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[ "BACKGROUND: Idiopathic thrombotic thrombocytopenic purpura (TTP) is a rare hematological emergency characterized by the pentad of microangiopathic hemolytic anemia, thrombocytopenia, neurological symptoms, renal injury, and fever that is invariably fatal if left untreated. Prompt intervention with plasma exchange minimizes mortality and is the cornerstone of therapy. Rare reports have described \"pseudo-TTP\" driven by extreme hematologic abnormalities resulting from deficiency of vitamin B12. Distinguishing between these entities can pose a diagnostic and therapeutic challenge.CASE PRESENTATION: A 77 year old female presented with altered mental status, renal insufficiency, thrombocytopenia and evidence of microangiopathic hemolytic anemia, suggesting TTP. Workup demonstrated macrocytosis and reticulocytopenia, and B12 level was unmeasurably low. Other elements of her clinical presentation, including volume loss and bleeding suggested a multifactorial pathogenesis could be contributing to her laboratory abnormalities, reducing the likelihood that she had TTP. The risks and benefits of treating aggressively with therapeutic plasma exchange (TPE) for TTP were considered given the diagnostic possibilities. The patient received TPE initially, with rapid de-escalation after her clinical response suggested \"pseudo-TTP\" from B12 deficiency was the driving the process. B12 supplementation corrected her hematologic abnormalities and she remains well two years after presenting.CONCLUSIONS: TTP is a rare condition with fatal consequences if left untreated. Guidelines recommend TPE even if there is uncertainty about the diagnosis of TTP. B12 deficiency is common, though not typically associated with severe hematologic abnormalities. We compare the presenting characteristics of all thirteen cases of pseudo-TTP reported in the literature with those from patients in case series of TTP to suggest a set of parameters that can help clinicians distinguish between pseudo-TTP and TTP and guide decision making regarding intervention. Evaluation of all TTP cases should include a B12, methylmalonic acid level and reticulocyte count. Reticulocytopenia suggests B12 deficiency. Finally an LDH level above 2500 IU/L is relatively uncommon in TTP and should suggest consideration of B12 deficiency.", "The present paper reviews classification and mode of action of agents that suppress extrasystoles and tachyarrhythmias. These are classified according to their electrophysiological effects observed in isolated cardiac tissues in vitro (Vaughan Williams, 1989). Fast sodium channel blockers (class I) which reduce the upstroke velocity of the action potential are usually subclassified into three groups, class I A-C, according to their effect on the action potential duration. Beta-adrenergic antagonists (class II) exert their effects by antagonizing the electrophysiological effects of beta-adrenergic catecholamines. Class III antiarrhythmic agents (eg amiodarone) prolong the action potential and slow calcium channel blockers (class IV) suppress the calcium inward current and calcium-dependent action potentials. The classification of antiarrhythmic drugs is still under debate. This particularly applies to agents of class I and III. The effect of class I agents is frequency-dependent because the binding affinity of these drugs to the sodium channel is modulated by the state of the channel (modulated receptor hypothesis). Class I agents bind to the channel in the activated and inactivated state and dissociate from the channel in the rested state. This occurs at a drug-specific rate so that class I agents can be subclassified into only two groups, namely in those of the slow- and fast-recovery type respectively (time constant of reactivation greater or smaller than 1 s). Slow-recovery class I agents affect regular action potentials at normal heart rates which can more easily lead to a lengthening of the QRS duration in the ECG, to conduction disturbances and hence to pro-arrhythmic effects.(ABSTRACT TRUNCATED AT 250 WORDS)", "Achalasia is one of the most studied esophageal motility disorders. However, the pathophysiology and reasons that patients develop achalasia are still unclear. Patients often present with dysphagia to solids and liquids, regurgitation, and varying degrees of weight loss. There is significant latency prior to diagnosis, which can have nutritional implications. The diagnosis is suspected based on clinical history and confirmed by esophageal high-resolution manometry testing. Esophagogastroduodenoscopy is necessary to rule out potential malignancy that can mimic achalasia. Recent data presented in abstract form suggest that patients with type II achalasia may be most likely, and patients with type III achalasia may be least likely, to report weight loss compared to patients with type I achalasia. Although achalasia cannot be permanently cured, palliation of symptoms is possible in over 90% of patients with the treatment modalities currently available (pneumatic dilation, Heller myotomy, or peroral endoscopic myotomy). This article reviews the clinical presentation, diagnosis, and management options in patients with achalasia, as well as potential insights into histopathologic differences and nutritional implications of the subtypes of achalasia.", "BACKGROUND: de Quervain's disease is an inadequacy into the first extensor compartment of wrist between the osteofibrous tunnel and the tendons. This mechanical conflict generates a tenosynovitis of the extensor pollicis brevis and the abductor pollicis longus tendons in first dorsal extensor compartment of the wrist.AIM: (1) To compare the clinical results obtained by longitudinal and transverse incisions and (2) the implication of clinical results in Indian population.MATERIALS AND METHODS: This study was conducted at Kalpana Chawla Government Medical College, Karnal, Haryana. The inclusion criteria were positive Finkelstein's test and no response to non-surgical treatment for 6 weeks. Forty-eight patients with de Quervain's disease who did not respond to conservative treatment were operated with two different incisions. The patients were followed at 6 weeks, 3 and 6 months to compare the surgical outcomes.RESULTS: During a three-month follow-up, a significant difference was shown between the two methods (p = 0.0001). Results of surgical treatment with longitudinal incision were better (only one hypertrophic scar), but there were 12 postoperative complications with transverse incision. Visual analog scale (VAS) was used to evaluate the hypertrophic scar. In transverse incision group, out of five patients, four patients who developed hypertrophic scar have poor score according to VAS.CONCLUSION: Overall, longitudinal incision should be used for surgical treatment for de Quervain's disease due to lower risk of complications.", "BACKGROUND: Canonical Notch signaling is initiated when ligand binding induces proteolytic release of the intracellular part of Notch (ICN) from the cell membrane. ICN then travels into the nucleus where it drives the assembly of a transcriptional activation complex containing the DNA-binding transcription factor CSL, ICN, and a specialized co-activator of the Mastermind family. A consensus DNA binding site motif for the CSL protein was previously defined using selection-based methods, but whether subsequent association of Notch and Mastermind-like proteins affects the DNA binding preferences of CSL has not previously been examined.PRINCIPAL FINDINGS: Here, we utilized protein-binding microarrays (PBMs) to compare the binding site preferences of isolated CSL with the preferred binding sites of CSL when bound to the CSL-binding domains of all four different human Notch receptors. Measurements were taken both in the absence and in the presence of Mastermind-like-1 (MAML1). Our data show no detectable difference in the DNA binding site preferences of CSL before and after loading of Notch and MAML1 proteins.CONCLUSIONS/SIGNIFICANCE: These findings support the conclusion that accrual of Notch and MAML1 promote transcriptional activation without dramatically altering the preferred sites of DNA binding, and illustrate the potential of PBMs to analyze the binding site preferences of multiprotein-DNA complexes.", "Circular RNAs (circRNAs) are a class of newly-identified non-coding RNA molecules. CircRNAs are conserved across different species and display specific organization, sequence, and expression in disease. Moreover, circRNAs' closed ring structure, insensitivity to RNase, and stability are advantages over linear RNAs in terms of development and application as a new kind of clinical marker. In addition, according to recent studies, circular RNA-7 (ciRS-7) acts as a sponge of miR-7 and thus inhibits its activity. Numerous evidences have confirmed expression of miR-7 is dysregulated in cancer tissues, however, whether ciRS-7 invovled in oncogenesis by acting as sponge of miR-7 remains unclear. Most recently, a study reported ciRS-7 acted as an oncogene in hepatocellular carcinoma through targeting miR-7 expression. This suggest ciRS-7/ miR-7 axis affects oncogenesis, and it provides a new perspective on the mechanisms of decreased miR-7 expression in cancer tissues. Discovery of sponge role of circRNAs caused researchers to more closely explore the underlying mechanism of carcinogenesis and has significant clinical implications, and may open a new chapter in research on the pathology and treatment of cancers. This review summarizes the structure and function of circRNAs and provides evidence for the impact of ciRS-7 in promoting the development of cancer by acting as sponge of miR-7.", "This paper reviews the current knowledge of leishmaniasis epidemiology in Venezuela, Colombia, Ecuador, Peru, and Bolivia. In all 5 countries leishmaniasis is endemic in both the Andean highlands and the Amazon basin. The sandfly vectors belong to subgenera Helcocyrtomyia, Nyssomiya, Lutzomyia, and Psychodopygus, and the Verrucarum group. Most human infections are caused by Leishmania in the Viannia subgenus. Human Leishmania infections cause cutaneous lesions, with a minority of L. (Viannia) infections leading to mucocutaneous leishmaniasis. Visceral leishmaniasis and diffuse cutaneous leishmaniasis are both rare. In each country a significant proportion of Leishmania transmission is in or around houses, often close to coffee or cacao plantations. Reservoir hosts for domestic transmission cycles are uncertain. The paper first addresses the burden of disease caused by leishmaniasis, focusing on both incidence rates and on the variability in symptoms. Such information should provide a rational basis for prioritizing control resources, and for selecting therapy regimes. Secondly, we describe the variation in transmission ecology, outlining those variables which might affect the prevention strategies. Finally, we look at the current control strategies and review the recent studies on control." ]

[ "Vision screening tests within the limits of industrial medicine examinations, together with physical examinations, were done on human individuals by means of pseudo-isochromatic charts in order to detect \"red-green blindness\". The tests were carried out on 1589 individuals (males and females) from 10 medium-scale plants of the Saarbrücken area (Federal Republic of Germany). The results obtained from male individuals by 919 Ishihara-tests were only considered, categorized and graphically represented according to their age groups. The data have been collected from the cases examined mostly between the years 1976 to 1977. About 1500 cases were examined per year. Because the samples were not selected at random, one has to be cautious with regard to the statistical interpretations of the results. However, due to the large number of cases included in the study, it can be statistically represented. The histogram illustrating the distribution of colour-vision deficiency, according to each age group, shows the highest peak at an age range of 30 to 35 years. This indicates that a considerable number of cases with colour-vision deficiency was discovered late. The individuals have to be early examined by school physicians, house physicians, occupational physicians, internists or ophthalmologists with this colour-vision screening test, before they enter professional life. Some symptomatical complexes of internal diseases and human genetics, i.e. related to \"colour-vision blindness\" are also emphasized hemophilia and hemolytic anemia due to glucose-6-phosphate dehydrogenase deficiency.", "OBJECTIVE: Describe the clinical presentation, diagnostic evaluation, and successful treatment of a case of symptomatic unilateral lumbosacral junction pseudarticulation using a novel radiofrequency nerve ablation technique.CASE: A 56-year-old female patient who had suffered with low back and right upper buttock pain for 16 years experienced incomplete relief with L4/5 facet joint radiofrequency ablation. She was found to have an elongated right L5 transverse process that articulated with the sacral ala (Bertolotti's syndrome). Fluoroscopically guided local anesthetic/corticosteroid injection into the pseudarthrosis eliminated her residual right buttock pain for the duration of the local anesthetic only. Complete pain relief was achieved by injecting local anesthetic circumferentially around the posterior pseudarthrosis articular margin. Accordingly, bipolar radiofrequency strip thermal lesions were created at the same locations. Complete pain relief and full restoration of function was achieved for 16 months postprocedure.CONCLUSION: This case report describes a novel radiofrequency technique for treating symptomatic lumbosacral junction pseudarticulation that warrants further evaluation.", "Author information:(1)Division of Genomic Technologies (DGT), RIKEN Center for Life Science Technologies (CLST), Kanagawa 230-0045, Japan.(2)RIKEN Omics Science Center (OSC), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.(3)Division of Genomic Technologies (DGT), RIKEN Center for Life Science Technologies (CLST), Kanagawa 230-0045, Japan RIKEN Omics Science Center (OSC), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.(4)RIKEN Omics Science Center (OSC), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama 351-0198, Japan.(5)Division of Genomic Technologies (DGT), RIKEN Center for Life Science Technologies (CLST), Kanagawa 230-0045, Japan RIKEN Omics Science Center (OSC), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, Western Australia, Australia.(6)Division of Genomic Technologies (DGT), RIKEN Center for Life Science Technologies (CLST), Kanagawa 230-0045, Japan takeya.kasukawa@riken.jp.(7)Division of Genomic Technologies (DGT), RIKEN Center for Life Science Technologies (CLST), Kanagawa 230-0045, Japan RIKEN Omics Science Center (OSC), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama 351-0198, Japan Preventive Medicine and Applied Genomics Unit, RIKEN Advanced Center for Computing and Communication, Kanagawa 230-0045, Japan kawaji@gsc.riken.jp.", "Bromodomains are present in many chromatin-associated proteins such as the SWI/SNF and RSC chromatin remodelling and the SAGA HAT (histone acetyltransferase) complexes, and can bind to acetylated lysine residues in the N-terminal tails of the histones. Lysine acetylation is a histone modification that forms a stable epigenetic mark on chromatin for bromodomain-containing proteins to dock and in turn regulate gene expression. In order to better understand how bromodomains read the 'histone code' and interact with acetylated histones, we have tested the interactions of several bromodomains within transcriptional co-activators with differentially acetylated histone tail peptides and HAT-acetylated histones. Using GST (glutathione S-transferase) pull-down assays, we show specificity of binding of some bromodomains to differentially acetylated H3 and H4 peptides as well as HAT-acetylated histones. Our results reveal that the Swi2/Snf2 bromodomain interacts with various acetylated H3 and H4 peptides, whereas the Gcn5 bromodomain interacts only with acetylated H3 peptides and tetra-acetylated H4 peptides. Additionally we show that the Spt7 bromodomain interacts with acetylated H3 peptides weakly, but not with acetylated H4 peptides. Some bromodomains such as the Bdf1-2 do not interact with most of the acetylated peptides tested. Results of the peptide experiments are confirmed with tests of interactions between these bromodomains and HAT-acetylated histones. Furthermore, we demonstrate that the Swi2/Snf2 bromodomain is important for the binding and the remodelling activity of the SWI/SNF complex on hyperacetylated nucleosomes. The selective recognition of the bromodomains observed in the present study accounts for the broad effects of bromodomain-containing proteins observed on binding to histones.", "Another unusual autopsy case of the Turcot syndrome is reported in a 23-year-old woman with polyposis coli, who developed primary carcinoma of the jejunum and glioblastoma multiforme of the left frontal lobe. Previously documented cases are reviewed. Discussion focuses on the occurrence of other extracolonic abnormalities observed with the Turcot syndrome.", "The haspins are divergent members of the eukaryotic protein kinase family that are conserved in many eukaryotic lineages including animals, fungi, and plants. Recently-solved crystal structures confirm that the kinase domain of human haspin has unusual structural features that stabilize a catalytically active conformation and create a distinctive substrate binding site. Haspin localizes predominantly to chromosomes and phosphorylates histone H3 at threonine-3 during mitosis, particularly at inner centromeres. This suggests that haspin directly regulates chromosome behavior by modifying histones, although it is likely that additional substrates will be identified in the future. Depletion of haspin by RNA interference in human cell lines causes premature loss of centromeric cohesin from chromosomes in mitosis and failure of metaphase chromosome alignment, leading to activation of the spindle assembly checkpoint and mitotic arrest. Haspin overexpression stabilizes chromosome arm cohesion. Haspin, therefore, appears to be required for protection of cohesion at mitotic centromeres. Saccharomyces cerevisiae homologues of haspin, Alk1 and Alk2, are also implicated in regulation of mitosis. In mammals, haspin is expressed at high levels in the testis, particularly in round spermatids, so it seems likely that haspin has an additional role in post-meiotic spermatogenesis. Haspin is currently the subject of a number of drug discovery efforts, and the future use of haspin inhibitors should provide new insight into the cellular functions of these kinases and help determine the utility of, for example, targeting haspin for cancer therapy.", "BACKGROUND: Multiple sclerosis (MS) is a disease of young and middle aged individuals with a demyelinative axonal damage nature in central nervous system that causes various signs and symptoms. As color vision needs normal function of optic nerve and macula, it is proposed that MS can alter it via influencing optic nerve. In this survey, we evaluated color vision abnormalities and its relationship with history of optic neuritis and abnormal visual evoked potentials (VEPs) among MS patients.MATERIALS AND METHODS: The case group was included of clinically definitive MS patients and the same number of normal population was enrolled as the control group. Color vision of all the participants was evaluated by Ishihara test and then visual evoked potential (VEPs) and history of optic neuritis (ON) was assessed among them. Then, frequency of color blindness was compared between the case and the control group. Finally, color blinded patients were compared to those with the history of ON and abnormal VEPs.RESULTS: 63 MS patients and the same number of normal populations were enrolled in this study. 12 patients had color blindness based on the Ishihara test; only 3 of them were among the control group, which showed a significant different between the two groups (P = 0.013). There was a significant relationship between the color blindness and abnormal VEP (R = 0.53, P = 0.023) but not for the color blindness and ON (P = 0.67).CONCLUSIONS: This study demonstrates a significant correlation between color blindness and multiple sclerosis including ones with abnormal prolonged VEP latencies. Therefore, in individuals with acquired color vision impairment, an evaluation for potentially serious underlying diseases like MS is essential.", "OBJECTIVES: Rheumatoid arthritis (RA) patients with moderate disease activity show progression of joint damage and have impaired quality of life, physical function, work and daily activities. Little is known about management of patients with moderate RA. The aim of the study was to assess the 1-year response to anti-TNF in biologic-naïve RA patients with moderate (3.2 <DAS28 ≤5.1) disease activity despite DMARD treatment, in the Italian clinical practice.METHODS: The MODERATE study is a multicentre prospective, cohort non-interventional study, conducted in 19 Italian rheumatology sites. Patients with moderate RA, diagnosed according to the 2010 American College of Rheumatology (ACR)/EULAR criteria, were enrolled if they also were aged ≥18 years, had disease onset after 16 years old, moderate disease at baseline (DAS28 score >3.2 and ≤5.1), and were naïve to anti-TNF treatment.RESULTS: Among 157 RA patients, 93 (59%) underwent etanercept, 43 (22%) adalimumab, 26 (17%) certolizumab, 10 golimumab and 2 infliximab; 80% of patients were still in treatment after 12-month observation. One-year clinical remission was achieved by 27 RA patients (21%), reduction of DAS28 score greater than 1.2 was observed in 75 (58%) patients. Moderate and good response according to EULAR criteria was observed in 59 (46%) and 45 (35%) patients, respectively.CONCLUSIONS: Results confirm the efficacy of anti-TNF alpha also in moderate RA patients, who may achieve a substantial decrease of disease activity, and improve their quality of life. The low rate of patients achieving remission may suggest that therapeutic strategies should be more timely and aggressive.", "OBJECTIVE: This is a retrospective study for risk assessment of acute kidney injury after allogeneic hematopoietic stem cell transplantation (allo HSCT) based on the Acute Kidney Injury Network (AKIN) criteria.METHODS: Two hundred and eighty-nine consecutive patients who received allo HSCT were studied retrospectively to identify the risk factors for AKI according to the AKIN criteria. The incidence of AKI based on AKIN staging and overall survival (OS) was evaluated using Cox proportional hazard regression models treating each AKIN stage as a time-dependent covariate.PATIENTS: We identified a total of 180 patients who developed AKI within 100 days after allo HSCT; AKI was classified as stage 1 in 88 patients (30.5%), stage 2 in 46 patients (15.9%) and stage 3 in 46 patients (15.9%).RESULTS: Patients who developed stage 3 AKI had a significantly worse survival compared to those who developed no AKI or lower stage AKI (HR: 7.6, 95%CI: 4.8-12.1; p<0.001). Multivariate analysis for risks for developing AKI revealed an episode of sepsis or sinusoidal obstruction syndrome (SOS) and the use of liposomal amphotericin as a major cause of the severe stage of AKI.CONCLUSION: On the basis of our analysis, sepsis, hemorrhagic cystitis, and acute GVHD were associated with severe AKI, and SOS was associated any stage of AKI.", "The Q-rich domain of the mouse sex determining gene, Sry, is encoded by an in-frame insertion of a repetitive sequence composed of mostly CAG repeats. The exact function of this Q-rich domain is unknown. Studies on the polymorphisms within this Q-rich domain among different domesticus and musculus mouse strains suggest a possible role for this domain in sex determination. Using the farwestern protein-blotting technique and recombinant fusion proteins containing the Sry Q-rich domain as probes, three Sry interactive proteins of 94, 32 and 28 kDa apparent molecular weight (Sip-1, -2 and -3 respectively) were consistently detected in adult testis. Sip expression was detected in somatic cells and was associated with the spermatogenic activity of the testis. During embryogenesis, Sips were readily detected in total tissue extracts of embryos as early as E8.5 day. In fetal gonads of both sexes, their expression peaked around E11.5-13.5 day, at the time of sex determination and differentiation, and decreased drastically towards late stages of gestation. These observations support the hypothesis that the Q-rich domain may contribute to the biological function(s) of mouse Sry through a protein-protein interactive role(s).", "Covalent modifications of histone tails play important roles in gene transcription and silencing. We recently identified an ERG ( ets -related gene)-associated protein with a SET (suppressor of variegation, enhancer of zest and trithorax) domain (ESET) that was found to have the activity of a histone H3-specific methyltransferase. In the present study, we investigated the interaction of ESET with other chromatin remodelling factors. We show that ESET histone methyltransferase associates with histone deacetylase 1 (HDAC1) and HDAC2, and that ESET also interacts with the transcription co-repressors mSin3A and mSin3B. Deletion analysis of ESET reveals that an N-terminal region containing a tudor domain is responsible for interaction with mSin3A/B and association with HDAC1/2, and that truncation of ESET enhances its binding to mSin3. When bound to a promoter, ESET represses the transcription of a downstream luciferase reporter gene. This repression by ESET is independent of its histone methyltransferase activity, but correlates with its binding to the mSin3 co-repressors. In addition, the repression can be partially reversed by treatment with the HDAC inhibitor trichostatin A. Taken together, these data suggest that ESET histone methyltransferase can form a large, multi-protein complex(es) with mSin3A/B co-repressors and HDAC1/2 that participates in multiple pathways of transcriptional repression.", "We reported five cases of Dyke-Davidoff-Masson syndrome (DDMS) with different clinical and radiological findings. The evaluated parameters were the location of the lesions, midline structural shift effect, pathological and morphological changes on the ipsilateral calvarium, paranasal sinuses and mesencephalon, presence of compensatory contralateral hypertrophy. With the help of both magnetic resonance (MR) and computerized tomography (CT) images, changing degrees of all the evaluated parameters were observed in all five of our patients. In conclusion, no relationship was found between parenchymal and calvarial changes and between the time after onset of the disease and amount of the morphologic and pathological changes.", "OBJECTIVE: To determine whether colour blindness affects batting in professional cricketers.DESIGN: Comparison of batting averages of colour blind cricketers and those with normal vision.SETTING: Players on 18 first class county cricket teams.SUBJECTS: 280 of 306 players were tested.MAIN OUTCOME MEASURES: Results of Isihara colour blindness tests.RESULTS: Batting average for the colour blind group (12 players) was slightly lower than for players with normal vision (20.88 v 26.31). There was no difference in the number of batsmen and bowlers affected. Batting averages before and after the introduction of the white ball into Sunday League cricket did not differ significantly.CONCLUSIONS: That batting performance is not significantly impaired by colour blindness suggests that to some extent these players are self selected. Routine testing of cricketers for colour blindness is not recommended.", "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.", "A new epoxy-based ink is reported, which enables 3D printing of lightweight cellular composites with controlled alignment of multiscale, high-aspectratio fiber reinforcement to create hierarchical structures inspired by balsa wood. Young's modulus values up to 10 times higher than existing commercially available 3D-printed polymers are attainable, while comparable strength values are maintained.", "BACKGROUND: The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment.METHODS: In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00548405.FINDINGS: 202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39-0·65]; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38-0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia.INTERPRETATION: For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab's main adverse effect of secondary autoimmunity.FUNDING: Genzyme (Sanofi) and Bayer Schering Pharma.", "The incidence of red-green colour vision defects was studied in a sample of 392 Basque students (174 males and 218 females), using the Ishihara test cards (1987). The frequency of red-green colour blindness was 4.02 percent in the males and 0.46 percent in the females. The colour blindness frequencies found among males are within the range of other Spanish samples. Nevertheless they are lower than the values reported in other European populations.", "The generation of patient-specific induced pluripotent stem cells (iPSCs) offers unprecedented opportunities for modeling and treating human disease. In combination with gene therapy, the iPSC technology can be used to generate disease-free progenitor cells of potential interest for autologous cell therapy. We explain a protocol for the reproducible generation of genetically corrected iPSCs starting from the skin biopsies of Fanconi anemia patients using retroviral transduction with OCT4, SOX2 and KLF4. Before reprogramming, the fibroblasts and/or keratinocytes of the patients are genetically corrected with lentiviruses expressing FANCA. The same approach may be used for other diseases susceptible to gene therapy correction. Genetically corrected, characterized lines of patient-specific iPSCs can be obtained in 4-5 months.", "Color-blindness is the inability to perceive differences between some color that other people can distinguish. Using a literature search, the results indicate the prevalence of color vision deficiency in the medical profession and its on medical skills. Medical laboratory technicians and technologists employees should also screen for color blindness. This research aimed to study color blindness prevalence among Hospitals' Clinical Laboratories' Employees and Students in Tehran University of Medical Sciences (TUMS). A cross-sectional descriptive and analytical study was conducted among 633 TUMS Clinical Laboratory Sciences' Students and Hospitals' Clinical Laboratories' Employees to detect color-blindness problems by Ishihara Test. The tests were first screened with certain pictures, then compared to the Ishihara criteria to be possible color defective were tested further with other plates to determine color - blindness defects. The data was saved using with SPSS software and analyzed by statistical methods. This is the first study to determine the prevalence of color - blindness in Clinical Laboratory Sciences' Students and Employees. 2.4% of TUMS Medical Laboratory Sciences Students and Hospitals' Clinical Laboratories' Employees are color-blind. There is significant correlation between color-blindness and sex and age. But the results showed that there is not significant correlation between color-blindness defect and exposure to chemical agents, type of job, trauma and surgery history, history of familial defect and race. It would be a wide range of difficulties by color blinded students and employees in their practice of laboratory diagnosis and techniques with a potentially of errors. We suggest color blindness as a medical conditions should restrict employment choices for medical laboratory technicians and technologists job in Iran.", "Cells continuously sense and respond to external mechanical forces through their cytoskeleton. Here we show that only a small subset of actin fibers, those forming the perinuclear actin cap that wraps around the nucleus, form in response to low physiological mechanical stresses in adherent fibroblasts. While conventional basal stress fibers form only past a threshold shear stress of 0.5 dyn/cm(2), actin-cap fibers are formed at shear stresses 50 times lower and orders-of-magnitude faster than biochemical stimulation. This fast differential response is uniquely mediated by focal adhesion protein zyxin at low shear stress and actomyosin fibers of the actin cap. We identify additional roles for lamin A/C of the nuclear lamina and linkers of nucleus to cytoskeleton (LINC) molecules nesprin2giant and nesprin3, which anchor actin cap fibers to the nucleus. These results suggest an interconnected physical pathway for mechanotransduction, from the extracellular milieu to the nucleus." ]

[ "Many genomic disorders occur as a result of chromosome rearrangements involving low-copy repeats (LCRs). To better understand the molecular basis of chromosome rearrangements, including translocations, we have investigated the mechanism of evolutionary rearrangements. In contrast to several intrachromosomal rearrangements, only two evolutionary translocations have been identified by cytogenetic analyses of humans and greater apes. Human chromosome 2 arose as a result of a telomeric fusion between acrocentric chromosomes, whereas chromosomes 4 and 19 in Gorilla gorilla are the products of a reciprocal translocation between ancestral chromosomes, syntenic to human chromosomes 5 and 17, respectively. Fluorescence in situ hybridization (FISH) was used to characterize the breakpoints of the latter translocation at the molecular level. We identified three BAC clones that span translocation breakpoints. One breakpoint occurred in the region syntenic to human chromosome 5q13.3, between the HMG-CoA reductase gene (HMGCR) and RAS p21 protein activator 1 gene (RASA1). The second breakpoint was in a region syntenic to human chromosome 17p12 containing the 24 kb region-specific low-copy repeat-proximal CMT1A-REP. Moreover, we found that the t(4;19) is associated with a submicroscopic chromosome duplication involving a 19p chromosome fragment homologous to the human chromosome region surrounding the proximal CMT1A-REP. These observations further indicate that higher order genomic architecture involving low-copy repeats resulting from genomic duplication plays a significant role in karyotypic evolution.", "Dicentric chromosomes are products of genomic rearrangements that place two centromeres on the same chromosome. Due to the presence of two primary constrictions, they are inherently unstable and overcome their instability by epigenetically inactivating and/or deleting one of the two centromeres, thus resulting in functionally monocentric chromosomes that segregate normally during cell division. Our understanding to date of dicentric chromosome formation, behavior and fate has been largely inferred from observational studies in plants and humans as well as artificially produced de novo dicentrics in yeast and in human cells. We investigate the most recent product of a chromosome fusion event fixed in the human lineage, human chromosome 2, whose stability was acquired by the suppression of one centromere, resulting in a unique difference in chromosome number between humans (46 chromosomes) and our most closely related ape relatives (48 chromosomes). Using molecular cytogenetics, sequencing, and comparative sequence data, we deeply characterize the relicts of the chromosome 2q ancestral centromere and its flanking regions, gaining insight into the ancestral organization that can be easily broadened to all acrocentric chromosome centromeres. Moreover, our analyses offered the opportunity to trace the evolutionary history of rDNA and satellite III sequences among great apes, thus suggesting a new hypothesis for the preferential inactivation of some human centromeres, including IIq. Our results suggest two possible centromere inactivation models to explain the evolutionarily stabilization of human chromosome 2 over the last 5-6 million years. Our results strongly favor centromere excision through a one-step process.", "BACKGROUND: Thyroid hormone acts via receptor subtypes (TRα1, TRβ1, TRβ2) with differing tissue distributions, encoded by distinct genes (THRA, THRB). THRB mutations cause a disorder with central (hypothalamic-pituitary) resistance to thyroid hormone action with markedly elevated thyroid hormone and normal TSH levels.SCOPE OF REVIEW: This review describes the clinical features, genetic and molecular pathogenesis of a homologous human disorder mediated by defective THRA. Clinical features include growth retardation, skeletal dysplasia and constipation associated with low-normal T4 and high-normal T3 levels and a low T4/T3 ratio, together with subnormal reverse T3 levels. Heterozygous TRa1 mutations in affected individuals generate defective mutant receptors which inhibit wild-type receptor action in a dominant negative manner.MAJOR CONCLUSIONS: Mutations in human TRα1 mediate RTH with features of hypothyroidism in particular tissues (e.g. skeleton, gastrointestinal tract), but are not associated with a markedly dysregulated pituitary-thyroid axis.GENERAL SIGNIFICANCE: Human THRA mutations could be more common but may have eluded discovery due to the absence of overt thyroid dysfunction. Nevertheless, in the appropriate clinical context, a thyroid biochemical signature (low T4/T3 ratio, subnormal reverse T3 levels), may enable future identification of cases. This article is part of a Special Issue entitled Thyroid hormone signalling.", "Human neutrophils exposed to 10(-4) M doxorubicin and the derivatives epirubicin and thepirubicin revealed a different intracellular penetration and distribution pattern as demonstrated by fluorescence microscopy and fluorimetric determination of drug intracellular concentration. While doxorubicin was found to be a potent inducer of superoxide generation from resting cells, epirubicin exhibited less superoxide-inducing power. Thepirubicin on the contrary did not show any superoxide-inducing effect. Moreover the anthracyclines tested all inhibited the phorbol ester-stimulated chemiluminescent response to the same extent, which suggested a common target for the drug action. Anthracycline-stimulated superoxide production seems to correlate with the cardiotoxic effects. The most cardiotoxic drug, doxorubicin, is the most potent inducer of superoxide generation, while epirubicin, which is less cardiotoxic, has a relatively limited effect on superoxide production. Thepirubicin which has been shown not to induce delayed cardiomyopathy has no effect on superoxide release from the cells.", "BACKGROUND: Patients with a hemispheric infarct and massive space-occupying brain oedema have a poor prognosis. Despite maximal conservative treatment, the case fatality rate may be as high as 80%, and most survivors are left severely disabled. Non-randomised studies suggest that decompressive surgery reduces mortality substantially and improves functional outcome of survivors. This study is designed to compare the efficacy of decompressive surgery to improve functional outcome with that of conservative treatment in patients with space-occupying supratentorial infarctionMETHODS: The study design is that of a multi-centre, randomised clinical trial, which will include 112 patients aged between 18 and 60 years with a large hemispheric infarct with space-occupying oedema that leads to a decrease in consciousness. Patients will be randomised to receive either decompressive surgery in combination with medical treatment or best medical treatment alone. Randomisation will be stratified for the intended mode of conservative treatment (intensive care or stroke unit care). The primary outcome measure will be functional outcome, as determined by the score on the modified Rankin Scale, at one year.", "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.", "Human chromosome 2 is a product of a telomere fusion of two ancestral chromosomes and loss/degeneration of one of the two original centromeres. Genomic signatures of this event are limited to inverted telomeric repeats at the precise site of chromosomal fusion and to the small amount of relic centromeric sequences that remain on 2q21.2. Unlike the site of fusion, which is enriched for sequences that are shared elsewhere in the human genome, the region of the nonfunctioning and degenerate ancestral centromere appears to share limited similarity with other sites in the human genome, thereby providing an opportunity to study this genomic arrangement in short, fragmented ancient DNA genomic datasets. Here, chromosome-assigned satellite DNAs are used to study shared centromere sequence organization in Denisovan and Neandertal genomes. By doing so, one is able to provide evidence for the presence of both active and degenerate centromeric satellite profiles on chromosome 2 in these archaic genomes, supporting the hypothesis that the chromosomal fusion event took place prior to our last common ancestor with Denisovan and Neandertal hominins and presenting a genomic reference for predicting karyotype in ancient genomic datasets.", "While modified vaccinia virus Ankara (MVA) is currently in clinical development as a safe vaccine against smallpox and heterologous infectious diseases, its immunogenicity is likely limited due to the inability of the virus to replicate productively in mammalian hosts. In light of recent data demonstrating that vaccinia viruses, including MVA, preferentially infect antigen-presenting cells (APCs) that play crucial roles in generating antiviral immunity, we hypothesized that expression of specific cytokines and chemokines that mediate APC recruitment and activation from recombinant MVA (rMVA) vectors would enhance the immunogenicity of these vectors. To test this hypothesis, we generated rMVAs that express murine granulocyte-macrophage colony-stimulating factor (mGM-CSF), human CCL20/human macrophage inflammatory protein 3alpha (hCCL20/hMIP-3alpha), or human fms-like tyrosine kinase 3 ligand (hFlt3-L), factors predicted to increase levels of dendritic cells (DCs), to recruit DCs to sites of immunization, or to promote maturation of DCs in vivo, respectively. These rMVAs also coexpress the well-characterized, immunodominant lymphocytic choriomeningitis virus nucleoprotein (NP) antigen that enabled sensitive and quantitative assessment of antigen-specific CD8(+) T-cell responses following immunization of BALB/c mice. Our results demonstrate that immunization of mice with rMVAs expressing mGM-CSF or hCCL20, but not hFlt3-L, results in two- to fourfold increases of cellular immune responses directed against vector-encoded antigens and 6- to 17-fold enhancements of MVA-specific antibody titers, compared to those responses elicited by nonadjuvanted rMVA. Of note, cytokine augmentation of cellular immune responses occurs when rMVAs are given as primary immunizations but not when they are used as booster immunizations, suggesting that these APC-modulating proteins, when used as poxvirus-encoded adjuvants, are more effective at stimulating naïve T-cell responses than in promoting recall of preexisting memory T-cell responses. Our results demonstrate that a strategy to express specific genetic adjuvants from rMVA vectors can be successfully applied to enhance the immunogenicity of MVA-based vaccines.", "p73 is a p53-related transcription factor with fundamental roles in development and tumor suppression. Transcription from two different promoters on the p73 gene results in generation of transcriptionally active TAp73 isoforms and dominant negative DeltaNp73 isoforms with opposing pro- and anti-apoptotic functions. Therefore, the relative ratio of each isoform is an important determinant of the cell fate. Proteasomal degradation of p73 is mediated by polyubiquitination-dependent and -independent processes both of which appear, thus far, to lack selectivity for the TAp73 and DeltaNp73 isoforms. Here, we describe the characterization of another transcriptional target of TAp73; a ring finger domain ubiquitin ligase p73 Induced RING 2 protein (PIR2). Although PIR2 was initially identified a p53-induced gene (p53RFP), low abundance of PIR2 transcript in mouse embryonic fibroblasts of TAp73 KO mice compared with WT mice and comparison of PIR2 mRNA and protein levels following TAp73 or p53 overexpression substantiate TAp73 isoforms as strong inducers of PIR2. Although PIR2 expression was induced by DNA damage, its expression did not alter apoptotic response or cell cycle profile per se. However, coexpression of PIR2 with TAp73 or DeltaNp73 resulted in an increase of the TA/DeltaNp73 ratio, due to preferential degradation of DeltaNp73. Finally, PIR2 was able to relieve the inhibitory effect of DeltaNp73 on TAp73 induced apoptosis following DNA damage. These results suggest that PIR2, by being induced by TAp73 and degrading DeltaNp73, differentially regulates TAp73/DeltaNp73 stability, and, hence, it may offer a therapeutic approach to enhance the chemosensitivity of tumor cells.", "We have identified two allelic genomic cosmids from human chromosome 2, c8.1 and c29B, each containing two inverted arrays of the vertebrate telomeric repeat in a head-to-head arrangement, 5'(TTAGGG)n-(CCCTAA)m3'. Sequences flanking this telomeric repeat are characteristic of present-day human pretelomeres. BAL-31 nuclease experiments with yeast artificial chromosome clones of human telomeres and fluorescence in situ hybridization reveal that sequences flanking these inverted repeats hybridize both to band 2q13 and to different, but overlapping, subsets of human chromosome ends. We conclude that the locus cloned in cosmids c8.1 and c29B is the relic of an ancient telomere-telomere fusion and marks the point at which two ancestral ape chromosomes fused to give rise to human chromosome 2.", "BACKGROUND: Glioblastoma multiforme (GBM) is a heterogeneous, highly aggressive primary brain tumor with strongly variable patient survival. Because reliable prognostic biomarkers are lacking, we investigated the relation between telomerase-associated parameters and the disease course.METHODS: Telomerase-associated parameters were determined in 100 GBM tissues and associated with clinical characteristics and overall survival. Expressions of telomere length, telomerase activity (TA), and human telomerase reverse transcriptase (hTERT) were analyzed by quantitative PCR, telomeric repeat amplification protocol assay, and reverse transcriptase-PCR, respectively. Mutation status of isocitrate dehydrogenase (IDH)1 was determined by direct sequencing, and O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation by methylation-specific PCR.RESULTS: Of 100 GBM tissues, 61 were positive for both hTERT mRNA and TA, with a highly significant correlation between both parameters (linear regression, P < .0001). Telomere length determination revealed a significant difference between the hTERT/TA-positive and -negative subgroups, with markedly longer telomeres in the hTERT/TA-negative cohort (unpaired Student's t-test, P = .0001). Accordingly, significantly shorter telomeres were detected in GBM tissues derived from older patients (>60 y at diagnosis, P < .0001). While no association of telomere parameters with MGMT promoter status was found, all tumors with IDH1 mutation (6/100) were negative for both hTERT expression and TA and harbored significantly longer telomeres. Patients with tumors lacking hTERT expression/TA showed a significant survival benefit (Kaplan-Meier test, both P < .01), which, however, was based exclusively on the younger patient subgroup (≤60 y, both P < .005; >60 y, both ns).CONCLUSIONS: Telomerase activation is not an independent prognostic parameter in GBM but predicts aggressive tumor behavior solely in a younger patient cohort.", "Carney's Triad comprises a triad of neoplasms: gastric stromal tumor, extra-adrenal paraganglioma (usually functional), and pulmonary chondroma. At least two of these are needed for the presumptive diagnosis of the Triad. This report presents a patient who had resected a gastric tumor and nonfunctional extra-adrenal paraganglioma. The gastric tumor resembled a gastric leiomyosarcoma by light microscopy, but electron microscopy revealed it to be a gastric autonomic nerve (GAN) tumor. Based on this evidence it appears that both the gastric lesions and the paragangliomata of Carney's Triad are tumors of the autonomic nervous system. Thus, the Triad may be a disorder of the autonomic nervous system rather than a multiple endocrine neoplasia syndrome or multiple hamartoma syndrome.", "BACKGROUND: Lasmiditan (COL-144) is a novel, centrally acting, highly selective 5-HT(1F) receptor agonist without vasoconstrictor activity that seemed effective when given as an intravenous infusion in a proof-of-concept migraine study. We aimed to assess the efficacy and safety of oral lasmiditan for the acute treatment of migraine.METHODS: In this multicentre, double-blind, parallel-group, dose-ranging study in 43 headache centres in five European countries, patients with migraine with and without aura and who were not using prophylaxis were randomly assigned (1:1:1:1:1) to treat one moderate or severe attack at home with 50 mg, 100 mg, 200 mg, or 400 mg lasmiditan, or placebo. Study drug and placebo were supplied in identical numbered tablet packs. The randomisation code was generated by an independent statistician. Patients and investigators were masked to treatment allocation. The primary endpoint was dose response for headache relief (moderate or severe becoming mild or none) at 2 h. The primary analysis was done in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00883051.FINDINGS: Between July 8 2009, and Feb 18, 2010, 512 patients were randomly assigned to treatment, 391 of whom received treatment. 86 patients received placebo (81 included in primary analysis) and 305 received lasmiditan (50 mg n=79, 100 mg n=81, 200 mg n=69, and 400 mg n=68 included in primary analysis). There was a linear association between headache response rate at 2 h and lasmiditan dose (Cochran-Armitage test p<0·0001). Every lasmiditan treatment dose significantly improved headache response at 2 h compared with placebo (lasmiditan 50 mg: difference 17·9%, 95% CI 3·9-32·1, p=0·022; 100 mg: 38·2%, 24·1-52·4, p<0·0001; 200 mg: 28·8%, 9·6-39·9, p=0·0018; 400 mg: 38·7%, 23·9-53·6, p<0·0001). The proportion of patients with treatment-emergent adverse events increased with increasing doses (53/82 [65%], 59/82 [72%], 61/71 [86%], and 59/70 [84%] for lasmiditan 50, 100, 200, and 400 mg, respectively vs 19/86 [22%] for placebo). Most adverse events were mild or moderate in intensity, with 16 of 82 (20%), 23 of 82 (28%), 28 of 71 (39%), and 31 of 70 (44%) of patients on lasmiditan 50, 100, 200, and 400 mg, respectively reporting a severe adverse event compared with five of 86 (6%) on placebo. The most common adverse events were CNS related and included dizziness, fatigue, vertigo, paraesthesia, and somnolence.INTERPRETATION: Oral lasmiditan seems to be safe and effective in the acute treatment of migraine. Further assessment in larger placebo-controlled and triptan-controlled trials are needed to assess the potential role of lasmiditan in acute migraine therapy.FUNDING: CoLucid Pharmaceuticals.", "Chimpanzee and gorilla chromosomes differ from human chromosomes by the presence of large blocks of subterminal heterochromatin thought to be composed primarily of arrays of tandem satellite sequence. We explore their sequence composition and organization and show a complex organization composed of specific sets of segmental duplications that have hyperexpanded in concert with the formation of subterminal satellites. These regions are highly copy number polymorphic between and within species, and copy number differences involving hundreds of copies can be accurately estimated by assaying read-depth of next-generation sequencing data sets. Phylogenetic and comparative genomic analyses suggest that the structures have arisen largely independently in the two lineages with the exception of a few seed sequences present in the common ancestor of humans and African apes. We propose a model where an ancestral human-chimpanzee pericentric inversion and the ancestral chromosome 2 fusion both predisposed and protected the chimpanzee and human genomes, respectively, to the formation of subtelomeric heterochromatin. Our findings highlight the complex interplay between duplicated sequences and chromosomal rearrangements that rapidly alter the cytogenetic landscape in a short period of evolutionary time.", "The expansion of a (G(4)C(2))n repeat within the human C9orf72 gene has been causally linked to a number of neurodegenerative diseases, most notably familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies have shown that the repeat expansion alters gene function in four ways, disrupting the gene's normal cellular roles and introducing toxic gain of function at the level of both DNA and RNA. (G(4)C(2))n DNA, as well as the RNA transcribed from it, are found to fold into four-stranded G-quadruplex structures. It has been shown that the toxicity of the RNA G-quadruplexes, often localized in intracellular RNA foci, lies in their ability to sequester many important RNA binding proteins. Herein we propose that a distinct toxic property of such RNA and DNA G-quadruplexes from the C9orf72 gene may arise from their ability to bind and oxidatively activate cellular heme. We show that G-quadruplexes formed by both (G(4)C(2))(4) RNA and DNA not only complex tightly with heme but also enhance its intrinsic peroxidase and oxidase propensities. By contrast, the antisense (C(4)G(2))(4) RNA and DNA neither bind heme nor influence its oxidative activity. Curiously, the ability of C9orf72 DNA and transcripts to bind and activate heme mirror similar properties that have been reported for the Aβ peptide and its oligomers in Alzheimer's disease neurons. It is therefore conceivable that C9orf72 RNA G-quadruplex tangles play roles in sequestering intracellular heme and promoting oxidative damage in ALS and FTD analogous to those proposed for Aβ peptide and its tangles in Alzheimer's Disease. Given that neurodegenerative diseases in general are characterized by mitochondrial and respiratory malfunctions, the role of C9orf72 DNA and RNA in heme sequestration as well as its inappropriate activation in ALS and FTD neurons may warrant examination.", "The cochlea, a coiled structure located in the ventral region of the inner ear, acts as the primary structure for the perception of sound. Along the length of the cochlear spiral is the organ of Corti, a highly derived and rigorously patterned sensory epithelium that acts to convert auditory stimuli into neural impulses. The development of the organ of Corti requires a series of inductive events that specify unique cellular characteristics and axial identities along its three major axes. Here, we review recent studies of the cellular and molecular processes regulating several aspects of cochlear development, such as axial patterning, cochlear outgrowth and cellular differentiation. We highlight how the precise coordination of multiple signaling pathways is required for the successful formation of a complete organ of Corti.", "MOTIVATION: Identification and characterization of protein-protein interactions (PPIs) is one of the key aims in biological research. While previous research in text mining has made substantial progress in automatic PPI detection from literature, the need to improve the precision and recall of the process remains. More accurate PPI detection will also improve the ability to extract experimental data related to PPIs and provide multiple evidence for each interaction.RESULTS: We developed an interaction detection method and explored the usefulness of various features in automatically identifying PPIs in text. The results show that our approach outperforms other systems using the AImed dataset. In the tests where our system achieves better precision with reduced recall, we discuss possible approaches for improvement. In addition to test datasets, we evaluated the performance on interactions from five human-curated databases-BIND, DIP, HPRD, IntAct and MINT-where our system consistently identified evidence for approximately 60% of interactions when both proteins appear in at least one sentence in the PubMed abstract. We then applied the system to extract articles from PubMed to annotate known, high-throughput and interologous interactions in I(2)D.AVAILABILITY: The data and software are available at: http://www.cs.utoronto.ca/ approximately juris/data/BI09/.", "BACKGROUND: Deep brain stimulation of the internal pallidum (GPi-DBS) is effective for various types of drug-refractory primary dystonias. Rare clinical forms as dystonic camptocormia may profit but available data are scarce.METHODS: We here report on a retrospective clinical assessment of three patients with primary dystonic camptocormia treated with GPi-DBS.RESULTS: All three patients showed marked response to bilateral GPi-DBS within days to weeks after surgery which was preserved in the long-term (38-45 months after implantation: mean improvement 82% as rated on the Burke Fahn Marsden Dystonia Rating Scale, 89% in the subitem \"trunk\"). Two patients developed mild stimulation induced speech problems (stuttering or dysarthria) which resolved with reprogramming or were acceptable in return for the control of dystonic symptoms.CONCLUSIONS: The diagnosis and treatment of camptocormia will continue to require expert knowledge in movement and neuromuscular disorders, but DBS may expand treatment options in this difficult patient population.", "It is known that human chromosome 2 originated from the fusion of two ancestral primate chromosomes. This has been confirmed by chromosome banding and fluorescence in-situ hybridization (FISH) with human chromosome-2-specific DNA libraries. In this study, the order of 38 cosmid clones derived from the human chromosome region 2q12-q14 was exactly determined by high-resolution FISH in human chromosome 2 and its homologous chromosomes in chimpanzees (Pan trogrodydes, 2n=48) and cynomolgus monkeys (Macacafascicularis, 2n = 42). This region includes the telomere-to-telomere fusion point of two ancestral ape-type chromosomes. As a result of comparative mapping, human chromosome region 2q12-q14 was found to correspond to the short arms of chimpanzee chromosomes 12 and 13 and cynomolgus monkey chromosomes 9 and 15. It is noted that no difference was detected in the relative order of the cosmid clones between human and chimpanzee chromosomes. This suggests that two ancestral ape-type chromosomes fused tandemly at telomeres to form human chromosome 2, and the genomic organization of this region is thought to be considerably conserved. In the cynomolgus monkey, however, the order of clones in each homologue was inverted. In addition to cosmid mapping, two chromosome-2-specific yeast artificial chromosome (YAC) clones containing the fusion point were identified by FISH.", "Hillier LW(1), Graves TA, Fulton RS, Fulton LA, Pepin KH, Minx P, Wagner-McPherson C, Layman D, Wylie K, Sekhon M, Becker MC, Fewell GA, Delehaunty KD, Miner TL, Nash WE, Kremitzki C, Oddy L, Du H, Sun H, Bradshaw-Cordum H, Ali J, Carter J, Cordes M, Harris A, Isak A, van Brunt A, Nguyen C, Du F, Courtney L, Kalicki J, Ozersky P, Abbott S, Armstrong J, Belter EA, Caruso L, Cedroni M, Cotton M, Davidson T, Desai A, Elliott G, Erb T, Fronick C, Gaige T, Haakenson W, Haglund K, Holmes A, Harkins R, Kim K, Kruchowski SS, Strong CM, Grewal N, Goyea E, Hou S, Levy A, Martinka S, Mead K, McLellan MD, Meyer R, Randall-Maher J, Tomlinson C, Dauphin-Kohlberg S, Kozlowicz-Reilly A, Shah N, Swearengen-Shahid S, Snider J, Strong JT, Thompson J, Yoakum M, Leonard S, Pearman C, Trani L, Radionenko M, Waligorski JE, Wang C, Rock SM, Tin-Wollam AM, Maupin R, Latreille P, Wendl MC, Yang SP, Pohl C, Wallis JW, Spieth J, Bieri TA, Berkowicz N, Nelson JO, Osborne J, Ding L, Meyer R, Sabo A, Shotland Y, Sinha P, Wohldmann PE, Cook LL, Hickenbotham MT, Eldred J, Williams D, Jones TA, She X, Ciccarelli FD, Izaurralde E, Taylor J, Schmutz J, Myers RM, Cox DR, Huang X, McPherson JD, Mardis ER, Clifton SW, Warren WC, Chinwalla AT, Eddy SR, Marra MA, Ovcharenko I, Furey TS, Miller W, Eichler EE, Bork P, Suyama M, Torrents D, Waterston RH, Wilson RK.", "Defects in DNA mismatch repair have been shown to lead to increased genomic instability and mutability. We recently found that human cells defective in the DNA mismatch repair gene, hMSH2, were deficient in the transcription-coupled repair (TCR) of both oxidative DNA damage, including thymine glycols, and UV-induced DNA damage. However, in a hMLH1 mutant, only a reduction in the TCR of UV damage was observed. In this study, we examined whether TCR of thymine glycols in Saccharomyces cerecisiae also requires the genes involved in DNA mismatch repair. We found that yeast cells containing mutations in MSH2 were deficient in the removal of thymine glycols from the transcribed strand of the RPB2 gene, while cells with mutations in either MLH1 or PMS1 alone showed near normal levels of TCR of thymine glycols. Interestingly, double mutants in the MLH1 and PMS1 genes were deficient in TCR of thymine glycols. Taken together, these results suggest that these two MutL homologues can act independently of each other, but that they have overlapping roles in TCR. Overall levels of thymine glycol removal were not reduced in the mismatch repair mutants. In contrast to the results with thymine glycols, no defects in TCR of pyrimidine dimers were found in cells with mutations in MSH2, MLH1, PMS1, and MLH1/PMS1.", "More than 6 million Americans work night shifts on a regular or rotating basis. The negative consequences of shift work have been established, and recent evidence suggests that patients with shift work sleep disorder (SWSD) are at increased risk of these consequences and co-morbidities. SWSD is a relatively common but under-recognised, and hence undertreated, condition with potentially serious medical, social, economic and quality-of-life consequences. In addition to increased risk of gastrointestinal and cardiovascular disease, patients with SWSD experience clinically significant excessive sleepiness or insomnia associated with work during normal sleep times, which has important safety implications. A number of studies have evaluated countermeasures or interventions in shift workers; proposed treatments include chronobiotic interventions, such as light exposure, melatonin, hypnotic agents, caffeine and CNS stimulants (amphetamine), and the wake-promoting agents modafinil and armodafinil. However, most studies evaluating pharmacological therapies and nonpharmacological interventions simulate night-shift work under conditions that may not accurately reflect real-world activities. Pharmacological and nonpharmacological countermeasures evaluated mostly in simulated laboratory conditions have been shown to improve alertness or sleep in shift workers but have not yet been evaluated in patients with SWSD. To date, three randomised, double-blind clinical studies have evaluated pharmacological therapies in patients with SWSD. These studies showed that modafinil and armodafinil significantly improve the ability to sustain wakefulness during waking activities (e.g. working, driving), overall clinical condition, and sustained attention or memory in patients with SWSD. In conclusion, SWSD is a common condition that remains under-recognised and undertreated. Further research is needed to evaluate different treatment approaches for this condition, to clarify the substantial health and economic consequences of SWSD, and to determine the potential for interventions or treatments to reduce the negative consequences of this condition.", "BACKGROUND: Triple-negative breast cancers (TNBC) do not represent a single disease subgroup and are often aggressive breast cancers with poor prognoses. Unlike estrogen/progesterone receptor and HER2 (human epidermal growth factor receptor 2) breast cancers, which are responsive to targeted treatments, there is no effective targeted therapy for TNBC, although approximately 50% of patients respond to conventional chemotherapies, including taxanes, anthracyclines, cyclophosphamide, and platinum salts.CONTENT: Genomic studies have helped clarify some of the possible disease groupings that make up TNBC. We discuss the findings, including copy number-transcriptome analysis, whole genome sequencing, and exome sequencing, in terms of the biological properties and phenotypes that make up the constellation of TNBC. The relationships between subgroups defined by transcriptome and genome analysis are discussed.SUMMARY: TNBC is not a uniform molecular or disease entity but a constellation of variably well-defined biological properties whose relationship to each other is not understood. There is good support for the existence of a basal expression subtype, p53 mutated, high-genomic instability subtype of TNBC. This should be considered a distinct TNBC subtype. Other subtypes with variable degrees of supporting evidence exist within the nonbasal/p53wt (wild-type p53) TNBC, including a group of TNBC with PI3K (phosphoinositide 3-kinase) pathway activation that have better overall prognosis than the basal TNBC. Consistent molecular phenotyping of TNBC by whole genome sequencing, transcriptomics, and functional studies with patient-derived tumor xenograft models will be essential components in clinical and biological studies as means of resolving this heterogeneity.", "BACKGROUND: Although major depressive disorder (MDD) is a treatable disease, the remission rates associated with antidepressant monotherapy are still far from optimal. Folate is an inexpensive, easily tolerated natural augmenting agent, which has been reported to improve medication treatment outcomes in patients with MDD.OBJECTIVE: The aim of this study was to review the literature on the clinical utility of folate augmentation for patients with MDD. FOLATE AND DEPRESSION: Patients with depression have consistently been found to have lower levels of serum and red blood cell folate than normal or nondepressed psychiatric patients. Decreased folate levels have been associated with lowered response rates to standard antidepressant pharmacotherapy. Recent studies have shown that augmentation with a folate supplement increases medication response in both treatment-naïve and treatment-resistant depressed patients irrespective of whether there is folate deficiency.CONCLUSIONS: Depressed patients with both low and normal folate levels may benefit from augmenting a primary antidepressant medication either initially, at the onset of treatment, or later after some degree of treatment resistance has been recognized.", "A portable Fourier transform infrared (FT-IR) multicomponent point-of-care analyzer was tested for the diagnosis of methanol intoxications. Breath analysis with FT-IR was fast and easy, and no sample preparation was needed. The analyzer was adequately sensitive and accurate in detecting and quantitating clinically relevant amounts of ethanol and methanol in the breath of seriously ill patients. FT-IR spectrometry was also suitable for nearly on-line monitoring of the exhaled ethanol and methanol during hemodialysis. The breath analysis results correlated well with blood samples. The FT-IR method used also has a traceable calibration to physical properties of the analyte, and the measured spectra can be saved for later analysis.", "BACKGROUND: Single-gene disorders related to ischemic stroke seem to be an important cause of stroke in young patients without known risk factors. To identify new genes responsible of such diseases, we studied a consanguineous Moroccan family with three affected individuals displaying hereditary leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa that appears to segregate in autosomal recessive pattern.METHODS: All family members underwent neurological and radiological examinations. A genome wide search was conducted in this family using the ABI PRISM linkage mapping set version 2.5 from Applied Biosystems. Six candidate genes within the region linked to the disease were screened for mutations by direct sequencing.RESULTS: Evidence of linkage was obtained on chromosome 17q24.2-25.3. Analysis of recombination events and LOD score calculation suggests linkage of the responsible gene in a genetic interval of 11 Mb located between D17S789 and D17S1806 with a maximal multipoint LOD score of 2.90. Sequencing of seven candidate genes in this locus, ATP5H, FDXR, SLC25A19, MCT8, CYGB, KCNJ16 and GRIN2C, identified three missense mutations in the FDXR gene which were also found in a homozygous state in three healthy controls, suggesting that these variants are not disease-causing mutations in the family.CONCLUSION: A novel locus for leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa has been mapped to chromosome 17q24.2-25.3 in a consanguineous Moroccan family.", "OBJECTIVE: (1) To determine the prevalence of depression and anxiety in patients with psoriatic arthritis (PsA) and to identify associated demographic and disease-related factors. (2) To determine whether there is a difference in the prevalence of depression and anxiety between patients with PsA and those with psoriasis without PsA (PsC).METHODS: Consecutive patients attending PsA and dermatology clinics were assessed for depression and anxiety using the Hospital Anxiety and Depression Scale. Patients underwent a clinical assessment according to a standard protocol and completed questionnaires assessing their health and quality of life. T tests, ANOVA, and univariate and multivariate models were used to compare depression and anxiety prevalence between patient cohorts and to determine factors associated with depression and anxiety.RESULTS: We assessed 306 patients with PsA and 135 with PsC. There were significantly more men in the PsA group (61.4% vs 48% with PsC) and they were more likely to be unemployed. The prevalence of both anxiety and depression was higher in patients with PsA (36.6% and 22.2%, respectively) compared to those with PsC (24.4% and 9.6%; p = 0.012, 0.002). Depression and/or anxiety were associated with unemployment, female sex, and higher actively inflamed joint count as well as disability, pain, and fatigue. In the multivariate reduced model, employment was protective for depression (OR 0.36) and a 1-unit increase on the fatigue severity scale was associated with an increased risk of depression (OR 1.5).CONCLUSION: The rate of depression and anxiety is significantly higher in patients with PsA than in those with PsC. Depression and anxiety are associated with disease-related factors.", "The envelope glycoprotein of small ruminant lentiviruses (SRLV) is a major target of the humoral immune response and contains several linear B-cell epitopes. We amplified and sequenced the genomic segment encoding the SU5 antigenic site of the envelope glycoprotein of several SRLV field isolates. With synthetic peptides based on the deduced amino acid sequences of SU5 in an enzyme-linked immunosorbent assay (ELISA), we have (i) proved the immunodominance of this region regardless of its high variability, (ii) defined the epitopes encompassed by SU5, (iii) illustrated the rapid and peculiar kinetics of seroconversion to this antigenic site, and (iv) shown the rapid and strong maturation of the avidity of the anti-SU5 antibody. Finally, we demonstrated the modular diagnostic potential of SU5 peptides. Under Swiss field conditions, the SU5 ELISA was shown to detect the majority of infected animals and, when applied in a molecular epidemiological context, to permit rapid phylogenetic classification of the infecting virus." ]

[ "Epithelial cell adhesion molecule (EpCAM) is a type I transmembrane glycoprotein overexpressed in human epithelioma but with relatively low expression in normal epithelial tissues. To exploit this differential expression pattern for targeted cancer therapy, an EpCAM-targeted immunotoxin was developed and its antitumor activity was investigated in vitro. An immunotoxin (scFv2A9-PE or APE) was constructed by genetically fusing a truncated form (PE38KDEL) of Pseudomonas aeruginosa exotoxin with an anti-EpCAM single-chain variable fragment (scFv). ELISA and flow cytometry were performed to verify immunotoxin (scFv2A9-PE or APE) antigen-binding activity with EpCAM. Cytotoxicity was measured by MTT assay. Confocal microscopy was used to observe its cellular localization. The results of ELISA and flow cytometry revealed that the immunotoxin efficiently recognized recombinant and natural EpCAM. Its antigen-binding activity was relatively lower than 2A9. MTT assay confirmed potent reduction in EpCAM-positive HHCC (human hepatocellular carcinoma) cell viability (IC50 50 pM). Immunofluorescence revealed that the immunotoxin localized to endoplasmic reticulum 24 h later. In conclusion, we described the development of an EpCAM-targeted immunotoxin with potent activity against tumor cells, which may lay the foundation for future development of therapeutic antibody for the treatment of EpCAM-positive tumors.", "Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein, which is frequently and highly expressed on carcinomas, tumor-initiating cells, selected tissue progenitors, and embryonic and adult stem cells. During liver development, EpCAM demonstrates a dynamic expression, since it can be detected in fetal liver, including cells of the parenchyma, whereas mature hepatocytes are devoid of EpCAM. Liver regeneration is associated with a population of EpCAM-positive cells within ductular reactions, which gradually lose the expression of EpCAM along with maturation into hepatocytes. EpCAM can be switched on and off through a wide panel of strategies to fine-tune EpCAM-dependent functional and differentiative traits. EpCAM-associated functions relate to cell-cell adhesion, proliferation, maintenance of a pluripotent state, regulation of differentiation, migration, and invasion. These functions can be conferred by the full-length protein and/or EpCAM-derived fragments, which are generated upon regulated intramembrane proteolysis. Control by EpCAM therefore not only depends on the presence of full-length EpCAM at cellular membranes but also on varying rates of the formation of EpCAM-derived fragments that have their own regulatory properties and on changes in the association of EpCAM with interaction partners. Thus spatiotemporal localization of EpCAM in immature liver progenitors, transit-amplifying cells, and mature liver cells will decisively impact the regulation of EpCAM functions and might be one of the triggers that contributes to the adaptive processes in stem/progenitor cell lineages. This review will summarize EpCAM-related molecular events and how they relate to hepatobiliary differentiation and regeneration.", "Apoptosis is frequently induced to inhibit virus replication during infection of Enterovirus 71 (EV71). On the contrary, anti-apoptotic pathway, such as PI3K/Akt pathway, is simultaneously exploited by EV71 to accomplish the viral life cycle. The relationship by which EV71-induced apoptosis and PI3K/Akt signaling pathway remains to be elucidated. In this study, we demonstrated that EV71 infection altered Bax conformation and triggered its redistribution from the cytosol to mitochondria in RD cells. Subsequently, cytochrome c was released from mitochondria to cytosol. We also found that c-Jun NH2-terminal kinase (JNK) was activated during EV71 infection. The JNK specific inhibitor significantly inhibited Bax activation and cytochrome c release, suggesting that EV71-induced apoptosis was involved into a JNK-dependent manner. Meanwhile, EV71-induced Akt phosphorylation involved a PI3K-dependent mechanism. Inhibition of the PI3K/Akt pathway enhanced JNK phosphorylation and the JNK-mediated apoptosis upon EV71 infection. Moreover, PI3K/Akt pathway phosphorylated apoptosis signal-regulating kinase 1 (ASK1) and negatively regulated the ASK1 activity. Knockdown of ASK1 significantly decreased JNK phosphorylation, which implied that ASK1 phosphorylation by Akt inhibited ASK1-mediated JNK activation. Collectively, these data reveal that activation of the PI3K/Akt pathway limits JNK-mediated apoptosis by phosphorylating and inactivating ASK1 during EV71 infection.", "BACKGROUND: Autotransplantation of frozen-thawed ovarian tissue is a method to preserve ovarian function and fertility in patients undergoing gonadotoxic therapy. In oncology patients, the safety cannot yet be guaranteed, since current tumor detection methods can only exclude the presence of malignant cells in ovarian fragments that are not transplanted. We determined the need for a novel detection method by studying the distribution of tumor cells in ovaries from patients with breast cancer. Furthermore, we examined which cell-surface proteins are suitable as a target for non-invasive tumor-specific imaging of ovarian metastases from invasive breast cancer.METHODS: Using the nationwide database of the Dutch Pathology Registry (PALGA), we identified a cohort of 46 women with primary invasive breast cancer and ovarian metastases. The localization and morphology of ovarian metastases were determined on hematoxylin-and-eosin-stained sections. The following cell-surface markers were immunohistochemically analyzed: E-cadherin, epithelial membrane antigen (EMA), human epidermal growth receptor type 2 (Her2/neu), carcinoembryonic antigen (CEA), αvβ6 integrin and epithelial cell adhesion molecule (EpCAM).RESULTS: The majority of ovarian metastases (71%) consisted of a solitary metastasis or multiple distinct nodules separated by uninvolved ovarian tissue, suggesting that ovarian metastases might be overlooked by the current detection approach. Combining the targets E-cadherin, EMA and Her2/neu resulted in nearly 100% detection of ductal ovarian metastases, whereas the combination of EMA, Her2/neu and EpCAM was most suitable to detect lobular ovarian metastases.CONCLUSIONS: Examination of the actual ovarian transplants is recommended. A combination of targets is most appropriate to detect ovarian metastases by tumor-specific imaging.", "Epithelial cell adhesion molecule (EpCAM) (CD326) is a surface glycoprotein expressed by invasive carcinomas and some epithelia. Herein, we report that EpCAM regulates the composition and function of tight junctions (TJ). EpCAM accumulated on the lateral interfaces of human colon carcinoma and normal intestinal epithelial cells but did not co-localize with TJ. Knockdown of EpCAM in T84 and Caco-2 cells using shRNAs led to changes in morphology and adhesiveness. TJ formed readily after EpCAM knockdown; the acquisition of trans-epithelial electroresistance was enhanced, and TJ showed increased resistance to disruption by calcium chelation. Preparative immunoprecipitation demonstrated that EpCAM bound tightly to claudin-7. Co-immunoprecipitation documented associations of EpCAM with claudin-7 and claudin-1 but not claudin-2 or claudin-4. Claudin-1 associated with claudin-7 in co-transfection experiments, and claudin-7 was required for association of claudin-1 with EpCAM. EpCAM knockdown resulted in decreases in claudin-7 and claudin-1 proteins that were reversed with lysosome inhibitors. Immunofluorescence microscopy revealed that claudin-7 and claudin-1 continually trafficked into lysosomes. Although EpCAM knockdown decreased claudin-1 and claudin-7 protein levels overall, accumulations of claudin-1 and claudin-7 in TJ increased. Physical interactions between EpCAM and claudins were required for claudin stabilization. These findings suggest that EpCAM modulates adhesion and TJ function by regulating intracellular localization and degradation of selected claudins.", "The thrombotic-thrombocytopenic purpura (TTP) is an acute, life-threatening disease, characterised by enhanced platelet aggregation, disturbed microcirculation and organ dysfunction. With the currently available treatment (plasma exchange, infusions, corticosteroids) mortality ist still as high as 10-15 %. Recent, pathophysiology-based developments may improve the outcome. The most promising candidates for future treatment of TTP are: rituximab for termination of the autoimmune process, caplacizumab for prevention of platelet-VWF-interaction, and recombinant ADAMTS13 for replacement of the inhibited or missing enzyme.", "Gluten sensitive enteropathy has various manifestations, of which the two major forms are classical coeliac disease (cCD) and dermatitis herpetiformis (DH). In cCD predominantly the small intestine is affected, whereas in DH also the skin is affected showing typical rash and IgA deposits. The symptoms in both forms are dependent on gluten intake. The factors diversifying these two clinical outcomes are unknown. In the present report we evaluated the role of the major genetic susceptibility locus, HLA DQ, in 25 families, in which both forms of the disease, cCD and DH, occurred in siblings. By using the family-based approach it can be assumed that within each family variation in environmental factors is substantially lower than in the standard case-control setting, and also the problems related to population stratification can be avoided. Results from the Finnish family material with 25 discordant and 85 concordant sib pairs, and from additional case-control material comprising 71 unrelated Hungarian DH and 68 cCD patients, together indicated that the HLA DQ locus did not differ between the two major outcomes of gluten sensitive enteropathy. The non-HLA DR;DQ factors are critical for the different clinical manifestations of gluten sensitivity.", "BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of both hospital and community infections globally. It's important to illuminate the differences between community-acquired MRSA (CA-MRSA) and hospital-acquired MRSA (HA-MRSA), but there have been confusions on the definition, especially for the MRSA isolates identified within 48 h of admission. This study aimed to determine the molecular characteristics and virulence genes profile of CA and HA-MRSA isolates identified less than 48 h after hospital admission in our region.METHODS: A total 62 MRSA isolates identified within 48 h after admission and the clinical data were collected. Antimicrobial susceptibility test (AST) of collected isolates were performed according to the guidelines of Clinical and Laboratory Standards Institute (CLSI) 2015, and staphylococcal cassette chromosome mec (SCCmec) typing, multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE) and virulence gene profiling were performed to explore the molecular diversity.RESULTS: SCCmec III and sequence type (ST) 239 were the most prevalent SCCmec type and ST in both CA and HA-MRSA groups. HA-MRSA group had higher prevalence of SCCmec III (87.2 %) and ST239 (79.5 %) compared with CA-MRSA (60.9 and 43.4 %, both P < 0.001), while the frequency of SCCmec IV (26.0 %) and ST59 (21.7 %) were higher in CA-MRSA than its counterpart (P < 0.001 and P = 0.003). MRSA-ST239-III was the predominant type in this study (61.3 %, 38/62), especially in HA-MRSA group (76.9 %, 30/39). However, CA-MRSA strains exhibited more diversity in genotypes in this study. Meanwhile, CA-MRSA tended to have lower resistant percentage to non-β-lactams antibiotics but more virulence genes carriage, especially the staphylococcal enterotoxins (SE) genes. Notably, seb gene was only detected in CA-MRSA isolates (52.2 %), likely a significant marker for CA-MRSA isolates. Panton-Valentine leukocidin gene (PVL) was highly detected in both groups, while appeared no significantly different between CA-MRSA (47.8 %) and HA-MRSA (43.6 %).CONCLUSIONS: Our findings support a difference in the molecular epidemiology and virulence genes profile of CA-MRSA and HA-MRSA. Furthermore, this study indicates a possible transmission from HA-MRSA to CA-MRSA, which may cause the overlap of the definition.", "Thomsen's (TM) and Becker's (BM) Myotonias are nondystrophic myotonias. At present, 150 mutations in the CLCN1 gene, which results in the development of TM and BM, have been described. c.2680C > T (p.Arg894*) is the most common mutation. In the Northern Scandinavian countries, the population frequency of this mutation is 0.87%, while in the Russian Federation, it is equal to 1.2% (this study). Based on the results of a molecular-genetic analysis of CLCN1 gene in patients with nondystrophic myotonias, the calculated frequency of TM and BM in Russia is 1:8165 and 1:710, respectively. We have conducted haplotype analysis using microsatellite markers and intragene SNP, which has shown that the prevalence of p.Arg894* mutation in Russia results from the founder effect, and the time of its scattering is 3680 ± 1240 years.", "Previous studies showed that the binding of p50/NFkappaB1 to particular kappaB DNA sites altered its conformation in a way that correlated with transcriptional activation. Here, we investigated the effects of protein-protein interactions on the transcriptional activity of p50. We show that the association of p50 with a mutant Rel-homology domain (RHD) defective for DNA binding led to synergistic activation of kappaB site-dependent transcription, whereas neither protein alone had any effect. Partial proteolytic analysis showed that the conformation of p50 in these complexes differed from that in wild-type c-Rel-RHD/p50 complexes, and correlated with activated transcription. These results suggest that the Rel-homology domain can act as an allosteric effector to promote transcription by p50/NFkappaB1 and that the configuration of p50 is important for its activity. This also suggests that Rel proteins can promote transcription by other Rel-family members without binding to their DNA recognition site. These studies emphasize the important role of protein-protein interactions in Rel and NFkappaB-mediated transcription.", "1. Human small-cell lung cancer (SCLC) cells are believed to express the antigens responsible for the production of pathological antibodies in the Lambert-Eaton syndrome (LES), a Ca2+ channel disorder in which quantal transmitter release from the motor nerve terminal is impaired. Whole-cell patch-clamp techniques were used to study the voltage-dependent Ca2+ channels expressed by H146 SCLC cells and the effects of LES antibodies on these channels. The types of Ca2+ channels were determined using biophysical properties and pharmacological sensitivity to several antagonists. 2. Whole-cell Ca2+ currents (ICa) in SCLC cells are sensitive to the dihydropyridine (DHP) nicardipine, omega-conotoxin GVIA (omega-CgTX GVIA) and omega-agatoxin IVA (omega-AgTX IVA). Nicardipine at 100 nM and 10 microM reduced ICa by 35 and 45% (n = 38 cells), respectively, while omega-CgTX GVIA (1 microM) inhibited ICa by 32% (n = 31). Application of omega-AgTX IVA at 50 and 100 nM to the cancer cells decreased ICa by 41 and 42%, respectively (n = 22). 3. Measurement of cell membrane capacitance (Cm) revealed that Ca(2+)-dependent exocytosis underlies the secretory activity of SCLC cells. Exocytosis, when induced by step depolarizing pulses and measured by increases in Cm, was markedly inhibited by nicardipine (10 microM) and omega-AgTX IVA (100 nM). In contrast, omega-CgTX GVIA (1 microM) was not as effective in altering increases in Cm. 4. From negative (-80 mV) and depolarized (-40 mV) holding potentials, both peak and plateau ICa were inhibited by the presence of LES antibodies (1 mg ml-1 IgG). LES serum also reduced depolarization-induced increases in Cm by 48% (n = 15). 5. To determine whether the LES antibodies are downregulating a specific type(s) of Ca2+ channel, nicardipine (10 microM), omega-CgTX GVIA (1 microM) or omega-AgTX IVA (100 nM) was applied to tumour cells that had been previously exposed to LES serum for 24 h. The most pronounced change was that omega-AgTX IVA was 38-84% less effective at reducing ICa after the IgG treatment. The effectiveness of nicardipine was diminished by 18% after incubation with the LES antibodies, whereas the omega-CgTX GVIA was seen to be more effective. These results suggest that LES IgG downregulates P-type Ca2+ channels and, possibly, to a lesser extent L-type channels. 6. In view of recent evidence that P-type Ca2+ channels mediate cholinergic transmitter release at the mammalian neuromuscular junction (NMJ), the expression of P-type Ca2+ channels in the SCLC cells and the reactivity of LES IgG with these channels support the hypothesis that P-type Ca2+ channels in these cancer cells may trigger the autoantibody production in this disorder. The antibodies so produced are implicated in the functional impairment of the Ca2+ channels characteristic of LES.", "Delafloxacin (Baxdela™) is a fluoroquinolone antibacterial with activity against both gram-positive and gram-negative pathogens being developed by Melinta Therapeutics. The drug is being investigated or considered as a treatment for various bacterial infections and in June 2017 received approval in the USA for the treatment of acute bacterial skin and skin structure infections. This article summarizes the milestones in the development of delafloxacin leading to this first global approval for the treatment of acute bacterial skin and skin structure infections.", "A large proportion of functional sequence within mammalian genomes falls outside protein-coding exons and can be transcribed into long RNAs. However, the roles in mammalian biology of long noncoding RNA (lncRNA) are not well understood. Few lncRNAs have experimentally determined roles, with some of these being lineage-specific. Determining the extent by which transcription of lncRNA loci is retained or lost across multiple evolutionary lineages is essential if we are to understand their contribution to mammalian biology and to lineage-specific traits. Here, we experimentally investigated the conservation of lncRNA expression among closely related rodent species, allowing the evolution of DNA sequence to be uncoupled from evolution of transcript expression. We generated total RNA (RNAseq) and H3K4me3-bound (ChIPseq) DNA data, and combined both to construct catalogues of transcripts expressed in the adult liver of Mus musculus domesticus (C57BL/6J), Mus musculus castaneus, and Rattus norvegicus. We estimated the rate of transcriptional turnover of lncRNAs and investigated the effects of their lineage-specific birth or death. LncRNA transcription showed considerably greater gain and loss during rodent evolution, compared with protein-coding genes. Nucleotide substitution rates were found to mirror the in vivo transcriptional conservation of intergenic lncRNAs between rodents: only the sequences of noncoding loci with conserved transcription were constrained. Finally, we found that lineage-specific intergenic lncRNAs appear to be associated with modestly elevated expression of genomically neighbouring protein-coding genes. Our findings show that nearly half of intergenic lncRNA loci have been gained or lost since the last common ancestor of mouse and rat, and they predict that such rapid transcriptional turnover contributes to the evolution of tissue- and lineage-specific gene expression.", "Cardiac muscle-restricted expression of the alpha-myosin heavy-chain (alpha-MHC) gene is regulated by multiple elements in the proximal enhancer/promoter. Within this region, an M-CAT site and an A-rich site were identified as potential regulatory elements. Site-specific mutations in each site, individually, reduced activity from the wild-type promoter by approximately 85% in the adult rat heart, demonstrating that these sites were positive regulatory elements. alpha-MHC, beta-MHC, and chicken cardiac troponin T (cTnT) M-CAT sites interacted with an M-CAT-binding factor (MCBF) from rat heart nuclear extracts that was immunologically related to transcriptional enhancer factor 1, a factor that binds within the simian virus 40 enhancer. The factor that bound the A-rich region (ARF) was antigenically related to the RSRF family of proteins, ARF was distinct from myocyte-specific enhancer factor 2 (MEF-2) on the basis of DNA-binding specificity and developmental expression. Like MEF-2, ARF DNA-binding activity was present in the heart and brain; however, no ARF activity was detected in extracts from skeletal muscle or C2C12 myotubes. MCBF and ARF DNA-binding activities were developmentally regulated with peak levels in the 1- to 2-day neonatal heart. The activity of both factors increased nearly fivefold in adult rat hearts subjected to a pressure overload. By comparison, the levels of alpha-MHC binding factor 2 did not change during hypertrophy. Binding sites for MCBF and ARF are present in several genes that are upregulated during cardiac hypertrophy. Our results suggest that these factors participate in the alterations in gene expression that occur during cardiac development and hypertrophy.", "Thirty fungal species grown on Cichorium intybus L. root extract as a sole carbon source, were screened for the production of exo-inulinase activities. The thermophile Thielavia terrestris NRRL 8126 and mesophile Aspergillus foetidus NRRL 337 gave the highest production levels of inulinases I & II at 50 and 24 ºC respectively. Yeast extract and peptone were the best nitrogen sources for highest production of inulinases I & II at five and seven days of incubation respectively. The two inulinases I & II were purified to homogeneity by gel-filtration and ion-exchange chromatography with 66.0 and 42.0 fold of purification respectively. The optimum temperatures of purified inulinases I & II were 75 and 50 ºC respectively. Inulinase I was more thermostable than the other one. The optimum pH for activity was found to be 4.5 and 5.5 for inulinases I & II respectively. A comparatively lower Michaelis-Menten constant (2.15 mg/ml) and higher maximum initial velocity (115 µmol/min/mg of protein) for inulinase I on inulin demonstrated the exoinulinase's greater affinity for inulin substrate. These findings are significant for its potential industrial application. The molecular mass of the inulinases I & II were estimated to be 72 & 78 kDa respectively by sodium dodecyl sulfate-polyacrylamide gel electrophoresis.", "OBJECTIVES: Heterozygous mutations in STXBP1, encoding the syntaxin binding protein 1, have recently been identified in Ohtahara syndrome, an epileptic encephalopathy with very early onset. In order to explore the phenotypic spectrum associated with STXBP1 mutations, we analyzed a cohort of patients with unexplained early-onset epileptic encephalopathies.METHODS: We collected and clinically characterized 106 patients with early-onset epileptic encephalopathies. Mutation analysis of the STXBP1 gene was done using sequence analysis of the exon and intron-exon boundaries and multiplex amplification quantification to detect copy number variations.RESULTS: We identified 4 truncating mutations and 2 microdeletions partially affecting STXBP1 in 6 of the 106 patients. All mutations are predicted to abolish STXBP1 function and 5 mutations were proven to occur de novo. None of the mutation-carrying patients had Ohtahara syndrome. One patient was diagnosed with West syndrome at disease onset, while the initial phenotype of 5 further patients did not fit into a specific recognized epilepsy syndrome. Three of these patients later evolved to West syndrome. All patients had severe to profound mental retardation, and ataxia or dyskinetic movements were present in 5 patients.CONCLUSION: This study shows that mutations in STXBP1 are not limited to patients with Ohtahara syndrome, but are also present in 10% (5/49) of patients with an early-onset epileptic encephalopathy that does not fit into either Ohtahara or West syndrome and rarely in typical West syndrome. STXBP1 mutational analysis should be considered in the diagnostic evaluation of this challenging group of patients.", "BACKGROUND AND PURPOSE: Age and stroke severity are inversely correlated with the odds of favorable outcome after ischemic stroke. A previously proposed score for Stroke Prognostication Using Age and NIHSS Stroke Scale (SPAN) indicated that SPAN-100-positive patients (ie, age + NIHSS score = 100 or more) do not benefit from IV-tPA. If this finding holds true for endovascular therapy, this score can impact patient selection for such interventions. This study investigated whether a score combining age and NIHSS score can improve patients' selection for endovascular stroke therapy.MATERIALS AND METHODS: The SPAN index was calculated for patients in the prospective Solitaire FR Thrombectomy for Acute Revascularization study: an international single-arm multicenter cohort for anterior circulation stroke treatment by using the Solitaire FR. The proportion with favorable outcome (90-day mRS score ≤2) was compared between SPAN-100-positive versus-negative patients.RESULTS: Of the 202 patients enrolled, 196 had baseline NIHSS scores. Fifteen (7.7%) patients were SPAN-100-positive. There was no difference in the rate of successful reperfusion (Thrombolysis In Cerebral Infarction 2b or 3) between SPAN-100-positive versus -negative groups (93.3% versus 82.8%, respectively; P = .3). Stroke SPAN-100-positive patients had a significantly lower proportion of favorable clinical outcomes (26.7% versus 60.8% in SPAN-100-negative, P = .01). In a multivariable analysis, SPAN-100-positive status was associated with lower odds of favorable outcome (OR, 0.3; 95% CI, 0.1-0.9; P = .04). A higher baseline Alberta Stroke Program Early CT Score and a short onset to revascularization time also predicted favorable outcome in the multivariable analysis.CONCLUSIONS: A significantly lower proportion of patients with a positive SPAN-100 achieved favorable outcome in this cohort. SPAN-100 was an independent predictor of favorable outcome after adjusting for time to treatment and the extent of preintervention tissue damage according to the Alberta Stroke Program Early CT Score.", "Conflict of interest statement: CONFLICT OF INTEREST: SS has received speaking fees from Chugai Pharmaceutical, Eisai, Bristol–Myers K.K, Asahikasei Pharma Corp, Pfizer Japan, and consultant fees from Asahikasei Pharma Corp. TT has received research grants from Astellas Pharma Inc, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahikasei Pharma Corp., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Taisho Toyama Pharmaceutical Co., Ltd., Eisai Co., Ltd., AYUMI Pharmaceutical Corporation, speaking fees from AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co,. Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Astellas Pharma Inc, and Daichi Sankyo Co., Ltd, and consultant fees from Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Abbvie GK, Nipponkayaku Co., Ltd, Janssen Pharmaceutical K.K., Astellas Pharma Inc.", "AIMS: Polymerase chain reaction (PCR) is the most rapid and sensitive method for diagnosing mycobacterial infections and identifying the aetiological Mycobacterial species in order to administer the appropriate therapy and for better patient management.METHODS AND RESULTS: Two hundred and thirty-five samples from 145 clinically suspected cases of tuberculosis were processed for the detection of Mycobacterial infections by ZN (Ziehl Neelsen) smear examination, L-J & BACTEC MGIT-960 culture and multiplex PCR tests. The multiplex PCR comprised of genus-specific primers targeting hsp65 gene, Mycobacterium tuberculosis complex-specific primer targeting cfp10 (Rv3875, esxB) region and Mycobacterium avium complex-specific primer pairs targeting 16S-23S Internal Transcribed Spacer sequences. The multiplex PCR developed had an analytical sensitivity of 10 fg (3-4 cells) of mycobacterial DNA. The multiplex PCR test showed the highest (77.24%) detection rate, while ZN smear examination had the lowest (20%) detection rate, which was bettered by L-J culture (34.4%) and BACTEC MGIT-960 culture (50.34%) methods. The mean isolation time for M. tuberculosis was 19.03 days in L-J culture and 8.7 days in BACTEC MGIT-960 culture. Using the multiplex PCR, we could establish M. tuberculosis + M. avium co-infection in 1.3% HIV-negative and 2.9% HIV-positive patients. The multiplex PCR was also highly useful in diagnosing mycobacteraemia in 38.09% HIV-positive and 15.38% HIV-negative cases.CONCLUSIONS: The developed in-house multiplex PCR could identify and differentiate the M. tuberculosis and M. avium complexes from other Mycobacterial species directly from clinical specimens.SIGNIFICANCE AND IMPACT OF THE STUDY: The triplex PCR developed by us could be used to detect and differentiate M. tuberculosis, M. avium and other mycobacteria in a single reaction tube.", "Propionic acidemia (PA) is an autosomal recessive inborn error in the catabolism of methionine, isoleucine, threonine, and valine, odd-numbered chain length fatty acids and cholesterol. Clinical symptoms are very heterogeneous and present as a severe neonatal-onset or a late-onset form. It is caused by a deficiency of propionyl-CoA carboxylase (PCC, EC 6.4.1.3), a biotin-dependent enzyme that catalyzes the carboxylation of propionyl-CoA to D-methylmalonyl-CoA. PCC is a heteropolymeric enzyme composed of alpha- and beta-subunits. A greater heterogeneity is observed in the PCCA gene, while for the PCCB gene, a limited number of mutations is responsible for the majority of the alleles characterized in both Caucasian and Oriental populations. We identified eight Korean patients with PA by organic acid analysis confirmed in five patients by the PCC enzyme assay in the lymphoblasts. Two neonatal-onset patients showed undetectable PCC activities while three cases with residual enzyme activities had relatively late manifestations. In the molecular analysis, we identified five novel mutations, Y439C, 1527del3, 1357insT, IVS12-8T-->A, and 31del10, and one known mutation, T428I in PCCB gene. Alleleic frequency of T428I in Korean patients with PA was 56.3% in this study. Two neonatal-onset patients with null enzyme activities were homozygotes with 1527del3 and T428I, respectively. This finding implies that T428I and 1527del3 mutation could be responsible for their severe clinical courses and null enzyme activities. The mRNA of PCCB gene in T428I and 1527del3 homozygotes were normal but in Western blot analysis, the betaPCC-subunit was only absent in 1527del3 homozygote patient suggesting different molecular pathology.", "Epithelial Cell Adhesion Molecule (EpCAM) has been discovered as one of the first tumor-specific antigens overexpressed in epithelial cancer. The present review focuses on the role of EpCAM in physiology and homeostasis of epithelia. Recent research pointed to a close interaction of EpCAM with other cell-cell contact molecules like E-cadherin and claudins and an intimate crosstalk with Wnt and TGF-beta signaling in the regulation of cell growth. Moreover, EpCAM has been shown to modulate trans-epithelial migration processes of white blood cells. Mutations of the EpCAM gene lead to disturbances of epithelial homeostasis and cellular differentiation from the stem cell compartment. In the intestinal tract EpCAM mutations contribute to congenital tufting enteropathy. Regarding tumorigenesis EpCAM can act as an oncogene still depending on additional driver mutations and epithelial phenotype of tumor cells. Tumor cells display increased EpCAM expression that often correlates with the loss of strict basolateral localization. Many tumors show enhanced regulated intramembrane proteolysis (RIP) of EpCAM and loose EpCAM expression under conditions of epithelial to mesenchymal transition. The resulting extracellular EpEX and intracellular EpICD fragments mediate proliferative signals to the cell. Resulting fragments can be validated either by sensitive enzyme-linked immune-sandwich assays (EpEX) or by immunohistochemistry (EpICD). The present review gives an overview on the detection of EpCAM fragments as predictive markers for disease progression and survival of cancer patients.", "OBJECTIVE: To study the expression of EpCAM and E-cadherin in papillary thyroid carcinoma and to analyze its correlation with various clinicopathologic parameters.METHODS: Immunohistochemical study for EpCAM and E-cadherin was carried out in 91 cases of papillary thyroid carcinoma. Twenty-four cases of papillary hyperplasia of thyroid were used as controls.RESULTS: In all of the 24 cases of papillary hyperplasia, EpCAM was located on the cell membrane, while in the 91 cases of papillary thyroid carcinoma studied, EpCAM was located within the cytoplasm, with 36.3% (33/91) showing nuclear localization as well. In all the papillary hyperplasia cases studied, E-cadherin showed membranous expression. E-cadherin expression was reduced in 84.6% (77/91) of papillary thyroid carcinoma, as compared with the surrounding native thyroid parenchyma. Amongst the 33 cases of papillary thyroid carcinoma which showed nuclear localization of EpCAM, 30 cases also showed reduced E-cadherin expression. There was a positive correlation between nuclear expression of EpCAM and loss of E-cadherin expression (P = 0.000; Spearman correlation coefficient = 0.857). Nuclear expression of EpCAM correlated with follicular variant of papillary thyroid carcinoma and presence of extrathyroidal extension ( P = 0.037 and 0.033, respectively). Loss of E-cadherin expression correlated with age of patients and presence of lymph node metastasis (P = 0.018 and 0.010, respectively).CONCLUSIONS: E-cadherin expression is reduced in papillary thyroid carcinoma, as compared with native thyroid parenchyma and papillary hyperplasia. Papillary thyroid carcinoma shows loss of EpCAM membranous expression and increased cytoplasmic/nuclear accumulation. Detection of these two markers may provide a valuable reference in defining the biologic behaviors of papillary thyroid carcinoma, including extrathyroidal extension and lymph node metastasis.", "Plasma-derived vesicles hold a promising potential for use in biomedical applications. Two major challenges, however, hinder their implementation into translational tools: (a) the incomplete characterization of the protein composition of plasma-derived vesicles, in the size range of exosomes, as mass spectrometric analysis of plasma sub-components is recognizably troublesome and (b) the limited reach of vesicle-based studies in settings where the infrastructural demand of ultracentrifugation, the most widely used isolation/purification methodology, is not available. In this study, we have addressed both challenges by carrying-out mass spectrometry (MS) analyses of plasma-derived vesicles, in the size range of exosomes, from healthy donors obtained by 2 alternative methodologies: size-exclusion chromatography (SEC) on sepharose columns and Exo-Spin™. No exosome markers, as opposed to the most abundant plasma proteins, were detected by Exo-Spin™. In contrast, exosomal markers were present in the early fractions of SEC where the most abundant plasma proteins have been largely excluded. Noticeably, after a cross-comparative analysis of all published studies using MS to characterize plasma-derived exosomes from healthy individuals, we also observed a paucity of \"classical exosome markers.\" Independent of the isolation method, however, we consistently identified 2 proteins, CD5 antigen-like (CD5L) and galectin-3-binding protein (LGALS3BP), whose presence was validated by a bead-exosome FACS assay. Altogether, our results support the use of SEC as a stand-alone methodology to obtain preparations of extracellular vesicles, in the size range of exosomes, from plasma and suggest the use of CD5L and LGALS3BP as more suitable markers of plasma-derived vesicles in MS.", "The anthracycline chemotherapeutic agent doxorubicin is converted by the enzyme carbonyl reductase 1 (CBR1) into its cardiotoxic metabolite doxorubicinol. Cbr1+/- mice have been shown to be protected from doxorubicin-induced cardiotoxicity, and the inhibition of CBR1 activity may be a useful means of ameliorating the side effects of doxorubicin in patients undergoing chemotherapy. Because reduced conversion to doxorubicinol increases circulating levels of the more effective parent drug doxorubicin, it was hypothesized that therapeutic efficacy against tumors might also be enhanced. Cbr1+/- mice were bred to mice transgenic for the polyomavirus middle T antigen (PyVT) to create offspring with palpable mammary tumors. Latency to initial tumor formation was similar in Cbr1+/- and Cbr1+/+ animals. Tumor regression was improved in Cbr1+/- animals, but only in male mice. Western blotting showed a marked sex difference in protein levels, with a much higher expression of Cbr1 in the female kidney and liver. Thus, the combined effects of a naturally low expression and the heterozygous Cbr1 null allele seem to have enhanced tumor regression in Cbr1+/- males. Future efforts to design a clinical CBR1 inhibitor to protect patients from the cardiac side effects of doxorubicin treatment should evaluate the effect of sex on anticancer efficacy." ]

[ "Albuminuria is an early marker of renovascular damage associated to an increase in oxidative stress. The Munich Wistar Frömter (MWF) rat is a model of chronic kidney disease (CKD), which exhibits endothelial dysfunction associated to low nitric oxide availability. We hypothesize that the new highly selective, non-steroidal mineralocorticoid receptor (MR) antagonist, finerenone, reverses both endothelial dysfunction and microalbuminuria. Twelve-week-old MWF (MWF-C; MWF-FIN) and aged-matched normoalbuminuric Wistar (W-C; W-FIN) rats were treated with finerenone (FIN, 10 mg/kg/day p.o.) or vehicle (C) for 4-week. Systolic blood pressure (SBP) and albuminuria were determined the last day of treatment. Finerenone lowered albuminuria by >40% and significantly reduced SBP in MWF. Aortic rings of MWF-C showed higher contractions to either noradrenaline (NA) or angiotensin II (Ang II), and lower relaxation to acetylcholine (Ach) than W-C rings. These alterations were reversed by finerenone to W-C control levels due to an upregulation in phosphorylated Akt and eNOS, and an increase in NO availability. Apocynin and 3-amino-1,2,4-triazole significantly reduced contractions to NA or Ang II in MWF-C, but not in MWF-FIN rings. Accordingly, a significant increase of Mn-superoxide dismutase (SOD) and Cu/Zn-SOD protein levels were observed in rings of MWF-FIN, without differences in p22phox, p47phox or catalase levels. Total SOD activity was increased in kidneys from MWF-FIN rats. In conclusion, finerenone improves endothelial dysfunction through an enhancement in NO bioavailability and a decrease in superoxide anion levels due to an upregulation in SOD activity. This is associated with an increase in renal SOD activity and a reduction of albuminuria.", "During the H1N1 (swine flu) pandemic of 2009, the World Health Organization (WHO) confirmed more than 14,000 deaths globally; this included a death toll of 147 in Iran. In order to evaluate (a) the appropriateness of the Oseltamivir dose through calculation of a patient’s creatinine clearance (CrCl) and (b) the quality of data in the medical charts, we conducted a retrospective study at the Shariati Hospital in Tehran. All admissions to the hospital between the dates 1 October 2009 and 31 January 2010 were evaluated, amounting to a total of 51 patients’ charts, including 8 outpatient charts. Of these 51 charts, 26 (51%) contained all the information necessary to evaluate the CrCl. However, there was at least one piece of information missing (e.g. the patient’s weight; serum creatinine) from each of the remaining 25 charts (49% of the sample), which made it impossible for us to evaluate the dose. These results demonstrate how crucially important it is to ensure that all the necessary patient information is correctly registered at the time of admission in order to minimise medication errors.", "Reported here is a piggyBac transposon-based expression system for the generation of doxycycline-inducible, stably transfected mammalian cell cultures for large-scale protein production. The system works with commonly used adherent and suspension-adapted mammalian cell lines and requires only a single transfection step. Moreover, the high uniform expression levels observed among clones allow for the use of stable bulk cell cultures, thereby eliminating time-consuming cloning steps. Under continuous doxycycline induction, protein expression levels have been shown to be stable for at least 2 mo in the absence of drug selection. The high efficiency of the system also allows for the generation of stable bulk cell cultures in 96-well format, a capability leading to the possibility of generating stable cell cultures for entire families of membrane or secreted proteins. Finally, we demonstrate the utility of the system through the large-scale production (140-750 mg scale) of an endoplasmic reticulum-resident fucosyltransferase and two potential anticancer protein therapeutic agents.", "MOTIVATION: mRNA sequences and expressed sequence tags represent some of the most abundant experimental data for identifying genes and alternatively spliced products in metazoans. These transcript sequences are frequently studied by aligning them to a genomic sequence template. For existing programs, error-prone, polymorphic and cross-species data, as well as non-canonical splice sites, still present significant barriers to producing accurate, complete alignments.RESULTS: We took a novel approach to spliced alignment that meaningfully combined information from sequence similarity with that obtained from PSSM splice site models. Scoring systems were chosen to maximize their power of discrimination, and dynamic programming (DP) was employed to guarantee optimal solutions would be found. The resultant program, EXALIN, performed better than other popular tools tested under a wide range of conditions that included detection of micro-exons and human-mouse cross-species comparisons. For improved speed with only a marginal decrease in splice site prediction accuracy, EXALIN could perform limited DP guided by a result from BLASTN.AVAILABILITY: The source code, binaries, scripts, scoring matrices and splice site models for human, mouse, rice and Caenorhabditis elegans utilized in this study are posted at http://blast.wustl.edu/exalin. The software (scripts, source code and binaries) is copyrighted but free for all to use.", "In metazoans, the nuclear lamina is thought to play an important role in the spatial organization of interphase chromosomes, by providing anchoring sites for large genomic segments named lamina-associated domains (LADs). Some of these LADs are cell-type specific, while many others appear constitutively associated with the lamina. Constitutive LADs (cLADs) may contribute to a basal chromosome architecture. By comparison of mouse and human lamina interaction maps, we find that the sizes and genomic positions of cLADs are strongly conserved. Moreover, cLADs are depleted of synteny breakpoints, pointing to evolutionary selective pressure to keep cLADs intact. Paradoxically, the overall sequence conservation is low for cLADs. Instead, cLADs are universally characterized by long stretches of DNA of high A/T content. Cell-type specific LADs also tend to adhere to this \"A/T rule\" in embryonic stem cells, but not in differentiated cells. This suggests that the A/T rule represents a default positioning mechanism that is locally overruled during lineage commitment. Analysis of paralogs suggests that during evolution changes in A/T content have driven the relocation of genes to and from the nuclear lamina, in tight association with changes in expression level. Taken together, these results reveal that the spatial organization of mammalian genomes is highly conserved and tightly linked to local nucleotide composition.", "Rickettsia felis was first recognised two decades ago and has now been described as endemic to all continents except Antarctica. The rickettsiosis caused by R. felis is known as flea-borne spotted fever or cat-flea typhus. The large number of arthropod species found to harbour R. felis and that may act as potential vectors support the view that it is a pan-global microbe. The main arthropod reservoir and vector is the cat flea, Ctenocephalides felis, yet more than 20 other species of fleas, ticks, and mites species have been reported to harbour R. felis. Few bacterial pathogens of humans have been found associated with such a diverse range of invertebrates. With the projected increase in global temperature over the next century, there is concern that changes to the ecology and distribution of R. felis vectors may adversely impact public health.", "OBJECTIVE: To investigate the effects of quercetin on cell morphology and VEGF expression of acute myeloblastic leukemia cells NB4 in vitro.METHODS: The cytomorphology of NB4 cells was assessed by Wright-stain, apoptosis rate by apoptotic marker Annexin V, and VEGF secretion level by ELISA.RESULTS: Typical apoptosis was found in NB4 cells after treatment with quercetin. Apoptotic marker Annexin V analysis showed that the apoptotic rate of NB4 cells was increased after treatment with quercetin. The secretion of VEGF of NB4 cells was significantly decreased after treatment with quercetin.CONCLUSION: Quercetin can induce apoptosis and inhibit secretion of VEGF in NB4 leukemia cells." ]

[ "Immune checkpoint inhibition as a new treatment approach is undergoing extensive investigation in non-small cell lung cancer (NSCLC) and other malignancies. Unlike standard chemotherapy or targeted agents, which act directly on the tumor cells, immune checkpoint inhibitors work by restoring the immune system's capacity to eradicate tumors. Agents currently in active clinical development for lung cancer include ipilimumab, which modulates the cytotoxic T-lymphocyte-associated antigen 4 pathway, and multiple agents targeting the programmed death protein 1 (PD-1) pathway, both anti-PD-1 compounds (nivolumab, pembrolizumab [MK-3475]) and those that target programmed death ligand 1 (PD-L1), a key ligand for PD-1 (BMS-936559, MPDL3280A). Preliminary evidence shows activity for these agents in NSCLC as monotherapy or in combination with chemotherapy. This article reviews the immune checkpoint inhibitors and the available data to date on their use in lung cancer. Clinical implications for the use of these therapies in NSCLC are discussed as they relate to their novel mechanisms of action, response patterns, and safety profiles.", "BACKGROUND: To enhance the acknowledgement of Lambert-Eaton syndrome in patients with small cell lung cancer.METHODS: Retrospective case analysis of Lambert-Eaton syndrome in patients with small cell lung cancer in our hospital.RESULTS: The characteristics of electromyography for Lambert-Eaton syndrome was reduction in action potential amplitude after repetitive peripheral nerve stimulation at low frequency and increased amplitude at high frequency.There were 10 cases of Lambert-Eaton syndrome in 332 pathologically diagnosed small cell lung cancer,9 male and 1 female with an average age of 57.6±4.9.Nine of 10 cases were among 50 to 69.All patients except one experienced myasthenia,mainly in lower extremities,2 to 36 months (median:6 months) before the diagnosis of small cell lung cancer.Treatment of small cell lung cancer may improve the symptoms of Lambert-Eaton syndrome.CONCLUSIONS: Improving the recognition of Lambert-Eaton syndrome may be helpful to identify early small cell lung cancer and improve the prognosis,as the symptom of muscular weakness usually appears early before the diagnosis of small cell lung cancer.", "BACKGROUND: Signaling by transmembrane receptors such as G protein-coupled receptors (GPCRs) occurs at the cell surface and throughout the endocytic pathway, and signaling from the cell surface may differ in magnitude and downstream output from intracellular signaling. As a result, the rate at which signaling molecules traverse the endocytic pathway makes a significant contribution to downstream output. Modulation of the core endocytic machinery facilitates differential uptake of individual cargoes. Clathrin-coated pits are a major entry portal where assembled clathrin forms a lattice around invaginating buds that have captured endocytic cargo. Clathrin assembles into triskelia composed of three clathrin heavy chains and associated clathrin light chains (CLCs). Despite the identification of clathrin-coated pits at the cell surface over 30 years ago, the functions of CLCs in endocytosis have been elusive.RESULTS: In this work, we identify a novel role for CLCs in the regulated endocytosis of specific cargoes. Small interfering RNA-mediated knockdown of either CLCa or CLCb inhibits the uptake of GPCRs. Moreover, we demonstrate that phosphorylation of Ser204 in CLCb is required for efficient endocytosis of a subset of GPCRs and identify G protein-coupled receptor kinase 2 (GRK2) as a kinase that can phosphorylate CLCb on Ser204. Overexpression of CLCb(S204A) specifically inhibits the endocytosis of those GPCRs whose endocytosis is GRK2-dependent.CONCLUSIONS: Together, these results indicate that CLCb phosphorylation acts as a discriminator for the endocytosis of specific GPCRs.", "The clathrin triskelion, which is a three-legged pinwheel-shaped heteropolymer, is a major component in the protein coats of certain post-Golgi and endocytic vesicles. At low pH, or at physiological pH in the presence of assembly proteins, triskelia will self-assemble to form a closed clathrin cage, or \"basket\". Recent static light scattering and dynamic light scattering studies of triskelia in solution showed that an individual triskelion has an intrinsic pucker similar to, but differing from, that inferred from a high resolution cryoEM structure of a triskelion in a clathrin basket. We extend the earlier solution studies by performing small-angle neutron scattering (SANS) experiments on isolated triskelia, allowing us to examine a higher q range than that probed by static light scattering. Results of the SANS measurements are consistent with the light scattering measurements, but show a shoulder in the scattering function at intermediate q values (0.016 A(-1)), just beyond the Guinier regime. This feature can be accounted for by Brownian dynamics simulations based on flexible bead-spring models of a triskelion, which generate time-averaged scattering functions. Calculated scattering profiles are in good agreement with the experimental SANS profiles when the persistence length of the assumed semiflexible triskelion is close to that previously estimated from the analysis of electron micrographs.", "Publisher: PATHOPHYSIOLOGISCHE DIFFERENZIERUNG: Das Krankheitsbild der thrombotischen Mikroangiopathie (TMA) wird pathophysiologisch in verschiedene Gruppen differenziert: TTP, HUS, aHUS, medikamentös induzierte, Systemerkrankungs-assoziierte und posttherapeutische TMA. Diese Unterscheidung ist auch im klinischen Alltag essenziell zur Auswahl der optimalen Therapiestrategie.KLINISCHE MANIFESTATION UND DIAGNOSESTELLUNG: Das kombinierte Auftreten einer Thrombopenie und einer hämolytischen Anämie in Verbindung mit neurologischen oder renalen Organschädigungen sollte an das Vorliegen einer TMA denken lassen. Laborchemisch essenziell zu bestimmen sind ADAMTS-13 bei TTP, bakterieller bzw. Shiga-Toxin-Nachweis beim STEC-HUS sowie spezifische Komplement-Untersuchungen beim aHUS.THERAPIE: Bis vor wenigen Jahren waren Plasmapheresen und ggf. immunsuppressive Behandlungen die einzigen wirksamen Behandlungsansätze. Inzwischen gibt es weitere Therapiemöglichkeiten: So steht der Antikörper Caplacizumab kurz vor der Zulassung zur supportiven Therapie der TTP. Der Komplement-blockierende Antikörper Eculizumab ist bereits zugelassen und besitzt einen festen Stellenwert in der Behandlung des aHUS. Zudem hat Defibrotide 2016 von der amerikanischen Food and Drug Administration (FDA) eine Zulassung zur Behandlung des SOS/TMA-Syndroms erhalten.", "Cohesin is required to prevent premature dissociation of sister chromatids after DNA replication. Although its role in chromatid cohesion is well established, the functional significance of cohesin's association with interphase chromatin is not clear. Using a quantitative proteomics approach, we show that the STAG1 (Scc3/SA1) subunit of cohesin interacts with the CCTC-binding factor CTCF bound to the c-myc insulator element. Both allele-specific binding of CTCF and Scc3/SA1 at the imprinted IGF2/H19 gene locus and our analyses of human DM1 alleles containing base substitutions at CTCF-binding motifs indicate that cohesin recruitment to chromosomal sites depends on the presence of CTCF. A large-scale genomic survey using ChIP-Chip demonstrates that Scc3/SA1 binding strongly correlates with the CTCF-binding site distribution in chromosomal arms. However, some chromosomal sites interact exclusively with CTCF, whereas others interact with Scc3/SA1 only. Furthermore, immunofluorescence microscopy and ChIP-Chip experiments demonstrate that CTCF associates with both centromeres and chromosomal arms during metaphase. These results link cohesin to gene regulatory functions and suggest an essential role for CTCF during sister chromatid cohesion. These results have implications for the functional role of cohesin subunits in the pathogenesis of Cornelia de Lange syndrome and Roberts syndromes.", "A principal component in the protein coats of certain post-golgi and endocytic vesicles is clathrin, which appears as a three-legged heteropolymer (known as a triskelion) that assembles into polyhedral cages principally made up of pentagonal and hexagonal faces. In vitro, this assembly depends upon the pH, with cages forming more readily at low pH and less readily at high pH. We have developed procedures, on the basis of static and dynamic light scattering, to determine the radius of gyration, R(g), and hydrodynamic radius, R(H), of isolated triskelia, under conditions where cage assembly occurs. Calculations based on rigid molecular bead models of a triskelion show that the measured values can be accounted for by bending the legs and a puckering at the vertex. We also show that the values of R(g) and R(H) measured for clathrin triskelia in solution are qualitatively consistent with the conformation of a triskelion in a \"D6 barrel\" cage assembly measured by cryoelectron microscopy.", "Mutations in the gene encoding fibrillin-1 (FBN1), a component of the extracellular microfibril, cause Marfan syndrome (MFS). Frequent observation of cattle with a normal withers height, but lower body weight than age-matched normal cattle, was recently reported among cattle sired by phenotypically normal Bull A, in Japanese Black cattle. These cattle also showed other characteristic features similar to the clinical phenotype of human MFS, such as a long phalanx proximalis, oval face and crystalline lens cloudiness. We first screened a paternal half-sib family comprising 36 affected and 10 normal offspring of Bull A using the BovineSNP50 BeadChip (illumina). Twenty-two microsatellite markers mapped to a significant region on BTA10 were subsequently genotyped on the family. The bovine Marfan syndrome-like disease (MFSL) was mapped onto BTA10. As FBN1 is located in the significant region, FBN1 was sequenced in Bull A, and three affected and one normal cattle. A G>A mutation at the intron64 splicing accepter site (c.8227-1G>A) was detected in 31 of 36 affected animals (84.7%). The c.8227-1G>A polymorphism was not found in 20 normal offspring of Bull A or in 93 normal cattle unrelated to Bull A. The mutation caused a 1-base shift of the intron64 splicing accepter site to the 3' direction, and a 1-base deletion in processed mRNA. This 1-base deletion creates a premature termination codon, and a 125-amino acid shorter Fibrillin-1 protein is produced from the mutant mRNA. We therefore conclude that the c.8227-1G>A mutation is causative for MFSL. Furthermore, it was suggested that Bull A exhibited germline mosaicism for the mutation, and that the frequency of the mutant sperm was 14.9%.", "Aspergillus terreus is successfully used for industrial production of itaconic acid. The acid is formed from cis-aconitate, an intermediate of the tricarboxylic (TCA) cycle, by catalytic action of cis-aconitate decarboxylase. It could be assumed that strong anaplerotic reactions that replenish the pool of the TCA cycle intermediates would enhance the synthesis and excretion rate of itaconic acid. In the phylogenetic close relative Aspergillus niger, upregulated metabolic flux through glycolysis has been described that acted as a strong anaplerotic reaction. Deregulated glycolytic flux was caused by posttranslational modification of 6-phosphofructo-1-kinase (PFK1) that resulted in formation of a highly active, citrate inhibition-resistant shorter form of the enzyme. In order to avoid complex posttranslational modification, the native A. niger pfkA gene has been modified to encode for an active shorter PFK1 fragment. By the insertion of the modified A. niger pfkA genes into the A. terreus strain, increased specific productivities of itaconic acid and final yields were documented by transformants in respect to the parental strain. On the other hand, growth rate of all transformants remained suppressed which is due to the low initial pH value of the medium, one of the prerequisites for the accumulation of itaconic acid by A. terreus mycelium.", "Current epigenomics approaches have facilitated the genome-wide identification of regulatory elements based on chromatin features and transcriptional regulator binding and have begun to map long-range interactions between regulatory elements and their targets. Here, we focus on the emerging roles of CTCF and the cohesin in coordinating long-range interactions between regulatory elements. We discuss how species-specific transposable elements may influence such interactions by remodeling the CTCF binding repertoire and suggest that cohesin's association with enhancers, promoters, and sites defined by CTCF binding has the potential to form developmentally regulated networks of long-range interactions that reflect and promote cell-type-specific transcriptional programs.", "The discovery that the Human PapillomaVirus (HPV) is the necessary cause of cervical cancer has led to the development of prophylactic vaccines. Cervical cancer is the second most common cause of death from cancer among young women in Europe: mortality is still high, despite its important reduction due to screening programs for early detection. Besides cervical cancer, HPV is responsible for a significant proportion of other anogenital cancers and an increasing number of oropharyngeal cancers, representing together an at least equal burden compared to cervical cancer. HPV is also responsible for conditions such as condyloma acuminata (genital warts) and recurrent respiratory papillomatosis. Organized vaccination programs against HPV have the potential to prevent about 70% of cervical cancers and the vast majority of the other HPV-related conditions. Recommendations for HPV vaccination of at least one cohort of females have been issued in nearly all western European countries, and national/regional publicly funded vaccination programs have been introduced in most of them. Different approaches have been chosen for the implementation of HPV vaccination, based on the organization of each country's health care system. A brief outline of these programs in Europe is presented. As for all preventive public health interventions, high coverage of the target population with HPV vaccines pre-exposure is essential to achieve maximum reduction of cases: therefore, in order to obtain the maximum and most equitable coverage and future benefit, programs targeting adolescents before exposure to HPV should be preferred and population-based. Catch-up programs should also be implemented wherever possible, in order to deliver more and even earlier benefits, and effective communication strategies need to be adopted.", "When cDNA containing proteins enriched in the bovine cerebellar cortex were cloned, a clone which seemed to encode a selenoprotein P-like protein was isolated. The coding nucleotide sequence of its cDNA insert displayed high homology to rat and human selenoprotein P cDNA but contained 12 rather than 10 TGAs (12 rather than 10 selenocysteines in deduced amino acids), a tandem repeat of one CACTCC (His-Ser) and seven CATCCCs (His-Pro), and a 3' untranslated region approximately 890 bases shorter than that of rat liver selenoprotein P. RT-PCR using a set of primers flanking to the repeat displayed the existence of mRNA without the repeat. The tandem repeat and its adjacent region consisted of a similar motif of CAC/TCC/AC/T. Thus, these proteins included a (His-Pro) rich domain with a slightly negative free energy change irrespective of having the tandem repeat or not. Such His-Pro repeats reportedly exist in the segmentation gene paired or homeobox protein Om(1D) of Drosophila. Moreover, both this selenoprotein P-like protein mRNA and selenoprotein P mRNA were expressed in all the areas of the brain but most prominently in the cerebellar cortex, hippocampus, and olfactory bulb. These findings suggest the possibility that these selenoproteins are major selenium carriers in the brain and play a role in the morphological response of nerve or glial cells." ]

[ "Approximately 2-4% of genetic material in human populations outside Africa is derived from Neanderthals who interbred with anatomically modern humans. Recent studies have shown that this Neanderthal DNA is depleted around functional genomic regions; this has been suggested to be a consequence of harmful epistatic interactions between human and Neanderthal alleles. However, using published estimates of Neanderthal inbreeding and the distribution of mutational fitness effects, we infer that Neanderthals had at least 40% lower fitness than humans on average; this increased load predicts the reduction in Neanderthal introgression around genes without the need to invoke epistasis. We also predict a residual Neanderthal mutational load in non-Africans, leading to a fitness reduction of at least 0.5%. This effect of Neanderthal admixture has been left out of previous debate on mutation load differences between Africans and non-Africans. We also show that if many deleterious mutations are recessive, the Neanderthal admixture fraction could increase over time due to the protective effect of Neanderthal haplotypes against deleterious alleles that arose recently in the human population. This might partially explain why so many organisms retain gene flow from other species and appear to derive adaptive benefits from introgression.", "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.", "There is an ongoing debate in the field of human evolution about the possible contribution of Neanderthals to the modern human gene pool. To study how the Neanderthal private alleles may have spread over the genes of Homo sapiens, we propose a deterministic model based on recursive equations and ordinary differential equations. If the Neanderthal population was large compared to the Homo sapiens population at the beginning of the contact period, we show that genetic introgression should have been fast and complete meaning that most of the Neanderthal private alleles should be found in the modern human gene pool in case of ancient admixture. In order to test/reject ancient admixture from genome-wide data, we incorporate the model of genetic introgression into a statistical hypothesis-testing framework. We show that the power to reject ancient admixture increases as the ratio, at the time of putative admixture, of the population size of Homo sapiens over that of Neanderthal decreases. We find that the power to reject ancient admixture might be particularly low if the population size of Homo sapiens was comparable to the Neanderthal population size.", "Obesity is associated with metabolic derangements such as insulin resistance, inflammation and hypercoagulobility which can all be understood as consequences of adipose tissue dysfunction. The potential role for adipose tissue derived cytokines and adipokines in the development of vascular disease and diabetes may produce a clinical need to influence adipose tissue function. Various pharmacological and non-pharmacological interventions affect plasma cytokine and adipokine levels. The effects of these interventions depend on weight loss per se, changes in fat distribution without weight loss and/or direct effects on adipose tissue inflammation.Weight loss, as a result of diet, pharmacology and surgery, positively influences plasma adipokines and systemic inflammation. Several classes of drugs influence systemic inflammation directly through their anti-inflammatory actions. PPAR-γ agonism positively influences adipose tissue inflammation in several classes of intervention such as the thiazolidinediones and perhaps salicylates, CB1-antagonists and angiotensin II receptor blockers. Furthermore, within drug classes there are differential effects of individual pharmacologic agents on adipose tissue function.It can be concluded that several commonly used pharmacological and non-pharmacological interventions have unintended influences on adipose tissue function. Improving adipose tissue function may contribute to reducing the risk of vascular diseases and the development of type 2 diabetes.", "Dot1 is an evolutionarily conserved histone methyltransferase that methylates lysine-79 of histone H3 in the core domain. Unlike other histone methyltransferases, Dot1 does not contain a SET domain, and it specifically methylates nucleosomal histone H3. We have solved a 2.5 A resolution structure of the catalytic domain of human Dot1, hDOT1L, in complex with S-adenosyl-L-methionine (SAM). The structure reveals a unique organization of a mainly alpha-helical N-terminal domain and a central open alpha/beta structure, an active site consisting of a SAM binding pocket, and a potential lysine binding channel. We also show that a flexible, positively charged region at the C terminus of the catalytic domain is critical for nucleosome binding and enzymatic activity. These structural and biochemical analyses, combined with molecular modeling, provide mechanistic insights into the catalytic mechanism and nucleosomal specificity of Dot1 proteins.", "The processes that lead to the production of islet cell autoantibodies in insulin-dependent (type 1) diabetes mellitus (IDDM) are largely unknown. Humoral autoimmunity may be the result of an antigen-independent polyclonal B cell activation, or a consequence of an antigen driven B cell activation and selection for the antigen. We have analysed the gene elements encoding the immunoglobulin variable regions of seven human monoclonal islet cell antibodies (MICA) 1-7 directed to the major islet autoantigen glutamate decarboxylase (GAD65). These autoantibodies were derived from two patients with newly diagnosed IDDM. The variable gene regions of the MICA revealed different sequences, and no relation between V gene usage and shared epitope recognition of the MICA was evident. An elevated usage of VH 1, VH 4 and Vlambda 2 gene segments was observed. The underrepresentation of VH 3 family members in the MICA discriminated them from most autoantibodies. The high relative avidities for GAD65 of MICA 1, 3, 4 and 6 and their high, nonrandom ratio of replacement versus silent mutations in the antigen binding regions indicated that the humoral response to GAD65 is driven by the antigen. MICA 2, 5 and 7 showed as well an excess of replacement mutations in the antigen binding regions, but revealed lower relative avidities for their antigen. Since these clones accumulated many somatic mutations in their variable gene regions, they may be characteristic for later stages of the autoimmune disease. The results suggest that, in humans, an antigen driven B cell activation and affinity maturation process may contribute to the production of GAD65-autoantibodies found in patients with IDDM.", "Disorders of consciousness (DOC) include coma, vegetative state (VS) and minimally conscious state (MCS). Coma is a condition of unarousability with a complete absence of wakefulness and awareness, whereas VS is characterized by a lack of awareness despite a preserved wakefulness. Patients in coma are unconscious because they lack both wakefulness and awareness. Patients in a VS are unconscious because, although they are wakeful, they lack awareness. Patients in a MCS show minimal but definite behavioural evidence of self and environmental awareness. Coma results from diffuse bilateral hemispheric lesions or selective damage to the ascending reticular system (which is functionally connected to the cerebral cortex by intralaminar thalamic nuclei). VS is a syndrome that is considered to be the result of a disconnection of different cortical networks rather than a dysfunction of a single area or a global reduction in cortical metabolism. As revealed by functional imaging studies, clinical recovery is often associated with a functional restoration of cortico-thalamo-cortical connections. Depending on the amount of network restored, patients may regain full consciousness or remain in a MCS. Molecular and neural mediators may indirectly contribute to the above restoration processes owing to their role in the phenomenon of neural synaptic plasticity. Therefore, there is growing interest in the possible effects of drugs that act at the level of the CNS in promoting emergence from DOC. Sporadic cases of dramatic recovery from DOC after the administration of various pharmacological agents, such as baclofen, zolpidem and amantadine, have been recently supported by intriguing scientific observations. Analysis of the reported cases of recovery, with particular attention paid to the condition of the patients and to the association of their improvement with the start of drug administration, suggests that these treatments might have promoted the clinical improvement of some patients. These drugs are from various and diverging classes, but can be grouped into two main categories, CNS stimulants and CNS depressants. Some of these treatments seem to directly encourage a consciousness restoration, while others play a more determinant role in improving cognitive domains, especially in patients with residual cognitive impairment, than in the field of consciousness. Given the great interest recently generated in the scientific community by the increasing number of papers addressing this issue, further investigation of the above treatments, with particular attention paid to their mechanisms of action, the neurotransmitters involved and their effects on cortico-thalamo-cortical circuitry, is needed.", "Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis of proliferating cells. To date, 13 complementation groups of Fanconi anemia were identified. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability.", "Studies of the Neanderthal and Denisovan genomes demonstrate archaic hominin introgression in Eurasians. Here, we present evidence of Neanderthal introgression within the chromosome 3p21.31 region, occurring with a high frequency in East Asians (ranging from 49.4% to 66.5%) and at a low frequency in Europeans. We also detected a signal of strong positive selection in this region only in East Asians. Our data indicate that likely candidate targets of selection include rs12488302-T and its associated alleles--among which four are nonsynonymous, including rs35455589-G in HYAL2, a gene related to the cellular response to ultraviolet-B irradiation. Furthermore, suggestive evidence supports latitude-dependent selection, implicating a role of ultraviolet-B. Interestingly, the distribution of rs35455589-G suggests that this allele was lost during the exodus of ancestors of modern Eurasians from Africa and reintroduced to Eurasians from Neanderthals.", "Author information:(1)State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China.(2)State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China Department of Molecular Biology and Genetics, Cornell University.(3)CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China.(4)State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China lijin@fudan.edu.cn.", "Dysregulated secretion of IL-6 plays a pivotal role in the pathogenesis of Castleman disease (CD), a rare lymphoproliferative disorder. In contrast to unicentric CD for which surgery is considered the treatment of choice, there is no standard therapeutic approach for multicentric CD (MCD). Siltuximab (trade name: Sylvant, formerly known as CNTO 328) is a chimeric monoclonal antibody with high binding affinity for human IL-6. In a recent randomized placebo-controlled Phase II trial, subjects with HIV-negative, HHV8-negative MCD who received siltuximab demonstrated a significantly higher rate of durable tumor and symptomatic response with a tolerable safety profile, leading to its approval for the treatment of HIV-negative HHV8-negative MCD by the US FDA and the European Commission in April and May 2014, respectively. This article will cover the current treatment options of MCD, the drug profile of siltuximab and future directions in the management of MCD.", "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.", "Olanzapine was shown to be oxidized to a reactive intermediate by HOCl, which is the major oxidant produced by activated neutrophils. A mass spectrum obtained using a flow system in which the reactants were fed into a mixing chamber and the products flowed directly into a mass spectrometer revealed a reactive intermediate at m/z 311. This is 2 mass units less than the protonated molecular ion of parent olanzapine and suggests that the reactive intermediate is a nitrenium ion. The reactive intermediate could be trapped with glutathione or N-acetylcysteine to produce two conjugates. These data are analogous to results we reported previously with the structurally related atypical antipsychotic agent clozapine. However, the clozapine and olanzapine reactive metabolites showed differences in their ability to cause toxicity to human neutrophils. Toxicity to neutrophils was observed only at high concentrations of clozapine (>50 microM) when HOCl was used to generate reactive metabolite. In contrast, concentration-dependent toxicity (p < 0.05) was observed when neutrophils were incubated with clozapine (0-20 microM) and H2O2 to generate clozapine reactive metabolite. No toxicity was observed with clozapine alone (at concentrations of > 50 microM). Similar results were observed in monocytes and HL-60 cells. Olanzapine reactive metabolite only seemed to cause slight toxicity at the highest concentrations tested (20 microM), even when the reactive metabolite was generated using H2O2. Neutrophils from two patients with a history of clozapine-induced agranulocytosis seemed to be more sensitive to the toxic effects of the clozapine reactive metabolite; however, the numbers are too small to draw any definite conclusions.", "PURPOSE OF REVIEW: Historically, researchers have focused on the role of adaptive immunity in lupus pathogenesis; recently, however, there has been renewed interest in the contributions of a prototypical innate immune cell - the neutrophil.RECENT FINDINGS: Neutrophil extracellular traps (NETs) are released via a novel form of cell death called NETosis. NETs, consisting of a chromatin meshwork decorated with antimicrobial peptides, play an important role in the innate response to microbial infections. Some lupus patients do not clear NETs normally, a phenotype that correlates with disease activity. Further, lupus neutrophils - and, in particular, an aberrant subset called low-density granulocytes - have an increased propensity to undergo NETosis. Both interferon alpha (IFNα) and immune complexes are potential triggers of enhanced NETosis in lupus patients.SUMMARY: NETs are a potent stimulus for IFNα release by plasmacytoid dendritic cells, and, as such, may play an important role in propagation of the lupus phenotype. NETs can also directly damage tissues - including the endothelium - with implications for lupus nephritis and accelerated atherosclerosis. Whether aberrant NETosis is sufficient to trigger systemic lupus erythematosus, and whether inhibition of NETosis can ameliorate clinical manifestations of lupus, are open questions, and will be exciting topics of future research.", "Regulation of gene expression involves sequence elements in nucleic acids. In promoters, multiple sequence elements cooperate as functional modules, which in combination determine overall promoter activity. We previously developed computational tools based on this hierarchical structure for in silico promoter analysis. Here we address the functional organization of post-transcriptional control elements, using the HIV-1 genome as a model. Numerous mutagenesis studies demonstrate that expression of HIV structural proteins is restricted by inhibitory sequences (INS) in HIV mRNAs in the absence of the HIV-1 Rev protein. However, previous attempts to detect conserved sequence patterns of HIV-1 INS have failed. We defined four distinct sequence patterns for inhibitory motifs (weight matrices), which identified 22 out of the 25 known INS as well as several new candidate INS regions contained in numerous HIV-1 strains. The conservation of INS motifs within the HIV genome was not due to overall sequence conservation. The functionality of two candidate INS regions was analyzed with a new assay that measures the effect of non-coding mRNA sequences on production of red fluorescent reporter protein. Both new INS regions showed inhibitory activity in sense but not in antisense orientation. Inhibitory activity increased by combining both INS regions in the same mRNA. Inhibitory activity of known and new INS regions was overcome by co-expression of the HIV-1 Rev protein.", "Analyses of the genetic relationships among modern humans, Neanderthals and Denisovans have suggested that 1-4% of the non-Sub-Saharan African gene pool may be Neanderthal derived, while 6-8% of the Melanesian gene pool may be the product of admixture between the Denisovans and the direct ancestors of Melanesians. In the present study, we analyzed single nucleotide polymorphism (SNP) diversity among a worldwide collection of contemporary human populations with respect to the genetic constitution of these two archaic hominins and Pan troglodytes (chimpanzee). We partitioned SNPs into subsets, including those that are derived in both archaic lineages, those that are ancestral in both archaic lineages and those that are only derived in one archaic lineage. By doing this, we have conducted separate examinations of subsets of mutations with higher probabilities of divergent phylogenetic origins. While previous investigations have excluded SNPs from common ancestors in principal component analyses, we included common ancestral SNPs in our analyses to visualize the relative placement of the Neanderthal and Denisova among human populations. To assess the genetic similarities among the various hominin lineages, we performed genetic structure analyses to provide a comparison of genetic patterns found within contemporary human genomes that may have archaic or common ancestral roots. Our results indicate that 3.6% of the Neanderthal genome is shared with roughly 65.4% of the average European gene pool, which clinally diminishes with distance from Europe. Our results suggest that Neanderthal genetic associations with contemporary non-Sub-Saharan African populations, as well as the genetic affinities observed between Denisovans and Melanesians most likely result from the retention of ancient mutations in these populations.", "The genome has a non-random spatial distribution in the cell nucleus. In Schizosaccharomyces pombe, it has been shown that the centromeres, telomeres and the mating-type region localize to the nuclear membrane (NM), the former by attaching to the spindle pole body (SPB). In addition, reporter genes inserted into these areas are transcriptionally repressed because of the formation of specialized chromatin structures. Performing live cell analysis we found that in a wild-type strain the mating-type region was positioned in the proximity of the SPB, the location where the pericentromeric heterochromatin is also found. In a strain lacking the histone methyltransferase Clr4, crucial for the formation of heterochromatin, the mating-type region had a random localization in the nucleus. Moreover, in a strain in which the two boundary elements IR-L and IR-R had been deleted, the mating-type region was displaced from its position at the proximity of the SPB, but remained in the vicinity of the NM. Moreover, in all investigated strains with silencing deficiencies the distance between the mating-type region and the SPB increased. This result indicates a correlation between transcriptional derepression and displacement of the region. Two different models of how the mating-type chromatin is organized in the nucleus are discussed.", "The poor prognosis for patients with esophagogastric cancers (EGC) has resulted in an increased focus on the use of targeted agents in this disease. Targets include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), Her2, mammalian target of rapamycin (mTOR), MET, poly (ADP-ribose) polymerase (PARP) and claudin 18.2 (CLDN18.2). Trastuzumab, an anti-Her2 antibody, was approved by the U.S. FDA in 2010 as first-line therapy in combination with chemotherapy for Her2-positive disease. Since then, strategies targeting Her2 that have been successful in Her2-positive breast cancer, have failed in EGC. The one remaining study, the phase III Jacob study with pertuzumab, has yet to be presented. The anti-VEGF receptor 2 antibody, ramucirumab has been investigated as second-line therapy in 2 phase III trials, which resulted in improved survival, with subsequent FDA approval of ramucirumab in the second-line setting. Therapies targeting EGFR have been evaluated in a number of phase III studies, all of which have been negative. Phase III investigation of an mTOR inhibitor did not improve survival, although biomarker studies are awaited which may identify subgroups of patients that may benefit from its use. The results of the trials targeting MET in EGC have been disappointing, raising doubts about the usefulness of further testing agents that inhibit the MET pathway. PARP inhibition with olaparib, warrants further investigation, possibly in combination with other targeted therapies or immune checkpoint inhibition and in a biomarker-selected population. The identification of CLDN18.2 and its targeting with claudiximab is very promising and will be further investigated in a phase III study.", "A previous report of this work (Ringeissen et al. 2003) described the use of nuclear magnetic resonance (NMR) spectroscopy coupled with multivariate statistical data analysis (MVDA) to identify novel biomarkers of peroxisome proliferation (PP) in Wistar Han rats. Two potential biomarkers of peroxisome proliferation in the rat were described, N-methylnicotinamide (NMN) and N-methyl-4-pyridone-3-carboxamide (4PY). The inference from these results was that the tryptophan-nicotinamide adenine dinucleotide (NAD(+)) pathway was altered in correlation with peroxisome proliferation, a hypothesis subsequently confirmed by TaqMan analysis of the relevant genes encoding two key enzymes in the pathway, aminocarboxymuconate-semialdehyde decarboxylase (EC 4.1.1.45) and quinolinate phosphoribosyltransferase (EC 2.4.2.19). The objective of the present study was to investigate these data further and identify other metabolites in the NMR spectrum correlating equally with PP. MVDA Partial Least Squares (PLS) models were constructed that provided a better prediction of PP in Wistar Han rats than levels of 4PY and NMN alone. The resulting Wistar Han rat predictive models were then used to predict PP in a test group of Sprague Dawley rats following administration of fenofibrate. The models predicted the presence or absence of PP (above on arbitrary threshold of >2-fold mean control) in all Sprague Dawley rats in the test group.", "The chromatin regulatory factors CTCF and cohesin have been implicated in the coordinated control of multiple gene loci in Epstein-Barr virus (EBV) latency. We have found that CTCF and cohesin are highly enriched at the convergent and partially overlapping transcripts for the LMP1 and LMP2A genes, but it is not yet known how CTCF and cohesin may coordinately regulate these transcripts. We now show that genetic disruption of this CTCF binding site (EBVΔCTCF166) leads to a deregulation of LMP1, LMP2A, and LMP2B transcription in EBV-immortalized B lymphocytes. EBVΔCTCF166 virus-immortalized primary B lymphocytes showed a decrease in LMP1 and LMP2A mRNA and a corresponding increase in LMP2B mRNA. The reduction of LMP1 and LMP2A correlated with a loss of euchromatic histone modification H3K9ac and a corresponding increase in heterochromatic histone modification H3K9me3 at the LMP2A promoter region in EBVΔCTCF166. Chromosome conformation capture (3C) revealed that DNA loop formation with the origin of plasmid replication (OriP) enhancer was eliminated in EBVΔCTCF166. We also observed that the EBV episome copy number was elevated in EBVΔCTCF166 and that this was not due to increased lytic cycle activity. These findings suggest that a single CTCF binding site controls LMP2A and LMP1 promoter selection, chromatin boundary function, DNA loop formation, and episome copy number control during EBV latency.", "BACKGROUND: Morton's neuroma is a common cause of pain that radiates from between the third and fourth metatarsals and which, when symptomatic, creates sensations of burning or sharp pain and numbness on the forefoot. Many conservative and surgical interventions are employed to reduce associated pain, but not enough research has been conducted to recommend patients to any one approach as the most reliable source of pain management.PURPOSE: The objective of this case report is to describe the effect of massage therapy on one woman with symptomatic Morton's neuroma.PARTICIPANT: A physically active 25-year-old female with diagnosed symptomatic Morton's neuroma who has not found relief with previous conservative intervention.INTERVENTION: Six session of massage therapy once weekly for 60-75 minutes focused on postural alignment and localized foot and leg treatment. The client also completed an at-home exercise each day. Change was monitored each week by the massage therapist reassessing posture and by the client filling out a pain survey based on a Visual Analog Scale.RESULTS: The client reported progressive change in the character of the pain from burning and stabbing before the first session to a dull, pulsing sensation after the third session. She also recorded a reduction in pain during exercise from a 5/10 to 0/10 (on a scale where 10 is extreme pain).CONCLUSION: This study describes how massage therapy reduced pain from Morton's neuroma for one client; however, larger randomized control studies need to be done in order to determine the short- and long-term effects of massage therapy on this painful condition.", "BACKGROUND: Cis-regulatory modules (CRMs) are short stretches of DNA that help regulate gene expression in higher eukaryotes. They have been found up to 1 megabase away from the genes they regulate and can be located upstream, downstream, and even within their target genes. Due to the difficulty of finding CRMs using biological and computational techniques, even well-studied regulatory systems may contain CRMs that have not yet been discovered.RESULTS: We present a simple, efficient method (HexDiff) based only on hexamer frequencies of known CRMs and non-CRM sequence to predict novel CRMs in regulatory systems. On a data set of 16 gap and pair-rule genes containing 52 known CRMs, predictions made by HexDiff had a higher correlation with the known CRMs than several existing CRM prediction algorithms: Ahab, Cluster Buster, MSCAN, MCAST, and LWF. After combining the results of the different algorithms, 10 putative CRMs were identified and are strong candidates for future study. The hexamers used by HexDiff to distinguish between CRMs and non-CRM sequence were also analyzed and were shown to be enriched in regulatory elements.CONCLUSION: HexDiff provides an efficient and effective means for finding new CRMs based on known CRMs, rather than known binding sites.", "The nitrone compound PBN, α-phenyl-tert-butylnitrone, and closely related nitrones have anti-cancer activity in several experimental cancer models. The three experimental models most extensively studied include A) the rat choline deficiency liver cancer model, B) the rat C6 glioma model and C) the mouse APC(Min/+) colon cancer model. The two PBN-nitrones mostly studied are PBN and a PBN derivative 2,4-disulfophenyl-tert-butylnitrone, referred as OKN-007. OKN-007 is a proprietary compound that has had extensive commercial development (designated as NXY-059) for another indication, acute ischemic stroke, and after extensive clinical studies was shown to lack efficacy for this indication but was shown to be very safe for human use. This compound administered orally in the rat glioma model has potent activity in treating fully formed gliomas. In this report observations made on the PBN-nitrones in experimental cancer models will be summarized. In addition the experimental results will be discussed in the general framework of the properties of the compounds with a view to try to understand the mechanistic basis of how the PBN-nitrones act as anti-cancer agents. Possible mechanisms related to the suppression of NO production, S-nitrosylation of critical proteins and inhibition of NF-κB activation are discussed.", "Hybridization between humans and Neanderthals has resulted in a low level of Neanderthal ancestry scattered across the genomes of many modern-day humans. After hybridization, on average, selection appears to have removed Neanderthal alleles from the human population. Quantifying the strength and causes of this selection against Neanderthal ancestry is key to understanding our relationship to Neanderthals and, more broadly, how populations remain distinct after secondary contact. Here, we develop a novel method for estimating the genome-wide average strength of selection and the density of selected sites using estimates of Neanderthal allele frequency along the genomes of modern-day humans. We confirm that East Asians had somewhat higher initial levels of Neanderthal ancestry than Europeans even after accounting for selection. We find that the bulk of purifying selection against Neanderthal ancestry is best understood as acting on many weakly deleterious alleles. We propose that the majority of these alleles were effectively neutral-and segregating at high frequency-in Neanderthals, but became selected against after entering human populations of much larger effective size. While individually of small effect, these alleles potentially imposed a heavy genetic load on the early-generation human-Neanderthal hybrids. This work suggests that differences in effective population size may play a far more important role in shaping levels of introgression than previously thought." ]

[ "The way cells respond to DNA damage is important since inefficient repair or misrepair of lesions can have deleterious consequences, including mutation, genomic instability, neurodegenerative disorders, premature aging, cancer or death. Whether damage occurs spontaneously as a byproduct of normal metabolic processes, or after exposure to exogenous agents, cells muster a coordinated, complex DNA damage response (DDR) to mitigate potential harmful effects. A variety of activities are involved to promote cell survival, and include DNA repair, DNA damage tolerance, as well as transient cell cycle arrest to provide time for repair before entry into critical cell cycle phases, an event that could be lethal if traversal occurs while damage is present. When such damage is prolonged or not repairable, senescence, apoptosis or autophagy is induced. One major level of DDR regulation occurs via the orchestrated transcriptional control of select sets of genes encoding proteins that mediate the response. p53 is a transcription factor that transactivates specific DDR downstream genes through binding DNA consensus sequences usually in or near target gene promoter regions. The profile of p53-regulated genes activated at any given time varies, and is dependent upon type of DNA damage or stress experienced, exact composition of the consensus DNA binding sequence, presence of other DNA binding proteins, as well as cell context. RAD9 is another protein critical for the response of cells to DNA damage, and can also selectively regulate gene transcription. The limited studies addressing the role of RAD9 in transcription regulation indicate that the protein transactivates at least one of its target genes, p21/waf1/cip1, by binding to DNA sequences demonstrated to be a p53 response element. NEIL1 is also regulated by RAD9 through a similar DNA sequence, though not yet directly verified as a bonafide p53 response element. These findings suggest a novel pathway whereby p53 and RAD9 control the DDR through a shared mechanism involving an overlapping network of downstream target genes. Details and unresolved questions about how these proteins coordinate or compete to execute the DDR through transcriptional reprogramming, as well as biological implications, are discussed.", "Nonsense-mediated decay (NMD), also called mRNA surveillance, is an evolutionarily conserved pathway that degrades mRNAs that prematurely terminate translation. To date, the pathway in mammalian cells has been shown to depend on the presence of a cis-acting destabilizing element that usually consists of an exon-exon junction generated by the process of pre-mRNA splicing. Whether or not mRNAs that derive from naturally intronless genes, that is, mRNAs not formed by the process of splicing, are also subject to NMD has yet to be investigated. The possibility of NMD is certainly reasonable considering that mRNAs of Saccharomyces cerevisiae are subject to NMD even though most derive from naturally intronless genes. In fact, mRNAs of S. cerevisiae generally harbor a loosely defined splicing-independent destabilizing element that has been proposed to function in NMD analogously to the spliced exon-exon junction of mammalian mRNAs. Here, we demonstrate that nonsense codons introduced into naturally intronless genes encoding mouse heat shock protein 70 or human histone H4 fail to elicit NMD. Failure is most likely because each mRNA lacks a cis-acting destabilizing element, because insertion of a spliceable intron a sufficient distance downstream of a nonsense codon within either gene is sufficient to elicit NMD.", "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.", "As part of the adaptive immune system, T cells are vital for the eradication of infected and malignantly transformed cells. To perform their protective function, T cells produce effector molecules that are either directly cytotoxic, such as granzymes, perforin, interferon-γ and tumour necrosis factor α, or attract and stimulate (immune) cells, such as interleukin-2. As these molecules can also induce immunopathology, tight control of their production is required. Indeed, inflammatory cytokine production is regulated on multiple levels. Firstly, locus accessibility and transcription factor availability and activity determine the amount of mRNA produced. Secondly, post-transcriptional mechanisms, influencing mRNA splicing/codon usage, stability, decay, localization and translation rate subsequently determine the amount of protein that is produced. In the immune suppressive environments of tumours, T cells gradually lose the capacity to produce effector molecules, resulting in tumour immune escape. Recently, the role of post-transcriptional regulation in fine-tuning T-cell effector function has become more appreciated. Furthermore, several groups have shown that exhausted or dysfunctional T cells from cancer patients or murine models possess mRNA for inflammatory mediators, but fail to produce effector molecules, hinting that post-transcriptional events also play a role in hampering tumour-infiltrating lymphocyte effector function. Here, the post-transcriptional regulatory events governing T-cell cytokine production are reviewed, with a specific focus on the importance of post-transcriptional regulation in anti-tumour responses. Furthermore, potential approaches to circumvent tumour-mediated dampening of T-cell effector function through the (dis)engagement of post-transcriptional events are explored, such as CRISPR/Cas9-mediated genome editing or chimeric antigen receptors.", "Incontinentia pigmenti (IP) is an X-linked-dominant Mendelian disorder caused by mutation in the IKBKG/NEMO gene, encoding for NEMO/IKKgamma, a regulatory protein of nuclear factor kappaB (NF-kB) signaling. In more than 80% of cases, IP is due to recurrent or nonrecurrent deletions causing loss-of-function (LoF) of NEMO/IKKgamma. We review how the local architecture of the IKBKG/NEMO locus with segmental duplication and a high frequency of repetitive elements favor de novo aberrant recombination through different mechanisms producing genomic microdeletion. We report here a new microindel (c.436_471delinsT, p.Val146X) arising through a DNA-replication-repair fork-stalling-and-template-switching and microhomology-mediated-end-joining mechanism in a sporadic IP case. The LoF mutations of IKBKG/NEMO leading to IP include small insertions/deletions (indel) causing frameshift and premature stop codons, which account for 10% of cases. We here present 21 point mutations previously unreported, which further extend the spectrum of pathologic variants: 14/21 predict LoF because of premature stop codon (6/14) or frameshift (8/14), whereas 7/21 predict a partial loss of NEMO/IKKgamma activity (two splicing and five missense). We review how the analysis of IP-associated IKBKG/NEMO hypomorphic mutants has contributed to the understanding of the pathophysiological mechanism of IP disease and has provided important information on affected NF-kB signaling. We built a locus-specific database listing all IKBKG/NEMO variants, accessible at http://IKBKG.lovd.nl.", "Despite tremendous efforts worldwide from clinicians and cancer scientists, pancreatic ductal adenocarcinoma (PDA) remains a deadly disease for which no cure is available. Recently, microRNAs (miRNAs) have emerged as key actors in carcinogenesis and we demonstrated that microRNA-21 (miR-21), oncomiR is expressed early during PDA. In the present study, we asked whether targeting miR-21 in human PDA-derived cell lines using lentiviral vectors (LVs) may impede tumor growth. We demonstrated that LVs-transduced human PDA efficiently downregulated miR-21 expression, both in vitro and in vivo. Consequently, cell proliferation was strongly inhibited and PDA-derived cell lines died by apoptosis through the mitochondrial pathway. In vivo, miR-21 depletion stopped the progression of a very aggressive model of PDA, to induce cell death by apoptosis; furthermore, combining miR-21 targeting and chemotherapeutic treatment provoked tumor regression. We demonstrate herein for the first time that targeting oncogenic miRNA strongly inhibit pancreatic cancer tumor growth both in vitro and in vivo. Because miR-21 is overexpressed in most human tumors; therapeutic delivery of miR-21 antagonists may still be beneficial for a large number of cancers for which no cure is available.", "A new age has begun in the genetics of rheumatoid arthritis (RA), as genome-wide association studies scanning the human genome have been put into practical use. Among the RA-susceptibility genes identified by genetic studies, HLA-DRB1 gene appears to represent the most major determinant of genetic predisposition to RA. However, inconsistent results of the contributions of non-HLA susceptibility genes have been described, with the exception of a few genes repeatedly associated with RA-susceptibility, such as PTPN22 gene in populations of European ancestry and PADI4 gene in populations of Asian ancestry, revealing the presence of genetic heterogeneity in RA. We review herein recent advances in the genetics of RA and discuss the underlying differences among populations of European and Asian ancestries, taking as examples our previous findings for RA-susceptibility genes in the Japanese population: PADI4; FCRL3; and CD244.", "Mannarino, P, Matta, T, Lima, J, Simão, R, and Freitas de Salles, B. Single-Joint Exercise Results in Higher Hypertrophy of Elbow Flexors Than Multijoint Exercise. J Strength Cond Res 35(10): 2677-2681, 2021-Recent data suggest that single-joint exercises are unnecessary to maximize the resistance training (RT) results in novice to advanced individuals. However, the present literature is still inconsistent on this topic and controversy arises. The aim of this study was to compare the effects of the unilateral dumbbell row (DR) (multiple-joint) vs. unilateral biceps curl (BC) (single-joint) exercises on strength and elbow flexors muscle thickness (MT). Ten untrained men were assigned to an 8-week RT program for elbow flexors, one arm performing DR and the other performing BC in a within-subject design. After a familiarization, pretraining MT was measured using an ultrasound (US) technique, and strength was tested using 10 repetition maximum (10RM) tests. After pretesting, 8 weeks of RT (4-6 sets, 8-12 repetitions to concentric failure, 2 sessions per week) was performed. Post-testing was conducted in the same order as pretesting 48 and 72 hours after the last session. Single-joint BC exercise resulted in higher hypertrophy of elbow flexors (11.06%) than the DR (5.16%) multijoint exercise after 8 weeks of RT (p = 0.009). The 10RM improvement was higher for DR in DR-trained arm, whereas 10RM for BC was higher in BC-trained arm. The single-joint exercise resulted in higher hypertrophy of the elbow flexors than multijoint exercise after 8 weeks of RT, whereas strength improvements were greater in accordance with specificity of RT exercise. Therefore, in RT prescription for elbow flexors hypertrophy, single-joint exercises such as BC should be emphasized.", "The tumor-suppressor protein p53 is activated in response to numerous cellular stresses including DNA damage. p53 functions primarily as a sequence-specific transcription factor that controls the expression of hundreds of protein-coding genes and noncoding RNAs, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). While the role of protein-coding genes and miRNAs in mediating the effects of p53 has been extensively studied, the physiological function and molecular mechanisms by which p53-regulated lncRNAs act is beginning to be understood. In this review, we discuss recent studies on lncRNAs that are directly or indirectly regulated by p53 and how they contribute to the biological outcomes of p53 activation. WIREs RNA 2017, 8:e1410. doi: 10.1002/wrna.1410 For further resources related to this article, please visit the WIREs website.", "BACKGROUND: In adults with active lupus nephritis, the efficacy and safety of intravenous belimumab as compared with placebo, when added to standard therapy (mycophenolate mofetil or cyclophosphamide-azathioprine), are unknown.METHODS: In a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, 104-week trial conducted at 107 sites in 21 countries, we assigned adults with biopsy-proven, active lupus nephritis in a 1:1 ratio to receive intravenous belimumab (at a dose of 10 mg per kilogram of body weight) or matching placebo, in addition to standard therapy. The primary end point at week 104 was a primary efficacy renal response (a ratio of urinary protein to creatinine of ≤0.7, an estimated glomerular filtration rate [eGFR] that was no worse than 20% below the value before the renal flare (pre-flare value) or ≥60 ml per minute per 1.73 m2 of body-surface area, and no use of rescue therapy), and the major secondary end point was a complete renal response (a ratio of urinary protein to creatinine of <0.5, an eGFR that was no worse than 10% below the pre-flare value or ≥90 ml per minute per 1.73 m2, and no use of rescue therapy). The time to a renal-related event or death was assessed.RESULTS: A total of 448 patients underwent randomization (224 to the belimumab group and 224 to the placebo group). At week 104, significantly more patients in the belimumab group than in the placebo group had a primary efficacy renal response (43% vs. 32%; odds ratio, 1.6; 95% confidence interval [CI], 1.0 to 2.3; P = 0.03) and a complete renal response (30% vs. 20%; odds ratio, 1.7; 95% CI, 1.1 to 2.7; P = 0.02). The risk of a renal-related event or death was lower among patients who received belimumab than among those who received placebo (hazard ratio, 0.51; 95% CI, 0.34 to 0.77; P = 0.001). The safety profile of belimumab was consistent with that in previous trials.CONCLUSIONS: In this trial involving patients with active lupus nephritis, more patients who received belimumab plus standard therapy had a primary efficacy renal response than those who received standard therapy alone. (Funded by GlaxoSmithKline; BLISS-LN ClinicalTrials.gov number, NCT01639339.).", "BACKGROUND: Increasing studies implicate cancer stem cells (CSCs) as the source of resistance and relapse following conventional cytotoxic therapies. Few studies have examined the response of CSCs to targeted therapies, such as tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs would have differential effects on CSC populations depending on their mechanism of action (anti-proliferative vs. anti-angiogenic).METHODS: We exposed human sarcoma cell lines to sorafenib, regorafenib, and pazopanib and assessed cell viability and expression of CSC markers (ALDH, CD24, CD44, and CD133). We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.RESULTS: After functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P < 0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib. At low doses, there was progressive CSC enrichment in vitro after longer term exposure to sorafenib although the anti-proliferative effects were attenuated. In vivo, sorafenib improved median survival by 11 days (P < 0.05), but enriched ALDHbright cells 2.5 - 2.8 fold (P < 0.05). Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P < 0.05). Again, negligible effects from pazopanib were observed. TMA analysis of archived specimens from sarcoma patients treated with sorafenib demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen (P < 0.05), whereas clinical specimens obtained longitudinally from a patient treated with pazopanib showed no enrichment for ALDHbright cells (P > 0.05).CONCLUSIONS: Anti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not. The rational selection of targeted therapies for sarcoma patients may benefit from an awareness of the differential impact of TKIs on CSC populations.", "Myotonic dystrophy type 2 (DM2) is a subtype of the myotonic dystrophies, caused by expansion of a tetranucleotide CCTG repeat in intron 1 of the zinc finger protein 9 (ZNF9) gene. The expansions are extremely unstable and variable, ranging from 75-11,000 CCTG repeats. This unprecedented repeat size and somatic heterogeneity make molecular diagnosis of DM2 difficult, and yield variable clinical phenotypes. To better understand the mutational origin and instability of the ZNF9 CCTG repeat, we analyzed the repeat configuration and flanking regions in 26 primate species. The 3'-end of an AluSx element, flanked by target site duplications (5'-ACTRCCAR-3'or 5'-ACTRCCARTTA-3'), followed the CCTG repeat, suggesting that the repeat was originally derived from the Alu element insertion. In addition, our results revealed lineage-specific repetitive motifs: pyrimidine (CT)-rich repeat motifs in New World monkeys, dinucleotide (TG) repeat motifs in Old World monkeys and gibbons, and dinucleotide (TG) and tetranucleotide (TCTG and/or CCTG) repeat motifs in great apes and humans. Moreover, these di- and tetra-nucleotide repeat motifs arose from the poly (A) tail of the AluSx element, and evolved into unstable CCTG repeats during primate evolution. Alu elements are known to be the source of microsatellite repeats responsible for two other repeat expansion disorders: Friedreich ataxia and spinocerebellar ataxia type 10. Taken together, these findings raise questions as to the mechanism(s) by which Alu-mediated repeats developed into the large, extremely unstable expansions common to these three disorders." ]

[ "OBJECTIVE: To investigate the effects of quercetin on cell morphology and VEGF expression of acute myeloblastic leukemia cells NB4 in vitro.METHODS: The cytomorphology of NB4 cells was assessed by Wright-stain, apoptosis rate by apoptotic marker Annexin V, and VEGF secretion level by ELISA.RESULTS: Typical apoptosis was found in NB4 cells after treatment with quercetin. Apoptotic marker Annexin V analysis showed that the apoptotic rate of NB4 cells was increased after treatment with quercetin. The secretion of VEGF of NB4 cells was significantly decreased after treatment with quercetin.CONCLUSION: Quercetin can induce apoptosis and inhibit secretion of VEGF in NB4 leukemia cells.", "Methyltranscriptome is an exciting new area that studies the mechanisms and functions of methylation in transcripts. The MethylTranscriptome DataBase (MeT-DB, http://compgenomics.utsa.edu/methylation/) is the first comprehensive resource for N6-methyladenosine (m(6)A) in mammalian transcriptome. It includes a database that records publicaly available data sets from methylated RNA immunoprecipitation sequencing (MeRIP-Seq), a recently developed technology for interrogating m(6)A methyltranscriptome. MeT-DB includes ∼ 300 k m(6)A methylation sites in 74 MeRIP-Seq samples from 22 different experimental conditions predicted by exomePeak and MACS2 algorithms. To explore this rich information, MeT-DB also provides a genome browser to query and visualize context-specific m(6)A methylation under different conditions. MeT-DB also includes the binding site data of microRNA, splicing factor and RNA binding proteins in the browser window for comparison with m(6)A sites and for exploring the potential functions of m(6)A. Analysis of differential m(6)A methylation and the related differential gene expression under two conditions is also available in the browser. A global perspective of the genome-wide distribution of m(6)A methylation in all the data is provided in circular ideograms, which also act as a navigation portal. The query results and the entire data set can be exported to assist publication and additional analysis.", "Topical retapamulin (Altabax, Altargo) is the first pleuromutilin antibacterial approved for the treatment of uncomplicated superficial skin infections caused by Staphylococcus aureus (excluding meticillin-resistant S. aureus [MRSA]) and Streptococcus pyogenes in patients aged > or = 9 months. In the EU, retapamulin is indicated for use in patients with impetigo or with infected small lacerations, abrasions or sutured wounds (without abscesses); in the US, it is indicated for use in patients with impetigo. Retapamulin has a novel site of action on bacterial ribosomes. In clinical trials in patients with impetigo, topical retapamulin 1% ointment twice daily for 5 days (the approved regimen) was superior to placebo; treatment with retapamulin was noninferior to that with topical fusidic acid. In patients with secondarily infected traumatic lesions, treatment with retapamulin was noninferior to that with oral cefalexin, although the efficacy of retapamulin was reduced in patients with MRSA infections or superficial abscesses. Retapamulin was well tolerated in both paediatric and adult patients, and the majority of adverse events were of mild to moderate severity. Thus, the introduction of topical retapamulin 1% ointment extends the treatment options available in the management of impetigo and uncomplicated secondarily infected traumatic lesions.", "OBJECTIVE: To study the impact of genetic and lifestyle factors on protein biomarkers and develop personally normalized plasma protein profiles (PNPPP) controlling for non-disease-related variance.MATERIALS AND METHODS: Proximity extension assays were used to measure 145 proteins in 632 controls and 344 cases with non-communicable diseases.RESULTS: Genetic and lifestyle factors explained 20-88% of the variation in healthy controls. Adjusting for these factors reduced the number of candidate biomarkers by 63%.CONCLUSION: PNPPP efficiently controls for non-disease-related variance, allowing both for efficient discovery of novel biomarkers and for covariate-independent linear cut-offs suitable for clinical use.", "mRNA injection into the ventral blastomeres of Xenopus embryos of mRNA encoding Wnt pathway genes induces a secondary axis with complete head structures. To identify target genes of the pre-MBT dorsalization pathway that might be responsible for head formation in zebrafish, we have cloned zebrafish dickkopf1 (dkk1), which is expressed in tissues implicated in head patterning. We found that dkk1 blocks the post-MBT Wnt signaling and dkk1 is a target of the pre-MBT Wnt signaling. Dkk1 overexpression in the prechordal plate suggests that Dkk1, secreted from the prechordal plate, expands the forebrain at the expense of the midbrain in the anterior neural plate. Furthermore, dkk1 acts in parallel to the homeobox gene bozozok and bozozok is required for the maintenance of dkk1 expression. The nodal gene squint is also required for the maintenance of dkk1 expression. Among the mutually dependent target genes of the pre-MBT Wnt signaling, dkk1 plays an important role in patterning the anterior head of zebrafish.", "Non-vitamin K oral anticoagulants (NOACs) have been a major addition to our therapeutic armamentarium. They are at least as effective as warfarin in the thromboprophylaxis of non-valvular atrial fibrillation and management of thromboembolic disease, with a more favorable safety profile. Their predictable pharmacokinetics and pharmacodynamics allow for a fixed oral dosing without the need for anticoagulation monitoring. A major concern regarding NOACs is the lack of a readily available antidote to reverse their anticoagulation effect in case of life-threatening bleeding or need for emergent surgery. In this review, we summarize preclinical and clinical data on (a) hemostatic agents used to reverse NOACs, and (b) novel, target-specific NOACs reversal agents under development. The prothrombin complex concentrates, activated prothrombin complex concentrates and recombinant activated factor VII are hemostatic agents that have been assessed in reversing NOACs. Preclinical studies with hemostatic agents report variable results and there is only limited clinical data available to date. Idarucizumab and andexanet alfa are NOAC-specific reversal agents designed to reverse dabigatran and factor Xa inhibitors accordingly. Aripazine is a universal anticoagulation reversal agent. Preclinical studies show promising results and these agents are already in different stages of clinical development. Phase I and II clinical trials demonstrate efficacy in reversing NOACs without major side effects. Until these agents become commercially available, management of patients receiving NOACs who present with major bleeding or require emergent surgery should focus on (a) immediate discontinuation of NOACs, (b) supportive measures or postponing surgery for 12-24 h after the last NOAC dose, and/or", "RNA editing increases transcriptome diversity through post-transcriptional modifications of RNA. Adenosine deaminases that act on RNA (ADARs) catalyze the adenosine-to-inosine (A-to-I) conversion, the most common type of RNA editing in higher eukaryotes. Caenorhabditis elegans has two ADARs, ADR-1 and ADR-2, but their functions remain unclear. Here, we profiled the RNA editomes of C. elegans at different developmental stages of wild-type and ADAR mutants. We developed a new computational pipeline with a \"bisulfite-seq-mapping-like\" step and achieved a threefold increase in identification sensitivity. A total of 99.5% of the 47,660 A-to-I editing sites were found in clusters. Of the 3080 editing clusters, 65.7% overlapped with DNA transposons in noncoding regions and 73.7% could form hairpin structures. The numbers of editing sites and clusters were highest at the L1 and embryonic stages. The editing frequency of a cluster positively correlated with the number of editing sites within it. Intriguingly, for 80% of the clusters with 10 or more editing sites, almost all expressed transcripts were edited. Deletion of adr-1 reduced the editing frequency but not the number of editing clusters, whereas deletion of adr-2 nearly abolished RNA editing, indicating a modulating role of ADR-1 and an essential role of ADR-2 in A-to-I editing. Quantitative proteomics analysis showed that adr-2 mutant worms altered the abundance of proteins involved in aging and lifespan regulation. Consistent with this finding, we observed that worms lacking RNA editing were short-lived. Taken together, our results reveal a sophisticated landscape of RNA editing and distinct modes of action of different ADARs." ]

[ "Sequencing of pediatric gliomas has identified missense mutations Lys27Met (K27M) and Gly34Arg/Val (G34R/V) in genes encoding histone H3.3 (H3F3A) and H3.1 (HIST3H1B). We report that human diffuse intrinsic pontine gliomas (DIPGs) containing the K27M mutation display significantly lower overall amounts of H3 with trimethylated lysine 27 (H3K27me3) and that histone H3K27M transgenes are sufficient to reduce the amounts of H3K27me3 in vitro and in vivo. We find that H3K27M inhibits the enzymatic activity of the Polycomb repressive complex 2 through interaction with the EZH2 subunit. In addition, transgenes containing lysine-to-methionine substitutions at other known methylated lysines (H3K9 and H3K36) are sufficient to cause specific reduction in methylation through inhibition of SET-domain enzymes. We propose that K-to-M substitutions may represent a mechanism to alter epigenetic states in a variety of pathologies.", "Precision oncology is now the evidence-based standard of care for the management of many advanced non-small cell lung cancers (NSCLCs). Expert consensus has defined minimum requirements for routine testing and identification of epidermal growth factor (EGFR) mutations (15% of tumors harbor EGFR exon 19 deletions or exon 21 L858R substitutions) and anaplastic lymphoma kinase (ALK) rearrangements (5% of tumors) in advanced lung adenocarcinomas (ACs). Application of palliative targeted therapies with oral tyrosine kinase inhibitors (TKIs) in advanced/metastatic lung ACs harboring abnormalities in EGFR (gefitinib, erlotinib, afatinib) and ALK/ROS1/MET (crizotinib) has consistently led to more favorable outcomes compared with traditional cytotoxic agents. In addition, mutations leading to resistance to first-line EGFR and ALK TKIs can now be successfully inhibited by soon to be approved third-generation EGFR TKIs (osimertinib, rociletinib) and second-generation ALK TKIs (ceritinib, alectinib). Notably, increasing feasibility, accessibility, and application of molecular profiling technologies has permitted dynamic growth in the identification of actionable driver oncogenes. Emerging genomic aberrations for which TKIs have shown impressive results in clinical trials and expansion of drug labels for approved agents are awaited include ROS1 rearrangements (1-2% of tumors, drug: crizotinib) and BRAF-V600E mutations (1-3% of tumors, drugs: vemurafenib, dafrafenib + trametinib). Evolving genomic events in which TKI responses have been reported in smaller series include MET exon 14 skipping mutations (2-4% of tumors, drug: crizotinib); high-level MET amplification (1-2% of tumors, drug: crizotinib); RET rearrangements (1% of tumors, drug: cabozantinib); and ERBB2 mutations (2-3% of tumors, drug: afatinib), among others. Unfortunately, the most common genomic event in NSCLC, KRAS mutations (25-30% of tumors), is not targetable with approved or in development small molecule inhibitors. Here, we review currently approved, emerging, and evolving systemic precision therapies matched with their driver oncogenes for the management of advanced NSCLC.", "Instrumental variable analysis is an approach for obtaining causal inferences on the effect of an exposure (risk factor) on an outcome from observational data. It has gained in popularity over the past decade with the use of genetic variants as instrumental variables, known as Mendelian randomization. An instrumental variable is associated with the exposure, but not associated with any confounder of the exposure-outcome association, nor is there any causal pathway from the instrumental variable to the outcome other than via the exposure. Under the assumption that a single instrumental variable or a set of instrumental variables for the exposure is available, the causal effect of the exposure on the outcome can be estimated. There are several methods available for instrumental variable estimation; we consider the ratio method, two-stage methods, likelihood-based methods, and semi-parametric methods. Techniques for obtaining statistical inferences and confidence intervals are presented. The statistical properties of estimates from these methods are compared, and practical advice is given about choosing a suitable analysis method. In particular, bias and coverage properties of estimators are considered, especially with weak instruments. Settings particularly relevant to Mendelian randomization are prioritized in the paper, notably the scenario of a continuous exposure and a continuous or binary outcome.", "The underlying mechanism for low oral bioavailability of MK-0974, a potent calcitonin-gene related peptide (CGRP)-receptor antagonist, in monkeys and for species-dependent non-linear pharmacokinetics in monkeys and rats were investigated. In monkeys, MK-0974 displayed moderate clearance (14-20 ml min(-1) kg(-1)), while oral bioavailability was 6%. The pharmacokinetics of MK-0974 remained linear across 0.5-10 mg kg(-1) intravenous dose in monkeys, but the oral area under the plasma concentration-time curve (AUC) increase (5-30 mg kg(-1)) was 15-fold over dose-proportional. Based on a comparison of AUC following hepatic portal vein administration and cephalic vein infusion, MK-0974 exhibited a low-to-moderate hepatic extraction ratio (36%) in monkeys. Following oral dose of [14C]MK-0974 to monkeys, the hepatic portal AUC ratio of MK-0974 versus total radioactivity was 0.32, and the total radioactivity recovered in bile and urine was 45-83%. MK-0974 undergoes significant oxidative metabolism (cytochrome P450 (CYP) 3A) in monkey intestinal microsomes. In contrast, oral AUC of MK-0974 in rats was near dose-proportional (15-100 mg kg(-1)). Following oral administration of [14C]MK-0974 to rats, the hepatic portal AUC ratio of MK-0974 to total radioactivity (0.67) was higher than in monkeys. Additionally, the metabolic rate of MK-0974 was slower in rat than in monkey intestinal microsomes. Collectively, intestinal first-pass metabolism played a significant role in the low oral bioavailability in monkeys and contributed to the species-dependent non-linear oral pharmacokinetics in rats and monkeys of MK-0974.", "INTRODUCTION: The potential of proton therapy to improve the sparing of the healthy tissue has been demonstrated in several studies. However, even small doses delivered to the organs at risk (OAR) may induce long-term detriments after radiotherapy. In this study, we investigated the possibility to reduce the risk of radiation-induced secondary cancers with intensity modulated proton therapy (IMPT), when used for radiosurgery of liver metastases.MATERIAL AND METHODS: Ten patients, previously treated for liver metastases with photon-beam based stereotactic body radiation therapy (SBRT) were retrospectively planned for radiosurgery with IMPT. A treatment plan comparison was then performed in terms of calculated risk of radiation-induced secondary cancer. The risks were estimated using two distinct models (Dasu et al., 2005; Schneider et al., 2005, 2009). The plans were compared pairwise with a two-sided Wilcoxon signed-rank test with a significance level of 0.05.RESULTS: Reduced risks for induction of fatal and other types of cancers were estimated for the IMPT plans (p<0.05) with the Dasu et al.MODEL: Using the Schneider et al. model, lower risks for carcinoma-induction with IMPT were estimated for the skin, lungs, healthy part of the liver, esophagus and the remaining part of the body (p<0.05). The risk of observing sarcomas in the bone was also reduced with IMPT (p<0.05).CONCLUSION: The findings of this study indicate that the risks of radiation-induced secondary cancers after radiosurgery of liver metastases may be reduced, if IMPT is used instead of photon-beam based SBRT.", "We use the Young Finns Study (N=∼2000) on the measured height linked to register-based long-term labor market outcomes. The data contain six age cohorts (ages 3, 6, 9, 12, 15 and 18, in 1980) with the average age of 31.7, in 2001, and with the female share of 54.7. We find that taller people earn higher earnings according to the ordinary least squares (OLS) estimation. The OLS models show that 10cm of extra height is associated with 13% higher earnings. We use Mendelian randomization, with the genetic score as an instrumental variable (IV) for height to account for potential confounders that are related to socioeconomic background, early life conditions and parental investments, which are otherwise very difficult to fully account for when using covariates in observational studies. The IV point estimate is much lower and not statistically significant, suggesting that the OLS estimation provides an upward biased estimate for the height premium. Our results show the potential value of using genetic information to gain new insights into the determinants of long-term labor market success.", "A woman with atopy experienced anaphylaxis after taking, among other dietary supplements, a commercial extract of echinacea. Hypersensitivity was confirmed by skinprick and RAST testing. Regular ingestion of echinacea by up to 5% of surveyed patients with atopy, combined with detection of echinacea-binding IgE in atopic subjects (19% by skin testing; 20% with moderate to strong reactivity by RAST testing), raises the possibility of severe allergic reactions, even with first-time use, due to cross-reactivity with other structurally similar allergens. Patients with atopy should be cautioned about the risk of developing life-threatening reactions to complementary medicines, including echinacea.", "OBJECTIVE: To determine the activity and pharmacodynamics (PD) of bortezomib in platinum-sensitive epithelial ovarian or primary peritoneal cancer (EOC/PPC).PATIENTS AND METHODS: Eligible women with recurrent EOC/PPC progressing between 6 and 12 months after initial chemotherapy were treated with bortezomib on days 1, 4, 8, and 11 [1.5 (cohort I) and 1.3 (cohort II) mg/m(2)/dose]. Patients must have had initial chemotherapy only. Response Evaluation Criteria in Solid Tumors (RECIST) was assessed by computed tomography (CT) scan every 2 cycles. 20S proteasome activity was quantified in three pre-treatment and a 1-hour post-treatment (cycle one, day 1) whole blood lysates.RESULTS: Initially, 26 evaluable patients were treated at the 1.5 mg/m(2)/dose level. Objective response rate was 3.8% (1/26), a partial response. An additional 10 patients (38.5%) had stable disease. Given concerns that treatment discontinuations due to toxicity limited drug exposure/activity a second cohort of 29 evaluable patients was accrued at 1.3 mg/m(2)/dose. The 1.3 mg/m(2)/dose regimen is currently approved as an indication for multiple myeloma and mantle cell lymphoma. Treatment was more tolerable, although objective responses remained low at 6.9% (2/29, partial responses). Second stage accrual was not warranted at either dose. Bortezomib effectively inhibited 20S proteasome activity in whole blood lysates between 37 and 92% in 24/25 (96%) patients in cohort I, and 14-84% in 27/28 (96%) patients in cohort II who provided satisfactory pre- and post-treatment specimens for testing.CONCLUSION: Bortezomib has minimal activity as a single-agent in the treatment of recurrent platinum-sensitive EOC/PPC. Treatment with bortezomib at 1.5 mg/m(2)/dose was not feasible in this patient population due to excess toxicity. Bortezomib was well tolerated at 1.3 mg/m(2)/dose." ]

[ "The incorporation of ribonucleotides in DNA has attracted considerable notice in recent years, since the pool of ribonucleotides can exceed that of the deoxyribonucleotides by at least 10-20-fold, and single ribonucleotide incorporation by DNA polymerases appears to be a common event. Moreover ribonucleotides are potentially mutagenic and lead to genome instability. As a consequence, errantly incorporated ribonucleotides are rapidly repaired in a process dependent upon RNase H enzymes. On the other hand, global genomic nucleotide excision repair (NER) in prokaryotes and eukaryotes removes damage caused by covalent modifications that typically distort and destabilize DNA through the production of lesions derived from bulky chemical carcinogens, such as polycyclic aromatic hydrocarbon metabolites, or via crosslinking. However, a recent study challenges this lesion-recognition paradigm. The work of Vaisman et al. (2013) [34] reveals that even a single ribonucleotide embedded in a deoxyribonucleotide duplex is recognized by the bacterial NER machinery in vitro. In their report, the authors show that spontaneous mutagenesis promoted by a steric-gate pol V mutant increases in uvrA, uvrB, or uvrC strains lacking rnhB (encoding RNase HII) and to a greater extent in an NER-deficient strain lacking both RNase HI and RNase HII. Using purified UvrA, UvrB, and UvrC proteins in in vitro assays they show that despite causing little distortion, a single ribonucleotide embedded in a DNA duplex is recognized and doubly-incised by the NER complex. We present the hypothesis to explain the recognition and/or verification of this small lesion, that the critical 2'-OH of the ribonucleotide - with its unique electrostatic and hydrogen bonding properties - may act as a signal through interactions with amino acid residues of the prokaryotic NER complex that are not possible with DNA. Such a mechanism might also be relevant if it were demonstrated that the eukaryotic NER machinery likewise incises an embedded ribonucleotide in DNA.", "Although aberrant reactivation of embryonic gene programs is intricately linked to pathological heart disease, the transcription factors driving these gene programs remain ill-defined. Here we report that increased calcineurin/Nfat signalling and decreased miR-25 expression integrate to re-express the basic helix-loop-helix (bHLH) transcription factor dHAND (also known as Hand2) in the diseased human and mouse myocardium. In line, mutant mice overexpressing Hand2 in otherwise healthy heart muscle cells developed a phenotype of pathological hypertrophy. Conversely, conditional gene-targeted Hand2 mice demonstrated a marked resistance to pressure-overload-induced hypertrophy, fibrosis, ventricular dysfunction and induction of a fetal gene program. Furthermore, in vivo inhibition of miR-25 by a specific antagomir evoked spontaneous cardiac dysfunction and sensitized the murine myocardium to heart failure in a Hand2-dependent manner. Our results reveal that signalling cascades integrate with microRNAs to induce the expression of the bHLH transcription factor Hand2 in the postnatal mammalian myocardium with impact on embryonic gene programs in heart failure.", "The p73 gene is a p53 homologue which induces apoptosis and inhibits cell proliferation. Although p73 maps at 1p36.3 and is frequently deleted in neuroblastoma (NB), it does not act as a classic oncosuppressor gene. In developing sympathetic neurons of mice, p73 is predominantly expressed as a truncated anti-apoptotic isoform (DeltaNp73), which antagonizes both p53 and the full-length p73 protein (TAp73). This suggests that p73 may be part of a complex tumor-control mechanism. To determine the role of DeltaNp73 in NB we analyzed the pattern of expression of this gene in vivo and evaluated the prognostic significance of its expression. Our results indicate that DeltaNp73 expression is associated with reduced apoptosis in a NB tumor tissue. Expression of this variant in NB patients significantly correlates with age at diagnosis and VMA urinary excretion. Moreover it is strongly associated with reduced survival (HR=7.93; P<0.001) and progression-free survival (HR=5.3; P<0.001) and its role in predicting a poorer outcome is independent from age, primary tumor site, stage and MYCN amplification (OS: HR=5.24, P=0.012; PFS: HR=4.36, P=0.005). In conclusion our data seem to indicate that DeltaNp73 is a crucial gene in neuroblastoma pathogenesis.", "BACKGROUND: The Morel-Lavallée lesion is a post-traumatic collection of fluid arising after a 'closed degloving injury' has caused the separation of the skin and subcutis from the underlying muscular fascia. It usually occurs in the trochanteric region or proximal thigh.CASE DESCRIPTION: A 36-year-old obese man was referred to the emergency department by his general practitioner for fever and pain in the right lower abdominal quadrant. Blood testing revealed elevated infection parameters. As appendicitis was suspected, a CT scan of the abdomen was performed. This revealed a Morel-Lavallée lesion, which he had sustained 9 months earlier when he had been hit by a car while riding his bicycle. A rapid recovery ensued after ultrasound-guided percutaneous drainage and treatment with antibiotics.CONCLUSION: A Morel-Lavallée lesion, which could manifest even months later, should be considered after any traumatic injury. Ultrasound, CT and MRI are useful tools for proper diagnosis. There is no consensus about treatment in either the acute or the chronic phase to date.", "Critical cellular processes are regulated, in part, by maintaining the appropriate intracellular levels of proteins. Whereas de novo protein synthesis is a comparatively slow process, proteins are rapidly degraded at a rate compatible with the control of cell cycle transitions and cell death induction. A major pathway for protein degradation is initiated by the addition of multiple 76-amino acid ubiquitin monomers via a three-step process of ubiquitin activation and substrate recognition. Polyubiquitination targets proteins for recognition and processing by the 26S proteasome, a cylindrical organelle that recognizes ubiquitinated proteins, degrades the proteins, and recycles ubiquitin. The critical roles played by ubiquitin-mediated protein turnover in cell cycle regulation makes this process a target for oncogenic mutations. Oncogenes of several common malignancies, for example colon and renal cell cancer, code for ubiquitin ligase components. Cervical oncogenesis by human papillomavirus is also mediated by alteration of ubiquitin ligase pathways. Protein degradation pathways are also targets for cancer therapy, as shown by the successful introduction of bortezomib, an inhibitor of the 26S proteasome. Further work in this area holds great promise toward our understanding and treatment of a wide range of cancers.", "Transcription factor Growth factor independence 1 (Gfi1) is required for multilineage blood cell development, from stem and progenitor cells to differentiated lymphoid and myeloid cells. Gfi1 expression is rapidly induced by cytokines that control both the adaptive and innate immune systems. Gfi1 itself represses the expression of genes implicated in cell survival, proliferation and differentiation. Changes in Gfi1 expression and function have not only been implicated in neutropenia, allergy, autoimmunity and hyperinflammatory responses, but also in lymphoma and more recently in the development of leukemia. In this study, we review how Gfi1 and its paralogue Gfi1b control the development of blood cells, discuss how changes in Gfi1 and Gfi1b function contribute to hematological disease and report on the molecular function of these proteins.", "BACKGROUND: Prior work identified the fibroblast growth factor (FGF) pathway as a mediator of resistance to anti-vascular endothelial growth factor (VEGF) therapy. We tested dovitinib, an inhibitor of both FGF and VEGF receptors, in patients progressing on anti-VEGF treatment.METHODS: Patients with measurable advanced colorectal or non-small cell lung cancer with progression despite anti-VEGF treatment within 56 days, good performance status and adequate organ function were eligible. A research tumor biopsy was followed by treatment with dovitinib 500 mg on a 5-day on/2-day off schedule for 28-day cycles. The primary endpoint of tumor response was evaluated every 2 cycles. Secondary endpoints included toxicity and 8-week disease control rate. Intratumor mRNA expression of angiogenic mediators was analyzed using a next generation sequencing based expression array.RESULTS: Ten patients treated previously with bevacizumab or ziv-aflibercept enrolled. The study closed with termination of dovitinib development. No responses were observed in 7 evaluable patients. The best response was stable disease in 1 patient. Common toxicities included gastrointestinal, metabolic, and biochemical derangements. All patients experienced at least one grade ≥ 3 treatment-related adverse event, most commonly fatigue, elevated GGT, and lymphopenia. Expression of multiple angiogenic mediators was common in tumors progressing on anti-VEGF therapy including high levels of FGFR1 and VEGFA.CONCLUSIONS: We found no evidence for the activity of dovitinib in patients who had recently progressed on anti-VEGF therapy and toxicities were significant. In tumors progressing despite anti-VEGF therapy, a multitude of pro-angiogenic mediators are expressed, including members of the FGF pathway." ]

[ "The discovery that bupropion is an effective treatment for tobacco dependence has triggered a rapid increase in development of potential new non-nicotine pharmacotherapies, including bromocriptine, glucose, GTS-21, reboxetine, rimonabant, selegeline and varenicline. Successful new products will need to have excellent side-effect profiles in addition to proven efficacy. New faster delivery nicotine replacement products have the promise of addressing a broader list of indications, including treatment of nicotine withdrawal during temporary abstinence and long-term nicotine maintenance. Nicotine vaccines will need to demonstrate efficacy and also improve certain consumer acceptability characteristics (e.g., frequency of injections required) before they can become widely used and successful therapies. The best hope of improved treatment comes from combining existing and new pharmacotherapies with effective behavioural therapy.", "SUMMARY: FunImageJ is a Lisp framework for scientific image processing built upon the ImageJ software ecosystem. The framework provides a natural functional-style for programming, while accounting for the performance requirements necessary in big data processing commonly encountered in biological image analysis.AVAILABILITY AND IMPLEMENTATION: Freely available plugin to Fiji (http://fiji.sc/#download). Installation and use instructions available at http://imagej.net/FunImageJ.CONTACT: kharrington@uidaho.edu.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "With advancing age most aspects of the peptidergic regulation of energy balance are altered. The alteration involves both the peripheral peptides derived from the adipose tissue or the gastrointestinal tract and the peptides of the central nervous system (brainstem and hypothalamus). In general, the expression of orexigenic peptides and their receptors decreases with age, while that of the anorexic ones rather increases, but not simultaneously and not in a linear fashion. Apart from such quantitative changes, the efficacy of the related peptides may also change with age. These changes are not necessarily linear, either: instead of continuous decline or increase of its effects, the effects of a peptide may become less pronounced in some phases of aging and much enhanced in other ones. Comparing the individual peptides, the phasic alterations in their anabolic or catabolic roles in the regulation of energy balance may exhibit dissimilar time-patterns. In addition, within the overall anabolic or catabolic effects, the feeding and metabolic actions of certain peptides may not change simultaneously. Altogether, as compared with young adults, in middle-aged animals or individuals the anabolic processes (increased food intake with decreased energy expenditure) seem to prevail, which processes may contribute to the explanation of age-related obesity, while in the old ones the catabolic processes (anorexia with enhanced metabolic rate) dominate, which possibly explain the aging anorexia, frailty and sarcopenia.", "Oedema is the commonest presenting symptom and sign in nephrotic syndrome. Hypercholesterolaemia, thromboembolic events, and infectious complications may also be features. Three patients are described, each of whose nephrotic syndrome presented with a less common symptom or sign--recurrent pleural effusion, hypercholesterolaemia and oedema, pulmonary embolism--and, as a result, experienced some diagnostic delay. By forgetting to consider nephrotic syndrome, and its underlying causes, there may be inappropriate investigations and treatment for the patient.", "ACE2 (angiotensin converting enzyme 2) plays a critical role in the local tissue RAS (renin-angiotensin system) by hydrolysing the potent hypertensive and mitogenic peptide AngII (angiotensin II). Changes in the levels of ACE2 have been observed in a number of pathologies, including cardiovascular disease, but little is known of the mechanisms regulating its expression. In the present study, therefore, the potential role of miRNAs in the regulation of ACE2 expression in primary human cardiac myofibroblasts was examined. Putative miRNA-binding sites were identified in the 3'-UTR of the ACE2 transcript using online prediction algorithms. Two of these, miR-200b and miR-421, were selected for further analysis. A reporter system using the 3'-UTR of ACE2 fused to the coding region of firefly luciferase was used to determine the functionality of the identified binding sites in vitro. This identified miR-421, but not miR-200b, as a potential regulator of ACE2. The ability of miR-421, an miRNA implicated in the development of thrombosis, to down-regulate ACE2 expression was subsequently confirmed by Western blot analysis of both primary cardiac myofibroblasts and transformed cells transfected with a synthetic miR-421 precursor. Real-time PCR analysis of miR-421 revealed widespread expression in human tissues. miR-421 levels in cardiac myofibroblasts showed significant inter-patient variability, in keeping with the variability of ACE2 expression we have observed previously. In conclusion, the present study is the first to demonstrate that ACE2 may be subject to post-transcriptional regulation and reveals a novel potential therapeutic target, miR-421, which could be exploited to modulate ACE2 expression in disease.", "A review of 119 patients (88 males and 31 females) with carcinoma of the lung seen at the Hospital University Sains Malaysia (HUSM) from 1984 to 1989 was done. The mean age of the patients was 60.3 years with a high proportion (76.6%) of them were between 41 and 70 years. Seventy five percent of patients (84% of men and 26% of women) were smokers. The Chinese have a significantly higher preponderance to carcinoma of the lung. The commonest histological type found was squamous cell carcinoma in men and adenocarcinoma in women. Small cell carcinoma was uncommon. Squamous cell and large cell/undifferentiated type of carcinoma were significantly associated with smoking behaviour of the patients.", "BACKGROUND: Ranolazine (Ran), an antianginal agent, inhibits late Na(+) current. The purpose of this study was to determine whether there was an added benefit of adding Ran to cardioplegia (CP) in a model of global ischemia/reperfusion.METHODS AND RESULTS: Isolated rat hearts were Langendorff-perfused and exposed to 40-minute normothermic, cardioplegic global ischemia and 30 minutes of reperfusion. Before ischemia and during reperfusion, hearts were treated with no drug (control) or with the late Na(+) current inhibitors Ran (5 micromol/L) or tetrodotoxin (1 micromol/L). Ischemic cardioplegic arrest led to an increase of left ventricular end-diastolic pressure (LVEDP) by > or =20 mm Hg (ie, cardiac contracture). Ten out of 11 hearts treated with CP alone developed contracture, whereas 6 out of 11 hearts treated with CP plus Ran developed contracture. Ran added to CP reduced LVEDP at the end of ischemia from 41+/-5 mm Hg in CP alone to 26+/-3 mm Hg in CP plus Ran (P=0.024). Area under the curve for LVEDP during the entire ischemic period was also smaller in CP plus Ran versus CP alone. The percent increase (from baseline) of LVEDP measured at the end of 30-minute reperfusion was smaller for CP plus Ran (66+/-18%) versus CP alone (287+/-90%; P=0.035). The area under the curve for LVEDP during reperfusion was smaller in CP plus Ran versus CP alone. Tetrodotoxin (1 micromol/L) also reduced cardiac contracture during ischemia/reperfusion, compared to CP alone.CONCLUSIONS: Our results suggest that Ran may have therapeutic potential as an adjunct to CP and further support a protective role of Na(+) current inhibition during ischemia/reperfusion." ]

[ "The potential for cancer immunotherapy by adoptive transfer of CD4(+) T cells is gaining increased attention. Most cancer cells lack major histocompatibility complex (MHC) class II molecules and cannot present tumour-specific antigens (TSA) directly to CD4(+) T cells. We have reported that tumour-specific CD4(+) T cells collaborate with macrophages and dendritic cells. These professional antigen-presenting cells endocytose and process TSA to display antigenic peptides on their MHC class II molecules for indirect cancer cell recognition by CD4(+) T cells. We hypothesized that this critical step may depend on secretion of TSA by cancer cells. This was investigated in a mouse model for myeloma immunosurveillance mediated by CD4(+) T cells. From this study, several conclusions could be drawn. First, TSA secretion facilitates cancer immunosurveillance. Second, TSA secretion results in stronger activation of naïve tumour-specific CD4(+) T cells in lymph nodes. Third, TSA concentration within the tumour extracellular matrix must reach a certain threshold to allow successful cancer immunosurveillance. Fourth, treatment by local injection of purified TSA enhances immunity against cancer cells that do not secrete TSA. Fifth, secretion of TSA by at least some cancer cells within a tumour favours antitumour immunity. Therefore, we propose that CD4(+) T cells that recognize secreted TSA may be superior for immunotherapy by T cell transfer, because the local extracellular antigen concentration will be higher for secreted TSA. Thus, it is anticipated that secreted TSA will be more readily detected in vivo by transferred CD4(+) T cells, resulting in more efficient tumour eradication.", "The assessment of BRCA1 and BRCA2 coding sequences to identify pathogenic mutations associated with inherited breast/ovarian cancer syndrome has provided a method to identify high-risk individuals, allowing them to seek preventative treatments and strategies. However, the current test is expensive, and cannot differentiate between pathogenic variants and those that may be benign. Focusing only on one of the two BRCA partners, we have developed a biological assay for haploinsufficiency of BRCA1. Using a series of EBV-transformed cell lines, we explored gene expression patterns in cells that were BRCA1 wildtype compared to those that carried (heterozygous) BRCA1 pathogenic mutations. We identified a subset of 43 genes whose combined expression pattern is a sensitive predictor of BRCA1 status. The gene set was disproportionately made up of genes involved in cellular differentiation, lending credence to the hypothesis that single copy loss of BRCA1 function may impact differentiation, rendering cells more susceptible to undergoing malignant processes.", "This report describes the volatile organic compounds (VOCs) associated with human cerumen (earwax) and the effects of ethnicity/race and variation on the ATP-binding cassette, sub-family C, member 11 gene (ABCC11). A single nucleotide polymorphism (SNP) in ABCC11 affects the cerumen VOC profiles of individuals from African, Caucasian, and Asian descent. Employing gas chromatography/mass spectrometry (GC/MS) we have identified the nature and relative abundance of cerumen VOCs from 32 male donors. Our results show that cerumen contains a complex mixture of VOCs and that the amounts of these compounds vary across individuals as well as across ethnic/racial groups. In six of the seven compounds whose detected concentrations were found to be statistically different across groups, individuals of African descent (AfD) > Caucasian descent (CaD) > Asians descent (AsD). Our findings also reveal that ABCC11 genotype alone does not predict the type and relative levels of volatiles found in human cerumen, and suggest that other biochemical pathways must be involved. Examination of the composition and diversity of external auditory canal microbiota in a small subset of our subject population revealed that the ear microbiota may not be directly correlated with either ethnic group membership or ABCC11 genotype.", "Publisher: Zusammenfassung. Sekundäre hämophagozytische Lymphohistiozytose-Syndrome beschreiben eine vom Erscheinungsbild heterogene Gruppe überschiessender entzündlicher Reaktionen des Immunsystems, die durch Hyperinflammation mit Vermehrung zytotoxischer T-Lymphozyten und Makrophagen bei gesteigerter Hämophagozytose-Aktivität reagieren. Das sekundäre hämophagozytische Lymphohistiozytose-Syndrom wird häufig unterdiagnostiziert, was zu einer hohen Morbidität und Mortalität beiträgt. Die Abfrage der etablierten diagnostischen Kriterien in einem systematischen Abklärungsalgorithmus soll helfen, durch frühzeitige Diagnosestellung und Initiation einer passenden Therapie höhere Heilungsraten zu erreichen.", "We report here the initial examination of volatile organic compounds (VOCs) emanating from human earwax (cerumen). Recent studies link a single nucleotide polymorphism (SNP) in the adenosine triphosphate (ATP) binding cassette, sub-family C, member 11 gene (ABCC11) to the production of different types of axillary odorants and cerumen. ABCC11 encodes an ATP-driven efflux pump protein that plays an important function in ceruminous apocrine glands of the auditory canal and the secretion of axillary odor precursors. The type of cerumen and underarm odor produced by East Asians differ markedly from that produced by non-Asians. In this initial report we find that both groups emit many of the same VOCs but differ significantly in the amounts produced. The principal odorants are volatile organic C2-to-C6 acids. The physical appearance of cerumen from the two groups also matches previously reported ethnic differences, viz., cerumen from East Asians appears dry and white while that from non-Asians is typically wet and yellowish-brown.", "Leprechaunism (Donohue syndrome) is the most severe type of insulin receptor (INSR) gene anomaly with the majority of patients surviving for only 2 years. We report a surviving 2 -year-old male with leprechaunism, bearing novel compound heterozygous mutations in the INSR. The patient is a Japanese boy with acanthosis nigricans, lack of subcutaneous fat, hirsutism, thick lips, gum hypertrophy and extremely high insulin levels (6702 mU/mL). He was as having identified novel compound heterozygous mutations in INSR (p.T910M and p. E1047K). At 24 day-old, recombinant human insulin-like growth factor 1 (rh-IGF1) treatment was started because of poor weight gain. At 2 years old, the patient's serum glucose level and HbA1C value had worsened, and both a bolus of rh-IGF-1 and a subcutaneous injection of a rapid-acting insulin analog after meals, in addition to α-glycosidase inhibitor, were initiated from 2 years onward. Oxygen administration and biphasic positive airway pressure treatment were also initiated from 2 years old due to upper airway obstruction with adenoidal hypertrophy. In the experiments conducted using COS7 cells homozygously transfected with the INSR mutation, T910M INSR failed to process the proreceptor and decreased insulin-stimulated tyrosine phosphorylation. E1047K INSR resulted in a complete absence of insulin-stimulated tyrosine phosphorylation. These findings suggest the near absence of INSR in this patient. We consider that the rhIGF1 treatment contributed to his long survival, but it was not able to prevent his diabetic condition. Our report provides important insights into the function of INSR, and for the treatment of leprechaunism.", "5-Methylcytosine (5 mC) in genomic DNA has important epigenetic functions in embryonic development and tumor biology. 5-Hydroxymethylcytosine (5 hmC) is generated from 5 mC by the action of the TET (Ten-Eleven-Translocation) enzymes and may be an intermediate to further oxidation and finally demethylation of 5 mC. We have used immunohistochemistry (IHC) and isotope-based liquid chromatography mass spectrometry (LC-MS) to investigate the presence and distribution of 5 hmC in human brain and brain tumors. In the normal adult brain, IHC identified 61.5% 5 hmC positive cells in the cortex and 32.4% 5 hmC in white matter (WM) areas. In tumors, positive staining of cells ranged from 1.1% in glioblastomas (GBMs) (WHO Grade IV) to 8.9% in Grade I gliomas (pilocytic astrocytomas). In the normal adult human brain, LC-MS also showed highest values in cortical areas (1.17% 5 hmC/dG [deoxyguanosine]), in the cerebral WM we measured around 0.70% 5 hmC/dG. levels were related to tumor differentiation, ranging from lowest values of 0.078% 5 hmC/dG in GBMs (WHO Grade IV) to 0.24% 5 hmC/dG in WHO Grade II diffuse astrocytomas. 5 hmC measurements were unrelated to 5 mC values. We find that the number of 5 hmC positive cells and the amount of 5 hmC/dG in the genome that has been proposed to be related to pluripotency and lineage commitment in embryonic stem cells is also associated with brain tumor differentiation and anaplasia.", "The identification of anaplastic lymphoma kinase (ALK), an oncogenetic driver mutation, in lung cancer has paved the way for a new era in the treatment of non-small cell lung cancer (NSCLC). Targeting ALK using tyrosine kinase inhibitors (TKI) has dramatically improved the prognosis of patients with ALK-rearranged NSCLC. However, most patients relapse on ALK-TKI therapy within a few years because of acquired resistance. One mechanism of acquiring resistance is a second mutation on the ALK gene, and the representative mutation is L1996M in the gatekeeper residue. In particular, the solvent-front ALK G1202R mutation is the common cause of resistance against first- and second-generation ALK-TKIs. Another major concern regarding ALK-TKI is metastasis to the central nervous system, commonly observed in patients relapsing after ALK-TKI therapy. The next-generation ALK inhibitor lorlatinib (PF-06463922) has therefore been developed to inhibit resistant ALK mutations, including ALK G1202R, and to penetrate the blood-brain barrier. In a Phase I/II trial, the safety and efficacy of lorlatinib were demonstrated in patients with advanced ALK-positive NSCLC, most of whom had central nervous system metastases and had previous ALK-TKI treatment. In this review, we discuss the structure, pharmacodynamics, and pharmacokinetics of lorlatinib and compare its characteristics with those of other ALK inhibitors. Furthermore, clinical trials for lorlatinib are summarized, and future perspectives in the management of patients with ALK-rearranged NSCLC are discussed." ]

[ "In growing cells, apurinic/apyrimidinic (AP) sites generated spontaneously or resulting from the enzymatic elimination of oxidized bases must be processed by AP endonucleases before they compromise cell integrity. Here, we investigated how AP sites and the processing of these noncoding lesions by the AP endonucleases Nfo, ExoA, and Nth contribute to the production of mutations (hisC952, metB5, and leuC427) in starved cells of the Bacillus subtilis YB955 strain. Interestingly, cells from this strain that were deficient for Nfo, ExoA, and Nth accumulated a greater amount of AP sites in the stationary phase than during exponential growth. Moreover, under growth-limiting conditions, the triple nfo exoA nth knockout strain significantly increased the amounts of adaptive his, met, and leu revertants produced by the B. subtilis YB955 parental strain. Of note, the number of stationary-phase-associated reversions in the his, met, and leu alleles produced by the nfo exoA nth strain was significantly decreased following disruption of polX. In contrast, during growth, the reversion rates in the three alleles tested were significantly increased in cells of the nfo exoA nth knockout strain deficient for polymerase X (PolX). Therefore, we postulate that adaptive mutations in B. subtilis can be generated through a novel mechanism mediated by error-prone processing of AP sites accumulated in the stationary phase by the PolX DNA polymerase.", "Tocilizumab (TCZ), is a recombinant humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody which has a main use in the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis (sJIA) and polyarticular juvenile idiopathic arthritis (pJIA). This article provides an overview of TCZ including looking into the past at the discovery of interleukin-6 (IL-6) as a pro-inflammatory cytokine. It also looks at how tocilizumab was developed, manufactured and tested to ensure both safety and efficacy in a human population. The article then explores the advantages and disadvantages of using TCZ when compared to other biologics approved in RA, sJIA and pJIA and finally looks ahead to the future and the emerging role of IL-6 and its blockade by TCZ as a treatment for giant cell arteritis (GCA), polymyalgia rheumatica (PMR) and large vessel vasculitis (LVV).", "Identifying co-expressed gene clusters can provide evidence for genetic or physical interactions. Thus, co-expression clustering is a routine step in large-scale analyses of gene expression data. We show that commonly used clustering methods produce results that substantially disagree and that do not match the biological expectations of co-expressed gene clusters. We present clust, a method that solves these problems by extracting clusters matching the biological expectations of co-expressed genes and outperforms widely used methods. Additionally, clust can simultaneously cluster multiple datasets, enabling users to leverage the large quantity of public expression data for novel comparative analysis. Clust is available at https://github.com/BaselAbujamous/clust .", "RhoB is a small GTP-binding protein that is involved in apoptotic signal transduction. We have cloned the mouse RhoB mRNA including a 1377 nucleotide 3'-untranslated region (UTR) that contains six AU-rich elements (AREs) as well as several uridine-rich stretches. There is 94% homology overall between the mouse and rat RhoB genes and 92% homology between the mouse and a putative human clone. Ultraviolet light (UVL) induces RhoB production through regulated changes in gene transcription and mRNA stabilization although the latter mechanism is unknown. We observed that UVL increased the half-life of RhoB mRNA from 63 min to 3.3 h in NIH/3T3 cells and from 87 min to 2.7 h in normal human keratinocyte cells. In vitro mobility shift assays demonstrated that HuR bound the 3'-UTR of RhoB at three distinct locations (nucleotides 1342-1696, 1765-1920 and 1897-1977) suggesting a regulatory role for this RNA-binding protein. HuR immunoprecipitations were positive for RhoB mRNA indicating an in vivo association, and Western blot analysis and immunofluorescence demonstrated that HuR rapidly partitions from the nucleus to the cytoplasm after UVL. Therefore, we propose a model in which UVL induces stress-activated signal transduction leading to nuclear/cytoplasmic shuttling of HuR and subsequent stabilization of RhoB mRNA.", "Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-1(VEGFR1), -2(VEGFR2), and -3(VEGFR3). Analog of Tivozanib with deuterium-for-hydrogen replacement in metabolically active site was prepared and evaluated in vitro. Compared to its prototype, deuterated Tivozanib compound HC-1144 retained in vitro activity against VEGFR tyrosine kinases. In vivo pharmacokinetic studies indicated HC-1144 clearly altered the blood circulation behavior, which was proved by significantly prolonged blood circulation half life time (t1/2) and increased AUC0-∞. Therefore, HC-1144 has the potential to be a novel inhibitor against VEGFR tyrosine kinases with long-acting plasma exposure.", "We assessed expression of the BRCA1, CTCF and DNMT3b methyltransferase genes along with BRCA1 promoter methylation to better define the epigenetic events involved in BRCA1 inactivation in sporadic breast cancer. These gene expression patterns were determined in 54 sporadic breast tumours by immunohistochemistry and the methylation status of the BRCA1 promoter was evaluated using methylation-specific PCR. We observed significant DNMT3b expression in 80% of the tumours and that 43% of tumours exhibited novel cytoplasmic CTCF expression. Pairwise analyses of gene expression patterns showed that 28/32 tumours lacked BRCA1 expression and also exhibited cytoplasmic CTCF staining, while 24/32 of these tumours also overexpressed DNMT3b. Furthermore, 86% of the BRCA1 low-expressing tumours were methylated at the BRCA1 promoter and a subset of these tumours displayed both cytoplasmic CTCF and increased DNMT3b expression. Thus, tumour subsets exist that display concurrent decreased BRCA1 expression, BRCA1 promoter methylation, cytoplasmic CTCF expression and with DNMT3b over-expression. We suggest that these altered CTCF and DNMT3b expression patterns represent (a) critical events responsible for the epigenetic inactivation of BRCA1 and (b) a diagnostic signature for epigenetic inactivation of other tumour suppressor genes in sporadic breast tumours.", "OBJECTIVE: To determine the natural history of dissecting aneurysm (DA) and whether DA is associated with an increased recurrent stroke risk and whether type of antithrombotic drugs (antiplatelets vs anticoagulants) modifies the persistence or development of DA.METHODS: We included 264 patients with extracranial cervical artery dissection (CAD) from the Cervical Artery Dissection in Stroke Study (CADISS), a multicenter prospective study that compared antiplatelet with anticoagulation therapy. Logistic regression was used to estimate age- and sex-adjusted odds ratios. We conducted a systematic review of published studies assessing the natural history of DA and stroke risk in patients with non-surgically-treated extracranial CAD with DA.RESULTS: In CADISS, DA was present in 24 of 264 patients at baseline. In 36 of 248 patients with follow-up neuroimaging at 3 months, 12 of the 24 baseline DAs persisted, and 24 new DA had developed. There was no association between treatment allocation (antiplatelets vs anticoagulants) and whether DA at baseline persisted at follow-up or whether new DA developed. During 12 months of follow-up, stroke occurred in 1 of 48 patients with DA and in 7 of 216 patients without DA (age- and sex-adjusted odds ratio 0.84; 95% confidence interval 0.10-7.31; p = 0.88). Published studies, mainly retrospective, showed a similarly low risk of stroke and no evidence of an increased stroke rate in patients with DA.CONCLUSIONS: The results of CADISS provide evidence suggesting that DAs may have benign prognosis and therefore medical treatment should be considered." ]

[ "Propionic acidemia is a metabolic disorder (OMIM 606054) caused by deficiency of the propionyl-coenzyme A (CoA) carboxylase, which subsequently results in accumulation of propionic acid. Patients may initially present with poor feeding, vomiting, loss of appetite, hypotonia, and lethargy. Later, most children will show different degrees of motor, social and language delay even more serious medical problems, including heart abnormalities, seizures, coma, and possibly death. Two siblings affected with propionic acidemia were screened for putative mutations in PCCA and PCCB genes coding alpha and beta subunits of propionyl-coenzyme A (CoA) carboxylase, respectively. Both patients had a mild-severe form of propionic acidemia. The investigations using PCR, long-PCR, array comparative genomic hybridization (aCGH), and sequencing techniques showed a approximately 73kb deletion extending from intron 16 to intron 19 and an 18bp insertion at the distal end of the deletion in PCCA gene. The deletion so far is the largest gross change reported in the literature for the PCCA gene.", "BACKGROUND: Genital herpes and herpes labialis are prevalent, physically and psychologically painful, and often disabling. Herpes zoster is often very painful and may result in months or years of postherpetic neuralgia (PHN). Over the past two decades, the treatment of these conditions has been transformed by guanosine nucleoside antivirals such as valacyclovir (Valtrex, a highly bioavailable prodrug of acyclovir (Zovirax, and famciclovir (Famvir), a highly bioavailable prodrug of penciclovir (Denavir).OBJECTIVE: We describe the pharmacology, pharmacokinetics, and clinical efficacy of valacyclovir for the treatment of herpes simplex, herpes zoster, and other viral infections. Valacyclovir is also compared with acyclovir and famciclovir.METHODS: All published literature containing the word \"valacyclovir\" was reviewed and summarized.RESULTS: Valacyclovir is the only oral antiviral agent approved for therapy of herpes labialis, the only antiviral drug approved for a 3-day course in the episodic treatment of recurrent genital herpes, as well as the only antiviral drug approved for once daily dosing for suppressive therapy. In herpes zoster, valacyclovir is more effective than acyclovir and equally effective as famciclovir at hastening the healing of zoster-associated pain and PHN.CONCLUSION: Valacyclovir is safe and effective in the therapy of patients with herpes simplex and herpes zoster and may be useful in other viral infections.", "BACKGROUND: Early-life exposure to household pets has the capacity to reduce risk for overweight and allergic disease, especially following caesarean delivery. Since there is some evidence that pets also alter the gut microbial composition of infants, changes to the gut microbiome are putative pathways by which pet exposure can reduce these risks to health. To investigate the impact of pre- and postnatal pet exposure on infant gut microbiota following various birth scenarios, this study employed a large subsample of 746 infants from the Canadian Healthy Infant Longitudinal Development Study (CHILD) cohort, whose mothers were enrolled during pregnancy between 2009 and 2012. Participating mothers were asked to report on household pet ownership at recruitment during the second or third trimester and 3 months postpartum. Infant gut microbiota were profiled with 16S rRNA sequencing from faecal samples collected at the mean age of 3.3 months. Two categories of pet exposure (i) only during pregnancy and (ii) pre- and postnatally were compared to no pet exposure under different birth scenarios.RESULTS: Over half of studied infants were exposed to at least one furry pet in the prenatal and/or postnatal periods, of which 8% were exposed in pregnancy alone and 46.8% had exposure during both time periods. As a common effect in all birth scenarios, pre- and postnatal pet exposure enriched the abundance of Oscillospira and/or Ruminococcus (P < 0.05) with more than a twofold greater likelihood of high abundance. Among vaginally born infants with maternal intrapartum antibiotic prophylaxis exposure, Streptococcaceae were substantially and significantly reduced by pet exposure (P < 0.001, FDRp = 0.03), reflecting an 80% decreased likelihood of high abundance (OR 0.20, 95%CI, 0.06-0.70) for pet exposure during pregnancy alone and a 69% reduced likelihood (OR 0.31, 95%CI, 0.16-0.58) for exposure in the pre- and postnatal time periods. All of these associations were independent of maternal asthma/allergy status, siblingship, breastfeeding exclusivity and other home characteristics.CONCLUSIONS: The impact of pet ownership varies under different birth scenarios; however, in common, exposure to pets increased the abundance of two bacteria, Ruminococcus and Oscillospira, which have been negatively associated with childhood atopy and obesity.", "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.", "Directional cell migration requires the formation of a dominant pseudopodium in the direction toward which the cell migrates. When a migratory cell is stimulated with a chemoattractant or extracellular matrix (ECM) gradient, it responds with localized amplification of signals on the side facing the gradient. The signals mediate reorganization of the actin-myosin cytoskeleton, leading to morphological polarization of the cell and pseudopodium extension. To identify these signals, we developed an approach to biochemically isolate the pseudopodium from the cell body using 3.0-micrometer porous filters for large-scale quantitative proteomic and phosphoproteomic analysis. Here, we detail the methodology for pseudopodium purification and proteomic analysis. This model system should be widely applicable for the analysis of the pseudopodium proteome from various migratory cell lines, including primary and cancer cell lines stimulated with a diverse array of chemoattractants, ECM proteins, or both.", "We have used a linear DNA template (239 bp) containing a nucleosome positioning sequence (NX1) downstream of the T7 RNA polymerase promoter to study the mechanism of transcription elongation through a nucleosome. Under ionic strength approaching physiological conditions we have observed that transcription causes nucleosome dissociation and histone redistribution within the template. We have examined the role of the different elements that, in principle, could induce nucleosome dissociation during transcription. The high affinity of histones for single-stranded DNA observed in titration experiments performed using the purified (+) and (-) strands of the NX1 fragment suggests that nucleosome dissociation is not due to the formation of segments of single-stranded DNA by RNA polymerase in the elongation process. Furthermore, our results show that although RNA can interact with core histones, the synthesized RNA is not bound to the histones dissociated by transcription. Our results indicate that core histones released during transcription can be bound to naked DNA and chromatin (with or without histones H1-H5). From the dynamic properties of excess histones bound to chromatin, we suggest a nucleosome transcription mechanism in which displaced histones are transiently bound to chromatin and finally are reassembled with DNA after the passage of the polymerase.", "IMPORTANCE: Criteria for preclinical Alzheimer disease (AD) propose β-amyloid (Aβ) plaques to initiate neurodegeneration within AD-affected regions. However, some cognitively normal older individuals harbor neural injury similar to patients with AD, without concurrent Aβ burden. Such findings challenge the proposed sequence and suggest that Aβ-independent precursors underlie AD-typical neurodegenerative patterns. OBJECTIVE To examine relationships between Aβ and non-Aβ factors as well as neurodegeneration within AD regions in cognitively normal older adults. The study quantified neurodegenerative abnormalities using imaging biomarkers and examined cross-sectional relationships with Aβ deposition; white matter lesions (WMLs), a marker of cerebrovascular disease; and cognitive functions.DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study in a community-based convenience sample of 72 cognitively normal older individuals (mean [SD] age, 74.9 [5.7] years; 48 women; mean [SD] 17.0 [1.9] years of education) of the Berkeley Aging Cohort.INTERVENTION: Each individual underwent a standardized neuropsychological test session, magnetic resonance imaging, and positron emission tomography scanning.MAIN OUTCOMES AND MEASURES: For each individual, 3 AD-sensitive neurodegeneration biomarkers were measured: hippocampal volume, glucose metabolism, and gray matter thickness, the latter 2 sampled from cortical AD-affected regions. To quantify neurodegenerative abnormalities, each biomarker was age adjusted, dichotomized into a normal or abnormal status (using cutoff thresholds derived from an independent AD sample), and summarized into 0, 1, or more than 1 abnormal neurodegenerative biomarker. Degree and topographic patterns of neurodegenerative abnormalities were assessed and their relationships with cognitive functions, WML volume, and Aβ deposition (quantified using carbon 11-labeled Pittsburgh compound B positron emission tomography).RESULTS: Of our cognitively normal elderly individuals, 40% (n = 29) displayed at least 1 abnormal neurodegenerative biomarker, 26% (n = 19) of whom had no evidence of elevated Pittsburgh compound B retention. In those people who were classified as having abnormal cortical thickness, degree and topographic specificity of neurodegenerative abnormalities were similar to patients with AD. Accumulation of neurodegenerative abnormalities was related to poor memory and executive functions as well as larger WML volumes but not elevated Pittsburgh compound B retention.CONCLUSIONS AND RELEVANCE: Our study confirms that a substantial proportion of cognitively normal older adults harbor neurodegeneration, without Aβ burden. Associations of neurodegenerative abnormalities with cerebrovascular disease and cognitive performance indicate that neurodegenerative pathology can emerge through non-Aβ pathways within regions most affected by AD." ]

[ "The rare combination of intestinal lymphangiectasia with malrotation of the duodenum in a child of three months of life is described. Basing on the literature review only 3 similar cases were described in the world practice. The boy with protein-losing enteropathy was examined at Moscow Scientific Centre of Children's Health. The child had vomiting, diarrhea, loss in body weight, hypoproteinemia, lymphopenia. The infectious nature of the disease was excluded. It had been suggested the Waldman desease (primary intestinal lymphangiectasia). The prognosis for such disease is unfavorable. An examination of the child was continued against the backdrop of ongoing symptomatic therapy. Complete physical examination included monitoring laboratory blood tests, X-ray examination with contrast, CT-scan, gastroduodenoscopy with biopsy of the mucosa of the small intestine. Malrotation duodenum with the recurrent mid-gut volvulus with the development of secondary intestinal lymphangiectasia was diagnosed. Modern methods of examination and multidisciplinary approach made it possible to diagnose the case. Operation to eliminate fixation duodenum resulted in the recovery of the patient. At the present time the child grows and develops according to age and does not require treatment. The prognosis for this disease is regarded as favorable.", "INTRODUCTION: Former investigations of Koebner phenomenon had demonstrated its higher incidence in patients with severe generalized and/or unstable forms of psoriasis which expressed increased resistance to various treatment modalities. The aim of this study was to establish the correlation between the presence of Koebner phenomenon and the PUVA therapy effects, total number of PUVA treatments, total dose of UVA radiation and the duration of remission after PUVA therapy discontinuation.MATERIAL AND METHODS: Sixty patients with severe clinical picture of psoriasis vulgaris, treated with PUVA therapy, were included in this research. According to the presence of Koebner phenomenon they were divided into two groups, 20 patients with positive and 40 patients with negative Koebner reaction, who were the control group at the same time.RESULTS AND DISCUSSION: 95% of patients treated with PUVA, were cleared of psoriatic changes in the Koebner positive, as well as in the Koebner negative group. There were also no differences between the Koebner positive and Koebner negative group in the mean number of PUVA treatments, mean total dose and the last dose of UVA radiation, which led up to the clinical remission of psoriasis. Our results of investigation have demonstrated increased relapse of psoriasis, during the first 6 months after cessation of PUVA therapy, in the Koebner positive group, with a high statistical significance (p < 0.001), comparing with Koebner negative group in the same period. Furthermore, the tendency of relapse of Koebner positive and Koebner negative psoriatic patients was higher in Koebner positive group even in the first 3 months after PUVA therapy.CONCLUSIONS: PUVA therapy effects, total number of PUVA treatments, total dose of UVA radiation didn't depend on presence of Koebner phenomenon. However, Koebner phenomenon was a mark of high relapsing tendency of psoriasis in the first 6 months after PUVA therapy cessation.", "New anticoagulant and antiplatelet medications have been approved and are prescribed with increased frequency. Intracranial hemorrhage is associated with the use of these medications. Therefore, neurosurgeons need to be aware of these new medications, how they are different from their predecessors, and the strategies for the urgent reversal of their effects. Utilization of intraluminal stents by endovascular neurosurgeons has resulted in the need to have a thorough understanding of antiplatelet agents. Increased use of dabigatran, rivaroxaban, and apixaban as oral anticoagulants for the treatment of atrial fibrillation and acute deep venous thrombosis has increased despite the lack of known antidotes to these medications.", "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.", "Deciding appropriate therapy for multiple myeloma (MM) is challenging because of the occurrence of multiple chromosomal changes and the fatal nature of the disease. In the current study, gamabufotalin (GBT) was isolated from toad venom, and its tumor-specific cytotoxicity was investigated in human MM cells. We found GBT inhibited cell growth and induced apoptosis with the IC50 values <50 nM. Mechanistic studies using functional approaches identified GBT as an inhibitor of c-Myc. Further analysis showed that GBT especially evoked the ubiquitination and degradation of c-Myc protein, thereby globally repressing the expression of c-Myc target genes. GBT treatment inhibited ERK and AKT signals, while stimulating the activation of JNK cascade. An E3 ubiquitin-protein ligase, WWP2, was upregulated following JNK activation and played an important role in c-Myc ubiquitination and degradation through direct protein-protein interaction. The antitumor effect of GBT was validated in a xenograft mouse model and the suppression of MM-induced osteolysis was verified in a SCID-hu model in vivo. Taken together, our study identified the potential of GBT as a promising therapeutic agent in the treatment of MM.", "Achondroplasia is the most prevalent chondrodysplasia and numerous authors have documented the varied social and medical complications that may compromise a full and productive life. Complications include cervicomedullary compression, spinal stenosis, restrictive and obstructive lung disease, otitis media, and tibial bowing, among others. These known complications have led to recommendations for the anticipatory management of such patients. There are relatively few data on the actual rates and timing of these problems. This paper reports data on the rates and age of occurrence of several of these complications based on a review of recorded chart information of 193 patients ascertained from several well established genetic centres with a known interest in the chondrodysplasias. The length of follow up varied and the rates of occurrence at specific age intervals were used to estimate the cumulative percentage affected for each complication. The report includes information on otitis media, ventilation tubes, hearing loss, tonsillectomy, speech problems, tibial bowing and osteotomy, ventricular shunting, apnoea, cervicomedullary decompression, and neurological signs attributable to spinal stenosis.", "Mast cells (MCs) are known to participate in a variety of patho-physiological processes depending largely on the intragranular mediators and the production of cytokines and chemokines during degranulation. Recently, extracellular vesicles (EVs) have been implicated important functions for MCs, but the components of MC-derived EVs have not yet been well-characterized. In this study, we aimed to identify signatures of proteins, long non-coding RNAs (lncRNAs), and microRNAs (miRNAs) in EVs derived from resting (Rest-EV) and degranulated (Sti-EV) MCs by differential ultracentrifugation. Using tandem mass tag (TMT)-based quantitative proteomics technology and RNA sequencing, we identified a total of 1988 proteins, 397 lncRNAs, and 272 miRNAs in Rest-EV and Sti-EV. The proteins include common EVs markers (cytoskeletal proteins), MCs markers (FcεRI and tryptase), and some preformed MCs mediators (lysosomal enzymes) as well. The global expression profiles of lncRNAs and miRNAs identified, for the first time, from Rest-EV and Sti-EV, strongly suggest a potential regulatory function of MC-derived EVs. We have also performed Western blotting and qRT-PCR analysis to further verify some of the proteins, lncRNAs, and miRNAs identified from Rest-EV and Sti-EV. Our findings will help to elucidate the functions of MC-derived EVs, and provide a reference dataset for future translational studies involving MC-derived EVs." ]

[ "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.", "Fertilization is fundamental for sexual reproduction, yet its molecular mechanisms are poorly understood. We found that an oocyte-expressed Ly6/uPAR protein, which we call Bouncer, is a crucial fertilization factor in zebrafish. Membrane-bound Bouncer mediates sperm-egg binding and is thus essential for sperm entry into the egg. Remarkably, Bouncer not only is required for sperm-egg interaction but is also sufficient to allow cross-species fertilization between zebrafish and medaka, two fish species that diverged more than 200 million years ago. Our study thus identifies Bouncer as a key determinant of species-specific fertilization in fish. Bouncer's closest homolog in tetrapods, SPACA4, is restricted to the male germline in internally fertilizing vertebrates, which suggests that our findings in fish have relevance to human biology.", "Drug and alcohol abuse continue to be commonly encountered problems in most patient populations. To deal effectively with these problems, the primary care physician must have a thorough knowledge of the pharmacology of commonly abused drugs and the adjunctive agents used in treatment. Management of alcoholism may involve a range of medical interventions, including the treatment of alcohol intoxication, the use of benzodiazepines for alcohol withdrawal, and possibly the short-term administration of disulfiram to maintain sobriety. Successful management of cocaine or amphetamine abuse requires an understanding of the powerful reinforcing properties of these drugs and the unique problems that arise in the recovery period. Barbiturate intoxication and withdrawal are potentially life-threatening events requiring skilled in-patient treatment. Prolonged use of benzodiazepines can lead to drug dependence; successful withdrawal involves gradual dosage reduction. Acute intoxication from marijuana or hallucinogenic drugs may occasionally result in adverse reactions requiring medical intervention, but significant withdrawal reactions are rare. Management of opioid overdose, whether illicit or iatrogenic, requires the prompt and skillful use of opioid overdose, whether illicit or iatrogenic, requires the prompt and skillful use of opioid antagonists. Promising new pharmacologic approaches are now being successfully applied to the management of opioid dependence. An acceptance of nicotine as the addictive component of tobacco smoke has led to the development of nicotine gum as substitution therapy for cigarette smoking. Successful pharmacologic management of overdose or withdrawal is often the prerequisite for effective long-term treatment and recovery.", "Calciphylaxis is a rare condition characterized by medial calcification of small- and medium-sized vessels that subsequently leads to ischemic necrosis. Calciphylaxis most often occurs in patients with end-stage renal disease and secondary hyperparathyroidism. We present a unique case of calciphylaxis in which the patient did not have end-stage renal disease. Instead, primary hyperparathyroidism and/or alcoholic cirrhosis were the more likely causes of her calciphylaxis. In addition, our case demonstrated not only calciphylaxis but also fragmentation and calcification of elastic fibers within the dermis, changes that are most often seen in pseudoxanthoma elasticum. This is the first reported case of calciphylaxis, to our knowledge, with histopathologic changes of pseudoxanthoma elasticum in a patient who is nonuremic.", "The subventricular zone of the rodent brain retains the capacity of generating new neurons in adulthood. The newly formed neuroblasts migrate rostrally toward the olfactory bulb, where they differentiate as granular and periglomerular interneurons. The reported presence of differentiated neurons expressing the neuronal isoform of nitric oxide synthase (NOS) in the periphery of the neurogenic region and the organization of their varicose axons as a network in which the precursors are immersed raised the hypothesis that endogenous nitric oxide (NO) may participate in the control of neurogenesis in the subventricular zone. Systemic administration of the NOS inhibitors N(omega)-nitro-L-arginine methyl ester or 7-nitroindazole to adult mice produced a dose- and time-dependent increase in the number of mitotic cells in the subventricular zone, rostral migratory stream, and olfactory bulb, but not in the dentate gyrus of the hippocampus, without affecting apoptosis. In the subventricular zone, this effect was exerted selectively on a precursor subpopulation expressing nestin but not neuronal or glial cell-specific proteins. In addition, in the olfactory bulb, analysis of maturation markers in the newly generated neurons indicated that chronic NOS inhibition caused a delay in neuronal differentiation. Postmitotic cell survival and migration were not affected when NO production was impaired. Our results suggest that NO, produced by nitrergic neurons in the adult mouse subventricular zone and olfactory bulb, exerts a negative control on the size of the undifferentiated precursor pool and promotes neuronal differentiation.", "OBJECTIVE: To evaluate the role of idarucizumab, a humanized monoclonal antibody fragment, as a specific reversal agent for the anticoagulant activity of dabigatran and to review the pharmacology, pharmacokinetic properties, efficacy, and safety of this agent.METHODS: A literature search was conducted consisting of a PubMed database using the MeSH term idarucizumab and the key word dabigatran antidote. Studies evaluating the pharmacology, pharmacokinetics, safety, and efficacy of idarucizumab for the reversal of the anticoagulant activity of dabigatran were included.RESULTS: Idarucizumab represents a novel treatment option as it is the only humanized, monoclonal antibody fragment that specifically binds to dabigatran. Studies evaluating reversal of dabigatran-induced anticoagulation have demonstrated immediate, complete, and sustained effects with idarucizumab. Idarucizumab did not overcorrect thrombin generation. Additionally, evaluations have shown that dabigatran can be safely reinitiated 24 hours after the administration of idarucizumab. The United States Food and Drug Administration granted priority review for the biologic license application and accelerated approval for idarucizumab.CONCLUSION: Idarucizumab represents an encouraging development in the reversal of dabigatran. Its novel mechanism of action, pharmacokinetics, tolerability, and lack of thrombotic events contribute positively to its use in patients who experience bleeding or for those who require emergent surgery or procedures.", "BACKGROUND AND PURPOSE: Spontaneous animal mutants affected by abnormal formation of myelin in the central nervous system (CNS) are useful in studies on myelinogenesis and remyelination leading to better understanding of cellular and molecular interactions involved in myelin repair. A novel rat mutant, Bouncer Long Evans (LE-bo) is severely dysmyelinated, but with exceptional longevity, and its clinical and pathologic phenotype are described.METHODS: Clinical observations, genetic studies, and determination of longevity were performed in a colony of rats, including carriers of LE-bo phenotype producing the mutant animals. Comprehensive histologic studies were performed on all perfusion-fixed tissues, and ultrastructural examination of the optic nerve and thoracic part of the spinal cord also was done in rats 1 to 14 weeks old.RESULTS: The LE-bo phenotype is characterized by whole body tremor, progressively severe ataxia, and severe seizure activity. The LE-bo phenotype is transferred as an autosomal recessive trait and is stable. The LE-bo rat can survive in good health beyond 45 weeks. Neuropathologic changes include severe global dysmyelination, with thin uncompacted myelin sheaths in young rats forming no major dense line, whereas the myelin sheaths of the peripheral nervous system appear normal. Oligodendrocytes degenerate with apparently progressing accumulation of membranous material in the perikaryon. Large numbers of immature glial cells were detected in the CNS of LE-bo rats at 4 to 14 weeks.CONCLUSION: The LE-bo rat is severely dysmyelinated due to inability of its oligodendrocytes to form myelin sheaths. Similarities of the LE-bo rat and Long Evans Shaker (les) rat neuropathologic features, such as severe dysmyelination, lack of major dense line in uncompacted myelin sheaths, apparent proliferation of oligodendroglial cells, and considerable longevity, are striking and suggest that a LE-bo mutation may functionally affect the myelin basic protein gene.", "BACKGROUND/AIMS: Reports of outcomes in treating dystonia secondary to stroke with deep brain stimulation (DBS) are limited. We report our experience with 3 patients, all with infarcts involving the striatum, who developed hemidystonia and were treated with unilateral globus pallidus interna DBS.METHODS: Case series describing characteristics and outcomes based on the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores before and after DBS at 3, 6 and at least 12 months.RESULTS: All patients reported subjective improvements after surgery. At 1 year or more after surgery, none of the 3 patients displayed a measureable improvement in the BFMDRS movement score.CONCLUSION: Our findings are consistent with previous reports of limited benefits from pallidal DBS in secondary dystonia. Future work should focus on predictive factors for DBS outcomes and the development of more sensitive assessment tools specifically for secondary dystonias as well as the exploration of alternative brain targets for stimulation." ]

[ "Cabozantinib is an oral small-molecule multitargeted tyrosine kinase inhibitor (TKI) that may confer an advantage over other TKIs that target a single receptor. It was approved by the U.S. Food and Drug Administration for the treatment of both advanced renal cell carcinoma and progressive metastatic medullary thyroid cancer, and it is being investigated for a wide array of other malignancies. Rationale for use, clinical trial data, and current recommendations for cabozantinib in renal cell cancer, thyroid cancer, prostate cancer, hepatocellular cancer, and lung cancer are detailed in this article. Common adverse events are reviewed, and management strategies for select adverse events are discussed. Implications for contemporary practitioners are also provided because use of this novel agent is likely to increase as more studies are completed.", "A 46-year-old man of Iranian origin presented with a 4-day history of colicky abdominal pain and absolute constipation on a background of several weeks of irritability and malaise. He had smoked 10 g of opium per week for a year and a half. On examination, he had diffuse abdominal tenderness and faecal loading. This was cleared, but the abdominal pain, nausea and vomiting persisted. He had extravascular haemolytic anaemia with punctate basophilic stippling on blood film. The patient's serum lead concentration was substantially elevated and he perhaps demonstrated Burton's line. The patient underwent chelation therapy and has recovered clinically and biochemically. Public health experts were notified and conducted an assessment of the risk to the patient and others; their lead exposure questionnaire was subsequently amended. This is an important case report of a UK resident describing lead toxicity secondary to the inhalation of opium.", "BACKGROUND: Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC).METHODS: We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00982111.FINDINGS: Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5-13·4) in the necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1-13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 [95% CI 0·84-1·21]; p=0·96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51%] of 304 vs 127 [41%] of 312 patients). Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3-4 rash (45 [15%] of 304 vs one [<1%] of 312 patients in the pemetrexed and cisplatin alone group), hypomagnesaemia (23 [8%] vs seven [2%] patients), and grade 3 or higher venous thromboembolic events (23 [8%] vs 11 [4%] patients) than did those in the pemetrexed and cisplatin alone group.INTERPRETATION: Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin.FUNDING: Eli Lilly and Company.", "The uptake and metabolism of T3 and rT3 was studied in human liver-derived HepG2 cells. The results showed a saturable, time-dependent, and ouabain-sensitive increase in nuclear bound T3. The effects of ouabain (0.5 mmol/L) and unlabeled T3 (10 nmol/L and 10 mumol/L) were much more pronounced at the nuclear level, suggesting the presence of a nonspecific component in total cellular binding. Nuclear binding of rT3 remained below the detection limit in all experiments. Comparison of rT3 metabolism in HepG2 cells and primary cultures of rat hepatocytes showed an approximately 10-fold lower iodide production in HepG2 cells. Iodide production was decreased in the presence of ouabain and almost absent in the presence of propylthiouracil (100 mumol/L). Our data confirmed the presence of a carrier-mediated uptake system for both T3 and rT3. Metabolism data indicated functional type I deiodinase activity in HepG2 cells, the presence of glucuronidating enzymes, and the absence of thyroid hormone sulfotransferase activity. Based on these data, we propose that HepG2 cells provide an appropriate model for thyroid hormone handling by human liver. In addition, we suggest that in human liver sulfation of thyroid hormone, and therefore deiodination of T3 is of only minor importance.", "Mismatch repair (MMR) increases the fidelity of DNA replication by identifying and correcting replication errors. Processivity clamps are vital components of DNA replication and MMR, yet the mechanism and extent to which they participate in MMR remains unclear. We investigated the role of the Bacillus subtilis processivity clamp DnaN, and found that it serves as a platform for mismatch detection and coupling of repair to DNA replication. By visualizing functional MutS fluorescent fusions in vivo, we find that MutS forms foci independent of mismatch detection at sites of replication (i.e. the replisome). These MutS foci are directed to the replisome by DnaN clamp zones that aid mismatch detection by targeting the search to nascent DNA. Following mismatch detection, MutS disengages from the replisome, facilitating repair. We tested the functional importance of DnaN-mediated mismatch detection for MMR, and found that it accounts for 90% of repair. This high dependence on DnaN can be bypassed by increasing MutS concentration within the cell, indicating a secondary mode of detection in vivo whereby MutS directly finds mismatches without associating with the replisome. Overall, our results provide new insight into the mechanism by which DnaN couples mismatch recognition to DNA replication in living cells.", "BACKGROUND AND OBJECTIVE: Lead poisoning is normally caused by repeated occupational inhalation of lead. However, lead may also be absorbed through the digestive route. Some alternative medical treatments, such as Ayurvedic medicine, can also contain lead and may result in poisoning.PATIENTS AND METHOD: We collected cases of lead poisoning related to Ayurvedic treatments attended at the Hospital Clinic of Barcelona.RESULTS: Two female patients, aged 45 and 57 years, respectively, who initiated Ayurvedic treatments which involved the ingestion of various medicaments, were included. The first patient presented with anemia and abdominal pain. The lead level was 74μg/dL and free erythrocyte protoporphyrin was 163μg/dL. She was treated with intravenous calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA) and later with oral dimercaptosuccinic acid (DMSA) with a good evolution. The second patient presented with abdominal pain and a Burton's line. The lead level was 52μg/dL and free erythrocyte protoporphyrin was 262μg/dL. She was treated with oral DMSA and evolved favorably. Lead concentrations in some of the tablets supplied to the patients reached 2,003 and 19,650μg/g of tablet.CONCLUSIONS: Lead poisoning may result from treatments based on Ayurvedic medicine and may reach epidemic proportions. Health control of alternative medicines is necessary.", "Mitochondrial myopathies belong to a larger group of systemic diseases caused by morphological or biochemical abnormalities of mitochondria. Mitochondrial disorders can be caused by mutations in either the mitochondrial or nuclear genome. Only 5% of all mitochondrial disorders are autosomal dominant. We analyzed DNA from members of the previously reported Puerto Rican kindred with an autosomal dominant mitochondrial myopathy (Heimann-Patterson et al. 1997). Linkage analysis suggested a putative locus on the pericentric region of the long arm of chromosome 22 (22q11). Using the tools of integrative genomics, we established chromosome 22 open reading frame 16 (C22orf16) (later designated as CHCHD10) as the only high-scoring mitochondrial candidate gene in our minimal candidate region. Sequence analysis revealed a double-missense mutation (R15S and G58R) in cis in CHCHD10 which encodes a coiled coil-helix-coiled coil-helix protein of unknown function. These two mutations completely co-segregated with the disease phenotype and were absent in 1,481 Caucasian and 80 Hispanic (including 32 Puerto Rican) controls. Expression profiling showed that CHCHD10 is enriched in skeletal muscle. Mitochondrial localization of the CHCHD10 protein was confirmed using immunofluorescence in cells expressing either wild-type or mutant CHCHD10. We found that the expression of the G58R, but not the R15S, mutation induced mitochondrial fragmentation. Our findings identify a novel gene causing mitochondrial myopathy, thereby expanding the spectrum of mitochondrial myopathies caused by nuclear genes. Our findings also suggest a role for CHCHD10 in the morphologic remodeling of the mitochondria.", "OBJECTIVE: Long-term treatment with topiramate reduces body weight and improves insulin sensitivity in obese humans. Our aim was to evaluate the effect of topiramate treatment for 4 weeks on insulin sensitivity and secretion, independent of weight loss.DESIGN: Randomized, double-blind, crossover, placebo-controlled study.METHODS: Thirteen obese (BMI 36.6 ± 1.3 kg/m(2) (mean ± s.e.m.)), insulin-resistant (homeostasis model of assessment-insulin resistance 2.0 ± 0.2) women received topiramate (T, maximum dose of 75 mg) and placebo (P) for 4 weeks, separated by a 4-week washout period. Insulin sensitivity and β-cell function were assessed using a two-step hyperinsulinemic euglycemic clamp with stable isotopes and a hyperglycemic clamp.RESULTS: Hepatic and peripheral insulin sensitivities were not affected by topiramate treatment (glucose disposal rate (step 1 (insulin infusion rate 10 MU/M(2) per min) T: 17.5 ± 0.8 vs P: 18.5 ± 1.0 μmol/kg(LBM) per min, t=1.016, P=0.33; step 2 (insulin infusion rate 40 mU/m(2) per min) T: 27.9 ± 3.2 vs P: 28.8 ± 1.9 μmol/kg(LBM) per min, t=0.418, P=0.68)). Subjects lost a small amount of weight during the topiramate period (T: -1.0 ± 0.2 vs P: -0.1 ± 0.2 kg, t=2842, P=0.15). There were no changes in body fat mass, blood pressure, and fasting glucose. β-Cell function was not affected by topiramate as evidenced by an unaltered area under the curve of early (0-10 min; T: 1929.6 ± 265.7 vs P: 2024.7 ± 333.6 pmol/l, t=-0.357, P=0.73) and late (80-120 min; T: 28,017.7 ± 5029.9 vs P: 31,567.7 ± 5376.2 pmol/l, t=-1.481, P=0.16) phase insulin levels during hyperglycemia. The use of topiramate was associated with significant side effects such as paresthesia, nausea, dizziness, and concentration problems.CONCLUSIONS: Low-dose topiramate treatment for 4 weeks, relative to placebo, had no significant effect on insulin sensitivity in overweight/obese adult females without established diabetes.", "BACKGROUND: Smokers need effective support to maximise the chances of successful quit attempts. Current smoking cessation medications, such as nicotine replacement therapy (NRT), bupropion, nortriptyline or varenicline, have been shown to be effective in clinical trials but are underused by smokers attempting to quit due to adverse effects, contraindications, low acceptability and/or high cost. Cytisine is a low-cost, plant-based alkaloid that has been sold as a smoking cessation aid in Eastern Europe for 50 years. A systematic review of trial evidence suggests that cytisine has a positive impact on both short- and long-term abstinence rates compared to placebo. However, the quality of the evidence is poor and insufficient for licensing purposes in many Western countries. A large, well-conducted placebo-controlled trial (n = 740) of cytisine for smoking cessation has recently been published and confirms the findings of earlier studies, with 12-month continuous abstinence rates of 8.4% in the cytisine group compared to 2.4% in the placebo group (Relative risk = 3.4, 95% confidence intervals 1.7-7.1). No research has yet been undertaken to determine the effectiveness of cytisine relative to that of NRT.METHODS/DESIGN: A single-blind, randomised controlled, non-inferiority trial has been designed to determine whether cytisine is at least as effective as NRT in assisting smokers to remain abstinent for at least one month. Participants (n = 1,310) will be recruited through the national telephone-based Quitline service in New Zealand and randomised to receive a standard 25-day course of cytisine tablets (Tabex®) or usual care (eight weeks of NRT patch and/or gum or lozenge). Participants in both study arms will also receive a behavioural support programme comprising an average of three follow-up telephone calls delivered over an eight-week period by Quitline. The primary outcome is continuous abstinence from smoking at one month, defined as not smoking more than five cigarettes since quit date. Outcome data will also be collected at one week, two months and six months post-quit date.DISCUSSION: Cytisine appears to be effective compared with placebo, and given its (current) relative low cost may be an acceptable smoking cessation treatment for smokers, particularly those in low- and middle-income countries. Cytisine's 'natural' product status may also increase its acceptability and use among certain groups of smokers, such as indigenous people, smokers in countries where the use of natural medicines is widespread (e.g. China, India), and in those people who do not want to use NRT or anti-depressants to help them quit smoking. However it is important to ascertain the effectiveness of cytisine compared with that of existing cessation treatments.TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12610000590066).", "Lead poisoning in both its acute and chronic forms has been recognised since the second century BCE. Lead colic, anaemia, renal tubulopathies and motor neuropathies are well recognised. This paper sketches the early history and remembers the important contribution of Henry Burton, who described the gums to be bordered by a narrow leaden-blue line, about the one-twentieth part of an inch in width, whilst the substance of the gum apparently retained its ordinary colour and condition. The sign though inconstant, is still a valuable clinical clue.", "Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia characterized as a normochromic macrocytic anemia with a selective deficiency in red blood cell precursors in otherwise normocellular bone marrow. In 40% of DBA patients, various physical anomalies are also present. Currently two genes are associated with the DBA phenotype--the ribosomal protein (RP) S19 mutated in 25% of DBA patients and RPS24 mutated in approximately 1.4% of DBA patients. Here we report the identification of a mutation in yet another ribosomal protein, RPS17. The mutation affects the translation initiation start codon, changing T to G (c.2T>G), thus eliminating the natural start of RPS17 protein biosynthesis. RNA analysis revealed that the mutated allele was expressed, and the next downstream start codon located at position +158 should give rise to a short peptide of only four amino acids (Met-Ser-Arg-Ile). The mutation arose de novo, since all healthy family members carry the wild-type alleles. The identification of a mutation in the third RP of the small ribosomal subunit in DBA patients further supports the theory that impaired translation may be the main cause of DBA pathogenesis.", "PURPOSE OF REVIEW: Marfan syndrome, the founding member of connective tissue disorders, is characterized by involvement of three major systems (skeletal, ocular, and cardiovascular) due to alteration in microfibrils. FBN1 at 15q21.1 was found to cause Marfan syndrome in 1991, and in 2004 TGFBR2 at 3p24.1 was newly identified as the Marfan syndrome type II gene. Several studies implied that fibrillin-1 and transforming growth factor-beta (TGF-beta) signaling are functionally related in extracellular matrix. Identification of TGFBR2 mutations in Marfan syndrome type II provided the direct evidence of the relation in humans.RECENT FINDINGS: More than 500 FBN1 mutations have been found in Marfan syndrome, tentative genotype - phenotype correlations have emerged, and mouse models are providing insight into pathogenic mechanisms. TGFBR2 mutations are still limited, however, in 2005 were also reported to cause a new aneurysm syndrome. Functional association between fibrillin-1 and TGF-beta signaling in extracellular matrix has been presented.SUMMARY: This review focuses on recent molecular genetics advances in Marfan syndrome and overlapping connective tissue disorders. Mutation spectrum of FBN1 and TGFBR2 in relation to phenotype is presented. Functional relation between fibrillin-1 and TGF-beta signaling is discussed. Future prospects in the study of Marfan syndrome are presented." ]

[ "Collaborators: Marmarou A, Maas AI, Narayan R, Skolnick BE, Ward J, Stocchetti N, Dearden NM, Clarence-Smith K, Genazzani AR, Grady MS, Steyerberg EW, Okonkwo D, Grieve G, Zaaroor M, Levi L, Smrcka M, May A, Pachl J, Manji M, Chen J, Pichon N, Lobato RD, Norasetthada T, Puybasset L, Petit L, Meisel H, Fakhry S, Wilberger J, Sahuquillo J, Rabb C, Walsh J, Mokry M, Yutthakasemsunt S, Huynh T, Rumana C, Audibert G, Citerio G, Agazzi S, Gruen J, O'Leary S, Ransom K, Trimmel H, Turner M, Zucker L, Umansky F, Nardi G, Dominguez JI, Zauberman J, Claridge J, Bulters D, Mace JC, McCarthy M, Colpaert K, Ratanalert S, Couture D, Choi K, Verma V, Cheng Y, Wang E, Rosen C, Medow J, Patterson L, Alberico A, Avila RA, Vega E, Unterberg A, Stocchetti N, Zhou L, Wong S, Beretta L, Laskowitz D, Vincent JL, Dominguez-Roldán J, Molina JM, Wang Z, Coimbra R, German J, Emhoff T, Boakye M, Surdell DL, García E, Leone M, Nimsky C, Sandesc D, Nagy L, Badenes R, Öhman J, Barnes S, Jacoby M, Shillinglaw W, Orlandi C, Vander Laenen M, Grigoriev R, Rohde V, Vajkoczy P, Raventós AA, Minguillón MA, Oram J, Kuang Y, Chou N, Grindlinger G, Rodgers R, Tinti M, Nagy K, Pellegrini J, George R, Brevard SB, Barbozà A, Payen JF, Troubleyn J, Lavicka P, van der Naalt J, Spoelstra-de Man A, Molina JA, Miranda P, Lopez PM, Wright J, Thambinayagam H, Cheng W, Fulda G, Garrote M, Schmutzhard E, Depreitere B, Greiner C, Zacharowski K, Nevo M, Kang D, Yu R, Alias A, Nor MM, Espinosa J, Shaffrey M, Beauchamp K, Faber T, Dailler F, Cejpek P, Belkin S, Sardaryan I, Kobyakov G, Orel V, Weber F, Procaccio F, Della Corte F, Barzó P, Laha S, Zhang B, Cheang V, Arnold P, Badr A, Andersen B, Putnam A 2nd, Murali R, Videtta W, Regelsberger J, Rappaport ZH, Büki A, Mendiluce RM, Kumar D, Ng I, Tu YK.", "Thyroid hormone (TH) is critical for cardiac development and heart function. In heart disease, TH metabolism is abnormal, and many biochemical and functional alterations mirror hypothyroidism. Although TH therapy has been advocated for treating heart disease, a clear benefit of TH has yet to be established, possibly because of peripheral actions of TH. To assess the potential efficacy of TH in treating heart disease, type 2 deiodinase (D2), which converts the prohormone thyroxine to active triiodothyronine (T3), was expressed transiently in mouse hearts by using the tetracycline transactivator system. Increased cardiac D2 activity led to elevated cardiac T3 levels and to enhanced myocardial contractility, accompanied by increased Ca(2+) transients and sarcoplasmic reticulum (SR) Ca(2+) uptake. These phenotypic changes were associated with up-regulation of sarco(endo)plasmic reticulum calcium ATPase (SERCA) 2a expression as well as decreased Na(+)/Ca(2+) exchanger, beta-myosin heavy chain, and sarcolipin (SLN) expression. In pressure overload, targeted increases in D2 activity could not block hypertrophy but could completely prevent impaired contractility and SR Ca(2+) cycling as well as altered expression patterns of SERCA2a, SLN, and other markers of pathological hypertrophy. Our results establish that elevated D2 activity in the heart increases T3 levels and enhances cardiac contractile function while preventing deterioration of cardiac function and altered gene expression after pressure overload.", "The short and intense pulses of the new X-ray free electron lasers, now operational or under construction, may make possible diffraction experiments on single molecule-sized objects with high resolution, before radiation damage destroys the sample. In a single molecule imaging (SMI) experiment thousands of diffraction patterns of single molecules with random orientations are recorded. One of the most challenging problems of SMI is how to assemble these noisy patterns of unknown orientations into a consistent single set of diffraction data. Here we present a new method which can solve the orientation problem of SMI efficiently even for large biological molecules and in the presence of noise. We show on simulated diffraction patterns of a large protein molecule, how the orientations of the patterns can be found and the structure to atomic resolution can be solved. The concept of our algorithm could be also applied to experiments where images of an object are recorded in unknown orientations and/or positions like in cryoEM or tomography.", "Changes in muscle elasticity are expected in patients with untreated myositis. The purpose of this study was to define the accuracy of shear-wave elastography (SWE) in diagnosing myositis. This case control study included 21 patients (mean age, 49.4 y; 12 women) with myositis who underwent SWE, magnetic resonance imaging (MRI) and biopsy of the involved muscle group. SWE was performed accordingly in a control group (n = 24; mean age, 51.2 y; 8 women). Blood tests consisted of creatine kinase (CK) and aldolase. Two operators performed SWE in longitudinal and transverse planes of muscular fibers, quantifying the mean shear-wave velocity (SWV) and the pattern of stiffness. On MRI, short-TI inversion recovery (STIR) signal hyperintensity and T1 contrast enhancement of muscle was considered diagnostic for myositis. The patient group suffered from different types of myositis (nine patients with polymyositis, eight with dermatomyositis and four with other types of myositis). Blood tests showed significantly increased CK and aldolase values in patients with myositis (p < 0.001 and p < 0.0001). MRI showed a sensitivity of 0.95. In the patient group, the mean SWVs of longitudinal and transverse measurements were 2.8 ± 1.4 m/s and 3.1 ± 1.2 m/s, respectively. In the control group, SWVs were 2.3 ± 0.5 m/s and 2.4 ± 0.5 m/s, respectively. The difference between transverse measurements was significant (p = 0.02). Increased heterogeneity as a marker for myositis in transverse SWE showed a sensitivity of 0.8, specificity of 0.79, positive predictive value (PPV) of 0.76 and negative predictive value (NPV) of 0.82. Inter-observer difference was very low (κ = 0.92). Increased heterogeneity in both planes compared with histologic results showed a sensitivity of 0.56, specificity of 0.93, PPV of 0.91 and NPV of 0.62. Spearman correlation between CK <1000 U/L and SWE was 0.54. In conclusion, transverse orientation SWE may serve as an imaging biomarker for the diagnosis of myositis through the display of a heterogeneous pattern and increased absolute SWV values of inflamed muscles.", "The oral microbial community (microbiota) plays a critical role in human health and disease. Alterations in the oral microbiota may be associated with disorders such as gingivitis, periodontitis, childhood caries, alveolar osteitis, oral candidiasis and endodontic infections. In the immunosuppressed population, the spectrum of potential oral disease is even broader, encompassing candidiasis, necrotizing gingivitis, parotid gland enlargement, Kaposi's sarcoma, oral warts and other diseases. Here, we used 454 pyrosequencing of bacterial 16S rRNA genes to examine the oral microbiome of saliva, mucosal and tooth samples from HIV-positive and negative children. Patient demographics and clinical characteristics were collected from a cross-section of patients undergoing routine dental care. Multiple specimens from different sampling sites in the mouth were collected for each patient. The goal of the study was to observe the potential diversity of the oral microbiota among individual patients, sample locations, HIV status and various dental characteristics. We found that there were significant differences in the microbiome among the enrolled patients, and between sampling locations. The analysis was complicated by uneven enrollment in the patient cohorts, with only five HIV-negative patients enrolled in the study and by the rapid improvement in the health of HIV-infected children between the time the study was conceived and completed. The generally good oral health of the HIV-negative patients limited the number of dental plaque samples that could be collected. We did not identify significant differences between well-controlled HIV-positive patients and HIV-negative controls, suggesting that well-controlled HIV-positive patients essentially harbor similar oral flora compared to patients without HIV. Nor were significant differences in the oral microbiota identified between different teeth or with different dental characteristics. Additional studies are needed to better characterize the oral microbiome in children and those with poorly-controlled HIV infections.", "Considerable interest has emerged over the last decade regarding the role of aspirin in prevention of colorectal cancer. This disease is one of the commonest cancers in the Western World, therefore, the existence of a simple \"everyday\" agent, which could have the ability to prevent the disease, represents an invaluable opportunity clinicians may be able to exploit. Evidence from case-control and cohort studies, and recent updates of randomised controlled trials have been very encouraging-indicating benefit from long term use of aspirin at low dose. Possible mechanisms of chemoprevention include inhibition of the cyclooxygenase (COX) pathway, or COX-independent mechanisms, for example, the PIK3CA pathway, or therapy-induced senescence of cancer cells. The most serious side effect of prolonged aspirin treatment is haemorrhage, especially from the GI tract. This is likely to be less of a problem with chemoprevention at lower doses. One also needs to consider the impact if aspirin resistance, an increasingly recognised clinical entity.", "Evolutionary relationships among birds in Neoaves, the clade comprising the vast majority of avian diversity, have vexed systematists due to the ancient, rapid radiation of numerous lineages. We applied a new phylogenomic approach to resolve relationships in Neoaves using target enrichment (sequence capture) and high-throughput sequencing of ultraconserved elements (UCEs) in avian genomes. We collected sequence data from UCE loci for 32 members of Neoaves and one outgroup (chicken) and analyzed data sets that differed in their amount of missing data. An alignment of 1,541 loci that allowed missing data was 87% complete and resulted in a highly resolved phylogeny with broad agreement between the Bayesian and maximum-likelihood (ML) trees. Although results from the 100% complete matrix of 416 UCE loci were similar, the Bayesian and ML trees differed to a greater extent in this analysis, suggesting that increasing from 416 to 1,541 loci led to increased stability and resolution of the tree. Novel results of our study include surprisingly close relationships between phenotypically divergent bird families, such as tropicbirds (Phaethontidae) and the sunbittern (Eurypygidae) as well as between bustards (Otididae) and turacos (Musophagidae). This phylogeny bolsters support for monophyletic waterbird and landbird clades and also strongly supports controversial results from previous studies, including the sister relationship between passerines and parrots and the non-monophyly of raptorial birds in the hawk and falcon families. Although significant challenges remain to fully resolving some of the deep relationships in Neoaves, especially among lineages outside the waterbirds and landbirds, this study suggests that increased data will yield an increasingly resolved avian phylogeny." ]

[ "Phycobilisomes are aggregates of light-harvesting proteins attached to the stroma side of the thylakoid membranes of the cyanobacteria (blue-green algae) and red algae. The water-soluble phycobiliproteins, of which there are three major groups, tetrapyrrole chromophores covalently bound to apoprotein. Several additional protiens are found within the phycobilisome and serve to link the phycobiliproteins to each other in an ordered fashion and also to attach the phycobilisome to the thylakoid membrane. Excitation energy absorbed by phycoerythrin is transferred through phycocyanin to allophycocyanin with an efficiency approximating 100%. This pathway of excitation energy transfer, directly confirmed by time-resolved spectroscopic measurements, has been incorporated into models describing the ultrastructure of the phycobilisome. The model for the most typical type of phycobilisome describes an allophycocyanin-containing core composed of three cylinders arranged so that their longitudinal axes are parallel and their ends form a triangle. Attached to this core are six rod structures which contain phycocyanin proximal to the core and phycoerythrin distal to the core. The axes of these rods are perpendicular to the longitudinal axis of the core. This arrangement ensures a very efficient transfer of energy. The association of phycoerythrin and phycocyanin within the rods and the attachment of the rods to the core and the core to the thylakoid require the presence of several 'linker' polypeptides. It is recently possible to assemble functionally and structurally intact phycobilisomes in vitro from separated components as well as to reassociate phycobilisomes with stripped thylakoids. Understanding of the biosynthesis and in vivo assembly of phycobilisomes will be greatly aided by the current advances in molecular genetics, as exemplified by recent identification of several genes encoding phycobilisome components.Combined ultrastructural, biochemical and biophysical approaches to the study of cyanobacterial and red algal cells and isolated phycobilisome-thylakoid fractions are leading to a clearer understanding of the phycobilisome-thylakoid structural interactions, energy transfer to the reaction centers and regulation of excitation energy distribution. However, compared to our current knowledge concerning the structural and functional organization of the isolated phycobilisome, this research area is relatively unexplored.", "To launch an effective antiviral immune response, cells must recognize the virus, activate a cytokine response, and initiate inflammatory processes. Herpes simplex virus 1 (HSV-1) and HSV-2 are nuclear-replicating viruses composed of a double-stranded DNA genome plus glycoproteins that are incorporated into a lipid bilayer envelope that surrounds an icosahedral capsid. Several novel receptors that mediate innate recognition of HSV and that activate the innate immune response have been identified in recent years. The host-virus interactions that lead to type I interferon (IFN), type III IFN, and cytokine production include cellular recognition of viral envelope and structural proteins, recognition of viral genomic DNA and recognition of virus-derived double-stranded RNAs. Such RNAs can interact with cellular pattern-recognition receptors, including Toll-like receptors and a number of cytoplasmic and nuclear receptors for virus DNA and virus-derived RNAs. In this review, I present a systematic overview of innate cellular recognition of HSV infection that leads to immune activation, and I discuss the implications of the known cell-host interactions. In addition, I discuss the use of innate stimulation to improve anti-HSV treatment and vaccine response and I discuss future research aims.", "Glycosylphosphatidylinositol anchored proteins (GPI-APs) represent a class of soluble proteins attached to the external leaflet of the plasma membrane by a post-translation modification, the GPI anchor. The 28 genes currently involved in the synthesis and remodelling of the GPI anchor add to the ever-growing class of congenital glycosylation disorders. Recent advances in next generation sequencing technology have led to the discovery of Mabry disease and CHIME syndrome genetic aetiology. Moreover, with each described mutation known phenotypes expand and new ones emerge without clear genotype-phenotype correlation. A protein database search was made for human GPI-APs with defined pathology to help building-up a physio-pathological mechanism from a clinical perspective. GPI-APs function in vitamin-B6 and folate transport, nucleotide metabolism and lipid homeostasis. Defining GPI-APs role in disease bears significant clinical implications.", "Andersen syndrome is a rare entity and comprises potassium sensitive periodic paralysis, ventricular arrhythmia, and an unusual facial appearance; syncope and sudden death have also been reported. The recognition of the characteristic face permits an early diagnosis in order to detect the severe systemic manifestations that are associated with this syndrome. The genetic defect is not linked to any other form of potassium sensitive periodic paralysis nor is it related to that of the long QT syndrome; nevertheless, a prolonged QT interval can be detected in a significant proportion of the cases. Sixteen cases of this syndrome have been described. We report on a three-generation family with 10 affected members. To our knowledge, this is the largest number of cases reported in one family. We noted some additional minor anomalies such as broad forehead and malar hypoplasia. Our patients had variable expression in the classical triad and of the severity of the systemic manifestations. Five of 8 affected studied members did not have a long QTc, which has been suggested as a constant finding in this syndrome.", "Skin Therapy Letter © (ISSN 1201–5989) Copyright 2019 by SkinCareGuide.com Ltd. Skin Therapy Letter © is published 6 times annually by SkinCareGuide.com Ltd, 1003 - 1166 Alberni Street, Vancouver, British Columbia, Canada, V6E 3Z3. All rights reserved. Reproduction in whole or in part by any process is strictly forbidden without prior consent of the publisher in writing. While every effort is made to see that no inaccurate or misleading data, opinion, or statement appears in the Skin Therapy Letter ©, the Publishers and Editorial Board wish to make it clear that the data and opinions appearing in the articles herein are the responsibility of the contributor. Accordingly, the Publishers, the Editorial Committee and their respective employees, officers, and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion, or statement. While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and techniques involving drug usage, and described herein, should only be followed in conjunction with the drug manufacturer’s own published literature.", "In eukaryotes, the glycosylphosphatidylinositol (GPI) modification of many glycoproteins on the cell surface is highly conserved. The lipid moieties of GPI-anchored proteins undergo remodelling processes during their maturation. To date, the products of the PER1, GUP1 and CWH43 genes of the yeast Saccharomyces cerevisiae have been shown to be involved in the lipid remodelling. Here, we focus on the putative GPI remodelling pathway in the methylotrophic yeast Ogataea minuta. We found that the O. minuta homologues of PER1, GUP1 and CWH43 are functionally compatible with those of S. cerevisiae. Disruption of GUP1 or CWH43 in O. minuta caused a growth defect under non-permissive conditions. The O. minuta per1Δ mutant exhibited a more fragile phenotype than the gup1Δ or cwh43Δ mutants. To address the role of GPI modification in O. minuta, we assessed the effect of these mutations on the processing and localization of the O. minuta homologues of the Gas1 protein; in S. cerevisiae, Gas1p is an abundant and well-characterized GPI-anchored protein. We found that O. minuta possesses two copies of the GAS1 gene, which we designate GAS1A and GAS1B. Microscopy and western blotting analysis showed mislocalization and/or lower retention of Gas1Ap and Gas1Bp within the membrane fraction in per1Δ or gup1Δ mutant cells, suggesting the significance of lipid remodelling for GPI-anchored proteins in O. minuta. Localization behaviour of Gas1Bp differed from that of Gas1Ap. Our data reveals, for the first time (to our knowledge), the existence of genes related to GPI anchor remodelling in O. minuta cells.", "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.", "p300, a transcriptional co-activator with histone acetyl transferase (HAT) activity, plays an essential role in the pathogenesis of cardiomyocyte hypertrophy in response to multiple pro-hypertrophic stimuli including hyperglycemia. However, the precise mechanisms by which p300 expression is regulated remain unclear. The purpose of this study was to investigate the role of miR-150, a potential p300-targeting microRNA (miRNA), in the post-transcriptional control of p300 expression and cardiomyocyte hypertrophy induced by high glucose. We observed that the expression of miR-150 was significantly reduced, whereas the expression of p300 was strongly elevated, concomitant with cardiomyocyte hypertrophy, in the hearts of diabetic rats compared with normal controls. Similar alterations were observed in neonatal rat cardiomyocytes that had been exposed to high levels of glucose. miR-150 mimics inhibited p300 3'-UTR luciferase reporter activity, as well as endogenous p300 expression. In addition, miR-150 mimics prevented glucose-induced cardiomyocyte hypertrophy. Co-transfection with a p300 expression vector and miR-150 mimics reversed the protective effect of miR-150 on cardiomyocyte hypertrophy. We further showed that the high glucose-mediated activation of PKCβ(2) in turn mediated the down-regulation of miR-150 expression. These data demonstrated a novel upstream role for miR-150 in p300-mediated cardiomyocyte hypertrophy and revealed a previously uncharacterized miRNAs and HATs cross-talk mechanism for the hypertrophic phenotype induced by high glucose.", "Glycosylphosphatidylinositol (GPI) anchoring of proteins is a conserved posttranslational modification in the endoplasmic reticulum (ER). Soon after GPI is attached, an acyl chain on the GPI inositol is removed by post-GPI attachment to proteins 1 (PGAP1), a GPI-inositol deacylase. This is crucial for switching GPI-anchored proteins (GPI-APs) from protein folding to transport states. We performed haploid genetic screens to identify factors regulating GPI-inositol deacylation, identifying seven genes. In particular, calnexin cycle impairment caused inefficient GPI-inositol deacylation. Calnexin was specifically associated with GPI-APs, dependent on N-glycan and GPI moieties, and assisted efficient GPI-inositol deacylation by PGAP1. Under chronic ER stress caused by misfolded GPI-APs, inositol-acylated GPI-APs were exposed on the cell surface. These results indicated that N-glycans participate in quality control and temporal ER retention of GPI-APs, ensuring their correct folding and GPI processing before exiting from the ER. Once the system is disrupted by ER stress, unprocessed GPI-APs become exposed on the cell surface.", "In the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related chemicals, the Ah receptor nuclear translocator (Arnt) forms a heterodimeric complex with the ligand-bound Ah receptor, leading to recognition of dioxin-responsive elements within the enhancer of the CYP1A1 gene and transcription activation by an unknown mechanism. To understand the role of Arnt in transcription activation by the Ah receptor-Arnt heterodimer, we performed a deletion analysis of Arnt to locate domains that are directly involved in transcription activation. We showed that the C-terminal 34 amino acids of Arnt encode a transcription activation domain (TAD) that functions independently of other sequences in the Ah receptor complex when attached to the heterologous Gal4 DNA binding domain. Deletion of the C-terminal acidic-rich 14 amino acids completely abolishes activity. Sequences important in Arnt TAD function were independent of the glutamine-rich region which is an important structural feature in the TAD of other transcription factors. The strength of the Arnt TAD when compared with the strong TAD from the herpes simplex virus VP16 protein was cell-type specific. Both the Arnt and VP16 TAD were equally strong in COS-1 cells, but the Arnt TAD had weak activity in an Arnt-deficient mouse hepatoma cell line and was not needed for restoration of CYP1A1 activation. These results imply that for CYP1A1 activation the Ah receptor provides the dominant activation function for the heterodimer in hepatoma cells. The potential of the Arnt TAD to contribute to activation by the Ah receptor complex is likely determined by availability or activity of cell-specific factors with which the TAD interacts.", "Glycosylphosphatidylinositols (GPIs) are lipid anchors allowing the exposure of proteins at the outer layer of the plasma membrane. In fungi, a number of GPI-anchored proteins (GPI-APs) are involved in the remodeling of the cell wall polymers. GPIs follow a specific biosynthetic pathway in the endoplasmic reticulum. After the transfer of the protein onto the GPI-anchor, a lipid remodeling occurs to substitute the diacylglycerol moiety by a ceramide. In addition to GPI-APs, A. fumigatus produces a GPI-anchored polysaccharide, the galactomannan (GM), that remains unique in the fungal kingdom. To investigate the role of the GPI pathway in the biosynthesis of the GM and cell wall organization, the deletion of PER1-coding for a phospholipase required for the first step of the GPI lipid remodeling-was undertaken. Biochemical characterization of the GPI-anchor isolated from GPI-APs showed that the PER1 deficient mutant produced a lipid anchor with a diacylglycerol. The absence of a ceramide on GPI-anchors in the Δper1 mutant led to a mislocation of GPI-APs and to an alteration of the composition of the cell wall alkali-insoluble fraction. On the other hand, the GM isolated from the Δper1 mutant membranes possesses a ceramide moiety as the parental strain, showing that GPI anchor of the GM follow a distinct unknown biosynthetic pathway.", "It has been claimed that synonymous sites in mammals are under selective constraint. Furthermore, in many studies the selective constraint at such sites in primates was claimed to be more stringent than that in rodents. Given the larger effective population sizes in rodents than in primates, the theoretical expectation is that selection in rodents would be more effective than that in primates. To resolve this contradiction between expectations and observations, we used processed pseudogenes as a model for strict neutral evolution, and estimated selective constraint on synonymous sites using the rate of substitution at pseudosynonymous and pseudononsynonymous sites in pseudogenes as the neutral expectation. After controlling for the effects of GC content, our results were similar to those from previous studies, i.e., synonymous sites in primates exhibited evidence for higher selective constraint that those in rodents. Specifically, our results indicated that in primates up to 24% of synonymous sites could be under purifying selection, while in rodents synonymous sites evolved neutrally. To further control for shifts in GC content, we estimated selective constraint at fourfold degenerate sites using a maximum parsimony approach. This allowed us to estimate selective constraint using mutational patterns that cause a shift in GC content (GT ↔ TG, CT ↔ TC, GA ↔ AG, and CA ↔ AC) and ones that do not (AT ↔ TA and CG ↔ GC). Using this approach, we found that synonymous sites evolve neutrally in both primates and rodents. Apparent deviations from neutrality were caused by a higher rate of C → A and C → T mutations in pseudogenes. Such differences are most likely caused by the shift in GC content experienced by pseudogenes. We conclude that previous estimates according to which 20-40% of synonymous sites in primates were under selective constraint were most likely artifacts of the biased pattern of mutation.", "Time-related changes in the incidences of spontaneous neoplasms in skin (fibroma and keratoacanthoma), thyroid (C-cell and follicular cell adenomas/carcinomas), uterus (stromal polyp), testes (Leydig cell tumor) and hemolymphoreticular system (mesenteric lymph node hemangioma and malignant granular lymphocytic leukemia) were assessed statistically in Wistar, Sprague-Dawley and F344 rats employed by the BASF, Germany and major European contract research organizations over the last 20 years. Negative trends (5 out of 80 cases) were observed for skin fibromas in F344 males, for follicular cell adenomas in Han Wistar females and in Sprague-Dawley males and females, and for follicular cell carcinomas in Sprague-Dawley males. Positive trends (8 out of 80 cases) were observed for skin keratoacanthomas in Han Wistar males, for C-cell adenomas in BASF Wistar males and females, for stromal polyps in Han Wistar and Sprague-Dawley females, and for mesenteric lymph node hemangiomas in Han Wistar and Sprague-Dawley males and in BASF Wistar females. In 67 out of 80 cases there were no statistically significant trends. Tumor drift was not common but occurred far more often in outbred rat strains (Wistar and Sprague-Dawley) than in the inbred rat strain (F344). This observation suggests that tumor predisposition is genetically determined, that tumor drift is primarily caused by genetic drift and that non-genotoxic carcinogens operate by facilitating the expression of tumor predisposition in target cells.", "Alagille syndrome (AGS) is an autosomal dominant disorder characterized by five major symptoms: cholestasis, vertebral deformity, heart malformations, ocular defects and peculiar facial appearance. The previously described Jagged1 (JAG1) gene on chromosome 20p12 has been identified as being responsible for AGS. JAG1 encodes a transmembrane protein acting as ligand for the evolutionarily conserved Notch signaling pathway. Here we report 36 novel mutations in the JAG1 gene. We identified 12 novel deletions, 4 insertions, 8 missense, 7 nonsense and 5 splice site mutations. All mutations map to the sequence encoding the extracellular part of the Jagged1 protein. The mutations spread over the entire gene with slightly increased rates in exons 2 to 6 and exon 23 and 24. Eight novel missense mutations map to the Delta-Serrate-Lag2 (DSL) domain and adjacent sequences which are important for ligand-receptor interaction. Inheritance was determined in 27 families. Sixteen mutations (55%) were de novo and eleven mutations (45%) were transmitted. Altogether 226 different JAG1 mutations have been described in association with AGS, including our novel 36 mutations. AGS variants are spread over the entire gene with only a few mutations in exon 26. A relatively high number of mutations are clustered in exons 2 to 6. This sequence region shows high interspecies conservation and encodes the Notch receptor-binding region (DSL domain).", "BACKGROUND: Obesity is known to be associated with higher risks of cardiovascular disease, metabolic syndrome, and diabetes mellitus. Thyroid-stimulating hormone (TSHR) is the receptor for thyroid-stimulating hormone (TSH, or thyrotropin), the key regulator of thyroid functions. The expression of TSHR, once considered to be limited to thyrocytes, has been so far detected in many extrathyroidal tissues including liver and fat. Previous studies have shown that TSHR expression is upregulated when preadipocytes differentiate into mature adipocytes, suggestive of a possible role of TSHR in adipogenesis. However, it remains unclear whether TSHR expression in adipocytes is implicated in the pathogenesis of obesity.METHODS: In the present study, TSHR expression in adipose tissues from both mice and human was analyzed, and its association with obesity was evaluated.RESULTS: We here showed that TSHR expression was increased at both mRNA and protein levels when 3T3-L1 preadipocytes were induced to differentiate. Knockdown of TSHR blocked the adipocyte differentiation of 3T3-L1 preadipocytes as evaluated by Oil-red-O staining for lipid accumulation and by RT-PCR analyses of PPAR-γ and ALBP mRNA expression. We generated obesity mice (C57/BL6) by high-fat diet feeding and found that the TSHR protein expression in visceral adipose tissues from obesity mice was significantly higher in comparison with the non-obesity control mice (P < 0.05). Finally, the TSHR expression in adipose tissues was determined in 120 patients. The results showed that TSHR expression in subcutaneous adipose tissue is correlated with BMI (body mass index).CONCLUSION: Taken together, these results suggested that TSHR is an important regulator of adipocyte differentiation. Dysregulated expression of TSHR in adipose tissues is associated with obesity, which may involve a mechanism of excess adipogenesis.", "BRAF inhibitors elicit rapid antitumor responses in the majority of patients with BRAF(V600)-mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that mitogen-activated protein kinase reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification, and alternative splicing being most common. We also detected PI3K-PTEN-AKT-upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions in both core drug escape pathways were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma regrowth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, cotargeting of two core pathways as an essential strategy for durable responses." ]

[ "Prostaglandin endoperoxide H (PGH) synthases 1 and 2 are both membrane-associated proteins localized to the endoplasmic reticulum (ER) and nuclear envelope. The carboxyl terminal tetrapeptides of PGH synthases 1 and 2 are of the form -P/STEL. These sequences are similar to the -KDEL retention signal sequence characteristic of many proteins localized to the ER. To determine if the -PTEL sequence (residues 597-600) functions as an ER retention signal for ovine PGH synthase-1, we prepared and analyzed five mutants (L600N, L600R, L600V, E599Q, and delta 597), all having modifications that would be expected to alter the subcellular location of PGH synthase-1 if the -PTEL sequence were involved in ER targeting. Native ovine PGH synthase-1 and each of the five mutants were subcloned into the pSVT7 expression vector and were expressed transiently in cos-1 cells. The L600N, L600R, E599Q, and delta 597 mutants retained both cyclooxygenase and peroxidase activities. Moreover, when subjected to immunocytofluorescent staining, cos-1 cells expressing native and mutant enzymes showed similar patterns of fluorescence corresponding to ER and nuclear envelope localization. Finally, culture media bathing cos-1 cells transfected with native or mutant PGH synthases were tested for secreted PGH synthase-1 protein by Western blotting, but no PGH synthase-1 was detected in any of the culture media. Our results demonstrate that mutations in the C-terminal sequence-PTEL do not change the subcellular location of ovine PGH synthase-1. Thus, targeting of PGH synthase-1 to the ER can occur independent of its -PTEL sequence.", "The vast noncoding portion of the human genome harbors a rich array of functional elements and disease-causing regulatory variants. Recent high-throughput chromosome conformation capture studies have outlined the principles of these elements interacting and regulating the expression of distal target genes through three-dimensional (3D) chromatin looping. Here we present 3DSNP, an integrated database for annotating human noncoding variants by exploring their roles in the distal interactions between genes and regulatory elements. 3DSNP integrates 3D chromatin interactions, local chromatin signatures in different cell types and linkage disequilibrium (LD) information from the 1000 Genomes Project. 3DSNP provides informative visualization tools to display the integrated local and 3D chromatin signatures and the genetic associations among variants. Data from different functional categories are integrated in a scoring system that quantitatively measures the functionality of SNPs to help select important variants from a large pool. 3DSNP is a valuable resource for the annotation of human noncoding genome sequence and investigating the impact of noncoding variants on clinical phenotypes. The 3DSNP database is available at http://biotech.bmi.ac.cn/3dsnp/.", "OBJECTIVE: Given recent reports about the off-label use of modafinil as an adjuvant for the treatment of antipsychotic-associated sedation in schizophrenia patients and the recent interest in its putative cognitive-enhancing effects in this population, we present a systematic review of available data on trials of modafinil as an adjuvant in the treatment of cognitive deficits, negative symptoms, and antipsychotic-induced fatigue, and its tolerability.DATA SOURCES: PubMed was searched for trials published in English up to January 2008 evaluating modafinil's effects on fatigue, negative symptoms, and cognition in schizophrenia with combinations of the following terms: schizophrenia, modafinil, cognition, negative symptoms, and fatigue.STUDY SELECTION: Six trials were identified: 2 randomized, prospective, double-blind placebo-controlled trials; 3 randomized, prospective, double-blind placebo-controlled crossover trials; and 1 open-label pilot study. Case series and case reports were excluded in the data analysis, except to identify potential adverse reactions to modafinil.DATA EXTRACTION: Studies were examined for number of subjects, trial duration, design, dosing, and outcomes with respect to sedation, negative symptoms, cognitive function, and tolerability.RESULTS: One of 4 reviewed studies found a significant effect of modafinil as an alerting agent for antipsychotic-induced fatigue and sedation. Neither of 2 reviewed studies found modafinil to improve negative symptoms of schizophrenia. Three of 6 reviewed studies showed that modafinil may improve short-term memory, attention, and the ability to shift mental sets. Two neuroimaging studies identified functional correlates in areas associated with working memory functions. The main adverse effect was found to be a small risk of psychosis exacerbation, which was seen in 5 of 83 patients (6.0%) in the active treatment groups as compared to 2 of 70 patients (2.9%) in the placebo groups.CONCLUSIONS: While the available data suggest that modafinil is generally well tolerated and may have some efficacy in the treatment of antipsychotic-induced sedation and cognitive domains, the small sample sizes, contradictory results, and methodological differences between trials, especially with respect to cognitive testing, make it difficult to draw firm conclusions about the overall effectiveness of modafinil as an adjunct in the treatment of schizophrenia. Well-powered, prospective, randomized placebo-controlled trials using the MATRICS battery concomitantly with functional outcome measures are necessary to elucidate modafinil's efficacy and effectiveness as an adjunctive treatment for sedation, negative symptoms, and cognitive deficits in schizophrenia. Hence, before prescribing modafinil to a schizophrenia patient, the possible risks and benefits of each particular case should be evaluated.", "Twenty-four hours after a tetracycline injection, the unimpeded, and more rapidly erupting, mouse mandibular incisor contained 20% to 44% more tetracycline than the contralateral, uncut incisor. It was concluded that the increased tetracycline incorporation reflected a higher rate of mineralization associated with faster tooth formation in the unimpeded tooth. By measuring the amount of tetracycline which became incorporated at different times after an incisor was shortened, it was possible to investigate an early stage of the response of the incisor to cutting. A significant increase in the capacity of the tooth to incorporate tetracycline was detectable 4 h after shortening the tooth, and this was maximal after another 4 h.", "The article describes the controversy about the question whether statutory social health insurances are obliged to reimburse the costs for the treatment of erectile dysfunction. Next to the question whether the 'Bundesausschuss der Arzte und Krankenkassen' was entitled to decide it was highly controversial whether erectile dysfunction is a disease according to the laws of social insurance. This enforces more general considerations regarding the possibility to define disease and the relevancy of a concept of disease for the justification and limitation of socially financed services in medicine.", "OBJECTIVE: To explore what considerations patients have when deciding about disease-modifying antirheumatic drugs (DMARDs) and what information patients need to participate in the decision-making process.METHODS: In-depth face-to-face interviews were conducted with 32 patients with inflammatory arthritis who recently consulted their rheumatologist and discussed initiating DMARDs.RESULTS: Beliefs in the necessity of DMARDs, either for relief of symptoms or prevention of future joint damage, were reasons to initiate DMARDs. Furthermore, trust in the rheumatologist and the health care system was important in this respect. Patients expressed many concerns about initiating DMARDS. These related to the perceived aggressive and harmful nature of DMARDs, potential (or unknown) side effects, influence on fertility and pregnancy, combination with other medicines, time to benefit, and manner of administration. Participants also worried about the future regarding long-term medication use and drug dependency, and if a medicine proved to be ineffective, about the risks of future treatments and running out of options. To decrease uncertainty, participants wanted to be informed about multiple treatment options, both current and future. They not only wanted clinical information but also information on how the medications could affect their daily lives.CONCLUSION: Health education should inform patients about multiple treatment options, for the present as well as for the future. It should enable patients to compare treatments with regard to both clinical aspects as well as possible consequences for their daily lives.", "PURPOSE: Endostatin, a peptide derived from proteolysis of collagen XVIII, is an endogenous inhibitor of angiogenesis and tumor growth. We have synthesized five peptide fragments designed to cover the whole length of the endostatin molecule (containing 40-50 amino acids each) with the aim of exploring the possibility that a specific sequence within the molecule might be responsible for its antiangiogenic effects.EXPERIMENTAL DESIGN: The five peptide sequences, termed fragments I, II, III, IV, and IVox, the latter bearing the original disulfide bond Cys(135)-Cys(165), were investigated for their effects on cultured endothelial cells, on enzyme activities related to angiogenesis, on tube formation in three-dimensional gel matrices, in vivo in the avascular rabbit cornea assay, and in an experimental tumor burden paradigm.RESULTS: Both the fragment covering the COOH-terminal endostatin region, fragment IV, and particularly fragment IVox, retained the angioinhibitory effects of endostatin. Fragment IVox strongly inhibited endothelial cell migration and proliferation, in vitro tube formation, and in vivo angiogenesis, displaying a potency comparable with that of endostatin. When tested in vivo on tumor growth, fragment IVox demonstrated to be more effective than full-length endostatin. Unexpectedly, fragment III exhibited proangiogenic activity, increasing endothelial cell migration, producing neovascularization to an extent similar to that of vascular endothelial growth factor, and enhancing the angiogenic response to vascular endothelial growth factor in the cornea assay. Peptides encompassing the NH(2)-terminal region of endostatin (fragments I and II) had negligible effects on angiogenesis.CONCLUSIONS: In view of these results, which show strikingly distinct profiles of endostatin fragments, we propose that the amino acid sequence of endostatin contains both angiosuppressive and angiostimulatory domains." ]

[ "PURPOSE OF REVIEW: Arterial tortuosity is emerging as a common feature in genetically mediated thoracic aortic disease that may be prognostic. This review will summarize recent literature on arterial tortuosity in the setting of genetic arteriopathies.RECENT FINDINGS: Although arterial tortuosity has been primarily described in Loeys-Dietz syndrome due to TGFBR1 and TGFBR2 mutations and in arterial tortuosity syndrome due to SLC210A mutations, recent studies that use quantitative measures of tortuosity suggest that tortuosity is present in many other genetic conditions associated with aortic dilation and dissection. The mechanisms of the development of tortuosity in these disorders are not fully understood, but are founded in the concept that there is abnormal, pathologic arterial lengthening in a fixed space, resulting in more tortuous vessels. Further studies suggest that patients with increased arterial tortuosity are at increased risk of adverse cardiovascular events, including aortic surgery, aortic dissection, and death.SUMMARY: Arterial tortuosity is commonly present in genetically mediated aortic disease. Given the suboptimal performance of aortic dimension alone in predicting aortic dissection, quantification of tortuosity may augment the current algorithms for determining risk in patients with aortic disease.", "The United Nations Millennium Development Goal of reversing the global spread of tuberculosis by 2015 has been offset by the rampant re-emergence of drug-resistant tuberculosis, in particular fluoroquinolone-resistant multidrug-resistant and extensively drug-resistant tuberculosis. After decades of quiescence in the development of antituberculosis medications, bedaquiline and delamanid have been conditionally approved for the treatment of drug-resistant tuberculosis, while several other novel compounds (AZD5847, PA-824, SQ109 and sutezolid) have been evaluated in phase II clinical trials. Before novel drugs can find their place in the battle against drug-resistant tuberculosis, linezolid has been compassionately used with success in the treatment of fluoroquinolone-resistant multidrug-resistant tuberculosis. This review largely discusses six novel drugs that have been evaluated in phase II and III clinical trials, with focus on the clinical evidence for efficacy and safety, potential drug interactions, and prospect for using multiple novel drugs in new regimens.", "All viruses target host cell factors for successful life cycle completion. Transcriptional control of DNA viruses by host cell factors is important in the temporal and spatial regulation of virus gene expression. Many of these factors are recruited to enhance virus gene expression and thereby increase virus production, but host cell factors can also restrict virus gene expression and productivity of infection. CCCTC binding factor (CTCF) is a host cell DNA binding protein important for the regulation of genomic chromatin boundaries, transcriptional control and enhancer element usage. CTCF also functions in RNA polymerase II regulation and in doing so can influence co-transcriptional splicing events. Several DNA viruses, including Kaposi's sarcoma-associated herpesvirus (KSHV), Epstein-Barr virus (EBV) and human papillomavirus (HPV) utilize CTCF to control virus gene expression and many studies have highlighted a role for CTCF in the persistence of these diverse oncogenic viruses. CTCF can both enhance and repress virus gene expression and in some cases CTCF increases the complexity of alternatively spliced transcripts. This review article will discuss the function of CTCF in the life cycle of DNA viruses in the context of known host cell CTCF functions.", "Neurofibromatosis type 1 (NF1) is caused by deletions, insertions, translocations, and point mutations in the NF1 gene, which spans 350 kb on the long arm of human chromosome 17. Although several point mutations have been described, large molecular abnormalities have rarely been characterized in detail. We describe here the molecular breakpoints of a 12-kb deletion of the NF1 gene, which is responsible for the NF1 phenotype in a kindred with two children affected because of germline mosaicism in the unaffected father, who has the mutation in 10% of his spermatozoa. The mutation spans introns 31-39, removing 12,021 nt and inserting 30 bp, of which 19 bp are a direct repetition of a sequence located in intron 31, just 4 bp before the 5' breakpoint. The 5' and 3' breakpoints contain the sequence TATTTTA, which could be involved in the generation of the deletion. The most plausible explanation for the mechanism involved in the generation of this 12-kb deletion is homologous/nonhomologous recombination. Since sperm of the father does not contain the corresponding insertion of the 12-kb deleted sequence, this deletion could have occurred within the NF1 chromosome through loop formation. RNA from lymphocytes of one of the NF1 patients showed similar levels of the mutated and normal transcripts, suggesting that the NF1-mRNA from mutations causing frame shifts of the reading frame or stop codons in this gene is not degraded during its processing. The mutation was not detected in fresh lymphocytes from the unaffected father by PCR analysis, supporting the case for true germ-line mosaicism.", "Hypersomnia (excessive sleepiness) refers to an increased sleep propensity with a subjective craving for sleep, involuntary naps and \"sleep attacks\" during the day and/or prolonged nighttime sleep with sleep drunkeness. Excessive sleepiness should be separated from fatigue and lack of energy associated with a variety of medical and psychiatric diseases. Hypersomnia is reported by 2-5% of the adult population and can lead to poor work, accidents and neuropsychiatric disturbances. Sleep apnea syndrome (SAS), narcolepsy, chronic sleep deprivation (insufficiency), and restless legs/periodic limb movements in sleep syndrome (RLS/PLMS) represent the most common causes of hypersomnia. The diagnosis of these conditions can often be suspected on clinical grounds. However, an overnight polysomnography and a multiple sleep latency test are often additionally required for definite diagnosis. Treatment options include nasal CPAP for SAS, stimulants for narcolepsy, sleep prolongation for sleep insufficiency, and dopaminergic agents for RLS/PLMS.", "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.", "Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Mutations of the ELA2 gene encoding neutrophil elastase (NE) are responsible for most cases of SCN and cyclic neutropenia (CN), a related but milder disorder of granulopoiesis. However, the mechanisms by which these mutations disrupt granulopoiesis are unclear. We hypothesize that the ELA2 mutations result in the production of misfolded NE protein, activation of the unfolded protein response (UPR), and ultimately apoptosis of granulocytic precursors. Expression of mutant NE but not wild-type NE strongly induced BiP/GRP78 mRNA expression and XBP1 mRNA splicing, 2 classic markers of the UPR. The magnitude of UPR activation by a specific ELA2 mutation correlated with its associated clinical phenotype. Consistent with the UPR model, expression of mutant NE in primary human granulocytic precursors increased expression of CHOP (DDITS) and induced apoptosis in a protease-independent fashion. Most strikingly, UPR activation and decreased NE protein expression were detected in primary granulocytic precursors from SCN patients. Collectively, these data provide strong support for a UPR model of SCN disease pathogenesis and place SCN in a growing list of human diseases caused by misfolded proteins." ]

[ "OBJECTIVE: To evaluate the predictive value of the Tokuhashi revised scoring system for the life expectancy of patients with spinal metastases.METHODS: A retrospective review of 447 patients with spinal metastases was performed, which comprised 291 men and 156 women with a mean age of 56. 1 years. All of the patients were scored with the Tokuhashi revised scoring system based on the available clinical, pathological and radiographic data. The relation between the survival time and the Tokuhashi revised score was analyzed.RESULTS: The patients had a median survival time of 7. 9 months and a mean Tokuhashi revised score of 8. 23 points. The median survival time of 155 patients with high grade primary tumor of lung, liver, gastrointestinal tract, esophagus, bladder and pancreas was 4. 7 months. The median survival time of 146 patients with low grade primary tumor of thyroid, breast and prostate was 12 months. The median survival time of 146 patients with medium grade primary tumor of kidney, lymphoma, ovary and uterus, and unknown primary tumor was 7. 1 months. The median survival time of 211 patients with the Tokuhashi revised score of 0 to 8 points was 4 months. The median survival time of 147 patients with the Tokuhashi revised score of 9 to 11 points was 10 months. The median survival time of 89 patients with the Tokuhashi revised score of 12 to 15 points was 29 months. The differences between the groups were significant (P<0. 01 or 0. 0001). The Tokuhashi revised score was positively correlated with survival time (r=0. 833, P<0. 001).CONCLUSION: The Tokuhashi revised score could support decision making with reliable estimation of life expectancy of patients with spinal metastases. Surgery could be a better choice to extend life span for those patients with solitary spinal metastasis of slow-growth primary tumor and those with the Tokuhashi revised score of 12 to 15 points.", "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.", "Studies on the relationship between thyroid stimulating hormone (TSH) within the reference range and coronary artery disease (CAD) have produced conflicting results. Furthermore, the effect of age on this relationship has never been explored. The aim of this study was to investigate the association between TSH levels and CAD among euthyroid subjects and whether age influenced this relationship. A total of 318 subjects who underwent coronary angiography were included. Serum TSH, T3, T4, lipid, blood glucose and creatinine levels were measured and compared between the groups with and without CAD. Age-stratified analysis and multivariate logistic regression analysis were performed. Levels of TSH, T3 and T4 did not differ significantly between CAD (n=196) and non-CAD group (n=122) (TSH: 1.77 ± 0.99 vs 1.89 ± 0.98 mIU/L, T3: 1.45 ± 0.36 vs 1.51 ± 0.35 nmol/L, T4: 100.06 ± 20.49 vs 103.95 ± 24.06 nmol/L, respectively) when comparisons were performed among all subjects. A significant between-group difference in levels of TSH was observed among subjects less than or equal to 65 years old (CAD group: n=121, non-CAD group: n=106), with higher TSH levels in CAD group (2.03 ± 0.94 vs 1.75 ± 0.97 mIU/L, adjusted p=0.024). Multivariate logistic regression analysis revealed that elevated level of TSH was an independent predictor for CAD (odds ratio: 1.512, p=0.011). No significant between-group difference in TSH levels was observed among subjects older than 65 years (CAD group: n=75, non-CAD group: n=16). The results showed that higher levels of TSH within the reference range were independently associated with the presence of CAD only among subjects less than or equal to 65 years old, suggesting age might influence the relationship.", "IMPORTANCE: Ocular/oculodermal (oculo[dermal]) melanocytosis is a congenital periocular pigmentary condition that can lead to the development of uveal melanoma, estimated at 1 in 400 affected patients. In this study, patients with melanocytosis who developed uveal melanoma were found to have double the risk for metastasis compared with those without melanocytosis.OBJECTIVE: To determine the relationship of oculo(dermal) melanocytosis to the prognosis of patients with uveal melanoma.DESIGN, SETTING, AND PATIENTS: Retrospective chart review of 7872 patients with uveal melanoma treated at the Ocular Oncology Service, Wills Eye Institute, from August 25, 1970, through August 27, 2008.EXPOSURES: Enucleation, plaque radiotherapy, local resection, or thermotherapy.MAIN OUTCOMES AND MEASURES: Metastasis and death.RESULTS: Of 7872 patients with uveal melanoma, oculo(dermal) melanocytosis was present in 230 (3%). The melanocytosis involved the sclera (92%), iris (17%), choroid (12%), eyelid (8%), and temporal fossa (1%). Eyes with melanoma and oculo(dermal) melanocytosis had a relative risk for metastasis 1.6 times greater compared with those with no melanocytosis (P < .001). Metastasis of uveal melanoma was 2.8 times higher in patients with iris melanocytosis (P < .001), 2.6 times higher with choroidal melanocytosis (P = .02), and 1.9 times higher with scleral melanocytosis (P < .001). By Kaplan-Meier estimates, metastasis in patients with oculo(dermal) melanocytosis vs no melanocytosis was 2% vs 1.8% at 1 year, 27% vs 15% at 5 years, and 48% vs 24% at 10 years (P < .001). By multivariable analysis, the factors predictive of metastasis in patients harboring uveal melanoma associated with oculo(dermal) melanocytosis were increased tumor thickness (P = .001) and the presence of subretinal fluid (P = .05), and the only factor predictive of death was increased tumor thickness (P = .009). CONCLUSIONS AND RELEVANCE Patients with uveal melanoma associated with oculo(dermal) melanocytosis have double the risk for metastasis compared with those with no melanocytosis. All patients with oculo(dermal) melanocytosis should undergo ophthalmic examination and imaging on a twice-yearly basis because this could help with the early detection of melanoma.", "Nucleosomes are implicated in transcriptional regulation as well as in packing and stabilizing the DNA. Nucleosome positions affect the transcription by impeding or facilitating the binding of transcription factors. The DNA sequence, especially the periodic occurrences of dinucleotides, is a major factor that affects the nucleosome positioning. We analyzed the Drosophila DNA sequences bound by H2A and H2A.Z nucleosomes. Periodic patterns of dinucleotides (weak-weak/strong-strong or purine-purine/pyrimidine-pyrimidine) were identified as WW/SS and RR/YY nucleosome positioning sequence (NPS) patterns. The WW/SS NPS pattern of the H2A nucleosome has a 10-bp period of weak-weak/strong-strong (W = A or T; S = G or C) dinucleotides. The 10-bp periodicity, however, is disrupted in the middle of the sequence. At the dyad, the SS dinucleotide is preferred. On the other hand, the RR/YY NPS pattern has an 18-bp periodicity of purine-purine/pyrimidine-pyrimidine (R = A or G; Y = T or C) dinucleotides. The NPS patterns from H2A.Z nucleosomes differ from the NPS patterns from H2A nucleosomes. The RR/YY pattern of H2A.Z nucleosomes has major peaks shifted by 10 bp deviated from the H2A nucleosome pattern. The H2A and H2A.Z nucleosomes have different sequence preferences. The shifted peaks coincide with DNA regions interacting with the histone loops.", "Tuberculosis is very much rampant in our society and accounts for a large number of deaths annually. In spite of consistent efforts being made, the disease has not been curtailed yet. The emergence of MDR and XDR strains in the society along with an increase in the number of HIV cases and that of latent TB, have further aggravated the problem making the disease very much persistent. The current situation clearly manifests the need to discover and develop new potent molecules/approaches that could help to tackle drug resistance. Various molecules, such as derivatives of fluoroquinolones (e.g. gatifloxacin, moxifloxacin and DC-159a), rifamycins (rifapentine), oxazolidinones (linezolid, sutezolid/PNU-100480), diarylquinolines (TMC207/bedaquiline), antifungal azoles, pyrrole (LL3858), nitroimidazopyran (PA824), nitroimidazole (OPC67683, TBA-354), diamine (SQ109) and benzothiazinone (BTZ043) are being developed in an attempt to combat the disease. This review presents a general introduction to the current status of the disease, the biology of the pathogen as well as the state of drug development against tuberculosis (TB) with emphasis on the major problems and bottlenecks associated with the same. Starting from the first drug against TB, the review discusses the entire history and the course of development of the drugs which are available today in the market as well as those which are under various phases of clinical and pre-clinical trials along with their mechanism of action. It also talks about the possible role of nanosciences in combating TB.", "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." ]

[ "We have investigated in detail the interactions between the Escherichia coli mutT, mutM, and mutY error-prevention systems. Jointly, these systems protect the cell against the effects of the oxidative stress product, 8-oxoguanine (8-oxoG), a base analog with ambiguous base-pairing properties, pairing with either A or C during DNA synthesis. mutT mutator strains display a specific increase in A.T-->C.G transversions, while mutM and mutY mutator strains show specific G.C-->T.A increases. To study in more detail the in vivo processing of the various mutational intermediates leading to A.T-->C.G and G.C-->T.A transversions, we analyzed defined A.T-->C.G and G.C-->T.A events in strains containing all possible combinations of these mutator alleles. We report three major findings. First, we do not find evidence that the mutT allele significantly increases G.C-->T.A transversions in either mut(+), mutM, mutY or mutMmutY backgrounds. We interpret this result to indicate that incorporation of 8-oxodGTP opposite template C may not be frequent relative to incorporation opposite template A. Second, we show that mutT-induced A.T-->C.G transversions are significantly reduced in strains carrying mutY and mutMmutY deficiencies suggesting that 8-oxoG, when present in DNA, preferentially mispairs with dATP. Third, the mutY and mutMmutY deficiencies also decrease A.T-->C.G transversions in the mutT(+) background, suggesting that, even in the presence of functional MutT protein, A.T-->C.G transversions may still result from 8-oxodGTP misincorporation.", "Animal models of focal ischaemia induced by middle cerebral artery occlusion (MCAO) provide most evidence for cellular inflammatory responses in stroke. Permanent MCAO results in a modest neutrophil infiltration at 24 h after ischaemia, predominantly around arterial vessels at the margins of infarction, whereas MCAO with subsequent reperfusion is associated with substantial infiltration by neutrophils throughout the entire infarct. Several studies show that C-reactive protein (CRP), an inflammatory marker, is associated with stroke outcomes and future vascular events. Several drugs, especially hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), have been demonstrated to reduce hsCRP levels independently of their effects on plasma cholesterol. Various cytokines were shown to be expressed in the injured brain. Recent investigations demonstrated that mRNAs of above cytokines were induced in the ischemic rat brain. TNF-alpha is a pleiotropic cytokine that mediates key roles in many physiological and pathological cellular processes including acute and chronic inflammation, programmed cell death or apoptosis, anti-tumor responses, and infection. Pharmaceutical industry to search a small molecule TNF inhibitor have taken multiple strategies. Significant protection after in vivo oral use of SB-239063 from brain injury and neurological deficits was observed in one study. In the same study significant protection from brain injury and neurological deficits was also demonstrated due to i.v post-stroke treatment with the same compound. Leukocyte-endothelial adhesion process consists of several steps, beginning with rolling of the leukocyte on the endothelial surface until it has slowed down to such a degree that it sticks to the endothelium. Treatment with a murine anti-ICAM-1 antibody (enlimomab) has been investigated in patients with acute ischemic stroke in the Enlimomab Acute Stroke Trial (EAST). Unfortunately, the case fatality rate in this trial was significantly higher in the enlimomab patient group than in the placebo group. Furthermore, experimental data have shown that focal cerebral ischemia induces a time-dependent activation of granulocytes, lymphocytes, and macrophages. Dissipation of ATP by CD39 reduced P2X7 receptor stimulation and thereby suppressed baseline leukocyte alphaMbeta2-integrin expression. As alphaMbeta2-integrin blockade reversed the postischemic, inflammatory phenotype of Cd39-/- mice, these data suggest that phosphohydrolytic activity on the leukocyte surface suppresses cell-cell interactions that would otherwise promote thrombosis or inflammation.", "BACKGROUND: The 28-joint Disease Activity Score (DAS28) combines scores on a 28-tender and swollen joint count (TJC28 and SJC28), a patient-reported measure for general health (GH), and an inflammatory marker (either the erythrocyte sedimentation rate [ESR] or the C-reactive protein [CRP]) into a composite measure of disease activity in rheumatoid arthritis (RA). This study examined the reliability of the DAS28 in patients with early RA using principles from generalizability theory and evaluated whether it could be increased by adjusting individual DAS28 component weights.METHODS: Patients were drawn from the DREAM registry and classified into a \"fast response\" group (N = 466) and \"slow response\" group (N = 80), depending on their pace of reaching remission. Composite reliabilities of the DAS28-ESR and DAS28-CRP were determined with the individual components' reliability, weights, variances, error variances, correlations and covariances. Weight optimization was performed by minimizing the error variance of the index.RESULTS: Composite reliabilities of 0.85 and 0.86 were found for the DAS28-ESR and DAS28-CRP, respectively, and were approximately equal across patients groups. Component reliabilities, however, varied widely both within and between sub-groups, ranging from 0.614 for GH (\"slow response\" group) to 0.912 for ESR (\"fast response\" group). Weight optimization increased composite reliability even further. In the total and \"fast response\" groups, this was achieved mostly by decreasing the weight of the TJC28 and GH. In the \"slow response\" group, though, the weights of the TJC28 and SJC28 were increased, while those of the inflammatory markers and GH were substantially decreased.CONCLUSIONS: The DAS28-ESR and the DAS28-CRP are reliable instruments for assessing disease activity in early RA and reliability can be increased even further by adjusting component weights. Given the low reliability and weightings of the general health component across subgroups it is recommended to explore alternative patient-reported outcome measures for inclusion in the DAS28.", "BACKGROUND: Web-based decision aids are known to have an effect on knowledge, attitude, and behavior; important components of informed decision making. We know what decision aids achieve in randomized controlled trials (RCTs), but we still know very little about how they are used and how this relates to the informed decision making outcome measures.OBJECTIVE: To examine men's use of an online decision aid for prostate cancer screening using website transaction log files (web-logs), and to examine associations between usage and components of informed decision making.METHODS: We conducted an observational web-log analysis of users of an online decision aid, Prosdex. Men between 50 and 75 years of age were recruited for an associated RCT from 26 general practices across South Wales, United Kingdom. Men allocated to one arm of the RCT were included in the current study. Time and usage data were derived from website log files. Components of informed decision making were measured by an online questionnaire.RESULTS: Available for analysis were 82 web-logs. Overall, there was large variation in the use of Prosdex. The mean total time spent on the site was 20 minutes. The mean number of pages accessed was 32 (SD 21) out of a possible 60 pages. Significant associations were found between increased usage and increased knowledge (Spearman rank correlation [rho] = 0.69, P < .01), between increased usage and less favorable attitude towards PSA testing (rho = -0.52, P < .01), and between increased usage and reduced intention to undergo PSA testing (rho = -0.44, P < .01). A bimodal distribution identified two types of user: low access and high access users.CONCLUSIONS: Increased usage of Prosdex leads to more informed decision making, the key aim of the UK Prostate Cancer Risk Management Programme. However, developers realistically have roughly 20 minutes to provide useful information that will support informed decision making when the patient uses a web-based interface. Future decision aids need to be developed with this limitation in mind. We recommend that web-log analysis should be an integral part of online decision aid development and analysis.TRIAL REGISTRATION: ISRCTN48473735; http://www.controlled-trials.com/ISRCTN48473735 (Archived by WebCite at http://www.webcitation.org/5pqeF89tS).", "Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among solid malignancies and improved therapeutic strategies are needed to improve outcomes. Patient-derived xenografts (PDX) and patient-derived organoids (PDO) serve as promising tools to identify new drugs with therapeutic potential in PDAC. For these preclinical disease models to be effective, they should both recapitulate the molecular heterogeneity of PDAC and validate patient-specific therapeutic sensitivities. To date however, deep characterization of the molecular heterogeneity of PDAC PDX and PDO models and comparison with matched human tumour remains largely unaddressed at the whole genome level. We conducted a comprehensive assessment of the genetic landscape of 16 whole-genome pairs of tumours and matched PDX, from primary PDAC and liver metastasis, including a unique cohort of 5 'trios' of matched primary tumour, PDX, and PDO. We developed a pipeline to score concordance between PDAC models and their paired human tumours for genomic events, including mutations, structural variations, and copy number variations. Tumour-model comparisons of mutations displayed single-gene concordance across major PDAC driver genes, but relatively poor agreement across the greater mutational load. Genome-wide and chromosome-centric analysis of structural variation (SV) events highlights previously unrecognized concordance across chromosomes that demonstrate clustered SV events. We found that polyploidy presented a major challenge when assessing copy number changes; however, ploidy-corrected copy number states suggest good agreement between donor-model pairs. Collectively, our investigations highlight that while PDXs and PDOs may serve as tractable and transplantable systems for probing the molecular properties of PDAC, these models may best serve selective analyses across different levels of genomic complexity.", "Methylation of lysine residues of histones is an important epigenetic mark that correlates with functionally distinct regions of chromatin. We present here the crystal structure of a ternary complex of the enzyme Pr-Set7 (also known as Set8) that methylates Lys 20 of histone H4 (H4-K20). We show that the enzyme is exclusively a mono-methylase and is therefore responsible for a signaling role quite distinct from that established by other enzymes that target this histone residue. We provide evidence from NMR for the C-flanking domains of SET proteins becoming ordered upon addition of AdoMet cofactor and develop a model for the catalytic cycle of these enzymes. The crystal structure reveals the basis of the specificity of the enzyme for H4-K20 because a histidine residue within the substrate, close to the target lysine, is required for completion of the active site. We also show how a highly variable component of the SET domain is responsible for many of the enzymes' interactions with its target histone peptide and probably also how this part of the structure ensures that Pr-Set7 is nucleosome specific.", "Gepotidacin is a first-in-class, novel triazaacenaphthylene antibiotic that inhibits bacterial DNA replication and has in vitro activity against susceptible and drug-resistant pathogens. Reference in vitro methods were used to investigate the MICs and minimum bactericidal concentrations (MBCs) of gepotidacin and comparator agents for Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli Gepotidacin in vitro activity was also evaluated by using time-kill kinetics and broth microdilution checkerboard methods for synergy testing and for postantibiotic and subinhibitory effects. The MIC90 of gepotidacin for 50 S. aureus (including methicillin-resistant S. aureus [MRSA]) and 50 S. pneumoniae (including penicillin-nonsusceptible) isolates was 0.5 μg/ml, and for E. coli (n = 25 isolates), it was 4 μg/ml. Gepotidacin was bactericidal against S. aureus, S. pneumoniae, and E. coli, with MBC/MIC ratios of ≤4 against 98, 98, and 88% of the isolates tested, respectively. Time-kill curves indicated that the bactericidal activity of gepotidacin was observed at 4× or 10× MIC at 24 h for all of the isolates. S. aureus regrowth was observed in the presence of gepotidacin, and the resulting gepotidacin MICs were 2- to 128-fold higher than the baseline gepotidacin MICs. Checkerboard analysis of gepotidacin combined with other antimicrobials demonstrated no occurrences of antagonism with agents from multiple antimicrobial classes. The most common interaction when testing gepotidacin was indifference (fractional inhibitory concentration index of >0.5 to ≤4; 82.7% for Gram-positive isolates and 82.6% for Gram-negative isolates). The postantibiotic effect (PAE) of gepotidacin was short when it was tested against S. aureus (≤0.6 h against MRSA and MSSA), and the PAE-sub-MIC effect (SME) was extended (>8 h; three isolates at 0.5× MIC). The PAE of levofloxacin was modest (0.0 to 2.4 h), and the PAE-SME observed varied from 1.2 to >9 h at 0.5× MIC. These in vitro data indicate that gepotidacin is a bactericidal agent that exhibits a modest PAE and an extended PAE-SME against Gram-positive and -negative bacteria and merits further study for potential use in treating infections caused by these pathogens." ]

[ "Contrary to long-held dogma, human milk is not sterile. Instead, it provides infants a rich source of diverse bacteria, particularly microbes belonging to the Staphylococcus, Streptococcus, and Pseudomonas genera. Very little is known about factors that influence variation in the milk microbiome among women and populations, although time postpartum, delivery mode, and maternal factors such as diet and antibiotic use might be important. The origins of the bacteria in milk are thought to include the maternal gastrointestinal tract (via an entero-mammary pathway) and through bacterial exposure of the breast during nursing. Currently, almost nothing is known about whether variation in microbe consumption by the infant via human milk and that of the mammary gland, itself, impacts short-term and/or long-term infant and maternal health although several studies suggest this is likely. We urge the clinical and public health communities to be patient, however, in order to allow human milk and lactation researchers to first understand what constitutes 'normal' in terms of the milk microbiome (as well as factors that impact microbial community structure) prior to jumping the gun to investigate if and how this important source of microbes impacts maternal and infant health.", "Combinatorial effects of epigenetic modifications on transcription activity have been proposed as \"histone codes\". However, it is unclear whether there also exist inter-nucleosomal communications among epigenetic modifications at single nucleosome level, and if so, what functional roles they play. Meanwhile, how clear nucleosome patterns, such as nucleosome phasing and depletion, are formed at functional regions remains an intriguing enigma. To address these questions, we developed a Bayesian network model for interactions among different histone modifications across neighboring nucleosomes, based on the framework of dynamic Bayesian network (DBN). From this model, we found that robust inter-nucleosomal interactions exist around transcription start site (TSS), transcription termination sites (TTS) or around CTCF binding sites; and these inter-nucleosomal interactions are often involved in transcription regulation. In addition to these general principles, DBN also uncovered a novel specific epigenetic interaction between H2A.Z and H4K20me1 on neighboring nucleosomes, involved in nucleosome free region (NFR) and nucleosome phasing establishment or maintenance. The level of negative correlation between neighboring H2A.Z and H4K20me1 strongly correlate with the size of NFR and the strength of nucleosome phasing around TSS. Our study revealed inter-nucleosomal communications as important players in signal propagation, chromatin remodeling and transcription regulation.", "At the initial stage of carcinogenesis, cell competition often occurs between newly emerging transformed cells and the neighboring normal cells, leading to the elimination of transformed cells from the epithelial layer. For instance, when RasV12-transformed cells are surrounded by normal cells, RasV12 cells are apically extruded from the epithelium. However, the underlying mechanisms of this tumor-suppressive process still remain enigmatic. We first show by electron microscopic analysis that characteristic finger-like membrane protrusions are projected from both normal and RasV12 cells at their interface. In addition, FBP17, a member of the F-BAR proteins, accumulates in RasV12 cells, as well as surrounding normal cells, which plays a positive role in the formation of finger-like protrusions and apical elimination of RasV12 cells. Furthermore, cdc42 acts upstream of these processes. These results suggest that the cdc42/FBP17 pathway is a crucial trigger of cell competition, inducing \"protrusion to protrusion response\" between normal and RasV12-transformed cells.", "Author information:(1)Department of Psychiatry, Program in Neuroscience, Rock Hall, University of California at San Francisco, San Francisco, CA 94158-2324, USA.(2)Division of Bioinformatics, Department of Biology, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.(3)Department of Functional Genomics, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA; Center for Neuroscience, University of California Davis, Davis, CA 95618, USA.(4)Department of Psychiatry, Program in Neuroscience, Rock Hall, University of California at San Francisco, San Francisco, CA 94158-2324, USA; PLOS, 1160 Battery Street, San Francisco, CA 94111, USA.(5)Department of Anatomy, Faculty of Medicine, University Murcia E-30100 and IMIB (Instituto Murciano de Investigación Biosanitaria), 30100 Murcia, Spain.(6)Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA 15213, USA.(7)Department of Psychiatry, Program in Neuroscience, Rock Hall, University of California at San Francisco, San Francisco, CA 94158-2324, USA; Acetylon Pharmaceuticals Inc., Boston, MA 02210, USA.(8)Allen Institute for Brain Science, Seattle, WA 98103, USA.(9)Department of Functional Genomics, 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.(10)Department of Psychiatry, Program in Neuroscience, Rock Hall, University of California at San Francisco, San Francisco, CA 94158-2324, USA. Electronic address: john.rubenstein@ucsf.edu.", "We have recently described an autosomal dominant hereditary inclusion body myopathy (h-IBM). Clinically it is is characterized by congenital joint contractures and slowly progressive, proximal muscle weakness and ophthalmoplegia. There is deterioration of muscle function between 30 and 50 years of age. While young patients show minor pathological changes in muscle, the middle-aged and old patients show rimmed vacuoles and inclusions of filaments measuring 15-18 nm in diameter. Except for the absence of significant inflammation the histopathology is similar to that found in sporadic inclusion body myositis (s-IBM). In s-IBM mitochondrial alterations including cytochrome c oxidase (COX) -deficient muscle fibers are common. These are due to multiple mitochondrial DNA (mtDNA) deletions. In this study we investigated the occurrence of mitochondrial alterations in autosomal dominant h-IBM. Young affected individuals showed no mitochondrial changes but three patients aged 38, 51 and 59 years, respectively, showed ragged red fibers and COX-deficient muscle fibers. Polymerase chain reaction analysis showed multiple mtDNA deletions. By in situ hybridization clonal expansions of mtDNA with deletions were demonstrated in COX-deficient muscle fibers. Most of the analyzed deletion breakpoints showed nucleotide repeats flanking the deletions. The results show that COX-deficient muscle fibers and somatic mtDNA deletions are present in this family with h-IBM. The same factors may be involved in the development of mtDNA deletions in s-IBM and this family with h-IBM.", "Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate with a topoisomerase I inhibitor exatecan derivative (DX-8951 derivative, DXd), has been reported to exert potent antitumor effects in xenograft mouse models and clinical trials. In this study, the immune system-activating ability of DS-8201a was assessed. DS-8201a significantly suppressed tumor growth in an immunocompetent mouse model with human HER2-expressing CT26.WT (CT26.WT-hHER2) cells. Cured immunocompetent mice rejected not only rechallenged CT26.WT-hHER2 cells, but also CT26.WT-mock cells. Splenocytes from the cured mice responded to both CT26.WT-hHER2 and CT26.WT-mock cells. Further analyses revealed that DXd upregulated CD86 expression on bone marrow-derived dendritic cells (DC) in vitro and that DS-8201a increased tumor-infiltrating DCs and upregulated their CD86 expression in vivo DS-8201a also increased tumor-infiltrating CD8+ T cells and enhanced PD-L1 and MHC class I expression on tumor cells. Furthermore, combination therapy with DS-8201a and anti-PD-1 antibody was more effective than either monotherapy. In conclusion, DS-8201a enhanced antitumor immunity, as evidenced by the increased expression of DC markers, augmented expression of MHC class I in tumor cells, and rejection of rechallenged tumor cells by adaptive immune cells, suggesting that DS-8201a enhanced tumor recognition by T cells. Furthermore, DS-8201a treatment benefited from combination with anti-PD-1 antibody, possibly due to increased T-cell activity and upregulated PD-L1 expression induced by DS-8201a. Mol Cancer Ther; 17(7); 1494-503. ©2018 AACR.", "CK2 is an essential protein kinase implicated in various cellular processes. In this study, we address a potential role of this kinase in chromatin modulations associated with transcription. We found that CK2 depletion from yeast cells leads to replication-independent increase of histone H3K56 acetylation and global activation of H3 turnover in coding regions. This suggests a positive role of CK2 in maintenance/recycling of the histone H3/H4 tetramers during transcription. Interestingly, strand-specific RNA-seq analyses show that CK2 inhibits global cryptic promoters driving both sense and antisense transcription. This further indicates a role of CK2 in the modulation of chromatin during transcription. Next, we showed that CK2 interacts with the major histone chaperone Spt6, and phosphorylates it in vivo and in vitro. CK2 phosphorylation of Spt6 is required for its cellular levels, for the suppression of histone H3 turnover and for the inhibition of spurious transcription. Finally, we showed that CK2 and Spt6 phosphorylation sites are important to various transcriptional responses suggesting that cryptic intragenic and antisense transcript production are associated with a defective adaptation to environmental cues. Altogether, our data indicate that CK2 mediated phosphorylation of Spt6 regulates chromatin dynamics associated with transcription, and prevents aberrant transcription." ]

[ "MOTIVATION: Identification and characterization of protein-protein interactions (PPIs) is one of the key aims in biological research. While previous research in text mining has made substantial progress in automatic PPI detection from literature, the need to improve the precision and recall of the process remains. More accurate PPI detection will also improve the ability to extract experimental data related to PPIs and provide multiple evidence for each interaction.RESULTS: We developed an interaction detection method and explored the usefulness of various features in automatically identifying PPIs in text. The results show that our approach outperforms other systems using the AImed dataset. In the tests where our system achieves better precision with reduced recall, we discuss possible approaches for improvement. In addition to test datasets, we evaluated the performance on interactions from five human-curated databases-BIND, DIP, HPRD, IntAct and MINT-where our system consistently identified evidence for approximately 60% of interactions when both proteins appear in at least one sentence in the PubMed abstract. We then applied the system to extract articles from PubMed to annotate known, high-throughput and interologous interactions in I(2)D.AVAILABILITY: The data and software are available at: http://www.cs.utoronto.ca/ approximately juris/data/BI09/.", "Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by joint pain, swelling, stiffness, and progressive destruction of the small joints of the hands and feet. Treatment of RA has improved over the past decade. With multiple cytokines well-known now to play a role in the pathogenesis of RA, including tumor necrosis factor alpha, interleukin (IL)-1β, and IL-6, many targeted biological treatments against these cytokines have emerged, changing the treatment of this disease. Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody against the IL-6 receptor and has been approved in many countries, including the United States, for the treatment of moderate to severe RA in patients who have not adequately responded to one or more disease-modifying antirheumatic drugs (DMARDs) or cannot tolerate other approved drug classes for RA. The aim of this review is to discuss the role of IL-6 in RA, and to provide an overview of the mode of action, pharmacokinetics, and safety of TCZ. Furthermore, efficacy studies of TCZ as both monotherapy and combination therapy will be evaluated. There have been several important clinical trials evaluating the efficacy and safety of TCZ in RA patients; this review summarizes this data from 14 key trials with emphasis on Phase III trials. Review of these trials provides strong evidence that its use, both as monotherapy and in combination with methotrexate or other DMARDs, is an effective treatment in reducing the signs and symptoms of RA. TCZ showed tolerable safety but care is required for its use since there are some important safety concerns including elevated liver enzymes, elevated low-density lipoprotein, infections, and gastrointestinal perforations. Additionally, given the efficacy of TCZ in the treatment of RA, this review discusses how TCZ may be beneficial in the treatment of other autoimmune diseases, spinal disease, cardiovascular disease, organ transplantation, and malignancies where elevated levels of IL-6 may play a role in the pathogenesis of these diseases.", "BACKGROUND: Early-life exposure to household pets has the capacity to reduce risk for overweight and allergic disease, especially following caesarean delivery. Since there is some evidence that pets also alter the gut microbial composition of infants, changes to the gut microbiome are putative pathways by which pet exposure can reduce these risks to health. To investigate the impact of pre- and postnatal pet exposure on infant gut microbiota following various birth scenarios, this study employed a large subsample of 746 infants from the Canadian Healthy Infant Longitudinal Development Study (CHILD) cohort, whose mothers were enrolled during pregnancy between 2009 and 2012. Participating mothers were asked to report on household pet ownership at recruitment during the second or third trimester and 3 months postpartum. Infant gut microbiota were profiled with 16S rRNA sequencing from faecal samples collected at the mean age of 3.3 months. Two categories of pet exposure (i) only during pregnancy and (ii) pre- and postnatally were compared to no pet exposure under different birth scenarios.RESULTS: Over half of studied infants were exposed to at least one furry pet in the prenatal and/or postnatal periods, of which 8% were exposed in pregnancy alone and 46.8% had exposure during both time periods. As a common effect in all birth scenarios, pre- and postnatal pet exposure enriched the abundance of Oscillospira and/or Ruminococcus (P < 0.05) with more than a twofold greater likelihood of high abundance. Among vaginally born infants with maternal intrapartum antibiotic prophylaxis exposure, Streptococcaceae were substantially and significantly reduced by pet exposure (P < 0.001, FDRp = 0.03), reflecting an 80% decreased likelihood of high abundance (OR 0.20, 95%CI, 0.06-0.70) for pet exposure during pregnancy alone and a 69% reduced likelihood (OR 0.31, 95%CI, 0.16-0.58) for exposure in the pre- and postnatal time periods. All of these associations were independent of maternal asthma/allergy status, siblingship, breastfeeding exclusivity and other home characteristics.CONCLUSIONS: The impact of pet ownership varies under different birth scenarios; however, in common, exposure to pets increased the abundance of two bacteria, Ruminococcus and Oscillospira, which have been negatively associated with childhood atopy and obesity.", "Ozanimod (RPC1063) is an oral selective modulator of the sphingosine-1-phosphate 1 and 5 receptors under development for the treatment of relapsing multiple sclerosis and inflammatory bowel disease. The effects of high-fat and low-fat meals on the pharmacokinetics (PK) of a single oral dose of ozanimod were evaluated in 24 healthy volunteers in a randomized, open-label crossover trial. Each subject received a 1-mg dose of ozanimod hydrochloride under 3 meal conditions (fasted, high-fat, and low-fat), each separated by 7 days. Mean plasma concentration-time profiles for ozanimod and its active metabolites (RP101988 [major], RP101075 [minor]) were similar under all 3 conditions. Moreover, all PK parameters for ozanimod, RP101988, and RP101075 were similar under the 3 meal conditions. The 90% confidence intervals (CIs) for the ratios of geometric least-squares mean (fed/fasted) were within the equivalence limits of 0.80 to 1.25 for area under the concentration-time curve from time 0 to infinity (AUC0-∞ ) and maximum plasma concentration (Cmax ) for ozanimod, RP101988, and RP101075, except for the high-fat effect on RP101075 Cmax (90%CI, 0.76-0.88). Given this lack of a food effect on the exposure of ozanimod and its active metabolites, ozanimod can be taken without regard to meals.", "AIM: Many studies have reported that the generation of reactive oxygen species (ROS) increases during the differentiation of muscle-derived C2C12 cells. Peroxiredoxin-2 (Prx-2) is an abundant mammalian enzyme that protects against oxidative stress. However, the role of Prx-2 in muscle differentiation has not been investigated.RESULTS: In this study, we demonstrated that Prx-2 expression increases during muscle differentiation and regeneration in response to exogenous H(2)O(2). This increase occurs only in myoblast cell lines because no increase in Prx-2 expression was observed in the NIH3T3, MEF, Chang, or HEK293 cell lines. The antioxidants, N-acetyl L-cysteine (NAC) and 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron), both suppressed myogenesis and Prx-2 expression. Moreover, Prx-2 was upregulated at the transcriptional level by NF-κB during the differentiation of muscle-derived C2C12 cells. We also found that inhibition of phosphatidylinositol 3-kinase (PI3K) blocks NF-κB activation and suppresses Prx-2 expression. Interestingly, Prx-2 knockdown increased the expression levels of other antioxidant enzymes, including all of the other Prx family member, thioredoxin-1 (Trx-1) and catalase, but also enhanced the accumulation of endogenous ROS during muscle differentiation.INNOVATION: In this study, we demonstrated for the first time that Prx-2 is unregulated during the muscle differentiation and regeneration.CONCLUSION: Prx-2 is upregulated via the PI3K/NF-κB pathway and attenuates oxidative stress during muscle differentiation and regeneration.", "Highly conserved sequences at the 5' splice site and branch site of U12-dependent introns are important determinants for splicing by U12-dependent spliceosomes. This study investigates the in vivo splicing phenotypes of mutations in the branch site consensus sequence of the U12-dependent intron F from a human NOL1 (P120) minigene. Intron F contains a fully consensus branch site sequence (UUCCUUAAC). Mutations at each position were analyzed for their effects on U12-dependent splicing in vivo. Mutations at most positions resulted in a significant reduction of correct U12-dependent splicing. Defects observed included increased unspliced RNA levels, the activation of cryptic U2-dependent 5' and 3' splice sites, and the activation of cryptic U12-dependent branch/3' splice sites. A strong correlation was observed between the predicted thermodynamic stability of the branch site: U12 snRNA interaction and correct U12-dependent splicing. The lack of a polypyrimidine tract between the branch site and 3' splice site of U12-dependent introns and the observed reliance on base-pairing interactions for correct U12-dependent splicing emphasize the importance of RNA/RNA interactions during U12-dependent intron recognition and proper splice site selection.", "The eukaryotic replisome is a crucial determinant of genome stability, but its structure is still poorly understood. We found previously that many regulatory proteins assemble around the MCM2-7 helicase at yeast replication forks to form the replisome progression complex (RPC), which might link MCM2-7 to other replisome components. Here, we show that the RPC associates with DNA polymerase alpha that primes each Okazaki fragment during lagging strand synthesis. Our data indicate that a complex of the GINS and Ctf4 components of the RPC is crucial to couple MCM2-7 to DNA polymerase alpha. Others have found recently that the Mrc1 subunit of RPCs binds DNA polymerase epsilon, which synthesises the leading strand at DNA replication forks. We show that cells lacking both Ctf4 and Mrc1 experience chronic activation of the DNA damage checkpoint during chromosome replication and do not complete the cell cycle. These findings indicate that coupling MCM2-7 to replicative polymerases is an important feature of the regulation of chromosome replication in eukaryotes, and highlight a key role for Ctf4 in this process." ]

[ "Immunoprecipitation (IP) and coimmunoprecipitation (co-IP) are key techniques for studying protein-protein interactions. These methods utilize immobilized Protein A or Protein G to isolate antibody-bound target antigens. The main disadvantage of traditional IP and co-IP is that the conditions used to elute the precipitated antigen also release the antibody thus contaminating the antigen and destroying the antibody support. To overcome these problems, we describe two methods to generate a reusable antibody support by cross-linking the antibody to immobilized Protein A or Protein G, or by coupling it directly to the resin (see Scheme 1). Antibody cross-linking can be done in 1 h while antibody coupling requires 4 h. IP or co-IP is accomplished by incubating the antibody resin with the protein sample. Washes and elutions are carried out in a spin column to reduce resin loss and decrease assay time. Target proteins are eluted with 0.1 M glycine (pH 2.8) and the resin-bound antibody is re-equilibrated in phosphate-buffered saline (PBS) for reuse. Our studies have demonstrated that the immobilization efficiency for the antibody coupling method was similar for several species of antibody. Furthermore, we illustrate that using both methods of antibody immobilization yield IP and co-IP results similar to traditional protocols but eliminate the antibody heavy and light chain contamination.", "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.", "Although constitutive activation of beta-catenin/Tcf signalling is implicated in the development of human cancers, the mechanisms by which the beta-catenin/Tcf pathway promotes tumorigenesis are incompletely understood. Messenger RNA turnover has a major function in regulating gene expression and is responsive to developmental and environmental signals. mRNA decay rates are dictated by cis-acting elements within the mRNA and by trans-acting factors, such as RNA-binding proteins (reviewed in refs 2, 3). Here we show that beta-catenin stabilizes the mRNA encoding the F-box protein betaTrCP1, and identify the RNA-binding protein CRD-BP (coding region determinant-binding protein) as a previously unknown target of beta-catenin/Tcf transcription factor. CRD-BP binds to the coding region of betaTrCP1 mRNA. Overexpression of CRD-BP stabilizes betaTrCP1 mRNA and elevates betaTrCP1 levels (both in cells and in vivo), resulting in the activation of the Skp1-Cullin1-F-box protein (SCF)(betaTrCP) E3 ubiquitin ligase and in accelerated turnover of its substrates including IkappaB and beta-catenin. CRD-BP is essential for the induction of both betaTrCP1 and c-Myc by beta-catenin signalling in colorectal cancer cells. High levels of CRD-BP that are found in primary human colorectal tumours exhibiting active beta-catenin/Tcf signalling implicates CRD-BP induction in the upregulation of betaTrCP1, in the activation of dimeric transcription factor NF-kappaB and in the suppression of apoptosis in these cancers.", "The calcium ion (Ca2+) is a key intracellular signaling molecule with far-reaching effects on many cellular processes. One of the most important such Ca2+ regulated processes is transcription. A body of literature describes the effect of Ca2+ signaling on transcription initiation as occurring mainly through activation of gene-specific transcription factors by Ca2+-induced signaling cascades. However, the reach of Ca2+ extends far beyond the first step of transcription. In fact, Ca2+ can regulate all phases of transcription, with additional effects on transcription-associated events such as alternative splicing. Importantly, Ca2+ signaling mediates reduced transcription termination in response to certain stress conditions. This reduction allows readthrough transcription, generating a highly inducible and diverse class of downstream of gene containing transcripts (DoGs) that we have recently described.", "At the intersection between neuroscience, microbiology, and psychiatry, the enteric microbiome has potential to become a novel paradigm for studying the psychobiological underpinnings of mental illness. Several studies provide support for the view that the enteric microbiome influences behavior through the microbiota-gut-brain axis. Moreover, recent findings are suggestive of the possibility that dysregulation of the enteric microbiota (i.e., dysbiosis) and associated bacterial translocation across the intestinal epithelium may be involved in the pathophysiology of stress-related psychiatric disorders, particularly depression. The current article reviews preliminary evidence linking the enteric microbiota and its metabolites to psychiatric illness, along with separate lines of empirical inquiry on the potential involvement of psychosocial stressors, proinflammatory cytokines and neuroinflammation, the hypothalamic-pituitary-adrenal axis, and vagal nerve activation, respectively, in this relationship. Finally, and drawing on these independent lines of research, an integrative conceptual model is proposed in which stress-induced enteric dysbiosis and intestinal permeability confer risk for negative mental health outcomes through immunoregulatory, endocrinal, and neural pathways. (PsycINFO Database Record", "OBJECTIVE: To assess the usefulness of triple-marker screening for Down syndrome in Venezuela.METHOD: Maternal serum concentrations of alpha fetoprotein (AFP), beta human chorionic gonadotropin (beta-hCG), and unconjugated estriol (uE3) were measured weekly in 3895 women from the 15th to the 20th week of pregnancy. Population-specific likelihood ratios were determined and used to calculate the risk of fetal Down syndrome for each pregnancy.RESULTS: The median multiple of the median values for AFP, beta-hCG, and uE3 concentrations were 0.69, 2.10, and 0.67 for the affected pregnancies. The likelihood ratio for a positive result was 1:19. The detection and false-positive rates were 69.23% and 5.8%.CONCLUSION: These findings were consistent with reported data and therefore confirmed triple-marker serum screening as effective and suitable for prenatal care in Venezuela. Latin American governments and Health Agencies should recommend offering this screening method to all pregnant women.", "Krabbe disease (KD) is a rare disease caused by the deficiency of β-galactocerebrosidase. This study investigated 22 unrelated Chinese patients, including their clinical presentations, plasma psychosine levels and β-galactocerebrosidase gene mutations. We found the late-onset form of KD present in 82% of the patients in our study, which was more prevalent than in patients from other populations. Plasma psychosine levels were elevated in KD, which were correlated with the severity of clinical presentations. Sanger sequencing identified 8 novel mutations, including 7 missense mutations, p.H253Y, p.S259L, p.P318L, p.F350V, p.T428A, p.L530P, p.G586D, and 1 splicing mutation, c.1251+1G>A. Quantitative real-time polymerase chain reaction (PCR) and multiplex ligation-dependent probe amplification identified a novel exon 12 and 14 deletion, separately. Next generation sequencing, applied at the final step, revealed 2 missense mutant alleles missed using Sanger sequencing. The most common mutation in Chinese population is p.P154H, which accounts for 20.5% of alleles. Consistent with the higher prevalence of the late-onset form of KD, missense mutations predominated in our study, different with the common mutation types in Europe and Japan. This work was the first large-scale study of Chinese KD patients describing their clinical, biochemical and genetic characteristics, which furthered our understanding of this classical neurological lysosomal storage disease." ]

[ "In germ cells, early embryos, and stem cells of animals, PIWI-interacting RNAs (piRNAs) have an important role in silencing retrotransposons, which are vicious genomic parasites, through transcriptional and post-transcriptional mechanisms. To examine whether the piRNA pathway can be used to silence genes of interest in germ cells, we have generated knock-in mice in which a foreign DNA fragment was inserted into a region generating pachytene piRNAs. The knock-in sequence was transcribed, and the resulting RNA was processed to yield piRNAs in postnatal testes. When reporter genes possessing a sequence complementary to portions of the knock-in sequence were introduced, they were greatly repressed after the time of pachytene piRNA generation. This repression mainly occurred at the post-transcriptional level, as degradation of the reporter RNAs was accelerated. Our results show that the piRNA pathway can be used as a tool for sequence-specific gene silencing in germ cells and support the idea that the piRNA generating regions serve as traps for retrotransposons, enabling the host cell to generate piRNAs against active retrotransposons.", "The regulation of gene expression was studied, for the Escherichia coli rpoBC operon, which includes the genes, rpoB and rpoC, for the beta and beta subunits of RNA polymerase, and rplJ and rplL, for the two proteins, L10 and L7/12, of the 50S ribosome. The gene organization agrees well with the accumulated observations indicating the coordinate synthesis of RNA polymerase and ribosomes under various growth conditions for wild-type E. coli cells. On the other hand, the differential regulation of the two essential components observed under restrictive growth conditions, after addition of various drugs or with certain mutants, in particular those carrying mutations in the RNA polymerase genes, was found to take place through two novel regulation systems: The transcriptional termination at an internal attenuation site and the two autogenous and posttranscriptional controls, being specific for the two ribosomal protein genes and the two RNA polymerase subunit genes, respectively. The majority of the transcription initiated from the promoter rpoP beta terminates at an attenuator site between the promoter-proximal rplJL and the promoter-distal rpoBC genes. The frequency of the attenuation seems to control the relative level of RNA polymerase synthesis to that of ribosomes. The expression of rpoBC genes is subject to an autogenous regulation, in which both RNA polymerase holoenzyme and alpha 2 beta complex function as regulatory molecules with repressor activity. The autogenous regulation was found to operate at post-transcriptional step(s), probably at the level of translation. During the study on the regulation of RNA polymerase synthesis, we noticed that the rpoBC operon contained another autogenous regulation circuit, in which the synthesis of L10 and L7/12 was specifically repressed by the L10-L7/12 complex. Molecular mechanisms and physiological meanings of the novel regulations are discussed.", "BACKGROUND: Patients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. Chemotherapy and targeted therapies offer short-lived disease control. We assessed pembrolizumab, an anti-PD-1 antibody, for safety and activity in patients with advanced soft-tissue sarcoma or bone sarcoma.METHODS: In this two-cohort, single-arm, open-label, phase 2 study, we enrolled patients with soft-tissue sarcoma or bone sarcoma from 12 academic centres in the USA that were members of the Sarcoma Alliance for Research through Collaboration (SARC). Patients with soft-tissue sarcoma had to be aged 18 years or older to enrol; patients with bone sarcoma could enrol if they were aged 12 years or older. Patients had histological evidence of metastatic or surgically unresectable locally advanced sarcoma, had received up to three previous lines of systemic anticancer therapy, had at least one measurable lesion according to the Response Evaluation Criteria In Solid Tumors version 1.1, and had at least one lesion accessible for biopsy. All patients were treated with 200 mg intravenous pembrolizumab every 3 weeks. The primary endpoint was investigator-assessed objective response. Patients who received at least one dose of pembrolizumab were included in the safety analysis and patients who progressed or reached at least one scan assessment were included in the activity analysis. Accrual is ongoing in some disease cohorts. This trial is registered with ClinicalTrials.gov, number NCT02301039.FINDINGS: Between March 13, 2015, and Feb 18, 2016, we enrolled 86 patients, 84 of whom received pembrolizumab (42 in each disease cohort) and 80 of whom were evaluable for response (40 in each disease cohort). Median follow-up was 17·8 months (IQR 12·3-19·3). Seven (18%) of 40 patients with soft-tissue sarcoma had an objective response, including four (40%) of ten patients with undifferentiated pleomorphic sarcoma, two (20%) of ten patients with liposarcoma, and one (10%) of ten patients with synovial sarcoma. No patients with leiomyosarcoma (n=10) had an objective response. Two (5%) of 40 patients with bone sarcoma had an objective response, including one (5%) of 22 patients with osteosarcoma and one (20%) of five patients with chondrosarcoma. None of the 13 patients with Ewing's sarcoma had an objective response. The most frequent grade 3 or worse adverse events were anaemia (six [14%]), decreased lymphocyte count (five [12%]), prolonged activated partial thromboplastin time (four [10%]), and decreased platelet count (three [7%]) in the bone sarcoma group, and anaemia, decreased lymphocyte count, and prolonged activated partial thromboplastin time in the soft-tissue sarcoma group (three [7%] each). Nine (11%) patients (five [12%] in the bone sarcoma group and four [10%] in the soft-tissue sarcoma group) had treatment-emergent serious adverse events (SAEs), five of whom had immune-related SAEs, including two with adrenal insufficiency, two with pneumonitis, and one with nephritis.INTERPRETATION: The primary endpoint of overall response was not met for either cohort. However, pembrolizumab showed encouraging activity in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. Enrolment to expanded cohorts of those subtypes is ongoing to confirm and characterise the activity of pembrolizumab.FUNDING: Merck, SARC, Sarcoma Foundation of America, QuadW Foundation, Pittsburgh Cure Sarcoma, and Ewan McGregor.", "OBJECTIVE: Chondrocytes of the epiphyseal growth zone are regulated by the Indian hedgehog (IHH)-parathyroid hormone-related protein (PTHrP) axis. In weight-bearing joints, this growth zone comes to be subdivided by the secondary ossification center into distinct articular and growth cartilage structures. The purpose of this study was to explore the cells of origin, localization, regulation of expression, and putative functions of IHH and PTHrP in articular cartilage in the mouse.METHODS: We assessed IHH and PTHrP expression in an allelic PTHrP-LacZ-knockin mouse and several versions of PTHrP-null mice. Selected joints were unloaded surgically to examine load-induction of PTHrP and IHH.RESULTS: The embryonic growth zone appears to serve as the source of PTHrP-expressing proliferative chondrocytes that populate both the forming articular cartilage and growth plate structures. In articular cartilage, these cells take the form of articular chondrocytes in the midzone. In PTHrP-knockout mice, mineralizing chondrocytes encroach upon developing articular cartilage but appear to be prevented from mineralizing the joint space by IHH-driven surface chondrocyte proliferation. In growing and adult mice, PTHrP expression in articular chondrocytes is load-induced, and unloading is associated with rapid changes in PTHrP expression and articular chondrocyte differentiation.CONCLUSION: We conclude that the IHH-PTHrP axis participates in the maintenance of articular cartilage. Dysregulation of this system might contribute to the pathogenesis of arthritis.", "The transcription factor Zelda plays a pivotal role in promoting the maternal to zygotic transition during embryogenesis in Drosophila melanogaster. However, little is known about its role later in development. Here we are showing that Zelda is essential for proper wing development through gain and loss of function experiments. Zelda's transcript variants RB, RC and RD are present in imaginal wing discs of third instar larvae and the production of 2 protein isoforms of ∼180 and ∼70kD was detected in the same tissue. In ChIP experiments using larval wing discs, Zelda was found to bind to a region of the optomotor-blind gene, suggesting an interaction with a Dpp target that promotes wing growth and patterning.", "Author information:(1)Northwestern Medicine Developmental Therapeutics Institute, Northwestern University, United States; Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, United States; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, United States. Electronic address: raquelmorais@hotmail.com.(2)Northwestern Medicine Developmental Therapeutics Institute, Northwestern University, United States; Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, United States; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, United States. Electronic address: benedito.carneiro@northwestern.edu.(3)Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, United States; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, United States. Electronic address: mark.agulnik@nmff.org.(4)Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, United States; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, United States. Electronic address: p-kopp@northwestern.edu.(5)Northwestern Medicine Developmental Therapeutics Institute, Northwestern University, United States; Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, United States; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, United States. Electronic address: francis.giles@northwestern.edu.", "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." ]

[ "Dravet syndrome is an intractable epileptic syndrome beginning in the first year of life. De novo mutations of SCN1A, which encode the Na(v)1.1 neuronal voltage-gated sodium channel, are considered the major cause of Dravet syndrome. In this study, we investigated genetic modifiers of this syndrome. We performed a mutational analysis of all coding exons of CACNA1A in 48 subjects with Dravet syndrome. To assess the effects of CACNA1A variants on the epileptic phenotypes of Dravet syndrome, we compared clinical features in two genotype groups: 1) subjects harboring SCN1A mutations but no CACNA1A variants (n=20) and 2) subjects with SCN1A mutations plus CACNA1A variants (n=20). CACNA1A variants detected in patients were studied using heterologous expression of recombinant human Ca(v)2.1 in HEK 293 cells and whole-cell patch-clamp recording. Nine CACNA1A variants, including six novel ones, were detected in 21 of the 48 subjects (43.8%). Based on the incidence of variants in healthy controls, most of the variants seemed to be common polymorphisms. However, the subjects harboring SCN1A mutations and CACNA1A variants had absence seizures more frequently than the patients with only SCN1A mutations (8/20 vs. 0/20, p=0.002). Moreover, the former group of subjects exhibited earlier onset of seizures and more frequent prolonged seizures before one year of age, compared to the latter group of subjects. The electrophysiological properties of four of the five novel Ca(v)2.1 variants exhibited biophysical changes consistent with gain-of-function. We conclude that CACNA1A variants in some persons with Dravet syndrome may modify the epileptic phenotypes.", "The infiltration of myeloid cells helps tumors to overcome immune surveillance and imparts resistance to cancer immunotherapy. Thus, strategies to modulate the effects of these immune cells may offer a potential therapeutic benefit. We report here that tasquinimod, a novel immunotherapy which targets S100A9 signaling, reduces the immunosuppressive properties of myeloid cells in preclinical models of bladder cancer (BCa). As single anticancer agent, tasquinimod treatment was effective in preventing early stage tumor growth, but did not achieve a clear antitumor effect in advanced tumors. Investigations of this response revealed that tasquinimod induces an increase in the expression of a negative regulator of T cell activation, Programmed-death-ligand 1 (PD-L1). This markedly weakens its antitumor immunity, yet provokes an \"inflamed\" milieu rendering tumors more prone to T cell-mediated immune attack by PD-L1 blockade. Interestingly, the combination of tasquinimod with an Anti-PD-L1 antibody enhanced the antitumor immune response in bladder tumors. This combination synergistically modulated tumor-infiltrating myeloid cells, thereby strongly affecting proliferation and activation of effector T cells. Together, our data provide insight into the rational combination of therapies that activate both innate and adaptive immune system, such as the association of S100A9-targeting agents with immune checkpoints inhibitors, to improve the response to cancer immunotherapeutic agents in BCa.", "BACKGROUND:  Helicobacter pylori infection is a most frequent cause of chronic gastritis. H. pylori may decrease absorption of oral thyroxine by decreasing gastric acid secretion in the stomach. In this study, we aimed to investigate the change in thyroid function tests of the cases after H. pylori eradication who were not responding to high doses of thyroxine treatment before H. pylori eradication.METHODS:  Hypothyroid cases who were not responding to high doses of thyroxine among the ones presented to Endocrinology and Gastroenterohepatology Clinics of Sisli Etfal Training and Research Hospital between 2009 and 2010 were included in the study. Thyroid function tests were performed two times in all cases before and after H. pylori eradication. Duodenal, antral and corporal biopsies, and jejunal aspirates and biopsies were taken during upper gastrointestinal system endoscopies performed in all patients. Cases without intestinal pathology were included in the study.RESULTS: Serum thyrotropin (TSH), free T3, and free T4 values before H. pylori eradication were 30.5 ± 28.8 IU/mL, 2.64 ± 0.56 pg/mL, and 0.92 ± 0.32 ng/mL, respectively, and after eradication were found to be 4.2 ± 10.6 IU/mL, 3.02 ± 0.61 pg/mL, and 1.3 ± 0.34 ng/mL, respectively (p values <.001, .002, and <.001, respectively). After H. pylori eradication treatment, TSH decreased in all of the cases, factitious thyrotoxicosis developed in % 21 of these cases.CONCLUSION: In hypothyroid cases, H. pylori gastritis may be responsible for an inadequate response to the treatment. H. pylori eradication in the cases receiving high doses of thyroxine has a risk for thyrotoxicosis.", "Objective - To evaluate 12-week changes from baseline of 2 disease-specific patient-reported outcome (PRO) measures in adults with migraine treated with galcanezumab, an investigational humanized antibody binding calcitonin gene-related peptide (CGRP), or placebo. Background - Preventing headache-related functional impairment is an important goal of migraine preventive treatment and a measurement target for PROs. Understanding which drugs have the potential to improve patient functioning in addition to preventing migraine headaches is vital to lessening patient burden. Design/Methods - This Phase 2b double-blind, randomized, placebo-controlled study enrolled adults with episodic migraine. Galcanezumab (120 mg subcutaneous injection; n = 60) or placebo (n = 127) was administered every 28 days for 12 weeks. Post hoc secondary analyses were conducted for those who completed 12 weeks of treatment on 2 PROs: The Migraine-Specific Quality of Life Questionnaire (MSQ) v2.1 and the Headache Impact Test™ (HIT-6). Results - Analysis of covariance revealed significant differences in least square mean changes from baseline between galcanezumab and placebo for all MSQ domains including total mean change placebo of 18.63, galcanezumab of 27.36 (95% CI 2.449, 15.008; P-value of .0067); Role Function-Restrictive mean change placebo of 22.40, galcanezumab of 31.92 (95% CI 2.636, 16.518; P-value of .0071); Role Function-Preventive mean change placebo of 13.43, galcanezumab of 19.76 (95% CI 0.476, 12.185; P-value of .0342); and Emotional Function mean change placebo of 16.88, galcanezumab of 26.61 (95% CI 2.789, 16.674; P-value of .0063). At baseline, mean number of migraine headache days (MHDs) did not correlate with MSQ total scores or HIT-6. At 12 weeks post-treatment, MHD correlated with MSQ and HIT-6 scores (all P < .0001). Change in MHD was associated with change in MSQ domains and change in HIT-6 scores (all P < .0001). Conclusions - In comparison with placebo, treatment with galcanezumab was associated with significant functional improvements as reflected by changes in MSQ scores. Change in MHD was associated with improvements in MSQ and reductions in HIT-6 scores, indicating the clinical importance of these changes in relation to PROs that measure function.", "SECIS elements are stem-loop structures located in the 3' untranslated regions (UTRs) of eukaryotic selenoprotein mRNAs that are required for directing cotranslational selenocysteine incorporation at UGA codons. In prokaryotes, stem-loops mediating selenocysteine incorporation are located immediately downstream of the UGA selenocysteine codon, in the coding region. Previous characterization studies of the mammalian SECIS elements of type 1 deiodinase, glutathione peroxidase, and selenoprotein P showed that conserved nucleotides in the loops and unpaired bulges, and base pairing in the stems are required for SECIS function. These initial studies utilized approximately 175-230-nt segments of the 3'UTRs of the selenoprotein mRNAs. Here we define the minimal functional rat type 1 deiodinase SECIS element, a 45-nt segment, the 5' boundary of which corresponds precisely to the 5'-most critical conserved nucleotide identified previously. We also define base pairing requirements in the stem of this element. In view of the presence of SECIS elements in the open reading frames (ORFs) of bacterial selenoproteins, we examine the effects in the type 1 deiodinase of extending the ORF into the SECIS element, and find that this dramatically inhibits SECIS function. Finally, we define a minimal spacing requirement of 51-111 nt between a eukaryotic UGA selenocysteine codon and SECIS element.", "BACKGROUND: Diabetes mellitus is a known risk factor in the development of peripheral vascular disease. Hemoglobin A1c (HbA1c) has been used by clinicians as a means to measure short to intermediate term glucose control in diabetics. Trials evaluating tight glucose control using HbA1c measurements have recently been conducted for several medical conditions. The goal of this study is to determine if the level of hemoglobin A1c has any effect on disease severity in diabetic patients with limb threatening ischemia.METHODS: A retrospective review of all patients presenting with limb threatening ischemia between January 1 and December 31, 2007 was conducted. All patients underwent conventional arteriography prior to intervention. Of 148 patients, 73 were diabetics with a hemoglobin A1c level performed within 3 mo of presentation. Patients were placed into high (>7) and low (<7) hemoglobin A1c groups and data was collected on type of presentation, comorbidities, anatomic level of disease, tibial artery patency, need for amputation, contralateral disease, need for an open versus an endovascular procedure, and freedom from intervention. Fisher's exact t-test was used to compare the two groups. A P value <0.05 was considered statistically significant.RESULTS: Thirty-six patients had HbA1c levels above 7.0 and 37 had levels below 7.0 (mean 7.64 ± 2.04, range 5.1-14.7). There were no statistically significant differences in the two groups in comorbities, average age, initial gangrene at presentation, aspirin or statin use, or smoking status. Patients in the high group were more likely to have had a previous attempt at revascularization (23 versus 11, P = 0.0049). There was no difference in the presence of contralateral disease (7 versus 4, P = 0.3447) or in the number of patent tibial vessels. Patients with low HbA1c levels were more likely to have the peroneal artery affected (17 versus 8, P = 0.048). In addition, TASC II classifications of iliac and femoral popliteal disease was similar between the two groups. Freedom from intervention is depicted graphically by life table analysis.CONCLUSION: Glucose control measured by hemoglobin A1c does not appear to affect severity of disease or need for reintervention in diabetics with limb threatening ischemia. This suggests other factors related to diabetes may play a role in peripheral vascular disease. Larger, prospective studies are needed to assess the affect of glucose control in limb threatening ischemia.", "Functional characterization of the noncoding genome is essential for biological understanding of gene regulation and disease. Here, we introduce the computational framework PINES (Phenotype-Informed Noncoding Element Scoring), which predicts the functional impact of noncoding variants by integrating epigenetic annotations in a phenotype-dependent manner. PINES enables analyses to be customized towards genomic annotations from cell types of the highest relevance given the phenotype of interest. We illustrate that PINES identifies functional noncoding variation more accurately than methods that do not use phenotype-weighted knowledge, while at the same time being flexible and easy to use via a dedicated web portal." ]

[ "Long noncoding RNAs (lncRNAs) have been detected in nearly every cell type and found to be fundamentally involved in many biological processes. The characterization of lncRNAs has immense potential to advance our comprehensive understanding of cellular processes and gene regulation, along with implications for the treatment of human disease. The recent ENCODE (Encyclopedia of DNA Elements) study reported 9,640 lncRNA loci in the human genome, which corresponds to around half the number of protein-coding genes. Because of this sheer number and their functional diversity, it is crucial to identify a pool of potentially relevant lncRNAs early on in a given study. In this review, we evaluate the methods for isolating lncRNAs by immunoprecipitation and review the advantages, disadvantages, and applications of three widely used approaches - microarray, tiling array, and RNA-seq - for identifying lncRNAs involved in gene regulation. We also look at ways in which data from publicly available databases such as ENCODE can support the study of lncRNAs.", "Beside the digestion of the extracellular matrix during tumor invasion and metastasis, more recently, new functions for matrix metalloproteinases (MMPs) have been proposed. We studied the expression and function of these enzymes in pituitary cells. We observed the activities of MMP-2 and MMP-9 together with expression of membrane-type MMP and tissue inhibitor of metalloproteinase-1 in all types of human pituitary adenomas. We found surprisingly high levels of MMP activity and low levels of tissue inhibitor of metalloproteinases, indicating a high level of extracellular matrix-degrading activity in pituitary adenomas. To examine the function of metalloproteinase activity in pituitary cells we used the synthetic MMP inhibitor batimastat. These studies demonstrate that MMPs secreted by pituitary cells can release growth factors anchored to the extracellular matrix that, in turn, control pituitary cell proliferation and hormone secretion. These results define a new additional mechanism for the control of pituitary hormone secretion and indicate new potential therapeutic targets for pituitary adenomas.", "OBJECTIVE: The choice of adequate proxy for long-term survival, the ultimate outcome in randomised clinical trials (RCT) assessing disease-modifying treatments for amyotrophic lateral sclerosis (ALS), is a key issue. The intrinsic limitations of the ALS Functional Rating Scale-Revised (ALSFRS-R), including non-linearity, multidimensionality and floor-effect, have emerged and its usefulness argued. The ALS Milano-Torino staging (ALS-MITOS) system was proposed as a novel tool to measure the progression of ALS and overcome these limitations. This study was performed to validate the ALS-MITOS as a 6-month proxy of survival in 200 ALS patients followed up to 18 months.METHODS: Analyses were performed on data from the recombinant human erythropoietin RCT that failed to demonstrate differences between groups for both primary and secondary outcomes. The ALS-MITOS system is composed of four key domains included in the ALSFRS-R scale (walking/self-care, swallowing, communicating and breathing), each with a threshold reflecting the loss of function in the specific ALSFRS-R subscores. Sensitivity, specificity and the area under the curve of the receiver operating characteristic curves of the ALS-MITOS system stages and ALSFRS-R decline at 6 months were calculated and compared with the primary outcome (survival, tracheotomy or >23-hour non-invasive ventilation) at 12 and 18 months Predicted probabilities of the ALS-MITO system at 6 months for any event at 12 and 18 months were computed through logistic regression models.RESULTS: Disease progression from baseline to 6 months as defined by the ALS-MITOS system predicted death, tracheotomy or >23-hour non-invasive ventilation at 12 months with 82% sensitivity (95% CI 71% to 93%, n=37/45) and 63% specificity (95% CI 55% to 71%, n=92/146), and at 18 months with 71% sensitivity (95% CI 61% to 82%, n=50/70) and 68% specificity (95% CI 60% to 77%, n=76/111). The analysis of ALS-MITOS and ALSFRS-R progression at 6-month follow-up showed that the best cut-off to predict survival at 12 and 18 months was 1 for the ALS-MITOS (ie, loss of at least one function) and a decline ranging from 6 to 9 points for the ALSFRS-R.CONCLUSIONS: The ALS-MITOS system can reliably predict the course of ALS up to 18 months and can be considered a novel and valid outcome measure in RCTs.", "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.", "Author information:(1)Neuromuscular Disease, IRCCS Foundation, \"Carlo Besta\" Neurological Institute, Milan, Italy.(2)NESMOS Department, Neuromuscular Disease Unit, Sant'Andrea Hospital and University of Rome \"Sapienza\", Rome, Italy.(3)Neurologic Unit, Monserrato University Hospital, Cagliari, Italy.(4)Neurologic Clinic, SS. Annunziata Hospital, Chieti, Italy.(5)Departments of Neurosciences, Rehabilitation, Ophtalmology, Genetics, Mother and Child Disease, IRCCS University Hospital San Martino IST, Genova, Italy.(6)Department of Neurosciences, ALS Centre, \"Rita Levi Montalcini\" Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.(7)NEMO Clinical Centre, Milan, Italy Department of Neurorehabilitaton, Casa Cura Policlinico, Milan, Italy.(8)Neurology Unit, S. Maria della Misericordia University Hospital, Udine, Italy.(9)Department of Neurology, IRCCS \"San Raffaele\" Hospital, Milan, Italy.(10)Neurologic Clinic, University of Brescia, Brescia, Italy.(11)Department of Medical and Surgery Sciences and Neurosciences, University of Siena, Siena, Italy.(12)Neurologic Clinic, University of Ferrara, Italy.(13)ALS Research Centre, BioNeC, University of Palermo, Palermo, Italy.(14)Department of Neurology and Psychiatry, University of Bari, Bari, Italy.(15)Department of Neurosciences, S. Agostino-Estense Hospital, Modena, Italy.(16)ALS Centre, Neurologic Clinic, Maggiore della Carità University Hospital, Novara, Italy.(17)2nd Neurologic Clinic, 2nd University of Naples, Naples, Italy.(18)IRCCS \"Salvatore Maugeri\" Foundation, Milan, Italy.(19)Department of Neurosciences, Neurology Unit, University of Parma, Parma, Italy.(20)Neurology Unit, dell'Angelo Hospital, Mestre, Italy.(21)Neurology Unit, Department of Neuro-Motor Diseases, IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.(22)IRCCS Neurological Sciences Institute, Bologna, Italy.(23)Department of Clinical and Experimental Medicine, Neurology Unit, University of Pisa, Pisa, Italy.(24)Department of Neurosciences, University of Padua, Padua, Italy.(25)Intensive Neurorehabilitation Unit, IRCCS \"Salvatore Maugeri\" Foundation, Mistretta, Italy.(26)Neuroepidemiology Units, IRCCS Foundation, \"Carlo Besta\" Neurological Institute, Milan, Italy.", "OBJECTIVE: Neuroimaging and other biomarker assays suggest that the pathological processes of Alzheimer's disease (AD) begin years prior to clinical dementia onset. However, some 30 to 50% of older individuals who harbor AD pathology do not become symptomatic in their lifetime. It is hypothesized that such individuals exhibit cognitive resilience that protects against AD dementia. We hypothesized that in cases with AD pathology, structural changes in dendritic spines would distinguish individuals who had or did not have clinical dementia.METHODS: We compared dendritic spines within layer II and III pyramidal neuron dendrites in Brodmann area 46 dorsolateral prefrontal cortex using the Golgi-Cox technique in 12 age-matched pathology-free controls, 8 controls with AD pathology (CAD), and 21 AD cases. We used highly optimized methods to trace impregnated dendrites from bright-field microscopy images that enabled accurate 3-dimensional digital reconstruction of dendritic structure for morphologic analyses.RESULTS: Spine density was similar among control and CAD cases but was reduced significantly in AD. Thin and mushroom spines were reduced significantly in AD compared to CAD brains, whereas stubby spine density was decreased significantly in CAD and AD compared to controls. Increased spine extent distinguished CAD cases from controls and AD. Linear regression analysis of all cases indicated that spine density was not associated with neuritic plaque score but did display negative correlation with Braak staging.INTERPRETATION: These observations provide cellular evidence to support the hypothesis that dendritic spine plasticity is a mechanism of cognitive resilience that protects older individuals with AD pathology from developing dementia. Ann Neurol 2017;82:602-614.", "BACKGROUND: Patients with congestive heart failure (CHF) often have low serum triiodothyronine (T(3)) concentrations. In a rodent model of myocardial infarction-induced CHF and low serum T(3), we hypothesized that replacing T(3) to euthyroid levels would improve left ventricular function without producing untoward signs of thyrotoxicosis.METHODS AND RESULTS: Adult male Sprague-Dawley rats were subjected to left anterior descending coronary artery ligation (myocardial infarction). One week post-myocardial infarction, left ventricular fractional shortening was significantly reduced to 22+/-1% in CHF animals versus 38+/-1% for sham-operated controls (P<0.001). Serum T(3) concentration was also significantly reduced (80+/-3 versus 103+/-6 ng/dL; P<0.001), in CHF animals versus Shams. At 9 weeks post-myocardial infarction, systolic function (+dP/dt max) was significantly attenuated in CHF animals (4773+/-259 versus 6310+/-267 mmHg/s; P<0.001) as well as diastolic function measured by half time to relaxation (15.9+/-1.2 versus 11.1+/-0.3 ms; P<0.001). alpha-myosin heavy chain expression was also significantly reduced by 77% (P<0.001), and beta-myosin heavy chain expression was increased by 21%. Continuous T(3) replacement was initiated 1 week post-myocardial infarction with osmotic mini-pumps (6 microg/kg/d), which returned serum T(3) concentrations to levels similar to Sham controls while resting conscious heart rate, arterial blood pressure and the incidence of arrhythmias were not different. At 9 weeks, systolic function was significantly improved by T(3) replacement (6279+/-347 mmHg/s; P<0.05) and a trend toward improved diastolic function (12.3+/-0.6 ms) was noted. T(3) replacement in CHF animals also significantly increased alpha- and reduced beta-MHC expression, (P<0.05).CONCLUSIONS: These data indicate that T(3) replacement to euthyroid levels improves systolic function and tends to improve diastolic function, potentially through changes in myocardial gene expression.", "RATIONALE: Pulmonary lymphangioleiomyomatosis is a progressive cystic lung disease that is associated with infiltration of atypical smooth muscle-like cells. Previous descriptions of clinical characteristics of subjects with lymphangioleiomyomatosis have been based on a limited number of patients.OBJECTIVES: To describe the clinical characteristics of subjects with pulmonary lymphangioleiomyomatosis, both sporadic and tuberous sclerosis-related forms.METHODS: Over a 3-yr period, from 1998 to 2001, 243 subjects with pulmonary lymphangioleiomyomatosis were enrolled into a national registry; 13 subjects who had already undergone lung transplantation were excluded for the purposes of this report.MEASUREMENTS AND MAIN RESULTS: All 230 subjects were women, aged 18 to 76 yr (mean +/- SE, 44.5 +/- 0.65 yr). The average age at onset of symptoms was 38.9 +/- 0.73 yr and at diagnosis was 41.0 +/- 0.65 yr. Tuberous sclerosis complex was present in 14.8% of subjects. Pulmonary manifestations, most commonly spontaneous pneumothorax, were the primary events leading to the diagnosis in 86.5% of cases. Nearly 55% of the subjects were being treated with a progesterone derivative. An obstructive pattern on pulmonary function testing was observed in 57.3% of the subjects, whereas 33.9% had normal spirometric results. Women with tuberous sclerosis-related lymphangioleiomyomatosis were younger and had less impaired lung function compared with those with the sporadic form.CONCLUSIONS: The age range of women afflicted with pulmonary lymphangioleiomyomatosis is broader than previously appreciated and the degree of pulmonary function can be quite variable, with one-third of subjects having normal spirometry at enrollment into this registry." ]

[ "Integrating and expressing stably a transgene into the cellular genome remain major challenges for gene-based therapies and for bioproduction purposes. While transposon vectors mediate efficient transgene integration, expression may be limited by epigenetic silencing, and persistent transposase expression may mediate multiple transposition cycles. Here, we evaluated the delivery of the piggyBac transposase messenger RNA combined with genetically insulated transposons to isolate the transgene from neighboring regulatory elements and stabilize expression. A comparison of piggyBac transposase expression from messenger RNA and DNA vectors was carried out in terms of expression levels, transposition efficiency, transgene expression and genotoxic effects, in order to calibrate and secure the transposition-based delivery system. Messenger RNA reduced the persistence of the transposase to a narrow window, thus decreasing side effects such as superfluous genomic DNA cleavage. Both the CTF/NF1 and the D4Z4 insulators were found to mediate more efficient expression from a few transposition events. We conclude that the use of engineered piggyBac transposase mRNA and insulated transposons offer promising ways of improving the quality of the integration process and sustaining the expression of transposon vectors.", "PURPOSE: A 70-gene prognostic signature has prognostic value in patients with node-negative breast cancer in Europe. This diagnostic test known as \"MammaPrint™ (70-gene prognostic signature)\" was recently validated and implementation was feasible. Therefore, we assessed the 70-gene prognostic signature in Korean patients with breast cancer. We compared the risk predicted by the 70-gene prognostic signature with commonly used clinicopathological guidelines among Korean patients with breast cancer. We also analyzed the 70-gene prognostic signature and clinicopathological feature of the patients in comparison with a previous validation study.METHODS: Forty-eight eligible patients with breast cancer (clinical T1-2N0M0) were selected from four hospitals in Korea. Fresh tumor samples were analyzed with a customized microarray for the 70-gene prognostic signature. Concordance between the risk predicted by the 70-gene prognostic signature and risk predicted by commonly used clinicopathological guidelines (St. Gallen guidelines, National Institutes of Health [NIH] guideline, and Adjuvant! Online) was evaluated.RESULTS: Prognosis signatures were assessed in 36 patients. No significant differences were observed in the clinicopathological features of patients compared with previous studies. The 70-gene prognosis signature identified five (13.9%) patients with a low-risk prognosis signature and 31 (86.1%) patients with a high-risk prognosis signature. Clinical risk was concordant with the prognosis signature for 29 patients (80.6%) according to the St. Gallen guidelines; 30 patients (83.4%) according to the NIH guidelines; and 23 patients (63.8%) according to the Adjuvant! Online. Our results were different from previous validation studies in Europe with about a 40% low-risk prognosis and about a 60% high-risk prognosis. The high incidence in the high-risk group was consistent with data in Japan.CONCLUSION: The results of 70-gene prognostic signature of Korean patients with breast cancer were somewhat different from those identified in Europe. This difference should be studied as whether there is a gene disparity between Asians and Europeans. Further large-scale studies with a follow-up evaluation are required to assess whether the use of the 70-gene prognostic signature can predict the prognosis of Korean patients with breast cancer.", "TAS-102/Lonsurf is a new oral anti-tumor drug consisting of trifluridine and tipiracil in a 1:0.5 molar ratio. Lonsurf has been approved globally, including US, Europe Union, and China, to treat patients with advanced colorectal cancer. Ongoing clinical trials are currently conducted for the treatment of other solid cancers. However, the therapeutic potential of TAS-102 in hematological malignancies has not been explored. In this study, we investigate the therapeutic efficacy of TAS-102 in multiple myeloma both in vitro and in vivo. We demonstrate that TAS-102 treatment inhibits tumor cell proliferation in six human myeloma cell lines with IC50 values in a range from 0.64 to 9.10 μM. Dot blotting and immunofluorescent staining show that trifluridine is predominately incorporated into genomic DNAs of myeloma cells. TAS-102 treatment induces myeloma cell apoptosis through cell cycle arrest in G1 phase and activation of cGAS-STING signaling in myeloma cells. In the human myeloma xenograft models, TAS-102 treatment reduces tumor progression and prolongs mouse survival. TAS-102 has shown its efficacies in the drug-resistant myeloma cells, and the combination of TAS-102 and bortezomib has a synergistic anti-myeloma activity. Our preclinical studies indicate that TAS-102 is a potential novel agent for myeloma therapy.", "BACKGROUND: A wide variety of short-read alignment programmes have been published recently to tackle the problem of mapping millions of short reads to a reference genome, focusing on different aspects of the procedure such as time and memory efficiency, sensitivity, and accuracy. These tools allow for a small number of mismatches in the alignment; however, their ability to allow for gaps varies greatly, with many performing poorly or not allowing them at all. The seed-and-extend strategy is applied in most short-read alignment programmes. After aligning a substring of the reference sequence against the high-quality prefix of a short read--the seed--an important problem is to find the best possible alignment between a substring of the reference sequence succeeding and the remaining suffix of low quality of the read--extend. The fact that the reads are rather short and that the gap occurrence frequency observed in various studies is rather low suggest that aligning (parts of) those reads with a single gap is in fact desirable.RESULTS: In this article, we present libgapmis, a library for extending pairwise short-read alignments. Apart from the standard CPU version, it includes ultrafast SSE- and GPU-based implementations. libgapmis is based on an algorithm computing a modified version of the traditional dynamic-programming matrix for sequence alignment. Extensive experimental results demonstrate that the functions of the CPU version provided in this library accelerate the computations by a factor of 20 compared to other programmes. The analogous SSE- and GPU-based implementations accelerate the computations by a factor of 6 and 11, respectively, compared to the CPU version. The library also provides the user the flexibility to split the read into fragments, based on the observed gap occurrence frequency and the length of the read, thereby allowing for a variable, but bounded, number of gaps in the alignment.CONCLUSIONS: We present libgapmis, a library for extending pairwise short-read alignments. We show that libgapmis is better-suited and more efficient than existing algorithms for this task. The importance of our contribution is underlined by the fact that the provided functions may be seamlessly integrated into any short-read alignment pipeline. The open-source code of libgapmis is available at http://www.exelixis-lab.org/gapmis.", "Athelia is a very rare entity that is defined by the absence of the nipple-areola complex. It can affect either sex and is mostly part of syndromes including other congenital or ectodermal anomalies, such as limb-mammary syndrome, scalp-ear-nipple syndrome, or ectodermal dysplasias. Here, we report on three children from two branches of an extended consanguineous Israeli Arab family, a girl and two boys, who presented with a spectrum of nipple anomalies ranging from unilateral hypothelia to bilateral athelia but no other consistently associated anomalies except a characteristic eyebrow shape. Using homozygosity mapping after single nucleotide polymorphism (SNP) array genotyping and candidate gene sequencing we identified a homozygous frameshift mutation in PTPRF as the likely cause of nipple anomalies in this family. PTPRF encodes a receptor-type protein phosphatase that localizes to adherens junctions and may be involved in the regulation of epithelial cell-cell contacts, peptide growth factor signaling, and the canonical Wnt pathway. Together with previous reports on female mutant Ptprf mice, which have a lactation defect, and disruption of one allele of PTPRF by a balanced translocation in a woman with amastia, our results indicate a key role for PTPRF in the development of the nipple-areola region.", "OBJECTIVE: To determine whether chronic treatment with celecoxib, a cyclooxygenase-2 inhibitor that has been shown to be beneficial in preclinical testing, is safe and effective in amyotrophic lateral sclerosis (ALS).METHODS: A double-blind, placebo-controlled, clinical trial was conducted. Three hundred research subjects with ALS were randomized (2:1) to receive celecoxib (800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function measured by the maximum voluntary isometric contraction strength. Secondary end points included safety, survival, change in cerebrospinal fluid prostaglandin E(2) levels, and changes in the rate of decline of leg and grip strength, vital capacity, ALS Functional Rating Scale-Revised, and motor unit number estimates.RESULTS: Celecoxib did not slow the decline in muscle strength, vital capacity, motor unit number estimates, ALS Functional Rating Scale-Revised, or affect survival. Celecoxib was well tolerated and was not associated with an increased frequency of adverse events. Prostaglandin E(2) levels in cerebrospinal fluid were not elevated at baseline and did not decline with treatment.INTERPRETATION: At the dosage studied, celecoxib did not have a beneficial effect on research subjects with ALS, and it was safe. A biological effect of celecoxib was not demonstrated in the cerebrospinal fluid. Further studies of celecoxib at a dosage of 800 mg/day in ALS are not warranted.", "Dominantly acting, allelic mutations of the fibroblast growth factor receptor 2 (FGFR2) gene have been described in five craniosynostosis syndromes. In Apert syndrome, characterised by syndactyly of the hands and feet, recurrent mutations of a serine-proline dipeptide (either Ser252Trp or Pro253Arg) in the linker between the IgII and IgIII extracellular immunoglobulin-like domains, have been documented in more than 160 unrelated individuals. We have identified three novel mutations of this dipeptide, associated with distinct phenotypes. A C-->T mutation that predicts a Ser252Leu substitution, ascertained in a boy with mild Crouzon syndrome (craniosynostosis with normal limbs) is also present in three clinically normal members of his family. A CG-->TT mutation that predicts a Ser252Phe substitution results in a phenotype consistent with Apert syndrome. Finally, a CGC-->TCT mutation that predicts a double amino acid substitution (Ser252Phe and Pro253Ser) causes a Pfeiffer syndrome variant with mild craniosynostosis, broad thumbs and big toes, fixed extension of several digits, and only minimal cutaneous syndactyly. The observation that the Ser252Phe mutation causes Apert syndrome, whereas the other single or double substitutions are associated with milder or normal phenotypes, highlights the exquisitely specific molecular pathogenesis of the limb and craniofacial abnormalities associated with Apert syndrome. Ser252Phe is the first noncanonical mutation to be identified in this disorder, its rarity being explained by the requirement for two residues of the serine codon to be mutated. The description of independent, complex nucleotide substitutions involving identical nucleotides is unprecedented, and we speculate that this may result from functional selection of FGFR mutations in sperm." ]

[ "LHCII, the largest plant photosynthetic pigment-protein complex of photosystem II, is a most abundant membrane protein in living organisms and comprises approximately half of the pool of chlorophyll molecules in the biosphere. The principal role of this pigment-protein complex is to collect sunlight quanta and transfer electronic excitations toward the reaction centers, where the primary photosynthetic electric charge separation reactions take place. The LHCII protein, as a major protein component of the photosynthetic membranes, modulates also the structural and dynamic properties of the lipid phase of the membranes. According to the recent concepts, one of the physiological roles of LHCII is also a protection of the photosynthetic apparatus against oxidative damage caused by illumination with high intensity light. Detailed examination of all those physiological functions of LHCII, in relation to the complex structure, was possible owing to the application of several molecular spectroscopy techniques. Some examples of such studies are presented in this chapter. The examples of application of steady-state and time-resolved fluorescence spectroscopy, Fourier-transform infrared absorption spectroscopy, and resonance Raman scattering spectroscopy are presented and discussed.", "BACKGROUND & AIMS: Vesatolimod (GS-9620) is an oral agonist of toll-like receptor 7, an activator of innate and adaptive immune responses. Herein the safety and efficacy of vesatolimod is assessed after once-weekly treatment in patients with chronic hepatitis B (CHB) infection suppressed on oral antiviral treatment.METHODS: In a phase II, double-blind, randomized, placebo (PBO)-controlled study, 162 patients stratified by hepatitis B surface antigen (HBsAg) levels and serum hepatitis B e antigen (HBeAg) status were randomized 1:3:3:3 to once-weekly oral PBO or vesatolimod (1-, 2-, or 4-mg doses) for 4, 8 or 12 weeks per cohort. Efficacy was assessed by change in baseline HBsAg (log10 IU/ml) at the primary endpoint (Week 24). Safety assessments included adverse events (AE) and laboratory abnormality monitoring. Pharmacodynamic assessments included peripheral cytokine level quantification and interferon-stimulated gene (ISG) mRNA expression evaluation.RESULTS: The majority of patients were male (76%) and HBeAg-negative (79%) at baseline. Most (41-80%) experienced ≥1 AE during the study with the majority of AEs mild or moderate in severity. No significant declines in HBsAg were observed at the primary (Week 24) or secondary endpoints (Weeks 4, 8, 12, and 48). ISG15 induction was dose-dependent and consistent after repeat dosing, returning closer to baseline by one week after treatment at all dose levels; no patient demonstrated significant serum interferon alpha (IFNα) expression at any timepoint evaluated. Multivariate analyses showed that ≥2-fold ISG15 induction is associated with 2- or 4-mg vesatolimod dose and female sex.CONCLUSIONS: Vesatolimod was safe and well-tolerated in patients with CHB, demonstrating consistent dose-dependent pharmacodynamic induction of ISG15 without significant systemic induction of IFNα expression or related symptoms. However, no significant HBsAg declines were observed.LAY SUMMARY: In a phase II study, vesatolimod, an oral, once-weekly, experimental immune-activating drug for the treatment of hepatitis B virus (HBV), is safe and well-tolerated in chronic HBV patients who are virally suppressed on oral antiviral treatment. Despite demonstrating on-target biomarker responses in patients, no significant declines in hepatitis B surface antigen were observed. Clinical Trial Number: GS-US-283-1059; NCT 02166047.", "Author information:(1)a Medical University of Vienna , Department of Cell- and Developmental Biology , Vienna , Austria.(2)b UNIVERSITA DEGLI STUDI DI TRENTO , Italy.(3)c CEITEC, Masaryk University , Brno , Czech Republic.(4)d Johannes Gutenberg Universitat Mainz , Mainz , Germany.(5)e University of Cambridge , Cambridge , United Kingdom.(6)f Hospital Complex of Malaga (Virgen de la Victoria) , Malaga , Spain.(7)g Stockholm University , Sweden.(8)h IMBA - Institute of Molecular Biotechnology , Vienna , Austria.(9)i Molecular and Cellular Epigenetics, Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege , Sart Tilman , Belgium.(10)j ULB-Faculty of Medicine , Brussels , Belgium.(11)k The Cyprus Institute of Neurology & Genetics (CING) , Cyprus.(12)l University of Copenhagen , Copenhagen , Denmark.(13)m CNRS, University of Perpignan , Perpignan , France.(14)n Lorraine University -CNRS Biopole UL , Lorraine , France.(15)o Institute of Molecular Biology , Mainz , Germany.(16)p University of Thessaly , Department of Biochemistry and Biotechnology Thessaly , Greece.(17)q Biotalentum Ltd Gödöllö , Hungary.(18)r University College Cork Biochemistry Department , Cork , Ireland.(19)s Trinity College Dublin Trinity Biomedical Sciences Institute , Dublin , Ireland.(20)t Technion - Israel institute of technology , Haifa , Israel.(21)u Tel Aviv University , Tel Aviv , Israel.(22)v Center for Genomic Science of IIT@SEMM , Milano , Italy.(23)w University of Latvia , Riga , Latvia.(24)x Riga Stradins University A.Kirhensteins Institute of Microbiology , Riga , Latvia.(25)y National Blood Transfusion Service, St. Luke's Hospital , Malta.(26)z University of Malta Centre for Molecular Medicine and Biobanking Biomedical sciences , Malta.(27)aa Norwegian University of Science and Technology Department of Cancer Research and Molecular Medicine, Faculty of Medicine Norwegian , Trondheim , Norway.(28)ab Oslo University Hospital , Oslo , Norway.(29)ac International Institute of Molecular and Cell Biology in Warsaw , Poland.(30)ad Instituto Portugues de Oncologia do Porto , Porto , Portugal.(31)ae IPATIMUP , Porto , Portugal.(32)af \"Victor Babes\" National Institute of Pathology Bucharest , Romania.(33)ag Faculty of Biology , University o Bucharest , Bucharest , Romania.(34)ah Institute for Biological Research \"Sinisa Stankovic\" , Belgrade , Serbia.(35)ai Institute of Molecular Genetics and Genetic Engineering, University of Belgrade , Belgrade , Serbia.(36)aj Faculty of Pharmacy, University of Bratislava , Slovakia.(37)ak Fundacion para la Gestion de la Investigacion Biomedica de Cadiz , Cadiz , Spain.(38)al Polygene AG , Zürich , Switzerland.(39)am Gebze Technical University , Gebze , Turkey.(40)an Istanbul Medipol University , Istanbul , Turkey.(41)ao University of Dundee Centre for Gene Regulation and Expression School of Life Sciences , Dundee , United Kingdom.(42)ap Universite Libre de Bruxelles , Gosselies , Belgium.(43)aq Institut de Genomique Fonctionnelle , Montpellier , France.(44)ar Institut de Biologie Paris Seine - Pierre et Marie Curie University Institut de Biologie Paris , Paris , France.(45)as German Cancer Research Center , Heidelberg , Germany.(46)at University of Kassel , Kassel , Germany.(47)au Weizmann Institute of Science , Rehovot , Israel.(48)av Institute for Advanced Bioscience , Grenoble , France.(49)aw Fundacion IMDEA Alimentacion Ctra . de Canto Blanco, Madrid , Spain.(50)ax Germans Trias i Pujol Research Institute , Barcelona , Spain.(51)ay University of Edinburgh MRC Centre for Regenerative Medicine , Edinburgh , United Kingdom.(52)az The Francis Crick Institute , London , United Kingdom.(53)ba University of Nottingham School of Biosceinces , Nottingham , United Kingdom.", "The hallmark of Ewing's sarcoma (EWS) is a translocation--t(11;22)(q24;q12)--that most frequently results in the EWS/FLI1 aberrant chimeric gene. Because EWS afflicts young patients, it stands out among the diverse sarcoma subtypes. The frontline, standard-of-care cytotoxic chemotherapy regimens produce minimal benefit in patients with metastases at presentation or those with relapsed disease. While the outcomes of chemorefractory EWS patients are generally poor, recent developments have led to the promising use of targeted therapy. Specifically, inhibition of insulin-like growth factor 1 receptor (IGF1R) signaling and the mammalian target of rapamycin (mTOR) pathways has emerged as a targeted therapy in EWS, with select patients experiencing dramatic therapeutic responses. However, targeted therapies in general, and these responders in particular, are faced with the ultimate conundrum of eventual resistance. To optimize response, combining IGF1R and mTOR inhibitor-based regimens with chemotherapy in the upfront setting in newly diagnosed high-risk EWS may clarify the true benefit of IGF1R inhibitors in these patients. Another option is to explore novel targeted multikinase inhibitors and poly(ADP-ribose) polymerase (PARP) inhibitors, which have experienced a surge in supporting preclinical data. Drugs inhibiting the downstream targets of EWS/FLI1 are also in preclinical development. However, ultimately, the underlying biomarker correlates of resistance and response must be delineated along with ways to overcome them. Novel agents, together with integration of advances in multimodal approaches (including surgery and radiation), as well as offering targeted therapies early in the disease course represent new strategies for confronting the challenges of EWS.", "BACKGROUND: Mitogen-activated protein kinase (MAPK) cascades (p38, JNK, ERK pathways) are involved in cell fate acquisition during development. These kinase modules are associated with scaffold proteins that control their activity. In Drosophila, dMP1, that encodes an ERK scaffold protein, regulates ERK signaling during wing development and contributes to intervein and vein cell differentiation. Functional relationships during wing development between a chromatin regulator, the Enhancer of Trithorax and Polycomb Corto, ERK and its scaffold protein dMP1, are examined here.RESULTS: Genetic interactions show that corto and dMP1 act together to antagonize rolled (which encodes ERK) in the future intervein cells, thus promoting intervein fate. Although Corto, ERK and dMP1 are present in both cytoplasmic and nucleus compartments, they interact exclusively in nucleus extracts. Furthermore, Corto, ERK and dMP1 co-localize on several sites on polytene chromosomes, suggesting that they regulate gene expression directly on chromatin. Finally, Corto is phosphorylated. Interestingly, its phosphorylation pattern differs between cytoplasm and nucleus and changes upon ERK activation.CONCLUSIONS: Our data therefore suggest that the Enhancer of Trithorax and Polycomb Corto could participate in regulating vein and intervein genes during wing tissue development in response to ERK signaling.", "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.", "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." ]

[ "OBJECTIVE: Ruptured vertebrobasilar (VB) saccular aneurysm is a difficult lesion to treat, and is associated with high rates of morbidity and mortality. The aim of this study is to investigate the risk factors associated with the clinical outcome of ruptured VB aneurysms.METHODS: A retrospective review of 29 patients with ruptured VB saccular aneurysms between 2002 and 2010 was conducted between Jan 2002 and Dec 2010. Univariate and multivariate analyses were performed for determination of the statistical significance of the Glasgow Outcome Scale (GOS) at three months, according to age, initial Hunt-Hess grade, the presence of acute hydrocephalus, and treatment modality.RESULTS: The study included 24 (82.7%) females and five (17.3%) males, with a mean age of 59 years (range, 22-78 years). Seventeen patients were treated with surgical clipping and 12 patients were treated with endovascular coil embolization. No statistical significance was observed between clinical outcome and treatment modalities (clipping or coiling; p = 0.803). Seventeen (58.6%) patients achieved favorable outcome, defined as GOS score of 4-5, at 3 months. Procedure-related complications occurred in seven patients (24.1%). Results of multivariate analysis indicated that initial Hunt-Hess grade and the presence of acute hydrocephalus were independent predictors of unfavorable outcome, defined as GOS score of 1-3 (Odds ratio (OR) = 8.63, Confidence interval (CI) [95%] 1.11-66.84, p = 0.039 and OR = 36.64, CI [95%] 2.23-599.54, p = 0.012, respectively).CONCLUSION: The present study suggests that the clinical outcomes are related to the initial Hunt-Hess grade and the presence of acute hydrocephalus in ruptured saccular VB aneurysms.", "Statins have been shown to decrease depressive symptoms in certain groups of patients, an effect that is mostly attributed to their anti-inflammatory and neurotransmitter modulatory potentials. We aimed to investigate the antidepressant effects of simvastatin as an adjuvant therapy in patients with moderate to severe depression. In this double-blind placebo-controlled clinical trial, 48 patients were randomly allocated to receive simvastatin or placebo as an adjunct to fluoxetine for six weeks. Patients were evaluated with the Hamilton Depression Rating Scale (HDRS) at baseline and weeks 2, 4 and 6. Probable clinical and laboratory adverse events were also monitored and compared between the two groups. Simvastatin-treated patients experienced significantly more reductions in HDRS scores compared to the placebo group by the end of the trial (p=0.02). Early improvement and response rates were significantly greater in the simvastatin group than the placebo group (p=0.02 and p=0.01, respectively) but remission rate was not significantly different between the two groups (p=0.36). No serious adverse event was reported during this trial. In conclusion, simvastatin seems to be a safe and effective adjuvant therapy for patients suffering from major depressive disorder. However, more confirmatory studies are warranted.", "The origin recognition complex (ORC) of Saccharomyces cerevisiae binds origin DNA and cooperates with Cdc6 and Cdt1 to load the replicative helicase MCM2-7 onto DNA. Helicase loading involves two MCM2-7 hexamers that assemble into a double hexamer around double-stranded DNA. This reaction requires ORC and Cdc6 ATPase activity, but it is unknown how these proteins control MCM2-7 double hexamer formation. We demonstrate that mutations in Cdc6 sensor-2 and Walker A motifs, which are predicted to affect ATP binding, influence the ORC-Cdc6 interaction and MCM2-7 recruitment. In contrast, a Cdc6 sensor-1 mutant affects MCM2-7 loading and Cdt1 release, similar as a Cdc6 Walker B ATPase mutant. Moreover, we show that Orc1 ATP hydrolysis is not involved in helicase loading or in releasing ORC from loaded MCM2-7. To determine whether Cdc6 regulates MCM2-7 double hexamer formation, we analysed complex assembly. We discovered that inhibition of Cdc6 ATPase restricts MCM2-7 association with origin DNA to a single hexamer, while active Cdc6 ATPase promotes recruitment of two MCM2-7 hexamer to origin DNA. Our findings illustrate how conserved Cdc6 AAA+ motifs modulate MCM2-7 recruitment, show that ATPase activity is required for MCM2-7 hexamer dimerization and demonstrate that MCM2-7 hexamers are recruited to origins in a consecutive process.", "INTRODUCTION: Pediatric Index of Mortality 2 (PIM2) and Pediatric Risk of Mortality (PRISM) are scoring systems to predict mortality likehood; thus, it is necessary to validate such predictors in Pediatric Intensive Care Units' population.OBJECTIVE: To assess the validity of PRISM and PIM2 models of Mortality in Pediatrics Intensive Care Units at Hospital Infantil de Córdoba (PICUHI).POPULATION, MATERIAL AND METHODS: 435 critically ill admitted patients were retrospectively analized in PICUHI from January 1st 2008 to January 31st 2008; 416 were included in the study, ruling out elective admitted patients with less than 12 hour at PICU length stay. There were no deaths in this Group. Original equations for each models, were used. Calibration was performed (p> 0.05) using Hosmer- Lemeshow (HL) goodness-of-fit tests. Scores were assessed through Standardized Mortality Ratio (SMR) and discrimination between patients alived and dead, was estimated calculating the area under ROC curve.RESULTS: 416 admitted patients were included, (55.04%) were male 55.04%, median age was 3 years (1 month-17 years), with a median of 2 (1-76) admitted days in PICU. Mortality was 6.66%. PIM2 had an area under ROC curve of 0.88 (CI 95% 0.82-0.95) and PRIMS: 0.85 (CI 95% 0.78-0.92), with p 0.3570 value. HL calibration for PRISM was: x2 5.93 (p 0.54), and PIM2 was: x2 14.19 (p 0.07). PRISM, Standardized Mortality Ratio (SMR) was: 1.00 (CI 95% 0.50-1.50) and PIM2 was 1.00 (CI 95% 0.55-1.55).CONCLUSIONS: Both scores discriminated and calibrated well as the p-value of the HL test, althougt the analysis of the HL table appears inadequate to PIM2 calibration, in terms of severity-adjusted mortality.", "Platelet-derived growth factor (PDGF) receptor (PDGFR) expression correlates with metastatic medulloblastoma. PDGF stimulation of medulloblastoma cells phosphorylates extracellular signal-regulated kinase (ERK) and promotes migration. We sought to determine whether blocking PDGFR activity effectively inhibits signaling required for medulloblastoma cell migration and invasion. DAOY and D556 human medulloblastoma cells were treated with imatinib mesylate (Gleevec), a PDGFR tyrosine kinase inhibitor, or transfected with small interfering RNA (siRNA) to PDGFRB to test the effects of blocking PDGFR phosphorylation and expression, respectively. PDGFR cell signaling, migration, invasion, survival, and proliferation following PDGF-BB stimulation, with and without PDGFR inhibition, were measured. PDGF-BB treatment of cells increased PDGFRB, Akt and ERK phosphorylation, and transactivated epidermal growth factor receptor (EGFR), which correlated with enhanced migration, survival, and proliferation. Imatinib (1 μmol/L) treatment of DAOY and D556 cells inhibited PDGF-BB- and serum-mediated migration and invasion at 24 and 48 h, respectively, and concomitantly inhibited PDGF-BB activation of PDGFRB, Akt, and ERK but increased PTEN expression and activity. Imatinib treatment also induced DAOY cell apoptosis at 72 h and inhibited DAOY and D556 cell proliferation at 48 h. siRNA silencing of PDGFRB similarly inhibited signaling, migration, and survival and both siRNA and imatinib treatment inhibited PDGF-BB-mediated EGFR transactivation, indicating that the effects of imatinib treatment are specific to PDGFRB target inhibition. These results indicate that PDGFRB tyrosine kinase activity is critical for migration and invasion of medulloblastoma cells possibly by transactivating EGFR; thus, imatinib may represent an important novel therapeutic agent for the treatment of medulloblastoma.", "Portable, on-site blood typing methods will help provide life-saving blood transfusions to patients during an emergency or natural calamity, such as significant earthquakes. We have previously developed waveguide-mode (WM) sensors for forward ABO and Rh(D) blood typing and detection of antibodies against hepatitis B virus and hepatitis C virus. In this study, we evaluated a WM-sensor for reverse ABO blood typing. Since reverse ABO blood typing is a method for detection of antibodies against type A and type B oligosaccharide antigens on the surface of red blood cells (RBCs), we fixed a synthetic type A or type B trisaccharide antigen on the sensor chip of the WM sensor. We obtained significant changes in the reflectance spectra from a WM sensor on type A antigen with type B plasma and type O plasma and on type B antigen with type A plasma and type O plasma, and no spectrum changes on type A antigen or type B antigen with type AB plasma. Signal enhancement with the addition of a peroxidase reaction failed to increase the sensitivity for detection on oligosaccharide chips. By utilizing hemagglutination detection using regent type A and type B RBCs, we successfully determined reverse ABO blood groups with higher sensitivity compared to a method using oligosaccharide antigens. Thus, functionality of a portable device utilizing a WM sensor can be expanded to include reverse ABO blood typing and, in combination with forward ABO typing and antivirus antibody detection, may be useful for on-site blood testing in emergency settings.", "Growth factor independence 1b (GFI1B) is a DNA binding repressor of transcription with vital functions in hematopoiesis. Gfi1b-null embryos die at midgestation very likely due to defects in erythro- and megakaryopoiesis. To analyze the full functionality of Gfi1b, we used conditionally deficient mice that harbor floxed Gfi1b alleles and inducible (Mx-Cre, Cre-ERT) or erythroid specific (EpoR-Cre) Cre expressing transgenes. In contrast to the germline knockout, EpoR-Cre mediated erythroid specific ablation of Gfi1b allows full gestation, but causes perinatal lethality with very few mice surviving to adulthood. Both the embryonic deletion of Gfi1b by EpoR-Cre and the deletion in adult mice by Mx-Cre or Cre-ERT leads to reduced numbers of erythroid precursors, perturbed and delayed erythroid maturation, anemia and extramedullary erythropoiesis. Global expression analyses showed that the Hba-x, Hbb-bh1 and Hbb-y embryonic globin genes were upregulated in Gfi1b deficient TER119+ fetal liver cells over the gestation period from day 12.5-17.5 p.c. and an increased level of Hbb-bh1 and Hbb-y embryonic globin gene expression was even maintained in adult Gfi1b deficient mice. While the expression of Bcl11a, a regulator of embryonic globin expression was not affected by Gfi1b deficiency, the expression of Gata1 was reduced and the expression of Sox6, also involved in globin switch, was almost entirely lost when Gfi1b was absent. These findings establish Gfi1b as a regulator of embryonic globin expression and embryonic and adult erythroid maturation." ]

[ "BACKGROUND: The Joint Asia Diabetes Evaluation (JADE) Program is a web-based program incorporating a comprehensive risk engine, care protocols, and clinical decision support to improve ambulatory diabetes care.METHODS: The JADE Program uses information technology to facilitate healthcare professionals to create a diabetes registry and to deliver an evidence-based care and education protocol tailored to patients' risk profiles. With written informed consent from participating patients and care providers, all data are anonymized and stored in a databank to establish an Asian Diabetes Database for research and publication purpose.RESULTS: The JADE electronic portal (e-portal: http://www.jade-adf.org) is implemented as a Java application using the Apache web server, the mySQL database and the Cocoon framework. The JADE e-portal comprises a risk engine which predicts 5-year probability of major clinical events based on parameters collected during an annual comprehensive assessment. Based on this risk stratification, the JADE e-portal recommends a care protocol tailored to these risk levels with decision support triggered by various risk factors. Apart from establishing a registry for quality assurance and data tracking, the JADE e-portal also displays trends of risk factor control at each visit to promote doctor-patient dialogues and to empower both parties to make informed decisions.CONCLUSIONS: The JADE Program is a prototype using information technology to facilitate implementation of a comprehensive care model, as recommended by the International Diabetes Federation. It also enables health care teams to record, manage, track and analyze the clinical course and outcomes of people with diabetes.", "BACKGROUND: Human protein-protein interaction (PPIs) data are the foundation for understanding molecular signalling networks and the functional roles of biomolecules. Several human PPI databases have become available; however, comparisons of these datasets have suggested limited data coverage and poor data quality. Ongoing collection and integration of human PPIs from different sources, both experimentally and computationally, can enable disease-specific network biology modelling in translational bioinformatics studies.RESULTS: We developed a new web-based resource, the Human Annotated and Predicted Protein Interaction (HAPPI) database, located at http://bio.informatics.iupui.edu/HAPPI/. The HAPPI database was created by extracting and integrating publicly available protein interaction databases, including HPRD, BIND, MINT, STRING, and OPHID, using database integration techniques. We designed a unified entity-relationship data model to resolve semantic level differences of diverse concepts involved in PPI data integration. We applied a unified scoring model to give each PPI a measure of its reliability that can place each PPI at one of the five star rank levels from 1 to 5. We assessed the quality of PPIs contained in the new HAPPI database, using evolutionary conserved co-expression pairs called \"MetaGene\" pairs to measure the extent of MetaGene pair and PPI pair overlaps. While the overall quality of the HAPPI database across all star ranks is comparable to the overall qualities of HPRD or IntNetDB, the subset of the HAPPI database with star ranks between 3 and 5 has a much higher average quality than all other human PPI databases. As of summer 2008, the database contains 142,956 non-redundant, medium to high-confidence level human protein interaction pairs among 10,592 human proteins. The HAPPI database web application also provides ...\" should be \"The HAPPI database web application also provides hyperlinked information of genes, pathways, protein domains, protein structure displays, and sequence feature maps for interactive exploration of PPI data in the database.CONCLUSION: HAPPI is by far the most comprehensive public compilation of human protein interaction information. It enables its users to fully explore PPI data with quality measures and annotated information necessary for emerging network biology studies.", "Recent releases of genome three-dimensional (3D) structures have the potential to transform our understanding of genomes. Nonetheless, the storage technology and visualization tools need to evolve to offer to the scientific community fast and convenient access to these data. We introduce simultaneously a database system to store and query 3D genomic data (3DBG), and a 3D genome browser to visualize and explore 3D genome structures (3DGB). We benchmark 3DBG against state-of-the-art systems and demonstrate that it is faster than previous solutions, and importantly gracefully scales with the size of data. We also illustrate the usefulness of our 3D genome Web browser to explore human genome structures. The 3D genome browser is available at http://3dgb.cs.mcgill.ca/.", "Mature cystic teratomas have been widely studied relative to their tissue components derived from all 3 embryonic layers, and immunohistochemical methods have demonstrated a variety of neurohormonal polypeptides. To our knowledge, Langerhans cells (LCs), which are a peculiar component of epidermis, have not been reported in ovarian teratomas. The origin of these cells is still a matter of debate, ranging from bone marrow stem cells to neural elements. Thirty mature teratomas of the ovary were studied by immunohistochemistry using CD1 (specific against dendritic LCs), S100 protein (against LCs and melanocytes), and melan-A and HMB45 (against melanocytes). Furthermore, antibodies for identifying subsets of lymphocytes and monocytes (CD3, CD4, CD8, CD20, and CD68) were used. Histologic examination showed teratomas with the presence of all 3 embryonic layers in variable proportions in 23 cases, while 7 teratomas were composed only of epidermis without appendages or other tissues. Immunohistochemistry identified LCs among the suprabasal layers of epidermis in the same sites at which melanocytes were seen in the basal layer. CD1-positive LCs sometimes appeared to cross the basal membrane and penetrate the subepidermal tissue (related to their known migratory ability), and they were associated there with T-cell line lymphocytes (CD3 positive). These findings were commonly observed in teratomas that included all 3 embryonic layers and neural tissues. Notably, LCs and melanocytes were undetectable in the 7 teratomas composed of epidermis only. Our observations of LCs in ovarian teratomas led us to consider these cells to be derived from neural cells, possibly related to Schwann cells, in accord with the original description by Langerhans. In fact, LCs are always associated with melanocytes, which are universally considered to be derived from the neural crest, as are Schwann cells and peripheral nerves. Finally, we propose that LCs may be part of a cytoimmunologic system related to the T-cell compartment, with a stem cell derived from the neural crest.", "OBJECTIVE: To examine the 1-month prevalence of generalized anxiety disorder (GAD) according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), Diagnostic and Statistical Manual of Mental, Fifth Edition (DSM-V), and International Classification of Diseases, Tenth Revision (ICD-10), and the overlap between these criteria, in a population sample of 75-year-olds. We also aimed to examine comorbidity between GAD and other psychiatric diagnoses, such as depression.METHOD: During 2005-2006, a comprehensive semistructured psychiatric interview was conducted by trained nurses in a representative population sample of 75-year-olds without dementia in Gothenburg, Sweden (N = 777; 299 men and 478 women). All psychiatric diagnoses were made according to DSM-IV. GAD was also diagnosed according to ICD-10 and DSM-V.RESULTS: The 1-month prevalence of GAD was 4.1% (N = 32) according to DSM-IV, 4.5% (N = 35) according to DSM-V, and 3.7% (N = 29) according to ICD-10. Only 46.9% of those with DSM-IV GAD fulfilled ICD-10 criteria, and only 51.7% and 44.8% of those with ICD-10 GAD fulfilled DSM-IV/V criteria. Instead, 84.4% and 74.3% of those with DSM-IV/V GAD and 89.7% of those with ICD-10 GAD had depression. Also other psychiatric diagnoses were common in those with ICD-10 and DSM-IV GAD. Only a small minority with GAD, irrespective of criteria, had no other comorbid psychiatric disorder. ICD-10 GAD was related to an increased mortality rate.CONCLUSIONS: While GAD was common in 75-year-olds, DSM-IV/V and ICD-10 captured different individuals. Current definitions of GAD may comprise two different expressions of the disease. There was greater congruence between GAD in either classification system and depression than between DSM-IV/V GAD and ICD-10 GAD, emphasizing the close link between these entities.", "Author information:(1)Bioinformatics and Genomics Program, The Pennsylvania State University, University Park, State College, PA, 16802, USA.(2)Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State Hershey, Hershey, PA, 17033, USA.(3)Department of Computer and Information Science, University of Pennsylvania, Philadelphia, PA, 19104, USA.(4)Department of Genetics, The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, 63108, USA.(5)Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA.(6)Department of Biostatistics, University of North Carolina, Chapel Hill, NC, 27599, USA.(7)Department of Computer Science, University of North Carolina, Chapel Hill, NC, 27599, USA.(8)Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA.(9)Center for Computational Biology and Bioinformatics, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, State College, PA, 16802, USA.(10)Department of Genetics, The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, 63108, USA. twang@genetics.wustl.edu.(11)Bioinformatics and Genomics Program, The Pennsylvania State University, University Park, State College, PA, 16802, USA. fyue@hmc.psu.edu.(12)Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State Hershey, Hershey, PA, 17033, USA. fyue@hmc.psu.edu.", "The expression level of the HER family is unreliable as a predictive marker for targeted therapies in cancer. Thus, there is a need to develop other biomarkers, which can be used to accurately select responsive patients for targeted therapies. The HER dimerization status may be more important than HER receptor expression per se in determining sensitivity or resistance to a given therapeutic agent. The aim of the study is to develop a FRET assay using dye conjugated secondary antibodies to assess HER receptor dimerization. Using primary antibodies from different species in conjunction with Alexa488 and Alexa546 conjugated secondary antibodies, we validated our EGFR/HER2 dimerization assay in three cell lines, EGFR positive A431 cells as well as HER2 positive breast cell lines BT474 and SKBR3 cells. Finally, we applied our assay to assess EGFR/HER2 dimerization in paraffin embedded cell pellets. Our results show promise for the assay to be applied to tumor samples in order to assess the prognostic significance and predictive value of HER receptor dimerization in various cancers.", "Couvelaire uterus is rare in modern obstetrics, a state of the hematic infiltration uterine myometrium due to the formation of a massive hematoma retroplacental that can not be sold to the vaginal cavity through the cervical route. In all cases described in the present there is a history of placental abruption during labor or trauma, and drugs that affect the collapse of the uterus-placental circulation" ]

[ "Miller-Dieker syndrome involves a severe type of lissencephaly, which is caused by defects in the lissencephaly gene (LIS1). We report the case of a female infant with der(17)t(12;17)(q24.33;p13.3)pat caused by an unbalanced segregation of the parental balanced translocation of 17p with other chromosomes. The proband presented with facial dysmorphism, arthrogryposis, and intrauterine growth retardation. Most cases of Miller-Dieker syndrome have a de novo deletion involving 17p13.3. When Miller-Dieker syndrome is caused by an unbalanced translocation, mild-to-severe phenotypes occur according to the extension of the involved partner chromosome. However, a pure partial monosomy derived from a paternal balanced translocation is relatively rare. In this case, the submicroscopic cryptic deletion in the proband was initially elucidated by FISH, and karyotype analysis did not reveal additional chromosome abnormalities such as translocation. However, a family history of recurrent pregnancy abnormalities strongly suggested familial translocation. Sequential G-banding and FISH analysis of the father's chromosomes showed that the segment of 17p13.3→pter was attached to the 12qter. Thus, we report a case that showed resemblance to the findings in cases of a nearly pure 17p deletion, derived from t(12;17), and delineated by whole genome array comparative genomic hybridization (CGH). If such cases are incorrectly diagnosed as Miller-Dieker syndrome caused by de novo 17p13.3 deletion, the resultant improper genetic counseling may make it difficult to exactly predict the potential risk of recurrent lissencephaly for successive pregnancies.", "Author information:(1)Queen Mary University of London, London E1 4NS, UK; Genomics England Ltd., London EC1M 6BQ, UK.(2)Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.(3)Skarnes Faculty Group, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.(4)Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61-704 Poznan, Poland.(5)Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany.(6)Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.(7)Department of Biomedical Informatics and Intelligent Systems Program, University of Pittsburgh, Pittsburgh, PA 15206, USA.(8)Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.(9)Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR 97239, USA.(10)Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine University of New South Wales, Darlinghurst, NSW 2010, Australia.(11)Anacleto Lab Department of Computer Science, University of Milan, Via Comelico, 20135 Milan, Italy.(12)Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Institute for Bioinformatics, Department of Mathematics and Computer Science, Freie Universität Berlin, Takustrasse, 14195 Berlin, Germany. Electronic address: peter.robinson@jax.org.", "Mexico City Metropolitan Area children chronically exposed to high concentrations of air pollutants exhibit an early brain imbalance in genes involved in oxidative stress, inflammation, innate and adaptive immune responses along with accumulation of misfolded proteins observed in the early stages of Alzheimer and Parkinson's diseases. A complex modulation of serum cytokines and chemokines influences children's brain structural and gray/white matter volumetric responses to air pollution. The search for biomarkers associating systemic and CNS inflammation to brain growth and cognitive deficits in the short term and neurodegeneration in the long-term is our principal aim. We explored and compared a profile of cytokines, chemokines (Multiplexing LASER Bead Technology) and Cellular prion protein (PrP(C)) in normal cerebro-spinal-fluid (CSF) of urban children with high vs. low air pollution exposures. PrP(C) and macrophage inhibitory factor (MIF) were also measured in serum. Samples from 139 children ages 11.91 ± 4.2 years were measured. Highly exposed children exhibited significant increases in CSF MIF (p = 0.002), IL6 (p = 0.006), IL1ra (p = 0.014), IL-2 (p = 0.04), and PrP(C) (p = 0.039) vs. controls. MIF serum concentrations were higher in exposed children (p = 0.009). Our results suggest CSF as a MIF, IL6, IL1Ra, IL-2, and PrP(C) compartment that can possibly differentiate air pollution exposures in children. MIF, a key neuro-immune mediator, is a potential biomarker bridge to identify children with CNS inflammation. Fine tuning of immune-to-brain communication is crucial to neural networks appropriate functioning, thus the short and long term effects of systemic inflammation and dysregulated neural immune responses are of deep concern for millions of exposed children. Defining the linkage and the health consequences of the brain / immune system interactions in the developing brain chronically exposed to air pollutants ought to be of pressing importance for public health.", "Interactions between malignant B lymphocytes and the tissue microenvironment play a major role in the pathogenesis of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. The coexistence and coevolution of CLL cells with their tissue neighbors provided the basis for discovery of critical cellular and molecular drivers of the disease and identification of new therapeutic targets. Bone marrow stromal cells (BMSC), monocyte-derived nurselike cells (NLC), and T cells are key players in the CLL microenvironment, which activate and protect CLL cells within the tissues. CLL surface molecules, such as the B-cell antigen receptor (BCR), chemokine receptors, adhesion molecules, and TNF receptor superfamily members (e.g., CD40, BCMA, and BAFF-R) engage in cross-talk with respective tissue ligands. This cross-talk results in survival and expansion of the CLL clone, and protects CLL cells from conventional cytotoxic drugs. Inhibiting these pathways represents an alternative therapeutic strategy to more conventional chemoimmunotherapy. Here, we review central components of the CLL microenvironment, with a particular emphasis on BCR signaling, and we summarize the most relevant clinical advances with inhibitors that target the BCR-associated spleen tyrosine kinase/SYK (fostamatinib), Bruton's tyrosine kinase/BTK (ibrutinib), and PI3Kδ (idelalisib).", "Patients with familial hypertrophic cardiomyopathy (FHC) are at risk for ventricular arrhythmias and sudden death. Regional variability in the QT interval [QT dispersion (QTd)] is significantly increased in humans with FHC and ventricular arrhythmias. A mouse model of FHC resulting from a mutation in the alpha-myosin heavy-chain (Arg403Gln) was used to study the electrophysiologic phenotype of this disease. Cardiac electrophysiology studies and surface ECGs were performed in FHC mice and wild-type controls to evaluate the feasibility and significance of QTd measurements in predicting the risk for ventricular arrhythmias. Atrial and ventricular pacing electrodes were placed by either a transvenous or epicardial approach. Standard pacing and extrastimulus protocols were followed. The QT interval was measured in six surface ECG leads. QTd was defined as the difference between the maximum and minimum measured QT intervals. Male FHC mice had greater QTd than wild-type controls (37.1 +/- 3.0 ms versus 23.9 +/- 1.9 ms, p = 0.001). There was also a significant gender difference in QTd within each genotype; female wild-type mice had greater QTd than male wild-type mice (37.4 +/- 5.3 ms versus 23.9 +/- 1.9 ms, p = 0.005), and male FHC mice had greater QTd than female FHC mice (37.1 +/- 3.0 ms versus 27.2 +/- 2.0 ms, p = 0.02). Twelve of 23 FHC mice had inducible ventricular arrhythmias, whereas only 2 of 32 wild-type mice were inducible (p = 0.004). Although a significantly increased number of FHC mice had arrhythmias compared with wild-type mice, QTd did not correlate with arrhythmia inducibility. The importance of this study is that it validates the mouse model for further investigation of arrhythmogenic risk and gender differences in the electrophysiologic phenotype in FHC. It also suggests that although gender- and genotype-specific QTd values are increased, they do not predict arrhythmia risk in FHC mice.", "Allostery, or allosteric regulation, is the phenomenon in which protein functional activity is altered by the binding of an effector at an allosteric site that is topographically distinct from the orthosteric, active site. As one of the most direct and efficient ways to regulate protein function, allostery has played a fundamental role in innumerable biological processes of all living organisms, including enzyme catalysis, signal transduction, cell metabolism, and gene transcription. It is thus considered as \"the second secret of life\". The abnormality of allosteric communication networks between allosteric and orthosteric sites is associated with the pathogenesis of human diseases. Allosteric modulators, by attaching to structurally diverse allosteric sites, offer the potential for differential selectivity and improved safety compared with orthosteric drugs that bind to conserved orthosteric sites. Harnessing allostery has thus been regarded as a novel strategy for drug discovery. Despite much progress having been made in the repertoire of allostery since the turn of the millennium, the identification of allosteric drugs for therapeutic targets and the elucidation of allosteric mechanisms still present substantial challenges. These challenges are derived from the difficulties in the identification of allosteric sites and mutations, the assessment of allosteric protein-modulator interactions, the screening of allosteric modulators, and the elucidation of allosteric mechanisms in biological systems. To address these issues, we have developed a panel of allosteric services for specific allosteric applications over the past decade, including (i) the creation of the Allosteric Database, with the aim of providing comprehensive allosteric information such as allosteric proteins, modulators, sites, pathways, etc., (ii) the construction of the ASBench benchmark of high-quality allosteric sites for the development of computational methods for predicting allosteric sites, (iii) the development of Allosite and AllositePro for the prediction of the location of allosteric sites in proteins, (iv) the development of the Alloscore scoring function for the evaluation of allosteric protein-modulator interactions, (v) the development of Allosterome for evolutionary analysis of query allosteric sites/modulators within the human proteome, (vi) the development of AlloDriver for the prediction of allosteric mutagenesis, and (vii) the development of AlloFinder for the virtual screening of allosteric modulators and the investigation of allosteric mechanisms. Importantly, we have validated computationally predicted allosteric sites, mutations, and modulators in the real cases of sirtuin 6, casein kinase 2α, phosphodiesterase 10A, and signal transduction and activation of transcription 3. Furthermore, our developed allosteric methods have been widely exploited by other users around the world for allosteric research. Therefore, these allosteric services are expected to expedite the discovery of allosteric drugs and the investigation of allosteric mechanisms.", "Dominantly acting, allelic mutations of the fibroblast growth factor receptor 2 (FGFR2) gene have been described in five craniosynostosis syndromes. In Apert syndrome, characterised by syndactyly of the hands and feet, recurrent mutations of a serine-proline dipeptide (either Ser252Trp or Pro253Arg) in the linker between the IgII and IgIII extracellular immunoglobulin-like domains, have been documented in more than 160 unrelated individuals. We have identified three novel mutations of this dipeptide, associated with distinct phenotypes. A C-->T mutation that predicts a Ser252Leu substitution, ascertained in a boy with mild Crouzon syndrome (craniosynostosis with normal limbs) is also present in three clinically normal members of his family. A CG-->TT mutation that predicts a Ser252Phe substitution results in a phenotype consistent with Apert syndrome. Finally, a CGC-->TCT mutation that predicts a double amino acid substitution (Ser252Phe and Pro253Ser) causes a Pfeiffer syndrome variant with mild craniosynostosis, broad thumbs and big toes, fixed extension of several digits, and only minimal cutaneous syndactyly. The observation that the Ser252Phe mutation causes Apert syndrome, whereas the other single or double substitutions are associated with milder or normal phenotypes, highlights the exquisitely specific molecular pathogenesis of the limb and craniofacial abnormalities associated with Apert syndrome. Ser252Phe is the first noncanonical mutation to be identified in this disorder, its rarity being explained by the requirement for two residues of the serine codon to be mutated. The description of independent, complex nucleotide substitutions involving identical nucleotides is unprecedented, and we speculate that this may result from functional selection of FGFR mutations in sperm." ]

[ "PURPOSE: RNA activation (RNAa) is a mechanism of gene activation triggered by promoter-targeted small double stranded RNAs (dsRNAs), also known as small activating RNAs (saRNAs). Myogenic regulatory factor MyoD is regarded as the master activator of myogenic differentiation cascade by binding to enhancer of muscle specific genes. Stress urinary incontinence (SUI) is a condition primarily resulted from urethral sphincter deficiency. It is thus expected that by promoting differentiation of adipose-derived stem cells (ADSCs) into myoblasts by activating MyoD gene through RNAa may offer benefits to SUI.MATERIALS AND METHODS: Rats ADSCs were isolated, proliferated in vitro, and identified by flow cytometry. Purified ADSCs were then transfected with a MyoD saRNA or control transfected. Real-time polymerase chain reaction (RT-PCR) and western blotting were used to detect MyoD mRNA and protein expression, respectively. Immunocytochemical staining was applied to determine the expression of desmin protein in transfected cells. Cell viability was measured by using CellTiter 96R AQueous One Solution Cell Proliferation Assay kit.RESULTS: Transfection of a MyoD saRNA (dsMyoD) into ADSCs significantly induced the expression of MyoD at both the mRNA and protein levels, and inhibited cell proliferation. Desmin protein expression was detected in dsMyoD treated ADSCs 2 weeks later.CONCLUSION: Our findings show that RNAa mediated overexpression of MyoD can promote transdifferentiation of ADSCs into myoblasts and may help treat stress urinary incontinence (SUI)-a condition primarily resulted from urethral sphincter deficiency.", "The intracellular sensing protein termed NLRP3 (for NACHT, LRR, and PYD domains-containing protein 3) forms a macromolecular structure called the NLRP3 inflammasome. The NLRP3 inflammasome plays a major role in inflammation, particularly in the production of IL (interleukin)-1β. IL-1β is the most studied of the IL-1 family of cytokines, including 11 members, among which are IL-1α and IL-18. Here, we summarize preclinical and clinical findings supporting the key pathogenetic role of the NLRP3 inflammasome and IL-1 cytokines in the formation, progression, and complications of atherosclerosis, in ischemic (acute myocardial infarction), and nonischemic injury to the myocardium (myocarditis) and the progression to heart failure. We also review the clinically available IL-1 inhibitors, although not currently approved for cardiovascular indications, and discuss other IL-1 inhibitors, not currently approved, as well as oral NLRP3 inflammasome inhibitors currently in clinical development. Canakinumab, IL-1β antibody, prevented the recurrence of ischemic events in patients with prior acute myocardial infarction in a large phase III clinical trial, including 10 061 patients world-wide. Phase II clinical trials show promising data with anakinra, recombinant IL-1 receptor antagonist, in patients with ST-segment-elevation acute myocardial infarction or heart failure with reduced ejection fraction. Anakinra also improved outcomes in patients with pericarditis, and it is now considered standard of care as second-line treatment for patients with recurrent/refractory pericarditis. Rilonacept, a soluble IL-1 receptor chimeric fusion protein neutralizing IL-1α and IL-1β, has also shown promising results in a phase II study in recurrent/refractory pericarditis. In conclusion, there is overwhelming evidence linking the NLRP3 inflammasome and the IL-1 cytokines with the pathogenesis of cardiovascular diseases. The future will likely include targeted inhibitors to block the IL-1 isoforms, and possibly oral NLRP3 inflammasome inhibitors, across a wide spectrum of cardiovascular diseases.", "Autophagy is a highly regulated-cell pathway for degrading long-lived proteins as well as for clearing cytoplasmic organelles. Autophagy is a key contributor to cellular homeostasis and metabolism. Warburg hypothesized that cancer growth is frequently associated with a deviation of a set of energy generation mechanisms to a nonoxidative breakdown of glucose. This cellular phenomenon seems to rely on a respiratory impairment, linked to mitochondrial dysfunction. This mitochondrial dysfunction results in a switch to anaerobic glycolysis. It has been recently suggested that epithelial cancer cells may induce the Warburg effect in neighboring stromal fibroblasts in which autophagy was activated. These series of observations drove to the proposal of a putative reverse Warburg effect of pathophysiological relevance for, at least, some tumor phenotypes. In this review we introduce the autophagy process and its regulation and its selective pathways and role in cancer cell metabolism. We define and describe the Warburg effect and the newly suggested \"reverse\" hypothesis. We also discuss the potential value of modulating autophagy with several pharmacological agents able to modify the Warburg effect. The association of the Warburg effect in cancer and stromal cells to tumor-related autophagy may be of relevance for further development of experimental therapeutics as well as for cancer prevention.", "Characterization of the donor and acceptor specificities of mRNA guanylyltransferase and mRNA (guanine-7-)-methyltransferase isolated from vaccinia virus cores has enabled us to discriminate between alternative reaction sequences leading to the formation of the 5'-terminal m7G(5')pppN-structure. The mRNA guanylyltransferase catalyzes the transfer of a residue of GMP from GTP to acceptors which possess a 5'-terminal diphosphate. A diphosphate-terminated polyribonucleotide is preferred to a mononucleoside diphosphate as an acceptor suggesting that the guanylyltransferase reaction occurs after initiation of RNA synthesis. Although all of the homopolyribonucleotides tested (pp(A)n, pp(G)n, pp(I)n, pp(U)n, and pp(C)n) are acceptors for the mRNA guanylyltransferase indicating lack of strict sequence specificity, those containing purines are preferred. Only GTP and dGTP are donors in the reaction; 7-methylguanosine (m7G) triphosphate specifically is not a donor indicating that guanylylation must precede guanine-7-methylation. The preferred acceptor of the mRNA (guanine-7-)-methyltransferase is the product of the guanylyltransferase reaction, a polyribonucleotide with the 5'-terminal sequence G(5')pppN-. The enzyme can also catalyze, but less efficiently methylation of the following: dinucleoside triphosphates with the structure G(5')pppN, GTP, dGTP, ITP, GDP, GMP, and guanosine. The enzyme will not catalyze the transfer of methyl groups to ATP, XTP, CTP, UTP, or to guanosine-containing compounds with phosphate groups in either positions 2' or 3' or in 3'-5' phosphodiester linkages. The latter specificity provides an explanation for the absence of internal 7-methylguanosine in mRNA. In the presence of PPi, the mRNA guanylyltransferase catalyzes the pyrophosphorolysis of the dinucleoside triphosphate G(5')pppA, but not of m7G(5')pppA. Since PPi is generated in the process of RNA chain elongation, stabilization of the 5'-terminal sequences of mRNA is afforded by guanine-7-methylation.", "BACKGROUND: The underlying pathophysiology of heart failure with preserved ejection fraction (HFPEF) is incompletely understood, but myocardial extracellular matrix accumulation is thought to play a major role. Our aims were to estimate myocardial extracellular matrix using cardiac magnetic resonance T1 mapping and to assess the relationship between pathobiology/pathophysiology and prognosis.METHODS AND RESULTS: Patients with suspected HFPEF (n=100) were enrolled in this prospective, observational study. Confirmatory diagnostic tests, cardiac magnetic resonance imaging including T1 mapping, and invasive hemodynamic assessments were performed at baseline. Sixty-one patients with confirmed HFPEF entered a longitudinal outcome-monitoring phase (mean, 22.9±5.0 months), during which 16 had a cardiac event. Cardiac magnetic resonance T1 time (hazard ratio, 0.99; 95% confidence interval, 0.98-0.99; P=0.046), left atrial area (hazard ratio, 1.08; 95% confidence interval, 1.03-1.13; P<0.01), and pulmonary vascular resistance (hazard ratio, 1.01; 95% confidence interval, 1.00-1.01; P=0.03) were significantly associated with cardiac events. Patients with T1 times below the median (<388.3 ms) were at greater risk of cardiac events than the rest of the group (P<0.01). Extracellular matrix of left ventricular biopsies (n=9), quantified by TissueFAXS technology correlated with T1 time (R=0.98; P<0.01). T1 time also correlated with right ventricular-pulmonary arterial coupling (pulmonary vascular resistance: R=-0.36; P<0.01; right ventricular ejection fraction: R=0.28; P=0.01).CONCLUSIONS: In the present preliminary study, cardiac magnetic resonance postcontrast T1 time is associated with prognosis in HFPEF, suggesting postcontrast T1 as possible biomarker for HFPEF.", "The aim was to investigate patients and therapists perception of receiving and giving dialectical behavioral therapy (DBT). Ten deliberate self-harm patients with borderline personality disorder and four DBT-therapists were interviewed. The interviews were analyzed with qualitative content analysis. The patients unanimously regard the DBT-therapy as life saving and something that has given them a bearable life situation. The patients and the therapists are concordant on the effective components of the therapy: the understanding, respect, and confirmation in combination with the cognitive and behavioral skills. The experienced effectiveness of DBT is contrasted by the patient's pronouncedly negative experiences from psychiatric care before entering DBT.", "There are many procaryotic and eucaryotic organisms in plant kingdom. It is hoped that the study of plant histones will be useful in evolutionary studies. The histones of great variety of animal species have been studied and well characterized. Less information is available concerning plant histones. The general conclusion drawn from these investigations is that most organisms of eucaryotic plant and animal species contain the same five major histone fractions. Recently the histone-like proteins were found in some primitive eucaryotes and procaryotes. Data on histones from higher and lower eucaryotes and histone-like proteins of procaryotes are reviewed. Evolution of histones and their appearance prior to that of eucaryotic cell is postulated. The role of histones in evolution of nucleosomes is discussed." ]

[ "The production performance of pigs has been significantly improved due to long-term artificial selection, and the specific variation characterizations (selection signatures) emerged from the selected genome regions. Different types of breeds are subjected to different selection intensities and had different selection signatures. Selective sweep analysis is one of major methods to detect the selection signatures. In this study, based on the 60K BeadChip genotyping data of both commercial Large White (n=45) and local Tongcheng pigs (n=45), genetic differentiation coefficient Fst was applied to detect the selection signatures. Using gPLINK software to set quality control standards, a total of 34 304 SNPs were selected for statistical analysis. Fst values between two breeds were estimated with Genepop package and the average Fst value was 0.3209. Setting Fst>0.7036 (1% of total number of Fst values) as selection threshold, 344 SNPs were obtained and SNP location annotation indicated that there were 79 candidate genes (Sus scrofa Build 9). Furthermore, network analysis was performed using Ingenuity Pathway Analysis and the preliminary results suggested that most genes were involved in growth, reproduction, and immune response, such as NCOA6, ERBB4, RUNX2, and APOB genes. The findings from this study will contribute to further identification of candidate genes and causal mutations implying for meat production and disease resistance in pig.", "We sought to evaluate the efficacy and safety data of a combination regimen using weekly irinotecan in combination with capecitabine and concurrent radiotherapy (CapIri-RT) as neoadjuvant treatment in rectal cancer in a phase-II trial. Patients with rectal cancer clinical stages T3/4 Nx or N+ were recruited to receive irinotecan (50 mg m(-2) weekly) and capecitabine (500 mg m(-2) bid days 1-38) with a concurrent RT dose of 50.4 Gy. Surgery was scheduled 4-6 weeks after the completion of chemoradiation. A total of 36 patients (median age 62 years; m/f: 27:9) including three patients with local recurrence were enclosed onto the trial. The median distance of the tumour from the anal verge was 5 cm. The main toxicity observed was (NCI-CTC grades 1/2/3/4 (n)): Anaemia 23/9/-/-; leucocytopenia 12/7/7/2, diarrhoea 13/15/4/-, nausea/vomiting 9/10/2/-, and increased activity of transaminases 3/3/1/-. One patient had a reversible episode of ventricular fibrillation during chemoradiation, most probably caused by capecitabine. The relative dose intensity was (median/mean (%)): irinotecan 95/91, capecitabine 100/92). Thirty-four patients underwent surgery (anterior resection n=25; abdomino-perineal resection n=6; Hartmann's procedure n=3). R0-resection was accomplished in all patients. Two patients died in the postoperative course from septic complications. Pathological complete remission was observed in five out of 34 resected patients (15%), and nine patients showed microfoci of residual tumour (26%). After a median follow-up of 28 months one patient had developed a local recurrence, and five patients distant metastases. Three-year overall survival for all patients with surgery (excluding three patients treated for local relapse or with primary metastatic disease) was 80%. In summary, preoperative chemoradiation with CapIri-RT exhibits promising efficacy whereas showing managable toxicity. The local recurrence and distant failure rates observed after a median 28 months are low compared with standard 5-fluorouracil based therapy.", "Glucocorticoids have been shown repeatedly to inhibit the release of prolactin (PRL) in the rat but their site and mode of action is unknown. In the present study, we used an in vitro model to examine the requirement for protein synthesis for dexamethasone to suppress the release of immunoreactive (ir)-PRL release from the rat pituitary gland. In addition we have performed a series of in vitro and in vivo experiments to investigate the potential role in this regard of lipocortin 1 (LC1), a protein shown previously not only to mediate aspects of the anti-inflammatory and anti-proliferative actions of the glucocorticoids but also to contribute to the regulatory actions of the steroids in the brain-neuroendocrine system. In vitro, the release of ir-PRL from rat anterior pituitary tissue initiated by submaximal concentrations of VIP (10 nM). TRH (10 nM) or the adenyl cyclase activator forskolin (100 microM) was reduced significantly (p < 0.01) by preincubation (2 h) of the tissue with dexamethasone (0.1 microM). By contrast, ir-PRL release evoked by a submaximal concentration of the L-Ca2+ channel opener BAY K8644 (10 microM) was unaffected by the steroid although readily antagonised (p < 0.01) by nifedipine (1-100 microM). Exposure of the pituitary tissue to dexamethasone (0.1 microM) also caused a pronounced and highly significant increase in de novo protein synthesis, as assessed by the incorporation of 14C-lysine into the tissue (p < 0.001). This response was reduced markedly by the inclusion of the RNA and protein synthesis inhibitors, actinomycin-D (0.5 micrograms/ml) or cycloheximide (1.0 micrograms/ml), in the incubation medium (p < 0.001), both of which also effectively abrogated (p < 0.01) the dexamethasone-induced inhibition of the release of ir-PRL evoked by TRH. VIP and forskolin. Lipocortin I was readily detectable by Western blotting in protein extracts of freshly excised anterior pituitary tissue: a small proportion of the protein was found to be attached to the outer surface of the cells where it was retained by a Ca(2+)-dependent mechanism. Exposure of the tissue in vitro to dexamethasone (0.1 microM) or corticosterone (0.1 microM) but not 17 beta-oestradiol (0.1 microM) caused a pronounced increase in the amount of LC1 attached to the outer surface of the cells and concomitant decrease in the LC1 content of the intracellular LC1 pool. Addition of an N-terminal LC1 fragment. LC11-188 (10 pg-10 ng/ml), to the incubation medium reduced significantly (p < 0.01) the increases in ir-PRL release induced in vitro by VIP (10 nM) and forskolin (100 microM). By contrast, at all concentrations tested. LC11-188 (10 pg-10 ng/ml) failed to influence (p < 0.05) the highly significant (p < 0.01) ir-PRL response to TRH (10 nM). Similarly, the inhibitory actions of dexamethasone (0.1 microM) on the release of ir-PRL induced by VIP (10 nM) or forskolin (100 microM) but not by TRH (10 nM) were substantially reversed (p < 0.01) by a specific monoclonal anti-LC1 antibody while an isotype-matched control antibody was without effect. In vivo, rats pretreated with either a polyclonal anti LC1 antiserum (anti-LC1 pAb, 1 ml/day s.c. for 2 days) or a corresponding volume of non-immune sheep serum (NSS) responded to stress (laparotomy under ether anaesthesia) with significant (p < 0.05) increases in the serum ir-PRL concentration. In the NSS-treated group, the ir-PRL response to stress was effectively inhibited by dexamethasone (100 micrograms/kg i.p.) which had no effect on the pre-stress serum ir-PRL concentration. By contrast, in rats pretreated with anti-LC1 pAb dexamethasone failed to block the stress-induced release of ir-PRL. The results show clearly that the inhibitory actions of dexamethasone on PRL release are dependent on de novo protein synthesis and provide novel evidence for the involvement of both LC1-dependent and LC1-independent mechanisms.", "New antidiabetic drugs are being developed today that expand the range of pharmacological intervention, in particular for patients with type 2 diabetes (imeglimin, semaglutide, dulaglutide, FGF 21 analogue). At the same time innovations take place that \"better\" the well-proven molecules, they offer new application forms we have no experience of diabetology (osmotic pump for exenatide, faster acting insulin aspart). New properties are brought by just the change of concentration (insulin glargine in a concentration of 300 U/ml), unexpected positive results are also brought by new fixed-ratio combinations of antidiabetics (fixed-ratio combination of insulin degludec and liraglutide, fixed-ratio combination of insulin glargine and lixisenatide). Also results of clinical studies appear that concern molecules already in use which facilitate the formulation of new recommendations regarding treatment type 2 diabetes.Key words: type 2 diabetes mellitus - dulaglutide - FGF 21 - imeglimin - insulin aspart - insulin degludek - insulin glargine - ITCA 650 - liraglutide - national information diabetes system - semaglutide.", "The authors reported the neurological disease spectrum associated with autoantibodies against minor gangliosides GM1b and GalNAc-GD1a. IgG and IgM antibody reactivity against gangliosides GM1, GM2, GM1b, GD1a, GalNAc-GD1a and GQ1b was investigated in sera from 7000 consecutive patients who had various neurological conditions. The clinical diagnoses for 456 anti-GM1b-positive patients were Guillain-Barré syndrome (GBS, 71%), atypical GBS with preserved deep tendon reflexes (12%), Fisher syndrome (10%), Bickerstaff's brainstem encephalitis (2%), ataxic GBS (2%) and acute ophthalmoparesis (1%). For 193 anti-GalNAc-GD1a-positive patients, the diagnoses were GBS (70%), atypical GBS (16%), Fisher syndrome (10%) and Bickerstaff's brainstem encephalitis (3%). Of the patients with GBS or atypical GBS, 28% of 381 anti-GM1b-positive and 31% of 166 anti-GalNAc-GD1a-positive patients had neither anti-GM1 nor anti-GD1a antibodies. Of those patients with Fisher syndrome, Bickerstaff's brainstem encephalitis, ataxic GBS or acute ophthalmoparesis, 33% of 67 anti-GM1b-positive, and 52% of 25 anti-GalNAc-GD1a-positive patients had no anti-GQ1b antibodies. Autoantibodies against GM1b and GalNAc-GD1a are associated with GBS, Fisher syndrome and related conditions. These antibodies should provide useful serological markers for identifying patients who have atypical GBS with preserved deep tendon reflexes, ataxic GBS, Bickerstaff's brainstem encephalitis or acute ophthalmoparesis, especially for those who have no antibodies to GM1, GD1a or GQ1b. A method to prepare GM1b was developed.", "Author information:(1)Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.(2)Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Genomics and Computational Biology Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.(3)Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.(4)The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USA.(5)Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, CA 95616, USA; MIND Institute, UC Davis, Sacramento, CA 95616, USA.(6)Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: jcremins@seas.upenn.edu.", "Cholesteryl ester storage disease (CESD, OMIM #278000) and Wolman disease (OMIM #278000) are autosomal recessive lysosomal storage disorders caused by a deficient activity of lysosomal acid lipase (cholesteryl ester hydrolase, LAL). Human lysosomal acid lipase is essential for the metabolism of cholesteryl esters and triglycerides. In Wolman disease, LAL activity is usually absent, whereas CESD usually presents some residual LAL activity. In infants, poor weight gain, massive hepatosplenomegaly, calcified adrenal glands (present about 2/3 of the time), vomiting, diarrhea and failure to thrive are indicative of Wolman disease. The clinical picture is more variable in CESD. Hepatomegaly and/or elevation of liver transaminases are almost always present. Hepatic steatosis often leads to fibrosis and cirrhosis. Other signs often include splenomegaly, high total cholesterol and LDL-cholesterol, elevated triglycerides, and low HDL-cholesterol. The diagnosis of LAL deficiency requires clinical experience and specialized laboratory tests. The diagnosis is based on finding deficient activity of acid lipase and/or molecular tests. Pilot screening projects using dried blood spot testing in 1) children with atypical fatty liver disease in the absence of overweight, 2) patients with dyslipidaemia and presence of hepatomegaly and/or elevated transaminases, 3) newborns/neonates with hepatomegaly and abdominal distension/failure to thrive/elevated transaminases are currently underway. Early diagnosis is particularly important for the enzyme replacement therapy. Human trials with recombinant LAL are currently ongoing, raising the prospect for specific correction of LAL deficiency in this progressive and often debilitating disorder." ]

[ "Attribution of specific roles to the two ubiquitously expressed PI 3-kinase (PI3K) isoforms p110α and p110β in biological functions they have been implicated, such as in insulin signalling, has been challenging. While p110α has been demonstrated to be the principal isoform activated downstream of the insulin receptor, several studies have provided evidence for a role of p110β. Here we have used isoform-selective inhibitors to estimate the relative contribution of each of these isoforms in insulin signalling in adipocytes, which are a cell type with essential roles in regulation of metabolism at the systemic level. Consistent with previous genetic and pharmacological studies, we found that p110α is the principal isoform activated downstream of the insulin receptor under physiological conditions. p110α interaction with Ras enhanced the strength of p110α activation by insulin. However, this interaction did not account for the selectivity for p110α over p110β in insulin signalling. We also demonstrate that p110α is the principal isoform activated downstream of the β-adrenergic receptor (β-AR), another important signalling pathway in metabolic regulation, through a mechanism involving activation of the cAMP effector molecule EPAC1. This study offers further insights in the role of PI3K isoforms in the regulation of energy metabolism with implications for the therapeutic application of selective inhibitors of these isoforms.", "Autophagy has been predominantly studied as a nonselective self-digestion process that recycles macromolecules and produces energy in response to starvation. However, autophagy independent of nutrient status has long been known to exist. Recent evidence suggests that this form of autophagy enforces intracellular quality control by selectively disposing of aberrant protein aggregates and damaged organelles--common denominators in various forms of neurodegenerative diseases. By definition, this form of autophagy, termed quality-control (QC) autophagy, must be different from nutrient-regulated autophagy in substrate selectivity, regulation and function. We have recently identified the ubiquitin-binding deacetylase, HDAC6, as a key component that establishes QC. HDAC6 is not required for autophagy activation per se; rather, it is recruited to ubiquitinated autophagic substrates where it stimulates autophagosome-lysosome fusion by promoting F-actin remodeling in a cortactin-dependent manner. Remarkably, HDAC6 and cortactin are dispensable for starvation-induced autophagy. These findings reveal that autophagosomes associated with QC are molecularly and biochemically distinct from those associated with starvation autophagy, thereby providing a new molecular framework to understand the emerging complexity of autophagy and therapeutic potential of this unique machinery.", "In eukaryotic cells, degradation of most intracellular proteins is carried out by the ubiquitin-proteasome pathway. Recent investigations suggest that bone metabolism is also regulated by this pathway. The clinical efficacy of bortezomib, a 26S proteasome inhibitor used as an anticancer drug, has been linked to an increase in bone formation. In this study, we show that proteasome inhibitors induce expression of osteoblastic differentiation-related genes such as osteocalcin and alkaline phosphatase in C2C12 cells. In contrast, myogenic differentiation is inhibited. Among the proteasome inhibitors tested, bortezomib induced the greatest increase in osteocalcin expression. Although these effects were similar to that of bone morphogenetic protein (BMP) 2, proteasome inhibitors did not induce transcriptional activity of Smad1/4-dependent reporter or BMP2 signaling target gene expression. Transient transfection of osteocalcin promoter-luciferase constructs with bortezomib resulted in an increase in luciferase activity. Mutation of OSE2, but not OSE1, sites of the osteocalcin promoter diminished the bortezomib-induced activity. Also, Runx2 binding activity and protein levels were induced by bortezomib treatment. These results suggest that the bortezomib induces osteoblastic differentiation by modifying the activity of Runx2 and that the function of the proteasome in controlling degradation of differentiation-related transcription factors plays an important role in osteoblast differentiation.", "SUMMARY: RNA-Seq data analysis results in lists of genes that may have a similar function, based on differential gene expression analysis or co-expression network analysis. While tools have been developed to identify biological processes that are enriched in the genes sets, there remains a need for tools that identify enrichment of tissue-specific genes. Therefore, we developed TissueEnrich, a tool that calculates tissue-specific gene enrichment in an input gene set. We demonstrated that TissueEnrich can assign tissue identities to single cell clusters and differentiated embryonic stem cells.AVAILABILITY AND IMPLEMENTATION: The TissueEnrich web application is freely available at http://tissueenrich.gdcb.iastate.edu/. The R package is available through Bioconductor at https://bioconductor.org/packages/TissueEnrich. Both the web application and R package are for non-profit academic use under the MIT license.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "Integrin alpha11 (ITGA11/alpha11) is localized to stromal fibroblasts and commonly overexpressed in non-small-cell lung carcinoma (NSCLC). We hypothesized that stromal alpha11 could be important for the tumorigenicity of NSCLC cells. SV40 immortalized mouse embryonic fibroblasts established from wild-type (WT) and Itga11-deficient [knockout (KO)] mice were tested for their tumorigenicity in immune-deficient mice when implanted alone or coimplanted with the A549 human lung adenocarcinoma cells. A549 coimplanted with the fibroblasts showed a markedly enhanced tumor growth rate compared with A549, WT, or KO, which alone formed only small tumors. Importantly, the growth was significantly greater for A549+WT compared with A549+KO tumors. Reexpression of human alpha11 cDNA in KO cells rescued a tumor growth rate to that comparable with the A549+WT tumors. These findings were validated in two other NSCLC cell lines, NCI-H460 and NCI-H520. Gene expression profiling indicated that IGF2 mRNA expression level was >200 times lower in A549+KO compared with A549+WT tumors. Stable short-hairpin RNA (shRNA) down-regulation of IGF2 in WT (WT(shIGF2)) fibroblasts resulted in a decreased growth rate of A549+WT(shIGF2), compared with A549+WT tumors. The results indicate that alpha11 is an important stromal factor in NSCLC and propose a paradigm for carcinoma-stromal interaction indirectly through interaction between the matrix collagen and stromal fibroblasts to stimulate cancer cell growth.", "When many ligands bind to cell-surface receptors, ligand-receptor complexes are internalized via clathrin coated pits by a process called receptor-mediated endocytosis. The cytoplasmic fate of ligands internalized within endocytic vesicles or endosomes is variable. For example, maternal immunoglobulins are transported through the cytoplasm of neonatal intestinal epithelial cells and are exocytosed at the basolateral surface. However, other ligands are degraded as a result of their delivery to the lysosomal compartment of cells. Although the translocation of endosomes to the Golgi region in the cell centre seems to be a general phenomenon presumably coupled to ligand degradation by lysosomes and endosomes and lysosomes undergo saltatory movements within the cytoplasm, the spatial control of interaction between the two structures is not understood. To address this problem we have begun to examine the spatial and temporal intracellular distribution of endosomes and lysosomes. Utilizing a new fluorescent microscopic approach, we have now been able simultaneously to visualize endosome and lysosome populations in living cells. Our results suggest that a specific relocation of lysosomes is rapidly induced upon binding of different types of ligands to the cell surface; this migration of lysosomes to the Golgi region of the cell precedes the translocation of endosomes into the same area.", "BACKGROUND: Ninety-three patients undergoing surgical or endovascular operation secondary to aneurysmal subarachnoid hemorrhage (SAH) were retrospectively analyzed to determine the influence of the different time points of C-reactive protein (CRP) measurement on the prediction of vasospasm and clinical outcome.METHODS: Laboratory data such as the CRP level and the white blood cell count, preoperative demographic and clinical data, intraoperative and postoperative data, and complications such as intracerebral hemorrhage, hydrocephalus, vasospasm, and surgical decompression were collected at hospital discharge or symptomatic vasospasm and used as predictable factors for poor outcome (Modified Rankin Scale score 4 to 6).RESULTS: Twenty-three and 28 patients showed poor outcome and symptomatic vasospasm after SAH, respectively. Both preoperative and postoperative CRP levels were significantly higher in patients with a poor outcome compared with patients with a good outcome (P<0.05). The area under the receiver operating characteristic curve of CRP measured on postoperative day 1 or 2 (CRP POD1-2) for predicting a poor clinical outcome was 0.870, and its cutoff point of 4 mg/dL had a sensitivity of 0.826 and a specificity of 0.843. A high CRP level after aneurysm treatment was associated with severe neurological deterioration on admission, cerebral infarction, intracerebral hemorrhage, and surgical decompression (P<0.05). CRP POD1-2, and not the preoperative CRP, was an independent factor in predicting symptomatic vasospasm (P<0.05). In patients with symptomatic vasospasm, an increase in the postoperative CRP was associated with the time profile of developing symptomatic vasospasm.CONCLUSION: Postoperative CRP, especially CRP POD1-2, can be a useful prognostic factor for both poor outcome and symptomatic vasospasm in patients with aneurysmal SAH." ]

[ "Plasmodium falciparum, the causative agent of the most severe form of malaria in humans invades erythrocytes using multiple ligand-receptor interactions. The P. falciparum reticulocyte binding-like homologue proteins (PfRh or PfRBL) are important for entry of the invasive merozoite form of the parasite into red blood cells. We have analysed two members of this protein family, PfRh2a and PfRh2b, and show they undergo a complex series of proteolytic cleavage events before and during merozoite invasion. We show that PfRh2a undergoes a cleavage event in the transmembrane region during invasion consistent with activity of the membrane associated PfROM4 protease that would result in release of the ectodomain into the supernatant. We also show that PfRh2a and PfRh2b bind to red blood cells and have defined the erythrocyte-binding domain to a 15 kDa region at the N-terminus of each protein. Antibodies to this receptor-binding region block merozoite invasion demonstrating the important function of this domain. This region of PfRh2a and PfRh2b has potential in a combination vaccine with other erythrocyte binding ligands for induction of antibodies that would block a broad range of invasion pathways for P. falciparum into human erythrocytes.", "The cyclin D-cyclin dependent kinase (CDK) 4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway controls cell cycle progression by regulating the G1-S checkpoint. Dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway results in increased proliferation, and is frequently observed in many types of cancer. Pathway activation can occur through a variety of mechanisms, including gene amplification or rearrangement, loss of negative regulators, epigenetic alterations, and point mutations in key pathway components. Due to the importance of CDK4/6 activity in cancer cells, CDK4/6 inhibitors have emerged as promising candidates for cancer treatment. Moreover, combination of a CDK4/6 inhibitor with other targeted therapies may help overcome acquired or de novo treatment resistance. Ongoing studies include combinations of CDK4/6 inhibitors with endocrine therapy and phosphatidylinositol 3-kinase (PI3K) pathway inhibitors for hormone receptor-positive (HR+) breast cancers, and with selective RAF and MEK inhibitors for tumors with alterations in the mitogen activated protein kinase (MAPK) pathway such as melanoma. In particular, the combination of CDK4/6 inhibitors with endocrine therapy, such as palbociclib's recent first-line approval in combination with letrozole, is expected to transform the treatment of HR+ breast cancer. Currently, three selective CDK4/6 inhibitors have been approved or are in late-stage development: palbociclib (PD-0332991), ribociclib (LEE011), and abemaciclib (LY2835219). Here we describe the current preclinical and clinical data for these novel agents and discuss combination strategies with other agents for the treatment of cancer.", "Author information:(1)Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA.(2)Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.(3)Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA.(4)Howard Hughes Medical Institute, Cambridge, MA, 02138, USA.(5)Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, 02138, USA.(6)Department of Developmental Biology, Stanford University, Stanford, CA, 94305, USA.(7)Department of Physics, Harvard University, Cambridge, MA, 02138, USA.(8)Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA. py@hms.harvard.edu.(9)Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA. py@hms.harvard.edu.(10)Howard Hughes Medical Institute, Cambridge, MA, 02138, USA. zhuang@chemistry.harvard.edu.(11)Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, 02138, USA. zhuang@chemistry.harvard.edu.(12)Department of Physics, Harvard University, Cambridge, MA, 02138, USA. zhuang@chemistry.harvard.edu.(13)Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA. twu@genetics.med.harvard.edu.", "Glypicans are heparan sulfate proteoglycans that are bound to the outer surface of the plasma membrane by a glycosyl-phosphatidylinositol anchor. Homologs of glypicans are found throughout the Eumetazoa. There are six family members in mammals (GPC1 to GPC6). Glypicans can be released from the cell surface by a lipase called Notum, and most of them are subjected to endoproteolytic cleavage by furin-like convertases. In vivo evidence published so far indicates that the main function of membrane-attached glypicans is to regulate the signaling of Wnts, Hedgehogs, fibroblast growth factors and bone morphogenetic proteins (BMPs). Depending on the context, glypicans may have a stimulatory or inhibitory activity on signaling. In the case of Wnt, it has been proposed that the stimulatory mechanism is based on the ability of glypicans to facilitate and/or stabilize the interaction of Wnts with their signaling receptors, the Frizzled proteins. On the other hand, GPC3 has recently been reported to inhibit Hedgehog protein signaling during development by competing with Patched, the Hedgehog receptor, for Hedgehog binding. Surprisingly, the regulatory activity of glypicans in the Wnt, Hedgehog and BMP signaling pathways is only partially dependent on the heparan sulfate chains.", "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.", "The extracellular domain of plasma membrane integrin αvβ3 contains a cell surface receptor for thyroid hormone analogues. The receptor is largely expressed and activated in tumor cells and rapidly dividing endothelial cells. The principal ligand for this receptor is l-thyroxine (T4), usually regarded only as a prohormone for 3,5,3'-triiodo-l-thyronine (T3), the hormone analogue that expresses thyroid hormone in the cell nucleus via nuclear receptors that are unrelated structurally to integrin αvβ3. At the integrin receptor for thyroid hormone, T4 regulates cancer and endothelial cell division, tumor cell defense pathways (such as anti-apoptosis), and angiogenesis and supports metastasis, radioresistance, and chemoresistance. The molecular mechanisms involve signal transduction via mitogen-activated protein kinase and phosphatidylinositol 3-kinase, differential expression of multiple genes related to the listed cell processes, and regulation of activities of other cell surface proteins, such as vascular growth factor receptors. Tetraiodothyroacetic acid (tetrac) is derived from T4 and competes with binding of T4 to the integrin. In the absence of T4, tetrac and chemically modified tetrac also have anticancer effects that culminate in altered gene transcription. Tumor xenografts are arrested by unmodified and chemically modified tetrac. The receptor requires further characterization in terms of contributions to nonmalignant cells, such as platelets and phagocytes. The integrin αvβ3 receptor for thyroid hormone offers a large panel of cellular actions that are relevant to cancer biology and that may be regulated by tetrac derivatives.", "Aberrant promoter DNA-hypermethylation and repressive chromatin constitutes a frequent mechanism of gene inactivation in cancer. There is great interest in dissecting the mechanisms underlying this abnormal silencing. Studies have shown changes in the nuclear organization of chromatin in tumor cells as well as the association of aberrant methylation with long-range silencing of neighboring genes. Furthermore, certain tumors show a high incidence of promoter methylation termed as the CpG island methylator phenotype. Here, we have analyzed the role of nuclear chromatin architecture for genes in hypermethylated inactive versus nonmethylated active states and its relation with long-range silencing and CpG island methylator phenotype. Using combined immunostaining for active/repressive chromatin marks and fluorescence in situ hybridization in colorectal cancer cell lines, we show that aberrant silencing of these genes occurs without requirement for their being positioned at heterochromatic domains. Importantly, hypermethylation, even when associated with long-range epigenetic silencing of neighboring genes, occurs independent of their euchromatic or heterochromatic location. Together, these results indicate that, in cancer, extensive changes around promoter chromatin of individual genes or gene clusters could potentially occur locally without preference for nuclear position and/or causing repositioning. These findings have important implications for understanding relationships between nuclear organization and gene expression patterns in cancer." ]

[ "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.", "Contrary to long-held dogma, human milk is not sterile. Instead, it provides infants a rich source of diverse bacteria, particularly microbes belonging to the Staphylococcus, Streptococcus, and Pseudomonas genera. Very little is known about factors that influence variation in the milk microbiome among women and populations, although time postpartum, delivery mode, and maternal factors such as diet and antibiotic use might be important. The origins of the bacteria in milk are thought to include the maternal gastrointestinal tract (via an entero-mammary pathway) and through bacterial exposure of the breast during nursing. Currently, almost nothing is known about whether variation in microbe consumption by the infant via human milk and that of the mammary gland, itself, impacts short-term and/or long-term infant and maternal health although several studies suggest this is likely. We urge the clinical and public health communities to be patient, however, in order to allow human milk and lactation researchers to first understand what constitutes 'normal' in terms of the milk microbiome (as well as factors that impact microbial community structure) prior to jumping the gun to investigate if and how this important source of microbes impacts maternal and infant health.", "To apply safely an aggressive chemotherapy regimen like CESS 81 requires intensive supportive care. Bleomycin is evaluated as part of the protocol for treatment of primary Ewing's sarcoma. Bleomycin might cause pulmonary fibrosis at higher cumulative doses as toxic effect directly to the lungs or most likely in addition by the formation of vascular microthrombi. A randomized study is designed to evaluate if pulmonary changes due to Bleomycin can be prevented using heparin. As severe bone marrow depression is anticipated the effect of lithium on the leucocyte nadir is also subject of a randomized study.", "The existence of whole genome sequences makes it possible to search for global structure in the genome. We consider modeling the occurrence frequencies of discrete patterns (such as starting points of ORFs or other interesting phenomena) along the genome. We use piecewise constant intensity models with varying number of pieces, and show how a reversible jump Markov Chain Monte Carlo (RJMCMC) method can be used to obtain a posteriori distribution on the intensity of the patterns along the genome. We apply the method to modeling the occurrence of ORFs in the human genome. The results show that the chromosomes consist of 5-35 clearly distinct segments, and that the posteriori number and length of the segments shows significant variation. On the other hand, for the yeast genome the intensity of ORFs is nearly constant.", "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.", "The target of rapamycin (Tor) is a Ser/Thr protein kinase that regulates a range of anabolic and catabolic processes. Tor is present in two complexes, TORC1 and TORC2, in which the Tor-Lst8 heterodimer forms a common sub-complex. We have determined the cryo-electron microscopy (EM) structure of Tor bound to Lst8. Two Tor-Lst8 heterodimers assemble further into a dyad-symmetry dimer mediated by Tor-Tor interactions. The first 1,300 residues of Tor form a HEAT repeat-containing α-solenoid with four distinct segments: a highly curved 800-residue N-terminal 'spiral', followed by a 400-residue low-curvature 'bridge' and an extended 'railing' running along the bridge leading to the 'cap' that links to FAT region. This complex topology was verified by domain insertions and offers a new interpretation of the mTORC1 structure. The spiral of one TOR interacts with the bridge of another, which together form a joint platform for the Regulatory Associated Protein of TOR (RAPTOR) regulatory subunit.", "In 3 recent randomized controlled trials of intra-arterial treatment of acute ischemic stroke - IMS-III, SYNTHESIS and MR RESCUE - intra-arterial treatment increased the proportion of patients with recanalization and the treatment appeared safe. However, the trials did not show an effect on functional recovery, although a substantial effect could not be excluded. The delay between onset of symptoms and treatment was long, and stent retrievers were used in only a few patients. In our view, a rational and ethical approach would now be to treat quickly with IV rtPA and when possible, refer and include in new randomized clinical trials that compare intra-arterial treatment with standard care, such as MR CLEAN or BASICS in the Netherlands." ]

[ "Physical activity is an important aspect of health behavior and life-style, when considering the possibilities to prevent premature deaths and sustain functional capacity. We studied former Finnish male athletes and controls to investigate the effects of long-lasting participation in vigorous sports on health, and the main findings are reviewed here. The athletes represented Finland between the years 1920-1965 at least once in international competitions. The following sports were selected: track and field athletics, cross-country skiing, soccer, ice hockey, basketball, boxing, wrestling, weight lifting, and shooting. The full name, place and date of birth were traced for 2613 (97.7%) men. The referent subjects (N = 1712) were selected among those Finnish men who, at the age of 20, were classified completely healthy at the medical examination for induction into military service. In most analyses we grouped the sports according to the type of training needed to achieve maximal results, i.e., principally aerobic training, principally anaerobic training or mixed. In 1985, a questionnaire on physical activity, health and health habits was mailed to surviving former athletes and referents (N = 2851, 65.9% of the original cohort). Follow-up for morbidity and mortality was based on national medical registries. We found that former aerobic sports athletes (endurance and mixed sports) in particular have high total and active life expectancy and low risk for ischemic heart disease and diabetes in later years. On the other hand, they have slightly higher risk for lower-limb osteoarthritis. Overall, the benefits of physically active life-style on health were clearly higher than the adverse effects.", "Deficiency of protein phosphatase-2A is a key event in Alzheimer's disease. An endogenous inhibitor of protein phosphatase-2A, inhibitor-1, I1PP2A, which inhibits the phosphatase activity by interacting with its catalytic subunit protein phosphatase-2Ac, is known to be upregulated in Alzheimer's disease brain. In the present study, we overexpressed I1PP2A by intracerebroventricular injection with adeno-associated virus vector-1-I1PP2A in Wistar rats. The I1PP2A rats showed a decrease in brain protein phosphatase-2A activity, abnormal hyperphosphorylation of tau, neurodegeneration, an increase in the level of activated glycogen synthase kinase-3beta, enhanced expression of intraneuronal amyloid-beta and spatial reference memory deficit; littermates treated identically but with vector only, i.e., adeno-associated virus vector-1-enhanced GFP, served as a control. Treatment with memantine, a noncompetitive NMDA receptor antagonist which is an approved drug for treatment of Alzheimer's disease, rescued protein phosphatase-2A activity by decreasing its demethylation at Leu309 selectively and attenuated Alzheimer's disease-like pathology and cognitive impairment in adeno-associated virus vector-1-I1PP2A rats. These findings provide new clues into the possible mechanism of the beneficial therapeutic effect of memantine in Alzheimer's disease patients.", "BACKGROUND: Takotsubo cardiomyopathy (TSC) and its complications, such as cardiac rupture (CR), are increasingly being reported in the literature. CR is associated with rapid clinical decline and is uniformly fatal if not surgically repaired. To identify patients who developed CR we performed an analysis of all available indexed cases in the literature and compared them with a control group of patients with TSC without rupture.HYPOTHESIS: Takotsubo cardiomyopathy patients with cardiac rupture do not differ significantly from those without rupture.METHODS: MEDLINE (2009) was searched for all TSC case reports with CR. Eleven case reports were identified. Using a random sampling method, we selected 12 case reports of TSC without rupture (control). We included our patient with TSC with rupture as the 12th case of TSC cohort with CR (CR group). Demographic and clinical characteristics were compared between CR group and control.RESULTS: All patients in the TSC group with rupture were female and were significantly older than controls. TSC group with rupture had significantly higher frequency of ST elevation in lead II and absence of T-wave inversion in lead V5 on hospital admission than controls. Mean ejection fraction, systolic blood pressure, and double product, a measure of oxygen demand, was significantly higher in the rupture group compared to controls. The CR group was associated with less frequent use of β-blocker as compared to controls.CONCLUSIONS: CR as a complication of TSC could be more common than recognized. Higher double product and ejection fraction suggest higher fluctuation of intracardiac pressure and may cause CR in TSC. Use of β blockers in TSC may provide protection against CR.", "Exosomes are small extracellular membrane-based vesicles with a variety of cargoes that are involved in numerous physiological and pathological processes in the nervous system. Accumulating evidence has implicated that exosomes are emerging as a novel form of intercellular communication within the nervous system. In this review, we first illustrate exosome metabolism including its formation, secretion, transport, and uptake. Second, we compare exosomes to synaptic vesicles in terms of intercellular messengers and communicators. Third, we discuss the roles and prospects of exosomes in the diagnosis and treatment of neurodegenerative diseases.", "Insulin resistance plays a major role in the development of type 2 diabetes and obesity and affects a number of biological processes such as mitochondrial biogenesis. Though mitochondrial dysfunction has been linked to the development of insulin resistance and pathogenesis of type 2 diabetes, the precise mechanism linking the two is not well understood. We used high fat diet (HFD)-induced obesity dependent diabetes mouse models to gain insight into the potential pathways altered with metabolic disease, and carried out quantitative proteomic analysis of liver mitochondria. As previously reported, proteins involved in fatty acid oxidation, branched chain amino acid degradation, tricarboxylic acid cycle, and oxidative phosphorylation were uniformly up-regulated in the liver of HFD fed mice compared with that of normal diet. Further, our studies revealed that retinol metabolism is distinctly down-regulated and the mitochondrial structural proteins-components of mitochondrial inter-membrane space bridging (MIB) complex (Mitofilin, Sam50, and ChChd3), and Tim proteins-essential for protein import, are significantly up-regulated in HFD fed mice. Structural and functional studies on HFD and normal diet liver mitochondria revealed remodeling of HFD mitochondria to a more condensed form with increased respiratory capacity and higher ATP levels compared with normal diet mitochondria. Thus, it is likely that the structural remodeling is essential to accommodate the increased protein content in presence of HFD: the mechanism could be through the MIB complex promoting contact site and crista junction formation and in turn facilitating the lipid and protein uptake.", "The pesticide rotenone has been shown to cause systemic inhibition of mitochondrial complex I activity, with consequent degeneration of dopamine neurons along the nigrostriatal pathway, as observed in Parkinson's disease (PD). Recently, intracranial infusion of rotenone was found to increase the protein levels of the Lewy body constituents, α-synuclein and small ubiquitin-related modifier-1(SUMO-1), in the lesioned hemisphere of the mouse brain. These findings are supportive of a mouse model of PD, but information about the dopamine-synthesizing enzyme, tyrosine hydroxylase (TH), an essential marker of dopaminergic status, was not reported. Clarification of this issue is important because an intracranial rotenone mouse model of Parkinson's disease has not been established. Towards this end, the present study examined the effects of intracranial rotenone treatment on TH and α-synuclein immunohistochemistry in addition to forelimb motor function. Mice were unilaterally infused with either vehicle or rotenone (2μg/site) in both the medial forebrain bundle and the substantia nigra. The forelimb asymmetry (cylinder) test indicated a significant decrease in use of the contralateral forelimb in lesioned animals as compared to the sham group. Densitometric analysis revealed a significant depletion of TH immunofluorescence within the ipsilateral striatum and substantia nigra of lesioned animals. Moreover, a significant bilateral increase in α-synuclein immunofluorescence was found in the substantia nigra of lesioned mice, as compared to control animals. These findings indicate that this intracranial rotenone mouse model will be useful for studies of neurodegenerative disorders such as PD.", "The AL1 protein of tomato golden mosaic virus (TGMV), a member of the geminivirus family, is essential for viral replication in plants. Its N terminus contains three conserved motifs that mediate origin recognition and DNA cleavage during the initiation of rolling-circle replication. We used the N-terminal domain of TGMV AL1 as bait in a yeast two-hybrid screen of a random peptide aptamer library constrained in the active site of the thioredoxin A (TrxA) gene. The screen selected 88 TrxA peptides that also bind to the full-length TGMV AL1 protein. Plant expression cassettes corresponding to the TrxA peptides and a TGMV A replicon encoding AL1 were cotransfected into tobacco protoplasts, and viral DNA replication was monitored by semiquantitative PCR. In these assays, 31 TrxA peptides negatively impacted TGMV DNA accumulation, reducing viral DNA levels to 13 to 64% of those of the wild type. All of the interfering aptamers also bound to the AL1 protein of cabbage leaf curl virus. A comparison of the 20-mer peptides revealed that their sequences are not random. The alignments detected seven potential binding motifs, five of which are more highly represented among the interfering peptides. One motif was present in 18 peptides, suggesting that these peptides interact with a hot spot in the AL1 N terminus. The peptide aptamers characterized in these studies represent new tools for studying AL1 function and can serve as the basis for the development of crops with broad-based resistance to single-stranded DNA viruses.", "Neuronal loss in specific brain regions and neurons with intracellular inclusions termed Lewy bodies are the pathologic hallmark in both Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Lewy bodies comprise of aggregated intracellular vesicles and proteins and α-synuclein is reported to be a major protein component. Using human brain tissue from control, PD and DLB and light and confocal immunohistochemistry with antibodies to superoxide dismutase 2 as a marker for mitochondria, α-synuclein for Lewy bodies and βIII Tubulin for microtubules we have examined the relationship between Lewy bodies and mitochondrial loss. We have shown microtubule regression and mitochondrial and nuclear degradation in neurons with developing Lewy bodies. In PD, multiple Lewy bodies were often observed with α-synuclein interacting with DNA to cause marked nuclear degradation. In DLB, the mitochondria are drawn into the Lewy body and the mitochondrial integrity is lost. This work suggests that Lewy bodies are cytotoxic. In DLB, we suggest that microtubule regression and mitochondrial loss results in decreased cellular energy and axonal transport that leads to cell death. In PD, α-synuclein aggregations are associated with intact mitochondria but interacts with and causes nuclear degradation which may be the major cause of cell death.", "Multiple advances have been made in our understanding of pathobiology of chronic lymphocytic leukemia (CLL). These developments in the laboratory include new prognostic markers, risk stratification of the disease and newer therapeutic agents in CLL. These advances in CLL have come a long way in the past three decades since the development of Rai and Binet clinical staging systems. Important strides in the pathobiology, from defining mutational status of IGHV, to B-cell receptor (BCR) signaling pathways and CLL microenvironment have made a major difference in our understanding of this disease. Mutational status of immunoglobulin heavy chain genes (IGHV), CD38 and Zap-70, chromosomal aberrations and newer mutations, are the most clinically relevant prognostic markers. Chemoimmunotherapy (CIT) has become the treatment of choice for young and fit CLL patients. Various inhibitors of BCR signaling pathways and immunomodulatory drugs have shown efficacy in clinical trials. The most recent advance is the use of chimeric antigen receptor therapy (CAR) based on autologous T-lymphocytes. Nevertheless, CLL remains an incurable disease today. Coordinated developments between laboratory and clinic will hopefully translate into a cure for CLL. This short review focuses on advances in prognostication and therapy in CLL.", "The detection of anomalous extra-spinal left-right skeletal length asymmetries in the upper limbs, periapical ribs, ilia and lower limbs of subjects with adolescent idiopathic scoliosis (AIS) raises questions about skeletal bilateral symmetry of vertebrates in health and disorder, its origin and control. The vertebrate body plan externally has mirror-image bilateral symmetries that are highly conserved culminating in the adult form. The normal human body can be viewed as containing paired skeletal structures in the axial and appendicular skeleton as 1) separate left and right paired forms (eg long limb bones, ribs, ilia), and 2) united in paired forms (eg vertebrae, sternum, skull, mandible). Each of these separate and united pairs are mirror-image forms--enantiomorphs. Left-right asymmetries of growth plates (physes) may cause (1) in long bones length asymmetries, (2) within one or more vertebral physes putative growth conflict with distortion as deformity, and (3) between ribs and vertebrae putative growth conflict that triggers thoracic AIS suggesting preventive surgery on spine and ribs. There is evidence of a possible role for environmental factors in AIS development. Genes and the environment (nature/nurture) may interact pre- and/or post-natally to explain both the deformity of AIS and its association with widespread anomalous skeletal length asymmetries. If substantiated there may ultimately be a place for the prevention of AIS in some subjects.", "Cardiac-type sarco(endo)plasmic reticulum Ca(2)-ATPase (SERCA2a) plays a major role in cardiac muscle contractility. Phospholamban (PLN) regulates the function of SERCA2a via its Ser(16)-phosphorylation. Since it has been proposed that the Ser/Thr residues on cytoplasmic and nuclear proteins are modified by O-linked N-acetylglucosamine (O-GlcNAc), we examined the effect of O-GlcNAcylation on PLN function in rat adult cardiomyocytes. Studies using enzymatic labeling and co-immunoprecipitation of wild type and a series of mutants of PLN showed that PLN was O-GlcNAcylated and Ser(16) of PLN might be the site for O-GlcNAcylation. In cardiomyocytes treated with O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc), the O-GlcNAcylation was significantly increased compared to non-treated cells. Simultaneously, Ser(16)-phosphorylation of PLN was reduced. In Chinese hamster ovary cells where PLN cDNA and O-GlcNAc transferase siRNA were co-transfected, the Ser(16)-phosphorylation of PLN was significantly increased compared to controls. The same results were observed in heart homogenates from diabetic rats. In a co-immunoprecipitation of PLN with SERCA2a, the physical interaction between the two proteins was increased in PUGNAc-treated cardiomyocytes. Unlike non-treated cells, the activity of SERCA2a and the profiles of calcium transients in PUGNAc-treated cardiomyocytes were not significantly changed even after treatment with catecholamine. These data suggest that PLN is O-GlcNAcylated to induce the inhibition of its phosphorylation, which correlates to the deterioration of cardiac function. This might define a novel mechanism by which PLN regulation of SERCA2a is altered under conditions where O-GlcNAcylation is increased, such as those occurring in diabetes.", "The sphincter of Oddi (SO) is critically located at the junction of the common bile duct (CBD), main pancreatic duct, and the duodenum. It is a high-pressure zone with phasic contractions that regulate bile and pancreatic juice flow. The SO is probably regulated by several gastrointestinal hormones, and its basal pressure and phasic contractions can be elevated or decreased significantly by exogenous drugs. Its role in gallstone formation is probably negligible, but severing the SO allows one to extract CBD stones with an endoscope. Abnormal function of the SO can cause biliarylike pain. Of patients with persistent pain after cholecystectomy, 14% have abnormal SO manometric findings. Endoscopic or surgical sphincterotomy can cure these patients of their pain. The SO may play a significant role in the development of pancreatitis in certain patients, either because of the relationship of the CBD orifice to the pancreatic duct orifice created by the SO or because of the response of the SO to exogenous agents, such as alcohol.", "Exon skipping has been demonstrated to be a successful strategy for the gene therapy of Duchenne muscular dystrophy (DMD): the rational being to convert severe Duchenne forms into milder Becker ones. Here, we show the selection of U1 snRNA-antisense constructs able to confer effective rescue of dystrophin synthesis in a Δ44 Duchenne genetic background, through skipping of exon 45; moreover, we demonstrate that the resulting dystrophin is able to recover timing of myogenic marker expression, to relocalize neuronal nitric oxide synthase (nNOS) and to rescue expression of miRNAs previously shown to be sensitive to the Dystrophin-nNOS-HDAC2 pathway. Becker mutations display different phenotypes, likely depending on whether the shorter protein is able to reconstitute the wide range of wild-type functions. Among them, efficient assembly of the dystrophin-associated protein complex (DAPC) and nNOS localization are important. Comparing different Becker deletions we demonstrate the correlation between the ability of the mutant dystrophin to relocalize nNOS and the expression levels of two miRNAs, miR-1 and miR29c, known to be involved in muscle homeostasis and to be controlled by the Dys-nNOS-HDAC2 pathway.", "It took almost 100 years before a meaningful advance occurred in any basic science understanding of Parkinson disease (PD) following James Parkinson's description in 1817. The Lewy body was described in 1912, and the substantia nigra was found to be depigmented with neuronal loss and gliosis in 1919. The link between dopamine and PD began in 1957, 140 years after Parkinson's Essay. Arvid Carlsson and Oleh Hornykiewicz were the major pioneers. The revolutionary therapeutic breakthrough was the introduction of high dosage levodopa therapy by George Cotzias in 1967. Following 40 years of the dopa/dopamine era, we have entered the era of alpha-synuclein, the protein present in Lewy bodies. Heiko Braak found that alpha-synuclein accumulates initially in the olfactory system and lower brainstem and then travels in an anatomic pattern to involve other regions of the brain and thereby cause progressive symptoms. Alpha-synuclein was somehow converted to a rogue protein. Where this originates and how it is propagated are under intense investigation. At the same time that the alpha-synuclein era was developing, clinical advances took place by recognizing PD as hosting a wide variety of nonmotor features with eventual cognitive impairment in many. Therapeutics has also evolved. Although the most effective therapy for the motor features remains levodopa, surgical approaches and drugs for nonmotor problems continue to expand our ability to treat people with PD. We can expect therapeutic advances in neuroprotection as the basic science discoveries uncovered in the alpha-synuclein era are translated into effective treatments.", "Upc2p, a transcription factor of the zinc cluster family, is an important regulator of sterol biosynthesis and azole drug resistance in Candida albicans. To better understand Upc2p function in C. albicans, we used genomewide location profiling to identify the transcriptional targets of Upc2p in vivo. A triple hemagglutinin epitope, introduced at the C terminus of Upc2p, conferred a gain-of-function effect on the fusion protein. Location profiling identified 202 bound promoters (P < 0.05). Overrepresented functional groups of genes whose promoters were bound by Upc2p included 12 genes involved in ergosterol biosynthesis (NCP1, ERG11, ERG2, and others), 18 genes encoding ribosomal subunits (RPS30, RPL32, RPL12, and others), 3 genes encoding drug transporters (CDR1, MDR1, and YOR1), 4 genes encoding transcription factors (INO2, ACE2, SUT1, and UPC2), and 6 genes involved in sulfur amino acid metabolism (MET6, SAM2, SAH1, and others). Bioinformatic analyses suggested that Upc2p binds to the DNA motif 5'-VNCGBDTR that includes the previously characterized Upc2p binding site 5'-TCGTATA. Northern blot analysis showed that increased binding correlates with increased expression for the analyzed Upc2p targets (ERG11, MDR1, CDR1, YOR1, SUT1, SMF12, and CBP1). The analysis of ERG11, MDR1, and CDR1 transcripts in wild-type and upc2Delta/upc2Delta strains grown under Upc2p-activating conditions (lovastatin treatment and hypoxia) showed that Upc2p regulates its targets in a complex manner, acting as an activator or as a repressor depending upon the target and the activating condition. Taken together, our results indicate that Upc2p is a key regulator of ergosterol metabolism. They also suggest that Upc2p may contribute to azole resistance by regulating the expression of drug efflux pump-encoding genes in addition to ergosterol biosynthesis genes.", "INTRODUCTION: Parkinson's disease (PD) is characterized by bradykinesia, rigidity, postural instability and tremor. Several pathologic processes can produce this syndrome, but neurodegeneration accompanied by neuronal inclusions composed of α-synuclein (Lewy bodies) is considered the typical pathologic correlate of PD.METHODS: The neuropathologic features of PD are reviewed based upon personal experience and review of the literature. Molecular pathology of PD is summarized from cell biological and animal studies.RESULTS: The pathologic feature that correlates with signs and symptoms of PD is neuronal loss in the substantia nigra with dopaminergic denervation of the striatum. Neuronal degeneration in the substantia nigra preferentially affects the ventrolateral cell group that projects to posterolateral putamen and is accompanied by formation of Lewy bodies composed of aggregated α-synuclein. Some patients with PD are found at autopsy to have other pathologic processes, such as multiple system atrophy, progressive supranuclear palsy and cerebrovascular disease (vascular Parkinsonism). The peripheral autonomic nervous system is also affected. The triggering event in PD is unknown, but recent studies suggest a role for loss of nuclear membrane integrity. Once α-synuclein aggregates forms, evidence supports cell-to-cell propagation.CONCLUSION: PD is a multisystem synucleinopathy caused by poorly characterized genetic and environmental factors that produces degeneration in selectively vulnerable neuronal populations." ]

[ "Posterior cruciate ligament (PCL) injuries have a reported incidence of between 3 and 37%, depending on the clinical setting. The most common mechanism of injury in motor vehicle accidents is a dashboard injury or direct force to the proximal anterior tibia. Sports related injuries result from hyperflexion of the knee with the foot typically plantarflexed. The latter mechanism is the most common cause of isolated PCL injuries, while in the trauma population as many as 95% of patients with knee injuries have combined ligamentous damage. Improved knowledge at an anatomical, biomechanical and clinical level has provided the orthopaedist with a more defined treatment algorithm. Isolated, partial PCL injuries (grades I and II) can best be treated nonoperatively while complete injuries (grade III) may require operative treatment based on clinical symptoms. All combined ligamentous injuries usually respond best with surgical management.", "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.", "Atrial fibrillation is a major risk factor for first and recurrent ischaemic stroke, and anticoagulation, mainly by use of coumarin medications, is an effective strategy for reducing ischaemic stroke occurrence in these patients. However, the coumarin medications have disadvantages. Over the past decade, important strides have been made towards developing improved anticoagulant medications. This review discusses these new developments and what they mean for the future of primary and secondary ischaemic stroke prevention in patients with atrial fibrillation. Relevant papers were identified with electronic searches of the Medline and EMBASE databases. Ongoing trials were checked using the Trials Results Centre website. The direct thrombin inhibitors, and the factor Xa inhibitors are the two major new anticoagulant drug classes under development at present. In phase III trials, dabigatran and rivaroxaban demonstrated at least as good performance as warfarin at reducing the rate of ischaemic stroke, systemic embolus, and haemorrhagic ischaemic stroke, whilst maintaining a comparable or lower rate of major bleeding events. Drug level monitoring was not required due to stable pharmacodynamics. AZD0837, apixaban, YM-150, edoxaban and betrixaban all showed promising results in phase II trials, as did S35972 in animal, in vitro and ex vivo models. The future of these new anticoagulants looks encouraging, although there are still some significant challenges to overcome. We need to consider the accumulation of long-term safety and efficacy data, and the development of effective means of reversal of anticoagulation for the direct thrombin inhibitors and factor Xa inhibitors.", "Small ubiquitin-like modifier (SUMO), a reversible post-translational protein modifier, plays important roles in diverse cellular mechanisms. Three enzymes, E1 (activating enzyme), E2 (conjugating enzyme) and E3 (ligase), are involved in SUMO modification. SUMOylation system and process in higher eukaryotes have been well studied. However, in protozoa, such as Trypanosoma brucei (T. brucei), these remain poorly understood. Herein, we identified the E1 (TbAos1/TbUba2) and E2 (TbUbc9) enzymes of SUMOylation pathway in T. brucei by sequence analysis and GST pull-down assay. Furthermore, we successfully reconstructed the SUMOylation system in vitro with recombinant enzymes. Using this system, the active site of TbUba2 and TbUbc9 was revealed to be located at Cys343 and Cys132, respectively, and a centrin homologue (TbCentrin3) was identified to be a target of SUMOylation in T. brucei. Altogether, our results demonstrate that TbAos1/TbUba2 and TbUbc9 are the bona fide E1 and E2 enzymes of the SUMOylation system in T. brucei.", "INTRODUCTION: Both non-Group A streptococcal (non-GAS) pharyngitis and Group A streptococcal (GAS) pharyngitis are commonly found in patients with sore throat. It is not known whether or not they present with similar signs and symptoms compared to patients with non-streptococcal pharyngitis.METHODS: MEDLINE was searched for prospective studies that reported throat culture for both GAS and non-GAS as a reference standard, and reported at least one sign, symptom, or the Centor score. Summary estimates of sensitivity, specificity, likelihood ratios (LR+ and LR-), and diagnostic odds ratios (DOR) were calculated using a bivariate random effects model. Summary receiver operating characteristic (ROC) curves were created for key signs and symptoms.RESULTS: Eight studies met our inclusion criteria. Tonsillar exudate had the highest LR+ for both GAS and non-GAS pharyngitis (1.53 versus 1.71). The confidence intervals of sensitivity, LR+, LR-, and DOR for all signs, symptoms, and the Centor score between two groups overlapped, with the relative difference between sensitivities within 15% for arthralgia or myalgia, fever, injected throat, tonsillar enlargement, and tonsillar exudate. Larger differences in sensitivities were observed for sore throat, cervical adenopathy, and lack of a cough, although the difference for lack of a cough largely due to a single outlier.DISCUSSION: Signs and symptoms of patients with GAS and non-GAS pharyngitis are generally similar. No signs or symptoms clearly distinguish GAS from non-GAS infection. Further work is needed to determine whether Group C streptococcus is a pathogen that should be treated.", "OBJECTIVE: Serum uric acid (SUA) levels correlate with many recognized cardiovascular risk factors, including age, male sex, hypertension, diabetes mellitus, hypertriglyceridemia, obesity, and insulin resistance. The aim of our study was to verify in a large well characterized population sample the relationship between SUA values, hypertension, arterial stiffness and subclinical atherosclerosis.METHODS: For this study, we selected 248 men and 371 women adult patients enrolled in the last Brisighella Heart Study population survey for which a full set of data were available and not consuming antihypertensive, antidiabetic, lipid-lowering and uric acid-lowering drugs. SUA and other available variables were related to blood pressure level, carotid-femoral pulse wave velocity (cfPWV) and carotid intima-media thickness (cIMT).RESULTS: Hypertension prevalence was strongly related to SUA quartiles: we found significant differences between the 2nd (23.0%) and the 3rd quartiles (36.4%; P vs. 2nd < 0.05), and between the 3rd and the 4th quartile (56.3%; P vs. 3rd < 0.05). Similarly, the metabolic syndrome prevalence increased significantly at 39.5% in the 3rd SUA quartile (P < 0.05 vs. 2nd) and at 58.9% in the 4th quartile (P < 0.05 vs. 3rd). Intima-media thickness gradually and significantly rose along quartiles of SUA (P for trend < 0.0001), in particular, it was 0.86  mm in the 1st quartile, 0.90 in the 2nd, 0.94 in the 3rd, and 0.97 in the last quartile, with significant differences between each quartiles (all P < 0.05). In multivariate regression analyses, SUA resulted to be significantly associated to hypertension and metabolic syndrome prevalence, and IMT. Even if a significant association between SUA and cfPWV was found in univariate analysis (P = 0.002), when adjusting for age, the trend became nonsignificant (0.20).CONCLUSION: In the studied population sample, after adjustment for a large number of parameters, SUA appears to be significantly correlated to hypertension and IMT, but not to aortic stiffness.", "OBJECTIVE: To evaluate the predictive values for disease progression of various antibodies against citrullinated peptide proteins (ACPA) and their relation to PTPN22 1858C/T polymorphism and HLA-DRB1 alleles in early rheumatoid arthritis (RA).METHODS: The ACPA, e.g., antibodies against mutated citrullinated vimentin (MCV), cyclic citrullinated peptides (CCP) type 2 and 3 (both of IgG isotype) and 3.1 (of both IgG and IgA isotypes), were analyzed at baseline in patients with early RA (n = 210) and in population controls (n = 102) using an enzyme immunoassay. A receiver-operating characteristic curve was constructed for each antibody. Disease activity [swollen and tender joints, visual analog scale for global health, and erythrocyte sedimentation rate (ESR)] was evaluated at baseline and regularly for 24 months. Radiographs of hands and feet were graded using the Larsen score.RESULTS: Patients with anti-MCV antibodies had significantly less reduction in Disease Activity Score (DAS28) over time (p < 0.01), and significantly increased area under the curve (AUC) for DAS28 (p < 0.05), ESR (p < 0.01), C-reactive protein (p < 0.01), and swollen joint count (p = 0.057) compared to those without. Corresponding differences were not found in patients with anti-CCP2, CCP3, and CCP3.1 antibodies. Radiological progression (p < 0.0001-0.01) and radiological outcome (p < 0.0001-0.01) at 24 months were significantly predicted by all ACPA after baseline adjustments. PTPN22 T variant and HLA-DRB1 alleles were not related to radiological progression or inflammatory activity over time.CONCLUSION: Anti-MCV antibodies are associated with a more severe RA disease, as measured by DAS28, ESR, and swollen joint count over time, compared with anti-CCP2, CCP3, and CCP3.1 antibodies. Radiological progression was predicted equally by all 4 autoantibodies.", "AIM: Determine the long-term efficacy, safety and tolerability of avanafil, a highly specific, rapidly absorbed phosphodiesterase type 5 inhibitor in male patients with mild to severe erectile dysfunction (ED), with or without diabetes.METHODS: This was a 52-week, open-label extension of two 12-week, randomised, placebo-controlled, phase 3 trials. Patients were assigned to avanafil 100 mg, but could request 200 mg (for increased efficacy; '100/200-mg' group) or 50 mg (for improved tolerability). Primary end points included percentage of sexual attempts ending in successful vaginal penetration [Sexual Encounter Profile 2 (SEP2)] and intercourse (SEP3) and erectile function domain score per the International Index of Erectile Function (IIEF-EF).RESULTS: Some 712 patients enrolled; 686 were included in the intent to treat population and contributed to the data. All primary end points showed sustained improvement. SEP2 and SEP3 success rates improved from 44% to 83% and from 13% to 68% (100-mg group) and from 43% to 79% and from 11% to 66% (100/200-mg group), respectively. Mean IIEF-EF domain scores improved from 13.6 to 22.2 (100-mg group) and from 11.9 to 22.7 (100/200-mg group). Avanafil was effective in some patients ≤ 15 min and > 6 h postdose. Sixty-five per cent (112/172) of 'nonresponders' to avanafil 100 mg responded to the 200-mg dose. The most common (≥ 2%) treatment-emergent adverse events were headache, flushing, nasopharyngitis and nasal congestion; < 3% of patients discontinued therapy because of adverse events.CONCLUSIONS: The long-term tolerability and improvement in sexual function, coupled with rapid onset, suggest that avanafil is well suited for the on-demand treatment of ED.", "Author information:(1)Laboratory of Functional Genomics and Bioinformatics, A. I. Virtanen Institute for Molecular Sciences, Department of Neurobiology, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland. Electronic address: vuokko.aarnio@uef.fi.(2)Laboratory of Functional Genomics and Bioinformatics, A. I. Virtanen Institute for Molecular Sciences, Department of Neurobiology, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland. Electronic address: liisa.heikkinen@uef.fi.(3)Laboratory of Functional Genomics and Bioinformatics, A. I. Virtanen Institute for Molecular Sciences, Department of Neurobiology, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland. Electronic address: juhanip@student.uef.fi.(4)Laboratory of Molecular Brain Research, A. I. Virtanen Institute for Molecular Sciences, Department of Neurobiology, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland. Electronic address: gundars.goldsteins@uef.fi.(5)Laboratory of Functional Genomics and Bioinformatics, A. I. Virtanen Institute for Molecular Sciences, Department of Neurobiology, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland. Electronic address: merja.lakso@uef.fi.(6)Laboratory of Functional Genomics and Bioinformatics, A. I. Virtanen Institute for Molecular Sciences, Department of Neurobiology, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland. Electronic address: garry.wong@uef.fi.", "Optogenetic methods have emerged as a powerful tool for elucidating neural circuit activity underlying a diverse set of behaviors across a broad range of species. Optogenetic tools of microbial origin consist of light-sensitive membrane proteins that are able to activate (e.g., channelrhodopsin-2, ChR2) or silence (e.g., halorhodopsin, NpHR) neural activity ingenetically-defined cell types over behaviorally-relevant timescales. We first demonstrate a simple approach for adeno-associated virus-mediated delivery of ChR2 and NpHR transgenes to the dorsal subiculum and prelimbic region of the prefrontal cortex in rat. Because ChR2 and NpHR are genetically targetable, we describe the use of this technology to control the electrical activity of specific populations of neurons (i.e., pyramidal neurons) embedded in heterogeneous tissue with high temporal precision. We describe herein the hardware, custom software user interface, and procedures that allow for simultaneous light delivery and electrical recording from transduced pyramidal neurons in an anesthetized in vivo preparation. These light-responsive tools provide the opportunity for identifying the causal contributions of different cell types to information processing and behavior.", "Hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. HUS is classified as either diarrhea associated, most commonly caused by infection with Escherichia coli O157, or the less common atypical HUS (aHUS), which may be familial or sporadic. Approximately 50% of patients with aHUS have mutations in one of the complement control proteins: factor H, factor I, or membrane cofactor protein (MCP). These proteins regulate complement activation through cofactor activity, the inactivation of C3b by limited proteolytic cleavage, a desirable event in the fluid phase (no target) or on healthy self-tissue (wrong target). Complement activation follows the endothelial cell injury that characterizes HUS. This disease represents a model of what takes place when inappropriate complement activation occurs on self-tissues due to the presence of mutated complement regulatory proteins. Screening for mutations in factor H, factor I, or MCP is expensive and time consuming. One approach is to perform antigenic screening for factor H and factor I deficiency and to look for low levels of MCP (CD46) expression by flow cytometry. Complement regulatory protein deficiency impacts treatment decisions as patients with aHUS have a recurrence rate in renal transplants of approximately 50%, whereas those with factor H mutations have an even higher risk (approximately 80%). By contrast, MCP deficiency can be corrected in part by a renal allograft. However, caution in the use of live-related donations is needed because of the high rates of incomplete penetrance of the described mutations.", "Only a minority of the genes, identified in the Caenorhabditis elegans genome sequence data by computer analysis, have been characterized experimentally. We attempted to determine the expression patterns for a random sample of the annotated genes using reporter gene fusions. A low success rate was obtained for evolutionarily recently duplicated genes. Analysis of the data suggests that this is not due to conditional or low-level expression. The remaining explanation is that most of the annotated genes in the recently duplicated category are pseudogenes, a proportion corresponding to 20% of all of the annotated C. elegans genes. Further support for this surprisingly high figure was sought by comparing sequences for families of recently duplicated C. elegans genes. Although only a preliminary analysis, clear evidence for a gene having been recently inactivated by genetic drift was found for many genes in the recently duplicated category. At least 4% of the annotated C. elegans genes can be recognized as pseudogenes simply from closer inspection of the sequence data. Lessons learned in identifying pseudogenes in C. elegans could be of value in the annotation of the genomes of other species where, although there may be fewer pseudogenes, they may be harder to detect." ]

[ "Within the past several years, no chemotherapy has been sufficient to increase the overall survival of patients with chemorefractory colorectal cancer. TAS-102 (Lonsurf) is an oral fluoropyrimidine that is formed by the combination of 2 active drugs: trifluridine (a nucleoside analog) and tipiracil hydrochloride (a thymidine phosphorylase inhibitor). This drug extended the median overall survival by approximately 2 months compared with placebo in a randomized phase III trial composed of Asian and non-Asian patients with refractory (or intolerant) metastatic colorectal cancer. The clinical development of TAS-102 began approximately a decade ago and included 2 pivotal randomized studies, which are discussed in this review. This drug has just been approved in Japan, and as soon as possible, it will be marketed in Western countries as well; it will therefore become the standard of care for this patient population. The optimal combination of TAS-102 with other agents, as well as the mechanism of resistance to this regimen should be defined in the near future.", "Nucleosomes must be deacetylated behind elongating RNA polymerase II to prevent cryptic initiation of transcription within the coding region. RNA polymerase II signals for deacetylation through the methylation of histone H3 lysine 36 (H3K36), which provides the recruitment signal for the Rpd3S histone deacetylase complex (HDAC). The recognition of methyl H3K36 by Rpd3S requires the chromodomain of its Eaf3 subunit. Paradoxically, Eaf3 is also a subunit of the NuA4 acetyltransferase complex, yet NuA4 does not recognize methyl H3K36 nucleosomes. In Saccharomyces cerevisiae, we found that methyl H3K36 nucleosome recognition by Rpd3S also requires the plant homeobox domain (PHD) of its Rco1 subunit. Thus, the coupled chromo and PHD domains of Rpd3S specify recognition of the methyl H3K36 mark, demonstrating the first combinatorial domain requirement within a protein complex to read a specific histone code.", "Water is the major component of cells and tissues throughout all forms of life. Fluxes of water and solutes through cell membranes and epithelia are essential for osmoregulation and energy homeostasis. Aquaporins are membrane channels expressed in almost every organism and involved in the bidirectional transfer of water and small solutes across cell membranes. Aquaporins have important biological roles and have been implicated in several pathophysiological conditions suggesting a great translational potential in aquaporin-based diagnostics and therapeutics. Detecting aquaporin function is critical for assessing regulation and screening for new activity modulators that can prompt the development of efficient medicines. Appropriate methods for functional analysis comprising suitable cell models and techniques to accurately evaluate water and solute membrane permeability are essential to validate aquaporin function and assess short-term regulation. The present review describes established assays commonly used to assess aquaporin function in cells and tissues, as well as the experimental biophysical strategies required to reveal functional regulation and identify modulators, the first step for aquaporin drug discovery.", "OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy and lacks effective treatment. We aimed to understand molecular mechanisms of the intertwined interactions between tumour stromal components in metastasis and to provide a new paradigm for PDAC therapy.DESIGN: Two unselected cohorts of 154 and 20 patients with PDAC were subjected to correlation between interleukin (IL)-33 and CXCL3 levels and survivals. Unbiased expression profiling, and genetic and pharmacological gain-of-function and loss-of-function approaches were employed to identify molecular signalling in tumour-associated macrophages (TAMs) and myofibroblastic cancer-associated fibroblasts (myoCAFs). The role of the IL-33-ST2-CXCL3-CXCR2 axis in PDAC metastasis was evaluated in three clinically relevant mouse PDAC models.RESULTS: IL-33 was specifically elevated in human PDACs and positively correlated with tumour inflammation in human patients with PDAC. CXCL3 was highly upregulated in IL-33-stimulated macrophages that were the primary source of CXCL3. CXCL3 was correlated with poor survival in human patients with PDAC. Mechanistically, activation of the IL-33-ST2-MYC pathway attributed to high CXCL3 production. The highest level of CXCL3 was found in PDAC relative to other cancer types and its receptor CXCR2 was almost exclusively expressed in CAFs. Activation of CXCR2 by CXCL3 induced a CAF-to-myoCAF transition and α-smooth muscle actin (α-SMA) was uniquely upregulated by the CXCL3-CXCR2 signalling. Type III collagen was identified as the CXCL3-CXCR2-targeted adhesive molecule responsible for myoCAF-driven PDAC metastasis.CONCLUSIONS: Our work provides novel mechanistic insights into understanding PDAC metastasis by the TAM-CAF interaction and targeting each of these signalling components would provide an attractive and new paradigm for treating pancreatic cancer.", "Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic re uptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia.Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.", "BACKGROUND: Oseltamivir phosphate (OP; Tamiflu) is a prodrug of the anti-influenza neuraminidase inhibitor oseltamivir carboxylate (OC) and has been developed for the treatment and prevention of both A and B strains of influenza. The recent increase in OP resistance in influenza A virus (H1N1; commonly called \"swine flu\") has raised questions about the widespread use of Tamiflu in seasonal epidemics and the potential ecotoxicologic risk associated with its use in the event of a pandemic.OBJECTIVES: The objectives of this study were to develop an analytical method for quantitative determination of OC in sewage treatment plant (STP) effluent and receiving river water, and to investigate the occurrence of OC in STP effluent and river water in Japan during a seasonal flu outbreak.METHODS: We developed an analytical method based on solid-phase extraction followed by liquid chromatography-tandem mass spectrometry. Using this method, we analyzed samples from three sampling campaigns conducted during the 2008-2009 flu season in Kyoto City, Japan.RESULTS: The highest concentration of OC detected in STP discharge was 293.3 ng/L from a conventional activated-sludge-based STP; however, we detected only 37.9 ng/L from an advanced STP with ozonation as a tertiary treatment. In the receiving river water samples, we detected 6.6-190.2 ng/L OC, during the peak of the flu season.CONCLUSION: OC is present in STP effluent and river water only during the flu season. Ozonation as tertiary treatment in STP will substantially reduce the OC load in STP effluent during an influenza epidemic or pandemic.", "Triple-negative breast cancer (TNBC) cells overexpress the epidermal growth factor receptor (EGFR). Nuclear EGFR (nEGFR) drives resistance to anti-EGFR therapy and is correlated with poor survival in breast cancer. Inhibition of EGFR nuclear translocation may be a reasonable approach for the treatment of TNBC. The anti-malarial drugs chloroquine and primaquine have been shown to promote an anticancer effect. The aim of the present study was to investigate the effect and mechanism of chloroquine- and primaquine-induced apoptosis of breast cancer cells. We showed that primaquine, a malaria drug, inhibits the growth, migration, and colony formation of breast cancer cells in vitro, and inhibits tumor growth in vivo. Primaquine induces damage to early endosomes and inhibits the nuclear translocation of EGFR. Primaquine inhibits the interaction of Stat3 and nEGFR and reduces the transcript and protein levels of c-Myc. Moreover, primaquine and chloroquine induce the apoptosis of breast cancer cells through c-Myc/Bcl-2 downregulation, induce early endosome damage and reduce nEGFR levels, and induce apoptosis in breast cancer through nEGFR/Stat3-dependent c-Myc downregulation. Our study of primaquine and chloroquine provides a rationale for targeting EGFR signaling components in the treatment of breast cancer." ]

[ "Recently, advanced text-mining techniques have been shown to speed up manual data curation by providing human annotators with automated pre-annotations generated by rules or machine learning models. Due to the limited training data available, however, current annotation systems primarily focus only on common concept types such as genes or diseases. To support annotating a wide variety of biological concepts with or without pre-existing training data, we developed ezTag, a web-based annotation tool that allows curators to perform annotation and provide training data with humans in the loop. ezTag supports both abstracts in PubMed and full-text articles in PubMed Central. It also provides lexicon-based concept tagging as well as the state-of-the-art pre-trained taggers such as TaggerOne, GNormPlus and tmVar. ezTag is freely available at http://eztag.bioqrator.org.", "Nephropathic cystinosis is a rare lysosomal storage disorder caused by mutations in the CTNS gene ncoding the lysosomal cystine transporter cystinosin. Cystinosin deficiency leads to accumulation of cystine in the lysosomes of cells throughout the body and deregulation of endocytosis, trafficking of intracellular vesicles and related cell signalling processes. One of the early features of the disease is renal Fanconi syndrome characterized by polyuria, proteinuria and urinary loss of various solutes. Later in life, extrarenal complications become apparent, and decline of kidney function leads to the development of end-stage renal disease. Modern therapy of the disease is based on treatment with cystine-lowering drug cysteamine, which helps to postpone the disease progression and development of extra-renal pathologies, but offers no cure for the Fanconi syndrome. Besides the improvement of cystine-lowering therapy based on new formulations of cysteamine, further development of therapy is necessary. Some steps forward were done in the recent years, including studies of cell signalling abnormalities in cystinosis and development of stem cell and gene therapy approaches.", "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.", "Reprogramming of DNA methylation patterns during mammalian preimplantation development involves the concurrent maintenance of methylation on differentially methylated domains (DMDs) of imprinted genes and a marked reduction of global (non-DMD) genomic methylation. In the developing mammalian embryo, one allele of a DMD is unmethylated, and the opposite parental allele is methylated, having inherited this methylation from the parental gamete. The maintenance of DMDs is important for monoallelic imprinted gene expression and normal development of the embryo. Because the DNMT1 cytosine methyltransferase governs maintenance methylation in mammals, rearrangements of non-DMD, but not DMD methylation in preimplantation embryos suggest that the preimplantation DNMT1-dependent maintenance mechanism specifically targets DMD sequences. We explored this possibility using an engineered mouse ES cell line to screen for mutant DNMT1 proteins that protect against the loss of DMD and/or global (non-DMD) methylation in the absence of the wild-type endogenous DNMT1 methyltransferase. We identified DNMT1 mutants that were defective in maintenance of either DMD and/or non-DMD methylation. Among these, one mutant maintained non-DMD methylation but not imprinted DMD methylation and another mutant maintained just DMD methylation. The mutated amino acids of these mutants reside in a mammal-specific, disordered region near the amino terminus of DNMT1. These findings suggest that DNMT1 participates in epigenetic reprogramming through its ability to distinguish different categories of methylated sequences.", "In sub-Saharan Africa, cryptococcal meningitis (CM) continues to be a predominant cause of AIDS-related mortality. Understanding virulence and improving clinical treatments remain important. To characterize the role of the fungal strain genotype in clinical disease, we analyzed 140 Cryptococcus isolates from 111 Ugandans with AIDS and CM. Isolates consisted of 107 nonredundant Cryptococcus neoformans var. grubii strains and 8 C. neoformans var. grubii/neoformans hybrid strains. Multilocus sequence typing (MLST) was used to characterize genotypes, yielding 15 sequence types and 4 clonal clusters. The largest clonal cluster consisted of 74 isolates. The results of Burst and phylogenetic analysis suggested that the C. neoformans var. grubii strains could be separated into three nonredundant evolutionary groups (Burst group 1 to group 3). Patient mortality was differentially associated with the different evolutionary groups (P = 0.04), with the highest mortality observed among Burst group 1, Burst group 2, and hybrid strains. Compared to Burst group 3 strains, Burst group 1 strains were associated with higher mortality (P = 0.02), exhibited increased capsule shedding (P = 0.02), and elicited a more pronounced Th(2) response during ex vivo cytokine release assays with strain-specific capsule stimulation (P = 0.02). The results of these analyses suggest that cryptococcal strain variation can be an important determinant of human immune responses and mortality.IMPORTANCE: Cryptococcus neoformans is a common life-threatening human fungal pathogen that is responsible for an estimated 1 million cases of meningitis in HIV-infected patients annually. Virulence factors that are important in human disease have been identified, yet the impacts of the fungal strain genotype on virulence and outcomes of human infection remain poorly understood. Using an analysis of strain variation based on in vitro assays and clinical data from Ugandans living with AIDS and cryptococcal infection, we report that strain genotype predicts the type of immune response and mortality risk. These studies suggest that knowledge of the strain genotype during human infections could be used to predict disease outcomes and lead to improved treatment approaches aimed at targeting the specific combination of pathogen virulence and host response.", "BACKGROUND: Mass spectrometry has become a powerful tool for the analysis of large numbers of proteins in complex samples, enabling much of proteomics. Due to various analytical challenges, so far no proteome has been sequenced completely. O'Shea, Weissman and co-workers have recently determined the copy number of yeast proteins, making this proteome an excellent model system to study factors affecting coverage.RESULTS: To probe the yeast proteome in depth and determine factors currently preventing complete analysis, we grew yeast cells, extracted proteins and separated them by one-dimensional gel electrophoresis. Peptides resulting from trypsin digestion were analyzed by liquid chromatography mass spectrometry on a linear ion trap-Fourier transform mass spectrometer with very high mass accuracy and sequencing speed. We achieved unambiguous identification of more than 2,000 proteins, including very low abundant ones. Effective dynamic range was limited to about 1,000 and effective sensitivity to about 500 femtomoles, far from the subfemtomole sensitivity possible with single proteins. We used SILAC (stable isotope labeling by amino acids in cell culture) to generate one-to-one pairs of true peptide signals and investigated if sensitivity, sequencing speed or dynamic range were limiting the analysis.CONCLUSION: Advanced mass spectrometry methods can unambiguously identify more than 2,000 proteins in a single proteome. Complex mixture analysis is not limited by sensitivity but by a combination of dynamic range (high abundance peptides preventing sequencing of low abundance ones) and by effective sequencing speed. Substantially increased coverage of the yeast proteome appears feasible with further development in software and instrumentation.", "Genomic hypomethylation is a consistent finding in both human and animal tumors and mounting experimental evidence suggests a key role for epigenetic events in tumorigenesis. Furthermore, it has been suggested that early changes in DNA methylation and histone modifications may serve as sensitive predictive markers in animal testing for carcinogenic potency of environmental agents. Alterations in metabolism of methyl donors, disturbances in activity and/or expression of DNA methyltransferases, and presence of DNA single-strand breaks could contribute to the loss of cytosine methylation during carcinogenesis; however, the precise mechanisms of genomic hypomethylation induced by chemical carcinogens remain largely unknown. This study examined the mechanism of DNA hypomethylation during hepatocarcinogenesis induced by peroxisome proliferators WY-14,643 (4-chloro-6-(2,3-xylidino)-pyrimidynylthioacetic acid) and DEHP (di-(2-ethylhexyl)phthalate), agents acting through non-genotoxic mode of action. In the liver of male Fisher 344 rats exposed to WY-14,643 (0.1% (w/w), 5 months), the level of genomic hypomethylation increased by approximately 2-fold, as compared to age-matched controls, while in the DEHP group (1.2% (w/w), 5 months) DNA methylation did not change. Global DNA hypomethylation in livers from WY-14,643 group was accompanied by the accumulation of DNA single-strand breaks, increased cell proliferation, and diminished expression of DNA methyltransferase 1, while the metabolism of methyl donors was not affected. In contrast, none of these parameters changed significantly in rats fed DEHP. Since WY-14,643 is much more potent carcinogen than DEHP, we conclude that the extent of loss of DNA methylation may be related to the carcinogenic potential of the chemical agent, and that accumulation of DNA single-strand breaks coupled to the increase in cell proliferation and altered DNA methyltransferase expression may explain genomic hypomethylation during peroxisome proliferator-induced carcinogenesis." ]

[ "Carbon dioxide (CO₂) retention, or hypercapnia, is a known risk of diving that can cause mental and physical impairments leading to life-threatening accidents. Often, such accidents occur due to elevated inspired carbon dioxide. For instance, in cases of CO₂ elimination system failures during rebreather dives, elevated inspired partial pressure of carbon dioxide (PCO₂) can rapidly lead to dangerous levels of hypercapnia. Elevations in PaCO₂ (arterial pressure of PCO₂) can also occur in divers without a change in inspired PCO₂. In such cases, hypercapnia occurs due to alveolar hypoventilation. Several factors of the dive environment contribute to this effect through changes in minute ventilation and dead space. Predominantly, minute ventilation is reduced in diving due to changes in respiratory load and associated changes in respiratory control. Minute ventilation is further reduced by hyperoxic attenuation of chemosensitivity. Physiologic dead space is also increased due to elevated breathing gas density and to hyperoxia. The Haldane effect, a reduction in CO₂ solubility in blood due to hyperoxia, may contribute indirectly to hypercapnia through an increase in mixed venous PCO₂. In some individuals, low ventilatory response to hypercapnia may also contribute to carbon dioxide retention. This review outlines what is currently known about hypercapnia in diving, including its measurement, cause, mental and physical effects, and areas for future study.", "To explore mechanism of intestinal flora dysregulation promoting constipation, 60 specific pathogen-free (SPF) mice were used as research objects and were treated with constipation population fecal fluid gavage and distilled water gavage. Then, relationship between intestinal dysregulation and constipation in mice with biofilm-mediated intestinal flora was investigated in vitro. The results showed that recombinant serotonin transporter (SERT) messenger ribonucleic acid (mRNA) level of the constipation population fecal fluid gavage group and the relative expression level of SERT mRNA were 1.61 ± 0.08 and 1.49 ± 0.06, which were higher markedly than those of distilled water group (P < 0.05). The level of 5-hydroxytryptamine (5-HT) in colonic tissue of the constipation population fecal fluid gavage group was 145.36 ± 14.12 ng/mL, and the expression level of 5-HT on the surface of epithelial cells of biofilm-positive colonic tissue was 20.11 ± 2.03, which were significantly lower than those of the distilled water group, with statistical significance (P < 0.05). Besides, the microbial sequencing of fecal flora indicated that The Akk and bacteroidetes ofconstipation population fecal fluid gavage group were higher hugely than those of distilled water group (P < 0.05).In conclusion, after the occurrence of constipation, the diversity of intestinal microflora decreased, and the probiotics reduced. Iintestinal microflora dysregulation would lead to increase of SERT expression level in defecation function and intestinal motility in mice, and the decrease of 5-HT, thereby changing the intestinal movement resulting in mucosal protective barrier damage,thereby causing changes in intestinal movement and the destruction of the intestinal mucosal protective barrier, which eventually resulted in constipation. The occurrence of constipation could be improved by regulating balance of intestinal flora, increasing the diversity of flora, and reducing the genus of opportunistic pathogens.", "Heterozygous mutations in MECOM (MDS1 and EVI1 complex locus) have been reported to be causative of a rare association of congenital amegakaryocytic thrombocytopenia and radioulnar synostosis. Here we report on 12 patients with congenital hypomegakaryocytic thrombocytopenia caused by MECOM mutations (including 10 novel mutations). The mutations affected different functional domains of the EVI1 protein. The spectrum of phenotypes was much broader than initially reported for the first 3 patients; we found familial as well as sporadic cases, and the clinical spectrum ranged from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormality. The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss. No single clinical manifestation was detected in all patients affected by MECOM mutations. Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1. We propose the term MECOM-associated syndrome for this heterogeneous hereditary disease and inclusion of MECOM sequencing in the diagnostic workup of congenital bone marrow failure.", "Borna disease virus (BDV) causes central nervous system (CNS) disease in several vertebrate species, which is frequently accompanied by behavioral abnormalities. In the adult rat, intracerebral (i.c.) BDV infection leads to immunomediated meningoencephalitis. In contrast, i.c. infection of neonates causes a persistent infection in the absence of overt signs of brain inflammation. These rats (designated PTI-NB) display distinct behavioral and neurodevelopmental abnormalities. However, the molecular mechanisms for these virally induced CNS disturbances are unknown. Cytokines play an important role in CNS function, both under normal physiological and pathological conditions. Astrocytes and microglia are the primary resident cells of the central nervous system with the capacity to produce cytokines. Strong reactive astrocytosis is observed in the PTI-NB rat brain. We have used a ribonuclease protection assay to investigate the mRNA expression levels of proinflammatory cytokines in different brain regions of PTI-NB and control rats. We show here evidence of a chronic upregulation of proinflammatory cytokines interleukin-6, tumor necrosis factor alpha, interleukins-1alpha, and -1beta in the hippocampus and cerebellum of the PTI-NB rat brain. These brain regions exhibited only a very mild and transient immune infiltration. In contrast, in addition to reactive astrocytes, a strong and sustained microgliosis was observed in the PTI-NB rat brains. Our data suggest that CNS resident cells, namely astrocytes and microglia, are the major source of cytokine expression in the PTI-NB rat brain. The possible implications of these findings are discussed.", "Low-density lipoprotein receptor-related protein (LRP) mediates internalization of urokinase:plasminogen activator inhibitor complexes (uPA:PAI-1) and the urokinase receptor (uPAR). Here we investigated whether direct interaction between uPAR, a glycosyl-phosphatidylinositol-anchored protein, and LRP, a transmembrane receptor, is required for clearance of uPA:PAI-1, regeneration of unoccupied uPAR, activation of plasminogen, and the ability of HT1080 cells to invade extracellular matrix. We found that in the absence of uPA:PAI-1, uPAR is randomly distributed along the plasma membrane, whereas uPA:PAI-1 promotes formation of uPAR-LRP complexes and initiates redistribution of occupied uPAR to clathrin-coated pits. uPAR-LRP complexes are endocytosed via clathrin-coated vesicles and traffic together to early endosomes (EE) because they can be coimmunoprecipitated from immunoisolated EE, and internalization is blocked by depletion of intracellular K(+). Direct binding of domain 3 (D3) of uPAR to LRP is required for clearance of uPA-PAI-1-occupied uPAR because internalization is blocked by incubation with recombinant D3. Moreover, uPA-dependent plasmin generation and the ability of HT1080 cells to migrate through Matrigel-coated invasion chambers are also inhibited in the presence of D3. These results demonstrate that GPI-anchored uPAR is endocytosed by piggybacking on LRP and that direct binding of occupied uPAR to LRP is essential for internalization of occupied uPAR, regeneration of unoccupied uPAR, plasmin generation, and invasion and migration through extracellular matrix.", "Genetic and pharmacological research on aging is hampered by the lifespan of available vertebrate models. We recently initiated studies on Nothobranchius furzeri, a species with a maximum life expectancy in captivity of just three months which represents the shortest documented captive lifespan for a vertebrate. Further research on N. furzeri has demonstrated that 1. Short lifespan is tied with explosive growth and accelerated sexual maturation. 2. Short lifespan is correlated with expression of age-related behavioral and histological changes. 3. Lifespan and expression of age-related markers can be modulated by water temperature. 4. Resveratrol, a drug characterized for its life-extending action in Caenorhabditis elegans and Drosophila, increases lifespan and retards expression of age-related markers. 5. Aging-related genes can be easily isolated by homology cloning. Finally, different populations or species of Nothobranchius show large-scale differences in captive lifespan. In the last three years, N. furzeri has moved from biological curiosity to a promising model system for drug validation. Furthermore, this species occupies a favorable position in the Teleost's \"tree of life\". It is very close to the Japanese Medaka, and close to the pufferfishes and stickleback and might represent a very useful model for comparative genomics of aging.", "BACKGROUND: The urokinase receptor (uPAR/CD87) is highly expressed in malignant tumours. uPAR, as a GPI anchored protein, is preferentially located at the cell surface, where it interacts with its ligands urokinase (uPA) and the extracellular matrix protein vitronectin, thus promoting plasmin generation, cell-matrix interactions and intracellular signalling events. Interaction with a complex formed by uPA and its inhibitor PAI-1 induces cell surface down regulation and recycling of the receptor via the clathrin-coated pathway, a process dependent on the association to LRP-1.METHODOLOGY/PRINCIPAL FINDINGS: In this study, we have found that along with the ligand-induced down-regulation, uPAR also internalizes and recycles constitutively through a second pathway that is independent of LRP-1 and clathrin but shares some properties with macropinocytosis. The ligand-independent route is amiloride-sensitive, does not require uPAR partitioning into lipid rafts, is independent of the activity of small GTPases RhoA, Rac1 and Cdc42, and does not require PI3K activity. Constitutively endocytosed uPAR is found in EEA1 positive early/recycling endosomes but does not reach lysosomes in the absence of ligands. Electron microscopy analysis reveals the presence of uPAR in ruffling domains at the cell surface, in macropinosome-like vesicles and in endosomal compartments.CONCLUSIONS/SIGNIFICANCE: These results indicate that, in addition to the ligand-induced endocytosis of uPAR, efficient surface expression and membrane trafficking might also be driven by an uncommon macropinocytic mechanism coupled with rapid recycling to the cell surface.", "Mice with a complete deficiency of p73 have severe neurological and immunological defects due to the absence of all TAp73 and DeltaNp73 isoforms. As part of our ongoing program to distinguish the biological functions of these isoforms, we generated mice that are selectively deficient for the DeltaNp73 isoform. Mice lacking DeltaNp73 (DeltaNp73(-/-) mice) are viable and fertile but display signs of neurodegeneration. Cells from DeltaNp73(-/-) mice are sensitized to DNA-damaging agents and show an increase in p53-dependent apoptosis. When analyzing the DNA damage response (DDR) in DeltaNp73(-/-) cells, we discovered a completely new role for DeltaNp73 in inhibiting the molecular signal emanating from a DNA break to the DDR pathway. We found that DeltaNp73 localizes directly to the site of DNA damage, can interact with the DNA damage sensor protein 53BP1, and inhibits ATM activation and subsequent p53 phosphorylation. This novel finding may explain why human tumors with high levels of DeltaNp73 expression show enhanced resistance to chemotherapy." ]

[ "OBJECTIVES: A developed population pharmacokinetic model of the humanized monoclonal antibody (mAb) matuzumab was evaluated by external evaluation. Based on the estimates of the final model, simulations of different dosing regimens and the covariate effect were performed.METHODS: The development dataset included 90 patients, and the evaluation dataset included 81 patients; the two sets of patients were from three different studies. In all studies, the patients had different types of advanced carcinoma - mainly colon, rectal and pancreatic cancer. They received matuzumab as multiple 1-hour intravenous infusions in a wide range of dosing regimens (development dataset: from 400 mg every 3 weeks to 2000 mg in the first week followed by 1600 mg weekly; evaluation dataset: from 100 mg weekly to 800 mg weekly). In addition to 1256 serum mAb concentrations for model development, there were 1124 concentrations available for model evaluation. Serum concentration-time data were simultaneously fitted using NONMEM software. The developed two-compartment model - with the parameters central volume of distribution (V(1)) and peripheral volume of distribution (V(2)), intercompartmental clearance and linear clearance (CLL), an additional nonlinear elimination pathway (Michaelis-Menten constant: the concentration with the half-maximal elimination rate and V(max): the maximum elimination rate) and covariate relations - was evaluated by an external dataset. Different simulation scenarios were performed to demonstrate the impact of the incorporated covariate effect and the influence of different dosing regimens and dosing strategies on the concentration-time profiles.RESULTS: The developed model included the covariate fat-free mass (FFM) on V(1) and on CLL. The evaluation did not support the covariate FFM on V(1) and, after deletion of this covariate, the model parameters of the refined model were estimated. The model showed good precision for all parameters: the relative standard errors (RSEs) were <42% for the development dataset and < or = 51% for the evaluation dataset (excluding the higher RSEs for the correlation between V(2) and V(max) and the interindividual variability on V(2) for the evaluation dataset). The model showed good robustness for the ability to estimate highly precise parameters for the combined dataset of 171 patients (RSE <29%). Simulations revealed that variability in concentration-time profiles for minimum and maximum steady-state concentrations was reduced to a marginal extent by a proposed dose adaptation.CONCLUSION: The population pharmacokinetic model for matuzumab was improved by evaluation with an external dataset. The new model obtained precise parameter estimates and demonstrated robustness. After correlation with efficacy data simulation results in particular could serve as a tool to guide dose selection for this 'targeted' cancer therapy.", "INTRODUCTION: Burning mouth syndrome mainly affects women, particularly after the menopause, when its prevalence may be 18-33%.METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for burning mouth syndrome? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).RESULTS: We found 12 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: anaesthetics (local), antidepressants, benzodiazepines (topical clonazepam), benzydamine hydrochloride, cognitive behavioural therapy (CBT), dietary supplements, and hormone replacement therapy (HRT) in postmenopausal women.", "OBJECTIVE: To assess the effectiveness of preoperative phone counseling by junior medical staff for improving the standard of informed consent for tonsillectomy.STUDY DESIGN: Prospective randomized controlled trial.SETTING: District general hospital.SUBJECTS AND METHODS: A total of 43 patients undergoing tonsillectomy were randomly allocated to 2 groups. Group A (n = 25) underwent the conventional consent process by the consultant ear, nose, and throat surgeon at the time of assessment (which generally takes place 6 to 12 months prior to surgery due to wait-list times). Group B (n = 18) underwent this same consent process but received a structured preoperative phone call 2 to 3 weeks prior to the day of surgery. A preoperative questionnaire assessing the knowledge of tonsillectomy, perioperative course, and risks was completed on the day of surgery.RESULTS: Group B had a better recall of the risks of tonsillectomy, recalling 7.1 of the 10 most significant risks, as compared with 4.6 for group A (P = .017). Group B had a better awareness of tooth damage (78% vs 30% of patients, P ≤ .001), voice change (61 vs 19%, P = .005), and burns to lips and mouth (44% vs 8%, P = .005). Finally, 35% more patients from group B rated their understanding of tonsillectomy as good or very good (P = .017).CONCLUSION: Preoperative phone counseling by junior medical staff closer to the time of surgery reinforces and clarifies the information previously provided by senior consultants at the time of initial consent for tonsillectomy.", "Refractive surgery includes all procedures which are primarily targeted at changing the refractive power of the eye. Currently laser-assisted in situ keratomileusis (LASIK) is indicated to correct myopia of up to - 8 D, hyperopia up to + 3 D and astigmatism up to 5 D. Photorefractive keratectomy (PRK) and laser epithelial keratomileusis (LASEK) are primarily recommended for myopia up to - 6 D and for greater refractive errors, phakic intraocular lenses (IOL) are the first choice (myopia greater than - 6 D and hyperopia greater than + 3 D). If presbyopia is present in addition to the high refractive error, refractive lens exchange is another alternative.", "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.", "Phthiriasis palpebrarum is an unusual cause of blepharoconjunctivitis and may easily be overlooked because of the failure of physicians to recognize Phthirus pubis. We report a case of a 30-year-old woman with persistent itching in the left eyelid which was unsuccessfully treated under the diagnosis of allergic blepharoconjunctivitis. Careful ophthalmic examination revealed seven bugs with multiple red pinpoint excretions and numerous small translucent oval eggs (nits) coating the eyelashes. The patient was successfully treated with mechanical removal of all the lice and nits from the eyelashes. The specimen proved histopathologically to be the Phthirus pubis infestation. The Phthirus pubis infestation is usually associated with poor hygiene in overcrowded or undeveloped country. However, it may become a notable problem because of frequent traveling and commercial activities across the different countries.", "MOTIVATION: DNA methylation is important for gene silencing and imprinting in both plants and animals. Recent advances in bisulfite sequencing allow detection of single nucleotide variations (SNVs) achieving high sensitivity, but accurately identifying heterozygous SNVs from partially C-to-T converted sequences remains challenging.RESULTS: We designed two methods, BayesWC and BinomWC, that substantially improved the precision of heterozygous SNV calls from ∼80% to 99% while retaining comparable recalls. With these SNV calls, we provided functions for allele-specific DNA methylation (ASM) analysis and visualizing the methylation status on reads. Applying ASM analysis to a previous dataset, we found that an average of 1.5% of investigated regions showed allelic methylation, which were significantly enriched in transposon elements and likely to be shared by the same cell-type. A dynamic fragment strategy was utilized for DMR analysis in low-coverage data and was able to find differentially methylated regions (DMRs) related to key genes involved in tumorigenesis using a public cancer dataset. Finally, we integrated 40 applications into the software package CGmapTools to analyze DNA methylomes. This package uses CGmap as the format interface, and designs binary formats to reduce the file size and support fast data retrieval, and can be applied for context-wise, gene-wise, bin-wise, region-wise and sample-wise analyses and visualizations.AVAILABILITY AND IMPLEMENTATION: The CGmapTools software is freely available at https://cgmaptools.github.io/.CONTACT: guoweilong@cau.edu.cn.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online." ]

[ "Context • Excoriation (skin picking) disorder is characterized by the need or urge to pick, scratch, pinch, touch, rub, scrub, squeeze, bite, or dig the skin, and it can be a perplexing condition for the inexperienced physician. Treatments include pharmacotherapy, psychotherapy, and alternative therapies. Alternative therapies for excoriation disorder and other body-focused repetitive behaviors include yoga, aerobic exercise, acupuncture, biofeedback, hypnosis, and inositol and N-acetylcysteine, among others. Objective • This review article intended to review the current literature on the alternative therapies to provide a brief update on their benefits for the treatment of excoriation disorder for use in conjunction with psychotherapy and pharmacotherapy in the management of a challenging group of patients. Design • This review (focusing on literature published in the last 15 y, selected from a search of PubMed) critically considers the evidence for the use of alternative therapies in the treatment of excoriation disorder. Setting • This review was conducted at the National University of Asunción (San Lorenzo, Paraguay). Results • Results for yoga were as follows: This technique may influence the structure and functioning of the areas of emotional processing involved in the pathophysiology of excoriation disorder and other body-focused repetitive behaviors, such as trichotillomania. Although still limited, the current research team's use of yoga as a treatment has given useful results. Results for aerobic exercise were as follows: People suffering from excoriation disorder and other-body focused repetitive behaviors generally have a worsening of their behaviors in times of negative mood and anxiety. As exercise has qualities that allow individuals to improve their mood and reduce their anxiety, it is likely that it also can help reduce behaviors like hair pulling or scratching, and it should be considered to be an adjunctive therapy. Results for acupuncture were as follows: The mechanism of action of acupuncture increases serotonergic activity and releases endorphins in the hypothalamus and limbic region, which could be beneficial in patients with trichotillomania and excoriation disorder. Results for biofeedback were as follows: Several case reports have suggested the value of biofeedback in reducing tics, which bear some psychophysiological similarities to body-focused repetitive behaviors, such as trichotillomania and excoriation disorder. Results for hypnosis were as follows: When used as a channel for other types of interventions, such as psychotherapy, hypnosis can help counteract the stress that triggers the picking behaviors in some patients. Results for inositol and N-acetylcysteine were as follows: Although more research is needed, these are promising drugs that may be helpful in reducing the picking behavior. Conclusions • The review indicates that yoga, aerobic exercise, acupuncture, biofeedback, hypnosis, and inositol and N-acetylcysteine all show promise in the treatment of excoriation disorder and other body-focused repetitive behaviors, such as trichotillomania. In the current research team's experience, mainly yoga and aerobic exercise have been shown useful in combination with psychotherapy and pharmacotherapy. Obtaining solid evidence about the long-term beneficial effects of these alternative therapies for the treatment of excoriation disorder requires more investigation.", "BACKGROUND: Inhibitors of DNA-binding proteins (Id1-4), lacking the basic DNA-binding domain, function as dominant inhibitors of cell-cycle regulators. Overexpression of Id proteins promotes cancer cell proliferation and resistance against apoptosis. Level of Id protein expression, especially of Id1, correlates with poor differentiation, enhanced malignant potential and more aggressive clinical behaviour of ovarian tumours. Although overexpression of Ids has been found and shown to correlate with poor clinical outcome, their inhibition at protein level has never been studied.METHODS: A peptide aptamer, Id1/3-PA7, targeting Id1 and Id3, was isolated from a randomised combinatorial expression library using yeast and mammalian two-hybrid systems. Id1/3-PA7 was fused, expressed and purified with a cell-penetrating protein transduction domain.RESULTS: Intracellular-delivered Id1/3-PA7 colocalised to Id1 and Id3. It induced cell-cycle arrest and apoptosis in ovarian cancer cells ES-2 and PA-1. It activated the E-box promoter and increased the expression level of cyclin-dependent kinase inhibitor (CDKN2A) in a dose-dependent manner that is paralleled by the cleavage of poly-ADP ribose polymerase. These effects were counteracted by ectopically overexpressed Id1 and Id3.CONCLUSION: Id1/3-PA7 could represent an exogenous anti-tumour agent that can significantly trigger cell-cycle arrest and apoptosis in ovarian cancer.", "Trichotillomania is characterized by repetitive pulling that causes noticeable hair loss. Data on the pharmacological treatment of trichotillomania are limited, with no clear first-line agent. The aim of the current study was to determine the efficacy and tolerability of inositol in adults with trichotillomania. A total of 38 individuals (35 women; mean age: 28.9±11.4) with trichotillomania entered a 10-week, double-blind, placebo-controlled trial to evaluate the safety and efficacy of inositol (dosing ranging from 6 to 18 g/day). Patients were assessed using the Massachusetts General Hospital Hair Pulling Scale, the NIMH Trichotillomania Severity Scale, Clinical Global Impression Scale, and measures of depression, anxiety, and psychosocial functioning. Outcomes were examined using a linear mixed-effects model. Patients assigned to inositol failed to show significantly greater reductions on primary or secondary outcomes measures compared with placebo (all P>0.05). At study endpoint, 42.1% of patients were 'much or very much improved' on inositol compared with 35.3% on placebo. This is the first study assessing the efficacy of inositol in the treatment of trichotillomania, but found no differences in symptom reductions between inositol and placebo. Future studies should examine whether inositol may be beneficial in controlling pulling behavior in a subgroup of individuals with trichotillomania.", "Fanconi anemia (FA) is a rare autosomal recessive disease characterized by a greatly increased risk of cancer among those diagnosed with the syndrome. The question as to whether FA heterozygotes are at increased risk for cancer is of great importance to those at risk for being a carrier. To address this question, we formed a cohort of grandparents of probands identified through the International Fanconi Anemia Registry. We obtained informed consent, a short questionnaire, and either blood or buccal swab DNA. After diagnosis of the proband was confirmed and complementation studies or DNA sequencing on the proband were completed, mutation analyses of the putative carriers and noncarriers was carried out. Standardized incidence ratios (SIR) were calculated to compare the observed cancer incidence of the grandparents and other relatives with the expected rates of cancer, using the Surveillance, Epidemiology, and End Results registries and the Connecticut Cancer registry. In the 944 study subjects who participated (784 grandparents and 160 other relatives), there was no suggestion of an increase in overall cancer incidence. On the other hand, a significantly higher rate of breast cancer than expected was observed among carrier grandmothers [SIR, 1.7; 95% confidence interval (95% CI), 1.1-2.7]. Among the grandmothers, those who were carriers of FANCC mutations were found to be at highest risk (SIR, 2.4; 95% CI, 1.1-5.2). Overall, there was no increased risk for cancer among FA heterozygotes in this study of Fanconi relatives, although there is some evidence that FANCC mutations are possibly breast cancer susceptibility alleles.", "We have previously shown that Fibroblast growth factor 21 (Fgf21) is expressed in the thymus as well as in the liver. In line with this expression profile, Fgf21 was recently reported to protect against ageing-related thymic senescence by improving the function of thymic epithelial cells (TECs). However, the function of Fgf21 in the juvenile thymus remained to be elucidated. We investigated the physiological roles of Fgf21 in the juvenile thymus and found that young Fgf21 knockout mice, but not β-Klotho knockout mice nor adult Fgf21 knockout mice, showed a significant reduction in the percentage of single-positive CD4+ and CD8+ thymocytes without obvious alteration in TECs. Furthermore, treatment with recombinant FGF21 protein rescued the impairment in fetal thymus organ culture (FTOC) of Fgf21 knockout mice. Annexin V staining revealed FGF21 protein enhanced apoptosis of immature thymocytes undergoing selection process in FTOC, suggesting that FGF21 may facilitate the selection of developing T cells. Endocrine Fgf21 from the liver induced by metabolic stimulation did not affect juvenile thymocyte development. Our data suggest that Fgf21 acts as one of intrathymic cytokines in the neonatal and juvenile thymus, involving thymocyte development in a β-Klotho-independent manner.", "PURPOSE: One of the components of radiotherapy (RT) in medulloblastoma/primitive neuroectodermal tumors is the prophylactic irradiation of the whole brain (WBI). With the aim of reducing late neuropsychologic morbidity a CT-scan-based dosimetric study was undertaken in which treatment was confined mainly or exclusively to supratentorial sites considered at high risk for disease recurrence.METHODS AND MATERIALS: A comparative dosimetric study is presented in which a three field (two laterals and one posterior) proton plan (spot scanning method) is compared with a two-field conventional WBI 6 MV x-ray plan, to a 6-field \"hand-made\" 6 MV x-ray plan, and to a computer-optimized 9-field \"inverse\" 15 MV x-ray plan. For favorable patients, 30 Gy were delivered to the ventricles and main cisterns, the subfrontal and subtemporal regions, and the posterior fossa. For the unfavorable patients, 10 Gy WBI preceeded a boost to 30 Gy to the same treatment volume chosen for favorable patients. The dose distribution was evaluated with dose-volume histograms to examine the coverage of the targets as well as the dose to the nontarget brain and optical structures. In addition, the risks of radiation-related late neuropsychologic effects after WBI were collected from the literature and used to predict normal tissue complication probabilities (NTCPs) for an intelligence quotient deficit after treatment with photon or proton beams.RESULTS: Proton beams succeeded better in reducing the dose to the brain hemispheres and eye than any of the photon plans. A 25.1% risk of an IQ score <90 was predicted after 30 Gy WBI. Almost a 10% drop in the predicted risk was observed when using proton beams in both favorable and unfavorable patients. However, predicted NTCPs for both optimized photon plans (\"hand made\" and \"inverse\") were only slightly higher (0.3-2.5%) than those of proton beams. An age-modifying factor was introduced in the predictive NTCP model to assess for IQ differences in relation with age at irradiation. Children with ages between age 4 to 8 benefitted most from the dose reduction in this exercise (similar NTCP predictions for both proton and \"inverse\" plans).CONCLUSION: Modulated proton beams may help to significantly reduce the irradiation of normal brain while optimally treating the supratentorial subsites at higher risk for relapse. A decrease in morbidity can be expected from protons and both optimized proton plans compared to WBI.", "Macitentan is a dual endothelin receptor antagonist under phase 3 investigation in pulmonary arterial hypertension. We investigated the effect of cyclosporine (Cs) and rifampin on the pharmacokinetics of macitentan and its metabolites ACT-132577 and ACT-373898 in healthy male subjects. In addition, in vitro studies were performed to investigate interactions between macitentan and its active metabolite ACT-132577 with human organic anion-transporting polypeptides (OATPs). The clinical study (AC-055-111) was conducted as a two-part, one-sequence, crossover study. Ten subjects in each part received multiple-dose macitentan followed by multiple-dose co-administration of Cs (part A) or rifampin (part B). In the presence of Cs, steady-state area under the plasma concentration-time profiles during a dose interval (AUC(τ)) for macitentan and ACT-373898 increased 10% and 7%, respectively, and decreased 3% for ACT-132577. Steady-state AUC(τ) of macitentan and ACT-373898 in the presence of rifampin decreased 79% and 64%, respectively. For ACT-132577, no relevant difference in AUC(τ) between the two treatments was observed. Macitentan co-administered with Cs or rifampin was well tolerated. The complementary in vitro studies demonstrated no marked differences in uptake rates of macitentan and ACT-132577 between the wild-type and OATP over-expressing cells over the concentration range tested. Concomitant treatment with Cs did not have any clinically relevant effect on the exposure to macitentan or its metabolites, at steady-state. Concomitant treatment with rifampin reduced significantly the exposure to macitentan and its metabolite ACT-373898 at steady-state but did not affect the exposure to the active metabolite ACT-132577 to a clinically relevant extent.", "BACKGROUND: Evidence concerning the importance of glucose lowering in the prevention of cardiovascular (CV) outcomes remains controversial. Given the multi-faceted pathogenesis of atherosclerosis in diabetes, it is likely that any intervention to mitigate this risk must address CV risk factors beyond glycemia alone. The SGLT-2 inhibitor empagliflozin improves glucose control, body weight and blood pressure when used as monotherapy or add-on to other antihyperglycemic agents in patients with type 2 diabetes. The aim of the ongoing EMPA-REG OUTCOME™ trial is to determine the long-term CV safety of empagliflozin, as well as investigating potential benefits on macro-/microvascular outcomes.METHODS: Patients who were drug-naïve (HbA1c ≥7.0% and ≤9.0%), or on background glucose-lowering therapy (HbA1c ≥7.0% and ≤10.0%), and were at high risk of CV events, were randomized (1:1:1) and treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo (double blind, double dummy) superimposed upon the standard of care. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. CV events will be prospectively adjudicated by an independent Clinical Events Committee. The trial will continue until ≥691 confirmed primary outcome events have occurred, providing a power of 90% to yield an upper limit of the adjusted 95% CI for a hazard ratio of <1.3 with a one-sided α of 0.025, assuming equal risks between placebo and empagliflozin (both doses pooled). Hierarchical testing for superiority will follow for the primary outcome and key secondary outcomes (time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina pectoris) where non-inferiority is achieved.RESULTS: Between Sept 2010 and April 2013, 592 clinical sites randomized and treated 7034 patients (41% from Europe, 20% from North America, and 19% from Asia). At baseline, the mean age was 63 ± 9 years, BMI 30.6 ± 5.3 kg/m2, HbA1c 8.1 ± 0.8%, and eGFR 74 ± 21 ml/min/1.73 m2. The study is expected to report in 2015.DISCUSSION: EMPA-REG OUTCOME™ will determine the CV safety of empagliflozin in a cohort of patients with type 2 diabetes and high CV risk, with the potential to show cardioprotection.TRIAL REGISTRATION: Clinicaltrials.gov NCT01131676." ]

[ "Today, the assessment of liver function in patients suffering from acute or chronic liver disease is based on liver biopsy and blood tests including synthetic function, liver enzymes and viral load, most of which provide only circumstantial evidence as to the degree of hepatic impairment. Most of these tests lack the degree of sensitivity to be useful for follow-up of these patients at the frequency that is needed for decision making in clinical hepatology. Accurate assessment of liver function is essential to determine both short- and long-term prognosis, and for making decisions about liver and non-liver surgery, TIPS, chemoembolization or radiofrequency ablation in patients with chronic liver disease. Liver function tests can serve as the basis for accurate decision-making regarding the need for liver transplantation in the setting of acute failure or in patients with chronic liver disease. The liver metabolic breath test relies on measuring exhaled (13) C tagged methacetin, which is metabolized only by the liver. Measuring this liver-specific substrate by means of molecular correlation spectroscopy is a rapid, non-invasive method for assessing liver function at the point-of-care. The (13) C methacetin breath test (MBT) is a powerful tool to aid clinical hepatologists in bedside decision-making. Our recent findings regarding the ability of point-of-care (13) C MBT to assess the hepatic functional reserve in patients with acute and chronic liver disease are reviewed along with suggested treatment algorithms for common liver disorders.", "MOTIVATION: Oxidative stress and protein damage have been associated with over 200 human ailments including cancer, stroke, neuro-degenerative diseases and aging. Protein carbonylation, a chemically diverse oxidative post-translational modification, is widely considered as the biomarker for oxidative stress and protein damage. Despite their importance and extensive studies, no database/resource on carbonylated proteins/sites exists. As such information is very useful to research in biology/medicine, we have manually curated a data-resource (CarbonylDB) of experimentally-confirmed carbonylated proteins/sites.RESULTS: The CarbonylDB currently contains 1495 carbonylated proteins and 3781 sites from 21 species, with human, rat and yeast as the top three species. We have made further analyses of these carbonylated proteins/sites and presented their occurrence and occupancy patterns. Carbonylation site data on serum albumin, in particular, provides a fine model system to understand the dynamics of oxidative protein modifications/damage.AVAILABILITY AND IMPLEMENTATION: The CarbonylDB is available as a web-resource and for download at http://digbio.missouri.edu/CarbonylDB/.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "PURPOSE: To determine the efficacy and safety of different doses of secukinumab, a fully human monoclonal antibody for targeted interleukin-17A blockade, in patients with noninfectious uveitis.DESIGN: Three multicenter, randomized, double-masked, placebo-controlled, dose-ranging phase III studies: SHIELD, INSURE, and ENDURE.PARTICIPANTS: A total of 118 patients with Behçet's uveitis (SHIELD study); 31 patients with active, noninfectious, non-Behçet's uveitis (INSURE study); and 125 patients with quiescent, noninfectious, non-Behçet's uveitis (ENDURE study) were enrolled.METHODS: After an initial subcutaneous (s.c.) loading phase in each treatment arm, patients received s.c. maintenance therapy with secukinumab 300 mg every 2 weeks (q2w), secukinumab 300 mg monthly (q4w), or placebo in the SHIELD study; secukinumab 300 mg q2w, secukinumab 300 mg q4w, secukinumab 150 mg q4w, or placebo in the INSURE study; or secukinumab 300 mg q2w, secukinumab 300 mg q4w, secukinumab 150 mg q4w, or placebo in the ENDURE study.MAIN OUTCOME MEASURES: Reduction of uveitis recurrence or vitreous haze score during withdrawal of concomitant immunosuppressive medication (ISM). Other end points included best-corrected visual acuity, ISM use (expressed as a standardized ISM score), and safety outcomes.RESULTS: After completion or early termination of each trial, there were no statistically significant differences in uveitis recurrence between the secukinumab treatment groups and placebo groups in any study. Secukinumab was associated with a significant reduction in mean total post-baseline ISM score (P = 0.019; 300 mg q4w vs. placebo) in the SHIELD study. Likewise, secukinumab was associated with a greater median reduction in ISM score versus placebo in the INSURE study, although no statistical analysis of the difference was conducted because of the small sample size. Overall, there was no loss in visual acuity reported in any treatment group during follow-up in all 3 studies. According to descriptive safety statistics, the frequencies of ocular and nonocular adverse events seemed to be slightly higher among secukinumab groups versus placebo across the 3 studies.CONCLUSIONS: The primary efficacy end points of the 3 studies were not met. The secondary efficacy data from these studies suggest a beneficial effect of secukinumab in reducing the use of concomitant ISM.", "Fanconi anemia is a genetically heterogeneous disorder associated with chromosome instability and a highly elevated risk for developing cancer. The mutated genes encode proteins involved in the cellular response to DNA replication stress. Fanconi anemia proteins are extensively connected with DNA caretaker proteins, and appear to function as a hub for the coordination of DNA repair with DNA replication and cell cycle progression. At a molecular level, however, the raison d'être of Fanconi anemia proteins still remains largely elusive. The thirteen Fanconi anemia proteins identified to date have not been embraced into a single and defined biological process. To help put the Fanconi anemia puzzle into perspective, we begin this review with a summary of the strategies employed by prokaryotes and eukaryotes to tolerate obstacles to the progression of replication forks. We then summarize what we know about Fanconi anemia with an emphasis on biochemical aspects, and discuss how the Fanconi anemia network, a late acquisition in evolution, may function to permit the faithful and complete duplication of our very large vertebrate chromosomes.", "Melanin biosynthesis is reduced in oculocutaneous albinism, an autosomal recessive disorder. Hermansky-Pudlak syndrome is associated with oculocutaneous albinism but also has systemic complications. The ocular and systemic phenotypes vary, depending, in part, on the genetic mutations. This report presents a case of a patient with Hermansky-Pudlak syndrome and the unique association of iris heterochromia.", "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.", "OBJECTIVE: We report a very rare case of Hoffmann's syndrome with musclehypertrophy complicating hypothyroidism.CLINICAL PRESENTATION: A 24-year-old man presented with a 2-year history of forgetfulness, swelling in his face, shoulder and calf, and motor weakness in his lower extremities. His calf and shoulder muscles were hypertrophic. Neurological examination revealed hoarseness of the voice, proximal muscle weakness, reduced deep tendon reflexes and a mildly ataxic gait. Laboratory tests indicated markedly elevated serum muscle enzymes and lipids, a high thyroid-stimulating hormone level and low free triiodothyronine and free thyroxine levels. Electromyographic evaluation showed myopathy.INTERVENTION: Oral L-thyroxine treatment was started and at a 1-month follow-up examination, mental status and physical performance were improved.CONCLUSION: This report shows that in the differential diagnosis of myopathy with pseudohypertrophy, Hoffmann's syndrome should be considered." ]

[ "The vertebrate pore protein Nup153 plays pivotal roles in nuclear pore function. In addition to being important to pore architecture, Nup153 is a key participant in both import and export. The scope of Nup153 function also extends beyond the canonical view of the pore as a trafficking gateway. During the transition into mitosis, Nup153 directs proteins involved in membrane remodeling to the nuclear envelope. As cells exit mitosis, Nup153 is recruited to the chromosomal surface, where nuclear pores are formed anew in a complicated process still under much experimental scrutiny. In addition, Nup153 is targeted for protease cleavage during apoptosis and in response to certain viral infections, providing molecular insight into pore reconfiguration during cell response. Overall, the versatile nature of Nup153 underscores an emerging view of the nuclear pore at the nexus of many key cellular processes.", "The epithelial cells lining intrahepatic bile ducts (i.e., cholangiocytes), like many cell types in the body, have primary cilia extending from the apical plasma membrane into the bile ductal lumen. Cholangiocyte cilia express proteins such as polycystin-1, polycystin-2, fibrocystin, TRPV4, P2Y12, AC6, that account for ciliary mechano-, osmo-, and chemo-sensory functions; when these processes are disturbed by mutations in genes encoding ciliary-associated proteins, liver diseases (i.e., cholangiociliopathies) result. The cholangiociliopathies include but are not limited to cystic and fibrotic liver diseases associated with mutations in genes encoding polycystin-1, polycystin-2, and fibrocystin. In this review, we discuss the functions of cholangiocyte primary cilia, their role in the cholangiociliopathies, and potential therapeutic approaches.", "OBJECTIVE: To review information pertinent to bone health and osteoporosis in men.METHODS: A review of pertinent literature was conducted.RESULTS: Osteoporosis affects approximately 2 million men in the US and accounts for an estimated 600,000 fractures each year. There are significant differences in skeletal size and structure between men and women that account for differences in fracture incidence, location, and outcomes. Bone density testing is appropriate for men age 70 and older and younger men (50-69) who have risk factors for osteoporosis. Lifestyle management, including adequate calcium and vitamin D intake, appropriate physical activity, and avoidance of tobacco and heavy alcohol use, is appropriate for all men. Pharmacologic therapy to reduce fracture risk is advisable for men with a clinical diagnosis of osteoporosis (a spine or hip fracture) or a T-score of -2.5 or below in the spine, femoral neck, total hip or 1/3 radius; however, the majority of men at high risk will only be identified using a fracture risk assessment tool, such as FRAX. Alendronate, risedronate, zoledronic acid, denosumab, and teriparatide are Food and Drug Administration (FDA)-approved therapeutic options.CONCLUSIONS: Osteoporosis in men presents an important public health problem with significant morbidity and mortality. There are recommended strategies for identifying men at high risk of fracture, and effective agents are available for treatment.", "By data mining in the sequence of the Corynebacterium glutamicum ATCC 13032 genome, six putative mycolyltransferase genes were identified that code for proteins with similarity to the N-terminal domain of the mycolic acid transferase PS1 of the related C. glutamicum strain ATCC 17965. The genes identified were designated cop1, cmt1, cmt2, cmt3, cmt4, and cmt5 ( cmt from corynebacterium mycolyl transferases). cop1 encodes a protein of 657 amino acids, which is larger than the proteins encoded by the cmt genes with 365, 341, 483, 483, and 411 amino acids. Using bioinformatics tools, it was shown that all six gene products are equipped with signal peptides and esterase domains. Proteome analyses of the cell envelope of C. glutamicum ATCC 13032 resulted in identification of the proteins Cop1, Cmt1, Cmt2, and Cmt4. All six mycolyltransferase genes were used for mutational analysis. cmt4 could not be mutated and is considered to be essential. cop1 was found to play an additional role in cell shape formation. A triple mutant carrying mutations in cop1, cmt1, and cmt2 aggregated when cultivated in MM1 liquid medium. This mutant was also no longer able to synthesize trehalose di coryno mycolate (TDCM). Since single and double mutants of the genes cop1, cmt1, and cmt2 could form TDCM, it is concluded that the three genes, cop1, cmt1, and cmt2, are involved in TDCM biosynthesis. The presence of the putative esterase domain makes it highly possible that cop1, cmt1, and cmt2 encode enzymes synthesizing TDCM from trehalose monocorynomycolate.", "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.", "Magnetoreception is essential for magnetic orientation in animal migration. The molecular basis for magnetoreception has recently been elucidated in fruitfly as complexes between the magnetic receptor magnetoreceptor (MagR) and its ligand cryptochrome (Cry). MagR and Cry are present in the animal kingdom. However, it is unknown whether they perform a conserved role in diverse animals. Here we report the identification and expression of zebrafish MagR and Cry homologs towards understanding their roles in lower vertebrates. A single magr gene and 7 cry genes are present in the zebrafish genome. Zebrafish has four cry1 genes (cry1aa, cry1ab, cry1ba and cry1bb) homologous to human CRY1 and a single ortholog of human CRY2 as well as 2 cry-like genes (cry4 and cry5). By RT-PCR, magr exhibited a high level of ubiquitous RNA expression in embryos and adult organs, whereas cry genes displayed differential embryonic and adult expression. Importantly, magr depletion did not produce apparent abnormalities in organogenesis. Taken together, magr and cry2 exist as a single copy gene, whereas cry1 exists as multiple gene duplicates in zebrafish. Our result suggests that magr may play a dispensable role in organogenesis and predicts a possibility to generate magr mutants for analyzing its role in zebrafish.", "OBJECTIVE: To compare the long term survival of a group of athletes taking prolonged vigorous physical exercise to that of the general population.DESIGN: Follow up of a cohort of participants in the Dutch eleven cities ice skating tour (a race and recreational tour) over a distance of 200 kilometers.SETTING: Data on participation from the organising committee and data on mortality from all municipalities in The Netherlands.SUBJECTS: 2259 Male athletes.MAIN OUTCOME MEASURES: Comparison of all cause mortality in male participants in the tour with that in the general population of The Netherlands.RESULTS: The standardised mortality ratio for all participants during 32 years of follow up was 0.76 (95% confidence interval 0.68 to 0.85), and 0.90 (0.48 to 1.44) for participants in the race, and 0.72 (0.60 to 0.86) for participants in the recreational tour who finished within the time limit.CONCLUSIONS: The capacity for prolonged and vigorous physical exercise, particularly if the exercise is recreational, is a strong indicator of longevity.", "Conjoined twins are rare phenomena occurring in one in 1 in 50,000 live births. Successful surgical separation of conjoined twins is a major undertaking requiring careful planning by a multidisciplinary team. Reports of seperation of joined twins in developing countries like Nigeria are rare. Ten cases of conjoined twins were separated between 1936 and January 2003 (including the authors two new cases). There were five omphalopagus, two pygopagus, two heterpagus and one ishiopagus twins. Three underwent emergency separation with 83.3% mortality while seven underwent elective seperation with 64.3% survival. The overall mortality rate was 50%. Despite the absence of advanced technological resource selected group of conjoined twins can be successfully separated in a developing country like Nigeria. An improvement in facilities and availability of trained personnel in likely to be associated with improved outcome.", "Fanconi anemia (FA) is a human autosomal disorder characterized by cancer susceptibility and cellular sensitivity to DNA crosslinking agents such as mitomycin C and diepoxybutane. Six FA genes have been cloned including a gene designated XRCC9 (for X-ray Repair Cross Complementing), isolated using a mitomycin C-hypersensitive Chinese hamster cell mutant termed UV40, and subsequently found to be identical to FANCG. A nuclear complex containing the FANCA, FANCC, FANCE, FANCF and FANCG proteins is needed for the activation of a sixth FA protein FANCD2. When monoubiquitinated, the FANCD2 protein co-localizes with the breast cancer susceptibility protein BRCA1 in DNA damage induced foci. In this study, we have assigned NM3, a nitrogen mustard-hypersensitive Chinese hamster mutant to the same genetic complementation group as UV40. NM3, like human FA cell lines (but unlike UV40) exhibits a normal spontaneous level of sister chromatid exchange. We show that both NM3 and UV40 are also hypersensitive to other DNA crosslinking agents (including diepoxybutane and chlorambucil) and to non-crosslinking DNA damaging agents (including bleomycin, streptonigrin and EMS), and that all these sensitivities are all corrected upon transfection of the human FANCG/XRCC9 cDNA. Using immunoblotting, NM3 and UV40 were found not to express the active monoubiquitinated isoform of the FANCD2 protein, although expression of the FANCD-L isoform was restored in the FANCG cDNA transformants, correlating with the correction of mutagen-sensitivity. These data indicate that cellular resistance to these DNA damaging agents requires FANCG and that the FA gene pathway, via its activation of FANCD2 and that protein's subsequent interaction with BRCA1, is involved in maintaining genomic stability in response not only to DNA interstrand crosslinks but also a range of other DNA damages including DNA strand breaks. NM3 and other \"FA-like\" Chinese hamster mutants should provide an important resource for the study of these processes in mammalian cells.", "OBJECTIVES: To use proteomics to identify and characterize proteins in maternal serum from patients at high-risk for fetal trisomy 21, trisomy 18, and trisomy 13 on the basis of ultrasound and maternal serum triple tests.METHODS: We performed a comprehensive proteomic analysis on 23 trisomy cases and 85 normal cases during the early second trimester of pregnancy. Protein profiling along with conventional sodium dodecyl sulfate polyacrylamide gel electrophoresis/Tandem mass spectrometry analysis was carried out to characterize proteins associated with each trisomy condition and later validated using Western blot.RESULTS: Protein profiling approach using surface enhanced laser desorption/ionization time-of-flight mass (SELDI-TOF/MS) spectrometry resulted in the identification of 37 unique hydrophobic proteomic features for three trisomy conditions. Using sodium dodecyl sulfate polyacrylamide gel electrophoresis followed by Matrix Assisted Laser Desorption Ionization - Time of Flight/Time of Flight (MALDI-TOF/TOF) and western blot, glyco proteins such as alpha-1-antitrypsin, apolipoprotein E, apolipoprotein H, and serum carrier protein transthyretin were identified as potential maternal serum markers for fetal trisomy condition. The identified proteins showed differential expression at the subunit level.CONCLUSIONS: Maternal serum protein profiling using proteomics may allow non-invasive diagnostic testing for the most common trisomies and may complement ultrasound-based methods to more accurately determine pregnancies with fetal aneuploidies.", "Author information:(1)Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada.(2)Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA.(3)Centre Hospitalier de l'Université de Montréal Research Center, Montreal, QC H2X 0A9, Canada; Department of Neurosciences, Université de Montréal, Montreal, QC H3T1J4, Canada.(4)Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A2B4, Canada.(5)McGill University and Genome Quebec Innovation Center, Montreal, QC H3A 1A4, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.(6)Centre Hospitalier de l'Université de Montréal Research Center, Montreal, QC H2X 0A9, Canada; Center for Pediatric Genomic Medicine, Children's Mercy Kansas City, Kansas City, MO 64108, USA; Department of Pathology and Laboratory Medicine, Children's Mercy Kansas City, Kansas City, MO 64108, USA.(7)Centre Hospitalier de l'Université de Montréal Research Center, Montreal, QC H2X 0A9, Canada.(8)GeneDx, Gaithersburg, MD 20877, USA.(9)Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.(10)Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX 77021, USA.(11)Program in Genetics and Genome Biology, Division of Neurology, Department of Pediatrics, Hospital for Sick Children and University of Toronto, Toronto, ON M5G 0A4, Canada.(12)Division of Neurology, Epilepsy Genetics Program, Krembil Neuroscience Centre, Toronto Western Hospital, University of Toronto, Toronto, ON M5G 2C4, Canada.(13)Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.(14)Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.(15)MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.(16)Clinical Genetics Service, University Hospitals Bristol NHS Foundation Trust, St. Michael's Hospital, St. Michael's Hill, Bristol BS2 8DT, UK.(17)North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Northwick Park Hospital, Watford Road, Harrow HA1 3UJ, UK.(18)Oxford Centre for Genomic Medicine, ACE building Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7HE, UK.(19)Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK.(20)Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK.(21)MRC Centre for Neuropsychiatric Genetics & Genomics, Hadyn Ellis Building, Cathays, Cardiff University, Cardiff CF24 4HQ, UK.(22)West of Scotland Regional Genetics Service, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.(23)North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.(24)Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK.(25)Department of Pediatrics, Section of Medical Genetics, SUNY Upstate Medical University, Syracuse, NY 13210, USA.(26)University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, the Netherlands.(27)University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57117, USA.(28)Augustana-Sanford Genetic Counseling Graduate Program, Sioux Falls, SD 57197, USA.(29)Departments of Medicine and Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.(30)Baptist Hospital, Miami, FL 33176 USA.(31)Joe DiMaggio Children's Hospital, Hollywood, FL 33021, USA.(32)Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.(33)Department of Human Genetics, Donders Centre for Brain, Cognition and Behavior, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.(34)Centre de Génétique des Anomalies du Développement, Centre Hospitalier Universitaire de Dijon, 21000 Dijon, France; Équipe INSERM 1231, Génétique des Anomalies du Développement, Université de Bourgogne, 21000 Dijon, France.(35)Genetics Department, Assistance Publique - Hôpitaux de Paris, Robert-Debré University Hospital, 75000 Paris, France.(36)Department of Clinical Genetics, United Laboratories, Tartu University Hospital and Institute of Clinical Medicine, University of Tartu, Tartu 51014, Estonia.(37)Division of Genetics and Genomics and Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.(38)Nationwide Children's Hospital and Ohio State University, Department of Pediatrics, Division of Neurology, Columbus, OH 43205, USA.(39)Division of Neurology, Children's Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada.(40)University of Tasmania, Royal Hobart Hospital, Department of Paediatrics, Hobart, TAS 7000, Australia.(41)School of Medicine, University of Tasmania, Hobart, TAS 7000, Australia.(42)Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.(43)Children's Hospital at Westmead Clinical School, University of Sydney, Westmead, NSW 2145, Australia.(44)Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.(45)Dipartimento di Pediatria e di Neuropsichiatria Infantile, Università La Sapienza, 00185 Rome, Italy.(46)Dipartimento di Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, 00161 Rome, Italy.(47)Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy.(48)Metabolic Neurogenetic Clinic and Pediatric Movement Disorders Clinic, Wolfson Medical Center, Holon 5822012, Israel.(49)University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.(50)University of British Columbia, BC Children's Hospital, Vancouver, BC V6H 3N1, Canada.(51)Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.(52)Département de Génétique, Centre de Référence des Déficiences Intellectuelles de Causes Rares, Groupe de Recherche Clinique \"Déficiences Intellectuelles et Autisme,\" Université Pierre et Marie Curie, Hôpital de la Pitié-Salpêtrière, Paris 75013, France; Sorbonne Universités, Université Pierre et Marie Curie (Université Paris 06), UMRS 1127, INSERM U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle Épinière, Paris 75013, France.(53)Assistance Publique - Hôpitaux de Paris, Hôpital d'Enfants Armand Trousseau, Service de Neuropédiatrie, Paris 75012, France.(54)Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR 1141, Paris 75019, France; Assistance Publique - Hôpitaux de Paris, Hôpital Robert Debré, Service de Neurologie Pédiatrique, Paris 75019, France.(55)HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA.(56)Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.(57)Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; Arkansas Children's Research Institute, Little Rock, AR 72205, USA.(58)Texas Children's Hospital and Baylor College of Medicine, Houston, TX 77030, USA.(59)Centre Hospitalier Rouyn-Noranda, Rouyn-Noranda, QC J9X 2B2, Canada.(60)Division of Neurology, Centre Hospitalier Universitaire de Québec, Quebec, QC G1V 4G2, Canada.(61)Department of Pediatrics, Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.(62)Department of Pediatrics, McGill University, Montreal, QC H3A 1A4, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 1A4, Canada.(63)Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada; Department of Neurosciences, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Pediatrics, Université de Montréal, Montreal, QC H3T1C5, Canada.(64)Department of Neurosciences, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Pediatrics, Université de Montréal, Montreal, QC H3T1C5, Canada.(65)Department of Pediatrics and Child Health, University of Otago, Wellington 9016, New Zealand.(66)Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada; Department of Pediatrics, Université de Montréal, Montreal, QC H3T1C5, Canada.(67)Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada; Department of Neurosciences, Université de Montréal, Montreal, QC H3T1J4, Canada.(68)Centre Hospitalier de l'Université de Montréal Research Center, Montreal, QC H2X 0A9, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Chicoutimi, QC G7H 2B1, Canada.(69)Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.(70)Division of Neurology, BC Children's Hospital, Vancouver, BC V6H 3N1, Canada.(71)Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia; Department of Pediatrics, University of Melbourne Royal Children's Hospital, Parkville, VIC 3052, Australia; Florey Institute of Neuroscience and Mental Health, Melbourne, VIC 3084, Australia.(72)Program in Genetics and Genome Biology, Division of Neurology, Department of Pediatrics, Hospital for Sick Children and University of Toronto, Toronto, ON M5G 0A4, Canada; Division of Child Neurology, Department of Pediatrics, University of Texas Southwestern, Dallas, TX 75390, USA. Electronic address: berge.minassian@sickkids.ca.(73)Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada; Department of Neurosciences, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Pediatrics, Université de Montréal, Montreal, QC H3T1C5, Canada. Electronic address: jacques.michaud@recherche-ste-justine.qc.ca.", "Nup153 is a large (153 kD) O-linked glyco-protein which is a component of the basket structure located on the nucleoplasmic face of nuclear pore complexes. This protein exhibits a tripartite structure consisting of a zinc finger domain flanked by large (60-70 kD) NH2- and COOH-terminal domains. When full-length human Nup153 is expressed in BHK cells, it accumulates appropriately at the nucleoplasmic face of the nuclear envelope. Targeting information for Nup153 resides in the NH2-terminal domain since this region of the molecule can direct an ordinarily cytoplasmic protein, pyruvate kinase, to the nuclear face of the nuclear pore complex. Overexpression of Nup153 results in the dramatic accumulation of nuclear poly (A)+ RNA, suggesting an inhibition of RNA export from the nucleus. This is not due to a general decline in nucleocytoplasmic transport or to occlusion or loss of nuclear pore complexes since nuclear protein import is unaffected. While overexpression of certain Nup153 constructs was found to result in the formation of unusual intranuclear membrane arrays, this structural phenotype could not be correlated with the effects on poly (A)+ RNA distribution. The RNA trafficking defect was, however, dependent upon the Nup153 COOH-terminal domain which contains most of the XFXFG repeats. It is proposed that this region of Nup153, lying within the distal ring of the nuclear basket, represents a docking site for mRNA molecules exiting the nucleus.", "The posttranslational modification of chromatin through acetylation at selected histone lysine residues is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The significance of this subset of the epigenetic code is interrogated and interpreted by an acetyllysine-specific protein-protein interaction with bromodomain reader modules. Selective inhibition of the bromo and extra C-terminal domain (BET) family of bromodomains with a small molecule is feasible, and this may represent an opportunity for disease intervention through the recently disclosed antiproliferative and anti-inflammatory properties of such inhibitors. Herein, we describe the discovery and structure-activity relationship (SAR) of a novel, small-molecule chemical probe for BET family inhibition that was identified through the application of structure-based fragment assessment and optimization techniques. This has yielded a potent, selective compound with cell-based activity (PFI-1) that may further add to the understanding of BET family function within the bromodomains.", "Human Immunodeficiency Virus (HIV) is a chronic infection that depletes the immune system of essential components causing those infected to be at risk for multiple life-threatening infections. Worldwide, millions live with this infection, the vast majority attributable to HIV-1. Transmission persists with hundreds of thousands of new infections reported yearly. Implementation of combination antiretroviral therapy (cART) has been effective in improving outcomes and decreasing transmission. Newer co-formulated agents have provided simpler medication regimens, fewer side effects, and, in some cases, a higher barrier to the emergence of medication resistance. Areas covered: Here, we review trials of cabotegravir (CAB) as treatment of HIV-1 infection and its potential use as pre-exposure prophylaxis (PrEP) in high risk individuals, including issues around oral lead in and potential resistance emergence. Expert opinion: CAB is efficacious when used in combination therapy orally or given intramuscularly every 4 to 8 weeks. Its availability in a long-acting injectable formulation (CAB-LA) makes it a valuable, novel drug to treat HIV-1 infection when combined with long-acting injectable rilpivirine (RPV-LA). Moreover, pre-clinical and early Phase 2a studies support its testing as monotherapy as PrEP. Studies are underway comparing the efficacy of every 8 week CAB-LA to tenofovir disoproxil fumarate/emtricitabine (TDF/FTC).", "Portal vein involvement is considered one of the most fearful complications of hepatocellular carcinoma (HCC). Portal vein tumor thrombosis (PVTT) is associated with aggressive tumor biology (high grade), high tumor burden (number and size of lesions), high levels of serum markers (AFP), poor liver function (deranged LFT), and poor performance status of patients. The Barcelona Clinic Liver Cancer staging system places HCC patients with PVTT in advanced stage (BCLC Stage-C). This group contains a fairly heterogeneous patient population, previously considered candidates for palliative systemic therapy with sorafenib. However, this provided modest overall survival (OS) benefit. The results of a recent Phase III (IMbrave150) trial favor the combination of atezolizumab and bevacizumab over sorafenib as a standard of care in advanced unresectable HCC. While only lenvatinib proved to be non-inferior against sorafenib in a phase III (REFLECT trial), regorafenib (RESORCE trial), ramucirumab (REACH-2), and cabozantinib (CELESTIAL) have been approved second-line therapy in phase III clinical trials. Recently, the data on the prospect of other modalities in the management of HCC with PVTT is mounting with favorable results. Targeting multiple pathways in the HCC cascade using a combination of drugs and other modalities such as RT, TACE, TARE, and HAIC appear effective for systemic and loco-regional control. The quest for the ideal combination therapy and the sequence set is still widely unanswered and prospective trials are lacking. With the armament of available therapeutic options and the advances and refinements in the delivery system, down-staging patients to make them eligible for curative resection has been reported. In a rapidly evolving treatment landscape, performing surgery when appropriate, in the form of LR and even LT to achieve cure does not seem farfetched. Likewise, adjuvant therapy and prompt management of the recurrences holds the key to prolong OS and DFS. This review discusses the management options of HCC patients with PVTT.", "PURPOSE: Hot flashes are common experience for menopausal women, and for many, are severe enough to significantly compromise their overall sense of well being and quality of life. The aim of this study was to compare the efficacy of evening primrose with placebo in improvement of menopausal hot flashes.METHODS: In a 6-week randomized clinical trial, a total of 56 menopausal women aged 45-59 years were participated in this study. The patients were asked for their hot flashes characteristics and responded to HFRDIS (hot flash related daily interference scale) questionnaire before and after the intervention. The participants were randomly assigned to take two capsules per day (totally 90 capsules for 6 weeks) of placebo or evening primrose (500 mg) for continuous 6 weeks. Then, the improvement in hot flashes was compared between two groups.RESULTS: The percent of improvement in hot flash frequency, severity and duration were 39, 42 and 19 %, in evening primrose group compared with 32, 32 and 18 % in placebo group, respectively. Although all three characters of hot flash was ameliorated in evening primrose arm, only its severity was significantly better in this arm compared with placebo group (P < 0.05). All HFRDIS score were significantly improved in two groups, but the percentage of improvement in social activities, relations with others, and sexuality was significantly superior to placebo group (P < 0.05).CONCLUSIONS: The application of oral evening primrose oil compared with placebo for controlling hot flashes may decrease more the intensity of attacks as well as ameliorating the HFRDIS score.", "Author information:(1)Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.(2)Centre Hospitalier Universitaire Sainte-Justine Research Center, University of Montreal, Montreal, QC H3T 1C5, Canada.(3)Department of Biology, Faculty of Science, Western University, London, ON N6A 5B7, Canada; Division of Genetics and Development, Children's Health Research Institute, London, ON N6C 2V5, Canada.(4)Department of Biology, Faculty of Science, Western University, London, ON N6A 5B7, Canada.(5)Department of Pediatrics, Central Hospital, Aichi Human Service Center, Kasugai 480-0392, Japan.(6)Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.(7)Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK.(8)Belfast City Hospital, Belfast BT9 7AB, Northern Ireland, UK.(9)Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.(10)APHP, Département de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié Salpêtrière et GHUEP Hôpital Trousseau, Paris, France.(11)Institut National de la Santé et de la Recherche Médicale (INSERM), U 1127, CNRS UMR 7225, Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UMR 7104, INSERM U964, Université de Strasbourg, 67400 Illkirch, France; Institute of Human Genetics, University Hospital Essen, University of Duisburg, Essen, 45147 Essen, Germany.(12)Birmingham Women's and Children's National Health Service Foundation Trust, Mindelsohn Way, Birmingham B15 2TG, UK.(13)Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada; Department of Biology, Faculty of Science, Western University, London, ON N6A 5B7, Canada; Division of Genetics and Development, Children's Health Research Institute, London, ON N6C 2V5, Canada. Electronic address: james.kramer@schulich.uwo.ca.(14)Centre Hospitalier Universitaire Sainte-Justine Research Center, University of Montreal, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, University of Montreal, Montreal, QC H4A 3J1, Canada. Electronic address: p.campeau@umontreal.ca.", "Urinary incontinence is defined as \"the complaint of any involuntary leakage of urine\" and is a common problem in the female population with prevalence rates varying between 10% and 55% in 15- to 64-year-old women. The most frequent form of urinary incontinence in women is stress urinary incontinence, defined as \"involuntary leakage on effort or exertion, or on sneezing or coughing\". The aim of this article is to systematically review the literature on urinary incontinence and participation in sport and fitness activities with a special emphasis on prevalence and treatment in female elite athletes. Stress urinary incontinence is a barrier to women's participation in sport and fitness activities and, therefore, it may be a threat to women's health, self-esteem and well-being. The prevalence during sports among young, nulliparous elite athletes varies between 0% (golf) and 80% (trampolinists). The highest prevalence is found in sports involving high impact activities such as gymnastics, track and field, and some ball games. A 'stiff' and strong pelvic floor positioned at an optimal level inside the pelvis may be a crucial factor in counteracting the increases in abdominal pressure occurring during high-impact activities. There are no randomised controlled trials or reports on the effect of any treatment for stress urinary incontinence in female elite athletes. However, strength training of the pelvic floor muscles has been shown to be effective in treating stress urinary incontinence in parous females in the general population. In randomised controlled trials, reported cure rates, defined as <2g of leakage on pad tests, varied between 44% and 69%. Pelvic floor muscle training has no serious adverse effects and has been recommended as first-line treatment in the general population. Use of preventive devices such as vaginal tampons or pessaries can prevent leakage during high impact physical activity. The pelvic floor muscles need to be much stronger in elite athletes than in other women. There is a need for more basic research on pelvic floor muscle function during physical activity and the effect of pelvic floor muscle training in female elite athletes.", "One of the popular ideas is that decline in methyl-directed mismatch repair (MMR) in carbon-starved bacteria might facilitate occurrence of stationary-phase mutations. We compared the frequency of accumulation of stationary-phase mutations in carbon-starved Pseudomonas putida wild-type and MMR-defective strains and found that knockout of MMR system increased significantly emergence of base substitutions in starving P. putida. At the same time, the appearance of 1-bp deletion mutations was less affected by MMR in this bacterium. The spectrum of base substitution mutations which occurred in starving populations of P. putida wild-type strain was distinct from mutation spectrum identified in MMR-defective strains. The spectrum of base substitutions differed also in this case when mutants emerged in starved populations of MutS or MutL-defective strains were comparatively analyzed. Based on our results we suppose that other mechanisms than malfunctioning of MMR system in resting cells might be considered to explain the accumulation of stationary-phase mutations in P. putida. To further characterize populations of P. putida starved on selective plates, we stained bacteria with LIVE/DEAD kit in situ on agar plates. We found that although the overall number of colony forming units (CFU) did not decline in long-term-starved populations, these populations were very heterogeneous on the plates and contained many dead cells. Our results imply that slow growth of subpopulation of cells at the expenses of dead cells on selective plates might be important for the generation of stationary-phase mutations in P. putida. Additionally, the different survival patterns of P. putida on the same selective plates hint that competitive interactions taking place under conditions of prolonged starvation of microbial populations on semi-solid surfaces might be more complicated than previously assumed.", "BACKGROUND: Volatile organic compounds (VOCs) in breath may contain biomarkers of active pulmonary tuberculosis derived from the infectious organism (metabolites of Mycobacterium tuberculosis) and from the infected host (products of oxidative stress).METHODS: We analyzed breath VOCs in 226 symptomatic high-risk patients in USA, Philippines, and UK, using gas chromatography/mass spectroscopy. Diagnosis of disease was based on sputum culture, smear microscopy, chest radiography and clinical suspicion of tuberculosis (CSTB). Chromatograms were converted to a series of 8s overlapping time slices. Biomarkers of active pulmonary tuberculosis were identified with a Monte Carlo analysis of time-slice alveolar gradients (abundance in breath minus abundance in room air).RESULTS: Breath VOCs contained apparent biomarkers of active pulmonary tuberculosis comprising oxidative stress products (alkanes and alkane derivatives) and volatile metabolites of M. tuberculosis (cyclohexane and benzene derivatives). Breath biomarkers identified active pulmonary tuberculosis with C-statistic (area under curve of receiver operating characteristic)=0.85 (i.e. 85% overall accuracy, sensitivity=84.0%, specificity=64.7%) when sputum culture, microscopy, and chest radiography were either all positive or all negative. Employing a single criterion of disease, C-statistic=0.76 (smear microscopy), 0.68 (sputum culture), 0.66 (chest radiography) and 0.65 (CSTB).CONCLUSION: A breath test identified apparent biomarkers of active pulmonary tuberculosis with 85% accuracy in symptomatic high-risk subjects.", "AIMS: Beyond the control of nuclear-cytoplasmic trafficking nucleoporins regulate gene expression and are involved in cardiac diseases. Notably, a number of cardiovascular disorders have been linked to alterations in epigenetic mechanisms. Here we aimed to determine the contribution of Nup153 to the epigenetic alterations occurring in cardiomyopathy of dystrophin-deficient mdx mice (C57BL/10ScSn-Dmd mdx /J).METHODS AND RESULTS: Nup153 was lysine-acetylated and its expression was significantly increased at protein level in mdx hearts compared with controls. Accordingly, lysine acetyl transferase (KAT) activity associated with Nup153 was higher in mdx hearts paralleling increased binding with the lysine acetylases P300/CBP-associated factor (PCAF) and p300. Interestingly, Nup153 silencing in mdx organotypic heart tissue slices caused a reduction in PCAF- and p300-specific activities. Remarkably, the level of nitric oxide (NO), which is reduced in mdx mice, was important for KAT-dependent regulation of Nup153. In fact, treatment of mdx heart tissue with an NO donor or the KAT inhibitor anacardic acid normalized Nup153 protein expression. Nup153 was recruited to chromatin and regulated the transcription of genes involved in cardiac remodelling, including the actin-binding protein nexilin. Accordingly, nexilin protein expression was abrogated by Nup153 silencing in mdx organotypic cultures. Electrophysiological and molecular experiments revealed that Nup153 overexpression in normal cardiomyocytes increases Ca v 1.2 calcium channel expression and function. Alterations in Nup153 protein expression and intracellular localization were also found in dystrophic cardiomyocytes derived from patient-specific induced pluripotent stem cells. Importantly, Nup153 up-regulation and increased acetylation were also found in the heart of Duchenne muscular dystrophy patients.CONCLUSIONS: Our data indicate that Nup153 is an epigenetic regulator which, upon altered NO signalling, mediates the activation of genes potentially associated with early dystrophic cardiac remodelling.", "Women from site-specific hereditary breast cancer families who carry a BRCA1 or BRCA2 mutation are at increased risk for ovarian cancer. It is less clear, however, whether individuals from hereditary breast cancer families who do not carry such a mutation are also at increased ovarian cancer risk. To determine whether women from BRCA mutation-negative hereditary breast cancer families are at increased risk for ovarian cancer, 199 probands from BRCA mutation-negative, site-specific breast cancer kindreds who consented to prospective follow-up at the time of genetic testing were identified. The incidence of new breast and ovarian cancers in probands and their families since receipt of their genetic test results was determined by questionnaire. The expected number of cancers and standardized incidence ratios (SIRs) were determined from age-specific cancer incidence rates from the Surveillance, Epidemiology, and End Results (SEER) program by using the method of Byar. All statistical tests were two-sided. During 2534 women-years of follow-up in 165 kindreds, 19 new cases of breast cancer were diagnosed, whereas only 6.07 were expected (SIR = 3.13, 95% confidence interval [CI] = 1.88 to 4.89; P < .001), and one case of ovarian cancer was diagnosed, whereas only 0.66 was expected (SIR = 1.52, 95% CI = 0.02 to 8.46; P = .48). These results suggest that women from BRCA mutation-negative, site-specific breast cancer families are not at increased risk for ovarian cancer.", "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.", "We determined the times when the nuclear membrane, nuclear pore complex (NPC) components, and nuclear import function were recovered during telophase in living HeLa cells. Simultaneous observation of fluorescently-labeled NLS-bearing proteins, lamin B receptor (LBR)-GFP, and Hoechst33342-stained chromosomes revealed that nuclear membranes reassembled around chromosomes by 5 minutes after the onset of anaphase (early telophase) whereas nuclear import function was recovered later, at 8 minutes. GFP-tagged emerin also accumulated on chromosomes 5 minutes after the onset of anaphase. Interestingly, emerin and LBR initially accumulated at distinct, separate locations, but then became uniform 8 minutes after the onset of anaphase, concurrent with the recovery of nuclear import function. We further determined the timing of NPC assembly by immunofluorescence staining of cells fixed at precise times after the onset of anaphase. Taken together, these results showed that emerin, LBR, and several NPC components (RanBP2, Nup153, p62), but not Tpr, reconstitute around chromosomes very early in telophase prior to the recovery of nuclear import activity.", "SUMMARY: Somatic mutations and gene fusions can produce immunogenic neoantigens mediating anticancer immune responses. However, their computational prediction from sequencing data requires complex computational workflows to identify tumor-specific aberrations, derive the resulting peptides, infer patients' Human Leukocyte Antigen types and predict neoepitopes binding to them, together with a set of features underlying their immunogenicity. Here, we present nextNEOpi (nextflow NEOantigen prediction pipeline) a comprehensive and fully automated bioinformatic pipeline to predict tumor neoantigens from raw DNA and RNA sequencing data. In addition, nextNEOpi quantifies neoepitope- and patient-specific features associated with tumor immunogenicity and response to immunotherapy.AVAILABILITY AND IMPLEMENTATION: nextNEOpi source code and documentation are available at https://github.com/icbi-lab/nextNEOpi.CONTACT: dietmar.rieder@i-med.ac.at or francesca.finotello@uibk.ac.at.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "We report that the fission yeast nucleoporin Nup124p is required for the nuclear import of both, retrotransposon Tf1-Gag as well as the retroviral HIV-1 Vpr. Failure to import Tf1-Gag into the nucleus in a nup124 null mutant resulted in complete loss of Tf1 transposition. Similarly, nuclear import of HIV-1 Vpr was impaired in nup124 null mutant strains and cells became resistant to Vpr's cell-killing activity. On the basis of protein domain similarity, the human nucleoporin Nup153 was identified as a putative homolog of Nup124p. We demonstrate that in vitro-translated Nup124p and Nup153 coimmunoprecipitate Tf1-Gag or HIV-1 Vpr. Though full-length Nup153 was unable to complement the Tf1 transposition defect in a nup124 null mutant, we provide evidence that both nucleoporins share a unique N-terminal domain, Nup124p(AA264-454) and Nup153(AA448-634) that is absolutely essential for Tf1 transposition. Epigenetic overexpression of this domain in a wild-type (nup124(+)) background blocked Tf1 activity implying that sequences from Nup124p and the human Nup153 challenged the same pathway affecting Tf1 transposition. Our results establish a unique relationship between two analogous nucleoporins Nup124p and Nup153 wherein the function of a common domain in retrotransposition is conserved.", "Cohesin, a critical mediator of genome organization including sister chromatid cohesion, is a ring-shaped multi-subunit ATPase that topologically embraces DNA. Its loading and function on chromosomes require the Scc2-Scc4 loader. Using biochemical reconstitution, we show here that the ability of the loader to bind DNA plays a critical role in promoting cohesin loading. Two distinct sites within the Mis4Scc2 subunit are found to cooperatively bind DNA. Mis4Scc2 initially forms a tertiary complex with cohesin on DNA and promotes subsequent topological DNA entrapment by cohesin through its DNA binding activity, a process that requires an additional DNA binding surface provided by Psm3Smc3, the ATPase domain of cohesin. Furthermore, we show that mutations in the two DNA binding sites of Mis4 impair the chromosomal loading of cohesin. These observations demonstrate the physiological importance of DNA binding by the loader and provide mechanistic insights into the process of topological cohesin loading.", "BACKGROUND: Hypertrophic cardiomyopathy (HCM), the most common mendelian heart disorder, remains an orphan of disease-specific pharmacological treatment because of the limited understanding of cellular mechanisms underlying arrhythmogenicity and diastolic dysfunction.METHODS AND RESULTS: We assessed the electromechanical profile of cardiomyocytes from 26 HCM patients undergoing myectomy compared with those from nonfailing nonhypertrophic surgical patients by performing patch-clamp and intracellular Ca(2+) (Ca(2+)(i)) studies. Compared with controls, HCM cardiomyocytes showed prolonged action potential related to increased late Na(+) (I(NaL)) and Ca(2+) (I(CaL)) currents and decreased repolarizing K(+) currents, increased occurrence of cellular arrhythmias, prolonged Ca(2+)(i) transients, and higher diastolic Ca(2+)(i). Such changes were related to enhanced Ca(2+)/calmodulin kinase II (CaMKII) activity and increased phosphorylation of its targets. Ranolazine at therapeutic concentrations partially reversed the HCM-related cellular abnormalities via I(NaL) inhibition, with negligible effects in controls. By shortening the action potential duration in HCM cardiomyocytes, ranolazine reduced the occurrence of early and delayed afterdepolarizations. Finally, as a result of the faster kinetics of Ca(2+)(i) transients and the lower diastolic Ca(2+)(i), ranolazine accelerated the contraction-relaxation cycle of HCM trabeculae, ameliorating diastolic function.CONCLUSIONS: We highlighted a specific set of functional changes in human HCM myocardium that stem from a complex remodeling process involving alterations of CaMKII-dependent signaling, rather than being a direct consequence of the causal sarcomeric mutations. Among the several ion channel and Ca(2+)(i) handling proteins changes identified, an enhanced I(NaL) seems to be a major contributor to the electrophysiological and Ca(2+)(i) dynamic abnormalities of ventricular myocytes and trabeculae from patients with HCM, suggesting potential therapeutic implications of I(NaL) inhibition.", "DNA double-strand breaks are typically repaired through either the high-fidelity process of homologous recombination (HR), in which BRCA1 plays a key role, or the more error-prone process of non-homologous end joining (NHEJ), which relies on 53BP1. The balance between NHEJ and HR depends, in part, on whether 53BP1 predominates in binding to damage sites, where it protects the DNA ends from resection. The nucleoporin Nup153 has been implicated in the DNA damage response, attributed to a role in promoting nuclear import of 53BP1. Here, we define a distinct requirement for Nup153 in 53BP1 intranuclear targeting to damage foci and report that Nup153 likely facilitates the role of another nucleoporin, Nup50, in 53BP1 targeting. The requirement for Nup153 and Nup50 in promoting 53BP1 recruitment to damage foci induced by either etoposide or olaparib is abrogated in cells deficient for BRCA1 or its partner BARD1, but not in cells deficient for BRCA2. Together, our results further highlight the antagonistic relationship between 53BP1 and BRCA1, and place Nup153 and Nup50 in a molecular pathway that regulates 53BP1 function by counteracting BRCA1-mediated events.", "Sacubitril/valsartan (Entresto™; LCZ696) is an orally administered supramolecular sodium salt complex of the neprilysin inhibitor prodrug sacubitril and the angiotensin receptor blocker (ARB) valsartan, which was recently approved in the US and the EU for the treatment of chronic heart failure (NYHA class II-IV) with reduced ejection fraction (HFrEF). In the large, randomized, double-blind, PARADIGM-HF trial, sacubitril/valsartan reduced the incidence of death from cardiovascular causes or first hospitalization for worsening heart failure (composite primary endpoint) significantly more than the angiotensin converting enzyme (ACE) inhibitor enalapril. Sacubitril/valsartan was also superior to enalapril in reducing death from any cause and in limiting the progression of heart failure. Sacubitril/valsartan was generally well tolerated, with no increase in life-threatening adverse events. Symptomatic hypotension was significantly more common with sacubitril/valsartan than with enalapril; the incidence of angio-oedema was low. Therefore, sacubitril/valsartan is a more effective replacement for an ACE inhibitor or an ARB in the treatment of HFrEF, and is likely to influence the basic approach to treatment.", "Synesthesia is an unusual condition in which stimulation of one modality evokes sensation or experience in another modality. Although discussed in the literature well over a century ago, synesthesia slipped out of the scientific spotlight for decades because of the difficulty in verifying and quantifying private perceptual experiences. In recent years, the study of synesthesia has enjoyed a renaissance due to the introduction of tests that demonstrate the reality of the condition, its automatic and involuntary nature, and its measurable perceptual consequences. However, while several research groups now study synesthesia, there is no single protocol for comparing, contrasting and pooling synesthetic subjects across these groups. There is no standard battery of tests, no quantifiable scoring system, and no standard phrasing of questions. Additionally, the tests that exist offer no means for data comparison. To remedy this deficit we have devised the Synesthesia Battery. This unified collection of tests is freely accessible online (http://www.synesthete.org). It consists of a questionnaire and several online software programs, and test results are immediately available for use by synesthetes and invited researchers. Performance on the tests is quantified with a standard scoring system. We introduce several novel tests here, and offer the software for running the tests. By presenting standardized procedures for testing and comparing subjects, this endeavor hopes to speed scientific progress in synesthesia research.", "53BP1 is a mediator of DNA damage response (DDR) and a tumor suppressor whose accumulation on damaged chromatin promotes DNA repair and enhances DDR signaling. Using foci formation of 53BP1 as a readout in two human cell lines, we performed an siRNA-based functional high-content microscopy screen for modulators of cellular response to ionizing radiation (IR). Here, we provide the complete results of this screen as an information resource, and validate and functionally characterize one of the identified 'hits': a nuclear pore component NUP153 as a novel factor specifically required for 53BP1 nuclear import. Using a range of cell and molecular biology approaches including live-cell imaging, we show that knockdown of NUP153 prevents 53BP1, but not several other DDR factors, from entering the nuclei in the newly forming daughter cells. This translates into decreased IR-induced 53BP1 focus formation, delayed DNA repair and impaired cell survival after IR. In addition, NUP153 depletion exacerbates DNA damage caused by replication stress. Finally, we show that the C-terminal part of NUP153 is required for effective 53BP1 nuclear import, and that 53BP1 is imported to the nucleus through the NUP153-importin-β interplay. Our data define the structure-function relationships within this emerging 53BP1-NUP153/importin-β pathway and implicate this mechanism in the maintenance of genome integrity." ]

[ "Cellular mechanisms involved in multiple neurodegenerative diseases converge on mitochondria to induce overproduction of reactive oxygen species, damage to mitochondria, and subsequent cytochrome c release. Little is currently known regarding the contribution mitochondrial dynamics play in cytochrome c release following oxidative stress in neurodegenerative disease. Here we induced oxidative stress in the HT22 cell line with glutamate and investigated key mediators of mitochondrial dynamics to determine the role this process may play in oxidative stress induced neuronal death. We report that glutamate treatment in HT22 cells induces increase in reactive oxygen species (ROS), release of the mitochondrial fusion protein Opa1 into the cytosol, with concomitant release of cytochrome c. Furthermore, following the glutamate treatment alterations in cell signaling coincide with mitochondrial fragmentation which culminates in significant cell death in HT22 cells. Finally, we report that treatment with the antioxidant tocopherol attenuates glutamate induced-ROS increase, release of mitochondrial Opa1 and cytochrome c, and prevents cell death.", "A cohort of genes associated with embryonic stem (ES) cell behaviour, including NANOG, are expressed in a number of human cancers. They form an ES-like signature we first described in glioblastoma multiforme (GBM), a highly invasive and incurable brain tumour. We have also shown that HEDGEHOG-GLI (HH-GLI) signalling is required for GBM growth, stem cell expansion and the expression of this (ES)-like stemness signature. Here, we address the function of NANOG in human GBMs and its relationship with HH-GLI activity. We find that NANOG modulates gliomasphere clonogenicity, CD133(+) stem cell cell behavior and proliferation, and is regulated by HH-GLI signalling. However, GLI1 also requires NANOG activity forming a positive loop, which is negatively controlled by p53 and vice versa. NANOG is essential for GBM tumourigenicity in orthotopic xenografts and it is epistatic to HH-GLI activity. Our data establish NANOG as a novel HH-GLI mediator essential for GBMs. We propose that this function is conserved and that tumour growth and stem cell behaviour rely on the status of a functional GLI1-NANOG-p53 network.", "The mouse testis determining gene Sry is expressed in somatic cells of the differentiating male gonad as a linear transcript, encoding a transcription factor containing an HMG box. In the adult mouse testis, Sry expression occurs in meiotic and postmeiotic germ cells. The mouse genomic Sry locus is characterized by two arms of a large inverted repeat, flanking a unique region that, between an acceptor and a donor splice site, contains a single exon encoding the Sry protein. In germ cells from the adult mouse testis, Sry RNA is a circular molecule, which is generated by an inverted splicing event that utilizes the above-mentioned splice sites. Thus, a circular exon is spliced out starting from a large linear RNA precursor containing both arms of the inverted repeat, which pair and generate a large stem-loop structure. Using reverse transcription-polymerase chain reaction and an RNase protection assay, we have now mapped the 5' end of this precursor RNA in the 5' arm of the inverted repeat. Gel mobility shift assay and in vitro transcription with nuclear extracts from adult germ cells further confirm that a region immediately 5' upstream of two transcriptional initiation sites of the precursor RNA contains a promoter sequence in which two consensus Sry binding sequences are specifically recognized by nuclear factors present in adult germ cells but not in Sertoli cells. We also show that the linear precursor of the Sry circular transcript and its splicing product are specifically expressed not only in adult germ cells but also in male embryonal gonads between 11.5 and 13.5 days postcoitum, immediately after the expression of the linear transcript starting from the unique region.", "BACKGROUND: The epidermal growth factor family members: EGF, EGFR and the c-erbB-2(HER-2/neu) gene product have been found to play a role in carcinomas of the stomach, liver, breast, ovary and lungs. Recent reports have indicated that they are also involved in the growth of pancreatic ductal carcinoma, its invasiveness and metastasis.PATIENTS AND METHODS: Thirty-six patients with pancreatic ductal carcinoma were analysed with respect to sex, age, histological type, malignancy grade (G), pTN status (pTN), local lymph node involvement and distant metastasis. The tumor levels of EGF, EGFR and c-erbB-2 expression were determined immunohistochemically.RESULTS: Expression of c-erbB-2 was observed in 24/36 cases, EGF in 13/36 cases and EGFR in 18/36 cases. Overexpression of EGF and EGFR was associated with metastasis to lymph nodes and other organs. A correlation was also found between EGF expression and the presence of EGFR in the tumour. The expression of c-erbB-2 protein was not found to correlate with any parameters.CONCLUSION: EGF and EGFR play a key role in neoplastic spread through lymph node involvement and metastasis to other organs.", "Early-onset breast cancer characterize genetic predisposition to cancer in women. BRCA-1 gene was identified as one of the predisposition genes of breast/ovarian cancer. About 90% of the reported mutations in the hereditary breast and ovarian cancer gene, BRCA-1, result in truncated proteins. The aim of our study is to detect rapidly BRCA-1 mutations by the protein truncation test (PTT) in Tunisian women with early breast cancer. Population and methods. We underwent molecular analysis in families with more than: (a) a women under 40 years-old with breast cancer, uni or bilateral; (b) two 1st degree relatives women under 50 years-old with beast cancer. Sixteen women from 12 families were studied by PTT to screen mutations in exon 11 which encodes 61% of BRCA-1.RESULTS: PTT analysis of exon 11 revealed a normal and truncated protein in one patient between 16 from 12 families.CONCLUSION: BRCA-1 gene seems to contribute to at least 1/16 or 6.25% in women with hereditary predisposition to breast/ovarian cancer in Tunisia. PTT promises to be a valuable technique in detecting BRCA-1 mutations in our country.", "Protein and peptide drugs hold great promise as therapeutic agents. But there are shortcomings: Many recombinant proteins are quickly degraded by proteolytic enzymes or are rapidly cleared by kidney filtration resulting in a short circulating half-life. Additionally they are prone to be recognized by the immune system resulting in the generation of neutralizing and non-neutralizing antibodies. PEGylation, a process by which polyethylene glycol chains are attached to protein and peptide drugs, can overcome these and other shortcomings. By increasing the molecular mass of proteins and peptides and shielding them from proteolytic enzymes, PEGylation primarily improves pharmacokinetics and helps to prevent adverse drug reactions.", "Using rabbit polyclonal antibodies, we have shown that the Dcm cytosine methylase of Escherichia coli is maintained at a constant level during cell growth, while Vsr endonuclease levels are growth phase dependent. Decreased production of Vsr relative to Dcm during the log phase may contribute substantially to the mutability of 5-methylcytosine." ]

[ "A family with the Romano-Ward syndrome is presented. This family showed typical features of this syndrome with QT prolongation, torsades de pointes ventricular tachycardia, sudden death and an autosomal dominant inheritance pattern. The index case presented with an exacerbation of torsades de pointes ventricular tachycardia from diuretic induced hypokalaemia, and responded to diuretic withdrawal and beta blocker therapy.", "Author information:(1)Department of Urology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.(2)Department of Urology, The Jikei University School of Medicine, Tokyo, Japan.(3)Research Center for Evidence Based Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.(4)Deaprtment of Urology, PRES Centre Val de Loire, CHRU Tours, France, Université François Rabelais de Tours, Tours, France.(5)Department of Urology, King Fahad Specialist Hospital, Dammam, Saudi Arabia.(6)Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia.(7)Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.(8)Division of Urology, Department of Special Surgery, The University of Jordan, Amman, Jordan.(9)Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Centre, Montreal, Canada.(10)Department of Urology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria. shahrokh.shariat@meduniwien.ac.at.(11)Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia. shahrokh.shariat@meduniwien.ac.at.(12)Division of Urology, Department of Special Surgery, The University of Jordan, Amman, Jordan. shahrokh.shariat@meduniwien.ac.at.(13)Department of Urology, Weill Cornell Medical College, New York, NY, USA. shahrokh.shariat@meduniwien.ac.at.(14)Department of Urology, University of Texas Southwestern, Dallas, TX, USA. shahrokh.shariat@meduniwien.ac.at.(15)Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria. shahrokh.shariat@meduniwien.ac.at.(16)Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic. shahrokh.shariat@meduniwien.ac.at.(17)European Association of Urology Research Foundation, Arnhem, Netherlands. shahrokh.shariat@meduniwien.ac.at.", "BACKGROUND: The primary aim of this randomized study was to describe the feasibility of early administration of surfactant via a thin catheter during spontaneous breathing (Take Care) and compare early mechanical ventilation (MV) requirement with the InSurE (Intubate, Surfactant, Extubate) procedure.METHODS: Preterm infants, who were <32 weeks and stabilized with nasal continuous positive airway pressure (nCPAP) in the delivery room, were randomized to receive early surfactant treatment either by the Take Care or InSurE technique. Tracheal instillation of 100 mg/kg poractant α via 5-F catheter during spontaneous breathing under nCPAP was performed in the intervention group. In the InSurE procedure, infants were intubated, received positive pressure ventilation for 30 seconds after surfactant instillation, and placed on nCPAP immediately.RESULTS: One hundred infants in each group were analyzed. The MV requirement in the first 72 hours of life was significantly lower in the Take Care group when compared with the InSurE group (30% vs 45%, P = .02, odds ratio -0.52, 95% confidence interval -0.94 to -0.29). Mean duration of both nCPAP and MV were significantly shorter in the Take Care group (P values .006 and .002, respectively). Bronchopulmonary dysplasia rate was significantly lower among the infants treated with the Take Care technique (relative risk -0.27, 95% confidence interval -0.1 to -0.72)CONCLUSIONS: The Take Care technique is feasible for the treatment of respiratory distress syndrome in infants with very low birth weight. It significantly reduces both the need and duration of MV, and thus the bronchopulmonary dysplasia rate in preterm infants.", "BACKGROUND: Timothy syndrome is a multisystem disorder associated with QT interval prolongation and ventricular cardiac arrhythmias. The syndrome has been linked to mutations in Ca(V)1.2 resulting in gain of function of the L-type calcium current (I(Ca,L)). Ranolazine is an antianginal agent shown to exert an antiarrhythmic effect in experimental models of long QT syndrome.OBJECTIVE: The purpose of this study was to develop and characterize an experimental model of Timothy syndrome by using BayK8644 to mimic the gain of function of I(Ca,L) and to examine the effects of ranolazine.METHODS: Action potentials from epicardial and M regions and a pseudo-electrocardiogram (ECG) were simultaneously recorded from coronary-perfused left ventricular wedge preparations, before and after addition of BayK8644 (1 microM).RESULTS: BayK8644 preferentially prolonged action potential duration of the M cell, leading to prolongation of the QT interval and an increase in transmural dispersion of repolarization (from 44.3 +/- 7 ms to 86.5 +/- 25 ms). Stimulation at cycle lengths of 250-500 ms led to ST-T wave alternans due to alternation of the plateau voltage of the M cell action potential as well as development of delayed afterdepolarizations in epicardial and M cell action potentials. Ventricular extrasystoles and tachycardia (monomorphic, bidirectional, or torsades de pointes) developed spontaneously or after rapid pacing. Peak and late I(Na) were unaffected by BayK8644. Clinically relevant concentrations of ranolazine (10 microM) suppressed all actions of BayK8644.CONCLUSION: A left ventricular wedge model of long QT syndrome created by augmentation of I(Ca,L) recapitulates the ECG and arrhythmic manifestations of Timothy syndrome, which can be suppressed by ranolazine.", "PURPOSE: Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. This phase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors.EXPERIMENTAL DESIGN: Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for the 7- and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration-time profiles. AAK inhibition in skin and tumor biopsies was evaluated and antitumor activity assessed.RESULTS: Neutropenia and stomatitis were the most common DLTs. The MTD for the 7- and 21-day schedules was 50 mg twice daily and 50 mg once daily, respectively. MLN8237 absorption was fast (median time to maximum concentration, 2 hours). Mean terminal half-life was approximately 19 hours. At steady state, pharmacodynamic effects were shown by accumulation of mitotic and apoptotic cells in skin, and exposure-related increases in numbers of mitotic cells with characteristic spindle and chromosomal abnormalities in tumor specimens, supporting AAK inhibition by MLN8237. Stable disease was observed and was durable with repeat treatment cycles, administered over 6 months, in 6 patients, without notable cumulative toxicity.CONCLUSIONS: The recommended phase II dose of MLN8237 is 50 mg twice daily on the 7-day schedule, which is being evaluated further in a variety of malignancies, including in a phase III trial in peripheral T-cell lymphoma.", "BACKGROUND: Nonmelanoma skin cancers, such as basal-cell carcinoma and squamous-cell carcinoma, are common cancers that are caused principally by ultraviolet (UV) radiation. Nicotinamide (vitamin B3) has been shown to have protective effects against damage caused by UV radiation and to reduce the rate of new premalignant actinic keratoses.METHODS: In this phase 3, double-blind, randomized, controlled trial, we randomly assigned, in a 1:1 ratio, 386 participants who had had at least two nonmelanoma skin cancers in the previous 5 years to receive 500 mg of nicotinamide twice daily or placebo for 12 months. Participants were evaluated by dermatologists at 3-month intervals for 18 months. The primary end point was the number of new nonmelanoma skin cancers (i.e., basal-cell carcinomas plus squamous-cell carcinomas) during the 12-month intervention period. Secondary end points included the number of new squamous-cell carcinomas and basal-cell carcinomas and the number of actinic keratoses during the 12-month intervention period, the number of nonmelanoma skin cancers in the 6-month postintervention period, and the safety of nicotinamide.RESULTS: At 12 months, the rate of new nonmelanoma skin cancers was lower by 23% (95% confidence interval [CI], 4 to 38) in the nicotinamide group than in the placebo group (P=0.02). Similar differences were found between the nicotinamide group and the placebo group with respect to new basal-cell carcinomas (20% [95% CI, -6 to 39] lower rate with nicotinamide, P=0.12) and new squamous-cell carcinomas (30% [95% CI, 0 to 51] lower rate, P=0.05). The number of actinic keratoses was 11% lower in the nicotinamide group than in the placebo group at 3 months (P=0.01), 14% lower at 6 months (P<0.001), 20% lower at 9 months (P<0.001), and 13% lower at 12 months (P=0.001). No noteworthy between-group differences were found with respect to the number or types of adverse events during the 12-month intervention period, and there was no evidence of benefit after nicotinamide was discontinued.CONCLUSIONS: Oral nicotinamide was safe and effective in reducing the rates of new nonmelanoma skin cancers and actinic keratoses in high-risk patients. (Funded by the National Health and Medical Research Council; ONTRAC Australian New Zealand Clinical Trials Registry number, ACTRN12612000625875.).", "Collaborators: Aitman T, Bennett D, Caulfield M, Chinnery P, Gale D, Koziell A, Kuijpers TW, Laffan MA, Maher E, Markus HS, Morrell NW, Ouwehand WH, Perry DJ, Raymond FL, Roberts I, Smith KGC, Thrasher A, Watkins H, Williamson C, Woods G, Ashford S, Bradley JR, Fletcher D, Hammerton T, James R, Kingston N, Penkett CJ, Stirrups K, Veltman M, Young T, Brown M, Clements-Brod N, Davis J, Dewhurst E, Dolling H, Erwood M, Frary A, Linger R, Martin JM, Papadia S, Rehnstrom K, Stark H, Allsup D, Austin S, Bakchoul T, Bariana TK, Bolton-Maggs P, Chalmers E, Collins J, Collins P, Erber WN, Everington T, Favier R, Freson K, Furie B, Gattens M, Gebhart J, Gomez K, Greene D, Greinacher A, Gresele P, Hart D, Heemskerk JWM, Henskens Y, Kazmi R, Keeling D, Kelly AM, Lambert MP, Lentaigne C, Liesner R, Makris M, Mangles S, Mathias M, Millar CM, Mumford A, Nurden P, Payne J, Pasi J, Peerlinck K, Revel-Vilk S, Richards M, Rondina M, Roughley C, Schulman S, Schulze H, Scully M, Sivapalaratnam S, Stubbs M, Tait RC, Talks K, Thachil J, Toh CH, Turro E, Van Geet C, De Vries M, Warner TQ, Watson H, Westbury S, Furnell A, Mapeta R, Rayner-Matthews P, Simeoni I, Staines S, Stephens J, Watt C, Whitehorn D, Attwood A, Daugherty L, Deevi SVV, Halmagyi C, Hu F, Matser V, Meacham S, Megy K, Shamardina O, Titterton C, Tuna S, Yu P, von Ziegenweldt J, Astle W, Bleda M, Carss KJ, Gräf S, Haimel M, Lango-Allen H, Richardson S, Calleja P, Rankin S, Turek W, Anderson J, Bryson C, Carmichael J, McJannet C, Stock S, Allen L, Ambegaonkar G, Armstrong R, Arno G, Bitner-Glindzicz M, Brady A, Canham N, Chitre M, Clement E, Clowes V, Deegan P, Deshpande C, Doffinger R, Firth H, Flinter F, French C, Gardham A, Ghali N, Gissen P, Grozeva D, Henderson R, Hensiek A, Holden S, Holder M, Holder S, Hurst J, Josifova D, Krishnakumar D, Kurian MA, Lees M, MacLaren R, Maw A, Mehta S, Michaelides M, Moore A, Murphy E, Park SM, Parker A, Patch C, Paterson J, Rankin J, Reid E, Rosser E, Sanchis-Juan A, Sandford R, Santra S, Scott R, Sohal A, Stein P, Thomas E, Thompson D, Tischkowitz M, Vogt J, Wakeling E, Wassmer E, Webster A, Ali S, Ali S, Boggard HJ, Church C, Coghlan G, Cookson V, Corris PA, Creaser-Myers A, DaCosta R, Dormand N, Eyries M, Gall H, Ghataorhe PK, Ghio S, Ghofrani A, Gibbs JSR, Girerd B, Greenhalgh A, Hadinnapola C, Houweling AC, Humbert M, In't Veld AH, Kennedy F, Kiely DG, Kovacs G, Lawrie A, Ross RVM, Machado R, Masati L, Meehan S, Moledina S, Montani D, Othman S, Peacock AJ, Pepke-Zaba J, Pollock V, Polwarth G, Ranganathan L, Rhodes CJ, Rue-Albrecht K, Schotte G, Shipley D, Soubrier F, Southgate L, Scelsi L, Suntharalingam J, Tan Y, Toshner M, Treacy CM, Trembath R, Vonk Noordegraaf A, Walker S, Wanjiku I, Wharton J, Wilkins M, Wort SJ, Yates K, Alachkar H, Antrobus R, Arumugakani G, Bacchelli C, Baxendale H, Bethune C, Bibi S, Booth C, Browning M, Burns S, Chandra A, Cooper N, Davies S, Devlin L, Drewe E, Edgar D, Egner W, Ghurye R, Gilmour K, Goddard S, Gordins P, Grigoriadou S, Hackett S, Hague R, Harper L, Hayman G, Herwadkar A, Huissoon A, Jolles S, Kelleher P, Kumararatne D, Lear S, Longhurst H, Lorenzo L, Maimaris J, Manson A, McDermott E, Murng S, Nejentsev S, Noorani S, Oksenhendler E, Ponsford M, Qasim W, Quinti I, Richter A, Samarghitean C, Sargur R, Savic S, Seneviratne S, Sewell C, Staples E, Stauss H, Thaventhiran J, Thomas M, Welch S, Willcocks L, Yeatman N, Yong P, Ancliff P, Babbs C, Layton M, Louka E, McGowan S, Mead A, Roy N, Chambers J, Dixon P, Estiu C, Hague B, Marschall HU, Simpson M, Chong S, Emmerson I, Ginsberg L, Gosal D, Hadden R, Horvath R, Mahdi-Rogers M, Manzur A, Marshall A, Matthews E, McCarthy M, Reilly M, Renton T, Rice A, Themistocleous A, Vale T, Van Zuydam N, Walker S, Ormondroyd L, Hudson G, Wei W, Yu Wai Man P, Whitworth J, Afzal M, Colby E, Saleem M, Alavijeh OS, Cook HT, Johnson S, Levine AP, Wong EKS, Tan R, Boycott KM, MacKenzie A, Majewski J, Brudno M, Bulman D, Dyment D." ]

[ "In the post-reperfusion era, molecular and genetic mechanisms of cardioprotection and regeneration represent new therapeutic challenges to limit infarct size and minimize post-ischemic remodeling after acute myocardial infarction (AMI). Activation of cell survival mechanisms can be promoted by the administration of external drugs, stimulation of internal mechanisms, and genetic manipulation to delete or replace pathological genes or enhance gene expression. Among internal cardiovascular regulatory mechanisms, thyroid hormones (THs) may play a fundamental role. TH has a critical role in cardiovascular development and homeostasis in both physiological and pathological conditions. In experimental AMI, TH has been shown to affect cardiac contractility, left ventricular (LV) function, and remodeling. Several experimental studies have clearly shown that THs participate in the regulation of molecular mechanisms of angiogenesis, cardioprotection, cardiac metabolism, and ultimately myocyte regeneration, changes that can reverse left ventricular remodeling by favorably improving myocyte shape and geometry of LV cavity, thus improving systolic and diastolic performance. This review is focused on the role of thyroid on AMI evolution and on the potential novel option of thyroid-related treatment of AMI.", "The best therapeutic approach to acute schistosomiasis (Katayama fever) is still unsettled. In this paper we report a synergistic effect between schistosomicides and steroids in the treatment of the early stages of Schistosoma mansoni infection in the mouse. CBA mice infected with 150 S. mansoni cercariae were treated with oxamniquine or praziquantel and dexamethasone or prednisolone. The rate of parasite egg excretion by treated mice and appropriate controls was monitored, and the mice were perfused 43 d after infection for estimation of worm burdens and tissue egg densities. Mice treated with schistosomicides alone or with schistosomicides plus steroids had worm burdens of similar size. Significant reductions in egg counts were, however, recorded in faeces, and in the intestines and livers (with consequent reduction in liver pathology), of mice treated with schistosomicide and steroid, when compared to mice treated with schistosomicide alone or steroid alone. The apparent inhibition of fecundity of S. mansoni by combining these drugs has clear implications for treatment of the Katayama syndrome.", "Chediak-Higashi syndrome is a genetic disorder caused by mutations in a gene encoding a protein named LYST in humans (\"lysosomal trafficking regulator\") or Beige in mice. A prominent feature of this disease is the accumulation of enlarged lysosome-related granules in a variety of cells. The genome of Dictyostelium discoideum contains six genes encoding proteins that are related to LYST/Beige in amino acid sequence, and disruption of one of these genes, lvsA (large volume sphere), results in profound defects in cytokinesis. To better understand the function of this family of proteins in membrane trafficking, we have analyzed mutants disrupted in lvsA, lvsB, lvsC, lvsD, lvsE, and lvsF. Of all these, only lvsA and lvsB mutants displayed interesting phenotypes in our assays. lvsA-null cells exhibited defects in phagocytosis and contained abnormal looking contractile vacuole membranes. Loss of LvsB, the Dictyostelium protein most similar to LYST/Beige, resulted in the formation of enlarged vesicles that by multiple criteria appeared to be acidic lysosomes. The rates of endocytosis, phagocytosis, and fluid phase exocytosis were normal in lvsB-null cells. Also, the rates of processing and the efficiency of targeting of lysosomal alpha-mannosidase were normal, although lvsB mutants inefficiently retained alpha-mannosidase, as well as two other lysosomal cysteine proteinases. Finally, results of pulse-chase experiments indicated that an increase in fusion rates accounted for the enlarged lysosomes in lvsB-null cells, suggesting that LvsB acts as a negative regulator of fusion. Our results support the notion that LvsB/LYST/Beige function in a similar manner to regulate lysosome biogenesis.", "Chronic myelogenous leukemia (CML) accounts for 15-20% of adult leukemias but is very rare in children (2%). Fewer than 10% of CML patients are younger than 20 years. CML is a myeloproliferative disorder characterized by the presence of the Philadelphia chromosome or the BCR-ABL fusion oncogene. The objective of this paper is to present the monitoring of imatinib therapy in two children with CML by the BCR-ABL fusion gene expression assessment from peripheral blood with quantitative real-time polymerase chain reaction (PCR) method.PATIENTS AND METHODS: The 18 and six months follow-up of the patients included clinical examination, routine laboratory tests, bone marrow aspirate investigation including cytogenetic tests and the major BCR-ABL fusion gene expression measurement with qRT-PCR method from the peripheral blood.RESULTS: Patient No. 1 diagnosed with chronic phase CML showed excellent adherence to daily 400 mg imatinib treatment and achieved complete hematologic (CHR) and cytogenetic response (CCR) by three months and major molecular response (MMR) by 12 months, with lack of side effects due to imatinib. Patient No. 2 experienced severe hematologic toxicity, which necessitated temporary withdrawal of the drug. Transient non-compliance together with imatinib dose reduction has driven to treatment failure. In this case, mutational analysis is warranted.CONCLUSIONS: BCR-ABL fusion gene expression level measurement from peripheral blood with qRT-PCR method is an excellent tool in the follow-up of CML patients.", "The ability of brown adipocytes (fat cells) to dissipate energy as heat shows great promise for the treatment of obesity and other metabolic disorders. Employing pluripotent stem cells, with an emphasis on directed differentiation, may overcome many issues currently associated with primary fat cell cultures. In addition, three-dimensional (3D) cell culture systems are needed to better understand the role of brown adipocytes in energy balance and treating obesity. To address this need, we created 3D \"Brown-Fat-in-Microstrands\" by microfluidic synthesis of alginate hydrogel microstrands that encapsulated cells and directly induced cell differentiation into brown adipocytes, using mouse embryonic stem cells (ESCs) as a model of pluripotent stem cells, and brown preadipocytes as a positive control. Brown adipocyte differentiation within microstrands was confirmed by immunocytochemistry and qPCR analysis of the expression of the brown adipocyte-defining marker uncoupling protein 1 (UCP1), as well as other general adipocyte markers. Cells within microstrands were responsive to a β-adrenergic agonist with an increase in gene expression of thermogenic UCP1, indicating that these \"Brown-Fat-in-Microstrands\" are functional. The ability to create \"Brown-Fat-in-Microstrands\" from pluripotent stem cells opens up a new arena to understanding brown adipogenesis and its implications in obesity and metabolic disorders.", "PURPOSE: CPX-351 is a novel liposomal formulation of cytarabine and daunorubicin which has recently been FDA approved for treatment of acute myeloid leukemia (AML). The current study investigated the pharmacokinetics (PK) of this liposomal formulation.METHODS: CPX-351 PK data (cytarabine, daunorubicin, and metabolites) from a phase I study of relapsed and refractory AML were used for the analysis. Therapy was given days 1, 3, and 5 of induction (3-134 units/m2). We developed a population PK model to characterize CPX-351 disposition.RESULTS: 39 patients (3589 samples) were evaluated. Liposomal cytarabine and daunorubicin were modeled separately with their respective metabolites. A one-compartment model fit the parent compounds well; the metabolites required two-compartment models. Weight was an independent predictor of liposomal volumes; mild renal and liver dysfunction were not predictors of clearance or volume (maximum creatinine 1.6 mg/dL and total bilirubin 1.8 mg/dL). Liposomal clearances of the two drugs were highly correlated and 1000-fold smaller than published non-encapsulated values supporting prolonged encapsulation in the liposome.CONCLUSIONS: The PK model demonstrates prolonged exposure to cytarabine and daunorubicin without increases in non-hematologic toxicity that indicates retention of the drugs within the liposome. The unique pharmacology of this formulation may allow for simplified regimens and improved outcomes.", "Arachidonic acid metabolites contribute to the regulation of vascular tone and therefore tissue blood flow. The vascular endothelium metabolizes arachidonic acid by cytochrome P450 epoxygenases to epoxyeicosatrienoic acids or EETs. The placement of the epoxide group can occur on any of the double bonds of arachidonic acid resulting in four EET regioisomers; 5,6-, 8,9-, 11,12- and 14,15-EET. In the vasculature, EETs are key components of cellular signaling cascades that culminate in the activation of smooth muscle potassium channels to induce membrane hyperpolarization and vascular relaxation. In some vasculatures such as bovine coronary arteries, EET regioisomers are equipotent in inducing relaxations, while in other arteries, a specific EET regioisomer induces relaxation while others do not. Therefore, the position of the double bonds and/or the epoxide group may alter vascular agonist activity. This observation suggests that small alterations in the chemical structure of EETs can significantly impact vascular activity. To explore this hypothesis, we synthesized a series of EET analogs and characterized their vasodilator agonist and antagonist activity in bovine coronary arteries. In this chapter, we first review the mechanisms of EET-dependent relaxations in bovine coronary arteries to familiarize the reader with the role of EETs in these arteries. The second component is a synopsis of the functional characterization of the 14,15-EET analogs and the resulting description of structural components required for vascular dilator activity. Lastly, we discussed the characterization of three 14,15-EET analogs with specific EET-antagonist activity and compared this to the activity of similar 11,12-EET analogs. These studies have revealed that specific structural components of the 14,15-EET molecule are critical for dilator activity and that alteration of these components influences agonist activity and may confer antagonist properties." ]

[ "SUMMARY: Copy number variation (CNV) is a major type of structural genomic variation that is increasingly studied across different species for association with diseases and production traits. Established protocols for experimental detection and computational inference of CNVs from SNP array and next-generation sequencing data are available. We present the CNVRanger R/Bioconductor package which implements a comprehensive toolbox for structured downstream analysis of CNVs. This includes functionality for summarizing individual CNV calls across a population, assessing overlap with functional genomic regions, and genome-wide association analysis with gene expression and quantitative phenotypes.AVAILABILITY AND IMPLEMENTATION: http://bioconductor.org/packages/CNVRanger.", "Anti-amyloid-beta immunization leads to amyloid clearance in patients with Alzheimer's disease, but the effect of vaccination on amyloid-beta-induced neuronal pathology has not been quantitatively examined. The objectives of this study were to address the effects of anti-amyloid-beta active immunization on neurite trajectories and the pathological hallmarks of Alzheimer's disease in the human hippocampus. Hippocampal sections from five patients with Alzheimer's disease enrolled in the AN1792 Phase 2a trial were compared with those from 13 non-immunized Braak-stage and age-matched patients with Alzheimer's disease, and eight age-matched non-demented controls. Analyses included neurite curvature ratio as a quantitative measure of neuritic abnormalities, amyloid and tau loads, and a quantitative characterization of plaque-associated neuritic dystrophy and astrocytosis. Amyloid load and density of dense-core plaques were decreased in the immunized group compared to non-immunized patients (P < 0.01 and P < 0.001, respectively). The curvature ratio in non-immunized patients with Alzheimer's disease was elevated compared to non-demented controls (P < 0.0001). In immunized patients, however, the curvature ratio was normalized when compared to non-immunized patients (P < 0.0001), and not different from non-demented controls. In the non-immunized patients, neurites close to dense-core plaques (within 50 microm) were more abnormal than those far from plaques (i.e. beyond 50 microm) (P < 0.0001). By contrast, in the immunized group neurites close to and far from the remaining dense-core plaques did not differ, and both were straighter compared to the non-immunized patients (P < 0.0001). Compared to non-immunized patients, dense-core plaques remaining after immunization had similar degree of astrocytosis (P = 0.6060), more embedded dystrophic neurites (P < 0.0001) and were more likely to have mitochondrial accumulation (P < 0.001). In addition, there was a significant decrease in the density of paired helical filament-1-positive neurons in the immunized group as compared to the non-immunized (P < 0.05), but not in the density of Alz50 or thioflavin-S positive tangles, suggesting a modest effect of anti-amyloid-beta immunization on tangle pathology. Clearance of amyloid plaques upon immunization with AN1792 effectively improves a morphological measure of neurite abnormality in the hippocampus. This improvement is not just attributable to the decrease in plaque load, but also occurs within the halo of the remaining dense-core plaques. However, these remaining plaques still retain some of their toxic potential. Anti-amyloid-beta immunization might also ameliorate the hippocampal tau pathology through a decrease in tau phosphorylation. These data agree with preclinical animal studies and further demonstrate that human anti-amyloid-beta immunization does not merely clear amyloid from the Alzheimer's disease brain, but reduces some of the neuronal alterations that characterize Alzheimer's disease.", "Author information:(1)From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.).", "BACKGROUND: Medicare payment reforms will reimburse accountable care organizations (ACOs) for providing high-quality healthcare. Quality measures that reliably predict health outcomes are required.OBJECTIVES: To compare the ability of alternative wait time measures to predict glycated hemoglobin (A1C) levels among diabetes patients.STUDY DESIGN: This retrospective observational study relied on Veterans Health Administration utilization data and Medicare claims data from 2005 to 2010.METHODS: Outcomes included an average A1C level and uncontrolled A1C. Heckman selection models simultaneously predicted the presence of an A1C value and its level. Models were risk adjusted for prior individual health status. The main explanatory variables of interest were facility-level primary care wait times measured in days. Several measures were tested, including capacity measures and retrospective and prospective time stamp measures. The time stamp measures used either the date the appointment was created in the scheduling system (create date) or the date the patient or provider desired the appointment (desired date) as the start date for wait time computation. All measures were calculated separately for new and returning patients.RESULTS: New patient capacity and create date measures significantly predicted outcomes, but desired date measures did not. The returning patient retrospective create date and desired date wait time measures significantly predicted higher and uncontrolled A1C, but capacity and prospective create date measures did not.CONCLUSIONS: Different administrative wait times predict A1C for new and returning patients. To properly measure quality, ACOs should use wait time measures that demonstrate relationships with outcomes for subpopulations of patients.", "Caveolae are submicroscopic, plasma membrane pits that are abundant in many mammalian cell types. The past few years have seen a quantum leap in our understanding of the formation, dynamics and functions of these enigmatic structures. Caveolae have now emerged as vital plasma membrane sensors that can respond to plasma membrane stresses and remodel the extracellular environment. Caveolae at the plasma membrane can be removed by endocytosis to regulate their surface density or can be disassembled and their structural components degraded. Coat proteins, called cavins, work together with caveolins to regulate the formation of caveolae but also have the potential to dynamically transmit signals that originate in caveolae to various cellular destinations. The importance of caveolae as protective elements in the plasma membrane, and as membrane organizers and sensors, is highlighted by links between caveolae dysfunction and human diseases, including muscular dystrophies and cancer.", "Lucatumumab is a fully humanized anti-CD40 antibody that blocks interaction of CD40L with CD40 and also mediates antibody-dependent cell-mediated cytotoxicity (ADCC). We evaluated lucatumumab in a phase I clinical trial in chronic lymphocytic leukemia (CLL). Twenty-six patients with relapsed CLL were enrolled on five different dose cohorts administered weekly for 4 weeks. The maximally tolerated dose (MTD) of lucatumumab was 3.0 mg/kg. Four patients at doses of 4.5 mg/kg and 6.0 mg/kg experienced grade 3 or 4 asymptomatic elevated amylase and lipase levels. Of the 26 patients enrolled, 17 patients had stable disease (mean duration of 76 days, range 29-504 days) and one patient had a nodular partial response for 230 days. Saturation of CD40 receptor on CLL cells was uniform at all doses post-treatment but also persisted at trough time points in the 3.0 mg/kg or greater cohorts. At the MTD, the median half-life of lucatumumab was 50 h following the first infusion, and 124 h following the fourth infusion. In summary, lucatumumab had acceptable tolerability, pharmacokinetics that supported chronic dosing and pharmacodynamic target antagonism at doses of 3.0 mg/kg, but demonstrated minimal single-agent activity. Future efforts with lucatumumab in CLL should focus on combination-based therapy.", "BACKGROUND: Pulled elbow (nursemaid's elbow) is a common injury in young children. It often results from a sudden pull on the arm, usually by an adult or taller person, which pulls the radius through the annular ligament, resulting in subluxation (partial dislocation) of the radial head. It can also be caused by a fall or twist. The child experiences sudden acute pain and loss of function in the affected arm. Pulled elbow is usually treated by manual reduction of the subluxed radial head. Various manoeuvres can be applied; most commonly, supination of the forearm, often combined with flexion, and (hyper-)pronation. It is unclear which is most successful. This is an update of a Cochrane review first published in 2009 and last updated in 2011.OBJECTIVES: To compare the effects (benefits and harms) of the different methods used to manipulate pulled elbow in young children.SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, LILACS, PEDro, clinical trial registers and reference lists of articles. Date of last search: September 2016.SELECTION CRITERIA: Randomised or quasi-randomised controlled clinical trials evaluating manipulative interventions for pulled elbow were included. Our primary outcome was failure at the first attempt, necessitating further treatment.DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated trials for inclusion, assessed risk of bias, and extracted data. We pooled data using a fixed-effect model.MAIN RESULTS: Overall, nine trials with 906 children (all younger than seven years old and 58% of whom were female) were included, of which five trials were newly identified in this update. Eight trials were performed in emergency departments or ambulatory care centres, and one was performed in a tertiary paediatric orthopaedic unit. Four trials were conducted in the USA, three in Turkey, one in Iran, and one in Spain. Five trials were at high risk of selection bias because allocation was not concealed and all trials were at high risk of detection bias due to the lack of assessor blinding. Eight trials compared hyperpronation with supination-flexion. We found low-quality evidence that hyperpronation resulted in less failure at first attempt than supination-flexion (9.2% versus 26.4%, risk ratio (RR) 0.35; 95% confidence interval (CI) 0.25 to 0.50; 811 participants, 8 studies). Based on an illustrative risk of 268 failures at first attempt per 1000 children treated using supination-flexion, this amounted to 174 fewer failures per 1000 children treated using hyperpronation (95% CI 134 to 201 fewer). Based on risk differences data, we also estimated a number needed to treat of 6 (95% CI 5 to 8); this means that six children would need to be treated with the hyperpronation method rather than the supination-flexion method to avoid one additional failure at the first attempt.The very low-quality evidence (from four studies) for pain during or after manipulation means that it is uncertain whether there is or is not a difference between pronation and supination-flexion. There was very low-quality evidence from six studies that repeat pronation may be more effective than repeat supination-flexion for the second attempt after initial failure. The remaining outcomes were either not reported (adverse effects, recurrence) or unsuitable for pooling (ultimate failure). Ultimate failure, reported for the overall population only because of the differences in the study protocols with respect to what to do after the first attempt failed, ranged from no ultimate failures in two studies to six failures (4.1% of 148 episodes) in one study.One trial compared supination-extension versus supination-flexion. It provided very low-quality evidence (downgraded three levels for very serious risk of bias and serious imprecision) of no clear difference in failure at first attempt between the two methods.AUTHORS' CONCLUSIONS: There was low-quality evidence from eight small trials that the pronation method may be more effective at first attempt than the supination method for manipulating pulled elbow in young children. For other outcomes, no conclusions could be drawn either because of very low-quality evidence or the outcomes not being reported. We suggest that a high-quality randomised clinical trial comparing hyperpronation and supination-flexion is required to provide definitive evidence. We recommend that this is preceded by a survey among clinicians to establish the extent of clinical equipoise and to optimise the study design and recruitment." ]

[ "An operon is a set of neighboring genes in a genome that is transcribed as a single polycistronic message. Genes that are part of the same operon often have related functional roles or participate in the same metabolic pathways. The majority of all bacterial genes are co-transcribed with one or more other genes as part of a multi-gene operon. Thus, accurate identification of operons is important in understanding co-regulation of genes and their functional relationships. Here, we present a computational system that uses RNA-seq data to determine operons throughout a genome. The system takes the name of a genome and one or more files of RNA-seq data as input. Our method combines primary genomic sequence information with expression data from the RNA-seq files in a unified probabilistic model in order to identify operons. We assess our method's ability to accurately identify operons in a range of species through comparison to external databases of operons, both experimentally confirmed and computationally predicted, and through focused experiments that confirm new operons identified by our method. Our system is freely available at https://cs.wellesley.edu/~btjaden/Rockhopper/.", "Pancreatic cancer has a very high mortality rate and affects approximately 230,000 individuals worldwide. Gemcitabine has become established as the standard therapy for advanced pancreatic cancer; however, the survival advantage is small. Adjuvant chemotherapy using either 5-fluorouracil or gemcitabine is now established in pancreatic cancer as an alternative therapy. Combinations of gemcitabine with either platin agents or capecitabine may be advantageous. Anti-EGFR and anti-VEGF agents have been unsuccessful but multiple tyrosine kinase inhibitors are under investigation. Of the increasing number of immunological agents, the GV1001 antitelomerase vaccine holds some interest. Targeted agents against important mitogenic pathways, including MEK/ERK, Src, PI3K/Akt, mTOR, Hedgehog and NF-kappaB, as well as agents targeting histone deacetylase, poly(ADP-ribose) polymerase, heat shock protein 90 and other agents such as beta-lapachone, hold considerable interest for further development. However, the probability of individual success is low.", "Human karyopherin alpha2 (KPNA2), a member of the karyopherin alpha family, plays a key role in the nuclear import of proteins with a classical nuclear localization signal (NLS). KPNA2, as part of a karyopherin alpha-beta heterodimer, directly binds to the NLS of proteins and functions as an adaptor that binds NLS-containing proteins via karyopherin beta to the nuclear pore complex. The NLS protein-receptor complex is translocated through the pore by an energy-dependent mechanism. Recently, we have identified and mapped the gene for KPNA2 in close proximity to a translocation breakpoint within 17q23-q24 associated with Russell-Silver syndrome (RSS). Therefore, we considered KPNA2 as a positional candidate gene for this heterogeneous disorder. RSS is mainly characterized by pre- and postnatal growth retardation, lateral asymmetry, and other dysmorphic features. Here, we present the genomic organization of the human KPNA2 gene with 11 exons spanning approximately 10 kb on chromosome 17q23-q24. Screening for mutations within all exons and adjacent intronic sequences from 31 unrelated RSS patients revealed three single nucleotide polymorphisms (SNPs) in exons 1, 5, and 7, and five SNPs in introns 1, 4 (2 SNPs), 8, and 9, respectively. No disease-related mutation was identified by comparing the sequence data of the RSS patients with their clinically normal parents and controls.", "Poly(ADP-ribose)polymerase-1 (PARP1) is a chromatin-associated enzyme that was described to affect chromatin compaction. Previous reports suggested a dynamic modulation of the chromatin landscape during adipocyte differentiation. We thus hypothesized that PARP1 plays an important transcriptional role in adipogenesis and metabolism and therefore used adipocyte development and function as a model to elucidate the molecular action of PARP1 in obesity-related diseases. Our results show that PARP1-dependent ADP-ribose polymer (PAR) formation increases during adipocyte development and, at late time points of adipogenesis, is involved in the sustained expression of PPARγ2 and of PPARγ2 target genes. During adipogenesis, PARP1 was recruited to PPARγ2 target genes such as CD36 or aP2 in a PAR-dependent manner. Our results also reveal a PAR-dependent decrease in repressory histone marks (e.g. H3K9me3) and an increase in stimulatory marks (e.g. H3K4me3) at the PPARγ2 promoter, suggesting that PARP1 may exert its regulatory function during adipogenesis by altering histone marks. Interestingly, activation of PARP1 enzymatic activity was prevented with a topoisomerase II inhibitor. These data hint at topoisomerase II-dependent, transient, site-specific double-strand DNA breaks as the cause for poly(ADP)-ribose formation, adipogenic gene expression, and adipocyte function. Together, our study identifies PARP1 as a critical regulator of PPARγ2-dependent gene expression with implications in adipocyte function and obesity-related disease models.", "We report a woman with malignant meningioma diagnosed 9 years after the treatment of a choroidal melanoma with proton beam therapy. The risk of secondary cancers is a well-known adverse late effect of radiation therapy, especially with the use of advanced techniques such as intensity-modulated radiation therapy. However, this risk may be less with the use of proton beam therapy. A 79-year-old woman presented with symptoms of enophthalmos, ptosis and paralysis of the left medial rectus muscle. She had previously been successfully treated for a choroidal melanoma of the left eye with proton beam therapy (total dose: 60 cobalt gray equivalents) following local resection. MRI showed a lesion in the left cavernous sinus with extension into the orbit and a subsequent biopsy revealed a papillary meningioma. The cavernous tumor was treated with photon radiotherapy (total dose: 54Gy) which achieved an initial partial response. However, 8 months later the tumor extensively metastasized to the skull and the spine and the patient died 1 year after the treatment. The incidence of secondary malignancies after proton beam therapy is low but not negligible, therefore, it must be taken into account when planning a treatment as secondary tumors may present with a highly aggressive behaviour.", "INTRODUCTION. It has been shown that inflammation affects thyroid function. In patients with end-stage renal disease, low plasma triiodothyronine (T3) may be an unsuspected expression of the inflammatory state of these patients. This study evaluated the correlation between T3 and high-sensitivity C-reactive protein (HSCRP) levels in patients on peritoneal dialysis (PD) and hemodialysis. MATERIALS AND METHODS. This is a cross-sectional study aiming at the correlation between T3 and HSCRP levels among 30 patients on PD, 30 patients on hemodialysis, and 20 healthy individuals. Serum levels of HSCRP, T3, thyroxine (T4), thyroid stimulating hormone, T3 resin uptake, and free T3 index (FT3I) and free T4 index (FT4I) were compared between the three groups. RESULTS. There were no significant differences between hemodialysis and PD patients in respect to T3, T4, FT3I, and FT4I. In PD and hemodialysis patients, T3 and FT3I were lower than in controls (P < .001), but there was no significant difference between PD and hemodialysis patients. T3 resin uptake and thyroid stimulating hormone differed significantly between PD and hemodialysis patients. There was a significant inverse correlation between HSCRP and T3 and FT3I among hemodialysis patients (P = .04); however, there was no such correlations in PD patients. CONCLUSIONS. The relationship between T3 and HSCRP suggests that inflammation might be involved in the low T3 syndrome in hemodialysis patients, but we did not find a significant correlation between T3 and HSCRP levels in patients on peritoneal dialysis.", "The introduction of measles vaccination programs and broad coverage worldwide has meant this infection a rare encounter for pediatricians. In Oman, with almost 100% measles vaccination coverage for children, this infection disappeared from the list of fever and rash differential diagnoses. Encephalitis is a well-known complication of measles infection and sometimes can be the only manifestation especially in adults. We report a seven-year-old Syrian immigrant who was admitted to the Royal Hospital, Muscat, with acute encephalitis secondary to wild measles infection. Although she had a classical presentation of measle infection, the diagnosis was missed in the private and regional hospital she attended before getting referred to Royal Hospital. She was later identified to be exposed to an outbreak of the infection in an unvaccinated population. Magnetic resonance imaging showed high signal intensity of both basal ganglia suggestive of measles encephalitis. The diagnosis was confirmed by detection of measles virus from her urine and blood, and a throat swab. The isolated measles virus was D8 serotype, which was prevalent in Syria around the same time. The child was treated with steroids and vitamin A. She achieved full recovery despite her severe presentation. A high degree of suspicion for measles infection should be maintained in unvaccinated children with a compatible presentation of the infection or its complications. There might be a role for steroid use in cases of acute measles encephalitis.", "BACKGROUND: Recent studies have described a widespread induction of transcriptional readthrough as a consequence of various stress conditions in mammalian cells. This novel phenomenon, initially identified from analysis of RNA-seq data, suggests intriguing new levels of gene expression regulation. However, the mechanism underlying naturally occurring transcriptional readthrough, as well as its regulatory consequences, still remain elusive. Furthermore, the readthrough response to stress has thus far not been investigated outside of mammalian species, and the occurrence of readthrough in many physiological and disease conditions remains to be explored.RESULTS: To facilitate a wider investigation into transcriptional readthrough, we created the DoGFinder software package, for the streamlined identification and quantification of readthrough transcripts, also known as DoGs (Downstream of Gene-containing transcripts), from any RNA-seq dataset. Using DoGFinder, we explore the dependence of DoG discovery potential on RNA-seq library depth, and show that stress-induced readthrough induction discovery is robust to sequencing depth, and input parameter settings. We further demonstrate the use of the DoGFinder software package on a new publically available RNA-seq dataset, and discover DoG induction in human PME cells following hypoxia - a previously unknown readthrough inducing stress type.CONCLUSIONS: DoGFinder will enable users to explore, in a few simple steps, the readthrough phenomenon in any condition and organism. DoGFinder is freely available at https://github.com/shalgilab/DoGFinder .", "Author information:(1)Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA.(2)Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA; College of Veterinary Medicine, Aristotle University, Thessaloniki, Greece.(3)Neurobiology of Social Behavior Laboratory, Department of Psychology, Boston College, Chestnut Hill, MA, USA.(4)Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA; Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.(5)University of Massachusetts Medical School and Memorial Medical Center, Worcester, MA, USA.(6)College of Veterinary Medicine, Aristotle University, Thessaloniki, Greece.(7)Clinical Research Center, Institute for Medical Engineering & Science, Massachusetts Institute or Technology, Cambridge, MA, USA.(8)Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Civil and Environmental Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.(9)Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: serdman@mit.edu.", "Vertebrates have four clusters of Hox genes (HoxA, HoxB, HoxC, and HoxD). A variety of expression and mutation studies indicate that posterior members of the HoxA and HoxD clusters play an important role in vertebrate limb development. In humans, mutations in HOXD13 have been associated with type II syndactyly or synpolydactyly, and, in HOXA13, with hand-foot-genital syndrome. We have investigated two unrelated children with a previously unreported pattern of severe developmental defects on the anterior-posterior (a-p) limb axis and in the genitalia, consisting of a single bone in the zeugopod, either monodactyly or oligodactyly in the autopod of all four limbs, and penoscrotal hypoplasia. Both children are heterozygous for a deletion that eliminates at least eight (HOXD3-HOXD13) of the nine genes in the HOXD cluster. We propose that the patients' phenotypes are due in part to haploinsufficiency for HOXD-cluster genes. This hypothesis is supported by the expression patterns of these genes in early vertebrate embryos. However, the involvement of additional genes in the region could explain the discordance, in severity, between these human phenotypes and the milder, non-polarized phenotypes present in mice hemizygous for HoxD cluster genes. These cases represent the first reported examples of deficiencies for an entire Hox cluster in vertebrates and suggest that the diploid dose of human HOXD genes is crucial for normal growth and patterning of the limbs along the anterior-posterior axis.", "This study reports on molecular analysis of a Measles virus (MV) isolate from a patient who was infected in Japan but showed symptoms after arriving to Brazil. This patient had typical clinical measles infection symptoms: fever, rash, cough and coryza. After isolating the virus in B95a cells, a fragment of the nucleoprotein (N) gene was amplified by reverse transcription-polymerase chain reaction (RT-PCR) and subjected to direct nucleotide sequencing. The sequence data showed that the MV isolate of concern is of the D5 genotype.", "BACKGROUND: Epigenetic regulation such as aberrant hypermethylation of CpG islands in promoter plays a key role in tumorigenesis. 5-Aza-2'-deoxycytidine (5-aza-CdR) which is a potent inhibitor of DNA methylation can reverse the abnormal hypermethylation of the silenced tumor suppressor genes (TSGs). It has been reported that hepatocyte cell adhesion molecule (hepaCAM) acts as a tumor suppressor gene and expression of its mRNA and protein were down-regulated in bladder cancer. Over-expression of hepaCAM can inhibit cancer growth and arrest renal cancer cells at G0/G1 phase. In this study, we investigated the methylation status of hepaCAM gene, as well as the influence of 5-aza-CdR on expression of hepaCAM gene in bladder cancer cells.METHODS: CpG islands in hepaCAM promoter and methprimers were predicted and designed using bioinformatics program. Methylation status of hepaCAM promoter was evaluated in bladder cancer tissues and two cell lines (T24 and BIU-87) by Methylation-specific PCR; Western blot and Immunofluorescence were used to detect expression of hepaCAM protein after 5-aza-CdR treatment; Flow cytometry assay was performed to determine effectiveness of 5-aza-CdR on cell cycle profile.RESULTS: CpG island in promoter of hepaCAM gene was hyper-methylated both in bladder carcinoma tissues and cell lines (T24 and BIU-87). Otherwise, aberrant methylation of its promoter was associated with its decreased expression. Hypermethylation of hepaCAM gene was reversed and expression of its mRNA and protein were re-activated in two cell lines by DNA methyltransferases inhibitor 5-aza-CdR. Flow cytometry assay demonstrated that 5-aza-CdR can inhibit growth of cancer cells by arresting cancer cells at G0/G1 phase.CONCLUSION: Abnormal hypermethylation in CpG island of hepaCAM promoter is involved in absence of hepaCAM gene expression when bladder cancer occurs. Re-activation of hepaCAM gene by 5-aza-CdR can inhibit growth of cancer cells and arrest cells at G0/G1 phase.", "Ibalizumab (formerly TNX-355) is a humanized monoclonal antibody that binds CD4, the primary receptor for human immunodeficiency virus type 1 (HIV-1), and inhibits the viral entry process. A phase lb multidose study of the safety, pharmacokinetics, and antiviral activity of ibalizumab was conducted with 22 HIV-1-infected patients. Nineteen patients were randomized to receive either 10 mg/kg of body weight weekly (arm A) or a 10-mg/kg loading dose followed by 6 mg/kg every 2 weeks (arm B) intravenously for 9 weeks. Three patients were assigned to receive 25 mg/kg every 2 weeks for five doses (arm C). During the study, the patients remained off other antiretrovirals or continued a stable failing regimen. Treatment with ibalizumab resulted in substantial reductions in HIV-1 RNA levels (0.5 to 1.7 log(10)) in 20 of 22 subjects. In most patients, HIV-1 RNA fell to nadir levels after 1 to 2 weeks of treatment and then returned to baseline despite continued treatment. Baseline viral isolates were susceptible to ibalizumab in vitro, regardless of coreceptor tropism. Emerging resistance to ibalizumab was manifested by reduced maximal percent inhibition in a single-cycle HIV infectivity assay. Resistant isolates remained CD4 dependent and were susceptible to enfuvirtide in vitro. Complete coating of CD4(+) T-cell receptors was correlated with serum ibalizumab concentrations. There was no evidence of CD4(+) T-cell depletion in ibalizumab-treated patients. Ibalizumab was not immunogenic, and no serious drug-related adverse effects occurred. In conclusion, ibalizumab administered either weekly or biweekly was safe and well tolerated and demonstrated antiviral activity. Further studies with ibalizumab in combination with standard antiretroviral treatments are warranted.", "BACKGROUND: In April 2015, Kamwenge District, western Uganda reported a measles outbreak. We investigated the outbreak to identify potential exposures that facilitated measles transmission, assess vaccine effectiveness (VE) and vaccination coverage (VC), and recommend prevention and control measures.METHODS: For this investigation, a probable case was defined as onset of fever and generalized maculopapular rash, plus ≥1 of the following symptoms: Coryza, conjunctivitis, or cough. A confirmed case was defined as a probable case plus identification of measles-specific IgM in serum. For case-finding, we reviewed patients' medical records and conducted in-home patient examination. In a case-control study, we compared exposures of case-patients and controls matched by age and village of residence. For children aged 9 m-5y, we estimated VC using the percent of children among the controls who had been vaccinated against measles, and calculated VE using the formula, VE = 1 - ORM-H, where ORM-H was the Mantel-Haenszel odds ratio associated with having a measles vaccination history.RESULTS: We identified 213 probable cases with onset between April and August, 2015. Of 23 blood specimens collected, 78% were positive for measles-specific IgM. Measles attack rate was highest in the youngest age-group, 0-5y (13/10,000), and decreased as age increased. The epidemic curve indicated sustained propagation in the community. Of the 50 case-patients and 200 controls, 42% of case-patients and 12% of controls visited health centers during their likely exposure period (ORM-H = 6.1; 95% CI = 2.7-14). Among children aged 9 m-5y, VE was estimated at 70% (95% CI: 24-88%), and VC at 75% (95% CI: 67-83%). Excessive crowding was observed at all health centers; no patient triage-system existed.CONCLUSIONS: The spread of measles during this outbreak was facilitated by patient mixing at crowded health centers, suboptimal VE and inadequate VC. We recommended emergency immunization campaign targeting children <5y in the affected sub-counties, as well as triaging and isolation of febrile or rash patients visiting health centers.", "Measles is a highly contagious viral infection associated with clinical symptoms such as fever, cough, conjunctivitis, coryza, eruption and increased serum immunoglobulin M (IgM) antibodies. A clinical diagnosis is easily established when the chain of infection can be followed. However, Japan is currently experiencing sporadic measles outbreaks, which complicate the establishment of diagnosis. Furthermore, other exanthematous infections such as rubella, human parvovirus B19, human herpesvirus 6 (HHV-6) and HHV-7 present with clinical symptoms and IgM antibody levels similar to those in measles. Therefore, real-time polymerase chain reaction virogene testing has been part of Japan's standard diagnostic protocol for measles since 2010. This report presents two pediatric cases clinically resembling measles that were diagnosed as HHV-6 based on a virogene detection test. This underscores the importance of performing pathogen testing to confirm a diagnosis when measles is suspected.", "FBW7 (F-box and WD repeat domain-containing 7) is the substrate recognition component of an evolutionary conserved SCF (complex of SKP1, CUL1 and F-box protein)-type ubiquitin ligase. SCF(FBW7) degrades several proto-oncogenes that function in cellular growth and division pathways, including MYC, cyclin E, Notch and JUN. FBW7 is also a tumour suppressor, the regulatory network of which is perturbed in many human malignancies. Numerous cancer-associated mutations in FBW7 and its substrates have been identified, and loss of FBW7 function causes chromosomal instability and tumorigenesis. This Review focuses on structural and functional aspects of FBW7 and its role in the development of cancer." ]

[ "Author information:(1)McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland.(2)The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.(3)Centre for Computational Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.(4)Department of Pediatrics, University of Washington, Seattle, Washington.(5)Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, United Kingdom.(6)FS Consulting LLC, Seattle, Washington.(7)Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.(8)St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales, Australia.(9)William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.(10)Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon.(11)Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.(12)McKusick-Nathans Institute of Genetic Medicine (IGM), Clinical Director, IGM. Scientific Director, OMIM. Johns Hopkins University. Baltimore, Maryland.", "AIM: Favipiravir and oseltamivir are antiviral compounds used for the treatment of influenza infections. We have aimed to investigate the efficacy of the compounds in combination to treat influenza H1N1 virus infections in mice.MATERIALS & METHODS: Mice infected with pandemic influenza A/California/04/2009 (H1N1pdm) virus or an oseltamivir-resistant (H275Y neuraminidase mutation) influenza A/Mississippi/ 3/2001 (H1N1) virus were treated orally with inhibitors twice a day for 5 days starting 4 h after infection.RESULTS: Complete protection from death was afforded by favipiravir treatments of 100 mg/kg/day, but lower doses were less effective. Combinations of oseltamivir (1 and 3 mg/kg/day) with favipiravir (3, 10 and 30 mg/kg/day) resulted in a synergistic improvement in survival rates against H1N1pdm infections. Significant reductions in lung virus titers also occurred. Against the H275Y virus infection, oseltamivir alone was only 30% protective from death at 100 mg/kg/day, but combinations of the two compounds produced a synergistic improvement in survival rate.CONCLUSION: The utility of treating H1N1 influenza virus infections with oseltamivir and favipiravir in combination has been established.", "Amblyopia is the most common cause of monocular visual impairment in children, with a prevalence of 2-3%. Not only is visual acuity reduced in one eye but binocular vision is affected, fellow eye deficits may be present, eye-hand coordination and reading can be affected, and self-perception may be diminished. New technologies for preschool vision screening hold promise for accessible, early, and accurate detection of amblyopia. Together with recent advances in our theoretical understanding of amblyopia and technological advances in amblyopia treatment, we anticipate improved visual outcomes for children affected by this very common eye condition. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.", "BACKGROUND: A recent multicenter prospective Canadian study presented prospective evidence supporting the Low Risk Ankle Rules (LRAR) as a means of reducing the number of ankle radiographs ordered for children presenting with an ankle injury while maintaining nearly 100% sensitivity. This is in contrast to a previous prospective study which showed that this rule yielded only 87% sensitivity.OBJECTIVE: It is important to further investigate the LRAR and compare them with the already validated Ottawa Ankle Rules (OAR) to potentially curb healthcare costs and decrease unnecessary radiation exposure without compromising diagnostic accuracy.METHODS: We conducted a retrospective chart review of 980 qualifying patients ages 12months to 18years presenting with ankle injury to a commonly staffed 310 bed children's hospital and auxiliary site pediatric emergency department.RESULTS: There were 28 high-risk fractures identified. The Ottawa Ankle Rules had a sensitivity of 100% (95% CI 87.7-100), specificity of 33.1% (95% CI 30.1-36.2), and would have reduced the number of ankle radiographs ordered by 32.1%. The Low Risk Ankle Rules had a sensitivity of 85.7% (95% CI 85.7-96), specificity of 64.9% (95% CI 61.8-68), and would have reduced the number of ankle radiographs ordered by 63.1%. The latter rule missed 4 high-risk fractures.CONCLUSION: The Low Risk Ankle Rules may not be sensitive enough for use in Pediatric Emergency Departments, while the Ottawa Ankle Rules again demonstrated 100% sensitivity. Further research on ways to implement the Ottawa Ankle Rules and maximize its ability to decrease wait times, healthcare costs, and improve patient satisfaction are needed.", "We report the discovery of conopressin-T, a novel bioactive peptide isolated from Conus tulipa venom. Conopressin-T belongs to the vasopressin-like peptide family and displays high sequence homology to the mammalian hormone oxytocin (OT) and to vasotocin, the endogenous vasopressin analogue found in teleost fish, the cone snail's prey. Conopressin-T was found to act as a selective antagonist at the human V 1a receptor. All peptides in this family contain two conserved amino acids within the exocyclic tripeptide (Pro7 and Gly9), which are replaced with Leu7 and Val9 in conopressin-T. Whereas conopressin-T binds only to OT and V 1a receptors, an L7P analogue had increased affinity for the V 1a receptor and weak V2 receptor binding. Surprisingly, replacing Gly9 with Val9 in OT and vasopressin revealed that this position can function as an agonist/antagonist switch at the V 1a receptor. NMR structures of both conopressin-T and L7P analogue revealed a marked difference in the orientation of the exocyclic tripeptide that may serve as templates for the design of novel ligands with enhanced affinity for the V 1a receptor.", "OBJECTIVE: Chronically elevated free fatty acids contribute to insulin resistance and pancreatic β-cell failure. Among numerous potential factors, the involvement of endoplasmic reticulum (ER) stress has been postulated to play a mechanistic role. Here we examined the efficacy of the chemical chaperone, sodium phenylbutyrate (PBA), a drug with known capacity to reduce ER stress in animal models and in vitro, on lipid-induced insulin resistance and β-cell dysfunction in humans.RESEARCH DESIGN AND METHODS: Eight overweight or obese nondiabetic men underwent four studies each, in random order, 4 to 6 weeks apart. Two studies were preceded by 2 weeks of oral PBA (7.5 g/day), followed by a 48-h i.v. infusion of intralipid/heparin or saline, and two studies were preceded by placebo treatment, followed by similar infusions. Insulin secretion rates (ISRs) and sensitivity (S(I)) were assessed after the 48-h infusions by hyperglycemic and hyperinsulinemic-euglycemic clamps, respectively.RESULTS: Lipid infusion reduced S(I), which was significantly ameliorated by pretreatment with PBA. Absolute ISR was not affected by any treatment; however, PBA partially ameliorated the lipid-induced reduction in the disposition index (DI = ISR × S(I)), indicating that PBA prevented lipid-induced β-cell dysfunction.CONCLUSIONS: These results suggest that PBA may provide benefits in humans by ameliorating the insulin resistance and β-cell dysfunction induced by prolonged elevation of free fatty acids.", "The cysteinyl aspartate-specific proteases (caspases) have been identified as key players in the cellular process termed programmed cell death or apoptosis. During apoptosis, activated apoptotic caspases cleave selected target proteins to execute cell death. Additionally to their established function in cell death, a variety of recent publications have provided increasing evidence that apoptotic caspases also participate in several non-apoptotic cellular processes. Activated caspases exhibit functions during T-cell proliferation and cell cycle regulation, but are also involved in the differentiation of a diverse array of cell types. In some cell types, their differentiation can be morphologically viewed as a kind of incomplete apoptosis. Analysis of well-known apoptotic targets of caspases implicates that the cleavage of a limited number of selected substrates plays a major role during non-apoptotic functions of caspases. Selective substrate cleavage might be regulated by activation of anti-apoptotic factors, via a compartmentalized activation of caspases, or through limited activity of caspases during apoptosis-independent functions. The increasing evidence for caspase function in non-apoptotic cellular events suggests that caspases play a much more diverse role than previously assumed." ]

[ "West Nile virus (WNV) is a zoonotic arthropod-borne pathogen with continued geographical expansion in Europe. We present and evaluate data on the temporal, spatial and bird species focus of the WNV surveillance programme in dead wild birds in Great Britain (2002-2009). During this period all bird samples tested negative for WNV. Eighty-two per cent of the 2072 submissions occurred during the peak period of vector activity with 53% tested during April-July before human and equine infection would be expected. Samples were received from every county, but there was significant geographical clustering (nearest neighbour index=0·23, P<0·001). Over 240 species were represented, with surveillance more likely to detect WNV in resident bird species (92% of submissions) than migrants (8%). Evidence indicates that widespread avian mortality is not generally a reported feature of WNV in Europe and hence additional activities other than dead bird surveillance may maximize the ability to detect WNV circulation before the onset of human and equine infections.", "Altered cell motility is considered to be a key factor in determining tumor invasion and metastasis. Epidermal growth factor (EGF) signaling has been implicated in this process by affecting cytoskeletal organization and dynamics in multiple ways. To sort the temporal and spatial regulation of EGF-dependent cytoskeletal re-organization in relation to a cell's motile behavior time-lapse microscopy was performed on EGF-responsive gastric carcinoma-derived MKN1 cells co-expressing different fluorescently labeled cytoskeletal filaments and focal adhesion components in various combinations. The experiments showed that EGF almost instantaneously induces a considerable increase in membrane ruffling and lamellipodial activity that can be inhibited by Cetuximab EGF receptor antibodies and is not elicited in non-responsive gastric carcinoma Hs746T cells. The transient cell extensions are rich in actin but lack microtubules and keratin intermediate filaments. We show that this EGF-induced increase in membrane motility can be measured by a simple image processing routine. Microtubule plus-ends subsequently invade growing cell extensions, which start to accumulate focal complexes at the lamellipodium-lamellum junction. Such paxillin-positive complexes mature into focal adhesions by tyrosine phosphorylation and recruitment of zyxin. These adhesions then serve as nucleation sites for keratin filaments which are used to enlarge the neighboring peripheral keratin network. Focal adhesions are either disassembled or give rise to stable zyxin-rich fibrillar adhesions which disassemble in the presence of EGF to support formation of new focal adhesion sites in the cell periphery. Taken together the results serve as a basis for modeling the early cytoskeletal EGF response as a tightly coordinated and step-wise process which is relevant for the prediction of the effectiveness of anti-EGF receptor-based tumor therapy.", "INTRODUCTION: Immune therapies have dramatically changed the treatment landscape for melanoma in the past decade. Ipilimumab, nivolumab, and pembrolizumab have been approved by U.S. Food and Drug Administration for the treatment of metastatic melanoma sequentially. Toripalimab, a humanized IgG4 monoclonal antibody against programmed cell death protein-1 (PD-1), was approved by National Medical Product Administration in China in 2018 as second-line therapy for metastatic melanoma.AREAS COVERED: This is a comprehensive review of the literature and studies of toripalimab in melanoma, including clinical trials and translational research.EXPERT OPINION: Toripalimab is not inferior to pembrolizumab as a second-line therapy for metastatic melanoma. Prospective validated predictive markers are lacking. Programmed cell death ligand 1 expression and tumor mutational burden are two common recognized biomarkers, but the predictability of these markers requires additional improvement. A number of studies have confirmed that PD-1 inhibitors, including toripalimab, are not as effective in mucosal and acral melanomas as in non-acral cutaneous subtype. Toripalimab in combination with tyrosine kinase inhibitor axitinib has shown a promising result for metastatic mucosal melanoma. It is crucial to explore the mechanisms underlying the varying biological behavior of melanoma subtypes, which may also provide clues of innate and acquired resistance to PD-1 blockade.", "The objective of this phase II single-arm study was to evaluate the efficacy and safety of pazopanib, a multi-targeted tyrosine kinase inhibitor, against vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, platelet-derived growth factor receptor-alpha and -beta, and c-Kit, in recurrent glioblastoma. Patients with < or =2 relapses and no prior anti-VEGF/VEGFR therapy were treated with pazopanib 800 mg daily on 4-week cycles without planned interruptions. Brain magnetic resonance imaging and clinical reassessment were made every 8 weeks. The primary endpoint was efficacy as measured by 6-month progression-free survival (PFS6). Thirty-five GBM patients with a median age of 53 years and median Karnofsky performance scale of 90 were accrued. Grade 3/4 toxicities included leukopenia (n = 1), lymphopenia (n = 2), thrombocytopenia (n = 1), ALT elevation (n = 3), AST elevation (n = 1), CNS hemorrhage (n = 1), fatigue (n = 1), and thrombotic/embolic events (n = 3); 8 patients required dose reduction. Two patients had a partial radiographic response by standard bidimensional measurements, whereas 9 patients (6 at the 8-week point and 3 only within the first month of treatment) had decreased contrast enhancement, vasogenic edema, and mass effect but <50% reduction in tumor. The median PFS was 12 weeks (95% confidence interval [CI]: 8-14 weeks) and only 1 patient had a PFS time > or =6 months (PFS6 = 3%). Thirty patients (86%) had died and median survival was 35 weeks (95% CI: 24-47 weeks). Pazopanib was reasonably well tolerated with a spectrum of toxicities similar to other anti-VEGF/VEGFR agents. Single-agent pazopanib did not prolong PFS in this patient population but showed in situ biological activity as demonstrated by radiographic responses. ClinicalTrials.gov identifier: NCT00459381.", "Multiple novel therapeutic agents against acute myeloid leukemia (AML) have been evaluated in the past several decades without meaningful clinical improvement in outcomes, especially for AML patients age ≥60, where the overall incidence of AML is highest. Therapeutic options mainly consist of hypomethylating agents, ongoing clinical trials and, less commonly, intensive cytotoxic chemotherapy. CPX-351, a novel liposomal formulation which encapsulates cytarabine and daunorubicin in 5:1 molar ratio, has shown promising efficacy, leading to recent US FDA approval for front-line therapy for patients with therapy-related AML and AML with myelodysplasia-related changes based on a large multicenter Phase III clinical trial. This review summarizes the clinical development of CPX-351 as induction therapy.", "Recent reports have described a distinct and recurrent pattern of systemic malformation that associates craniosynostosis and neurodevelopmental abnormalities with many clinical features of the Marfan syndrome (MFS), an autosomal dominant disorder of the extracellular microfibril caused by defects in the gene encoding fibrillin-1, FBN1 (ref. 8). Additional common findings include other craniofacial anomalies, hypotonia, obstructive apnea, foot deformity, and congenital weakness of the abdominal wall. So far, only 11 cases have been reported precluding the assignment of definitive diagnostic criteria. While it remains unclear whether these cases represent a discrete clinical entity with a single aetiology, they have been pragmatically grouped under the rubric Marfanoid-craniosynostosis or Shprintzen-Goldberg syndrome (SGS). Because of the significant clinical overlap between MFS and SGS, we proposed that they may be caused by allelic mutations. We now report two SGS patients who harbour mutations in FBN1. While it remains unclear whether these mutations are sufficient for the clinical expression of the entire SGS phenotype, these data suggest a role for fibrillin-1 in early craniofacial and central nervous system development. Our recent observation that FBN1 transcript is expressed as early as the 8-cell stage of human embryogenesis is consistent with this hypothesis.", "OBJECTIVES: Single-size vials of drugs may be a source of waste and increase in treatment costs. Bortezomib, indicated for multiple myeloma (MM) treatment, is available in 3.5-mg vials, a quantity higher than the average dose commonly prescribed. This analysis aimed to demonstrate, through real-world data, which would be the optimal vial presentation for bortezomib in Brazil and quantify the reduction in medication waste related to this option.METHODS: From November 2007 to October 2009 all patients with MM treated with bortezomib were identified via the Evidências database. Analysis of prescribed, dispensed, and wasted doses, their costs and projections of the ideal vial size were performed.RESULTS: Thirty-five patients (mean body surface area of 1.73 m(2)) received 509 infusions in 131 cycles of treatment (average of 3.77 cycles per patient). The average dose prescribed was 2.1 mg per infusion (95% confidence interval [CI] 1.97-2.26) with average waste of 39.5% of the vial content (95% CI 35.35-43.76). The mean waste per patient per day was 1.38 mg (95% CI 1.24-1.52). If a 3-mg vial were available, the average drug waste per patient per day would be 0.88 mg (95% CI 0.74-1.03) or 36.2% less. With a 2.5-mg vial the waste would be 1.05 mg (95% CI 0.81-1.29) or 23.9% less. If two presentations were available (2.5 mg and 0.5 mg), the waste would be 0.52 mg (95% CI 0.4-0.63) or 62.5% less. Considering the price of the different vials to be proportional to the original 3.5-mg vial, the cost would be also reduced by the same rates described above.CONCLUSIONS: A simple adjustment in vial size may reduce the waste of bortezomib by 36% to 62% and can also reduce the cost of treatment.", "PURPOSE: Increased mitogenic signaling and angiogenesis, frequently facilitated by somatic activation of EGF receptor (EGFR; ErbB1) and/or loss of PTEN, and VEGF overexpression, respectively, drive malignant glioma growth. We hypothesized that patients with recurrent glioblastoma would exhibit differential antitumor benefit based on tumor PTEN/EGFRvIII status when treated with the antiangiogenic agent pazopanib and the ErbB inhibitor lapatinib.EXPERIMENTAL DESIGN: A phase II study evaluated the antitumor activity of pazopanib 400 mg/d plus lapatinib 1,000 mg/d in patients with grade 4 malignant glioma and known PTEN/EGFRvIII status not receiving enzyme-inducing anticonvulsants (EIAC). The phase II study used a two-stage Green-Dahlberg design for futility. An independent, parallel phase I component determined the maximum-tolerated regimen (MTR) of pazopanib and lapatinib in patients with grade 3/4 glioma receiving EIACs.RESULTS: The six-month progression-free survival (PFS) rates in phase II (n = 41) were 0% and 15% in the PTEN/EGFRvIII-positive and PTEN/EGFRvIII-negative cohorts, respectively, leading to early termination. Two patients (5%) had a partial response and 14 patients (34%) had stable disease lasting 8 or more weeks. In phase I (n = 34), the MTR was not reached. On the basis of pharmacokinetic and safety review, a regimen of pazopanib 600 mg plus lapatinib 1,000 mg, each twice daily, was considered safe. Concomitant EIACs reduced exposure to pazopanib and lapatinib.CONCLUSIONS: The antitumor activity of this combination at the phase II dose tested was limited. Pharmacokinetic data indicated that exposure to lapatinib was subtherapeutic in the phase II evaluation. Evaluation of intratumoral drug delivery and activity may be essential for hypothesis-testing trials with targeted agents in malignant glioma." ]

[ "We previously estimated that 42% of patients with severe developmental disorders carry pathogenic de novo mutations in coding sequences. The role of de novo mutations in regulatory elements affecting genes associated with developmental disorders, or other genes, has been essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 patients with developmental disorders. Here we show that de novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant twofold enrichment of recurrently mutated elements. We estimate that, genome-wide, 1-3% of patients without a diagnostic coding variant carry pathogenic de novo mutations in fetal brain-active regulatory elements and that only 0.15% of all possible mutations within highly conserved fetal brain-active elements cause neurodevelopmental disorders with a dominant mechanism. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasize the importance of combining functional and evolutionary evidence to identify regulatory causes of genetic disorders.", "Mammalian dosage compensation requires silencing of one of the two X chromosomes in females and is controlled by the X inactivation center (Xic). Xic contains many of the regulatory elements for the mutual interplay of X-inactive specific transcript (Xist) and Tsix, the antisense counterpart of Xist. The regulatory elements control X chromosome inactivation (XCI) via the formation of DNA-DNA and DNA-protein complexes with cis- and trans-acting factors. However, the process-dependent regulation of Xist/Tsix by these elements in each XCI process remains largely unknown. In this study, a 6-thioguanine-resistant female F(1) hybrid mouse cell line (designated HOBMSKI2) was constructed from a cross between a female HPRT-deficient transgenic mouse (designated BM3) and a male wild type Mus spretus mouse (designated MS), which enabled the direct discrimination of both allele-specific expression of X-linked genes and allele-specific binding of proteins associated with XCI due to DNA polymorphisms between BM3 and MS. Using this cell line, we found that Tsix on the active X chromosome (Xa) was not expressed in somatic cells despite the fact that CTCF, which ensures Tsix expression in embryonic stem cells, was still bound to the 5' end of Tsix on Xa, implying that CTCF may function differently during each XCI process and its trans-activating activity for Tsix expression may be lost in the maintenance process. In addition, the monoallelic expression of Tsix on Xa was inhibited by epigenetic modification of the chromatin in the maintenance process, which was mediated by protein complexes recruited by MeCP2. The results indicate the value of HOBMSKI2 in directly detecting the allele-specific binding of CTCF and MeCP2 to the 5' end of Tsix. The HOBMSKI2 mouse line is a versatile and useful resource for studying the molecular mechanism of the XCI process.", "Compliance and patience is needed when meeting patients with personality disorder To encounter patients with personality disorders in health care settings is often challenging. Most treatment studies published have included only patients with borderline personality disorder. Of evaluated psychological treatments in borderline personality disorder, dialectical behaviour therapy (DBT) has the strongest research support, followed by mentalization based therapy (MBT). Pharmacological treatment in personality disorders should focus on time-limited crisis intervention and treatment of comorbidity. There are few studies on inpatient care of persons with personality disorder. However, there are some interesting projects on brief self-directed inpatient stays as crisis intervention. There is a consensus to avoid long inpatient stays and coercive measures as far as possible.", "Author information:(1)LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Wöhrendamm 80, 22927 Grosshansdorf, Germany. Electronic address: m.reck@lungenclinic.de.(2)Centrul de Oncologie Sf Nectarie, 23A Caracal St, Craiova, 200347, Romania. Electronic address: mike_schenker@yahoo.com.(3)Chungbuk National University Hospital, 776, 1 Sunhwan-ro, Seowon-gu, Cheongju-si, Chungcheonbuk-do, 28644, South Korea. Electronic address: kihlee@chungbuk.ac.kr.(4)Universidad Autónoma de Madrid, Instituto de Investigación Puerta de Hierro, Hospital Puerta de Hierro de Majadahonda, C / Manuel de Falla 1, Madrid, Majadahonda, 28222, Spain. Electronic address: mprovenciop@gmail.com.(5)The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Tokyo, Koto-ku, 135-8550, Japan. Electronic address: mnishio@jfcr.or.jp.(6)Oddzial Onkologii Radioterapii Szpital/Gdansk Medical University, UI. Powstania Styczniowego 1, Gdynia, 81-519, Poland. Electronic address: krzychu03@hotmail.com.(7)Cross Cancer Institute, 11560 University Ave, Edmonton, Alberta, T6G 1Z2, Canada. Electronic address: randeep.sangha@albertahealthservices.ca.(8)University Hospitals of Leicester NHS Trust, Department of Infection, Leicester, Leicestershire, LE1 5WW, UK. Electronic address: samreen.ahmed@uhl-tr.nhs.uk.(9)Institut de Cancérologie de l'Ouest, Centre Rene Gauducheau, Boulevard Jacques Monod, 44805 Nantes-Saint Herblain Cedex, France. Electronic address: judith.raimbourg@ico.unicancer.fr.(10)Notre Dame University and Edith Cowan University, 100 Murdoch Drive, Murdoch, Perth, Western Australia, 6150, Australia. Electronic address: kynan@oncowest.com.au.(11)CHU de Rennes, 2 Rue Henri le Guilloux, Rennes, 35033, France. Electronic address: romain.corre@chu-rennes.fr.(12)CACON, Hospital de Caridade de Ijuí, Av David Jose Martins, Centro, Ijuí, Rio Grande do Sul, 98700-000, Brazil. Electronic address: ff.oncosite@gmail.com.(13)IONC - Universidad Católica de Córdoba, Parana 560. 2 Piso, Cordoba, 5000, Argentina. Electronic address: eduardorichardet@gmail.com.(14)Bristol-Myers Squibb, 3401 Princeton Pike, Lawrenceville, NJ, 08648, USA. Electronic address: john.penrod@bms.com.(15)Bristol-Myers Squibb, 3401 Princeton Pike, Lawrenceville, NJ, 08648, USA. Electronic address: yong.yuan@bms.com.(16)Bristol-Myers Squibb, 3401 Princeton Pike, Lawrenceville, NJ, 08648, USA. Electronic address: faith.nathan@bms.com.(17)Bristol-Myers Squibb, 3401 Princeton Pike, Lawrenceville, NJ, 08648, USA. Electronic address: prabhu.bhagavatheeswaran@bms.com.(18)Adelphi Values, 290 Congress Street 7th Floor, Boston, MA, 02210, USA. Electronic address: michael.derosa@adelphivalues.com.(19)Adelphi Values, 290 Congress Street 7th Floor, Boston, MA, 02210, USA. Electronic address: fiona.taylor@adelphivalues.com.(20)Adelphi Values, Adelphi Mill, Grimshaw Ln, Bollington, Cheshire, SK10 5JB, UK. Electronic address: rachael.lawrance@adelphivalues.com.(21)Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans St, CRB1-G94, Baltimore, MD, 21287, USA. Electronic address: brahmju@jhmi.edu.", "The global area for Plasmodium ovale is small as compared with that for other species of human malaria pathogens. It has expanded in Asian areas and remained as before in the African ones. In the past 20 years, there have been 2129 malaria cases imported from far abroad to Russia, including 84 (4%) cases of vivax malaria (P. ovale). The patients were most foreign citizens: 70 from 20 African countries and 7 from two countries of Oceania, such as Papua New Guinea and Indonesia. The other 7 patients were Russia's people who had returned from different countries of Africa. For this period there have been a total of 5 cases of mixed infection: tropical P. falciparum malaria + vivax P. ovale malaria. The mission of detected new sympatric subspecies (P. ovale curtisi and P. ovale wallikeri) inhabiting the tropical countries with continuous local transmission remains unclear. Only a thorough study of these subspecies will be able to effectively apply preventive measures and to carry out their elimination in future.", "A 37-year-old woman was diagnosed with chronic phase chronic myeloid leukemia. Nilotinib treatment was initiated; however, it had to be discontinued due to an allergic reaction one month later, and dasatinib treatment was provided. Although favorable response was obtained, she started complaining of shortness of breath 7 months after initiating dasatinib treatment. Chest X-ray and echocardiography indicated pulmonary congestion and hypertension. Further, she was diagnosed with mixed connective tissue disease (MCTD) based on Raynaud phenomenon, swollen fingers, sclerodactyly, pancytopenia, hypocomplementemia, and positive anti-U1-RNP antibody. Consequently, dasatinib treatment was discontinued, and she was administered prednisolone (1 mg/kg/day), which was effective and successfully tapered with concomitant administration of cyclophosphamide. This is the first case of MCTD that developed during dasatinib treatment. However, because the present case was a young woman, the development of MCTD could probably be attributed to autoimmune diatheses or it may be a coincidence. However, the possibility of patients receiving dasatinib treatment developing autoimmune diseases needs to be assessed.", "The activity of the p53 tumor suppressor protein and the c-Jun protooncogene is regulated by posttranslational modifications, such as phosphorylation or ubiquitination. In addition, covalent attachment of the ubiquitin-like modifier SUMO appears to modulate their transcriptional activity. Sumoylation proceeds via an enzymatic pathway that is mechanistically analogous to ubiquitination, but requires a different E1-activating enzyme and Ubc9, a SUMO-specific E2-conjugating enzyme. Here, we show that two members of the PIAS family, PIAS1 and PIASxbeta, act as specific E3-like ligases that promote sumoylation of p53 and c-Jun in vitro and in vivo. The PIAS proteins physically interact with both p53 and c-Jun. In addition, they bind to Ubc9, suggesting that they recruit the E2 enzyme to their respective substrate. The SUMO ligase activity requires the conserved zinc-finger domain, which is distantly related to the essential RING-finger motif, found in a subset of ubiquitin ligases. Furthermore, similar to RING-type ubiquitin ligases, PIASxbeta can catalyze its own modification. Hence, these data further extend the analogy between the ubiquitin and SUMO pathway. Strikingly, PIAS proteins strongly repress the transcriptional activity of p53, suggesting that the PIAS-SUMO pathway plays a crucial role in the regulation of p53 and presumably other transcription factors." ]

[ "Several lines of evidence suggest a major role of calcitonin gene-related peptide (CGRP) in the pathogenesis of migraine and other primary headaches. Inhibition of CGRP receptors by olcegepant and telcagepant has been successfully used to treat acute migraine and to reduce the activity of spinal trigeminal neurons involved in meningeal nociception in rodents. The site of CGRP receptor inhibition is unclear, however. In adult Wistar rats anaesthetized with isofluorane systemic intravenous infusion (0.9 mg/kg) or unilateral facial injection (1 mM in 100 microl) of capsaicin was used to induce activity in the trigeminal nociceptive system. Animals were pre-treated either by saline or olcegepant. In comparison with vehicle infusion or the non-injected side of the face, capsaicin significantly increased the expression of the activation markers Fos in the spinal trigeminal nucleus and phosphorylated extracellular signal-regulated kinase in the trigeminal ganglion. Pre-treatment with olcegepant (900 microg/kg) inhibited the capsaicin-induced expression of Fos throughout the spinal trigeminal nucleus by 57%. In contrast, the expression of phosphorylated extracellular signal-regulated kinase in the trigeminal ganglion was not changed by olcegepant pre-treatment. CGRP receptor inhibition, which has been shown to decrease spinal trigeminal activity, is likely to occur in the central nervous system rather than in the periphery including the trigeminal ganglion. This may be important for future therapeutic interventions with CGRP receptor antagonists in migraine.", "BACKGROUND: Immune checkpoint inhibitors (ICI) therapies have demonstrated significant benefit in the treatment of many tumors including high grade urothelial cancer (HGUC) of the bladder. However, variability in patients' clinical responses highlights the need for biomarkers to aid patient stratification. ICI relies on an intact host immune response. In this context, we hypothesize that key players in the antitumor immune response such as markers of activated cytotoxic T lymphocytes (CD8, granzyme-B) and immune suppression (FOXP3) may help to identify patients who will derive the greatest therapeutic benefit from ICI. A major obstacle for deployment of such a strategy is the limited quantities of tumor-derived biopsy material. Therefore, in this technical study, we develop a multiplex biomarker with digital workflow. We explored the (1) concordance of conventional single stain results using digital image analysis, and (2) agreement between digital scoring versus manual analysis.METHODS: (1) For concordance study of single and multiplex stains, triplicate core tissue microarrays of 207 muscle invasive, HGUC of bladder had sequential 4-micron sections cut and stained with CD8, FOXP3 and granzyme-B. An inhouse developed tri-chromogen multiplex immunohistochemistry (m-IHC) assay consisting of CD8 (green), granzyme B (brown), and FOXP3 (red) was used to stain the next sequential tissue section. (2) Agreement between manual and digital analysis was performed on 19 whole slide sections of HGUC cystectomy specimens. All slides were scanned using Aperio ScanScope AT Digital Scanner at 40X. Quantitative digital image analysis was performed using QuPath version 0.2.3 open-source software. Scores from triplicate cores were averaged for each HGUC specimen for each marker. Intraclass correlation coefficients were used to compare percent positive cells between the single- and multi-plex assays. Lin's concordance correlation coefficients were used for manual versus digital analysis.RESULTS AND CONCLUSIONS: m-IHC offers significant advantages in characterizing the host immune microenvironment particularly in limited biopsy tissue material. Utilizing a digital image workflow resulted in significant concordance between m-IHC and individual single stains (p < 0.001 for all assessments). Moderate to good agreements were achieved between manual and digital scoring. Our technical work demonstrated potential uses of multiplex marker in assessing the host immune status and could be used in conjunction with PD-L1 as a predictor of response to ICI therapy.", "INTRODUCTION: The measles virus is a major human pathogen responsible for approximately 150,000 deaths annually. The disease is vaccine preventable and eradication of the virus is considered feasible, in principle. However, a herd immunity exceeding 95% is required to prevent sporadic viral outbreaks in a population. Declining disease prevalence, combined with public anxiety over the vaccination's safety, has led to increased vaccine refusal, especially in Europe. This has led to the resurgence of measles in some areas.AREAS COVERED: This article discusses whether synergizing effective measles therapeutics with the measles vaccination could contribute to finally eradicating measles. The authors identify key elements in a desirable drug profile and review current disease management strategies and the state of experimental inhibitor candidates. The authors also evaluate the risk associated with viral escape from inhibition, and consider the potential of measles therapeutics in the management of persistent central nervous system (CNS) viral infection. Finally, the authors contemplate the possible impact of therapeutics in controlling the threat imposed by closely related zoonotic pathogens of the same genus as measles.EXPERT OPINION: Efficacious therapeutics used for post-exposure prophylaxis of high-risk social contacts of confirmed index cases may aid measles eradication by closing herd immunity gaps; this is due to vaccine refusal or failure in populations with overall good vaccination coverage. The envisioned primarily prophylactic application of measles therapeutics to a predominantly pediatric and/or adolescent population, dictates the drug profile. It also has to be safe and efficacious, orally available, shelf-stable at ambient temperature and amenable to cost-effective manufacturing.", "Chaperonins are universally conserved molecular machines that facilitate the proper -folding of nascent and partially folded polypeptides into their respective three-dimensional structures. These multimeric protein complexes utilize the energy derived from ATP hydrolysis to fuel a protein-folding mechanism that consists of multiple rounds of substrate binding, encapsulation, and eventual expulsion back into the cytosolic environment. In this portion of the chapter, the structure and function of group I and group II chaperonins are discussed. Furthermore, the general mechanism of chaperonin-mediated protein folding is addressed in addition to illustrating how viral phages such as Lambda, T4, and RB49 exploit the host machinery for the proper folding of viral gene products. Lastly, the phiEL chaperonin from phage EL is revealed to be the first virally encoded chaperonin and is proposed to function independently of the host chaperonin machinery. The molecular architecture of the phiEL chaperonin, coupled with its unique functional abilities, renders its characterization a challenge and further highlights its novelty as a potentially whole new class of chaperonins.", "R-phycoerythrin is the major light-harvesting pigment protein of most red algal phycobilisomes. It is composed of three pigmented polypeptide subunits, the alpha, beta, and gamma. While alpha and beta phycoerythrin subunits are each unique in the red alga Aglaothamnion neglectum, there are two different gamma subunits with distinct molecular masses. Both gamma subunits are pigmented by virtue of covalently attached linear tetrapyrroles. The amino acid sequence of one of the gamma subunits, as deduced from the nucleotide sequence of a cDNA clone, has no significant similarity to any known sequence in the data bases. This result is surprising, since the gamma subunit of phycoerythrin is thought to have a function that is similar to cyanobacterial linker polypeptides. The A. neglectum gamma subunit is synthesized as a 36-kDa precursor protein that is processed at the amino terminus to yield a 33-kDa mature protein. The amino-terminal extension was able to direct the pea small subunit of Rubisco into isolated pea chloroplasts. This result suggests that red algae transport proteins into the plastid by a mechanism similar to that of higher plants. There are significant changes in levels of mRNA encoding the gamma 33 subunit when A. neglectum is grown under different conditions of illumination and in nitrogen-deficient medium. These changes parallel those previously observed for transcripts encoding the alpha and beta phycoerythrin subunits. Hence, there may be coordinated expression of nuclear and plastid-encoded phycoerythrin subunit genes.", "The identification and characterization of the exosome complex has shown that the exosome is a complex of 3' --> 5' exoribonucleases that plays a key role in the processing and degradation of a wide variety of RNA substrates. Advances in the understanding of exosome function have led to the identification of numerous cofactors that are required for a selective recruitment of the exosome to substrate RNAs, for their structural alterations to facilitate degradation, and to aid in their complete degradation/processing. Structural data obtained by two-hybrid interaction analyses and X-ray crystallography show that the core of the exosome adopts a doughnut-like structure and demonstrates that probably not all exosome subunits are active exoribonucleases. Despite all data obtained on the structure and function of the exosome during the last decade, there are still a lot of unanswered questions. What is the molecular mechanism by which cofactors select and target substrate RNAs to the exosome and modulate its function for correct processing or degradation? How can the exosome discriminate between processing or degradation of a specific substrate RNA? What is the precise structure of exosome subunits and how do they contribute to its function? Here we discuss studies that provide some insight to these questions and speculate on the mechanisms that control the exosome.", "The calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that plays an essential role in maintaining calcium homeostasis. In the present study, we analyzed the CaSR gene in a Korean family with familial hypocalciuric hypercalcemia (FHH). Genetic studies were performed by direct sequence analysis of the CaSR gene in genomic DNA obtained from peripheral leukocytes. A novel heterozygous G to T substitution at nucleotide position 1711 in exon 6, resulting in the G571W mutation, was identified in the CaSR gene in a 26-year-old female with asymptomatic hypercalcemia, a low calcium/creatinine clearance ratio, and normal intact parathyroid hormone. To study CaSR expression, the mutation was introduced by site-directed mutagenesis into a wild-type (WT) CaSR-expressing pCR3.1 vector, and COS-7 cells were transfected with either the WT or mutant CaSR-containing vector. Transfected cells loaded with Fura-2/AM, a fluorescent indicator of Ca2+, were assessed for CaSR function by the change in intracellular calcium [as measured by the 340 nm/380 nm fluorescence intensity ratio (F340/F380)] made in response to challenge with extracellular Ca2+. Both WT and G571W cells had equivalent amounts of CaSR protein in the cell membrane. However, after challenge with extracellular Ca2+, cells transfected with G571W CaSR responded with a lower F340/F380 ratio than those transfected with WT CaSR and showed decreased sensitivity to extracellular Ca2+ concentrations. The G571W mutation had therefore impaired the CaSR function. In conclusion, we identified a novel loss-of-function mutation, G571W, in the CaSR gene in a Korean family with FHH." ]

[ "INTRODUCTION: Cardiovascular complications are the major cause of morbidity and mortality in Marfan syndrome (MS), a common connective tissue disorder. Currently it is considered that the prognosis and morphologic characteristics in infantile Marfan syndrome may be quite different from those reported in older patients. The objective of this study was to analyze the cardiovascular manifestations and evolution of the patients with Marfan syndrome followed at our pediatric cardiac unit.METHODS: The authors reviewed the clinical files of all the patients that fulfilled the diagnostic criteria for MS according to De Paepe et al. (1996). We analyzed the following parameters: gender, age at referral, race, family history, clinical examination, diagnostic exams, therapy and evolution. The patients were divided into two groups according to the age at diagnosis: infants (group 1) and older patients (group 2).RESULTS: Group 1 included 3 infants, two boys and one girl, sporadic cases, presenting congestive heart failure. The major cardiac diagnoses were aortic dilatation (1/3) and mitral valve prolapse with severe mitral regurgitation (2/3). Congenital heart disease was associated in two cases (patent ductus arteriosus and atrial septal defect). Two needed cardiac surgery at an early age and one was recently proposed for surgery. There were no deaths. Group 2 included 20 patients, 14 boys and 6 girls, first seen at a mean age of 8 years. Ten had a positive family history and none presented cardiac symptoms. The major cardiac manifestations were mitral valve prolapse (18/20) and aortic dilatation (17/20). There was no significant progression of the cardiac lesions, except for one case, during the 12 years of follow-up.CONCLUSION: Infantile MS presented high morbidity; mitral regurgitation was severe in two cases. All patients presented heart failure, two needing early operations. In classic MS evolution was favorable, and the commonest cardiac lesions were mitral valve prolapse and aortic dilatation. We emphasize the need for beta-blockers to prevent progression of aortic dilatation. The decision for surgery rests upon the severity of valve regurgitation and the rate of progression of aortic dilatation. It is important to inform patients and family about physical exercise, prevention of endocarditis, risks associated with pregnancy and genetic counseling.", "BACKGROUND: The vast amount of data published in the primary biomedical literature represents a challenge for the automated extraction and codification of individual data elements. Biological databases that rely solely on manual extraction by expert curators are unable to comprehensively annotate the information dispersed across the entire biomedical literature. The development of efficient tools based on natural language processing (NLP) systems is essential for the selection of relevant publications, identification of data attributes and partially automated annotation. One of the tasks of the Biocreative 2010 Challenge III was devoted to the evaluation of NLP systems developed to identify articles for curation and extraction of protein-protein interaction (PPI) data.RESULTS: The Biocreative 2010 competition addressed three tasks: gene normalization, article classification and interaction method identification. The BioGRID and MINT protein interaction databases both participated in the generation of the test publication set for gene normalization, annotated the development and test sets for article classification, and curated the test set for interaction method classification. These test datasets served as a gold standard for the evaluation of data extraction algorithms.CONCLUSION: The development of efficient tools for extraction of PPI data is a necessary step to achieve full curation of the biomedical literature. NLP systems can in the first instance facilitate expert curation by refining the list of candidate publications that contain PPI data; more ambitiously, NLP approaches may be able to directly extract relevant information from full-text articles for rapid inspection by expert curators. Close collaboration between biological databases and NLP systems developers will continue to facilitate the long-term objectives of both disciplines.", "BACKGROUND: LDL cholesterol (LDL-C) is a well established risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds LDL receptors, targeting them for degradation. We therefore assessed the efficacy, safety, and tolerability of AMG 145, a human monoclonal IgG2 antibody against PCSK9, in stable patients with hypercholesterolemia on a statin.METHODS: In a phase 2, dose-ranging study done in 78 centres in the USA, Canada, Denmark, Hungary, and Czech Republic, patients (aged 18-80 years) with LDL-C greater than 2·2 mmol/L on a stable dose of statin (with or without ezetimibe), were randomly assigned equally, through an interactive voice response system, to subcutaneous injections of AMG 145 70 mg, 105 mg, or 140 mg, or matching placebo every 2 weeks; or subcutaneous injections of AMG 145 280 mg, 350 mg, or 420 mg, or matching placebo every 4 weeks. Everyone was masked to treatment assignment within the every 2 weeks and every 4 weeks schedules. The primary endpoint was the percentage change in LDL-C concentration from baseline after 12 weeks. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01380730.FINDINGS: 631 patients with hypercholesterolaemia were randomly assigned to AMG 145 70 mg (n=79), 105 mg (n=79), or 140 mg (n=78), or matching placebo (n=78) every 2 weeks; or AMG 145 280 mg (n=79), 350 mg (n=79), and 420 mg (n=80), and matching placebo (n=79) every 4 weeks. At the end of the dosing interval at week 12, the mean LDL-C concentrations were reduced generally dose dependently by AMG 145 every 2 weeks (ranging from 41·8% to 66·1%; p<0·0001 for each dose vs placebo) and AMG 145 every 4 weeks (ranging from 41·8% to 50·3%; p<0·0001). No treatment-related serious adverse events occurred. The frequencies of treatment-related adverse events were similar in the AMG 145 and placebo groups (39 [8%] of 474 vs 11 [7%] of 155); none of these events were severe or life-threatening.INTERPRETATION: The results suggest that PCSK9 inhibition could be a new model in lipid management. Inhibition of PCSK9 warrants assessment in phase 3 clinical trials.FUNDING: Amgen.", "Immunotherapy is an emerging therapeutic strategy with a promising clinical outcome in some solid tumors, particularly metastatic melanoma. One approach to immunotherapy is immune checkpoint inhibitors, such as blockage of CTLA-4 and PD-1/PD-L1. This special report aims to describe the state of clinical trials of tremelimumab in patients with unresectable malignant mesothelioma (MM) in particular with regard to the clinical efficacy, safety and tolerability. Criticism and perspective of this treatment are also discussed. Biological and clinical considerations rule out the use of tremelimumab as single agent for MM and, more generally, the use of immune checkpoint inhibitors for MM is still largely questionable and not supported by evidences.", "In the present study the pineal gland was examined in 2 outbred stocks and 6 inbred strains of rats some of which were pigmented to varying degrees, to see whether inbreeding affects the variability and whether differences exist between albino and pigmented rats. The animals were kept under 12 h light: 12 h darkness (12 L:12 D) and killed 7 h after the onset of light and darkness, respectively. The parameters examined were pineal protein content, serotonin and melatonin levels and hydroxyindole-O-methyltransferase (HIOMT) activity. All the parameters examined revealed interstrain differences, independently of whether the data were expressed per pineal or per mg protein. The variation coefficients for the various parameters were relatively high. They were mostly smaller when the data were expressed per pineal rather than per mg protein. No striking differences existed between the variation coefficients in inbred and outbred rats. When pineal size and the melatonin-related parameters expressed per pineal were used to assess the melatonin-synthesizing capacity of the pineal glands, it was found that the outbred Wistar and Sprague-Dawley rats and the inbred LEWIS-derived (LEW/Han) rats, all of which were albinos, had the most active pineals. Intermediate activity was noted in the hooded E3/Han and BDE/Han and the albino BDII/Han rats. The smallest and least active pineals were found in the totally pigmented BN/Han and DA/Han rats. The results taken together show that different stocks and strains exhibit significant differences in pineal size and melatonin-forming capacity. Albino rats appear to have larger and more active pineals than pigmented rats.", "Kawasaki's disease is a disease of unknown cause. The characteristic clinical features of Kawasaki's disease are fever> or =102 degrees F for> or =5 days accompanied by a bilateral bulbar conjunctivitis/conjunctival suffusion, erythematous rash, cervical adenopathy, pharyngeal erythema, and swelling of the dorsum of the hands/feet. Kawasaki's disease primarily affects children and is rare in adults. In children, Kawasaki's disease is more likely to be associated with aseptic meningitis, coronary artery aneurysms, and thrombocytosis. In adult Kawasaki's disease, unilateral cervical adenopathy, arthritis, conjunctival suffusion/conjunctivitis, and elevated serum transaminases (serum glutamic oxaloacetic transaminase [SGOT]/serum glutamate pyruvate transaminase [SGPT]) are more likely. Kawasaki's disease in adults may be mimicked by other acute infections with fever and rash, that is, group A streptococcal scarlet fever, toxic shock syndrome (TSS), and Rocky Mountain Spotted Fever (RMSF). Because there are no specific tests for Kawasaki's disease, diagnosis is based on clinical criteria and the syndromic approach. In addition to rash and fever, scarlet fever is characterized by circumoral pallor, oropharyngeal edema, Pastia's lines, and peripheral eosinophilia, but not conjunctival suffusion, splenomegaly, swelling of the dorsum of the hands/feet, thrombocytosis, or an elevated SGOT/SGPT. In TSS, in addition to rash and fever, there is conjunctival suffusion, oropharyngeal erythema, and edema of the dorsum of the hands/feet, an elevated SGOT/SGPT, and thrombocytopenia. Patients with TSS do not have cervical adenopathy or splenomegaly. RMSF presents with fever and a maculopapular rash that becomes petechial, first appearing on the wrists/ankles after 3 to 5 days. RMSF is accompanied by a prominent headache, periorbital edema, conjunctival suffusion, splenomegaly, thrombocytopenia, an elevated SGOT/SGPT, swelling of the dorsum of the hands/feet, but not oropharyngeal erythema. We present a case of adult Kawasaki's disease with myocarditis and splenomegaly. The patient's myocarditis rapidly resolved, and he did not develop coronary artery aneurysms. In addition to splenomegaly, this case of adult Kawasaki's disease is remarkable because the patient had highly elevated serum ferritin levels of 944-1303 ng/mL; (normal<189 ng/mL). To the best of our knowledge, this is the first report of adult Kawasaki's disease with highly elevated serum ferritin levels. This is also the first report of splenomegaly in adult Kawasaki's disease. We conclude that Kawasaki's disease should be considered in the differential diagnosis in adult patients with rash/fever for> or =5 days with conjunctival suffusion, cervical adenopathy, swelling of the dorsum of the hands/feet, thrombocytosis and otherwise unexplained highly elevated ferritin levels.", "BACKGROUND: New therapeutic strategies for malignant mesothelioma are urgently needed. In the DETERMINE study, we investigated the effects of the cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody tremelimumab in patients with previously treated advanced malignant mesothelioma.METHODS: DETERMINE was a double-blind, placebo-controlled, phase 2b trial done at 105 study centres across 19 countries in patients with unresectable pleural or peritoneal malignant mesothelioma who had progressed after one or two previous systemic treatments for advanced disease. Eligible patients were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and measurable disease as defined in the modified Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 for pleural mesothelioma or RECIST version 1.1 for peritoneal mesothelioma. Patients were randomly assigned (2:1) in blocks of three, stratified by European Organisation for Research and Treatment of Cancer status (low risk vs high risk), line of therapy (second line vs third line), and anatomic site (pleural vs peritoneal), by use of an interactive voice or web system, to receive intravenous tremelimumab (10 mg/kg) or placebo every 4 weeks for 7 doses and every 12 weeks thereafter until a treatment discontinuation criterion was met. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. The trial is ongoing but no longer recruiting participants, and is registered with ClinicalTrials.gov, number NCT01843374.FINDINGS: Between May 17, 2013, and Dec 4, 2014, 571 patients were randomly assigned to receive tremelimumab (n=382) or placebo (n=189), of whom 569 patients received treatment (two patients in the tremelimumab group were excluded from the safety population because they did not receive treatment). At the data cutoff date (Jan 24, 2016), 307 (80%) of 382 patients had died in the tremelimumab group and 154 (81%) of 189 patients had died in the placebo group. Median overall survival in the intention-to-treat population did not differ between the treatment groups: 7·7 months (95% CI 6·8-8·9) in the tremelimumab group and 7·3 months (5·9-8·7) in the placebo group (hazard ratio 0·92 [95% CI 0·76-1·12], p=0·41). Treatment-emergent adverse events of grade 3 or worse occurred in 246 (65%) of 380 patients in the tremelimumab group and 91 (48%) of 189 patients in the placebo group; the most common were dyspnoea (34 [9%] patients in the tremelimumab group vs 27 [14%] patients in the placebo group), diarrhoea (58 [15%] vs one [<1%]), and colitis (26 [7%] vs none). The most common serious adverse events were diarrhoea (69 [18%] patients in the tremelimumab group vs one [<1%] patient in the placebo group), dyspnoea (29 [8%] vs 24 [13%]), and colitis (24 [6%] vs none). Treatment-emergent events leading to death occurred in 36 (9%) of 380 patients in the tremelimumab group and 12 (6%) of 189 in the placebo group; those leading to the death of more than one patient were mesothelioma (three [1%] patients in the tremelimumab group vs two [1%] in the placebo group), dyspnoea (three [1%] vs two [1%]); respiratory failure (one [<1%] vs three [2%]), myocardial infarction (three [1%] vs none), lung infection (three [1%] patients vs none), cardiac failure (one [<1%] vs one [<1%]), and colitis (two [<1%] vs none). Treatment-related adverse events leading to death occurred in five (1%) patients in the tremelimumab group and none in the placebo group. The causes of death were lung infection in one patient, intestinal perforation and small intestinal obstruction in one patient; colitis in two patients, and neuritis and skin ulcer in one patient.INTERPRETATION: Tremelimumab did not significantly prolong overall survival compared with placebo in patients with previously treated malignant mesothelioma. The safety profile of tremelimumab was consistent with the known safety profile of CTLA-4 inhibitors. Investigations into whether immunotherapy combination regimens can provide greater efficacy than monotherapies in malignant mesothelioma are ongoing.FUNDING: AstraZeneca.", "We describe a case of quick recovery of myocardium damage in a 15-year-old adolescent with subacute thyroiditis. After 1 week of admission, his cardiovascular status began to show signs of improvement accompanied by the recovery of electrocardiogram and indicators of myocardial damage. We speculate that myocardium damage associated with subacute thyroiditis is a complication of common virus, although we did not detect any abnormal virus antibody and deoxyribonucleic acid in the patient's serum.", "BACKGROUND: Tremelimumab, an anti-CTLA4 monoclonal antibody, initially showed good activity when used alone in patients with mesothelioma, but did not improve the overall survival of patients who failed on first-line or second-line chemotherapy compared with placebo in the DETERMINE study. We aimed to investigate the efficacy and safety of first-line or second-line tremelimumab combined with durvalumab, an anti-PD-L1 monoclonal antibody, in patients with malignant mesothelioma.METHODS: In this open-label, non-randomised, phase 2 trial, patients with unresectable pleural or peritoneal mesothelioma received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. The primary endpoint was the proportion of patients with an immune-related objective response according to the immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST; for pleural mesothelioma) or immune-related RECIST version 1.1 (for peritoneal mesothelioma). The primary analysis was done by intention to treat, whereas the safety analysis included patients who received at least one dose of study drug. This trial is registered with the European Clinical Trials Database, number 2015-001995-23, and ClinicalTrials.gov, number NCT02588131, and is ongoing but no longer recruiting patients.FINDINGS: From Oct 30, 2015, to Oct 12, 2016, 40 patients with mesothelioma were enrolled and received at least one dose each of tremelimumab and durvalumab. Patients were followed-up for a median of 19·2 months (IQR 13·8-20·5). 11 (28%) of 40 patients had an immune-related objective response (all partial responses; confirmed in ten patients), with a median response duration of 16·1 months (IQR 11·5-20·5). 26 (65%) patients had immune-related disease control and 25 (63%) had disease control. Median immune-related progression-free survival was 8·0 months (95% CI 6·7-9·3), median progression-free survival was 5·7 months (1·7-9·7), and median overall survival was 16·6 months (13·1-20·1). Baseline tumour PD-L1 expression did not correlate with the proportion of patients who had an immune-related objective response or immune-related disease control, with immune-related progression-free survival, or with overall survival. 30 (75%) patients experienced treatment-related adverse events of any grade, of whom seven (18%) had grade 3-4 treatment-related adverse events. Treatment-related toxicity was generally manageable and reversible with protocol guidelines.INTERPRETATION: The combination of tremelimumab and durvalumab appeared active, with a good safety profile in patients with mesothelioma, warranting further exploration.FUNDING: Network Italiano per la Bioterapia dei Tumori Foundation, Associazione Italiana per la Ricerca sul Cancro, AstraZeneca, and Istituto Toscano Tumori.", "Although reactive oxygen species have been proposed to play a major role in the aging process, the exact molecular mechanisms remain elusive. In this study we investigate the effects of a perturbation in the ratio of Cu/Zn-superoxide dismutase activity (Sod1 dismutases .O2-to H2O2) to glutathione peroxidase activity (Gpx1 catalyses H2O2 conversion to H2O) on cell growth and development. Our data demonstrate that Sod1 transfected cell lines that have an elevation in the ratio of Sod1 activity to Gpx1 activity produce higher levels of H2O2 and exhibit well characterised markers of cellular senescence viz. slower proliferation and altered morphology. On the contrary, Sod1 transfected cell lines that have an unaltered ratio in the activity of these two enzymes, have unaltered levels of H2O2 and fail to show characteristics of senescence. Furthermore, fibroblasts established from individuals with Down syndrome have an increase in the ratio of Sod1 to Gpx1 activity compared with corresponding controls and senesce earlier. Interestingly, cells treated with H2O2 also show features of senescence and/or senesce earlier. We also show that Cip1 mRNA levels are elevated in Down syndrome cells, Sod1 transfectants with an altered Sod1 to Gpx1 activity ratio and those treated with H2O2, thus suggesting that the slow proliferation may be mediated by Cip1. Furthermore, our data demonstrate that Cip1 mRNA levels are induced by exposure of cells to H2O2. These data give valuable insight into possible molecular mechanisms that contribute tribute to cellular senescence and may be useful in the evolution of therapeutic strategies for aging.", "OBJECTIVES: Monoamine oxidase A (MAOA) modulates metabolism of serotonin and dopamine metabolism, neurotransmitters involved in regulation of appetite and food intake. The gene coding for MAOA contains a 30-bp tandem repeat (uVNTR) polymorphism in its promoter region that has been previously identified to be associated with obesity with mixed findings in the literature. Our goals were to replicate the population effects of this functional polymorphism on obesity risk, and to further explore gender differences and interaction effects with negative stressors.METHODS: Analyses were conducted with data on genotypes, measured weight and height, and self-reported behavioural characteristics among 1101 Chinese adolescents 11-15 years old living in Wuhan, China.RESULTS: Girls with the high-activity allele had significantly lower body mass index (BMI; β = -0.25 ± 0.98, P = 0.011) compared to those with the low activity allele. Experience of negative familial stressors (e.g., death or illness of family members, hit or scolded by parents and increased quarrelling with parents, parents argued frequently) significantly weakened this protective genetic effect on BMI (P for interaction = 0.043). Stratified analyses showed a significant protective genetic effect on BMI only within the stratum of low stress level (β = -0.44 ± 0.14, P = 0.002). No similar effect was observed among boys.CONCLUSIONS: Our findings confirm the genetic effects of MAOA uVNTR polymorphism on BMI in a Chinese adolescent population and suggest potential genetic interactions with negative familial stressors.", "OBJECTIVES: Till date, mutations in the genes PAX3 and MITF have been described in Waardenburg syndrome (WS), which is clinically characterised by congenital hearing loss and pigmentation anomalies. Our study intended to determine the frequency of mutations and deletions in these genes, to assess the clinical phenotype in detail and to identify rational priorities for molecular genetic diagnostics procedures.DESIGN: Prospective analysis.PATIENTS: 19 Caucasian patients with typical features of WS underwent stepwise investigation of PAX3 and MITF. When point mutations and small insertions/deletions were excluded by direct sequencing, copy number analysis by multiplex ligation-dependent probe amplification was performed to detect larger deletions and duplications. Clinical data and photographs were collected to facilitate genotype-phenotype analyses.SETTING: All analyses were performed in a large German laboratory specialised in genetic diagnostics.RESULTS: 15 novel and 4 previously published heterozygous mutations in PAX3 and MITF were identified. Of these, six were large deletions or duplications that were only detectable by copy number analysis. All patients with PAX3 mutations had typical phenotype of WS with dystopia canthorum (WS1), whereas patients with MITF gene mutations presented without dystopia canthorum (WS2). In addition, one patient with bilateral hearing loss and blue eyes with iris stroma dysplasia had a de novo missense mutation (p.Arg217Ile) in MITF. MITF 3-bp deletions at amino acid position 217 have previously been described in patients with Tietz syndrome (TS), a clinical entity with hearing loss and generalised hypopigmentation.CONCLUSIONS: On the basis of these findings, we conclude that sequencing and copy number analysis of both PAX3 and MITF have to be recommended in the routine molecular diagnostic setting for patients, WS1 and WS2. Furthermore, our genotype-phenotype analyses indicate that WS2 and TS correspond to a clinical spectrum that is influenced by MITF mutation type and position." ]

[ "BACKGROUND: Milvexian (BMS-986177/JNJ-70033093) is an orally bioavailable factor XIa (FXIa) inhibitor currently in phase 2 clinical trials.OBJECTIVES: To evaluate in vitro properties and in vivo characteristics of milvexian.METHODS: In vitro properties of milvexian were evaluated with coagulation and enzyme assays, and in vivo profiles were characterized with rabbit models of electrolytic-induced carotid arterial thrombosis and cuticle bleeding time (BT).RESULTS: Milvexian is an active-site, reversible inhibitor of human and rabbit FXIa (Ki 0.11 and 0.38 nM, respectively). Milvexian increased activated partial thromboplastin time (APTT) without changing prothrombin time and potently prolonged plasma APTT in humans and rabbits. Milvexian did not alter platelet aggregation to ADP, arachidonic acid, or collagen. Milvexian was evaluated for in vivo prevention and treatment of thrombosis. For prevention, milvexian 0.063 + 0.04, 0.25 + 0.17, and 1 + 0.67 mg/kg+mg/kg/h preserved 32 ± 6*, 54 ± 10*, and 76 ± 5%* of carotid blood flow (CBF) and reduced thrombus weight by 15 ± 10*, 45 ± 2*, and 70 ± 4%*, respectively (*p < .05; n = 6/dose). For treatment, thrombosis was initiated for 15 min and CBF decreased to 40% of control. Seventy-five minutes after milvexian administration, CBF averaged 1 ± 0.3, 39 ± 10, and 66 ± 2%* in groups treated with vehicle and milvexian 0.25 + 0.17 and 1 + 0.67 mg/kg+mg/kg/h, respectively (*p < .05 vs. vehicle; n = 6/group). The combination of milvexian 1 + 0.67 mg/kg+mg/kg/h and aspirin 4 mg/kg/h intravenous did not increase BT versus aspirin monotherapy.CONCLUSIONS: Milvexian is an effective antithrombotic agent with limited impact on hemostasis, even when combined with aspirin in rabbits. This study supports inhibition of FXIa with milvexian as a promising antithrombotic therapy with a wide therapeutic window.", "Author information:(1)Neurology Clinic, University of Heidelberg, Heidelberg, Germany. Clinical Cooperation Unit (CCU) Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. wolfgang.wick@med.uni-heidelberg.de.(2)European Organisation for Research and Treatment of Cancer (EORTC), Lausanne, Switzerland.(3)SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland. Neuroscience Research Center, University Hospital Lausanne (CHUV), Lausanne, Switzerland.(4)Neurology Clinic, University of Heidelberg, Heidelberg, Germany. CCU Brain Tumor Immunology, DKFZ, Heidelberg, Germany.(5)Department of Neurology/Neuro-Oncology, Erasmus MC - Cancer Institute, Rotterdam, the Netherlands.(6)Neuro-oncology Unit, MC Haaglanden, The Hague, the Netherlands.(7)Department of Medical Oncology, Ospedale Bellaria, Bologna, Italy.(8)Neuroscience Research Center, University Hospital Lausanne (CHUV), Lausanne, Switzerland. Department of Neurosurgery, CHUV, Lausanne, Switzerland.(9)Neurology Clinic, University of Heidelberg, Heidelberg, Germany.(10)Pfizer, Berlin, Germany.(11)Department of Neurology, University Hospital and University of Zurich, Switzerland.(12)Department of Neurosurgery, CHUV, Lausanne, Switzerland.(13)1-Institut de Cancérologie de l'OUEST, Saint Herblain-Nantes Cedex, France.(14)AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, UMR8257 MD4 Cognac G, CNRS, Service de Santé des Armées, Université Paris Descartes, Paris, France.(15)General Hospital AKH, Medical University Vienna, Austria.(16)Institut Catala d'Oncologia (ICO), Hospital Germans Trias Pujol, Badalona, Barcelona, Spain.(17)Department of Neurosurgery, Medical Center, University of Freiburg, Germany.(18)University Hospitals Bristol NHS Foundation Trust - Bristol Haematology and Oncology Centre, Bristol, United Kingdom.(19)Department of Oncology, CHUV, Lausanne, Switzerland.(20)Institute of Pathology, CHUV, Lausanne, Switzerland.(21)Department of Radio-oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.", "The nerve center responsible for controlling our circadian rhythm is located in a cluster of cells known as the suprachiasmatic nucleus in the hypothalamus. Various physiological functions such as sleep, arousal, blood pressure, body temperature, and hormone secretion are regulated in a 24-hour rhythm by this circuit. Somatic cells of other organs have a peripheral clock gene and by synchronizing the rhythm of the central and peripheral clocks, it is possible to live a healthy life. Due to aging and degenerative disease, circadian rhythm gradually collapses. Factors that can contribute to this include reduced expression of the time gene associated with photo stimulation, a reduction in neurotransmitter levels, and reduced melatonin production. Biological clocks play an important role in our emotions, cognitive function, and behavior. Sleep disorders and metabolic disease related to the circadian rhythm affect metabolic and endocrine activities via the autonomic nervous system and the intestinal bacterial flora. Shift work disorder is associated with insomnia and excessive drowsiness as individuals often work during their sleeping hours. Now time management is placed at the center of our society, and it is important to evaluate the medical risk of engaging in shift work. In frontotemporal dementia (FTD), the stereotypical behaviors may be associated with time. In some patients, multiple timed behaviors occupy a considerable part of the patient's daily life. Stereotypical behaviors in FTD are often considered in contrast to obsessive-compulsive disease (OCD). Studies of OCD have found a close correlation between clinical symptoms, cognitive function, and brain function.", "In August 2017, the United States Federal Drug Administration (FDA) approved enasidenib (Idhifa, Celgene/Agios) for adults with relapsed and refractory acute myelogenous leukemia (AML) with an IDH2 mutation. Enasidenib targets cells with mutant copies of isocitrate dehydrogenase-2 (IDH2), inhibiting the oncometabolite 2-hydroxyglutarte (2-HG) formed by the mutant IDH2. Areas covered: We review the studies leading to enasidenib's approval, as well as common side effects and safety issues experienced during the clinical trials. There is a focus on the diagnosis and treatment of these side effects including differentiation syndrome. Expert commentary: We are experiencing a revolution in the understanding of the mechanism of AML. A majority of the effort has been concentrated on targeting gene mutations or pathway activations with precision therapeutics. Enasidenib is beneficial in a patient population that previously had limited treatment options. However, given the fact that enasidenib is a highly specific inhibitor of an early stable mutation, it is questionable whether a strategy of targeting a single mutation or pathway in relapsed AML will allow for better than the 20% complete remission (CR) rate observed with this therapy. The proper role for single mutation targeting in AML needs to be carefully considered.", "Ozone, the main component of photochemical smog and air pollution, can damage the skin by oxidizing stratum corneum enzymes, lipids and structural proteins. We have developed a rapid screening assay to determine free radical scavenging capacity of various active ingredients that are frequently used in personal care products. Several known antioxidants including vitamin C, vitamin E analog Trolox, walnut seed extract, lipoic acid and ergothioneine inner salt were assayed for their ability to neutralize ozone-induced oxidation of beta-phycoerythrin, a fluorescent reporter protein derived from algae. The free radical scavenging capacities of these antioxidants were quantified and compared. The results demonstrate that this assay is a valuable primary screening tool for identifying antioxidant activity of natural or synthetic substrates that can be used in personal care products to protect the uppermost layer of our skin from oxidizing damage induced by O3.", "Mycobacterium tuberculosis residing within pulmonary granulomas and cavities represents an important reservoir of persistent organisms during human latent tuberculosis infection. We present a novel in vivo model of tuberculosis involving the encapsulation of bacilli in semidiffusible hollow fibers that are implanted subcutaneously into mice. Granulomatous lesions develop around these hollow fibers, and in this microenvironment, the organisms demonstrate an altered physiologic state characterized by stationary-state colony-forming unit counts and decreased metabolic activity. Moreover, these organisms show an antimicrobial susceptibility pattern similar to persistent bacilli in current models of tuberculosis chemotherapy in that they are more susceptible to the sterilizing drug, rifampin, than to the bactericidal drug isoniazid. We used this model of extracellular persistence within host granulomas to study both gene expression patterns and mutant survival patterns. Our results demonstrate induction of dosR (Rv3133c) and 20 other members of the DosR regulon believed to mediate the transition into dormancy, and that rel(Mtb) is required for Mycobacterium tuberculosis survival during extracellular persistence within host granulomas. Interestingly, the dormancy phenotype of extracellular M. tuberculosis within host granulomas appears to be immune mediated and interferon-gamma dependent.", "Ceritinib is an oral anaplastic lymphoma kinase (ALK) inhibitor developed by Novartis for the treatment of tumours characterised by genetic abnormalities in ALK. ALK is a member of the insulin receptor family of tyrosine kinases that can become oncogenic when fused to other proteins. Ceritinib has been approved in the US under 'Breakthrough Therapy' designation for the second-line treatment of ALK-positive non-small cell lung cancer (NSCLC). Regulatory submissions have also been made in the EU and other countries. Phase III development is ongoing worldwide to evaluate ceritinib both as a first- and second-line therapy for ALK-positive NSCLC. This article summarizes the milestones in the development of ceritinib leading to this first approval for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib." ]

[ "BACKGROUND: Vitamin C acts as a potent antioxidant; however, it can also be a prooxidant and glycate protein under certain circumstances in vitro. These observations led us to hypothesize that a high intake of vitamin C in diabetic persons might promote atherosclerosis.OBJECTIVE: The objective was to examine the relation between vitamin C intake and mortality from cardiovascular disease.DESIGN: We studied the relation between vitamin C intake and mortality from total cardiovascular disease (n = 281), coronary artery disease (n = 175), and stroke (n = 57) in 1923 postmenopausal women who reported being diabetic at baseline. Diet was assessed with a food-frequency questionnaire at baseline, and subjects initially free of coronary artery disease were prospectively followed for 15 y.RESULTS: After adjustment for cardiovascular disease risk factors, type of diabetes medication used, duration of diabetes, and intakes of folate, vitamin E, and beta-carotene, the adjusted relative risks of total cardiovascular disease mortality were 1.0, 0.97, 1.11, 1.47, and 1.84 (P for trend < 0.01) across quintiles of total vitamin C intake from food and supplements. Adjusted relative risks of coronary artery disease were 1.0, 0.81, 0.99, 1.26, and 1.91 (P for trend = 0.01) and of stroke were 1.0, 0.52, 1.23, 2.22, and 2.57 (P for trend < 0.01). When dietary and supplemental vitamin C were analyzed separately, only supplemental vitamin C showed a positive association with mortality endpoints. Vitamin C intake was unrelated to mortality from cardiovascular disease in the nondiabetic subjects at baseline.CONCLUSION: A high vitamin C intake from supplements is associated with an increased risk of cardiovascular disease mortality in postmenopausal women with diabetes.", "Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest red cell enzymopathy in humans and has an X-linked inheritance. It has been reported from India more than 30 years ago and the prevalence varies from 0-27% in different caste, ethnic and linguistic groups. The major clinical manifestations are drug induced hemolytic anemia, neonatal jaundice and chronic non-spherocytic hemolytic anemia. Individuals with G6PD deficiency have a selective advantage against falciparum malaria. Thirteen biochemically characterized variants have been reported from India. At the molecular level, G6PD Mediterranean is the most common deficient variant in the caste groups whereas, G6PD Orissa is more prevalent among the tribal of India. The third common variant seen in India is G6PD Kerala-Kalyan.", "Since dose intensity of doxorubicin is correlated with the clinical response of patients with soft tissue sarcomas and since doxorubicin dose intensity may be compromised in combination chemotherapy, we evaluated the use of recombinant granulocytemacrophage colony-stimulating factor (rGM-CSF) to ameliorate myelosuppression and allow doxorubicin dose escalation in a phase I trial utilizing the MAID combination [Mesna 2.5 g/m2/day x 4 days, Adriamycin (doxorubicin) 15 mg/m2/day x 4 days, ifosfamide 2.0 g/m2/day x 3 days, dacarbazine 250 mg/m2/day x 4 days; to be repeated every 21 days]. Thirteen patients were treated. The doxorubicin dose for the first 6 patients was at the standard dose of 15 mg/m2/day x 4 days (level 1), while the doxorubicin dose for the next 7 patients was escalated by 25% to 18.75 mg/m2/day x 4 days (level 2). rGM-CSF was given at 5 micrograms/kg/day, days 5-14. All patients experienced moderate to severe myelosuppression, with all patients at dose level 2 requiring doxorubicin dose reduction to dose level 1 or lower by their third course of treatment. rGM-CSF failed to allow sustained escalation of the doxorubicin dose in the MAID regimen.", "The vertebrate clustered protocadherin (Pcdh) cell surface proteins are encoded by three closely linked gene clusters (Pcdhα, Pcdhβ, and Pcdhγ). Here, we show that all three gene clusters functionally cooperate to provide individual mouse olfactory sensory neurons (OSNs) with the cell surface diversity required for their assembly into distinct glomeruli in the olfactory bulb. Although deletion of individual Pcdh clusters had subtle phenotypic consequences, the loss of all three clusters (tricluster deletion) led to a severe axonal arborization defect and loss of self-avoidance. By contrast, when endogenous Pcdh diversity is overridden by the expression of a single-tricluster gene repertoire (α and β and γ), OSN axons fail to converge to form glomeruli, likely owing to contact-mediated repulsion between axons expressing identical combinations of Pcdh isoforms.", "Multiple sclerosis (MS) is a neurodegenerative disease with a major inflammatory component that constitutes the most common progressive and disabling neurological condition in young adults. Injectable immunomodulatory medicines such as interferon drugs and glatiramer acetate have dominated the MS market for over the past two decades but this situation is set to change. This is because of: (i) patent expirations, (ii) the introduction of natalizumab, which targets the interaction between leukocytes and the blood-CNS barrier, (iii) the launch of three oral immunomodulatory drugs (fingolimod, dimethyl fumarate and teriflunomide), with another (laquinimod) under regulatory review and (iv) a number of immunomodulatory monoclonal antibodies (alemtuzumab, daclizumab and ocrelizumab) about to enter the market. Current and emerging medicines are reviewed and their impact on people with MS considered.", "State-of-the-art small interfering RNA (siRNA) therapeutics such as givosiran and fitusiran are constructed from three variable components: a fully-modified RNA core that conveys metabolic stability, a targeting moiety that mediates target-cell uptake, and a linker. This structural complexity poses challenges for metabolite characterization and risk assessment after long-term patient exposure. In this study, we show that basic phosphorothioate modification of a siRNA targeting the oncoprotein Lin28B provides a useful increase in metabolic stability, without greatly compromising potency. We found that its stability in vitro matched that of nanoparticle-free patisiran in serum and surpassed it in liver tritosome extracts, although it did not reach the stability of the fitusiran siRNA core structure. Liver and kidney were the main sites of accumulation after its subcutaneous administration in mice. Despite the lack of a delivery agent-free antitumor effect, we anticipate our study to be a starting point to develop alternative siRNA scaffolds that can be degraded into naturally-occurring metabolites and help alleviate the aforementioned challenges. Furthermore, Lin28B is a promising target for cancers, and the development of such simplified siRNA analogs, possibly together with novel targeting units, holds potential.", "The nucleosome, which is composed of DNA wrapped around a histone octamer, is a fundamental unit of chromatin and is duplicated during the eukaryotic DNA replication process. The evolutionarily conserved histone chaperone cell cycle gene 1 (CCG1) interacting factor A/anti-silencing function 1 (CIA/Asf1) is involved in histone transfer and nucleosome reassembly during DNA replication. CIA/Asf1 has been reported to split the histone (H3-H4)(2) tetramer into histone H3-H4 dimer(s) in vitro, raising a possibility that, in DNA replication, CIA/Asf1 is involved in nucleosome disassembly and the promotion of semi-conservative histone H3-H4 dimer deposition onto each daughter strand in vivo. Despite numerous studies on the functional roles of CIA/Asf1, its mechanistic role(s) remains elusive because of lack of biochemical analyses. The biochemical studies described here show that a V94R CIA/Asf1 mutant, which lacks histone (H3-H4)(2) tetramer splitting activity, does not form efficiently a quaternary complex with histones H3-H4 and the minichromosome maintenance 2 (Mcm2) subunit of the Mcm2-7 replicative DNA helicase. Interestingly, the mutant enhances nascent DNA strand synthesis in a cell-free chromosomal DNA replication system using Xenopus egg extracts. These results suggest that CIA/Asf1 in the CIA/Asf1-H3-H4-Mcm2 complex, which is considered to be an intermediate in histone transfer during DNA replication, negatively regulates the progression of the replication fork." ]

[ "Sarcoidosis is a systemic disease of unknown etiology characterized by the development of non-caseating epitheloid granulomas. The lungs are the most commonly involved organ (>90% of cases), followed by the lymph nodes, the skin, and the eyes. Areas covered: This review summarizes current pharmacotherapy options and future directions for the development of new therapies. Glucocorticoids are the first-line therapy for sarcoidosis. For patients with the most severe forms of sarcoidosis (who will need glucocorticoids for long periods) and for those intolerant or refractory, immunosuppressive drugs are used as sparing agents. The management of extrathoracic sarcoidosis must be tailored to the specific organ or organs involved; however, there is limited data from controlled trials to guide the treatment of these patients. The emergence of biological therapies has increased the therapeutic armamentarium available to treat sarcoidosis, with monoclonal anti-TNF agents being the most promising, but their use is still limited by a lack of licensing and costs. Expert commentary: The treatment of sarcoidosis is still not totally standardized. New effective therapies are urgently needed to enable the reduction or replacement of long-term therapy with glucocorticoids in patients with sarcoidosis.", "PURPOSE: To assess the potential influence of improved dose distribution with proton beams compared to conventional or intensity-modulated (IM) X-ray beams on the incidence of treatment-induced secondary cancers in pediatric oncology.METHODS AND MATERIALS: Two children, one with a parameningeal rhabdomyosarcoma (RMS) and a second with a medulloblastoma, were used as models for the purpose of this study. After defining the target and critical structures, treatment plans were calculated and optimized, four for the RMS case (conventional X-ray, IM X-rays, protons, and IM protons) and three for the irradiation of the spinal axis in medulloblastoma (conventional X-ray, IM X-rays, protons). Secondary cancer incidence was estimated using a model based on Publication No. 60 of the International Commission on Radiologic Protection. This model allowed estimation of absolute risks of secondary cancer for each treatment plan based on dose-volume distributions for the nontarget organs.RESULTS: Proton beams reduced the expected incidence of radiation-induced secondary cancers for the RMS patient by a factor of >or=2 and for the medulloblastoma case by a factor of 8 to 15 when compared with either IM or conventional X-ray plans.CONCLUSIONS: The potential for a significant reduction in secondary cancers with pediatric cancers after using proton beams (forward planned or IM) in the treatment of RMS and MBD in children and adolescents represents an additional argument supporting the development of proton therapy for most radiotherapy indications in pediatric oncology.", "During the development of multiple sclerosis the destruction of the myelin sheath surrounding the neurites is accompanied by citrullination of several central nervous system (CNS) proteins, including myelin basic protein and glial fibrillary acidic protein. In experimental autoimmune encephalomyelitis (EAE), a disease induced in animals by immunization with proteins or peptides from the CNS, the animals develop symptoms similar to multiple sclerosis (MS). The increased levels of citrullinated CNS proteins associated with MS are also observed during the development of EAE. To study the role of CNS protein citrullination in EAE development, we induced EAE with a peptide derived from myelin oligodendrocyte glycoprotein (MOG(35-55)) in mice lacking the peptidylarginine deiminase 2 (PAD2) protein, because this enzyme was the most likely candidate to be involved in catalyzing CNS protein citrullination in the diseased state. Even though the PAD2 knockout mice displayed a dramatic reduction in the amount of citrullination present in the CNS, indicating that PAD2 is indeed responsible for the majority of detectable citrullination observed in EAE, the development of EAE was not impaired by genetic deletion of PAD2, suggesting that PAD2 catalyzed citrullination is not essential to the development of EAE.", "INTRODUCTION: To evaluate the safety and efficacy of incobotulinumtoxinA (IncoA) injection for treatment of essential hand tremor. In essential tremor and Parkinson's disease tremor, administration of onabotulinumtoxinA via a fixed injection approach improves the tremor but a high percentage of patients (30-70%) develop moderate to severe hand weakness which has limited its use in clinical practice.METHODS: This study was performed from July 2013 to July 2016 on 33 subjects. This is a double-blind, placebo-controlled, crossover trial injecting 80-120 units of IncoA into 8-14 hand and forearm muscles using a customized approach. The subjects were followed for 28 weeks. The treatment efficacy was evaluated by the Fahn Tolosa Marin tremor rating score and NIH genetic criteria for tremor severity at 4 and 8 weeks after each of the two sets of treatments. Hand strength was assessed by an ergometer.RESULTS: There was statistically significant improvement in clinical rating score of tremor at 4 and 8 weeks following the IncoA injection.CONCLUSION: In this study, injection of IncoA treatment via a customized approach improved essential tremor on the clinical scales and patient's perception with a low occurrence of significant hand weakness.", "INTRODUCTION: Although having high clinical efficacy in the treatment of human epidermal growth factor receptor-2 (HER2+) metastatic breast cancer, trastuzumab has been associated with cardiotoxicity, and the etiology and pathogenesis of this condition is currently under investigation.METHODS: This paper reviews the cardiotoxicity, associated with trastuzumab use and discusses the risk assessment and management of cardiac dysfunction.RESULTS: The increased risk of cardiotoxicity is lower when trastuzumab is given as monotherapy (3%-7%) compared with anthracyclines + trastuzumab therapy (27%). Type II cardiac changes occur in trastuzumab-treated patients, which do not appear to be dose-related, are not associated with histological changes, and are generally reversible. Several risk factors for cardiac events have been identified and assessing levels of troponin I and N-terminal pro-brain B-type natriuretic peptide before and after treatment with trastuzumab may allow early detection of cardiotoxicity. A symptomatic and functional evaluation scheme for patients indicated for treatment with trastuzumab has also been proposed to work alongside therapeutic options for the treatment of heart failure.CONCLUSION: The risk of cardiac dysfunction associated with trastuzumab can be justified given the increase in overall survival. This risk is lower when trastuzumab is given as monotherapy. The paradigm for cardiologists remains the same: treat the cancer effectively whilst preventing cardiotoxicity.", "Multiple novel therapeutic agents against acute myeloid leukemia (AML) have been evaluated in the past several decades without meaningful clinical improvement in outcomes, especially for AML patients age ≥60, where the overall incidence of AML is highest. Therapeutic options mainly consist of hypomethylating agents, ongoing clinical trials and, less commonly, intensive cytotoxic chemotherapy. CPX-351, a novel liposomal formulation which encapsulates cytarabine and daunorubicin in 5:1 molar ratio, has shown promising efficacy, leading to recent US FDA approval for front-line therapy for patients with therapy-related AML and AML with myelodysplasia-related changes based on a large multicenter Phase III clinical trial. This review summarizes the clinical development of CPX-351 as induction therapy.", "Somatostatin (Som), one of the most concentrated neuropeptides in the brain, is highly expressed in the olfactory bulb (OB). However, the temporal profile by which OB somatostatin-expressing (Som+) interneurons are produced and the molecular mechanisms controlling this profile are totally unknown. In the present study, we found that all the Som+ interneurons in the mouse external plexiform layer (EPL) and the rat glomerular layer (GL) express the transcription factor Sp8.Using the 5-bromo-2'-deoxyuridine (BrdU) birth dating method, combined with immunostaining, we showed that the generation of Som+ interneurons in the mouse and rat OB is confined to the later embryonic and earlier postnatal stages. Within the mouse OB, the production of Som+ interneurons is maximal during late embryogenesis and decreases after birth, whereas the generation of Som+ interneurons is low during embryogenesis and increases gradually after birth in the rat OB. Interestingly, genetic ablation of Sp8 by cre/loxP-based recombination severely reduces the number of Som+ interneurons in the EPL of the mouse OB. Taken together, these results suggest that Sp8 is required for the normal production of Som+ interneurons in the EPL of the mouse OB." ]

[ "Cell culture is a fundamental tool in proteomics where mammalian cells are cultured in vitro using a growth medium often supplemented with 5-15% FBS. Contamination by bovine proteins is difficult to avoid because of adherence to the plastic vessel and the cultured cells. We have generated peptides from bovine serum using four sample preparation methods and analyzed the peptides by high mass accuracy LC-MS/MS. Distinguishing between bovine and human peptides is difficult because of a considerable overlap of identical tryptic peptide sequences. Pitfalls in interpretation, different database search strategies to minimize erroneous identifications and an augmented contaminant database are presented.", "INTRODUCTION: Although 4 mast cell mediators can be routinely measured, the results of initial testing to evaluate symptoms of mast cell activation have not been widely reported.OBJECTIVE: We examined the results of mast cell mediator tests used to assess patients with mast cell activation symptoms during a 5-year time span.METHODS: After excluding patients with alternative diagnoses, records of 108 patients were reviewed for initial mediator test results. Mediators included serum tryptase plus urinary N-methyl histamine (N-MH), leukotriene (LT)E4, and 11β-prostaglandin (PG) F2α or 2,3-dinor-11β-PGF2α (BPG).RESULTS: Most commonly, either a single measured elevation of 1 mediator (48.1%) or elevations of 2 (33.3%) mediators was found at baseline, during symptoms or at both time points. Elevated levels of a single mediator in order of frequency were: BPG > tryptase > LTE4 > N-MH, and for two mediators: BPG + tryptase (n = 16 cases) > BPG + LTE4 (n = 9) > BPG + N-MH (n = 6). Elevations in 3 mediators (n = 8) or 4 mediators (n = 2) were much less frequent. Monoclonal mast cell activation syndrome (n = 6), and systemic and cutaneous mastocytosis (n = 4) were also infrequent. Baseline plus symptom-associated tryptase values were obtained in only 7 patients.CONCLUSIONS: This survey suggests that elevations of 1 or 2 mediators are the most common (total 81.4% of cases) findings from initial tests for mast cell activation. Elevated levels of BPG were most commonly found both singly and in combination with other mediators, followed by the finding of elevated levels of tryptase. Baseline plus symptom-associated tryptase levels were measured in only a minority of patients.", "Weight loss is associated with improved quality of life in some, but not all, weight loss trials. We evaluated changes at 56 weeks in quality of life, measured by the Impact of Weight on Quality of Life-Lite (IWQOL-Lite) questionnaire, in a pooled analysis of patient-level data from four randomized controlled Phase 3 studies of naltrexone/bupropion (NB32 or Contrave®). The total number of subjects was 3362 (NB32 = 2043; placebo = 1319; mean body mass index = 36.3 kg m(2); mean age = 46). Improvements in IWQOL-Lite Total Score were greater in subjects treated with NB32 (11.9 points [SE 0.3]) vs. placebo (8.2 points [SE 0.3]; P < 0.001), corresponding to weight reductions of 7.0% (SE 0.2) and 2.3% (SE 0.2), respectively. Greater improvements were also observed for NB32 vs. placebo on all five subscale scores of the IWQOL-Lite. Fifty per cent of NB32-treated subjects achieved clinically meaningful improvements in IWQOL-Lite Total Score vs. 32.3% of placebo-treated subjects (odds ratio, 95% confidence interval; 2.09, 1.79-2.44). Subjects losing the most weight (≥ 15% of baseline weight) experienced the greatest improvement in IWQOL-Lite Total Score (19.3 points [SE 0.7] for NB32 and 18.7 points [SE 1.3] for placebo; P = 0.624). Improved quality of life was associated with weight reduction and was achieved in more subjects treated with NB32 than placebo.", "Ustekinumab, a human immunoglobulin G1 kappa (IgG1k) monoclonal antibody that binds with high affinity to human interleukin-12 and interleukin-23, has demonstrated efficacy in patients with psoriasis. The objective of this study was to perform exposure-response modeling to increase the understanding of reduction in disease severity following treatment with ustekinumab in patients with moderate to severe psoriasis who participate in two phase III studies (PHOENIX 1 and PHOENIX 2). Patients were randomly assigned to receive ustekinumab 45 mg or 90 mg (n = 1312; 11,624 Psoriasis Area and Severity Index [PASI] scores) or placebo (n = 665; 3278 PASI scores). Disease severity was assessed using PASI scores. A population mechanism-based exposure-response model of ustekinumab using NONMEM was developed using serum ustekinumab concentrations and PASI scores. The pharmacodynamic response effect was the reduction in PASI score. The placebo effect, although minor, was also integrated into the model. None of the covariate factors evaluated (eg, demographics, baseline disease characteristics, comorbidities) significantly contributed to the between-subject variability in the pharmacodynamic parameters. The developed exposure-response model can serve as a basis to support future alternative dosing regimens for ustekinumab in patients with moderate to severe plaque psoriasis. A robust exposure-response relationship has been confirmed for ustekinumab in psoriasis.", "Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.", "OBJECTIVE: To evaluate the predictive values for disease progression of various antibodies against citrullinated peptide proteins (ACPA) and their relation to PTPN22 1858C/T polymorphism and HLA-DRB1 alleles in early rheumatoid arthritis (RA).METHODS: The ACPA, e.g., antibodies against mutated citrullinated vimentin (MCV), cyclic citrullinated peptides (CCP) type 2 and 3 (both of IgG isotype) and 3.1 (of both IgG and IgA isotypes), were analyzed at baseline in patients with early RA (n = 210) and in population controls (n = 102) using an enzyme immunoassay. A receiver-operating characteristic curve was constructed for each antibody. Disease activity [swollen and tender joints, visual analog scale for global health, and erythrocyte sedimentation rate (ESR)] was evaluated at baseline and regularly for 24 months. Radiographs of hands and feet were graded using the Larsen score.RESULTS: Patients with anti-MCV antibodies had significantly less reduction in Disease Activity Score (DAS28) over time (p < 0.01), and significantly increased area under the curve (AUC) for DAS28 (p < 0.05), ESR (p < 0.01), C-reactive protein (p < 0.01), and swollen joint count (p = 0.057) compared to those without. Corresponding differences were not found in patients with anti-CCP2, CCP3, and CCP3.1 antibodies. Radiological progression (p < 0.0001-0.01) and radiological outcome (p < 0.0001-0.01) at 24 months were significantly predicted by all ACPA after baseline adjustments. PTPN22 T variant and HLA-DRB1 alleles were not related to radiological progression or inflammatory activity over time.CONCLUSION: Anti-MCV antibodies are associated with a more severe RA disease, as measured by DAS28, ESR, and swollen joint count over time, compared with anti-CCP2, CCP3, and CCP3.1 antibodies. Radiological progression was predicted equally by all 4 autoantibodies.", "Neuronal and/or axonal hyperactivity and hyperexcitability is an important feature of motor neuron diseases. It results clinically in cramps and fasciculations. It is not specific to motor neuron diseases, and can occur in healthy subjects, as well as in various pathologies of the peripheral nervous system, including nerve hyperexcitability syndromes. Hyperexcitability plays an important and debated role in the pathophysiology of motor neuron diseases, especially in amyotrophic lateral sclerosis (ALS). The mechanisms causing hyperexcitability are not yet clearly identified. While most studies favor a distal axonal origin site of fasciculations, some of the fasciculations could be of cortical origin. The consequences of hyperexcitability are also discussed, whether it is rather protective or deleterious in the disease course. Fasciculations are depicted both clinically and using electromyogram, and more recently the interest of ultrasound has been highlighted. The importance of fasciculation potentials in the diagnosis of ALS led to changes in electrophysiological criteria at Awaji consensus conference. The contribution of these modifications to ALS diagnosis has been the subject of several studies. In clinical practice, it is necessary to distinguish fasciculations potentials of motor neuron disease from benign fasciculations. In most studies of fasciculation potentials in ALS, the presence of complex fasciculation potentials appears to be relevant for the diagnosis and the prognosis of the disease." ]

[ "Arctic yeast Leucosporidium sp. produces a glycosylated ice-binding protein (LeIBP) with a molecular mass of ∼25 kDa, which can lower the freezing point below the melting point once it binds to ice. LeIBP is a member of a large class of ice-binding proteins, the structures of which are unknown. Here, we report the crystal structures of non-glycosylated LeIBP and glycosylated LeIBP at 1.57- and 2.43-Å resolution, respectively. Structural analysis of the LeIBPs revealed a dimeric right-handed β-helix fold, which is composed of three parts: a large coiled structural domain, a long helix region (residues 96-115 form a long α-helix that packs along one face of the β-helix), and a C-terminal hydrophobic loop region ((243)PFVPAPEVV(251)). Unexpectedly, the C-terminal hydrophobic loop region has an extended conformation pointing away from the body of the coiled structural domain and forms intertwined dimer interactions. In addition, structural analysis of glycosylated LeIBP with sugar moieties attached to Asn(185) provides a basis for interpreting previous biochemical analyses as well as the increased stability and secretion of glycosylated LeIBP. We also determined that the aligned Thr/Ser/Ala residues are critical for ice binding within the B face of LeIBP using site-directed mutagenesis. Although LeIBP has a common β-helical fold similar to that of canonical hyperactive antifreeze proteins, the ice-binding site is more complex and does not have a simple ice-binding motif. In conclusion, we could identify the ice-binding site of LeIBP and discuss differences in the ice-binding modes compared with other known antifreeze proteins and ice-binding proteins.", "Author information:(1)Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Division of Medical Oncology, National Cancer Centre, Singapore; Oncology Academic Clinical Program, Duke-NUS Graduate Medical School, Singapore.(2)Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.(3)Institute of Molecular and Cell Biology, A∗STAR, Singapore.(4)Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.(5)Centre for Computational Biology, Duke-NUS Graduate Medical School, Singapore.(6)Department of Pathology, Singapore General Hospital, Singapore.(7)Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio. Electronic address: engc@ccf.org.", "The depressed sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) and Ca2+-release channels (ryanodine receptor RyR2) are involved in the diabetic cardiomyopathy. However, an implication of a down-regulation of FK506-binding protein or calstabin-2 (FKBP12.6) is undefined. It was hypothesized that the down-regulation of FKBP12.6 and SERCA2a of the intracellular calcium handling system is closely related to an up-regulated endothelin (ET) system. An ET receptor antagonist CPU0213 is newly discovered and expected to ameliorate cardiac insufficiency which is mediated by the depressed FKBP12.6 and SERCA2a in diabetic rat heart. Diabetes was developed in male Sprague-Dawley rats 8 weeks after an injection of streptozotocin (60 mg/kg IP), and CPU0213 was instituted 30 mg/kg, SC in the last 4 weeks. The assessment of the cardiac function, cardiac calcium handling proteins, endothelin system, and redox enzyme system were conducted. The compromised cardiac function in diabetic rats was accompanied by a significant down-regulation of expression of FKBP12.6 as well as SERCA2a and phospholamban. These were closely linked with an increased ET-1 and up-regulation of endothelin converting enzyme, PropreET1, and inducible nitric oxide synthase mRNA in diabetic cardiomyopathy. After 4-week treatment, CPU0213 was capable to attenuate completely the down-regulated FKBP12.6 and SERCA2a, and up-regulated ET system in association with a recovery of the cardiac insufficiency of diabetic cardiomyopathy.", "PURPOSE: The zonule of Zinn (ciliary zonule) is a system of fibers that centers the crystalline lens on the optical axis of the eye. Mutations in zonule components underlie syndromic conditions associated with a broad range of ocular pathologies, including microspherophakia and ectopia lentis. Here, we used HPLC-mass spectrometry to determine the molecular composition of the zonule.METHODS: Tryptic digests of human and bovine zonular samples were analyzed by HPLC-mass spectrometry. The distribution of selected components was confirmed by immunofluorescence confocal microscopy. In bovine samples, the composition of the equatorial zonule was compared to that of the hyaloid zonule and vitreous humor.RESULTS: The 52 proteins common to the zonules of both species accounted for >95% of the zonular protein. Glycoproteins constituted the main structural components, with two proteins, FBN1 and LTBP2, constituting 70%-80% of the protein. Other abundant components were MFAP2, EMILIN-1, and ADAMTSL-6. Lysyl oxidase-like 1, a crosslinking enzyme implicated in collagen and elastin biogenesis, was detected at significant levels. The equatorial and hyaloid zonular samples were compositionally similar to each other, although the hyaloid sample was relatively enriched in the proteoglycan opticin and the fibrillar collagens COL2A1, COL11A1, COL5A2, and COL5A3.CONCLUSIONS: The zonular proteome was surprisingly complex. In addition to structural components, it contained signaling proteins, protease inhibitors, and crosslinking enzymes. The equatorial and hyaloid zonules were similar in composition, but the latter may form part of a composite structure, the hyaloid membrane, that stabilizes the vitreous face.", "Ice binding proteins (IBPs) have been attracting significant interest on account of their characteristic of inhibiting ice growth and recrystallization. Owing to their unique characteristics, IBPs have been studied for applications in food, pharmaceuticals, and medicine, as well as from a general scientific point of view. In this study, we have used differential scanning calorimetry (DSC) and Raman spectroscopy as tools to understand the ice binding activity of the Arctic-yeast-originating extracellular ice binding glycoprotein (LeIBP) isolated from Leucosporidium sp. AY30. From the DSC results, an increase in the specific heat capacity was confirmed for 1 mg/mL LeIBP, which suggested that additional heat flow was required for the change in temperature. In addition, the temperature corresponding to the phase change of the solution was measured, and Raman spectroscopy was carried out on the frozen and molten phases, respectively. From the results of Raman analysis, we confirmed that the helical vibrations related to the ice binding sites on LeIBP were dramatically suppressed when the LeIBP solution was frozen. Furthermore, principal component analysis (PCA) of the Raman spectra yielded the contrast factor between the freezing and melting states. Both DSC and Raman spectroscopy are widely used to study the ice binding activity and the structural changes associated with molecular vibrations in cryobiology.", "Though the field has moved with glacial speed, gene therapies have been carried out successfully in patients with bone marrow disorders including immune deficiencies. The field may be poised to move forward more rapidly, but many barriers have yet to be surmounted.", "The aim of tissue engineering is to produce functional three-dimensional (3D) tissue substitutes. Regarding native organ and tissue complexity, cell density and cell spatial 3D organization, which influence cell behavior and fate, are key parameters in tissue engineering. Laser-Assisted Bioprinting (LAB) allows one to print cells and liquid materials with a cell- or picoliter-level resolution. Thus, LAB seems to be an emerging and promising technology to fabricate tissue-like structures that have the physiological functionality of their native counterparts. This technology has additional advantages such as automation, reproducibility, and high throughput. It makes LAB compatible with the (industrial) fabrication of 3D constructs of physiologically relevant sizes. Here we present exhaustively the numerous steps that allow printing of viable cells with a well-preserved micrometer pattern. To facilitate the understanding of the whole cell patterning experiment using LAB, it is discussed in two parts: (1) preprocessing: laser set-up, bio-ink cartridge and bio-paper preparation, and pattern design; and (2) processing: bio-ink printing on the bio-paper.", "Ice-binding proteins (IBPs) can bind to the ice crystal and inhibit its growth. Because this property of IBPs can increase the freeze-thaw survival of cells, IBPs have attracted the attention from industries for their potential use in biotechnological applications. However, their use was largely hampered by the lack of the large-scale recombinant production system. In this study, the codon-optimized IBP from Leucosporidium sp. (LeIBP) was constructed and subjected to high-level expression in methylotrophic Pichia pastoris system. In a laboratory-scale fermentation (7 L), the optimal induction temperature and pH were determined to be 25 °C and 6.0, respectively. Further, employing glycerol fed-batch phase prior to methanol induction phase enhanced the production of recombinant LelBP (rLeIBP) by ∼100 mg/l. The total amount of secreted proteins at these conditions (25 °C, pH 6.0, and glycerol fed-batch phase) was ∼443 mg/l, 60 % of which was rLeIBP, yielding ∼272 mg/l. In the pilot-scale fermentation (700 L) under the same conditions, the yield of rLeIBP was 300 mg/l. To our best knowledge, this result reports the highest production yield of the recombinant IBP. More importantly, the rLeIBP secreted into culture media was stable and active for 6 days of fermentation. The thermal hysteresis (TH) activity of rLeIBP was about 0.42 °C, which is almost the same to those reported previously. The availability of large quantities of rLeIBP may accelerate further application studies.", "The fractal globule is a compact polymer state that emerges during polymer condensation as a result of topological constraints which prevent one region of the chain from passing across another one. This long-lived intermediate state was introduced in 1988 (Grosberg et al. 1988) and has not been observed in experiments or simulations until recently (Lieberman-Aiden et al. 2009). Recent characterization of human chromatin using a novel chromosome conformational capture technique brought the fractal globule into the spotlight as a structural model of human chromosome on the scale of up to 10 Mb (Lieberman-Aiden et al. 2009). Here, we present the concept of the fractal globule, comparing it to other states of a polymer and focusing on its properties relevant for the biophysics of chromatin. We then discuss properties of the fractal globule that make it an attractive model for chromatin organization inside a cell. Next, we connect the fractal globule to recent studies that emphasize topological constraints as a primary factor driving formation of chromosomal territories. We discuss how theoretical predictions, made on the basis of the fractal globule model, can be tested experimentally. Finally, we discuss whether fractal globule architecture can be relevant for chromatin packing in other organisms such as yeast and bacteria.", "The aim of the study was to determine the frequency and type of MRSA strains and antibiotic susceptibility in Al-Zahra Hospital, Isfahan, Iran. In an analytic descriptive survey in 2005 and early 2006, patients admitted to the hospital who contracted S. aureus nosocomial infections were enrolled in the study. All isolates were identified by the conventional laboratory tests. Minimal Inhibitory Concentration (MIC) of oxacillin on isolated bacteria was determined by E-Test method. According to Clinical and Laboratory Standard Institute (CLSI) criteria all strains with MIC of > or = 4 microg for oxacillin were identified as MRSA. Intrinsic high level resistance (mecA positive) and borderline oxacillin resistant Staphylococcus aureus (BORSA) were detected by amoxicillin-clavulanate E-test strips. Strains with MIC of > or = 4 microg for oxacillin and > or = 8 microg for amoxicillin-clavulanate were identified as mecA positive MRSA. Other staphylococcus with MIC > or = 4 microg for oxacillin and < or = 4 for amoxicillin-clavulanate were identified as mecA negative MRSA (BORSA). MIC of vancomycin also was determined on isolated bacteria. Data were analyzed by SPSS version 13 and Who net version 5. Out of 134 Staphylococcus aureus samples which were isolated from nosocomial infections 90 (67.2%) were MRSA. Sixty seven out of 90 (74.5%) MRSA were mecA positive and 23 out of 90 (25.5%) were mecA negative (BORSA). Although most of the MRSA strains were isolated from surgical site infections, there were no statistically significant differences between types of Staphylococcus aureus growing from variant sites of infections. Only one (1.49) of the mecA positive MRSA had reduced susceptibility to vancomycin but all of the mecA-negative MRSA (BORSA) were sensitive to it. Because one fourth of our staphylococcus strains are mecA negative BORSA and there is no alternative for vancomycin against mecA positive MRSA and Enterococcus spp. in our hospital, vancomycin should be reserved only for life threatening infections due to these organisms. Thus MRSA typing should be done to choose appropriate antibiotic for optimal treatment of MRSA infections.", "BACKGROUND/AIMS: Some sodium glucose co-transporter 2 (SGLT2) inhibitors are approved for the treatment of patients with type 2 diabetes mellitus (T2DM) with an estimated glomerular filtration rate (eGFR) of ≥45 ml/min/1.73 m(2). The efficacy and safety of canagliflozin, an approved SGLT2 inhibitor, was evaluated in patients with stage 3 chronic kidney disease (CKD; eGFR ≥30 to <60 ml/min/1.73 m(2)).METHODS: This analysis used integrated data from four randomized, placebo-controlled, phase 3 studies that enrolled patients with T2DM and stage 3 CKD. RESULTS are presented for the overall population as well as subgroups with stage 3a CKD (eGFR ≥45 and <60 ml/min/1.73 m(2)) and stage 3b CKD (eGFR ≥30 and <45 ml/min/1.73 m(2)).RESULTS: Among all subjects studied with stage 3 CKD, placebo-subtracted reductions in HbA1c (-0.38 and -0.47%; p < 0.001), body weight (-1.6 and -1.9%; p < 0.001), and systolic blood pressure (-2.8 and -4.4 mm Hg; p < 0.01) were seen with canagliflozin 100 and 300 mg, respectively. Decreases in HbA1c, body weight, and systolic blood pressure were examined in the stage 3a and 3b CKD subgroups, with greater decreases in HbA1c, -0.47% (-0.61, -0.32) and body weight in subjects in stage 3a CKD, -1.8% (-2.3, -1.2) with canagliflozin 100 mg. Initial declines in eGFR were seen early following treatment initiation with canagliflozin, but trended towards baseline over time. The most common adverse events with canagliflozin included genital mycotic infections and adverse events related to reduced intravascular volume likely secondary to osmotic diuresis.CONCLUSION: In subjects with T2DM and stage 3 CKD, canagliflozin reduced HbA1c, body weight, and blood pressure, and was generally well tolerated.", "Rigel Pharmaceuticals Inc is developing fostamatinib, a prodrug of the spleen tyrosine kinase (Syk) inhibitor R-406, for the potential treatment of autoimmune diseases such as rheumatoid arthritis (RA), idiopathic thrombocytopenic purpura (ITP) and B-cell lymphomas. Syk is a key mediator of Fc and B-cell receptor signaling in inflammatory cells, such as B-cells, mast cells, macrophages and neutrophils. Preclinical studies of R-406 or fostamatinib demonstrated a significant reduction in major inflammatory mediators such as TNFalpha, IL-1, IL-6 and IL-18, leading to reduced inflammation and bone degradation in models of RA. In a phase II clinical trial, fostamatinib treatment effectively improved American College of Rheumatology response rates in patients with RA. Preclinical studies and phase II trials also suggested the potential of using fostamatinib for the treatment of ITP and B-cell lymphomas, by increasing platelet counts and inducing response rates, respectively. Fostamatinib is orally bioavailable and was well tolerated in phase I and II trials, with the most common side effect being gastrointestinal symptoms. At the time of publication, phase II trials for fostamatinib were ongoing in patients with RA, ITP and B-cell lymphomas. The Syk inhibitor appears to be a promising therapeutic for immunological diseases, but further data are required to establish the efficacy and long-term safety of the drug in humans.", "Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder caused by mutation in either Tsc1 or Tsc2 genes that leads to the hyper activation of the mTOR pathway, a key signalling pathway for synaptic plasticity. TSC is characterized by benign tumors arising in different organs and severe neuropsychiatric symptoms, such as epilepsy, intellectual disability, autism, anxiety and depressive behaviour. Rapamycin is a potent inhibitor of mTOR and its efficacy in treating epilepsy and neurological symptoms remains elusive. In a mouse model in which Tsc1 has been deleted in embryonic telencephalic neural stem cells, we analyzed anxiety- and depression-like behaviour by elevated-plus maze (EPM), open-field test (OFT), forced-swim test (FST) and tail-suspension test (TST), after chronic administration of rapamycin. In addition, spectral analysis of background EEG was performed. Rapamycin-treated mutant mice displayed a reduction in anxiety- and depression-like phenotype, as shown by the EPM/OFT and FST, respectively. These results were inline with EEG power spectra outcomes. The same effects of rapamycin were observed in wild-type mice. Notably, in heterozygous animals we did not observe any EEG and/or behavioural variation after rapamycin treatment. Together these results suggest that both TSC1 deletion and chronic rapamycin treatment might have a role in modulating behaviour and brain activity, and point out to the potential usefulness of background EEG analysis in tracking brain dysfunction in parallel with behavioural testing.", "1. ", "Ice-binding proteins (IBPs) inhibit ice growth through direct interaction with ice crystals to permit the survival of polar organisms in extremely cold environments. FfIBP is an ice-binding protein encoded by the Antarctic bacterium Flavobacterium frigoris PS1. The X-ray crystal structure of FfIBP was determined to 2.1 Å resolution to gain insight into its ice-binding mechanism. The refined structure of FfIBP shows an intramolecular disulfide bond, and analytical ultracentrifugation and analytical size-exclusion chromatography show that it behaves as a monomer in solution. Sequence alignments and structural comparisons of IBPs allowed two groups of IBPs to be defined, depending on sequence differences between the α2 and α4 loop regions and the presence of the disulfide bond. Although FfIBP closely resembles Leucosporidium (recently re-classified as Glaciozyma) IBP (LeIBP) in its amino-acid sequence, the thermal hysteresis (TH) activity of FfIBP appears to be tenfold higher than that of LeIBP. A comparison of the FfIBP and LeIBP structures reveals that FfIBP has different ice-binding residues as well as a greater surface area in the ice-binding site. Notably, the ice-binding site of FfIBP is composed of a T-A/G-X-T/N motif, which is similar to the ice-binding residues of hyperactive antifreeze proteins. Thus, it is proposed that the difference in TH activity between FfIBP and LeIBP may arise from the amino-acid composition of the ice-binding site, which correlates with differences in affinity and surface complementarity to the ice crystal. In conclusion, this study provides a molecular basis for understanding the antifreeze mechanism of FfIBP and provides new insights into the reasons for the higher TH activity of FfIBP compared with LeIBP.", "Angiosperms require light for chlorophyll biosynthesis because one reaction in the pathway, the reduction of protochlorophyllide (Pchlide) to chlorophyllide, is catalyzed by the light-dependent protochlorophyllide oxidoreductase (POR). Here, we report that Cell growth defect factor1 (Cdf1), renamed here as chaperone-like protein of POR1 (CPP1), an essential protein for chloroplast development, plays a role in the regulation of POR stability and function. Cdf1/CPP1 contains a J-like domain and three transmembrane domains, is localized in the thylakoid and envelope membranes, and interacts with POR isoforms in chloroplasts. CPP1 can stabilize POR proteins with its holdase chaperone activity. CPP1 deficiency results in diminished POR protein accumulation and defective chlorophyll synthesis, leading to photobleaching and growth inhibition of plants under light conditions. CPP1 depletion also causes reduced POR accumulation in etioplasts of dark-grown plants and as a result impairs the formation of prolamellar bodies, which subsequently affects chloroplast biogenesis upon illumination. Furthermore, in cyanobacteria, the CPP1 homolog critically regulates POR accumulation and chlorophyll synthesis under high-light conditions, in which the dark-operative Pchlide oxidoreductase is repressed by its oxygen sensitivity. These findings and the ubiquitous presence of CPP1 in oxygenic photosynthetic organisms suggest the conserved nature of CPP1 function in the regulation of POR." ]

[ "Author information:(1)1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.(2)1] Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan [2].(3)Division of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.(4)1] Division of Radiation Information Registry, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan [2].(5)1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] Department of Hematology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.(6)1] Division of Pathology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3026, USA [2] Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3026, USA.(7)Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.(8)1] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan [2] Laboratory for Lymphocyte Development, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.(9)Division of Cellular Therapy and Division of Stem Cell Signaling, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo 108-8639, Japan.", "Author information:(1)Department of Ophthalmology, Department of Clinical Chemistry and Hematology.(2)Department of Medical Genetics.(3)Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA, Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.(4)The Rotterdam Eye Hospital, Rotterdam, The Netherlands.(5)Department of Ophthalmology.(6)Department of Ophthalmology and Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.(7)Department of Ophthalmology and.(8)Unidad de Uveitis. Servicio de Oftalmología, Hospital Universitario de León, León, Spain.(9)Instituto de Parasitología y Biomedicina López-Neyra, IPBLN, CSIC, Granada, Spain.(10)Institut Clinic d'Oftalmologia (ICOF), Hospital Clinic de Barcelona, Barcelona, Spain.(11)Moorfields Eye Hospital NHS Foundation Trust, London, UK.(12)Department of Psychiatry, Rudolph Magnus Institute of Neuroscience.(13)Department of Psychiatry, Rudolph Magnus Institute of Neuroscience, Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA and.(14)Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, The Netherlands.(15)Department of Medical Genetics, Department of Epidemiology, University Medical Center Utrecht, Utrecht, The Netherlands.(16)Department of Clinical Chemistry and Hematology.(17)Department of Medical Genetics, B.P.C.Koeleman@umcutrecht.nl.", "Insomnia has become a major public health issue in recent times. Although quality of sleep is affected by environmental, psychophysiological, and pharmacological factors, diet and nutrient intake also contribute to sleep problems. This study investigated the association between nutrient intake and co-morbid symptoms associated with sleep status among selected adults. Subjects in this study included 87 men and women aged 21-45 years. Presence of insomnia was assessed using the Insomnia Screening Questionnaire, and dietary intake was measured over three consecutive days by dietary survey. Descriptive analysis, ANOVA, and Chi-Square tests were performed to compute and interpret the data. Approximately 60% of the participants were insomniacs. People with insomnia consumed significantly lesser quantities of nutrients as compared to normal sleepers. Differences in intakes of energy, carbohydrates, folic acid, and B(12) were highly significant (P < 0.002). Further, intakes of protein, fat, and thiamine were significantly different (P < 0.021) between insomniacs and normal sleepers. The nutrient intake pattern of the insomniacs with co-morbid symptoms was quite different from that of the normal sleepers. Based on these results, it is probable that there is an association between nutrition deficiency, co-morbid symptoms, and sleep status. More studies are required to confirm these results.", "Virtually all patients of the rare inflammatory eye disease birdshot chorioretinopathy (BSCR) carry the HLA-A*29:02 allele. BSCR is also associated with endoplasmic reticulum aminopeptidase 2 (ERAP2), an enzyme involved in processing HLA class I ligands, thus implicating the A*29:02 peptidome in this disease. To investigate the relationship between both risk factors we employed label-free quantitative mass spectrometry to characterize the effects of ERAP2 on the A*29:02-bound peptidome. An ERAP2-negative cell line was transduced with lentiviral constructs containing GFP-ERAP2 or GFP alone, and the A*29:02 peptidomes from both transduced cells were compared. A similar analysis was performed with two additional A*29:02-positive, ERAP1-concordant, cell lines expressing or not ERAP2. In both comparisons the presence of ERAP2 affected the following features of the A*29:02 peptidome: 1) Length, with increased amounts of peptides >9-mers, and 2) N-terminal residues, with less ERAP2-susceptible and more hydrophobic ones. The paradoxical effects on peptide length suggest that unproductive binding to ERAP2 might protect some peptides from ERAP1 over-trimming. The influence on N-terminal residues can be explained by a direct effect of ERAP2 on trimming, without ruling out and improved processing in concert with ERAP1. The alterations in the A*29:02 peptidome suggest that the association of ERAP2 with BSCR is through its effects on peptide processing. These differ from those on the ankylosing spondylitis-associated HLA-B*27. Thus, ERAP2 alters the peptidome of distinct HLA molecules as a function of their specific binding preferences, influencing different pathological outcomes in an allele-dependent way.", "Mood and anxiety disorders are common in women during their childbearing years. The prevalence of depression has been reported to be between 10% and 16% during pregnancy. The use of selective serotonin reuptake inhibitors during pregnancy or lactation is, to date, not promoted because of lack of safety documentation. However, the off-label use of these drugs has been common for several years. In the treatment of mood and anxiety disorders during pregnancy, the serotonin reuptake inhibitors are often preferred over tricyclic antidepressants because of their relatively few adverse effects and safety in overdose. This has created concern among women planning pregnancies and pregnant women, as well as among their families and physicians. Several studies and reports of the use of serotonin reuptake inhibitors during both pregnancy and lactation have been published and advanced our knowledge. We here review and discuss those studies which have been published so far on this subject.", "Apolipoprotein (apo) E is a 299-residue protein which functions as a key regulator of plasma lipid levels. Human apoE exists as three common isoforms and the parent form, apoE3, operates optimally in promoting clearance of triglyceride (TG)-rich lipoproteins and is associated with normal plasma lipid levels. This result occurs because apoE3 possesses both the requisite lipid-binding ability and affinity for the low density lipoprotein receptor (LDLR) to mediate appropriate lipolytic processing and endocytosis of TG-rich lipoprotein remnant particles. ApoE2 which differs from apoE3 by the single amino acid substitution Arg158Cys located near the LDLR recognition site exhibits impaired binding to the receptor and an inability to promote clearance of TG-rich lipoprotein remnant particles; this isoform is associated with Type-III hyperlipoproteinemia. ApoE4 which differs from apoE3 by the single amino acid substitution Cys112Arg is also associated with dyslipidemia although binding of this isoform to the LDLR is unaffected. The amino acid substitution affects the organization and stability of both the N-terminal helix bundle domain and separately folded C-terminal domain so that apoE4 has enhanced lipid binding ability. As a consequence, apoE4 binds better than apoE3 to the surface of very low density lipoprotein (VLDL) particles and impairs their lipolytic processing in the circulation so that apoE4 is associated with a more pro-atherogenic lipoprotein-cholesterol distribution (higher VLDL-cholesterol/high density lipoprotein-cholesterol ratio). This review summarizes current understanding of the structural differences between apoE2, apoE3, and apoE4, and the molecular mechanisms responsible for the alterations in lipoprotein metabolism resulting from this polymorphism of apoE. Detailed knowledge of how expression of structurally distinct apoE variants modifies lipoprotein metabolism provides a basis for developing ways to manipulate the functionality of apoE in vivo.", "Oncogenic BRAF and NRAS mutations are frequent in malignant melanoma. BRAF that is activated by the common V600E and other mutations, as well as by upstream NRAS mutations, has been shown to require the molecular chaperone heat shock protein 90 (HSP90) for stabilization and is depleted by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG)]. Here, we explore the possible relationship between tumor BRAF and NRAS mutations and clinical response to 17-AAG in six patients with metastatic malignant melanoma who received pharmacologically active doses of 17-AAG as part of a phase I clinical trial. One patient with disease stabilization for 49 months had a (G13D)NRAS mutation and (WT)BRAF. A second patient who had stable disease for 15 months had a (V600E)BRAF mutation and (WT)NRAS. These preliminary results suggest that BRAF and NRAS mutation status should be determined in prospective phase II studies of HSP90 inhibitors in melanoma.", "Permanent modification of the human genome in vivo is impractical owing to the low frequency of homologous recombination in human cells, a fact that hampers biomedical research and progress towards safe and effective gene therapy. Here we report a general solution using two fundamental biological processes: DNA recognition by C2H2 zinc-finger proteins and homology-directed repair of DNA double-strand breaks. Zinc-finger proteins engineered to recognize a unique chromosomal site can be fused to a nuclease domain, and a double-strand break induced by the resulting zinc-finger nuclease can create specific sequence alterations by stimulating homologous recombination between the chromosome and an extrachromosomal DNA donor. We show that zinc-finger nucleases designed against an X-linked severe combined immune deficiency (SCID) mutation in the IL2Rgamma gene yielded more than 18% gene-modified human cells without selection. Remarkably, about 7% of the cells acquired the desired genetic modification on both X chromosomes, with cell genotype accurately reflected at the messenger RNA and protein levels. We observe comparably high frequencies in human T cells, raising the possibility of strategies based on zinc-finger nucleases for the treatment of disease." ]

[ "Osteolytic bone disease is the most common complication of multiple myeloma, resulting in skeletal complications that cause significant morbidity and mortality. Currently, bisphosphonates (BPs) are the mainstay for the treatment of myeloma bone disease. Zoledronic acid which has been found to be superior to clodronate, both in terms of reduction of skeletal-related events (SREs) and survival, and pamidronate are used for the management of myeloma-related bone disease. Patients with active disease (not in CR or VGPR) should receive BPs (especially zoledronic acid) even after two years of administration. Radiotherapy and surgical interventions can also be used for specific conditions, such as pathological fractures, spinal cord compression or uncontrolled pain. The better understanding of the biology of myeloma bone disease has led to the production of several novel agents, such as denosumab (targeting RANKL), sotatercept (activin-A antagonist) and romosozumab (targeting sclerostin) that appear very promising and have entered to clinical development.", "Author information:(1)Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA.(2)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.(3)Gene Regulation, Laboratory of Pathology, NCI, NIH, Bethesda, MD 20892, USA.(4)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA.(5)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.(6)Laboratory of Genome Integrity, NCI, NIH, Bethesda, MD 20892, USA.(7)The Jackson Laboratory for Genomic Medicine and Department of Genetic and Development Biology, University of Connecticut, Farmington, CT 06030, USA.(8)Laboratory of Immunogenetics, NIAID, NIH, Rockville, MD 20852, USA.(9)Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA.(10)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China. Electronic address: erez@erez.com.(11)Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA; Center of Cancer Research, NCI, NIH, Bethesda, MD 20892, USA. Electronic address: rafael.casellas@nih.gov.", "The Unipept web application (http://unipept.ugent.be) supports biodiversity analysis of large and complex metaproteome samples using tryptic peptide information obtained from shotgun MS/MS experiments. Its underlying index structure is designed to quickly retrieve all occurrences of a tryptic peptide in UniProtKB records. Taxon-specificity of the tryptic peptide is successively derived from these occurrences using a novel lowest common ancestor approach that is robust against taxonomic misarrangements, misidentifications, and inaccuracies. Not taking into account this identification noise would otherwise result in drastic loss of information. Dynamic treemaps visualize the biodiversity of metaproteome samples, which eases the exploration of samples with highly complex compositions. The potential of Unipept to gain novel insights into the biodiversity of a sample is evaluated by reanalyzing publicly available metaproteome data sets taken from the bacterial phyllosphere and the human gut.", "Deleterious mutations inevitably emerge in any evolutionary process and are speculated to decisively influence the structure of the genome. Meiosis, which is thought to play a major role in handling mutations on the population level, recombines chromosomes via non-randomly distributed hot spots for meiotic recombination. In many genomes, various types of genetic elements are distributed in patterns that are currently not well understood. In particular, important (essential) genes are arranged in clusters, which often cannot be explained by a functional relationship of the involved genes. Here we show by computer simulation that essential gene (EG) clustering provides a fitness benefit in handling deleterious mutations in sexual populations with variable levels of inbreeding and outbreeding. We find that recessive lethal mutations enforce a selective pressure towards clustered genome architectures. Our simulations correctly predict (i) the evolution of non-random distributions of meiotic crossovers, (ii) the genome-wide anti-correlation of meiotic crossovers and EG clustering, (iii) the evolution of EG enrichment in pericentromeric regions and (iv) the associated absence of meiotic crossovers (cold centromeres). Our results furthermore predict optimal crossover rates for yeast chromosomes, which match the experimentally determined rates. Using a Saccharomyces cerevisiae conditional mutator strain, we show that haploid lethal phenotypes result predominantly from mutation of single loci and generally do not impair mating, which leads to an accumulation of mutational load following meiosis and mating. We hypothesize that purging of deleterious mutations in essential genes constitutes an important factor driving meiotic crossover. Therefore, the increased robustness of populations to deleterious mutations, which arises from clustered genome architectures, may provide a significant selective force shaping crossover distribution. Our analysis reveals a new aspect of the evolution of genome architectures that complements insights about molecular constraints, such as the interference of pericentromeric crossovers with chromosome segregation.", "The evidence that specific vitamins may be beneficial in the prevention of cardiovascular disease (CVD) is supported by mechanistic models of atherogenesis. We and others have published observational epidemiologic studies in support of vitamins in the primary prevention of CVD, but the results from intervention studies are mixed. This article summarizes the recent results for vitamin E, vitamin D, and the B vitamins, comparing study populations, study designs, and potential methodologic reasons for differences in findings. For vitamin E, observational data suggest benefit at doses of 100 to 400 IU/d. Results from recent large-scale trials are mixed, with some showing modest benefit but others suggesting no benefit, especially for secondary prevention. Results for B vitamins are also mixed and further complicated by the recent folate fortification of the flour supply. If greater B vitamin intake does reduce CVD, the benefits are likely to be greatest for primary prevention and in populations with intake below dietary reference standards. Research on vitamin D and CVD is just beginning to emerge, but current data suggest that if there is benefit it likely needs to be at intake levels much higher than the current reference intakes of 200 to 600 IU/d for American adults.", "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.", "Toripalimab is a monoclonal antibody targeting programmed cell death protein 1 (PD-1). It has recently been approved as an immune checkpoint inhibitor in second-line therapies in patients with unresectable or metastatic melanoma; however, it may be associated with various immune-related adverse events (irAEs). Here we report a case of toripalimab-induced dermatomyositis in a patient receiving treatment for metastatic melanoma. The symptoms were relieved by discontinuing toripalimab and administering once-daily intravenous methylprednisolone 1 mg/kg. We suggest that this case serves a warning to clinicians of the need to be aware of the possiblilty of toripalimab-induced dermatomyositis. Early recognition and treatment may prevent progression and improve prognosis of this irAE." ]

[ "The costimulatory molecule CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily and is expressed on various antigen presenting cells (APCs) as well as some tumor cells. The binding to the natural ligand CD40L, which is expressed on T helper cells, leads to APC activation and thus enhancement of immune responses. Treatment with anti-CD40 monoclonal antibodies has been exploited in several cancer immunotherapy studies in mice and led to the development of anti-CD40 antibodies for clinical use. Here, Dacetuzumab and Lucatumumab are in the most advanced stage and are being tested as treatment for malignancies such as chronic lymphatic leukemia (CLL), Multiple Myeloma (MM), and non-Hodgkin's lymphoma (NHL). The promising results from these early clinical trials have encouraged clinical drug development in order to investigate the effect of CD40 mAbs in combination with other cancer immunotherapies, in particular interleukin (IL)-2. An in-depth analysis of this immunotherapy is provided elsewhere. In the present review, we provide an update of the most recent clinical trials with anti-CD40 antibodies. We present and discuss recent and ongoing clinical trials in this field, including clinical studies which combine anti-CD40 treatment with other cancer-treatments, such as Rituximab and Tremelimumab.", "Arboviruses differ from other viruses in their need to replicate in both vertebrate and invertebrate hosts. The invertebrate is a blood-sucking arthropod that is competent to transmit the virus between susceptible animals. Arboviruses transmitted by ticks must adapt to the peculiar physiological and behavioral characteristics of ticks, particularly with regard to blood feeding, bloodmeal digestion, and molting. Virus imbibed with the blood meal first infects cells of the midgut wall. During this phase the virus must contend with the heterophagic bloodmeal digestion of ticks (an intracellular process occurring within midgut cells) and overcome the as yet undefined \"gut barrier\" to infection. Genetic and molecular data for a number of tick-borne viruses indicate ways in which such viruses may have adapted to infecting ticks, but far more information is needed. After infection of midgut cells, tick-borne viruses pass to the salivary glands for transmission during the next blood-feeding episode. To do this, the virus must survive molting by establishing an infection in at least one cell type that does not undergo histolysis. Different tick-borne viruses have different strategies for surviving the molting period, targeting a variety of tick tissues. The infection can then persist for the life span of the tick with little evidence of any detrimental effects on the tick. Transmission to a vertebrate host during feeding most probably occurs via saliva that contains virus secreted from infected salivary gland cells. The virus then enters the skin site of feeding, which has been profoundly modified by the pharmacological effects of tick saliva. At least three tick-borne viruses exploit such tick-induced host changes. This phenomenon (saliva-activated transmission) is believed to underlie \"nonviremic transmission,\" whereby a virus is transmitted from an infected to an uninfected cofeeding tick through a host that has an undetectable or very low viremia. Thus tick-borne viruses that have adapted to the feeding characteristics of their tick vectors may not need to induce a virulent infection (with high viremia) in their natural vertebrate hosts. Efficient transmission of tick-borne viruses between cofeeding ticks may be a means of amplifying virus infection prevalence in F1 generations infected by transovarial transmission.", "Histone H2A variants generate diversity in chromatin structure and functions, as nucleosomes containing variant H2A histones have altered physical, chemical, and biological properties. H2A.Z is an evolutionarily ancient and highly conserved H2A variant that regulates processes ranging from gene expression to the DNA damage response. Here we find that the unstructured portion of the C-terminal tail of H2A.Z is required for the normal functions of this histone variant in budding yeast. We have also identified a novel splice isoform of the human H2A.Z-2 gene that encodes a C-terminally truncated H2A.Z protein that is similar to the truncation mutants we identified in yeast. The short forms of H2A.Z in both yeast and human cells are more loosely associated with chromatin than the full-length proteins, indicating a conserved function for the H2A.Z C-terminal tail in regulating the association of H2A.Z with nucleosomes.", "In this study, chemical feature based pharmacophore models of MMP-1, MMP-8 and MMP-13 inhibitors have been developed with the aid of HypoGen module within Catalyst program package. In MMP-1 and MMP-13, all the compounds in the training set mapped HBA and RA, while in MMP-8, the training set mapped HBA and HY. These features revealed responsibility for the high molecular bioactivity, and this is further used as a three dimensional query to screen the knowledge based designed molecules. These pharmacophore models for collagenases picked up some potent and novel inhibitors. Subsequently, docking studies were performed for the potent molecules and novel hits were suggested for further studies based on the docking score and active site interactions in MMP-1, MMP-8 and MMP-13.", "Collaborators: Teerlink JR, Díaz R, Santa Fe R, Felker GM, McMurray JJV, Metra M, Solomon SD, Malik FI, Kurtz CE, Abbasi S, Knusel B, Hucko T, Groarke J, Honarpour N, Legg JC, Sharpsten L, Varin C, Konstam MA, Butler J, Dargie H, Massaro J, Greenberg BH, Januzzi JL, Lesko LJ, Upshaw JN, Lopes R, Jones WS, Alexander KP, Al-Khatib SM, Harrison RW, Jordan JD, Kong DF, Mathews R, McGarrah RW, Metha RH, Melloni C, Povsic TJ, Shah S, Claggett B, Adams K, Anand I, Arias Mendoza A, Biering-Sørensen T, Böhm M, Bonderman D, Cleland J, Corbalan Herreros R, Crespo Leiro M, Dahlstrom U, Diaz R, Echeverria LE, Fang J, Filippatos G, Fonseca C, Goncalvesova E, Goudev A, Howlett J, Jiang L, Lanfear D, Li J, Lund M, Mareev V, Momomura SI, O'Meara E, Parkhomenko A, Ponikowski P, Ramires F, Serpytis P, Sliwa K, Spinar J, Suter T, Tomcsanyi J, Vandekerckhove H, Vinereanu D, Davila C, Voors A, Yilmaz MB, Zannad F, Besada DA, Majul CR, Litvak Bruno MR, Sassone S, Avaca HA, Rasmussen M, Aiub JR, Hominal MA, Perna E, Garcia Duran RO, Schiavi L, Lobo Marquez LL, Gomez Vilamajo OA, Mackinnon I, Leon de la Fuente RA, Montana OR, Novaretto L, Ahuad Guerrero RA, Garcia Brasca D, Prado A, Garrido MA, Luquez H, Martinez DF, Nicolosi L, Parody ML, Zaidman C, Colombo Berra F, Ibañez J, Zapata G, Amuchastegui M, Caccavo A, Colque R, Diez M, Poy C, Salomone OA, Vogel D, Bordonava AP, Fernandez A, French J, Atherton J, Hamilton A, Begg A, Abhayaratna W, Judkins C, Macdonald P, De Pasquale C, McKenzie S, Amerena J, Szto G, Kearney L, Zimmet H, Sverdlov A, Beltrame J, Korczyk D, Sindone A, Moertl D, Huber K, Huelsmann M, Jakl-Kotauschek G, Ablasser K, Fruhwald F, Ebner C, Siostrzonek P, Drexel H, Poelzl G, Dujardin K, Dupont M, Buysschaert I, Lancellotti P, Pierard L, Droogne W, Chouchane I, Silveira F, Rassi S, Reis G, Pimentel Filho P, Simoes MV, Braga JC, Giorgeto FE, Duda N, Ferraz A, Pederneiras Jaeger C, Rech RL, Saraiva JF, Tognon A, Cardoso J, Greco O, Sanali Paiva M, Paolino B, Coelho Filho O, Nigro Maia L, da Silva R, Canesin M, Ferreira Rossi PR, Zytynski Moura LA, Ribas Fortes JA, Cerci RJ, Fernandes Manenti ER, Leaes PE, Beck da Silva Neto L, Barroso de Souza WK, Bacal F, Chaves R, Vidotti MH, Brito F, Melo de Barros E Silva PG, Soares Piegas L, Todorov G, Tzekova M, Mincheva V, Manolova A, Vasilev I, Tisheva-Gospodinova S, Petrov I, Postadzhiyan A, Velikov C, Dimov B, Constance C, Phaneuf DC, Mielniczuk L, Pandey AS, Senaratne M, Zieroth S, Savard D, Stewart R, Huynh T, Al-Hesayen A, Giannetti N, Moe G, Bourgeois R, Ezekowitz J, Hartleib M, Sussex B, Babapulle M, Chehayeb R, Gaudet D, McKelvie R, Nguyen V, Roth S, Gupta M, Pesant Y, Rupka D, Bhargava R, Costa-Vitali A, Proulx G, Vega M, Potthoff S, Schnettler Cid MC, Villablanca Sepulveda AM, Lanas Zanetti FT, Corbalan R, Saavedra Gajardo VA, Conejeros Kindel C, Pincetti Jofre CP, Cobos Segarra JL, Rodriguez Venegas ME, Yanez Hidalgo M, Vejar Jalaf MG, Li W, Zhang J, Fu X, Zhang X, Li D, Wang Z, Qu Y, Zheng Z, Tang H, Yang P, Zhang Y, Zheng Y, Mi Y, Huang H, Bu P, Chen G, Chen J, Han Y, Li Z, Ma S, Yang X, Yuan Z, Dong Y, Li Z, Mahemuti A, Niu W, Yang Z, Zhang Y, Sun Y, Wu W, Liu F, Yan J, Li Y, Wang Y, Zhang S, Zhou C, Cui H, Li J, Li T, Han Q, Wei Y, Echeverria LE, Manzur Jattin F, Accini Mendoza JL, Castaño Osorio W, Sanchez Vallejo G, Luengas CA, Coronel Arroyo JA, Moncada Corredor MA, Saldarriaga Giraldo CI, Botero Lopez R, Molina de Salazar DI, Urina Triana M, Atehortua Lopez LH, Olaya Rojas P, Velez Pelaez S, Lopez Pareja M, Cadena Bonfanti A, Polasek R, Monhart Z, Sochor K, Motovska Z, Belohlavek J, Busak L, Krupicka J, Tyl P, Jerabek O, Podpera I, Skrobakova J, Peterka K, Spacek R, Cech V, Kellnerova I, Nechvatal L, Pozdisek Z, Houra M, Kryza R, Machova V, Brabec T, Cepelak M, Stepek D, Zeman K, Klimsa Z, Koleckar P, Schee A, Spinarova L, Coufal Z, Jeppesen J, Vraa S, Wiggers H, Nyvad O, Nielsen T, Gadsboll N, Kaiser-Nielsen P, Eifer Moller J, Videbaek L, Galinier M, Lefebvre JM, Tartiere JM, De Geeter G, Roubille F, Ricci JE, Salvat M, Gueffet JP, Decoulx E, Berdague P, Jondeau G, Mewton N, Ovize M, De Groote P, Donal E, Isnard R, Sabatier R, Trochu JN, Damy T, Georges JL, Rosamel Y, Picard F, Aboyans V, Laperche T, Mitrovic V, Taggeselle J, Störk S, Ebelt H, Genth-Zotz S, Rassaf T, Duengen HD, Mittag M, Menck N, von Haehling S, Zeymer U, Boehm M, Frankenstein L, Killat H, Bourhaial H, Beug D, Horacek T, Pfister R, Sandri M, Westenfeld R, Kadel C, Karvounis H, Patsilinakos S, Mantas I, Karavidas A, Giamouzis G, Tsioufis K, Naka K, Tziakas D, Parissis J, Styliadis I, Barbetseas I, Manolis A, Kochiadakis G, Parthenakis F, Herczeg B, Nagy L, Nyolczas N, Toth K, Merkely B, Laszlo Z, Mark L, Szakal I, Papp A, Bezzegh K, Peterfai E, Lakatos F, Hajko E, Papp A, Forster T, Lupkovics G, Mohacsi A, Salamon C, Aradi D, Andreka P, Szasz G, Zilahi Z, Kazinczy R, Margonato A, Agostoni P, Fucili A, Piovaccari G, Senni M, Ambrosio G, Carluccio E, Bilato C, Frigerio M, Indolfi C, Sinagra G, Brunetti ND, Di Biase M, Perna G, Pini D, Volterrani M, De Ferrari GM, Leonardi S, Raineri C, Achilli F, Bonaduce D, Mortara A, Musumeci G, Francisco Polo Friz HE, Rossini R, Tocchetti CG, Vincenzi A, Cavallini C, Floresta AM, Zaca V, Giudici V, Quinto Villani G, Higashino Y, Oishi S, Wada A, Yasaka Y, Fukuzawa S, Kawata H, Onoue K, Saito Y, Koike A, Koizumi T, Masuda S, Meno H, Mitsuo K, Nakayama K, Taguchi S, Takahashi N, Takenaka T, Tanabe J, Tsuboi H, Watanabe N, Yoshida T, Amano T, Ishikawa M, Kida K, Kubota T, Nakamura K, Sakamoto T, Sato N, Shimomura M, Uehara H, Yamamoto F, Yuge M, Akatsuka Y, Doi M, Domae H, Ebato M, Fujii K, Fujiwara W, Gohara S, Hata Y, Hirayama A, Izawa H, Kagiyama S, Kanda J, Kitaoka H, Kiyokawa H, Makino K, Matsumoto T, Michishita I, Miura S, Miyazaki T, Nakahama M, Nakamura A, Nakazato Y, Ogawa T, Okumura T, Okumura Y, Sakai T, Saku K, Sato Y, Shimizu W, Sugino H, Suzuki M, Takagi A, Takaishi H, Tanaka T, Terasaki T, Tsujimoto M, Ueda Y, Ujino K, Usui M, Yamamoto M, Yoshikawa M, Ajioka M, Ando K, Asakura M, Asano H, Fujii S, Hara H, Inomata T, Isshiki T, Kadokami T, Kai H, Kasai T, Kawamitsu K, Kawasaki T, Koga T, Komiyama N, Maejima Y, Manita M, Miyamoto N, Nagase K, Node K, Numaguchi K, Sakata Y, Serikawa T, Sugimura K, Takama N, Tatebe S, Ueno H, Urabe Y, Hidaka T, Hiroi S, Iseki H, Ito H, Kajinami K, Kawakami H, Kihara Y, Momiyama Y, Mori M, Morita Y, Okishige K, Sakagami S, Takeishi Y, Terasawa A, Utsu N, Badariene J, Celutkiene J, Sakalyte G, Slapikas R, Jarasuniene D, Garcia Castillo A, De Los Rios Ibarra MO, Ramos Lopez GA, Bayram Llamas EA, Llamas Esperon GA, Salcido Vazquez E, Garcia Gonzalez R, Arenas Leon JL, Gonzalez SL, Arias Mendoza MA, Contreras Rodriguez A, Mendez Machado GF, Alpizar Salazar M, Bazzoni Ruiz AE, De Leon Flores AM, Pagola Carrasco JA, Reyes Araiza R, Römer T, Remmen J, Van Eck J, Elvan A, Kedhi E, Smilde T, van de Wal R, Lok D, Schaap J, van der Sluis A, Linssen G, Magro M, Willems F, Schellings D, van der Zwaan C, van Hal J, Beelen D, Boswijk D, Hermans W, van Huysduynen-Monraats P, Van Kesteren H, Scott R, Hart H, Szczasny M, Blicharski T, Kafara M, Stankiewicz A, Skonieczny G, Zabowka M, Kania G, Borkowski T, Kopaczewski J, Pawlowicz L, Spyra J, Wlodarczyk A, Sciborski R, Balsam P, Drozdz J, Sobkowicz B, Konieczynska M, Lelonek M, Bednarkiewicz Z, Trebacz J, Jankowski P, Sidor M, Berkowski P, Chmielak Z, Lenartowska L, Nessler J, Straburzynska-Migaj E, Kalarus Z, Kowalski R, Kalecinska-Krystkiewicz E, Gola Z, Pijanowski Z, Wozakowska-Kaplon B, Cymerman K, Rynkiewicz A, Miekus P, Monteiro P, Morais Sarmento P, Almeida F, Duarte T, Oliveira L, Soares Goncalves S, Santos L, Brito D, Stanciulescu G, Spiridon MR, Militaru C, Podoleanu CG, Zdrenghea D, Popescu MI, Macarie C, Giuca A, Mitu F, Voicu OC, Dorobantu M, Lighezan D, Stamate S, Bykov A, Kobalava Z, Zrazhevskiy K, Semenova I, Vishnevsky A, Shutemova E, Tereschenko S, Shvarts Y, Barbarash O, Lukyanov Y, Voevoda M, Dovgolis S, Dronov D, Goloshchekin B, Sitnikova M, Ezhov M, Tarasov N, Kotelnikov M, Kostenko V, Solovev O, Boytsov S, Goncharov I, Myasnikov R, Villevalde S, Rafalskiy V, Ryabov V, Kosmacheva E, Motylev I, Nosov V, Osipova I, Salukhov V, Belenkiy D, Bolshakova O, Pimenov L, Shilkina N, Kulibaba E, Mareev V, Repin A, Timofeev A, Mitrokhin V, Popov V, Sherenkov A, Arbolishvili G, Antalik L, Dzupina A, Fulop P, Majercak I, Gonsorcik J, Vinanska D, Lenner E, Lukacova J, Margoczy R, Smik R, Stevlik J, Uhliar R, Burgess L, Badat A, Klug E, Van Zyl L, Abelson M, Moodley R, Tsabedze N, Fourie N, Almenar Bonet L, Arizon Del Prado JM, Martinez-Selles D Oliveira Soares M, Nuñez Villota JE, Generosa Crespo Leiro M, Gonzalez Juanatey JR, Pascual Figal DA, Bonilla Palomas JL, Mirabet Perez S, Delgado Jimenez JF, Padron AL, Iñiguez Romo A, Jimenez Diaz VA, Soto Loureiro F, Segovia Cubero J, Castro Fernandez AJ, Climent Paya VE, Recio Mayoral A, de la Fuente Galan L, Gomez Doblas JJ, Bover Freire R, Blasco Peiro MT, Diaz Molina B, Jordan Martinez L, Lambert Rodriguez JL, Lopez Fernandez S, Gonzalez Vilchez F, Boman K, Karlstrom P, Berglund S, Szabo B, Peterson M, Wodlin P, Lindholm CJ, Moccetti T, Mueller C, Hullin R, Meyer P, Noll G, Yigit Z, Onur Turgut O, Birhan Yilmaz M, Bekar L, Sahin T, Lale Koldas Z, Celik A, Cavusoglu Y, Demir M, Onrat E, Duzenli M, Cosansu K, Vural M, Haldun Muderrisoglu I, Tuncer M, Badak O, Nalbantgil S, Kirma C, Okuyan E, Guray U, Prokhorov O, Karpenko O, Vakaliuk I, Yagensky A, Kraiz I, Stanislavchuk M, Kulynych O, Rishko M, Stets R, Tseluyko V, Mishchenko L, Rudenko L, Svishchenko Y, Rudyk I, Alieksieieva L, Korzh O, Mostovoy Y, Reshotko D, Parkhomenko O, Rasputina L, Voronkov L, Dzyak G, Lymar Y, Vasilyeva L, Keeling P, Barr C, Wong K, Price D, Skaria B, Clark A, Chandrasekaran B, Trevelyan J, Gordon B, Donnelly P, Glover J, Ryding A, Weir R, Lang C, Roy D, Adhya S, Clifford P, Ludman A, Cowan E, Kalra P, Lynch M, Mahmood S, Al Mohammad A, Asubiaro J, Chhokar B, Davey P, Elmahi E, Muthumala A, Taylor J, Gupta D, Nadar V, Henderson D, Zolty R, Sauer A, Chandra L, Jaffrani N, Grewal G, Mancini D, McLean D, Vasallo J, Bindra A, Gottlieb S, Joseph S, Barua R, Ginwalla M, Gorodeski E, Mouhaffel A, Chung E, Desai P, Portnay E, Rama B, Shandling A, Stahl L, Thomas G, Heilman K, Jacob B, Londono J, Sandoval O, Starling R, Almousalli O, Ashcom T, Bauerlein EJ, Chaparro S, Koo C, Letarte L, McGrew F, Rajagopalan N, Robinson S, Schultz D, Zucker M, Allen L, Ambardekar A, Bhagwat R, Boehmer J, Bouza M, Farris N, Feitell S, Ganji J, Geltman E, Javier J, Morrow JA, Pianko L, Smart F, Adler A, Brinkley D, Cardona J, Coletti A, Harris J, Hunter V, Krantz M, Lang C, Lenihan D, Lovell C, Murray D, Pillutla P, Shah A, Arrieta Garcia C, Bogaev R, Dauber I, Franchi F, Fremont R, Haines P, Hart T, Hattler B, Janik M, Khalife W, Lemus B, Malhotra S, Mamdani S, Murray J, Nelson W, Orgera M, Ortiz A, Rahko P, Rennyson S, Rollini F, Shin J, Tsao L, Uretsky B, Wahid F, Wilkett M, Amanullah A, Baker M, Berk M, Boccalandro F, Cruz K, Doyle T, Franczek S, Galitz L, Geronilla G, Gianfagna R, Jones A, King A, Krueger S, Lepor N, Martinez-Castrillon M, Meholick A, Pamganamamula M, Pham M, Radin M, Radojevic J, Ramanathan K, Schmalfuss C, Schnitzler R, Shah K, Takata T, Bertolet B, Bostick B, Civitello A, Collins J, Danila C, Dib N, Drakos S, Gilmore R, Gray W, Grazette L, Haddad T, Hasni S, Hearne S, Janmohamed M, Katz R, Kazemi N, Llerena S, Lohr N, Marzouka G, Mignone J, Misra A, Ooi H, Panjrath G, Paszczuk A, Pickett C, Rahman J, Sampognaro G, Santana Izquierdo A, Sawyer D, Shayani S, Singh I, Treasure C, Vaz G, Vijay N, Watts J, Williams C, Yeoman G, Zhang L, Aaronson K, AboAuda W, Alharethi R, Anderson W, Ariani M, Banerji S, Baweja P, Carson P, Corbelli J, Eberly A 3rd, Elliott J, Fernando R, Fisher D, Forman S, Gabriel G, Gogia H, Hametz C, Hamroff G, Houston B, Ibrahim H, Jadbabaie F, Kassiotis C, Krishnamoorthy A, Kwan M, Lupovitch S, Macias L, Malik A, Martel D, Martinez L, Miyamoto M, Mody F, Papademetriou V, Patel D, Pauly D, Peart B, Pisani B, Ramos M, Rivero M, Shah A, Sharma M, Sharma R, Sichrovsky T, Simon M, Singh D, Smith M, Tallet J, Vaccari C, Villoch M, Weinberg B, Wheeler M, Yehya A, Yousuf K, Abadier R, Abdullah S, Arora R, Aslam S, Boyle A, Buynak R, Chang D, Chu AA, Contreras J, Halpern S, Hamilton M, Handel F, Heitner J, Herzog W, Jackson B, Kao J, Kondo N, Koren M, LeWinter M, Martindale J, Martinez-Arraras J, Olsen S, Piatek M, Ranadive N, Randall W, Rao S, Rawitscher D, Reeves G, Rider J, Sokos G, Strader JR, Sulemanjee N, Tahirkheli N, Thohan V, Trichon B, Vanhecke T, Whellan D, Abuannadi M, Aggarwala G, Ahmad S, Artis A, Cheirif J, Cook J, Cotarlan V, Cox J, Eaton C, Florea V, Frank T, Friedman K, Ganeshram V, Gass A, Gemignani A, Hedgepeth C, Itchhaporia D, Kaluski E, Karim A, Kono A, Lader E, Lakshminarayanan B, Lewis N, Malhotra V, Mayer N, Mohapatra R, Nair N, O'Brien T, Pauwaa S, Rothenberg F, Rowan C, Saxena S, Seto A, Shah N, Singh P, Skopicki H, Stoddard M, Sweitzer N, To TD.", "Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a breakdown of tolerance to nuclear antigens and the development of immune complexes. Genomic approaches have shown that human SLE leukocytes homogeneously express type I interferon (IFN)-induced and neutrophil-related transcripts. Increased production and/or bioavailability of IFN-α and associated alterations in dendritic cell (DC) homeostasis have been linked to lupus pathogenesis. Although neutrophils have long been shown to be associated with lupus, their potential role in disease pathogenesis remains elusive. Here, we show that mature SLE neutrophils are primed in vivo by type I IFN and die upon exposure to SLE-derived anti-ribonucleoprotein antibodies, releasing neutrophil extracellular traps (NETs). SLE NETs contain DNA as well as large amounts of LL37 and HMGB1, neutrophil proteins that facilitate the uptake and recognition of mammalian DNA by plasmacytoid DCs (pDCs). Indeed, SLE NETs activate pDCs to produce high levels of IFN-α in a DNA- and TLR9 (Toll-like receptor 9)-dependent manner. Our results reveal an unsuspected role for neutrophils in SLE pathogenesis and identify a novel link between nucleic acid-recognizing antibodies and type I IFN production in this disease.", "The Gi/o protein-coupled histamine H3 receptor is distributed throughout the central nervous system including areas like cerebral cortex, hippocampus and striatum with the density being highest in the posterior hypothalamus, i.e. the area in which the histaminergic cell bodies are located. In contrast to the other histamine receptor subtypes (H1, H2 and H4), the H3 receptor is located presynaptically and shows a constitutive activity. In detail, H3 receptors are involved in the inhibition of histamine release (presynaptic autoreceptor), impulse flow along the histaminergic neurones (somadendritic autoreceptor) and histamine synthesis. Moreover, they occur as inhibitory presynaptic heteroreceptors on serotoninergic, noradrenergic, dopaminergic, glutamatergic, GABAergic and perhaps cholinergic neurones. This review shows for four functions of the brain that the H3 receptor represents a brake against the wake-promoting, anticonvulsant and anorectic effect of histamine (via postsynaptic H1 receptors) and its procognitive activity (via postsynaptic H1 and H2 receptors). Indeed, H1 agonists and H3 inverse agonists elicit essentially the same effects, at least in rodents; these effects are opposite in direction to those elicited by brain-penetrating H1 receptor antagonists in humans. Although the benefit for H3 inverse agonists for the symptomatic treatment of dementias is inconclusive, several members of this group have shown a marked potential for the treatment of disorders associated with excessive daytime sleepiness. In March 2016, the European Commission granted a marketing authorisation for pitolisant (WakixR) (as the first representative of the H3 inverse agonists) for the treatment of narcolepsy." ]

[ "Chromatin immunoprecipitation (ChIP) is the gold-standard technique for localizing nuclear proteins in the genome. We used ChIP, in combination with deep sequencing (Seq), to study the genome-wide distribution of the Silent information regulator (Sir) complex in Saccharomyces cerevisiae. We analyzed ChIP-Seq peaks of the Sir2, Sir3, and Sir4 silencing proteins and discovered 238 unexpected euchromatic loci that exhibited enrichment of all three. Surprisingly, published ChIP-Seq datasets for the Ste12 transcription factor and the centromeric Cse4 protein indicated that these proteins were also enriched in the same euchromatic regions with the high Sir protein levels. The 238 loci, termed \"hyper-ChIPable\", were in highly expressed regions with strong polymerase II and polymerase III enrichment signals, and the correlation between transcription level and ChIP enrichment was not limited to these 238 loci but extended genome-wide. The apparent enrichment of various proteins at hyper-ChIPable loci was not a consequence of artifacts associated with deep sequencing methods, as confirmed by ChIP-quantitative PCR. The localization of unrelated proteins, including the entire silencing complex, to the most highly transcribed genes was highly suggestive of a technical issue with the immunoprecipitations. ChIP-Seq on chromatin immunoprecipitated with a nuclear-localized GFP reproduced the above enrichment in an expression-dependent manner: induction of the GAL genes resulted in an increased ChIP signal of the GFP protein at these loci, with presumably no biological relevance. Whereas ChIP is a broadly valuable technique, some published conclusions based upon ChIP procedures may merit reevaluation in light of these findings.", "BACKGROUND: Inhalational anthrax caused by Bacillus anthracis is associated with high mortality primarily due to toxin-mediated injury. Raxibacumab is a human IgG1lambda monoclonal antibody directed against protective antigen, a component of the anthrax toxin.METHODS: We evaluated the efficacy of raxibacumab as a prophylactic agent and after disease onset in a total of four randomized, placebo-controlled studies conducted in rabbits and monkeys. Animals were exposed to an aerosolized target exposure of B. anthracis spores that was approximately 100 times (in the prophylactic studies) and 200 times (in the therapeutic-intervention studies) the median lethal dose. In the therapeutic-intervention studies, animals were monitored for the onset of symptoms. Animals with detectable protective antigen in serum, a significant increase in temperature, or both received a single intravenous bolus of placebo or raxibacumab at a dose of either 20 mg per kilogram of body weight or 40 mg per kilogram. The primary end point was survival at day 14 (in rabbits) or at day 28 (in monkeys). Safety studies were conducted with intravenous raxibacumab (40 mg per kilogram) in 333 healthy human volunteers.RESULTS: In both rabbits and monkeys, the time to detection of protective antigen correlated with the time to bacteremia (r=0.9, P<0.001). In the therapeutic-intervention studies, the survival rate was significantly higher among rabbits that received raxibacumab at a dose of 40 mg per kilogram (44% [8 of 18]) than among rabbits that received placebo (0% [0 of 18]; P=0.003). Raxibacumab treatment also significantly increased survival in monkeys (64% [9 of 14], vs. 0% [0 of 12] with placebo; P<0.001). In human subjects, intravenous raxibacumab at a dose of 40 mg per kilogram had a half-life of 20 to 22 days and provided a maximum concentration of the drug in excess of levels that are protective in animals. Concentrations of raxibacumab provide a surrogate end point that should be predictive of clinical benefit.CONCLUSIONS: A single dose of raxibacumab improved survival in rabbits and monkeys with symptomatic inhalational anthrax. (ClinicalTrials.gov number, NCT00639678.)", "Using nuclear factor-κB (NF-κB) ChIP-Seq data, we present a framework for iterative learning of regulatory networks. For every possible transcription factor-binding site (TFBS)-putatively regulated gene pair, the relative distance and orientation are calculated to learn which TFBSs are most likely to regulate a given gene. Weighted TFBS contributions to putative gene regulation are integrated to derive an NF-κB gene network. A de novo motif enrichment analysis uncovers secondary TFBSs (AP1, SP1) at characteristic distances from NF-κB/RelA TFBSs. Comparison with experimental ENCODE ChIP-Seq data indicates that experimental TFBSs highly correlate with predicted sites. We observe that RelA-SP1-enriched promoters have distinct expression profiles from that of RelA-AP1 and are enriched in introns, CpG islands and DNase accessible sites. Sixteen novel NF-κB/RelA-regulated genes and TFBSs were experimentally validated, including TANK, a negative feedback gene whose expression is NF-κB/RelA dependent and requires a functional interaction with the AP1 TFBSs. Our probabilistic method yields more accurate NF-κB/RelA-regulated networks than a traditional, distance-based approach, confirmed by both analysis of gene expression and increased informativity of Genome Ontology annotations. Our analysis provides new insights into how co-occurring TFBSs and local chromatin context orchestrate activation of NF-κB/RelA sub-pathways differing in biological function and temporal expression patterns.", "BACKGROUND: Citicoline is approved in some countries for the treatment of acute ischaemic stroke. The drug has shown some evidence of efficacy in a pooled analysis. We sought to confirm the efficacy of citicoline in a larger trial.METHODS: We undertook a randomised, placebo-controlled, sequential trial in patients with moderate-to-severe acute ischaemic stroke admitted at university hospitals in Germany, Portugal, and Spain. Using a centralised minimisation process, patients were randomly assigned in a 1:1 ratio to receive citicoline or placebo within 24 h after the onset of symptoms (1000 mg every 12 h intravenously during the first 3 days and orally thereafter for a total of 6 weeks [2×500 mg oral tablets given every 12 h]). All study participants were masked. The primary outcome was recovery at 90 days measured by a global test combining three measures of success: National Institutes of Health Stroke Scale ≤1, modified Rankin score ≤1, and Barthel Index ≥95. Safety endpoints included symptomatic intracranial haemorrhage in patients treated with recombinant tissue plasminogen activator, neurological deterioration, and mortality. This trial is registered, NCT00331890.RESULTS: 2298 patients were enrolled into the study from Nov 26, 2006, to Oct 27, 2011. 37 centres in Spain, 11 in Portugal, and 11 in Germany recruited patients. Of the 2298 patients who gave informed consent and underwent randomisation, 1148 were assigned to citicoline and 1150 to placebo. The trial was stopped for futility at the third interim analysis on the basis of complete data from 2078 patients. The final randomised analysis was based on data for 2298 patients: 1148 in citicoline group and 1150 in placebo group. Global recovery was similar in both groups (odds ratio 1·03, 95% CI 0·86-1·25; p=0·364). No significant differences were reported in the safety variables nor in the rate of adverse events.INTERPRETATION: Under the circumstances of the ICTUS trial, citicoline is not efficacious in the treatment of moderate-to-severe acute ischaemic stroke.FUNDING: Ferrer Grupo.", "PURPOSE: Patients with recurrent prostate cancer are commonly treated with androgen withdrawal therapy (AWT); however, almost all patients eventually progress to castration resistant prostate cancer (CRPC), indicating failure of AWT to eliminate androgen-sensitive prostate cancer. The overall goal of these studies is to determine whether dual inhibition of the receptor tyrosine kinases epidermal growth factor receptor (EGFR) and HER2 would prolong the effectiveness of this treatment in prostate cancer.EXPERIMENTAL DESIGN: We used androgen-dependent LNCaP cells and its CRPC sublines LNCaP-AI and C4-2. Additional data were collected in pRNS-1-1 cells stably expressing a mutant androgen receptor (AR-T877A), and in nude mice harboring CWR22 tumors. Studies utilized EGFR inhibitors erlotinib and AG1478, and HER2 inhibitors trastuzumab and AG879.RESULTS: Dual EGFR/HER2 inhibition induced apoptosis selectively in androgen-sensitive prostate cancer cells undergoing AWT, but not in the presence of androgens, or in CRPC cells. We show that AWT alone failed to induce significant apoptosis in androgen-dependent cells, due to AWT-induced increase in HER2 and ErbB3, which promoted survival by increasing Akt phosphorylation. AWT-induced ErbB3 stabilized the AR and stimulated PSA, while it was inactivated only by inhibition of both its dimerization partners EGFR and HER2 (prostate cancer cells do not express ErbB4); but not the inhibition of any one receptor alone, explaining the success of dual EGFR/HER2 inhibition in sensitizing androgen-dependent cells to AWT. The effectiveness of the inhibitors in suppressing growth correlated with its ability to prevent Akt phosphorylation.CONCLUSION: These studies indicate that dual EGFR/HER2 inhibition, administered together with AWT, sensitize prostate cancer cells to apoptosis during AWT.", "The transcription factor NF-κB is a critical regulator of immune responses. To determine how NF-κB builds transcriptional control networks, we need to obtain a topographic map of the factor bound to the genome and correlate it with global gene expression. We used a ChIP cloning technique and identified novel NF-κB target genes in response to virus infection. We discovered that most of the NF-κB-bound genomic sites deviate from the consensus and are located away from conventional promoter regions. Remarkably, we identified a novel abundant NF-κB-binding site residing in specialized Alu-repetitive elements having the potential for long range transcription regulation, thus suggesting that in addition to its known role, NF-κB has a primate-specific function and a role in human evolution. By combining these data with global gene expression profiling of virus-infected cells, we found that most of the sites bound by NF-κB in the human genome do not correlate with changes in gene expression of the nearby genes and they do not appear to function in the context of synthetic promoters. These results demonstrate that repetitive elements interspersed in the human genome function as common target sites for transcription factors and may play an important role in expanding the repertoire of binding sites to engage new genes into regulatory networks.", "Recent reports have described a distinct and recurrent pattern of systemic malformation that associates craniosynostosis and neurodevelopmental abnormalities with many clinical features of the Marfan syndrome (MFS), an autosomal dominant disorder of the extracellular microfibril caused by defects in the gene encoding fibrillin-1, FBN1 (ref. 8). Additional common findings include other craniofacial anomalies, hypotonia, obstructive apnea, foot deformity, and congenital weakness of the abdominal wall. So far, only 11 cases have been reported precluding the assignment of definitive diagnostic criteria. While it remains unclear whether these cases represent a discrete clinical entity with a single aetiology, they have been pragmatically grouped under the rubric Marfanoid-craniosynostosis or Shprintzen-Goldberg syndrome (SGS). Because of the significant clinical overlap between MFS and SGS, we proposed that they may be caused by allelic mutations. We now report two SGS patients who harbour mutations in FBN1. While it remains unclear whether these mutations are sufficient for the clinical expression of the entire SGS phenotype, these data suggest a role for fibrillin-1 in early craniofacial and central nervous system development. Our recent observation that FBN1 transcript is expressed as early as the 8-cell stage of human embryogenesis is consistent with this hypothesis.", "Bacterial viruses (bacteriophages, phages) of the gut have increasingly become a focus in microbiome studies, with an understanding that they are likely key players in health and disease. However, characterization of the virome remains largely based on bioinformatic approaches, with the impact of these viromes inferred based on a century of knowledge from aerobic phage work. Studying the phages infecting anaerobes is difficult, as they are often technically demanding to isolate and propagate. In this review, we primarily discuss the phages infecting three well-studied anaerobes in the gut: Bifidobacterium, Clostridia and Bacteroides, with a particular focus on the challenges in isolating and characterizing these phages. We contrast the lessons learned from these to other anaerobic work on phages infecting facultative anaerobes of the gut: Enterococcus and Lactobacillus. Phages from the gut do appear to adhere to the lessons learned from aerobic work, but the additional challenges of working on them has required ingenious new approaches to enable their study. This, in turn, has uncovered remarkable biology likely underpinning phage-host relationships in many stable environments." ]

[ "Interferon-gamma (IFN-gamma) and tumor necrosis factor (TNF) are essential cytokines for successful clearance of microbial infections. Activation of macrophages by synergistic effects of these cytokines leads to induction of antimicrobial effector systems like reactive oxygen and reactive nitrogen intermediates. Strikingly, IFN-gammaR(-/-) and TNFRp55(-/-) mice are considerably more susceptible to infections than inducible nitric oxide synthase(-/-) and p47phox(-/-) mice. Thus we applied transcriptome-profiling studies to identify genes synergistically upregulated by IFN-gamma and TNF in macrophages which are potentially involved in the defense against intracellular pathogens. From a total of 234 regulated genes we found 35 genes that were upregulated by combined effects of IFN-gamma and TNF and were at least 2-fold induced. The majority of these genes are involved in signal transduction and transcriptional regulation. However, we found several genes were poorly characterized with regard to immunological functions. As a prototypic TNF- and IFN-gamma-coregulated gene we characterized the expression and the subcellular localization of immunoresponsive gene 1 (IRG1) in murine macrophages. IRG1 is highly upregulated in murine ANA-1 macrophages by several proinflammatory cytokines and Toll-like receptor (TLR) agonists, as well as in spleen and lung of Listeria monocytogenes or Toxoplasma gondii infected mice, respectively. Furthermore, this study identifies 35 genes that constitute the IFN-gamma/TNF-triggered effector program in innate immunity.", "This is a case report of a 44-year-old male living in Teresópolis, RJ, Brazil, probably poisoned by contact with a Lonomia caterpillar, who presented hemolytic anemia, decreased platelet count and acute renal insufficiency. Lonomia erucism diagnosis was established by anamnesis and clinical and laboratory manifestations. Therapeutic measures consisting of hemotransfusion and hemodialysis were successful. Physiopathologic and clinical features of erucism by Lonomia are discussed.", "Ferroptosis is a form of oxidative cell death and has become a chemotherapeutic target for cancer treatment. BAY 11-7085 (BAY), which is a well-known IκBα inhibitor, suppressed viability in cancer cells via induction of ferroptotic death in an NF-κB-independent manner. Reactive oxygen species scavenging, relief of lipid peroxidation, replenishment of glutathione and thiol-containing agents, as well as iron chelation, rescued BAY-induced cell death. BAY upregulated a variety of Nrf2 target genes related to redox regulation, particularly heme oxygenase-1 (HO-1). Studies with specific inhibitors and shRNA interventions suggested that the hierarchy of induction is Nrf2-SLC7A11-HO-1. SLC7A11 inhibition by erastin, sulfasalazine, or shRNA interference sensitizes BAY-induced cell death. Overexperession of SLC7A11 attenuated BAY-inhibited cell viability. The ferroptotic process induced by hHO-1 overexpression further indicated that HO-1 is a key mediator of BAY-induced ferroptosis that operates through cellular redox regulation and iron accumulation. BAY causes compartmentalization of HO-1 into the nucleus and mitochondrion, and followed mitochondrial dysfunctions, leading to lysosome targeting for mitophagy. In this study, we first discovered that BAY induced ferroptosis via Nrf2-SLC7A11-HO-1 pathway and HO-1 is a key mediator by responding to the cellular redox status.", "Twist1 is the mouse ortholog of TWIST1, the human gene mutated in Saethre-Chotzen syndrome. Previously, a Twist1 null allele was generated by gene targeting in mouse embryonic stem cells. Twist1 heterozygous mice develop polydactyly and a craniofacial phenotype similar to Saethre-Chotzen patients. Mice homozygous for the Twist1 null allele die around embryonic day 11.5 (E11.5) with cranial neural tube closure and vascular defects, hindering in vivo studies of Twist1 function at later stages of development. Here, we report the generation of a Twist1 conditional null allele in mice that functions like a wild-type allele but can be converted to a null allele upon Cre-mediated recombination.", "The base cleavage specificity of angiogenin toward naturally occurring polyribonucleotides has been determined by using rapid RNA sequencing technology. With 5S RNAs from Saccharomyces cerevisiae and Escherichia coli, angiogenin cleaves phosphodiester bonds exclusively at cytidylic or uridylic residues, preferably when the pyrimidines are followed by adenine. However, not all of the existent pyrimidine bonds in the 5S RNAs are cleaved, likely owing to elements of structure in the substrate. Despite the high degree of sequence homology between angiogenin and ribonuclease A (RNase A), which includes all three catalytic as well as substrate binding residues, the cleavage patterns with natural RNAs are unique to each enzyme. Angiogenin significantly hydrolyzes certain bonds that are not appreciably attacked by RNase A and vice versa. The different cleavage specificities of angiogenin and RNase A may account for the fact that the former is angiogenic while the latter is not.", "We have examined the expression of lamins A, B1, and C in human tissues and cancer cell lines and the function of the lamin A/C and B1 gene promoters in transfected cells. Northern analysis and immunoblotting demonstrated that lamin A/C mRNA and protein were not detectable in some human cell lines whereas lamin B1 was always present. Sequencing of approximately 2.6 kb of the lamin A/C and 1.6 kb of the lamin B1 genes 5' to the translation initiation sites showed that they did not contain typical TATA boxes near the transcription start sites. The lamin B1 and A/C proximal promoter regions were transcribed in transfected HeLa, Raji, and NT2/D1 cell lines even if the cells did not contain detectable endogenous lamin A/C mRNA or protein. These results show that, similar to most cytoplasmic intermediate filament genes, transcriptional regulatory elements in the promoters of the human nuclear lamin A/C and B1 genes do not control their cell type-specific expression in culture lines.", "Amyloidosis prognosis is often related to the onset of heart failure and a worsening that is concomitant with kidney-liver dysfunction; thus the Model for End-stage Liver disease (MELD) may be an ideal instrument to summarize renal-liver function. Our aim has been to test the MELD score as a prognostic tool in amyloidosis. We evaluated 128 patients, 46 with TTR-related amyloidosis and 82 with AL amyloidosis. All patients had a complete clinical and echocardiography evaluation; overall biohumoral assessment included troponin I, NT-proBNP, creatinine, total bilirubin and INR ratio. The study population was dichotomized at the 12 cut-off level of MELD scores; those with MELD score >12 had a lower survival compared to controls in the study cohort (40.7 vs 66.3 %; p = 0.006). Either as a continuous and dichotomized variable, MELD shows its independent prognostic value at multivariable analysis (HR = 1.199, 95 % CI 1.082-1.329; HR = 2.707, 95 % CI 1.075-6.817, respectively). MELD shows a lower prognostic sensitivity/specificity ratio than troponin I and NT-proBNP in the whole study population and AL subgroup, while in TTR patients MELD has a higher sensitivity/specificity ratio compared to troponin and NT-proBNP (ROC analysis-AUC: 0.853 vs 0.726 vs 0.659). MELD is able to predict prognosis in amyloidosis. A MELD score >12 selects a subgroup of patients with a higher risk of death. The predictive accuracy seems to be more evident in TTR patients in whom currently no effective scoring systems have been validated.", "PURPOSE: Ferroptosis is a new mode of regulated cell death, which is completely distinct from other cell death modes based on morphological, biochemical, and genetic criteria. This study evaluated the therapeutic role of ferroptosis in classic chemotherapy drugs, including the underlying mechanism.MATERIALS AND METHODS: Cell viabilitywas detected by using the methylthiazoltetrazlium dye uptake method. RNAiwas used to knockout iron-responsive element binding protein 2, and polymerase chain reaction, western blot was used to evaluate the efficiency. Intracellular reduced glutathione level and glutathione peroxidases activitywere determined by related assay kit. Intracellularreactive oxygen species levelswere determined by flowcytometry. Electron microscopywas used to observe ultrastructure changes in cell.RESULTS: Among five chemotherapeutic drugs screened in this study, cisplatin was found to be an inducer for both ferroptosis and apoptosis in A549 and HCT116 cells. The depletion of reduced glutathione caused by cisplatin and the inactivation of glutathione peroxidase played the vital role in the underlying mechanism. Besides, combination therapy of cisplatin and erastin showed significant synergistic effect on their anti-tumor activity.CONCLUSION: Ferroptosis had great potential to become a new approach in anti-tumor therapies and make up for some classic drugs, which open up a new way for their utility in clinic.", "Clinical studies have suggested that myocardial iron is a risk factor for left ventricular remodeling in patients after myocardial infarction. Ferroptosis has recently been reported as a mechanism of iron-dependent nonapoptotic cell death. However, ferroptosis in the heart is not well understood. Mechanistic target of rapamycin (mTOR) protects the heart against pathological stimuli such as ischemia. To define the role of cardiac mTOR on cell survival in iron-mediated cell death, we examined cardiomyocyte (CM) cell viability under excess iron and ferroptosis conditions. Adult mouse CMs were isolated from cardiac-specific mTOR transgenic mice, cardiac-specific mTOR knockout mice, or control mice. CMs were treated with ferric iron [Fe(III)]-citrate, erastin, a class 1 ferroptosis inducer, or Ras-selective lethal 3 (RSL3), a class 2 ferroptosis inducer. Live/dead cell viability assays revealed that Fe(III)-citrate, erastin, and RSL3 induced cell death. Cotreatment with ferrostatin-1, a ferroptosis inhibitor, inhibited cell death in all conditions. mTOR overexpression suppressed Fe(III)-citrate, erastin, and RSL3-induced cell death, whereas mTOR deletion exaggerated cell death in these conditions. 2',7'-Dichlorodihydrofluorescein diacetate measurement of reactive oxygen species (ROS) production showed that erastin-induced ROS production was significantly lower in mTOR transgenic versus control CMs. These findings suggest that ferroptosis is a significant type of cell death in CMs and that mTOR plays an important role in protecting CMs against excess iron and ferroptosis, at least in part, by regulating ROS production. Understanding the effects of mTOR in preventing iron-mediated cell death will provide a new therapy for patients with myocardial infarction. NEW & NOTEWORTHY Ferroptosis has recently been reported as a new form of iron-dependent nonapoptotic cell death. However, ferroptosis in the heart is not well characterized. Using cultured adult mouse cardiomyocytes, we demonstrated that the mechanistic target of rapamycin plays an important role in protecting cardiomyocytes against excess iron and ferroptosis.", "BACKGROUND: We previously reported that olaparib led to significantly longer imaging-based progression-free survival than the physician's choice of enzalutamide or abiraterone among men with metastatic castration-resistant prostate cancer who had qualifying alterations in homologous recombination repair genes and whose disease had progressed during previous treatment with a next-generation hormonal agent. The results of the final analysis of overall survival have not yet been reported.METHODS: In an open-label, phase 3 trial, we randomly assigned patients in a 2:1 ratio to receive olaparib (256 patients) or the physician's choice of enzalutamide or abiraterone plus prednisone as the control therapy (131 patients). Cohort A included 245 patients with at least one alteration in BRCA1, BRCA2, or ATM, and cohort B included 142 patients with at least one alteration in any of the other 12 prespecified genes. Crossover to olaparib was allowed after imaging-based disease progression for patients who met certain criteria. Overall survival in cohort A, a key secondary end point, was analyzed with the use of an alpha-controlled, stratified log-rank test at a data maturity of approximately 60%. The primary and other key secondary end points were reported previously.RESULTS: The median duration of overall survival in cohort A was 19.1 months with olaparib and 14.7 months with control therapy (hazard ratio for death, 0.69; 95% confidence interval [CI], 0.50 to 0.97; P = 0.02). In cohort B, the median duration of overall survival was 14.1 months with olaparib and 11.5 months with control therapy. In the overall population (cohorts A and B), the corresponding durations were 17.3 months and 14.0 months. Overall, 86 of 131 patients (66%) in the control group crossed over to receive olaparib (56 of 83 patients [67%] in cohort A). A sensitivity analysis that adjusted for crossover to olaparib showed hazard ratios for death of 0.42 (95% CI, 0.19 to 0.91) in cohort A, 0.83 (95% CI, 0.11 to 5.98) in cohort B, and 0.55 (95% CI, 0.29 to 1.06) in the overall population.CONCLUSIONS: Among men with metastatic castration-resistant prostate cancer who had tumors with at least one alteration in BRCA1, BRCA2, or ATM and whose disease had progressed during previous treatment with a next-generation hormonal agent, those who were initially assigned to receive olaparib had a significantly longer duration of overall survival than those who were assigned to receive enzalutamide or abiraterone plus prednisone as the control therapy, despite substantial crossover from control therapy to olaparib. (Funded by AstraZeneca and Merck Sharp and Dohme; PROfound ClinicalTrials.gov number, NCT02987543.).", "OBJECTIVE: To use mathematical and economic models to predict the epidemiological and economic impact of vaccination with Bexsero, designed to protect against group B meningococcal disease, to help inform vaccine policy in the United Kingdom.DESIGN: Modelling study.SETTING: England.POPULATION: People aged 0-99.INTERVENTIONS: Incremental impact of introductory vaccine strategies simulated with a transmission dynamic model of meningococcal infection and vaccination including potential herd effects. Model parameters included recent evidence on the vaccine characteristics, disease burden, costs of care, litigation costs, and loss of quality of life from disease, including impacts on family and network members. The health impact of vaccination was assessed through cases averted and quality adjusted life years (QALYs) gained.MAIN OUTCOME MEASURES: Cases averted and cost per QALY gained through vaccination; programmes were deemed cost effective against a willingness to pay of £20,000 (€25,420, $32,677) per QALY gained from an NHS and personal and social services perspective.RESULTS: In the short term, case reduction is greatest with routine infant immunisation (26.3% of cases averted in the first five years). This strategy could be cost effective at £3 (€3.8, $4.9) a vaccine dose, given several favourable assumptions and the use of a quality of life adjustment factor. If the vaccine can disrupt meningococcal transmission more cases are prevented in the long term with an infant and adolescent combined programme (51.8% after 30 years), which could be cost effective at £4 a vaccine dose. Assuming the vaccine reduces acquisition by 30%, adolescent vaccination alone is the most favourable strategy economically, but takes more than 20 years to substantially reduce the number of cases.CONCLUSIONS: Routine infant vaccination is the most effective short term strategy and could be cost effective with a low vaccine price. Critically, if the vaccine reduces carriage acquisition in teenagers, the combination of infant and adolescent vaccination could result in substantial long term reductions in cases and be cost effective with competitive vaccine pricing.", "Proprotein convertase subtilisin/kexin 9 (PCSK9) is the ninth member of the proprotein convertase family. It is an important regulator of cholesterol metabolism. PCSK9 can bind to low-density lipoprotein receptors (LDLRs) and induce the degradation of these receptors through the endosome/lysosome pathway, thus decreasing the LDLR levels on the cell surface of hepatocytes, resulting in increased serum low-density lipoprotein cholesterol (LDL-C) concentrations. Recent studies have found that gene polymorphisms of PCSK9 are associated with hypercholesterolemia, risk of atherosclerosis, and ischemic stroke. Furthermore, monoclonal antibodies, peptide mimetics, small molecule inhibitors and gene silencing agents that are associated with PCSK9 are some of the newer pharmaceutical therapeutic strategies and approaches for lowering serum LDL-C levels. In this review, we will discuss recent advances in PCSK9 research, which show that PCSK9 is correlated with lipid metabolism, atherosclerosis, and, in particular, ischemic stroke. We will also discuss the current state of PCSK9 therapeutics and their potential in modulating these diseases.", "Tocilizumab is a recombinant humanized antihuman interleukin-6 receptor monoclonal antibody, which inhibits binding of IL-6 to its soluble (sIL-6R) and membrane-expressed (mIL-6R) receptors. The work investigated whether the observed decline in peripheral neutrophil and platelet counts after tocilizumab administration can be directly explained by tocilizumab IL-6R blockade, thus demonstrating the mechanism of tocilizumab action. Tocilizumab and total sIL-6R concentrations, neutrophil and platelet counts from 4 phase 3 studies in rheumatoid arthritis patients were available. Patients received 4 or 8 mg/kg tocilizumab intravenous infusions every 4 weeks for a total of 6 doses. A population approach was applied to describe the relationship between tocilizumab and sIL-6R concentrations and subsequent changes in neutrophil and platelet counts. Following tocilizumab administration, concentrations of total sIL-6R increased, while neutrophil and platelet counts declined. These changes were transient, with counts returning to their respective baseline levels soon after tocilizumab is eliminated from the body. Tocilizumab concentrations were described by a two compartment model with parallel linear and Michaelis-Menten elimination. The quasi-steady-state target-mediated drug disposition model described tocilizumab relationships to total sIL-6R, which allowed computation of unobserved unbound sIL-6R concentrations. The neutrophil counts were described as a direct function of unbound sIL-6R concentrations. The platelet counts were described by the transit-compartment life-span model with inhibition of production that depended on the unbound sIL-6R concentrations. Thus, the observed changes in sIL-6R, neutrophil, and platelet data are consistent with the tocilizumab mechanism of action and can be fully explained by tocilizumab binding to sIL-6R and mIL-6R.", "Vitamin E consists of a number of compounds, tocopherols and tocotrienols, that function as lipid-soluble antioxidants. A hypothesis is that vitamin E may slow the progression of atherosclerosis by blocking the oxidative modification of low-density lipoprotein cholesterol and thus decrease its uptake into the arterial lumen. Basic science and animal studies have generally supported this hypothesis. Observational studies have primarily assessed patients with no established coronary heart disease (CHD), and results have generally supported a protective role of vitamin E in CHD. Early primary and secondary prevention clinical trials (Alpha-Tocopherol, Beta-Carotene Cancer Protection study and Cambridge Heart Antioxidant Study) showed mixed results. Despite years of encouraging evidence from basic science and observational studies, 3 large randomized clinical trials (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico, Heart Outcomes Prevention Evaluation, and Primary Prevention Project) with a combined total of more than 25,000 patients failed to show a significant benefit with vitamin E taken as a dietary supplement for the prevention of CHD. Four large randomized primary prevention trials currently under way should add to our knowledge. The American Heart Association has recommended consumption of a balanced diet with emphasis on antioxidant-rich fruits and vegetables but has made no recommendations regarding vitamin E supplementation for the general population. Although vitamin E supplementation seems to be safe for most people, recommendations from health care professionals should reflect the uncertainty of established benefit as demonstrated in clinical trials.", "Patients affected by hemophilia A often require frequent prophylactic and therapeutic self-infusion. For those who develop inhibitors, treatment options are limited and mortality is increased. Emicizumab, a bispecific antibody to Factors IXa and X that carries out the function of Factor VIII (FVIII), represents a novel therapeutic approach. Areas covered: We review the clinical trials and key laboratory assay research for emicizumab. Emicizumab reduced the annualized bleeding rate by 87% compared to placebo in patients with inhibitors. For patients without inhibitors, emicizumab reduced the annualized bleeding rate 96-97% compared to no prophylaxis and 68% compared to prior FVIII prophylaxis. Three patients developed a thrombotic microangiopathy (TMA) and two patients had thrombotic events while on emicizumab in combination with activated prothrombin complex concentration (aPCC) alone or concurrent with activated recombinant factor FVII (rFVIIa). Expert opinion: Emicizumab represents a much-needed alternative approach to managing Factor VIII deficiency, especially for those with inhibitors or limited ability to self-infuse. For patients with inhibitors, thrombotic complications including TMA, not seen with other bypassing agents, raises concern about the use of emicizumab in combination with aPCC and how patients who have breakthrough bleeding can be safely managed.", "Laser interstitial thermal therapy (LITT) is a minimally invasive technique for treating intracranial tumors, originally introduced in 1983. Its use in neurosurgical procedures was historically limited by early technical difficulties related to the monitoring and control of the extent of thermal damage. The development of magnetic resonance thermography and its application to LITT have allowed for real-time thermal imaging and feedback control during laser energy delivery, allowing for precise and accurate provision of tissue hyperthermia. Improvements in laser probe design, surgical stereotactic targeting hardware, and computer monitoring software have accelerated acceptance and clinical utilization of LITT as a neurosurgical treatment alternative. Current commercially available LITT systems have been used for the treatment of neurosurgical soft-tissue lesions, including difficult to access brain tumors, malignant gliomas, and radiosurgery-resistant metastases, as well as for the ablation of such lesions as epileptogenic foci and radiation necrosis. In this review, the authors aim to critically analyze the literature to describe the advent of LITT as a neurosurgical, laser excision tool, including its development, use, indications, and efficacy as it relates to neurosurgical applications.", "The 2014-2015 outbreak of Ebola virus disease is the largest epidemic to date in terms of the number of cases, deaths, and affected areas. In October 2015, no antiviral agents had proven antiviral efficacy in patients. However, in September 2014, the World Health Organization inventoried and has since regularly updated a list of potential drug candidates with demonstrated antiviral efficacy in in vitro or animal models. This includes agents belonging to various therapeutic classes, namely direct antiviral agents (favipiravir and BCX4430), a combination of antibodies (ZMapp), type I interferons, RNA interference-based drugs (TKM-Ebola and AVI-7537), and anticoagulant drugs (rNAPc2). Here, we review the pharmacokinetic and pharmacodynamic information presently available for these drugs, using data obtained in healthy volunteers for pharmacokinetics and data obtained in human clinical trials or animal models for pharmacodynamics. Future studies evaluating these drugs in clinical trials are critical to confirm their efficacy in humans, propose appropriate doses, and evaluate the possibility of treatment combinations.", "BACKGROUND: Anti-glutamic acid decarboxylase antibody (GAD-ab)-associated cerebellar ataxia is a rare neurological disorder characterized by cerebellar symptoms concomitant with high GAD-ab levels in serum and cerebrospinal fluid (CSF).CASE REPORT: We report on 2 female siblings (aged 74 and 76 years) presenting with gradual progression of rotational vertigo, gait ataxia and vertical diplopia, continuously progressing for 6 months and 6 years, respectively. Autoimmune laboratory examinations showed remarkably increased serum and CSF GAD-ab levels. Their medical histories revealed late-onset type 1 diabetes mellitus (T1DM) and other concomitant autoimmune disorders (Grave's disease, Hashimoto's thyroiditis). Cerebral MRI and laboratory examinations were unremarkable. The diagnosis of GAD-ab-associated cerebellar ataxia with particular brainstem involvement was established in both women. After the exclusion of an underlying malignancy, immunosuppressive therapy has been initiated in both patients, which resulted in stabilization in one and in clinical improvement in the other patient.DISCUSSION: The unique association of autoantibody-mediated cerebellar ataxia and late-onset T1DM in 2 siblings with similar clinical and paraclinical phenotypes strengthens the concept that hereditary factors might play a relevant role also in autoimmune diseases so far considered to be sporadic. Moreover, the occurrence of continuous vertical diplopia broadens the clinical spectrum of GAD-ab-associated neurological syndromes.", "Ferroptosis is a newly defined iron-dependent, non-apoptotic mode of cell death with necrotic morphology. Distinctive from other death mechanisms, ferroptosis requires cellular iron and lipid peroxides, and is dictated by specific cellular metabolic processes. Importantly, ferroptosis has been implicated in a plethora of human diseases. This paper reviews the recent advances and outstanding questions of the field by focusing on the role of cellular metabolism in ferroptosis. The relevance of ferroptosis to disease and therapy is also discussed.", "Ferroptosis is an iron-dependent form of regulated nonapoptotic cell death, which contributes to damage in models of acute kidney injury (AKI). Heme oxygenase-1 (HO-1) is a cytoprotective enzyme induced in response to cellular stress, and is protective against AKI because of its antiapoptotic and anti-inflammatory properties. However, the role of HO-1 in regulating ferroptosis is unclear. The purpose of this study was to elucidate the role of HO-1 in regulating ferroptotic cell death in renal proximal tubule cells (PTCs). Immortalized PTCs obtained from HO-1+/+ and HO-1-/- mice were treated with erastin or RSL3, ferroptosis inducers, in the presence or absence of antioxidants, an iron source, or an iron chelator. Cells were assessed for changes in morphology and metabolic activity as an indicator of cell viability. Treatment of HO-1+/+ PTCs with erastin resulted in a time- and dose-dependent increase in HO-1 gene expression and protein levels compared with vehicle-treated controls. HO-1-/- cells showed increased dose-dependent erastin- or RSL3-induced cell death in comparison to HO-1+/+ PTCs. Iron supplementation with ferric ammonium citrate in erastin-treated cells decreased cell viability further in HO-1-/- PTCs compared with HO-1+/+ cells. Cotreatment with ferrostatin-1 (ferroptosis inhibitor), deferoxamine (iron chelator), or N-acetyl-l-cysteine (glutathione replenisher) significantly increased cell viability and attenuated erastin-induced ferroptosis in both HO-1+/+ and HO-1-/- PTCs. These results demonstrate an important antiferroptotic role of HO-1 in renal epithelial cells." ]

[ "Mutations in ribosomal proteins RPS19, RPS24 and RPS17 have been reported in Diamond-Blackfan Anemia (DBA), an autosomal dominant disease characterised by pure red cell aplasia. DBA is the prototype of ribosomapathies: a protein synthesis defect in a tissue with a high cellular turnover is considered the cause of the erythroid progenitor failure. We have created the Diamond-Blackfan Anemia mutation database to curate and record DBA gene mutations, together with their functional consequences and clinical phenotypes. This locus-specific resource is open to future submissions and is available online (http://www.dbagenes.unito.it). It is founded on the Leiden Open (source) Variation Database (LOVD) system and includes data from sequence and structure analysis tools, genomic database resources and published reports. It lists all identified variants and background genomic information. Phenotypic data are accessed by selecting a particular mutation. The database includes 219 unique variants of which 86 are disease-causing mutations. The database will be supplemented with other DBA genes as soon as they are reported and their mutations are identified and it should be of assistance to clinicians and investigators involved in DBA research and care.", "The pineal hormone, melatonin, is an important regulator of seasonal reproduction and circadian rhythms. Its effects are mediated via high-affinity melatonin receptors, located on cells of the pituitary pars tuberalis (PT) and suprachiasmatic nucleus (SCN), respectively. Two subtypes of mammalian melatonin receptors have been cloned and characterized, the MT1 (Mel(1a)) and the MT2 (Mel(1b)) melatonin receptor subtypes. Both subtypes are members of the seven-transmembrane G protein-coupled receptor family. By using recombinant melatonin receptors it has been shown that the MT1 melatonin receptor is coupled to different G proteins that mediate adenylyl cyclase inhibition and phospholipase C beta activation. The MT2 receptor is also coupled to inhibition of adenylyl cyclase and additionally it inhibits the soluble guanylyl cyclase pathway. In mice with a targeted deletion of the MT1 receptor, the acute inhibitory effects of melatonin on SCN multiunit activity are completely abolished, while the phase-shifting responses to melatonin (given in physiological concentrations) appear normal. Furthermore, melatonin inhibits the phosphorylation of the transcription factor cyclic AMP response element binding protein, induced by the pituitary adenylate cyclase-activating polypeptide in SCN cells predominantly via the MT1 receptor. However, a functional MT2 receptor in the rodent SCN is partially able to compensate for the absence of the MT1 receptor in MT1 receptor-deficient mice. These findings indicate redundant and non-redundant roles of the receptor subtypes in regulating SCN function. In the PT, a functional MT1 receptor is essential for the rhythmic synthesis of the clock gene product mPER1. Melatonin produces a long-lasting sensitization of adenylyl cyclase and thus amplifies cyclic AMP signaling when melatonin levels decline at dawn. This action of melatonin amplifies gene expression rhythms in the PT and provides a mechanism for reinforcing rhythmicity in peripheral tissues which themselves lack the capacity for self-sustained oscillation. Mice with targeted deletion of melatonin receptor subtypes provide an excellent model to understand cellular mechanisms through which melatonin modulates circadian and photoperiodic rhythmicity.", "DNA methyltransferase inhibitors (DNMTIs), including decitabine (DAC) and azacitidine (AZA), have recently been highlighted for the treatment of high-risk myelodysplastic syndrome (MDS); however, their action mechanisms have not been clearly defined. Therefore, we investigated the effects of DNMTIs on MDS-derived cell lines in vitro. An MDS-derived cell line MDS92 and its blastic subline MDS-L and HL-60 were used. All three cell lines were sensitive to DNMTIs, but MDS-L was the most susceptible. DAC-induced cell death in MDS-L was preceded by DNA damage-induced G2 arrest via a p53-independent pathway. AZA did not influence the pattern of cell cycle, although it induced DNA damage response. The IC(50) of DAC or AZA on MDS-L cells was associated with the dose inducing the maximal hypomethylation in long interspersed nuclear elements-1 (LINE-1) methylation assay. AZA suppressed the level of methylation in a time-dependent manner (days 4, 7, and 10), whereas DAC maintained the level of methylation from day 4 to 11. The protein expression of DNMT1 and DNMT3a decreased with the suppression of growth and methylation. We conclude that this study provides in vitro models for understanding the effects of DNMTIs on cell growth and gene regulation, including differences in the possible action mechanism of DAC and AZA.", "BACKGROUND: Acute myeloid leukemia is the collective name for different types of leukemias of myeloid origin affecting blood and bone marrow. The overproduction of immature myeloblasts (white blood cells) is the characteristic feature of AML, thus flooding the bone marrow and reducing its capacity to produce normal blood cells. USFDA on August 1, 2017, approved a drug named Enasidenib formerly known as AG-221 which is being marketed under the name Idhifa to treat R/R AML with IDH2 mutation. The present review depicts the broad profile of enasidenib including various aspects of chemistry, preclinical, clinical studies, pharmacokinetics, mode of action and toxicity studies.METHODS: Various reports and research articles have been referred to summarize different aspects related to chemistry and pharmacokinetics of enasidenib. Clinical data was collected from various recently published clinical reports including clinical trial outcomes.RESULT: The various findings of enasidenib revealed that it has been designed to allosterically inhibit mutated IDH2 to treat R/R AML patients. It has also presented good safety and efficacy profile along with 9.3 months overall survival rates of patients in which disease has relapsed. The drug is still under study either in combination or solely to treat hematological malignancies. Molecular modeling studies revealed that enasidenib binds to its target through hydrophobic interaction and hydrogen bonding inside the binding pocket. Enasidenib is found to be associated with certain adverse effects like elevated bilirubin level, diarrhea, differentiation syndrome, decreased potassium and calcium levels, etc.CONCLUSION: Enasidenib or AG-221was introduced by FDA as an anticancer agent which was developed as a first in class, a selective allosteric inhibitor of the tumor target i.e. IDH2 for Relapsed or Refractory AML. Phase 1/2 clinical trial of Enasidenib resulted in the overall survival rate of 40.3% with CR of 19.3%. Phase III trial on the Enasidenib is still under process along with another trial to test its potency against other cell lines. Edasidenib is associated with certain adverse effects, which can be reduced by investigators by designing its newer derivatives on the basis of SAR studies. Hence, it may come in the light as a potent lead entity for anticancer treatment in the coming years.", "Following chronic liver injury, hepatic stellate cells (HSCs) transdifferentiate into myofibroblast-like cells, which develop contractile properties and contribute to increased resistance to blood flow. We investigated whether this phenotypic activation includes changes in the expression of L-type voltage-operated Ca2+ channels (VOCC), which mediate Ca2+ influx and regulate cell contraction in vascular cell types. Rat HSCs were studied in the quiescent phenotype and after their activation in vitro (cultured on plastic for 14 days) and in vivo (isolated from rats with CCl(4)-induced cirrhosis). Patch-clamp studies showed Ca2+ currents through L-type VOCC in HSCs activated both in vitro and in vivo, whereas no currents were detected in quiescent HSCs. Moreover, binding studies with (3)H-isradipine, a specific L-type VOCC antagonist, showed a large number of binding sites in activated HSCs, while no specific binding was found in quiescent HSCs. Finally, messenger RNA (mRNA) encoding L-type VOCC was not detected in quiescent HSCs as assessed by reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis, whereas it was present in activated HSCs. Stimulation of L-type VOCC with KCl resulted in a marked increase in [Ca2+](i) followed by cell contraction in HSCs activated both in vitro and in vivo, whereas no effects were observed in quiescent HSCs. We conclude that the activation of HSCs is associated with up-regulation of L-type VOCC that mediate Ca2+ influx and cell contraction. These results may be relevant to the pathogenesis of portal hypertension.", "CONTEXT: Throughout the past 40 years, a vast and sometimes contradictory literature has accumulated regarding hypertrophic cardiomyopathy (HCM), a genetic cardiac disease caused by a variety of mutations in genes encoding sarcomeric proteins and characterized by a broad and expanding clinical spectrum.OBJECTIVES: To clarify and summarize the relevant clinical issues and to profile rapidly evolving concepts regarding HCM.DATA SOURCES: Systematic analysis of the relevant HCM literature, accessed through MEDLINE (1966-2000), bibliographies, and interactions with investigators.STUDY SELECTION AND DATA EXTRACTION: Diverse information was assimilated into a rigorous and objective contemporary description of HCM, affording greatest weight to prospective, controlled, and evidence-based studies.DATA SYNTHESIS: Hypertrophic cardiomyopathy is a relatively common genetic cardiac disease (1:500 in the general population) that is heterogeneous with respect to disease-causing mutations, presentation, prognosis, and treatment strategies. Visibility attached to HCM relates largely to its recognition as the most common cause of sudden death in the young (including competitive athletes). Clinical diagnosis is by 2-dimensional echocardiographic identification of otherwise unexplained left ventricular wall thickening in the presence of a nondilated cavity. Overall, HCM confers an annual mortality rate of about 1% and in most patients is compatible with little or no disability and normal life expectancy. Subsets with higher mortality or morbidity are linked to the complications of sudden death, progressive heart failure, and atrial fibrillation with embolic stroke. Treatment strategies depend on appropriate patient selection, including drug treatment for exertional dyspnea (beta-blockers, verapamil, disopyramide) and the septal myotomy-myectomy operation, which is the standard of care for severe refractory symptoms associated with marked outflow obstruction; alcohol septal ablation and pacing are alternatives to surgery for selected patients. High-risk patients may be treated effectively for sudden death prevention with the implantable cardioverter-defibrillator.CONCLUSIONS: Substantial understanding has evolved regarding the epidemiology and clinical course of HCM, as well as novel treatment strategies that may alter its natural history. An appreciation that HCM, although an important cause of death and disability at all ages, does not invariably convey ominous prognosis and is compatible with normal longevity should dictate a large measure of reassurance for many patients.", "BACKGROUND: By reducing the amount of nicotine that reaches the brain when a person smokes a cigarette, nicotine vaccines may help people to stop smoking or to prevent recent quitters from relapsing.OBJECTIVES: The aims of this review are to assess the efficacy of nicotine vaccines for smoking cessation and for relapse prevention, and to assess the frequency and type of adverse events associated with the use of nicotine vaccines.SEARCH METHODS: We searched the Cochrane Tobacco Addiction Review Group specialised register for trials, using the term 'vaccine' in the title or abstract, or in a keyword (date of most recent search April 2012). To identify any other material including reviews and papers potentially relevant to the background or discussion sections, we also searched MEDLINE, EMBASE, and PsycINFO, combining terms for nicotine vaccines with terms for smoking and tobacco use, without design limits or limits for human subjects. We searched the Annual Meeting abstracts of the Society for Research on Nicotine and Tobacco up to 2012, using the search string 'vaccin'. We searched Google Scholar for 'nicotine vaccine'. We also searched company websites and Google for information related to specific vaccines. We searched clinicaltrials.gov in March 2012 for 'nicotine vaccine' and for the trade names of known vaccine candidates.SELECTION CRITERIA: We included randomized controlled trials of nicotine vaccines, at Phase II and Phase III trial stage and beyond, in adult smokers or recent ex-smokers. We included studies of nicotine vaccines used as part of smoking cessation or relapse prevention interventions.DATA COLLECTION AND ANALYSIS: We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, blinding of participants and personnel, reporting of outcomes, and completeness of follow-up.Our primary outcome measure was a minimum of six months abstinence from smoking. We used the most rigorous definition of abstinence, and preferred cessation rates at 12 months and biochemically validated rates where available. We have used the risk ratio (RR) to summarize individual trial outcomes. We have not pooled the current group of included studies as they cover different vaccines and variable regimens.MAIN RESULTS: There are no nicotine vaccines currently licensed for public use, but there are a number in development. We found four trials which met our inclusion criteria, three comparing NicVAX to placebo and one comparing NIC002 (formerly NicQbeta) to placebo. All were smoking cessation trials conducted by pharmaceutical companies as part of the drug development process, and all trials were judged to be at high or unclear risk of bias in at least one domain. Overall, 2642 smokers participated in the included studies in this review. None of the four included studies detected a statistically significant difference in long-term cessation between participants receiving vaccine and those receiving placebo. The RR for 12 month cessation in active and placebo groups was 1.35 (95% Confidence Interval (CI) 0.82 to 2.22) in the trial of NIC002 and 1.74 (95% CI 0.73 to 4.18) in one NicVAX trial. Two Phase III NicVAX trials, for which full results were not available, reported similar quit rates of approximately 11% in both groups. In the two studies with full results available, post hoc analyses detected higher cessation rates in participants with higher levels of nicotine antibodies, but these findings are not readily generalisable. The two studies with full results showed nicotine vaccines to be well tolerated, with the majority of adverse events classified as mild or moderate. In the study of NIC002, participants receiving the vaccine were more likely to report mild to moderate adverse events, most commonly flu-like symptoms, whereas in the study of NicVAX there was no significant difference between the two arms. Information on adverse events was not available for the large Phase III trials of NicVAX.Vaccine candidates are likely to undergo significant changes before becoming available to the general public, and those included in this review may not be the first to reach market; this limits the external validity of the results reported in this review in terms of both effectiveness and tolerability.AUTHORS' CONCLUSIONS: There is currently no evidence that nicotine vaccines enhance long-term smoking cessation. Rates of serious adverse events recorded in the two trials with full data available were low, and the majority of adverse events reported were at mild to moderate levels. The evidence available suggests nicotine vaccines do not induce compensatory smoking or affect withdrawal symptoms. No nicotine vaccines are currently licensed for use in any country but a number are under development.Further trials of nicotine vaccines are needed, comparing vaccines with placebo for smoking cessation. Further trials are also needed to explore the potential of nicotine vaccines to prevent relapse. Results from past, current and future research should be reported in full. Adverse events and serious adverse events should continue to be carefully monitored and thoroughly reported." ]

[ "The activity of 5-hydroxytryptaminergic neurons has been estimated from measurements of: concentrations of 5-hydroxyindoleacetic acid; the ratio of the concentrations of 5-hydroxyindoleacetic acid to 5-hydroxytryptamine; the rate of accumulation of 5-hydroxytryptophan following the administration of an aromatic L-amino acid decarboxylase inhibitor (e.g., NSD 1015); the rate of accumulation of 5-hydroxytryptamine, and the rate of decline of 5-hydroxyindoleacetic acid following the administration of a monoamine oxidase inhibitor (e.g., pargyline). The purpose of the present study was to compare these different methods under conditions of changing neuronal impulse traffic produced by electrical stimulation of 5-hydroxytryptaminergic neurons. Male rats anesthetized with chloral hydrate were killed following 0, 15, or 30 min of electrical stimulation of the dorsal raphe nucleus at a frequency of 0, 5, or 10 Hz. The concentrations of 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, and 5-hydroxytryptophan in nucleus accumbens, amygdala, suprachiasmatic nucleus, and dorsomedial nucleus were measured using HPLC coupled to an electrochemical detector. In each brain region, stimulation elicited an increase in the concentration of 5-hydroxyindoleacetic acid and the 5-hydroxyindoleacetic acid/5-hydroxytryptamine concentration ratio in saline-treated animals and an increase in 5-hydroxytryptophan accumulation in NSD 1015-treated animals, but did not alter the concentration of 5-hydroxytryptamine or 5-hydroxyindoleacetic acid in pargyline-treated rats. The results o f this study indicate that although the first three methods serve as valid indices of 5-hydroxytryptaminergic neuronal activity, the pargyline-dependent techniques are not responsive to changes in the rate of 5-hydroxytryptamine nerve firing.", "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.", "In this open-label, multicentre, phase 1 study a fully human anti-CD40 antagonist monoclonal antibody, lucatumumab, was evaluated in patients with relapsed/refractory multiple myeloma (MM). The primary objective was to determine the maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs). Secondary objectives included safety, pharmacokinetics, pharmacodynamics and antimyeloma activity. Twenty-eight patients, enrolled using a standard '3 + 3' dose escalation, received one or two (n = 3) cycles of lucatumumab 1·0, 3·0, 4·5 or 6·0 mg/kg once weekly for 4 weeks. Common lucatumumab-related adverse events were reversible, mild-to-moderate infusion reactions. Severe adverse events were anaemia, chills, hypercalcaemia and pyrexia (7% each). DLTs included grade 4 thrombocytopenia, grade 3 increased alanine aminotransferase and grade 4 increased lipase (n = 1 each). The MTD was 4·5 mg/kg. At doses ≥3·0 mg/kg, sustained receptor occupancy (≥87%), observed throughout weekly infusions up to 5 weeks after the last infusion, correlated with an estimated half-life of 4-19 d. Twelve patients (43%) had stable disease, and one patient (4%) maintained a partial response for ≥8 months. These findings indicate that single-agent lucatumumab was well tolerated up to 4·5 mg/kg with modest clinical activity in relapsed/refractory MM, warranting further study as a combination therapy.", "Histone modifications are implicated in regulating chromatin condensation but it is unclear how they differ between constitutive heterochromatin and unexpressed euchromatin. Chromatin immunoprecipitation (ChIP) assays were done on various human cell populations using antibodies specific for acetylated or methylated forms of histone H3 or H4. Analysis of the immunoprecipitates was by quantitative real-time PCR or semi-quantitative PCR (SQ-PCR). Of eight tested antibodies, the one for histone H4 acetylated at lysine 4, 8, 12, or 16 was best for distinguishing constitutive heterochromatin from unexpressed euchromatin, but differences in the extent of immunoprecipitation of these two types of chromatin were only modest, although highly reproducible. With this antibody, there was an average of 2.5-fold less immunoprecipitation of three constitutive heterochromatin regions than of four unexpressed euchromatic gene regions and about 15-fold less immunoprecipitation of these heterochromatin standards than of two constitutively expressed gene standards (P <0.001). We also analyzed histone acetylation and methylation by immunocytochemistry with antibodies to H4 acetylated at lysine 8, H3 trimethylated at lysine 9, and H3 methylated at lysine 4. In addition, immunocytochemical analysis was done with an antibody to heterochromatin protein 1alpha (HP1alpha), whose preferential binding to heterochromatin has been linked to trimethylation of H3 at lysine 9. Our combined ChIP and immunocytochemical results suggest that factors other than hypoacetylation of the N-terminal tails of H4 and hypermethylation of H3 at lysine 9 can play an important role in determining whether a chromatin sequence in mammalian cells is constitutively heterochromatic.", "Via building computational (typically mathematical and computer simulation) models, human performance modeling (HPM) quantifies, predicts, and maximizes human performance, human-machine system productivity and safety. This paper describes and summarizes the five key questions of human performance modeling: 1) Why we build models of human performance; 2) What the expectations of a good human performance model are; 3) What the procedures and requirements in building and verifying a human performance model are; 4) How we integrate a human performance model with system design; and 5) What the possible future directions of human performance modeling research are. Recent and classic HPM findings are addressed in the five questions to provide new thinking in HPM's motivations, expectations, procedures, system integration and future directions.", "The five B-subunits (CTB5) of the Vibrio cholerae (cholera) toxin can bind to the intestinal cell surface so the entire AB5 toxin can enter the cell. Simultaneous binding can occur on more than one of the monosialotetrahexosylganglioside (GM1) units present on the cell surface. Such simultaneous binding arising from the toxins multivalency is believed to enhance its affinity. Thus, blocking the initial attachment of the toxin to the cell surface using inhibitors with GM1 subunits has the potential to stop the disease. Previously we showed that tetravalent GM1 molecules were sub-nanomolar inhibitors of CTB5. In this study, we synthesized a pentavalent version and compared the binding and potency of penta- and tetravalent cholera toxin inhibitors, based on the same scaffold, for the first time. The pentavalent geometry did not yield major benefits over the tetravalent species, but it was still a strong inhibitor, and no major steric clashes occurred when binding the toxin. Thus, systems which can adopt more geometries, such as those described here, can be equally potent, and this may possibly be due to their ability to form higher-order structures or simply due to more statistical options for binding.", "Musclin is a novel skeletal muscle-derived secretory factor found in the signal sequence trap of mouse skeletal muscle cDNAs. Musclin possesses a region homologous to the natriuretic peptide family. Thus, musclin is found to bind with the natriuretic peptide clearance receptors. However, the role of musclin in vascular regulation remains unclear. In this study, we aim to investigate the direct effect of musclin on vascular tone and to analyze its role in hypertension using the spontaneously hypertensive rats (SHR). In aortic strips isolated from SHR, musclin induced contractions in a dose-dependent manner. We found that the musclin-induced vasoconstriction was more marked in SHR than in normal rats (WKY). Moreover, this contraction was reduced by blockade of natriuretic peptide receptor C using the ab14355 antibody. Therefore, mediation of the natriuretic peptide receptor in musclin-induced vasoconstriction can be considered. In addition, similar to the natriuretic peptide receptor, expression of the musclin gene in blood vessels was higher in SHR than in WKY. Injection of musclin markedly increased the blood pressure in rats that can be inhibited by anti-musclin antibodies. Musclin-induced vasoconstriction was more pronounced in SHR than in WKY as in its expression. Taken together, these results suggest that musclin is involved in blood pressure regulation. The higher expression of musclin in hypertension indicates that musclin could be used as a new target for the treatment of hypertension in the future." ]

[ "We have reviewed some of the important studies published within the last 18 months that have advanced our understanding of the epilepsies, their aetiology and treatment. Clinical studies have revealed new insights into old themes including seizure prediction, mortality in epilepsy, febrile seizures and the pathophysiology of focal cortical dysplasias. The rapid advances in genetics and particularly whole exome sequencing have had an impact on our understanding of epileptic encephalopathies, and the aetiology of hippocampal sclerosis. Experimental research techniques such as viral vector gene delivery, optogenetics and cell based transplantation techniques have set the framework for novel approaches to the treatment of pharmacoresistant epilepsy. These few examples are indicative of the great strides that have recently been made in epilepsy research.", "Natural killer (NK) cell-based immunotherapy is a promising novel approach to treat cancer. However, NK cell function has been shown to be potentially diminished by factors common in the tumor microenvironment (TME). In this study, we assessed the synergistic potential of antibody-dependent cell-mediated cytotoxicity (ADCC) and killer immunoglobin-like receptor (KIR)-ligand mismatched NK cells to potentiate NK cell antitumor reactivity in multiple myeloma (MM). Hypoxia, lactate, prostaglandin E2 (PGE2) or combinations were selected to mimic the TME. To investigate this, NK cells from healthy donors were isolated and NK cell ADCC capacity in response to MM cells was assessed in flow cytometry-based cytotoxicity and degranulation (CD107a) assays in the presence of TME factors. Hypoxia, lactate and PGE2 reduced cytotoxicity of NK cells against myeloma target cells. The addition of daratumumab (anti-CD38 antibody) augmented NK-cell cytotoxicity against target cells expressing high CD38, but not against CD38 low or negative target cells also in the presence of TME. Co-staining for inhibitory KIRs and NKG2A demonstrated that daratumumab enhanced degranulation of all NK cell subsets. Nevertheless, KIR-ligand mismatched NK cells were slightly better effector cells than KIR-ligand matched NK cells. In summary, our study shows that combination therapy using strategies to maximize activating NK cell signaling by triggering ADCC in combination with an approach to minimize inhibitory signaling through a selection of KIR-ligand mismatched donors, can help to overcome the NK-suppressive TME. This can serve as a platform to improve the clinical efficacy of NK cells.", "The principle of heterotachy states that the substitution rate of sites in a gene can change through time. In this article, we propose a powerful statistical test to detect sites that evolve according to the process of heterotachy. We apply this test to an alignment of 1289 eukaryotic rRNA molecules to 1) determine how widespread the phenomenon of heterotachy is in ribosomal RNA, 2) to test whether these heterotachous sites are nonrandomly distributed, that is, linked to secondary structure features of ribosomal RNA, and 3) to determine the impact of heterotachous sites on the bootstrap support of monophyletic groupings. Our study revealed that with 21 monophyletic taxa, approximately two-thirds of the sites in the considered set of sequences is heterotachous. Although the detected heterotachous sites do not appear bound to specific structural features of the small subunit rRNA, their presence is shown to have a large beneficial influence on the bootstrap support of monophyletic groups. Using extensive testing, we show that this may not be due to heterotachy itself but merely due to the increased substitution rate at the detected heterotachous sites.", "The expansion of normally polymorphic CTG microsatellites in certain human genes has been identified as the causative mutation of a number of hereditary neurological disorders, including Huntington's disease and myotonic dystrophy. Here, we have investigated the effect of methyl-directed mismatch repair (MMR) on the stability of a (CTG)43 repeat in Escherichia coli over 140 generations and find two opposing effects. In contrast to orientation-dependent repeat instability in wild-type E. coli and yeast, we observed no orientation dependence in MMR- E. coli cells and suggest that, for the repeat that we have studied, orientation dependence in wild-type cells is mainly caused by functional mismatch repair genes. Our results imply that slipped structures are generated during replication, causing single triplet expansions and contractions in MMR- cells, because they are left unrepaired. On the other hand, we find that the repair of such slipped structures by the MMR system can go awry, resulting in large contractions. We show that these mutS-dependent contractions arise preferentially when the CTG sequence is encoded by the lagging strand. The nature of this orientation dependence argues that the small slipped structures that are recognized by the MMR system are formed primarily on the lagging strand of the replication fork. It also suggests that, in the presence of functional MMR, removal of 3 bp slipped structures causes the formation of larger contractions that are probably the result of secondary structure formation by the CTG sequence. We rationalize the opposing effects of MMR on repeat tract stability with a model that accounts for CTG repeat instability and loss of orientation dependence in MMR- cells. Our work resolves a contradiction between opposing claims in the literature of both stabilizing and destabilizing effects of MMR on CTG repeat instability in E. coli.", "BACKGROUND: Interleukin (IL)-17 is an important factor in rheumatoid arthritis (RA) pathogenesis. MicroRNA (miRNA)s are a family of non coding RNAs and associated with human diseases including RA. The purpose of this study is to identify the miRNAs in the differentiation of IL-17 producing cells, and analyze their expression pattern in the peripheral blood mononuclear cells (PBMC) and synovium from RA patients.METHODS: IL-17 producing cells were expanded from CD4+T cell. MiRNA microarray was performed to identify the miRNAs in the differentiation of IL-17 producing cells. Quantitative polymerase chain reaction was performed to examine the expression patterns of the identified miRNAs in the PBMC and synovium from RA and osteoarthritis (OA) patients. Double staining combining in situ hybridization and immunohistochemistry of IL-17 was performed to analyze the expression pattern of identified miRNA in the synovium.RESULTS: Six miRNAs, let-7a, miR-26, miR-146a/b, miR-150, and miR-155 were significantly up regulated in the IL-17 producing T cells. The expression of miR-146a and IL-17 was higher than in PBMC in the patients with low score of Larsen grade and short disease duration. MiR-146a intensely expressed in RA synovium in comparison to OA. MiR-146a expressed intensely in the synovium with hyperplasia and high expression of IL-17 from the patients with high disease activity. Double staining revealed that miR-146a expressed in IL-17 expressing cells.CONCLUSION: These results indicated that miR-146a was associated with IL-17 expression in the PBMC and synovium in RA patients. There is the possibility that miR-146a participates in the IL-17 expression.", "There is accumulating evidence that tumour necrosis factor (TNF) plays a major role in the pathogenesis of rheumatoid arthritis (RA). Recent biotechnological advances have allowed for the development of agents that directly target TNF, a pro-inflammatory cytokine. In the last 2 years, the US FDA and the EU's Commission of the European Communities have approved two biological agents for the treatment of refractory RA, etanercept and infliximab. Etanercept is a fusion protein, composed of the Fc portion of IgG1 and the extracellular domain of the TNF receptor (p75). Infliximab is a chimeric monoclonal antibody (mAb) composed of murine variable and human constant regions. In placebo-controlled trials, both agents have proven to be effective and well-tolerated in RA patients. This review evaluates the available TNF inhibitors, summarises pertinent clinical trials and underscores differences between the two agents in terms of molecular structure, efficacy, safety data, antigenicity and pharmacokinetics.", "Dravet syndrome, or as it was called in the past 'severe myoclonic epilepsy in infancy', is a drug-resistant epilepsy first described by Charlotte Dravet in 1978. Besides the well-known and well-described therapy resistance, Dravet syndrome dramatically impacts the development and behaviour of the affected children. As it is still not a curable disease, families need to be taught how to cope with the disorder and will require assistance from both clinical and non-clinical structures. At the onset of the disease, many questions arise regarding the diagnosis of Dravet syndrome, the severity of the illness and its deleterious effects, and the management of seizures, especially the long-lasting status epilepticus. Once the diagnosis has been established, severe convulsions, often unpredictable and long-lasting, are still a major worry, but developmental and behavioural problems also rapidly become a serious concern. Later on, nearly all parents will have a child who becomes an adult with special needs, requiring specialised attention from professionals." ]

[ "Eighteen boys with Duchenne muscular dystrophy (DMD) were assessed for their ability to perform tasks involving wrist and hand function. Each subject was assessed using the Jebsen Test of Hand Function, range of motion measurements, and muscle strength tests. Writing and simulated page turning were performed successfully by boys in all age groups. Boys over age 15 had difficulty completing simulated feeding and picking up large and small objects. The muscle strength of the wrist extensors and the radial deviation range of motion at the wrist were found to be strongly correlated with six of the seven tasks assessed. These two clinical assessments appear to be good indicators of overall wrist and hand function. Life expectancy with DMD is increasing with advances in respiratory care making preservation of wrist and hand function, the major activity remaining with advanced disease, increasingly important.", "The human ether-a-go-go-related gene (hERG) encodes the pore-forming α-subunit of the rapidly activating delayed rectifier K(+) channel in the heart, which plays a critical role in cardiac action potential repolarization. Dysfunction of IKr causes long QT syndrome, a cardiac electrical disorder that predisposes affected individuals to fatal arrhythmias and sudden death. The homeostasis of hERG channels in the plasma membrane depends on a balance between protein synthesis and degradation. Our recent data indicate that hERG channels undergo enhanced endocytic degradation under low potassium (hypokalemia) conditions. The GTPase Rab4 is known to mediate rapid recycling of various internalized proteins to the plasma membrane. In the present study, we investigated the effect of Rab4 on the expression level of hERG channels. Our data revealed that overexpression of Rab4 decreases the expression level of hERG in the plasma membrane. Rab4 does not affect the expression level of the Kv1.5 or EAG K(+) channels. Mechanistically, our data demonstrate that overexpression of Rab4 increases the expression level of endogenous Nedd4-2, a ubiquitin ligase that targets hERG but not Kv1.5 or EAG channels for ubiquitination and degradation. Nedd4-2 undergoes self- ubiquitination and degradation. Rab4 interferes with Nedd4-2 degradation, resulting in an increased expression level of Nedd4-2, which targets hERG. In summary, the present study demonstrates a novel pathway for hERG regulation; Rab4 decreases the hERG density at the plasma membrane by increasing the endogenous Nedd4-2 expression.", "Viroids, subviral pathogens of plants, are composed of a single-stranded circular RNA of 246-399 nucleotides. Within the 27 viroids sequenced, avocado sunblotch, peach latent mosaic and chrysanthemum chlorotic mottle viroids (ASBVd, PLMVd and CChMVd, respectively) can form hammerhead structures in both of their polarity strands. These ribozymes mediate self-cleavage of the oligomeric RNAs generated in the replication through a rolling circle mechanism, whose two other steps are catalyzed by an RNA polymerase and an RNA ligase. ASBVd, and presumably PLMVd and CChMVd, replicate and accumulate in the chloroplast, whereas typical viroids replicate and accumulate in the nucleus. PLMVd and CChMVd do not adopt a rod-like or quasi rod-like secondary structure as typical viroids do but have a highly branched conformation. A pathogenicity determinant has been mapped in a defined region of the CChMVd molecule.", "Routine and mass administration of oral polio vaccine (OPV) since 1961 has prevented many millions of cases of paralytic poliomyelitis. The public health value of this inexpensive and easily administered product has been extraordinary. Progress of the Global Polio Eradication Initiative has further defined the value of OPV as well as its risk through vaccine-associated paralytic poliomyelitis (VAPP) and vaccine-derived polioviruses (VDPV). Although both are rare, once wild poliovirus transmission has been interrupted by OPV, the only poliomyelitis due to poliovirus will be caused by OPV. Poliovirus will be eradicated only when OPV use is discontinued. This paradox provides a major incentive for eventually stopping polio immunization or replacing OPV, but it also introduces complexity into the process of identifying safe and scientifically sound strategies for doing so. The core post eradication immunization issues include the risk/benefits of continued OPV use, the extent of OPV replacement with IPV, possible strategies for discontinuing OPV, and the potential for development and licensure of a safe and effective replacement for OPV. Formulation of an informed post eradication immunization policy requires careful evaluation of polio epidemiology, surveillance capability, vaccine availability, laboratory containment, and the risks posed by the very tool responsible for successful interruption of wild poliovirus transmission.", "Renewal of nongermative epithelia is poorly understood. The novel mitogen \"lacritin\" is apically secreted by several nongermative epithelia. We tested 17 different cell types and discovered that lacritin is preferentially mitogenic or prosecretory for those types that normally contact lacritin during its glandular outward flow. Mitogenesis is dependent on lacritin's C-terminal domain, which can form an alpha-helix with a hydrophobic face, as per VEGF's and PTHLP's respective dimerization or receptor-binding domain. Lacritin targets downstream NFATC1 and mTOR. The use of inhibitors or siRNA suggests that lacritin mitogenic signaling involves Galpha(i) or Galpha(o)-PKCalpha-PLC-Ca2+-calcineurin-NFATC1 and Galpha(i) or Galpha(o)-PKCalpha-PLC-phospholipase D (PLD)-mTOR in a bell-shaped, dose-dependent manner requiring the Ca2+ sensor STIM1, but not TRPC1. This pathway suggests the placement of transiently dephosphorylated and perinuclear Golgi-translocated PKCalpha upstream of both Ca2+ mobilization and PLD activation in a complex with PLCgamma2. Outward flow of lacritin from secretory cells through ducts may generate a proliferative/secretory field as a different unit of cellular renewal in nongermative epithelia where luminal structures predominate.", "OBJECTIVE: To review the clinical trials, pharmacologic characteristics, safety, and efficacy of the elvitegravir/cobicistat/emtricitabine/tenofovir single tablet formulation (Stribild).DATA SOURCES: Literature searches were performed in MEDLINE (1948-September 2012) and PubMed (1966-September 2012) using the search terms GS-9137, elvitegravir, GS 9350, cobicistat, quad pill, Stribild, and integrase inhibitors. Abstracts from HIV/AIDS conferences were reviewed.STUDY SELECTION AND DATA EXTRACTION: Phase 3 studies evaluating the safety and efficacy of Stribild were preferentially evaluated, as well as relevant references from the published studies.DATA SYNTHESIS: Stribild contains complete antiretroviral therapy for HIV-1 infection in a single tablet. It is the first once-daily therapy option available with an integrase inhibitor and a novel pharmacokinetic boosting agent. Stribild has shown noninferiority in viral load suppression at 48 weeks when compared with dual nucleoside/nucleotide reverse transcriptase inhibitor and either a ritonavir-boosted protease inhibitor or nonnucleoside reverse transcriptase inhibitor regimen. Stribild was well tolerated, but some patients experienced increases in serum creatinine early in treatment that stabilized over time.CONCLUSIONS: Stribild is the first single-tablet regimen for HIV-1 infection treatment containing an integrase inhibitor. It is expected to have a prominent place in the formularies of health plans providing care for individuals with HIV-1 infection.", "MOTIVATION: The alignment of bisulfite-treated DNA sequences (BS-seq reads) to a large genome involves a significant computational burden beyond that required to align non-bisulfite-treated reads. In the analysis of BS-seq data, this can present an important performance bottleneck that can be mitigated by appropriate algorithmic and software-engineering improvements. One strategy is to modify the read-alignment algorithms by integrating the logic related to BS-seq alignment, with the goal of making the software implementation amenable to optimizations that lead to higher speed and greater sensitivity than might otherwise be attainable.RESULTS: We evaluated this strategy using Arioc, a short-read aligner that uses GPU (general-purpose graphics processing unit) hardware to accelerate computationally-expensive programming logic. We integrated the BS-seq computational logic into both GPU and CPU code throughout the Arioc implementation. We then carried out a read-by-read comparison of Arioc's reported alignments with the alignments reported by well-known CPU-based BS-seq read aligners. With simulated reads, Arioc's accuracy is equal to or better than the other read aligners we evaluated. With human sequencing reads, Arioc's throughput is at least 10 times faster than existing BS-seq aligners across a wide range of sensitivity settings.AVAILABILITY AND IMPLEMENTATION: The Arioc software is available for download at https://github.com/RWilton/Arioc. It is released under a BSD open-source license.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online." ]

[ "Src family kinases (SFKs) are a family of protein tyrosine kinases containing nine members: Src, Lyn, Fgr, Hck, Lck, Fyn, Blk, Yes, and Ylk. Although SFK activation is a major immediate signaling event in LPS/Toll-like receptor 4 (TLR4) signaling, its precise role has remained elusive due to various contradictory results obtained from a certain SFK member-deficient mice or cells. The observed inconsistencies may be due to the compensation or redundancy by other SFKs upon a SFK deficiency. The chemical rescuing approach was suggested to induce temporal and precise SFK activation in living cells, thereby limiting the chance of cellular adaption to a SFK-deficient condition. Using the rescuing approach, we demonstrate that restoring SFK activity not only induces tyrosine phosphorylation of TLR4, but also inhibits LPS-induced NFκB and JNK1/2 activation and consequently suppresses LPS-induced cytokine production. TLR4 normally recruits TIR domain-containing adaptors in response to LPS, however, temporally restored SFK activation disrupts the LPS-induced association of MyD88 and Mal/Tirap with TLR4. Additionally, using kinase-dead SFK-Lyn (Y397/508F) and constitutively active SFK-Lyn (Y508F), we found that the kinase-dead SFK inhibits TLR4 tyrosine phosphorylation with reduced binding affinity to TLR4, while the kinase-active SFK strongly binds to TLR4 and promotes TLR4 tyrosine phosphorylation, suggesting that SFK kinase activity is required for TLR4 tyrosine phosphorylation and TLR4-SFK interaction. Together, our results demonstrate that SFK activation induces TLR4 tyrosine phosphorylation, consequently dissociating MyD88 and Mal/Tirap from TLR4 and inhibiting LPS-induced inflammatory responses, suggesting a negative feedback loop regulated by SFK-induced tyrosine phosphorylation in TLR4.", "PURPOSE: This study investigated the metabolism and excretion of dovitinib (TKI258), a tyrosine kinase inhibitor that inhibits fibroblast, vascular endothelial, and platelet-derived growth factor receptors, in patients with advanced solid tumors.METHODS: Four patients (cohort 1) received a single 500 mg oral dose of (14)C-dovitinib, followed by the collection of blood, urine, and feces for ≤10 days. Radioactivity concentrations were measured by liquid scintillation counting and plasma concentrations of dovitinib by liquid chromatography-tandem mass spectrometry. Both techniques were applied for metabolite profiling and identification. A continuous-dosing extension phase (nonlabeled dovitinib 400 mg daily) was conducted with the 3 patients from cohort 1 and 9 additional patients from cohort 2.RESULTS: The majority of radioactivity was recovered in feces (mean 61 %; range 52-69 %), as compared with urine (mean 16 %; range 13-21 %). Only 6-19 % of the radioactivity was recovered in feces as unchanged dovitinib, suggesting high oral absorption. (14)C-dovitinib was eliminated predominantly via oxidative metabolism, with prominent primary biotransformations including hydroxylation on the fluorobenzyl ring and N-oxidation and carbon oxidation on the methylpiperazine moiety. Dovitinib was the most prominent radioactive component in plasma. The high apparent volume of distribution (2,160 L) may indicate that dovitinib distributes extensively to tissues. Adverse events were predominantly mild to moderate, and most common events included nausea, vomiting, constipation, diarrhea, and fatigue.CONCLUSIONS: Dovitinib was well absorbed, extensively distributed, and eliminated mainly by oxidative metabolism, followed by excretion, predominantly in feces. The adverse events were as expected for this class of drug.", "Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody-drug conjugate for the treatment of acute myeloid leukemia (AML). Although GO shows a narrow therapeutic window in early clinical studies, recent reports detailing a modified dosing regimen of GO can be safely combined with induction chemotherapy, and the combination provides significant survival benefits in AML patients. Here we tested whether the survival benefits seen with the combination arise from the enhanced reduction of chemoresidual disease and leukemic initiating cells (LICs). Herein, we use cell line and patient-derived xenograft (PDX) AML models to evaluate the combination of GO with daunorubicin and cytarabine (DA) induction chemotherapy on AML blast growth and animal survival. DA chemotherapy and GO as separate treatments reduced AML burden but left significant chemoresidual disease in multiple AML models. The combination of GO and DA chemotherapy eliminated nearly all AML burden and extended overall survival. In two small subsets of AML models, chemoresidual disease following DA chemotherapy displayed hallmark markers of leukemic LICs (CLL1 and CD34). In vivo, the two chemoresistant subpopulations (CLL1+/CD117- and CD34+/CD38+) showed higher ability to self-renewal than their counterpart subpopulations, respectively. CD33 was coexpressed in these functional LIC subpopulations. We demonstrate that the GO and DA induction chemotherapy combination more effectively eliminates LICs in AML PDX models than either single agent alone. These data suggest that the survival benefit seen by the combination of GO and induction chemotherapy, nonclinically and clinically, may be attributed to the enhanced reduction of LICs.", "Recent evidence indicates that CXCR2 signaling is crucial for cancer progression, and its antagonist SB225002 induces apoptosis in Wilms' tumor cells. Here, we investigated the effect of SB225002 on cell cycle progression and apoptosis induction in vitro, using CDDP-sensitive and -resistant OVCA cell lines with different p53 status (wild type, mutant or null). Adenovirus infection of wild-type p53 or transfection of p53 siRNA was used to over-express or knock-down p53. Cell cycle and apoptosis were determined by flow cytometry or Hoechst staining and observation of nuclear morphology. Our data demonstrated that SB225002 induced apoptosis in both wild-type and p53-deficient ovarian cancer (OVCA) cells through alternative mechanisms. SB225002 promoted mitotic catastrophe, as evidenced by the accumulation of mitotic cells with spindle abnormalities, chromosome mis-segregation, multi-polar cell division, multiple nuclei, aneuploidy/polyploidy and subsequent extensive apoptosis. SB225002-induced mitotic catastrophe appeared to be mediated by down-regulation of checkpoint kinase Chk1 and Cdk1-cyclin B activation. In cells expressing wild-type p53 (OV2008 and C13*), SB225002 increased total and phospho-Ser p53 levels, and p53 knock-down decreased SB225002-induced apoptosis, without affecting premature mitosis. These results suggest that SB225002 induces p53-dependent apoptosis, and provokes mitotic catastrophe in p53-independent manner in p53 wild-type cells. Reconstitution with wild-type P53 in P53-null SKOV3 cell attenuated SB225002-induced mitotic catastrophe, suggesting p53 prevented mitotic catastrophe induced by SB225002 in p53-deficient OVCA cells. Finally, the effect of SB225002 could not be prevented by pretreatment with CXCR2 ligand or its neutralizing antibody. The present studies demonstrate for the first time that SB225002 has dual actions in OVCA cells, inducing classic apoptosis through p53 activation and provoking mitotic catastrophe in both p53 wild-type and deficient cells by Chk1 inhibition and Cdk activation. These findings raise the possibility of SB225002 as a new candidate molecule for OVCA therapy independent of the p53 status.", "We recently developed a cell printer (Wilson and Boland, 2003) that enables us to place cells in positions that mimic their respective positions in organs. However, this technology was limited to the printing of two-dimensional (2D) tissue constructs. Here we describe the use of thermosensitive gels to generate sequential layers for cell printing. The ability to drop cells on previously printed successive layers provides a real opportunity for the realization of three-dimensional (3D) organ printing. Organ printing will allow us to print complex 3D organs with computer-controlled, exact placing of different cell types, by a process that can be completed in several minutes. To demonstrate the feasibility of this novel technology, we showed that cell aggregates can be placed in the sequential layers of 3D gels close enough for fusion to occur. We estimated the optimum minimal thickness of the gel that can be reproducibly generated by dropping the liquid at room temperature onto a heated substrate. Then we generated cell aggregates with the corresponding (to the minimal thickness of the gel) size to ensure a direct contact between printed cell aggregates during sequential printing cycles. Finally, we demonstrated that these closely-placed cell aggregates could fuse in two types of thermosensitive 3D gels. Taken together, these data strongly support the feasibility of the proposed novel organ-printing technology.", "The uptake and metabolism of T3 and rT3 was studied in human liver-derived HepG2 cells. The results showed a saturable, time-dependent, and ouabain-sensitive increase in nuclear bound T3. The effects of ouabain (0.5 mmol/L) and unlabeled T3 (10 nmol/L and 10 mumol/L) were much more pronounced at the nuclear level, suggesting the presence of a nonspecific component in total cellular binding. Nuclear binding of rT3 remained below the detection limit in all experiments. Comparison of rT3 metabolism in HepG2 cells and primary cultures of rat hepatocytes showed an approximately 10-fold lower iodide production in HepG2 cells. Iodide production was decreased in the presence of ouabain and almost absent in the presence of propylthiouracil (100 mumol/L). Our data confirmed the presence of a carrier-mediated uptake system for both T3 and rT3. Metabolism data indicated functional type I deiodinase activity in HepG2 cells, the presence of glucuronidating enzymes, and the absence of thyroid hormone sulfotransferase activity. Based on these data, we propose that HepG2 cells provide an appropriate model for thyroid hormone handling by human liver. In addition, we suggest that in human liver sulfation of thyroid hormone, and therefore deiodination of T3 is of only minor importance.", "Nephrotic syndrome is basically a set of signs or symptoms that may point to kidney problems, a condition when large amounts of protein leak out into the urine. In children protein excretion greater than 40 mg/m2.hr(-1) indicate presence of nephrotic syndrome. Edema is the prominent feature of nephrotic syndrome and initially develops around the eyes and legs. The 1st line treatment given is steroid therapy. The prospective study was conducted to determine the rational use of steroidal therapy, steroid sensitive nephrotic syndrome and causes of remission. 10 children were selected randomly presenting with the complaint of steroid sensitive nephrotic syndrome. The result of this study provide some evidence that steroidal therapy is effective in treating childhood nephrotic syndrome and they recover more rapidly if the steroidal regimen is carefully followed. It is concluded that rational use of steroid (prednisolone) has a very effective role in the prevention and control of nephrotic syndrome either at initial stage or in complicated cases. Corticosteroids have decreased the mortality rate upto 3%. Some very interesting findings have been observed and thus recorded and reported in this paper." ]

[ "BACKGROUND & AIMS: Haemochromatosis type 4, also known as ferroportin disease, is an autosomal dominant genetic disorder caused by pathogenic mutations in the SLC40A1 gene, which encodes ferroportin 1 (FPN1). We have identified a novel SLC40A1 p.Y333H mutation in our previous study. In the present study, we tried to investigate the frequency and pathogenicity of the SLC40A1 p.Y333H mutation in haemochromatosis in China.METHODS: Patients were analysed for SLC40A1 p.Y333H as well as mutations in the other classic haemochromatosis-related genes by Sanger sequencing. To analyse iron export capacity of the SLC40A1 p.Y333H mutant, the 293T cells were transfected with the SLC40A1 p.Y333H construct and then treated with hepcidin after exposure to ferric ammonium citrate. Cellular localization of mutant FPN1, expression of FPN1 and intracellular ferritin were analysed by immunofluorescence and Western blotting.RESULTS: Of 22 unrelated cases with primary iron overload, three cases (3/22, 13.6%) harboured the SLC40A1 p.Y333H, with no missense mutations identified in any other classical haemochromatosis-related genes including HFE, HJV, HAMP and TFR2. Pedigree analysis showed that three probands and the son of one proband had haemochromatosis of stage 3, while the son of another proband with age of 16 showed elevated transferrin saturation but normal serum ferritin level. In vitro studies showed the mutant p.Y333H ferroportin was resistant to hepcidin, affecting the subsequent internalization and degradation of FPN1, and was associated with ferroportin gain of function.CONCLUSIONS: The SLC40A1 p.Y333H mutation is associated with gain of function of ferroportin, representing one of the major aetiological factors of haemochromatosis in China.", "AIM: The molecular mechanisms by which hepatocyte nuclear factor (HNF)4α regulates fetal liver development have not been fully elucidated. We screened the downstream molecules of HNF4α during liver development and identified sodium-coupled neutral amino acid transporter (SNAT)4. The aim of this study is to investigate the regulation of SNAT4 by HNF4α and to clarify its roles in differentiating hepatocytes.METHODS: HNF4α was overexpressed in cultured liver buds using adenovirus, and suppression subtractive hybridization screening was performed. Temporal and spatial expression of SNAT4 during liver development was investigated. Regulation of SNAT4 by HNF4α was examined by promoter analyses and electrophoretic mobility shift assays (EMSA). Metabolic labeling and western blotting were carried out using primary hepatoblasts with SNAT4 overexpression.RESULTS: The expression of Slc38a4 encoding SNAT4 showed a marked perinatal increase, and was predominant among system A amino acid transporters. It was first detected in embryonic day 18.5 liver, and found in most hepatocytes after birth. Three alternative first exons were found in the SNAT4 gene. Promoter analyses using approximately 3-kb fragments corresponding to each first exon (AP1, AP2, AP3) revealed that AP1 and AP2 exhibited strong promoter activity in mouse hepatoblasts with endogenous HNF4α. Transactivation of AP2 was upregulated by HNF4α in HeLa cells without endogenous HNF4α. EMSA has demonstrated that HNF4α directly binds to cis-elements in AP2. Overexpression of SNAT4 facilitated amino acid uptake and de novo protein synthesis in primary hepatoblasts.CONCLUSION: SNAT4 functions downstream of HNF4α and plays significant roles in liver development through mechanisms of amino acid uptake and protein synthesis.", "The chromatin organizer modifier domain (chromodomain) is present in proteins that contribute to chromatin organization and mediates their binding to methylated histone H3. Despite a high level of sequence conservation, individual chromodomains manifest substantial differences in binding preference for methylated forms of histone H3, suggesting that posttranslational modification of the chromodomain might be an important determinant of binding specificity. We now show that mouse Cbx2 (also known as M33), a homolog of Drosophila Polycomb protein, is highly phosphorylated in some cell lines. A low-mobility band of Cbx2 observed on SDS-polyacrylamide gel electrophoresis was thus converted to a higher-mobility band by treatment with alkaline phosphatase. Mass spectrometric analysis revealed serine-42, a conserved amino acid in the chromodomain, as a phosphorylation site of Cbx2. Phosphorylation of the chromodomain of Cbx2 on this residue in vitro resulted in a reduced level of binding to an H3 peptide containing trimethylated lysine-9 as well as an increase in the extent of binding to an H3 peptide containing trimethylated lysine-27, suggesting that such phosphorylation changes the binding specificity of Cbx2 for modified histone H3. Phosphorylation of the chromodomain of Cbx2 may therefore serve as a molecular switch that affects the reading of the histone modification code and thereby controls epigenetic cellular memory.", "The epithelial-to-mesenchymal transition is a highly dynamic cell process and tools such as fluorescence recovery after photobleaching (FRAP), which allow the study of rapid protein dynamics, enable the following of this process in vivo. This technique uses a short intense pulse of photons to disrupt the fluorescence of a tagged protein in a region of a sample. The fluorescent signal intensity after this bleaching is then recorded and the signal recovery used to provide an indicator of the dynamics of the protein of interest. This technique can be applied to any fluorescently tagged protein, but membrane-bound proteins present an interesting challenge as they are spatially confined and subject to specialized cellular trafficking. Several methods of analysis can be applied which can disentangle these various processes and enable the extraction of information from the recovery curves. Here we describe this technique when applied to the quantification of the plasma membrane-bound E-cadherin protein in vivo using the epidermis of the late embryo of Drosophila melanogaster (Drosophila) as an example of this technique.", "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.", "Processing of NF-kappaB2 precursor protein p100 to generate p52 is tightly controlled, which is important for proper function of NF-kappaB. Accordingly, constitutive processing of p100, caused by the loss of its C-terminal processing inhibitory domain due to nfkappab2 gene rearrangements, is associated with the development of various lymphomas and leukemia. In contrast to the physiological processing of p100 triggered by NF-kappaB-inducing kinase (NIK) and its downstream kinase, IkappaB kinase alpha (IKKalpha), which requires the E3 ligase, beta-transducin repeat-containing protein (beta-TrCP), and occurs only in the cytoplasm, the constitutive processing of p100 is independent of beta-TrCP but rather is regulated by the nuclear shuttling of p100. Here, we show that constitutive processing of p100 also requires IKKalpha, but not IKKbeta (IkappaB kinase beta) or IKKgamma (IkappaB kinase gamma). It seems that NIK is also dispensable for this pathogenic processing of p100. These results demonstrate a general role of IKKalpha in p100 processing under both physiological and pathogenic conditions. Additionally, we find that IKKalpha is not required for the nuclear translocation of p100. Thus, these results also indicate that p100 nuclear translocation is not sufficient for the constitutive processing of p100.", "Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP) is a rare dermatologic disorder of autosomal dominant inheritance with intraepidermal blistering after minor trauma, reticular hyperpigmentation unrelated to the blistering, nail dystrophy, and mild palmoplantar keratosis. Keratin 5 and keratin 14 are known to be essential for the basal keratinocyte cytoskeleton and are defective in several forms of epidermolysis bullosa simplex. Recently, a 71C-->T transition in the keratin 5 gene (KRT5) causing a P24L substitution was identified in some patients with EBS-MP. We present a family with three affected members and a sporadic patient with EBS-MP. They exemplify clinically mild expression with intrafamilial variability and the possibility of improvement with time. In all of them, mutation analysis of the KRT5 gene showed the P24L mutation. So far, other mutations in the same or in other genes have not been reported in patients with EBS-MP." ]

[ "The promutagenic and genotoxic exocyclic DNA adduct 1,N(2)-ethenoguanine (1,N(2)-epsilonG) is a major product formed in DNA exposed to lipid peroxidation-derived aldehydes in vitro. Here, we report that two structurally unrelated proteins, the Escherichia coli mismatch-specific uracil-DNA glycosylase (MUG) and the human alkylpurine-DNA-N-glycosylase (ANPG), can release 1,N(2)-epsilonG from defined oligonucleotides containing a single modified base. A comparison of the kinetic constants of the reaction indicates that the MUG protein removes the 1,N(2)-epsilonG lesion more efficiently (k(cat)/K(m) = 0.95 x 10(-3) min(-1) nm(-1)) than the ANPG protein (k(cat)/K(m) = 0.1 x 10(-3) min(-1) nm(-1)). Additionally, while the nonconserved, N-terminal 73 amino acids of the ANPG protein are not required for activity on 1,N(6)-ethenoadenine, hypoxanthine, or N-methylpurines, we show that they are essential for 1,N(2)-epsilonG-DNA glycosylase activity. Both the MUG and ANPG proteins preferentially excise 1,N(2)-epsilonG when it is opposite dC; however, unlike MUG, ANPG is unable to excise 1,N(2)-epsilonG when it is opposite dG. Using cell-free extracts from genetically modified E. coli and murine embryonic fibroblasts lacking MUG and mANPG activity, respectively, we show that the incision of the 1,N(2)-epsilonG-containing duplex oligonucleotide has an absolute requirement for MUG or ANPG. Taken together these observations suggest a possible role for these proteins in counteracting the genotoxic effects of 1,N(2)-epsilonG residues in vivo.", "Inflammasomes are cytosolic multiprotein complexes that assemble in response to a variety of infectious and noxious insults. Inflammasomes play a critical role in the initiation of innate immune responses, primarily by serving as platforms for the activation of inflammatory caspase proteases. One such caspase, CASPASE-1 (CASP1), initiates innate immune responses by cleaving pro-IL-1β and pro-IL-18, leading to their activation and release. CASP1 and another inflammatory caspase termed CASP11 can also initiate a rapid and inflammatory form of cell death termed pyroptosis. Several distinct inflammasomes have been described, each of which contains a unique sensor protein of the NLR (nucleotide-binding domain, leucine-rich repeat-containing) superfamily or the PYHIN (PYRIN and HIN-200 domain-containing) superfamily. Here we describe the surprisingly diverse mechanisms by which NLR/PYHIN proteins sense bacteria and initiate innate immune responses. We conclude that inflammasomes represent a highly adaptable scaffold ideally suited for detecting and initiating rapid innate responses to diverse and rapidly evolving bacteria.", "NELF and DSIF collaborate to inhibit elongation by RNA polymerase IIa in extracts from human cells. A multifaceted approach was taken to investigate the potential role of these factors in promoter proximal pausing on the hsp70 gene in Drosophila. Immunodepletion of DSIF from a Drosophila nuclear extract reduced the level of polymerase that paused in the promoter proximal region of hsp70. Depletion of one NELF subunit in salivary glands using RNA interference also reduced the level of paused polymerase. In vivo protein-DNA cross-linking showed that NELF and DSIF associate with the promoter region before heat shock. Immunofluorescence analysis of polytene chromosomes corroborated the cross-linking result and showed that NELF, DSIF, and RNA polymerase IIa colocalize at the hsp70 genes, small heat shock genes, and many other chromosomal locations. Finally, following heat shock induction, DSIF and polymerase but not NELF were strongly recruited to chromosomal puffs harboring the hsp70 genes. We propose that NELF and DSIF cause polymerase to pause in the promoter proximal region of hsp70. The transcriptional activator, HSF, might cause NELF to dissociate from the elongation complex. DSIF continues to associate with the elongation complex and could serve a positive role in elongation.", "BACKGROUND & AIMS: The Notch signaling pathway is activated in leukemia and solid tumors (such as lung cancer), but little is known about its role in liver cancer.METHODS: The intracellular domain of Notch was conditionally expressed in hepatoblasts and their progeny (hepatocytes and cholangiocytes) in mice. This was achieved through Cre expression under the control of an albumin and α-fetoprotein (AFP) enhancer and promoter (AFP-Notch intracellular domain [NICD]). We used comparative functional genomics to integrate transcriptome data from AFP-NICD mice and human hepatocellular carcinoma (HCC) samples (n = 683). A Notch gene signature was generated using the nearest template prediction method.RESULTS: AFP-NICD mice developed HCC with 100% penetrance when they were 12 months old. Activation of Notch signaling correlated with activation of 3 promoters of insulin-like growth factor 2; these processes appeared to contribute to hepatocarcinogenesis. Comparative functional genomic analysis identified a signature of Notch activation in 30% of HCC samples from patients. These samples had altered expression in Notch pathway genes and activation of insulin-like growth factor signaling, despite a low frequency of mutations in regions of NOTCH1 associated with cancer. Blocking Notch signaling in liver cancer cells with the Notch activation signature using γ-secretase inhibitors or by expressing a dominant negative form of mastermind-like 1 reduced their proliferation in vitro.CONCLUSIONS: Notch signaling is activated in human HCC samples and promotes formation of liver tumors in mice. The Notch signature is a biomarker of response to Notch inhibition in vitro.", "Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance. One exemplar gene is HUWE1, which has been found to be mutated in numerous studies. However, due to the large size of this gene and a lack of functional analysis of identified mutations, their significance to carcinogenesis is unclear. To determine the importance of HUWE1, we chose to examine its function in colorectal cancer, where it is mutated in up to 15 per cent of tumours. Modelling of identified mutations showed that they inactivate the E3 ubiquitin ligase activity of HUWE1. Genetic deletion of Huwe1 rapidly accelerated tumourigenic in mice carrying loss of the intestinal tumour suppressor gene Apc, with a dramatic increase in tumour initiation. Mechanistically, this phenotype was driven by increased MYC and rapid DNA damage accumulation leading to loss of the second copy of Apc The increased levels of DNA damage sensitised Huwe1-deficient tumours to DNA-damaging agents and to deletion of the anti-apoptotic protein MCL1. Taken together, these data identify HUWE1 as a bona fide tumour suppressor gene in the intestinal epithelium and suggest a potential vulnerability of HUWE1-mutated tumours to DNA-damaging agents and inhibitors of anti-apoptotic proteins.", "Author information:(1)The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.(2)Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.(3)Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.(4)Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.(5)The Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.(6)The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. The Department of Pediatrics and the Pediatric Immunology Unit, Rambam Medical Center, and the B. Rappaport Faculty of Medicine, Technion, Haifa, Israel.(7)Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.(8)The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. jacob.hanna@weizmann.ac.il noa.novershtern@weizmann.ac.il gidi.rechavi@sheba.health.gov.il.(9)Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. jacob.hanna@weizmann.ac.il noa.novershtern@weizmann.ac.il gidi.rechavi@sheba.health.gov.il.", "Epilepsy is the main neurological condition in children and adolescents. Unfortunately patients with medical refractory epilepsy are more susceptible for clinical complications and death. We report a prospectively evaluated cohort of children followed for approximately 10 years. Fifty-three of 1012 patients died. Forty-two patients died due to epilepsy or its clinical complications and the main causes of death were pneumonia (in 16 cases), sepsis (in 9 patients), status epilepticus (in 8 patients). In 11 patients cause of death was sudden unexpected death in epilepsy (SUDEP). Mental retardation was significantly more frequent in patients who did not die from SUDEP. SUDEP may be a significant condition associated with mortality in children and adolescents with epilepsy." ]

[ "BACKGROUND: Delayed enhancement (DE) on cardiac magnetic resonance imaging (CMR) is a marker of myocardial fibrosis. The absence of DE in CMR is a predictor of left ventricular (LV) functional improvement in patients with non-ischemic cardiomyopathy (NICM), so in the present study it was investigated whether presence of DE has prognostic significance in patients with NICM at long-term follow-up.METHODS AND RESULTS: The 79 patients (56.4+/-13.5 years, 48 males) with NICM (LV ejection fraction <35%, no significant coronary artery disease) were monitored for occurrence of cardiac events. CMR was performed to assess DE. Cardiac events were defined as rehospitalization (because of worsening of heart failure), cardiac transplantation or death. There were 37 patients without and 42 patients with DE. The mean follow-up duration was 19+/-10 months. There was 1 event (2.7%, 1 rehospitalization) in the DE (-) group, whereas 13 events (30.9%, 1 death, 1 transplantation, 11 rehospitalizations) occurred in the DE (+) group. The event-free survival was significantly longer in the DE (-) group than in the DE (+) group (38.9+/-1.0 vs 28.4+/-2.7 months, P<0.01). Multivariate regression analysis revealed that presence of DE was the most potent, independent predictor of cardiac events (hazard ratio 8.06, confidence interval 1.03+/-63.41, P<0.05).CONCLUSIONS: The presence of DE in CMR is a significant predictor of future cardiac events in patients with NICM.", "BACKGROUND: The increased oxidative stress resulting from the inflammatory responses in sepsis initiates changes in mitochondrial function which may result in organ damage, the most common cause of death in the intensive care unit (ICU). Deficiency of coenzyme Q10 (CoQ10), a key cofactor in the mitochondrial respiratory chain, could potentially disturb mitochondrial bioenergetics and oxidative stress, and may serve as a biomarker of mitochondrial dysfunction. Hence, we aimed to investigate in initially non-septic patients whether CoQ10 levels are decreased in sepsis and septic shock compared to ICU admission, and to evaluate its associations with severity scores, inflammatory biomarkers, and ICU outcomes.METHODS: Observational retrospective analysis on 86 mechanically-ventilated, initially non-septic, ICU patients. CoQ10 was sequentially measured on ICU admission, sepsis, septic shock or at ICU discharge. CoQ10 was additionally measured in 25 healthy controls. Inflammatory biomarkers were determined at baseline and sepsis.RESULTS: On admission, ICU patients who developed sepsis had lower CoQ10 levels compared to healthy controls (0.89 vs. 1.04 µg/ml, p < 0.05), while at sepsis and septic shock CoQ10 levels decreased further (0.63 µg/ml; p < 0.001 and 0.42 µg/ml; p < 0.0001, respectively, from admission). In ICU patients who did not develop sepsis, admission CoQ10 levels were also lower than healthy subjects (0.81 µg/ml; p < 0.001) and were maintained at the same levels until discharge.CONCLUSION: CoQ10 levels in critically-ill patients are low on ICU admission compared to healthy controls and exhibit a further decrease in sepsis and septic shock. These results suggest that sepsis severity leads to CoQ10 depletion.", "Two transcriptional activators, Aft1 and Aft2, regulate iron homeostasis in Saccharomyces cerevisiae. These factors induce the expression of iron regulon genes in iron-deficient yeast but are inactivated in iron-replete cells. Iron inhibition of Aft1/Aft2 is abrogated in cells defective for Fe-S cluster biogenesis within the mitochondrial matrix (Chen, O. S., Crisp, R. J., Valachovic, M., Bard, M., Winge, D. R., and Kaplan, J. (2004) J. Biol. Chem. 279, 29513-29518). To determine whether iron sensing by Aft1/Aft2 requires the function of the mitochondrial Fe-S export and cytosolic Fe-S protein assembly systems, we evaluated the expression of the iron regulon in cells depleted of glutathione and in cells depleted of Atm1, Nar1, Cfd1, and Nbp35. The iron regulon is induced in cells depleted of Atm1 with Aft1 largely responsible for the induced gene expression. Aft2 is activated at a later time in Atm1-depleted cells. Likewise, the iron regulon is induced in cells depleted of glutathione. In contrast, repression of NAR1, CFD1, or NBP35 fails to induce the iron regulon despite strong inhibition of cytosolic/nuclear Fe-S protein assembly. Thus, iron sensing by Aft1/Aft2 is not linked to the maturation of cytosolic/nuclear Fe-S proteins, but the mitochondrial inner membrane transporter Atm1 is important to transport the inhibitory signal. Although Aft1 and Aft2 sense a signal emanating from the Fe-S cluster biogenesis pathway, there is no indication that the proteins are inhibited by direct binding of an Fe-S cluster.", "Gepotidacin, a novel triazaacenaphthylene antibacterial agent, is the first in a new class of type IIA topoisomerase inhibitors with activity against many biothreat and conventional pathogens, including Neisseria gonorrhoeae To assist ongoing clinical studies of gepotidacin to treat gonorrhea, a multilaboratory quality assurance investigation determined the reference organism (N. gonorrhoeae ATCC 49226) quality control MIC range to be 0.25 to 1 μg/ml (88.8% of gepotidacin MIC results at the 0.5 μg/ml mode).", "Cold agglutinin disease is a difficult-to-treat autoimmune hemolytic anemia in which immunoglobulin M antibodies bind to erythrocytes and fix complement, resulting in predominantly extravascular hemolysis. This trial tested the hypothesis that the anti-C1s antibody sutimlimab would ameliorate hemolytic anemia. Ten patients with cold agglutinin disease participated in the phase 1b component of a first-in-human trial. Patients received a test dose of 10-mg/kg sutimlimab followed by a full dose of 60 mg/kg 1 to 4 days later and 3 additional weekly doses of 60 mg/kg. All infusions were well tolerated without premedication. No drug-related serious adverse events were observed. Seven of 10 patients with cold agglutinin disease responded with a hemoglobin increase >2 g/dL. Sutimlimab rapidly increased hemoglobin levels by a median of 1.6 g/dL within the first week, and by a median of 3.9 g/dL (interquartile range, 1.3-4.5 g/dL; 95% confidence interval, 2.1-4.5) within 6 weeks (P = .005). Sutimlimab rapidly abrogated extravascular hemolysis, normalizing bilirubin levels within 24 hours in most patients and normalizing haptoglobin levels in 4 patients within 1 week. Hemolytic anemia recurred when drug levels were cleared from the circulation 3 to 4 weeks after the last dose of sutimlimab. Reexposure to sutimlimab in a named patient program recapitulated the control of hemolytic anemia. All 6 previously transfused patients became transfusion-free during treatment. Sutimlimab was safe, well tolerated, and rapidly stopped C1s complement-mediated hemolysis in patients with cold agglutinin disease, significantly increasing hemoglobin levels and precluding the need for transfusions. This trial was registered at www.clinicaltrials.gov as #NCT02502903.", "OBJECTIVE: To evaluate the efficacy and safety of intermittent, luteal phase-only administration of paroxetine (10 mg and 20 mg) in the treatment of premenstrual dysphoric disorder (PMDD).METHOD: In this multicenter trial, female outpatients (aged 18-45 years) from 4 Canadian health centers meeting DSM-IV criteria for PMDD were asked to perform daily ratings of their premenstrual symptoms for 2 consecutive menstrual cycles. Those displaying the symptoms of irritability and/or depressed mood in the luteal phases but not in the follicular phases of their menstrual cycles were randomly assigned to intermittent, luteal phase-only treatment with paroxetine 10 mg or 20 mg or placebo for 4 additional cycles. The primary efficacy endpoint was the percent change from baseline at study endpoint on the visual analog scale irritability score. Treatment differences were tested using analysis of covariance ad hoc. Estimated treatment mean differences and their associated 95% confidence intervals were also calculated. Data were collected from May 1999 to November 2002.RESULTS: Ninety-nine patients were included in the intention-to-treat population. When compared with placebo, patients treated with paroxetine 20 mg attained a significant reduction in irritability (difference in median percent change: -23.9, 95% CI = -51.3 to -6.2, p = .014; difference in mean absolute change: -18.6, 95% CI = -32.5 to -4.6, p = .007). A statistically significant difference was not observed when the patients treated with the lower dose of paroxetine (10 mg) were compared with placebo. Treatment was well tolerated with no unexpected side effects.CONCLUSIONS: Intermittent administration of paroxetine 20 mg significantly reduced irritability symptoms in patients with PMDD. These results are consistent with previous studies suggesting that PMDD may be treated effectively by luteal phase-only administration of a selective serotonin reuptake inhibitor.TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00620581.", "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." ]

[ "BACKGROUND: Prevention of chemotherapy-induced nausea and vomiting (CINV) can be improved with guideline-consistent use of antiemetics. However, adherence to antiemetic guidelines remains often insufficient. Therefore, new strategies that improve adherence are needed.OBJECTIVES: To review the latest antiemetic guideline recommendations and provide an update on the use of NEPA, a fixed combination antiemetic composed of the neurokinin-1 receptor antagonist (RA) netupitant and the 5-hydroxytryptamine-3 RA palonosetron (Akynzeo®).METHODS: Analysis of the literature was performed, including guidelines, published literature, congress data on NEPA, and relevant articles on CINV.FINDINGS: Nurses are in a unique position to promote guideline-consistent antiemetic prophylaxis and are central in the education of patients and caregivers. Thus, nurses’ continuous education on antiemetic treatments is key for the prevention and management of CINV. NEPA offers a simplified antiemetic therapy with the potential to increase guideline adherence.", "Brown and beige adipocytes expend chemical energy to produce heat and are therefore important in regulating body temperature and body weight. Brown adipocytes develop in discrete and relatively homogenous depots of brown adipose tissue, whereas beige adipocytes are induced to develop in white adipose tissue in response to certain stimuli - notably, exposure to cold. Fate-mapping analyses have identified progenitor populations that give rise to brown and beige fat cells, and have revealed unanticipated cell-lineage relationships between vascular smooth muscle cells and beige adipocytes, and between skeletal muscle cells and brown fat. In addition, non-adipocyte cells in adipose tissue, including neurons, blood vessel-associated cells and immune cells, have crucial roles in regulating the differentiation and function of brown and beige fat.", "Author information:(1)Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Bâtiment 3 de la Faculté de Médecine, 11 rue Humann, 67000, Strasbourg, France. nicolas.collongues@chru-strasbourg.fr.(2)Département de Neurologie, Centre Hospitalier Universitaire de Strasbourg, Avenue Molière, 67200, Strasbourg, France. nicolas.collongues@chru-strasbourg.fr.(3)Centre d'investigation Clinique, INSERM U1434, Centre Hospitalier Universitaire de Strasbourg, 1 Place de l'Hôpital, 67000, Strasbourg, France. nicolas.collongues@chru-strasbourg.fr.(4)Laboratoire de Pharmacologie et Toxicologie Neurocardiovasculaire, Fédération de Médecine Translationnelle, Faculté de Médecine, Université de Strasbourg, 11 rue Humann, 67000, Strasbourg, France.(5)Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Bâtiment 3 de la Faculté de Médecine, 11 rue Humann, 67000, Strasbourg, France.(6)Département de Neurologie, Centre Hospitalier Universitaire de Strasbourg, Avenue Molière, 67200, Strasbourg, France.(7)Centre d'investigation Clinique, INSERM U1434, Centre Hospitalier Universitaire de Strasbourg, 1 Place de l'Hôpital, 67000, Strasbourg, France.", "OBJECTIVE: To characterize the hepatic effects of tacrine treatment in patients with Alzheimer's disease.DESIGN: Controlled trials of tacrine therapy consisting of two blinded, parallel-group trials; three blinded, enrichment-design trials; and their respective open-label extensions.SETTING: Multicenter clinical trials in the United States, France, and Canada.PATIENTS: A total of 2446 men and women at least 50 years of age with a diagnosis of probable Alzheimer's disease of mild to moderate severity and in good health without significant hepatic, cardiovascular, or renal disease.INTERVENTION: Administration of tacrine vs placebo, with weekly measurement of serum hepatic enzymes.MAIN OUTCOME MEASURES: Incidence, maximum severity, and timing of event for serum alanine aminotransferase (ALT) elevation.RESULTS: Among the 2446 patients who received tacrine in clinical trials, ALT levels greater than the upper limit of normal (ULN) occurred on at least one occasion in 1203 patients (49%), ALT levels greater than three times the ULN occurred in 621 patients (25%), and ALT levels greater than 20 times the ULN occurred in 40 patients (2%). The elevated ALT levels were generally asymptomatic and occurred more frequently in women than men. The mean time from initiation of tacrine treatment to first ALT level greater than three times the ULN was 50 days, and 90% of all initial ALT levels greater than three times the ULN occurred during the first 12 weeks of treatment. Of 145 patients who discontinued tacrine treatment because of an ALT level greater than three times the ULN and were rechallenged, 127 (88%) were able to resume long-term therapy with the drug. In all instances, discontinuing tacrine completely reversed elevations in ALT levels, and no deaths related to hepatotoxicity occurred.CONCLUSIONS: These data suggest that the potential for serious hepatic toxicity can be reduced through careful monitoring of ALT levels in patients who may benefit from tacrine therapy.", "Information is one of the main interventions given to cancer patients. Important research into information disclosure has been conducted and major advances have been made. We present the main theoretical models used to understand the information field and describe the current situation regarding the principal factors related to information: patients' needs, coping strategies, illness representations, cross-cultural differences, the role of the family, and strategies to enhance information giving, such as professional training and patient-targeted interventions. We highlight the need to assess patients' characteristics and desires through questionnaires and interviews and present the European Organisation for Research and Treatment of Cancer Quality of Life Group information questionnaire (EORTC QLQ-INFO 25). This instrument evaluates the level of information patients have received in different areas of their disease, treatment and care, and evaluates qualitative aspects. Finally, we describe the key areas of the information field and discuss how these areas could change in the future.", "Attachment of a chain of poly(ethylene glycol) (PEG) to a therapeutic protein, a process widely known as PEGylation, can lead to several beneficial effects. It has the potential to significantly delay aggregation of the protein by steric shielding, a frequently encountered issue in the development of protein drugs. Moreover, it can modify the pharmacokinetic profile of the PEGylated protein by delaying renal excretion, leading to a longer half-life (t1/2) of the drug. By steric hindrance, it can also inhibit interactions between the protein drug and proteases as well as the host immune system, thereby inhibiting inactivation of the PEGylated protein and also attenuating its immunogenicity. Unfortunately, the effect of steric hindrance also applies to protein drug-target interaction, leading to a (partial) loss of efficacy. In order to avoid this undesirable effect, several efforts have been made to link PEG to a protein in a noncovalent way, providing the protein with several of the beneficial effects of PEGylation while also taking advantage of its native affinity to its target.", "Conflict of interest statement: Conflict of Interest Disclosures: Dr Gruber is a member of the board for Tocagen Inc. Drs Rao, Hogan, Accomando, Ostertag, Montellano, Kheoh, and Kabbinavar were Tocagen employees. Dr Cloughesy reported personal fees from Roche, personal fees from Trizel, personal fees from Medscape, personal fees from Bayer, personal fees from Amgen, personal fees from Odonate Therapeutics, personal fees from Pascal Biosciences, personal fees from Del Mar Pharmaceuticals, personal fees from Tocagen, personal fees from Kayopharm, personal fees from GW Pharma, personal fees from Kiyatec, personal fees from AbbVie, personal fees from Boehringer Ingelheim, personal fees from VBL, personal fees from VBI, personal fees from Deciphera, personal fees from Agios, personal fees from QED, personal fees from Merck, personal fees from Genocea, personal fees from Celgene, personal fees from Puma, personal fees from Lilly, and personal fees from BMS outside the submitted work; in addition, Dr Cloughesy had a patent to 62/819322 issued and licensed; and Member of the board for the 501c3 Global Coalition for Adaptive Research and CMO for the entity; Co-founder and board member of Katmai Pharmaceuticals. Dr Petrecca reported other from Tocagen during the conduct of the study. Dr Walbert reported personal fees from Tocagen outside the submitted work. Dr Damek reported grants from Tocagen during the conduct of the study; grants from NovoCure, grants from Kazia Therapeutics, grants from Genentech, grants from Orbus, grants from Roche, and grants from Forma outside the submitted work. Dr Bota reported personal fees from NovoCure and personal fees from Zai Lab outside the submitted work. Dr Bettegowda reported he is a consultant for Depuy-Synthes and Bionaut Pharmaceuticals. The activities associated with those entities are not related to the work presented in this manuscript. Dr Zhu reported grants from Tocagen, Inc and personal fees from Tocagen, Inc during the conduct of the study. Dr Iwamoto reported personal fees from Tocagen during the conduct of the study; personal fees from Merck, personal fees from Guidepoint, grants from BMS, personal fees from NovoCure, personal fees from Alexion, personal fees from AbbVie, and personal fees from Regeneron outside the submitted work. Dr Placantonakis reported personal fees from Tocagen during the conduct of the study; personal fees from Monteris, personal fees from Synaptive, and personal fees from Robeaute outside the submitted work; in addition, Dr Placantonakis had a patent to “Method to treat high grade glioma” pending. Dr Brem reported personal fees from Tocagen during the conduct of the study. Dr Piccioni reported personal fees from Tocagen during the conduct of the study. Dr Chen reported other from Tocagen during the conduct of the study; personal fees from Tocagen outside the submitted work. Dr Gruber reported grants from the US Food and Drug Administration orphan drug grant, other from Apollo Bio, other from Abentis, and other from Denovo Pharma during the conduct of the study; other from Apollo Bio, other from Abentis, and other from Denovo pharma outside the submitted work; in addition, Dr Gruber had a patent to many pending, issued, licensed, and with royalties paid, a patent to many pending, issued, and licensed, and a patent to many pending, issued, and licensed; and Stock and option ownership in Tocagen. Dr Hogan reported other from Tocagen Inc during the conduct of the study. Dr Accomando reported personal fees from Tocagen Inc. during the conduct of the study; personal fees from Tocagen Inc. outside the submitted work. Dr Ostertag reported a patent to US20130130986A1 issued, a patent to US20130323301A1, a patent to US20180021365A1, and a patent to US20140178340A1 . Dr Montellano reported grants from the US Food and Drug Administration Office of Orphan Products Development during the conduct of the study. Dr Kheoh reported other from Tocagen Inc during the conduct of the study. Dr Kabbinavar reported other from Tocagen Inc during the conduct of the study; other from Tocagen outside the submitted work; and Employee of Tocagen Inc. Dr Vogelbaum reported personal fees and other from Tocagen during the conduct of the study; other from Infuseon Theraepeutics and personal fees from Celgene outside the submitted work. No other disclosures were reported." ]

[ "Maintenance of genomic methylation patterns is mediated primarily by DNA methyltransferase-1 (DNMT1). We have solved structures of mouse and human DNMT1 composed of CXXC, tandem bromo-adjacent homology (BAH1/2), and methyltransferase domains bound to DNA-containing unmethylated CpG sites. The CXXC specifically binds to unmethylated CpG dinucleotide and positions the CXXC-BAH1 linker between the DNA and the active site of DNMT1, preventing de novo methylation. In addition, a loop projecting from BAH2 interacts with the target recognition domain (TRD) of the methyltransferase, stabilizing the TRD in a retracted position and preventing it from inserting into the DNA major groove. Our studies identify an autoinhibitory mechanism, in which unmethylated CpG dinucleotides are occluded from the active site to ensure that only hemimethylated CpG dinucleotides undergo methylation.", "BACKGROUND: Asthma is a common chronic respiratory disease that influences 300 million people all over the world. However, the pathogenesis of asthma has not been fully elucidated. It has been reported that transforming growth factor-β (TGF-β) can activate myofibroblasts. Moreover, the fibroblast to myofibroblast transformation (FMT) can be triggered by TGF-β, which is a major mediator of subepithelial fibrosis. Secreted modular calcium-binding protein 2 (SMOC2) is a member of cysteine (SPARC) family and is involved in the progression of multiple diseases. However, its role in asthma remains poorly understood. RT-qPCR evaluated the expression of SMOC2. Bromodeoxyuridine assay and wound-healing assay detected the proliferation and migration of lung fibroblasts, respectively. IF staining was performed to assess the expression of α-smooth muscle actin (α-SMA). Western blot analysis detected the levels of proteins. Flow cytometry was utilized for determination of the number of myofibroblasts.RESULTS: We found the expression of SMOC2 was upregulated by the treatment of TGF-β1 in lung fibroblasts. In addition, SMOC2 promoted the proliferation and migration of lung fibroblasts. More importantly, SMOC2 accelerated FMT of lung fibroblasts. Furthermore, SMOC2 was verified to control the activation of AKT and ERK. Rescue assays showed that the inhibition of AKT and ERK pathway reversed the promoting effect of SMOC2 overexpression on proliferation, migration and FMT in lung fibroblasts.CONCLUSIONS: This work demonstrated that SMOC2 modulated TGF-β1-induced proliferation, migration and FMT in lung fibroblasts and may promote asthma, which potentially provided a novel therapeutic target for the management of asthma.", "Lung cancer is the leading cause of death worldwide. Adenocarcinomas, the most common histologic subtype of non-small cell lung cancer (NSCLC), are frequently associated with activating mutations in the epidermal growth factor receptor (EGFR) gene. Although these patients often respond clinically to the EGFR tyrosine kinase inhibitors erlotinib and gefitinib, relapse inevitably occurs, suggesting the development of escape mechanisms that promote cell survival. Using a loss-of-function, whole genome short hairpin RNA (shRNA) screen, we identified that the canonical Wnt pathway contributes to the maintenance of NSCLC cells during EGFR inhibition, particularly the poly-ADP-ribosylating enzymes tankyrase 1 and 2 that positively regulate canonical Wnt signaling. Inhibition of tankyrase and various other components of the Wnt pathway with shRNAs or small molecules significantly increased the efficacy of EGFR inhibitors both in vitro and in vivo. Our findings therefore reveal a critical role for tankyrase and the canonical Wnt pathway in maintaining lung cancer cells during EGFR inhibition. Targeting the Wnt-tankyrase-β-catenin pathway together with EGFR inhibition may improve clinical outcome in patients with NSCLC.", "A patient with reflex epilepsy is described, in whom seizures were induced by bathing in hot water. The literature is reviewed.", "BACKGROUND: Acute myeloid leukemia is the collective name for different types of leukemias of myeloid origin affecting blood and bone marrow. The overproduction of immature myeloblasts (white blood cells) is the characteristic feature of AML, thus flooding the bone marrow and reducing its capacity to produce normal blood cells. USFDA on August 1, 2017, approved a drug named Enasidenib formerly known as AG-221 which is being marketed under the name Idhifa to treat R/R AML with IDH2 mutation. The present review depicts the broad profile of enasidenib including various aspects of chemistry, preclinical, clinical studies, pharmacokinetics, mode of action and toxicity studies.METHODS: Various reports and research articles have been referred to summarize different aspects related to chemistry and pharmacokinetics of enasidenib. Clinical data was collected from various recently published clinical reports including clinical trial outcomes.RESULT: The various findings of enasidenib revealed that it has been designed to allosterically inhibit mutated IDH2 to treat R/R AML patients. It has also presented good safety and efficacy profile along with 9.3 months overall survival rates of patients in which disease has relapsed. The drug is still under study either in combination or solely to treat hematological malignancies. Molecular modeling studies revealed that enasidenib binds to its target through hydrophobic interaction and hydrogen bonding inside the binding pocket. Enasidenib is found to be associated with certain adverse effects like elevated bilirubin level, diarrhea, differentiation syndrome, decreased potassium and calcium levels, etc.CONCLUSION: Enasidenib or AG-221was introduced by FDA as an anticancer agent which was developed as a first in class, a selective allosteric inhibitor of the tumor target i.e. IDH2 for Relapsed or Refractory AML. Phase 1/2 clinical trial of Enasidenib resulted in the overall survival rate of 40.3% with CR of 19.3%. Phase III trial on the Enasidenib is still under process along with another trial to test its potency against other cell lines. Edasidenib is associated with certain adverse effects, which can be reduced by investigators by designing its newer derivatives on the basis of SAR studies. Hence, it may come in the light as a potent lead entity for anticancer treatment in the coming years.", "Methylsulfonylmethane (MSM) is a natural organosulfur compound that exhibits antioxidative and anti-inflammatory effects. This study was carried out to investigate the effect of MSM on paraquat (PQ)-induced acute lung and liver injury in mice. A single dose of PQ (50 mg/kg, i.p.) induced acute lung and liver toxicity. Mice were treated with MSM (500 mg/kg/day, i.p.) for 5 days. At the end of the experiment, animals were euthanized, and lung and liver tissues were collected for histological and biochemical analysis. Tissue samples were used to determine malondialdehyde (MDA), myeloperoxidase (MPO), catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), and tumor necrosis factor-α (TNF-α) levels. Blood samples were used to measure plasma alanine transaminase (ALT), γ-glutamyl transferase (GGT), and alkaline phosphatase (ALP). Histological examination indicated that MSM decreased lung and liver damage caused by PQ. Biochemical results showed that MSM treatment significantly reduced tissue levels of MDA, MPO, and TNF-α, while increased the levels of SOD, CAT, and GSH compared with PQ group. MSM treatment also significantly reduced plasma levels of ALT, GGT, and ALP. These findings suggest that MSM as a natural product attenuates PQ-induced pulmonary and hepatic oxidative injury.", "OBJECTIVE: To review the efficacy and safety of vericiguat indicated to reduce the risk of cardiovascular death and heart failure (HF) hospitalization following hospitalization or need for outpatient intravenous diuretics in adult patients with chronic symptomatic HF and ejection fraction (EF) less than 45%.DATA SOURCES: A literature search through MEDLINE with search terms MK1242, BAY 1021189, and vericiguat was conducted. Product labeling and English-language studies assessing pharmacokinetics, pharmacodynamics, efficacy, or safety of vericiguat were included.STUDY SELECTION AND DATA EXTRACTION: Preclinical and clinical studies describing the efficacy and safety of vericiguat were included.DATA SYNTHESIS: The phase 3 VICTORIA clinical trial demonstrated a lower composite primary outcome of death from cardiovascular causes or first hospitalization in the vericiguat group compared to placebo. Total hospitalizations for HF in the vericiguat group were significantly less compared to placebo. The composite secondary outcome of death from any cause or first HF hospitalization was significantly less in the vericiguat group.RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The addition of vericiguat offers a new treatment option for those in whom rehospitalization or recurrent outpatient intravenous diuretic treatment is a concern. Given high rates of nonadherence in HF patients, vericiguat represents an additional treatment option, especially for patients who do not tolerate available HF therapies.CONCLUSION: Vericiguat is a novel soluble guanylate cyclase stimulator that is safe and effective for reducing the risk of cardiovascular death and HF hospitalization in adults with symptomatic chronic HF and reduced EF." ]

[ "Alzheimer's disease (AD) is a neurodegenerative disorder that impairs mainly the memory and cognitive function in elderly. Extracellular beta amyloid deposition and intracellular tau hyperphosphorylation are the two pathological events that are thought to cause neuronal dysfunction in AD. Since the detailed mechanisms that underlie the pathogenesis of AD are still not clear, the current treatments are those drugs that can alleviate the symptoms of AD patients. Recent studies have indicated that these symptom-reliving drugs also have the ability of regulating amyloid precursor protein processing and tau phosphorylation. Thus the pharmacological mechanism of these drugs may be too simply-evaluated. This review summarizes the current status of AD therapy and some potential preclinical considerations that target beta amyloid and tau protein are also discussed.", "Cohesin mediates sister chromatid cohesion and contributes to the organization of interphase chromatin through DNA looping. In vertebrate somatic cells, cohesin consists of Smc1, Smc3, Rad21, and either SA1 or SA2. Three additional factors Pds5, Wapl, and Sororin bind to cohesin and modulate its dynamic association with chromatin. There are two Pds5 proteins in vertebrates, Pds5A and Pds5B, but their functional specificity remains unclear. Here, we demonstrate that Pds5 proteins are essential for cohesion establishment by allowing Smc3 acetylation by the cohesin acetyl transferases (CoATs) Esco1/2 and binding of Sororin. While both proteins contribute to telomere and arm cohesion, Pds5B is specifically required for centromeric cohesion. Furthermore, reduced accumulation of Aurora B at the inner centromere region in cells lacking Pds5B impairs its error correction function, promoting chromosome mis-segregation and aneuploidy. Our work supports a model in which the composition and function of cohesin complexes differs between different chromosomal regions.", "The purpose of this study was to determine whether exogenous zinc prevents cardiac reperfusion injury by targeting the mitochondrial permeability transition pore (mPTP) via glycogen synthase kinase-3beta (GSK-3beta). The treatment of cardiac H9c2 cells with ZnCl2 (10 microM) in the presence of zinc ionophore pyrithione for 20 min significantly enhanced GSK-3beta phosphorylation at Ser9, indicating that exogenous zinc can inactivate GSK-3beta in H9c2 cells. The effect of zinc on GSK-3beta activity was blocked by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY-294002 but not by the mammalian target of rapamycin (mTOR) inhibitor rapamycin or the PKC inhibitor chelerythrine, implying that PI3K but not mTOR or PKC accounts for the action of zinc. In support of this interpretation, zinc induced a significant increase in Akt but not mTOR phosphorylation. Further experiments found that zinc also increased mitochondrial GSK-3beta phosphorylation. This may indicate an involvement of the mitochondria in the action of zinc. The effect of zinc on mitochondrial GSK-3beta phosphorylation was not altered by the mitochondrial ATP-sensitive K+ channel blocker 5-hydroxydecanoic acid. Zinc applied at reperfusion reduced cell death in cells subjected to simulated ischemia/reperfusion, indicating that zinc can prevent reperfusion injury. However, zinc was not able to exert protection in cells transfected with the constitutively active GSK-3beta (GSK-3beta-S9A-HA) mutant, suggesting that zinc prevents reperfusion injury by inactivating GSK-3beta. Cells transfected with the catalytically inactive GSK-3beta (GSK-3beta-KM-HA) also revealed a significant decrease in cell death, strongly supporting the essential role of GSK-3beta inactivation in cardioprotection. Moreover, zinc prevented oxidant-induced mPTP opening through the inhibition of GSK-3beta. Taken together, these data suggest that zinc prevents reperfusion injury by modulating the mPTP opening through the inactivation of GSK-3beta. The PI3K/Akt signaling pathway is responsible for the inactivation of GSK-3beta by zinc.", "Automated methods for NMR structure determination of proteins are continuously becoming more robust. However, current methods addressing larger, more complex targets rely on analyzing 6-10 complementary spectra, suggesting the need for alternative approaches. Here, we describe 4D-CHAINS/autoNOE-Rosetta, a complete pipeline for NOE-driven structure determination of medium- to larger-sized proteins. The 4D-CHAINS algorithm analyzes two 4D spectra recorded using a single, fully protonated protein sample in an iterative ansatz where common NOEs between different spin systems supplement conventional through-bond connectivities to establish assignments of sidechain and backbone resonances at high levels of completeness and with a minimum error rate. The 4D-CHAINS assignments are then used to guide automated assignment of long-range NOEs and structure refinement in autoNOE-Rosetta. Our results on four targets ranging in size from 15.5 to 27.3 kDa illustrate that the structures of proteins can be determined accurately and in an unsupervised manner in a matter of days.", "Many pathophysiological processes are activated in patients with congestive heart failure, and several of these have been implicated in the progression of the disease. The most important processes to be activated in heart failure are the neurohormonal systems, which include the reninangiotensin system, the sympathetic nervous system and the endothelin system. In addition to the neurohormonal systems, the formation of reactive oxygen free radicals is increased in congestive heart failure. It has been proposed that the activation of neurohormonal pathways and the formation of oxygen free radicals ultimately lead to the activation of a family of transcription factors that are involved in cardiac and vascular remodelling which are hallmarks of congestive heart failure. In addition, the formation of oxygen free radicals has been implicated in the process of apoptosis, or programmed cell death, which may contribute to the continued loss of myocardial cells resulting in progressive decreases in left ventricular function, while at the same time contributing to the cardiac remodelling process which subsequently creates a pro-arrhythmic environment in the myocardium. Carvedilol is a novel multiple-action neurohormonal antagonist that has been shown to be effective in the management of congestive heart failure. Carvedilol also possesses a number of additional activities which may inhibit many of the chronic pathophysiological processes that are involved in the progression of congestive heart failure.", "Identifying the pathways that are significantly impacted in a given condition is a crucial step in understanding the underlying biological phenomena. All approaches currently available for this purpose calculate a P-value that aims to quantify the significance of the involvement of each pathway in the given phenotype. These P-values were previously thought to be independent. Here we show that this is not the case, and that many pathways can considerably affect each other's P-values through a \"crosstalk\" phenomenon. Although it is intuitive that various pathways could influence each other, the presence and extent of this phenomenon have not been rigorously studied and, most importantly, there is no currently available technique able to quantify the amount of such crosstalk. Here, we show that all three major categories of pathway analysis methods (enrichment analysis, functional class scoring, and topology-based methods) are severely influenced by crosstalk phenomena. Using real pathways and data, we show that in some cases pathways with significant P-values are not biologically meaningful, and that some biologically meaningful pathways with nonsignificant P-values become statistically significant when the crosstalk effects of other pathways are removed. We describe a technique able to detect, quantify, and correct crosstalk effects, as well as identify independent functional modules. We assessed this novel approach on data from four experiments involving three phenotypes and two species. This method is expected to allow a better understanding of individual experiment results, as well as a more refined definition of the existing signaling pathways for specific phenotypes.", "This work is focused on the synthesis of the fructooligosaccharides (FOS) from sucrose and inulin, using free, immobilized and pre-treated immobilized inulinase from Kluyveromyces marxianus NRRL Y 7571 and Aspergillus niger in an aqueous-organic system. Initially, the influence of pre-treatment using four different gases, propane, n-butane, CO(2) and liquefied petroleum gas (LPG), was investigated towards FOS production and best results were found when both enzymes were previously treated with LPG. The best reaction yields were obtained when the immobilized enzymes were treated with LPG. Considering FOS synthesis using the enzyme from A. niger, yields of 26.62% of GF2 (kestose), 30.62% of GF3 (nystose) and 8.47% of GF4 (fructosyl nystose) were achieved using sucrose as substrate. Using inulinases from K. marxianus NRRL Y 7571, 11.89% of GF2 and 20.83% of GF3 were obtained, using inulin as substrate. However, promising results were achieved using the free form of inulinase from A. niger (77.19% of GF2; 14.03% of GF3 and 0.07% of GF4) using inulin as substrate." ]

[ "The present study investigated whether changes in thyroid hormone (TH) signalling can occur after acute myocardial infarction (AMI) with possible physiological consequences on myocardial performance. TH may regulate several genes encoding important structural and regulatory proteins particularly through the TR alpha 1 receptor which is predominant in the myocardium. AMI was induced in rats by ligating the left coronary artery while sham-operated animals served as controls. This resulted in impaired cardiac function in AMI animals after 2 and 13 weeks accompanied by a shift in myosin isoforms expression towards a fetal phenotype in the non-infarcted area. Cardiac hypertrophy was evident in AMI hearts after 13 weeks but not at 2 weeks. This response was associated with a differential pattern of TH changes at 2 and 13 weeks; T(3) and T(4) levels in plasma were not changed at 2 weeks but T(3) was significantly lower and T(4) remained unchanged at 13 weeks. A twofold increase in TR alpha 1 expression was observed after 13 weeks in the non-infarcted area, P<0.05 versus sham operated, while TR alpha 1 expression remained unchanged at 2 weeks. A 2.2-fold decrease in TR beta 1 expression was found in the non-infarcted area at 13 weeks, P<0.05, while no change in TR beta 1 expression was seen at 2 weeks. Parallel studies with neonatal cardiomyocytes showed that phenylephrine (PE) administration resulted in 4.5-fold increase in the expression of TR alpha 1 and 1.6-fold decrease in TR beta 1 expression versus untreated, P<0.05. In conclusion, cardiac dysfunction which occurs at late stages after AMI is associated with increased expression of TR alpha 1 receptor and lower circulating tri-iodothyronine levels. Thus, apo-TR alpha 1 receptor state may prevail contributing to cardiac fetal phenotype. Furthermore, down-regulation of TR beta 1 also contributes to fetal phenotypic changes. alpha1-adrenergic signalling is, at least in part, involved in this response.", "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.", "PURPOSE: Infantile Pompe disease is caused by deficiency of lysosomal acid alpha-glucosidase. Trials with recombinant human acid alpha-glucosidase enzyme replacement therapy (ERT) show a decrease in left ventricular mass and improved function. We evaluated 24-hour ambulatory electrocardiograms (ECGs) at baseline and during ERT in patients with infantile Pompe disease.METHODS: Thirty-two ambulatory ECGs were evaluated for 12 patients with infantile Pompe disease from 2003 to 2005. Patients had a median age of 7.4 months (2.9-37.8 months) at initiation of ERT. Ambulatory ECGs were obtained at determined intervals and analyzed.RESULTS: Significant ectopy was present in 2 of 12 patients. Patient 1 had 211 and 229 premature ventricular contractions (0.2% of heart beats) at baseline and at 11.5 weeks of ERT, respectively. Patient 2 had 10,445 premature ventricular contractions (6.7% of heart beats) at 11 weeks of therapy.CONCLUSION: Infantile Pompe disease may have preexisting ectopy; it may also develop during the course of ERT. Therefore, routinely monitoring patients using 24-hour ambulatory ECGs is useful. Periods of highest risk may be early in the course of ERT when there is a substantial decrease in left ventricular mass and an initial decrease in ejection fraction.", "Dot1 is an evolutionarily conserved histone methyltransferase that methylates lysine-79 of histone H3 in the core domain. Unlike other histone methyltransferases, Dot1 does not contain a SET domain, and it specifically methylates nucleosomal histone H3. We have solved a 2.5 A resolution structure of the catalytic domain of human Dot1, hDOT1L, in complex with S-adenosyl-L-methionine (SAM). The structure reveals a unique organization of a mainly alpha-helical N-terminal domain and a central open alpha/beta structure, an active site consisting of a SAM binding pocket, and a potential lysine binding channel. We also show that a flexible, positively charged region at the C terminus of the catalytic domain is critical for nucleosome binding and enzymatic activity. These structural and biochemical analyses, combined with molecular modeling, provide mechanistic insights into the catalytic mechanism and nucleosomal specificity of Dot1 proteins.", "Concern about the appropriate role of nonsteroidal anti-inflammatory drugs (NSAIDs) in COVID-19 speculate that NSAIDs, in particular ibuprofen, may upregulate the entry point for the virus, the angiotensin-converting enzyme (ACE) 2 receptors and increase susceptibility to the virus or worsen symptoms in existing disease. Adverse outcomes with COVID-19 have been linked to cytokine storm but the most effective way to address exaggerated inflammatory response is complex and unclear. The Expert Working Group on the Commission of Human Medicines in the UK and other organizations have stated that there is insufficient evidence to establish a link between ibuprofen and susceptibility to or exacerbation of COVID-19. NSAID use must also be categorized by whether the drugs are relatively low-dose over-the-counter oral products taken occasionally versus higher-dose or parenteral NSAIDs. Even if evidence emerged arguing for or against NSAIDs in this setting, it is unclear if this evidence would apply to all NSAIDs at all doses in all dosing regimens. Paracetamol (acetaminophen) has been proposed as an alternative to NSAIDs but there are issues with liver toxicity at high doses. There are clearly COVID-19 cases where NSAIDs should not be used, but there is no strong evidence that NSAIDs must be avoided in all patients with COVID-19; clinicians must weigh these choices on an individual basis.", "MOTIVATION: Protein solubility plays a vital role in pharmaceutical research and production yield. For a given protein, the extent of its solubility can represent the quality of its function, and is ultimately defined by its sequence. Thus, it is imperative to develop novel, highly accurate in silico sequence-based protein solubility predictors. In this work we propose, DeepSol, a novel Deep Learning-based protein solubility predictor. The backbone of our framework is a convolutional neural network that exploits k-mer structure and additional sequence and structural features extracted from the protein sequence.RESULTS: DeepSol outperformed all known sequence-based state-of-the-art solubility prediction methods and attained an accuracy of 0.77 and Matthew's correlation coefficient of 0.55. The superior prediction accuracy of DeepSol allows to screen for sequences with enhanced production capacity and can more reliably predict solubility of novel proteins.AVAILABILITY AND IMPLEMENTATION: DeepSol's best performing models and results are publicly deposited at https://doi.org/10.5281/zenodo.1162886 (Khurana and Mall, 2018).SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "Disease modifying antirheumatic drugs (DMARDs) is a category of drugs which is used as medication in various arthritic conditions to arrest the progression of disease along with relief from pain. About 83% of population worldwide uses DMARDs. Withdrawal of COX-2 inhibitors because of cardiovascular side effects and short-term action associated with glucocorticoids provided a motivation for development of newer DMARDs. Currently non- biological DMARDs like methotrexate, sulfasalazine, hydroxychloroquine and azathioprine serve the purpose of relieving pain and inhibiting the progression of disease. Biological DMARDs like toclizumab, adalimumab, infliximab, golimumab and abatacept have shown more efficacy and lesser side effects as compared to non- biological DMARDs but their access to patient is less because of higher cost. DMARDs act by different mechanisms against inflammation like inhibition of tumor necrosis factor, suppression of IL-1 and TNF-α, induction of apoptosis of inflammatory cells, by increasing chemotactic factors, inhibition of purine synthesis, pyrimidine metabolism or purine embolism. DMARDs have important applications in diseases like rheumatoid arthritis, Crohn's disease, juvenile idiopathic arthritis, psoriatic arthritis and myasthenia gravis. Present review mainly focuses on DMARDs and their clinical applications giving an overview of their mechanism of action, pharmacokinetic properties, advantages over conventional therapies, shortcomings and recent trends." ]

[ "The embryonic heart precursors of Drosophila are arranged in a repeated pattern of segmental units. There is growing evidence that the development of individual elements of this pattern depends on both mesoderm intrinsic patterning information and inductive signals from the ectoderm. In this study, we demonstrate that two homeobox genes, ladybird early and ladybird late, are involved in the cardiogenic pathway in Drosophila. Their expression is specific to a subset of cardioblast and pericardial cell precursors and is critically dependent on mesodermal tinman function, epidermal Wingless signaling and the coordinate action of neurogenic genes. Negative regulation by hedgehog is required to restrict ladybird expression to two out of six cardioblasts in each hemisegment. Overexpression of ladybird causes a hyperplasia of heart precursors and alters the identity of even-skipped-positive pericardial cells. Loss of ladybird function leads to the opposite transformation, suggesting that ladybird participates in the determination of heart lineages and is required to specify the identities of subpopulations of heart cells. We find that both early Wingless signaling and ladybird-dependent late Wingless signaling are required for proper heart formation. Thus, we propose that ladybird plays a dual role in cardiogenesis: (i) during the early phase, it is involved in specification of a segmental subset of heart precursors as a component of the cardiogenic tinman-cascade and (ii) during the late phase, it is needed for maintaining wingless activity and thereby sustaining the heart pattern process. These events result in a diversification of heart cell identities within each segment.", "OBJECTIVE: Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1-3. This analysis compared efficacy and safety of axitinib plus gemcitabine in patients with advanced pancreatic cancer from Japan, North America and the European Union, enrolled in a randomized Phase III study.METHODS: Patients (n = 632), stratified by disease extent, were randomly assigned (1:1) to receive axitinib/gemcitabine or placebo/gemcitabine. Axitinib was administered at a starting dose of 5 mg orally twice daily and gemcitabine at 1000 mg/m(2) once weekly for 3 weeks in 4 week cycles. Primary endpoint was overall survival.RESULTS: Among Japanese patients, median overall survival was not estimable (95% confidence interval, 7.4 months-not estimable) with axitinib/gemcitabine (n = 58) and 9.9 months (95% confidence interval, 7.4-10.5) with placebo/gemcitabine (n = 56) (hazard ratio 1.093 [95% confidence interval, 0.525-2.274]). Median survival follow-up (range) was 5.1 months (0.02-12.3) with axitinib/gemcitabine vs. 5.4 months (1.8-10.5) with placebo/gemcitabine. Similarly, no difference was detected in overall survival between axitinib/gemcitabine and placebo/gemcitabine in patients from North America or the European Union. Common adverse events with axitinib/gemcitabine in Japanese patients were fatigue, anorexia, dysphonia, nausea and decreased platelet count. Axitinib safety profile was generally similar in patients from the three regions, although there were differences in incidence of some adverse events. An exploratory analysis did not show any correlation between axitinib/gemcitabine-related hypertension and overall survival.CONCLUSIONS: Axitinib/gemcitabine, while tolerated, did not provide survival benefit over gemcitabine alone in patients with advanced pancreatic cancer from Japan or other regions.", "Atrial arrhythmias resistant to medical therapy are still a common indication for ablation of the normal atrioventricular conduction pathway (Tawara node and His Bundle). However, the development of catheter techniques of intra-atrial ablation to destroy arrhythmogenic myocardial zones enables radical cure of the arrhythmias with the respect of the nodo-hisian pathway. With respect to common flutter, a number of series, including our own, show a 50 to 75% long-term success rate. We believe that a very high success rate in the ablation of flutter will probably be achieved in a reproducible manner but this will require a more accurate understanding of the tachycardia circuit and technological developments allowing controlled radio-frequency destruction of bigger atrial myocardial zone. Experience of radio-frequency ablation atrial of atrial extrasystoles is more limited than that of flutter and there are fewer published series. Globally, catheter ablation of atrial tachycardia remains a more difficult and a less well codified procedure than that of accessory pathways or of intra-nodal reentry. Radio-frequency ablation in this indication is not without danger in view of the thinness of the atrial wall. We believe that radio-frequency catheter ablation for atrial arrhythmias should, for the moment, be reserved for centres specialised in the techniques of electro-physiological investigation and ablation.", "The impressive selectivity and efficacy of BH3 mimetics for treating cancer has largely been limited to BCL-2 dependent hematological malignancies. Most solid tumors depend on other anti-apoptotic proteins, including MCL-1, for survival. The recent description of S63845 as the first specific and potent MCL-1 inhibitor represents an important therapeutic advance, since MCL-1 is not targeted by the currently available BH3 mimetics, Navitoclax or Venetoclax, and is commonly associated with chemoresistance. In this study, we confirm a high binding affinity and selectivity of S63845 to induce apoptosis in MCL-1-dependent cancer cell lines. Furthermore, S63845 synergizes with other BH3 mimetics to induce apoptosis in cell lines derived from both hematological and solid tumors. Although the anti-apoptotic BCL-2 family members in these cell lines interact with a spectrum of pro-apoptotic BH3-only proteins to regulate apoptosis, these interactions alone do not explain the relative sensitivities of these cell lines to BH3 mimetic-induced apoptosis. These findings necessitated further investigation into the requirement of BH3-only proteins in BH3 mimetic-mediated apoptosis. Concurrent inhibition of BCL-XL and MCL-1 by BH3 mimetics in colorectal HCT116 cells induced apoptosis in a BAX- but not BAK-dependent manner. Remarkably this apoptosis was independent of all known BH3-only proteins. Although BH3-only proteins were required for apoptosis induced as a result of BCL-XL inhibition, this requirement was overcome when both BCL-XL and MCL-1 were inhibited, implicating distinct mechanisms by which different anti-apoptotic BCL-2 family members may regulate apoptosis in cancer.", "Major depressive disorder (MDD) is a highly prevalent and debilitating mental illness, which is associated with disorder of gut microbiota. However, few studies focusing on detection of the signatures of bacteria in feces of MDD patients using proteomics approach have been carried out. Here, a comparative metaproteomics analysis on the basis of an isobaric tag for relative and absolute quantification coupled with tandem mass spectrometry was carried out to explore the signature of gut microbiota in patients with MDD. Ten patients (age: 18-56 years, five women) who had MDD and a score over 20 on the Hamilton's Depression Scale and 10 healthy controls (age: 24-65 years, five women) group matched for sex, age, and BMI were enrolled. As a result, 279 significantly differentiated bacterial proteins (P<0.05) were detected and used for further bioinformatic analysis. According to phylogenetic analysis, statistically significant differences were observed for four phyla: Bacteroidetes, Proteobacteria, Firmicutes, Actinobacteria (P<0.05, for each). Abundances of 16 bacterial families were significantly different between the MDD and healthy controls (P<0.05). Furthermore, Cluster of Orthologous Groups analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that disordered metabolic pathways of bacterial proteins were mainly involved in glucose metabolism and amino acid metabolism. In conclusion, fecal microbiota signatures were altered significantly in MDD patients. Our findings provide a novel insight into the potential connection between gut microbiota and depression.", "Advanced cardiac imaging, using cardiac magnetic resonance imaging (MRI) and multidetector computed tomography (CT), is increasingly used in the work-up of athletes with suspected abnormalities on screening. Both imaging modalities produce highly accurate and reproducible structural and functional cardiac information. Cardiac MRI has the advantage of imaging without radiation exposure or the use of iodine-containing contrast agents, but is sometimes not possible due to claustrophobia or other contraindications. Although cardiac MRI can rule out coronary artery anomalies, multidetector CT is superior to cardiac MRI for visualising the full extent of the coronary arteries and atherosclerotic coronary artery disease. For patients less than 35 years of age, cardiac MRI is the first option after initial echocardiography for further assessment of cardiomyopathies, myocarditis and coronary anomalies, which are major causes of sudden cardiac death in young athletes. For athletes over 35 years of age the most common cause of sudden cardiac death is coronary artery disease, whereby cardiovascular screening requires further diagnostic modalities and may include multidetector CT.", "Evidence indicates that major depression is accompanied by increased translocation of gut commensal Gram-negative bacteria (leaky gut) and consequent activation of oxidative and nitrosative (O&NS) pathways. This present study examined the associations among chronic apical periodontitis (CAP), root canal endotoxin levels (lipopolysaccharides, LPS), O&NS pathways, depressive symptoms, and quality of life. Measurements included advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), lipid peroxides (LOOH), -sulfhydryl (SH) groups, total radical trapping antioxidant parameter (TRAP), and paraoxonase (PON)1 activity in participants with CAP, with and without depression, as well as healthy controls (no depression, no CAP). Root canal LPS levels were positively associated with CAP, clinical depression, severity of depression (as measured with the Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory) and O&NS biomarkers, especially NOx and TRAP. CAP-related depression was accompanied by increased levels of NOx, LOOH, AOPP, and TRAP. In CAP participants, there was a strong correlation (r = 0.734, p < 0.001) between root canal LPS and the HDRS score. There were significant and positive associations between CAP or root canal endotoxin with the vegetative and physio-somatic symptoms of the HDRS as well as a significant inverse association between root canal endotoxin and quality of life with strong effects on psychological, environmental, and social domains. It is concluded that increased root canal LPS accompanying CAP may cause depression and a lowered quality of life, which may be partly explained by activated O&NS pathways, especially NOx thereby enhancing hypernitrosylation and thus neuroprogressive processes. Dental health and \"leaky teeth\" may be intimately linked to the etiology and course of depression, while significantly impacting quality of life.", "Despite the declaration of smallpox eradication in 1980, the existence of variola stockpiles and the threat of bioterrorism demand that immunity to smallpox through vaccination be maintained. Although the currently available vaccine was used for the most successful medical intervention ever accomplished, it also is associated with side effects that are difficult to accept in a vaccine for a disease that has not been present for >25 years. Herein, we review alternative approaches to maintaining immunity to smallpox through vaccination with attenuated poxviruses, and we suggest modified vaccinia Ankara (MVA) as a leading candidate for an alternative smallpox vaccine.", "The complex bidirectional communication between the gut and the brain is finely orchestrated by different systems, including the endocrine, immune, autonomic, and enteric nervous systems. Moreover, increasing evidence supports the role of the microbiome and microbiota-derived molecules in regulating such interactions; however, the mechanisms underpinning such effects are only beginning to be resolved. Microbiota-gut peptide interactions are poised to be of great significance in the regulation of gut-brain signaling. Given the emerging role of the gut-brain axis in a variety of brain disorders, such as anxiety and depression, it is important to understand the contribution of bidirectional interactions between peptide hormones released from the gut and intestinal bacteria in the context of this axis. Indeed, the gastrointestinal tract is the largest endocrine organ in mammals, secreting dozens of different signaling molecules, including peptides. Gut peptides in the systemic circulation can bind cognate receptors on immune cells and vagus nerve terminals thereby enabling indirect gut-brain communication. Gut peptide concentrations are not only modulated by enteric microbiota signals, but also vary according to the composition of the intestinal microbiota. In this review, we will discuss the gut microbiota as a regulator of anxiety and depression, and explore the role of gut-derived peptides as signaling molecules in microbiome-gut-brain communication. Here, we summarize the potential interactions of the microbiota with gut hormones and endocrine peptides, including neuropeptide Y, peptide YY, pancreatic polypeptide, cholecystokinin, glucagon-like peptide, corticotropin-releasing factor, oxytocin, and ghrelin in microbiome-to-brain signaling. Together, gut peptides are important regulators of microbiota-gut-brain signaling in health and stress-related psychiatric illnesses.", "The use of anticancer drugs is beneficial for patients with malignancies but is frequently associated with the occurrence of electrolyte disorders, which can be hazardous and in many cases fatal. The review presents the electrolyte abnormalities that can occur with the use of anticancer drugs and provides the related mechanisms. Platinum-containing anticancer drugs induce hypomagnesemia, hypokalemia and hypocalcemia. Moreover, platinum-containing drugs are associated with hyponatremia, especially when combined with large volumes of hypotonic fluids aiming to prevent nephrotoxicity. Alkylating agents have been linked with the occurrence of hyponatremia [due to syndrome of inappropriate antidiuretic hormone secretion (SIADH)] and Fanconi's syndrome (hypophosphatemia, aminoaciduria, hypouricemia and/or glucosuria). Vinca alkaloids are associated with hyponatremia due to SIADH. Epidermal growth factor receptor monoclonal antibody inhibitors induce hypomagnesemia, hypokalemia and hypocalcemia. Other, monoclonal antibodies, such as cixutumumab, cause hyponatremia due to SIADH. Tyrosine kinase inhibitors are linked to hyponatremia and hypophosphatemia. Mammalian target of rapamycin inhibitors induce hyponatremia (due to aldosterone resistance), hypokalemia and hypophosphatemia. Other drugs such as immunomodulators or methotrexate have been also associated with hyponatremia. The administration of estrogens at high doses, streptozocin, azacitidine and suramin may induce hypophosphatemia. Finally, the drug-related tumor lysis syndrome is associated with hyperphosphatemia, hyperkalemia and hypocalcemia. The prevention of electrolyte derangements may lead to reduction of adverse events during the administration of anticancer drugs.", "Thiamine (vitamin B1) deficiency, associated with a variety of conditions, including chronic alcoholism and bariatric surgery for morbid obesity, can result in the neurological disorder Wernicke's encephalopathy (WE). Recent work building upon early observations in animal models of thiamine deficiency has demonstrated an inflammatory component to the neuropathology observed in thiamine deficiency. The present, multilevel study including in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS) and postmortem quantification of chemokine and cytokine proteins sought to determine whether a combination of these in vivo neuroimaging tools could be used to characterize an in vivo MR signature for neuroinflammation. Thiamine deficiency for 12days was used to model neuroinflammation; glucose loading in thiamine deficiency was used to accelerate neurodegeneration. Among 38 animals with regional brain tissue assayed postmortem for cytokine/chemokine protein levels, three groups of rats (controls+glucose, n=6; pyrithiamine+saline, n=5; pyrithiamine+glucose, n=13) underwent MRI/MRS at baseline (time 1), after 12days of treatment (time 2), and 3h after challenge (glucose or saline, time 3). In the thalamus of glucose-challenged, thiamine deficient animals, correlations between in vivo measures of pathology (lower levels of N-acetyle aspartate and higher levels of lactate) and postmortem levels of monocyte chemotactic protein-1 (MCP-1, also known as chemokine ligand 2, CCL2) support a role for this chemokine in thiamine deficiency-related neurodegeneration, but do not provide a unique in vivo signature for neuroinflammation.", "The term alpha-synucleinopathy is used to name a group of disorders having in common the abnormal deposition of alpha-synuclein in the cytoplasm of neurons or glial cells, as well as in extracellular deposits of amyloid. In Parkinson's disease and Lewy body dementia, alpha-synuclein is the main component of Lewy bodies and dystrophic neurites; alpha-synuclein also accumulates in the cytoplasm of glial cells. In multiple system atrophy, alpha-synuclein conforms the cytoplasmic oligodendroglial inclusions and the neuronal inclusions which are the hallmark of this disease. Finally, the amyloidogenic fragment 61-95 amino acids of alpha-synuclein is the non-Abeta component of senile plaque amyloid in Alzheimer disease. Accumulations of alpha-synuclein in all these disorders have in common a fibrilar configuration, but they differ in the binding of alpha-synuclein to distinct proteins with the exception of ubiquitin whose binding to alpha-synuclein is common to all alpha-synuclein inclusions. The mechanisms leading to alpha-synuclein fragmentation and aggegation into extracellular amyloid are not known, although alpha-synuclein fragment and betaA4 aggregates are the result of abnormal cleavage of large precursors. On the other hand, several studies have shown that alpha-synuclein may adopt a fibrilar conformation and give rise to insoluble forms and high molecular weight aggregates in vitro. Similar complexes have also been observed in alpha-synucleinopathies. Although studies in vitro and in vivo have shown toxic effects of alpha-synuclein, the consequence of alpha-synuclein deposition on cell survival in alpha-synucleinopathies is not known.", "The human gut is a composite anaerobic environment with a large, diverse and dynamic enteric microbiota, represented by more than 100 trillion microorganisms, including at least 1000 distinct species. The discovery that a different microbial composition can influence behavior and cognition, and in turn the nervous system can indirectly influence enteric microbiota composition, has significantly contributed to establish the well-accepted concept of gut-brain axis. This hypothesis is supported by several evidence showing mutual mechanisms, which involve the vague nerve, the immune system, the hypothalamic-pituitaryadrenal (HPA) axis modulation and the bacteria-derived metabolites. Many studies have focused on delineating a role for this axis in health and disease, ranging from stress-related disorders such as depression, anxiety and irritable bowel syndrome (IBS) to neurodevelopmental disorders, such as autism, and to neurodegenerative diseases, such as Parkinson Disease, Alzheimer's Disease etc. Based on this background, and considering the relevance of alteration of the symbiotic state between host and microbiota, this review focuses on the role and the involvement of bioactive lipids, such as the N-acylethanolamine (NAE) family whose main members are N-arachidonoylethanolamine (AEA), palmitoylethanolamide (PEA) and oleoilethanolamide (OEA), and short chain fatty acids (SCFAs), such as butyrate, belonging to a large group of bioactive lipids able to modulate peripheral and central pathologic processes. Their effective role has been studied in inflammation, acute and chronic pain, obesity and central nervous system diseases. A possible correlation has been shown between these lipids and gut microbiota through different mechanisms. Indeed, systemic administration of specific bacteria can reduce abdominal pain through the involvement of cannabinoid receptor 1 in the rat; on the other hand, PEA reduces inflammation markers in a murine model of inflammatory bowel disease (IBD), and butyrate, producted by gut microbiota, is effective in reducing inflammation and pain in irritable bowel syndrome and IBD animal models. In this review, we underline the relationship among inflammation, pain, microbiota and the different lipids, focusing on a possible involvement of NAEs and SCFAs in the gut-brain axis and their role in the central nervous system diseases.", "Mutational activation of the K-Ras oncogene is well established as a key genetic step in the development and growth of pancreatic adenocarcinomas. However, the mechanism by which aberrant Ras signaling promotes uncontrolled pancreatic tumor cell growth remains to be fully elucidated. The recent use of primary human cells to study Ras-mediated oncogenesis provides important model cell systems to dissect this mechanism. We have used a model of telomerase-immortalized human pancreatic duct-derived cells (E6/E7/st) to study mechanisms of Ras growth transformation. First, we found that human papillomavirus E6 and E7 oncogenes, which block the function of the p53 and Rb tumor suppressors, respectively, and SV40 small t antigen were required to allow mutant K-Ras(12D) growth transformation. Second, K-Ras(12D) caused growth transformation in vitro, including enhanced growth rate and loss of density dependency for growth, anchorage independence, and invasion through reconstituted basement membrane proteins, and tumorigenic transformation in vivo. Third, we determined that the Raf, phosphatidylinositol 3-kinase (PI3K), and Ral guanine nucleotide exchange factor effector pathways were activated, although extracellular signal-regulated kinase (ERK) activity was not up-regulated persistently. Finally, pharmacologic inhibition of Raf/mitogen-activated protein kinase/ERK and PI3K signaling impaired K-Ras-induced anchorage-independent growth and invasion. In summary, our studies established, characterized, and validated E6/E7/st cells for the study of Ras-induced oncogenesis.", "BACKGROUND: Axitinib is a potent, selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. A randomised phase 2 trial of gemcitabine with or without axitinib in advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients. On the basis of these results, we aimed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial.METHODS: In this double-blind, placebo-controlled, phase 3 study, eligible patients had metastatic or locally advanced pancreatic adenocarcinoma, no uncontrolled hypertension or venous thrombosis, and Eastern Cooperative Oncology Group performance status 0 or 1. Patients, stratified by disease extent (metastatic vs locally advanced), were randomly assigned (1:1) to receive gemcitabine 1000 mg/m(2) intravenously on days 1, 8, and 15 every 28 days plus either axitinib or placebo. Axitinib or placebo were administered orally with food at a starting dose of 5 mg twice a day, which could be dose-titrated up to 10 mg twice daily if well tolerated. A centralised randomisation procedure was used to assign patients to each treatment group, with randomised permuted blocks within strata. Patients, investigators, and the trial sponsor were masked to treatment assignments. The primary endpoint was overall survival. All efficacy analyses were done in all patients assigned to treatment groups for whom data were available; safety and treatment administration and compliance assessments were based on treatment received. This study is registered at ClinicalTrials.gov, number NCT00471146.FINDINGS: Between July 27, 2007, and Oct 31, 2008, 632 patients were enrolled and assigned to treatment groups (316 axitinib, 316 placebo). At an interim analysis in January, 2009, the independent data monitoring committee concluded that the futility boundary had been crossed. Median overall survival was 8·5 months (95% CI 6·9-9·5) for gemcitabine plus axitinib (n=314, data missing for two patients) and 8·3 months (6·9-10·3) for gemcitabine plus placebo (n=316; hazard ratio 1·014, 95% CI 0·786-1·309; one-sided p=0·5436). The most common grade 3 or higher adverse events for gemcitabine plus axitinib and gemcitabine plus placebo were hypertension (20 [7%] and 5 [2%] events, respectively), abdominal pain (20 [7%] and 17 [6%]), fatigue (27 [9%] and 21 [7%]), and anorexia (19 [6%] and 11 [4%]).INTERPRETATION: The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer. These results add to increasing evidence that targeting of VEGF signalling is an ineffective strategy in this disease.FUNDING: Pfizer.", "Comet assay under neutral conditions allows detection of DNA double-strand breaks (DSBs), which has consequence to genome instability and carcinogenesis. The present study aims to validate the neutral Comet assay for genotoxicity assessment in Drosophila melanogaster (Oregon R(+)) with three well known DSBs inducers i.e. cyclophosphamide (CP), bleomycin (BLM), cisplatin (CPT) and subsequently its efficacy in detecting DSBs in the organism exposed to a well known environmental chemical, chromium [Cr(VI)]. Third instar larvae of D. melanogaster were fed different concentrations of BLM, CPT and CP (50.0-200.0μg/ml) or Cr(VI) (5.0-20.0μg/ml) mixed standard Drosophila food for 48h. Neutral Comet assay was performed in cells of mid gut and brain from control and treated larvae. Our results show a dose-dependent increase in the migration of DNA in cells of the exposed organisms. A comparison among DNA lesions per mole number of the test chemical in the exposed groups showed that both BLM and CPT induce more DSBs than CP. Interestingly, Cr(VI) at 20.0μg/ml was found to induce significantly increased (p<0.001) DSBs in the exposed organism as compared to the control. The study while validating neutral Comet assay in D. melanogaster suggests its use for in vivo assessment of environmental chemical induced DSBs." ]

[ "PURPOSE/OBJECTIVES: To investigate cancer surveillance behaviors of women at risk for hereditary breast and ovarian cancer (HBOC) who presented for clinical BRCA cancer susceptibility testing, specifically to describe cancer surveillance behaviors and reasons for not engaging in behaviors, compare surveillance behaviors with existing surveillance guidelines, and evaluate associations of cancer surveillance behaviors with BRCA results.DESIGN: Cross-sectional, descriptive.SETTING: Genetic risk-assessment programs in a National Cancer Institute-designated comprehensive cancer center and a community cancer center, both in the southwestern region of the United States.SAMPLE: Purposive sample of 107 at-risk women.METHODS: Self-report survey.MAIN RESEARCH VARIABLES: Breast and ovarian cancer surveillance behaviors and BRCA test results.FINDINGS: Ninety percent of participants had a personal history of breast cancer; 84% had a negative BRCA result. About 60% of participants engaged in at least the minimum recommended breast cancer surveillance behaviors, but 70% had suboptimal ovarian cancer surveillance behaviors. Lack of physician recommendation was the most frequently reported reason for not having surveillance procedures. BRCA results were not associated with the breast cancer surveillance categories and the ovarian cancer surveillance recommendations.CONCLUSIONS: Although most participants were not carriers of a mutation, the presence of other risk factors for breast and ovarian cancer dictates continued cancer surveillance. At-risk women may not be informed adequately about cancer surveillance.IMPLICATIONS FOR NURSING: Healthcare providers should be aware of changing breast and ovarian cancer surveillance recommendations and counsel their at-risk patients accordingly.", "Midostaurin (PKC412, Rydapt®) is an oral multiple tyrosine kinase inhibitor. Main targets are the kinase domain receptor, vascular endothelial-, platelet derived-, and fibroblast growth factor receptor, stem cell factor receptor c-KIT, as well as mutated and wild-type FLT3 kinases. Midostaurin was approved by the Food and Drug Administration (FDA) and the European Medical Agency (EMA) for acute myeloid leukemia with activating FLT3 mutations in combination with intensive induction and consolidation therapy as well as aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN) or mast cell leukemia (MCL). Several clinical trials are active or are planned to further investigate the role of midostaurin in myeloid malignancies and mastocytosis.", "The fifth wave of A(H7N9) virus infection in China from 2016 to 2017 caused great concern due to the large number of individuals infected, the isolation of drug-resistant viruses, and the emergence of highly pathogenic strains. Antibodies against neuraminidase (NA) provide added benefit to hemagglutinin-specific immunity and may be important contributors to the effectiveness of A(H7N9) vaccines. We generated a panel of mouse monoclonal antibodies (MAbs) to identify antigenic domains on NA of the novel A(H7N9) virus and compared their functional properties. The loop formed in the region of residue 250 (250 loop) and the domain formed by the loops containing residues 370, 400, and 430 were identified as major antigenic regions. MAbs 1E8, 2F6, 10F4, and 11B2, which recognize these two antigenic domains, were characterized in depth. These four MAbs differ in their abilities to inhibit cleavage of small and large substrates (methyl-umbelliferyl-acetyl neuraminic acid [MU-NANA] and fetuin, respectively) in NA inhibition assays. 1E8 and 11B2 did not inhibit NA cleavage of either MU-NANA or fetuin, and 2F6 inhibited cleavage of fetuin alone, whereas 10F4 inhibited cleavage of both substrates. All four MAbs reduced the in vitro spread of viruses carrying either the wild-type N9 or N9 with antiviral-resistant mutations but to different degrees. These MAbs have different in vivo levels of effectiveness: 10F4 was the most effective in protecting mice against challenge with A(H7N9) virus, 2F6 was less effective, and 11B2 failed to protect BALB/c mice at the doses tested. Our study confirms that NA-specific antibodies can protect against A(H7N9) infection and suggests that in vitro properties can be used to rank antibodies with therapeutic potential.IMPORTANCE The novel A(H7N9) viruses that emerged in China in 2013 continue to infect humans, with a high fatality rate. The most recent outbreak resulted in a larger number of human cases than previous epidemic waves. Due to the absence of a licensed vaccine and the emergence of drug-resistant viruses, there is a need to develop alternative approaches to prevent or treat A(H7N9) infection. We have made a panel of mouse monoclonal antibodies (MAbs) specific for neuraminidase (NA) of A(H7N9) viruses; some of these MAbs are effective in inhibiting viruses that are resistant to antivirals used to treat A(H7N9) patients. Binding avidity, inhibition of NA activity, and plaque formation correlated with the effectiveness of these MAbs to protect mice against lethal A(H7N9) virus challenge. This study identifies in vitro measures that can be used to predict the in vivo efficacy of NA-specific antibodies, providing a way to select MAbs for further therapeutic development.", "The 2016 Conference on Retroviruses and Opportunistic Infections (CROI) highlighted hot spots in HIV infection. Men who have sex with men (MSM), transgender populations, people who inject drugs, fisherfolk, migrants, adolescents, and older adults are heavily impacted in a number of regions. Stigma contributes to risk behaviors and HIV acquisition across populations. HIV testing is a crucial first step in the HIV care continuum, and several large community-based surveys are underway in Africa to increase HIV testing, linkage to care, and uptake of antiretroviral treatment. Advances in preexposure prophylaxis (PrEP) featured prominently at CROI 2016. Two large efficacy trials of a vaginal ring containing the investigational drug dapivirine demonstrated efficacy and safety in preventing HIV infections in women in Africa. Data on the safety of long-acting injectable PrEP and several investigational PrEP drugs and formulations were also presented. Knowledge and use of PrEP among MSM in the United States appears to be increasing, and high uptake was seen among black MSM when provided as part of a culturally tailored support program. The use of broadly neutralizing antibodies for HIV prevention is a novel and promising approach to be evaluated in efficacy trials.", "CONTEXT: Monocarboxylate transporter 8 (MCT8) is a thyroid hormone-specific cell membrane transporter. MCT8 deficiency causes severe psychomotor retardation and abnormal thyroid tests. The great majority of affected children cannot walk or talk, and all have elevated serum T(3) levels, causing peripheral tissue hypermetabolism and inability to maintain weight. Treatment with thyroid hormone is ineffective. In Mct8-deficient mice, the thyroid hormone analog, diiodothyropropionic acid (DITPA), does not require MCT8 to enter tissues and could be an effective alternative to thyroid hormone treatment in humans.OBJECTIVE: The objective of the study was to evaluate the effect and efficacy of DITPA in children with MCT8 deficiency.METHODS: This was a multicenter report of four affected children given DITPA on compassionate grounds for 26-40 months. Treatment was initiated at ages 8.5-25 months, beginning with a small dose of 1.8 mg, increasing to a maximal 30 mg/d (2.1-2.4 mg/kg · d), given in three divided doses.RESULTS: DITPA normalized the elevated serum T(3) and TSH when the dose reached 1 mg/kg · d and T(4) and rT(3) increased to the lower normal range. The following significant changes were also observed: decline in SHBG (in all subjects), heart rate (in three of four), and ferritin (in one of four). Cholesterol increased in two subjects. There was no weight loss and weight gain occurred in two. None of the treated children required a gastric feeding tube or developed seizures. No adverse effects were observed.CONCLUSION: DITPA (1-2 mg/kg · d) almost completely normalizes thyroid tests and reduces the hypermetabolism and the tendency for weight loss. The effects of earlier commencement and long-term therapy remain to be determined.", "BACKGROUND: Dysregulation of the vasopressin (AVP) system has been implicated in the pathogenesis of autistic spectrum disorder (ASD). Apelin is a recently discovered neuropeptide that could counteract AVP actions and whose receptors are colocalized with vasopressin in hypothalamic magnocellular neurons. Aims of the present study were to investigate circulating levels of apelin in patients with ASD and to assess their correlation with plasma AVP concentrations.METHODS: Plasma levels of apelin and AVP were measured in a total of 18 patients with ASD and 21 age- and gender-matched healthy comparison subjects. The Childhood Autism Rating Scale (CARS) was used to assess the severity of autistic symptoms.RESULTS: Significantly reduced levels of apelin (p < 0.001) and elevated concentrations of AVP (p = 0.02) were found in ASD patients as compared to controls. Additionally, a significant inverse correlation between apelin and AVP levels was found within the ASD group (r = -0.61; p = 0.007), but not in healthy participants (r = -0.26; p = 0.25). Multivariate linear regression analysis showed that only AVP concentrations independently predicted apelin values in ASD individuals (beta = -0.42, t = 2.63, p = 0.014). No correlation was seen between apelin levels and CARS scores (r = -0.10; p = 0.68).CONCLUSIONS: Our findings of a significantly reduced peripheral level of apelin coupled with elevated AVP point to a subtle but definite vasopressinergic dysfunction in autism that could play a role in the etiopathophysiology of this disorder in humans.", "Since the first living-donor kidney transplantation in 1954, more than half a million living kidney donations have occurred and research has advanced knowledge about long-term donor outcomes. Donors in developed countries have a similar life expectancy and quality of life as healthy non-donors. Living kidney donation is associated with an increased risk of end-stage renal disease, although this outcome is uncommon (<0·5% increase in incidence at 15 years). Kidney donation seems to elevate the risks of gestational hypertension and pre-eclampsia. Many donors incur financial expenses due to factors such as lost wages, need for sick days, and travel expenses. Yet, most donors have no regrets about donation. Living kidney donation is practised ethically when informed consent incorporates information about risks, uncertainty about outcomes is acknowledged when it exists, and a donor's risks are proportional to benefits for the donor and recipient. Future research should determine whether outcomes are similar for donors from developing countries and donors with pre-existing conditions such as obesity." ]

[ "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.", "Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder notably characterized by precocious and deadly atherosclerosis. Almost 90% of HGPS patients carry a LMNA p.G608G splice variant that leads to the expression of a permanently farnesylated abnormal form of prelamin-A, referred to as progerin. Endothelial dysfunction is a key determinant of atherosclerosis, notably during aging. Previous studies have shown that progerin accumulates in HGPS patients' endothelial cells but also during vascular physiological aging. However, whether progerin expression in human endothelial cells can recapitulate features of endothelial dysfunction is currently unknown. Herein, we evaluated the direct impact of exogenously expressed progerin and wild-type lamin-A on human endothelial cell function and senescence. Our data demonstrate that progerin, but not wild-type lamin-A, overexpression induces endothelial cell dysfunction, characterized by increased inflammation and oxidative stress together with persistent DNA damage, increased cell cycle arrest protein expression and cellular senescence. Inhibition of progerin prenylation using a pravastatin-zoledronate combination partly prevents these defects. Our data suggest a direct proatherogenic role of progerin in human endothelial cells, which could contribute to HGPS-associated early atherosclerosis and also potentially be involved in physiological endothelial aging participating to age-related cardiometabolic diseases.", "Angiotensin-converting enzyme 2 (ACE2) is a recently described member of the renin-angiotensin system that hydrolyzes angiotensin (Ang) II to Ang-(1-7), and may thereby protect against cardiovascular and renal diseases. ACE2 is a type 1 integral membrane protein and contains a catalytically active ectodomain that can be shed from the cell surface into the extracellular space, via cleavage by a disintegrin and metalloproteinase-17 (ADAM-17). ACE2 enzymatic activity and protein can be detected in biological fluids, including urine, plasma, and conditioned cell culture media. We present a detailed method for measurement of ACE2 activity in biological fluids, using hydrolysis of an intramolecularly quenched fluorogenic ACE2 substrate, in the absence or presence of the ACE2 inhibitors MLN-4760 or DX600. Recombinant human or mouse ACE2 is used to generate standard curves for this assay, with ACE2 detection ranging from 1.56 to 50 ng/ml. While MLN-4760 potently inhibits the activity of both human and mouse ACE2, DX600 (linear form) only effectively blocks human ACE2 activity in this assay. In biological samples of human and mouse urine, cell culture medium from mouse proximal tubular cells, and mouse plasma, the mean intra- and inter-assay coefficients of variation (CVs) of the assay range from 1.43 to 4.39 %, and from 7.01 to 13.17 %, respectively. We present data on the time and substrate concentration dependence of the assay, and show that exogenous D -glucose, creatinine, urea, and albumin do not interfere with its performance. In biological fluids, this assay is a simple and reliable method to study the role of ACE2 and its shed fragments in cardiovascular and renal diseases.", "AIMS: Polymerase chain reaction (PCR) is the most rapid and sensitive method for diagnosing mycobacterial infections and identifying the aetiological Mycobacterial species in order to administer the appropriate therapy and for better patient management.METHODS AND RESULTS: Two hundred and thirty-five samples from 145 clinically suspected cases of tuberculosis were processed for the detection of Mycobacterial infections by ZN (Ziehl Neelsen) smear examination, L-J & BACTEC MGIT-960 culture and multiplex PCR tests. The multiplex PCR comprised of genus-specific primers targeting hsp65 gene, Mycobacterium tuberculosis complex-specific primer targeting cfp10 (Rv3875, esxB) region and Mycobacterium avium complex-specific primer pairs targeting 16S-23S Internal Transcribed Spacer sequences. The multiplex PCR developed had an analytical sensitivity of 10 fg (3-4 cells) of mycobacterial DNA. The multiplex PCR test showed the highest (77.24%) detection rate, while ZN smear examination had the lowest (20%) detection rate, which was bettered by L-J culture (34.4%) and BACTEC MGIT-960 culture (50.34%) methods. The mean isolation time for M. tuberculosis was 19.03 days in L-J culture and 8.7 days in BACTEC MGIT-960 culture. Using the multiplex PCR, we could establish M. tuberculosis + M. avium co-infection in 1.3% HIV-negative and 2.9% HIV-positive patients. The multiplex PCR was also highly useful in diagnosing mycobacteraemia in 38.09% HIV-positive and 15.38% HIV-negative cases.CONCLUSIONS: The developed in-house multiplex PCR could identify and differentiate the M. tuberculosis and M. avium complexes from other Mycobacterial species directly from clinical specimens.SIGNIFICANCE AND IMPACT OF THE STUDY: The triplex PCR developed by us could be used to detect and differentiate M. tuberculosis, M. avium and other mycobacteria in a single reaction tube.", "Groucho related gene 5 (GRG5) is a multifunctional protein that has been implicated in late embryonic and postnatal mouse development. Here, we describe a previously unknown role of GRG5 in early developmental stages by analyzing its function in stem cell fate decisions. By both loss and gain of function approaches we demonstrate that ablation of GRG5 deregulates the Embryonic Stem Cell (ESC) pluripotent state whereas its overexpression leads to enhanced self-renewal and acquisition of cancer cell-like properties. The malignant characteristics of teratomas generated by ESCs that overexpress GRG5 reveal its pro-oncogenic potential. Furthermore, transcriptomic analysis and cell differentiation approaches underline GRG5 as a multifaceted signaling regulator that represses mesendodermal-related genes. When ESCs exit pluripotency, GRG5 promotes neuroectodermal specification via Wnt and BMP signaling suppression. Moreover, GRG5 promotes the neuronal reprogramming of fibroblasts and maintains the self-renewal of Neural Stem Cells (NSCs) by sustaining the activity of Notch/Hes and Stat3 signaling pathways. In summary, our results demonstrate that GRG5 has pleiotropic roles in stem cell biology functioning as a stemness factor and a neural fate specifier.", "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.", "Tardive dyskinesia (TD) is a serious, often disabling, movement disorder that is caused by medications that block dopamine receptors (i.e., neuroleptics, anti-emetics). There is currently no standard treatment approach for physicians confronted with such patients. This may be the result of notions that TD is disappearing because of the switch to second-generation antipsychotic agents and that it is largely reversible. In this article we demonstrate that second-generation antipsychotics do, indeed, cause TD and, in fact, the frequency is likely higher than expected because of growing off-label uses and a tripling of prescriptions written in the last 10 years. In addition, studies demonstrate that TD actually remits in only a minority of patients when these drugs are withdrawn. Furthermore, neuroleptic agents are often utilized to treat TD, despite prolonged exposure being a risk factor for irreversibility. The outcome of these trends is a growing population afflicted with TD. We review non-neuroleptic agents that have shown positive results in small, early-phase, blinded trials, including tetrabenazine, amantadine, levetiracetam, piracetam, clonazepam, propranolol, vitamin B6, and Ginkgo biloba. Other options, such as botulinum toxin and deep brain stimulation, will also be discussed, and a suggested treatment algorithm is provided. While these agents are reasonable treatment options at this time there is a need, with a concerted effort between neurology and psychiatry, for full-scale drug development, including multicenter, randomized, blinded trials to confirm the effectiveness of the agents that were positive in phase 2 trials and the development of newer ones." ]

[ "Publisher: IMMUNONKOLOGISCHE MONOTHERAPIE DES NICHTKLEINZELLIGEN LUNGENKARZINOMS:  5-Jahres-Überlebensdaten der KEYNOTE-024-Studie bestätigen die anhaltende Wirksamkeit einer immunonkologischen Monotherapie bei Patienten mit nichtkleinzelligem Lungenkarzinom (NSCLC) mit hoher PD-L1-Expression (≥ 50 %). DUALE IMMUNTHERAPIE IN KOMBINATION MIT CHEMOTHERAPIE ALS ERSTLINIENTHERAPIE DES NICHTKLEINZELLIGEN LUNGENKARZINOMS:  Nivolumab plus Impilimumab in Kombination mit 2 Zyklen platinhaltiger Chemotherapie verbessern das Überleben von NSCLC-Patienten. NEUE TARGETS UND THERAPIEOPTIONEN:  Entrectinib und Larotrectinib mit Wirksamkeit bei NTRK-Fusions-positivem NSCLC. Selpercatinib und Pralsetinib mit Wirksamkeit bei RET-Fusions-positivem NSCLC. Mobocertinib mit Wirksamkeit bei EGFRex20ins-Mutation des EGFR-Gens. Sotorasib mit Wirksamkeit bei kRAS-G12C-Mutation des NSCLC. NATIONALES NETZWERK GENOMISCHE MEDIZIN LUNGENKREBS: Das bundesweite Nationale Netzwerk Genomische Medizin Lungenkrebs (nNGM) ermöglicht NSCLC-Patienten den Zugang zu modernster molekularer Diagnostik und neuesten Therapieoptionen.", "In Saccharomyces, an ancient whole-genome duplication (WGD) and widespread duplicate gene deletion resulted in extensive reorganization of adjacent gene relationships. We have studied the evolution of adjacent gene pairs' identity, orientation, and spacing following whole-genome duplication and deletion (WGD-D) using comparative genomic analyses and simulations. Surveying adjacent gene organization across the Saccharomyces species complex, we find a genome-wide bias toward divergently and convergently transcribed gene pairs in all species but a reduction in this bias in the species that underwent WGD-D. Among neutral models of WGD-D, only single-gene deletion can produce the appropriate reduction in orientation bias and recapitulate the pattern of short, highly dispersed deletions we observe in Saccharomyces cerevisiae. To characterize the dynamics of WGD-D, we trace the conservation and creation of adjacent gene pairs along the S. cerevisiae lineage. We find that newly created adjacencies have a tandem orientation bias, while adjacencies conserved from prior to WGD-D have the same divergent-convergent bias as found in the species that diverged before WGD. We also find that adjacent gene pairs produced by WGD-D gained greater intergenic spacing but that this is reduced in the older adjacencies. Given this, and the preponderance of short deleted blocks, we argue that the deletion phase of WGD-D occurred primarily by small inactivating mutations followed by numerous small deletions. Newly created adjacent gene pairs also have an initial increase in mean log2 expression ratios and maximal expression levels, suggesting that increased intergenic spacing caused a genome-wide reduction in transcriptional interference.", "Inflammatory immune responses play an important role in mucosal homeostasis and gut diseases. Nuclear factor κB (NF-κB), central to the proinflammatory cascade, is activated in necrotizing enterocolitis (NEC), a devastating condition of intestinal injury with extensive inflammation in premature infants. TGF-β is a strong immune suppressor and a factor in breast milk, which has been shown to be protective against NEC. In an NEC animal model, oral administration of the isoform TGF-β1 activated the downstream effector Smad2 in intestine and significantly reduced NEC incidence. In addition, TGF-β1 suppressed NF-κB activation, maintained levels of the NF-κB inhibitor IκBα in the intestinal epithelium, and systemically decreased serum levels of IL-6 and IFN-γ. The immature human fetal intestinal epithelial cell line H4 was used as a reductionistic model of the immature enterocyte to investigate mechanism. TGF-β1 pretreatment inhibited the TNF-α-induced IκBα phosphorylation that targets the IκBα protein for degradation and inhibited NF-κB activation. Chromatin immunoprecipitation (ChIP) assays demonstrated decreased NF-κB binding to the promoters of IL-6, IL-8, and IκBα in response to TNF-α with TGF-β1 pretreatment. These TGF-β1 effects appear to be mediated through the canonical Smad pathway as silencing of the TGF-β central mediator Smad4 resulted in loss of the TGF-β1 effects. Thus, TGF-β1 is capable of eliciting anti-inflammatory effects by inhibiting NF-κB specifically in the intestinal epithelium as well as by decreasing systemic IL-6 and IFN-γ levels. Oral administration of TGF-β1 therefore can potentially be used to protect against gastrointestinal diseases.", "The ability of Frzb/secreted Frizzled-related protein 3 (sFRP3) to inhibit Wnt signaling and the localization of Frzb/sFRP3 on chromosome 2q to a region frequently deleted in cancers have led some investigators to hypothesize that Frzb/sFRP3 is a tumor suppressor gene. Here, we examined the biological effects of Frzb/sFRP3 on an androgen-independent prostate cancer cell model. We showed that expression of Frzb/sFRP3 in PC-3 cells resulted in decreased colony formation in soft agar and a dramatic inhibition of tumor growth in a xenograft mouse model. When cellular morphology was examined, PC-3 cells expressing Frzb/sFRP3 exhibited an increase in cell-cell contact formation accompanied by a pronounced induction of epithelial markers E-cadherin and keratin-8 and down-regulation of mesenchymal markers N-cadherin, fibronectin, and vimentin. This phenomenon suggested a reversal of epithelial-to-mesenchymal transition and a less invasive phenotype. Indeed, further in vitro studies with a Matrigel assay showed that Frzb/sFRP3 decreased the invasive capacity of PC-3 cells. These changes in the biology of PC-3 cells are associated with a decrease in the expression and activities of both matrix metalloproteinase (MMP)-2 and MMP-9 as well as decreases in AKT activation, cytosolic beta-catenin levels, T-cell factor transcription activity, and expression of Slug and Twist. In addition, transfection of PC-3 with a dominant-negative low-density lipoprotein receptor-related protein 5 (DN-LRP5) coreceptor showed similar biological effects as Frzb/sFRP3 transfection. Together, these data suggest that Frzb/sFRP3 and DN-LRP5 exhibit antitumor activity through the reversal of epithelial-to-mesenchymal transition and inhibition of MMP activities in a subset of prostate cancer.", "MOTIVATION: Whole genome sequencing is becoming a diagnostics of choice for the identification of rare inherited and de novo copy number variants in families with various pediatric and late-onset genetic diseases. However, joint variant calling in pedigrees is hampered by the complexity of consensus breakpoint alignment across samples within an arbitrary pedigree structure.RESULTS: We have developed a new tool, Canvas SPW, for the identification of inherited and de novo copy number variants from pedigree sequencing data. Canvas SPW supports a number of family structures and provides a wide range of scoring and filtering options to automate and streamline identification of de novo variants.AVAILABILITY AND IMPLEMENTATION: Canvas SPW is available for download from https://github.com/Illumina/canvas.CONTACT: sivakhno@illumina.com.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "The 'fruity' attributes of ripe apples (Malus × domestica) arise from our perception of a combination of volatile ester compounds. Phenotypic variability in ester production was investigated using a segregating population from a 'Royal Gala' (RG; high ester production) × 'Granny Smith' (GS; low ester production) cross, as well as in transgenic RG plants in which expression of the alcohol acyl transferase 1 (AAT1) gene was reduced. In the RG × GS population, 46 quantitative trait loci (QTLs) for the production of esters and alcohols were identified on 15 linkage groups (LGs). The major QTL for 35 individual compounds was positioned on LG2 and co-located with AAT1. Multiple AAT1 gene variants were identified in RG and GS, but only two (AAT1-RGa and AAT1-GSa) were functional. AAT1-RGa and AAT1-GSa were both highly expressed in the cortex and skin of ripe fruit, but AAT1 protein was observed mainly in the skin. Transgenic RG specifically reduced in AAT1 expression showed reduced levels of most key esters in ripe fruit. Differences in the ripe fruit aroma could be perceived by sensory analysis. The transgenic lines also showed altered ratios of biosynthetic precursor alcohols and aldehydes, and expression of a number of ester biosynthetic genes increased, presumably in response to the increased substrate pool. These results indicate that the AAT1 locus is critical for the biosynthesis of esters contributing to a 'ripe apple' flavour.", "Inverted formin 2 (INF2) encodes a member of the diaphanous subfamily of formin proteins. Mutations in INF2 cause human kidney disease characterized by focal and segmental glomerulosclerosis. Disease-causing mutations occur only in the diaphanous inhibitory domain (DID), suggesting specific roles for this domain in the pathogenesis of disease. In a yeast two-hybrid screen, we identified the diaphanous autoregulatory domains (DADs) of the mammalian diaphanous-related formins (mDias) mDia1, mDia2, and mDia 3 as INF2_DID-interacting partners. The mDias are Rho family effectors that regulate actin dynamics. We confirmed in vitro INF2_DID/mDia_DAD binding by biochemical assays, confirmed the in vivo interaction of these protein domains by coimmunoprecipitation, and observed colocalization of INF2 and mDias in glomerular podocytes. We investigated the influence of this INF2_DID/mDia_DAD interaction on mDia mediated actin polymerization and on serum response factor (SRF) activation. We find that the interaction of INF2_DID with mDia_DAD inhibited mDia-mediated, Rho-activated actin polymerization, as well as SRF-responsive gene transcriptional changes. Similar assays using the disease-causing E184K and R218Q mutations in INF2_DID showed a decreased effect on SRF activation and gene transcription. The binding of INF2_DID to mDia_DAD may serve as a negative regulatory mechanism for mDias' function in actin-dependent cell processes. The effects of disease-causing INF2 mutations suggest an important role for this protein and its interaction with other formins in modulating glomerular podocyte phenotype and function." ]

[ "Iso-electric focusing (IEF) was the first method established to discriminate endogenous and recombinant erythropoietins (rEPOs). It is still approved by the World Anti-Doping Agency (WADA) as an initial testing procedure to detect erythropoiesis stimulating agents (ESAs) in doping control samples. However EPO-Fc, one of the prohibited rEPOs designated by WADA, is not detectable with the actual IEF conditions. Other newly developed ESAs - luspatercept and sotatercept, both activin receptor type II-Fc fusion proteins (ActRII-Fc) - are also now prohibited and could be used in combination with rEPOs. Methods of identification of ActRII-Fc in blood by SAR/SDS-PAGE have been described, but not by IEF. Here we detail improvements in blood sample preparation and IEF analysis: A combined immuno-purification of EPOs and ActRII-Fc proteins in a single procedure, an appropriate isoforms separation for all proteins using new pre-loading and gel conditions, and a single detection of all rEPOs and ActRII-Fc proteins after successive incubation with anti-EPO and anti-ActRII antibodies. With these changes, distinctive profiles for all the ESAs were obtained by IEF. Therefore, IEF could be used as a screening method to detect a wide spectrum of prohibited ESAs in blood samples prior to specific confirmation for the identified rEPO or ActRII-Fc.", "Background: Despite an increase in the familiarity of the medical community with the epidemiological and clinical characteristics of coronavirus disease 2019 (COVID-19), there is presently a lack of rapid and effective risk stratification indicators to predict the poor clinical outcomes of COVID-19 especially in severe patients. Methods: In this retrospective single-center study, we included 117 cases confirmed with COVID-19. The clinical, laboratory, and imaging features were collected and analyzed during admission. The Multi-lobular infiltration, hypo-Lymphocytosis, Bacterial coinfection, Smoking history, hyper-Tension and Age (MuLBSTA) Score and Confusion, Urea, Respiratory rate, Blood pressure, Age 65 (CURB65) score were used to assess the death and intensive care unit (ICU) risks in all patients. Results: Among of all 117 hospitalized patients, 21 (17.9%) patients were admitted to the ICU care, and 5 (4.3%) patients were died. The median hospital stay was 12 (10-15) days. There were 18 patients with MuLBSTA score ≥ 12 points and were all of severe type. In severe type, ICU care and death patients, the proportion with MuLBSTA ≥ 12 points were greater than that of CURB65 score ≥ 3 points (severe type patients, 50 vs. 27.8%; ICU care, 61.9 vs. 19.0%; death, 100 vs. 40%). For the MuLBSTA score, the ROC curve showed good efficiency of diagnosis death (area under the curve [AUC], 0.956; cutoff value, 12; specificity, 89.5%; sensitivity, 100%) and ICU care (AUC, 0.875; cutoff value, 11; specificity, 91.7%; sensitivity, 71.4%). The K-M survival analysis showed that patients with MuLBSTA score ≥ 12 had higher risk of ICU (log-rank, P = 0.001) and high risk of death (log-rank, P = 0.000). Conclusions: The MuLBSTA score is valuable for risk stratification and could effectively screen high-risk patients at admission. The higher score at admission have higher risk of ICU care and death in patients infected with COVID.", "BACKGROUND: Breast cancer associated (BRCA) genes are critical for DNA repair. Mutations in BRCA1 and BRCA2 (BRCAm) result in loss of these repair mechanisms and potential carcinogenesis. Germline BRCAm are common in ovarian carcinomas, particularly in platinum-sensitive disease. The increased prevalence of BRCAm in platinum-sensitive disease is likely due to enhanced responsiveness to platinum chemotherapy from homologous recombination repair deficiency. The purpose of this study was to explore BRCA testing, treatment patterns and survival in platinum-sensitive recurrent (PSR) ovarian cancer.METHODS: This was an observational cohort analysis of PSR ovarian cancer treated at the Huntsman Cancer Institute from 1995 to 2012. Germline BRCA status was ascertained through chart review and categorized as BRCAm (BRCA1/2 positive), BRCAwt (BRCA wild type or variant of uncertain significance), and untested. Treatment patterns and survival were assessed from recurrence until death or last follow-up. The Kaplan-Meier method was used to evaluate survival from recurrence by BRCA status. Logistic regression and COX proportional hazard model was used to estimate predictors of BRCA testing and survival, respectively.RESULTS: Of the 168 PSR patients, 15 (9 %) were BRCAm, 25 (15 %) were BRCAwt, and 128 (76 %) were untested. Median age at PSR was 56 years for BRCAm and BRCAwt (p = 0.90) and 63 years for those untested (p = 0.033 vs BRCAm). Overall survival was similar between BRCAm and BRCAwt (median 50.4 vs 67.5 months, p = 0.86) and was 24.9 months in untested patients. Significant predictors for the likelihood of BRCA testing were age (OR = 0.93, 95 % CI 0.89, 0.97, p = 0.002), family history of breast or ovarian cancer (OR = 8.33, 95 % CI: 3.08, 22.59, p < 0.001), and cancer diagnosis year (OR = 10.02, 95 % CI: 3.22, 31.21, p < 0.001). BRCA-tested patients had a lower risk of death versus untested (HR 0.35, 95 % CI 0.17, 0.68, p = 0.001).CONCLUSIONS: BRCAwt patients had similar outcomes to BRCAm patients, potentially owing to similar age at diagnosis, representing a BRCA testing channeling bias. Younger patients, those with a family history of breast or ovarian cancer, and those diagnosed more recently were more likely to be BRCA tested. BRCA tested patients had a lower risk of death.", "Chronic symptoms of abdominal pain and irregular bowel habits in women evoke a broad differential diagnosis including irritable bowel syndrome, infection, malabsorption, and inflammatory bowel disease. Endometriosis, a common disorder in young women that can involve the intestinal tract, deserves consideration as well. Intestinal endometriosis is typically asymptomatic; however, when symptoms occur, they can mimic those of irritable bowel syndrome. Identifying intestinal endometriosis can be challenging, but historical points and key clinical features aid in diagnosis.", "We report the identification of the first histone-like protein of Mycobacterium tuberculosis (MTB) (HLPMt). The T cell blot assay was used to identify antigens of MTB associated with human immune response in healthy contacts. Fraction 21 corresponding to proteins in the molecular weight range of approximately 30 kDa were found to be immunogenic in tuberculin reactors. None of the fractions were found to be immunogenic by this assay in non-reactors to tuberculin. All sera, irrespective of the source, showed reactivity with MTB antigen(s) over a wide molecular weight range (205-->16 kDa). In the present study fraction 21 was processed for the generation of murine polyclonal sera and amino acid sequencing. The sequence of a 16-amino acid long peptide showed a 100% homology with an open reading frame (ORF) in the translated sequence of cosmid cY349 (Sanger Centre, Cambridge, UK). The ORF was predicted to code for a protein of 214 amino acids. Oligonucleotide primers were synthesized based on the nucleotide sequence located at the 5' and 3' regions of the gene. The gene encoding the predicted protein was PCR-amplified, cloned, sequenced and expressed in Escherichia coli as a protein of 28 kDa. The expressed HLPMt protein was shown to react with the polyclonal murine sera originally raised against fraction 21. Human immune response to the recombinant HLPMt protein was demonstrated by its ability to induce lymphoproliferation in peripheral blood derived mononuclear cells, and the presence of anti-HLPMt antibodies in pooled patient sera by immunoblot. The recombinant HLPMt protein elicited a vigorous lymphoproliferative response especially in healthy tuberculin reactors compared to non-reactors and patients of tuberculosis, (P < 0.05). The protein has unique dual domains with homology to both bacterial histone-like proteins (HU) and eukaryotic histone H1. Homology to prokaryotic and eukaryotic deoxyribonucleic acid (DNA)-binding proteins suggested that HLPMt could bind DNA. DNA-binding properties were confirmed by South-Western analysis strongly suggesting an interaction between HLPMt and the MTB chromosome.", "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.", "Delafloxacin, an investigational anionic fluoroquinolone, is active against a broad range of Gram-positive and Gram-negative bacteria. In this study, 200 Streptococcus pneumoniae (plus 30 levofloxacin-resistant isolates), 200 Haemophilus influenzae, and 100 Moraxella catarrhalis isolates selected primarily from the United States (2014) were tested against delafloxacin and comparator agents. Delafloxacin was the most potent agent tested. MIC50 and MIC90 values against all S. pneumoniae isolates were 0.008 and 0.015 μg/ml. Delafloxacin susceptibility was not affected by β-lactamase status against H. influenzae and M. catarrhalis.", "Delafloxacin is a broad-spectrum anionic fluoroquinolone under development for the treatment of bacterial pneumonia. The goal of the study was to determine the pharmacokinetic/pharmacodynamic (PK/PD) targets in the murine lung infection model for Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae Four isolates of each species were utilized for in vivo studies: for S. aureus, one methicillin-susceptible and three methicillin-resistant isolates; S. pneumoniae, two penicillin-susceptible and two penicillin-resistant isolates; K. pneumoniae, one wild-type and three extended-spectrum beta-lactamase-producing isolates. MICs were determined using CLSI methods. A neutropenic murine lung infection model was utilized for all treatment studies, and drug dosing was by the subcutaneous route. Single-dose plasma pharmacokinetics was determined in the mouse model after administration of 2.5, 10, 40, and 160 mg/kg. For in vivo studies, 4-fold-increasing doses of delafloxacin (range, 0.03 to 160 mg/kg) were administered every 6 h (q6h) to infected mice. Treatment outcome was measured by determining organism burden in the lung (CFU counts) at the end of each experiment (24 h). The Hill equation for maximum effect (Emax) was used to model the dose-response data. The magnitude of the PK/PD index, the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC), associated with net stasis and 1-log kill endpoints was determined in the lung model for all isolates. MICs ranged from 0.004 to 1 mg/liter. Single-dose PK parameter ranges include the following: for maximum concentration of drug in serum (Cmax), 2 to 70.7 mg/liter; AUC from 0 h to infinity (AUC0-∞), 2.8 to 152 mg · h/liter; half-life (t1/2), 0.7 to 1 h. At the start of therapy mice had 6.3 ± 0.09 log10 CFU/lung. In control mice the organism burden increased 2.1 ± 0.44 log10 CFU/lung over the study period. There was a relatively steep dose-response relationship observed with escalating doses of delafloxacin. Maximal organism reductions ranged from 2 log10 to more than 4 log10 The median free-drug AUC/MIC magnitude associated with net stasis for each species group was 1.45, 0.56, and 40.3 for S. aureus, S. pneumoniae, and K. pneumoniae, respectively. AUC/MIC targets for the 1-log kill endpoint were 2- to 5-fold higher. Delafloxacin demonstrated in vitro and in vivo potency against a diverse group of pathogens, including those with phenotypic drug resistance to other classes. These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints for delafloxacin for the treatment of lower respiratory tract infections involving these pathogens." ]

[ "BACKGROUND: Etizolam is an anxiolytic drug with a pharmacologic profile similar to that of the classic benzodiazepines. Neurochemical research suggests that etizolam may have selectivity for the subpopulation of Y-aminobutyric acid type A receptors associated with anxiety (ie, alpha1, beta2, gamma2). This property, plus its characterization as a ligand with fewer of the adverse events typical of full agonists (impaired cognitive function, tolerance, and dependence), led to its selection for this study.OBJECTIVES: The primary aim of this study was to test for the noninferiority of etizolam 0.5 mg BID versus placebo in affecting cognitive function in patients with mild to moderate anxiety disorder of recent onset (<1 month). Anxiety measures and tolerability were also assessed.METHODS: Patients between the ages of 18 and 65 years were eligible for enrollment. This double-blind, placebo-controlled study was performed in 5 centers in Italy using a 2-treatment, 3-period crossover design. Patients were randomized to 3-week sequences of either etizolam-placebo-placebo or placebo-etizolam-etizolam. They were evaluated at 4 scheduled visits (screening and days 7, 14, and 21). Cognitive function was assessed using scores from the Wechsler Adult Intelligence Scale (WAIS) Digit Span test (total forward and backward scores and the time required to perform the test). Anxiety was measured using the Hamilton Anxiety Rating Scale (HAM-A) and the State-Trait Anxiety Inventory (STAI) for screening and to monitor adequacy of therapy. Blood pressure, heart rate, weight, and adverse events were also recorded.RESULTS: A total of 77 white patients were enrolled (mean age, 33.3 years [range, 22-60 years]; 62.3% female; mean weight, 65.2 kg). With a power of 0.80, the difference between the effects of etizolam and placebo on WAIS Digit Span performance was not significant for total score (0.102 [90% CI, -0.130 to 0.335]) or time required for completion (0.029 second [90% CI, -0.574 to 0.632]). Anxiety, as measured using the HAM-A and STAI instruments, did not differ significantly between groups. No significant differences were found between etizolam 0.5 mg BID and placebo for cardiovascular events, weight changes, or adverse events. Mild or moderate somnolence was reported by 7 of 77 patients (9.1% [3 patients while receiving etizolam and 4 patients while receiving etizolam and placebo]).CONCLUSIONS: No significant differences between etizolam 0.5 mg BID and placebo were found for cognitive function or anxiety measures in these patients with anxiety. Etizolam was well tolerated.", "Hypertrophic cardiomyopathy (HCM) is a disease that typically has heterogeneous hypertrophy and dysfunction of the myocardium. Cardiac magnetic resonance imaging (CMR) can be used to accurately assess ventricular wall thickness and regional fibrosis. We investigated the effects of hypertrophy and fibrosis on the heterogeneity of regional and global myocardial function in HCM. Forty patients who were diagnosed with HCM were consecutively enrolled. Echocardiography and CMR with delayed hyper-enhancement imaging (DHE) was performed for each patient. Left ventricular (LV) regional and global longitudinal strain (SL(R) and SL(G)) were obtained by two-dimensional speckle tracking method on echocardiography. With CMR, regional myocardial wall thickness was measured, and the amount of DHE was calculated semi-quantitatively in each segment. Overall, 720 segments were analyzed. SL(R) was significantly decreased in the hypertrophied segments (thickness > 11 mm) and segments with DHE (P < 0.001). SL(R) was correlated with myocardial wall thickness (r = 0.47, P = 0.001) and amount of regional DHE (r = 0.39, P < 0.001). On multivariate analysis, regional LV wall thickness and amount of DHE were the only independent determinants of SL(R). SL(G) was associated with LV diastolic functional parameters in echocardiography, total DHE volume, and LV mass index. Total DHE volume and LV mass index were independent determinants of SL(G) on multivariate analysis. The extent of regional myocardial fibrosis is associated with regional myocardial function independently of morphological changes of the myocardium, and the correlation extended to global LV function. In this context, DHE may be a useful parameter to discover early myocardial dysfunction independently of LV hypertrophy.", "The gene for the mismatch-specific uracil DNA glycosylase (MUG) was identified in the Escherichia coli genome as a sequence homolog of the human thymine DNA glycosylase with activity against mismatched uracil base pairs. Examination of cell extracts led us to detect a previously unknown xanthine DNA glycosylase (XDG) activity in E. coli. DNA glycosylase assays with purified enzymes indicated the novel XDG activity is attributable to MUG. Here, we report a biochemical characterization of xanthine DNA glycosylase activity in MUG. The wild type MUG possesses more robust activity against xanthine than uracil and is active against all xanthine-containing DNA (C/X, T/X, G/X, A/X and single-stranded X). Analysis of potentials of mean force indicates that the double-stranded xanthine base pairs have a relatively narrow energetic difference in base flipping, whereas the tendency for uracil base flipping follows the order of C/U > G/U > T/U > A/U. Site-directed mutagenesis performed on conserved motifs revealed that Asn-140 and Ser-23 are important determinants for XDG activity in E. coli MUG. Molecular modeling and molecular dynamics simulations reveal distinct hydrogen-bonding patterns in the active site of E. coli MUG that account for the specificity differences between E. coli MUG and human thymine DNA glycosylase as well as that between the wild type MUG and the Asn-140 and Ser-23 mutants. This study underscores the role of the favorable binding interactions in modulating the specificity of DNA glycosylases.", "Voltage-gated, dihydropyridine-sensitive L-type Ca(2+) channels are multimeric proteins composed of a pore-forming transmembrane α(1) subunit (Ca(v)1.2) and accessory β, α(2)δ, and γ subunits. Ca(2+) entry via Ca(v)1.2 channels shapes the action potential (AP) of cardiac myocytes and is required for excitation-contraction coupling. Two de novo point mutations of Ca(v)1.2 glycine residues, G406R and G402S, cause a rare multisystem disorder called Timothy syndrome (TS). Here, we discuss recent work on the mechanisms by which Ca(v)1.2 channels bearing TS mutations display slowed inactivation that leads to increased Ca(2+) influx, prolonging the cardiac AP and promoting lethal arrhythmias. Based on these studies, we propose a model in which the scaffolding protein AKAP79/150 stabilizes the open conformation of Ca(v)1.2-TS channels and facilitates physical interactions among adjacent channels via their C-tails, increasing the activity of adjoining channels and amplifying Ca(2+) influx.", "BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1) causes the debilitating neuroinflammatory disease HTLV-1-associated myelopathy-tropical spastic paraparesis (HAM-TSP) as well as adult T-cell leukemia-lymphoma (ATLL). In patients with HAM-TSP, HTLV-1 infects mainly CCR4+ T cells and induces functional changes, ultimately causing chronic spinal cord inflammation. We evaluated mogamulizumab, a humanized anti-CCR4 monoclonal antibody that targets infected cells, in patients with HAM-TSP.METHODS: In this uncontrolled, phase 1-2a study, we assessed the safety, pharmacokinetics, and efficacy of mogamulizumab in patients with glucocorticoid-refractory HAM-TSP. In the phase 1 dose-escalation study, 21 patients received a single infusion of mogamulizumab (at doses of 0.003 mg per kilogram of body weight, 0.01 mg per kilogram, 0.03 mg per kilogram, 0.1 mg per kilogram, or 0.3 mg per kilogram) and were observed for 85 days. Of those patients, 19 continued on to the phase 2a study and received infusions, over a period of 24 weeks, of 0.003 mg per kilogram, 0.01 mg per kilogram, or 0.03 mg per kilogram at 8-week intervals or infusions of 0.1 mg per kilogram or 0.3 mg per kilogram at 12-week intervals.RESULTS: The side effects of mogamulizumab did not limit administration up to the maximum dose (0.3 mg per kilogram). The most frequent side effects were grade 1 or 2 rash (in 48% of the patients) and lymphopenia and leukopenia (each in 33%). The dose-dependent reduction in the proviral load in peripheral-blood mononuclear cells (decrease by day 15 of 64.9%; 95% confidence interval [CI], 51.7 to 78.1) and inflammatory markers in cerebrospinal fluid (decrease by day 29 of 37.3% [95% CI, 24.8 to 49.8] in the CXCL10 level and of 21.0% [95% CI, 10.7 to 31.4] in the neopterin level) was maintained with additional infusions throughout the phase 2a study. A reduction in spasticity was noted in 79% of the patients and a decrease in motor disability in 32%.CONCLUSIONS: Mogamulizumab decreased the number of HTLV-1-infected cells and the levels of inflammatory markers. Rash was the chief side effect. The effect of mogamulizumab on clinical HAM-TSP needs to be clarified in future studies. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare; UMIN trial number, UMIN000012655 .).", "MOTIVATION: Circular RNAs (circRNAs) are a poorly characterized class of molecules that have been identified decades ago. Emerging high-throughput sequencing methods as well as first reports on confirmed functions have sparked new interest in this RNA species. However, the computational detection and quantification tools are still limited.RESULTS: We developed the software tandem, DCC and CircTest DCC uses output from the STAR read mapper to systematically detect back-splice junctions in next-generation sequencing data. DCC applies a series of filters and integrates data across replicate sets to arrive at a precise list of circRNA candidates. We assessed the detection performance of DCC on a newly generated mouse brain data set and publicly available sequencing data. Our software achieves a much higher precision than state-of-the-art competitors at similar sensitivity levels. Moreover, DCC estimates circRNA versus host gene expression from counting junction and non-junction reads. These read counts are finally used to test for host gene-independence of circRNA expression across different experimental conditions by our R package CircTest We demonstrate the benefits of this approach on previously reported age-dependent circRNAs in the fruit fly.AVAILABILITY AND IMPLEMENTATION: The source code of DCC and CircTest is licensed under the GNU General Public Licence (GPL) version 3 and available from https://github.com/dieterich-lab/[DCC or CircTest].CONTACT: christoph.dieterich@age.mpg.deSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by cytochrome (CYP) P450 epoxygenases, and to ω-terminal hydroxyeicosatetraenoic acids (HETEs) by ω-hydroxylases. EETs and HETEs often have opposite biologic effects; EETs are vasodilatory and protect against ischemia/reperfusion injury, while ω-terminal HETEs are vasoconstrictive and cause vascular dysfunction. Other oxylipins, such as epoxyoctadecaenoic acids (EpOMEs), hydroxyoctadecadienoic acids (HODEs), and prostanoids also have varied vascular effects. Post-ischemic vasodilation in the heart, known as coronary reactive hyperemia (CRH), protects against potential damage to the heart muscle caused by ischemia. The relationship among CRH response to ischemia, in mice with altered levels of CYP2J epoxygenases has not yet been investigated. Therefore, we evaluated the effect of endothelial overexpression of the human cytochrome P450 epoxygenase CYP2J2 in mice (Tie2-CYP2J2 Tr) on oxylipin profiles and CRH. Additionally, we evaluated the effect of pharmacologic inhibition of CYP-epoxygenases and inhibition of ω-hydroxylases on CRH. We hypothesized that CRH would be enhanced in isolated mouse hearts with vascular endothelial overexpression of human CYP2J2 through modulation of oxylipin profiles. Similarly, we expected that inhibition of CYP-epoxygenases would reduce CRH, whereas inhibition of ω-hydroxylases would enhance CRH. Compared to WT mice, Tie2-CYP2J2 Tr mice had enhanced CRH, including repayment volume, repayment duration, and repayment/debt ratio (P < 0.05). Similarly, inhibition of ω-hydroxylases increased repayment volume and repayment duration, in Tie2-CYP2J2 Tr compared to WT mice (P < 0.05). Endothelial overexpression of CYP2J2 significantly changed oxylipin profiles, including increased EETs (P < 0.05), increased EpOMEs (P < 0.05), and decreased 8-iso-PGF2α (P < 0.05). Inhibition of CYP epoxygenases with MS-PPOH attenuated CRH (P < 0.05). Ischemia caused a decrease in mid-chain HETEs (5-, 11-, 12-, 15-HETEs P < 0.05) and HODEs (P < 0.05). These data demonstrate that vascular endothelial overexpression of CYP2J2, through changing the oxylipin profiles, enhances CRH. Inhibition of CYP epoxygenases decreases CRH, whereas inhibition of ω-hydroxylases enhances CRH." ]

[ "Hemophilic pseudotumor gradually erodes bone and induces fracture or deformity, causing joint dysfunction or destructive osteoarthropathy. Reports about surgery for hemophilic pseudotumor complicated by destructive osteoarthropathy are scarce. The object of this study was to evaluate the results and complications of surgical management for patients of pseudotumor complicated by destructive osteoarthropathy. We retrospectively reviewed records from July 1996 to July 2013, and found eight patients with pseudotumor complicated by destructive osteoarthropathy. We recorded their demographic data, time of surgery, amount of blood loss and transfusion, bone union, and complications. Seven patients were diagnosed with hemophilia A and one with hemophilia B. The mean age at surgery was 31.9 ± 8.3 years. Two of the eight underwent excision of the pseudotumor and metallic fixation, one had amputation, and five underwent autogenous or exogenous bone grafting and fixation with an absorbable screw. The median operating time was 170 min (135-315 min). The median amount of intraoperative blood loss was 1350 ml (100-4000 ml). The amount of red blood cells, plasma, and whole blood transfusion after surgery were 0-24 units, 0-2000 ml, and 0-4600 ml, respectively. After a median follow-up of 75 months, the numbers of pseudotumor recurrence, fracture nonunion, coagulation factor inhibitor formation, and wound complications were one, one, two, and four, respectively. Surgery is an effective treatment for hemophilic pseudotumor complicated by destructive osteoarthropathy. However, the incidences of wound infection, coagulation factor inhibitor formation, hemophilic pseudotumor recurrence, and fracture nonunion are high.", "Guillain-Barre Syndrome is a well described acute demyelinating polyradiculoneuropathy with a likely autoimmune basis characterized by progressive ascending muscle paralysis. Classically, GBS is attributed to antecedent upper respiratory and gastrointestinal infections. We present the first case of GBS after Robotically Assisted Laparoscopic Prostatectomy using the daVinci(®) Surgical System.", "MOTIVATION: Conserved non-coding elements (CNEs) represent an enigmatic class of genomic elements which, despite being extremely conserved across evolution, do not encode for proteins. Their functions are still largely unknown. Thus, there exists a need to systematically investigate their roles in genomes. Towards this direction, identifying sets of CNEs in a wide range of organisms is an important first step. Currently, there are no tools published in the literature for systematically identifying CNEs in genomes.RESULTS: We fill this gap by presenting CNEFinder; a tool for identifying CNEs between two given DNA sequences with user-defined criteria. The results presented here show the tool's ability of identifying CNEs accurately and efficiently. CNEFinder is based on a k-mer technique for computing maximal exact matches. The tool thus does not require or compute whole-genome alignments or indexes, such as the suffix array or the Burrows Wheeler Transform (BWT), which makes it flexible to use on a wide scale.AVAILABILITY AND IMPLEMENTATION: Free software under the terms of the GNU GPL (https://github.com/lorrainea/CNEFinder).", "Etizolam is a novel psychoactive substance and novel benzodiazepine of the thienotriazolodiazepine class, which has recently seen an increasing trend in use worldwide. We report a case series of 10 decedents with etizolam and opioids in their systems. Death investigation, expanded toxicology and medical investigation information were included for contextualization of etizolam in death. Etizolam was detected and confirmed within peripheral and cardiac blood, urine, vitreous humor and, in one case, gastric fluid, by liquid chromatography-tandem mass spectrometry and liquid chromatography-quadrupole time of flight mass spectrometry methodologies. Death investigation indicated nonmedical use of most drugs. Medical investigation commonly noted pulmonary edema, cardiomegaly and cerebral swelling. The majority of the decedents appeared to be unaware of the presence of etizolam and succumbed to the mixed drug toxicity of their routine depressant and narcotic analgesic drug of abuse in combination with etizolam. Etizolam use continues to be observed and poses as a potentially lethal contribution to multiple drug toxicity, especially in the age of the opioid crisis. Assessment of analytes like etizolam requires up-to-date methodologies and vigilance in testing to better characterize the toxicology and interpret the contribution to death.", "OBJECTIVE: The primary objective of this study was to evaluate the safety and tolerability of the investigational drug vortioxetine (Lu AA21004) in the long-term treatment of patients with major depressive disorder.METHODS: Patients entered this 52-week, open-label extension study after completing an 8-week lead-in study. Safety and tolerability were evaluated at regular intervals on the basis of spontaneously reported adverse events (AEs), clinical safety laboratory tests, vital signs, ECG and physical examination. Effectiveness of treatment was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) total score.RESULTS: A total of 535 patients were treated and 61.3% (n = 328) completed the study, resulting in 393 patient years of exposure to vortioxetine. AEs reported by ≥10% of patients were nausea, headache, and nasopharyngitis. Taken together, six patients had eight AEs related to sexual dysfunction. There were no clinically significant safety findings with respect to mean changes of vital signs, weight, ECG parameters, or clinical laboratory values. Patients entered the extension study with a mean MADRS total score of 13.5 ± 8.7. The mean MADRS total score decreased (improved) by approximately 8 points to 5.5 ± 6.0 at Week 52 (OC). By the end of the study, the proportion of responders had increased from 63% to 94% (OC), as had the proportion in remission (MADRS ≤10), increasing from 42% to 83% (OC). Patients in remission (n = 226) at the start of this study had a relapse rate (MADRS ≥22) of 9.7%.CONCLUSIONS: As with all open-label studies, the conclusions that can be drawn are limited by the lack of a placebo control, making it difficult to assess causality of any changes in outcome measures. However, on the basis of these findings, vortioxetine (2.5, 5, 10 mg/day) demonstrated a favourable safety and tolerability profile and maintained effectiveness over 12 months of treatment.TRIAL REGISTRATION: This study has the ClinicalTrials.gov identifier: NCT00694304.", "Magnetic resonance imaging (MRI) has been shown to be a good method of visualizing the lesions in MS. We have studied several applications of MRI to the evaluation of patients and experimental models. In diagnosis, MRI is the most sensitive test for the demonstration of dissemination of lesions in space. Pathological correlation studies show that MRI reliably measures the extent of chronic demyelination. Experimental studies show that MRI detects acute inflammatory lesions and measures their evolution. MRI also is a reliable measure of the extent of the MS process, serial MRI scans detect evidence of disease activity in MS not always disclosed by clinical evaluation. MRI will have an enormous future impact on the evaluation of patients in clinical studies and in understanding the evolution of pathological processes.", "Ferroportin disease, autosomal-dominant reticuloendothelial iron overload, may be more prevalent than hemochromatosis in Japan. Hyperferritinemia of 822 ng/ml with 24.8% transferrin saturation of iron was incidentally noted in a 43-year-old man. His iron overload was selective in Kupffer cells of the liver. Subsequently, his father was found to have asymptomatic hyperferritinemia of 2,283 ng/ml with 62.1% saturation. These affected subjects were heterozygous for 1467A>C (R489S) in SLC40A1, and without other mutations of the hemochromatosis genes. Here, we report a Japanese family with ferroportin disease, characterized by hyperferritinemia with relatively low transferrin saturations of iron." ]

[ "Protein phosphatase inhibitor-1 was purified from bovine adipose tissue. The protein had an apparent molecular mass of 32 kDa by SDS/PAGE and a Stokes' radius of 3.4 nm. It was phosphorylated by cAMP-dependent protein kinase on a threonyl residue; this phosphorylation was necessary for inhibition of protein phosphatase-1. Bovine adipose tissue inhibitor-1 was compared directly with rabbit skeletal muscle inhibitor-1 and with a 32000-Mr, dopamine- and cAMP-regulated phosphoprotein from bovine brain (DARPP-32), also an inhibitor of protein phosphatase-1. By the following biochemical and immunochemical criteria, bovine adipose tissue inhibitor-1 was found to be very similar and possibly identical to DARPP-32 and was clearly distinct from skeletal muscle inhibitor-1: molecular mass by SDS/PAGE; Stokes' radii; phosphorylation on threonine residues; Staphylococcus-aureus-V8-protease-generated peptide patterns analyzed by SDS/PAGE; tryptic phosphopeptide maps analysed by two-dimensional thin-layer electrophoresis/chromatography; elution on reverse-phase HPLC; chymotryptic peptide maps as analysed by reverse-phase HPLC; amino acid composition; antibody recognition by immunoprecipitation and immunoblotting; effect of cyanogen bromide cleavage on protein phosphatase inhibitor activity. Based on these results we conclude that bovine brain and adipose tissue contain an identical phosphoprotein inhibitor of protein phosphatase-1 (DARPP-32), which is distinct from that of skeletal muscle (inhibitor-1).", "The FDA approved ivosidenib for patients with IDH1-mutant relapsed/refractory acute myeloid leukemia. The approval was based on results of a phase I trial in which 32.8% of patients treated with the drug had a complete remission or a complete remission with a partial hematologic recovery.", "BACKGROUND: Optic nerve hypoplasia (ONH) has been described as an increasingly prevalent cause of congenital blindness. Its association with hypopituitarism and absent septum pellucidum has been recognized for more than 40 years as \"septo-optic dysplasia\" or \"de Morsier syndrome.\" More recent studies have suggested that these associations are independent of one another. This review was designed to assess the historical and recent evidence for associations of neuroradiologic, endocrinologic, and developmental problems in patients with ONH.EVIDENCE ACQUISITION: Historical and contemporary literature review.RESULTS: The medical literature does not support the notion that Georges de Morsier ever described a case of ONH or recognized its association with hypopituitarism or missing septum pellucidum. Recognition of the critical association of ONH with hypopituitarism should be attributed to William Hoyt. Hypopituitarism and other more recently identified associations with ONH, such as developmental delay, hypothalamic dysfunction, and autism, are independent of septum pellucidum development. Other common neuroradiographic associations, such as corpus callosum hypoplasia, gyrus dysplasia, and cortical heterotopia, may have prognostic significance.CONCLUSIONS: Children with ONH need to be monitored for many systemic, developmental, and even life-threatening problems independent of the status of the septum pellucidum. \"Septo-optic dysplasia\" and \"de Morsier syndrome\" are historically inaccurate and clinically misleading terms that should be abandoned.", "A variety of alkylated base adducts are repaired by 3-methyladenine DNA glycosylases, one of the base excision repair enzymes. In this study, we examined the DNA adducts induced by hepsulfam and determined whether alkylated base adducts can be substrates for bacterial and mammalian 3-methyladenine DNA glycosylases by electrophoresis methods. Hepsulfam, a synthetic analogue of busulfan, is known to alkylate DNA and form interstrand cross-links. The extent of DNA interstrand cross-links induced by hepsulfam and busulfan was found to be similar but significantly lower than that induced by chlorambucil, as measured by an agarose gel assay. The major monofunctional alkylation site of hepsulfam was observed at the N7 position of guanine, and not at the N3 position of adenine. Both compounds did not exhibit any sequence selective DNA alkylation patterns. The excision of hepsulfam-induced DNA adducts has been determined by treatment with homogeneous recombinant bacterial, rat and human 3-methyladenine DNA glycosylases and successive treatments by formamidopyrimidine-DNA glycosylase. The Escherichia coli alkA protein was shown to completely excise N7 guanine adducts, whereas mammalian 3-methyladenine DNA glycosylase failed to excise them. In addition, the cytotoxicity assay showed that E. coli mutant strains defective in the alkA gene or the uvrA gene were more sensitive to killing by hepsulfam than the wild type.", "HIV-1 Vpr-binding protein (VprBP) has been implicated in the regulation of both DNA replication and cell cycle progression, but its precise role remains unclear. Here we report that VprBP regulates the p53-induced transcription and apoptotic pathway. VprBP is recruited to p53-responsive promoters and suppresses p53 transactivation in the absence of stress stimuli. To maintain target promoters in an inactive state, VprBP stably binds to nucleosomes by recognizing unacetylated H3 tails. Promoter-localized deacetylation of H3 tails is a prerequisite for VprBP to tether and act as a bona fide inhibitor at p53 target genes. VprBP knockdown leads to activation of p53 target genes and causes an increase in DNA damage-induced apoptosis. Moreover, phosphorylation of VprBP at serine 895 impairs the ability of VprBP to bind H3 tails and to repress p53 transactivation. Our results thus reveal a new role for VprBP in regulation of the p53 signaling pathway, as well as molecular mechanisms of cancer development related to VprBP misregulation.", "MOTIVATION: Alternative splicing (AS) is a pre-mRNA maturation process leading to the expression of multiple mRNA variants from the same primary transcript. More than 90% of human genes are expressed via AS. Therefore, quantifying the inclusion level of every exon is crucial for generating accurate transcriptomic maps and studying the regulation of AS.RESULTS: Here we introduce SpliceTrap, a method to quantify exon inclusion levels using paired-end RNA-seq data. Unlike other tools, which focus on full-length transcript isoforms, SpliceTrap approaches the expression-level estimation of each exon as an independent Bayesian inference problem. In addition, SpliceTrap can identify major classes of alternative splicing events under a single cellular condition, without requiring a background set of reads to estimate relative splicing changes. We tested SpliceTrap both by simulation and real data analysis, and compared it to state-of-the-art tools for transcript quantification. SpliceTrap demonstrated improved accuracy, robustness and reliability in quantifying exon-inclusion ratios.CONCLUSIONS: SpliceTrap is a useful tool to study alternative splicing regulation, especially for accurate quantification of local exon-inclusion ratios from RNA-seq data.AVAILABILITY AND IMPLEMENTATION: SpliceTrap can be implemented online through the CSH Galaxy server http://cancan.cshl.edu/splicetrap and is also available for download and installation at http://rulai.cshl.edu/splicetrap/.CONTACT: michael.zhang@utdallas.edu.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "Ziconotide has been introduced as a new nonopioid treatment for chronic pain. Structurally, it is a peptide, the synthetic analog of the omega-conotoxin, derived from the marine snail, Conus magus. N-type voltage-sensitive calcium channels play a role in the transmission of nociceptive stimuli and also are involved in the release of neurotransmitters important in pain transmission. Ziconotide's therapeutic benefit derives from its potent and selective blockade of neuronal-type voltage-sensitive calcium channels. Blockade of the channels results in suppression of abnormal ectopic discharges from the injury site or the dorsal root ganglia, possibly resulting in decreased neuroplasticity, and decreased synaptic transmission that leads to the generation of chronic pain syndromes. The advantage of ziconotide is that tolerance does not occur, while disadvantages associated with ziconotide are the need for intrathecal administration and significant neurotoxicites associated with its use. When tested in clinical trials, ziconotide has been shown to have synergistic or additive value to the effect of morphine. Ziconotide, formerly known also as SNX- 111, represents a new class of agents, the N-type calcium channel blockers. These may represent another option for patients with refractory pain and refractory pain syndromes." ]

[ "FACT complex is involved in elongation and ensures fidelity in the initiation step of transcription by RNA polymerase (pol) II. Histone variant H2A.Z is found in nucleosomes at the 5'-end of many genes. We report here H2A.Z-chaperone activity of the yeast FACT complex on the short, nucleosome-free, non-coding, pol III-transcribed yeast tRNA genes. On a prototype gene, yeast SUP4, chromatin remodeler RSC and FACT regulate its transcription through novel mechanisms, wherein the two gene-flanking nucleosomes containing H2A.Z, play different roles. Nhp6, which ensures transcription fidelity and helps load yFACT onto the gene flanking nucleosomes, has inhibitory role. RSC maintains a nucleosome abutting the gene terminator downstream, which results in reduced transcription rate in active state while H2A.Z probably helps RSC in keeping the gene nucleosome-free and serves as stress-sensor. All these factors maintain an epigenetic state which allows the gene to return quickly from repressed to active state and tones down the expression from the active SUP4 gene, required probably to maintain the balance in cellular tRNA pool.", "Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors of the adrenal glands and the sympathetic and parasympathetic paraganglia. They can occur sporadically or as a part of different hereditary tumor syndromes. About 30% of PCCs and PGLs are currently believed to be caused by germline mutations and several novel susceptibility genes have recently been discovered. The clinical presentation, including localization, malignant potential, and age of onset, varies depending on the genetic background of the tumors. By reviewing more than 1700 reported cases of hereditary PCC and PGL, a thorough summary of the genetics and clinical features of these tumors is given, both as part of the classical syndromes such as multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau disease, neurofibromatosis type 1, and succinate dehydrogenase-related PCC-PGL and within syndromes associated with a smaller fraction of PCCs/PGLs, such as Carney triad, Carney-Stratakis syndrome, and MEN1. The review also covers the most recently discovered susceptibility genes including KIF1Bβ, EGLN1/PHD2, SDHAF2, TMEM127, SDHA, and MAX, as well as a comparison with the sporadic form. Further, the latest advances in elucidating the cellular pathways involved in PCC and PGL development are discussed in detail. Finally, an algorithm for genetic testing in patients with PCC and PGL is proposed.", "BACKGROUND: There is often a poor correlation observed between protein and RNA in eukaryotic systems, supporting the emerging pardigm that many of the abnormalities in a cancer cell's proteome may be achieved by differential recruitment of mRNAs to polysomes referred to as the translational profile. The MCT-1 oncogene product has recently been shown to interact with the cap complex and to modulate the translational profile of cell lines when MCT-1 was highly expressed. The MCT-1 protein modifies mRNA translational profiles through its interaction with DENR/DRP, a protein containing an SUI1 domain involved in recognition of the translation initiation codon. It has been shown previously that the protein levels of DENR/DRP go up in parallel with increasing cell density, however the mechanism(s) underlying this increase is poorly understood at present. The 3'-untranslated region (3'UTR) of DENR/DRP was found to have a high number of uracyl (U)- and adenine (A)-rich sequences (AREs). Many RNA-binding proteins (RBPs) have been shown to recognize and bind to mRNAs that contains AREs generally present in the 3'UTR of mRNAs. RBPs binding to AREs such as AUF1, BRF1, KSRP, and TTP are known to regulate mRNA turnover, while TIAR and TIA-1 influence mRNA translation.MATERIALS AND METHODS: We assessed the association of several ARE binding proteins with DENR/DRP mRNA by reverse transcription of the RNA obtained after immunoprecipitation of cell lysates from HEK 293 cells growing at varying levels of cell density. HEK 293 cells were transfected with an AUF1 silencing vector (shRNA), and protein levels of DENR/DRP were analyzed by Western blotting.RESULTS: We demonstrated that both HuR and AUF1 bind to discrete regions of DENR/DRP mRNA and that AUF1 silencing increases DENR/DRP protein levels.CONCLUSION: Our data established a cell density-dependent interaction of AUF1 protein with DENR/DRP mRNA that modulates DENR/DRP protein levels.", "Cariprazine (RGH-188, trans-4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexyl-amine hydrochloride), is a novel antipsychotic with dopamine D2 and D3 receptors antagonist-partial agonist properties. Cariprazine has also moderate affinity for serotonin 5-hydroxytryptophan (5-HT) 1A receptors, high affinity for 5-HT1B receptors with pure antagonism and low affinity for 5-HT2A receptors. Randomized, double blind, placebo controlled, flexible-dose (3-12 mg/day) studies have demonstrated cariprazine is effective in both schizophrenia and acute manic episodes associated with bipolar disorder. The incidence of serious adverse events in cariprazine arm was no different than in placebo arm in these studies. The most common adverse events were extrapyramidal symptoms, headache, akathisia, constipation, nausea, and dyspepsia which can be explained with cariprazine's partial dopamine agonism. Although cariprazine treatment was associated with a higher incidence of treatment-emergent adverse events, particularly akathisia and tremor, common side effects of marketed second generation antipsychotics such as weight gain, metabolic disturbances, prolactin increase or QTc prolongation were not associated with cariprazine, probably due to its moderate to low binding affinity for histamine H1 and 5-HT2C receptors. Animal studies show that cariprazine may have additional therapeutic benefit on impaired cognitive functioning with D3 receptor activity, however clinical data is still scarce. The aim of this article is to review the potential use of cariprazine for the treatment of acute manic episodes in the light of the preclinical and clinical trials reported to date.", "Biomedical research has been previously reported to primarily focus on a minority of all known genes. Here, we demonstrate that these differences in attention can be explained, to a large extent, exclusively from a small set of identifiable chemical, physical, and biological properties of genes. Together with knowledge about homologous genes from model organisms, these features allow us to accurately predict the number of publications on individual human genes, the year of their first report, the levels of funding awarded by the National Institutes of Health (NIH), and the development of drugs against disease-associated genes. By explicitly identifying the reasons for gene-specific bias and performing a meta-analysis of existing computational and experimental knowledge bases, we describe gene-specific strategies for the identification of important but hitherto ignored genes that can open novel directions for future investigation.", "Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies and is known for its high resistance and low response to treatment. Tumor immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Karyopherin alpha 2 (KPNA2), a member of the nuclear transporter family, is elevated in multiple human cancers and accelerates carcinogenesis. However, the specific role of KPNA2 in PDAC remains unclear. In this study, we found that expression of KPNA2 was significantly upregulated in PDAC compared to adjacent nontumor tissue and its high expression was correlated with poor survival outcome by analyzing the GEO datasets. Similar KPNA2 expression pattern was also found in both human patient samples and KPC mouse models through IHC staining. Although KPNA2 knockdown failed to impair the vitality and migration ability of PDAC cells in vitro, the in vivo tumor growth was significantly impeded and the expression of immune checkpoint ligand PD-L1 was reduced by silencing KPNA2. Furthermore, we uncovered that KPNA2 modulated the expression of PD-L1 by mediating nuclear translocation of STAT3. Collectively, our data suggested that KPNA2 has the potential to serve as a promising biomarker for diagnosis in PDAC.", "Nephropathic cystinosis is a rare lysosomal storage disorder caused by mutations in the CTNS gene ncoding the lysosomal cystine transporter cystinosin. Cystinosin deficiency leads to accumulation of cystine in the lysosomes of cells throughout the body and deregulation of endocytosis, trafficking of intracellular vesicles and related cell signalling processes. One of the early features of the disease is renal Fanconi syndrome characterized by polyuria, proteinuria and urinary loss of various solutes. Later in life, extrarenal complications become apparent, and decline of kidney function leads to the development of end-stage renal disease. Modern therapy of the disease is based on treatment with cystine-lowering drug cysteamine, which helps to postpone the disease progression and development of extra-renal pathologies, but offers no cure for the Fanconi syndrome. Besides the improvement of cystine-lowering therapy based on new formulations of cysteamine, further development of therapy is necessary. Some steps forward were done in the recent years, including studies of cell signalling abnormalities in cystinosis and development of stem cell and gene therapy approaches." ]

[ "Arterial foam cells are central players of atherogenesis. Cholesterol acceptors, apolipoprotein A-I (apoA-I) and high-density lipoprotein (HDL), take up cholesterol and phospholipids effluxed from foam cells into the circulation. Due to the high abundance of cholesterol in foam cells, most previous studies focused on apoA-I/HDL-mediated free cholesterol (FC) transport. However, recent lipidomics of human atherosclerotic plaques also identified that oxidized sterols (oxysterols) and non-sterol lipid species accumulate as atherogenesis progresses. While it is known that these lipids regulate expression of pro-inflammatory genes linked to plaque instability, how cholesterol acceptors impact the foam cell lipidome, particularly oxysterols and non-sterol lipids, remains unexplored. Using lipidomics analyses, we found cholesterol acceptors remodel foam cell lipidomes. Lipid subclass analyses revealed various oxysterols, sphingomyelins, and ceramides, species uniquely enriched in human plaques were significantly reduced by cholesterol acceptors, especially by apoA-I. These results indicate that the function of lipid-poor apoA-I is not limited to the efflux of cholesterol and phospholipids but suggest that apoA-I serves as a major regulator of the foam cell lipidome and might play an important role in reducing multiple lipid species involved in the pathogenesis of atherosclerosis.", "Head and neck cancers (HNCs) include a series of malignant tumors arising in epithelial tissues, typically oral cancer, laryngeal cancer, nasopharynx cancer and thyroid cancer. HNCs are important contributors to cancer incidence and mortality, leading to approximately 225,100 new patients and 77,500 deaths in China every year. Determination of the mechanisms of HNC carcinogenesis and progression is an urgent priority in HNC treatment. Long noncoding RNAs (lncRNAs) are noncoding RNAs longer than 200 bps. lncRNAs have been reported to participate in a broad scope of biological processes, and lncRNA dysregulation leads to diverse human diseases, including cancer. In this review, we focus on lncRNAs that are dysregulated in HNCs, summarize the latest findings regarding the function and molecular mechanisms of lncRNAs in HNC carcinogenesis and progression, and discuss the clinical application of lncRNAs in HNC diagnosis, prognosis and therapy.", "BACKGROUND AND PURPOSE: Preclinical and retrospective clinical data indicate that glyburide, a selective inhibitor of sulfonylurea receptor 1-transient receptor potential melastatin 4, is effective in preventing edema and improving outcome after focal ischemia. We assessed the feasibility of recruiting and treating patients with severe stroke while obtaining preliminary information on the safety and tolerability of RP-1127 (glyburide for injection).METHODS: We studied 10 patients with acute ischemic stroke, with baseline diffusion-weighted imaging lesion volumes of 82 to 210 cm3, whether treated with intravenous recombinant tissue-type plasminogen activator, age 18 to 80 years, and time to RP-1127≤10 hours.RESULTS: Recruitment was completed within 10 months. The mean age was 50.5 years, and baseline diffusion-weighted image lesion volume was 102±23 cm3. There were no serious adverse events related to drug and no symptomatic hypoglycemia. The increase in ipsilateral hemisphere volume was 50±33 cm3. The proportion of 90-day modified Rankin Scale≤4 was 90% (40% modified Rankin Scale, ≤3).CONCLUSIONS: RP-1127 at a dose of 3 mg/d was well tolerated and did not require any dose reductions. A clinical trial of RP-1127 is feasible.CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01268683.", "MOTIVATION: DNA methylation is important for gene silencing and imprinting in both plants and animals. Recent advances in bisulfite sequencing allow detection of single nucleotide variations (SNVs) achieving high sensitivity, but accurately identifying heterozygous SNVs from partially C-to-T converted sequences remains challenging.RESULTS: We designed two methods, BayesWC and BinomWC, that substantially improved the precision of heterozygous SNV calls from ∼80% to 99% while retaining comparable recalls. With these SNV calls, we provided functions for allele-specific DNA methylation (ASM) analysis and visualizing the methylation status on reads. Applying ASM analysis to a previous dataset, we found that an average of 1.5% of investigated regions showed allelic methylation, which were significantly enriched in transposon elements and likely to be shared by the same cell-type. A dynamic fragment strategy was utilized for DMR analysis in low-coverage data and was able to find differentially methylated regions (DMRs) related to key genes involved in tumorigenesis using a public cancer dataset. Finally, we integrated 40 applications into the software package CGmapTools to analyze DNA methylomes. This package uses CGmap as the format interface, and designs binary formats to reduce the file size and support fast data retrieval, and can be applied for context-wise, gene-wise, bin-wise, region-wise and sample-wise analyses and visualizations.AVAILABILITY AND IMPLEMENTATION: The CGmapTools software is freely available at https://cgmaptools.github.io/.CONTACT: guoweilong@cau.edu.cn.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "Simultaneous detection of small copy number variations (CNVs) (<0.5 kb) and single-nucleotide variants in clinically significant genes is of great interest for clinical laboratories. The analytical variability in next-generation sequencing (NGS) and artifacts in coverage data because of issues with mappability along with lack of robust bioinformatics tools for CNV detection have limited the utility of targeted NGS data to identify CNVs. We describe the development and implementation of a bioinformatics algorithm, copy number variation-random forest (CNV-RF), that incorporates a machine learning component to identify CNVs from targeted NGS data. Using CNV-RF, we identified 12 of 13 deletions in samples with known CNVs, two cases with duplications, and identified novel deletions in 22 additional cases. Furthermore, no CNVs were identified among 60 genes in 14 cases with normal copy number and no CNVs were identified in another 104 patients with clinical suspicion of CNVs. All positive deletions and duplications were confirmed using a quantitative PCR method. CNV-RF also detected heterozygous deletions and duplications with a specificity of 50% across 4813 genes. The ability of CNV-RF to detect clinically relevant CNVs with a high degree of sensitivity along with confirmation using a low-cost quantitative PCR method provides a framework for providing comprehensive NGS-based CNV/single-nucleotide variant detection in a clinical molecular diagnostics laboratory.", "Monoamine Oxidase A (MAOA) is a critical enzyme in the catabolism of monoaminergic neurotransmitters. MAOA transcriptional activity is thought to be regulated by a well characterized 30 base pair (bp) variable nucleotide repeat (VNTR) that lies approximately ∼1000 bp upstream of the transcriptional start site (TSS). However, clinical associations between this VNTR genotype and behavioral states have been inconsistent. Herein, we describe a second, 10 bp VNTR that lies ∼1500 bp upstream of the TSS. We provide in vitro and in silico evidence that this new VNTR region may be more influential in regulating MAOA transcription than the more proximal VNTR and that methylation of this CpG-rich VNTR is genotype dependent in females. Finally, we demonstrate that genotype at this new VNTR interacts significantly with history of child abuse to predict antisocial personality disorder (ASPD) in women and accounts for variance in addition to that explained by the prior VNTR.", "BACKGROUND: Herpes Simplex virus types 1 and 2 are enveloped viruses with a linear dsDNA genome of approximately 120-200 kb. Genital infection with HSV-2 has been denoted as a major risk factor for acquisition and transmission of HIV-1. Developing biomedical strategies for HSV-2 prevention is thus a central strategy in reducing global HIV-1 prevalence. This paper details the protocol for the isolation of restriction endunucleases (REases) with potent activity against the HSV-2 genome and models two biomedical interventions for preventing HSV-2.METHODS AND RESULTS: Using the whole genome of HSV-2, 289 REases and the bioinformatics software Webcutter2; we searched for potential recognition sites by way of genome wide palindromics. REase application in HSV-2 biomedical therapy was modeled concomitantly. Of the 289 enzymes analyzed; 77(26.6%) had potential to cleave the HSV-2 genome in > 100 but < 400 sites; 69(23.9%) in > 400 but < 700 sites; and the 9(3.1%) enzymes: BmyI, Bsp1286I, Bst2UI, BstNI, BstOI, EcoRII, HgaI, MvaI, and SduI cleaved in more than 700 sites. But for the 4: PacI, PmeI, SmiI, SwaI that had no sign of activity on HSV-2 genomic DNA, all 130(45%) other enzymes cleaved < 100 times. In silico palindromics has a PPV of 99.5% for in situ REase activity (2) Two models detailing how the REase EcoRII may be applied in developing interventions against HSV-2 are presented: a nanoparticle for microbicide development and a \"recombinant lactobacillus\" expressing cell wall anchored receptor (truncated nectin-1) for HSV-2 plus EcoRII.CONCLUSION: Viral genome slicing by way of these bacterially- derived R-M enzymatic peptides may have therapeutic potential in HSV-2 infection; a cofactor for HIV-1 acquisition and transmission." ]

[ "Author information:(1)Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Barcelona, Catalonia, Spain; Jeffrey Model Foundation Excellence Center, Barcelona, Catalonia, Spain.(2)Area of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron (HUVH), Barcelona, Catalonia, Spain.(3)Pathology Department, Hospital Universitari Vall d'Hebron (HUVH), Barcelona, Catalonia, Spain.(4)Pneumology Department, Hospital Universitari Vall d'Hebron (HUVH), Barcelona, Catalonia, Spain.(5)Exocrine Pancreas Research Unit, Department of Digestive Diseases, Hospital Universitari Vall d'Hebron (HUVH), Autonomous University of Barcelona (UAB), CiberEHD, Barcelona, Catalonia, Spain.(6)Jeffrey Model Foundation Excellence Center, Barcelona, Catalonia, Spain; Pediatric Infectious Diseases and Immunodeficiencies Unit (UPIIP), Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Catalonia, Spain.(7)Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Barcelona, Catalonia, Spain; Jeffrey Model Foundation Excellence Center, Barcelona, Catalonia, Spain; Area of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron (HUVH), Barcelona, Catalonia, Spain. Electronic address: rcolobran@vhebron.net.", "BACKGROUND/AIMS: Despite the presence of several diagnosis scales for delirium, no prediction scale that is specific for postoperative delirium after abdominal surgery is available. We sought to create a novel delirium prediction system that is specific for abdominal surgery.METHODS: This study included 213 consecutive patients who required management in the surgical ICU following abdominal surgery. The Neelon and Champagne (NEECHAM) Confusion score was monitored throughout the postoperative course and patients with low NEECHAM score (≤26) were diagnosed as having delirium.RESULTS: Seventy-three patients (34%) were categorized in the delirium group. Multivariate analyses indicated that an age >70 years, hypertension, those undergoing hepatopancreatobiliary or upper gastrointestinal surgeries, a serum albumin level <2.5 g/dl on postoperative day (POD) 3 or 5 and a ≥6 mEq/l gap in the serum sodium level between the preoperative value and that on POD 3 were independently associated with a low NEECHAM score (≤26). When the presence of each risk was counted as 1 point, 21 patients had ≥4 points and 15 of them (71%) had low NEECHAM score.CONCLUSION: The scoring system combining multiple risk factors may be useful for predicting patients with an elevated risk for postoperative delirium after abdominal surgery.", "Hereditary spastic paraplegia (HSP) and spastic diplegia (SD) patients share a strong clinical resemblance. Thus, HSP patients are frequently misdiagnosed with a mild form of SD. Clinical gait analysis (CGA) has been highlighted as a possible tool to support the differential diagnosis of HSP and SD. Previous analysis has focused on the lower-body but not the upper-body, where numerous compensations during walking occur. The aim of this study was to compare the full-body movements of HSP and SD groups and, in particular, the movement of the upper limbs. Ten HSP and 12 SD patients were evaluated through a CGA (VICON 460 and Mx3+; ViconPeak(®), Oxford, UK) between 2008 and 2012. The kinematic parameters were computed using the ViconPeak(®) software (Plug-In-Gait). In addition, the mean amplitude of normalised (by the patient's height) arm swing was calculated. All patients were asked to walk at a self-selected speed along a 10-m walkway. The mean kinematic parameters for the two populations were analysed with Mann-Whitney comparison tests, with a significant P-value set at 0.05. The results demonstrated that HSP patients used more spine movement to compensate for lower limb movement alterations, whereas SD patients used their arms for compensation. SD patients had increased shoulder movements in the sagittal plane (Flexion/extension angle) and frontal plane (elevation angle) compared to HSP patients. These arm postures are similar to the description of the guard position that toddlers exhibit during the first weeks of walking. To increase speed, SD patients have larger arm swings in the sagittal, frontal and transversal planes. Upper-body kinematics, and more specifically arm movements and spine movements, may support the differential diagnosis of HSP and SD.", "Author information:(1)Vascular Malformations Section, Institute of Medical and Molecular Genetics, INGEMM-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.(2)Bioinformatics Section, Institute of Medical and Molecular Genetics, INGEMM-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.(3)CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.(4)Clinical Genetics Section, Institute of Medical and Molecular Genetics, INGEMM-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.(5)Structural and Functional Genomics Section, Institute of Medical and Molecular Genetics, INGEMM-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.(6)Department of Genetics, IIS-Fundación Jiménez Díaz UAM, Madrid, Spain.(7)Instituto de Investigaciones Biomédicas \"Alberto Sols,\" CSIC-UAM, Madrid, Spain.(8)Vascular Anomalies Center, Plastic Surgery, Hospital Universitario La Paz, Madrid, Spain. queminfantil.hulp@salud.madrid.org.(9)Vascular Malformations Section, Institute of Medical and Molecular Genetics, INGEMM-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain. vmartineglez@salud.madrid.org.(10)CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain. vmartineglez@salud.madrid.org.", "1. The adenosine triphosphate (ATP) binding cassette (ABC) transporters form one of the largest protein families encoded in the human genome, and more than 48 genes encoding human ABC transporters have been identified and sequenced. It has been reported that mutations of ABC protein genes are causative in several genetic disorders in humans. 2. Many human ABC transporters are involved in membrane transport of drugs, xenobiotics, endogenous substances or ions, thereby exhibiting a wide spectrum of biological functions. According to the new nomenclature of human ABC transporter genes, the 'ABCC' gene sub-family comprises three classes involving multidrug resistance-associated proteins (MRPs), sulfonylurea receptors (SURs), and a cystic fibrosis transmembrane conductance regulator (CFTR). 3. Molecular cloning studies have identified a total of ten members of the human MRP class including ABCC11, ABCC12, and ABCC13 (pseudo-gene) that have recently been characterized. 4. This review addresses the historical background and discovery of the ATP-driven xenobiotic export pumps (GS-X pumps) encoded by MRP genes, biological functions of ABC transporters belonging to the MRP class, and regulation of gene expression of MRPs by oxidative stress.", "OBJECTIVE: Diffusion tensor imaging (DTI) is sensitive to white matter tract pathology. A core signature involving the corticospinal tracts (CSTs) has been identified in amyotrophic lateral sclerosis (ALS). Raised neurofilament light chain protein (NfL) in cerebrospinal fluid (CSF) is thought to reflect axonal damage in a range of neurological disorders. The relationship between these two measures was explored.METHODS: CSF and serum NfL concentrations and DTI acquired at 3 Tesla on the same day were obtained from ALS patients (n = 25 CSF, 40 serum) and healthy, age-similar controls (n = 17 CSF, 25 serum). Within-group correlations between NfL and DTI measures of microstructural integrity in major white matter tracts (CSTs, superior longitudinal fasciculi [SLF], and corpus callosum) were performed using tract-based spatial statistics.RESULTS: NfL levels were higher in patients compared to controls. CSF levels correlated with clinical upper motor neuron burden and rate of disease progression. Higher NfL levels were significantly associated with lower DTI fractional anisotropy and increased radial diffusivity in the CSTs of ALS patients, but not in controls.INTERPRETATION: Elevated CSF and serum NfL is, in part, a result of CST degeneration in ALS. This highlights the wider potential for combining neurochemical and neuroimaging-based biomarkers in neurological disease.", "BACKGROUND: Duchenne muscular dystrophy (DMD) is the most common disease in children caused by mutations in the DMD gene, and DMD and Becker muscular dystrophy (BMD) are collectively called dystrophinopathies. Dystrophinopathies show a complex mutation spectrum. The importance of mutation databases, with clinical phenotypes and protein studies of patients, is increasingly recognized as a reference for genetic diagnosis and for the development of gene therapy.METHODS: We used the data from the Japanese Registry of Muscular Dystrophy (Remudy) compiled during from July 2009 to March 2017, and reviewed 1497 patients with dystrophinopathies.RESULTS: The spectrum of identified mutations contained exon deletions (61%), exon duplications (13%), nonsense mutations (13%), small deletions (5%), small insertions (3%), splice-site mutations (4%), and missense mutations (1%). Exon deletions were found most frequently in the central hot spot region between exons 45-52 (42%), and most duplications were detected in the proximal hot spot region between exons 3-25 (47%). In the 371 patients harboring a small mutation, 194 mutations were reported and 187 mutations were unreported.CONCLUSIONS: We report the largest dystrophinopathies mutation dataset in Japan from a national patient registry, \"Remudy\". This dataset provides a useful reference to support the genetic diagnosis and treatment of dystrophinopathy." ]

[ "BACKGROUND: The high growth of Next Generation Sequencing data currently demands new knowledge extraction methods. In particular, the RNA sequencing gene expression experimental technique stands out for case-control studies on cancer, which can be addressed with supervised machine learning techniques able to extract human interpretable models composed of genes, and their relation to the investigated disease. State of the art rule-based classifiers are designed to extract a single classification model, possibly composed of few relevant genes. Conversely, we aim to create a large knowledge base composed of many rule-based models, and thus determine which genes could be potentially involved in the analyzed tumor. This comprehensive and open access knowledge base is required to disseminate novel insights about cancer.RESULTS: We propose CamurWeb, a new method and web-based software that is able to extract multiple and equivalent classification models in form of logic formulas (\"if then\" rules) and to create a knowledge base of these rules that can be queried and analyzed. The method is based on an iterative classification procedure and an adaptive feature elimination technique that enables the computation of many rule-based models related to the cancer under study. Additionally, CamurWeb includes a user friendly interface for running the software, querying the results, and managing the performed experiments. The user can create her profile, upload her gene expression data, run the classification analyses, and interpret the results with predefined queries. In order to validate the software we apply it to all public available RNA sequencing datasets from The Cancer Genome Atlas database obtaining a large open access knowledge base about cancer. CamurWeb is available at http://bioinformatics.iasi.cnr.it/camurweb .CONCLUSIONS: The experiments prove the validity of CamurWeb, obtaining many classification models and thus several genes that are associated to 21 different cancer types. Finally, the comprehensive knowledge base about cancer and the software tool are released online; interested researchers have free access to them for further studies and to design biological experiments in cancer research.", "The identification of monogenic variants of Parkinson's disease (PD) has provided novel insights into its unknown pathogenesis. As the first protein linked to autosomal-recessive forms of PD, Parkin became a welcome tool to explain biochemical and neuropathological observations that had suggested involvement of the ubiquitin-proteasome system (UPS) in PD. Based on cellular expression studies and biochemical in vitro experiments, several researchers ascribed an E3-type, E2-dependent ubiquitin protein ligase activity to wild-type (but not mutant) Parkin proteins. Although the individual components of the proposed Parkin ubiquitin ligase complex in the normal human brain remain to be identified and the E3 ligase effect of Parkin function has not yet been confirmed in an animal model, the scientific exploration of a protein with several links to the UPS has provided many leads in PD research. This chapter describes assays that the authors have used to examine the cellular and in vitro effects of neural Parkin.", "Avascular necrosis of a vertebral body, a relatively uncommon entity, is caused by malignancy, infection, radiation, systemic steroid treatment, trauma, and the like.1 Vertebral osteonecrosis induced by trauma is called Kvmell's disease, because it was initially described by Hermann Kvmell of Germany in 1891.2 This paper reported a young female with posttraumatic vertebral osteonecrosis and analyzed the causes. She was treated by thoracoscopic surgery successfully.", "Multiple protein arginine methyltransferases are involved in transcriptional activation of nuclear receptors. Coactivator-associated arginine methyltransferase 1 (CARM1)-mediated histone methylation has been shown to activate nuclear receptor-dependent transcription; however, little is known about the regulation of its enzymatic activity. Here, we report that the methyltransferase activity of CARM1 is negatively regulated through phosphorylation at a conserved serine residue. When the serine residue is mutated to glutamic acid, which mimics the phosphorylated serine residue, the mutant CARM1 exhibits diminished ability to bind the methyl donor adenosylmethionine and diminished histone methylation activity. Moreover, such mutation leads to the inhibition of CARM1 transactivation of estrogen receptor-dependent transcription. Our results provide an example for the regulation of protein arginine methyltransferase activity by phosphorylation. As CARM1 is a potent transcriptional coactivator of estrogen receptor, our results suggest that phosphorylation of CARM1 serves as a unique mechanism for inactivating CARM1-regulated estrogen-dependent gene expression.", "PURPOSE: Valproic acid (VA) is an antiepileptic drug (AED) and histone deacetylase (HDAC) inhibitor taken by patients with glioblastoma (GB) to manage seizures, and it can modulate the biologic effects of radiation therapy (RT). We investigated whether VA use during RT for GB was associated with overall survival (OS).METHODS AND MATERIALS: Medical records of 544 adults with GB were retrospectively reviewed. Analyses were performed to determine the association of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) class, seizure history, and concurrent temozolomide (TMZ) and AED use during RT with OS.RESULTS: Seizures before the end of RT were noted in 217 (40%) patients, and 403 (74%) were taking an AED during RT; 29 (7%) were taking VA. Median OS in patients taking VA was 16.9 months (vs 13.6 months taking another AED, P=.16). Among patients taking an AED during RT, OS was associated with VA (P=.047; hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.27-1.07), and RTOG RPA class (P<.0001; HR, 1.49; 95% CI, 1.37-1.61). Of the 5 most common AEDs, only VA was associated with OS. Median OS of patients receiving VA and TMZ during RT was 23.9 months (vs 15.2 months for patients taking another AED, P=.26). When the analysis was restricted to patients who received concurrent TMZ, VA use was marginally associated with OS (P=.057; HR, 0.54; 95% CI, -0.09 to 1.17), independently of RTOG RPA class and seizure history.CONCLUSIONS: VA use during RT for GB was associated with improved OS, independently of RTOG RPA, seizure history, and concurrent TMZ use. Further studies of treatment that combines HDAC inhibitors and RT are warranted.", "The challenges in identifying genetic polymorphisms that influence the susceptibility to rheumatoid arthritis are the same as those faced in most complex diseases; genetic and phenotypic heterogeneity, an unknown number of loci presumed to have small genetic effects, non-genetic modifying effects that have yet to be fully characterised and a history of unconfirmed genetic associations. Despite the difficulties, the chronic nature of the disease, incomplete efficacy of existing therapies and resultant heavy healthcare burden for the developed world in managing patients with this condition, mean that an understanding of the genetic basis of disease susceptibility, severity and response to therapy is keenly sought. Many linkage and association studies have been carried out and in this article the results of linkage studies are summarised. Recently a number of convincing candidate genes have begun to emerge and an update has been provided for three of these: PTPN22, CTLA-4 and MIF.", "INTRODUCTION: Gastrointestinal stromal tumors are the commonest mesenchymal tumors of the gastrointestinal tract, the stomach and small intestine are the favored sites of occurrence. They rarely occur in the colon, rectum and esophagus. GIST is neoplasm of mesenchymal origin originating from precursors of the interstitial cells of cajal. The symptoms of gastrointestinal stromal tumor depend on the site and size of the tumor, and may include abdominal pain, gastrointestinal bleeding or signs of obstruction; small tumors may, however, be asymptomatic. Majority of the patients with gastrointestinal stromal tumor have bloody stools and abdominal pain as the commonest manifestation. We describe a young female with extra luminal colonic gastrointestinal stromal tumor presenting as mass abdomen.CASE PRESENTATION: We describe 34-year-old female from north Indian state of Jammu and Kashmir who had presented with history of slowly increasing epigastric lump associated with abdominal discomfort of 4 months duration. She had no features of luminal obstruction. Her contrast enhanced computed tomography abdomen revealed a large extra-colonic mass in relation to transverse colon. The tumor was resected and histology was suggestive of gastrointestinal stromal tumor.CONCLUSION: Extra luminal colonic gastrointestinal stromal tumors are very rare and can present as mass abdomen. Resection is the treatment of choice." ]

[ "The advantage of BCG immunotherapy over intravesical chemotherapy in superficial bladder cancer has been most apparent in patients with carcinoma in situ (CIS), where complete response is increased from 50% to more than 70% and the proportion of patients remaining disease free for 5 years is increased from 20% to 40%. Similar advantages have been reported using suboptimal BCG treatment schedules in patients with recurrent stage Ta, T1 tumours. BCG provides long term protection from tumour recurrence and, unlike chemotherapy, reduces tumour progression. The observed relative increased sensitivity of CIS to BCG and the occasional failure of BCG to demonstrate significant superiority over mitomycin C in the prevention of tumour appear to be related to the use of suboptimal BCG treatment schedules. With maintenance BCG using 3 weekly instillations at 6 month intervals, patients with papillary tumours fare even better than patients with CIS, and tumour progressio is even further reduceld. Chemotherapy is appropriate for patients who are at very low risk of tumour progression and those who fail to respond to BCG, but overall the results of BCG immunotherapy are superior for patients with either CIS or Ta, T1 transitional cell carcinoma.", "Whereas most endogenous and exogenous DNA damaging agents typically generate lesions that are relatively isolated and can be repaired easily, ionizing radiation (IR) also induces clustered lesions causing DNA double strand breaks (DSBs). Moreover, forms of IR characterized by high linear energy transfer (LET) induce not only isolated DSBs but also DSB clusters - multiple DSBs in close proximity -that pose increased risks for the cell. DSB clusters can destabilize chromatin locally and compromise processing of individual DSBs within the cluster. Since the discovery of chromothripsis, a phenomenon whereby multiple DSBs locally generated by a catastrophic event causes genomic rearrangements that feed carcinogenesis, DSB clusters receive increased attention also in the field of cancer. While formation of DSB clusters after exposure to high LET is a direct and inherent consequence of the spatial distribution of the constituting energy deposition events, also called track structure, the sources of local genomic shattering underpinning chromothripsis are under investigation. Notably, many consequences of DSB clusters in the affected genome reflect processing by pathways that have evolved to repair DSBs, but which operate with widely different degrees of fidelity. The molecular underpinnings and the basis of the underlying repair pathway choices that ultimately lead to the observed consequences from DSB clusters remain unknown. We developed a tractable model of DSB clustering that allows direct analysis in cells of the consequences of certain configurations of DSB clusters. We outline the rationale for the development of this model and describe its key characteristics. We summarize results suggesting that DSB clusters compromise the first-line DSB-processing pathways of c-NHEJ and HRR, increasing as a consequence the contribution of alt-EJ, which has high propensity of generating chromosomal rearrangements. The results suggest a mechanism for the increased toxicity of high LET radiation and the extensive genomic rearrangements associated with chromothripsis.", "Advances in high-throughput sequencing techniques now allow relatively easy and affordable sequencing of large portions of the genome, even for nonmodel organisms. Many phylogenetic studies reduce costs by focusing their sequencing efforts on a selected set of targeted loci, commonly enriched using sequence capture. The advantage of this approach is that it recovers a consistent set of loci, each with high sequencing depth, which leads to more confidence in the assembly of target sequences. High sequencing depth can also be used to identify phylogenetically informative allelic variation within sequenced individuals, but allele sequences are infrequently assembled in phylogenetic studies. Instead, many scientists perform their phylogenetic analyses using contig sequences which result from the de novo assembly of sequencing reads into contigs containing only canonical nucleobases, and this may reduce both statistical power and phylogenetic accuracy. Here, we develop an easy-to-use pipeline to recover allele sequences from sequence capture data, and we use simulated and empirical data to demonstrate the utility of integrating these allele sequences to analyses performed under the multispecies coalescent model. Our empirical analyses of ultraconserved element locus data collected from the South American hummingbird genus Topaza demonstrate that phased allele sequences carry sufficient phylogenetic information to infer the genetic structure, lineage divergence, and biogeographic history of a genus that diversified during the last 3 myr. The phylogenetic results support the recognition of two species and suggest a high rate of gene flow across large distances of rainforest habitats but rare admixture across the Amazon River. Our simulations provide evidence that analyzing allele sequences leads to more accurate estimates of tree topology and divergence times than the more common approach of using contig sequences.", "We have investigated the hematopoietic phenotype of mice with a hypomorphic mutation in the Brca2/Fancd1 gene (Brca2(Delta27/Delta27) mutation). In contrast to observations made in other Fanconi anemia (FA) mouse models, low numbers of hematopoietic colony-forming cells (CFCs) were noted in Brca2(Delta27/Delta27) mice, either young or adult. Additionally, a high incidence of spontaneous chromosomal instability was observed in Brca2(Delta27/Delta27) bone marrow (BM) cells, but not in Brca2(+/Delta27) or Fanca(-/-) BM cells. Although Brca2(Delta27/Delta27) CFCs were not hypersensitive to ionizing radiation, a very severe hematopoietic syndrome was observed in irradiated Brca2(Delta27/Delta27) mice. Conventional BM competition experiments showed a marked repopulation defect in Brca2(Delta27/Delta27) hematopoietic stem cells (HSCs), compared to wild-type HSCs. Moreover, we have observed for the first time in a DNA repair disease model a very significant proliferation defect in Brca2(Delta27/Delta27) HSCs maintained in their natural physiological environment. The progressive repopulation of wild-type HSCs transplanted into unconditioned Brca2(Delta27/Delta27) recipients is reminiscent of the somatic mosaicism phenomenon observed in a number of genetic diseases, including FA. The hematopoietic phenotype associated with the Brca2(Delta27/Delta27) mutation suggests that this FA-D1 mouse model will constitute an important tool for the development of new therapies for FA, including gene therapy.", "The purpose of the present literature review is to assess the screening value of trisomy 21 by measurement of fetal nuchal translucency (NT) thickness in the first trimester. NT is a subcutaneous translucency between the skin and the soft tissues overlying the cervical spine, which disappears in the second trimester. Ultrasound examination was used to image a sagittal section of the fetus to measure the maximum thickness of the subcutaneous translucency. NT is physiological for a measurement < 3 mm but the incidence of chromosomal abnormalities (essentially trisomies 21, 18 and 13) increases when NT > or = 3 mm. Differential diagnoses include cystic hygroma and fetal hydrops. For screening purposes, a cut-off threshold value of > or = 3 mm, with a standardized technique, gave a sensitivity > or = 50%, a false positive rate < 5% and a positive predictive value > 1%. In the chromosomally normal group, prognosis was good, but incidence of structural defects and fetal loss increased, with a sharp rise in these complications for fetal translucency thickness > or = 5 mm.", "BACKGROUND: Tremelimumab, an anti-CTLA4 monoclonal antibody, initially showed good activity when used alone in patients with mesothelioma, but did not improve the overall survival of patients who failed on first-line or second-line chemotherapy compared with placebo in the DETERMINE study. We aimed to investigate the efficacy and safety of first-line or second-line tremelimumab combined with durvalumab, an anti-PD-L1 monoclonal antibody, in patients with malignant mesothelioma.METHODS: In this open-label, non-randomised, phase 2 trial, patients with unresectable pleural or peritoneal mesothelioma received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. The primary endpoint was the proportion of patients with an immune-related objective response according to the immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST; for pleural mesothelioma) or immune-related RECIST version 1.1 (for peritoneal mesothelioma). The primary analysis was done by intention to treat, whereas the safety analysis included patients who received at least one dose of study drug. This trial is registered with the European Clinical Trials Database, number 2015-001995-23, and ClinicalTrials.gov, number NCT02588131, and is ongoing but no longer recruiting patients.FINDINGS: From Oct 30, 2015, to Oct 12, 2016, 40 patients with mesothelioma were enrolled and received at least one dose each of tremelimumab and durvalumab. Patients were followed-up for a median of 19·2 months (IQR 13·8-20·5). 11 (28%) of 40 patients had an immune-related objective response (all partial responses; confirmed in ten patients), with a median response duration of 16·1 months (IQR 11·5-20·5). 26 (65%) patients had immune-related disease control and 25 (63%) had disease control. Median immune-related progression-free survival was 8·0 months (95% CI 6·7-9·3), median progression-free survival was 5·7 months (1·7-9·7), and median overall survival was 16·6 months (13·1-20·1). Baseline tumour PD-L1 expression did not correlate with the proportion of patients who had an immune-related objective response or immune-related disease control, with immune-related progression-free survival, or with overall survival. 30 (75%) patients experienced treatment-related adverse events of any grade, of whom seven (18%) had grade 3-4 treatment-related adverse events. Treatment-related toxicity was generally manageable and reversible with protocol guidelines.INTERPRETATION: The combination of tremelimumab and durvalumab appeared active, with a good safety profile in patients with mesothelioma, warranting further exploration.FUNDING: Network Italiano per la Bioterapia dei Tumori Foundation, Associazione Italiana per la Ricerca sul Cancro, AstraZeneca, and Istituto Toscano Tumori.", "Oculocutaneous albinism is an autosomal recessive genetic disorder. Several types of oculocutaneous albinism are caused by mutation in related genes. Oculocutaneous albinism 1 is associated with the tyrosinase gene. The human tyrosinase gene (TYR) encodes tyrosinase, a key enzyme in melanin biosynthesis. As exon 1 of the gene shows an MboI-RFLP within codon 192 in Caucasians, we studied allele frequencies of MboI 192 polymorphism in 200 chromosomes from 100 unrelated normal Korean individuals. As a result, only one allele system, the presence of the MboI 192 site, was detected in the Korean." ]

[ "BACKGROUND: The authors investigated the role of different voltage-sensitive calcium channels expressed at presynaptic afferent terminals in substance P release and on nociceptive behavior evoked by intraplantar formalin by examining the effects of intrathecally delivered N- (ziconotide), T- (mibefradil), and L-type voltage-sensitive calcium channel blockers (diltiazem and verapamil).METHODS: Rats received intrathecal pretreatment with saline or doses of morphine, ziconotide, mibefradil, diltiazem, or verapamil. The effect of these injections upon flinching evoked by intraplantar formalin (5%, 50 μl) was quantified. To assess substance P release, the incidence of neurokinin-1 receptor internalization in the ipsilateral and contralateral lamina I was determined in immunofluorescent-stained tissues.RESULTS: Intrathecal morphine (20 μg), ziconotide (0.3, 0.6, and 1 μg), mibefradil (100 μg, but not 50 μg), diltiazem (500 μg, but not 300 μg), and verapamil (200 μg, but not 50 and 100 μg) reduced paw flinching in phase 2 compared with vehicle control (P < 0.05), with no effect on phase 1. Ziconotide (0.3, 0.6, and 1 μg) and morphine (20 μg) significantly inhibited neurokinin-1 receptor internalization (P < 0.05), but mibefradil, diltiazem, and verapamil at the highest doses had no effect.CONCLUSION: These results emphasize the role in vivo of N-type but not T- and L-type voltage-sensitive calcium channel blockers in mediating the stimulus-evoked substance P release from small primary afferents and suggest that T- and L-type voltage-sensitive calcium channel blockers exert antihyperalgesic effects by an action on other populations of afferents or mechanisms involving postsynaptic excitability.", "Embryonic stem (ES) cells have been considered as a valuable renewable source of materials in regenerative medicine. Recently, we identified the homeoprotein EGAM1 both in preimplantation mouse embryos and mouse ES cells. Expression of the Egam1 transcript and its encoded protein was detectable in differentiating mouse ES cells, while it was almost undetectable in undifferentiated cells. In the present study, in order to clarify the effect of forced expression of EGAM1 on the differentiation of mouse ES cells in vitro, transfectants expressing exogenous EGAM1 were generated. Egam1 transfectants promoted differentiation into cell types expressing Gata6, Gata4, Afp, or Plat, genes associated with emergence of the extra-embryonic endoderm lineages. On the other hand, Egam1 transfectants inhibited the expression of specific genes for the embryonic lineages, including Fgf5 (epiblast) and T (mesoderm), in addition to Cdx2, a specific gene for the extra-embryonic trophectoderm lineages. Changes in the percentage of cells recognizing by antibodies against specific marker proteins closely correlated with the expression patterns of their transcripts. Taken together, the results obtained in this study suggested that mouse ES cells expressing exogenous EGAM1 preferentially differentiate into extra-embryonic primitive endoderm lineages, rather than embryonic lineages or extra-embryonic trophectoderm lineages.", "BACKGROUND: Adult stem cells come from many sources and have the capacity to differentiate into many cell types, including those of the skin. The most commonly studied stem cells are those termed mesenchymal stem cells (MSCs), which are easily isolated from bone marrow and adipose tissue. Mesenchymal stem cells are known to produce a wide array of cytokines that modulate the regeneration process. The ease of collection, propagation and use of these MSCs in therapy of traumatic, ischaemic and immune-mediated skin conditions is emerging.APPROACH AND EVIDENCE: In traumatic and ischaemic skin damage, MSCs are used in tissue-engineered skin and by direct injection into damaged tissue. For immune-mediated diseases, systemic administration of stem cells can modulate the immune system. The earliest clinical work has been with autologous stem cell sources, such as adipose tissue and bone marrow. In immune-mediated diseases, the MSCs are used to downregulate production of inflammatory cytokines and to block T-cell activation. Cells are generally given intravenously. Multiple sclerosis, rheumatoid arthritis and lupus have been successfully treated in human clinical trials. Mesenchymal stem cells can also stimulate resident local cells, such as keratinocytes and progenitor cells, to proliferate, migrate and repair skin injury and disease.LOOKING AHEAD: The discovery of the MSC in adipose tissue has spawned a global effort to utilize these cells in therapy of a wide range of diseases of the skin. Reconstructive surgery, scar blocking and resolution and skin regeneration have all been shown to be possible in human and animal studies.", "Repression of excessive increase and enlargement of adipocytes that is closely associated with obesity is effective in the prevention and treatment of metabolic syndrome. Generally, apoptosis is induced in cells via a wide variety of intracellular or extracellular substances, and recently, it has been suggested that the FoxO subfamily is involved in the induction of apoptosis. We aimed to elucidate the mechanism of FoxO-mediated apoptosis-induction in the adipocytes under the reactive oxygen species (ROS) stimulus. The treatment of differentiated and undifferentiated 3T3-L1 cells with glucose oxidase (GOD), an enzyme that generates H(2)O(2), induced apoptosis and led to the accumulation of 8-OHdG. Apoptosis analysis revealed that GOD treatment induced apoptosis in differentiated 3T3-L1 cells less efficiently than in undifferentiated preadipocytes. GOD remarkably increased the levels of Bad, Bax, and Bim-the genes that are actively involved in cell apoptosis. GOD treatment also increased the expression of FoxO3a mRNA and protein. The introduction of FoxO3a-siRNA into 3T3-L1 cells suppressed the oxidative stress-induced expression of Bim mRNA, as well as the GOD-induced apoptosis. Furthermore, the expression of MnSOD, Cu/ZnSOD, and catalase, as well as of FoxO, increased significantly along with the progression of adipocyte differentiation. These results indicated that ROS-induced apoptosis in undifferentiated 3T3-L1 cells via the expression of FoxO3a, whereas FoxO expression suppressed the ROS-induced apoptosis in differentiated 3T3-L1 cells via the expression of ROS-scavenging enzymes.", "Increased arterial endothelial cell permeability (ECP) is considered an initial step in atherosclerosis. Atrial natriuretic peptide (ANP) which is rapidly degraded by neprilysin (NEP) may reduce injury-induced endothelial cell leakiness. Omapatrilat represents a first in class of pharmacological agents which inhibits both NEP and angiotensin converting enzyme (ACE). We hypothesized that ANP prevents thrombin-induced increases of ECP in human aortic ECs (HAECs) and that omapatrilat would reduce aortic leakiness and atherogenesis and enhance ANP mediated vasorelaxation of isolated aortas. Thrombin induced ECP determined by I(125) albumin flux was assessed in HAECs with and without ANP pretreatment. Next we examined the effects of chronic oral administration of omapatrilat (12 mg/kg/day, n=13) or placebo (n=13) for 8 weeks on aortic leakiness, atherogenesis and ANP-mediated vasorelaxation in isolated aortas in a rabbit model of atherosclerosis produced by high cholesterol diet. In HAECs, thrombin-induced increases in ECP were prevented by ANP. Omapatrilat reduced the area of increased aortic leakiness determined by Evans-blue dye and area of atheroma formation assessed by Oil-Red staining compared to placebo. In isolated arterial rings, omapatrilat enhanced vasorelaxation to ANP compared to placebo with and without the endothelium. ANP prevents thrombin-induced increases in ECP in HAECs. Chronic oral administration of omapatrilat reduces aortic leakiness and atheroma formation with enhanced endothelial independent vasorelaxation to ANP. These studies support the therapeutic potential of dual inhibition of NEP and ACE in the prevention of increased arterial ECP and atherogenesis which may be linked to the ANP/cGMP system.", "Weevils (Curculionoidea) comprise one of the most diverse groups of organisms on earth. There is hardly a vascular plant or plant part without its own species of weevil feeding on it and weevil species diversity is greater than the number of fishes, birds, reptiles, amphibians and mammals combined. Here, we employ ultraconserved elements (UCEs) designed for beetles and a novel partitioning strategy of loci to help resolve phylogenetic relationships within the radiation of Australasian smurf-weevils (Eupholini). Despite being emblematic of the New Guinea fauna, no previous phylogenetic studies have been conducted on the Eupholini. In addition to a comprehensive collection of fresh specimens, we supplement our taxon sampling with museum specimens, and this study is the first target enrichment phylogenomic dataset incorporating beetle specimens from museum collections. We use both concatenated and species tree analyses to examine the relationships and taxonomy of this group. For species tree analyses we present a novel partitioning strategy to better model the molecular evolutionary process in UCEs. We found that the current taxonomy is problematic, largely grouping species on the basis of similar color patterns. Finally, our results show that most loci required multiple partitions for nucleotide rate substitution, suggesting that single partitions may not be the optimal partitioning strategy to accommodate rate heterogeneity for UCE loci.", "Research in the nineteenth and early twentieth century established that the brain awakens reproduction, governs reproductive activity in the adult of virtually all vertebrates. By 1950, nearly 100 years later, scientists realized that the hypothalamus and its neurosecretory products play a key role in regulating gonadal function in both males and females. Another 20 years would be required to reveal the chemical identity of GnRH and establish that neurons producing GnRH represent the final common pathway through which the brain regulates gonadotropin secretion. It had also become clear that GnRH neurons behave more like motor neurons-better perhaps at going than stopping-and are themselves regulated by a complex network of afferent inputs, which guide the tempo of sexual maturation, regulate estrous and menstrual cycles, control seasonal breeding, and stop reproduction under adversity. In 2003, the revelation that kisspeptin and its receptor are critical for reproduction opened a floodgate of research documenting the role of kisspeptin neurons as central processors of reproduction. Today, there is wide consensus that kisspeptin signaling in the brain is essential, providing the impetus to GnRH neurons to awaken at puberty and reigning the activity of these neurons when discretion is advised. We celebrate this watershed moment-with full knowledge that time and discovery will provide context and perspective to even these heady days." ]

[ "The cation-independent mannose 6-phosphate receptor (CIMPR) cycles between the trans-Golgi network (TGN) and endosomes to mediate sorting of lysosomal hydrolases. The endosome-to-TGN retrieval of the CIMPR requires the retromer complex. Genetic, biochemical and structural data support the hypothesis that the retromer can directly bind to the tail of the CIMPR, to sort the CIMPR into vesicles and tubules for retrieval to the TGN. Presently, however, no known retromer sorting motif in the tail of the CIMPR has been identified. Using CD8-reporter proteins carrying the cytoplasmic tail of the CIMPR we have systematically dissected the CIMPR tail to identify a novel, conserved aromatic-containing sorting motif that is critical for the endosome-to-TGN retrieval of the CIMPR and for the interaction with retromer and the clathrin adaptor AP-1.", "PURPOSE: The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with ALK-rearranged non-small cell lung cancer (NSCLC). Several next-generation ALK-TKIs have entered the clinic and have shown promising activity in crizotinib-resistant patients. As patients still relapse even on these next-generation ALK-TKIs, we examined mechanisms of resistance to the next-generation ALK-TKI alectinib and potential strategies to overcome this resistance.EXPERIMENTAL DESIGN: We established a cell line model of alectinib resistance, and analyzed a resistant tumor specimen from a patient who had relapsed on alectinib. We developed Ba/F3 models harboring alectinib-resistant ALK mutations and evaluated the potency of other next-generation ALK-TKIs in these models. We tested the antitumor activity of the next-generation ALK-TKI ceritinib in the patient with acquired resistance to alectinib. To elucidate structure-activity relationships of ALK mutations, we performed computational thermodynamic simulation with MP-CAFEE.RESULTS: We identified a novel V1180L gatekeeper mutation from the cell line model and a second novel I1171T mutation from the patient who developed resistance to alectinib. Both ALK mutations conferred resistance to alectinib as well as to crizotinib, but were sensitive to ceritinib and other next-generation ALK-TKIs. Treatment of the patient with ceritinib led to a marked response. Thermodynamics simulation suggests that both mutations lead to distinct structural alterations that decrease the binding affinity with alectinib.CONCLUSIONS: We have identified two novel ALK mutations arising after alectinib exposure that are sensitive to other next-generation ALK-TKIs. The ability of ceritinib to overcome alectinib-resistance mutations suggests a potential role for sequential therapy with multiple next-generation ALK-TKIs.", "BACKGROUND: Transplantation of marrow stromal cells (MSC) has been shown to improve heart perfusion and cardiac function after ischemia. Erythropoietin (EPO) is capable of inducing angiogenesis and inhibiting cell apoptosis. The aim of this study was to investigate the effect of EPO on the therapeutic potency of MSC transplantation in a rat model of myocardial infarction.METHODS: MSC viability was detected by MTT and flow cytometry following culture in serum-free medium for 24 h with or without EPO. Release of vascular endothelial growth factor (VEGF) by MSC incubated with different doses of EPO was assayed using ELISA. Immediately after coronary ligation, autologous MSC (3 x 10(6) cells) were injected into the ischemic myocardium (MSC and MSC-EPO groups). EPO (3,000 U/kg body weight) was injected daily for 3 consecutive days starting 1 day prior to ligation. The same EPO dose was also injected for consecutive 3 days starting 15 days after surgery (EPO and MSC-EPO groups). Control animals were injected saline solution for the same time period. Cardiac function was assessed by echocardiography 2 and 21 days after surgery, respectively. Western blot and immunohistological assessments were performed to examine the effects of treatments.RESULTS: In vitro, EPO inhibited MSC apoptosis induced by serum-free medium and increased vascular endothelial growth factor (VEGF) release by MSC. In vivo, cardiac infarct size was significantly smaller, cardiac function significantly improved, and capillary density obviously higher in the MSC and EPO groups than in the control group. Combined treatment with EPO infusion and MSC transplantation demonstrated a further decrease in infarct size, a further improvement in cardiac function, and a further increase in capillary density compared with MSC or EPO alone. Furthermore, a higher ratio of phosphorylated Akt to total Akt was measured by Western blot; Bcl-2 was upregulated and Bax was downregulated by immunohistochemistry in the MSC-EPO group compared to the other three groups.CONCLUSION: Transplantation of MSC combined with EPO infusion is superior to MSC monotherapy for angiogenesis and cardiac function recovery.", "Clinical genomic sequencing can identify pathogenic variants unrelated to the initial clinical question, but of medical relevance to the patients and their families. With ongoing discussions on the utility of disclosing or searching for such variants, it is of crucial importance to obtain unbiased insight in the prevalence of these incidental or secondary findings, in order to better weigh potential risks and benefits. Previous studies have reported a broad range of secondary findings ranging from 1 to 9%, merely attributable to differences in study design, cohorts tested, sequence technology used and genes analyzed. Here, we analyzed WES data of 1640 anonymized healthy Dutch individuals to establish the frequency of medically actionable disease alleles in an outbred population of European descent. Our study shows that 1 in 38 healthy individuals (2.7%) has a (likely) pathogenic variant in one of 59 medically actionable dominant disease genes for which the American College of Medical Genetics and Genomics (ACMG) recommends disclosure. Additionally, we identified 36 individuals (2.2%) to be a carrier of a recessive pathogenic disease allele. Whereas these frequencies of secondary findings are in line with what has been reported in the East-Asian population, the pathogenic variants are differently distributed across the 59 ACMG genes. Our results contribute to the debate on genetic risk factor screening in healthy individuals and the discussion whether the potential benefits of this knowledge and related preventive options, outweigh the risk of the emotional impact of the test result and possible stigmatization.", "OBJECTIVE: Dexmedetomidine (DEX) may provide a sedation level that enables sleep and communication, with less amnesia and pain medication requirements, during mechanical ventilation. Our study directly assessed patient-perceived satisfaction with coronary artery bypass graft surgery after administration of DEX or propofol for intensive care unit (ICU) sedation.DESIGN: Prospective, randomized clinical study with subsequent questionnaire administration.SETTING: Tertiary care surgical ICU.PATIENTS: A total of 89 adult, nonemergent, coronary artery bypass graft patients with an expected length of intubation of <24 hrs.INTERVENTIONS: Patients were randomized to either DEX or propofol; drug administration was performed via standardized anesthesia and nursing protocols.MEASUREMENTS: Patients reported perceptions of their ICU experience after mechanical ventilation with a modified numerical-scale Hewitt questionnaire, validated specifically for ICU patients. Patients were questioned regarding awareness, recall, generalized comfort, level of pain, ability to interact with healthcare providers and family, feelings of agitation and anxiety, perceived ease of extubation, ability to sleep or rest, and satisfaction with ICU experience.MAIN RESULTS: Groups were well matched at baseline, with a mean +/- sd age of 63.0 +/- 10.4 yrs and weight of 88.7 +/- 16.7 kg. No difference was observed for length of surgery, length of intubation, or ICU stay (p > .05). DEX patients perceived a shorter length of intubation (p = .044). A deeper sedation level was found in the propofol group (p = .021), with similar morphine and midazolam requirements (p = .317). Patient-rated level of overall awareness as a marker of amnesia did not differ between groups (p = .653). The ability to rest or sleep trended toward significance favoring propofol (p = .051). On evaluation of questionnaire ratings, DEX patients expressed more discomfort (p = .046), pain (p = .096), and sleeping difficulty (p = .036). Similar comfort levels were reported during extubation (p = .179).CONCLUSIONS: Despite theoretical advantages of DEX to improve overall patient satisfaction, the two agents provide similar responses to amnesia and pain control. According to our findings, DEX does not seem to have any advantage compared with propofol for short-term sedation after coronary artery bypass graft surgery.", "The discovery of alterations in the EGFR and ALK genes, amongst others, in NSCLC has driven the development of targeted-drug therapy using selective tyrosine kinase inhibitors (TKIs). To optimize the use of these TKIs, the discovery of new biomarkers for early detection and disease progression is mandatory. These plasma-isolated exosomes can be used as a non-invasive and repeatable way for the detection and follow-up of these biomarkers. One ml of plasma from 12 NSCLC patients, with different mutations and treatments (and 6 healthy donors as controls), were used as exosome sources. After RNAse treatment, in order to degrade circulating miRNAs, the exosomes were isolated with a commercial kit and resuspended in specific buffers for further analysis. The exosomes were characterized by western blotting for ALIX and TSG101 and by transmission electron microscopy (TEM) analysis, the standard techniques to obtain biochemical and dimensional data of these nanovesicles. Total RNA extraction was performed with a high yield commercial kit. Due to the limited miRNA-content in exosomes, we decided to perform retro-transcription PCR using an individual assay for each selected miRNA. A panel of miRNAs (30b, 30c, 103, 122, 195, 203, 221, 222), all correlated with NSCLC disease, were analyzed taking advantage of the remarkable sensitivity and specificity of Real-Time PCR analysis; mir-1228-3p was used as endogenous control and data were processed according to the formula 2(-) (ΔΔct) (13). Control values were used as baseline and results are shown in logarithmic scale.", "Moyamoya disease is a well-known cerebrovascular disorder of unknown pathogenesis affecting terminal portion of internal carotid arteries and causing ischemic attacks. Its familial occurrence suggests genetic background. We hypothesized that paternally imprinted gene might be associated with this disorder. To identify the expressed sequence tags (ESTs) with monoallelic expressions on chromosome 3, we used mouse A9 hybrid cells having human chromosome 3. Two ESTs showed only maternal expression in mouse A9 hybrid cells, and four showed non-expression in the lymphocytes derived from moyamoya patients. Although these ESTs are clustered on the same 150 kb region, we finally failed to identify cDNA in this region." ]

[ "PURPOSE: Internationally adopted variant interpretation guidelines from the American College of Medical Genetics and Genomics (ACMG) are generic and require disease-specific refinement. Here we developed CardioClassifier ( http://www.cardioclassifier.org ), a semiautomated decision-support tool for inherited cardiac conditions (ICCs).METHODS: CardioClassifier integrates data retrieved from multiple sources with user-input case-specific information, through an interactive interface, to support variant interpretation. Combining disease- and gene-specific knowledge with variant observations in large cohorts of cases and controls, we refined 14 computational ACMG criteria and created three ICC-specific rules.RESULTS: We benchmarked CardioClassifier on 57 expertly curated variants and show full retrieval of all computational data, concordantly activating 87.3% of rules. A generic annotation tool identified fewer than half as many clinically actionable variants (64/219 vs. 156/219, Fisher's P = 1.1  ×  10-18), with important false positives, illustrating the critical importance of disease and gene-specific annotations. CardioClassifier identified putatively disease-causing variants in 33.7% of 327 cardiomyopathy cases, comparable with leading ICC laboratories. Through addition of manually curated data, variants found in over 40% of cardiomyopathy cases are fully annotated, without requiring additional user-input data.CONCLUSION: CardioClassifier is an ICC-specific decision-support tool that integrates expertly curated computational annotations with case-specific data to generate fast, reproducible, and interactive variant pathogenicity reports, according to best practice guidelines.", "BACKGROUND: Sudden death in athletes can occur during sport activities and is presumably related to ventricular arrhythmias. There are no guidelines concerning athletes who develop ventricular arrhythmias during an exercise test. It is unclear whether they should be allowed to continue with their competitive activity or not.OBJECTIVES: To investigate the long-term follow-up of athletes with ventricular arrhythmias during an exercise test.METHODS: From a database of 56,462 athletes we identified 192 athletes, less than 35 years old, who had ventricular arrhythmias during an exercise test. Ninety athletes had > or = 3 ventricular premature beats (group A) and 102 athletes had ventricular couplets or non-sustained ventricular tachycardia during an exercise test (group B). A control group of 92 athletes without ventricular arrhythmias was randomly selected from the database (group C).RESULTS: All athletes, except one who died from a dilated cardiomyopathy, were alive during a follow-up period of 70 +/- 25 months. An abnormal echocardiogram was obtained in seven athletes from group A (10%), four from group B (5%), and one from group C (3%) (not significant). An abnormal echocardiogram was more likely to be present in competitive athletes (P = 0.001) and in female athletes (P = 0.01).CONCLUSIONS: Our results showed that ventricular arrhythmias during exercise are more commonly associated with cardiovascular abnormalities in young competitive athletes and in female athletes. When present, they necessitate a thorough investigation and follow-up.", "FTY720 (Fingolimod) is a known sphingosine-1-phosphate (S1P) receptor agonist that exerts strong anti-inflammatory effects and was approved as the first oral drug for the treatment of multiple sclerosis by the US Food and Drug Administration (FDA) in 2010. FTY720 is mainly associated with unique functional \"antagonist\" and \"agonist\" mechanisms. The functional antagonistic mechanism is mediated by the transient down-regulation and degradation of S1P receptors on lymphocytes, which prevents lymphocytes from entering the blood stream from the lymph node. This subsequently results in the development of lymphopenia and reduces lymphocytic inflammation. Functional agonistic mechanisms are executed through S1P receptors expressed on the surface of various cells including neurons, astrocytes, microglia, and blood vessel endothelial cells. These functions might play important roles in regulating anti-apoptotic systems, modulating brain immune and phagocytic activities, preserving the Blood-Brain-Barrier (BBB), and the proliferation of neural precursor cells. Recently, FTY720 have shown receptor-independent effects, including intracellular target bindings and epigenetic modulations. Many researchers have recognized the positive effects of FTY720 and launched basic and clinical experiments to test the use of this agent against stroke. Although the mechanism of FTY720 has not been fully elucidated, its efficacy against cerebral stroke is becoming clear, not only in animal models, but also in ischemic stroke patients through clinical trials. In this article, we review the data obtained from laboratory findings and preliminary clinical trials using FTY720 for stroke treatment.", "Lymphocyte infiltration into the intestinal tract in inflammatory bowel disease (IBD) is mediated by interaction between α4 integrin and its specific ligands. Development of monoclonal antibodies against α4 integrin allowed targeting of lymphocyte trafficking into the intestine as a novel therapeutic intervention. Natalizumab, vedolizumab, alicaforsen AJM300, rhuMAb β7, CCX282-B, and PF-00547,659 are few of monoclonal antibodies that have shown high promise in trials with the potential for more attractive benefit:risk ratio than currently available therapies. In this review, an attempt is made to underline the therapeutic potential and the safety of anti-adhesion molecule treatment in IBD.", "Juvenile polyposis syndrome (JPS) is an autosomal dominant predisposition to the occurrence of hamartomatous polyps in the gastrointestinal tract. Diagnosis of JPS is based on the occurrence of numerous colon and rectum polyps or any number of polyps with family history and, in the case of juvenile polyps, their occurrence also outside the large intestine. The JPS is caused by mutations in SMAD4 and BMPR1A. Products of the SMAD4 gene are involved in signal transduction in the transforming growth factor β pathway and BMPR1A protein is a receptor belonging to the family of transmembrane serine/threonine kinases. Both proteins are responsible for processes determining appropriate development of colonic mucosa. The JPS belongs to the group of hamartomatous polyposes. The hamartomatous polyposis syndromes constitute a group of diseases in which manifestations differ slightly and only molecular diagnostics gives the possibility of verifying the clinical diagnosis.", "Conditions in the body during aerobic exercise increase the level of lipid peroxidation (LP). LP is associated with elevated concentration of modified low-density lipoproteins that are implicated in development of cardiovascular disease. Supplementation with antioxidant vitamin E to athletes at 267 mg (400 IUs) or greater has been reported to reduce levels of LP associated with exercise. Little is currently known about the effects of modest supplementation of vitamin E on previously sedentary adults who initiate an aerobic fitness program. In the present study, sedentary subjects (n = 14) kept 24-hour diet records to establish antioxidant intake of vitamins E and C and collected 24-hour urine samples that were used to determine baseline urinary malondialdehyde (MDA) concentrations, one measure of in vivo LP. No significant differences were noted in the parameters between groups. Seven subjects were randomly selected and supplemented daily with 133 mg (200 IUs) of vitamin E. All subjects participated in moderate-intensity aerobic training for 8 weeks. Post-training, non-supplemented subjects excreted significantly more MDA (p<0.05) and consumed significantly fewer antioxidants than the supplemented group. Vitamin E supplementation appears to suppress elevated LP associated with beginning an aerobic exercise regimen in previously sedentary subjects.", "BACKGROUND: With the advancement in high-throughput technologies, researchers can simultaneously investigate gene expression and copy number alteration (CNA) data from individual patients at a lower cost. Traditional analysis methods analyze each type of data individually and integrate their results using Venn diagrams. Challenges arise, however, when the results are irreproducible and inconsistent across multiple platforms. To address these issues, one possible approach is to concurrently analyze both gene expression profiling and CNAs in the same individual.RESULTS: We have developed an open-source R/Bioconductor package (iGC). Multiple input formats are supported and users can define their own criteria for identifying differentially expressed genes driven by CNAs. The analysis of two real microarray datasets demonstrated that the CNA-driven genes identified by the iGC package showed significantly higher Pearson correlation coefficients with their gene expression levels and copy numbers than those genes located in a genomic region with CNA. Compared with the Venn diagram approach, the iGC package showed better performance.CONCLUSION: The iGC package is effective and useful for identifying CNA-driven genes. By simultaneously considering both comparative genomic and transcriptomic data, it can provide better understanding of biological and medical questions. The iGC package's source code and manual are freely available at https://www.bioconductor.org/packages/release/bioc/html/iGC.html ." ]

[ "A case of the cytologically verified intrathecal dissemination of benign meningiomas was reported. A 36-year-old man was admitted to our hospital because trans-sphenoidal surgery was planned for the repair of CSF rhinorrhea caused by a recurrent pituitary adenoma. The CT scan demonstrated incidental multiple tumors spread throughout in the pontomedullary and ambient cisterns. The head and spinal MRI showed more than fifteen small tumors in the posterior fossa and the thoracic spinal canal. CSF cytology revealed benign fibroblastic or meningotheliomatous meningioma with whorl formation and psammoma body. Several comments were made on the mechanism of the intrathecal dissemination of the meningiomas.", "Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is generally believed that mitochondria and mtDNA are exclusively maternally inherited in humans. Here, we identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a total of 17 individuals. Heteroplasmy of mtDNA was independently examined by high-depth whole mtDNA sequencing analysis in our research laboratory and in two Clinical Laboratory Improvement Amendments and College of American Pathologists-accredited laboratories using multiple approaches. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominantlike inheritance mode. Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent to offspring and may even lead to the development of new avenues for the therapeutic treatment for pathogenic mtDNA transmission.", "Misfolded proteins in the endoplasmic reticulum (ER) are dislocated out of the ER to the cytosol, polyubiquitinated, and degraded by the ubiquitin-proteasome system in a process collectively termed ER-associated degradation (ERAD). Recent studies have established that a mammalian ER-localized transmembrane J-protein, DNAJB12, cooperates with Hsc70, a cytosolic Hsp70 family member, to promote the ERAD of misfolded membrane proteins. Interestingly, mammalian genomes have another J-protein called DNAJB14 that shows a high sequence similarity to DNAJB12. Yet, very little was known about this protein. Here, we report the characterization of DNAJB14. Immunofluorescence study and protease protection assay showed that, like DNAJB12, DNAJB14 is an ER-localized, single membrane-spanning J-protein with its J-domain facing the cytosol. We used co-immunoprecipitation assay to find that DNAJB14 can also specifically bind Hsc70 via its J-domain to recruit this chaperone to ER membrane. Remarkably, the overexpression of DNAJB14 accelerated the degradation of misfolded membrane proteins including a mutant of cystic fibrosis transmembrane conductance regulator (CFTRΔF508), but not that of a misfolded luminal protein. Furthermore, the DNAJB14-dependent degradation of CFTRΔF508 was compromised by MG132, a proteasome inhibitor, indicating that DNAJB14 can enhance the degradation of a misfolded membrane protein using the ubiquitin-proteasome system. Thus, the mammalian ER possesses two analogous J-proteins (DNAJB14 and DNAJB12) that both can promote the ERAD of misfolded transmembrane proteins. Compared with DNAJB12 mRNA that was widely expressed in mouse tissues, DNAJB14 mRNA was expressed more weakly, being most abundant in testis, implying its specific role in this tissue.", "Immune privilege (IP) is believed to exist in the anagen hair follicle (HF). Studies have shown that downregulation of major histocompatibility complex Class I occurs and immunosuppressive factors are expressed in the HF bulb and bulge. However, demonstration and quantification of functional IP in HF cells are required. We examined the middle (sheath) and lower (bulb) portions of the human HF using quantitative real-time RT-PCR (qPCR), immunohistology, ELISA, in vitro coculture with peripheral blood mononuclear cells (PBMCs), and flow cytometry. We found that HF cells, relative to non-follicular epidermal cells, failed to promote allogeneic PBMC proliferation and CD4(+) and CD8(+) IFNγ production. By qPCR, we found significant downregulation of Class I and Class II HLA alleles in both the bulb and sheath, and upregulation of multiple immunoregulatory genes. It is noteworthy that somatostatin (SST) was significantly upregulated relative to epidermis. By immunohistochemistry, SST was most strongly expressed in the HF outer root sheath, and, by ELISA, cultured sheath cells secreted SST. PBMCs, cultured with stimulatory allogeneic epidermal cells and SST, secreted significantly less IFNγ than controls. Addition of SST antagonists to PBMCs cocultured with allogeneic HF cells increased IFNγ secretion. The data identify SST as a secretory factor potentially contributing to the HF IP repertoire.", "BACKGROUND AND AIM: Selumetinib is a promising and interesting targeted therapy agent as it may reverse radioiodine uptake in patients with radioiodine-refractory differentiated thyroid cancer. We conduct this meta- analysis to compare the efficacy and safety of selumetinib with current therapies in patients with advanced cancer.METHODS: An electronic search was conducted using PubMed/ Medicine, EMBASE and Cochrane library databases. Statistical analyses were carried out using either random-effects or fixed-effects models according to the heterogeneity of eligible studies.RESULTS: Six eligible trials involved 601 patients were identified. Compared with current therapies, treatment schedules with selumetinib did not improve progression free survival (hazard ratio, 0.91; 95%CI 0.70-1.17, P= 0.448), but did identify better clinical benefits (odds ratio, 1.24; 95%CI 0.69- 2.24, P = 0.472) and less disease progression (hazard ratio, 0.72; 95%CI 0.51-1.00, P = 0.052) though its impact was not statistically significant. Sub-group analysis resulted in significantly improved progression free survival (hazard ratio, 0.61; 95%CI 0.49-0.57, P = 0.00), clinical benefits (odds ratio, 3.04; 95%CI 1.60-5.77, P = 0.001) and reduced disease progression (hazard ratio, 0.35; 95%CI 0.18-0.67, P = 0.001) in patients administrated selumetinib. Dermatitis acneiform (risk ratio, 9.775; 95%CI 3.143-30.395, P = 0.00) and peripheral edema (risk ratio, 2.371; 95%CI 1.690-3.327, P = 0.00) are the most frequently observed adverse effects associated with selumetinib.CONCLUSIONS: Compared with current chemotherapy, selumetinib has modest clinical activity as monotherapy in patients with advanced cancer, but combinations of selumetinib with cytotoxic agents in patients with BRAF or KRAS mutations hold great promise for cancer treatment. Dermatitis acneiform and peripheral edema are the most frequently observed adverse effects in patients with selumetinib.", "MOTIVATION: RNA sequencing (RNA-Seq) is a powerful new technology for mapping and quantifying transcriptomes using ultra high-throughput next-generation sequencing technologies. Using deep sequencing, gene expression levels of all transcripts including novel ones can be quantified digitally. Although extremely promising, the massive amounts of data generated by RNA-Seq, substantial biases and uncertainty in short read alignment pose challenges for data analysis. In particular, large base-specific variation and between-base dependence make simple approaches, such as those that use averaging to normalize RNA-Seq data and quantify gene expressions, ineffective.RESULTS: In this study, we propose a Poisson mixed-effects (POME) model to characterize base-level read coverage within each transcript. The underlying expression level is included as a key parameter in this model. Since the proposed model is capable of incorporating base-specific variation as well as between-base dependence that affect read coverage profile throughout the transcript, it can lead to improved quantification of the true underlying expression level.AVAILABILITY AND IMPLEMENTATION: POME can be freely downloaded at http://www.stat.purdue.edu/~yuzhu/pome.html.CONTACT: yuzhu@purdue.edu; zhaohui.qin@emory.eduSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD) are the two disorders which are known to share pertinent pathological and therapeutic links. Sodium glucose co-transporter-2 (SGLT2) and Acetylcholinesterase (AChE) are established inhibition targets for T2DM and AD treatments, respectively. Reports suggest that anti-diabetic drugs could be used for AD treatment also. The present study used molecular docking by Autodock4.2 using our \"Click-By-Click\"-protocol, Ligplot1.4.3 and \"change in accessible surface area (ΔASA)-calculations\" to investigate the binding of two investigational anti-diabetic drugs, Ertugliflozin and Sotagliflozin to an established target (SGLT2) and a research target (human brain AChE). Sotagliflozin appeared more promising for SGLT2 as well as AChE-inhibition with reference to ΔG and Ki values in comparison to Ertugliflozin. The ΔG and Ki values for \"Sotagliflozin:AChE-binding\" were -7.16 kcal/mol and 5.6 μM, respectively while the same were found to be -8.47 kcal/mol and 0.62 μM, respectively for its interaction with SGLT2. Furthermore, \"Sotagliflozin:SGLT2-interaction\" was subjected to (un)binding simulation analyses by \"Molecular-Motion-Algorithms.\" This information is significant as the exact binding mode, interacting amino acid residues and simulation results for the said interaction have not been described yet. Also no X-ray crystal is available for the same. Finally, the results described herein indicate that Sotagliflozin could have an edge over Ertugliflozin for treatment of Type 2 diabetes. Future design of drugs based on Sotagliflozin scaffolds for treatment of Type 2 and/or Type 3 diabetes are highly recommended. As these drugs are still in late phases of clinical trials, the results described herein appear timely. J. Cell. Biochem. 118: 3855-3865, 2017. © 2017 Wiley Periodicals, Inc." ]

[ "The effect of combinations of the anthracyclines aclarubicin and daunorubicin was investigated in a clonogenic assay using the human small cell lung cancer cell line OC-NYH and a multidrug-resistant (MDR) murine subline of Ehrlich ascites tumor (EHR2/DNR+). It was found that the cytotoxicity of daunorubicin in OC-NYH cells was antagonized by simultaneous exposure to nontoxic concentrations of aclarubicin. Coordinately, aclarubicin inhibited the formation of daunorubicin-induced protein-concealed DNA single-strand breaks and DNA-protein cross-links in OC-NYH cells when assayed by the alkaline elution technique. Aclarubicin had no influence on the accumulation of daunorubicin in these cells. In contrast, the accumulation of daunorubicin in EHR2/DNR+ cells was enhanced by more than 300% when the cells were simultaneously incubated with the MDR modulator verapamil, aclarubicin, or the two agents combined. Yet the cytotoxicity of daunorubicin was potentiated significantly only by verapamil. The increased cytotoxicity of daunorubicin in the presence of verapamil was completely antagonized when aclarubicin was used together with the MDR modulator. Finally, the effect of daunorubicin on the DNA cleavage activity of purified topoisomerase II in the presence and absence of aclarubicin was examined. It was found that daunorubicin stimulated DNA cleavage by topoisomerase II at specific DNA sites. The addition of aclarubicin completely inhibited the daunorubicin-induced stimulation of DNA cleavage. Taken together, these data indicate that aclarubicin-mediated inhibition of daunorubicin-induced cytotoxicity is due mainly to a drug interaction with the nuclear enzyme topoisomerase II. This antagonism at the nuclear level explains why aclarubicin is a poor modulator of daunorubicin resistance even though aclarubicin is able to increase the intracellular accumulation of daunorubicin in a MDR cell line.", "MOTIVATION: Allele-specific expression (ASE) refers to the differential abundance of the allelic copies of a transcript. RNA sequencing (RNA-seq) can provide quantitative estimates of ASE for genes with transcribed polymorphisms. When short-read sequences are aligned to a diploid transcriptome, read-mapping ambiguities confound our ability to directly count reads. Multi-mapping reads aligning equally well to multiple genomic locations, isoforms or alleles can comprise the majority (>85%) of reads. Discarding them can result in biases and substantial loss of information. Methods have been developed that use weighted allocation of read counts but these methods treat the different types of multi-reads equivalently. We propose a hierarchical approach to allocation of read counts that first resolves ambiguities among genes, then among isoforms, and lastly between alleles. We have implemented our model in EMASE software (Expectation-Maximization for Allele Specific Expression) to estimate total gene expression, isoform usage and ASE based on this hierarchical allocation.RESULTS: Methods that align RNA-seq reads to a diploid transcriptome incorporating known genetic variants improve estimates of ASE and total gene expression compared to methods that use reference genome alignments. Weighted allocation methods outperform methods that discard multi-reads. Hierarchical allocation of reads improves estimation of ASE even when data are simulated from a non-hierarchical model. Analysis of RNA-seq data from F1 hybrid mice using EMASE reveals widespread ASE associated with cis-acting polymorphisms and a small number of parent-of-origin effects.AVAILABILITY AND IMPLEMENTATION: EMASE software is available at https://github.com/churchill-lab/emase.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "BACKGROUND: RNA-Seq is currently used routinely, and it provides accurate information on gene transcription. However, the method cannot accurately estimate duplicated genes expression. Several strategies have been previously used (drop duplicated genes, distribute uniformly the reads, or estimate expression), but all of them provide biased results.RESULTS: We provide here a tool, called mmquant, for computing gene expression, included duplicated genes. If a read maps at different positions, the tool detects that the corresponding genes are duplicated; it merges the genes and creates a merged gene. The counts of ambiguous reads is then based on the input genes and the merged genes.CONCLUSION: mmquant is a drop-in replacement of the widely used tools htseq-count and featureCounts that handles multi-mapping reads in an unabiased way.", "Pendred syndrome is an autosomal recessive inherited disorder. Obligatory features are profound deafness in childhood and defective organic binding of iodine in the thyroid gland. Therefore, goiter is a common symptom. Hypoplasia of the cochlea is another feature. Recently, the gene for Pendred syndrome was identified. We describe a boy whose sensorineural hearing loss in both ears progressed rapidly from about 50 to 60 dB at the age of 3 years and 3 months to more than 100 dB at the age of 4 years and 4 months. This loss was preceded by a medical history of a progressive hearing loss. The progressive nature of the hearing loss motivated a search for the cause. Dysplasia of the cochlea and a widened vestibular aqueduct were found. The results of thyroid function tests were normal, but he had an elevated level of thyroglobulin. The diagnosis of Pendred syndrome was confirmed by the positive results of a potassium perchlorate test, indicating defective organic binding of iodine in the thyroid gland. It is possible that the widened vestibular aqueduct was responsible for the increase in the hearing impairment. Aside from the branchio-otorenal syndrome, Pendred syndrome is the only other known genetic disorder with a widened vestibular aqueduct. If a child has progressive sensorineural deafness and a widened vestibular aqueduct, it is important to consider a diagnosis of Pendred syndrome. A widened vestibular aqueduct may help to elucidate the pathophysiologic characteristics of hearing loss in these genetic types of deafness in childhood.", "Cell-to-cell variation is a universal feature of life that affects a wide range of biological phenomena, from developmental plasticity to tumour heterogeneity. Although recent advances have improved our ability to document cellular phenotypic variation, the fundamental mechanisms that generate variability from identical DNA sequences remain elusive. Here we reveal the landscape and principles of mammalian DNA regulatory variation by developing a robust method for mapping the accessible genome of individual cells by assay for transposase-accessible chromatin using sequencing (ATAC-seq) integrated into a programmable microfluidics platform. Single-cell ATAC-seq (scATAC-seq) maps from hundreds of single cells in aggregate closely resemble accessibility profiles from tens of millions of cells and provide insights into cell-to-cell variation. Accessibility variance is systematically associated with specific trans-factors and cis-elements, and we discover combinations of trans-factors associated with either induction or suppression of cell-to-cell variability. We further identify sets of trans-factors associated with cell-type-specific accessibility variance across eight cell types. Targeted perturbations of cell cycle or transcription factor signalling evoke stimulus-specific changes in this observed variability. The pattern of accessibility variation in cis across the genome recapitulates chromosome compartments de novo, linking single-cell accessibility variation to three-dimensional genome organization. Single-cell analysis of DNA accessibility provides new insight into cellular variation of the 'regulome'.", "Lung cancer (LC) represents the most common solid tumor in survivors of Hodgkin's disease (HD), and the assessment of the mutational status of oncogenic driver mutations in LC is now standard. We compiled clinical and mutation data (EGFR, KRAS, and ALK) from the medical records of patients with LC and a remote history of HD. 13 cases of LC following HD were seen, including seven with mutational data. Two had EGFR mutations, none had KRAS mutations or ALK translocations. Our conclusions are limited by the small sample size, however this report reinforces the need to identify driver mutations in lung cancers.", "The human beta-globin dominant control region (DCR) which flanks the multigene beta-globin locus directs high level, site of integration independent, copy number dependent expression on a linked human beta-globin gene in transgenic mice and stably transfected mouse erythroleukemia (MEL) cells. We have assayed each of the individual DNaseI hypersensitive regions present in the full 15kb DCR for position independence and copy number dependence of a linked beta-globin gene in transgenic mice. The results show that at least three of the individual DNaseI hypersensitive site regions (sites 1, 2 and 3), though expressing at lower levels than the full DCR, are capable of position independent, copy number dependent expression. Site 2 alone directs the highest level of expression of the single site constructs, producing nearly 70% of the level of the full DCR. Sites 1 and 3 each provide 30% of the full activity. Deletion of either site 2 or 3 from the complete set significantly reduces the level of expression, but does not effect position independence or copy number dependence. This demonstrates that sites 2 and 3 are required for full expression and suggests that all the sites are required for the full expression of even a single gene from this multigene locus.", "A novel naphthylmethylimidazole derivative 1 and its related compounds were identified as 17,20-lyase inhibitors. Based on the structure-activity relationship around the naphthalene scaffold and the results of a docking study of 1a in the homology model of 17,20-lyase, the 6,7-dihydro-5H-pyrrolo[1,2-c]imidazole derivative (+)-3c was synthesized and identified as a potent and highly selective 17,20-lyase inhibitor. Biological evaluation of (+)-3c at a dose of 1mg/kg in a male monkey model revealed marked reductions in both serum testosterone and dehydroepiandrosterone concentrations. Therefore, (+)-3c (termed orteronel [TAK-700]) was selected as a candidate for clinical evaluation and is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer." ]

[ "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.", "CONTEXT: Six-transmembrane protein of prostate 2 (STAMP2) is a counter-regulator of inflammation and insulin resistance according to findings in mice. However, there have been contradictory reports in humans.OBJECTIVE: We aimed to explore STAMP2 in association with inflammatory and metabolic status of human obesity.DESIGN, PATIENTS, AND METHODS: STAMP2 gene expression was analyzed in adipose tissue samples (171 visceral and 67 sc depots) and during human preadipocyte differentiation. Human adipocytes were treated with macrophage-conditioned medium, TNF-α, and rosiglitazone.RESULTS: In visceral adipose tissue, STAMP2 gene expression was significantly decreased in obese subjects, mainly in obese subjects with type 2 diabetes. STAMP2 gene expression and protein were significantly and inversely associated with obesity phenotype measures (body mass index, waist, hip, and fat mass) and obesity-associated metabolic disturbances (systolic blood pressure and fasting glucose). In addition, STAMP2 gene expression was positively associated with lipogenic (FASN, ACC1, SREBP1, THRSP14, TRα, and TRα1), CAV1, IRS1, GLUT4, and CD206 gene expression. In sc adipose tissue, STAMP2 gene expression was not associated with metabolic parameters. In both fat depots, STAMP2 gene expression in stromovascular cells was significantly higher than in mature adipocytes. STAMP2 gene expression was significantly increased during the differentiation process in parallel to adipogenic genes, being increased in preadipocytes derived from lean subjects. Macrophage-conditioned medium (25%) and TNF-α (100 ng/ml) administration increased whereas rosiglitazone (2 μM) decreased significantly STAMP2 gene expression in human differentiated adipocytes.CONCLUSIONS: Decreased STAMP2 expression (mRNA and protein) might reflect visceral adipose dysfunction in subjects with obesity and type 2 diabetes.", "Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene. Fabry disease (FD) is an X-linked lysosomal storage disorder with a heterogeneous spectrum of clinical manifestations that are caused by the deficiency of α-galactosidase A (α-Gal-A) activity. Although useful for diagnosis in males, enzyme activity is not a reliable biochemical marker in heterozygous females due to random X-chromosome inactivation, thus rendering DNA sequencing of the α-Gal-A gene, alpha-galactosidase gene (GLA), the most reliable test for the confirmation of diagnosis in females. The spectrum of GLA mutations is highly heterogeneous. Many polymorphic GLA variants have been described, but it is unclear if haplotypes formed by combinations of such variants correlate with FD, thus complicating molecular diagnosis in females with normal α-Gal-A activity. We tested 67 female probands with clinical manifestations that may be associated with FD and 110 control males with normal α-Gal-A activity. Five different combinations of GLA polymorphic variants were identified in 14 of the 67 females, whereas clearcut pathogenetic alterations, p.Met51Ile and p.Met290Leu, were identified in two cases. The latter has not been reported so far, and both mutant forms were found to be responsive to the pharmacological chaperone deoxygalactonojirimycin (DGJ; migalastat hydrochloride). Analysis of the male control population, as well as male relatives of a suspected FD female proband, permitted the identification of seven different GLA gene haplotypes in strong linkage disequilibrium. The identification of haplotypes in control males provides evidence against their involvement in the development of FD phenotypic manifestations.", "Delafloxacin (Baxdela™) is a fluoroquinolone antibacterial with activity against both gram-positive and gram-negative pathogens being developed by Melinta Therapeutics. The drug is being investigated or considered as a treatment for various bacterial infections and in June 2017 received approval in the USA for the treatment of acute bacterial skin and skin structure infections. This article summarizes the milestones in the development of delafloxacin leading to this first global approval for the treatment of acute bacterial skin and skin structure infections.", "OBJECTIVE: Chronic infection by Helicobacter pylori is regarded as an etiological factor for vascular diseases. However, there are conflicting results on the relevance of chronic infection by Helicobacter pylori as a risk factor for ischemic stroke. The aim of our study was to investigate the association between Helicobacter pylori infection and ischemic stroke subtypes in Chinese.METHOD: A total of 150 patients with ischemic stroke were enrolled in the patient group. Analyses were stratified for etiologic stroke subtypes according to 2007 modified Trial of Org 10172 in Acute Stroke Treatment criteria: 119 patients with atherothrombosis, 15 patients with cardioembolism, and 12 patients with small artery disease. One hundred and thirty-one control subjects without clinical and instrumental evidence of atherosclerotic diseases were randomly selected from health check-up center. The potential risk factors for Helicobacter pylori infection and traditional risk factors for ischemic stroke of all subjects were analyzed. The serum specific antibody IgG of Helicobacter pylori was detected by enzyme-linked immunosorbent assay. Conditional logistic regression was used to analyze the data.RESULTS: The Helicobacter pylori/IgG-positive rate in the patient group was higher than that in the healthy control group, but the difference was not statistically significant [67.3% versus 61.8%; odds ratio (OR) = 1.272; P = 0.336]. This result remained non-significant after adjustment for other established risk factors [OR = 1.222; 95% confidence interval (CI): 0.688-2.171; P = 0.494]. Subgroup analysis using univariate and multivariate analyses yielded similar results in all etiologic stroke subtypes (univariate analysis, atherothrombosis: OR = 1.368, 95%CI: 0.810-2.311, P = 0.241; cardioembolism: OR = 0.926, 95%CI:0.311-2.758, P = 0.890; small artery disease: OR = 1.852, 95%CI: 0.478-7.167, P = 0.366; multivariate analysis, atherothrombosis: OR = 1.385, 95%CI: 0.726-2.639, P = 0.323; cardioembolism: OR = 0.832, 95%CI: 0.236-2.932, P = 0.775; small artery disease: OR = 1.836, 95%CI: 0.396-8.503, P = 0.437).CONCLUSIONS: This case-control study does not reveal any strong association between chronic Helicobacter pylori infection and ischemic stroke. Large case-control prospective studies are required for further investigation of the potential association between Helicobacter pylori infection and ischemic stroke risk, particularly in certain subgroups.", "Transcription-coupled repair (TCR) is a cellular process by which some forms of DNA damage are repaired more rapidly from transcribed strands of active genes than from nontranscribed strands or the overall genome. In humans, the TCR coupling factor, CSB, plays a critical role in restoring transcription following both UV-induced and oxidative DNA damage. It also contributes indirectly to the global repair of some forms of oxidative DNA damage. The Escherichia coli homolog, Mfd, is similarly required for TCR of UV-induced lesions. However, its contribution to the restoration of transcription and to global repair of oxidative damage has not been examined. Here, we report the first direct study of transcriptional recovery following UV-induced and oxidative DNA damage in E. coli. We observed that mutations in mfd or uvrA reduced the rate that transcription recovered following UV-induced damage. In contrast, no difference was detected in the rate of transcription recovery in mfd, uvrA, fpg, nth, or polB dinB umuDC mutants relative to wild-type cells following oxidative damage. mfd mutants were also fully resistant to hydrogen peroxide (H(2)O(2)) and removed oxidative lesions from the genome at rates comparable to wild-type cells. The results demonstrate that Mfd promotes the rapid recovery of gene expression following UV-induced damage in E. coli. In addition, these findings imply that Mfd may be functionally distinct from its human CSB homolog in that it does not detectably contribute to the recovery of gene expression or global repair following oxidative damage.", "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." ]