208, P<0.05).CONCLUSION: Salivary cortisol concentration is positively correlated with occupational stress and increases with the increasing degree of occupational stress, and can be used as an objective biomarker for the identification and evaluation of occupational stress.", "A substantial proportion of Ashkenazi Jewish (AJ) breast and ovarian cancer families carry one of three founder mutations in BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT). Non-founder mutations are identified in another 2-4% of such families. The extent to which major genomic rearrangements in BRCA contribute to breast and ovarian cancer in the Ashkenazim is not well understood. We identified AJ individuals with breast and/or ovarian cancer undergoing hereditary breast/ovarian cancer risk assessment since 2006 without evidence of a deleterious mutation on BRCA gene sequencing who were screened for major gene rearrangements in BRCA1 and BRCA2. For each proband, the pre-test probability of identifying a deleterious BRCA mutation was estimated using the Myriad II model. We identified 108 affected individuals who underwent large rearrangement testing (80 breast cancer, 19 ovarian cancer, nine both breast and ovarian cancer). The mean estimated AJ specific pre-test probability of a deleterious mutation in BRCA1 and BRCA2 was 24.7% (range: 4.4-88.9%). No genomic rearrangements were identified in either the entire group or in the 26 subjects with pre-test mutation prevalence estimates exceeding 30%. Major gene rearrangements involving the BRCA1 and BRCA2 genes appear to contribute little to the burden of inherited predisposition to breast and ovarian cancer in the Ashkenazim.", "Epigenetic alterations, including methylation, have been shown to be an important mechanism of gene silencing in cancer. Ependymoma has been well characterized at the DNA copy number and mRNA expression levels. However little is known about DNA methylation changes. To gain a more global view of the methylation profile of ependymoma we conducted an array-based analysis. Our data demonstrated tumors to segregate according to their location in the CNS, which was associated with a difference in the global level of methylation. Supratentorial and spinal tumors displayed significantly more hypermethylated genes than posterior fossa tumors, similar to the 'CpG island methylator phenotype' (CIMP) identified in glioma and colon carcinoma. This hypermethylated profile was associated with an increase in expression of genes encoding for proteins involved in methylating DNA, suggesting an underlying mechanism. An integrated analysis of methylation and mRNA expression array data allowed us to identify methylation-induced expression changes. Most notably genes involved in the control of cell growth and death and the immune system were identified, including members of the JNK pathway and PPARG. In conclusion, we have generated a global view of the methylation profile of ependymoma. The data suggests epigenetic silencing of tumor suppressor genes is an important mechanism in the pathogenesis of supratentorial and spinal, but not posterior fossa ependymomas. Hypermethylation correlated with a decrease in expression of a number of tumor suppressor genes and pathways that could be playing an important role in tumor pathogenesis.", "Arginine is a conditionally essential amino acid. To elucidate the influence of l-arginine on the activation of endogenous antioxidant defence, male Wistar rats were orally administered daily with l-arginine at different levels of 25, 50, 100 mg/100 g body weight. After 7 and 14 days feeding, the antioxidative capacities and glutathione (GSH) contents in the plasma and in the liver were uniformly enhanced with the increasing consumption of l-arginine, whereas the oxidative stress was effectively suppressed by l-arginine treatment. After 14 days feeding, the mRNA levels and protein expressions of Keap1 and Cul3 were gradually reduced by increasing l-arginine intake, resulting that the nuclear factor Nrf2 was activated. Upon activation of Nrf2, the expressions of antioxidant responsive element (ARE)-dependent genes and proteins (GCLC, GCLM, GS, GR, GST, GPx, CAT, SOD, NQO1, HO-1) were up-regulated by l-arginine feeding, indicating an upward trend in antioxidant capacity uniformly with the increasing consumption of l-arginine. The present study demonstrates that the supplementation of l-arginine stimulates GSH synthesis and activates Nrf2 pathway, leading to the up-regulation of ARE-driven antioxidant expressions via Nrf2-Keap1 pathway. Results suggest the availability of l-arginine is a critical factor to suppress oxidative stress and induce an endogenous antioxidant response." ]

[ "The classic eye-color gene white (w) in Drosophila melanogaster (fruitfly) has unexpected behavioral consequences. How w affects locomotion of adult flies is largely unknown. Here, we show that a mutant allele (w1118 ) selectively increases locomotor components at relatively high frequencies (> 0.1 Hz). The w1118 flies had reduced transcripts of w+ from the 5' end of the gene. Male flies of w1118 walked continuously in circular arenas while the wildtype Canton-S walked intermittently. Through careful control of genetic and cytoplasmic backgrounds, we found that the w1118 locus was associated with continuous walking. w1118 -carrying male flies showed increased median values of path length per second (PPS) and 5-min path length compared with w+ -carrying males. Additionally, flies carrying 2-4 genomic copies of mini-white+ (mw+ ) in the w1118 background showed suppressed median PPSs and decreased 5-min path length compared with controls, and the suppression was dependent on the copy number of mw+ . Analysis of the time-series (i.e., PPSs over time) by Fourier transform indicated that w1118 was associated with increased locomotor components at relatively high frequencies (> 0.1 Hz). The addition of multiple genomic copies of mw+ (2-4 copies) suppressed the high-frequency components. Lastly, the downregulation of w+ in neurons but not glial cells resulted in increased high-frequency components. We concluded that mutation of w modified the locomotion in adult flies by selectively increasing high-frequency locomotor components.", "EDG-1, encoded by the endothelial differentiation gene-1, is a heterotrimeric guanine nucleotide binding protein-coupled receptor (GPCR) for sphingosine-1-phosphate (SPP) that has been shown to stimulate angiogenesis and cell migration in cultured endothelial cells. Unexpectedly, EDG-1 knockout embryos had a normal blood vessel network, vasculogenesis and angiogenesis, but died in utero owing to massive haemorrhaging as a result of failure of smooth muscle cells and pericytes to migrate around the circumference and reinforce endothelial tubes [Liu, Wada, Yamashita, Mi, Deng, Hobson, Rosenfeldt, Nava, Chae, Lee, et al. (2000) J. Clin. Invest. 106, 951-961]. This vascular maturation defect is similar to the phenotype of mice homozygous for disrupted alleles of platelet-derived growth factor B-subunit homodimer (PDGF-BB) or its receptor PDGFR-beta. We found that fibroblasts from EDG-1 null embryos did not migrate toward PDGF or SPP, and inhibition of motility correlated with defective activation of the small guanosine triphosphatase Rac, which is required for lamellipodia formation and directional locomotion [Hobson, Rosenfeldt, Barak, Olivera, Poulton, Caron, Milstien, and Spiegel (2001) Science 291, 1800-1803]. Moreover, we showed that PDGF-directed cell migration requires both sphingosine kinase activation and expression of EDG-1, suggesting a functional link between PDGF signalling and EDG-1. Indeed, treatment of wild-type cells with PDGF transactivated EDG-1 as determined by translocation of beta-arrestin and phosphorylation of EDG-1. These findings reveal a new paradigm for receptor cross-communication in which activation of a GPCR by a receptor tyrosine kinase is critical for cell motility. Our observations might also clarify the role of EDG-1 in vascular maturation and angiogenesis.", "Regulatory CD4(+) CD25(+) T (Treg) cells with the ability to suppress host immune responses against self- or non-self antigens play important roles in the processes of autoimmunity, transplant rejection, infectious diseases and cancers. The proper regulation of CD4(+) CD25(+) Treg cells is thus critical for optimal immune responses. Toll-like receptor (TLR)-mediated recognition of specific structures of invading pathogens initiates innate as well as adaptive immune responses via antigen-presenting cells (APCs). Interestingly, new evidence suggests that TLR signalling may directly or indirectly regulate the immunosuppressive function of CD4(+) CD25(+) Treg cells in immune responses. TLR signalling may shift the balance between CD4(+) T-helper cells and Treg cells, and subsequently influence the outcome of the immune response. This immunomodulation pathway may therefore have potential applications in the treatment of graft rejection, autoimmune diseases, infection diseases and cancers.", "Visceral leishmaniasis (VL) is caused by the protozoan parasite Leishmania donovani and transmitted by the bite of infected sandfly Phlebotomus argentipes. The protozoa is obliged intracellularly and causes a wide spectrum of clinical syndromes: VL ('kala azar'), cutaneous leishmaniasis and mucocutaneous leishmaniasis (espundia). Kala azar is the most aggressive form and if untreated causes high mortality. Here, we describe a case of VL that presented to us with high-grade fever and found to have Roth spots that were resolved after 15 days of therapy.", "We have previously shown that the EphA2 receptor tyrosine kinase is overexpressed in glioblastoma multiforme (GBM) and represents a novel, attractive therapeutic target for the treatment of brain tumors. Here, we have developed an EphA2-targeted agent, ephrinA1-PE38QQR, a novel cytotoxin composed of ephrinA1, a ligand for EphA2, and PE38QQR, a mutated form of Pseudomonas aeruginosa exotoxin A. EphrinA1-PE38QQR showed potent and dose-dependent killing of GBM cells overexpressing the EphA2 receptor in cell viability and clonogenic survival assays, with an average IC(50) of approximately 10(-11) mol/L. The conjugate was also highly effective in killing breast and prostate cancer cells overexpressing EphA2. The cytotoxic effect of ephrinA1-PE38QQR was specific, as it was neutralized by an excess of EphA2 ligands. Moreover, normal human endothelial cells and breast cancer cells that do not overexpress EphA2, as well as GBM cells that have down-regulated EphA2, were not susceptible to the cytotoxin. EphrinA1-PE38QQR-mediated cytotoxicity induced caspase-dependent apoptosis, which was, however, not responsible for cell death in response to the conjugate. In addition, the conjugate elicited no changes in the activity of survival pathways such as phosphoinositide 3-kinase, measured by AKT phosphorylation. This is the first attempt to create a cytotoxic therapy using any of the ephrin ligands of either class (A or B) conjugated to a bacterial toxin. EphrinA1-PE38QQR is very potent and specific, produces cell death that is caspase independent, and forms the basis for the further development of clinically applicable EphA2-targeted cytotoxins.", "Sedative-analgesic treatment of patients on long-term artificial ventilation aims at protection from stress related to their disease or therapy. By stabilising both the patient's vital functions and psychological state this treatment may contribute to therapeutic success. The choice of drugs depends primarily on the nature and course of the underlying disease. Midazolam and propofol are available as hypnotics for short-term sedation during the post-operative period. The purpose of this study was to evaluate the effects of both agents on cardiovascular function, cortisol production, lipometabolism, and the recovery period following 24-h sedation. METHODS. Twenty female patients (mean body weight: 72 kg, mean age: 60 years) were randomly assigned to receive either midazolam or propofol over 24 h following major abdominal surgery. Balanced anaesthesia (halothane/O2/N2O/fentanyl) was administered for the surgical procedure. Assisted ventilation was used in all patients during the post-operative sedation period. Sedation depth was maintained at III-IV on the Ramsey scale. On arrival in the intensive care unit (ICU), an initial i.v. bolus of midazolam 0.1 mg/kg or propofol 1 mg/kg was followed by a continuous infusion (midazolam: 0.1 mg/kg.h; propofol: 2 mg/kg.h). Supplementary boluses of one-half the initial dose were given if required. Post-operative analgesia was achieved with 3 mg intravenous piritramide at 2-h intervals. A 7F Swan-Ganz catheter was inserted in the pulmonary artery and haemodynamic and biochemical parameters were monitored at 4-h intervals over 24 h starting 2 h after arrival in the ICU. Catecholamines were measured by high-pressure lipid chromatography (HPLC), cortisol by radioimmunoassay, midazolam by HPLC and ultraviolet detection, and propofol by HPLC and fluorescence detection. Data were calculated as means. The statistical analysis was performed according to the Mann-Whitney test, and significance was accepted for P less than 0.05. RESULTS. On administration of the propofol bolus at the onset of sedation, a decrease in blood pressure was particularly observed in patients with masked hypovolaemia, however, this decrease was easily controlled by volume administration. Independent of the type of sedation, the haemodynamic parameters remained unchanged throughout the observation period. At all times of measurement the mean heart rate was lower in the propofol group (90/min) when compared with the midazolam group (100/min), however, this difference did not reach significance. There were also no significant differences in cardiac index at all times of measurement, although it increased in both groups within the first 12 h by 0.6 l/min.min2. In both groups this increase was associated with a reduction in peripheral resistance and an increase in rectal temperature. To achieve the desired sedation depth, midazolam was administered at a mean dosage of 0.11 mg/kg.h and propofol at 1.9 mg/kg.h. Catecholamine levels decreased in both groups within the first 8 h: after 8 h of sedation the plasma levels of noradrenaline and adrenaline were 525 and 65 pg/ml, respectively, in the midazolam group and 327 and 51 pg/ml in the propofol group. (ABSTRACT TRUNCATED AT 400 WORDS)", "Author information:(1)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.(2)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.(3)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA.(4)Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.(5)Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA.(6)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.(7)Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.(8)Department of Chemistry, New York University, New York, NY 10003, USA.(9)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Departments of Computer Science and Computational and Applied Mathematics, Rice University, Houston, TX 77030, USA.(10)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Departments of Computer Science and Computational and Applied Mathematics, Rice University, Houston, TX 77030, USA; Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA.(11)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.(12)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.(13)Department of Chemistry, New York University, New York, NY 10003, USA; Courant Institute of Mathematical Sciences, New York University, New York, NY 10012, USA; NYU-ECNU Center for Computational Chemistry, NYU Shanghai, Shanghai 200062, China.(14)Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA; Center of Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.(15)Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.(16)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Departments of Computer Science and Computational and Applied Mathematics, Rice University, Houston, TX 77030, USA. Electronic address: erez@erez.com." ]

[ "MicroRNAs (miRNAs) are a broad class of small non-coding RNAs that control expression of complementary target messenger RNAs. Dysregulation of miRNAs has been described in various disease states including cancer and cardiac disease. A particular miRNA that was consistently reported to be upregulated in both cancer and various forms of cardiovascular diseases is miR-21. MiR-21 exerts oncogenic activity and therefore is considered as an oncomir. In the cardiovascular system miR-21 is enriched in fibroblasts and contributes to the development of fibrosis and heart failure. MiR-21 therefore emerges as an interesting candidate for the development of therapeutic strategies against many forms of cancer as well as heart diseases. Indeed, treatment with anti-miR-21 oligonucleotides reduced breast cancer growth. Inhibition of miR-21 by synthetic miRNA antagonists (antagomirs) improved heart function in a cardiac disease model. The same beneficial effects were observed in miR-21 knockout mice subjected to pressure-overload of the left ventricle underlining the key role of miR-21 as a therapeutic target. We here overview the current patent situation about the therapeutic use of miR-21 modulation in cancer and cardiovascular disease.", "The recent release of new, non-invasive prenatal tests for fetal aneuploidy using cell-free fetal DNA (cffDNA) has been hailed as a revolution in prenatal testing and has triggered significant commercial interest in the field. Ongoing research portends the arrival of a wide range of cffDNA tests. However, it is not yet clear how these tests will be integrated into well-established prenatal testing strategies in the USA, as the timing of such testing and the degree to which new non-invasive tests will supplement or replace existing screening and diagnostic tools remain uncertain. We argue that there is an urgent need for policy-makers, regulators and professional societies to provide guidance on the most efficient and ethical manner for such tests to be introduced into clinical practice in the USA.", "Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a dreadful disease common in South-East Asia and Northern Australia and is characterized by chronic suppurative lesions and pneumonia. Melioidosis may evolve into severe sepsis with multi-organ failure with high mortalities, despite proper antibiotic therapy. Besides activation of a strong pro-inflammatory host response, the coagulation system plays an important role during melioidosis, which is thought to be host-protective. In particular, a procoagulant state together with downregulation of anticoagulant pathways and activation of fibrinolysis are present, all closely interrelated with parameters of inflammation. This review presents an overview of recent studies in which the role of coagulation, anti-coagulation and fibrinolysis during melioidosis was investigated both in patients and in experimental settings.", "The recount2 resource is composed of over 70,000 uniformly processed human RNA-seq samples spanning TCGA and SRA, including GTEx. The processed data can be accessed via the recount2 website and the recount Bioconductor package. This workflow explains in detail how to use the recount package and how to integrate it with other Bioconductor packages for several analyses that can be carried out with the recount2 resource. In particular, we describe how the coverage count matrices were computed in recount2 as well as different ways of obtaining public metadata, which can facilitate downstream analyses. Step-by-step directions show how to do a gene-level differential expression analysis, visualize base-level genome coverage data, and perform an analyses at multiple feature levels. This workflow thus provides further information to understand the data in recount2 and a compendium of R code to use the data.", "MLN4924 is a first-in-class experimental cancer drug that inhibits the NEDD8-activating enzyme, thereby inhibiting cullin-RING E3 ubiquitin ligases and stabilizing many cullin substrates. The mechanism by which MLN4924 inhibits cancer cell proliferation has not been defined, although it is accompanied by DNA rereplication and attendant DNA damage. Here we show that stabilization of the DNA replication factor Cdt1, a substrate of cullins 1 and 4, is critical for MLN4924 to trigger DNA rereplication and inhibit cell proliferation. Even only 1 hour of exposure to MLN4924, which was sufficient to elevate Cdt1 for 4-5 hours, was found to be sufficient to induce DNA rereplication and to activate apoptosis and senescence pathways. Cells in S phase were most susceptible, suggesting that MLN4924 will be most toxic on highly proliferating cancers. Although MLN4924-induced cell senescence seems to be dependent on induction of p53 and its downstream effector p21(Waf1), we found that p53(-/-) and p21(-/-) cells were even more susceptible than wild-type cells to MLN4924. Our results suggested that apoptosis, not senescence, might be more important for the antiproliferative effect of MLN4924. Furthermore, our findings show that transient exposure to this new investigational drug should be useful for controlling p53-negative cancer cells, which often pose significant clinical challenge.", "We report a patient with multiple trichoepitheliomas whose biopsy material also demonstrated a range of other neoplasms with follicular differentiation, including small nodular trichoblastoma, small nodular basal cell carcinoma (BCC), and areas resembling infundibulocystic BCC/basaloid follicular hamartoma. These were all intimately associated with otherwise typical trichoepitheliomas that dominated the microscopic appearances. Peripheral blood and tumor tissues of the patient and his 2 daughters, who apparently had a milder phenotype, were studied for alterations in the CYLD and PTCH genes, but mutations or loss of heterozygosity was not found in either gene. The occurrence of multiple follicular neoplasms within a single lesion adds evidence that, although in most cases BCC and trichoblastoma are distinct lesions, the 2 neoplasms do encompass a morphological spectrum of follicular differentiation, which is probably more overtly expressed in syndromic patients.", "Magnetic resonance as an imaging modality provides an excellent soft tissue differentiation, which is an ideal choice for cardiac imaging. Cardiac magnetic resonance (CMR) allows myocardial tissue characterization, as well as comprehensive evaluation of the structures. Although late gadolinium enhancement after injection of the gadolinium extracellular contrast agent has further extended our ability to characterize the myocardial tissue, it also has limitations in the quantification of enhanced myocardial tissue pathology, and the detection of diffuse myocardial disease, which is not easily recognized by enhancement contrast. Recently, the remarkable advances in CMR technique, such as T1 mapping, which can quantitatively evaluate myocardial status, showed potentials to overcome limitations of existing CMR sequences and to expand the application of CMR. This article will review the technical and clinical points to be considered in the practical use of pre- and post-contrast T1 mapping." ]

[ "Sanfilippo syndrome (mucopolysaccharidosis type III, MPS III) is a progressive disorder in which patients are characterized by severe central nervous system degeneration together with mild somatic disease. MPS III results from a deficiency in one of the four enzymes involved in the heparan sulfate degradation, with sulfamidase (SGSH), α-N-acetylglucosaminidase (NAGLU), acetyl-coenzyme A: α-glucosaminide N-acetyltransferase (HGSNAT), and N-acetylglucosamine-6-sulfatase (GNS) being deficient respectively in MPS IIIA, MPS IIIB, MPS IIIC and MPS IIID. Mutation screening using PCR reaction/sequencing analysis on genomic DNA fragments was performed in seven Tunisian index cases with MPS IIIA, three with MPS IIIB and two with MPS IIIC. QMPSF (Quantitative Multiplex PCR of Short fluorescent Fragments) analysis was developed for the detection of genomic deletions and duplications in the SGSH gene. These approaches allowed the identification of 11 mutations, 8 of them were novel including a mutation involving the start codon (p.Met1?), one small duplication (p.Leu11AlafsX22), one small deletion (p.Val361SerfsX52) and a large deletion of exon 1 to exon 5 in the SGSH gene, one missense mutation (p.Pro604Leu) and one nonsense mutation (p.Tyr558X) in the NAGLU gene and, finally, one missense mutation (p.Trp627Cys) and one nonsense mutation (p.Trp403X) in the HGSNAT gene.", "Absence of dystrophin makes skeletal muscle more susceptible to injury, resulting in breaches of the plasma membrane and chronic inflammation in Duchenne muscular dystrophy (DMD). Current management by glucocorticoids has unclear molecular benefits and harsh side effects. It is uncertain whether therapies that avoid hormonal stunting of growth and development, and/or immunosuppression, would be more or less beneficial. Here, we discover an oral drug with mechanisms that provide efficacy through anti-inflammatory signaling and membrane-stabilizing pathways, independent of hormonal or immunosuppressive effects. We find VBP15 protects and promotes efficient repair of skeletal muscle cells upon laser injury, in opposition to prednisolone. Potent inhibition of NF-κB is mediated through protein interactions of the glucocorticoid receptor, however VBP15 shows significantly reduced hormonal receptor transcriptional activity. The translation of these drug mechanisms into DMD model mice improves muscle strength, live-imaging and pathology through both preventive and post-onset intervention regimens. These data demonstrate successful improvement of dystrophy independent of hormonal, growth, or immunosuppressive effects, indicating VBP15 merits clinical investigation for DMD and would benefit other chronic inflammatory diseases.", "Sudden unexpected death in epilepsy (SUDEP) accounts for approximately 2% of deaths in population-based cohorts of epilepsy, and up to 25% of deaths in cohorts of more severe epilepsy. When it occurs, SUDEP usually follows a generalised tonic-clonic seizure. Unresponsiveness, apnoea, and cardiac arrest occur in SUDEP, rather than the typical gradual recovery. The great majority of tonic-clonic seizures occur without difficulty and how the rare seizure associated with SUDEP differs from others is unknown.Three mechanisms have been proposed for SUDEP: cardiac arrhythmia, neurogenic pulmonary oedema, and postictal suppression of brainstem respiratory centres leading to central apnoea. Recent studies have found that the incidence of SUDEP increases with the severity of epilepsy in the population studied. The duration of epilepsy, number of tonic-clonic seizures, mental retardation, and simultaneous treatment with more than two antiepileptic drugs are independent risk factors for SUDEP. Some studies have reported that carbamazepine use, carbamazepine toxicity, and frequent, rapid changes in carbamazepine levels, may be associated with SUDEP. Other evidence indicates that carbamazepine could potentially increase the risk for SUDEP by causing arrhythmia or by altering cardiac autonomic function. However, this evidence is tenuous and most studies have not found an association between the use of carbamazepine or any other individual antiepileptic drug and SUDEP. There is little information regarding antiepileptic drugs other than phenytoin and carbamazepine. The incidence of SUDEP with gabapentin, tiagabine, and lamotrigine clinical development programmes is in the range found in other populations with refractory epilepsy. This suggests that these individual antiepileptic drugs are no more likely to cause SUDEP than antiepileptic drugs in general. Best current evidence indicates that the risk of SUDEP can be decreased by aggressive treatment of tonic-clonic seizures with as few antiepileptic drugs as necessary to achieve complete control. At present there is no strong reason to avoid any particular antiepileptic drug. Further studies are needed to elucidate the potential role of individual antiepileptic drugs in SUDEP and establish clinical relevance, if any. These studies may be challenging to conduct and interpret because SUDEP is relatively uncommon and large numbers will be necessary to narrow confidence intervals to determine the clinical relevance. Also adjustments will be needed to account for the potent risks associated with other independent factors.", "Given the current SARS-CoV-2 (COVID-19) pandemic, the availability of reliable information for clinicians and patients is paramount. There have been a number of reports stating that non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids may exacerbate symptoms in COVID-19 patients. Therefore, this review aimed to collate information available in published articles to identify any evidence behind these claims with the aim of advising clinicians on how best to treat patients. This review found no published evidence for or against the use of NSAIDs in COVID-19 patients. Meanwhile, there appeared to be some evidence that corticosteroids may be beneficial if utilised in the early acute phase of infection, however, conflicting evidence from the World Health Organisation surrounding corticosteroid use in certain viral infections means this evidence is not conclusive. Given the current availability of literature, caution should be exercised until further evidence emerges surrounding the use of NSAIDs and corticosteroids in COVID-19 patients.", "We analyzed data from 388 subjects with Fanconi anemia reported to the International Fanconi Anemia Registry (IFAR). Of those, 332 developed hematologic abnormalities at a median age of 7 years (range, birth to 31 years). Actuarial risk of developing hematopoietic abnormalities was 98% (95% confidence interval, 93% to 99%) by 40 years of age. Common hematologic abnormalities were thrombocytopenia and pancytopenia. These were often associated with decreased bone marrow (BM) cellularity (75% of cases studied). Clonal cytogenetic abnormalities developed in 23 of 68 persons with BM failure who had adequate studies. Actuarial risk of clonal cytogenetic abnormalities during BM failure was 67% (47% to 87%) by 30 years of age. Fifty-nine subjects developed myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). Actuarial risk of MDS or AML was 52% (37% to 67%) by 40 years of age. Risk was higher in persons with than in those without a prior clonal cytogenetic abnormality (3% [0% to 9%] v 35% [0% to 79%]; P = .006). One hundred twenty persons died of hematologic causes including BM failure, MDS or AML and treatment related complications. Actuarial risk of death from hematologic causes was 81% (67% to 90%) by 40 years of age.", "BACKGROUND: Scant data exists on melanoma in blacks from Africa. This study was undertaken to define factors affecting outcome of blacks from South Africa with melanoma.STUDY DESIGN: A retrospective analysis of the management and outcome of 63 black patients with malignant melanoma treated at a major referral center during a 14 year period is presented. Data evaluated included patient demographic and clinical characteristics, stage at presentation, tumor site, histologic type, treatment, and subsequent cure. Survival curves were calculated for stage and site of disease.RESULT: The mean age at presentation of the 39 women and 24 men was 60.5 years (range of 30 to 85 years), with a peak incidence in the sixth decade. The foot was the most common site of disease (45 patients). Seven patients had subungual melanoma, seven had primary mucosal lesions, and in six, the primary lesion could not be found. Thirty patients presented with stage I disease, two with stage II, 23 with stage III, and nine with disseminated metastatic disease. Acral lentiginous melanoma was the most common histogenetic type (34 patients), nodular melanoma occurred in ten patients, and superficial spreading melanoma occurred in three patients. The mean Breslow depth was 6.15 mm (range of 1 to 25 mm). Patients with localized disease were treated by wide local excision and split skin graft, while patients with melanoma in the nailbed were treated by amputation of the involved digit. Sixteen patients are alive after a mean follow-up period of 82.1 months, 44 have died after a mean of 12.7 months, and five patients have been unavailable for follow-up evaluation.CONCLUSIONS: The poor prognosis in black patients in South Africa is the result of delayed presentation with thick primary lesions and advanced disease. An active education program may reduce mortality by detecting the disease earlier.", "A hallmark of metazoan RNA polymerase II transcripts is the presence of numerous small exons surrounded by large introns. Abundant evidence indicates that splicing to excise introns occurs co-transcriptionally, prior to release of the nascent transcript from RNAP II. Here, we established an efficient model system for co-transcriptional splicing in vitro. In this system, CMV-DNA constructs immobilized on beads generate RNAP II transcripts containing two exons and an intron. Consistent with previous work, our data indicate that elongating nascent transcripts are tethered to RNAP II on the immobilized DNA template. We show that nascent transcripts that reach full length, but are still attached to RNAP II, are efficiently spliced. When the nascent transcript is cleaved within the intron using RNase H, both the 5' and 3' cleavage fragments are detected in the bound fraction, where they undergo splicing. Together, our work establishes a system for co-transcriptional splicing in vitro, in which the spliceosome containing the 5' and 3' exons are tethered to RNAP II for splicing." ]

[ "Proteins are the primary effectors of function in biology, and thus, complete knowledge of their structure and properties is fundamental to deciphering function in basic and translational research. The chemical diversity of proteins is expressed in their many proteoforms, which result from combinations of genetic polymorphisms, RNA splice variants, and posttranslational modifications. This knowledge is foundational for the biological complexes and networks that control biology yet remains largely unknown. We propose here an ambitious initiative to define the human proteome, that is, to generate a definitive reference set of the proteoforms produced from the genome. Several examples of the power and importance of proteoform-level knowledge in disease-based research are presented along with a call for improved technologies in a two-pronged strategy to the Human Proteoform Project.", "Systemic bacterial infection induces a hematopoietic response program termed \"emergency granulopoiesis\" that is characterized by increased de novo bone marrow (BM) neutrophil production. How loss of local immune control and bacterial dissemination is sensed and subsequently translated into the switch from steady-state to emergency granulopoiesis is, however, unknown. Using tissue-specific myeloid differentiation primary response gene 88 (Myd88)-deficient mice and in vivo lipopolysaccharide (LPS) administration to model severe bacterial infection, we here show that endothelial cells (ECs) but not hematopoietic cells, hepatocytes, pericytes, or BM stromal cells, are essential cells for this process. Indeed, ECs from multiple tissues including BM express high levels of Tlr4 and Myd88 and are the primary source of granulocyte colony-stimulating factor (G-CSF), the key granulopoietic cytokine, after LPS challenge or infection with Escherichia coli. EC-intrinsic MYD88 signaling and subsequent G-CSF production by ECs is required for myeloid progenitor lineage skewing toward granulocyte-macrophage progenitors, increased colony-forming unit granulocyte activity in BM, and accelerated BM neutrophil generation after LPS stimulation. Thus, ECs catalyze the detection of systemic infection into demand-adapted granulopoiesis.", "BACKGROUND: Filgotinib (GLPG0634, GS-6034) is a once-daily, orally administered, Janus kinase 1 (JAK1)-selective inhibitor. The FITZROY study examined the efficacy and safety of filgotinib for the treatment of moderate-to-severe Crohn's disease.METHODS: We did a randomised, double-blind, placebo-controlled phase 2 study, which recruited patients from 52 centres in nine European countries. We enrolled eligible patients aged 18-75 years with a documented history of ileal, colonic, or ileocolonic Crohn's disease for 3 months or more before screening, as assessed by colonoscopy and supported by histology, and a Crohn's Disease Activity Index (CDAI) score during screening between 220 and 450 inclusive. Patients were randomly assigned (3:1) to receive filgotinib 200 mg once a day or placebo for 10 weeks. Patients were stratified according to previous anti-tumour necrosis factor alpha exposure, C-reactive protein concentration at screening (≤10 mg/L or >10 mg/L), and oral corticosteroid use at baseline, using an interactive web-based response system. The primary endpoint was clinical remission, defined as CDAI less than 150 at week 10. After week 10, patients were assigned based on responder status to filgotinib 100 mg once a day, filgotinib 200 mg once a day, or placebo for an observational period lasting a further 10 weeks. The filgotinib and placebo treatment groups were compared using ANCOVA models and logistic regression models containing baseline values and randomisation stratification factors as fixed effects. Analyses were done on the intention-to-treat non-responder imputation set. The trial was registered at ClinicalTrials.gov, number NCT02048618.FINDINGS: Between Feb 3, 2014, and July 10, 2015, we enrolled 174 patients with active Crohn's disease confirmed by centrally read endoscopy (130 in the filgotinib 200 mg group and 44 in the placebo group). In the intention-to-treat population, 60 (47%) of 128 patients treated with filgotinib 200 mg achieved clinical remission at week 10 versus ten (23%) of 44 patients treated with placebo (difference 24 percentage points [95% CI 9-39], p=0·0077). In a pooled analysis of all periods of filgotinib and placebo exposure over 20 weeks, serious treatment-emergent adverse effects were reported in 14 (9%) of 152 patients treated with filgotinib and three (4%) of 67 patients treated with placebo.INTERPRETATION: Filgotinib induced clinical remission in significantly more patients with active Crohn's disease compared with placebo, and had an acceptable safety profile.FUNDING: Galapagos.", "Clioquinol (CQ), a once popular antibiotic, was used to inhibit the growth of microorganisms. Recently, CQ and its analog PBT2 have shown encouraging effects in the animal and clinical trials for Alzheimer's disease (AD). However, the mechanism by which this class of molecules works remains controversial. In this work, we used the yeast Saccharomyces cerevisiae as a model to study how CQ affects molecular and cellular functions and particularly, copper, iron, and zinc homeostasis. We observed a CQ-induced inhibition of yeast growth, which could be slightly relieved by supplementation of copper or iron. Microarray results indicated that yeast cells treated with CQ sense a general deficiency in metals, despite elevated total cellular contents of copper and iron. Consistent with this, reduced activities of some metal-sensitive enzymes were observed. Intriguingly, CQ can increase the SOD1 activity, likely through Ccs1's accessibility to CQ-bound copper ions. Further studies revealed that CQ sequestrates copper and iron at the cellular membrane, likely the plasma membrane, resulting overall metal accumulation but cytosolic metal depletion. CQ's effects on metal-sensitive metalloenzymes were also verified in mammalian cell line SH-SY5Y. Together, our results revealed that CQ can regulate metal homeostasis by binding metal ions, resulting the cell sensing a state of deficiency of bioavailable metal ions while simultaneously increasing available metals to SOD1 (via Ccs1) and possibly some other metalloproteins that can access CQ-bound metals. We hope this regulation of metal homeostasis may be helpful in explaining the therapeutic effects of CQ used in disease treatment.", "During the recent cloning of the mouse Lyst gene we developed both a high-resolution genetic map and a complete YAC and BAC contig of the Lyst critical region on mouse Chromosome 13. We also report the mapping of the human homologue of the mouse Lyst gene (LYST) to 1q43. These data are consistent with LYST being the gene for the human Chediak-Higashi Syndrome and strengthen the synteny relationship between MMU13 and human 1q43.", "Whole-genome hybridization studies have suggested that the nuclear genomes of accessions (natural strains) of Arabidopsis thaliana can differ by several percent of their sequence. To examine this variation, and as a first step in the 1001 Genomes Project for this species, we produced 15- to 25-fold coverage in Illumina sequencing-by-synthesis (SBS) reads for the reference accession, Col-0, and two divergent strains, Bur-0 and Tsu-1. We aligned reads to the reference genome sequence to assess data quality metrics and to detect polymorphisms. Alignments revealed 823,325 unique single nucleotide polymorphisms (SNPs) and 79,961 unique 1- to 3-bp indels in the divergent accessions at a specificity of >99%, and over 2000 potential errors in the reference genome sequence. We also identified >3.4 Mb of the Bur-0 and Tsu-1 genomes as being either extremely dissimilar, deleted, or duplicated relative to the reference genome. To obtain sequences for these regions, we incorporated the Velvet assembler into a targeted de novo assembly method. This approach yielded 10,921 high-confidence contigs that were anchored to flanking sequences and harbored indels as large as 641 bp. Our methods are broadly applicable for polymorphism discovery in moderate to large genomes even at highly diverged loci, and we established by subsampling the Illumina SBS coverage depth required to inform a broad range of functional and evolutionary studies. Our pipeline for aligning reads and predicting SNPs and indels, SHORE, is available for download at http://1001genomes.org.", "Specific nuclear domains are nonrandomly positioned within the nuclear space, and this preferential positioning has been shown to play an important role in genome activity and stability. Well-known examples include the organization of repetitive DNA in telomere clusters or in the chromocenter of Drosophila and mammalian cells, which may provide a means to control the availability of general repressors, such as the heterochromatin protein 1 (HP1). We have specifically characterized the intranuclear positioning of in vivo fluorescence of the Caenorhabditis elegans HP1 homologue HPL-2 as a marker for heterochromatin domains in developing embryos. For this purpose, the wavelet transform modulus maxima (WTMM) segmentation method was generalized and adapted to segment the small embryonic cell nuclei in three dimensions. The implementation of a radial distribution algorithm revealed a preferential perinuclear positioning of HPL-2 fluorescence in wild-type embryos compared with the diffuse and homogeneous nuclear fluorescence observed in the lin-13 mutants. For all other genotypes analyzed, the quantitative analysis highlighted various degrees of preferential HPL-2 positioning at the nuclear periphery, which directly correlates with the number of HPL-2 foci previously counted on 2D projections. Using a probabilistic 3D cell nuclear model, we found that any two nuclei having the same number of foci, but with a different 3D probabilistic positioning scheme, can have significantly different counts in the 2D maximum projection, thus showing the deceptive limitations of using techniques of 2D maximum projection foci counts. By this approach, a strong perinuclear positioning of HPL-2 foci was brought into light upon inactivation of conserved chromatin-associated proteins, including the HAT cofactor TRAPP.", "OBJECTIVES: To evaluate the efficacy and safety of different doses of filgotinib, an oral Janus kinase 1 inhibitor, as monotherapy in patients with active rheumatoid arthritis (RA) and previous inadequate response to methotrexate (MTX).METHODS: In this 24-week phase IIb study, patients with moderately to severely active RA were randomised (1:1:1:1) to receive 50, 100 or 200 mg filgotinib once daily, or placebo, after a ≥4-week washout from MTX. The primary end point was the percentage of patients achieving an American College of Rheumatology (ACR)20 response at week 12.RESULTS: Overall, 283 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib at any dose achieved ACR20 responses versus placebo (≥65% vs 29%, p<0.001). For other key end points at week 12 (ACR50, ACR70, ACR-N, Disease Activity Score based on 28 joints and C reactive protein, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index) significant differences from baseline in favour of filgotinib 100 and 200 mg versus placebo were seen; responses were maintained or improved through week 24. Rapid onset of action was observed for most efficacy end points. Dose-dependent increases in haemoglobin were observed. The percentage of patients with treatment-emergent adverse events (TEAE) was similar in the placebo and filgotinib groups (∼40%). Eight patients on filgotinib and one on placebo had a serious TEAE, and four patients, all of whom received filgotinib, experienced a serious infection. No tuberculosis or opportunistic infections were reported.CONCLUSIONS: Over 24 weeks, filgotinib as monotherapy was efficacious in treating the signs and symptoms of active RA, with a rapid onset of action. Filgotinib was generally well tolerated.TRIAL REGISTRATION NUMBER: NCT01894516." ]

[ "Activating mutations in NOTCH1, an essential regulator of T cell development, are frequently found in human T cell acute lymphoblastic leukemia (T-ALL). Despite important advances in our understanding of Notch signal transduction, the regulation of Notch functions in the nucleus remains unclear. Using immunoaffinity purification, we identified NOTCH1 nuclear partners in T-ALL cells and showed that, beyond the well-characterized core activation complex (ICN1-CSL-MAML1), NOTCH1 assembles a multifunctional complex containing the transcription coactivator AF4p12, the PBAF nucleosome remodeling complex, and the histone demethylases LSD1 and PHF8 acting through their demethylase activity to promote epigenetic modifications at Notch-target genes. Remarkably, LSD1 functions as a corepressor when associated with CSL-repressor complex and as a NOTCH1 coactivator upon Notch activation. Our work provides new insights into the molecular mechanisms that govern Notch transcriptional activity and represents glimpse into NOTCH1 interaction landscape, which will help in deciphering mechanisms of NOTCH1 functions and regulation.", "PURPOSE: In both the IMpassion 130 trial in the metastatic setting and in Keynote 522 in the neoadjuvant setting, patients with triple-negative breast cancer (TNBC) showed benefit from PD-1 axis immunotherapy. Here, we assess PD-L1 expression on both tumor and immune cells using quantitative immunofluorescence to assess association with benefit from neoadjuvant durvalumab concurrent with chemotherapy in TNBC.EXPERIMENTAL DESIGN: Pretreatment core needle biopsies (n = 69) were obtained from patients who participated in a phase I/II clinical trial (NCT02489448). The final analysis included 45 patients [pathologic complete response (pCR) = 18, non-pCR = 27] due to technical issues and insufficient tissue. Slides were stained using a previously validated Ultivue DNA-based Ultimapper kit (CD8, CD68, PD-L1, Cytokeratin/Sox10, and Hoechst counterstain). The PD-L1 expression was analyzed by molecular compartmentalization without segmentation using AQUA software (version 3.2.2.1) in three tissue compartments including tumor (cytokeratin-positive cells), CD68+ cells, and overall stroma.RESULTS: In patients with pCR, PD-L1 expression was significantly higher in tumor cells, in CD68+ cells and in the stroma compared with patients non-pCR. There was no difference in the amount of CD68+ cells in the tumor or stromal compartments between cases with pCR and non-pCR.CONCLUSIONS: Expression of PD-L1 in tumor cells, immune cells in stroma, and colocalized with CD68+ cells is associated with higher rates of pCR to durvalumab and chemotherapy in TNBC.", "A woman affected by Cushing's disease underwent bilateral adrenalectomy followed by radiotherapy of the hypothalamic-pituitary area when she was 18 years old. Thereafter, she used hydrocortisone acetate replacement therapy (35.5 mg divided into two daily doses). At the age of 26 years, the patient exhibited the clinical signs of the Nelson's syndrome, i.e. skin and gingival hyperpigmentation accompanied by amenorrhea, and elevated ACTH plasma levels (2,850 pg/ml, normal range 15-80 pg/ml). The magnetic resonance imaging (MRI) analysis of the sellar region evidenced a pituitary macroadenoma, measuring 14 x 13 mm. The patient was initially treated with cyproheptadine hydrochloride (12 mg/day) for 18 months. There was a partial improvement of the symptoms, with a reduction of the ACTH plasma levels to 112 pg/ml, but without any modification of the tumor mass. Due to sleepiness and weight gain, the cyproheptadine treatment was interrupted and substituted by a cabergoline (0.5 mg twice a week) therapy. Soon after cabergoline was applied an improvement of the clinical symptoms and signs was observed such as a regression of the tumor mass and the normalization of the ACTH plasma titers (38 pg/ml). Later, cabergoline was substituted by bromocriptine (7.5 mg/day) and the plasma levels of ACTH increased again (247 pg/ml), and headache and cutaneous hyperpigmentation were recorded. When cabergoline was reintroduced there was a clinical improvement and normalization of ACTH plasma levels (64 pg/ml). The MRI analysis of the sella region demonstrated a complete remission of the pituitary adenoma. The results obtained show for the first time that a long-term treatment with cabergoline also brings about a complete remission of Nelson's syndrome in the presence of a pituitary macroadenoma.", "Author information:(1)Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany.(2)Berlin Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany.(3)Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona, 08003, Spain.(4)Universitat Pompeu Fabra (UPF), Barcelona, Spain.(5)Faculty of Biology, Johannes Gutenberg University Mainz, Ackermannweg 4, Mainz, 55128, Germany.(6)Institute of Molecular Biology, Ackermannweg 4, Mainz, 55128, Germany.(7)Institute for Bioinformatics, Department of Mathematics and Computer Science, Freie Universität Berlin, Arnimallee 14, Berlin, 14195, Germany.(8)Labor für Pädiatrische Molekularbiologie, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany.(9)Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany. peter.robinson@jax.org.(10)Berlin Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany. peter.robinson@jax.org.(11)Institute for Bioinformatics, Department of Mathematics and Computer Science, Freie Universität Berlin, Arnimallee 14, Berlin, 14195, Germany. peter.robinson@jax.org.(12)Max Planck Institute for Molecular Genetics, Inhestr. 63-73, Berlin, 14195, Germany. peter.robinson@jax.org.(13)Current address: The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, 06032, CT, USA. peter.robinson@jax.org.", "The Tf1 retrotransposon represents a group of long terminal repeat retroelements that use an RNA self-primer for initiating reverse transcription while synthesizing the minus-sense DNA strand. Tf1 reverse transcriptase (RT) was found earlier to generate the self-primer in vitro. Here, we show that this RT can remove from the synthesized cDNA the entire self-primer as well as the complete polypurine tract (PPT) sequence (serving as a second primer for cDNA synthesis). However, these primer removals, mediated by the RNase H activity of Tf1 RT, are quite inefficient. Interestingly, the integrase of Tf1 stimulated the specific Tf1 RT-directed cleavage of both the self-primer and PPT, although there was no general enhancement of the RT's RNase H activity (and the integrase by itself is devoid of any primer cleavage). The RTs of two prototype retroviruses, murine leukemia virus and human immunodeficiency virus, showed only a partial and nonspecific cleavage of both Tf1-associated primers with no stimulation by Tf1 integrase. Mutagenesis of Tf1 integrase revealed that the complete Tf1 integrase protein (excluding its chromodomain) is required for stimulating the Tf1 RT primer removal activity. Nonetheless, a double mutant integrase that has lost its integration functions can still stimulate the RT's activity, though heat-inactivated integrase cannot enhance primer removals. These findings suggest that the enzymatic activity of Tf1 integrase is not essential for stimulating the RT-mediated primer removal, while the proper folding of this protein is obligatory for this function. These results highlight possible new functions of Tf1 integrase in the retrotransposon's reverse transcription process.", "The management of pain associated with chronic musculoskeletal conditions represents a significant challenge for the clinician. There remains a need for novel medications that have a significant analgesic benefit and are also safe and well tolerated. Both pre-clinical and clinical data have provided evidence of the role of nerve growth factor (NGF) in a multitude of pain eliciting conditions. Therefore, the development of monoclonal antibodies to NGF for chronic painful musculoskeletal conditions has generated interest. Areas covered: This manuscript is a review that examines both the pharmacological properties and clinical studies of tanezumab, the most widely studied antibody to NGF, for management of osteoarthritis (OA) and low back pain. In addition, the safety and tolerability profile and development history of tanezumab are also discussed. Expert opinion: Most studies provide strong support for the ability of tanezumab to provide clinically meaningful pain relief in individuals with these conditions, with longer-term studies suggesting durability of effect. The adverse event profile appears favorable, assuming the risk mitigation strategies are effective at reducing the incidence of joint-related side effects. Further data are being collected to define the optimal dose and dosing strategy in both OA and chronic low back pain.", "Gefitinib is a specific inhibitor of the epidermal growth factor receptor (EGFR) that causes growth delay in cancer cell lines and human tumor xenografts expressing high levels of EGFR. An understanding of the downstream cellular targets of gefitinib will allow the discovery of biomarkers for predicting outcomes and monitoring anti-EGFR therapies and provide information for key targets for therapeutic intervention. In this study, we investigated the role of FOXO3a in gefitinib action and resistance. Using two gefitinib-sensitive (i.e., BT474 and SKBR3) as well as three other resistant breast carcinoma cell lines (i.e., MCF-7, MDA-MB-231, and MDA-MB-453), we showed that gefitinib targets the transcription factor FOXO3a to mediate cell cycle arrest and cell death in sensitive breast cancer cells. In the sensitive cells, gefitinib treatment causes cell cycle arrest predominantly at the G(0)-G(1) phase and apoptosis, which is associated with FOXO3a dephosphorylation at Akt sites and nuclear translocation, whereas in the resistant cells, FOXO3a stays phosphorylated and remains in the cytoplasm. The nuclear accumulation of FOXO3a in response to gefitinib was confirmed in tumor tissue sections from breast cancer patients presurgically treated with gefitinib as monotherapy. We also showed that knockdown of FOXO3a expression using small interfering RNA (siRNA) can rescue sensitive BT474 cells from gefitinib-induced cell-proliferative arrest, whereas reintroduction of active FOXO3a in resistant MDA-MB-231 cells can at least partially restore cell-proliferative arrest and sensitivity to gefitinib. These results suggest that the FOXO3a dephosphorylation and nuclear localization have a direct role in mediating the gefitinib-induced proliferative arrest and in determining sensitivity to gefitinib." ]

[ "MOTIVATION: The increasing adoption of clinical whole-genome resequencing (WGS) demands for highly accurate and reproducible variant calling (VC) methods. The observed discordance between state-of-the-art VC pipelines, however, indicates that the current practice still suffers from non-negligible numbers of false positive and negative SNV and INDEL calls that were shown to be enriched among discordant calls but also in genomic regions with low sequence complexity.RESULTS: Here, we describe our method ReliableGenome (RG) for partitioning genomes into high and low concordance regions with respect to a set of surveyed VC pipelines. Our method combines call sets derived by multiple pipelines from arbitrary numbers of datasets and interpolates expected concordance for genomic regions without data. By applying RG to 219 deep human WGS datasets, we demonstrate that VC concordance depends predominantly on genomic context rather than the actual sequencing data which manifests in high recurrence of regions that can/cannot be reliably genotyped by a single method. This enables the application of pre-computed regions to other data created with comparable sequencing technology and software. RG outperforms comparable efforts in predicting VC concordance and false positive calls in low-concordance regions which underlines its usefulness for variant filtering, annotation and prioritization. RG allows focusing resource-intensive algorithms (e.g. consensus calling methods) on the smaller, discordant share of the genome (20-30%) which might result in increased overall accuracy at reasonable costs. Our method and analysis of discordant calls may further be useful for development, benchmarking and optimization of VC algorithms and for the relative comparison of call sets between different studies/pipelines.AVAILABILITY AND IMPLEMENTATION: RG was implemented in Java, source code and binaries are freely available for non-commercial use at https://github.com/popitsch/wtchg-rg/ CONTACT: niko@wtchg.ox.ac.ukSupplementary information: Supplementary data are available at Bioinformatics online.", "OBJECTIVES: Two different depletion strategies for removing albumin from human cerebrospinal fluid (CSF), Microcon Centrifugal Filter vs. Montage Albumin Deplete kit, were evaluated for improving protein profiling pattern and reproducibility in SELDI analysis.DESIGN AND METHODS: Pooled CSF was divided into 20 aliquots and these aliquots were subjected to SELDI analysis either after albumin depletion or without preprocessing. Protein profiles were obtained by using CM10, Q10 and IMAC chips.RESULTS: Both strategies resulted in reliable albumin depletion (<6.2 mg/L, filter; 8.1 mg/L, depletion kit). Investigated methods of albumin depletion showed no significant differences in coefficients of variation (CVs) of peak intensities compared to unprocessed CSF on almost all chip types. Peak intensities were significantly higher after albumin depletion compared to CSF without preprocessing on Q10 and on CM10 chips. Nevertheless, the two strategies of albumin depletion led to a decrease in the number of detected peaks on all chip types compared to unprocessed CSF, but several additional peaks, not detected in unprocessed CSF, occurred.CONCLUSIONS: This study demonstrates that reduction of sample complexity by albumin depletion of CSF can be performed without CV impairment. However, the significance of this strategy needs to be evaluated separately for each individual biomarker discovery study.", "Any scientific innovation needs to translate into a significant benefit. Peginesatide is noninferior to other erythropoiesis stimulating agents (ESAs) in terms of efficacy, and it shares the advantages of other long-acting ESAs: delayed administration frequency and no changes in dose needs according to the administration route. The molecular structure of peginesatide does not require the use of recombinant DNA technology during the manufacturing process, making its synthesis simpler and likely economically cheaper. During clinical development, its safety profile seemed to be safe, excepting the potential increase in the risk of safety end-point events in nondialysis CKD patients. However postmarketing serious hypersensitivity reactions have completely changed the scenario and urgently needs in-depth clarification. This promising drug seems to have prematurely finished its prospects.", "BACKGROUND: Cigarette smoking causes Chronic Obstructive Pulmonary Disease (COPD), the 3rd leading cause of death in the U.S. CFTR ion transport dysfunction has been implicated in COPD pathogenesis, and is associated with chronic bronchitis. However, susceptibility to smoke induced lung injury is variable and the underlying genetic contributors remain unclear. We hypothesized that presence of CFTR mutation heterozygosity may alter susceptibility to cigarette smoke induced CFTR dysfunction. Consequently, COPD patients with chronic bronchitis may have a higher rate of CFTR mutations compared to the general population.METHODS: Primary human bronchial epithelial cells derived from F508del CFTR heterozygotes and mice with (CFTR+/-) and without (CFTR+/+) CFTR heterozygosity were exposed to whole cigarette smoke (WCS); CFTR-dependent ion transport was assessed by Ussing chamber electrophysiology and nasal potential difference measurements, respectively. Caucasians with COPD and chronic bronchitis, age 40 to 80 with FEV1/FVC < 0.70 and FEV1 < 60% predicted, were selected for genetic analysis from participants in the NIH COPD Clinical Research Network's Azithromycin for Prevention of Exacerbations of COPD in comparison to 32,900 Caucasian women who underwent prenatal genetic testing. Genetic analysis involved an allele-specific genotyping of 89 CFTR mutations.RESULTS: Exposure to WCS caused a pronounced reduction in CFTR activity in both CFTR (+/+) cells and F508del CFTR (+/-) cells; however, neither the degree of decrement (44.7% wild-type vs. 53.5% F508del heterozygous, P = NS) nor the residual CFTR activity were altered by CFTR heterozygosity. Similarly, WCS caused a marked reduction in CFTR activity measured by NPD in both wild type and CFTR heterozygous mice, but the severity of decrement (91.1% wild type vs. 47.7% CF heterozygous, P = NS) and the residual activity were not significantly affected by CFTR genetic status. Five of 127 (3.9%) COPD patients with chronic bronchitis were heterozygous for CFTR mutations which was not significantly different from controls (4.5%) (P = NS).CONCLUSIONS: The magnitude of WCS induced reductions in CFTR activity was not affected by the presence of CFTR mutation heterozygosity. CFTR mutations do not increase the risk of COPD with chronic bronchitis. CFTR dysfunction due to smoking is primarily an acquired phenomenon and is not affected by the presence of congenital CFTR mutations.", "Twiddler's syndrome describes the intentional external manipulation or spontaneous rotation of implanted devices such as cardiac pacemakers. Here we report the same phenomenon occurring in a patient with an implanted deep brain stimulator generator. The clinical syndrome is described and potential technical nuances to prevent its occurrence are suggested.", "PURPOSE: Abacavir is associated with an infrequent but potentially serious hypersensitivity reaction (HSR) that can include a wide range of signs and symptoms. Identification of this reaction through medical insurance claims could provide a simple and efficient means of monitoring the incidence of abacavir hypersensitivity in large populations of patients.METHODS: Using data from a safety study of 948 abacavir users with 22 hypersensitivity events identified from claims and validated through medical record review, we used a recursive partitioning analysis to construct an algorithm to differentiate between patients with and without validated adverse events. Bootstrap resampling techniques provided validation for the analysis.RESULTS: The analysis produced a classification tree with three decision nodes that comprised the best indicators of HSRs. The predictors included any one of several specific symptoms commonly found with this reaction, a claims diagnosis of adverse effect of drug, anaphylactic shock or unspecified allergy, and a discontinuation in abacavir prior to completing a 90-day course of therapy. The algorithm demonstrated 95% sensitivity and 90% specificity when tested using a bootstrap resampling approach with the current data.CONCLUSIONS: A sensitive and specific algorithm for identifying abacavir hypersensitivity from claims was created. This algorithm would permit efficient identification of charts for medical review. Further testing of the algorithm with additional medical claims data for abacavir users will be required to ascertain its validity across databases.", "The sarcomatoid variant of renal-cell carcinoma (SRCC), a clinically aggressive subtype of renal parenchymal tumors, is typically resistant to systemic treatments and carries a poor prognosis. The authors report a case of a 57-year-old male with advanced SRCC who had a durable complete response after MAID (mesna, adriamycin, ifosfamide and dacarbazine) chemotherapy, and remains free of disease four years after completing treatment. To the authors' knowledge, this is the first report of a remission from MAID chemotherapy in SRCC. A review of published literature revealed occasional responses after systemic chemotherapy. Notably, all responses were seen with doxorubicin containing regimens, suggesting that doxorubicin is a critical component in chemotherapy regimens for SRCC." ]

[ "OBJECTIVE: Tofacitinib, which is a Janus kinase (JAK) inhibitor, has shown clinical effects in the treatment of rheumatoid arthritis. JAKs are important kinases in lymphocyte differentiation; however, their function in dendritic cells (DCs) is unknown. In this study, the function of JAKs in DCs was investigated with tofacitinib.METHODS: The effects of tofacitinib on the maturation of human monocyte-derived DCs induced by lipopolysaccharide (LPS) stimulation were investigated. In addition, its effects on T cell stimulatory capability was investigated by coculturing with naïve CD45RA-positive T cells.RESULTS: Tofacitinib decreased expression of CD80/CD86 in a concentration-dependent manner in LPS-stimulated DCs; however, it did not affect HLA-DR expression. Tofacitinib suppressed tumour necrosis factor, interleukin (IL)-6 and IL-1β production without affecting transforming growth factor (TGF)-β and IL-10 production. Meanwhile, CD80/CD86 expression in DCs was enhanced by type I interferon (IFN) stimulation, and the LPS-induced CD80/CD86 expression was inhibited by an antibody to type I IFN receptor. Furthermore, tofacitinib suppressed production of type I IFN and activation of interferon regulatory factor (IRF)-7, which is a transcription factor involved in CD80/CD86 and type I IFN expression. Tofacitinib also decreased the T cell stimulatory capability of DCs and increased expression of indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2.CONCLUSIONS: Tofacitinib, a JAK1/JAK3 inhibitor, affected the activities of human DCs. It decreased CD80/CD86 expression and T cell stimulatory capability through suppression of type I IFN signalling. These results suggest a novel mode of action for tofacitinib and a pivotal role for JAKs in the differentiation of DCs.", "Acute renal insufficiency in the setting of hemolysis and thrombocytopenia, a triad that constitutes adult or pediatric hemolytic uremic syndrome, can be associated with or triggered by diverse conditions such as verocytotoxin-producing Escherichia coli, viral infections, pregnancy, malignant hypertension, scleroderma, renal radiation, allograft rejection, lupus erythematosus, and assorted medications such as mitomycin C, cyclosporine, and oral contraceptives. Recurrent and de novo hemolytic uremic syndrome occur after renal transplantation. Relapses are also common and probably reflect incomplete resolution of the initial episode. The major differential diagnoses of hemolytic uremic syndrome in the renal allograft include acute vascular rejection, cyclosporine, FK506 or antilymphocyte antibody nephrotoxicity, and malignant hypertension, all of which may display overlapping clinical and histologic features with primary hemolytic uremic syndrome; in such instances, the exact diagnosis may be quite difficult. It is possible that the risk of recurrence may be reduced by proper timing of transplantation and suitable choice of immunosuppressive agents. Intensive plasmapheresis in conjunction with fresh frozen plasma and supportive management of renal failure may lessen mortality and morbidity even in recurrent hemolytic uremic syndrome after transplantation.", "DNA polymerase theta (pol θ) is encoded in the genomes of many eukaryotes, though not in fungi. Pol θ is encoded by the POLQ gene in mammalian cells. The C-terminal third of the protein is a family A DNA polymerase with additional insertion elements relative to prokaryotic homologs. The N-terminal third is a helicase-like domain with DNA-dependent ATPase activity. Pol θ is important in the repair of genomic double-strand breaks (DSBs) from many sources. These include breaks formed by ionizing radiation and topoisomerase inhibitors, breaks arising at stalled DNA replication forks, breaks introduced during diversification steps of the mammalian immune system, and DSB induced by CRISPR-Cas9. Pol θ participates in a route of DSB repair termed \"alternative end-joining\" (altEJ). AltEJ is independent of the DNA binding Ku protein complex and requires DNA end resection. Pol θ is able to mediate joining of two resected 3' ends harboring DNA sequence microhomology. \"Signatures\" of Pol θ action during altEJ are the frequent utilization of longer microhomologies, and the insertion of additional sequences at joining sites. The mechanism of end-joining employs the ability of Pol θ to tightly grasp a 3' terminus through unique contacts in the active site, allowing extension from minimally paired primers. Pol θ is involved in controlling the frequency of chromosome translocations and preserves genome integrity by limiting large deletions. It may also play a backup role in DNA base excision repair. POLQ is a member of a cluster of similarly upregulated genes that are strongly correlated with poor clinical outcome for breast cancer, ovarian cancer and other cancer types. Inhibition of pol θ is a compelling approach for combination therapy of radiosensitization.", "Daratumumab is a fully human anti-CD38 IgG1-κ monoclonal antibody (mAb) currently being evaluated in several Phase 2 and 3 clinical studies for the treatment of multiple myeloma (MM). In this clinical case study we demonstrate that daratumumab can be detected as an individual monoclonal band in serum immunofixation electrophoresis (IFE). M-protein follow-up by IFE is part of the International Myeloma Working Group (IMWG) criteria to assess treatment response. Therefore, it is crucial that the daratumumab band is not confused with the endogenous M-protein of the patient during IFE interpretation. Moreover, a significant number of IgG-κ M-proteins co-migrate with daratumumab. Co-migration introduces a bias in the M-protein quantification since pharmacokinetic studies show that daratumumab peak plasma concentrations reach up to 1 g/L. More importantly, co-migration can mask clearance of the M-protein by IFE which is necessary for classification of complete response by IMWG criteria (negative serum IFE). For optimal M-protein monitoring the laboratory specialist needs to be informed when patients receive daratumumab, and it is essential that the laboratory specialist is aware that a slow migrating band in the γ-region in those patients may be derived from the daratumumab. A daratumumab specific IFE reflex assay (DIRA) has been developed and can be utilized to abrogate interference. The here described mAb interference is not limited to daratumumab, and as therapeutic antibodies gain approval and enter into common clinical practice, laboratory specialists will need additional processes to characterize IFE interference and distinguish endogenous M-protein from therapeutic antibodies.", "BACKGROUND: Cytogenetic studies from past decades have shown that interphase cells of female cats contain a densely stained chromatin mass in their nuclei called as Barr bodies (BBs) named after the scientist Murray Barr. BBs are unique chromatin structures formed due to the condensation of the X-chromosome. Many psychopathic disorders originate from defective genes including the multiple X syndromes. Males with extra X-chromosome generally present with severe personality disorder. The present study was conducted to determine the presence of extra X-chromosome in male jail inmates through the detection of BB in peripheral blood and buccal smear.MATERIALS AND METHODS: Study included 100 male subjects (fifty jail inmates and fifty controls), after obtaining the consent, peripheral blood smears (PBS) and buccal smears (BS) were prepared and stained using Leishman's and cresyl violet stain respectively. One hundred neutrophils in PBS and epithelial cells in BS were screened for detection of the BB; accumulated data were tabulated and statistically analyzed using t-test and Chi-square test.RESULTS: 60% of cases in PBS and 36% in BS showed positivity for the presence of BB in jail inmates as compared to 14% of cases in PBS and none in BS were positive for BB in controls.CONCLUSION: Presence of BB in male suggests increased likelihood of criminal tendencies. Further studies are to be carried out to compare the results with karyotyping.", "Per cent stimulation of GR activity by FAD in vitro and PNP oxidase activity were measured in G6PD deficiency, heterozygous beta-thalassaemia and controls. It is confirmed that, in contrast to the high stimulation of GR by FAD commonly found in in thalassaemia indicating red-cell deficiency of FAD, and shown here to be greater in the Italian subjects, GR is usually saturated with FAD in G6PD deficiency, leading to high in vitro activity. Unexpectedly, on the other hand, low FMN-dependent PNP oxidase activity due to red-cell deficiency of FMN, confirmed by response to oral riboflavin, was found in the majority of subjects with G6PD deficiency, similar to that found in heterozygous beta-thalassaemia. Whereas this is explained in thalassaemia by an inherited slow red-cell metabolism of riboflavin to FMN, it is suggested that in G6PD deficiency an increased rate of red-cell metabolism of FMN to FAD leads to the low FMN and high FAD. When G6PD deficiency occurs with heterozygous beta-thalassaemia, GR is usually saturated with FAD as in G6PD deficiency alone, unless there is an inherited, very slow red-cell metabolism of riboflavin to FMN. The part played by GR in haemolytic crises in G6PD deficiency is discussed.", "Ubiquitination and deubiquitination have emerged as critical regulatory processes in the virus-triggered type I interferon (IFN) induction pathway. In this study, we carried out a targeted siRNA screen of 54 ubiquitin-specific proteases (USPs) and identified USP25 as a negative regulator of the virus-triggered type I IFN signaling pathway. Overexpression of USP25 inhibited virus-induced activation of IFN-β, interferon regulation factor 3 (IRF3) and nuclear factor-kappa B (NF-κB), as well as the phosphorylation of IRF3 and NF-κB subunit p65. Furthermore, Knockdown of USP25 potentiated virus-induced induction of the IFN-β. In addition, detailed analysis demonstrated that USP25 cleaved lysine 48- and lysine 63-linked polyubiquitin chains in vitro and in vivo, and its deubiquitinating enzyme (DUB) activity, were dependent on a cysteine residue (Cys178) and a histidine residue (His607). USP25 mutants lacking DUB activity lost the ability to block virus-induced type I IFN to some degree. Mechanistically, USP25 deubiquitinated retinoic acid-inducible gene I (RIG-I), tumornecrosis factor (TNF) receptor-associated factor 2 (TRAF2), and TRAF6 to inhibit RIG-I-like receptor-mediated IFN signaling. Our findings suggest that USP25 is a novel DUB negatively regulating virus-induced type I IFN production.", "Machine learning-based classification techniques provide support for the decision-making process in many areas of health care, including diagnosis, prognosis, screening, etc. Feature selection (FS) is expected to improve classification performance, particularly in situations characterized by the high data dimensionality problem caused by relatively few training examples compared to a large number of measured features. In this paper, a random forest classifier (RFC) approach is proposed to diagnose lymph diseases. Focusing on feature selection, the first stage of the proposed system aims at constructing diverse feature selection algorithms such as genetic algorithm (GA), Principal Component Analysis (PCA), Relief-F, Fisher, Sequential Forward Floating Search (SFFS) and the Sequential Backward Floating Search (SBFS) for reducing the dimension of lymph diseases dataset. Switching from feature selection to model construction, in the second stage, the obtained feature subsets are fed into the RFC for efficient classification. It was observed that GA-RFC achieved the highest classification accuracy of 92.2%. The dimension of input feature space is reduced from eighteen to six features by using GA.", "Ubiquitin-specific protease (USP) 25, belonging to the USP family of deubiquitinases, harbors two tandem ubiquitin-interacting motifs (UIMs), a ~20-amino-acid α-helical stretch that binds to ubiquitin. However, the role of the UIMs in USP25 remains unclear. Here we show that the tandem UIM region binds to Lys48-, but not Lys63-, linked ubiquitin chains, where the two UIMs played a critical and cooperative role. Purified USP25 exhibited higher ubiquitin isopeptidase activity to Lys48-, than to Lys63-, linked ubiquitin chains. Mutations that disrupted the ubiquitin-binding ability of the tandem UIMs resulted in a reduced ubiquitin isopeptidase activity of USP25, suggesting a role for the UIMs in exerting the full catalytic activity of USP25. Moreover, when mutations that convert the binding preference from Lys48- to Lys63-linked ubiquitin chains were introduced into the tandem UIM region, the USP25 mutants acquired elevated and reduced isopeptidase activity toward Lys63- and Lys48-linked ubiquitin chains, respectively. These results suggested that the binding preference of the tandem UIMs toward Lys48-linked ubiquitin chains contributes not only to the full catalytic activity but also to the ubiquitin chain substrate preference of USP25, possibly by selectively holding the Lys48-linked ubiquitin chain substrates in the proximity of the catalytic core.", "BACKGROUND: Histone modifications and DNA methylation are two major factors in epigenetic phenomenon. Unlike the histone deacetylase inhibitors, which are known to exert radiosensitizing effects, there have only been a few studies thus far concerning the role of DNA methyltransferase (DNMT) inhibitors as radiosensitizers. The principal objective of this study was to evaluate the effects of DNMT inhibitors on the radiosensitivity of human cancer cell lines, and to elucidate the mechanisms relevant to that process.METHODS: A549 (lung cancer) and U373MG (glioblastoma) cells were exposed to radiation with or without six DNMT inhibitors (5-azacytidine, 5-aza-2'-deoxycytidine, zebularine, hydralazine, epigallocatechin gallate, and psammaplin A) for 18 hours prior to radiation, after which cell survival was evaluated via clonogenic assays. Cell cycle and apoptosis were analyzed via flow cytometry. Expressions of DNMT1, 3A/3B, and cleaved caspase-3 were detected via Western blotting. Expression of γH2AX, a marker of radiation-induced DNA double-strand break, was examined by immunocytochemistry.RESULTS: Pretreatment with psammaplin A, 5-aza-2'-deoxycytidine, and zebularine radiosensitized both A549 and U373MG cells. Pretreatment with psammaplin A increased the sub-G1 fraction of A549 cells, as compared to cells exposed to radiation alone. Prolongation of γH2AX expression was observed in the cells treated with DNMT inhibitors prior to radiation as compared with those treated by radiation alone.CONCLUSIONS: Psammaplin A, 5-aza-2'-deoxycytidine, and zebularine induce radiosensitivity in both A549 and U373MG cell lines, and suggest that this effect might be associated with the inhibition of DNA repair.", "Ubiquitin Specific Protease 25 (USP25), a member of the deubiquitinase family, is involved in several disease-related signal pathways including myogenesis, immunity and protein degradation. It specially catalyzes the hydrolysis of the K48-linked and K63-linked polyubiquitin chains. USP25 contains one ubiquitin-associated domain and two ubiquitin-interacting motifs (UIMs) in its N-terminal region, which interact with ubiquitin and play a role in substrate recognition. Besides, it has been shown that the catalysis activity of USP25 is either impaired by sumoylation or enhanced by ubiquitination within its UIM. To elucidate the structural basis of the cross-regulation of USP25 function by non-covalent binding and covalent modifications of ubiquitin and SUMO2/3, a systematic structural biology study of USP25 is required. Here, we report the (1)H, (13)C and (15)N backbone and side-chain resonance assignments of the N-terminal ubiquitin binding domains (UBDs) of USP25 with BMRB accession number of 19111, which is the first step of the systematic structural biology study of the enzyme.", "Leber hereditary optic neuropathy (LHON) presents with sudden onset of visual loss mainly in young adult males. LHON is not uncommon in Australia, accounting for 2% of invalid blind pensions. We have identified 20 unrelated families carrying mitochondrial DNA mutations associated with LHON and 135 of 291 individuals with documented LHON are currently alive in Australia. The mean age of onset of visual loss for males was 26 years and for females 27 years, with a range from six to 65 years. The mean risk of visual loss was 20% for males and 4% for females. There are over 1750 male and female carriers living in Australia who have not yet lost vision; 600 carriers are under 24 years of age. The expected number of new cases of blindness from LHON is three to four per year." ]

[ "To discover safe and effective topical skin-lightening agents, we have evaluated alkyl esters of the natural product gentisic acid (GA), which is related to our lead compound methyl gentisate (MG), and four putative tyrosinase inhibitors, utilizing mammalian melanocyte cell cultures and cell-free extracts. Desirable characteristics include the ability to inhibit melanogenesis in cells (IC50 < 100 microg/mL) without cytotoxicity, preferably due to tyrosinase inhibition. Of the six esters synthesized, the smaller esters (e.g. methyl and ethyl) were more effective enzyme inhibitors (IC50 approximately 11 and 20 microg/mL, respectively). For comparison, hydroquinone (HQ), a commercial skin \"bleaching\" agent, was a less effective enzyme inhibitor (IC50 approximately 72 microg/mL), and was highly cytotoxic to melanocytes in vitro at concentrations substantially lower than the IC50 for enzymatic inhibition. Kojic acid was a potent inhibitor of the mammalian enzyme (IC50 approximately 6 microg/mL), but did not reduce pigmentation in cells. Both arbutin and magnesium ascorbyl phosphate were ineffective in the cell-free and cell-based assays. MG at 100 microg/mL exhibited a minimal inhibitory effect on DHICA oxidase (TRP 1) and no effect on DOPAchrome tautomerase (TRP-2), suggesting that MG inhibits melanogenesis primarily via tyrosinase inhibition. MG and GA were non-mutagenic at the hprt locus in V79 Chinese hamster cells, whereas HQ was highly mutagenic and cytotoxic. The properties of MG in vitro, including (1) pigmentation inhibition in melanocytes, (2) tyrosinase inhibition and selectivity, (3) reduced cytotoxicity relative to HQ, and (4) lack of mutagenic potential in mammalian cells, establish MG as a superior candidate skin-lightening agent.", "Genetic factors have been suggested to contribute to the etiology of moyamoya disease. The authors have previously reported an association between moyamoya disease and several alleles for human leukocyte antigens (HLA). To further specify the genetic component of moyamoya disease, a linkage study of moyamoya disease using markers on chromosome 6, where the HLA gene is located, was performed. The 15 microsatellite markers of chromosome 6 were studied in 20 affected sibling pairs. From an identical-by-descent analysis of these markers, an allele with possible linkage to moyamoya disease was identified. Sharing of the allele among affected members in 19 families was investigated, considering the haplotype. The marker, D6S441, might be linked to moyamoya disease. Considering the haplotype, the allele was shared among the affected members in 16 (82%) of the 19 families, but not in two others. In one family, sharing of the allele could not be determined because of low heterozygosity. Further studies are necessary to clarify multiple genetic factors that are definitely linked with moyamoya disease.", "DOI: 10.1038/sj.bjc.6603238PMCID: PMC2360496PMID: 16804530 [Indexed for MEDLINE]", "In the past several years, there have been significant advances in the therapeutic arsenal of agents used to treat multiple myeloma (MM). Despite these advances, MM remains incurable. One of the most recent therapeutic advances is the development of targeted monoclonal antibodies (MoAbs). The MoAbs have significantly improved disease response rates, and extended survival in MM patients. In this review, we highlight the current US Food and Drug Administration approved MoAbs, namely, belantamab mafodotin, daratumumab, elotuzumab, and isatuximab. The mechanisms of action and pivotal clinical trials that led to US Food and Drug Administration approval of these agents and their current therapeutic use in the management of patients with MM are discussed in detail. Lastly, we describe several novel MoAbs under clinical investigation with potential for approval in the future.", "INTRODUCTION: Osteopenia and osteoporosis because of hyperprolactinaemia caused by prolactinoma may be followed by an increased risk of fracture. There are no data on the bone effects of functional hyperprolactinaemia. The aim was to assess the influence of hyperprolactinaemia of various origins on bone turnover and density in different skeletal sites.MATERIAL AND METHODS: The study was carried out in 75 women (aged 30.53 +/- 7.8): Group I--32 women with prolactinoma and Group II--43 women with functional hyperprolactinaemia. Both groups of patients were subdivided into those with hypogonadism and those with normal gonadal function. The control group consisted of 29 healthy women aged (33.59 +/- 4.7). In all subjects PRL and bone turnover markers (BAP, OC, ICTP) were studied. BMD measurements (lumbar spine, forearm, proximal femur and total body) were carried out using DXA.RESULTS: Higher PRL concentrations were observed in patients than in controls. The values of bone turnover markers (BAP, ICTP) were shown to be higher in patient groups and subgroups than in controls. In patients with prolactinoma lumbar spine BMD was lower than in patients with functional hyperprolactinaemia and controls. Total body BMD was also lower, albeit to a lesser extent.CONCLUSIONS: Hyperprolactinaemia caused by prolactinoma in women influences bone metabolism unfavourably, more by the impact on the activity of bone turnover markers than on BMD. This provides an opportunity for earlier assessment of bone metabolism disturbances before the BMD changes can be observed. Functional hyperprolactinaemia does not determine such a harmful effect on bone metabolism as hyperprolactinemia due to prolactinoma.", "Organisms can often adapt surprisingly quickly to evolutionary challenges, such as the application of pesticides or antibiotics, suggesting an abundant supply of adaptive genetic variation. In these situations, adaptation should commonly produce 'soft' selective sweeps, where multiple adaptive alleles sweep through the population at the same time, either because the alleles were already present as standing genetic variation or arose independently by recurrent de novo mutations. Most well-known examples of rapid molecular adaptation indeed show signatures of such soft selective sweeps. Here, we review the current understanding of the mechanisms that produce soft sweeps and the approaches used for their identification in population genomic data. We argue that soft sweeps might be the dominant mode of adaptation in many species.", "Genome-wide association studies have identified strong associations between the risk of developing Parkinson's disease (PD) and polymorphisms in the genes encoding α-synuclein and the microtubule-associated protein tau. However, the contribution of tau and its phosphorylated form (p-tau) to α-synuclein-induced pathology and neuronal dysfunction remains controversial. We have assessed the effects of NAP (davunetide), an eight-amino acid peptide that decreases tau hyperphosphorylation, in mice overexpressing wild-type human α-synuclein (Thy1-aSyn mice), a model that recapitulates aspects of PD. We found that the p-tau/tau level increased in a subcortical tissue block that includes the striatum and brain stem, and in the cerebellum of the Thy1-aSyn mice compared to nontransgenic controls. Intermittent intranasal NAP administration at 2 μg/mouse per day, 5 days a week, for 24 weeks, starting at 4 weeks of age, significantly decreased the ratio of p-tau/tau levels in the subcortical region while a higher dose of 15 μg/mouse per day induced a decrease in p-tau/tau levels in the cerebellum. Both NAP doses reduced hyperactivity, improved habituation to a novel environment, and reduced olfactory deficits in the Thy1-aSyn mice, but neither dose improved the severe deficits of motor coordination observed on the challenging beam and pole, contrasting with previous data obtained with continuous daily administration of the drug. The data reveal novel effects of NAP on brain p-tau/tau and behavioral outcomes in this model of synucleinopathy and suggest that sustained exposure to NAP may be necessary for maximal benefits." ]

[ "Scarlet fever consists in a diffuse exanthem associated with mucous changes. Classical scarlet fever is rare now, but other severe streptococcal infections have become more frequent, such as streptococcal toxic shock syndrome. The scarlatiniform exanthem and the shock observed in this disease are due to a streptococcal pyrogenic exotoxin. Exfoliative toxins secreted by Staphylococcus aureus are responsible for the tender erythema and cutaneous scaling characteristic of staphylococcal scalded skin syndrome of infancy. The so-called staphylococcal scarlet fever is probably an attenuated variant of this disease. Toxic shock syndrome toxin 1 (TSST1) is another staphylococcal toxin implied in the staphylococcal toxic shock syndrome. This disease is characterized by general symptoms and a scarlatiniform exanthem which are due to the effects of TSST1, acting as a superantigen.", "The transcription factors Gli2 (glioma-associated factor 2), which is a transactivator of Sonic Hedgehog (Shh) signalling, and myocyte enhancer factor 2C (MEF2C) play important roles in the development of embryonic heart muscle and enhance cardiomyogenesis in stem cells. Although the physiological importance of Shh signalling and MEF2 factors in heart development is well known, the mechanistic understanding of their roles is unclear. Here, we demonstrate that Gli2 and MEF2C activated each other's expression while enhancing cardiomyogenesis in differentiating P19 EC cells. Furthermore, dominant-negative mutant proteins of either Gli2 or MEF2C repressed each other's expression, while impairing cardiomyogenesis in P19 EC cells. In addition, chromatin immunoprecipitation (ChIP) revealed association of Gli2 to the Mef2c gene, and of MEF2C to the Gli2 gene in differentiating P19 cells. Finally, co-immunoprecipitation studies showed that Gli2 and MEF2C proteins formed a complex, capable of synergizing on cardiomyogenesis-related promoters containing both Gli- and MEF2-binding elements. We propose a model whereby Gli2 and MEF2C bind each other's regulatory elements, activate each other's expression and form a protein complex that synergistically activates transcription, enhancing cardiac muscle development. This model links Shh signalling to MEF2C function during cardiomyogenesis and offers mechanistic insight into their in vivo functions.", "CONTEXT: Routine cancer screening with prostate-specific antigen (PSA) is controversial, and practice guidelines recommend that men be counseled about its risks and benefits.OBJECTIVE: To evaluate the process of decision making as men react to and use information after PSA counseling.DESIGN: Written surveys and semistructured qualitative interviews before and after a neutral PSA counseling intervention.PARTICIPANTS: Men 40 to 65 years of age in southeastern Michigan were recruited until thematic saturation--that is, the point at which no new themes emerged in interviews (n = 40).RESULTS: In a paper survey, 37 of 40 participants (93%) said that they interpreted the counseled information as unfavorable toward PSA. However, 30 participants (75%) said after the intervention that they intended to be tested in the future, including 29 of 30 men (97%) with prior PSA testing. In the interview, many participants cited underlying beliefs as a reason to dismiss the counseled information. Qualitative analysis found the seven most common beliefs cited were fear of cancer, relevance of salient anecdotes and analogies, distrust of statistics, enthusiasm for \"prevention,\" protection from \"bad luck,\" faith in science, and valuing PSA as knowledge for its own sake. Although some beliefs could be interpreted as judgment errors, most were credible on a personal level.CONCLUSIONS: Most men who underwent PSA counseling cited underlying beliefs rather than the content of counseled information as the basis for their decisions regarding future PSA screening. If widespread, such beliefs may render clinician counseling and decision support methods less effective. Eliciting patient beliefs prior to counseling may improve the shared decision-making process.", "The chemical structure of a drug determines its physicochemical properties, further determines its ADME/Tox properties, and ultimately affects its pharmacological activity. Medicinal chemists can regulate the pharmacological activity of drug molecules by modifying their structure. Ring systems and functional groups are important components of a drug. The proportion of non-hydrocarbon atoms among non-hydrogen atoms reflects the heavy atoms proportion of a drug. The three factors have considerable potential for the assessment of the drug-like properties of organic molecules. However, to the best of our knowledge, there have been no studies to systematically analyze the simultaneous effects of the number of aromatic and non-aromatic rings, the number of some special functional groups and the proportion of heavy atoms on the drug-like properties of an organic molecule. To this end, the numbers of aromatic and non-aromatic rings, the numbers of some special functional groups and the heavy atoms proportion of 6891 global approved small drugs have been comprehensively analyzed. We first uncovered three important structure-related criteria closely related to drug-likeness, namely: (1) the best numbers of aromatic and non-aromatic rings are 2 and 1, respectively; (2) the best functional groups of candidate drugs are usually -OH, -COOR and -COOH in turn, but not -CONHOH, -SH, -CHO and -SO3H. In addition, the -F functional group is beneficial to CNS drugs, and -NH2 functional group is beneficial to anti-infective drugs and anti-cancer drugs; (3) the best R value intervals of candidate drugs are in the range of 0.05-0.50 (preferably 0.10-0.35), and R value of the candidate CNS drugs should be as small as possible in this interval. We envision that the three chemical structure-related criteria may be applicable in a prospective manner for the identification of novel candidate drugs and will provide a theoretical foundation for designing new chemical entities with good drug-like properties.", "It is generally believed that splicing removes introns as single units from precursor messenger RNA transcripts. However, some long Drosophila melanogaster introns contain a cryptic site, known as a recursive splice site (RS-site), that enables a multi-step process of intron removal termed recursive splicing. The extent to which recursive splicing occurs in other species and its mechanistic basis have not been examined. Here we identify highly conserved RS-sites in genes expressed in the mammalian brain that encode proteins functioning in neuronal development. Moreover, the RS-sites are found in some of the longest introns across vertebrates. We find that vertebrate recursive splicing requires initial definition of an 'RS-exon' that follows the RS-site. The RS-exon is then excluded from the dominant mRNA isoform owing to competition with a reconstituted 5' splice site formed at the RS-site after the first splicing step. Conversely, the RS-exon is included when preceded by cryptic promoters or exons that fail to reconstitute an efficient 5' splice site. Most RS-exons contain a premature stop codon such that their inclusion can decrease mRNA stability. Thus, by establishing a binary splicing switch, RS-sites demarcate different mRNA isoforms emerging from long genes by coupling cryptic elements with inclusion of RS-exons.", "AIMS: To evaluate the safety, pharmacokinetics and pharmacodynamics of SAR425899, a novel polypeptide, active as an agonist at both the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCR), in healthy volunteers and in overweight/obese patients with type 2 diabetes (T2D).METHODS: Subcutaneous administrations of SAR425899 were tested in two randomized, placebo-controlled, double-blind clinical trials. In the first trial, healthy overweight volunteers (body mass index [BMI] 25-30 kg/m2 ; n = 32) received single-ascending doses (0.01-0.1 mg) of SAR425899 or placebo. In the second, a multiple-ascending-dose trial (NCT02411825), healthy normal- to overweight volunteers (BMI 20-30 kg/m2 ; n = 40) and overweight/obese patients with T2D (BMI 28-42 kg/m2 ; n = 36) received daily doses of SAR425899 or placebo over 21 or 28 days, respectively.RESULTS: The most frequently reported adverse events were gastrointestinal; gastrointestinal side effects were less pronounced in patients with T2D compared with healthy volunteers. SAR425899 significantly reduced levels of fasting plasma glucose (P < 0.05 vs. placebo) and glycated haemoglobin (P < 0.001 versus placebo) in patients with T2D. Additionally, SAR425899 led to reductions in body weight, with a maximal reduction of 5.32 kg in healthy volunteers and 5.46 kg in patients with T2D (P < 0.001 vs. placebo) at end of treatment.CONCLUSIONS: SAR425899 was well tolerated and led to favourable glycaemic effects in patients with T2D and weight reduction in both healthy volunteers and patients. Whether dual GLP-1R/GCR agonism represents a treatment method that is superior to pure GLP-1R agonists for obesity and diabetes treatment remains to be confirmed.", "Frequency of INherited Disorders database (FIND base; http://www.findbase.org) records frequencies of causative genetic variations worldwide. Database records include the population and ethnic group or geographical region, the disorder name and the related gene, accompanied by links to any related external resources and the genetic variation together with its frequency in that population. In addition to the regular data content updates, we report the following significant advances: (i) the systematic collection and thorough documentation of population/ethnic group-specific pharmacogenomic markers allele frequencies for 144 markers in 14 genes of pharmacogenomic interest from different classes of drug-metabolizing enzymes and transporters, representing 150 populations and ethnic groups worldwide; (ii) the development of new data querying and visualization tools in the expanded FINDbase data collection, built around Microsoft's PivotViewer software (http://www.getpivot.com), based on Microsoft Silverlight technology (http://www.silverlight.net) that facilitates querying of large data sets and visualizing the results; and (iii) the establishment of the first database journal, by affiliating FINDbase with Human Genomics and Proteomics, a new open-access scientific journal, which would serve as a prime example of a non-profit model for sustainable database funding.", "Recent clinical trials have demonstrated the potential of adeno-associated virus (AAV)-based vectors for treating rare diseases. However, significant barriers remain for the translation of these vectors into widely available therapies. In particular, exposure to the AAV capsid can generate an immune response of neutralizing antibodies. One approach to overcome this response is to map the AAV-specific neutralizing epitopes and rationally design an AAV capsid able to evade neutralization. To accomplish this, we isolated a monoclonal antibody against AAV9 following immunization of BALB/c mice and hybridoma screening. This antibody, PAV9.1, is specific for intact AAV9 capsids and has a high neutralizing titer of >1:160,000. We used cryo-electron microscopy to reconstruct PAV9.1 in complex with AAV9. We then mapped its epitope to the 3-fold axis of symmetry on the capsid, specifically to residues 496-NNN-498 and 588-QAQAQT-592. Capsid mutagenesis demonstrated that even a single amino acid substitution within this epitope markedly reduced binding and neutralization by PAV9.1. In addition, in vivo studies showed that mutations in the PAV9.1 epitope conferred a \"liver-detargeting\" phenotype to the mutant vectors, unlike AAV9, indicating that the residues involved in PAV9.1 interactions are also responsible for AAV9 tropism. However, we observed minimal changes in binding and neutralizing titer when we tested these mutant vectors for evasion of polyclonal sera from mice, macaques, or humans previously exposed to AAV. Taken together, these studies demonstrate the complexity of incorporating mapped neutralizing epitopes and previously identified functional motifs into the design of novel capsids able to evade immune response.IMPORTANCE Gene therapy utilizing viral vectors has experienced recent success, culminating in U.S. Food and Drug Administration approval of the first adeno-associated virus vector gene therapy product in the United States: Luxturna for inherited retinal dystrophy. However, application of this approach to other tissues faces significant barriers. One challenge is the immune response to viral infection or vector administration, precluding patients from receiving an initial or readministered dose of vector, respectively. Here, we mapped the epitope of a novel neutralizing antibody generated in response to this viral vector to design a next-generation capsid to evade immune responses. Epitope-based mutations in the capsid interfered with the binding and neutralizing ability of the antibody but not when tested against polyclonal samples from various sources. Our results suggest that targeted mutation of a greater breadth of neutralizing epitopes will be required to evade the repertoire of neutralizing antibodies responsible for blocking viral vector transduction.", "There are several reports of a closer-than-random colocalization of homologous chromosomes in the vegetative nuclei of diploid budding yeast. Here, we studied by fluorescence in situ hybridization (FISH) the nuclear distribution of chromosomes and found a slight tendency toward closer proximity between homologous (allelic) loci than between any nonhomologous chromosomal regions. We show that most of this preferential association is not due to vegetative (also known as somatic) pairing but is caused by the polar orientation of interphase chromosomes (Rabl orientation). We quantified the occasional loss of detectable fluorescence signals that is inherent to the FISH method. Signal loss leads to the occurrence of a single signal that may be misinterpreted as the close association of two homologous chromosomal sites. The nuclear distribution of homologous loci, when corrected for the influence of nuclear architecture and methodological faults, was not different or was only marginally different from a random relative positioning as predicted by computer simulation. We discuss here several possibilities for the residual homologous proximity that do not invoke homology-dependent vegetative pairing, and we conclude that, in diploid budding yeast, constitutive vegetative pairing is a negligible factor for the organization of the interphase nucleus.", "AIM: Osteoporosis is a frequent comorbidity in patients with chronic obstructive pulmonary disease (COPD). We have studied the risk of major osteoporotic fracture and hip fracture in patients with COPD.PATIENTS AND METHODS: A multicenter cross-sectional study was performed in Spain in 26 hospitals of 16 regional communities. Patients diagnosed with COPD who required admission to the Internal Medicine Service due to exacerbation of their respiratory disease were enrolled. COPD was confirmed by post-bronchodilator spirometry in stable state: maximum expiratory volume in the first second (FEV₁) < 80% of the theoretical value and quotient FEV(1)/FVC < 0.70 and percent predicted after the administration of a bronchodilator. Dyspnea was evaluated with the modified Medical Research Council (mMRC) dyspnea scale. The principal variable was the likelihood of fracture evaluated with the FRAX® tool for the Spanish population.RESULTS: Three hundred and ninety two patients, 347 (88%) men, with a mean (SD) age of 73.7 (8.9) years and a mean FEV₁ of 1.23 liters (43.3% of predicted) were enrolled. Only 37 patients (9.4%), 27 men and 10 women had been diagnosed previously of osteoporosis. Overall, 1.8% (95% CI: 0.9-3.6) had a 10-year probability of major osteoporotic fracture ≥ 20% and 49.7% (95% CI: 44.8-54.7) had a probability of hip fracture ≥ 3%. No relationship was observed between the probability of fracture and GOLD stage or mMRC dyspnea scale.CONCLUSIONS: The diagnosis of osteoporosis is uncommon in our COPD patients. However, half of them have a high probability of a hip fracture in the next 10 years.", "Chromosomes are not packed randomly in the nucleus. The Rabl orientation is an example of the non-random arrangement of chromosomes, centromeres are grouped in a limited area near the nuclear periphery and telomeres are located apart from centromeres. This orientation is established during mitosis and maintained through subsequent interphase in a range of species. We report that a Rabl-like configuration can be formed de novo without a preceding mitosis during the transition from the sexual phase to the vegetative phase of the life cycle in fission yeast. In this process, each of the dispersed centromeres is often associated with a novel Sad1-containing body that is contacting a cytoplasmic microtubule laterally (Sad1 is a component of the spindle pole body (SPB)). The Sad1-containing body was colocalized with other known SPB components, Kms1 and Spo15 but not with Cut12, indicating that it represents a novel SPB-related complex. The existence of the triplex structure (centromere-microtubule-Sad1 body) suggests that the clustering of centromeres is controlled by a cytoplasmic microtubular system. Accordingly, when microtubules are destabilized, clustering is markedly reduced.", "The TYR gene (MIM #6069333) is located at position 11q14.3 on the human chromosome, and encodes tyrosinase, which is expressed in melanocytes and controls the biosynthesis of melanin. Most TYR mutations eliminate the activity of tyrosinase, preventing melanocytes from producing any melanin throughout life. People with this form of albinism have white hair, light-coloured eyes and very pale skin. Some mutations in TYR reduce but do not completely eliminate tyrosinase activity, and allow some melanin to be produced. We report a Pakistani family with four members affected by oculocutaneous albinism (OCA). Blood samples were collected from all affected individuals, normal siblings and their parents. Genomic DNA was extracted, and sequence analysis of all the coding exons and adjacent intronic sequences of TYR was performed, which identified a novel missense substitution (p.Ile198Thr). Sequencing of TYR in 90 unrelated healthy individuals showed no sequence variant at this location. Our study expands the mutational spectrum of OCA1.", "The SCN5A gene encodes the alpha subunit of the human heart sodium channel (hH1), which plays a critical role in cardiac excitability. Mutations of SCN5A underlie Brugada syndrome, an inherited disorder that leads to ventricular fibrillation and sudden death. This study describes changes in cellular localization and functional expression of hH1 in a naturally occurring SCN5A mutation (R1432G) reported for Brugada syndrome. Using patch-clamp experiments, we show that there is an abolition of functional hH1 expression in R1432G mutants expressed in human tsA201 cells but not in Xenopus oocytes. In tsA201 cells, a conservative positively charged mutant, R1432K, produced sodium currents with normal gating properties, whereas other mutations at this site abolished functional sodium channel expression. Immunofluorescent staining and confocal microscopy showed that the wild-type alpha subunit expressed in tsA201 cells was localized to the cell surface, whereas the R1432G mutant was colocalized with calnexin within the endoplasmic reticulum. The beta(1) subunit was also localized to the cell surface in the presence of the alpha subunit; however, in its absence, the beta(1) subunit was restricted to a perinuclear localization. These results demonstrate that the disruption of SCN5A cell-surface localization is one mechanism that can account for the loss of functional sodium channels in Brugada syndrome. The full text of this article is available at http://www.circresaha.org.", "Botulinum neurotoxin (BoNT), the causative agent of the deadly neuroparalytic disease botulism, is the most poisonous protein known for humans. Produced by different strains of the anaerobic bacterium Clostridium botulinum, BoNT effects cellular intoxication via a multistep mechanism executed by the three modules of the activated protein. Endocytosis, the first step of cellular intoxication, is triggered by the ~50 kDa, heavy-chain receptor-binding domain (HCR) that is specific for a ganglioside and a protein receptor on neuronal cell surfaces. This dual receptor recognition mechanism between BoNT and the host cell's membrane is well documented and occurs via specific intermolecular interactions with the C-terminal sub-domain, Hcc, of BoNT-HCR. The N-terminal sub-domain of BoNT-HCR, Hcn, comprises ~50% of BoNT-HCR and adopts a β-sheet jelly roll fold. While suspected in assisting cell surface recognition, no unambiguous function for the Hcn sub-domain in BoNT has been identified. To obtain insights into the potential function of the Hcn sub-domain in BoNT, the first crystal structure of a BoNT with an organic ligand bound to the Hcn sub-domain has been obtained. Here, we describe the crystal structure of BoNT/CD-HCR determined at 1.70 Å resolution with a tetraethylene glycol (PG4) moiety bound in a hydrophobic cleft between β-strands in the β-sheet jelly roll fold of the Hcn sub-domain. The PG4 moiety is completely engulfed in the cleft, making numerous hydrophilic (Y932, S959, W966, and D1042) and hydrophobic (S935, W977, L979, N1013, and I1066) contacts with the protein's side chain and backbone that may mimic in vivo interactions with the phospholipid membranes on neuronal cell surfaces. A sulfate ion was also observed bound to residues T1176, D1177, K1196, and R1243 in the Hcc sub-domain of BoNT/CD-HCR. In the crystal structure of a similar protein, BoNT/D-HCR, a sialic acid molecule was observed bound to the equivalent residues suggesting that residues T1176, D1177, K1196, and R1243 in BoNT/CD may play a role in ganglioside binding.", "Biologists have been fascinated for more than 2 centuries about how the nucleus in eukaryotes is organised. Certain of the component parts are well known, but the overall picture is blurred and often confusing. Small genome species have chromosomes in their interphase nuclei disposed in diffuse chromosome territories, without any Rabl arrangement, while in large genomes the chromosomes run string-like through the nucleus with a Rabl orientation following through the cell cycle. What happens in genomes of intermediate size is either a bit of both, depending on the tissue being studied, or still remains to be determined. The centromeres are the most dynamic and least well understood part of the nucleus, subject to rapid evolutionary change and with an epigenetic mark based on a special form of histone CENH3. Nonetheless, the centromere epigenetic mark has been inherited for millions of years by a process that is a complete mystery. Centromeres are involved with the dynamic interactions between chromosomes and other parts of the nuclear environment, such as the nuclear matrix and inner nuclear membrane, and they also engage with the spindle when the order within the nucleus changes during its division. The nucleolus organizer regions have likewise posed tantalising problems about their massive amplification of rDNA sequences, and how they are regulated and expressed. Some of these issues are now becoming clearer with advances in the science and the ongoing development of new molecular tools. These developments are discussed in this contribution, with particular reference to the centromere and the nucleolus organizer.", "Measurements of distances between telocentric chromosomes, either homologous or representing the opposite arms of a metacentric chromosome (complementary telocentrics), were made at metaphase in root tip cells of common wheat carrying two homologous pairs of complementary telocentrics of chromosome 1 B or 6 B (double ditelosomic 1 B or 6 B). The aim was to elucidate the relative locations of the telocentric chromosomes within the cell. The data obtained strongly suggest that all four telocentrics of chromosome 1 B or 6 B are spacially and simultaneously co-associated. In plants carrying two complementary (6 B (S) and 6 B (L)) and a non-related (5 B (L)) telocentric, only the complementary chromosomes were found to be somatically associated. It is thought, therefore, that the somatic association of chromosomes may involve more than two chromosomes in the same association and, since complementary telocentrics are as much associated as homologous, that the homology between centromeres (probably the only homologous region that exists between complementary telocentrics) is a very important condition for somatic association of chromosomes. The spacial arrangement of chromosomes was studied at anaphase and prophase and the polar orientation of chromosomes at prophase was found to resemble anaphase orientation. This was taken as good evidence for the maintenance of the chromosome arrangement - the Rabl orientation - and of the peripheral location of the centromere and its association with the nuclear membrane. Within this general arrangement homologous telocentric chromosomes were frequently seen to have their centromeres associated or directed towards each other. The role of the centromere in somatic association as a spindle fibre attachment and chromosome binder is discussed. It is suggested that for non-homologous chromosomes to become associated in root tips, the only requirement needed should be the homology of centromeres such as exists between complementary telocentrics, or, as a possible alternative, common repeated sequences of DNA molecules around the centromere region.", "Although interstitial lung disease accounts for the majority of deaths of patients with systemic sclerosis, treatment options for this manifestation of the disease are limited. Few high-quality, randomized, controlled trials exist for systemic sclerosis-related interstitial lung disease, and historically, studies have favored the use of cyclophosphamide. However, the benefit of cyclophosphamide for this disease is tempered by its complex adverse event profile. More recent studies have demonstrated the effectiveness of mycophenolate for systemic sclerosis-related interstitial lung disease, including Scleroderma Lung Study II. This review highlights the findings of this study, which was the first randomized controlled trial to compare cyclophosphamide with mycophenolate for the treatment of systemic sclerosis-related interstitial lung disease. The results reported in this trial suggest that there is no difference in treatment efficacy between mycophenolate and cyclophosphamide; however, mycophenolate appears to be safer and more tolerable than cyclophosphamide. In light of the ongoing advances in our understanding of the pathogenic mechanisms underlying interstitial lung disease in systemic sclerosis, this review also summarizes novel treatment approaches, presenting clinical and preclinical evidence for rituximab, tocilizumab, pirfenidone, and nintedanib, as well as hematopoietic stem cell transplantation and lung transplantation. This review further explores how reaching a consensus on appropriate study end points, as well as trial enrichment criteria, is central to improving our ability to judiciously evaluate the safety and efficacy of emerging experimental therapies for systemic sclerosis-related interstitial lung disease.", "Cyclooxgenase-2 (COX-2) knock-out mouse experiments showed that COX-2 was necessary for in vivo allergic inflammation, such as passive cutaneous anaphylaxis, passive systemic anaphylaxis, and triphasic cutaneous allergic reaction. TargetScan analysis predicted COX-2 as a target of miR-26a and miR-26b. miR-26a/-26b decreased luciferase activity associated with COX-2-3'-UTR. miR-26a/-26b exerted negative effects on the features of in vitro and in vivo allergic inflammation by targeting COX-2. ChIP assays showed the binding of HDAC3 and SNAIL, but not COX-2, to the promoter sequences of miR-26a and miR-26b. Cytokine array analysis showed that the induction of chemokines, such as MIP-2, in the mouse passive systemic anaphylaxis model occurred in a COX-2-dependent manner. ChIP assays showed the binding of HDAC3 and COX-2 to the promoter sequences of MIP-2. In vitro and in vivo allergic inflammation was accompanied by the increased expression of MIP-2. miR-26a/-26b negatively regulated the expression of MIP-2. Allergic inflammation enhanced the tumorigenic and metastatic potential of cancer cells and induced positive feedback involving cancer cells and stromal cells, such as mast cells, macrophages, and endothelial cells. miR-26a mimic and miR-26b mimic negatively regulated the positive feedback between cancer cells and stromal cells and the positive feedback among stromal cells. miR-26a/-26b negatively regulated the enhanced tumorigenic potential by allergic inflammation. COX-2 was necessary for the enhanced metastatic potential of cancer cells by allergic inflammation. Taken together, our results indicate that the miR26a/-26b-COX-2-MIP-2 loop regulates allergic inflammation and the feedback relationship between allergic inflammation and the enhanced tumorigenic and metastatic potential.", "During interphase in the budding yeast, Saccharomyces cerevisiae, centromeres are clustered near one pole of the nucleus as a rosette with the spindle pole body at its hub. Opposite to the centromeric pole is the nucleolus. Chromosome arms extend outwards from the centromeric pole and are preferentially directed towards the opposite pole. Centromere clustering is reduced by the ndc10 mutation, which affects a kinetochore protein, and by the microtubule poison nocodazole. This suggests that clustering is actively maintained or enforced by the association of centromeres with microtubules throughout interphase. Unlike the Rabl-orientation known from many higher eukaryotes, centromere clustering in yeast is not only a relic of anaphase chromosome polarization, because it can be reconstituted without the passage of cells through anaphase. Within the rosette, homologous centromeres are not arranged in a particular order that would suggest somatic pairing or genome separation.", "One of the central systems responsible for bacterial motility is the flagellum. The bacterial flagellum is a macromolecular protein complex that is more than five times the cell length. Flagella-driven motility is coordinated via a chemosensory signal transduction pathway, and so bacterial cells sense changes in the environment and migrate towards more desirable locations. The flagellum of Salmonella enterica serovar Typhimurium is composed of a bi-directional rotary motor, a universal joint and a helical propeller. The flagellar motor, which structurally resembles an artificial motor, is embedded within the cell envelop and spins at several hundred revolutions per second. In contrast to an artificial motor, the energy utilized for high-speed flagellar motor rotation is the inward-directed proton flow through a transmembrane proton channel of the stator unit of the flagellar motor. The flagellar motor realizes efficient chemotaxis while performing high-speed movement by an ingenious directional switching mechanism of the motor rotation. To build the universal joint and helical propeller structures outside the cell body, the flagellar motor contains its own protein transporter called a type III protein export apparatus. In this chapter we summarize the structure and assembly of the Salmonella flagellar motor complex.", "The efficacy, safety, and tolerability of Lu AA21004 versus placebo, using duloxetine as active reference, in patients with DSM-IV-TR diagnosed major depressive disorder (MDD) were evaluated in this 8-week, multi-site study. Patients (n=766) had a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥26 and were randomly assigned (1:1:1:1:1) to 2.5, 5 or 10 mg Lu AA21004, placebo, or 60 mg duloxetine. The 5mg and 10mg doses of Lu AA21004 were tested separately versus placebo at p≤0.025 in a pre-specified order. In the pre-defined primary efficacy analysis [mean change from baseline in MADRS total score at Week 8, full analysis set, ANCOVA, last observation carried forward (LOCF)], the differences to placebo (n=145) of -1.7 (Lu AA21004 5 mg, n=155) and -1.5 points (Lu AA21004 10 mg, n=151) were not statistically significant; nor were those for Lu AA21004 2.5 mg (-1.4 points, n=155) or duloxetine (-2.0 points, n=149). Using mixed model, repeated measures (MMRM) analyses of the primary endpoint and most secondary endpoints were supportive of likely efficacy for Lu AA21004 5 mg and 10 mg and duloxetine. Treatment-emergent adverse events led to the withdrawal of 72 patients: 8% (placebo), 12% (duloxetine), and 6%, 11% and 9% in the Lu AA21004 groups (2.5 mg, 5 mg and 10 mg, respectively). The most common adverse events were nausea, headache, dizziness, and dry mouth. No clinically relevant changes were seen in vital signs, weight, ECG, or laboratory results. In summary, none of the active treatment groups, including duloxetine, separated from placebo in the primary analysis in this 'failed' study. Findings on secondary outcome measures, using MMRM instead of LOCF, were supportive of likely efficacy for Lu AA21004 5mg and 10mg and duloxetine. Lu AA21004 (2.5, 5 and 10 mg) was well tolerated.", "In budding yeast, the telomeric DNA is flanked by a combination of two subtelomeric repetitive sequences, the X and Y' elements. We have investigated the influence of these sequences on telomeric silencing. The telomere-proximal portion of either X or Y' dampened silencing when located between the telomere and the reporter gene. These elements were named STARs, for subtelomeric anti-silencing regions. STARs can also counteract silencer-driven repression at the mating-type HML locus. When two STARs bracket a reporter gene, its expression is no longer influenced by surrounding silencing elements, although these are still active on a second reporter gene. In addition, an intervening STAR uncouples the silencing of neighboring genes. STARs thus display the hallmarks of insulators. Protection from silencing is recapitulated by multimerized oligonucleotides representing Tbf1p- and Reb1p-binding sites, as found in STARs. In contrast, sequences located more centromere proximal in X and Y' elements reinforce silencing. They can promote silencing downstream of an insulated expressed domain. Overall, our results suggest that the silencing emanating from telomeres can be propagated in a discontinuous manner via a series of subtelomeric relay elements.", "Specific chromosome domains in interphase nuclei of neurons and glia were studied by three-dimensional (3-D) reconstruction of serial optical sections from in situ hybridized human CNS tissue. Overall patterns of centromere organization, delineated with alphoid repeats, were comparable to those seen in mouse, and are clearly conserved in mammalian evolution. Cloned probes from other individual chromosome domains were used to define interphase organization more precisely. Homologous chromosomes were spatially separated in nuclei. In large neurons, probes specific for 9q12, or 1q12 showed that at least one homolog was always compartmentalized together with centromeres on the nucleolus, while the second signal either abutted the nucleolus or was on the nuclear membrane. A telomeric Yq12 sequence also localized together with perinucleolar centromeres in a completely non-Rabl orientation. In astrocytes, these three chromosome regions were on the membrane and not necessarily associated with nucleoli. Therefore there are different patterns of interphase chromosome organization in functionally distinct cell types. In contrast to the above domains, a 1p36.3 telomeric sequence embedded in a large Alu-rich and early replicating chromosome region, was always found in an interior euchromatic nuclear compartment in both neurons and glial cells. In double hybridizations with 1q12 and 1p36.3 probes, 1p arms were clearly separated in all cells, and arms projected radially into the interior nucleoplasm with non-Rabl orientations. There was no absolute or rigid position for each 1p arm with respect to each other or to the major dendrite, indicating that individual chromosome arms may be dynamically positioned even in highly differentiated cell types. We suggest that centromeric and other highly repeated non-transcribed sequence domains may act as general organizing centers for cell type specific interphase patterns that are conserved in mammalian evolution. Such centers would allow selected groups of chromosome arms to extend into (and contract from) an interior, presumably transcriptionally active, nuclear compartment.", "Amyotrophic lateral sclerosis (ALS) is an adult onset disease but with an increasingly recognized preclinical prodrome. A wide spectrum of investigative approaches has identified loss of inhibitory function at the heart of ALS. In developing an explanation for the onset of ALS, it remains a consideration that ALS has its origins in neonatal derangement of the γ-aminobutyric acid (GABA)-ergic system, with delayed conversion from excitatory to mature inhibitory GABA and impaired excitation/inhibition balance. If this is so, the resulting chronic excitotoxicity could marginalize cortical network functioning very early in life, laying the path for neurodegeneration. The possibility that adult-onset neurodegenerative conditions might have their roots in early developmental derangements is worthy of consideration, particularly in relation to current models of disease pathogenesis. Unraveling the very early molecular events will be crucial in developing a better understanding of ALS and other adult neurodegenerative disorders. Muscle Nerve, 2019." ]

[ "Silencing at native yeast telomeres, in which the subtelomeric elements are intact, is different from silencing at terminal truncations. The repression of URA3 inserted in different subtelomeric positions at several chromosome ends was investigated. Many ends exhibit very little silencing close to the telomere, while others exhibit substantial repression in limited domains. Silencing at native ends is discontinuous, with maximal repression found adjacent to the ARS consensus sequence in the subtelomeric core X element. The level of repression declines precipitously towards the centromere. Mutation of the ARS sequence or an adjacent Abf1p-binding site significantly reduces silencing. The subtelomeric Y' elements are resistant to silencing along their whole length, yet silencing can be re-established at the proximal X element. Deletion of PPR1, the transactivator of URA3, and SIR3 overexpression do not increase repression or extend spreading of silencing to the same extent as with terminally truncated ends. sir1Delta causes partial derepression at X-ACS, in contrast to the lack of effect seen at terminal truncations. orc2-1 and orc5-1 have no effect on natural silencing yet cause derepression at truncated ends. X-ACS silencing requires the proximity of the telomere and is dependent on SIR2, SIR3, SIR4 and HDF1. The structures found at native yeast telomeres appear to limit the potential of repressive chromatin.", "Human mesenchymal stem cells (hMSCs) have attracted much attention for tissue repair and wound healing because of their self-renewal capacity and multipotentiality. In order to mediate an effective therapy, substantial numbers of cells are required, which necessitates extensive sub-culturing and expansion of hMSCs. Throughout ex vivo expansion, the cells undergo telomere shortening, and critically short telomeres can trigger loss of cell viability. Telomeres are nucleoprotein structures that cap the ends of chromosomes, and serve to protect the DNA from the degradation which occurs due to the end-replication problem in all eukaryotes. As hMSCs have only a finite ability for self-renewal like most somatic cells, assaying for telomere length in hMSCs provides critical information on the replicative capacity of the cells, an important criterion in the selection of hMSCs for therapy. Telomere length is generally quantified by Southern blotting and fluorescence in situ hybridization, and more recently by PCR-based methods. Here we describe the quantification of hMSC telomere length by real-time PCR; our results demonstrate the effect of telomere shortening on the proliferation and clonogenicity of hMSCs. Thus, this assay constitutes a useful tool for the determination of relative telomere length in hMSCs.", "The recent development of x-ray free electron lasers providing coherent, femtosecond-long pulses of high brilliance and variable energy opens new areas of scientific research in a variety of disciplines such as physics, chemistry, and biology. Pump-probe experimental techniques which observe the temporal evolution of systems after optical or x-ray pulse excitation are one of the main experimental schemes currently in use for ultrafast studies. The key challenge in these experiments is to reliably achieve temporal and spatial overlap of the x-ray and optical pulses. Here we present measurements of the x-ray pulse induced transient change of optical reflectivity from a variety of materials covering the soft x-ray photon energy range from 500eV to 2000eV and outline the use of this technique to establish and characterize temporal synchronization of the optical-laser and FEL x-ray pulses.", "Asciminib (previously ABL001), which binds the myristate-binding pocket of the Bcr-Abl kinase domain, is in phase I clinical trials as monotherapy and in combination with imatinib, nilotinib and dasatinib for the treatment of patients with refractory CML or Ph+ ALL. Asciminib sensitivity was evaluated in asciminib naïve BCR-ABL1+ cell lines K562 (negligible ABCB1/ABCG2 expression), K562-Dox (ABCB1-overexpressing through doxorubicin exposure) and K562-ABCG2 (ABCG2 overexpression via transduction) with results demonstrating asciminib efflux by both ABCB1 and ABCG2 transporters. K562-Dox and K562-ABCG2 cells demonstrated increased LD50asciminib vs K562 control cells: 256 and 299 nM respectively vs 24 nM, p < 0.001. Sensitivity was completely restored with specific inhibitors cyclosporine (ABCB1) and Ko143 (ABCG2): K562-Dox LD50asciminib+cyclosporine = 13 nM, K562-ABCG2 LD50asciminib+Ko143 = 15 nM (p < 0.001). When asciminib resistance was modelled in vitro, ABCB1 and ABCG2 overexpression was integral in the development of asciminib resistance. In K562 asciminib-resistant cells, ABCG2 expression increased prior to BCR-ABL1 overexpression and remained high (up to 7.6-fold greater levels in resistant vs control cells, p < 0.001). K562-Dox asciminib-resistant cells had increased ABCB1 expression (2.1-fold vs control cells p = 0.0033). KU812 asciminib-resistant cells overexpressed ABCB1 (5.4-fold increase, p < 0.001) and ABCG2 (6-fold increase, p < 0.001) before emergence of a novel myristate-binding pocket mutation (F497L). In all three cell lines, asciminib resistance was reversible upon chemical inhibition of ABCB1, ABCG2 or both (p < 0.001). When K562 asciminib-resistant cells were treated with asciminib in combination with clinically achievable doses of either imatinib or nilotinib, reversal of the resistance phenotype was also observed (p < 0.01). Overexpression of efflux transporters will likely be an important pathway for asciminib resistance in the clinical setting. Given the lack of evidence for ABCG2-mediated transport of nilotinib or imatinib at clinically relevant concentrations, our data provide an additional rationale for using asciminib in combination with either TKI.", "In budding yeast, the telomeric DNA is flanked by a combination of two subtelomeric repetitive sequences, the X and Y' elements. We have investigated the influence of these sequences on telomeric silencing. The telomere-proximal portion of either X or Y' dampened silencing when located between the telomere and the reporter gene. These elements were named STARs, for subtelomeric anti-silencing regions. STARs can also counteract silencer-driven repression at the mating-type HML locus. When two STARs bracket a reporter gene, its expression is no longer influenced by surrounding silencing elements, although these are still active on a second reporter gene. In addition, an intervening STAR uncouples the silencing of neighboring genes. STARs thus display the hallmarks of insulators. Protection from silencing is recapitulated by multimerized oligonucleotides representing Tbf1p- and Reb1p-binding sites, as found in STARs. In contrast, sequences located more centromere proximal in X and Y' elements reinforce silencing. They can promote silencing downstream of an insulated expressed domain. Overall, our results suggest that the silencing emanating from telomeres can be propagated in a discontinuous manner via a series of subtelomeric relay elements.", "Chromatin boundary elements serve as cis-acting regulatory DNA signals required to protect genes from the effects of the neighboring heterochromatin. In the yeast genome, boundary elements act by establishing barriers for heterochromatin spreading and are sufficient to protect a reporter gene from transcriptional silencing when inserted between the silencer and the reporter gene. Here we dissected functional topography of silencers and boundary elements within circular minichromosomes in Saccharomyces cerevisiae. We found that both HML-E and HML-I silencers can efficiently repress the URA3 reporter on a multi-copy yeast minichromosome and we further showed that two distinct heterochromatin boundary elements STAR and TEF2-UASrpg are able to limit the heterochromatin spreading in circular minichromosomes. In surprising contrast to what had been observed in the yeast genome, we found that in minichromosomes the heterochromatin boundary elements inhibit silencing of the reporter gene even when just one boundary element is positioned at the distal end of the URA3 reporter or upstream of the silencer elements. Thus the STAR and TEF2-UASrpg boundary elements inhibit chromatin silencing through an antisilencing activity independently of their position or orientation in S. cerevisiae minichromosomes rather than by creating a position-specific barrier as seen in the genome. We propose that the circular DNA topology facilitates interactions between the boundary and silencing elements in the minichromosomes.", "Primary burning mouth syndrome (BMS) is defined as an \"intraoral burning or dysaesthetic sensation, recurring daily… more than 3 months, without clinically evident causative lesions\" (IHS 2013). In addition to pain, taste alterations are frequent (dysgeusia, xerostomia). Although lacking clinical signs of neuropathy, more accurate diagnostic methods have shown neuropathic involvement at various levels of the neuraxis in BMS: peripheral small fiber damage (thermal quantitative sensory testing, electrogustatometry, epithelial nerve fiber density), trigeminal system lesions in the periphery or the brainstem (brainstem reflex recordings, trigeminal neurography, evoked potentials), or signs of decreased inhibition within the central nervous system (deficient brainstem reflex habituation, positive signs in quantitative sensory testing, neurotransmitter-positron emission tomography findings indicative of deficient striatal dopamine function). Abnormalities in electrogustatometry indicate the involvement of the small Aδ taste afferents, in addition to somatosensory small fibers. According to these findings, the clinical entity of BMS can be divided into 2 main subtypes compatible with either peripheral or central neuropathic pain, which may overlap in individual patients. The central type does not respond to local treatments and associates often with psychiatric comorbidity (depression or anxiety), whereas the peripheral type responds to peripheral lidocaine blocks and topical clonazepam. Burning mouth syndrome is most prevalent in postmenopausal women, having led to a hypothesis that BMS is triggered as a consequence of nervous system damage caused by neurotoxic factors affecting especially vulnerable small fibers and basal ganglia in a setting of decrease in neuroprotective gonadal hormones and increase in stress hormone levels, typical for menopause.", "PURPOSE OF REVIEW: The article is principally intended to describe the recent evolutions in the field of research concerned with the metabolic actions of thyroid hormones and those of some of their metabolites or derivatives. Mitochondria, as a result of their functions, represent the principal objective of scientists investigating the mechanisms underlying the effects of thyroid hormones or their metabolites/derivatives.RECENT FINDINGS: Indeed, some important recent findings concern these organelles, and in particular mitochondrial uncoupling and its modulation by effectors. Traditionally, thyroxine (T4) and tri-iodo-L-thyronine (T3) were the only thyroid hormones considered to have metabolic effects, and they alone were considered for potential as agents that might counteract some important abnormalities such as dyslipidaemias and obesity. Several observations, however, led to a reconsideration of this idea. In recent years, studies dealing with the biological activities of some natural metabolites or structural analogues of thyroid hormones have revealed abilities to ameliorate some major worldwide medical problems, such as artherosclerosis, obesity and cardiovascular diseases. Among natural metabolites, 3,5-diiodothyronine (T2) has been shown to powerfully reduce adiposity and dyslipidaemia and to reverse hepatic steatosis without unfavourable side-effects usually observed when T3 or T4 is used. Examples of synthetic analogues are GC-1 (or sobetirome) and KB2115 (or eprotirome) which show ipolipidaemic and antiaterogenic capacities. Clinical trials are in progress for these last agents.SUMMARY: In view of the above-mentioned actions, some of these compounds are now undergoing clinical trials and may have important implications for clinical practice or researches in the field of both endocrinology and metabolic-related abnormalities such as diabetes and dyslipidaemias.", "Author information:(1)Medical Oncology Department, University Hospital Fundación Jimenez Diaz, Madrid, Spain. jmartin@mustbesevilla.org.(2)University Hospital General de Villalba, Madrid, Spain.(3)Instituto de Investigacion Sanitaria Fundacion Jimenez Diaz (IIS/FJD), Madrid, Spain.(4)Institute of Biomedicine of Sevilla (IBIS, HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain.(5)Pathology Department, University Hospital Son Espases, Mallorca, Spain.(6)Soft Tissue and Bone Pathology, Histopathology and Pediatric Pathology Unit, Diagnostic Pathology and Laboratory Medicine Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Nazionale Tumori, Milan, Italy.(7)Pathology Department, University Hospital Vall D'Hebron, Barcelona, Spain.(8)Centro de Investigación Biomédica en RED (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain.(9)Pathology Department, Santa Creu I Sant Pau Hospital, Barcelona, Spain.(10)Anatomic Pathology Unit, Humanitas Clinical and Research Center - IRCCS -, Rozzano (MI), Italy.(11)Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy.(12)Pathology Department, Service d'Anatomie Pathologique, Institut Bergonié, Bordeaux, France.(13)Bergonie Institute, Department of Biopathology, Bordeaux, and Bordeaux University, Talence, France.(14)Clinical Bioinformatics Area. Fundación Progreso y Salud (FPS). CDCA, Hospital Virgen del Rocio, Sevilla, Spain.(15)Bioinformatics in Rare Diseases (BiER). Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), FPS, Hospital Virgen del Rocio, Sevilla, Spain.(16)INB-ELIXIR-es FPS, Hospital Virgen del Rocío, Sevilla, Spain.(17)Department of Anatomy and Pathological Histology, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy.(18)Research and Statistics Infrastructure, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy.(19)Chemotherapy Unit, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy.(20)Cancer Medicine Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy.(21)Department of Surgery, Istituto Clinico Humanitas, Rozzano, Italy.(22)Medical Oncology Department, Santa Creu I Sant Pau Hospital, Barcelona, Spain.(23)Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.(24)Department of Medical Oncology, Centre Léon Bérard & Université Claude Bernard Lyon I, Lyon, France.(25)Department of Oncology, Medical Oncology 1 Unit, Istituto Oncologico Veneto IOV, IRCCS, Padova, Italy.(26)Hematology Department, Son Espases University Hospital, Mallorca, Spain.(27)Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain.(28)Medical Oncology Department, University Hospital Fundación Jimenez Diaz, Madrid, Spain.(29)Department of Pathology, Treviso General Hospital, Treviso, Italy.(30)University of Padua, Padova, Italy.(31)Laboratory of Oncologic Research, Istituto Ortopedico Rizzoli, Bologna, Italy.(32)Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.(#)Contributed equally", "BACKGROUND: A new 1,4-benzothiazepine derivative, JTV519, has a strong protective effect against Ca(2+) overload-induced myocardial injury. We investigated the effect of JTV519 on ischemia/reperfusion injury in isolated rat hearts.METHODS AND RESULTS: At 30 minutes of reperfusion after 30-minute global ischemia, the percent recovery of left ventricular developed pressure was improved, and the creatine phosphokinase and lactate dehydrogenase leakage was reduced in a concentration-dependent manner when JTV519 was administered in the coronary perfusate both at 5 minutes before the induction of ischemia and at the time of reperfusion. The myocardial protective effect of JTV519 was completely blocked by pretreatment of the heart with GF109203X, a specific protein kinase C (PKC) inhibitor. In contrast, the effect of JTV519 was not affected by alpha(1)-, A(1)-, and B(2)-receptor blockers that couple with PKC in the cardiomyocyte. Both immunofluorescence images and immunoblots of JTV519-treated left ventricular myocardium and isolated ventricular myocytes demonstrated that this agent induced concentration-dependent translocation of the delta-isoform but not the other isoforms of PKC to the plasma membrane.CONCLUSIONS: The mechanism of cardioprotection by JTV519 against ischemia/reperfusion injury involves isozyme-specific PKC activation through a receptor-independent mechanism. This agent may provide a novel pharmacological approach for the treatment of patients with acute coronary diseases via a subcellular mechanism mimicking ischemic preconditioning.", "PURPOSE: ALK rearrangements predict for sensitivity to ALK tyrosine kinase inhibitors (TKIs). However, responses to ALK TKIs are generally short-lived. Serial molecular analysis is an informative strategy for identifying genetic mediators of resistance. Although multiple studies support the clinical benefits of repeat tissue sampling, the clinical utility of longitudinal circulating tumor DNA analysis has not been established in ALK-positive lung cancer.METHODS: Using a 566-gene hybrid-capture next-generation sequencing (NGS) assay, we performed longitudinal analysis of plasma specimens from 22 ALK-positive patients with acquired resistance to ALK TKIs to track the evolution of resistance during treatment. To determine tissue-plasma concordance, we compared plasma findings to results of repeat biopsies.RESULTS: At progression, we detected an ALK fusion in plasma from 19 (86%) of 22 patients, and identified ALK resistance mutations in plasma specimens from 11 (50%) patients. There was 100% agreement between tissue- and plasma-detected ALK fusions. Among 16 cases where contemporaneous plasma and tissue specimens were available, we observed 100% concordance between ALK mutation calls. ALK mutations emerged and disappeared during treatment with sequential ALK TKIs, suggesting that plasma mutation profiles were dependent on the specific TKI administered. ALK G1202R, the most frequent plasma mutation detected after progression on a second-generation TKI, was consistently suppressed during treatment with lorlatinib.CONCLUSIONS: Plasma genotyping by NGS is an effective method for detecting ALK fusions and ALK mutations in patients progressing on ALK TKIs. The correlation between plasma ALK mutations and response to distinct ALK TKIs highlights the potential for plasma analysis to guide selection of ALK-directed therapies.", "Thyroid hormones [predominantly 3, 5, 3 -I- iodothyronine (T3)] regulate cholesterol and lipoprotein metabolism but cardiac effects restrict their use as hypolipidemic drugs. New molecules have been developped which target specifically the thyroid hormone receptor ss, predominant isoform in liver. The first thyroid hormone agonist, called GC1, has selective actions compared to T3. In animals, GC1 reduced serum cholesterol and serum triglycerides, probably by stimulation important steps in reverse cholesterol transport. Other selective thyromimetic, KB- 2115 and KB - 141 have similar effects. Another class of thyroid hormone analogs, the thyronamines have emerged recently but the basic biology of this new class of endogenous thyroid hormone remains to better understood. Therefore, these molecules may be a potentially treatment for obesity and reduction cholesterol, triglycerides and lipoprotein (a). To date the studies in human are preliminary. Tolerance and efficacy of these drugs are still under investigation.", "Innate or acquired resistance to chemotherapy presents an important and predictable challenge in cancer therapy. Malignant tumors consist of both neoplastic and benign cells such as stromal fibroblasts, which can influence the tumor's response to cytotoxic therapy. In a recent article in Nature Medicine, Sun et al. show that increased expression of Wnt family member wingless-type MMTV integration site family member 16B (WNT16B) by the tumor microenvironment in response to cytotoxic damage and signals through the canonical Wnt pathway to promote tumor growth and chemotherapy resistance. Such findings outline a mechanism by which cytotoxic therapies given in cyclical doses can actually augment later treatment resistance and may open the door to new areas of research and to the development of new therapeutic targets that block the DNA damage response program.", "Ras-GTPase-activating protein SH3 domain-binding proteins (G3BP) are overexpressed in various human tumors and participate in several signaling pathways involved in growth, differentiation and apoptosis. G3BP interact with RasGAP (Ras-GTPase activating protein) only in growing cells and depend on Ras activation, and participate in the Ras signal pathway. Therefore, the blockage and downregulation of G3BP may be a new strategy for cancer therapy. In this report, we demonstrate that a novel peptide GAP161 blocked the functions of G3BP and markedly suppressed HCT116 cell growth through the induction of apoptosis. The peptide bound with G3BP, which interfered with the interaction of G3BP1 with RasGAP and further suppressed Ras signaling pathways. GAP161 downregulated G3BP1 and G3BP2 proteins. Similarly, the knockdown of G3BP substantially decreased the proliferation of HCT116 cells and inhibited Ras signal pathways. Furthermore, the downregulation of G3BP could enhance cisplatin-induced apoptosis and growth inhibition of HCT116 cells. We also found that GAP161 suppressed the growth of BALB/c mice bearing colon CT26 tumors and nude mice bearing HCT116 xenografts. These results suggest that downregulation of G3BP might be useful in cancer therapy and that GAP161 is a promising new therapeutic agent for cancers.", "Platelets play a fundamental role in hemostasis. Because they do not have a nucleus, proteomics is an ideal way to approach their biochemistry. Platelet proteomics is still a young field that emerged a decade ago. Initial platelet proteomic research focused on general proteome mapping followed by the exploration of sub-cellular compartments, the membrane proteome, and signaling pathways. The initial studies were later completed with the analysis of the platelet releasate and microparticle proteome. The success of these studies led to the application of platelet proteomics to the study of several pathologies where platelets play a fundamental role. Those include platelet-related disorders, such as storage pool disease, gray platelet syndrome, and Quebec platelet disorder; diseases where unwanted platelet activation is highly relevant, such as thrombosis and cardiovascular disease; and other diseases, such as cystic fibrosis, uremia, or Alzheimer's disease. In the present review article, we revise the most relevant proteomic studies on platelet-related diseases carried out to date, paying special attention to sample preparation requirements for platelet clinical proteomic studies. This article is part of a Special Issue entitled: Integrated omics.", "The distribution of the G+C content in the mouse genome has been studied using a windowless technique. We have found that: (i). Abrupt variations of the G+C content from a GC-rich region to a GC-poor region, and vice versa, occur frequently at some sites along the sequence of the mouse genome. (ii). Long domains with relatively homogeneous G+C content (isochores) exist, which usually have sharp boundaries. Consequently, 28 isochores longer than 1 Mb have been identified in the mouse genome. A homogeneity index was used to quantify the variations of the G+C content within isochores. The precise boundaries, sizes, and G+C contents of these isochores have been determined. The windowless technique for the G+C content computation was also used to analyze the DNA sequence containing the mouse MHC region, which has a GC-poor isochore. This isochore is located at the central part of the sequence with boundaries at 468459 and 812716 bp, where the sequence is extended from the centromeric end to the telomeric end. In addition, the analysis of a segment of the rat genome shows that the rat genome also has clear isochore structures.", "Approaches to improve the prognosis of patients with high-grade glioma, which is still grim despite combined therapy and major advances in the development of new drugs, are highly important. Chemotherapeutic agents have not consistently produced favorable results in the relapse setting so far, with tumor responses reported in a minority of cases. Among them, doxorubicin has not shown significant efficacy, despite being one of the most effective substances in vitro and in animal models. Nevertheless, encapsulation of doxorubicin using polyethylene-glycol significantly improves penetration across the blood-brain barrier. Moreover, recent clinical trials in other entities have demonstrated that similar clinical responses can be achieved using approximately half of the dose of polyethylene-glycol-liposomes compared with conventional liposomes. Considering these facts, polyethylene-glycol-liposomal doxorubicin with and without tamoxifen was evaluated within two sequential Phase II trials performed at our institution. Polyethylene-glycol-liposomal doxorubicin (Caelyx) was efficient in a reasonable number of patients with equivalent results in comparison with other successful Phase II studies. This article will discuss the literature and our own results on polyethylene-glycol-liposomal doxorubicin, with a special focus on toxicity and efficacy data raised in clinical trials on patients with high-grade glioma.", "Phycobilisomes, the major light-harvesting complexes of cyanobacteria are multimolecular structures made up of chromophoric proteins called phycobiliproteins and non chromophoric linker polypeptides. We report here the isolation and nucleotide sequence of the genes, cpeA and cpeB, which in Calothrix PCC 7601 encode the alpha and beta subunits of phycoerythrin, one of the major phycobiliproteins. In Calothrix PCC 7601, modulation of the polypeptide composition of the phycobilisomes occurs in response to changes of the light wavelength, a phenomenon known as complementary chromatic adaptation. Under green illumination, cells synthesize phycoerythrin and its two specifically associated linker polypeptides (LR35 and LR36), while under red illumination none of these proteins are detected. Using specific probes, a single transcript (1450 nucleotide long) corresponding to the cpe genes was detected but only in green-light-grown cells, establishing the occurrence of transcriptional regulation for the expression of this operon in response to light wavelength changes. The size of this transcript excludes the possibility that the phycoerythrin-associated LR35 and LR36 could be cotranscribed with the cpeA and cpeB genes.", "Telomere Position Effect (TPE) is governed by strong repression signals emitted by telomeres via the Sir2/3/4 Histone Deacetylase complex. These signals are then relayed by weak proto-silencers residing in the subtelomeric core X and Y' elements. Subtelomeres also contain Sub-Telomeric Anti-silencing Regions (STARs). In this study we have prepared telomeres built of different combinations of core X, Y' and STARs and have analyzed them in strains lacking Histone-Acetyltransferase genes as well as in cdc6-1 and Δrif1 strains. We show that core X and Y' dramatically reduce both positive and negative variations in TPE, that are caused by these mutations. We also show that the deletion of Histone-Acetyltransferase genes reduce the silencing activity of an ACS proto-silencer, but also reduce the anti-silencing activity of a STAR. We postulate that core X and Y' act as epigenetic \"cushioning\" cis-elements.", "Several reports from mammals indicate that an increase in the mutation rate in late-replicating regions may, in part, be responsible for the observed genomic heterogeneity in neutral substitution rates and levels of diversity, although the mechanisms for this remain poorly understood. Recent evidence also suggests that late replication is associated with high mutability in yeast. This then raises the question as to whether a similar effect is operating across all eukaryotes. Limited evidence from one chromosome arm in Drosophila melanogaster suggests the opposite pattern, with regions overlapping early-firing origins showing increased levels of diversity and divergence. Given the availability of genome-wide replication timing profiles for D. melanogaster, we now return to this issue. Consistent with what is seen in other taxa, we find that divergence at synonymous sites in exon cores, as well as divergence at putatively unconstrained intronic sites, is elevated in late-replicating regions. Analysis of genes with low codon usage bias suggests a ∼30% difference in mutation rate between the earliest and the latest replicating sequence. Intronic sequence suggests a more modest difference. We additionally show that an increase in diversity in late-replicating sequences is not owing to replication timing covarying with the local recombination rate. If anything, the effects of recombination mask the impact of replication timing. We conclude that, contrary to prior reports and consistent with what is seen in mammals and yeast, there is indeed a relationship between rates of nucleotide divergence and diversity and replication timing that is consistent with an increase in the mutation rate during late S-phase in D. melanogaster. It is therefore plausible that such an effect might be common among eukaryotes. The result may have implications for the inference of positive selection." ]

[ "Mast cells are involved in many disorders where the triggering mechanism that leads to degranulation and/or cytokine secretion has not been defined. Several chronic inflammatory diseases are associated with increased mast cell numbers and upregulation of the TNF receptor family member CD30, but the role of elevated CD30 expression is poorly understood. Here we report what we believe to be a novel way to activate mast cells with CD30 that leads to degranulation-independent secretion of chemokines. CD30 induced a de novo synthesis and secretion of the chemokines IL-8, macrophage inflammatory protein-1alpha (MIP-1alpha), and MIP-1beta, a process involving the MAPK/ERK pathway. Mast cells were found to be the predominant CD30 ligand-positive (CD30L-positive) cell in the chronic inflammatory skin diseases psoriasis and atopic dermatitis, and both CD30 and CD30L expression were upregulated in lesional skin in these conditions. Furthermore, the number of IL-8-positive mast cells was elevated both in psoriatic and atopic dermatitis lesional skin as well as in ex vivo CD30-treated healthy skin organ cultures. In summary, characterization of CD30 activation of mast cells has uncovered an IgE-independent pathway that is of importance in understanding the entirety of the role of mast cells in diseases associated with mast cells and CD30 expression. These diseases include Hodgkin lymphoma, atopic dermatitis, and psoriasis.", "Paired helical filaments (PHFs) are the structural constituents of neurofibrillary tangles in Alzheimer's disease and are composed of hyperphosphorylated forms of the microtubule-associated protein tau (PHF-tau). Pathological hyperphosphorylation of tau is believed to be an important contributor to the destabilisation of microtubules and their subsequent disappearance from tangle-bearing neurons in Alzheimer's disease, making elucidation of the mechanisms that regulate tau phosphorylation an important research goal. Thus, it is essential to identify, preferably by direct sequencing, all of the sites in PHF-tau that are phosphorylated, a task that is incomplete because of the difficulty to date of purifying insoluble PHF-tau to homogeneity and in sufficient quantities for structural analysis. Here we describe the solubilisation of PHF-tau followed by its purification by Mono Q chromatography and reversed-phase HPLC. Phosphopeptides from proteolytically digested PHF-tau were sequenced by nanoelectrospray mass spectrometry. We identified 22 phosphorylation sites in PHF-tau, including five sites not previously identified. The combination of our new data with previous reports shows that PHF-tau can be phosphorylated on at least 25 different sites.", "Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer.", "Motor neurone disease, or amyotrophic lateral sclerosis, is a serious progressive neurological disorder, characterized by loss of UMN and LMN. Pathological features include characteristic intracytoplasmic MN inclusion bodies and appearances on ubiquitin staining. The aetiopathogenesis of the disease remains unknown and there is, to date, no effective treatment. Several abnormalities have been demonstrated in neurotransmitter, neuropeptide and gene expression studies. Abnormalities in glutamate metabolism have led to the excitotoxin hypothesis of MN destruction. Other theories include deficits in MN trophic factors, trans-synaptic degeneration, impaired ability to detoxify putative toxic agents and impaired DNA/RNA metabolism. The existence of familial forms, some of which show linkage to markers in chromosome 21, allows a genetic approach to the mechanisms of disease. Recent studies suggest that mutations in the Cu/Zn SOD gene may be important in some of the familial forms. The atypical forms seen in the Western Pacific have stimulated a search for environmental agents. Agents undergoing therapeutic trials at present include CNTF, IGF1 glutamate antagonists, branched-chain amino acids and TRH analogue.", "BACKGROUND: Warfarin is a highly efficacious oral anticoagulant, but its use is limited by a well-founded fear of bleeding. Drug and food interactions are frequently cited as causes of adverse events with warfarin. We provide an updated systematic overview of the quality, clinical effect, and importance of these reported interactions.DATA SOURCES: MEDLINE, TOXLINE, IPA, and EMBASE databases from October 1993 to March 2004. Database searches combined the keyword warfarin with drug interactions, herbal medicines, Chinese herbal drugs, and food-drug interactions.STUDY SELECTION: Eligible articles contained original reports of warfarin drug or food interactions in human subjects. Non-English articles were included if sufficient information could be abstracted.DATA EXTRACTION: Reports were rated independently by 2 investigators for interaction direction, clinical severity, and quality of evidence. Quality of evidence was based on previously validated causation criteria and study design.DATA SYNTHESIS: Of 642 citations retrieved, 181 eligible articles contained original reports on 120 drugs or foods. Inter-rater agreement was excellent, with weighted kappa values of 0.84 to 1.00. Of all reports, 72% described a potentiation of warfarin's effect and 84% were of poor quality, 86% of which were single case reports. The 31 incidents of clinically significant bleeding were all single case reports. Newly reported interactions included celecoxib, rofecoxib, and herbal substances, such as green tea and danshen.CONCLUSIONS: The number of drugs reported to interact with warfarin continues to expand. While most reports are of poor quality and present potentially misleading conclusions, the consistency of reports of interactions with azole antibiotics, macrolides, quinolones, nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, selective serotonin reuptake inhibitors, omeprazole, lipid-lowering agents, amiodarone, and fluorouracil, suggests that coadministration with warfarin should be avoided or closely monitored. More systematic study of warfarin drug interactions in patients is urgently needed.", "BACKGROUND: Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy.METHODS: We conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks.RESULTS: In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels.CONCLUSIONS: In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo. (Funded by Pfizer; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain ClinicalTrials.gov numbers, NCT01465763 , NCT01458951 , and NCT01458574 , respectively.).", "Adalimumab is a human monoclonal antibody which targets tumor necrosis factor (TNF)-alpha. It is produced by recombinant DNA technology, using a mammalian cell expression system and is widely-known to treat a number of immune-mediated conditions, including psoriasis. There has been a growing concern regarding the possible association between TNF-alpha inhibitors and malignancy. In this case report, we describe the case of a 20-year-old woman, known to have been suffering from chronic plaque psoriasis for 12 years, and who developed Hodgkin's lymphoma within five weeks of beginning adalimumab treatment." ]

[ "BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease leading to recurrent ischemic stroke and vascular dementia. Numerous mutations in the 23 exons of the NOTCH3 gene have been reported to cause CADASIL in Caucasian populations, but the full spectrum of genetic changes leading to this disease is yet to be known and, especially, very few reports are available on CADASIL in Asian populations.METHODS AND RESULTS: We genotyped members of a 5-generational Han Chinese family with CADASIL patients and identified an R133C mutation in the NOTCH3 gene. Clinical analysis demonstrated that the penetrance of the mutation was not complete. Five of the mutation carriers, not exposed to the known vascular risk factors, did not show any clinical feature of CADASIL, suggesting the importance of environmental factors to the development of this disease.CONCLUSIONS: Members of a 5-generational Han Chinese family with CADASIL patients had an R133C mutation in the NOTCH3 gene but only individuals exposed to known vascular risk factors developed CADASIL.", "Several computational methods exist for the identification of transmembrane beta barrel proteins (TMBs) from sequence. Some of these methods also provide the transmembrane (TM) boundaries of the putative TMBs. The aim of this study is to (1) derive the propensities of the TM residues to be exposed to the lipid bilayer and (2) to predict the exposure status (i.e. exposed to the bilayer or hidden in protein structure) of TMB residues. Three novel propensity scales namely, BTMC, BTMI and HTMI were derived for the TMB residues at the hydrophobic core region of the outer membrane (OM), the lipid-water interface regions of the OM, and for the helical membrane proteins (HMPs) residues at the lipid-water interface regions of the inner membrane (IM), respectively. Separate propensity scales were derived for monomeric and functionally oligomeric TMBs. The derived propensities reflect differing physico-chemical properties of the respective membrane bilayer regions and were employed in a computational method for the prediction of the exposure status of TMB residues. Based on the these propensities, the conservation indices and the frequency profile of the residues, the transmembrane residues were classified into buried/exposed with an accuracy of 77.91% and 80.42% for the residues at the membrane core and the interface regions, respectively. The correlation of the derived scales with different physico-chemical properties obtained from the AAIndex database are also discussed. Knowledge about the residue propensities and burial status will be useful in annotating putative TMBs with unknown structure.", "INTRODUCTION: Allan-Herndon-Dudley syndrome is an X-linked condition caused by mutations of the monocarboxylate transporter 8 gene. This syndrome is characterized by axial hypotonia, severe mental retardation, dysarthria, athetoid movements, spastic paraplegia, and a typical thyroid hormone profile. In most of the cases reported so far, brain magnetic resonance imaging showed delayed myelination of the central white matter and this finding greatly affects the diagnosis of the syndrome.CASE REPORT: We present a new case studied with magnetic resonance imaging and spectroscopy and we reviewed all the articles published between 2004 and 2012 containing information on brain neuroimaging in this syndrome. An Italian boy, showing a classical phenotype of the syndrome, was diagnosed at 17months of age. Genetic analysis revealed a new frameshift mutation of the monocarboxylate transporter 8 gene. His brain magnetic resonance imaging and spectroscopy, performed at the age of 14months, were normal.DISCUSSION: Among the 33 cases reported in the literature, 3 cases had normal neuroimaging and in 7 of 14 cases, having a longitudinal follow-up, the initial finding of delayed myelination gradually improved. Our case and the review of the pertinent literature suggest that Allan-Herndon-Dudley syndrome should be suspected in males with the typical neurological and thyroid profile, even in cases with normal brain myelination.", "Denosumab (Prolia) is a fully human monoclonal antibody directed against receptor activator of nuclear factor-κB ligand (RANKL), which interferes with the formation, activation, and survival of osteoclasts. It was approved by the Food and Drug Administration in June 2010 as a new treatment for postmenopausal osteoporosis in women who are at high risk for fracture. Given its mechanism of action, it is an antiresorptive therapy that is administered as a 60-mg subcutaneous injection every 6 months. It is the first biologic antiresorptive therapy for osteoporosis, and the first osteoporosis therapy to show efficacy and safety in patients with renal impairment.", "Since the introduction of bisphosphonates to treat diseases that affect remodelling of bone, increasing numbers of patients with bisphosphonate-related osteonecrosis of the jaws have been reported; the number is currently unknown. Recently anti-RANKL agents (receptor activator of nuclear factor-kappaB ligand) such as denosumab (Prolia, Amgen Inc., California, USA) that have a similar mode of action to bisphosphonates have been introduced to treat such diseases. We report a case of osteonecrosis that was induced by anti-RANKL therapy. To our knowledge this is the first case to have been induced by these agents.", "Twist1 is a transcription factor driving epithelial-mesenchymal transition, invasion and metastasis of breast cancer cells. Mice with germ-line Twist1 knockout are embryonic lethal, while adult mice with inducible Twist1 knockout have no obvious health problems, suggesting that Twist1 is a viable therapeutic target for the inhibition of invasion and metastasis of breast cancer in adult patients. In this study, we expressed a luciferase protein or a Twist1-luciferase fusion protein in HeLa cells as part of a high throughput system to screen 1280 compounds in the Library of Pharmacologically Active Compounds (LOPAC) from Sigma-Aldrich for their effects on Twist1 protein expression. One of the most interesting compounds identified is tamoxifen, a selective estrogen receptor (ER) modulator used to treat ER-positive breast cancer. Tamoxifen treatment significantly accelerated Twist1 degradation in multiple cell lines including HEK293 human kidney cells, 4T1 and 168FARN mouse mammary tumor cells with either ectopically or endogenously expressed Twist1. Tamoxifen-induced Twist1 degradation could be blocked by the MG132 proteasome inhibitor, suggesting that tamoxifen induces Twist1 degradation through the ubiquitination-proteasome pathway. However, tamoxifen-induced Twist1 degradation was independent of Twist1 mRNA expression, estrogen signaling and MAPK-mediated Twist1 phosphorylation in these cells. Importantly, tamoxifen also significantly inhibited invasive behavior in Matrigel and lung metastasis in SCID-bg mice of ER-negative 4T1 mammary tumor cells, which depend on endogenous Twist1 to invade and metastasize. These results indicate that tamoxifen can significantly accelerate Twist1 degradation to suppress cancer cell invasion and metastasis, suggesting that tamoxifen can be used not only to treat ER-positive breast cancers but also to reduce Twist1-mediated invasion and metastasis in ER-negative breast cancers.", "A proteostasis view of neurodegeneration (ND) identifies protein aggregation as a leading causative reason for damage seen at the cellular and organ levels. While investigative therapies that aim at dissolving aggregates have failed, and the promises of silencing expression of ND associated pathogenic proteins or the deployment of engineered induced pluripotent stem cells (iPSCs) are still in the horizon, emerging literature suggests degrading aggregates through autophagy-related mechanisms hold the current potential for a possible cure. Macroautophagy (hereafter autophagy) is an intracellular degradative pathway where superfluous or unwanted cellular cargoes (such as peroxisomes, mitochondria, ribosomes, intracellular bacteria and misfolded protein aggregates) are wrapped in double membrane vesicles called autophagosomes that eventually fuses with lysosomes for their degradation. The selective branch of autophagy that deals with identification, capture and degradation of protein aggregates is called aggrephagy. Here, we cover the workings of aggrephagy detailing its selectivity towards aggregates. The diverse cellular adaptors that bridge the aggregates with the core autophagy machinery in terms of autophagosome formation are discussed. In ND, essential protein quality control mechanisms fail as the constituent components also find themselves trapped in the aggregates. Thus, although cellular aggrephagy has the potential to be upregulated, its dysfunction further aggravates the pathogenesis. This phenomenonwhen combined with the fact that neurons can neither dilute out the aggregates by cell division nor the dead neurons can be replaced due to low neurogenesis, makes a compelling case for aggrephagy pathway as a potential therapeutic option.", "Stress granules are non-membranous structures that transiently form in the cytoplasm during cellular stress, where they promote translational repression of non-essential RNAs and modulate cell signaling by sequestering key signal transduction proteins. These and other functions of stress granules facilitate an adaptive cellular response to environmental adversity. A key component of stress granules is the prion-related RNA-binding protein, T cell intracellular antigen-1 (TIA-1). Here, we report that recombinant TIA-1 undergoes rapid multimerization and phase separation in the presence of divalent zinc, which can be reversed by the zinc chelator, TPEN. Similarly, the formation and maintenance of TIA-1-positive stress granules in arsenite-treated cells are inhibited by TPEN. In addition, Zn2+ is released in cells treated with arsenite, before stress granule formation. These findings suggest that Zn2+ is a physiological ligand of TIA-1, acting as a stress-inducible second messenger to promote multimerization of TIA-1 and subsequent localization into stress granules.", "The methylation patterns of the MET1 gene in organs of Arabidopsis thaliana were studied by Southern blot hybridization of DNA samples hydrolyzed with differentially methylation-sensitive restriction endonucleases. A highly methylated on internal cytosine residue CCGG site was found 1.5 kb upstream of the gene, whereas CCGG sites located in more proximal parts of the 5'-flanking region and the gene itself are essentially unmethylated. This methylation pattern was observed in different organs of plants belonging to two different ecotypes as well as in different transgenic plant lines. The methylation level ofa CCGG site in exon 3 (2.1 kb from the gene's 5'-end) occurred to be variable between different transgenic plant lines and two ecotypes studied. Transcription levels of the MET1 gene vary slightly in organs of wild-type plants without any obvious correlation with its methylation. The transgenic antisense MET1 constructs expressed in plant genome do affect both MET1 methylation and its transcription but again without any obvious correlation. The comparative investigation of transcription levels of different genes of cytosine DNA methyltransferase family MET (MET1, MET2a, MET2b, MET3) and their methylation patterns shows that there may exist some mechanisms defending the most actively transcribed gene MET1 of this family from methylation mediated silencing. In contrast to DRM2 gene we could not find any adenine methylated GATC sites in the MET1 gene.", "AIM: To evaluate the efficacy and safety of Denosumab (Prolia), a first-line osteoporosis (OP) medication that is a fully human monoclonal antibody to the receptor activator of nuclear factor xB ligand (RANKL), within an open-label observational study.SUBJECTS AND METHODS: Patients aged 50 years or older with postmenopausal OP, who were treated with Prolia in clinical practice, were examined. The concentrations of the bone resorption (BR) marker of C-terminal telopeptide and other laboratory indicators (total serum calcium, total alkaline phosphatase, and creatinine) were measured following 3 months. Adverse drug reactions were recorded.RESULTS: Three months after initiation of the investigation, there was a significant decrease in the BR marker C-terminal telopeptide (by 89%; p<0.0001). There were rare adverse reactions: hypocalcemia in 3 (5.9%) patients, arthralgias in 2 (3.9%), and eczema in 1 (1.9%). There were neither serious adverse events nor study withdrawal cases.CONCLUSION: The preliminary results of the open-label study of Prolia in postmenopausal OP suggest that the significantly lower BR activity determines the efficacy of this drug and its high safety.", "Glutamate is the principal excitatory neurotransmitter in the nervous system. Inactivation of synaptic glutamate is handled by the glutamate transporter GLT1 (also known as EAAT2; refs 1, 2), the physiologically dominant astroglial protein. In spite of its critical importance in normal and abnormal synaptic activity, no practical pharmaceutical can positively modulate this protein. Animal studies show that the protein is important for normal excitatory synaptic transmission, while its dysfunction is implicated in acute and chronic neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, brain tumours and epilepsy. Using a blinded screen of 1,040 FDA-approved drugs and nutritionals, we discovered that many beta-lactam antibiotics are potent stimulators of GLT1 expression. Furthermore, this action appears to be mediated through increased transcription of the GLT1 gene. beta-Lactams and various semi-synthetic derivatives are potent antibiotics that act to inhibit bacterial synthetic pathways. When delivered to animals, the beta-lactam ceftriaxone increased both brain expression of GLT1 and its biochemical and functional activity. Glutamate transporters are important in preventing glutamate neurotoxicity. Ceftriaxone was neuroprotective in vitro when used in models of ischaemic injury and motor neuron degeneration, both based in part on glutamate toxicity. When used in an animal model of the fatal disease ALS, the drug delayed loss of neurons and muscle strength, and increased mouse survival. Thus these studies provide a class of potential neurotherapeutics that act to modulate the expression of glutamate neurotransmitter transporters via gene activation.", "INTRODUCTION: Septo-optic dysplasia (De Morsier syndrome) is defined as the association between optic nerve hypoplasia, midline central nervous system malformations and pituitary dysfunction.CASE REPORT: Third child born to nonconsanguineous parents, female, adequate pre-natal medical care, cesarean term delivery due to breech presentation, Apgar score 3 at the first minute and 8 at 5 minutes, symptomatic hypoglycemia at 18 hours. Neurological follow-up identified a delay in acquisition of motor and language developmental milestones. Epileptic generalized seizures began at 12 months and were controlled with phenobarbital. EEG was normal. MRI revealed agenesis of the pituitary stalk, hypoplasia of the optic chiasm and periventricular nodular heterotopia. Ophthalmologic evaluation showed bilateral optic disk hypoplasia. Endocrine function laboratory tests revealed primary hypothyroidism and hyperprolactinemia.CONCLUSION: The relevance of this case report relies on its uniqueness, since periventricular heterotopia had not been described in association with septo-optic dysplasia until 2006." ]

[ "Deficiency of propionyl CoA carboxylase (PCC), a dodecamer of alpha and beta subunits, causes inherited propionic acidemia. We have studied, at the molecular level, PCC in 54 patients from 48 families comprised of 96 independent alleles. These patients of various ethnic backgrounds came from research centers and hospitals in Germany, Austria and Switzerland. The thorough clinical characterization of these patients was described in the accompanying paper (Grünert et al. 2012). In all 54 patients, many of whom originated from consanguineous families, the entire PCCB gene was examined by genomic DNA sequencing and in 39 individuals the PCCA gene was also studied. In three patients we found mutations in both PCC genes. In addition, in many patients RT-PCR analysis of lymphoblast RNA, lymphoblast enzyme assays, and expression of new mutations in E.coli were carried out. Eight new and eight previously detected mutations were identified in the PCCA gene while 15 new and 13 previously detected mutations were found in the PCCB gene. One missense mutation, p.V288I in the PCCB gene, when expressed in E.coli, yielded 134% of control activity and was consequently classified as a polymorphism in the coding region. Numerous new intronic polymorphisms in both PCC genes were identified. This study adds a considerable amount of new molecular data to the studies of this disease.", "PURPOSE: Fibromyalgia is a syndrome of unknown origin with a high prevalence. Multimodal approaches seem to be the treatment of choice in fibromyalgia. A multidisciplinary program was developed and implemented for patients with fibromyalgia in the primary care setting. The program included education (seven sessions) and physical therapy (25 sessions).METHOD: Patients were referred to the program by their general practitioner or by a medical specialist. A prospective non-controlled treatment study was performed, patients were evaluated before, after and three months after the program (single group time series design). The following measurements were performed: The Fibromyalgia Impact Questionnaire, RAND 36, the Pain Coping and Cognition List, the Tampa scale for kinesiophobia, two physical tests and a qualitative evaluation. Data of 65 patients with fibromyalgia were analysed, of whom 97% were female. The mean age was 44 and the mean duration of pain was nine years.RESULTS: Data of 65 patients with fibromyalgia were analysed, patients significantly improved on the domains feeling good, pain, fatigue, stiffness, quality of life, catastrophizing and on the physical tests.CONCLUSION: The multidisciplinary program fibromyalgia implemented in primary care seems feasible and the results are promising.", "PURPOSE: The properties of three oral anticoagulant-specific reversal agents are reviewed, and guidance is presented to assist pharmacists in planning for the agents' introduction to the market.SUMMARY: Idarucizumab, which received Food and Drug Administration approval in October 2015, is a humanized monoclonal antibody fragment that immediately neutralizes the anticoagulant effect of dabigatran, as evidenced by reduced unbound dabigatran concentrations and normalized coagulation tests. Preliminary Phase III trial results demonstrated a median maximum reversal of 100%, a median time to bleeding cessation of 11.4 hours, and normal intraoperative hemostasis in 92% of patients requiring anticoagulation reversal before an urgent procedure. Andexanet alfa is a factor Xa (FXa) decoy that binds to direct and indirect FXa inhibitors. In Phase III trials in healthy volunteers, andexanet alfa reduced anti-FXa activity by more than 90%, reduced the concentration of unbound direct FXa inhibitor, and inhibited thrombin generation. Ciraparantag is a reversal agent under development for reversal of anticoagulation with direct and indirect FXa inhibitors and certain factor IIa inhibitors; it exerts its effect through hydrogen bonding. Concerns for thromboembolic events directly related to administration of idarucizumab, andexanet alfa, or ciraparantag have not arisen. Pharmacists need to begin preparing for the introduction of these specific reversal agents through protocol development and provider education; in addition, pharmacy departments need to plan for procurement and storage. The specific reversal agents should be incorporated into antithrombotic stewardship or other clinical pharmacy programs for surveillance.CONCLUSION: As agents that provide rapid reversal of direct oral anticoagulant activity become available, advance planning will help hospitals to optimize their use.", "Thyroid cancer in children and adolescents has to be considered as the most severe health consequence of a nuclear reactor emergency with release of radioiodine into the atmosphere. High doses of potassium iodide are effective to block radioiodine thyroid uptake and to prevent development of thyroid cancer years later. However, there are controversies concerning thyroid cancer risk induced by radioiodine exposure in adults. Further, the interaction of nutritional supply of potassium iodide and radioiodine uptake as well as the interaction of radioiodine with certain drugs has not been addressed properly in existing guidelines and recommendations. How to proceed in case of repeated release of radioiodine is an open, very important question which came up again recently during the Fukushima accident. Lastly, the side effects of iodine thyroid blocking and alternatives of this procedure have not been addressed systematically up to now in guidelines and recommendations. These questions can be answered as follows: in adults, the risk to develop thyroid cancer is negligible. In countries, where nutritional iodine deficiency is still an issue, the risk to develop thyroid cancer after a nuclear reactor emergency has to be considered higher because the thyroid takes up more radioiodine as in the replete condition. Similarly, in patients suffering from thyrotoxicosis, hypothyroidism or endemic goitre not being adequately treated radioiodine uptake is higher than in healthy people. In case of repeated or continued radioiodine release, more than one dose of potassium iodide may be necessary and be taken up to 1 week. Repeated iodine thyroid blocking obviously is not harmful. Side effects of iodine thyroid blocking should not be overestimated; there is little evidence for adverse effects in adults. Newborns and babies, however, may be more sensitive to side effects. In the rare case of iodine hypersensitivity, potassium perchlorate may be applied as an alternative to iodine for thyroid blocking.", "Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a well-characterized X-linked inherited disorder in humans but has not been reported in horses. We describe a persistent hemolytic anemia and hyperbilirubinemia due to a severe G6PD deficiency in an American Saddlebred colt. Other abnormalities in the colt's erythrocytes as compared with those of healthy horses (n = 22-35) included increased activities of hexokinase and pyruvate kinase, decreased concentrations of reduced glutathione and reduced nicotinamide adenine dinucleotide phosphate (NADP), and increased concentration of oxidized NADP. Morphologic abnormalities included eccentrocytosis, pyknocytosis, anisocytosis, macrocytosis, and increased number of Howell-Jolly bodies. Scanning and transmission electron microscopic examinations revealed that eccentrocytes had contracted to spherical regions and thin collapsed regions. Eccentrocytes were more electron dense than were normal erythrocytes when examined by transmission electron microscopy. When exposed to acetylphenylhydrazine, erythrocytes from the G6PD-deficient colt produced more and smaller Heinz bodies than did erythrocytes from normal horses. Abnormalities in the colt's dam included presence of eccentrocytes and pyknocytes; her average erythrocyte G6PD activity was slightly below the range of reference values.", "Histone H3.3 mutations are a hallmark of pediatric gliomas, but their core oncogenic mechanisms are not well-defined. To identify major effectors, we used CRISPR-Cas9 to introduce H3.3K27M and G34R mutations into previously H3.3-wildtype brain cells, while in parallel reverting the mutations in glioma cells back to wildtype. ChIP-seq analysis broadly linked K27M to altered H3K27me3 activity including within super-enhancers, which exhibited perturbed transcriptional function. This was largely independent of H3.3 DNA binding. The K27M and G34R mutations induced several of the same pathways suggesting key shared oncogenic mechanisms including activation of neurogenesis and NOTCH pathway genes. H3.3 mutant gliomas are also particularly sensitive to NOTCH pathway gene knockdown and drug inhibition, reducing their viability in culture. Reciprocal editing of cells generally produced reciprocal effects on tumorgenicity in xenograft assays. Overall, our findings define common and distinct K27M and G34R oncogenic mechanisms, including potentially targetable pathways.", "Deubiquitinating enzymes (DUBs) remove ubiquitin (Ub) from Ub-conjugated substrates to regulate the functional outcome of ubiquitylation. Here we report the discovery of a new family of DUBs, which we have named MINDY (motif interacting with Ub-containing novel DUB family). Found in all eukaryotes, MINDY-family DUBs are highly selective at cleaving K48-linked polyUb, a signal that targets proteins for degradation. We identify the catalytic activity to be encoded within a previously unannotated domain, the crystal structure of which reveals a distinct protein fold with no homology to any of the known DUBs. The crystal structure of MINDY-1 (also known as FAM63A) in complex with propargylated Ub reveals conformational changes that realign the active site for catalysis. MINDY-1 prefers cleaving long polyUb chains and works by trimming chains from the distal end. Collectively, our results reveal a new family of DUBs that may have specialized roles in regulating proteostasis." ]

[ "To evaluate the efficacy of dexamethasone for treatment of primary supratentorial intracerebral hemorrhage, we studied 93 patients 40 to 80 years old, using a double-blind randomized block design. After the subjects were stratified according to their level of consciousness (Glasgow Coma Scale), those with objectively documented primary supratentorial intracerebral hemorrhage were randomly assigned to either dexamethasone or placebo. For ethical reasons, three interim analyses were planned, to permit early termination of the trial if one study group did better than the other. During the third interim analysis, the death rate at the 21st day was identical in the two groups (dexamethasone vs. placebo, 21 of 46 vs. 21 of 47; chi-square = 0.01, P = 0.93). In contrast, the rate of complications (mostly infections and complications of diabetes) was much higher in the dexamethasone group (chi-square = 10.89, P less than 0.001), leading to early termination of the study. In the light of the absence of a demonstrable beneficial effect and the presence of a significant harmful effect, current practices of using dexamethasone for treatment of primary supratentorial hemorrhage should be reconsidered.", "BACKGROUND: On encountering a susceptible target, natural killer (NK) cells mediate cytotoxicity through highly regulated steps of directed degranulation. Cytotoxic granules converge at the microtubule organizing center and are polarized toward the immunological synapse (IS), followed by granule exocytosis. NK cell retargeting by chimeric antigen receptors (CARs) or mAbs represents a promising strategy for overcoming tumor cell resistance. However, little is known about the lytic granule dynamics of such retargeted NK cells toward NK-cell-resistant tumors.METHODS: Here, we used spinning disk confocal microscopy for live-cell imaging to analyze granule-mediated NK cell cytotoxicity in ErbB2-targeted CAR-expressing NK-92 cells (NK-92/5.28.z) and high-affinity FcR transgenic NK-92 cells plus Herceptin toward ErbB2-positive breast cancer cells (MDA-MB-453), which are resistant to parental NK-92.RESULTS: Unmodified NK-92 cells cocultured with resistant cancer cells showed stable conjugate formation and granule clustering, but failed to polarize granules to the IS. In contrast, retargeting by CAR or FcR+Herceptin toward the MDA-MB-453 cells enabled granule polarization to the IS, resulting in highly effective cytotoxicity. We found that in NK-92 the phosphoinositide 3-kinase pathway was activated after contact with resistant MDA-MB-453, while phospholipase C-γ (PLCγ) and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) were not activated. In contrast, retargeting by CAR or antibody-dependent cell-mediated cytotoxicity (ADCC) provided the missing PLCγ and MEK/ERK signals.CONCLUSIONS: These observations suggest that NK cells can create conjugates with resistant cancer cells and respond by granule clustering, but the activation signals are insufficient to induce granule polarization and consequent release of lytic enzymes. Retargeting by CAR and/or the FcR/mAb (ADCC) axis provide the necessary signals, leading to granule polarization and thereby overcoming tumor cell resistance.", "INTRODUCTION: Morel-Lavallée lesion (MLL) is a posttraumatic closed degloving soft tissue injury, in which the subcutaneous tissues are separated from the underlying fascia. Surgical treatment is recommended if conservative management fails. The conventional surgical treatment for the lesion is surgical drainage and debridement.PRESENTATION OF CASE: A 51-year-old male patient presented with swelling of the right thigh incurred during a traffic accident. The lesion was diagnosed with MLL. The MLL was successfully treated with a minimally invasive arthroscopic treatment after failure of conservative treatment. The arthroscopic treatment was chosen because of the patient's comorbidity that posed a risk of surgical wound complications. In addition, negative pressure wound therapy (NPWT) was performed postoperatively to ensure healing and to prevent recurrence of the lesion. The patient was successfully treated and the healing of the lesion was also confirmed with MRI.DISCUSSION: In a patient with a risk of wound complications due to a comorbidity, this minimally invasive arthroscopic treatment is useful. In addition, NPWT was used to ensure healing and to prevent recurrence. Although the use of NPWT combined with endoscopic treatment has not been reported, additional NPWT reported in this case may be helpful to ensure healing.CONCLUSION: In case of MLL with a risk of surgical complications, the arthroscopic treatment is a reasonable method and achieves the goal of an open surgical debridement without increased morbidity.", "BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a chronic central nervous (CNS) system infection caused by measles virus. Because changing immunization practices affect the epidemiology of measles and consequently SSPE, we examined the epidemiological data of our SSPE registry.MATERIALS AND METHODS: Age of onset, age at onset of measles, duration of Latent period and immunization status were examined in cases recorded at the SSPE Registry Center in Turkey between 1975 and 1999.RESULTS: Age of onset diminished from 13 years before 1994 to 7.6 years after 1995; age at onset of measles declined from 29 months to 20 months and the Latent interval from 9.9 years to 5.9 years. Age at onset of measles and immunization status did not directly affect the duration of the Latent period.CONCLUSION: Although its incidence has decreased in Turkey, SSPE has been seen at younger ages in recent years. This change cannot be attributed solely to younger age at onset of measles. Factors affecting the duration of the Latent period should be investigated further.", "BACKGROUND AND PURPOSE: Erb-B1 (epidermal growth factor receptor, EGFR) and Erb-B2 (HER-2) are two of the best-characterized members in the EGFR pathway. In many tumor types, overexpression of these proteins is associated with enhanced malignant potential. The aim of this study was to determine the prognostic impact of EGFR and HER-2 protein expression on colorectal cancer.METHOD: Immunohistochemistry was carried out in paraffin-embedded specimens of 115 colorectal carcinomas for the assessment of EGFR and HER-2 expression. Immunostaining for EGFR was graded negative, weak or strong according to extension and staining intensity. The results were correlated with traditional clinicopathologic parameters and patients' outcome.RESULTS: The mean survival time was 64 (range 9-78) months in the EGFR-negative group, 166 (range 2-293) months in the group with a low EGFR expression, and 51 (range 4-71) months in the group with a high EGFR expression. The median survival time was 31 (range 2-114) months in the HER-2 negative group, and 30 (range 4-293) months in the HER-2 positive group. None of the clinicopathologic parameters or patient prognoses had statistically significant association with EGFR or HER-2 expression.CONCLUSION: Conventional immunohistochemistry was unable to reveal any association between EGFR or HER-2 expression and outcome predicted by the biologic role of EGFR in tumor behavior and the established prognostic role of HER-2 in breast cancer.", "INTRODUCTION: Despite significant progress, a disease-modifying therapy for Alzheimer's disease (AD) has not yet been developed. Recent findings implicate soluble oligomeric amyloid beta as the most relevant protein conformation in AD pathogenesis. We recently described a signaling cascade whereby oligomeric amyloid beta binds to cellular prion protein on the neuronal cell surface, activating intracellular Fyn kinase to mediate synaptotoxicity. Fyn kinase has been implicated in AD pathophysiology both in in vitro models and in human subjects, and is a promising new therapeutic target for AD. Herein, we present a Phase Ib trial of the repurposed investigational drug AZD0530, a Src family kinase inhibitor specific for Fyn and Src kinase, for the treatment of patients with mild-to-moderate AD.METHODS: The study was a 4-week Phase Ib multiple ascending dose, randomized, double-blind, placebo-controlled trial of AZD0530 in AD patients with Mini-Mental State Examination (MMSE) scores ranging from 16 to 26. A total of 24 subjects were recruited in three sequential groups, with each randomized to receive oral AZD0530 at doses of 50 mg, 100 mg, 125 mg, or placebo daily for 4 weeks. The drug:placebo ratio was 3:1. Primary endpoints were safety, tolerability, and cerebrospinal fluid (CSF) penetration of AZD0530. Secondary endpoints included changes in clinical efficacy measures (Alzheimer's Disease Assessment Scale - cognitive subscale, MMSE, Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory, Neuropsychiatric Inventory, and Clinical Dementia Rating Scale - Sum of Boxes) and regional cerebral glucose metabolism measured by fluorodeoxyglucose positron emission tomography.RESULTS: AZD0530 was generally safe and well tolerated across doses. One subject receiving 125 mg of AZD0530 was discontinued from the study due to the development of congestive heart failure and atypical pneumonia, which were considered possibly related to the study drug. Plasma/CSF ratio of AZD0530 was 0.4. The 100 mg and 125 mg doses achieved CSF drug levels corresponding to brain levels that rescued memory deficits in transgenic mouse models. One-month treatment with AZD0530 had no significant effect on clinical efficacy measures or regional cerebral glucose metabolism.CONCLUSIONS: AZD0530 is reasonably safe and well tolerated in patients with mild-to-moderate AD, achieving substantial central nervous system penetration with oral dosing at 100-125 mg. Targeting Fyn kinase may be a promising therapeutic approach in AD, and a larger Phase IIa clinical trial of AZD0530 for the treatment of patients with AD has recently launched.TRIAL REGISTRATION: ClinicalTrials.gov: NCT01864655. Registered 12 June 2014.", "Anlotinib is a new, orally administered tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR), and c-kit. Compared to the effect of placebo, it improved both progression-free survival (PFS) and overall survival (OS) in a phase III trial in patients with advanced non-small-cell lung cancer (NSCLC), despite progression of the cancer after two lines of prior treatments. Recently, the China Food and Drug Administration (CFDA) approved single agent anlotinib as a third-line treatment for patients with advanced NSCLC. Moreover, a randomized phase IIB trial demonstrated that anlotinib significantly prolonged the median PFS in patients with advanced soft tissue sarcoma (STS). Anlotinib also showed promising efficacy in patients with advanced medullary thyroid carcinoma and metastatic renal cell carcinoma (mRCC). The tolerability profile of anlotinib is similar to that of other tyrosine kinase inhibitors that target VEGFR and other tyrosine kinase-mediated pathways; however, anlotinib has a significantly lower incidence of grade 3 or higher side effects compared to that of sunitinib. We review the rationale, clinical evidence, and future perspectives of anlotinib for the treatment of multiple cancers." ]

[ "Calcium ions are widely accepted as critically important in responses of neurons to a stimulus. We have show previously the central involvement of angiotensin II (ANGII) in water intake. This study determined whether voltage-dependent calcium channels are involved in ANGII-induced behavioral drinking implicating nitrergic mechanism. The antidipsogenic actions of L-type calcium channel antagonists nifedipine, on ANGII-induced drinking behavior were studied when it is injected into the median preoptic nucleus (MnPO). The influence of nitric oxide (NO) on nifedipine antidipsogenic action was also studied by utilizing the N(W)-nitro-L-arginine methyl ester (L-NAME) a constitutive nitric oxide synthase inhibitor constitutive (cNOSI) and 7-nitroindazol (7-NIT) a specific neuronal nitric oxide synthase inhibitor (nNOSI) and L-arginine a NO donor. Rats 200-250 g, with cannulae implanted into MnPO, pre-treated into MnPO with either nifedipine, followed by ANGII, drank significantly less water than controls during the first 15 min after injection. However, L-NAME potentiated the dipsogenic effect of ANGII that is blocked by prior injection of nifedipine and L-arginine. 7-NIT injected prior to ANGII into MnPO also potentiated the dipsogenic effect of ANGII but with a less intensity than L-NAME that it is also blocked by prior injection of nifedipine. The results described in this paper provide evidence that calcium channels play important roles in the ANGII-induced behavioral water intake. The structures containing NO in the brain such as MnPO include both endothelial cells and neurons might be responsible for the influence of nifedipine on dipsogenic effect of ANGII. These data shows the correlation between L-type calcium channel and a free radical gas NO produced endogenously from amino acids L-arginine by endothelial and neuronal NO synthase in the control of ANGII-dipsogenic effect. This suggests that an L-type calcium channel participates in both short- and longer-term neuronal actions of ANGII by nitrergic way.", "BACKGROUND: M-phase phosphoprotein 8 (MPP8) was initially identified to be a component of the RanBPM-containing large protein complex, and has recently been shown to bind to methylated H3K9 both in vivo and in vitro. MPP8 binding to methylated H3K9 is suggested to recruit the H3K9 methyltransferases GLP and ESET, and DNA methyltransferase 3A to the promoter of the E-cadherin gene, mediating the E-cadherin gene silencing and promote tumor cell motility and invasion. MPP8 contains a chromodomain in its N-terminus, which is used to bind the methylated H3K9.METHODOLOGY/PRINCIPAL FINDINGS: Here, we reported the crystal structures of human MPP8 chromodomain alone and in complex with the trimethylated histone H3K9 peptide (residue 1-15). The complex structure unveils that the human MPP8 chromodomain binds methylated H3K9 through a conserved recognition mechanism, which was also observed in Drosophila HP1, a chromodomain containing protein that binds to methylated H3K9 as well. The structure also reveals that the human MPP8 chromodomain forms homodimer, which is mediated via an unexpected domain swapping interaction through two β strands from the two protomer subunits.CONCLUSIONS/SIGNIFICANCE: Our findings reveal the molecular mechanism of selective binding of human MPP8 chromodomain to methylated histone H3K9. The observation of human MPP8 chromodomain in both solution and crystal lattice may provide clues to study MPP8-mediated gene regulation furthermore.", "Pharmacophore approaches have evolved to be one of the most successful tools in drug discovery, especially since the past two decades. 3D pharmacophore methods are now commonly used as part of more complex workflows in drug discovery campaigns, and have been successfully and extensively applied in virtual screening (VS) approaches. This review provides a perspective of how to assess the performance of 3D pharmacophore models to be used in VS. Since 3D VS protocols are in general assessed by their ability to discriminate between active and inactive compounds, we summarize the impact of the composition and preparation of modeling and external sets on the outcome of evaluations. Moreover, we highlight the significance of both classic enrichment parameters and advanced descriptors for the performance of 3D pharmacophore-based virtual screening methods.", "Among the wealth of information that we have gathered about Ras in the past decade, the introduction of the concept of space in the field has constituted a major revolution that has enabled many pieces of the Ras puzzle to fall into place. In the early days, it was believed that Ras functioned exclusively at the plasma membrane. Today, we know that within the plasma membrane, the 3 Ras isoforms-H-Ras, K-Ras, and N-Ras-occupy different microdomains and that these isoforms are also present and active in endomembranes. We have also discovered that Ras proteins are not statically associated with these localizations; instead, they traffic dynamically between compartments. And we have learned that at these localizations, Ras is under site-specific regulatory mechanisms, distinctively engaging effector pathways and switching on diverse genetic programs to generate different biological responses. All of these processes are possible in great part due to the posttranslational modifications whereby Ras proteins bind to membranes and to regulatory events such as phosphorylation and ubiquitination that Ras is subject to. As such, space and these control mechanisms act in conjunction to endow Ras signals with an enormous signal variability that makes possible its multiple biological roles. These data have established the concept that the Ras signal, instead of being one single, homogeneous entity, results from the integration of multiple, site-specified subsignals, and Ras has become a paradigm of how space can differentially shape signaling.", "RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various forms of RNAs may be used to selectively act on proteins, transcripts, and genes that cannot be targeted by conventional small molecules or proteins. Although development of RNA drugs faces unparalleled challenges, many strategies have been developed to improve RNA metabolic stability and intracellular delivery. A number of RNA drugs have been approved for medical use, including aptamers (e.g., pegaptanib) that mechanistically act on protein target and small interfering RNAs (e.g., patisiran and givosiran) and antisense oligonucleotides (e.g., inotersen and golodirsen) that directly interfere with RNA targets. Furthermore, guide RNAs are essential components of novel gene editing modalities, and mRNA therapeutics are under development for protein replacement therapy or vaccination, including those against unprecedented severe acute respiratory syndrome coronavirus pandemic. Moreover, functional RNAs or RNA motifs are highly structured to form binding pockets or clefts that are accessible by small molecules. Many natural, semisynthetic, or synthetic antibiotics (e.g., aminoglycosides, tetracyclines, macrolides, oxazolidinones, and phenicols) can directly bind to ribosomal RNAs to achieve the inhibition of bacterial infections. Therefore, there is growing interest in developing RNA-targeted small-molecule drugs amenable to oral administration, and some (e.g., risdiplam and branaplam) have entered clinical trials. Here, we review the pharmacology of novel RNA drugs and RNA-targeted small-molecule medications, with a focus on recent progresses and strategies. Challenges in the development of novel druggable RNA entities and identification of viable RNA targets and selective small-molecule binders are discussed. SIGNIFICANCE STATEMENT: With the understanding of RNA functions and critical roles in diseases, as well as the development of RNA-related technologies, there is growing interest in developing novel RNA-based therapeutics. This comprehensive review presents pharmacology of both RNA drugs and RNA-targeted small-molecule medications, focusing on novel mechanisms of action, the most recent progress, and existing challenges.", "Cebocephaly (hypotelorism, single-nostril nose) and ethmocephaly (hypotelorism, interorbital proboscis) lie in the middle of the spectrum of craniofacial changes associated with holoprosencephaly. Because these defects and thorough anatomic studies of them are rare, knowledge concerning morphologic as well as pathogenetic relationships is lacking. We report the autopsy findings and anatomic features of the dried skull of a 31 week fetus with cebocephaly and the craniofacial dissection of a 36 week fetus with ethmocephaly. Both manifested dysplastic changes of the ethmoid bone and anterior portion of the sphenoid bone, with concomitant hypotelorism and defects of the medial orbital walls. Through these latter defects, the eyes were joined in the ethmocephalic fetus (synophthalmia). Other changes of bone (single optic foramen, approximated maxillae, choanal atresia, thickened palate) and soft tissue (eccentric or fused extraocular muscles, single optic nerve) in both fetuses resembled those reported in other cases of cebocephaly and ethmocephaly, as well as cyclopia. In the 19th century, both cebocephaly and ethmocephaly were classified as two-orbit variants of cyclopia, a view supported by the present study.", "Cebocephaly is a very rare congenital midline facial anomaly characterized by a blind-ended single nostril and ocular hypotelorism, and is usually combined with alobar holoprosencephaly. We report here a case of alobar holoprosencephaly with cebocephaly and craniosynostosis. Chromosomal analysis revealed normal karyotyping. The facial dysmorphism was characterized by the single nostril, hypotelorism, absence of philtrum and small head girth. The failure of cleavage of the prosencephalon and the fusion of all cranial sutures except for the sagittal suture were documented by computed tomography (CT) and magnetic resonance image (MRI). Early detection by the prenatal ultrasound examination is important because of poor prognosis of alobar holoprosencephaly.", "Although splicing is essential for the expression of most eukaryotic genes, inactivation of splicing factors causes specific defects in mitosis. The molecular cause of this defect is unknown. Here, we show that the spliceosome subunits SNW1 and PRPF8 are essential for sister chromatid cohesion in human cells. A transcriptome-wide analysis revealed that SNW1 or PRPF8 depletion affects the splicing of specific introns in a subset of pre-mRNAs, including pre-mRNAs encoding the cohesion protein sororin and the APC/C subunit APC2. SNW1 depletion causes cohesion defects predominantly by reducing sororin levels, which causes destabilisation of cohesin on DNA. SNW1 depletion also reduces APC/C activity and contributes to cohesion defects indirectly by delaying mitosis and causing \"cohesion fatigue\". Simultaneous expression of sororin and APC2 from intron-less cDNAs restores cohesion in SNW1-depleted cells. These results indicate that the spliceosome is required for mitosis because it enables expression of genes essential for cohesion. Our transcriptome-wide identification of retained introns in SNW1- and PRPF8-depleted cells may help to understand the aetiology of diseases associated with splicing defects, such as retinosa pigmentosum and cancer.", "OBJECTIVES: Suicidal ideation is an uncommon but worrisome symptom than can emerge during antidepressant treatment. We have described earlier the association between treatment-emergent suicidal ideation (TESI) and markers in genes encoding glutamate receptor subunits GRIK2 and GRIA3. The present genome-wide association study was conducted to identify additional genetic markers associated with TESI that may help identify individuals at high risk who may benefit from closer monitoring, alternative treatments, and/or specialty care.METHODS: A clinically representative cohort of outpatients with nonpsychotic major depressive disorder enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were treated with citalopram under a standard protocol for up to 14 weeks. DNA samples from 90 White participants who developed TESI and a sex-matched and race-matched equal number of treated participants who denied any suicidal ideas were genotyped with 109 365 single nucleotide polymorphisms on the Illumina's Human-1 BeadChip.RESULTS: One marker was found to be associated with TESI in this sample at the experiment-wide adjusted P less than 0.05 level (marker rs11628713, allelic P = 6.2x10, odds ratio = 4.7, permutation P = 0.01). A second marker was associated at the experiment-wide adjusted P = 0.06 level (rs10903034, allelic P = 3.02x10, odds ratio = 2.7, permutation P = 0.06). These markers reside within the genes PAPLN and IL28RA, respectively. PAPLN encodes papilin, a protoglycan-like sulfated glycoprotein. IL28RA encodes an interleukin receptor.CONCLUSION: Together with our earlier report, these findings may shed light on the biological basis of TESI and may help identify patients at increased risk of this potentially serious adverse event.", "We report a case of alobar holoprosencephaly (HPE) and cebocephaly associated with uncontrolled maternal type 1 (insulin-dependent) diabetes mellitus. Alobar HPE is the most severe form of HPE. Patients with cebocephaly have ocular hypotelorism and a proboscis with a single, blind-ended nostril. Shortly after our patient was born, we were consulted for airway management, as the parents' goal was to bring their child home. A tracheostomy tube was placed, and choanal atresia repair was eventually performed. The infant was never decannulated, however, and she died at the age of 9 months of acute respiratory distress syndrome secondary to an upper respiratory infection. To the best of our knowledge, this case represents the longest reported survival of an infant with alobar HPE and cebocephaly. Decisions regarding the care of these infants should be made in a collaborative, multidisciplinary fashion, with special attention paid to the primary caregivers' goals of care.", "In the yeast Saccharomyces cerevisiae, origins of replication (autonomously replicating sequences; ARSs), centromeres, and telomeres have been isolated and characterized. The identification of these structures allows the construction of artificial chromosomes in which the architecture of eukaryotic chromosomes may be studied. A common feature of most, and possibly all, natural yeast chromosomes is that they have an ARS within 2 kilobases of their physical ends. To study the effects of such telomeric ARSs on chromosome maintenance, we introduced artificial chromosomes of approximately 15 and 60 kilobases into yeast cells and analyzed the requirements for telomeric ARSs and the effects of ARS-free chromosomal arms on the stability of these molecules. We find that terminal blocks of telomeric repeats are sufficient to be recognized as telomeres. Moreover, artificial chromosomes containing telomere-associated Y' sequences and telomeric ARSs were no more stable during both mitosis and meiosis than artificial chromosomes lacking terminal ARSs, indicating that yeast-specific blocks of telomeric sequences are the only cis-acting requirement for a functional telomere during both mitotic growth and meiosis. The results also show that there is no requirement for an origin of replication on each arm of the artificial chromosomes, indicating that a replication fork may efficiently move through a functional centromere region.", "The Bmi-1 oncoprotein regulates proliferation and oncogenesis in human cells. Its overexpression leads to senescence bypass in human fibroblasts and immortalization of human mammary epithelial cells. In this study, we report that compared with normal nasopharyngeal epithelial cells (NPEC), Bmi-1 is overexpressed in nasopharyngeal carcinoma cell lines. Importantly, Bmi-1 was also found to be overexpressed in 29 of 75 nasopharyngeal carcinoma tumors (38.7%) by immunohistochemical analysis. In contrast to nasopharyngeal carcinoma, there was no detectable expression of Bmi-1 in noncancerous nasopharyngeal epithelium. Moreover, high Bmi-1 expression positively correlated with poor prognosis of nasopharyngeal carcinoma patients. We also report that the overexpression of Bmi-1 leads to bypass of senescence and immortalization of NPECs, which normally express p16(INK4a) and exhibit finite replicative life span. Overexpression of Bmi-1 in NPECs led to the induction of human telomerase reverse transcriptase activity and reduction of p16(INK4a) expression. Mutational analysis of Bmi-1 showed that both RING finger and helix-turn-helix domains of it are required for immortalization of NPECs. Our findings suggest that Bmi-1 plays an important role in the development and progression of nasopharyngeal carcinoma, and that Bmi-1 is a valuable marker for assessing the prognosis of nasopharyngeal carcinoma patients. Furthermore, this study provides the first cellular proto-oncogene immortalized nasopharyngeal epithelial cell line, which may serve as a cell model system for studying the mechanisms involved in the tumorigenesis of nasopharyngeal carcinoma.", "Hepatitis C virus (HCV) infects over 170 million persons worldwide. It is the leading cause of liver disease in the U.S. and is responsible for most liver transplants. Current treatments for this infectious disease are inadequate; therefore, new therapies must be developed. Several labs have obtained evidence for a protein complex that involves many of the nonstructural (NS) proteins encoded by the virus. NS3, NS4A, NS4B, NS5A, and NS5B appear to interact structurally and functionally. In this study, we investigated the interaction between the helicase, NS3, and the RNA polymerase, NS5B. Pull-down experiments and surface plasmon resonance data indicate a direct interaction between NS3 and NS5B that is primarily mediated through the protease domain of NS3. This interaction reduces the basal ATPase activity of NS3. However, NS5B stimulates product formation in RNA unwinding experiments under conditions of excess nucleic acid substrate. When the concentrations of NS3 and NS5B are in excess of nucleic acid substrate, NS5B reduces the rate of NS3-catalyzed unwinding. Under pre-steady-state conditions, in which NS3 and substrate concentrations are similar, product formation increased in the presence of NS5B. The increase was consistent with 1:1 complex formed between the two proteins. A fluorescently labeled form of NS3 was used to investigate this interaction through fluorescence polarization binding assays. Results from this assay support interactions that include a 1:1 complex formed between NS3 and NS5B. The modulation of NS3 by NS5B suggests that these proteins may function together during replication of the HCV genome.", "Author information:(1)Medical Oncology Department, University Hospital Fundación Jimenez Diaz, Madrid, Spain. jmartin@mustbesevilla.org.(2)University Hospital General de Villalba, Madrid, Spain.(3)Instituto de Investigacion Sanitaria Fundacion Jimenez Diaz (IIS/FJD), Madrid, Spain.(4)Institute of Biomedicine of Sevilla (IBIS, HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain.(5)Pathology Department, University Hospital Son Espases, Mallorca, Spain.(6)Soft Tissue and Bone Pathology, Histopathology and Pediatric Pathology Unit, Diagnostic Pathology and Laboratory Medicine Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Nazionale Tumori, Milan, Italy.(7)Pathology Department, University Hospital Vall D'Hebron, Barcelona, Spain.(8)Centro de Investigación Biomédica en RED (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain.(9)Pathology Department, Santa Creu I Sant Pau Hospital, Barcelona, Spain.(10)Anatomic Pathology Unit, Humanitas Clinical and Research Center - IRCCS -, Rozzano (MI), Italy.(11)Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy.(12)Pathology Department, Service d'Anatomie Pathologique, Institut Bergonié, Bordeaux, France.(13)Bergonie Institute, Department of Biopathology, Bordeaux, and Bordeaux University, Talence, France.(14)Clinical Bioinformatics Area. Fundación Progreso y Salud (FPS). CDCA, Hospital Virgen del Rocio, Sevilla, Spain.(15)Bioinformatics in Rare Diseases (BiER). Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), FPS, Hospital Virgen del Rocio, Sevilla, Spain.(16)INB-ELIXIR-es FPS, Hospital Virgen del Rocío, Sevilla, Spain.(17)Department of Anatomy and Pathological Histology, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy.(18)Research and Statistics Infrastructure, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy.(19)Chemotherapy Unit, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy.(20)Cancer Medicine Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy.(21)Department of Surgery, Istituto Clinico Humanitas, Rozzano, Italy.(22)Medical Oncology Department, Santa Creu I Sant Pau Hospital, Barcelona, Spain.(23)Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.(24)Department of Medical Oncology, Centre Léon Bérard & Université Claude Bernard Lyon I, Lyon, France.(25)Department of Oncology, Medical Oncology 1 Unit, Istituto Oncologico Veneto IOV, IRCCS, Padova, Italy.(26)Hematology Department, Son Espases University Hospital, Mallorca, Spain.(27)Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain.(28)Medical Oncology Department, University Hospital Fundación Jimenez Diaz, Madrid, Spain.(29)Department of Pathology, Treviso General Hospital, Treviso, Italy.(30)University of Padua, Padova, Italy.(31)Laboratory of Oncologic Research, Istituto Ortopedico Rizzoli, Bologna, Italy.(32)Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.(#)Contributed equally", "Cebocephaly is a very rare congenital anomaly combining a severe midline facial malformation and holoprosencephaly. Here we report on first case of cebocephaly with semilobar holoprosencephaly, hypotelorism, and a single nostril due to intrauterine TORCH infection (Toxoplasmosis, other [syphilis, varicella-zoster, parvovirus B19], Rubella, Cytomegalovirus [CMV], and Herpes infections) in the English language literature. Chromosomal analysis showed normal karyotyping.", "In addition to its prominence in producing genetic diversity in bacterial species, homologous recombination (HR) plays a key role in DNA repair and damage tolerance. The frequency of HR depends on several factors, including the efficiency of DNA repair systems as HR is involved in recovery of replication forks perturbed by DNA damage. Nucleotide excision repair (NER) is one of the major DNA repair pathways involved in repair of a broad range of DNA lesions generally induced by exogenous chemicals or UV-irradiation and its functions in the cells not exposed to DNA-damaging agents have attracted less attention. In this study we have developed an assay that enables to investigate HR between chromosomal loci of the soil bacterium Pseudomonas putida both in growing and stationary-phase cells. The present assay detects HR events between two non-functional alleles of phenol degrading genes that produce a functional allele and allow the growth of bacteria on phenol as a sole carbon source. Our results indicate that HR between chromosomal loci takes place mainly in the growing cells and the frequency of HR is reduced during the following starvation in NER-proficient P. putida but not in the case when bacteria lack UvrA or UvrB enzymes. The absence of UvrA or UvrB resulted in a hyper-recombination phenotype in P. putida, the cells were filamented and their growth was impaired even in the absence of exogenous DNA damage. However, NER-deficient derivatives that overcame growth defects emerged rapidly. Such adaptation resulted in the decline of the frequency of HR. Although HR in actively replicating P. putida was still elevated in the adapted variants of the UvrA- and UvrB-deficient strains, the dynamics of emergence of the recombinants in these strains turned similar to NER-proficient bacteria. Additionally, we observed that HR was enhanced in the absence of the transcription repair coupling factor Mfd in growing cells but not during starvation. The frequency of HR was not affected by the UvrA homologue UvrA2 neither in NER-proficient bacteria nor in the absence of UvrA, suggesting a minor role of UvrA2 in NER. Thus, we conclude that NER functions are important also without exogenously induced DNA damage in P. putida and both transcription-coupled and global genome NER act to suppress HR in growing cells, whereas UvrA and UvrB are involved in the maintenance of the genome integrity also in stationary-phase cells." ]

[ "BACKGROUND: Histone acetylation of chromatin plays a key role in promoting the dynamic transcriptional responses in neurons that influence the neuroplasticity linked to cognitive ability, yet the specific histone acetyltransferases (HATs) that create such epigenetic marks remain to be elucidated.METHODS AND FINDINGS: Here we use the Drosophila neuromuscular junction (NMJ) as a well-characterized synapse model to identify HATs that control synaptic remodeling and structure. We show that the HAT dTip60 is concentrated both pre and post-synaptically within the NMJ. Presynaptic targeted reduction of dTip60 HAT activity causes a significant increase in synaptic bouton number that specifically affects type Is boutons. The excess boutons show a suppression of the active zone synaptic function marker bruchpilot, suggesting defects in neurotransmission function. Analysis of microtubule organization within these excess boutons using immunohistochemical staining to the microtubule associated protein futsch reveals a significant increase in the rearrangement of microtubule loop architecture that is required for bouton division. Moreover, α-tubulin acetylation levels of microtubules specifically extending into the terminal synaptic boutons are reduced in response to dTip60 HAT reduction.CONCLUSIONS: Our results are the first to demonstrate a causative role for the HAT dTip60 in the control of synaptic plasticity that is achieved, at least in part, via regulation of the synaptic microtubule cytoskeleton. These findings have implications for dTip60 HAT dependant epigenetic mechanisms underlying cognitive function.", "Vascular endothelial growth factors (VEGFs) control angiogenesis and lymphangiogenesis during development and in pathological conditions. In the zebrafish trunk, Vegfa controls the formation of intersegmental arteries by primary angiogenesis and Vegfc is essential for secondary angiogenesis, giving rise to veins and lymphatics. Vegfd has been largely thought of as dispensable for vascular development in vertebrates. Here, we generated a zebrafish vegfd mutant by genome editing. vegfd mutants display significant defects in facial lymphangiogenesis independent of vegfc function. Strikingly, we find that vegfc and vegfd cooperatively control lymphangiogenesis throughout the embryo, including during the formation of the trunk lymphatic vasculature. Interestingly, we find that vegfd and vegfc also redundantly drive artery hyperbranching phenotypes observed upon depletion of Flt1 or Dll4. Epistasis and biochemical binding assays suggest that, during primary angiogenesis, Vegfd influences these phenotypes through Kdr (Vegfr2) rather than Flt4 (Vegfr3). These data demonstrate that, rather than being dispensable during development, Vegfd plays context-specific indispensable and also compensatory roles during both blood vessel angiogenesis and lymphangiogenesis.", "BACKGROUND: Esophageal Crohn's disease is reported as a rare manifestation, although its prevalence may be underestimated because upper endoscopies are not routinely performed in asymptomatic adults. Tofacitinib, an oral janus kinase inhibitor, is a new biologic that has shown promise in the treatment of ulcerative colitis and may be effective in the treatment of Crohn's disease according to phase 2 trials. We report the first case of esophageal Crohn's disease successfully treated with tofacitinib in a patient with worsening symptoms despite maintenance therapy with a tumor necrosis factor-α inhibitor.CASE PRESENTATION: A 67-year-old Caucasian woman presented with new dysphagia and had findings of esophageal Crohn's disease on endoscopy. The dosage of her current biologic therapy-adalimumab-was increased in frequency, without improvement. Our patient was started on tofacitinib and demonstrated an improvement in symptoms, with a repeat endoscopy showing resolution of the previous lesions.CONCLUSION: Esophageal Crohn's disease is likely underdiagnosed but is an important consideration in a patient with new symptoms of dysphagia and known Crohn's disease. Tofacitinib, while a novel agent, could have a role in the treatment of esophageal Crohn's disease that does not improve with intensification of the current biologic therapy. It provides a different mechanism in patients who become refractory to maintenance therapy.", "OBJECTIVES: Preterm premature rupture of membranes (PPROM) is a leading complication following fetoscopic laser coagulation (FLC) for twin-twin transfusion syndrome (TTTS). Our primary objective was to describe the impact of improvements in surgical technique on survival and rate of PPROM over time. The secondary objective was to assess potential risk factors for PPROM.DESIGN AND SETTING: Single-centre retrospective observational study.POPULATION: 1092 consecutive cases of TTTS operated by FLC between 2000 and 2016, with a 6.8% rate of loss to follow up.METHODS: The incidence of PPROM and potential risk factors were analysed using competing risks models.MAIN OUTCOME MEASURES: PPROM, neonatal survival and neurological damage at 28 days.RESULTS: PPROM <32 weeks increased from 15 to 40% between 2000 and 2016 along with an overall improvement of perinatal outcomes: dual survival rose from 42 to 66% whereas dual losses dropped two-fold, from 19 to 9%. Gestational age at surgery at <17 weeks was a significant risk-factor for PPROM, with an additional risk of 10% within the first week of surgery. Although early PPROM at <20 weeks carried a 56% risk of miscarriage, the occurrence of PPROM at >20 weeks did not affect survival, despite an increase in preterm birth at <32 weeks.CONCLUSIONS: With significant improvement in perinatal outcomes, possibly related to improvements in surgical technique, postoperative complications have shifted to non-lethal obstetric complications such as PPROM, with rather reassuring postnatal outcomes, despite an increase in preterm birth and, potentially, morbidity. Early surgeries (<17 weeks) are at higher risk of postoperative PPROM.TWEETABLE ABSTRACT: Following laser/TTTS, rates of PPROM increased with perinatal survival; surgeries at <17 weeks are at highest risk.", "Lymphatic vessels are vital for the trafficking of immune cells from the interstitium to draining lymph nodes during inflammation. Hypertension is associated with renal infiltration of activated immune cells and inflammation; however, it is unknown how renal lymphatic vessels change in hypertension. We hypothesized that renal macrophage infiltration and inflammation would cause increased lymphatic vessel density in hypertensive rats. Spontaneously hypertensive rats (SHR) that exhibit hypertension and renal injury (SHR-A3 strain) had significantly increased renal lymphatic vessel density and macrophages at 40 wk of age compared with Wistar-Kyoto (WKY) controls. SHR rats that exhibit hypertension but minimal renal injury (SHR-B2 strain) had significantly less renal lymphatic vessel density compared with WKY rats. The signals for lymphangiogenesis, VEGF-C and its receptor VEGF-R3, and proinflammatory cytokine genes increased significantly in the kidneys of SHR-A3 rats but not in SHR-B2 rats. Fischer 344 rats exhibit normal blood pressure but develop renal injury as they age. Kidneys from 24-mo- and/or 20-mo-old Fischer rats had significantly increased lymphatic vessel density, macrophage infiltration, VEGF-C and VEGF-R3 expression, and proinflammatory cytokine gene expression compared with 4-mo-old controls. These data together demonstrate that renal immune cell infiltration and inflammation cause lymphangiogenesis in hypertension- and aging-associated renal injury.", "Canagliflozin, an oral inhibitor of sodium/glucose cotransporter 2 (SGLT2) in the kidneys, leads to glucosuria and provides a unique mechanism to lower blood glucose levels in diabetes. It corrects a novel pathophysiological defect, has an insulin-independent action, reduces HbA1c by 0.5 to 1.1%, promotes weight loss, has a low incidence of hypoglycemia, complements the action of other antidiabetic agents, can be used at any stage of diabetes and appears to be safe in patients with compromised renal function. Due to side effects such as urinary tract and genital infections and decrease in blood pressure, proper patient selection for drug initiation and close monitoring will be important. Results of ongoing cardiovascular safety trials are important to determine the risk-benefit ratio. Canagliflozin is the first oral SGLT2 inhibitor approved in the U.S. market and it represents a promising approach for the treatment of diabetes in this era of increasing obesity.", "Whole-genome association studies in rheumatoid arthritis have identified single-nucleotide polymorphisms (SNPs) predisposing to disease with moderate risk. We aimed to investigate the role of these markers in predicting methotrexate (MTX) response, measured by continuation on MTX monotherapy in patients with recent onset inflammatory polyarthritis (IP). In all, 19 SNPs were genotyped in 736 patients treated with MTX following registration, or not more than 3 months before registration, to the Norfolk Arthritis Register. The association of SNPs with MTX continuation by year 1 and by year 2 was investigated using Cox proportional hazard regression models. A SNP within the OLIG3/TNFAIP3 locus (rs6920220) was associated with being less likely to maintain MTX monotherapy at year 1, hazards ratio (HR) 1.73 (1.18, 2.52) and year 2, HR 1.49 (1.11, 2.00); correlating with an increased in adverse events. Weak evidence for an effect at the PTPN22 locus was also observed. These findings require replication in other large datasets.", "Although bronchial angiogenesis has been well documented in allergic asthma, lymphangiogenesis has not been widely studied. Therefore, we evaluated changes in lung lymphatics in a rat model of allergen-induced asthma using house dust mite (Der p 1; 100 μg/challenge). Additionally, properties of isolated lung lymphatic endothelial cells (CD45-, CD141+, LYVE-1+, Prox-1+) were studied in vitro. Three weeks after the onset of intranasal allergen exposure (twice-weekly), an increase in the number of lung lymphatic vessels was measured (34% increase) by lung morphometry. New lymphatic structures were seen predominantly in the peribronchial and periarterial interstitial space but also surrounding large airways. Isolated lymphatic endothelial cells from sensitized lungs showed enhanced proliferation (% Ki67+), chemotaxis, and tube formation (number and length) compared to lymphatic endothelial cells isolated from naive rat lungs. This hyper-proliferative lymphangiogenic phenotype was preserved through multiple cell passages (2-8). Lymphatic endothelial cells isolated from naive and HDM-sensitized rats produced similar in vitro levels of VEGF-C, VEGF-D, and VEGFR3 protein, each recognized as critical lymphangiogenic factors. Inhibition with anti-VEGFR (axitinib, 0.1 μM) blocked proliferation and chemotaxis. Results suggest that in vivo sensitization causes fundamental changes to lymphatic endothelium, which are retained in vitro, and may relate to VEGFR downstream signaling.", "BACKGROUND: The anti-cancer mechanism of neo-adjuvant hormonal therapy (NHT) is not well understood. Lymphangiogenesis plays an important role in cancer progression and is regulated by a complex mechanism that includes vascular endothelial growth factor (VEGF) signaling. However, there is little information regarding relationship between lymphangiogenesis and androgen deprivation. The aim of this study was to clarify changes in lymphangiogenesis and VEGF expression induced by androgen deprivation in prostate cancer in vivo and in vitro.METHODS: Patients who had undergone a radical prostatectomy were enrolled in the study (NHT, n = 60 and non-NHT, n = 64). Lymph vessels were identified by D2-40 immunoreactivity and lymph vessel density and lymph vessel area (LVD and LVA, respectively) were measured from micrographs. The expression of VEGF-A, -B, -C, and -D was evaluated by immunohistochemistry. The prognostic value of LVD and LVA for biochemical recurrence was also investigated.RESULTS: Mean LVD ± SD was higher in the NHT than in the non-NHT group (11.3 ± 3.0 vs. 7.1 ± 3.4 per high power field; P < 0.001). LVA was larger in the NHT than in the non-NHT group (512.8 ± 174.9 vs. 202.7 ± 72.8 µm2 ; P < 0.001). VEGF-A expression was lower whereas VEGF-C and -D levels were higher in the NHT than in the non-NHT group. VEGF-B expression in specimens with NHT was lower than that in biopsy specimens at diagnosis. These results were confirmed by in vitro studies used androgen-sensitive prostate cancer cell line. LVA was found to be an independent predictor of biochemical recurrence in patients who received NHT.CONCLUSIONS: Our results demonstrate that NHT stimulates lymphangiogenesis via upregulation of VEGF-C and -D, which may increase LVA and affect the outcome of prostate cancer patients. This findings were supported by in vitro data of prostate cancer cell. Prostate 77:255-262, 2017. © 2016 The Authors. The Prostate Published by Wiley Periodicals, Inc.", "Since reports that precursor cells in the adult subventricular zone (SVZ) contribute to regenerative neuro- and gliogenesis in CA1, we wondered whether a similar route of migration might also exist under physiological conditions. Permanent labeling of SVZ precursor cells with a lentiviral vector for green fluorescent protein did not reveal any migration from the SVZ into CA1 in the intact murine brain. However, in a nestin-GFP reporter mouse we found proliferating cells within the corpus callosum/alveus region expressing nestin and glial fibrillary acidic protein similar to precursor cells in the neighboring neurogenic region of the adult dentate gyrus. Within 3 weeks of BrdU administration, BrdU-positive nestin-GFP-expressing protoplasmic astrocytes emerged in CA1. Similar to precursor cells isolated from the dentate gyrus and the SVZ, nestin-GFP-expressing cells from corpus callosum/alveus were self-renewing and multipotent in vitro, whereas cells isolated from CA1 were not. Nestin-GFP-expressing cells in CA1 differentiated into postmitotic astrocytes characterized by S100beta expression. No new neurons were found in CA1. The number of nestin-GFP-expressing astrocytes in CA1 was increased by environmental enrichment. We conclude that astrogenesis in CA1 is influenced by environmental conditions. However, SVZ precursor cells do not contribute to physiological cellular plasticity in CA1.", "Lymphatic dysfunction is associated with the progression of many cardiovascular disorders due to their role in maintaining tissue fluid homeostasis. Promoting new lymphatic vessels (lymphangiogenesis) is a promising strategy to reverse these cardiovascular disorders via restoring lymphatic function. Vascular endothelial growth factor (VEGF) members VEGF-C and VEGF-D are both potent candidates for stimulating lymphangiogenesis, though maintaining spatial and temporal control of these factors represents a challenge to developing efficient therapeutic lymphangiogenic applications. Injectable alginate hydrogels have been useful for the controlled delivery of many angiogenic factors, including VEGF-A, to stimulate new blood vasculature. However, the utility of these tunable hydrogels for delivering lymphangiogenic factors has never been closely examined. Thus, the objective of this study was to utilize ionically cross-linked alginate hydrogels to deliver VEGF-C and VEGF-D for potential lymphangiogenic applications. We demonstrated that lymphatic endothelial cells (LECs) are sensitive to temporal presentation of VEGF-C and VEGF-D but with different responses between the factors. The greatest LEC mitogenic and sprouting response was observed for constant concentrations of VEGF-C and a high initial concentration that gradually decreased over time for VEGF-D. Additionally, alginate hydrogels provided sustained release of radiolabeled VEGF-C and VEGF-D. Finally, VEGF-C and VEGF-D released from these hydrogels promoted a similar number of LEC sprouts as exogenously added growth factors and new vasculature in vivo via a chick chorioallantoic membrane (CAM) assay. Overall, these findings demonstrate that alginate hydrogels can provide sustained and bioactive release of VEGF-C and VEGF-D which could have applications for therapeutic lymphangiogenesis.", "Since experimental and clinical evidence supports some role of musculature in determining the form and size of facial bones during the active periods of growth after birth, this study addresses the same basic relationships between muscle and bone during the periods of active growth before birth. The relationship between the masseter muscle and the mandible, including its ramal and body components, was chosen as the model for study in nineteen human fetuses (ages 16 to 36 weeks). Cross-sectional cephalometric data indicated that, although increases in the size of the muscle and mandible were linearly related to increasing age, the ramal portion of the mandible was more closely related to changes in the masseter muscle than to changes in the mandibular body. Moreover, it appears that reorientation of the muscle anteriorly and downward precedes a similar reorientation of the ramus, with the combination of both fetal events leading to the typical relationships of the two structures expected after birth. Although this study does not get to cause-and-effect relationships, and although the fetal specimens cannot be monitored longitudinally over time, the parallelisms between our prenatal findings and those reported for postnatal periods certainly lend further support to the observation that many aspects of morphogenesis and growth are continual processes spanning the periods on either side of birth.", "BACKGROUND CONTEXT: Crowned dens syndrome (CDS) is a rare form of calcium phosphate crystal depositions and often presents with recurrent neck pain, stiffness of neck, increased erythrocyte sedimentation rate, and episodes of fever.PURPOSE: The goal of this report is to identify the early and late stages of CDS and its consequences as the result of repeated attacks of CDS at cervical spine in its late stage.STUDY DESIGN: This is a case report.METHODS: We reported one case of early-stage CDS and one late-stage CDS.RESULTS: The two patients shared some common clinical features of acute attack of CDS, such as increased erythrocyte sedimentation rate, C-reactive protein, episode of fever, and increased white blood cells along with high blood glucose levels. The first case showed early phase of CDS with computed tomography (CT) scan that only showed mild calcification around the dens. The second case had appearance of late stage of CDS with more severe chronic degenerative changes of cervical spine.CONCLUSIONS: Early stage of CDS can be difficult to identify because of mild clinical symptoms, but CT scan is a preferable method to demonstrate densities surrounding the top and sides of the odontoid process. In the late stage of CDS, radiolographic features often include diffuse periodontoid calcifications, diffuse destructive discopathies, and apophyseal joint destruction, and patient might have severe neurological symptoms.", "OBJECTIVE: To assess geographic differences in the frequencies of HFE C282Y and H63D genotypes in six racial/ethnic groups recruited in the Hemochromatosis and Iron Overload Screening (HEIRS) Study.DESIGN: HFE C282Y and H63D genotypes of 97,551 participants, ages > or = 25 years, who reported that they belonged to one of six racial/ethnic groups, were analyzed. HFE genotype frequencies were compared among the racial/ethnic groups and among the HEIRS Study field centers within each racial/ethnic group.RESULTS: The distribution of HFE C282Y and H63D genotypes differed among racial/ethnic groups (P<.0001) and among field centers in Hispanics, Asians, Whites, and Blacks (each P<.05). Genotype frequencies were similar among field centers in Native Americans and Pacific Islanders. Frequencies of C282Y and H63D genotypes were greatest in Whites. The lowest frequencies of C282Y genotypes were observed in Asians; Blacks had the lowest H63D genotype frequencies and the highest frequency of the wild-type genotype. Among racial/ethnic groups, Hispanics had the greatest variation in HFE genotypes across geographic regions.CONCLUSION: HFE C282Y and H63D genotype frequencies vary significantly between racial/ethnic groups and within some racial/ethnic groups across geographic regions.", "Behavioral interventions have been used for decades to treat urge incontinence and other symptoms of overactive bladder. Perhaps the earliest form of treatment was the bladder drill, an intensive intervention designed to increase the interval between voids to establish a normal frequency of urination and normalization of bladder function. Bladder training is a modification of bladder drill that is conducted more gradually on an outpatient basis and has resulted in significant reduction of incontinence in older, community-dwelling women. Multicomponent behavioral training is another form of behavioral treatment that includes pelvic floor muscle training and exercise. This intervention focuses less on voiding habits and more on altering the physiologic responses of the bladder and pelvic floor muscles. Using biofeedback or other teaching methods, patients learn strategies to inhibit bladder contraction using pelvic floor muscle contraction and other urge suppression strategies. Although behavioral and drug therapies are known to be highly effective for reducing urge incontinence, few patients are cured with either treatment alone. Thus, future research should explore ways to enhance the effectiveness of these conservative therapies. Although the mechanisms by which behavioral treatments work have not been established, there is some evidence that behavioral and drug interventions may operate by different mechanisms, suggesting that they may have additive effects and that combining them may result in better outcomes. Future research needs to examine the mechanisms by which these therapies reduce incontinence and whether combining behavioral and drug treatment will result in better outcomes than either therapy alone.", "OBJECTIVES/HYPOTHESIS: In the treatment of burning mouth syndrome (BMS), various approaches have been tried with equivocal results. The aim of the present randomized clinical trial was to determine the efficacy of clonazepam, a GABA agonist designed as an antiepileptic drug that exerts the typical effects of benzodiazepines.STUDY DESIGN: Randomized clinical trial.METHODS: Twenty patients with idiopathic BMS were carefully selected. Clonazepam (0.5 mg/day, n = 10) or placebo (lactose, n = 10) were randomly assigned to the patients.RESULTS: Patients on clonazepam significantly improved in pain ratings (P < .001). These changes were less pronounced in the placebo group (P < .11). No significant changes were observed in a mood scale (P = .56) or for depression scores (P = .56). Taste test and salivary flow increased over sessions, but were not different between groups (P = .83 and P = .06, respectively).CONCLUSIONS: Clonazepam appears to have a positive effect on pain in BMS patients.", "Klotho is a transmembrane protein expressed primarily in kidney, parathyroid gland, and choroid plexus. The extracellular domain could be cleaved off and released into the systemic circulation. Klotho is in part effective as β-glucuronidase regulating protein stability in the cell membrane. Klotho is a major determinant of aging and life span.Overexpression of Klotho increases and Klotho deficiency decreases life span. Klotho deficiency may further result in hearing loss and cardiac arrhythmia. The present study explored whether Klotho modifies activity and protein abundance of KCNQ1/KCNE1, a K(+) channel required for proper hearing and cardiac repolarization. To this end, cRNA encoding KCNQ1/KCNE1 was injected in Xenopus oocytes with or without additional injection of cRNA encoding Klotho. KCNQ1/KCNE1 expressing oocytes were treated with human recombinant Klotho protein (30 ng/mL) for 24 h. Moreover, oocytes which express both KCNQ1/KCNE1 and Klotho were treated with 10 μM DSA L (D-saccharic acid-1,4-lactone), a β-glucuronidase inhibitor. The KCNQ1/KCNE1 depolarization-induced current (I(Ks)) was determined utilizing dual electrode voltage clamp, while KCNQ1/KCNE1 protein abundance in the cell membrane was visualized utilizing specific antibody binding and quantified by chemiluminescence. KCNQ1/KCNE1 channel activity and KCNQ1/KCNE1 protein abundance were upregulated by coexpression of Klotho. The effect was mimicked by treatment with human recombinant Klotho protein (30 ng/mL) and inhibited by DSA L (10 μM). In conclusion, Klotho upregulates KCNQ1/KCNE1 channel activity by “mainly” enhancing channel protein abundance in the plasma cell membrane, an effect at least partially mediated through the β-glucuronidase activity of Klotho protein.", "Currently DNA profiling methods only compare a suspect's DNA with DNA left at the crime scene. When there is no suspect, it would be useful for the police to be able to predict what the person of interest looks like by analysing the DNA left behind in a crime scene. Determination of the age of the suspect is an important factor in creating an identikit. Human somatic cells gradually lose telomeric repeats with age. This study investigated if one could use a correlation between telomere length and age, to predict the age of an individual from their DNA. Telomere length, in buccal cells, of 167 individuals aged between 1 and 96 years old was measured using real-time quantitative PCR. Telomere length decreased with age (r=-0.185, P<0.05) and the age of an individual could be roughly determined by the following formula: (age=relative telomere length -1.5/-0.005). The regression (R(2)) value between telomere length and age was approximately 0.04, which is too low to be use for forensics. The causes for the presence of large variation in telomere lengths in the population were further investigated. The age prediction accuracies were low even after dividing samples into non-related Caucasians, males and females (5%, 9% and 1%, respectively). Mean telomere lengths of eight age groups representing each decade of life showed non-linear decrease in telomere length with age. There were variations in telomere lengths even among similarly aged individuals aged 26 years old (n=10) and age 54 years old (n=9). Therefore, telomere length measurement by real-time quantitative PCR cannot be used to predict age of a person, due to the presence of large inter-individual variations in telomere lengths.", "The global epidemic of type 2 diabetes (T2DM) continues largely unabated due to an increasingly sedentary lifestyle and obesogenic environment. A cost-effective patient-centred approach, incorporating glucose-lowering therapy and modification of cardiovascular risk factors, could help prevent the inevitable development and progression of macrovascular and microvascular complications. Glycaemic optimization requires patient structured education, self-management and empowerment, and psychological support along with early and proactive use of glucose lowering therapies, which should be delivered in a system of care as shown by the Chronic Care Model. From diagnosis, intensive glycaemic control and individualised care is aimed at reducing complications. In older people, the goal is maintaining quality of life and minimizing morbidity, especially as overtreatment increases hypoglycaemia risk. Maintaining durable glycaemic control is challenging and complex to achieve without hypoglycaemia, weight gain and other significant adverse effects. Overcoming patient and physician barriers can help ensure adequate treatment initiation and intensification. Cardiovascular safety studies with newer glucose-lowering agents are now mandatory, with a sodium glucose co-transporter-2 inhibitor (empagliflozin), and two glucagon like peptide-1 receptor agonists (liraglutide and semaglutide) being the first to demonstrate superior CV outcomes compared with placebo.", "We report on a Brazilian kindred in which two sibs presented with the complete form of EEM (ectodermal dysplasia, ectrodactyly, and macular dystrophy) syndrome with hypotrichosis, dental anomalies, syndactyly, and retinal changes with prominent pigmentation in the posterior pole of the retina. In this family, we also observed another sib with syndactyly, as well as a first cousin with ectrodactyly. A 10-year follow-up demonstrated gradually decreasing visual acuity and progression of retinal degenerative anomalies." ]

[ "The integrin antagonist cilengitide has been explored as an adjunct with anti-angiogenic properties to standard of care temozolomide chemoradiotherapy (TMZ/RT → TMZ) in newly diagnosed glioblastoma. Preclinical data as well as anecdotal clinical observations indicate that anti-angiogenic treatment may result in altered patterns of tumor progression. Using a standardized approach, we analyzed patterns of progression on MRI in 21 patients enrolled onto a phase 2 trial of cilengitide added to TMZ/RT → TMZ in newly diagnosed glioblastoma. Thirty patients from the experimental treatment arm of the EORTC/NCIC pivotal TMZ trial served as a reference. MRIcro software was used to map location and extent of initial preoperative and recurrent tumors on MRI of both groups into the same stereotaxic space which were then analyzed using an automated tool of image analysis. Clinical and outcome data of the cilengitide-treated patients were similar to those of the EORTC/NCIC trial except for a higher proportion of patients with a methylated O(6)-methylguanyl-DNA-methyltransferase gene promoter. Analysis of recurrence pattern revealed neither a difference in the size of the recurrent tumor nor in the distance of the recurrences from the preoperative tumor location between groups. Overall frequencies of distant recurrences were 20 % in the reference group and 19 % (4/21 patients) in the cilengitide group. Compared with TMZ/RT → TMZ alone, the addition of cilengitide does not alter patterns of progression. This analysis does not support concerns that integrin antagonism by cilengitide may induce a more aggressive phenotype at progression, but also provides no evidence for an anti-invasive activity of cilengitide in patients with newly diagnosed glioblastoma.", "PURPOSE: The miniature biodegradable implant siG12D-LODER™ was inserted into a tumor and released a siRNA drug against KRAS(G12D) along four months. This novel siRNA based drug was studied, in combination with chemotherapy, as targeted therapy for Locally Advanced Pancreatic Cancer (LAPC).METHODS: An open-label Phase 1/2a study in the first-line setting of patients with non-operable LAPC was initiated. In this study patients were assigned to receive a single dose of siG12D-LODERs, in three escalating dose cohorts (0.025mg, 0.75mg and 3.0mg). Gemcitabine was given on a weekly basis, following the siG12D-LODERTM insertion, until disease progression. The recommended dose was further examined with modified FOLFIRINOX. The follow up period was eight weeks and survival until death.RESULTS: Fifteen patients with LAPC were enrolled. Among the 15 treated patients, the most frequent adverse events observed were grade 1or 2 in severity (89%); five patients experienced serious adverse events (SAEs). In 12 patients analyzed by CT scans, none showed tumor progression, the majority (10/12) demonstrated stable disease and two showed partial response. Decrease in tumor marker CA19-9 was observed in 70% (7/10) of patients. Median overall survival was 15.12 months; 18 month survival was 38.5%.CONCLUSIONS: The combination of siG12D-LODER™ and chemotherapy is well tolerated, safe and demonstrated a potential efficacy in patients with LAPC. NCT01188785.", "Conventional chemotherapy treatments for pancreatic cancer are mainly palliative. RNA interference (RNAi)-based drugs present the potential for a new targeted treatment. LOcal Drug EluteR (LODER(TM)) is a novel biodegradable polymeric matrix that shields drugs against enzymatic degradation and releases small interfering RNA (siRNA) against G12D-mutated KRAS (siG12D). siG12D-LODER has successfully passed a phase 1/2a clinical trial. Such a formulation necessitates biocompatibility and safety studies. We describe the safety and toxicity studies with siG12D-LODER in 192 Hsd:Sprague Dawley rats, after repeated subcutaneous administrations (days 1, 14, and 28). Animals were sacrificed on days 29 and 42 (recovery phase). In all groups, no adverse effects were noted, and all animals showed favorable local and systemic tolerability. Histopathologically, LODER implantation resulted in the expected capsule formation, composed of a thin fibrotic tissue. On the interface between the cavity and the capsule, a single layer composed of macrophages and multinucleated giant cells was observed. No difference was noted between the placebo and siG12D-LODER groups. These findings provide valuable information for future preclinical studies with siRNA-bearing biodegradable polymers and for the safety aspects of RNAi-based drugs as a targeted therapy.", "The present case study is on a 16-year-old woman who was suffering from nephrotic syndrome after recovery from complete type of hydatiform mole. She was admitted in hospital because of proteinurea and hematuria. Then she was showing a generalized edema compatible with neprhotic syndrome. In her past medical history she had a suction curettage for hydatiform mole. After she received 4 courses chemotherapy, she completely recovered and βhCG has fallen from 12127 IU/L to under 10 IU/mL. Then she showed generalized edema, proteinurea and hematuria compatible with nephritic syndrome. After six courses chemotherapy the symptoms of nephrotic syndrome and invasive mole diminished, she released from hospital and scheduled for follow-up.", "INTRODUCTION: Flibanserin, a novel 5-HT(1A) agonist and 5-HT(2A) antagonist, has the potential to treat sexual dysfunction.AIM: Provide historical perspective on the rationale for development of flibanserin to treat sexual dysfunction, based on post hoc analyses of data.MAIN OUTCOME MEASURES: The Arizona Sexual Experiences (ASEX) scale and the Hamilton depression rating scale (HAMD) Genital Symptoms item.METHODS: Sexual function outcomes are presented from four double-blind, randomized controlled studies involving a total of 369 men and 523 women diagnosed with Major Depressive Disorder. Each study had an active treatment arm to confirm assay sensitivity on the primary antidepressive endpoint. Two studies placebo, flibanserin (50mg bid), or fluoxetine (20mg qd) for 6 weeks and two involved placebo, flibanserin (50-100mg bid), or paroxetine (20-40mg qd) for 8 weeks.RESULTS: Individual study completion rates were 77-80%. At baseline, 38% of men and 67% of women reported sexual dysfunction. Assay sensitivity was not demonstrated in the fluoxetine trials and sexual function outcomes were inconsistent. Flibanserin and placebo were associated with low rates of treatment-emergent sexual dysfunction in women during the paroxetine studies. In one study, 70% of flibanserin-treated women with baseline sexual dysfunction reported improvement in sexual function, compared with 30% of placebo-treated women. Mean change from baseline on the HAMD \"Genital Symptoms\" item in one paroxetine study was significantly better among flibanserin- than placebo-treated women at weeks 4, 6, and 8 (P<0.05). Sexual function adverse events across flibanserin groups were generally comparable to placebo.CONCLUSIONS: Although these studies were not designed or powered to compare sexual function outcomes, results suggested a potential benefit of flibanserin on sexual function, particularly on female sexual desire, and provided a rationale to evaluate the efficacy of flibanserin as a treatment for female hypoactive sexual desire disorder.", "STUDY OBJECTIVE: To compare four common dosing regimens for vancomycin in preterm and term neonates by assessing the probability that each regimen would achieve the widely used therapeutic target serum trough concentrations of 5-15 mg/L and the newly suggested target of 15-20 mg/L.DESIGN: Retrospective population pharmacokinetic analysis using therapeutic drug monitoring data obtained from 1990-2007, with a subsequent simulation study performed on the pharmacokinetic model.SETTING: Tertiary-care children's hospital.PATIENTS: One hundred thirty-four preterm (66%) and term (34%) neonates, with a postnatal age of 1-121 days and postmenstrual age of 24.6-44 weeks.MEASUREMENTS AND MAIN RESULTS: Therapeutic drug monitoring data for vancomycin were used to develop a population pharmacokinetic model in the target population. Parameter estimates for the derived pharmacostatistical model were used to perform Monte Carlo simulations for four recommended dosing regimens: a standard dose for all neonates, postmenstrual age-based dosing, postmenstrual and postnatal age-based dosing, and serum creatinine-based dosing. Multivariate age-weight distributions were established for term and preterm neonates using Centers for Disease Control and Prevention growth charts and intrauterine and postnatal growth charts from the literature, respectively. Each dosing regimen was treated as a separate scenario in which 200 replicates with 100 patients/replicate were simulated. The 5-15-mg/L target trough serum concentration was achieved in 34% (90% confidence interval [CI] 20-53%), 42% (90% CI 31-55%), 52% (90% CI 43-60%), and 63% (90% CI 54-72%) of patients receiving the standard dose, postmenstrual age-based dose, postmenstrual and postnatal age-based dose, and serum creatinine-based dose, respectively. Serum creatinine-based dosing produced trough concentrations predominantly in the 5-15-mg/L target range, with the smallest variability in both term and preterm neonates. As expected, when the target range was narrow and higher (15-20 mg/L), only 13-21% of patients were within the range across the four dosing regimens.CONCLUSION: Monte Carlo simulations based on our population pharmacokinetic model suggest that vancomycin dosing guidelines based on serum creatinine concentration have a greater likelihood of achieving trough concentrations in the 5-15-mg/L range compared with other evaluated dosing regimens. None of the four dosing regimens is suitable to produce target trough concentration of 15-20 mg/L in an acceptable number of patients.", "BACKGROUND: An outbreak of Clostridium difficile ribotype 027 infection (CDI) occurred at an university hospital, involving 19 departments. To determine what hospital-associated factors drove the outbreak of this particular strain we performed a case-control study.METHODS: Cases (n = 79), diagnosed with CDI due to C. difficile ribotype 027 were matched for age and treating medical specialty to four control patients (n = 316). Patients diagnosed with CDI due to other ribotypes were included as a second control group. A random selection of C. difficile ribotype 027 strains (n = 10) was genotyped by Whole Genome Sequencing (WGS).FINDINGS: WGS showed the outbreak was likely caused by a single strain of C. difficile (two or less single-nucleotide variants between isolates). Ninety-five percent of cases had used antibiotics, compared to 56% of controls. Previous admission to the intensive care unit (ICU) (OR: 2.4, 95% CI 1.0-5.6), longer length of stay (LOS), and recent hospital admission were associated with CDI ribotype 027. Cases were less likely to have been admitted to a ward with a known isolated CDI patient (OR: 0.2, 95% CI 0.1-0.6). Analysis of patients who stayed at the ICU (35 cases; 51 controls), indicated that the use of selective decontamination of the digestive tract (SDD) and a longer LOS in the ICU were associated with CDI risk.INTERPRETATION: In this large outbreak, any antibiotic use, including SDD use, appeared as a prerequisite for acquisition of the outbreak strain. The role of use of SDD and prolonged stay on the ICU could not be disentangled, but both factors can play a biologically plausible role in C. difficile acquisition and infection.", "Movements of D. discoideum vegetative amoebae responding to pteridine chemoattractants, folate acid and pterin, were recorded. A vector analysis of these images was performed to partition the speed and orientation components of these motility patterns. This study demonstrates that in addition to orientation (chemotaxis), stimulated speed (chemokinesis) is an important component of the directed migration of these amoebae. Furthermore, the primary difference in their response to folate versus pterin is in speed rather than orientation. The data support a model of directed migration of these cells in which there are (1) separate signal translation pathways consequent from folate versus pterin reception and (2) specific pathways leading to increase in orientation versus speed." ]

[ "We undertook a longitudinal study of the histological and biochemical changes at the neuromuscular junction (NMJ) in muscles of SOD1-G93A mice. We also assessed these functions in mice treated with a known heat shock protein inducer, arimoclomol. Tissue samples of treated and untreated mSOD mice were analysed for AChE and ChAT enzyme activities as markers of neuromuscular function. Sections of hindlimb muscles (TA, EDL and soleus) were also stained for succinate dehydrogenase and silver cholinesterase activities as well as for immunohistochemistry. Hsp70 levels were also measured from muscle samples using ELISA. Results showed that denervation and nerve sprouting were present at symptom onset in fast muscles, although slow muscles remained fully innervated. Cholinergic enzyme activities were reduced prior to denervation and declined further with disease progression. Reduction of endplate size, a slow to fast shift in muscle phenotype was also observed. Treatment with arimoclomol delayed the appearance of these changes, increased innervation, cholinergic enzyme activities and endplate size and reversed muscle fibre transformation. These beneficial effects of arimoclomol in muscles were accompanied by an increase in Hsp70 expression. In conclusion, our results indicate that pharmacological targeting of muscles at early stages of disease may be a successful strategy to ameliorate disease progression in ALS.", "Capnocytophaga canimorsus is part of normal gingival flora of dogs and cats. The organism can cause septicemia, meningitis, and endocarditis in humans after contact with dogs or cats. In spite of the frequency of gastrointestinal symptoms in C. canimorsus infection patients, specific gastrointestinal disease or clinical images have not been reported. We report a case of C. canimorsus bacteremia presenting with acute cholecystitis in elderly woman. She suffered from general fatigue and right upper abdominal pain. She had leukocytosis and abnormal liver function tests. She showed abnormal findings of the gallbladder by abdominal computed tomography and ultrasonography. She was diagnosed with acute cholecystitis without gallstones and was administered with antibiotics. C. canimorsus was isolated from blood cultures. A history of an insignificant wound secondary to a dog bite was elicited. She recovered completely with antibiotic treatment. This case revealed that C. canimorsus bacteremia can be presented with acute cholecystitis, suggesting that C. canimorsus could cause cholecystitis. And this cholecystitis can be treated with antibiotics without operation. Physicians seeing patients with acute cholecysitis should ask questions regarding animal contact.", "Collaborators: Granger CB, Wallentin L, Alexander JH, Ansell J, Diaz R, Easton JD, Gersh BJ, Hanna M, Horowitz J, Hylek EM, McMurray JJ, Mohan P, Verheugt FW, Diaz R, Bahit MC, Aylward P, Amerena J, Huber K, Bartunek J, Avezum A, Ezekowitz JA, Dorian P, Lanas F, Lisheng L, Zhu J, Isaza D, Jansky P, Husted S, Harjola VP, Steg PG, Hohnloser SH, Keltai M, Pais P, Xavier D, Lewis BS, De Caterina R, Goto S, Hermosillo AG, Alings AM, Atar D, Segura L, Ruzyllo W, Vinereanu D, Varshavsky S, Golitsyn S, Oh BH, Commerford P, Lopez-Sendon JL, Rosenquist M, Erol C, McMurray JJ, Parkhomenko A, Flaker G, Garcia D, Pfeffer MA, Diener HC, Maggione A, Pocock S, Rouleau JL, Wyse G, Alexander JH, Al-Khatib S, Lopes RD, Held C, Hylek EM, Bushnell C, Terent A, Leonardi S, Subherwal S, Eapen Z, Vavalle J, Zomorodi A, Kolls B, Berger J, Vergara J, Parikh D, Zia S, Stashenko G, Lombardi C, Matthews R, Hagstrom E, Akerblom A, Varenhorst C, Berntsson SG, Stenborg A, Lundstrom E, Guimaraes H, Flato U, Nacif S, Barros P, Echenique L, Rodrigues P, Armaganijan L, Lopes AC, Albrecht A, Vico M, Mackinnon I, Vogel D, Vico M, Gabito A, Cassettari A, Zaidman C, Montaña O, Hrabar A, Jure H, Lastiri H, Poy C, Caccavo A, Cuneo C, Colombo H, Rolandi F, Hershson A, Garrido M, Sanchez A, Bruno ML, Piskorz D, Cuadrado J, Hasbani E, Serra J, Cartasegna L, Schygiel P, Muratore C, Marino J, Sosa Liprandi MI, Guerrero RA, Ramos H, Mercado D, Guzman L, Beneitez C, Estepo J, Torrijos R, Retyk E, Vita N, Luciardi H, Casey M, Orlando S, Labarta MB, Santos D, Amerena J, Purnell P, Horowitz J, Salem H, Liu A, Zimmet L, Roger S, de Looze F, de Looze F, Lehman R, de Looze F, Jackson B, Ashby D, Heddle W, Rogers J, Brieger D, Martin P, Cross D, Walters D, Waites J, Counsell J, Lowy A, de Looze F, Huber K, Stockenhuber F, Pieske B, Striekwold H, Wollaert B, Nachtergaele H, Vijgen J, El Allaf D, Mairesse G, Boxho G, De Deyn PP, Vanderheyden M, Semeraro O, Desfontaines P, Leroy J, Provenier F, Bruneel B, Vrolix M, Peeters A, Deceuninck O, Saraiva JF, Reis G, Rossi P, Zimmermann S, Jaber J, Botelho R, Manenti E, Jorge J, Maia L, Leães P, Villaça Guimaraes Filho F, Fichino M, De Paola A, Indio do Brasil CK, Albuquerque D, Bodanese L, Matsubara L, Mourilhe Rocha R, Genta P, Meneghelo Z, Oliveira L, Lorga Filho A, Garbelini B Jr, Oliveira G, Teixeira M, Precoma D, Pelloso E, Muniz A, Valéria Braile MC, Ueda R, Rabelo Alves A Jr, Pimentel Filho P, Zimerman L, Coutinho M, Silveira J, Reis H, Moreira D, Paiva M, Aziz JL, Gois J, Dutra O, Yao L, Syan G, Coutu B, Chehayeb R, Sabe-Affaki G, Fortin C, Borts D, Bhargava R, Fell D, Cha J, Pandey A, Boucher P, Sabbah E, Ma P, Talbot P, Spence D, Wade A, Green M, Berlingieri J, Vizel S, Chan YK, Blostein M, Talajic M, Sterns L, Grondin F, Hruczkowski T, Labonte R, O'Mahony M, Rupka D, Mangat I, Dowell A, Kelly A, St Maurice F, Henein S, Saunders K, Lasko B, Sami M, MacKinnon R, Rizvi Q, O'Keefe D, Ricci J, Gervais B, Hart R, Bose S, Nawaz S, Connors S, Winkler L, Boileau M, Healey J, Collette R, Rebane T, Ramjattan B, Senior R, Therrien R, Wells P, Raffo C, Cobos J, Potthoff S, Stockins B, Pincetti C, Corbalan R, Vejar M, Potthoff S, Li W, Zhao S, Chen X, Wu S, Tan H, Wu S, Qu P, Jiang X, Wei M, Yang X, Li J, Ma S, Gu S, Dai QY, Li L, Yu B, Yin Y, Wang N, Gao L, Zhou SX, Wang JA, Li ZQ, Bai F, Zhang F, Lu G, Chen Y, Zhang Y, Jiang D, Zonggui W, Li H, Cao K, Lu Q, Li L, Hu T, Li H, Wang X, Botero R, Reyes A, Jaramillo N, Urina M, Velez S, Gomez E, Pava L, Isaza D, Dunaj M, Hudcovic M, Jerabek O, Brat R, Spinar J, Dedek V, Zidkova E, Podpera I, Cech M, Gorican K, Micko M, Stribrna M, Frost L, Torp-Pedersen C, Toftager Larsen C, Tuxen C, May O, Pedersen KE, Jensen G, Nielsen T, Nyvad O, Husted S, Gilså Hansen M, Egstrup K, Lomholdt J, Skagen K, Joen Jakobsen T, Olsen M, Grande P, Melin J, Tynni M, Harjola VP, Strand J, Parikka H, Jääskeläinen T, Corbelli JL, Gosse P, Mirode A, Mansourati J, Lavabre G, Defaye P, Steg PG, Kahrmann G, Horacek T, Bauer A, Spitzer S, Schlegl M, Winkelmann B, Vöhringer HF, Stenzel G, Haverkamp W, Harenberg J, Schumacher M, Wunderlich J, Natour M, Rieker W, Gass S, Brachmann J, Jung J, Poppert H, Häge R, Lickfett L, Schoeller R, Goedel-Meinen L, Utech A, Buerke M, Maschke M, Haberl R, von Hodenberg E, Griewing B, Schlachetzki F, Hamer H, Hoch T, Zabel M, Jordan R, Stögbauer F, Hetzel A, Weimar C, Schauerte P, Fischer D, Mügge A, Bittersohl A, Mügge A, Lee K, Yu C, Lakatos F, Vértes A, Kovács A, Takács J, Pálinkás A, Bakai J, Papp A, Illés Á, Tomcsányi J, Szakál I, László Z, Katona A, Jobbágy L, Keltai K, Dézsi C, Lupkovics G, Cziraki A, Mohácsi A, Simon K, Gupta S, Agarwal D, Fulwani M, Naik A, Nambiar A, Chidambaram N, Srinivasasastry B, Joseph J, Padinhare M, Khanna P, Grant P, Arneja J, Gadkari M, Garg N, Pothineni RB, Sathe S, Ramesh S, Malipeddi B, Bharani A, Gowdappa HB, Prakash VS, Dharmadhikari A, Bhandari S, Desai N, Banerjee S, Ghaisas N, Ramagiri B, Sinha S, Gojanur G, Duggal J, Jain V, Dani S, Singh P, Srikanthan V, Puri VK, Gopal R, Viskin S, Shochat M, Hayek T, Reisin L, Rosenheck S, Lewis B, Zimlichman R, Weiss A, Marmor A, Turgeman Y, Klainman E, Francis A, Lahav M, Omary M, Morris M, Olivieri C, Santonastaso M, Fenici R, Mos L, Ghirarduzzi A, De Caterina R, Novo S, Richiardi E, Testa S, Pini M, D'Angelo A, Barsotti A, Donati M, Chiariello M, Galli M, Casolo G, Moretti L, Atsushi Y, Yamamoto K, Goto S, Kihara H, Akihiko T, Saito T, Yoshii H, Sasaki T, Suwa M, Adachi S, Usada K, Nakamura Y, Hayashida K, Yamada T, Iwasawa T, Kawase Y, Sugi K, Murakami T, Satake K, Iwao T, Maemura K, Koretsune Y, Tsubokou Y, Yamashita M, Sato Y, Kouichi F, Yura S, Matsushima A, Iwade K, Kamakura S, Tanaka S, Murata H, Yamamoto S, Kobayashi Y, Higashi Y, Shinozaki T, Ikeda H, Hisaoka T, Node K, Takagi H, Ong TK, Abidin IZ, Yusof Z, Yusoff K, Maskon O, De los Rios Ibarra M, Alcocer Gamba M, Lopez Rosas E, Calvo Vargas C, Fajardo Campos P, Cordero-Cabra JA, JerJes-Sanchez C, Hernandez Santamaria I, Molina L, Olvera Ruiz R, Arean Martinez C, Gonzalez Guerra J, Morales Gonzalez I, Cervantes-Escarcega J, Chuquiure-Valenzuela EJ, Riojas C, Gonzalez Hermosillo J, Galicia A, Nierop P, Verheugt F, Daniels M, Lok D, Alings A, Scholten M, Plomp J, Derksen R, Bredero A, Zwart P, Schaap A, Michels H, Van der Zwaan C, Hysing J, Elle S, Omland T, Rønnevik P, Øie B, Otterstad JE, Bogale N, Kjærnli T, Halvorsen S, Bryhni B, Vikenes K, Cabrera W, Rodriguez A, Chavez C, Gamboa R, Segura L, Araoz O, Azanero R, Toce L, Medina F, Bustamante G, Rios Vasquez C, Zubiate M, Collado F, Morales-Palomares E, Sy R, Morales D, Rogelio G, Abola MT, Ramos E, Yamamoto M, Collado F, De Leon F, Abelardo N, Kania G, Szpajer M, Rajzer M, Janion M, Bronisz M, Ruzyllo W, Piepiorka M, Wendland M, Czerski T, Korzeniak R, Budaj A, Wawrzynska L, Ogorek M, Miekus P, Tracz W, Ocicka-Kozakiewicz A, Stepinska J, Kiedrowicz Z, Pasierski T, Kasprzak J, Galewicz M, Podogrodzka B, Krauze-Wielicka M, Chmielinski A, Boruczkowska-Kaszkowiak A, Piotrowski W, Vinereanu D, Stamate S, Cinteza M, Tanaseanu CM, Dan GA, Benedek I, Ionescu RM, Lighezan D, Salajan A, Carasca E, Capalneanu R, Pop C, Fierbinteanu-Braticevici CG, Zdrenghea DT, Gaita D, Manitiu I, Nanea T, Arsenescu Georgescu C, Chizhov P, Kastanayan A, Oleynikov V, Treshkur T, Govorin A, Zhelninova T, Barbarash O, Novikova T, Reshetko O, Sivkova E, Obrezan A, Panchenko E, Popov S, Ivleva A, Zotov D, Gordienko A, Kamalov G, Chernichka I, Levin A, Zrazhevsky K, Golitsyn S, Shilkina N, Golovach A, Filonenko G, Bondarev S, Orlov V, Bragina A, Koziolova N, Svistov A, Shustov S, Libov I, Kisliak O, Privalova E, Aleksandrov O, Mazur E, Karpov Y, Belenky D, Kostenko V, Shubik Y, Ruda M, Arutyunov G, Eltishcheva V, Sidorenko B, Oseshnyuk R, Boyarkin M, Pozdnyakov Y, Staxhinskiy N, Sinopalnikov A, Yakushin S, Koniakhin A, Yarohno N, Sizova Z, Zadionchenko V, Klimov I, Duplyakov D, Kanorsky S, Mareev V, Terekhov V, Arkhipov V, Sotnikova T, Yakusevich V, Lesnov V, Gordeev I, Gratsiansky N, Shalaev S, Sulimov V, Talibov O, Zemtsovsky E, Azarin O, Tan RS, Thorne J, De Jong D, Basson M, van Zyl L, Commerford P, Weich H, van Nieuwenhuizen E, Roos J, Kelbe D, Viljoen J, Hong TJ, Oh BH, Park KS, Jeong MH, Rhim CY, Choi DJ, Sung JH, Kim YN, Bae JH, Tahk SJ, Ryu KH, Kwon SU, Rho TH, Cha TJ, Shin DG, Álvarez García P, Vida M, Galve E, Bruguera J, Roquer J, Olías de la Cruz F, Paz Bermejo MA, Segura T, Gómez Gómez JH, Ugarriza A, Plaza Pérez I, Villacastin J, Bertomeu V, Vargas R, Serena Leal J, Egido Herrero J, Bethencourt González A, Albert X, Gonzalez Juanatey C, Medrano V, Vivancos J, Andersson T, Lindholm CJ, Al-Khalili F, Höglund C, Rosenqvist M, Bergström O, Herlitz J, Rasmanis G, Johansson L, Christersson C, Fredholm O, Al-Khalili F, Callander M, Po H, Pan JP, Tseng CD, Shyu KG, Chu SH, Kultursay H, Gorenek B, Erol C, Lip G, Albazzaz M, Kadr H, Cohen A, Cooke J, Agarwal A, Brack M, Pye M, Anderson M, Dunn F, Wong YK, Glen S, Ford G, Alwail A, Yousef Z, Blagden M, Murdoch D, McInnes G, Camm J, Ridsdill Smith W, McMurray JJ, Senior R, Webster J, Dutka D, McClements B, Yousef Z, Levy T, Yogasundram S, Moriarty A, McCullagh M, Flather J, Gumbley M, Findlay I, Davies J, Cooke A, Ahsan A, Cannon J, Bakhai A, Jacob A, Trouton T, Ajala A, Bartkowiak A, Humiston D, Kufs W, Klancke K, Jetty P, Gupta D, Nadar V, Yousuf K, Sosa-Suarez G, Gill S, Wukelic M, Mayer N, Colan D, Haskel E, Grena P, Haught W, Walsh R, Carr K, Tahirkheli N, Jardula M, Cebe J, Bloom S, Bilazarian S, Gilmore R, Jaffrani N, Goldscher D, Lebowitz A, Friedlander I, Stein M, Promisloff S, Magnano A, Dean J, Gerber J, Perloff D, Cohen Y, Meholick A, Tobin T, Acheatel R, Levanovich P, Ip J, Porterfield J, Seshadri N, McKenzie M, Alfieri A, Gazmuri R, Beanblossom B, Van Hamersveld D, McCriskin J, Gelernt M, Bowden W, Sotolongo C, Lang J, Kaatz S, Agnone F, Hassman D, Flores E, Albrecht F, Hassel C, Quartner J, LaFata J, Bedwell N, Herzog W, Amin J, Usedom J, Brockmyre A, Abadier R, Corder C, Marple R, Lovell C, Henry W 3rd, Chhabra A, Baker S, Bedoya R, Sandoval R, Nathan M, Garcia D, Vora K, Sloan S, Kosinski E, Foster R, Salacata A, Weachter R, Bredlau C, Mehta P, Russo C, Swint R Sr, Rosenthal S, Bybee K, Peart B, Chaudhuri P, Iteld B, Staab M, Rhodes D, Kappler J, Mandviwala M, Niedermaier O, Sofley C, Heiman M, Gips S, Harris R, East C, Nguyen V, Huling R, Thadani U, Travis D, Maislos F, West M, Castello R, Cohen K, Karlsberg R, Schmedtje J Jr, Gottlieb D, MacKinnon A, Noble G, O'Neill P, Roth J, Kobayashi J, Honan M, Hanovich G, Ehrlich S, Wilson W, Warner A, Rubin A, Rivera E, Leu S, Smith L, Agaiby J, Jan M, Gould R, Weiner S, Fleming J, Hemphill J, Parr K, Stoddard M, Curran P, Kurrelmeyer K, Desai V, Kereiakes D, Schwarz E, Lillestol M, Vazquez-Tanus J, Vicari R, White J, Shroff R, Fierer R, Vijay N, Hamad A, Kozinn M, Young D, Fenton S, Ouyang P, Wellford A, Zwerner P, Meyer P, Foley J, Boyle A, Dotani M, Skolnick A, Rodriguez-Fierro C, Hattler B, Rubin M, Hartley P, Tami L, Ball E, McPherson C, Eisenberg S, Niazi I, Orlov M, Bachhuber B, Massey C, Phillips W, Mouhayar E, Griffin J, Blumberg E, Slabic S, Danisa K, Samal A, Rohrbeck S, McCullough P, Dohan D, Aycock G, Jones A, Anderson J, Silverman R, Smith W, Mishkel D, Patterson N, Moore H, Kabour A, Muttreja M, Jaffrani W, Vidic T, Kent S, Platt B, Goldberg R, Kulback S, Patel R, Bazzi A, Goldman S, Roman A, Levin C, Lachterman B, Chandrashekhar Y, Aisiku I, Powers C, Engeron E, Bernstein R, Shah S, Strobel J, Punatar H, Garcia R, Linden D, Al-Mudamgha A, Quick A, Kramer J, Feldman G, Stapleton D, Davis M, Graff J, Galizia J, Wassmer P, Chiu D, Ison R, Curry K, Finneran M, Solomon A, Schifferdecker B, Seger J, Alexander A, Yates S, Ashley R Jr, Cordero-Sepulveda J, Cowen P, Ayres T, Kowalski B, Anton S, Phillips J, Donovan D, Patel A, Smith R, Updegrove J, Buxton A, Clark D, Margolis J, Brooks G, Pernenkil R, Walters J, Richards M, Maccaro P, Pieniek M, Garcia Pulido J, Lee CW, Ilvento J, Riff D, Blue B, Welker J, Karunaratne H, Santucci P, Vatutin M, Kraiz I, Mostovoy Y, Karpenko O, Tseluyko V, Kononenko L, Volkov V, Parkhomenko A, Popik G, Chopey I, Burmak Y, Pavlyk S, Vizir V, Barna O, Sychov O, Vykhovanyuk I, Tashchuk V, Khomazjuk I, Andrievskaya S, Telyatnikova Z, Bondarchuk O, Netiazhenko V, Seredyuk N, Koval O, Kovalsky I, Bazylevych A, Lysenko G, Borschivsky M, Yagensky A, Dzyak G, Bereznyakov I, Rudenko L, Ignatenko G, Amosova K, Voloshyna O, Ivanova L, Tykhonova S, Suprun E.", "Chromatin insulators demarcate expression domains by blocking the cis effects of enhancers or silencers in a position-dependent manner. We show that the chromatin insulator protein CTCF carries a post-translational modification: poly(ADP-ribosyl)ation. Chromatin immunoprecipitation analysis showed that a poly(ADP-ribosyl)ation mark, which exclusively segregates with the maternal allele of the insulator domain in the H19 imprinting control region, requires the bases that are essential for interaction with CTCF. Chromatin immunoprecipitation-on-chip analysis documented that the link between CTCF and poly(ADP-ribosyl)ation extended to more than 140 mouse CTCF target sites. An insulator trap assay showed that the insulator function of most of these CTCF target sites is sensitive to 3-aminobenzamide, an inhibitor of poly(ADP-ribose) polymerase activity. We suggest that poly(ADP-ribosyl)ation imparts chromatin insulator properties to CTCF at both imprinted and nonimprinted loci, which has implications for the regulation of expression domains and their demise in pathological lesions.", "PURPOSE: Trifluridine/tipiracil (FTD/TPI; TAS-102, Lonsurf®), a novel form of chemotherapy for metastatic colorectal cancer (mCRC), has shown clinical benefit in the global, phase III RECOURSE trial, regardless of patient age. Here, we report the safety and tolerability profile of FTD/TPI from an expanded-access program (EAP) in the US patients with mCRC whose disease has progressed on the standard therapies.METHODS: A total of 549 patients (≥ 18 years) with histologically confirmed mCRC following two or more regimens of standard therapy and an Eastern Cooperative Oncology Group performance status of 0 or 1 participated in this open-label EAP. During the 28-day treatment cycle, patients took FTD/TPI 35 mg/m2 twice daily for 5 days followed by 2 days of rest for 2 weeks, with a 14-day rest period. Data were collected for therapy duration, treatment discontinuation, and adverse events. Age-based post hoc analysis was performed to determine the safety of FTD/TPI in elderly (≥ 65 years) versus younger (< 65 years) patients.RESULTS: FTD/TPI-treated patients in this EAP had a similar therapy duration and time to treatment discontinuation to those in the RECOURSE trial. The safety profile in elderly patients was consistent with that in younger patients, with no unexpected safety concerns.CONCLUSIONS: This USA-based, open-label EAP has confirmed a similar safety and tolerability profile for FTD/TPI to that observed in the RECOURSE trial. Furthermore, FTD/TPI is well tolerated and can be considered as a treatment option in elderly patients with mCRC.TRIAL REGISTRATION: NCT02286492.", "Notch-1 is a protein that influences cell fate decisions, with its expression occurring primarily during embryogenesis and development. However, Notch-1 is also expressed in the adult brain, in regions with high synaptic plasticity, particularly the hippocampus. Its role in adults is unknown; however, it may impact neurite outgrowth or cell differentiation in adult brain regions undergoing neurogenesis. Notch-1 is increased in Alzheimer's disease (AD); however, its expression in other CNS degenerative diseases has not been described. To begin to define the range of degenerative disorders where Notch-1 expression is altered, we examined Notch-1 immunoreactivity in a variety of neurodegenerative diseases to determine whether its increase is selective for AD. We examined sections of hippocampus from 13 AD, 13 classical Pick's disease (PiD; with Pick bodies), 4 dementia lacking distinctive histopathology (DLDH) and 8 control brains, emphasizing hippocampal (dentate gyrus) pathology. We determined that Notch-1 immunoexpression is increased in AD and PiD relative to control cases. DLDH cases were not significantly different than control cases with respect to Notch-1 expression. Given the increase in Notch-1 immunoexpression in AD and PiD, two diseases where abnormal tau aggregates are present, and the lack of Notch-1 immunoexpression in DLDH (where tau aggregates are absent), we cannot rule out the possibility that tau aggregates are associated with Notch-1 expression in neurodegenerative diseases.", "Bladder cancer arises from the epithelial lining of the urinary bladder, and it is known as transitional cell carcinoma (TCC). Tobacco smoking is the main known contributor to urinary bladder cancer. However thirty percent of bladder tumors probably result from occupational exposure in the workplace to carcinogens. Immunotherapy by intravesicular delivery of Bacillus Calmette–Guérin (BCG) is used to treat and prevent the recurrence of superficial bladder cancer. Successful BCG immunotherapy for bladder cancer is associated with proper induction of T helper (Th)1 immunity. In bladder cancer patients after intravesicular BCG, urine was found to contain high levels of IP-10, and Interferon (IFN)-γ. TCC and endothelial cell lines were able to secrete IP-10 in response to BCG or IFN stimulation in vitro. Furthermore intravesicular BCG induces a cytokine-rich urinary microenvironment that is inhibitory to human endothelial cells and it is anti-angiogenetic by the induction of Th1 chemokines. Other studies suggest that therapeutic strategies involving Th1 induction and Th2 dampening may improve responses to immunotherapy. Further studies are needed to evaluate the IP-10 in circulation, and urine, as prognostic marker of bladder cancer patients, also in relation to BCG immunotherapy", "The current Caenorhabditis elegans genomic annotation has many genes organized in operons. Using directionally stitched promoterGFP methodology, we have conducted the largest survey to date on the regulatory regions of annotated C. elegans operons and identified 65, over 25% of those studied, with internal promoters. We have termed these operons \"hybrid operons.\" GFP expression patterns driven from internal promoters differ in tissue specificity from expression of operon promoters, and serial analysis of gene expression data reveals that there is a lack of expression correlation between genes in many hybrid operons. The average length of intergenic regions with putative promoter activity in hybrid operons is larger than previous estimates for operons as a whole. Genes with internal promoters are more commonly involved in gene duplications and have a significantly lower incidence of alternative splicing than genes without internal promoters, although we have observed almost all trans-splicing patterns in these two distinct groups. Finally, internal promoter constructs are able to rescue lethal knockout phenotypes, demonstrating their necessity in gene regulation and survival. Our work suggests that hybrid operons are common in the C. elegans genome and that internal promoters influence not only gene organization and expression but also operon evolution.", "AIM: Brain natriuretic peptide (BNP) is a cardioactive molecule produced in the myocardium. BNP is a sensitive marker of cardiac failure and its measurement in blood could be useful to the diagnosis and the treatment of this disease. Sporting activities, especially endurance ones, can induce cardiac problems, owing to the high workload for the myocardium during long and ultralong heavy effort. There are 2 papers describing the behavior of BNP in endurance events. BNP was elevated in marathoners, immediately after the race and also after 4 h. We studied the behavior of BNP in the triathlon, which is a complex sport characterized by 3 different activities (swimming, cycling, running).METHODS: We recruited 49 athletes, all males, except for 4 females; 2 athletes did not finish the race and were not included in the statistical analysis in 2 different competitions. In these subjects we measured BNP using an immunological method before and after a triathlon.RESULTS: No statistical significance between BNP values, before and after the triathlon, was found.CONCLUSIONS: We found no significant differences between pre- and postcompetition BNP values. Moreover, the range of values in both the blood drawings are similar of those of the general population, representing the biological variability of the analyte. The values in regularly trained athletes,, are not different from the general population and BNP is not modified by a triathlon, a typical endurance sport performance. We can underline that BNP increases in plasma are induced by heavy pathologies and are not influenced by physical activities, even strenuous ones.", "INTRODUCTION: Increasing evidence indicates that microRNAs (miRNAs) play a critical role in the pathogenesis of inflammatory diseases. The aim of the study was to investigate the expression pattern and function of miRNAs in CD4+ T cells from patients with rheumatoid arthritis (RA).METHODS: The expression profile of miRNAs in CD4+ T cells from synovial fluid (SF) and peripheral blood of 33 RA patients was determined by microarray assay and validated by qRT-PCR analysis. The correlation between altered expression of miRNAs and cytokine levels was determined by linear regression analysis. The role of miR-146a overexpression in regulating T cell apoptosis was evaluated by flow cytometry. A genome-wide gene expression analysis was further performed to identify miR-146a-regulated genes in T cells.RESULTS: miRNA expression profile analysis revealed that miR-146a expression was significantly upregulated while miR-363 and miR-498 were downregulated in CD4+ T cells of RA patients. The level of miR-146a expression was positively correlated with levels of tumor necrosis factor-alpha (TNF-alpha), and in vitro studies showed TNF-alpha upregulated miR-146a expression in T cells. Moreover, miR-146a overexpression was found to suppress Jurkat T cell apoptosis. Finally, transcriptome analysis of miR-146a overexpression in T cells identified Fas associated factor 1 (FAF1) as a miR-146a-regulated gene, which was critically involved in modulating T cell apoptosis.CONCLUSIONS: We have detected increased miR-146a in CD4+ T cells of RA patients and its close correlation with TNF-alpha levels. Our findings that miR-146a overexpression suppresses T cell apoptosis indicate a role of miR-146a in RA pathogenesis and provide potential novel therapeutic targets.", "The interaction of DNA with proteins in the context of chromatin has to be tightly regulated to achieve so different tasks as packaging, transcription, replication and repair. The very rapid and transient post-translational modification of proteins by poly(ADP-ribose) has been shown to take part in all four. Originally identified as immediate cellular answer to a variety of genotoxic stresses, already early data indicated the ability of this highly charged nucleic acid-like polymer to modulate nucleosome structure, the basic unit of chromatin. At the same time the enzyme responsible for synthesizing poly(ADP-ribose), the zinc-finger protein poly(ADP-ribose) polymerase-1 (PARP1), was shown to control transcription initiation as basic factor TFIIC within the RNA-polymerase II machinery. Later research focused more on PARP-mediated regulation of DNA repair and cell death, but in the last few years, transcription as well as chromatin modulation has re-appeared on the scene. This review will discuss the impact of PARP1 on transcription and transcription factors, its implication in chromatin remodeling for DNA repair and probably also replication, and its role in controlling epigenetic events such as DNA methylation and the functionality of the insulator protein CCCTC-binding factor.", "CCCTC-binding factor (CTCF) is a ubiquitous Zn-finger-containing protein with numerous recognized functions, including, but not limited to, gene activation and repression, enhancer-blocking, X-chromosome inactivation, and gene imprinting. It is believed that the protein performs such a variety of functions by interacting with an array of very diverse proteins. In addition, CTCF undergoes several post-translational modifications, including poly(ADP-ribosyl)ation. The PARylated form of CTCF has recently been implicated in two important functions: gene imprinting and control of ribosomal gene transcription. Here, we summarize and critically discuss the available data on the interplay between CTCF and poly(ADP-ribosyl)ation in these two processes. We consider the newly described phenomena in the broader context of PARP's activities, including the crucial role of protein PARylation in the regulation of the genome methylation pattern.", "Our previous data have shown that in L929 mouse fibroblasts the control of methylation pattern depends in part on poly(ADP-ribosyl)ation and that ADP-ribose polymers (PARs), both present on poly(ADP-ribosyl)ated PARP-1 and/or protein-free, have an inhibitory effect on Dnmt1 activity. Here we show that transient ectopic overexpression of CCCTC-binding factor (CTCF) induces PAR accumulation, PARP-1, and CTCF poly(ADP-ribosyl)ation in the same mouse fibroblasts. The persistence in time of a high PAR level affects the DNA methylation machinery; the DNA methyltransferase activity is inhibited with consequences for the methylation state of genome, which becomes diffusely hypomethylated affecting centromeric minor satellite and B1 DNA repeats. In vitro data show that CTCF is able to activate PARP-1 automodification even in the absence of nicked DNA. Our new finding that CTCF is able per se to activate PARP-1 automodification in vitro is of great interest as so far a burst of poly(ADP-ribosyl)ated PARP-1 has generally been found following introduction of DNA strand breaks. CTCF is unable to inhibit DNMT1 activity, whereas poly(ADP-ribosyl)ated PARP-1 plays this inhibitory role. These data suggest that CTCF is involved in the cross-talk between poly(ADP-ribosyl)ation and DNA methylation and underscore the importance of a rapid reversal of PARP activity, as DNA methylation pattern is responsible for an important epigenetic code.", "BACKGROUND CONTEXT: The Morel-Lavallée lesion occurs from a compression and shear force that usually separates the skin and subcutaneous tissue from the underlying muscular fascia. A dead space is created that becomes filled with blood, liquefied fat, and lymphatic fluid from the shearing of vasculature and lymphatics. If not treated appropriately, these lesions can become infected, cause tissue necrosis, or form chronic seromas.PURPOSE: To review appropriate identification and treatment of Morel-Lavallée lesions in spinopelvic dissociation patients.STUDY DESIGN: Uncontrolled case series.METHODS: Retrospective review of medical records. No funding was received in support of this study. The authors report no conflicts of interest.RESULTS: We present four cases of patients with traumatic spinopelvic dissociation. All had concomitant lumbosacral Morel-Lavallée lesions. All four trauma patients suffered traumatic spinopelvic dissociation with concomitant lumbosacral Morel-Lavallée lesions. Appropriate treatment included irrigation and debridement, drainage, antibiotics, and vacuum-assisted wound closure.CONCLUSIONS: Our series reflects an association of Morel-Lavallée lesion in spinopelvic dissociation trauma patients. Possibly, the rotatory injury that occurs at the spinopelvic junction creates a shear force to form the Morel-Lavallée lesion. When presented with a spinopelvic dissociation patient, one should be prepared to treat a Morel-Lavallée lesion.", "Insulin-like growth factor 1 (IGF-1)-directed therapy is currently at a crossroads. After decades of research, several agents targeting the IGF pathway are now in clinical trials. One recent phase III trial of the IGF-1R inhibitor figitumumab in patients with non-small-cell lung cancer was discontinued after an interim analysis showed no survival improvement. Clinical trials for patients with sarcoma have demonstrated impressive anti-tumor activity in cases where the IGF-1 pathway is activated, such as in Ewing sarcoma; however, acquired resistance has been common. Recently, randomized phase II trials combining IGF-1 R with epidermal grown factor receptor (EGFR) inhibition in colorectal cancer have been completed. Preclinical studies have indicated that several biomarkers may have potential predictive value. Studies of IGF-1R inhibitors in gastrointestinal cancers are currently ongoing in pancreatic, gastroesophageal, hepatocellular, and colorectal cancers. A critical analysis of prior work in this field and a rational strategy for maximizing success on the basis of biomarker use are necessary.", "A large part of the mammalian genome is transcribed into noncoding RNAs. Long noncoding RNAs (lncRNAs) have emerged as critical epigenetic regulators of gene expression. Distinct molecular mechanisms allow lncRNAs either to activate or to repress gene expression, thereby participating in the regulation of cellular and tissue function. LncRNAs, therefore, have important roles in healthy and diseased hearts, and might be targets for therapeutic intervention. In this Review, we summarize the current knowledge of the roles of lncRNAs in cardiac development and ageing. After describing the definition and classification of lncRNAs, we present an overview of the mechanisms by which lncRNAs regulate gene expression. We discuss the multiple roles of lncRNAs in the heart, and focus on the regulation of embryonic stem cell differentiation, cardiac cell fate and development, and cardiac ageing. We emphasize the importance of chromatin remodelling in this regulation. Finally, we discuss the therapeutic and biomarker potential of lncRNAs." ]