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[ "BACKGROUND: Sustained lung inflation (SLI) applied at birth has been demonstrated to lead to clearance of lung fluid and achievement of a precocious functional residual capacity in animal studies.OBJECTIVES: To verify if the application of SLI in preterm infants at birth may reduce the need for mechanical ventilation and improve their respiratory outcome.METHODS: We prospectively studied 89 infants with respiratory distress (gestational age (GA) 28.1 ± 2.2 weeks) treated at birth with a SLI (25 cm H(2)O, sustained for 15 s) in addition to AAP recommendations versus a historical control group (n = 119; GA 28.1 ± 2.0 weeks) treated without SLI with the same device (controlled positive end-expiratory pressure of 5 cm H(2)O).RESULTS: The SLI group had less need for (51 vs. 76%, p < 0.0001) and shorter duration of mechanical ventilation (5 ± 11 vs. 11 ± 19 days, p = 0.008), a more frequent occurrence of exclusive nasal continuous airway pressure support (49 vs. 24%, p < 0.0001) and INtubation-SURfactant-Extubation (INSURE) treatment (16 vs. 3%, p = 0.01), less need for surfactant (45 vs. 61%, p = 0.027) and postnatal steroids (10 vs. 25%, p = 0.01), a shorter duration of oxygen therapy (21 ± 27 vs. 31 ± 31 days, p = 0.016), and, finally, a lower occurrence of bronchopulmonary dysplasia in survivors (7 vs. 25%, p = 0.004). Multiple regression analysis showed that 23-27 weeks of GA and birth weight <750 g increased the risk of mechanical ventilation, while a clinical risk index for babies (CRIB) score <3 as well as INSURE strategy and SLI treatment in the delivery room decreased it.CONCLUSIONS: The application of a SLI at birth in preterm infants with respiratory distress may decrease the need for mechanical ventilation without inducing evident adverse effects.", "Gram-negative and Gram-positive bacteria release a variety of membrane vesicles through different formation routes. Knowledge of the structure, molecular cargo and function of bacterial extracellular vesicles (BEVs) is primarily obtained from bacteria cultured in laboratory conditions. BEVs in human body fluids have been less thoroughly investigated most probably due to the methodological challenges in separating BEVs from their matrix and host-derived eukaryotic extracellular vesicles (EEVs) such as exosomes and microvesicles. Here, we present a step-by-step procedure to separate and characterize BEVs from human body fluids. BEVs are separated through the orthogonal implementation of ultrafiltration, size-exclusion chromatography (SEC) and density-gradient centrifugation. Size separates BEVs from bacteria, flagella and cell debris in stool; and blood cells, high density lipoproteins (HDLs) and soluble proteins in blood. Density separates BEVs from fibers, protein aggregates and EEVs in stool; and low-density lipoproteins (LDLs), very-low-density lipoproteins (VLDLs), chylomicrons, protein aggregates and EEVs in blood. The procedure is label free, maintains the integrity of BEVs and ensures reproducibility through the use of automated liquid handlers. Post-separation BEVs are characterized using orthogonal biochemical endotoxin and Toll-like receptor-based reporter assays in combination with proteomics, electron microscopy and nanoparticle tracking analysis (NTA) to evaluate BEV quality, abundance, structure and molecular cargo. Separation and characterization of BEVs from body fluids can be done within 72 h, is compatible with EEV analysis and can be readily adopted by researchers experienced in basic molecular biology and extracellular vesicle analysis. We anticipate that this protocol will expand our knowledge on the biological heterogeneity, molecular cargo and function of BEVs in human body fluids and steer the development of laboratory research tools and clinical diagnostic kits.", "Alkaptonuria (AKU) is an autosomal recessive disorder due to homogentisate 1,2-dioxygenase (HGD) deficiency in the liver and characterized by a triad of signs, according to chronology of appearance: homogentisic aciduria (HGA) or alkaptonuria, ochronosis then ochronotic arthropathy. This inborn error of metabolism is caused by mutations in the HGD gene. In this work we report observations of 96 AKU French patients from 81 families collected in the literature since 1882 and from our personal contribution since 1986, giving an incidence of the disease of around 1:680,000 (96/64.10(6)). As expected for an autosomal recessive disorder the main findings of this study were: a slight predominance of males (51/93, 54,8%) over females (42/93, 45,2%), a strong predominance of sibships with one affected individual (68/81, 84,0%) over sibships with two (11/81, 13.6%) and three(2/81, 2.4%) affected individuals. AKU families are scaterred among the French territory suggesting that most cases occured in non-consanguineous unions. Consanguinity was only found in five families. Other peculiarities of this study were (a) ten of these families have both parents from a foreign geographical origin: Poland(3), Italy(3), Portugal(2), Ukraine(1) and India(1) and four families with only one foreign parent (Algeria, Armenia, Serbia, UK), (b) HGD mutations were found in 23 families, (c) four of theses 96 patients were seen by us respectively 28, 29, 39 and 45 years after their report in the literature and (d) seven patients present cardiac and/or renal complications.", "INTRODUCTION: The formalin test is the most accepted chemical test for evaluation of nociception. It requires the injection of an adequate amount of formalin into the surface of the hindpaw. Formalin test consists of phase 1 (0-7 min) and phase 2 (15-60) in which the animal shows painful behaviors. These phases are separated with a quiet phase named interphase, in which the nociceptive responses are decreased or completely disappeared.METHODS: The goal of the current study was to evaluate the effects of swim stress at different heights of water on different phases of the formalin test in male rats.RESULTS: Swim stress decreased nociceptive behaviors in first phase and prolonged interphase or delayed the start of second phase in a water height dependent manner. Swim stress in 25 and 50cm completely abolished the nociceptive behaviors in phase 1.DISCUSSION: The present results showed different pain modulation during different phases of the formalin test and elucidated the impact of swim stress on duration of interphase. Interphase considered as an inactive period, but a recent research has shown that active inhibitory mechanisms are involved in the modulation of pain during this period. Therefore, swim stress may be considered as a useful tool for study of the basic inhibitory mechanisms underlying attenuation of nociceptive behaviors between phase 1 and 2 of the formalin test.", "Author information:(1)Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.(2)Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK.(3)Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne.(4)Division of Genetics and Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.(5)Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.(6)Precision Medicine Exeter, University of Exeter, Exeter, UK.(7)IBD Pharmacogenetics, Royal Devon and Exeter Foundation Trust, Exeter, UK.(8)Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK.(9)Christ Church, University of Oxford, St Aldates, UK.(10)Gastrointestinal Unit, Wester General Hospital University of Edinburgh, Edinburgh, UK.(11)Department of Gastroenterology, Torbay Hospital, Torbay, Devon, UK.(12)Department of Child Life and Health, University of Edinburgh, Edinburgh, UK.(13)Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children,Edinburgh, UK.(14)Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK.(15)Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, Department of Gastroenterology, London, UK.(16)Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.(17)Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.(18)Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK.(19)Child Life and Health, University of Edinburgh, Edinburgh, Scotland, UK.(20)Gastroenterology & General Medicine, Norfolk and Norwich University Hospital, Norwich, UK.(21)Department of Medicine, St Mark's Hospital, Harrow, Middlesex, UK.(22)Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King's College London, Guy's Hospital, London, UK.(23)Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of Witwatersrand, South Africa.(24)Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK.(25)The Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.(26)Translational Gastroenterology Unit and the Department of Paediatrics, University of Oxford, Oxford, United Kingdom.(27)Nottingham Digestive Diseases Centre, Queens Medical Centre, Nottingham, UK.(28)Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.(#)Contributed equally", "BACKGROUND: Gastroesophageal reflux disease (GERD) is a common chronic disease requiring adequate treatment since it represents one major cause of development of Barrett's esophagus and eventually carcinoma. Novel laparoscopic magnetic sphincter augmentation for GERD was evaluated prospectively.PATIENTS AND METHODS: A total of 23 patients with GERD underwent minimally invasive implantation of LINX™ Reflux Management System. Primary outcome measures were overall feasibility, short-term procedure safety and efficacy. Secondary GERD-related quality of life was assessed.RESULTS: All implantations were performed without serious adverse events. A significant decrease in all major GERD complaints were found: heartburn: 96%-22% (p<0.001); bloating: 70%-30% (p=0.006); respiratory complaints: 57%-17% (p=0.039); sleep disturbance: 65%-4% (p<0.001). A four-week follow-up reduction of ≥50% of proton pump inhibitor (PPI) dose was achieved in over 80% of patients. Self-limiting difficulty in swallowing was found in 70% within four weeks. One patient required for endoscopic dilation. GERD-related quality of life improved significantly.CONCLUSION: LINX™ implantation is a standardized, technically simple, safe and well-tolerated expeditious procedure.", "Regions of the genome that have been the target of positive selection specifically along the human lineage are of special importance in human biology. We used high throughput sequencing combined with methods to enrich human genomic samples for particular targets to obtain the sequence of 22 chromosomal samples at high depth in 40 kb neighborhoods of 49 previously identified 100-400 bp elements that show evidence for human accelerated evolution. In addition to selection, the pattern of nucleotide substitutions in several of these elements suggested an historical bias favoring the conversion of weak (A or T) alleles into strong (G or C) alleles. Here we found strong evidence in the derived allele frequency spectra of many of these 40 kb regions for ongoing weak-to-strong fixation bias. Comparison of the nucleotide composition at polymorphic loci to the composition at sites of fixed substitutions additionally reveals the signature of historical weak-to-strong fixation bias in a subset of these regions. Most of the regions with evidence for historical bias do not also have signatures of ongoing bias, suggesting that the evolutionary forces generating weak-to-strong bias are not constant over time. To investigate the role of selection in shaping these regions, we analyzed the spatial pattern of polymorphism in our samples. We found no significant evidence for selective sweeps, possibly because the signal of such sweeps has decayed beyond the power of our tests to detect them. Together, these results do not rule out functional roles for the observed changes in these regions-indeed there is good evidence that the first two are functional elements in humans-but they suggest that a fixation process (such as biased gene conversion) that is biased at the nucleotide level, but is otherwise selectively neutral, could be an important evolutionary force at play in them, both historically and at present." ]

[ "The objective of the present study is to evaluate the effect of epigallocatechin gallate (EGCG) on aging-mediated cardiac hypertrophy, fibrosis, and apoptosis. The Wistar albino rats were divided into 4 groups (n = 18). Group I: young (3 months), group II: aged (24-26 months), group III: aged + EGCG (200 mg/kg for 30 days), and group IV: young + EGCG. At the end of 30 days, EGCG administration to the aged animals showed significant (P < 0.001) reduction of low-density lipoprotein, very low-density lipoprotein, triglyceride, total cholesterol with concomitant increase of high-density lipoprotein (P < 0.001) when compared with aged rats. Increased (P < 0.001) heart volume, weight with concomitant increase of left ventricular wall thickness, and reduced ventricular cavity were observed in aged rats supplemented with EGCG compared with aged animals. Histology and histomorphometry study of aged animals treated with EGCG showed marked increases in the diameter and volume of cardiomyocytes with concomitant reduction of numerical density when compared with aged animals. Reduced reactive oxygen species (P < 0.001) production with association of increased antioxidant defense system (P < 0.001) in aged hearts supplemented with EGCG when compared with aged animals. TUNEL staining and fibrosis showed a marked increase in apoptotic cell death (P < 0.001) and collagen deposition (P < 0.001) in aged animals treated with EGCG when compared with aged animals. Aged animals treated with EGCG showed a marked increase in protein expression of TGFβ, TNFα, and nuclear factor kappa B (NF-κB) and significant (P < 0.001) alteration in the gene expression of TGFβ, TNFα, NF-κB, α-SMA, and Nrf2 when compared with aged animals. Taken together, it is evident that EGCG may potentially inhibit aging-induced cardiac hypertrophy, fibrosis, and apoptosis, thereby preserving cardiac function. The proposed mechanism would be inhibition of reactive oxygen species-dependent activation of TGFβ1, TNFα, and NF-κB signaling pathway. Hence, the present study suggests that EGCG can be useful to fight against aging-induced cardiac hypertrophy, fibrosis, and apoptosis.", "Carpal tunnel syndrome (CTS) is a focal compressive neuropathy of the median nerve at the level of the wrist. CTS is the most common type of compressive neuropathy that occurs in the upper extremity. Typically, patients with CTS have paresthesia, pain, and numbness in the radial three and one-half digits. Nighttime symptoms are more common earlier in the disease process, with daytime symptoms becoming more frequent as CTS progresses. Electrodiagnostic studies may be performed to confirm a diagnosis of CTS or to obtain a baseline before surgical treatment; however, electrodiagnostic studies may be normal in a subset of patients who have CTS. Patients who have mild CTS should undergo an initial trial of nonsurgical treatment that includes lifestyle modifications, nighttime splinting, and corticosteroid injections. Carpal tunnel release should be performed in patients in whom nonsurgical treatment fails and patients who have acute CTS secondary to infection or trauma or have advanced symptoms. Recalcitrant CTS, which may occur in as many as 25% of patients who undergo carpal tunnel release, most commonly results from an incomplete transverse carpal ligament release or an incorrect initial diagnosis. Patients with recurrent symptoms often have perineural fibrosis that tethers the median nerve.", "Occupational allergies are among the most common recorded occupational diseases. The skin and the upper and lower respiratory tract are the classical manifestation organs. More than 400 occupational agents are currently documented as being potential \"respiratory sensitizers\" and new reported causative agents are reported each year. These agents may induce occupational rhinitis (OR) or occupational asthma (OA) and can be divided into high-molecular weight (HMW) and low-molecular weight (LMW) agents. The most common occupational HMW agents are (glycol)proteins found in flour and grains, enzymes, laboratory animals, fish and seafood, molds, and Hevea brasiliensis latex. Typical LMW substances are isocyanates, metals, quaternary ammonium persulfate, acid anhydrides, and cleaning products/disinfectants. Diagnosis of occupational respiratory allergy is made by a combination of medical history, physical examination, positive methacholine challenge result or bronchodilator responsiveness, determination of IgE-mediated sensitization, and specific inhalation challenge tests as the gold standard. Accurate diagnosis of asthma is the first step to managing OA as shown above. Removal from the causative agent is of central importance for the management of OA. The best strategy to avoid OA is primary prevention, ideally by avoiding the use of and exposure to the sensitizer or substituting safer substances for these agents.", "Sacituzumab govitecan (sacituzumab govitecan-hziy; Trodelvy™) is a Trop-2-directed antibody conjugated to a topoisomerase I inhibitor (SN-38) that is being developed by Immunomedics for the treatment of solid tumours, including breast cancer. In April 2020, sacituzumab govitecan received accelerated approval in the USA for the treatment of adult patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies for metastatic disease. Sacituzumab govitecan is undergoing phase III development for breast cancer in the USA and EU, and phase II development for urothelial cancer. It is also being explored for brain metastases, glioblastoma, endometrial cancer and prostate cancer. This article summarizes the milestones in the development of sacituzumab govitecan leading to this first approval for mTNBC.", "Aagenaes syndrome, also called lymphoedema cholestasis syndrome 1 (LSC1), is characterized by neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age and severe chronic lymphoedema, mainly affecting the lower extremities. The condition is autosomal recessively inherited, and the gene is located on chromosome 15q. The locus, LCS1, was mapped to a 6.6 cM region on chromosome 15. Angioid streaks are visible irregular crack-like dehiscences in bruch's membrane that are associated with atrophic degeneration of the overlying retinal pigment epithelium. Angioid streaks have been described to be associated with pseudoxanthoma elasticum, paget's disease, sickle-cell anaemia, acromegaly, Ehlers-Danlos syndrome, and diabetes mellitus, but also appear in patients without any systemic diseases. Patients with angioid streaks are generally asymptomatic, unless the lesions extend towards the foveola or develop complications such as traumatic bruch's membrane rupture or macular choroidal neovascularization.", "Reactive oxygen species (ROS) in the brain are involved in the pathogenesis of hypertension. Epigallocatechin-3-O-gallate (EGCG), one of the active compounds in green tea, has anti-oxidant, anti-inflammatory and vascular protective properties. This study was designed to determine whether chronic infusion of EGCG into the hypothalamic paraventricular nucleus (PVN) attenuates ROS and sympathetic activity and delays the progression of hypertension by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs) and decreasing nuclear factor-kappa B (NF-κB) activity, as well as restoring the neurotransmitters balance in the PVN of spontaneously hypertensive rats (SHR). Adult normotensive Wistar-Kyoto (WKY) rats and SHR received bilateral PVN infusion of EGCG (20μg/h) or vehicle via osmotic minipumps for 4 weeks. SHR showed higher mean arterial pressure, plasma proinflammatory cytokines and circulating norepinephrine (NE) levels compared with WKY rats. SHR also had higher PVN levels of the subunit of NAD(P)H oxidase (gp91phox), ROS, tyrosine hydroxylase, and PICs; increased NF-κB activity; and lower PVN levels of interleukin-10 (IL-10) and 67kDa isoform of glutamate decarboxylase (GAD67) than WKY rats. PVN infusion of EGCG attenuated all these changes in SHR. These findings suggest that SHR have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between pro- and anti-inflammatory cytokines in the PVN. Chronic inhibition of ROS in the PVN restores the balance of neurotransmitters and cytokines in the PVN, thereby attenuating hypertensive response and sympathetic activity.", "UV-induced DNA damage plays a key role in the initiation phase of skin cancer. When left unrepaired or when damaged cells are not eliminated by apoptosis, DNA lesions express their mutagneic properties, leading to the activation of proto-oncogene or the inactivation of tumor suppression genes. The chemical nature and the amount of DNA damage strongly depend on the wavelength of the incident photons. The most energetic part of the solar spectrum at the Earth's surface (UVB, 280-320 nm) leads to the formation of cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (64PPs). Less energetic but 20-times more intense UVA (320-400 nm) also induces the formation of CPDs together with a wide variety of oxidatively generated lesions such as single strand breaks and oxidized bases. Among those, 8-oxo-7,8-dihydroguanine (8-oxoGua) is the most frequent since it can be produced by several mechanisms. Data available on the respective yield of DNA photoproducts in cells and skin show that exposure to sunlight mostly induces pyrimidine dimers, which explains the mutational signature found in skin tumors, with lower amounts of 8-oxoGua and strand breaks. The present review aims at describing the basic photochemistry of DNA and discussing the quantitative formation of the different UV-induced DNA lesions reported in the literature. Additional information on mutagenesis, repair and photoprotection is briefly provided.", "Neurofibromatosis is a collective name for a group of genetic conditions in which benign tumours affect the nervous system. Type 1 is caused by a genetic mutation in the NF1 gene (OMIM 613113) and symptoms can vary dramatically between individuals, even within the same family. Some people have very mild skin changes, whereas others suffer severe medical complications. The condition usually appears in childhood and is diagnosed if two of the following are present: six or more café-au-lait patches larger than 1.5 cm in diameter, axillary or groin freckling, 2 or more Lisch nodules (small pigmented areas in the iris of the eye), 2 or more neurofibromas, optic pathway gliomas, bone dysplasia, and a first-degree family relative with Neurofibromatosis type 1. The pattern of inheritance is autosomal dominant, however, half of all NF1 cases are 'sporadic' and there is no family history. Neurofibromatosis type 1 is an extremely variable condition whose morbidity and mortality is largely dictated by the occurrence of the many complications that may involve any of the body systems. We describe a family affected by NF1 in whom genetic molecular analysis identified the same mutation in the son and father. Routine MRI showed pontine focal lesions in the eight-year-old son, though not in the father. We performed a four years follow-up study and at follow-up pontine hamartoma size remained unchanged in the son, and the father showed still no brain lesions, confirming thus an intra-familial phenotype variability.", "Collaborators: Nikolova-Pavlova E, Stoyanova B, Vlaeva T, Alavi A, Gauvreau G, Henein S, Poulos E, Yang W, Lepage F, Wiseman M, Bissonnette R, Agner T, Deleuran M, Jemec G, Skov L, Kingo K, Konno P, Pender K, Põder A, Vahlberg A, Oksman R, Pasternack R, Remitz A, Bieber T, Dominicus R, Gerlach B, Kardorff B, Toader AL, Kleinheinz A, Gellrich S, Kreutzer K, Leitz N, Offers M, Pauser S, Radtke M, Roloff E, Rosenbach T, Schwarz B, Sell S, Simon JC, Staubach P, Weigel US, Werfel T, Wohlrab J, Wollenberg A, Rothenberger C, Walter A, Yazdi A, Aihara M, Hide M, Kataoka Y, Katoh N, Kawashima M, Kobayashi S, Mitsui H, Nakahara T, Saeki H, Sueki H, Arai S, Ikeda M, Kabashima K, Kawachi Y, Kume A, Moriwaki S, Natsuaki Y, Ogata F, Omi T, Seishima M, Sugaya M, Tsukamoto K, Tsuruta D, Urano S, Watanabe D, Yoshioka A, Furukawa F, Katoh A, Ang CC, Aw DC, Tang M, Lee HY, Orpinell FB, Hernández GC, De La Cueva P, Foraster CF, Iranzo P, Serra AJ, Luna PL, Moya SM, Ramírez DM, Muñoz JP, Carazo JS, Soong W, Hull C, Johnson S, Bhatia N, Limova M, Raikhel M, Sher L, Sofen H, Spector S, Tan R, Yamauchi P, Weber R, Kimura S, Nelson C, Randhawa S, Rendon M, Trevino M, Ling M, Rice Z, Silverberg J, Siri D, Fretzin S, Fowler JF, Boh E, Merola J, Murakawa G, Korenblat P, Campbell J, Bagel J, Beck L, Hazan C, Kalb R, Smith C, Bardelas J, Gawchik S, Schenkel E, Krause R, Allison D, Browning J, Davis S, Lee M, Duffin K, Fisher CT, Pariser D, Gower RG, Adams S, Sapijaszko MJ, Wasel N, Albrecht L, Hong CH, Gulliver W, Landells I, Adam D, Gooderham M, Lomaga M, Lynde C, Rosoph L, Raman M, Robern M, Sapra S, Toth D, Poulin Y, Bagot M, Barbarot S, Grob JJ, Guillet G, Lacour JP, Khemis A, Misery L, Staumont-Sallé D, Brüning H, Darsow U, Ekanayake-Bohlig S, Herbst R, Hoffmann M, Homey B, Niesmann J, Pinter A, Radny P, Reich K, Sattler G, Sebastian M, Thaçi D, Weidinger S, Wildfeuer T, Worm M, Chan H, Chan J, Amerio P, Carlesimo M, Di Lernia V, Emilia R, Didona B, Fargnoli M, Ferrucci SM, Naldi L, Papini M, Parodi A, Pellacani G, Peris K, Pimpinelli N, Romanelli M, Talamonti M, Bylaite-Bucinskiene M, Cesiene J, Narbutas R, Sidlauskiene RB, Kucinskiene V, Adamski Z, Bystrzanowska D, Dyczek A, Hofman T, Leszniewska L, Nowicki R, Owczarek W, Slowinska M, Sobieszek-Kundro A, Weglowska J, Zakrzewski M, Ahn HH, Ahn KJ, Chang SE, Choi GS, Kim MB, Kim KH, Lee KH, Park YM, Park CW, Park GH, Nahm DH, Park YL, Roh J, Seo SJ, Ameen M, Ardern-Jones M, Bewley A, Cooper H, Cork MJ, Guha-Niyogi B, Khan M, Marshall M, Foerster J, Smith C, Appell M, Elewski B, Haynes S, Jazayeri SS, Crowley J, Dhawan S, Ellis M, Kim S, Meltzer S, Mitchell J, Pearlman D, Moss J, Ehrlich A, Forman S, Kuttner B, Penate F, Vaca C, Hamilton T, Paull W, Weisman J, Glazer S, Mehlis S, Guenthner S, Lockshin B, Kimball A, Rosmarin D, Pickett-Baisden T, Halverson P, Kaiser H, Martin A, Stone M, Davis K, Mirkil V, Nossa R, Bretton E, Alexis A, Guttman-Yassky E, Peredo M, Weinberg J, Fleischer A, George R, Lugo-Somolinos A, Nasir A, Hussain I, Blauvelt A, Simpson E, Kalafer M, Hampton M, Humeniuk JM, Rupp N, Carrasco D, MacGillivray B, Moore A, Teller C, Tyring S, Harris D, Jenkin P.", "A growing number of X-ray sources based on the free-electron laser (XFEL) principle are presently under construction or have recently started operation. The intense, ultrashort pulses of these sources will enable new insights in many different fields of science. A key problem is to provide x-ray optical elements capable of collecting the largest possible fraction of the radiation and to focus into the smallest possible focus. As a key step towards this goal, we demonstrate here the first nanofocusing of hard XFEL pulses. We developed diamond based Fresnel zone plates capable of withstanding the full beam of the world's most powerful x-ray laser. Using an imprint technique, we measured the focal spot size, which was limited to 320 nm FWHM by the spectral band width of the source. A peak power density in the focal spot of 4×10(17)W/cm(2) was obtained at 70 fs pulse length.", "PURPOSE OF REVIEW: Breath testing has developed over the last 20 years. New techniques that can identify fingerprints for specific diseases and specific markers of respiratory pathogens have been applied to breath analysis. This review discusses the recent advances in breath analysis for the diagnosis of bacterial and fungal lower respiratory tract infections.RECENT FINDINGS: The current techniques continue to develop rapidly, but preconcentration techniques are needed to analyse many target volatile organic compounds for most systems. Breath testing with an electronic nose is promising for the diagnosis of tuberculosis (TB), and specific volatiles identifiable by gas chromatography with mass spectrometry have been identified in breath for Mycobacterium tuberculosis, Pseudomonas aeruginosa and Aspergillus fumigatus, but are found at very low concentrations in breath. Contamination from the environment is an ongoing confounding influence. Exhaled breath condensate (EBC) is disappointing as a diagnostic sample.SUMMARY: Careful attention needs to be paid to the sensitivity and specificity of a technique and confounding from the environment. The role of technologies such as selected ion flow tube-mass spectrometry is emerging. The electronic nose requires further validation for TB. The identification of specific microbial biomarkers aids the quest for improved accuracy. EBC is currently of limited value.", "Epigallocatechin gallate (EGCG), a bioactive ingredient of green tea, plays a protective role in the cardiovascular system. Homocysteine (Hcy) is a major risk factor for chronic kidney disease and cardiovascular disease. The present study aimed to investigate the role of EGCG in Hcy-induced proliferation of vascular smooth muscle cells (VSMCs) and its underlying mechanism. We also explored the roles of rennin-angiotensin system (RAS), extracellular signal-regulated kinases (ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK) in this process. Human aortic smooth muscle cells (HASMCs) were treated with different drugs for different periods. The proliferation rate of HASMCs was detected using the CCK-8 and BrdU labeling assays. The Western blot assay was used to determine the expression levels of angiotensin II type 1 receptor (AT-1R), ERK1/2, and p38 MAPK. Compared with the control group, the HASMCs treated with Hcy at different doses (100, 200, 500, and 1000 µM) showed significantly increased proliferation. Hcy increased the expression of AT-1R, whereas EGCG decreased the protein expression of AT-1R. Furthermore, we found that Hcy-induced expression of p-ERK1/2 and p-p38MAPK was dependent on AT-1R. Compared with Hcy (500 µM)-treated cells, EGCG (20 µM)-treated cells showed decreased proliferation as well as expression of AT-1R, p-ERK1/2, and p-p38MAPK. In addition, HASMC proliferation was suppressed by the addition of an AT-1R blocker (olmesartan), an ERK1/2 inhibitor (PD98059), and a p38MAPK inhibitor (SB202190). EGCG can inhibit AT-1R and affect ERK1/2 and p38MAPK signaling pathways, resulting in the decrease of VSMC proliferation induced by Hcy." ]

[ "Interest in DNA-intercalating ligands as anti-cancer drugs has developed greatly since the clinical success of doxorubicin. However, despite a great deal of 'rational design' of synthetic DNA-intercalators, only a few such compounds have proved clinically useful. This review briefly surveys the history of DNA-intercalators as clinically-used anti-cancer drugs, summarizes the known structure-experimental activity relationships and modes of action, and concludes that a factor in the slow progress is that much of the work on these compounds has been carried out by chemists, who were generally more interested in ligand/DNA interactions than drug development. Future development of the class rests on a careful consideration of the biochemical reasons behind the common limitations of the present drugs. The most important are: the inherent resistance of non-cycling cells, the rapid development (even by cycling cells) of resistance by the expression of both P-glycoprotein and altered topoisomerase II, limitations on drug distribution to and transport into tumours, low extravascular pH in tumours and the cardiotoxic side-effects of quinonoid chromophores. These considerations provide a set of constraints on physicochemical properties which must be considered in future design. However, within these constraints, there are useful future avenues for the development of DNA-intercalators as anti-cancer drugs. These include: (i) the production of improved topoisomerase inhibitors (by consideration of drug/protein as well as drug/DNA interactions); (ii) the development of reductively-activated chromophores as hypoxia-selective agents; and (iii) the use of DNA-intercalators of known DNA binding orientation as 'carriers' for the delivery of other reactive functionality specifically (sequence-, regio- and site-specifically) to DNA.", "BACKGROUND: Tucatinib is a potent and selective oral HER2 tyrosine kinase inhibitor, with the potential to provide a well tolerated new treatment option for patients whose disease has progressed on currently available therapies. We aimed to determine the recommended phase 2 dose, safety, pharmacokinetics, and preliminary activity of tucatinib in combination with capecitabine or trastuzumab in patients with HER2-positive breast cancer with or without brain metastases.METHODS: In this non-randomised, open-label, phase 1b trial done in five sites in the USA, we recruited patients aged 18 years or older with HER2-positive progressive breast cancer who had been previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. Eligible patients required HER2-positivity assessed locally, evaluable lesions as defined per Response Evaluation Criteria in Solid Tumors, version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Tucatinib was administered twice a day in conjunction with capecitabine 1000 mg/m2 orally twice a day for 14 days of a 21-day cycle, trastuzumab 6 mg/kg intravenously once every 21 days, or both. A modified 3 + 3 dose-escalation design was used to determine the recommended phase 2 dose, starting with tucatinib in combination with capecitabine or trastuzumab, and subsequently evaluating the triplet combination. The primary endpoint was to establish the maximum tolerated dose and recommended phase 2 dose of tucatinib, evaluated by toxicity assessments. Efficacy was assessed in all patients by contrast CT of the body. Analyses included all patients who had received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, number NCT02025192.FINDINGS: Between Jan 15, 2014, and Dec 15, 2015, 60 patients were enrolled and treated. The current report is from mature data as of June 30, 2017. The tucatinib recommended phase 2 dose was determined to be 300 mg orally twice a day, equivalent to single-agent maximum tolerated dose. Pharmacokinetic analysis showed that there was no drug-drug interaction with capecitabine. Adverse events seen at the recommended phase 2 dose regardless of causality, grade, and treatment group included diarrhoea (35 [67%] of 52 patients), nausea (31 [60%] patients), palmar-plantar erythrodysaesthesia syndrome (23 [44%] patients), fatigue (20 [38%] patients), and vomiting (20 [38%] patients). In all patients, treatment-related toxicities of grade 3 and worse included fatigue (five [8%] patients), diarrhoea (four [7%] patients), and palmar-plantar erythrodysaesthesia (four [7%] patients). No treatment-related deaths were reported. The proportion of patients with measurable disease achieving objective response was 83% (five of six patients) in the combination of tucatinib with capecitabine, 40% (six of 15 patients) in the combination of tucatinib with trastuzumab, and 61% (14 of 23 patients) in the combination of tucatinib with both capecitabine and trastuzumab.INTERPRETATION: Tucatinib in combination with capecitabine and trastuzumab had acceptable toxicity and showed preliminary anti-tumour activity. Validation of the current study results will be determined in the double-blinded randomised study, HER2CLIMB (ONT-380-206; NCT02614794).FUNDING: Cascadian Therapeutics, a wholly owned subsidiary of Seattle Genetics.", "Severe neutropenia disorders are characterized by extremely low levels of peripheral blood neutrophils, a maturation block of bone marrow progenitor cells and recurring severe bacterial and fungal infections. Recent reports indicated that severe neutropenia is a consequence of an impaired survival and abnormal cell cycle progression of myeloid progenitor cells in both cyclic and severe congenital neutropenia. Mutations in the neutrophil elastase gene were identified in all patients with cyclic neutropenia and most of the patients with severe congenital neutropenia. We hypothesize that expression of mutant neutrophil elastase protein results in deregulation of intracellular activity and premature cell death of myeloid-committed progenitor cells in these disorders, resulting in the lack of peripheral blood neutrophils. The potential molecular mechanisms of mutant-protein-mediated neutropenia is discussed.", "IMPORTANCE: Treatment options for patients with disease progression after treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1) are limited. Tucatinib is an oral, potent, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor (TKI) being developed as a novel treatment for ERBB2/HER2-positive breast cancer.OBJECTIVE: To determine the maximum tolerated dosage of tucatinib in combination with T-DM1 in the treatment of patients with ERBB2/HER2-positive metastatic breast cancer with and without brain metastases.DESIGN, SETTING, AND PARTICIPANTS: In this phase 1b open-label, multicenter, clinical trial, 57 participants enrolled between January 22, 2014, and June 22, 2015, were 18 years of age or older with ERBB2/HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Data were analyzed between January and March 2018.INTERVENTIONS: Tucatinib 300 mg or 350 mg administered orally twice per day for 21 days and T-DM1 3.6 mg/kg administered intravenously once every 21 days.MAIN OUTCOMES AND MEASURES: Safety assessments, pharmacokinetics, and response were assessed using RECIST 1.1 every 2 cycles for 6 cycles, followed by every 3 cycles.RESULTS: Fifty-seven T-DM1-naive patients (median [IQR] 51 [44.0-63.0] years of age) who had undergone a median of 2 earlier HER2 therapies (range, 1-3) were treated. The tucatinib maximum tolerated dosage was determined to be 300 mg administered twice per day with dose-limiting toxic reactions seen at 350 mg twice per day. Pharmacokinetic analysis showed that there was no drug-drug interaction with T-DM1. Adverse events seen among the 50 patients treated at the maximum tolerated dosage regardless of causality included nausea (36 patients; 72%), diarrhea (30 patients; 60%), fatigue (28 patients; 56%), epistaxis (22 patients; 44%), headache (22 patients; 44%), vomiting (21 patients; 42%), constipation (21 patients; 42%), and decreased appetite (20 patients; 40%); the majority of adverse events were grade 1 or 2. Tucatinib-related toxic reactions that were grade 3 and above included thrombocytopenia (7 patients; 14%) and hepatic transaminitis (6 patients; 12%).CONCLUSIONS AND RELEVANCE: In this study, tucatinib in combination with T-DM1 appeared to have acceptable toxicity and to show preliminary antitumor activity among heavily pretreated patients with ERBB2/HER2-positive metastatic breast cancer with and without brain metastases.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01983501.", "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.", "Generation of reliable pharmacophore models is a key strategy in drug design. The quality of a pharmacophore model is known to depend on several factors, with the quality of the conformer sets used perhaps being one of the most important. The goal of this study was to compare different conformational analysis methods to determine if one was superior to the others for pharmacophore generation using Catalyst/HypoGen. The five methods selected were Catalyst/Fast, Catalyst/Best, Omega, Chem-X and MacroModel. Data sets for which Catalysts models had previously been published were selected using defined quality measures. Hypotheses were generated for each of the data sets and the performance of the different conformational analysis methods was compared using both quantitative (cost and correlation coefficients) and qualitative measures (by comparing the hypotheses in terms of the features present and their spatial relationships). Two main conclusions emerged from the study. First, it was not always possible to replicate the literature results. The reasons for these failures are explored in detail, and a template for use in publications that apply the Catalyst methodology is proposed. Second, the faster rule-based methods for conformational analysis give pharmacophore models that are just as good as, and in some cases better than, the models generated using the slower, more rigorous approaches.", "PURPOSE: The effect of an AA deficiency on catecholamine biosynthesis in adult mice in vivo is unknown. Therefore, we quantified catecholamine and the expression of catecholamine synthetic enzymes in the adrenal glands of senescence marker protein-30 (SMP30)/gluconolactonase (GNL) knockout (KO) mice placed in an AA-deficient state.METHODS: At 30 days of age, mice were divided into the following 4 groups: AA (-) SMP30/GNL KO, AA (+) SMP30/GNL KO, AA (-) wild type (WT), and AA (+) WT. The AA (+) groups were given water containing 1.5 g/L AA, whereas the AA (-) groups received water without AA until the experiment ended. In addition, all mice were fed an AA-depleted diet. Catecholamine levels were measured by a liquid chromatographic method. Tyrosine hydroxylase, dopa decarboxylase, dopamine β-hydroxylase, and phenylethanolamine N-methyltransferase mRNA expression levels were measured with the quantitative real-time polymerase chain reaction (qPCR). Tyrosine hydroxylase and dopamine β-hydroxylase protein levels were quantified by Western blot analysis.RESULTS: In the adrenals of AA (-) SMP30/GNL KO mice, noradrenaline and adrenaline levels decreased significantly compared to other three groups of mice, although there were no significant differences in dopamine β-hydroxylase or phenylethanolamine N-methyltransferase mRNA content. Moreover, there was no significant difference in their dopamine β-hydroxylase protein levels. On the other hand, AA depletion did not affect dopamine levels in adrenal glands of mice.CONCLUSION: An AA deficiency decreases the noradrenaline and adrenaline levels in adrenal glands of mice in vivo.", "Approximately 50% of patients with advanced human epidermal growth factor 2 (HER2)-positive breast cancer and triple-negative breast cancer (TNBC) ultimately develop breast cancer brain metastases (BCBM), which are associated with significant morbidity and mortality. The advent of HER2-directed therapy resulted in greatly improved survival outcomes, but unfortunately at the price of an increased cumulative incidence of BCBM. We review challenges in the management of BCBM, and potential treatment strategies, including novel agents such as poly-adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors (olaparib, veliparib), cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (palbociclib, abemaciclib), and taxane derivatives (eg, ANG1005 and TPI-287). The utility of human epidermal growth factor 2 (HER2)-directed therapies-lapatinib, ado-trastuzumab emtansine (T-DM1), neratinib and tucatinib-is also being studied in this setting. We address the need for improved imaging techniques and innovation in clinical trial design. For example, the current practice is to initially administer whole-brain radiotherapy (WBRT) as treatment for patients with multiple BCBM. However, in selected circumstances, first-line systemic treatment may be more appropriate in order to avoid neurocognitive toxicities, and potential options should be evaluated in window of opportunity trials. Other strategies that may aid development of more effective clinical trials and expedite the development of promising agents include the use of different clinical endpoints and different imaging tools.", "The apolipoprotein E (APOE) E4 allele is associated with Alzheimer's disease, cardiovascular disease, and decreased longevity. To probe the mechanism of these associations, cell lines were created which secrete each apoE isoform. ApoE conditioned media, purified apoE, and commercially obtained apoE protected B12 cells from hydrogen peroxide cytotoxicity with E2 > E3 > E4. Physiological levels of apoE protected cells from beta-amyloid peptides, while higher doses of apoE led to increased cytotoxicity. E2 > E3 > E4 possessed antioxidant activity, and apoE bound certain metal ions. The decreased antioxidant activity of E4 could contribute to its association with Alzheimer's disease, cardiovascular disease and decreased longevity.", "OBJECTIVE: To review the literature and describe the pharmacologic, pharmacokinetic, and pharmacodynamic properties; clinical safety; and efficacy of dapagliflozin, a new drug currently under review by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes.DATA SOURCES: A MEDLINE (1995-November 2011) and ClinicalTrials.gov search was conducted using the terms dapagliflozin, sodium-glucose cotransporter 2 inhibitor, and SGLT2 inhibitor. Reference citations from publications identified were also reviewed.STUDY SELECTION AND DATA EXTRACTION: All English-language studies, including abstracts, evaluating dapagliflozin use in humans were included in this review.DATA SYNTHESIS: Dapagliflozin is the first-in-class oral sodium-glucose cotransporter 2 (SGLT2) inhibitor that represents a new potential therapeutic option for the treatment of type 2 diabetes mellitus. Its mechanism of action is insulin- and insulin-sensitivity independent. Preliminary data suggest that dapagliflozin decreases hemoglobin A(1c), fasting plasma glucose, and postprandial plasma glucose, while also promoting weight loss. In Phase 1, 2, and 3 clinical trials, dapagliflozin has exhibited a safety and tolerability profile similar to that of placebo.CONCLUSIONS: Dapagliflozin is a novel oral antihyperglycemic agent that has demonstrated promise as monotherapy and as synergistic combination therapy with currently available agents in Phase 3 clinical trials. On January 19, 2012, the FDA issued a complete response letter to AstraZeneca and Bristol-Myers Squibb regarding the new drug application for dapagliflozin. The FDA is requesting additional clinical data-from ongoing studies and potentially new clinical trials-to better describe the risk-benefit profile of the drug. Both manufacturers remain committed to the development of dapagliflozin, and there are currently 8 Phase 3 trials ongoing. Dapagliflozin has the potential to be the next new oral agent in the diabetes drug armamentarium.", "The amyloid-forming proteins tau, αB crystallin, and amyloid P protein are all found in lesions of multiple sclerosis (MS). Our previous work established that amyloidogenic peptides from the small heat shock protein αB crystallin (HspB5) and from amyloid β fibrils, characteristic of Alzheimer's disease, were therapeutic in experimental autoimmune encephalomyelitis (EAE), reflecting aspects of the pathology of MS. To understand the molecular basis for the therapeutic effect, we showed a set of amyloidogenic peptides composed of six amino acids, including those from tau, amyloid β A4, major prion protein (PrP), HspB5, amylin, serum amyloid P, and insulin B chain, to be anti-inflammatory and capable of reducing serological levels of interleukin-6 and attenuating paralysis in EAE. The chaperone function of the fibrils correlates with the therapeutic outcome. Fibrils composed of tau 623-628 precipitated 49 plasma proteins, including apolipoprotein B-100, clusterin, transthyretin, and complement C3, supporting the hypothesis that the fibrils are active biological agents. Amyloid fibrils thus may provide benefit in MS and other neuroinflammatory disorders.", "Cellular senescence is a program activated by normal cells in response to various types of stress. These include telomere uncapping, DNA damage, oxidative stress, oncogene activity and others. Senescence can occur following a period of cellular proliferation or in a rapid manner in response to acute stress. Once cells have entered senescence, they cease to divide and undergo a series of dramatic morphologic and metabolic changes. Cellular senescence is thought to play an important role in tumor suppression and to contribute to organismal aging, but a detailed description of its physiologic occurrence in vivo is lacking. Recent studies have provided important insights regarding the manner by which different stresses and stimuli activate the signaling pathways leading to senescence. These studies reveal that a population of growing cells may suffer from a combination of different physiologic stresses acting simultaneously. The signaling pathways activated by these stresses are funneled to the p53 and Rb proteins, whose combined levels of activity determine whether cells enter senescence. Here we review recent advances in our understanding of the stimuli that trigger senescence, the molecular pathways activated by these stimuli, and the manner by which these signals determine the entry of a population of cells into senescence.", "Agrobacterium tumefaciens infects plants and induces the formation of tumors called \"crown galls\" by integrating the transferred-DNA (T-DNA) region of the Ti-plasmid into the plant nuclear genome. Tumors are formed because the T-DNA encodes enzymes that modify the synthesis of two plant growth hormones, auxin and cytokinin (CK). Here, we show that a CK biosynthesis enzyme, Tmr, which is encoded by the Agrobacterium T-DNA region, is targeted to and functions in plastids of infected plant cells, despite having no typical plastid-targeting sequence. Evidence is provided that Tmr is an adenosine phosphate-isopentenyltransferase (IPT) that creates a new CK biosynthesis bypass by using 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate (HMBDP) as a substrate. Unlike in the conventional CK biosynthesis pathway in plants, trans-zeatin-type CKs are produced directly without the requirement for P450 monooxygenase-mediated hydroxylation. Consistent with the plastid localization of Tmr, HMBDP is an intermediate in the methylerythritol phosphate pathway, a plastid-localized biosynthesis route for universal isoprenoid precursors. These results demonstrate that A. tumefaciens modifies CK biosynthesis by sending a key enzyme into plastids of the host plant to promote tumorigenesis.", "Approximately 30-50% of advanced HER2-positive breast cancer patients will develop central nervous system (CNS) metastases, with an annual risk of around 10%, and a half of them will die from brain progression. An increased risk of brain metastases is also seen in patients with early HER2-positive breast cancer administered curative therapy. Brain metastases in HER2-positive breast cancer patients usually constitute the first site of recurrence. The administration of anti-HER2 monoclonal antibodies, trastuzumab and pertuzumab, considerably delays the onset of symptomatic brain disease: however, the limited penetration of these compounds into the CNS hinders their efficacy. The small-molecule tyrosine kinase inhibitors of epidermal growth factor receptors family have established activity in HER2-positive breast cancer in both advanced disease and neoadjuvant setting. Favorable physico-chemical properties of these compounds allow them for a more efficient penetration through the blood-brain barrier, and hold the promise for more effective prevention and treatment of brain metastases. In this article we review the role of currently available or investigational HER2 tyrosine kinase inhibitors: lapatinib, neratinib, afatinib and tucatinib in the treatment of brain metastases in HER2-positive breast cancer patients.", "Result of a family study based on 584 patients with craniostenosis brings some answers useful for genetic counselling. For 98 patients (15%) a syndrome is associated. Third part of them has Apert syndrome, an other third part has Crouzon syndrome, and for the last third more exceptional acrocephalosyndactyly syndrome (Saethre-Chotzen, Pfeiffer) or others atypical associations, sometimes not yet described, but with an autosomal dominant inheritance. Non syndromic craniostenosis involves differently according to the type of join, but the localization is the same if recurrence will be happen. Coronal craniostenosis seems to be a dominant autosomal character, when scaphocephaly is more often sporadic; for both, an autosomal dominant inheritance is not excluded for some pedigrees. If the recurrence risk exist in some cases, it is generally well accepted by parents on account of the good neurosurgeon prognosis.", "Borderline Personality Disorder (BPD) is characterized by affective instability, but self-injurious behavior appears to have an emotion-regulating effect. We investigated whether pain-mediated affect regulation can be altered at the neural level by residential Dialectical Behavior Therapy (DBT), providing adaptive emotion regulation techniques. Likewise, we investigated whether pain thresholds or the appraisal of pain change after psychotherapy. We investigated 28 patients with BPD undergoing DBT (self-referral), 15 patients with treatment as usual and 23 healthy control subjects at two time points 12 weeks apart. We conducted an fMRI experiment eliciting negative emotions with picture stimuli and induced heat pain to investigate the role of pain in emotion regulation. Additionally, we assessed heat and cold pain thresholds.At first measurement, patients with BPD showed amygdala deactivation in response to painful stimulation, as well as altered connectivity between left amygdala and dorsal anterior cingulate cortex. These effects were reduced after DBT, as compared with patients with treatment as usual. Pain thresholds did not differ between the patient groups. We replicated the role of pain as a means of affect regulation in BPD, indicated by increased amygdala coupling. For the first time, we could demonstrate that pain-mediated affect regulation can be changed by DBT." ]

[ "The skeletal muscle LIM protein 1 (SLIM1) is highly expressed in skeletal and cardiac muscle, and its expression is downregulated significantly in dilated human cardiomyopathy. However, the function of SLIM1 is unknown. In this study, we investigated the intracellular localization of SLIM1. Endogenous and recombinant SLIM1 localized to the nucleus, stress fibers, and focal adhesions in skeletal myoblasts plated on fibronectin, collagen, or laminin. However, after inhibition of integrin signaling either by plating on poly-l-lysine or by soluble RGD peptide, SLIM1 localized diffusely in the cytosol, with decreased nuclear expression. Disruption of the actin cytoskeleton by cytochalasin D did not inhibit nuclear localization of SLIM1 in integrin-activated cells. Green fluorescent protein-tagged SLIM1 shuttled in the nucleus of untransfected NIH 3T3 cells, in a heterokaryon fusion assay. Overexpression of SLIM1 in Sol8 myoblasts inhibited cell adhesion and promoted cell spreading and migration. These studies show SLIM1 localizes in an integrin-dependent manner to the nucleus and focal adhesions where it functions downstream of integrin activation to promote cell spreading and migration.", "Author information:(1)Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America. traub@pitt.edu", "In the large international phase III MAVORIC trial, patients with previously treated cutaneous T-cell lymphoma who received the anti-CCR4 monoclonal antibody mogamulizumab experienced significantly longer progression-free survival and higher response rates, as well as better quality of life, than those who received vorinostat, a standard therapy.", "A wide range of phenotypes have been reported in autosomal recessive (AR) Charcot-Marie-Tooth disease (CMT) patients carrying mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene, such as axonal, demyelinating, and intermediate forms of AR CMT. There have been very few reports of GDAP1 mutations in autosomal dominant (AD) CMT. Here, we report an AD CMT family with a novel Q218E mutation in the GDAP1 gene. The mutation was located within the well-conserved glutathione S-transferase (GST) core region and co-segregated with the affected members in the pedigree. The affected AD CMT individuals had a later disease onset and much milder phenotypes than the AR CMT patients, and the histopathologic examination revealed both axonal degeneration and demyelination.", "BACKGROUND: The malaria vaccine candidate antigen RTS,S includes parts of the pre-erythrocytic stage circumsporozoite protein fused to the Hepatitis B surface antigen. Two Adjuvant Systems are in development for this vaccine, an oil-in water emulsion--based formulation (AS02) and a formulation based on liposomes (AS01).METHODS & PRINCIPAL FINDINGS: In this Phase II, double-blind study (NCT00307021), 180 healthy Gabonese children aged 18 months to 4 years were randomized to receive either RTS,S/AS01(E) or RTS,S/AS02(D), on a 0-1-2 month vaccination schedule. The children were followed-up daily for six days after each vaccination and monthly for 14 months. Blood samples were collected at 4 time-points. Both vaccines were well tolerated. Safety parameters were distributed similarly between the two groups. Both vaccines elicited a strong specific immune response after Doses 2 and 3 with a ratio of anti-CS GMT titers (AS02(D)/AS01(E)) of 0.88 (95% CI: 0.68-1.15) post-Dose 3. After Doses 2 and 3 of experimental vaccines, anti-CS and anti-HBs antibody GMTs were higher in children who had been previously vaccinated with at least one dose of hepatitis B vaccine compared to those not previously vaccinated.CONCLUSIONS: RTS,S/AS01(E) proved similarly as well tolerated and immunogenic as RTS,S/AS02(D), completing an essential step in the age de-escalation process within the RTS,S clinical development plan.TRIAL REGISTRATION: ClinicalTrials.gov. NCT00307021.", "Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related death worldwide. Current treatments are extremely disappointing. SPARC (Secreted protein, acidic and rich in cysteine) is a matricellular glycoprotein with differential expression in several tumors, including HCC, which significance remains unclear. We infected HCC cells (HepG2, Hep3B and Huh7) with an adenovirus expressing SPARC (AdsSPARC) to examine the role of SPARC expression on HCC cells and its effect on tumor aggressiveness. The in vitro HCC cells substrate-dependent proliferation and cell cycle profile were unaffected; however, SPARC overexpression reduced HCC proliferation when cells were grown in spheroids. A mild induction of cellular apoptosis was observed upon SPARC overexpression. SPARC overexpression resulted in spheroid growth inhibition in vitro while no effects were found when recombinant SPARC was exogenously applied. Moreover, the clonogenic and migratory capabilities were largely decreased in SPARC-overexpressing HCC cells, altogether suggesting a less aggressive HCC cell phenotype. Consistently, AdsSPARC-transduced cells showed increased E-cadherin expression and a concomitant decrease in N-cadherin expression. Furthermore, SPARC overexpression was found to reduce HCC cell viability in response to 5-FU-based chemotherapy in vitro, partially through induction of apoptosis. In vivo experiments revealed that SPARC overexpression in HCC cells inhibited their tumorigenic capacity and increased animal survival through a mechanism that partially involves host macrophages. Our data suggest that SPARC overexpression in HCC cells results in a reduced tumorigenicity partially through the induction of mesenchymal-to-epithelial transition (MET). These evidences point to SPARC as a novel target for HCC treatment.", "BACKGROUND: Freeze-tolerant fish survive sub-zero temperatures by non-colligatively lowering the freezing temperature of their body fluids using anti-freeze proteins (AFPs). We sought to evaluate and compare the effects of prolonged sub-zero cryopreservation of transplanted rat hearts using AFP I or AFP III.METHODS: Two heterotopic rat heart transplantation protocols were used. In Protocol 1 (n = 104), hearts (n = 8/group) were preserved for 12, 18 and 24 hours in University of Wisconsin solution (UW) at 4 degrees C, UW at -1.3 degrees C, UW/AFP I at -1.3 degrees C and UW/AFP III at -1.3 degrees C, with and without nucleation. Post-operative evaluation consisted of visual viability scoring of the hearts after 60 minutes. Protocol 2 (n = 58) involved evaluation of 24-hour post-transplant viability, echocardiography (fractional shortening [FS], left ventricular end-systolic and -diastolic diameter [ESD, EDD] and anterior and posterior wall systolic and diastolic thickness [AWT-S, AWT-D, PWT-S, PWT-D]), TUNEL staining and electron microscopy (EM) findings for hearts preserved for 18, 21 and 24 hours in UW at 4 degrees C or UW/AFP III at -1.3 degrees C.RESULTS: Hearts preserved in UW at -1.3 degrees C with nucleation froze and died. Three of 8 hearts preserved in UW at 4 degrees C for 24 hours died, whereas all hearts preserved at -1.3 degrees C survived. Hearts preserved in UW/AFP for 18 and 24 hours at -1.3 degrees C had superior viability scores compared with those in UW at 4 degrees C. Hearts in AFP III at -1.3 degrees C displayed greater AWT-S and AWT-D (3.5 +/- 0.2 vs 2.4 +/- 0.2, p < 0.05, and 3.5 +/- 0.2 vs 2.2 +/- 0.2, p < 0.05, respectively) after 18-hour preservation. In the 21-hour preservation group, AFP-treated hearts displayed improved echocardiographic systolic contraction indices, including: improved FS (27 +/- 3.7 vs 15 +/- 4, p = 0.04); diminished ESD (0.28 +/- 0.57 vs 0.47 +/- 0.6, p < 0.05); greater AWT-S (3.4 +/- 0.18 vs 2.8 +/- 0.2, p < 0.05); and fewer positively TUNEL-stained nuclei per specimen (35 +/- 14 vs 5.3 +/- 2.7, p = 0.04). Also, improved EM scores were noted compared with UW at 4 degrees C.CONCLUSIONS: In prolonged sub-zero cryopreservation, AFPs protect the heart from freezing, improve survival and hemodynamics, and reduce apoptotic cell death." ]

[ "The omnigenic model of complex disease stipulates that the majority of the heritability will be explained by the effects of common variation on genes in the periphery of core disease pathways. Rare variant associations, expected to explain far less of the heritability, may be enriched in core disease genes and thus will be instrumental in the understanding of complex disease pathogenesis and their potential therapeutic targets. Here, using complementary whole-exome sequencing, high-density imputation, and in vitro cellular assays, we identify candidate core genes in the pathogenesis of systemic lupus erythematosus (SLE). Using extreme-phenotype sampling, we sequenced the exomes of 30 SLE parent-affected-offspring trios and identified 14 genes with missense de novo mutations (DNM), none of which are within the >80 SLE susceptibility loci implicated through genome-wide association studies. In a follow-up cohort of 10, 995 individuals of matched European ancestry, we imputed genotype data to the density of the combined UK10K-1000 genomes Phase III reference panel across the 14 candidate genes. Gene-level analyses indicate three functional candidates: DNMT3A, PRKCD, and C1QTNF4. We identify a burden of rare variants across PRKCD associated with SLE risk (P = 0.0028), and across DNMT3A associated with two severe disease prognosis sub-phenotypes (P = 0.0005 and P = 0.0033). We further characterise the TNF-dependent functions of the third candidate gene C1QTNF4 on NF-κB activation and apoptosis, which are inhibited by the p.His198Gln DNM. Our results identify three novel genes in SLE susceptibility and support extreme-phenotype sampling and DNM gene discovery to aid the search for core disease genes implicated through rare variation.", "Blood, from slaughterhouses, is an inevitable part of meat production, causing environmental problems due to the large volumes recovered and its low valorization. However, the α137-141 peptide, a natural antimicrobial peptide, can be obtained after hydrolysis of hemoglobin, the main constituent of blood red part. To recover it at a sufficient concentration for antimicrobial applications, a new sustainable technology, called electrodialysis with ultrafiltration membrane (EDUF), was investigated. The α137-141 concentration was increased about 4-fold at a feed peptide concentration of 8% with an enrichment factor above 24-fold. This feed peptide concentration also needed the lowest relative energy consumption. Moreover, this peptide fraction protected meat against microbial growth, as well as rancidity, during 14 days under refrigeration. This peptide fraction was validated as a natural preservative and substitute for synthetic additives against food spoilage. Finally, producing antimicrobial/antioxidant peptide from wastes by EDUF fits perfectly with the concept of circular economy.", "Rapid advances are occurring in multiple sclerosis disease modifying therapies. Recent therapeutic advances include modifications to improve tolerability of existing products (e.g. interferon beta and glatiramer acetate), development of novel anti-neuroinflammatory medications (e.g. fingolimod, teriflunomide and dimethyl fumarate, daclizumab, alemtuzumab, ocrelizumab) and investigation of treatments in progressive MS (e.g. natalizumab, mastinib, natalizumab, siponimod). The impact of vitamin D supplementation on the disease course in relapsing MS patients is also being studied in several clinical trials. This article reviews the current state of the field with a forward look to the next phase of MS research that could focus on strategies to promote remyelination and provide neuronal protection.", "Calcium/calmodulin-dependent kinase II (CaMKII) is a multifunctional serine/threonine kinase expressed abundantly in the heart. CaMKII targets numerous proteins involved in excitation-contraction coupling and excitability, and its activation may simultaneously contribute to heart failure and cardiac arrhythmias. In this review, we summarize the modulatory effects of CaMKII on cardiac ion channel function and expression and illustrate potential implications in the onset of arrhythmias via a computer model.", "The functional importance of gene enhancers in regulated gene expression is well established. In addition to widespread transcription of long non-coding RNAs (lncRNAs) in mammalian cells, bidirectional ncRNAs are transcribed on enhancers, and are thus referred to as enhancer RNAs (eRNAs). However, it has remained unclear whether these eRNAs are functional or merely a reflection of enhancer activation. Here we report that in human breast cancer cells 17β-oestradiol (E2)-bound oestrogen receptor α (ER-α) causes a global increase in eRNA transcription on enhancers adjacent to E2-upregulated coding genes. These induced eRNAs, as functional transcripts, seem to exert important roles for the observed ligand-dependent induction of target coding genes, increasing the strength of specific enhancer-promoter looping initiated by ER-α binding. Cohesin, present on many ER-α-regulated enhancers even before ligand treatment, apparently contributes to E2-dependent gene activation, at least in part by stabilizing E2/ER-α/eRNA-induced enhancer-promoter looping. Our data indicate that eRNAs are likely to have important functions in many regulated programs of gene transcription.", "Koebner phenomenon is the development of isomorphic pathological lesions in distant wounds of patients with pre-existing cutaneous diseases. More frequent in patients with psoriasis, it can occur in the presence of other cutaneous pathologies. Surgeons should be aware of this entity and warn patients about its possible occurrence.", "BACKGROUND: Low oxygen availability has been shown previously to stimulate M. tuberculosis to establish non-replicative persistence in vitro. The two component sensor/regulator dosRS is a major mediator in the transcriptional response of M. tuberculosis to hypoxia and controls a regulon of approximately 50 genes that are induced under this condition. The aim of this study was to determine whether the induction of the entire DosR regulon is triggered as a synchronous event or if induction can unfold as a cascade of events as the differential expression of subsets of genes is stimulated by different oxygen availabilities.RESULTS: A novel aspect of our work is the use of chemostat cultures of M. tuberculosis which allowed us to control environmental conditions very tightly. We exposed M. tuberculosis to a sudden drop in oxygen availability in chemostat culture and studied the transcriptional response of the organism during the transition from a high oxygen level (10% dissolved oxygen tension or DOT) to a low oxygen level (0.2% DOT) using DNA microarrays. We developed a Bayesian change point analysis method that enabled us to detect subtle shifts in the timing of gene induction. It results in probabilities of a change in gene expression at certain time points. A computational analysis of potential binding sites upstream of the DosR-controlled genes shows how the transcriptional responses of these genes are influenced by the affinity of these binding sites to DosR. Our study also indicates that a subgroup of DosR-controlled genes is regulated indirectly.CONCLUSION: The majority of the dosR-dependent genes were up-regulated at 0.2% DOT, which confirms previous findings that these genes are triggered by hypoxic environments. However, our change point analysis also highlights genes which were up-regulated earlier at levels of about 8% DOT indicating that they respond to small fluctuations in oxygen availability. Our analysis shows that there are pairs of divergent genes where one gene in the pair is up-regulated before the other, presumably for a flexible response to a constantly changing environment in the host." ]

[ "The unipolar brush cells are excitatory, cerebellar granular layer interneurons that receive mossy fiber input on their dendritic brushes in the form of a giant glutamatergic synapse. We investigated the postnatal development of the brush of the unipolar brush cell in lobules IX and X by light microscopy and defined the maturation of mossy fiber-unipolar brush cell synapses and mossy fiber-granule cell synapses by electron microscopy using calretinin immunocytochemistry to identify unipolar brush cells. During the first postnatal week, unipolar brush cells possessed one or two short, branched dendrites. The brush differentiated primarily during the successive 21 postnatal (P) days, during which it underwent progressive maturation. This developmental process was subdivided into stages 1-4, which were descriptively termed protodendritic unipolar brush cell (P2-12), filopodial brush (P12-16), intermediate brush (P16-21), and dendriolar brush (P21-28) stages. Electron microscopic measurements of individual mossy fiber-unipolar brush cell and mossy fiber-granule cell synaptic junctions were made at P12, 16, 21, and 28. While the average length of mossy fiber-unipolar brush cell synapses increased during development, that of mossy fiber-granule cell synapses decreased. Comparisons of the lengths of mossy fiber-unipolar brush cell and mossy fiber-granule cell synapses demonstrated that mossy fiber-unipolar brush cell synapses were longer on average than mossy fiber-granule cell synapses for all ages. Frequency distribution histograms also showed that the percentage of mossy fiber-unipolar brush cell synapses longer than 0.5 microm was lower in the pooled P12-P16 groups than in the pooled P21-P28 groups (8 versus 20%). In contrast, mossy fiber-granule cell synapses longer than 0.5 microm were a small minority at P12, 16, and 21, and occurred rarely at P28. The present study indicates that mossy fiber-unipolar brush cell synapses increase in length with the differentiation of the brush dendrioles, while that of mossy fiber-granule cell synapses decrease with differentiation of the granule cell dendritic claws. The finding that mossy fiber-unipolar brush cell synapses were generally longer than mossy fiber-granule cell synapses may indicate that the properties of the postsynaptic targets play a major role in shaping synaptic appositions within cerebellar glomeruli.", "AIMS: Mutations in the cardiac ryanodine receptor Ca(2+) release channel, RyR2, underlie catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited life-threatening arrhythmia. CPVT is triggered by spontaneous RyR2-mediated sarcoplasmic reticulum (SR) Ca(2+) release in response to SR Ca(2+) overload during beta-adrenergic stimulation. However, whether elevated SR Ca(2+) content--in the absence of protein kinase A activation--affects RyR2 function and arrhythmogenesis in CPVT remains elusive.METHODS AND RESULTS: Isolated murine ventricular myocytes harbouring a human RyR2 mutation (RyR2(R4496C+/-)) associated with CPVT were investigated in the absence and presence of 1 micromol/L JTV-519 (RyR2 stabilizer) followed by 100 micromol/L ouabain intervention to increase cytosolic [Na(+)] and SR Ca(2+) load. Changes in membrane potential and intracellular [Ca(2+)] were monitored with whole-cell patch-clamping and confocal Ca(2+) imaging, respectively. At baseline, action potentials (APs), Ca(2+) transients, fractional SR Ca(2+) release, and SR Ca(2+) load were comparable in wild-type (WT) and RyR2(R4496C+/-) myocytes. Ouabain evoked significant increases in diastolic [Ca(2+)], peak systolic [Ca(2+)], fractional SR Ca(2+) release, and SR Ca(2+) content that were quantitatively similar in WT and RyR2(R4496C+/-) myocytes. Ouabain also induced arrhythmogenic events, i.e. spontaneous Ca(2+) waves, delayed afterdepolarizations and spontaneous APs, in both groups. However, the ouabain-induced increase in the frequency of arrhythmogenic events was dramatically larger in RyR2(R4496C+/-) when compared with WT myocytes. JTV-519 greatly reduced the frequency of ouabain-induced arrhythmogenic events.CONCLUSION: The elevation of SR Ca(2+) load--in the absence of beta-adrenergic stimulation--is sufficient to increase the propensity for triggered arrhythmias in RyR2(R4496C+/-) cardiomyocytes. Stabilization of RyR2 by JTV-519 effectively reduces these triggered arrhythmias.", "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.", "SUMMARY: Measuring the similarity of graphs is a fundamental step in the analysis of graph-structured data, which is omnipresent in computational biology. Graph kernels have been proposed as a powerful and efficient approach to this problem of graph comparison. Here we provide graphkernels, the first R and Python graph kernel libraries including baseline kernels such as label histogram based kernels, classic graph kernels such as random walk based kernels, and the state-of-the-art Weisfeiler-Lehman graph kernel. The core of all graph kernels is implemented in C ++ for efficiency. Using the kernel matrices computed by the package, we can easily perform tasks such as classification, regression and clustering on graph-structured samples.AVAILABILITY AND IMPLEMENTATION: The R and Python packages including source code are available at https://CRAN.R-project.org/package=graphkernels and https://pypi.python.org/pypi/graphkernels.CONTACT: mahito@nii.ac.jp or elisabetta.ghisu@bsse.ethz.ch.SUPPLEMENTARY INFORMATION: Supplementary data are available online at Bioinformatics.", "BACKGROUND: Low intensity, intermediate frequency, alternating electric fields (Tumor Treating Fields; TTFields) exhibit anti-mitotic activity in cancer cells. Promising preclinical data have led to a single arm phase I/II trial in NSCLC patients.METHODS: Forty-two inoperable stage IIIB (with pleural effusion) and IV NSCLC patients who had had tumor progression received pemetrexed 500 mg/m(2) iv q3w together with daily TTFields therapy until disease progression. The primary endpoint was time to \"in-field\" progression.RESULTS: Median age for all patients was 63 years, 76% had stage IV disease, 78% had adenocarcinoma and 17% had performance status of 2. The median time to in-field progression was 28 weeks and the median time to systemic progression was 22 weeks. Six patients (14.6%) had a partial remission (PR) and 20 had stable disease (SD) (48.8%). Median overall survival was 13.8 months and 1 year survival rate was 57%. There were no TTFields-related serious adverse events.CONCLUSIONS: The combination of TTFields and pemetrexed as a second line therapy for NSCLC is safe and potentially more effective than pemetrexed alone. TTFields improved disease control within the treatment field and a phase III study is planned to further investigate its role as a novel treatment in NSCLC.", "The utility of immunohistochemistry (IHC) as a screening method for the identification of persons with mutations in the DNA mismatch repair (MMR) genes in hereditary nonpolyposis colorectal cancer (HNPCC) remains to be defined. In this study, we analyzed the value of IHC versus that of microsatellite instability (MSI) testing in predicting mutation status of the MLH1, MSH2, and MSH6 genes in colorectal carcinomas and adenomas, and explored the frequency and significance of immunohistochemical staining variability. The study samples included 83 carcinomas and 29 adenomas derived from 110 patients who had strong family histories of colorectal cancer. Our results showed that IHC correctly predicted MSI status in 76% of the cases with a specificity of 100%. The overall sensitivity of IHC in predicting a germline mutation was 79% (30 of 38) with a specificity of 89% (48 of 54), whereas that of MSI testing was 97% (30 of 31) with a specificity of 83% (35 of 42). Six of 31 analyzable cases that had a disease-causing mutation and exhibited MSI showed normal IHC. The lower sensitivity of IHC was caused mainly by its low sensitivity in detecting MLH1 gene mutation (4 of 9). Coexisting adenomas and carcinomas observed in the same slide (n=12) showed a similar or identical staining pattern for all three proteins. No significant difference was detected in the sensitivity of IHC or MSI in detecting a germline mutation between isolated adenomas and carcinomas. In IHC-positive cases, heterogeneous staining was noted in 30% to 40% of the cases with the three different antibodies, and cytoplasmic staining in 5% to 13%. Weak IHC (defined as positive staining in <10% of the tumor with weak intensity) was noted in 14 tumors: 5 for the MLH1 antibody, 1 for MSH2, and 8 for MSH6. One of the 5 MLH1 cases exhibited MSI and had an MLH1 germline mutation. Five of the 8 MSH6 cases exhibited MSI and had MSH2 germline mutations. In conclusion, our study shows that 1) IHC identifies a significant portion of colorectal tumors derived from MMR gene germline mutation carriers and can be used as an adjunct measure in the identification of HNPCC families, but IHC cannot replace MSI testing; 2) adenomas have similar MMR protein expression patterns as carcinomas and may serve as an adequate sample for screening purposes in the identification of patients with MMR mutations; 3) not all IHC-positive cases show uniform positivity throughout the tumor; and 4) weak and focal staining of an MMR protein may be associated with MSI or gene mutation or both, suggesting the need to incorporate staining intensity in further IHC studies.", "BACKGROUND: Our aim was to determine whether the changes in thyroid function after open-heart surgery in neonates depend on the postoperative course.METHODS: Twenty neonates undergoing open-heart surgery for congenital heart disease were prospectively studied in the cardiac intensive care unit of a university-affiliated children's hospital. The patients were divided into two groups by level of inotropic support (high or mild).RESULTS: The groups were similar in age, bypass time and ultrafiltration volume. In both groups, there was a significant reduction in levels of thyroid-stimulating hormone and FT4 at 24 h postoperatively. However, in the high inotropic support group, FT4 was lower for a longer time. This group also had a significantly higher score on The Pediatric Risk of Mortality (PRISM; P < 0.042) and a longer duration of ventilation (P < 0.014).CONCLUSIONS: Neonates after open-heart surgery undergo changes in thyroid function characteristic of euthyroid sick syndrome. The degree of hypothyroxinemia may be related to the severity of illness and the postoperative course." ]

[ "The polycomb protein Bmi-1 represses the INK4a locus, which encodes the tumor suppressors p16 and p14(ARF). Here we report that Bmi-1 is downregulated when WI-38 human fibroblasts undergo replicative senescence, but not quiescence, and extends replicative life span when overexpressed. Life span extension by Bmi-1 required the pRb, but not p53, tumor suppressor protein. Deletion analysis showed that the RING finger and helix-turn-helix domains of Bmi-1 were required for life span extension and suppression of p16. Furthermore, a RING finger deletion mutant exhibited dominant negative activity, inducing p16 and premature senescence. Interestingly, presenescent cultures of some, but not all, human fibroblasts contained growth-arrested cells expressing high levels of p16 and apparently arrested by a p53- and telomere-independent mechanism. Bmi-1 selectively extended the life span of these cultures. Low O(2) concentrations had no effect on p16 levels or life span extension by Bmi-1 but reduced expression of the p53 target, p21. We propose that some human fibroblast strains are more sensitive to stress-induced senescence and have both p16-dependent and p53/telomere-dependent pathways of senescence. Our data suggest that Bmi-1 extends the replicative life span of human fibroblasts by suppressing the p16-dependent senescence pathway.", "BACKGROUND: Rotor's syndrome is a rare congenital disorder characterized by functional hyperbilirubinemia. Treatment decision may be challenging in a cancer patient with Rotor's syndrome, since the majority of the antineoplastic agents are metabolized in the liver and excreted via the biliary system. We report the first case of paclitaxel administration in a patient with ovarian cancer and elevated bilirubin levels due to Rotor's syndrome.CASE: A 50-year-old woman with Rotor's syndrome had an exploratory laparotomy and was diagnosed to have stage IIIC epithelial ovarian cancer. The baseline serum bilirubin value was 15.3 mg/dL. She was started on a 50% dose of 87.5 mg/m(2) paclitaxel by 3-h infusion plus carboplatin AUC-6. The paclitaxel dose was increased by 25% at consecutive cycles until the standard dose of 175 mg/m(2)/3 h was achieved. Six cycles were administered without any metabolic derangement. The patient was rendered disease free with this treatment.CONCLUSION: Paclitaxel appears to be safe to administer to cancer patients with functional hyperbilirubinemia.", "BACKGROUND AND PURPOSE: Pulmonary veins are the most important focus for the generation of atrial fibrillation. Abnormal calcium homeostasis with ryanodine receptor dysfunction may underlie the arrhythmogenic activity in pulmonary veins. The preferential ryanodine receptor stabilizer (K201) possesses antiarrhythmic effects through calcium regulation. The purpose of this study was to investigate the effects of K201 on the arrhythmogenic activity and calcium regulation of pulmonary vein cardiomyocytes.EXPERIMENTAL APPROACH: The ionic currents and intracellular calcium were studied in isolated single cardiomyocytes from rabbit pulmonary vein before and after the administration of K201, by the whole-cell patch clamp and indo-1 fluorimetric ratio techniques.KEY RESULTS: K201 (0.1, 0.3, 1 microM) reduced the firing rates in pulmonary vein cardiomyocytes, decreased the amplitudes of the delayed afterdepolarizations and prolonged the action potential duration. K201 decreased the L-type calcium currents, Na(+)/Ca(2+) exchanger currents, transient inward currents and calcium transients. K201 (1 microM, but not 0.1 microM or 0.3 microM) also reduced the sarcoplasmic reticulum calcium content. Moreover, both the pretreatment and administration of K201 (0.3 microM) decreased the isoprenaline (10 nM)-induced arrhythmogenesis in pulmonary veins.CONCLUSIONS AND IMPLICATIONS: K201 reduced the arrhythmogenic activity of pulmonary vein cardiomyocytes and attenuated the arrhythmogenicity induced by isoprenaline. These findings may reveal the anti-arrhythmic potential of K201.", "Myelin is a specialized structure of the nervous system that both enhances electrical conductance and insulates neurons from external risk factors. In the central nervous system, polarized oligodendrocytes form myelin by wrapping processes in a spiral pattern around neuronal axons through myelin-related gene regulation. Since these events occur at a distance from the cell body, post-transcriptional control of gene expression has strategic advantage to fine-tune the overall regulation of protein contents in situ. Therefore, many research interests have been focused to identify RNA binding proteins and their regulatory mechanism in myelinating compartments. Fragile X mental retardation protein (FMRP) is one such RNA binding protein, regulating its target expression by translational control. Although the majority of works on FMRP have been performed in neurons, it is also found in the developing or mature glial cells including oligodendrocytes, where its function is not well understood. Here, we will review evidences suggesting abnormal translational regulation of myelin proteins with accompanying white matter problem and neurological deficits in fragile X syndrome, which can have wider mechanistic and pathological implication in many other neurological and psychiatric disorders.", "Cyps (cyclophilins) are ubiquitous proteins of the immunophilin superfamily with proposed functions in protein folding, protein degradation, stress response and signal transduction. Conserved cysteine residues further suggest a role in redox regulation. In order to get insight into the conformational change mechanism and functional properties of the chloroplast-located CYP20-3, site-directed mutagenized cysteine-->serine variants were generated and analysed for enzymatic and conformational properties under reducing and oxidizing conditions. Compared with the wild-type form, elimination of three out of the four cysteine residues decreased the catalytic efficiency of PPI (peptidyl-prolyl cis-trans isomerase) activity of the reduced CYP20-3, indicating a regulatory role of dithiol-disulfide transitions in protein function. Oxidation was accompanied by conformational changes with a predominant role in the structural rearrangement of the disulfide bridge formed between Cys(54) and Cys(171). The rather negative E(m) (midpoint redox potential) of -319 mV places CYP20-3 into the redox hierarchy of the chloroplast, suggesting the activation of CYP20-3 in the light under conditions of limited acceptor availability for photosynthesis as realized under environmental stress. Chloroplast Prx (peroxiredoxins) were identified as interacting partners of CYP20-3 in a DNA-protection assay. A catalytic role in the reduction of 2-Cys PrxA and 2-Cys PrxB was assigned to Cys(129) and Cys(171). In addition, it was shown that the isomerization and disulfide-reduction activities are two independent functions of CYP20-3 that both are regulated by the redox state of its active centre.", "Sodium channels are principal molecular determinants responsible for myocardial conduction and maintenance of the cardiac rhythm. Calcium ions (Ca2+) have a fundamental role in the coupling of cardiac myocyte excitation and contraction, yet mechanisms whereby intracellular Ca2+ may directly modulate Na channel function have yet to be identified. Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. Mutations targeted to the IQ domain disrupted CaM binding and eliminated Ca2+/CaM-dependent slow inactivation, whereas the gating effects of Ca2+/CaM were restored by intracellular application of a peptide modelled after the IQ domain. A naturally occurring mutation (A1924T) in the IQ domain altered hH1 function in a manner characteristic of the Brugada arrhythmia syndrome, but at the same time inhibited slow inactivation induced by Ca2+/CaM, yielding a clinically benign (arrhythmia free) phenotype.", "A sister and brother, with oculocutaneous albinism and reduced bone density are described. Autosomal recessive inheritance is possible. This association has not been previously described.", "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.", "Capillaria hepatica (C. hepatica) is a parasitic nematode causing hepatic capillariasis in numerous mammals. Ecologic studies showed that the first hosts of C. hepatica were rodents, among which rats had relatively high infection rates, which explains why C. hepatica spreads globally. Anatomical studies showed that the liver was the principal site of colonization by these parasites and physical damage tended to occur. Although C. hepatica might lead to serious liver disorders, relevant clinical reports were rare, because of the non-specific nature of clinical symptoms, leading to misdiagnosis. This review mainly focuses on the biological characteristics and epidemiology of C. hepatica in China and histopathologic changes in the liver, with expectation of gaining a better understanding of the disease and seeking more effective treatment.", "Capillaria hepatica which accidentally infects humans is a zoonotic parasite of mammalian liver, primarily rodents and causes hepatic capillariasis. The diagnosis is difficult because of the non-specific nature of clinical symptoms, leading to misdiagnosis and can be confirmed only through liver biopsy or on autopsy results. This paper is written with an objective to report a new case of hepatic capillariasis as a rare differential for peripheral eosinophilia and an imaging dilemma for abdominal lymphadenopathy.", "The packaging of eukaryotic genomes into nuclesomes plays critical roles in chromatin organization and gene regulation. Studies in Saccharomyces cerevisiae indicate that nucleosome occupancy is partially encoded by intrinsic antinucleosomal DNA sequences, such as poly(A) sequences, as well as by binding sites for trans-acting factors that can evict nucleosomes, such as Reb1 and the Rsc3/30 complex. Here, we use genome-wide nucleosome occupancy maps in 13 Ascomycota fungi to discover large-scale evolutionary reprogramming of both intrinsic and trans determinants of chromatin structure. We find that poly(G)s act as intrinsic antinucleosomal sequences, comparable to the known function of poly(A)s, but that the abundance of poly(G)s has diverged greatly between species, obscuring their antinucleosomal effect in low-poly(G) species such as S. cerevisiae. We also develop a computational method that uses nucleosome occupancy maps for discovering trans-acting general regulatory factor (GRF) binding sites. Our approach reveals that the specific sequences bound by GRFs have diverged substantially across evolution, corresponding to a number of major evolutionary transitions in the repertoire of GRFs. We experimentally validate a proposed evolutionary transition from Cbf1 as a major GRF in pre-whole-genome duplication (WGD) yeasts to Reb1 in post-WGD yeasts. We further show that the mating type switch-activating protein Sap1 is a GRF in S. pombe, demonstrating the general applicability of our approach. Our results reveal that the underlying mechanisms that determine in vivo chromatin organization have diverged and that comparative genomics can help discover new determinants of chromatin organization.", "Zoonotic infections are increasingly becoming public health menaces and are usually transmitted to humans due to unsuitable environmental conditions. One of them is hepatic capillariasis, caused by the parasite Capillaria hepatica, primarily a disease of rodents, with hepatic manifestations in humans. Although its prevalence is very low, it can cause significant morbidity and mortality, with cases reported from all over the world. The main infective form for humans is the embryonated egg of the parasite, which hatches in the intestine and ultimately colonize the liver. The larvae mature and reproduce, and eventually form embryonated eggs, which cause chronic focal inflammation and septal hepatic fibrosis. Clinical presentation mainly consists of fever, abdominal pain, hepatomegaly and eosinophilia. Spurious infection with unembryonated eggs cause gastrointestinal symptoms. Diagnostic modalities include liver biopsy, ultrasonography, CT scan, immunological tests like ELISA and IIFT. The infection can be treated mainly with a combination of benzimidazoles like thiabendazole, mebendazole and albendazole; with corticosteroids. The study emphasizes the need for hepatic capillariasis to be considered as a differential diagnosis in cases of suspected hepatitis, leptospirosis, abdominal lymphadenopathy or other hepatic or parasitic infections prevalent in the region concerned; and meticulously assess the cases to facilitate early diagnosis and prompt treatment, thus reducing the distress faced by patients." ]

[ "It is thought that during latent infection, Mycobacterium tuberculosis bacilli are retained within granulomas in a low-oxygen environment. The dormancy survival (Dos) regulon, regulated by the response regulator DosR, appears to be essential for hypoxic survival in M. tuberculosis, but it is not known how the regulon promotes survival. Here we report that mycobacteria, in contrast to enteric bacteria, do not form higher-order structures (e.g. ribosomal dimers) upon entry into stasis. Instead, ribosomes are stabilized in the associated form (70S). Using a strategy incorporating microfluidic, proteomic, and ribosomal profiling techniques to elucidate the fate of mycobacterial ribosomes during hypoxic stasis, we show that the dormancy regulator DosR is required for optimal ribosome stabilization. We present evidence that the majority of this effect is mediated by the DosR-regulated protein MSMEG_3935 (a S30AE domain protein), which is associated with the ribosome under hypoxic conditions. A Δ3935 mutant phenocopies the ΔdosR mutant during hypoxia, and complementation of ΔdosR with the MSMEG_3935 gene leads to complete recovery of dosR mutant phenotypes during hypoxia. We suggest that this protein is named ribosome-associated factor under hypoxia (RafH) and that it is the major factor responsible for DosR-mediated hypoxic survival in mycobacteria.", "Sarilumab (Kevzara) for moderately to severely active rheumatoid arthritis; valbenazine (Ingrezza), the first approval for tardive dyskinesia; and cerliponase alpha (Brineura) for late infantile neuronal ceroid lipofuscinosis type-2 disease.", "Cerliponase alfa (Brineura™) is a recombinant human tripeptidyl peptidase-1 (TPP1) being developed by BioMarin Pharmaceutical Inc. for use in patients with neuronal ceroid lipofuscinosis type 2 (CLN2), a paediatric neurodegenerative disease caused by a deficiency in TPP1. CLN2 is characterised by progressive impairment of motor function, language deficiencies, seizures, ataxia, blindness and early death, and intracerebroventricular infusion of cerliponase alfa has been shown to reduce the progression of functional decline. This article summarizes the milestones in the development of cerliponase alfa leading to its first global approval in the USA for the treatment of motor function loss in paediatric patients ≥3 years of age with CLN2, and subsequent approval in the EU for CLN2 in all ages.", "Both from a theoretical perspective and by means of several case examples, the article focuses on the issue of overcoming the disturbed pre-verbal communication behaviour presented by patients in the early stage following severe craniocerebral trauma. In patients with brain lesion, a pre-verbal, emotionally-focussed tonal language almost invariably is capable of reaching the still healthy sections of the person. Hence, it is possible for music therapy to both establish contact with the seemingly non-responsive patient and re-stimulate the person's fundamental communication competencies and experience at the emotional, social and cognitive levels.", "Until recently, the degradation of aberrant and unassembled proteins retained in the endoplasmic reticulum (ER) was thought to involve unidentified ER-localized proteases. We now show that the ER-associated degradation (ERAD) of two mutant proteins that accumulate in the ER lumen is inhibited in a proteasome-defective yeast strain and when cytosol from this mutant is used in an in vitro assay. In addition, ERAD is limited in vitro in the presence of the proteasome inhibitors, 3,4-dichloroisocoumarin and lactacystin. Furthermore, we find that an ERAD substrate is exported from ER-derived microsomes, and the accumulation of exported substrate is 2-fold greater when proteasome mutant cytosol is used in place of wild-type cytosol. We conclude that lumenal ERAD substrates are exported from the yeast ER to the cytoplasm for degradation by the proteasome complex.", "Ferritin gene transcription is regulated by heme as is ferritin mRNA translation, which is mediated by the well studied mRNA.IRE/IRP protein complex. The heme-sensitive DNA sequence in ferritin genes is the maf recognition/antioxidant response element present in several other genes that are induced by heme and repressed by Bach1. We now report that chromatin immunoprecipitated with Bach1 antiserum contains ferritin DNA sequences. In addition, overexpression of Bach1 protein in the transfected cells decreased ferritin expression, indicating insufficient endogenous Bach1 for full repression; decreasing Bach1 with antisense RNA increased ferritin expression. Thioredoxin reductase1, a gene that also contains a maf recognition/antioxidant response element but is less studied, responded similarly to ferritin, as did the positive controls heme oxygenase1 and NADP(H) quinone (oxido) reductase1. Bach1-DNA promoter interactions in cells were confirmed in vitro with soluble, recombinant Bach1 protein and revealed a quantitative range of Bach1/DNA stabilities: ferritin L approximately ferritin H approximately beta-globin, beta-globin approximately 2-fold >heme oxygenase1 = quinone reductase beta-globin approximately 4-fold >thioredoxin reductase1. Such results indicate the possibility that modulation of cellular Bach1 concentrations will have variable effects among the genes coordinately regulated by maf recognition/antioxidant response elements in iron/oxygen/antioxidant metabolism.", "Vaccination has become an important therapeutic approach to the treatment of Alzheimer's disease (AD), however, immunization with Abeta amyloid can have unwanted, potentially lethal, side effects. Here we demonstrate an alternative peptide-mimotope vaccine strategy using the SDPM1 peptide. SDPM1 is a 20 amino acid peptide bounded by cysteines that binds tetramer forms of Abeta(1-40)- and Abeta(1-42)-amyloids and blocks subsequent Abeta amyloid aggregation. Immunization of mice with SDPM1 induced peptide-mimotope antibodies with the same biological activity as the SDPM1 peptide. When done prior to the onset of amyloid plaque formation, SDPM1 vaccination of APPswePSEN1(A246E) transgenic mice reduced amyloid plaque burden and Abeta(1-40) and Abeta(1-42) levels in the brain, improved cognitive performance in Morris water maze tests, and resulted in no increased T cell responses to immunogenic or Abeta peptides or brain inflammation. When done after plaque burden was already significant, SDPM1 immunization still significantly reduced amyloid plaque burden and Abeta(1-40/1-42) peptide levels in APPswePSEN1(A246E) brain without inducing encephalitogenic T cell responses or brain inflammation, but treatment at this stage did not improve cognitive function. These experiments demonstrate the efficacy of a novel vaccine approach for Alzheimer's disease where immunization with an Abeta(1-40/1-42) amyloid-specific binding and blocking peptide is used to inhibit the development of neuropathology and cognitive dysfunction.", "BACKGROUND: Cetuximab is an IgG1 monoclonal antibody targeting the epidermal growth factor receptor and is able to reverse the resistance to irinotecan in patients with metastatic colorectal cancer (mCRC). This phase II trial evaluates the safety and efficacy of cetuximab combined with capecitabine and oxaliplatin (CAPOX) in the treatment of patients with mCRC progressing under oxaliplatin-based chemotherapy.PATIENTS AND TREATMENT: Forty patients with mCRC were treated with cetuximab (loading dose 400 mg/m(2) and then 250 mg/m(2) i.v. weekly) in combination with CAPOX (d(1): L-OHP 85 mg/m(2) and d(1-7) capecitabine 2000 mg/m(2) every 2 weeks). Thirty-one (77.5%) and nine (22.5%) patients had oxaliplatin-refractory and -resistant disease, respectively; in addition, 32 (80%) patients had also progressed on prior irinotecan-based chemotherapy.RESULTS: One hundred and thirty-four cycles were administered (median of four cycles per patient). Main toxic effects included grade 3-4 neutropenia (12.5%), grade 3/4 diarrhea (7.5%), grade 3 fatigue (2.5%), and grade 2-3 neurotoxicity (22.5%). One (2.5%) complete and seven (17.5%) partial responses were achieved [overall objective response rate (ORR): 20%; 95% confidence interval (CI): 9% to 32%)], whereas 11 (27.5%) patients had stable disease [disease control rate (DCR): 47.5%; 95% CI: 30.2% to 64.5%]. The ORR and DCR were 18.7% and 46.8%, respectively, in patients with oxaliplatin-refractory disease. The median time to tumor progression was 3 months, the median survival 10.7 months and the probability of 1-year survival rate 53.4%.CONCLUSIONS: The combination of cetuximab plus CAPOX is safe and has a promising activity in patients with mCRC refractory or resistant to oxaliplatin.", "Treatment with intracerebroventricular (ICV)-delivered cerliponase alfa enzyme replacement therapy (ERT) in a Phase 1/2 study of 24 subjects with CLN2 disease resulted in a meaningful preservation of motor and language (ML) function and was well tolerated. Treatment was associated with anti-drug antibody (ADA) production in the cerebrospinal fluid (CSF) of 6/24 (25%) and in the serum of 19/24 (79%) of clinical trial subjects, respectively, over a mean exposure of 96.4 weeks (range 0.1-129 weeks). Neutralizing antibodies (NAb) were not detected in the CSF of any of the subjects. No events of anaphylaxis were reported. Neither the presence of serum ADA nor drug-specific immunoglobulin E was associated with the incidence or severity of hypersensitivity adverse events. Serum and CSF ADA titers did not correlate with change in ML score. Therefore, the development of an ADA response to cerliponase alfa is not predictive of an adverse safety profile or poor treatment outcome.", "Polycomb repression controls the expression of hundreds of genes involved in development and is mediated by essentially two classes of chromatin-associated protein complexes. The Polycomb repressive complex 2 (PRC2) trimethylates histone H3 at lysine 27, an epigenetic mark that serves as a docking site for the PRC1 protein complex. Drosophila core PRC1 is composed of four subunits: Polycomb (Pc), Posterior sex combs (Psc), Polyhomeotic (Ph) and Sex combs extra (Sce). Each of these proteins has multiple orthologs in vertebrates, thus generating an enormous scope for potential combinatorial diversity. In particular, mammalian genomes encode five Pc family members: CBX2, CBX4, CBX6, CBX7 and CBX8. To complicate matters further, distinct isoforms might arise from single genes. Here, we address the functional role of the two human CBX2 isoforms. Owing to different polyadenylation sites and alternative splicing events, the human CBX2 locus produces two transcripts: a 5-exon transcript that encodes the 532-amino acid CBX2-1 isoform that contains the conserved chromodomain and Pc box and a 4-exon transcript encoding a shorter isoform, CBX2-2, lacking the Pc box but still possessing a chromodomain. Using biochemical approaches and a novel in vivo imaging assay, we show that the short CBX2-2 isoform lacking the Pc box, does not participate in PRC1 protein complexes, but self-associates in vivo and forms complexes of high molecular weight. Furthermore, the CBX2 short isoform is still able to repress transcription, suggesting that Polycomb repression might occur in the absence of PRC1 formation.", "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.", "Urgent surgery or life-threatening bleeding requires prompt reversal of the anticoagulant effects of dabigatran. This study assessed the ability of three- and four-factor prothrombin complex concentrate (PCC) and idarucizumab (specific antidote for dabigatran) to reverse the anticoagulant effects of dabigatran in a porcine model of trauma. Twelve animals were given dabigatran etexilate (DE) orally and dabigatran intravenously, before infliction of trauma. Six animals received tranexamic acid plus fibrinogen concentrate 12 minutes post-injury. Six PCCs (each 30 and 60 U/kg) and idarucizumab (30 and 60 mg/kg) were added to blood samples ex vivo. Coagulation was assessed by several coagulation assays. All coagulation parameters were altered after dabigatran infusion (plasma level: 442 ± 138 ng/ml). Both three- and four-factor PCCs mostly or completely reversed the effects of dabigatran on thromboelastometry variables and PT but not on aPTT. Idarucizumab neutralised plasma concentrations of dabigatran, and reversed the effects of the drug on coagulation variables. Thrombin generation showed dose-dependent over-correction following the addition of PCC, implying that elevated levels of thrombin are required to overcome dabigatran-induced coagulopathy. In contrast, treatment with idarucizumab returned thrombin generation to baseline levels. Following trauma, therapy with tranexamic acid plus fibrinogen improved correction of coagulation parameters by PCC, and thromboelastometry parameters by idarucizumab. All investigated PCCs improved dabigatran- and trauma-induced coagulopathy to a similar degree. In conclusion, this study shows that three- and four-factor PCCs are similarly effective for dabigatran reversal. Idarucizumab also reversed the effects of dabigatran and, unlike PCCs, was not associated with over-correction of thrombin generation.", "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.", "PURPOSE: In this randomized, double-blind, placebo controlled phase 2 study we investigated tanezumab, a humanized monoclonal antibody that specifically inhibits nerve growth factor as a treatment for interstitial cystitis pain.MATERIALS AND METHODS: Patients with interstitial cystitis received a single intravenous dose of 200 μg/kg tanezumab or placebo. Patients recorded daily pain scores (on an 11-point numerical rating scale) 7 days before attending study visits and completed a urinary symptom diary for 3 of those days. Patients also completed the Interstitial Cystitis Symptom Index questionnaire and a global response assessment. The primary end point was change in average daily numerical rating scale pain score from baseline to week 6. Secondary end points included global response assessment, Interstitial Cystitis Symptom Index score, micturition and urgency episode frequency per 24 hours, and mean voided volume per micturition. The incidence of adverse events was also assessed.RESULTS: A total of 34 patients received tanezumab and 30 received placebo. At week 6 tanezumab produced a significant reduction from baseline in average daily pain score vs placebo (treatment difference [LS mean, 90% CI] was -1.4 [-2.2, -0.5]). A significantly higher proportion of patients on tanezumab responded as improved in the global response assessment and tanezumab also significantly reduced urgency episode frequency vs placebo. Tanezumab had no significant effect on Interstitial Cystitis Symptom Index score, micturition frequency or mean voided volume per micturition. The most common adverse events were headache (tanezumab 20.6%, placebo 16.7%) and paresthesia (tanezumab 17.6%, placebo 3.3%).CONCLUSIONS: Tanezumab has shown preliminary efficacy in the treatment of pain associated with interstitial cystitis.", "BACKGROUND: Recombinant human tripeptidyl peptidase 1 (cerliponase alfa) is an enzyme-replacement therapy that has been developed to treat neuronal ceroid lipofuscinosis type 2 (CLN2) disease, a rare lysosomal disorder that causes progressive dementia in children.METHODS: In a multicenter, open-label study, we evaluated the effect of intraventricular infusion of cerliponase alfa every 2 weeks in children with CLN2 disease who were between the ages of 3 and 16 years. Treatment was initiated at a dose of 30 mg, 100 mg, or 300 mg; all the patients then received the 300-mg dose for at least 96 weeks. The primary outcome was the time until a 2-point decline in the score on the motor and language domains of the CLN2 Clinical Rating Scale (which ranges from 0 to 6, with 0 representing no function and 3 representing normal function in each of the two domains), which was compared with the time until a 2-point decline in 42 historical controls. We also compared the rate of decline in the motor-language score between the two groups, using data from baseline to the last assessment with a score of more than 0, divided by the length of follow-up (in units of 48 weeks).RESULTS: Twenty-four patients were enrolled, 23 of whom constituted the efficacy population. The median time until a 2-point decline in the motor-language score was not reached for treated patients and was 345 days for historical controls. The mean (±SD) unadjusted rate of decline in the motor-language score per 48-week period was 0.27±0.35 points in treated patients and 2.12±0.98 points in 42 historical controls (mean difference, 1.85; P<0.001). Common adverse events included convulsions, pyrexia, vomiting, hypersensitivity reactions, and failure of the intraventricular device. In 2 patients, infections developed in the intraventricular device that was used to administer the infusion, which required antibiotic treatment and device replacement.CONCLUSIONS: Intraventricular infusion of cerliponase alfa in patients with CLN2 disease resulted in less decline in motor and language function than that in historical controls. Serious adverse events included failure of the intraventricular device and device-related infections. (Funded by BioMarin Pharmaceutical and others; CLN2 ClinicalTrials.gov numbers, NCT01907087 and NCT02485899 .).", "Advances in understanding the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, make gene-based therapy a promising treatment option for heart conditions. Cardiovascular gene therapy has benefitted from recent advancements in vector technology, design, and delivery modalities. There is a critical need to explore new therapeutic approaches in heart failure, and gene therapy has emerged as a viable alternative. Advances in understanding of the molecular basis of myocardial dysfunction, together with the development of increasingly efficient gene transfer technology, has placed heart failure within reach of gene-based therapy. The recent successful and safe completion of a phase 2 trial targeting the cardiac sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump (SERCA2a) has the potential to open a new era for gene therapy for heart failure." ]

[ "Rapid detection of nucleic acids is integral for clinical diagnostics and biotechnological applications. We recently developed a platform termed SHERLOCK (specific high-sensitivity enzymatic reporter unlocking) that combines isothermal preamplification with Cas13 to detect single molecules of RNA or DNA. Through characterization of CRISPR enzymology and application development, we report here four advances integrated into SHERLOCK version 2 (SHERLOCKv2) (i) four-channel single-reaction multiplexing with orthogonal CRISPR enzymes; (ii) quantitative measurement of input as low as 2 attomolar; (iii) 3.5-fold increase in signal sensitivity by combining Cas13 with Csm6, an auxiliary CRISPR-associated enzyme; and (iv) lateral-flow readout. SHERLOCKv2 can detect Dengue or Zika virus single-stranded RNA as well as mutations in patient liquid biopsy samples via lateral flow, highlighting its potential as a multiplexable, portable, rapid, and quantitative detection platform of nucleic acids.", "Comparisons of DNA sequences among evolutionarily distantly related genomes permit identification of conserved functional regions in noncoding DNA. Hox genes are highly conserved in vertebrates, occur in clusters, and are uninterrupted by other genes. We aligned (PipMaker) the nucleotide sequences of the HoxA clusters of tilapia, pufferfish, striped bass, zebrafish, horn shark, human, and mouse, which are separated by approximately 500 million years of evolution. In support of our approach, several identified putative regulatory elements known to regulate the expression of Hox genes were recovered. The majority of the newly identified putative regulatory elements contain short fragments that are almost completely conserved and are identical to known binding sites for regulatory proteins (Transfac database). The regulatory intergenic regions located between the genes that are expressed most anteriorly in the embryo are longer and apparently more evolutionarily conserved than those at the other end of Hox clusters. Different presumed regulatory sequences are retained in either the Aalpha or Abeta duplicated Hox clusters in the fish lineages. This suggests that the conserved elements are involved in different gene regulatory networks and supports the duplication-deletion-complementation model of functional divergence of duplicated genes.", "Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a dominant neurodegenerative disease caused by the expansion of a CAG repeat tract in ATXN3. Anticipation and worsening of clinical picture in subsequent generations were repeatedly reported, but there is no indication that SCA3/MJD frequency is changing. Thus, we performed a systematic review and meta-analysis on phenomena with potential effect on SCA3/MJD recurrency in populations: instability of CAG repeat transmissions, anticipation, fitness, and segregation of alleles. Transmission of the mutant allele was associated with an increase of 1.23 CAG repeats in the next generation, and the average change in age at onset showed an anticipation of 7.75 years per generation; but biased recruitments cannot be ruled out. Affected SCA3/MJD individuals had 45% more children than related controls. Transmissions from SCA3/MJD carriers showed that the expanded allele was segregated in 64% of their children. In contrast, transmissions from normal subjects showed that the minor allele was segregated in 54%. The present meta-analysis concluded that there is a segregation distortion favoring the expanded allele, among children of carriers. Therefore, further studies on transmissions and anticipation phenomena as well as more observations about fertility are required to clarify these selective forces over SCA3/MJD.", "The Apert syndrome is characterized by craniosynostosis and syndactyly of hands and feet. Although most cases are sporadic, an autosomal dominant mode of inheritance is well documented. Two mutations in the FGFR2 gene (Ser252Trp and Pro253Arg) account for most of the cases. We report a patient with a rare form of Apert syndrome with polydactyly. The proposita has turribrachycephaly. complete syndactyly of 2nd to 5th digits (\"mitten hands\" and cutaneous fusion of all toes). The X-rays revealed craniosynostosis of the coronal suture and preaxial polydactyly of hands and feet with distal bony fusion. Molecular analysis found a C755G transversion (Ser252Trp) in the FGFR2 gene. Only eight patients with Apert syndrome and preaxial polydactyly have been reported and this is the first case in which molecular diagnosis is available. On the basis of the molecular findings in this patient, polydactyly should be considered part of the spectrum of abnormalities in the Apert syndrome. This assertion would establish the need for a new molecular classification of the acrocephalopolysyndactylies.", "Organic anion-transporting polypeptide 1c1 (Oatp1c1) (also known as Slco1c1 and Oatp14) belongs to the family of Oatp and has been shown to facilitate the transport of T(4). In the rodent brain, Oatp1c1 is highly enriched in capillary endothelial cells and choroid plexus structures where it may mediate the entry of T(4) into the central nervous system. Here, we describe the generation and first analysis of Oatp1c1-deficient mice. Oatp1c1 knockout (KO) mice were born with the expected frequency, were not growth retarded, and developed without any overt neurological abnormalities. Serum T(3) and T(4) concentrations as well as renal and hepatic deiodinase type 1 expression levels were indistinguishable between Oatp1c1 KO mice and control animals. Hypothalamic TRH and pituitary TSH mRNA levels were not affected, but brain T(4) and T(3) content was decreased in Oatp1c1-deficient animals. Moreover, increased type 2 and decreased type 3 deiodinase activities indicate a mild hypothyroid situation in the brain of Oatp1c1 KO mice. Consequently, mRNA expression levels of gene products positively regulated by T(3) in the brain were down-regulated. This central nervous system-specific hypothyroidism is presumably caused by an impaired passage of T(4) across the blood-brain barrier and indicates a unique function of Oatp1c1 in facilitating T(4) transport despite the presence of other thyroid hormone transporters such as Mct8.", "Publicly available RNA-seq data is routinely used for retrospective analysis to elucidate new biology. Novel transcript discovery enabled by joint analysis of large collections of RNA-seq data sets has emerged as one such analysis. Current methods for transcript discovery rely on a '2-Step' approach where the first step encompasses building transcripts from individual data sets, followed by the second step that merges predicted transcripts across data sets. To increase the power of transcript discovery from large collections of RNA-seq data sets, we developed a novel '1-Step' approach named Pooling RNA-seq and Assembling Models (PRAM) that builds transcript models from pooled RNA-seq data sets. We demonstrate in a computational benchmark that 1-Step outperforms 2-Step approaches in predicting overall transcript structures and individual splice junctions, while performing competitively in detecting exonic nucleotides. Applying PRAM to 30 human ENCODE RNA-seq data sets identified unannotated transcripts with epigenetic and RAMPAGE signatures similar to those of recently annotated transcripts. In a case study, we discovered and experimentally validated new transcripts through the application of PRAM to mouse hematopoietic RNA-seq data sets. We uncovered new transcripts that share a differential expression pattern with a neighboring gene Pik3cg implicated in human hematopoietic phenotypes, and we provided evidence for the conservation of this relationship in human. PRAM is implemented as an R/Bioconductor package.", "BACKGROUND: Scaffold proteins modulate cellular signaling by facilitating assembly of specific signaling pathways. However, there is at present little information if and how scaffold proteins functionally interact with each other.RESULTS: Here, we show that two scaffold proteins, caveolin-1 and IQGAP1, are required for phosphorylation of the actin associated pool of extracellular signal regulated kinase 1 and 2 (ERK1/2) in response to protein kinase C activation. We show by immunofluorescence and proximity ligation assays, that IQGAP1 tethers ERK1/2 to actin filaments. Moreover, siRNA experiments demonstrate that IQGAP1 is required for activation of actin-bound ERK1/2. Caveolin-1 is also necessary for phosphorylation of actin-bound ERK1/2 in response to protein kinase C, but is dispensible for ERK1/2 association with actin. Simultaneous knock down of caveolin-1 and IQGAP1 decreases total phorbol ester-induced ERK1/2 phosphorylation to the same degree as single knock down of either caveolin-1 or IQGAP1, indicating that caveolin-1 and IQGAP1 operate in the same ERK activation pathway. We further show that caveolin-1 knock down, but not IQGAP1 knock down, reduces C-Raf phosphorylation in response to phorbol ester stimulation.CONCLUSIONS: Based on our data, we suggest that caveolin-1 and IQGAP1 assemble distinct signaling modules, which are then linked in a hierarchical arrangement to generate a functional ERK1/2 activation pathway." ]

[ "This study was designed to investigate the antioxidant and anti-aging effects of D-galatose-induced (D-gal-induced) aging mice as well as monosaccharide compositions of acidic-extractable polysaccharides (AcAPS) and its major purified fractions (AcAPS-1, AcAPS-2 and AcAPS-3) from the fruiting body of Agaricus bisporus. In the in vitro assays, AcAPS-2 showed superior scavenging activities on hydroxyl (82.98±4.67%) and DPPH (64.47±4.05%) radicals at the concentration of 1.0mg/mL than AcAPS and other polysaccharides fractions. For in vivo anti-aging analysis, AcAPS-2 showed superior effects on hepatic and nephric protection by improving serum enzyme activities, biochemical levels, lipid contents and antioxidant status, respectively. The monosaccharide analysis showed that rhamnose (Rha) and glucose (Glu) may play vital roles in maintaining the antioxidant and anti-aging activities. The results suggested that both AcAPS and its purified fractions might be suitable for functional foods and natural drugs in preventing the acute aging-associated diseases.", "Gastrointestinal stromal tumours (GIST) occur mostly as sporadic solitary lesions involving the tubular GI tract and are only rarely associated with other benign or malignant neoplasms or occur as part of a multi-neoplastic disease as in the setting of Carney's triad and von Recklinghausen's disease. We analysed a total of 97 cases of surgically resected GIST looking for various types of associated non-GIST malignancies. 18 cases (18.6 %) were identified. There were 12 women and 6 men aged 43 to 87, average age 71.7 years. 12 GISTs were located in the stomach, four in the small intestine, and one each in the duodenum and the vermiform appendix. Associated malignancies (mostly carcinomas) were gastrointestinal/pancreatic (9), gynaecological (3), mammary (2), renal (1), prostatic (1), pulmonary (2) and haematolymphoid (2) in origin. Most GISTs (16/18) represented benign or low-risk lesions (innocent bystanders) detected during evaluation for the known cancer, either during staging, intra-operatively or on follow-up. Two women (43 and 72 years old) with large malignant GISTs (10.5 and 12 cm), one of them with two simultaneous hepatic metastases resected at the same time as the primary GIST, developed infiltrating ductal mammary carcinoma and were alive and well 75 and 95 months postoperatively, respectively. Furthermore, one of them developed endometrial carcinoma. We concluded that GISTs are not uncommonly encountered in cancer-patients during staging, intraoperatively or on follow-up and should be considered in the differential diagnosis of newly detected focal lesions to avoid their misinterpretation as metastasis from the known malignancy with consequently false therapeutic decisions.", "DNA methyltransferase 1 (DNMT1) is the primary enzyme that maintains DNA methylation. We describe a previously unknown mode of regulation of DNMT1 protein stability through the coordinated action of an array of DNMT1-associated proteins. DNMT1 was destabilized by acetylation by the acetyltransferase Tip60, which triggered ubiquitination by the E3 ligase UHRF1, thereby targeting DNMT1 for proteasomal degradation. In contrast, DNMT1 was stabilized by histone deacetylase 1 (HDAC1) and the deubiquitinase HAUSP (herpes virus-associated ubiquitin-specific protease). Analysis of the abundance of DNMT1 and Tip60, as well as the association between HAUSP and DNMT1, suggested that during the cell cycle the initiation of DNMT1 degradation was coordinated with the end of DNA replication and the need for DNMT activity. In human colon cancers, the abundance of DNMT1 correlated with that of HAUSP. HAUSP knockdown rendered colon cancer cells more sensitive to killing by HDAC inhibitors both in tissue culture and in tumor xenograft models. Thus, these studies provide a mechanism-based rationale for the development of HDAC and HAUSP inhibitors for combined use in cancer therapy.", "On the basis of amino acid sequence alignments and structural data of related enzymes, we have performed a mutational analysis of 14 amino acid residues in the catalytic domain of the murine Dnmt3a DNA-(cytosine C5)-methyltransferase. The target residues are located within the ten conserved amino acid sequence motifs characteristic for cytosine-C5 methyltransferases and in the putative DNA recognition domain of the enzyme (TRD). Mutant proteins were purified and tested for their catalytic properties and their abilities to bind DNA and AdoMet. We prepared a structural model of Dnmt3a to interpret our results. We demonstrate that Phe50 (motif I) and Glu74 (motif II) are important for AdoMet binding and catalysis. D96A (motif III) showed reduced AdoMet binding but increased activity under conditions of saturation with S-adenosyl-L-methionine (AdoMet), indicating that the contact of Asp96 to AdoMet is not required for catalysis. R130A (following motif IV), R241A and R246A (in the TRD), R292A, and R297A (both located in front of motif X) showed reduced DNA binding. R130A displayed a strong reduction in catalytic activity and a complete change in flanking sequence preferences, indicating that Arg130 has an important role in the DNA interaction of Dnmt3a. R292A also displayed reduced activity and changes in the flanking sequence preferences, indicating a potential role in DNA contacts farther away from the CG target site. N167A (motif VI) and R202A (motif VIII) have normal AdoMet and DNA binding but reduced catalytic activity. While Asn167 might contribute to the positioning of residues from motif VI, according to structural data Arg202 has a role in catalysis of cytosine-C5 methyltransferases. The R295A variant was catalytically inactive most likely because of destabilization of the hinge sub-domain of the protein.", "The DNA transposon piggyBac is widely used as a tool in mammalian experimental systems for transgenesis, mutagenesis, and genome engineering. We have characterized genome-wide insertion site preferences of piggyBac by sequencing a large set of integration sites arising from transposition from two separate genomic loci and a plasmid donor in mouse embryonic stem cells. We found that piggyBac preferentially integrates locally to the excision site when mobilized from a chromosomal location and identified other nonlocal regions of the genome with elevated insertion frequencies. piggyBac insertions were associated with expressed genes and markers of open chromatin structure and were excluded from heterochromatin. At the nucleotide level, piggyBac prefers to insert into TA-rich regions within a broader GC-rich context. We also found that piggyBac can insert into sites other than its known TTAA insertion site at a low frequency (2%). Such insertions introduce mismatches that are repaired with signatures of host cell repair pathways. Transposons could be mobilized from plasmids with the observed noncanonical flanking regions, indicating that piggyBac could generate point mutations in the genome.", "Skin is the most voluminous organ of the body. It assumes several important physiological functions and represents also a \"social interface\" between an individual and other members of society. This is the main reason its age-dependent modifications are in the forefront of dermatological research and of the \"anti-aging\" cosmetic industry. Here we concentrate on some aspects only of skin aging, as far as the cellular and extracellular matrix components of skin are concerned. Most well studied mechanisms of skin aging can be situated at the postgenetic level, both epigenetic and post-translational mechanisms being involved. Some of these mechanisms will be reviewed as well as the capacity of fucose- and rhamnose-rich oligo- and polysaccharides (FROP and RROP) to counteract several of the mechanisms involved in skin aging.", "This report describes a feasibility study concerning the use of a visible diode laser for two important fluorescence applications in a flow cytometer. With a 3 mW 635 nm diode laser, we performed immunofluorescence measurements using the fluorophore allophycocyanin (APC). We have measured CD8 positive lymphocytes with a two-step labeling procedure and the resulting histograms showed good separation between the negative cells and the dim and the bright fluorescent subpopulations. As a second fluorescence application, we chose DNA analysis with the recently developed DNA/RNA stains TOTO-3 and TO-PRO-3. In our setup TO-PRO-3 yielded the best results with a CV of 3.4%. Our results indicate that a few milliwatts of 635 nm light from a visible diode laser is sufficient to do single color immunofluorescence measurements with allophycocyanin and DNA analysis with TO-PRO-3. The major advantages of using a diode laser in a flow cytometer are the small size, the low price, the high efficiency, and the long lifetime.", "OBJECTIVE: Anti-TNF therapies have been highly efficacious in the management of rheumatoid arthritis (RA), but 25-30% of patients do not show a significant clinical response. There is increasing evidence that genetic variation at the Fc receptor FCGR2A is associated with the response to anti-TNF therapy. We aimed to validate this genetic association in a patient cohort from the Spanish population, and also to identify new genes functionally related to FCGR2A that are also associated with anti-TNF response.METHODS: A total of 348 RA patients treated with an anti-TNF therapy were included and genotyped for FCGR2A polymorphism rs1081274. Response to therapy was determined at 12 weeks, and was tested for association globally and independently for each anti-TNF drug (infliximab, etanercept and adalimumab). Using gene expression profiles from macrophages obtained from synovial fluid of RA patients, we searched for genes highly correlated with FCGR2A expression. Tag SNPs were selected from each candidate gene and tested for association with the response to therapy.RESULTS: We found a significant association between FCGR2A and the response to adalimumab (P=0.022). Analyzing the subset of anti-CCP positive RA patients (78%), we also found a significant association between FCGR2A and the response to infliximab (P=0.035). DHX32 and RGS12 were the most consistently correlated genes with FCGR2A expression in RA synovial fluid macrophages (P<0.001). We found a significant association between the genetic variation at DHX32 (rs12356233, corrected P=0.019) and a nominally significant association between RGS12 and the response to adalimumab (rs4690093, uncorrected P=0.040). In the anti-CCP positive group of patients, we also found a nominally significant association between RGS12 and the response to infliximab (rs2857859, uncorrected P=0.042).CONCLUSIONS: In the present study we have validated the FCGR2A association in an independent population, and we have identified new genes associated with the response to anti-TNF therapy in RA." ]

[ "Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and there is no approved pharmacotherapy. The efficacy of vitamin E and pioglitazone has been established in nonalcoholic steatohepatitis (NASH), a progressive form of NAFLD. GLP-1RA and SGLT2 inhibitors, which are currently approved for use in diabetes, have shown early efficacy in NASH, and also have beneficial cardiovascular or renal effects. Innovative NASH therapies include four main pathways. The first approach is targeting hepatic fat accumulation. Medications in this approach include modulation of peroxisome proliferator-activator receptors (e.g., pemafibrate, elafibranor), medications targeting farnesoid X receptor axis [obeticholic acid; OCA)], inhibitors of de novo lipogenesis (aramchol, ACC inhibitor), and fibroblast growth factor-21 analogues. A second target is oxidative stress, inflammation, and apoptosis. This class of drug includes apoptosis signaling kinase 1 (ASK1) inhibitor and emricasan (an irreversible caspase inhibitor). A third target is intestinal microbiomes and metabolic endotoxemia. Several agents are in ongoing trials, including IMMe124, TLR4 antagonist, and solithromycin (macrolide antibiotics). The final target is hepatic fibrosis, which is strongly associated with all-cause or liver-related mortality in NASH. Antifibrotic agents are a cysteine-cysteine motif chemokine receptor-2/5 antagonist (cenicriviroc; CVC) and galectin 3 antagonist. Among a variety of medications in development, four agents such as OCA, elafibranor, ASK1 inhibitor, and CVC are currently being evaluated in an international phase 3 trial for the treatment of NASH. Within the next few years, the availability of therapeutic options for NASH will hopefully curb the rising trend of NASH-related diseases.", "Mutations in the gene encoding fibrillin 1 (FBN1) cause Marfan syndrome (MFS), and related connective tissue disorders. The disease spectrum is wide and while many genotype-phenotype correlations have been reported, few have been consistent. In this study FBN1 was analyzed in 113 patients with MFS or Marfan-like features. Fifty-three mutations were identified in 52 individuals, 41 of which were novel. The mutations comprised 26 missense, 11 splice site, 7 frameshift, 6 nonsense, 1 in-frame deletion, and 2 whole exon deletions. In common with previous studies, genotype-phenotype analysis showed that a FBN1 mutation was more likely to be identified in patients fulfilling Ghent criteria (P = 0.005) and in those who had ectopia lentis (EL) (P < 0.0001). Other previously reported genotype-phenotype correlations were also considered and a new inverse association between a mutation in exons 59-65, and EL emerged (P = 0.002).", "Non-alcoholic fatty liver disease (NAFLD) has become one of the most prominent forms of chronic liver disease worldwide, reflecting the epidemic of global obesity. Those with the progressive variant of NAFLD, non-alcoholic steatohepatitis (NASH), are at significantly increased risk of multisystem morbidity and mortality. However, there are currently no approved pharmacologic therapies for NASH. Given the disease burden, there is an important unmet need for pharmacologic treatment options for this patient population. The underlying pathophysiologic mechanisms that contribute to the development and progression of NAFLD and NASH are complex and reflected by the myriad of therapies, with different targets, currently under investigation. In broad strokes, drug development has focused on modulation of metabolic pathways, inflammatory cascades, and/or mechanisms impacting fibrosis. Although much progress has been made in enhancing our understanding of NAFLD pathogenesis, development of pharmacologic treatments has been hindered by challenges in clinical trial enrollment and complexities in clinical trial design. The compounds in phase IIa have provided promising results in terms of potential benefits on various aspects of histopathology. Agents in later stages of development have shown fairly modest results in terms of reduction of hepatic steatosis, necroinflammation and fibrosis. If longer term safety and efficacy are established among heterogeneous cohorts, these medications may help mitigate potential morbidity and mortality for this burgeoning patient population.", "BACKGROUND: Selective chromogenic media allowing one-step meticillin-resistant Staphylococcus aureus (MRSA) isolation and identification are widely used. However, the changing epidemiology of MRSA means that the suitability of these chromogenic media requires investigation.AIM: To evaluate the following chromogenic media - Colorex MRSA, MRSA Select II, ChromID MRSA, and MRSA Brilliance 2 - for the detection of divergent strain types.METHODS: We used a diverse collection of S. aureus, including strains harbouring the mecC gene, strains expressing varying levels of meticillin resistance, and isolates recovered from patient samples.FINDINGS: MRSA Select II, Colorex MRSA, and ChromID each grew at a density of 1.5 × 10(1)cfu/mL for each SCCmec type investigated. Brilliance 2 demonstrated growth at 1.5 × 10(1)cfu/mL for mecC MRSA but at a higher density (1.5 × 10(4)cfu/mL) for the three mecA MRSA strains. All four media demonstrated excellent sensitivity for MRSA detection (≥99%), but reduced levels of specificity (85-73%) when challenged with a range of meticillin-susceptible S. aureus (MSSA) isolates. High levels of false positives (∼50%) were also obtained with all chromogenic media when tested with mec-negative borderline oxacillin-resistant S. aureus (BORSA) isolates.CONCLUSION: Although false positives may be obtained with some strains of MSSA and BORSA, the high sensitivity of these media and their ability to recover almost all MRSA tested (including oxacillin-susceptible and mecC-positive strains) confirm the value of chromogenic agar in MRSA detection.", "Nonalcoholic fatty liver disease (NAFLD) has an increasing prevalence worldwide. At present, no specific pharmacotherapy is approved for NAFLD. Simple steatosis and nonalcoholic steatohepatitis (NASH) can progress to liver fibrosis that is associated with mortality in NAFLD. The recruitment of inflammatory monocytes and macrophages via chemokine receptor CCR2 as well as of lymphocytes and hepatic stellate cells via CCR5 promote the progression of NASH to fibrosis. Areas covered: I summarize preclinical and clinical data on the efficacy and safety of the dual CCR2/CCR5 inhibitor cenicriviroc (CVC, also TBR-652 or TAK-652) for the treatment of NASH and fibrosis. In animal models of liver diseases, CVC potently inhibits macrophage accumulation in the liver and ameliorates fibrosis. In a phase 2b clinical trial (CENTAUR) on 289 patients with NASH and fibrosis, CVC consistently demonstrated liver fibrosis improvement after 1 year of therapy and had an excellent safety profile, leading to the implementation of a phase 3 trial (AURORA). Expert opinion: Preclinical and clinical data support the development of CVC as a safe and potent antifibrotic agent. However, open questions around CVC are the durability of antifibrotic responses, divergent effects on NASH versus fibrosis, potential long-term concerns and the expected path to approval.", "High levels of transcription in Saccharomyces cerevisiae are associated with increased genetic instability, which has been linked to DNA damage. Here, we describe a pGAL-CAN1 forward mutation assay for studying transcription-associated mutagenesis (TAM) in yeast. In a wild-type background with no alterations in DNA repair capacity, ≈50% of forward mutations that arise in the CAN1 gene under high-transcription conditions are deletions of 2-5 bp. Furthermore, the deletions characteristic of TAM localize to discrete hotspots that coincide with 2-4 copies of a tandem repeat. Although the signature deletions of TAM are not affected by the loss of error-free or error-prone lesion bypass pathways, they are completely eliminated by deletion of the TOP1 gene, which encodes the yeast type IB topoisomerase. Hotspots can be transposed into the context of a frameshift reversion assay, which is sensitive enough to detect Top1-dependent deletions even in the absence of high transcription. We suggest that the accumulation of Top1 cleavage complexes is related to the level of transcription and that their removal leads to the signature deletions. Given the high degree of conservation between DNA metabolic processes, the links established here among transcription, Top1, and mutagenesis are likely to extend beyond the yeast system.", "Biomarkers are currently widely used to diagnose diseases, monitor treatments, and evaluate potential drug candidates. Research of differential Omics accelerate the advancements of biomarkers' discovery. By extracting biological knowledge from the 'omics' through integration, integrative system biology creates predictive models of cells, organs, biochemical processes and complete organisms, in addition to identifying human disease biomarkers. Recent development in high-throughput methods enables analysis of genome, transcriptome, proteome, and metabolome at an unprecedented scale, thus contributing to the deluge of experimental data in numerous public databases. Several integrative system biology approaches have been developed and applied to the discovery of disease biomarkers from databases. In this review, we highlight several of these approaches and identify future steps in the context of the field of integrative system biology.", "Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. UMs are usually initiated by a mutation in GNAQ or GNA11, unlike cutaneous melanomas, which usually harbour a BRAF or NRAS mutation. The annual incidence in Europe and the USA is ~6 per million population per year. Risk factors include fair skin, light-coloured eyes, congenital ocular melanocytosis, ocular melanocytoma and the BAP1-tumour predisposition syndrome. Ocular treatment aims at preserving the eye and useful vision and, if possible, preventing metastases. Enucleation has largely been superseded by various forms of radiotherapy, phototherapy and local tumour resection, often administered in combination. Ocular outcomes are best with small tumours not extending close to the optic disc and/or fovea. Almost 50% of patients develop metastatic disease, which usually involves the liver, and is usually fatal within 1 year. Although UM metastases are less responsive than cutaneous melanoma to chemotherapy or immune checkpoint inhibitors, encouraging results have been reported with partial hepatectomy for solitary metastases, with percutaneous hepatic perfusion with melphalan or with tebentafusp. Better insight into tumour immunology and metabolism may lead to new treatments.", "Olmesartan (OL) is the pharmacologically active metabolite of Olmesartan medoxomil (OM), an FDA-approved angiotensin II receptor antagonist for administrating cardiovascular diseases. The drug has been found to have potential effects on diverse protein kinase signaling involved in the pathogenesis of atherosclerosis, either by directly inhibiting the hub kinases or by indirectly modulating marginal members in the signaling pathways. In the present study, we computationally model the kinase-chemical Interaction Profile between six OL-related chemicals (i.e. OL, OM, Valsartan [VL], Losartan [LS], Candesartan [CD] and Telmisartan [TL]) and 23 human protein kinases in atherosclerosis. The profile is analyzed systematically at molecular level to identify unexpected kinase targets for OL. There is a good consistence between co-citation frequency and affinity scoring for the chemical association with kinase candidates; the OL and its analogs VL and LS exhibit a similar binding profile to the atherosclerosis kinase spectrum. It is suggested that the Ser/Thr-specific kinases PI3Kα and ROCK1 are potential druggable targets of OL for atherosclerosis therapy. As a paradigm, kinase assays reveal that the inhibitory potency of OL and Y-27632 (positive control) on ROCK1 is determined at micromolar level, while the OM (negative control) possesses no detectable activity for the kinase.", "The pathological and radiological hallmarks of multiple sclerosis (MS) include multiple demyelinated lesions disseminated throughout the white matter of the central nervous system (CNS). More recently, the cerebral cortex has been shown to be affected in MS, but the elucidation of events causing cortical demyelination has been hampered by the lack of animal models reflecting such human cortical pathology. In this report, we have described the presence of cortical gray matter and callosal white matter demyelinating lesions in the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Similar to the pathological lesions of MS patients, EAE lesions have been classified as type I-leukocortical, type II-intracortical and type III-subpial. All of these lesions had varying degrees of demyelination, inflammatory cells and reactive astrocytes. Similar to MS, cortical layers during EAE showed demyelination, microglia activation, synaptic protein alterations and apoptotic cells. In addition, the callosal white matter during EAE had many inflammatory demyelinating lesions and axon degeneration. Functional electrophysiological conduction analysis showed deficits in both myelinated and unmyelinated callosal axons during early and late EAE. The chronic EAE mouse model has features that mimic cortical and callosal pathology of MS, and can be potentially used to screen agents to prevent these features of disease.", "Recent data support the view that transcription factors - in particular, homeoproteins - can be transferred from cell to cell and have direct non-cell-autonomous (and therefore paracrine) activities. This intercellular transfer, based on atypical internalization and secretion, has important biotechnological consequences. But the real excitement stems from the physiological and developmental implications of this mode of signal transduction.", "Several studies have shown effects of diesel exhaust (DE) on the central nervous system, but the mechanism is unclear. Fetal mice were exposed to whole DE (contains gases and particles) in an inhalation chamber, and cerebrum gene expression changes were examined by gene assay (microarray and quantitative real-time PCR). By microarray, upregulation of Xist, B-raf and Drwms2 were detected. Especially, mRNA expression of Xist was increased in a concentration-dependent manner in male and female mice. Xist (X-inactive specific transcript) is a major effector of the X-inactivation process, and X-linked genes are highly expressed in brain tissue and consistent with a role in brain developments. By quantitative real-time PCR, Tsix (crucial noncoding antisense partner of Xist) and other X-linked genes (Mecp2, Hprt1, and Sts) were examined; Tsix was upregulated, and other X-linked genes were unaffected in the male and female mice. Our findings suggest that exposure to DE increases Xist and Tsix gene expression in utero without influencing X-linked gene expression. An examination of Xist gene expression changes may provide an important biomarker for DE-induced effects. The possibility of avoiding X-chromosome inactivation (XCI) mechanisms by minimizing exposure to DE is expected.", "BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the leading chronic hepatic condition worldwide and new approaches to management and treatment are limited.SUMMARY: L-ornithine L-aspartate (LOLA) has hepatoprotective properties in patients with fatty liver of diverse etiology and results of a multicenter randomized clinical trial reveal that 12 weeks treatment with oral LOLA (6-9 g/d) results in a dose-related reduction in activities of liver enzymes and triglycerides together with significant improvements of liver/spleen CT ratios. A preliminary report described improvements of hepatic microcirculation in patients with non-alcoholic steatohepatitis (NASH) following treatment with LOLA. Mechanisms responsible for the beneficial effects of LOLA in NAFLD/NASH involve, in addition to its established ammonia-lowering effect, metabolic transformations of the LOLA-constituent amino acids L-ornithine and L-aspartate into L-glutamine, L-arginine, and glutathione. These metabolites have well-established actions implicated in the prevention of lipid peroxidation, improvement of hepatic microcirculation in addition to anti-inflammatory, and anti-oxidant properties. Key Messages: (1) LOLA is effective for the treatment of key indices in NAFLD/NASH. (2) Mechanisms other than LOLA's ammonia-lowering action have been postulated. (3) Further assessments in the clinical setting are now required.", "Pseudogenes, resulting from duplications of functional genes, contribute to the functional complexity of their parental genes. The glucocerebrosidase gene (GBA), located in a gene-rich region on chromosome 1q 21, is mutated in Gaucher disease. The presence of contiguous, highly homologous pseudogenes for both GBA and metaxin 1 at this locus increases the likelihood of DNA rearrangement. We describe a facile method to identify and analyze recombinant alleles in patients with Gaucher disease. Genomic DNA from 20 patients with recombinant GBA alleles and five controls was evaluated to identify DNA rearrangements or copy number variation using six probes specific for either the GBA gene or pseudogene. Quantitative real-time PCR was performed on genomic DNA, and Southern blot analyses using HincII together with sequencing confirmed the real-time results. Both GBA fusions and duplications could be detected. Different sites of crossover were identified, and alleles resulting from gene conversion could be distinguished from reciprocal recombinant alleles. Quantitative real-time PCR is a sensitive and rapid method to detect fusions and duplications in patients with recombinant GBA alleles. This technique is more sensitive, faster, and cheaper than Southern blot analysis, and can be used in diagnostic laboratories, and to detect other recombinant alleles within the genome.", "BACKGROUND: Oral health-related quality of life (OHRQoL) is a multidimensional, perception-based measure of how oral health affects social and physical functioning and self-image. OHRQoL is important for assessing women living with HIV (WLWH) who may have unmet dental needs and experience disparities that impact dental care accessibility.METHODS: In 2016, the authors conducted an assessment of OHRQoL among a national sample of 1,526 WLWH in the Women's Interagency HIV Study using the Oral Health Impact Profile instrument, which assesses the frequency of 14 oral health impact items. OHRQoL was measured using multivariable linear regression with a negative binomial distribution to assess the association between report of a recent unmet dental need and OHRQoL.RESULTS: \"Fair or poor\" oral health condition was reported by 37.8% (n = 576) of WLWH. Multivariable linear regression showed that unmet dental needs had the strongest positive association with poor OHRQoL (difference in Oral Health Impact Profile mean, 2.675; P < .001) compared with not having unmet needs. The frequency of dental care utilization was not associated with higher OHRQoL. Older age, fair or poor dental condition, smoking, symptoms of anxiety and loneliness, and poor OHRQoL were also associated with worse OHRQoL.CONCLUSION: Self-perceived impact of oral health on social and physical function and self-image, as measured by OHRQoL, may be an easily assessable but underrecognized aspect of OHRQoL, particularly among women aging with HIV.PRACTICAL IMPLICATIONS: Dentists should implement OHRQoL assessments in their management of the care of patients with HIV to identify those who do have significant oral health impacts.", "Calmodulin (CaM) and phosphatidylinositide-3 kinase (PI3Kα) are well known for their multiple roles in a series of intracellular signaling pathways and in the progression of several human cancers. Crosstalk between CaM and PI3Kα has been an area of intensive research. Recent experiments have shown that in adenocarcinoma, K-Ras4B is involved in the CaM-PI3Kα crosstalk. Based on experimental results, we have recently put forward a hypothesis that the coordination of CaM and PI3Kα with K-Ras4B forms a CaM-PI3Kα-K-Ras4B ternary complex, which leads to the formation of pancreatic ductal adenocarcinoma. However, the mechanism for the CaM-PI3Kα crosstalk is unresolved. Based on molecular modeling and molecular dynamics simulations, here we explored the potential interactions between CaM and the c/nSH2 domains of p85α subunit of PI3Kα. We demonstrated that CaM can interact with the c/nSH2 domains and the interaction details were unraveled. Moreover, the possible modes for the CaM-cSH2 and CaM-nSH2 interactions were uncovered and we used them to construct a complete CaM-PI3Kα complex model. The structural model of CaM-PI3Kα interaction not only offers a support for our previous ternary complex hypothesis, but also is useful for drug design targeted at CaM-PI3Kα protein-protein interactions." ]

[ "The genome of metazoan cells is organized into topologically associating domains (TADs) that have similar histone modifications, transcription level, and DNA replication timing. Although similar structures appear to be conserved in fission yeast, computational modeling and analysis of high-throughput chromosome conformation capture (Hi-C) data have been used to argue that the small, highly constrained budding yeast chromosomes could not have these structures. In contrast, herein we analyze Hi-C data for budding yeast and identify 200-kb scale TADs, whose boundaries are enriched for transcriptional activity. Furthermore, these boundaries separate regions of similarly timed replication origins connecting the long-known effect of genomic context on replication timing to genome architecture. To investigate the molecular basis of TAD formation, we performed Hi-C experiments on cells depleted for the Forkhead transcription factors, Fkh1 and Fkh2, previously associated with replication timing. Forkhead factors do not regulate TAD formation, but do promote longer-range genomic interactions and control interactions between origins near the centromere. Thus, our work defines spatial organization within the budding yeast nucleus, demonstrates the conserved role of genome architecture in regulating DNA replication, and identifies a molecular mechanism specifically regulating interactions between pericentric origins.", "We have identified a mutant of pea cultivar Alaska that has many of the characteristics normally associated with light-grown seedlings even when grown in complete darkness. We have designated this mutant lip1, for light independent photomorphogenesis. Etiolated wild-type pea seedlings are white to slightly yellow in color and have a distinct morphology characterized by elongated epicotyls and buds containing unexpanded leaves with small, undifferentiated cells. In contrast, mutant seedlings grown under the same conditions are yellow in color and have short epicotyls and expanded leaves showing clear cellular differentiation. Transmission electron microscopy revealed partially developed, agranal plastids in the dark-grown mutant, unlike wild-type seedlings that contain etioplasts with prolamellar bodies. The mutant also exhibits a much shorter lag period for chlorophyll accumulation when etiolated seedlings are transferred from darkness to white light. The dark-grown mutant has 10-fold less spectrally detectable phytochrome, which can be attributed to a 10-fold reduction in the level of the PHYA polypeptide. Cab, Fed1, and RbcS transcripts are present in dark-grown mutant seedlings at levels comparable to those produced in light-grown material. The levels of these transcripts show a normal decrease when green plants grown for 15 days in a light/dark cycle are transferred to continuous darkness. However, transcript levels remain high during dark treatment of seedlings grown for 9 days in continuous light, indicating that the dark adaptation response in this mutant is developmentally plastic. The lip1 mutant has several features in common with the deetiolated Arabidopsis mutants det1, det2, and cop1. However, there are also several important differences, including varying effects on phytochrome levels, organ-specific gene expression, plastid development, and response to dark adaptation.", "New treatment strategies in rheumatoid arthritis are targeted to interfere with critical mediators of inflammation. Proinflammatory cytokines like IL-1 beta and TNFalpha play a crucial role in induction and maintenance of synovitis, pannus formation and bone and cartilage destruction. Within a few years, these morphological changes may lead to joint destruction and consecutively to functional impairment. Since April 2002 a recombinant human interleukin-1 receptor antagonist (Anakinra) is available in Germany for treatment of patients with rheumatoid arthritis. Anakinra (Kineret(R)) is approved for therapy in combination with methotrexate and should be applied according to guidelines established by the German Rheumatology Society for the use of biologicals in treatment of patients with rheumatoid arthritis. The approval of anakinra as a new therapeutic is based on data obtained in large multicenter, placebo-controlled, and randomised trials in comparison to placebo. Treatment of Anakinra as monotherapy or in combination with methotrexate lead to significant improvement of signs and symptoms of disease as measured by the ACR 20 (or more) response and was associated with a slower radiographic progression with regard to joint space narrowing and development of erosions. Anakinra showed a favourable safety profile with injection side reactions as the predominant side effect that occurs in 70% of patients usually after 10-12 days of treatment and that are mostly mild to moderate and self-limiting. Patients with previous pneumonia or other risk factors for pulmonary infections such as chronic obstructive lung disease seem to show a slightly increased risk of developing infectious complications of the bronchopulmonary system while being on anakinra and should be monitored appropriately. Combining IL-1ra treatment with the use of anti-TNF agents showed an increased risk of infectious complications in clinical studies and is not recommended at present. Studies are currently assessing the use of anakinra for treatment of other rheumatic diseases like psoriatic arthritis, juvenile arthritis or spondylarthropathy.", "AIM: To analyze the clinical characteristics of patients diagnosed with Fitz-Hugh-Curtis syndrome.METHODS: The clinical courses of patients that visited St. Mary's Hospital with abdominal pain from January 2005 to December 2006 and were diagnosed with Fitz-Hugh-Curtis syndrome were examined.RESULTS: Fitz-Hugh-Curtis syndrome was identified in 22 female patients of childbearing age; their mean age was 31.0+/-8.1 years. Fourteen of these cases presented with pain in the upper right abdomen alone or together with pain in the lower abdomen, and six patients presented with pain only in the lower abdomen. The first impression at the time of visit was acute cholecystitis or cholangitis in 10 patients and acute appendicitis or pelvic inflammatory disease in eight patients. Twenty-one patients were diagnosed by abdominal computer tomography (CT), and the results of abdominal sonography were normal for 10 of these patients. Chlamydia trichomatis was isolated from 18 patients. Two patients underwent laparoscopic adhesiotomy and 20 patients were completely cured by antibiotic treatment.CONCLUSION: For women of childbearing age with acute pain in the upper right abdomen alone or together with pain in the lower abdomen, Fitz-Hugh-Curtis syndrome should be considered during differential diagnosis. Moreover, in cases suspected to be Fitz-Hugh-Curtis syndrome, abdominal CT, rather than abdominal sonography, assists in the diagnosis.", "CONTEXT: Familial hypophosphatemic rickets is usually transmitted as an X-linked dominant disorder (XLH), although autosomal dominant forms have also been observed. Genetic studies of these disorders have identified mutations in PHEX and FGF23 as the causes of X-linked dominant disorder and autosomal dominant forms, respectively.OBJECTIVE: The objective of the study was to describe the molecular genetic findings in a family affected by hypophosphatemic rickets with presumed autosomal dominant inheritance.PATIENTS: We studied a family in which the father and the elder of his two daughters, but not the second daughter, were affected by hypophosphatemic rickets. The pedigree interpretation of the family suggested that genetic transmission of the disorder occurred as an autosomal dominant trait.METHODS AND RESULTS: Direct nucleotide sequencing of FGF23 and PHEX revealed that the elder daughter was heterozygous for an R567X mutation in PHEX, rather than FGF23, suggesting that the genetic transmission occurred as an X-linked dominant trait. Unexpectedly, the father was heterozygous for this mutation. Single-nucleotide primer extension and denaturing HPLC analysis of the father using DNA from single hair roots revealed that he was a somatic mosaic for the mutation. Haplotype analysis confirmed that the father transmitted the genotypes for 18 markers on the X chromosome equally to his two daughters. The fact that the father transmitted the mutation to only one of his two daughters indicated that he was a germline mosaic for the mutation.CONCLUSIONS: Somatic and germline mosaicism for an X-linked dominant mutation in PHEX may mimic autosomal dominant inheritance.", "Although circadian rhythms in mammalian physiology and behavior are dependent upon a biological clock in the suprachiasmatic nuclei (SCN) of the hypothalamus, the molecular mechanism of this clock is in fact cell autonomous and conserved in nearly all cells of the body. Thus, the SCN serves in part as a \"master clock,\" synchronizing \"slave\" clocks in peripheral tissues, and in part directly orchestrates circadian physiology. In this chapter, we first consider the detailed mechanism of peripheral clocks as compared to clocks in the SCN and how mechanistic differences facilitate their functions. Next, we discuss the different mechanisms by which peripheral tissues can be entrained to the SCN and to the environment. Finally, we look directly at how peripheral oscillators control circadian physiology in cells and tissues.", "Recent advances in our understanding of the three-dimensional organization of the eukaryotic nucleus have rendered the spatial distribution of genes increasingly relevant. In a recent work (Tsochatzidou et al., Nucleic Acids Res 45:5818-5828, 2017), we proposed the existence of a functional compartmentalization of the yeast genome according to which, genes occupying the chromosomal regions at the nuclear periphery have distinct structural, functional and evolutionary characteristics compared to their centromeric-proximal counterparts. Around the same time, it was also shown that the genome of Saccharomyces cerevisiae is organized in topologically associated domains (TADs), which are largely associated with the replication timing. In this work, we proceed to investigate whether such units of three-dimensional genomic organization can be linked to transcriptional activity as a driving force for the shaping of genomic architecture. Through the application of a simple boundary-calling criterion in genome-wide 3C data, we define ~100 TAD-like domains which can be clustered in six different classes with radically different nucleosomal organizations, significant variations in transcription factor binding and uneven chromosomal distribution. Approximately ~20% of the genome is found to be confined in regions with \"closed\" chromatin structure around gene promoters. Most interestingly, we find both \"open\" and \"closed\" regions to be segregated, in the sense that they tend to avoid inter-chromosomal interactions. Our data further enforce the notion of a marked compartmentalization of the yeast genome in isolated territories, with implications in its function and evolution.", "Altered microRNA (miRNA) expression may occur early in bladder cancer and may play a role in carcinogenesis and tumor behavior. We evaluated whether alterations in miRNA expression could improve disease stratification and outcome prognosis in bladder tumors and noninvasive diagnosis in urinary samples. miR-143, miR-222, and miR-452 expression levels were analyzed by quantitative RT-PCR (RT-qPCR) in paired urinary and matching tumors and in two independent prospective series of tumors and urinary specimens. Differential expression of miR-143, miR-222, and miR-452 in urine were verified by in situ hybridization in matching tumors. Tumor miRNA expression by RT-qPCR correlated with tumor grade, size, and presence of carcinoma in situ for miR-222, recurrence (miR-222 and miR-143), progression (miR-222 and miR-143), disease-specific survival (miR-222), and overall survival (miR-222). Protein expression patterns of potential miRNA targets, including vascular endothelial growth factor, BCL2, v-erb-b2 erythroblastic leukemia viral oncogene (ERBB) homolog 3, and ERBB4, were evaluated by IHC in tissue arrays containing tumors for which miRNAs were assessed by RT-qPCR. Target expression correlated with expression of their predicted regulatory miRNAs, recurrence (ERBB3), progression (ERBB4), disease-specific survival (ERBB3 and ERBB4), and overall survival (ERBB3 and ERBB4). Furthermore, RT-qPCR of miR-452 (area under the curve, 0.848) and miR-222 (area under the curve, 0.718) in urine provided high accuracies for bladder cancer diagnosis. Thus, bladder tumors were characterized by changes in miRNA expression that could aid in tumor stratification and clinical outcome prognosis, and miRNAs were detected in urinary specimens for noninvasive diagnosis." ]

[ "BACKGROUND: The Dyskinesia Impairment Scale (DIS) is a new assessment scale for dystonia and choreoathetosis in children and youth with dyskinetic cerebral palsy. Today, the Burke-Fahn-Marsden Dystonia Rating Scale (BFM) is mostly used to assess dystonia in children with inherited dystonia. The aim of this study was to assess reliability and validity of the DIS in children and youth with inherited or idiopathic dystonia.METHODS: Reliability was measured by (1) the intraclass correlation coefficients (ICCs) for inter-rater and test-retest reliability, as well as (2) standard error of measurement (SEM) and minimal detectable difference (MDD). For concurrent validity of the DIS-dystonia subscale, the BFM was administered.RESULTS: In total, 11 males and 9 females (median age 16 years and 7 months, range 6 to 24 years) were included. For inter-rater reliability, the ICCs for the DIS total score and the dystonia and choreoathetosis subscale scores were 0.83, 0.87, and 0.71, respectively. For test-retest reliability, the ICCs for the DIS total score and the dystonia and choreoathetosis subscale scores were 0.95, 0.88, and 0.93, respectively. The SEM and MDD for the total DIS were 3.98% and 11.04%, respectively. The Spearman correlation coefficient between the dystonia subscale and the BFM was 0.88 (p < 0.01).CONCLUSIONS: Good to excellent inter-rater, test-retest reliability, and validity were found for the total DIS and the dystonia subscale. The choreoathetosis subscale showed moderate inter-rater reliability and excellent test-retest reliability. The DIS may be a promising tool to assess dystonia and choreoathetosis in children and young adults with inherited or idiopathic dystonia.", "PURPOSE: The aim of this study is to investigate anaplastic lymphoma kinase (ALK) protein expression and underlying genetic aberrations in rhabdomyosarcoma (RMS), with special attention to clinical and prognostic implications.PATIENTS AND METHODS: A total of 189 paraffin-embedded RMS tumor specimens from 145 patients were collected on tissue microarray. ALK protein expression was evaluated by immunohistochemistry. ALK gene (2p23) copy number and translocations were determined by in situ hybridization. cDNA sequencing of the receptor tyrosine kinase domain of the ALK gene was assessed in 43 samples.RESULTS: Strong cytoplasmic ALK protein expression was more frequently observed in alveolar RMS (ARMS) than in embryonal RMS (ERMS) (81% v 32%, respectively; P < .001). ALK gene copy number gain was detected in the vast majority of ARMS (88%), compared with 52% of ERMS (P < .001). ALK copy number correlated with protein expression in primary tumors (n = 107). We identified one point mutation (2%) and seven tumors harboring whole exon deletions (16%). In ERMS, specific ALK gain in the primary tumor correlated with metastatic disease (100% in metastatic disease v 29% in nonmetastatic disease; P = .004) and poor disease-specific survival (5-year disease-specific survival: 62% v 82% for nonspecific or no gain; P = .046).CONCLUSION: Because ALK aberrations on genomic and protein levels are frequently found in RMSs, in particular ARMS, and are associated with disease progression and outcome in ERMS, ALK may play a role in tumor biology and may provide a potential therapeutic target for these tumors. Future research should aim at the oncogenic role of ALK and the potential effect of ALK inhibitors in RMS.", "The phase II JULIET trial suggests that the CD19-targeting CAR T-cell therapy tisagenlecleucel produces durable responses in patients with relapsed and refractory diffuse large B-cell lymphoma. Three months after the therapy, 32% of the patients showed complete responses and 6% showed partial responses. After 6 months, those rates were 30% and 7%.", "The condensin complex is a key determinant of mitotic chromosome architecture. In addition, condensin promotes resolution of sister chromatids during anaphase, a function that is conserved from prokaryotes to human. Anaphase bridges observed in cells lacking condensin are reminiscent of chromosome segregation failure after inactivation of topoisomerase II (topo II), the enzyme that removes catenanes persisting between sister chromatids following DNA replication. Circumstantial evidence has linked condensin to sister chromatid decatenation but, because of the difficulty of observing chromosome catenation, this link has remained indirect. Alternative models for how condensin facilitates chromosome resolution have been put forward. Here, we follow the catenation status of circular minichromosomes of three sizes during the Saccharomyeces cerevisiae cell cycle. Catenanes are produced during DNA replication and are for the most part swiftly resolved during and following S-phase, aided by sister chromatid separation. Complete resolution, however, requires the condensin complex, a dependency that becomes more pronounced with increasing chromosome size. Our results provide evidence that condensin prevents deleterious anaphase bridges during chromosome segregation by promoting sister chromatid decatenation.", "Amniotic band syndrome is a rare congenital disorder caused by entrapment of fetal parts (usually a limb or digits) in fibrous amniotic bands while in utero that presents with complex multisystem anomalies. The authors report 2 children with amniotic band syndrome who presented to the ophthalmic unit of the authors' pediatric hospital. One of them presented with telecanthus, syndactyly, amputated toes, and unilateral epiphora diagnosed as congenital nasolacrimal duct obstruction. She was managed conservatively with lacrimal sac massage and provided with refractive correction while she simultaneously underwent multiple surgeries for correction of clubfoot and craniosynostosis. The second patient presented with cleft lip, cleft palate, multiple constriction bands in upper limbs and fingers with unilateral microphthalmos, microcornea, typical iris coloboma, and retinochoroidal coloboma, very similar to a case reported in literature. These 2 cases provide an overview of the clinical spectrum of ophthalmic manifestations along with their staged optimum rehabilitation.", "BACKGROUND: Loss of cortical neurons is a key pathological feature in neurodegenerative dementias. Cerebrospinal fluid (CSF) neurofilaments (Nf) are a biomarker for neuronal death and axonal loss.OBJECTIVE: To perform a meta-analysis to investigate the value of CSF Nf levels for the laboratory-supported differential diagnosis of neurodegenerative dementias.METHODS: A systematic review and meta-analysis of studies on CSF Nf heavy (NfH) and light (NfL) levels in patients with dementia. The dementia subgroups analysed were Alzheimer (AD), frontotemporal lobe dementia (FTLD), vascular dementia (SVD), minimal cognitive deficit (MCI).RESULTS: We identified 12 studies on CSF NfH and NfL levels which met the inclusion criteria and 11 were of a quality good enough to be used in this meta-analysis. CSF data was available on 818 patients (306 AD, 106 SVD, 98 FTLD, 25 MCI, 283 controls). Overall CSF NfH and NfL levels were higher in patients with AD, FTLD and SVD when compared to controls. The size of the effect ranged from 0.71 to 1.38. The strongest effect was observed for the comparison of FTLD patients with controls, both for NfL (1.38) and NfH (0.74). CSF NfL were also able to separate patients with FTLD from those with AD.CONCLUSION: At present we cannot recommend CSF NfH and NfL levels for use as a screening test in the diagnosis of dementia because of the rather small effect size. However, both neurofilament proteins may be of value for targeted investigation of some patients with FTLD, SVD and AD.", "BACKGROUND: Mov10 is an RNA helicase that modulates access of Argonaute 2 to microRNA recognition elements in mRNAs. We examined the role of Mov10 in Xenopus laevis development and show a critical role for Mov10 in gastrulation and in the development of the central nervous system (CNS).RESULTS: Knockdown of maternal Mov10 in Xenopus embryos using a translation blocking morpholino led to defects in gastrulation and the development of notochord and paraxial mesoderm, and a failure to neurulate. RNA sequencing of the Mov10 knockdown embryos showed significant upregulation of many mRNAs when compared with controls at stage 10.5 (including those related to the cytoskeleton, adhesion, and extracellular matrix, which are involved in those morphogenetic processes). Additionally, the degradation of the miR-427 target mRNA, cyclin A1, was delayed in the Mov10 knockdowns. These defects suggest that Mov10's role in miRNA-mediated regulation of the maternal to zygotic transition could lead to pleiotropic effects that cause the gastrulation defects. Additionally, the knockdown of zygotic Mov10 showed that it was necessary for normal head, eye, and brain development in Xenopus consistent with a recent study in the mouse.CONCLUSIONS: Mov10 is essential for gastrulation and normal CNS development. Developmental Dynamics 247:660-671, 2018. © 2017 Wiley Periodicals, Inc." ]

[ "Gangliosides are glycosphingolipids localized to the outer leaflet of the plasma membrane of vertebrate cells. The highest ganglioside concentration of any organ is found in the mammalian brain, where the gangliosides are enriched in the neuronal membrane, particularly in the synapses. There are four major brain gangliosides with the same neutral tetrasaccharide core to which one to three sialic acids are linked--the simplest being the GM1-ganglioside. These gangliosides have been shown to have neuritogenic and neuronotrophic activity and to facilitate repair of neuronal tissue after mechanical, biochemical or toxic injuries. Mixtures of native bovine brain gangliosides were adopted for pharmacological use in the treatment of peripheral nerve damage, and GM1-ganglioside has been applied for the treatment of CNS injuries and diseases. Beneficial effects of GM1 have been documented in the treatment of stroke and spinal cord injuries, particularly when the treatment has been initiated within a few hours of the acute event. Continuous intraventricular infusion of GM1 has recently been shown to have a significant beneficial effect in Alzheimer disease of early onset (AD Type I).", "Thyroid hormones are known to be essential for growth, development and metabolism. Recently mutations in the SLC16A2 gene coding for the monocarboxylate thyroid hormone transporter 8, MCT8, have been associated with Allan-Herndon-Dudley syndrome (AHDS), an X-linked condition characterized by severe mental retardation, dysarthria, athetoid movements, muscle hypoplasia and spastic paraplegia. Here we describe in detail the clinical and biochemical features in a boy affected by AHDS with severe neurological abnormalities and a novel de novo SLC16A2 gene insertion, 1343-1344insGCCC, resulting in a truncated protein lacking the last four transmembrane domains (TMDs) as well as the carboxyl cytoplasmic end. He presents mental retardation, axial hypotonia, hypertonia of arms and legs, paroxysmal dyskinesias, seizures. The endocrine phenotype showed low serum total and free thyroxine (T4), very elevated total and free triiodothyronine (T3) and normal thyrotropin (TSH) with blunted response to thyrotropin-releasing hormone (TRH). The latter finding was unexpected and suggested that the lack of functional MCT8 was counterbalanced at the thyrotrope cell level by high serum T3 concentration and/or by increased intrapituitary type 2 deiodinase (D2) activity. Our case constitutes a relevant contribution to better characterize this disorder and to elucidate the functional consequences of SLC16A2 gene mutations.", "Myotubularins, a large family of catalytically active and inactive proteins, belong to a unique subgroup of protein tyrosine phosphatases that use inositol phospholipids, rather than phosphoproteins, as physiological substrates. Here, by integrating crystallographic and deuterium-exchange mass spectrometry studies of human myotubularin-related protein-2 (MTMR2) in complex with phosphoinositides, we define the molecular basis for this unique substrate specificity. Phosphoinositide substrates bind in a pocket located on a positively charged face of the protein, suggesting an electrostatic mechanism for membrane targeting. A flexible, hydrophobic helix makes extensive interactions with the diacylglycerol moieties of substrates, explaining the specificity for membrane-bound phosphoinositides. An extensive H-bonding network and charge-charge interactions within the active site pocket determine phosphoinositide headgroup specificity. The conservation of these specificity determinants within the active, but not the inactive, myotubularins provides insight into the functional differences between the active and inactive members.", "Conversion of the soluble, nontoxic amyloid β-protein (Aβ) into an aggregated, toxic form rich in β-sheets is a key step in the onset of Alzheimer's disease (AD). It has been suggested that Aβ induces changes in neuronal membrane fluidity as a result of its interactions with membrane components such as cholesterol, phospholipids, and gangliosides. Gangliosides are known to bind Aβ. A complex of GM1 and Aβ, termed \"GAβ\", has been identified in AD brains. Abnormal ganglioside metabolism also may occur in AD brains. We have reported an increase of Chol-1α antigens, GQ1bα and GT1aα, in the brain of transgenic mouse AD model. GQ1bα and GT1aα exhibit high affinities to Aβs. The presence of Chol-1α gangliosides represents evidence for genesis of cholinergic neurons in AD brains. We evaluated the effects of GM1 and Aβ1-40 on mouse neuroepithelial cells. Treatment of these cells simultaneously with GM1 and Aβ1-40 caused a significant reduction of cell number, suggesting that Aβ1-40 and GM1 cooperatively exert a cytotoxic effect on neuroepithelial cells. An understanding of the mechanism on the interaction of GM1 and Aβs in AD may contribute to the development of new neuroregenerative therapies for this disorder.", "Telomerase is the enzyme that extends the chromosome ends, thereby contributing to eukaryotic cell genome stability. Telomerase is expressed in the majority of cells that have an unlimited proliferation such as stem cells and cancer cells. The increased interest in telomerase in cancer research, challenged by the low cellular abundance of the enzyme, has led to the development of a reliable and at the same time very sensitive approach to detect telomerase activity. The telomeric repeat amplification protocol (TRAP) represents an easy and rapid method for detection of telomerase activity in cells. A non-telomeric TS primer is extended by telomerase in the first step followed by the PCR amplification of the products. The PCR step renders this protocol very sensitive to detect telomerase activity at the single cell level making it compatible with the analysis of tumor samples. When run on a polyacrylamide gel, the PCR product is a characteristic ladder of bands due to the repetitive nature of telomeric DNA sequence. The densitometric analysis of the ladder allows the TRAP assay to be used for comparative quantification of telomerase activity in different samples.", "Currently, carcinogenesis is considered to be the result of mal-expression of tumour suppressor genes and oncogenes, leading either way to uncontrollable and disorganized cell mitosis. Recently a novel class of genes has drawn the interest of the scientific community. These are microRNAs (miRNAs), a class of noncoding RNAs, 20-23 nucleotides in length, that can up or downregulate gene expression of downstream gene targets (including transcription factors, oncogenes, and tumour suppressor genes) at the post-transcriptional level. Some members of this new class of genes seem to have the potential to act simultaneously either as oncogenes or as tumour suppressor genes depending on the molecular microenvironment of the cell. We elaborate on this hypothesis by giving examples of miRNAs (e.g. mir-9, miR-17-92) which seem to function by the abovementioned mechanism. This could mean that the deterministic notion of carcinogenesis as a result of merely tumour suppressor genes and oncogenes deregulation could be revised to contain the fact that certain members of this novel class of genes have the potential to play both roles simultaneously.", "Cholesterol is implicated in the development of late-onset Alzheimer's disease (AD). We sought to determine the associations between beta amyloid (Aβ) plaque deposition in vivo using Pittsburgh compound B (PiB) and several indices of cholesterol homeostasis (i.e., total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein E (ApoE), clusterin, oxysterol metabolites of cholesterol, and previously reported genes associated with late-onset AD) in 175 nondemented elderly subjects. High Aβ deposition was associated significantly with a lower Mini-Mental State Examination score (<27 points, p = 0.04), high systolic blood pressure (p = 0.04), carrying the apolipoprotein E epsilon 4 allele (p < 0.01), and lower plasma ApoE levels (p = 0.02), and variation in the ABCA7 (p = 0.02) and EPHA1 genes (p = 0.02). Cholesterol measures were not related to Aβ deposition in this cohort of nondemented elderly adults. However, plasma and genetic factors relating to cholesterol transport were associated with Aβ deposition in the brain. A better understanding of cholesterol transport mechanisms may lead to the design of potential targets for the prevention of Aβ deposition in the brain.", "Overexpression of the tight junction protein Junctional Adhesion Molecule-A (JAM-A) has been linked to aggressive disease in breast and other cancers, but JAM-targeting drugs remain elusive. Screening of a natural compound library identified the antibiotic Tetrocarcin-A as a novel downregulator of JAM-A and human epidermal growth factor receptor-2 (HER2) protein expression in breast cancer cells. Lysosomal inhibition partially rescued the downregulation of JAM-A and HER2 caused by Tetrocarcin-A, and attenuated its cytotoxic activity. Tetrocarcin-A treatment or JAM-A silencing reduced AKT and ERK phosphorylation, inhibited c-FOS phosphorylation at Threonine-232 (its transcriptional regulation site), inhibited nuclear localization of c-FOS, and downregulated expression of the inhibitor of apoptosis proteins (IAP). This was accompanied by Tetrocarcin-A-induced caspase-dependent apoptosis. To begin evaluating the potential clinical relevance of our findings, we extended our studies to other models. Encouragingly, Tetrocarcin-A downregulated JAM-A expression and caused cytotoxicity in primary breast cells and lung cancer stem cells, and inhibited the growth of xenografts in a semi-in vivo model involving invasion across the chicken egg chorioallantoic membrane. Taken together, our data suggest that Tetrocarcin-A warrants future evaluation as a novel cancer therapeutic by virtue of its ability to downregulate JAM-A expression, reduce tumorigenic signaling and induce apoptosis." ]

[ "It has been established that the urothelial mucin layer functions as a bacterial anti-adherence factor. Intravesical Bacillus Calmette-Guerin is used to treat patients with superficial bladder cancer. The proposed mechanism of action of Bacillus Calmette-Guerin is adherence to the urothelium with induction of an immunologic and/or inflammatory response. The current study was designed to determine if rabbit bladder mucin removal results in increased Bacillus Calmette-Guerin urothelial adherence. PAS and colloidal iron stains were used to demonstrate that intravesical instillation of 50% acetone renders rabbit bladder urothelium mucin deficient. The urothelium remains mucin deficient at two hours, but by 24 hours the mucin layer has been regenerated. Two hours following intravesical 3H-labeled Escherichia coli administration, bacterial adherence was 29-fold greater in mucin deficient than mucin intact rabbits (p = 0.05). By 12 hours, the difference in adherence was not significant. Two hours following intravesical administration of 3H-labeled Bacillus Calmette Guerin, mucosal adherence was 21-fold greater in mucin deficient compared to mucin intact rabbits (p = 0.002). After mucin removal, Bacillus Calmette Guerin urothelial adherence was significantly increased. The significant increase in Bacillus Calmette Guerin adherence after mucin removal may be clinically exploitable.", "Atopic dermatitis results when aberrant barrier function and immune activation occur within the skin. Standard therapies for atopic dermatitis have fallen short, prompting efforts to discover novel therapeutics for this disease. Of these, dupilumab, a fully human monoclonal antibody that inhibits the actions of both IL-4 and IL-13, has shown the greatest promise. Clinical trials of systemic dupilumab in moderate-to-severe atopic dermatitis have demonstrated marked improvement in patient symptoms, including pruritus and clinically visible disease. Importantly, dupilumab treatment has been correlated with changes in the molecular signature of diseased skin, with reduction of both inflammatory and proliferative markers. Dupilumab recently received US FDA breakthrough therapy designation for atopic dermatitis, with ongoing trials in both adult and pediatric populations. Altogether, dupilumab has shed new light on the pathomechanisms driving atopic dermatitis and is making unprecedented advances towards highly effective control of this debilitating disease.", "Cirrhosis in patients with chronic hepatitis C increases the risk of hepatocellular carcinoma (HCC), and surveillance with ultrasound (US) and alpha-fetoprotein (AFP) is recommended. This study aimed to estimate changes in the HCC incidence rate (IR) over time, HCC stage and prognosis, and AFP and US performed in patients with hepatitis C and cirrhosis. Eligible patients were identified in the Danish Database for Hepatitis B and C, and data from national health registries and patient charts were obtained. Tumour stage was based on Barcelona-Clinic Liver Cancer stage, TNM classification and size and number of lesions combined into stages 0-3. We included 1075 patients with hepatitis C and cirrhosis, free of HCC and liver transplant at baseline. During 4988 person years (PY), 115 HCC cases were diagnosed. The HCC incidence rate increased from 0.8/100 PY [CI95% 0.4-1.5] in 2002-2003 to 2.9/100 PY [2.4-3.4] in 2012-2013. One-year cumulative incidence of at least one AFP or US was 53% among all patients. The positive predictive value of an AFP ≥ 20 ng mL-1 was 17%. Twenty-three (21%) patients were diagnosed with early-stage HCC (stage 0/1) and 84 (79%) with late stage. Median survival after HCC for early-stage HCC disease was 30.1 months and 7.4 months for advanced HCC (stage 2/3). The incidence rate of HCC increased over time among patients with hepatitis C and cirrhosis in Denmark. Application of AFP and US was suboptimal, and most patients were diagnosed with advanced HCC with a poor prognosis.", "Ovarian Sertoli-Leydig cell tumors (SLCTs) are uncommon neoplasms that are occasionally associated with an elevated level of serum alpha fetoprotein (AFP), a marker of germ cell neoplasms, particularly yolk sac tumor (YST). We report 7 cases of ovarian SLCT (3 moderately differentiated, 2 poorly differentiated, 2 retiform) with heterologous intestinal-type glands, 6 of which were associated with elevated serum AFP. The intestinal-type mucinous glands were immunoreactive for SALL4 (4 cases), AFP (4 cases), glypican 3 (1 case), CDX2 (6 cases), and villin (7 cases), markers that are commonly expressed in YSTs, although the latter 2 markers would be expected to be positive in intestinal-type glands. We show that heterologous intestinal-type glands in ovarian SLCTs often have an endodermal sinus-like (YST-like) immunophenotype and stress that these should not be misinterpreted as microscopic foci of endodermal-type YST. Cases of ovarian SLCT with elevated serum AFP should be sampled extensively to look for foci of intestinal-type glands, the likely source of the AFP elevation in some of these neoplasms.", "Propionic acidemia is an autosomal recessive disorder caused by a deficiency in the mitochondrial enzyme propionyl-CoA carboxylase (PCC). PCC is composed of two subunits, alpha and beta, encoded by the PCCA and PCCB genes, respectively. We analyzed mutations of the PCCA gene using patients' fibroblasts diagnosed with alpha subunit deficiency. By RT-PCR, four of 12 cell lines examined appeared to have a larger transcript present at a level comparable with that of the expected normal species. Sequencing of the larger transcriptrevealed an 84 bp insertion at nt 1209 of the codingsequence. Its incorporation in the transcript results in translation termination due to the presence of two in-frame stop codons. The 84 bp insertion was found to originate from the intron between nt 1209 and 1210. Consensus splice donor and acceptor sites were found at the 3'- and 5'-ends of the insertion, respectively. The insertion was also found in the remaining eight cell lines as well as in normal cells, but at a muchreduced level compared with the normal lengthsequence. Mutation analysis of the four cell lines showing seemingly elevated levels of the insertion sequence revealed one nonsense mutation (R288X), two frameshift deletions (700del5 and 1115del4) and one splice mutation (1671IVS+5G-->C) as expressed alleles. We conclude that the common characteristic of the four cell lines is that they contain mRNA destabilizing mutations that reduce the mRNA level of the normal length sequence. Consequently, the low levels of cryptic mRNAs become detectable at a level similar to that of the residual level of the normal length mRNA. We suggest that screening for an increased proportion of the 84 bp insertion by RT-PCR can be used as a rapid assay for RNA destabilizing mutations. Our results suggest caution in associating such mutations with aberrant mRNA species, such as cryptic splice products, which may instead be part of the 'background noise' of the splicing machinery.", "BACKGROUND: The Ribosomal protein S19 gene locus (RPS19) has been linked to two kinds of red cell aplasia, Diamond-Blackfan Anemia (DBA) and Transient Erythroblastopenia in Childhood (TEC). Mutations in RPS19 coding sequences have been found in 25% of DBA patients, but not in TEC patients. It has been suggested that non-coding RPS19 sequence variants contribute to the considerable clinical variability in red cell aplasia. We therefore aimed at identifying non-coding variations associated with DBA or TEC phenotypes.METHODOLOGY/PRINCIPAL FINDINGS: We targeted a region of 19'980 bp encompassing the RPS19 gene in a cohort of 89 DBA and TEC patients for resequencing. We provide here a catalog of the considerable, previously unrecognized degree of variation in this region. We identified 73 variations (65 SNPs, 8 indels) that all are located outside of the RPS19 open reading frame, and of which 67.1% are classified as novel. We hypothesize that specific alleles in non-coding regions of RPS19 could alter the binding of regulatory proteins or transcription factors. Therefore, we carried out an extensive analysis to identify transcription factor binding sites (TFBS). A series of putative interaction sites coincide with detected variants. Sixteen of the corresponding transcription factors are of particular interest, as they are housekeeping genes or show a direct link to hematopoiesis, tumorigenesis or leukemia (e.g. GATA-1/2, PU.1, MZF-1).CONCLUSIONS: Specific alleles at predicted TFBSs may alter the expression of RPS19, modify an important interaction between transcription factors with overlapping TFBS or remove an important stimulus for hematopoiesis. We suggest that the detected interactions are of importance for hematopoiesis and could provide new insights into individual response to treatment.", "BACKGROUND & AIMS: Outcomes of liver transplantation for hepatocellular carcinoma (HCC) are determined by cancer-related and non-related events. Treatments for hepatitis C virus infection have reduced non-cancer events among patients receiving liver transplants, so reducing HCC-related death might be an actionable end point. We performed a competing-risk analysis to evaluate factors associated with survival of patients with HCC and developed a prognostic model based on features of HCC patients before liver transplantation.METHODS: We performed multivariable competing-risk regression analysis to identify factors associated with HCC-specific death of patients who underwent liver transplantation. The training set comprised 1018 patients who underwent liver transplantation for HCC from January 2000 through December 2013 at 3 tertiary centers in Italy. The validation set comprised 341 consecutive patients who underwent liver transplantation for HCC during the same period at the Liver Cancer Institute in Shanghai, China. We collected pretransplantation data on etiology of liver disease, number and size of tumors, patient level of α-fetoprotein (AFP), model for end-stage liver disease score, tumor stage, numbers and types of treatment, response to treatments, tumor grade, microvascular invasion, dates, and causes of death. Death was defined as HCC-specific when related to HCC recurrence after transplantation, disseminated extra- and/or intrahepatic tumor relapse and worsened liver function in presence of tumor spread. The cumulative incidence of death was segregated for hepatitis C virus status.RESULTS: In the competing-risk regression, the sum of tumor number and size and of log10 level of AFP were significantly associated with HCC-specific death (P < .001), returning an average c-statistic of 0.780 (95% confidence interval, 0.763-0.798). Five-year cumulative incidence of non-HCC-related death was 8.6% in HCV-negative patients and 18.1% in HCV-positive patients. For patients with HCC to have a 70% chance of HCC-specific survival 5 years after transplantation, their level of AFP should be <200 ng/mL and the sum of number and size of tumors (in centimeters) should not exceed 7; if the level of AFP was 200-400 ng/mL, the sum of the number and size of tumors should be ≤5; if their level of AFP was 400-1000 ng/mL, the sum of the number and size of tumors should be ≤4. In the validation set, the model identified patients who survived 5 years after liver transplantation with 0.721 accuracy (95% confidence interval, 0.648%-0.793%). Our model, based on patients' level of AFP and HCC number and size, outperformed the Milan; University of California, San Francisco; Shanghai-Fudan; Up-to-7 criteria (P < .001); and AFP French model (P = .044) to predict which patients will survive for 5 years after liver transplantation.CONCLUSIONS: We developed a model based on level of AFP, tumor size, and tumor number, to determine risk of death from HCC-related factors after liver transplantation. This model might be used to select end points and refine selection criteria for liver transplantation for patients with HCC. To predict 5-year survival and risk of HCC-related death using an online calculator, please see www.hcc-olt-metroticket.org/. ClinicalTrials.gov ID NCT02898415.", "Constrictive pericarditis is a complication of tuberculous pericarditis that necessitates surgical intervention. In this study, we sought to identify echocardiographic features that could predict the development of constrictive pericarditis from acute or subacute pericarditis. From January 1988 through May 1998, all patients with a discharge diagnosis of tuberculous pericarditis were enrolled in the study, and their clinical features, laboratory findings, sonographic images, treatments, and outcomes were analyzed. Tuberculous pericarditis was demonstrated on the basis of positive Mycobacterium tuberculosis cultures from pericardial fluid or tissue in 11 patients; pericardial biopsy specimens demonstrating caseating granulomas in seven; and bacteriologic or histologic evidence of active extra-pericardial tuberculosis in conjunction with major pericardial effusion in four. Seventeen patients had effusive tuberculous pericarditis and five had constrictive tuberculous pericarditis as the initial diagnosis. The echocardiographic findings of effusive pericarditis were classified as shaggy-type effusion (n = 8) and non-shaggy-type effusion (9). Shaggy effusion was defined as the presence of multiple fibrin strands or a mass-like exudate coating the pericardium and bridging the pericardial effusion. Non-shaggy effusion was characterized by an anechoic pericardial space with or without a thickened pericardium, but no shaggy exudative coating. The mean duration between the onset of symptoms and diagnosis was longer in patients with shaggy-type effusion (39.6 +/- 8.7 vs 21.0 +/- 13.9 days, p < 0.05). Prednisolone (20-30 mg/d) was used in addition to antituberculous chemotherapy in 11 of the 17 patients with effusive pericarditis. Two of 11 patients (18%) who received steroid therapy, and five of the six patients (83%) who did not, developed constrictive pericarditis in the following year. Therefore, we concluded that adjuvant therapy with steroids significantly decreased the risk of constrictive pericarditis in patients with non-shaggy, but not shaggy, effusion.", "Advanced hepatocellular carcinoma (HCC) has limited treatment options and poor survival, therefore early detection is critical to improving the survival of patients with HCC. Current guidelines for high-risk patients include ultrasound screenings every six months, but ultrasounds are operator dependent and not sensitive for early HCC. Serum α-Fetoprotein (AFP) is a widely used diagnostic biomarker, but it has limited sensitivity and is not elevated in all HCC cases so, we incorporate a second blood-based biomarker, des'γ carboxy-prothrombin (DCP), that has shown potential as a screening marker for HCC. The data from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial is a valuable source of data to study biomarker screening for HCC. We assume the trajectories of AFP and DCP follow a joint hierarchical mixture model with random changepoints that allows for distinct changepoint times and subsequent trajectories of each biomarker. The changepoint indicators are jointly modeled with a Markov Random Field distribution to help detect borderline changepoints. Markov chain Monte Carlo methods are used to calculate posterior distributions, which are used in risk calculations among future patients and determine whether a patient has a positive screen. The screening algorithm was compared to alternatives in simulations studies under a range of possible scenarios and in the HALT-C Trial using cross-validation.", "Brugada syndrome (BrS), one of the most frequently diagnosed inherited arrhythmogenic syndromes, is responsible for more than 4% of all sudden deaths and at least 20% of sudden deaths in patients with structurally normal hearts. The sudden death is often the first symptom of BrS and appears most often already during the fourth decade of life of BrS patients. Implantation of cardioverter--defibrillator was proved to be the only effective treatment, i.e. prevention of the sudden death, in BrS. Thus, it is uniquely determined to be used in case of symptomatic BrS patients. On the contrary, the individual risk of life-threatening arrhythmias has to be thoroughly considered in case of asymptomatic BrS patients due to substantial side effects of implantation of cardioverter-defibrillator. This review first provides a summary of factors recommended for the risk stratification in BrS patients in 2005 including their support or rejection in the following studies. Subsequently, we focused on the most important risk factors newly suggested after 2005.", "Erratum in Author's view on original publication: Dietsch GN, Randall TD, Gottardo R, Northfelt DW, Ramanathan RK, Cohen PA, Manjarrez KL, Newkirk M, Bryan JK, Hershberg RM. Late Stage Cancer Patients Remain Highly Responsive to Immune Activation by the Selective TLR8 Agonist Motolimod (VTX–2337). Clin Cancer Res 2015; 21(24):5445-52; PMID: ; http:/dx.doi.org/10.1158/1078-0432.CCR–15–0578.", "IMPORTANCE OF THE FIELD: Antiretroviral therapy exhibits significant potential to alter the metabolism of other medications. Warfarin is widely used for the management of clotting disorders and is prone to drug-drug interactions that can result in subtherapeutic anticoagulation or over-anticoagulation.AREAS COVERED IN THIS REVIEW: The mechanism and clinical significance of drug-drug interactions between warfarin and individual antiretrovirals are discussed. Literature searches were conducted in August of 2009 using multiple databases including Medline (1950 - 2009), EMBASE (1980 - 2009), International Pharmaceutical Abstracts (1970 - 2009) and the Cochrane Database of Systematic Reviews. The following search terms were utilized: warfarin, HIV, antiretroviral, drug interaction, protease inhibitor (PI), non-nucleoside reverse-transcriptase inhibitor (NNRTI), cytochrome P450 (CYP450), CYP2C9 and individual antiretrovirals by name. The manufacturers of PIs and NNRTIs were also contacted regarding unpublished data.WHAT THE READER WILL GAIN: Clinicians will gain an understanding of the antiretrovirals that are prone to alter warfarin metabolism and the implications for warfarin dose modification.TAKE HOME MESSAGE: Metabolic interaction between warfarin and antiretrovirals is likely, particularly if NNRTIs or PIs are included in the antiretroviral regimen. Titration of warfarin dose should be conducted on the basis of close monitoring of the international normalized ratio. Empiric warfarin dose modifications should be considered for individual antiretrovirals.", "With the recent introduction of inhibitors of mammalian target of rapamycin (mTOR) in oncology, distinct cutaneous and oral adverse events have been identified. In fact, stomatitis and rash are documented as the most frequent and potentially dose-limiting side effects. Clinically, mTOR inhibitor-associated stomatitis (mIAS) more closely resembles aphthous stomatitis than oral mucositis due to conventional anticancer therapies. While most cases of mIAS are mild to moderate and self-limiting, more severe and persistent mIAS can become a dose-limiting toxicity. Small ulcerations may cause significant pain and mucosal sensitivity may occur in the absence of clinical changes. Use of clinical assessment tools that are primarily driven by ulceration size may underestimate mIAS, and assessment should include patient-reported outcomes. This article provides an up-to-date review of the clinical presentation, terminology, pathogenesis, assessment and management of mIAS and other mTOR inhibitor-associated oral adverse events. In addition, areas of future research are considered.", "BACKGROUND: In most patients with type 1 diabetes, adequate glycemic control is not achieved with insulin therapy alone. We evaluated the safety and efficacy of sotagliflozin, an oral inhibitor of sodium-glucose cotransporters 1 and 2, in combination with insulin treatment in patients with type 1 diabetes.METHODS: In this phase 3, double-blind trial, which was conducted at 133 centers worldwide, we randomly assigned 1402 patients with type 1 diabetes who were receiving treatment with any insulin therapy (pump or injections) to receive sotagliflozin (400 mg per day) or placebo for 24 weeks. The primary end point was a glycated hemoglobin level lower than 7.0% at week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis after randomization. Secondary end points included the change from baseline in glycated hemoglobin level, weight, systolic blood pressure, and mean daily bolus dose of insulin.RESULTS: A significantly larger proportion of patients in the sotagliflozin group than in the placebo group achieved the primary end point (200 of 699 patients [28.6%] vs. 107 of 703 [15.2%], P<0.001). The least-squares mean change from baseline was significantly greater in the sotagliflozin group than in the placebo group for glycated hemoglobin (difference, -0.46 percentage points), weight (-2.98 kg), systolic blood pressure (-3.5 mm Hg), and mean daily bolus dose of insulin (-2.8 units per day) (P≤0.002 for all comparisons). The rate of severe hypoglycemia was similar in the sotagliflozin group and the placebo group (3.0% [21 patients] and 2.4% [17], respectively). The rate of documented hypoglycemia with a blood glucose level of 55 mg per deciliter (3.1 mmol per liter) or below was significantly lower in the sotagliflozin group than in the placebo group. The rate of diabetic ketoacidosis was higher in the sotagliflozin group than in the placebo group (3.0% [21 patients] and 0.6% [4], respectively).CONCLUSIONS: Among patients with type 1 diabetes who were receiving insulin, the proportion of patients who achieved a glycated hemoglobin level lower than 7.0% with no severe hypoglycemia or diabetic ketoacidosis was larger in the group that received sotagliflozin than in the placebo group. However, the rate of diabetic ketoacidosis was higher in the sotagliflozin group. (Funded by Lexicon Pharmaceuticals; inTandem3 ClinicalTrials.gov number, NCT02531035 .).", "BACKGROUND: Malar rash is one of the three cutaneous diagnostic criteria of systemic lupus erythematosus (SLE). Although its clinical recognition is often straightforward, the differential diagnosis with erythematotelangiectatic rosacea may sometimes be challenging.OBJECTIVE: To describe dermoscopic features of SLE malar rash and investigate the accuracy of dermoscopy for the differential diagnosis with erythematotelangiectatic rosacea.METHODS: A representative dermoscopic image of target areas was evaluated for the presence of specific features. Fisher's test was used to compare their prevalence between the two cohorts, and accuracy parameters (specificity, sensitivity, and positive and negative predictive values) were evaluated.RESULTS: Twenty-eight patients were included in the analysis, of which 13 had SLE malar rash and 15 erythematotelangiectatic rosacea. The main dermoscopic features of malar rash were reddish/salmon-coloured follicular dots surrounded by white halos ('inverse strawberry' pattern), being present in 53.9% of the cases, while network-like vessels (vascular polygons) turned out to be the main feature of erythematotelangiectatic rosacea, with a prevalence of 93.3%. The comparative analysis showed that the 'inverse strawberry' pattern was significantly more common in SLE malar rash, with a specificity of 86.7%, while vascular polygons were significantly more frequent in rosacea, with a specificity of 92.3%.CONCLUSION: Dermoscopy may be a useful support to distinguish SLE malar rash and erythematotelangiectatic rosacea by showing peculiar features.", "ALK positive anaplastic large cell lymphoma is a T-cell lymphoma usually occurring in children and young adults. It frequently involves lymph nodes and extranodal sites and is associated with favorable prognosis. A 20-year old man was admitted for painful mass in the left axilla with overlying skin redness. Clinical presentation and US findings were highly suspicious for sarcoma. Definitive diagnosis was established cytolologically and using ancillary technologies from cytological samples. Fine needle aspiration cytology of tumor mass (lymph node conglomerate and surrounding tissue) show predominance of large, pleomorphic, atypical cells with large nuclei and vacuolised cytoplasm. Atypical cells immunocytochemically were positive for LCA, CD30, CD3, EMA, and ALK; negative for CD15 and CD56. NPM-ALK transcript was detected by reverse transcriptase-polymerase chain reaction (RT-PCT). Molecular analysis of TCRß and TCRγ genes demonstrated clonal TCR genes rearrangement. Complex karyotype with multiple numerical and structural changes was found on conventional cytogenetics. These findings excluded sarcoma and corroborated the diagnosis of ALK positive ALCL. Cutaneous involvement in ALCL can clinically mimic sarcoma, especially in cases with localized disease without B symptoms. In those cases, immunostaining, PCR, and conventional cytogenetics are helpful to exclude sarcoma. Diagn. Cytopathol. 2017;45:51-54. © 2016 Wiley Periodicals, Inc.", "The microRNA miR-504 targets TP53 mRNA encoding the p53 tumor suppressor. miR-504 resides within the fibroblast growth factor 13 (FGF13) gene, which is overexpressed in various cancers. We report that the FGF13 locus, comprising FGF13 and miR-504, is transcriptionally repressed by p53, defining an additional negative feedback loop in the p53 network. Furthermore, we show that FGF13 1A is a nucleolar protein that represses ribosomal RNA transcription and attenuates protein synthesis. Importantly, in cancer cells expressing high levels of FGF13, the depletion of FGF13 elicits increased proteostasis stress, associated with the accumulation of reactive oxygen species and apoptosis. Notably, stepwise neoplastic transformation is accompanied by a gradual increase in FGF13 expression and increased dependence on FGF13 for survival (\"nononcogene addiction\"). Moreover, FGF13 overexpression enables cells to cope more effectively with the stress elicited by oncogenic Ras protein. We propose that, in cells in which activated oncogenes drive excessive protein synthesis, FGF13 may favor survival by maintaining translation rates at a level compatible with the protein quality-control capacity of the cell. Thus, FGF13 may serve as an enabler, allowing cancer cells to evade proteostasis stress triggered by oncogene activation.", "CCAAT/enhancer binding protein-α (C/EBPα) induces transdifferentiation of B cells into macrophages at high efficiencies and enhances reprogramming into induced pluripotent stem (iPS) cells when co-expressed with the transcription factors Oct4 (Pou5f1), Sox2, Klf4 and Myc (hereafter called OSKM). However, how C/EBPα accomplishes these effects is unclear. Here we find that in mouse primary B cells transient C/EBPα expression followed by OSKM activation induces a 100-fold increase in iPS cell reprogramming efficiency, involving 95% of the population. During this conversion, pluripotency and epithelial-mesenchymal transition genes become markedly upregulated, and 60% of the cells express Oct4 within 2 days. C/EBPα acts as a 'path-breaker' as it transiently makes the chromatin of pluripotency genes more accessible to DNase I. C/EBPα also induces the expression of the dioxygenase Tet2 and promotes its translocation to the nucleus where it binds to regulatory regions of pluripotency genes that become demethylated after OSKM induction. In line with these findings, overexpression of Tet2 enhances OSKM-induced B-cell reprogramming. Because the enzyme is also required for efficient C/EBPα-induced immune cell conversion, our data indicate that Tet2 provides a mechanistic link between iPS cell reprogramming and B-cell transdifferentiation. The rapid iPS reprogramming approach described here should help to fully elucidate the process and has potential clinical applications.", "BACKGROUND: While the promotion of health-related fitness is thereby widespread, less focus is currently being given on the biological influence that physical activity might exert on results of laboratory testing. As such, this study was undertaken to assess the kinetics of liver injury markers following physical exercise.DESIGN AND METHODS: Total and direct bilirubin as well as the activity of biochemical markers of liver injury including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGT) and creatine kinase (CK), were measured before and after a half-marathon.RESULTS: Significant increases occurred for GGT, AST, LDH, CK, total and direct bilirubin immediately after the run. AST, LDH, CK, total and direct bilirubin were still increased 24h thereafter, whereas GGT decreased after 6h. None of the athletes exceed the upper reference limit for ALT, ALP and GGT, whereas significant variations were instead observed for LDH, AST, CK, total and direct bilirubin.CONCLUSIONS: Taken together, the results of our prospective investigation clearly attest that an acute bulk of aerobic physical exercise, such as a half-marathon, might produce significant changes in the activity of traditional biomarkers of liver injury, which should be carefully considered when investigating physically active individuals undergoing laboratory testing.", "PURPOSE: To evaluate the diagnostic performance of the combination of tumor markers [alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9)] and imaging features in differentiating combined hepatocellular-cholangiocarcinoma (CHC) from hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC).METHODS: Forty consecutive patients with pathologically proven CHC were retrospectively evaluated with contrast-enhanced ultrasound (CEUS). Additionally, 40 HCC and 40 CC patients who were randomly selected from the same period served as a control group. Images were classified as HCC-like or CC-like pattern according to CEUS guidelines recommended by World and European Federation for Ultrasound in Medicine and Biology (WFUMB-EFSUMB). The diagnostic criteria of CHC were defined as follows: (1) both AFP and CA19-9 are simultaneously elevated (AFP > 20 ng/ml and CA19-9 > 100 units/ml); or (2) elevated AFP with a CC-like pattern on CEUS and without elevated CA19-9 level; or (3) elevated CA19-9 with an HCC-like pattern on CEUS and without elevated AFP level. The diagnostic tests were performed with calculation of the sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic curve (AUC).RESULTS: For the 40 CHC patients, the rates of elevated AFP and CA19-9 serology were 55.0 and 30.0%, respectively. Twenty-three (57.5%) patients exhibited an HCC-like pattern, and 15 (37.5%) showed a CC-like pattern. After applying the above diagnostic criteria of CHC in the 120 patients, the sensitivity, specificity, PPV, NPV, accuracy, and AUC were 32.5, 93.8, 72.2, 73.5, 73.3, and 0.631%, respectively. When the actual prevalence rate (0.4-14.3%) was taken into account, the PPV and NPV were modified from 2.1 to 46.7% and 89.3 to 99.7%, respectively.CONCLUSION: The combination of enhancement patterns on CEUS and serum tumor markers (AFP and CA19-9) may be a potentially specific diagnostic method to differentiate CHC from HCC and CC." ]

[ "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.", "The unipolar brush cell (UBC) is a medium-sized neuron located in the granular layer of the cerebellar cortex and morphologically characterized by a single dendritic shaft terminated by a brush-like tuft [Mugnaini and Floris, J. Comp. Neurol., in press]. This neuronal class is mostly encountered in the vestibular part of the cerebellum, although also present in the rest of the vermal folia. The UBC axon, as seen in Golgi impregnated material, has a tortuous course throughout the granular layer and gives off number of collaterals of variable diameter. Some of the axon collaterals enter the white matter only for a short distance, after which they ascend into the granular layer. Astonishingly, some of the thick granular collaterals of these axons display characteristic expansions resembling the rosette excrescences seen on mossy fibers. In our series these rosettes are mostly of the simple type [Palay, S. and Chan-Palay, V., Cerebellar Cortex. Cytology and Organization, Springer, Berlin, 1974], i.e. short swellings with simple globular contours. The exact projection targets and functional effect of the UBC axon and granular rosettes have still to be demonstrated.", "Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease affecting the joints and surrounding tissue. Identification of novel proteins associated with the progression of a disease is a prerequisite for understanding the pathogenesis of RA. The present study was undertaken to identify the potential biomarkers from a less explored biological sample such as synovial fluid (SF) cells which is specific for RA and to analyze their functional aspects using proteomic approach. Two-dimensional gel electrophoresis (2-DE) was performed using synovial fluid cells of RA and osteoarthritis (OA) patients, and 7 differentially expressed proteins were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS/MS). Αlpha-Taxilin (α-Taxilin) has been found as one of the novel, significantly up regulated protein in RA. It has been validated in the synovium, synovial fluid (SF), SF cells, and plasma samples by Western blot, enzyme-linked immunosorbent assay (ELISA), fluorescence-activated cell sorting (FACS), immunohistochemistry (IHC), and real-time PCR. The identification of autoantibody against α-Taxilin and in silico studies has further helped us to understand its involvement in disease mechanism. The present study will therefore provide knowledge towards the etiology of RA that pave the way for suitable prognostic marker identification along with other clinical parameters.", "Cerebral cavernous malformation (CCM) is a common vascular disease in central nervous system that frequently predisposes to stroke, seizure, and cerebral hemorrhage. CCM lesions are characterized by dilated and leaky intracranial capillaries composed of a thin layer of vascular endothelial cells with abnormal subendothelial extracellular matrix. Despite the understanding that genetic mutation of three CCM genes (CCM1, CCM2, and CCM3) results in hereditary CCM, the molecular mechanism underlying vascular defects in CCM lesions remains poorly understood. Recent studies have shown that integrin cytoplasmic domain-associated protein-1 (ICAP-1, also known as integrin β1 binding protein1, ITGB1BP), a cytoplasmic protein interacting with both β1 integrin subunit and CCM1 protein (also known as Krit1), is implicated in vascular development. Analysis of data on the biochemistry and cellular biology of ICAP-1 highlights that bidirectional interaction of ICAP-1 with CCM1 and integrin might regulate diverse pathological processes of CCM disorder. Specifically, emerging evidence supports the hypothesized involvement of ICAP-1 in CCM pathogenesis through its significant effect in attenuating excessive vascular growth, its indispensable function in activating CCM1 protein, and its essential role in regulating integrin functions.", "PURPOSE: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR1), -2, and -3. This phase III trial compared tivozanib with sorafenib as initial targeted therapy in patients with metastatic renal cell carcinoma (RCC).PATIENTS AND METHODS: Patients with metastatic RCC, with a clear cell component, prior nephrectomy, measurable disease, and 0 or 1 prior therapies for metastatic RCC were randomly assigned to tivozanib or sorafenib. Prior VEGF-targeted therapy and mammalian target of rapamycin inhibitor were not permitted. The primary end point was progression-free survival (PFS) by independent review.RESULTS: A total of 517 patients were randomly assigned to tivozanib (n = 260) or sorafenib (n = 257). PFS was longer with tivozanib than with sorafenib in the overall population (median, 11.9 v 9.1 months; hazard ratio [HR], 0.797; 95% CI, 0.639 to 0.993; P = .042). One hundred fifty-six patients (61%) who progressed on sorafenib crossed over to receive tivozanib. The final overall survival (OS) analysis showed a trend toward longer survival on the sorafenib arm than on the tivozanib arm (median, 29.3 v 28.8 months; HR, 1.245; 95% CI, 0.954 to 1.624; P = .105). Adverse events (AEs) more common with tivozanib than with sorafenib were hypertension (44% v 34%) and dysphonia (21% v 5%). AEs more common with sorafenib than with tivozanib were hand-foot skin reaction (54% v 14%) and diarrhea (33% v 23%).CONCLUSION: Tivozanib demonstrated improved PFS, but not OS, and a differentiated safety profile, compared with sorafenib, as initial targeted therapy for metastatic RCC.", "A hearing screening program was performed to determine the prevalence of hearing loss and abnormal tympanometry in individuals with short-stature skeletal dysplasias attending a national meeting. Behavioral audiometry, otoacoustic emission testing, and tympanometry were used to assess hearing. Failed hearing screen was defined as hearing ≥ 35 dB at one or more frequencies or by \"fail\" on otoacoustic emissions. One hundred ten of 112 subjects completed the screening. 58 (51.8%) were children. Seventy-three (65.2%) had achondroplasia, 34 (30.4%) had one of 11 other diagnoses, and 5(4.4%) were undiagnosed. 25.8% of children failed hearing screening in one or both ears, while 46.3% of adults failed in one or both ears. 55.1% of adults and 25.0% of children with achondroplasia failed screening. Abnormal hearing was also found in the some patients with spondyloepiphyseal dysplasia congenital (SEDC; 75%), diastrophic dysplasia (66%), and Morquio (66%). Hearing was normal in those with hypochondroplasia, pseudoachondroplasia, and microcephalic osteodysplastic primordial dwarfism. Tympanometry was abnormal in at least one ear in 53.3% of children and 38.5% of adults. Abnormal tympanometry in the absence of functioning tympanostomy tubes was associated with 9.5 greater odds of hearing loss in children and 2.8 greater odds of hearing loss in the total cohort. Only 3 (2.7%) respondents reported the use of hearing aids. Hearing loss and middle ear disease are common in both children and adults with skeletal dysplasia. Adults were more likely to fail hearing screening than children. Abnormal tympanometry is associated with hearing loss. Hearing screening with appropriate intervention is recommended for these patients.", "We have developed a fluorescent in situ hybridization (FISH) method to examine the structure of both natural chromosomes and small artificial chromosomes during the mitotic cycle of budding yeast. Our results suggest that the pairing of sister chromatids: (a) occurs near the centromere and at multiple places along the chromosome arm as has been observed in other eukaryotic cells; (b) is maintained in the absence of catenation between sister DNA molecules; and (c) is independent of large blocks of repetitive DNA commonly associated with heterochromatin. Condensation of a unique region of chromosome XVI and the highly repetitive ribosomal DNA (rDNA) cluster from chromosome XII were also examined in budding yeast. Interphase chromosomes were condensed 80-fold relative to B form DNA, similar to what has been observed in other eukaryotes, suggesting that the structure of interphase chromosomes may be conserved among eukaryotes. While additional condensation of budding yeast chromosomes were observed during mitosis, the level of condensation was less than that observed for human mitotic chromosomes. At most stages of the cell cycle, both unique and repetitive sequences were either condensed or decondensed. However, in cells arrested in late mitosis (M) by a cdc15 mutation, the unique DNA appeared decondensed while the repetitive rDNA region appeared condensed, suggesting that the condensation state of separate regions of the genome may be regulated differently. The ability to monitor the pairing and condensation of sister chromatids in budding yeast should facilitate the molecular analysis of these processes as well as provide two new landmarks for evaluating the function of important cell cycle regulators like p34 kinases and cyclins. Finally our FISH method provides a new tool to analyze centromeres, telomeres, and gene expression in budding yeast." ]

[ "Long interspersed nuclear element 1 is an autonomous non-long terminal repeat retrotransposon that comprises ∼17% of the human genome. Its spontaneous retrotransposition and the accumulation of heritable L1 insertions can potentially result in genome instability and sporadic disorders. Moloney leukemia virus 10 homolog (MOV10), a putative RNA helicase, has been implicated in inhibiting L1 replication, although its underlying mechanism of action remains obscure. Moreover, the physiological relevance of MOV10-mediated L1 regulation in human disease has not yet been examined. Using a proteomic approach, we identified RNASEH2 as a binding partner of MOV10. We show that MOV10 interacts with RNASEH2, and their interplay is crucial for restricting L1 retrotransposition. RNASEH2 and MOV10 co-localize in the nucleus, and RNASEH2 binds to L1 RNAs in a MOV10-dependent manner. Small hairpin RNA-mediated depletion of either RNASEH2A or MOV10 results in an accumulation of L1-specific RNA-DNA hybrids, suggesting they contribute to prevent formation of vital L1 heteroduplexes during retrotransposition. Furthermore, we show that RNASEH2-MOV10-mediated L1 restriction downregulates expression of the rheumatoid arthritis-associated inflammatory cytokines and matrix-degrading proteinases in synovial cells, implicating a potential causal relationship between them and disease development in terms of disease predisposition.", "OBJECTIVES: To evaluate the impact of neutralizing monoclonal antibody (mAb) treatment and to determine whether the selective pressure of mAbs could facilitate the proliferation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with spike protein mutations that might attenuate mAb effectiveness.PATIENTS AND METHODS: We evaluated the impact of mAbs on the nasopharyngeal (NP) viral load and virus quasispecies of mAb-treated patients using single-molecule real-time sequencing. The mAbs used were: Bamlanivimab alone (four patients), Bamlanivimab/Etesevimab (23 patients) and Casirivimab/Imdevimab (five patients).RESULTS: The NP SARS-CoV-2 viral load of mAb-treated patients decreased from 8.2 log10 copies/mL before administration to 4.3 log10 copies/mL 7 days after administration. Five immunocompromised patients given Bamlanivimab/Etesevimab were found to have mAb activity-reducing spike mutations. Two patients harboured SARS-CoV-2 variants with a Q493R spike mutation 7 days after administration, as did a third patient 14 days after administration. The fourth patient harboured a variant with a Q493K spike mutation 7 days post-treatment, and the fifth patient had a variant with a E484K spike mutation on day 21. The emergence of the spike mutation was accompanied by stabilization or rebound of the NP viral load in three of five patients.CONCLUSION: Two-mAb therapy can drive the selection of resistant SARS-CoV-2 variants in immunocompromised patients. Patients given mAbs should be closely monitored and measures to limit virus spread should be reinforced.", "IMPORTANCE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were recently approved for lowering low-density lipoprotein cholesterol in heterozygous familial hypercholesterolemia (FH) or atherosclerotic cardiovascular disease (ASCVD) and have potential for broad ASCVD prevention. Their long-term cost-effectiveness and effect on total health care spending are uncertain.OBJECTIVE: To estimate the cost-effectiveness of PCSK9 inhibitors and their potential effect on US health care spending.DESIGN, SETTING, AND PARTICIPANTS: The Cardiovascular Disease Policy Model, a simulation model of US adults aged 35 to 94 years, was used to evaluate cost-effectiveness of PCSK9 inhibitors or ezetimibe in heterozygous FH or ASCVD. The model incorporated 2015 annual PCSK9 inhibitor costs of $14,350 (based on mean wholesale acquisition costs of evolocumab and alirocumab); adopted a health-system perspective, lifetime horizon; and included probabilistic sensitivity analyses to explore uncertainty.EXPOSURES: Statin therapy compared with addition of ezetimibe or PCSK9 inhibitors.MAIN OUTCOMES AND MEASURES: Lifetime major adverse cardiovascular events (MACE: cardiovascular death, nonfatal myocardial infarction, or stroke), incremental cost per quality-adjusted life-year (QALY), and total effect on US health care spending over 5 years.RESULTS: Adding PCSK9 inhibitors to statins in heterozygous FH was estimated to prevent 316,300 MACE at a cost of $503,000 per QALY gained compared with adding ezetimibe to statins (80% uncertainty interval [UI], $493,000-$1,737,000). In ASCVD, adding PCSK9 inhibitors to statins was estimated to prevent 4.3 million MACE compared with adding ezetimibe at $414,000 per QALY (80% UI, $277,000-$1,539,000). Reducing annual drug costs to $4536 per patient or less would be needed for PCSK9 inhibitors to be cost-effective at less than $100,000 per QALY. At 2015 prices, PCSK9 inhibitor use in all eligible patients was estimated to reduce cardiovascular care costs by $29 billion over 5 years, but drug costs increased by an estimated $592 billion (a 38% increase over 2015 prescription drug expenditures). In contrast, initiating statins in these high-risk populations in all statin-tolerant individuals who are not currently using statins was estimated to save $12 billion.CONCLUSIONS AND RELEVANCE: Assuming 2015 prices, PCSK9 inhibitor use in patients with heterozygous FH or ASCVD did not meet generally acceptable incremental cost-effectiveness thresholds and was estimated to increase US health care costs substantially. Reducing annual drug prices from more than $14,000 to $4536 would be necessary to meet a $100,000 per QALY threshold.", "Chronic wasting disease (CWD), a contagious prion disease of the deer family, has the potential to severely harm deer populations and disrupt ecosystems where deer occur in abundance. Consequently, understanding the dynamics of this emerging infectious disease, and particularly the dynamics of its transmission, has emerged as an important challenge for contemporary ecologists and wildlife managers. Although CWD is contagious among deer, the relative importance of pathways for its transmission remains unclear. We developed seven competing models, and then used data from two CWD outbreaks in captive mule deer and model selection to compare them. We found that models portraying indirect transmission through the environment had 3.8 times more support in the data than models representing transmission by direct contact between infected and susceptible deer. Model-averaged estimates of the basic reproductive number (R0) were 1.3 or greater, indicating likely local persistence of CWD in natural populations under conditions resembling those we studied. Our findings demonstrate the apparent importance of indirect, environmental transmission in CWD and the challenges this presents for controlling the disease.", "Human mesenchymal stem cells (hMSCs) have attracted much attention for tissue repair and wound healing because of their self-renewal capacity and multipotentiality. In order to mediate an effective therapy, substantial numbers of cells are required, which necessitates extensive sub-culturing and expansion of hMSCs. Throughout ex vivo expansion, the cells undergo telomere shortening, and critically short telomeres can trigger loss of cell viability. Telomeres are nucleoprotein structures that cap the ends of chromosomes, and serve to protect the DNA from the degradation which occurs due to the end-replication problem in all eukaryotes. As hMSCs have only a finite ability for self-renewal like most somatic cells, assaying for telomere length in hMSCs provides critical information on the replicative capacity of the cells, an important criterion in the selection of hMSCs for therapy. Telomere length is generally quantified by Southern blotting and fluorescence in situ hybridization, and more recently by PCR-based methods. Here we describe the quantification of hMSC telomere length by real-time PCR; our results demonstrate the effect of telomere shortening on the proliferation and clonogenicity of hMSCs. Thus, this assay constitutes a useful tool for the determination of relative telomere length in hMSCs.", "Ashbya gossypii grows as multinucleated and constantly elongating hyphae. Nuclei are in continuous forward and backward motion, also move during mitosis, and frequently bypass each other. Whereas these nuclear movements are well documented, comparatively little is known about the density and morphology of organelles which very likely influence these movements. To understand the three-dimensional subcellular organization of hyphae at high resolution, we performed large-scale electron tomography of the tip regions in A. gossypii. Here, we present a comprehensive space-filling model in which most membrane-limited organelles including nuclei, mitochondria, endosomes, multivesicular bodies, vacuoles, autophagosomes, peroxisomes, and vesicles are modeled. Nuclei revealed different morphologies and protrusions filled by the nucleolus. Mitochondria are very abundant and form a tubular network with a polarized spherical fraction. The organelles of the degradative pathways show a clustered organization. By analyzing vesicle-like bodies, we identified three size classes of electron-dense vesicles (∼200, ∼150, and ∼100 nm) homogeneously distributed in the cytoplasm which most likely represent peroxisomes. Finally, coated and uncoated vesicles with approximately 40-nm diameters show a polarized distribution toward the hyphal tip with the coated vesicles preferentially localizing at the hyphal periphery.", "OBJECTIVES: Avanafil is a highly selective phosfosdiesterase 5 inhibitor (PDE5 inhibitor), with rapid onset of action, approved by the Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of erectile dysfunction (ED). It had been recently commercialized in Spain. This article presents a detailed review of the available literature, where the safety, tolerability and efficacy of avanafil were evaluated.METHODS: A systematic literature search using the Medline database was performed. The search included the terms Avanafil and erectile dysfunction. The pivotal studies of clinical development of the drug, and also those randomized, double-blind, placebo-controlled, well-designed studies were analyzed. We included those studies published in English up to January 2014. Likewise, studies of the pharmacokinetics and pharmacodynamics of the drug were also included.RESULTS: The avanafil pivotal studies, conducted in general population of patients with ED, patients with Diabetes mellitus type I and II and patients with ED secondary to nerve sparing radical prostatectomy were analyzed. In all these studies, avanafil demonstrated a statistically significant improvement in erectile function (IIEF), and all the coprimary outcomes (SEP2 and SEP3) compared to placebo. Also, a good tolerance profile and few side effects compared to placebo were evident.CONCLUSIONS: Avanafil is a selective PDE5 inhibitors, that is rapidly absorbed and that has a short time to peak response. It found to be effective in randomized, double-blind, placebo-controlled trials conducted in men with erectile dysfunction, including in patients with diabetes mellitus and after radical prostatectomy. It was generally well tolerated across trials, with very few patients withdrawing because of adverse effects. Similarly, avanafil had a significantly lower rate of hemodynamic side effects compared with sildenafil." ]

[ "Pathogens are known to release in their environment a large range of toxins and other virulence factors. Their pathogenicity relies on this arsenal of exoproteins and their orchestrated release upon changing environmental conditions. Exoproteomics aims at describing and quantifying the proteins found outside of the cells, thus takes advantage of the most recent methodologies of next-generation proteomics. This approach has been applied with great success to a variety of pathogens increasing the fundamental knowledge on pathogenicity. In this chapter, we describe how the exoproteome should be prepared and handled for high-throughput identification of exoproteins and their quantitation by label-free shotgun proteomics. We also mentioned some bioinformatics tools for extracting information such as toxin similarity search.", "A complex study on various evolutionary peculiarities of the mammalia dispersed Alu repeats (Alu repeats of primates and B1 of rodents) has been carried out by phylogenetic analysis. A phylogenetic tree, containing the 7SL RNA genes and the Alu repeats of primates and rodents has been constructed. It has been shown that the branch of the phyletic line leading to the Alu repeats of primates and B1 of rodents from the 7SL RNA genes occurred after the divergence of the 7SL RNA genes of amphibia and mammalia, but before the divergence of the 7SL RNA genes of primates and rodents (250.10 years ago). A statistically reliable slowing down in the evolutionary rates of one of two monomers for the human Alu repeats has been proved. It may be caused by the functional load of the corresponding monomer in connection with the presence of a definit regulatory site in it.", "The Notch signaling pathway is involved in a wide variety of highly conserved developmental processes in mammals. Importantly, mutations of the Notch protein and components of its signaling pathway have been implicated in an array of human diseases (T-cell leukemia and other cancers, Multiple Sclerosis, CADASIL, Alagille Syndrome, Spondylocostal Dysostosis). In mammals, Notch becomes activated upon binding of its extracellular domain to ligands (Delta and Jagged/Serrate) that are present on the surface of apposed cells. The extracellular domain of Notch contains up to 36 tandem Epidermal Growth Factor-like (EGF) repeats. Many of these EGF repeats are modified at evolutionarily-conserved consensus sites by an unusual form of O-glycosylation called O-fucose. Work from several groups indicates that O-fucosylation plays an important role in ligand mediated Notch signaling. Recent evidence also suggests that the enzyme responsible for addition of O-fucose to Notch, protein O-fucosyltransferase-1 (POFUT1), may serve a quality control function in the endoplasmic reticulum. Additionally, some of the O-fucose moieties are further elongated by the action of members of the Fringe family of beta-1,3-N-acetylglucosaminyltransferases. The alteration in O-fucose saccharide structure caused by Fringe modulates the response of Notch to its ligands. Thus, glycosylation serves an important role in regulating Notch activity. This review focuses on the role of glycosylation in the normal functioning of the Notch pathway. As well, potential roles for glycosylation in Notch-related human diseases, and possible roles for therapeutic targeting of POFUT1 and Fringe in Notch-related human diseases, are discussed.", "The prostacyclin analogues, iloprost and treprostinil are extensively used in treating pulmonary hypertension. Their binding profile and corresponding biochemical cellular responses on human prostanoid receptors expressed in cell lines, have now been compared. Iloprost had high binding affinity for EP1 and IP receptors (Ki 1.1 and 3.9 nM, respectively), low affinity for FP, EP3 or EP4 receptors, and very low affinity for EP2, DP1 or TP receptors. By contrast, treprostinil had high affinity for the DP1, EP2 and IP receptors (Ki 4.4, 3.6 and 32 nM, respectively), low affinity for EP1 and EP4 receptors and even lower affinity for EP3, FP and TP receptors. In functional assays, iloprost had similar high activity in elevating cyclic AMP levels in cells expressing the human IP receptor and stimulating calcium influx in cells expressing EP1 receptors (EC50 0.37 and 0.3 nM, respectively) with the rank order of activity on the other receptors comparable to the binding assays. As with binding studies, treprostinil elevated cyclic AMP with a similar high potency in cells expressing DP1, IP and EP2 receptors (EC50 0.6, 1.9 and 6.2 nM, respectively), but had low activity at the other receptors. Activation of IP, DP1 and EP2 receptors, as with treprostinil, can all result in vasodilatation of human pulmonary arteries. However, activation of EP1 receptors can provoke vasoconstriction, and hence may offset the IP-receptor mediated vasodilator effects of iloprost. Treprostinil may therefore differ from iloprost in its overall beneficial pulmonary vasorelaxant profile and other pharmacological actions, especially in diseases where the IP receptor is down-regulated.", "Collaborators: Stein JL, Medland SE, Arias Vasquez A, Hibar DP, Senstad RE, Winkler AM, Toro R, Appel K, Bartecek R, Bergmann Ø, Bernard M, Brown AA, Cannon DM, Chakravarty M, Christoforou A, Domin M, Grimm O, Hollinshead M, Holmes AJ, Homuth G, Hottenga JJ, Langan C, Lopez LM, Hansell NK, Hwang KS, Kim S, Laje G, Lee PH, Liu X, Loth E, Lourdusamy A, Maniega SM, Mattingsdal M, Mohnke S, Nho K, Nugent AC, O'Brien C, Papmeyer M, Pütz B, Ramasamy A, Rasmussen J, Rijpkema M, Risacher SL, Roddey JC, Rose EJ, Ryten M, Shen L, Sprooten E, Strengman E, Teumer A, Trabzuni D, Turner J, van Eijk K, van Erp TG, van Tol MJ, Wittfeld K, Wolf C, Woudstra S, Aleman A, Alhusaini S, Almasy L, Binder EB, Brohawn DG, Cantor RM, Carless MA, Corvin A, Czisch M, Curran JE, Davies G, de Almeida MA, Delanty N, Depondt C, Duggirala R, Dyer TD, Erk S, Fagerness J, Fox PT, Freimer NB, Gill M, Göring HH, Hagler DJ, Hoehn D, Holsboer F, Hoogman M, Hosten N, Jahanshad N, Johnson MP, Kasperaviciute D, Kent JW Jr, Kochunov P, Lancaster JL, Lawrie SM, Liewald DC, Mandl R, Matarin M, Mattheisen M, Meisenzahl E, Melle I, Moses EK, Mühleisen TW, Nauck M, Nöthen MM, Olvera RL, Pandolfo M, Pike GB, Puls R, Reinvang I, Rentería ME, Rietschel M, Roffman JL, Royle NA, Rujescu D, Savitz J, Schnack HG, Schnell K, Seiferth N, Smith C, Steen VM, Valdés Hernández MC, Van den Heuvel M, van der Wee NJ, Van Haren NE, Veltman JA, Völzke H, Walker R, Westlye LT, Whelan CD, Agartz I, Boomsma DI, Cavalleri GL, Dale AM, Djurovic S, Drevets WC, Hagoort P, Hall J, Heinz A, Jack CR Jr, Foroud TM, Le Hellard S, Macciardi F, Montgomery GW, Poline JB, Porteous DJ, Sisodiya SM, Starr JM, Sussmann J, Toga AW, Veltman DJ, Walter H, Weiner MW, Andreassen OA, Apostolova LG, Bastin ME, Blangero J, Brunner HG, Buckner RL, Cichon S, Coppola G, de Zubicaray GI, Deary IJ, Donohoe G, de Geus EJ, Espeseth T, Fernández G, Glahn DC, Grabe HJ, Hardy J, Hulshoff Pol HE, Jenkinson M, Kahn RS, McDonald C, McIntosh AM, McMahon FJ, McMahon KL, Meyer-Lindenberg A, Morris DW, Müller-Myhsok B, Nichols TE, Ophoff RA, Paus T, Pausova Z, Penninx BW, Potkin SG, Sämann PG, Saykin AJ, Schumann G, Smoller JW, Wardlaw JM, Weale ME, Martin NG, Franke B, Wright MJ, Thompson PM.", "Variegate porphyria (VP) is an autosomal-dominant disorder that is caused by inheritance of a partial deficiency of the enzyme protoporphyrinogen oxidase (EC 1.3.3.4). It is characterized by cutaneous photosensitivity and/or various neurological manifestations. Protoporphyrinogen oxidase catalyses the penultimate step of haem biosynthesis, and mutations in the PPOX gene have been coupled to VP. In the present study, sequencing analysis revealed 10 different mutations in the PPOX gene in 14 out of 17 apparently unrelated Swedish VP families. Six of the identified mutations, 3G > A (exon 2), 454C > T (exon 5), 472G > C (exon 6), 614C > T (exon 6), 988G > C (exon 10) and IVS12 + 2T > G (intron 12), are single nucleotide substitutions, while 604delC (exon 6), 916-17delCT (exon 9) and 1330-31delCT (exon 13) are small deletions, and IVS12 + 2-3insT (intron 12) is a small insertion. Only one of these 10 mutations has been reported previously. Three of the mutations were each identified in two or more families, while the remaining mutations were specific for an individual family. In addition to the 10 mutations, one previously unreported single nucleotide polymorphism was identified. Mutation analysis of family members revealed two adults and four children who were silent carriers of the VP trait. Genetic analysis can now be added to the conventional biochemical analyses and used in investigation of putative carriers of a VP trait in these families.", "Proteins that mediate cellular and subcellular membrane fusion are key factors in vesicular trafficking in all eukaryotic cells, including the secretion and transport of plant pathogen virulence factors. In this study, we identified vesicle-fusion components that included 22 soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), four Sec1/Munc18 (SM) family proteins, and 10 Rab GTPases encoded in the genome of the vascular wilt pathogen Verticillium dahliae Vd991. Targeted deletion of two SNARE-encoding genes in V. dahliae, VdSec22 and VdSso1, significantly reduced virulence of both mutants on cotton, relative to the wild-type Vd991 strain. Comparative analyses of the secreted protein content (exoproteome) revealed that many enzymes involved in carbohydrate hydrolysis were regulated by VdSec22 or VdSso1. Consistent with a role of these enzymes in plant cell-wall degradation, pectin, cellulose, and xylan utilization were reduced in the VdSec22 or VdSso1 mutant strains along with a loss of exoproteome cytotoxic activity on cotton leaves. Comparisons with a pathogenicity-related exoproteome revealed that several known virulence factors were not regulated by VdSec22 or VdSso1, but some of the proteins regulated by VdSec22 or VdSso1 displayed different characteristics, including the lack of a typical signal peptide, suggesting that V. dahliae employs more than one secretory route to transport proteins to extracellular sites during infection.", "Wound-colonizing microorganisms can form complex and dynamic polymicrobial communities where pathogens and commensals may co-exist, cooperate or compete with each other. The present study was aimed at identifying possible interactions between different bacteria isolated from the same chronic wound of a patient with the genetic blistering disease epidermolysis bullosa (EB). Specifically, this involved two different isolates of the human pathogen Staphylococcus aureus, and isolates of Bacillus thuringiensis and Klebsiella oxytoca. Particular focus was attributed to interactions of S. aureus with the two other species, because of the high staphylococcal prevalence among chronic wounds. Intriguingly, upon co-cultivation, none of the wound isolates inhibited each other's growth. Since the extracellular proteome of bacterial pathogens is a reservoir of virulence factors, the exoproteomes of the staphylococcal isolates in monoculture and co-culture with B. thuringiensis and K. oxytoca were characterized by Mass Spectrometry to explore the inherent relationships between these co-exisiting bacteria. This revealed a massive reduction in the number of staphylococcal exoproteins upon co-culturing with K. oxytoca or B. thuringiensis. Interestingly, this decrease was particularly evident for extracellular proteins with a predicted cytoplasmic localization, which were recently implicated in staphylococcal virulence and epidemiology. Furthermore, our exoproteome analysis uncovered potential cooperativity between the two different S. aureus isolates. Altogether, the observed exoproteome variations upon co-culturing are indicative of unprecedented adaptive mechanisms that set limits to the production of secreted staphylococcal virulence factors.", "Lung cancer is the leading cause of cancer-related death in the world. Prior to the era of targeted therapy, platinum-based doublet chemotherapy was the first-line therapy of choice for patients with metastatic non-small-cell lung cancer (NSCLC). The availability of agents that target epidermal growth factor receptor (EGFR)-tyrosine kinase, as well as inhibitors against anaplastic lymphoma kinase (ALK) gene rearrangement or ROS-1 gene rearrangement product, has provided promising clinical benefits in specific subpopulations of NSCLC. At present, only first-generation EGFR-tyrosine kinase inhibitors (TKIs) (erlotinib and gefitinib) are available for clinical use. Second-generation irreversible EGFR-TKIs, such as afatinib, are still in clinical trials. In current clinical practice, EGFR-TKI is the first-line treatment of choice for metastatic NSCLC patients with tumor EGFR mutation or as salvage therapy in NSCLC patients who received systemic chemotherapy previously. Platinum-based doublet chemotherapy continues to be the standard of care for those treatment-naïve patients with EGFR wild -type tumor or unknown EGFR status. Even though all investigators agree with the use of EGFR-TKI as the first-line treatment in tumor EGFR-mutated patients, only 10-30% of NSCLC patients have mutated EGFR, and there was no obvious survival difference when EGFR-TKIs were used in a second-line setting versus a first-line treatment in EGFR-mutated patients. Thus, the molecular complexity of lung cancer emphasizes the need for optimizing treatment by seeking a more personalized approach to care, including searching for driver oncogenes, managing the emergence of resistance and overcoming that resistance, and optimizing the sequence of treatment. Numerous other novel targeted agents are now in clinical development, including new agents targeting novel pathways and those that may have the potential to overcome the limitations or resistance associated with currently available EGFR-TKIs. In this report, we review the clinical data of EGFR-TKIs as molecular-targeted therapies in NSCLC.", "In severe congenital neutropenia (SCN), long-term therapy with granulocyte colony-stimulating factor (G-CSF) has reduced mortality from sepsis, revealing an underlying predisposition to myelodysplastic syndrome and acute myeloid leukaemia (MDS/AML). We have reported the early pattern of evolution to MDS/AML, but the long-term risk remains uncertain. We updated a prospective study of 374 SCN patients on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry. Long-term, the annual risk of MDS/AML attained a plateau (2.3%/year after 10 years). This risk now appears similar to, rather than higher than, the risk of AML in Fanconi anaemia and dyskeratosis congenita.", "Craniosynostosis represents a defection of the skull caused by early fusion of one or more cranial sutures. The shape alteration of the cranial vault varies, depending on the fused sutures, so that compensatory growth occurs in dimensions not restricted by sutures. Craniosynostosis can be divided into two main groups: syndromic and nonsyndromic. Nonsyndromic craniosynostosis is typically an isolated finding that is classified according to the suture(s) involved. Syndromic craniosynostosis is associated with various dysmorphisms involving the face, skeleton, nervous system and is usually accompanied by developmental delay. In the last 15 years, research on craniosynostosis has progressed from the description of gross abnormalities to the understanding of the genetic basis of certain cranial deformities. Mutations in the genes encoding fibroblast growth factor receptors 1, 2 and 3 (FGFR-1, FGFR-2, FGFR-3), TWIST and MSX2 (muscle segment homebox 2) have been identified in certain syndromic craniosynostosis. The molecular basis of many types of syndromic craniosynostosis is known and diagnostic testing strategies will often lead to a specific diagnosis. Although the clarification of a genetic lesion does not have a direct impact on the management of the patient in many cases, there is a significant benefit in providing accurate prenatal diagnosis. This review summarizes the available knowledge on cranisynostosis and presents a graduated strategy for the genetic diagnosis of these craniofacial defects.", "Hypertrophic cardiomyopathy (HCM) is a genetic cardiomyopathy. The prevalence of phenotypic expression, in the absence of another systemic or cardiac disease causing increased left ventricular (LV) wall thickness, is estimated to be 1:500. The frequency of clinical presentation is far less, highlighting the need for a non-invasive diagnostic imaging tool. Echocardiography is readily available and allows for structural characterization and hemodynamic assessment of the hypertrophic heart and to screen patients at-risk for HCM, such as first degree relatives of affected individuals, and differentiate HCM from the athletic heart. Echocardiography can also be used to assess for anatomic abnormalities of the mitral valve apparatus that may exacerbate LV outflow track obstruction and to further risk stratify patients during exercise. Finally, echocardiography plays an integral role in guiding alcohol septal ablation procedures." ]

[ "Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disorder associated with bone fragility and susceptibility to fractures after minimal trauma. OI type V has an autosomal-dominant pattern of inheritance and is not caused by mutations in the type I collagen genes COL1A1 and COL1A2. The most remarkable and pathognomonic feature, observed in ~65% of affected individuals, is a predisposition to develop hyperplastic callus after fractures or surgical interventions. To identify the molecular cause of OI type V, we performed whole-exome sequencing in a female with OI type V and her unaffected parents and searched for de novo mutations. We found a heterozygous de novo mutation in the 5'-untranslated region of IFITM5 (the gene encoding Interferon induced transmembrane protein 5), 14 bp upstream of the annotated translation initiation codon (c.-14C>T). Subsequently, we identified an identical heterozygous de novo mutation in a second individual with OI type V by Sanger sequencing, thereby confirming that this is the causal mutation for the phenotype. IFITM5 is a protein that is highly enriched in osteoblasts and has a putative function in bone formation and osteoblast maturation. The mutation c.-14C>T introduces an upstream start codon that is in frame with the reference open-reading frame of IFITM5 and is embedded into a stronger Kozak consensus sequence for translation initiation than the annotated start codon. In vitro, eukaryotic cells were able to recognize this start codon, and they used it instead of the reference translation initiation signal. This suggests that five amino acids (Met-Ala-Leu-Glu-Pro) are added to the N terminus and alter IFITM5 function in individuals with the mutation.", "The discovery of disease-causing mutations typically requires confirmation of the variant or gene in multiple unrelated individuals, and a large number of rare genetic diseases remain unsolved due to difficulty identifying second families. To enable the secure sharing of case records by clinicians and rare disease scientists, we have developed the PhenomeCentral portal (https://phenomecentral.org). Each record includes a phenotypic description and relevant genetic information (exome or candidate genes). PhenomeCentral identifies similar patients in the database based on semantic similarity between clinical features, automatically prioritized genes from whole-exome data, and candidate genes entered by the users, enabling both hypothesis-free and hypothesis-driven matchmaking. Users can then contact other submitters to follow up on promising matches. PhenomeCentral incorporates data for over 1,000 patients with rare genetic diseases, contributed by the FORGE and Care4Rare Canada projects, the US NIH Undiagnosed Diseases Program, the EU Neuromics and ANDDIrare projects, as well as numerous independent clinicians and scientists. Though the majority of these records have associated exome data, most lack a molecular diagnosis. PhenomeCentral has already been used to identify causative mutations for several patients, and its ability to find matching patients and diagnose these diseases will grow with each additional patient that is entered.", "In the present study, we investigated the role of Trichoderma virens (TriV_JSB100) spores or cell-free culture filtrate in the regulation of growth and activation of the defence responses of tomato (Solanum lycopersicum) plants against Fusarium oxysporum f. sp. lycopersici by the development of a biocontrol-plant-pathogen interaction system. Two-week-old tomato seedlings primed with TriV_JSB100 spores cultured on barley grains (BGS) or with cell-free culture filtrate (CF) were inoculated with Fusarium pathogen under glasshouse conditions; this resulted in significantly lower disease incidence in tomato Oogata-Fukuju plants treated with BGS than in those treated with CF. To dissect the pathways associated with this response, jasmonic acid (JA) and salicylic acid (SA) signalling in BGS- and CF-induced resistance was evaluated using JA- and SA-impaired tomato lines. We observed that JA-deficient mutant def1 plants were susceptible to Fusarium pathogen when they were treated with BGS. However, wild-type (WT) BGS-treated tomato plants showed a higher JA level and significantly lower disease incidence. SA-deficient mutant NahG plants treated with CF were also found to be susceptible to Fusarium pathogen and displayed low SA levels, whereas WT CF-treated tomato plants exhibited moderately lower disease levels and substantially higher SA levels. Expression of the JA-responsive defensin gene PDF1 was induced in WT tomato plants treated with BGS, whereas the SA-inducible pathogenesis-related protein 1 acidic (PR1a) gene was up-regulated in WT tomato plants treated with CF. These results suggest that TriV_JSB100 BGS and CF differentially induce JA and SA signalling cascades for the elicitation of Fusarium oxysporum resistance in tomato.", "Radiofrequency ablation (RFA) is an important standard therapy for cardiac arrhythmias, but direct monitoring of tissue treatment is currently lacking. We demonstrate an RFA catheter integrated with polarization sensitive optical coherence tomography (PSOCT) for directly monitoring the RFA process in real time. The integrated RFA/OCT catheter was modified from a standard clinical RFA catheter and includes a miniature forward-viewing cone-scanning OCT probe. The PSOCT system was validated with a quarter-wave plate while the RFA function of the integrated catheter was validated by comparing lesion sizes with those made with an unmodified RFA catheter. Additionally, the integrated catheter guided catheter-tissue apposition and monitored RFA lesion formation in cardiac tissue in real time. The results show that catheter-tissue contact can be characterized by observing the features of the blood and tissue in the acquired OCT images and that RFA lesion formation can be confirmed by monitoring the change in phase retardance in the acquired PSOCT images. This system demonstrates the feasibility of an integrated RFA/OCT catheter to deliver RF energy and image the cardiac wall simultaneously and justifies further research into use of this technology to aid RFA therapy for cardiac arrhythmias.", "signatureSearch is an R/Bioconductor package that integrates a suite of existing and novel algorithms into an analysis environment for gene expression signature (GES) searching combined with functional enrichment analysis (FEA) and visualization methods to facilitate the interpretation of the search results. In a typical GES search (GESS), a query GES is searched against a database of GESs obtained from large numbers of measurements, such as different genetic backgrounds, disease states and drug perturbations. Database matches sharing correlated signatures with the query indicate related cellular responses frequently governed by connected mechanisms, such as drugs mimicking the expression responses of a disease. To identify which processes are predominantly modulated in the GESS results, we developed specialized FEA methods combined with drug-target network visualization tools. The provided analysis tools are useful for studying the effects of genetic, chemical and environmental perturbations on biological systems, as well as searching single cell GES databases to identify novel network connections or cell types. The signatureSearch software is unique in that it provides access to an integrated environment for GESS/FEA routines that includes several novel search and enrichment methods, efficient data structures, and access to pre-built GES databases, and allowing users to work with custom databases.", "The amniotic band syndrome is a collection of congenital deformities presumably due to rupture of amniotic sac. It appears to cause fetal injury through three basic mechanisms including malformation, disruption, and deformation. The associated anomalies vary from minor digital defect to major craniofacial and visceral defects. They can be categorized as neural tube-like defects, craniofacial anomalies, limb anomalies, abdominal and thoracic wall defects, visceral anomalies, and constriction bands. We present two autopsy cases and discuss the diagnostic features. Our findings support Torpin's theory that the fibrous constriction bands generated from early rupture of the amnion. An accurate diagnosis may be achieved by looking for the major features of amniotic band syndrome and a routine chromosome study and placental examination in cases with multiple congenital deformities.", "INTRODUCTION: KRAS mutations have been recognized as undruggable for many years. Recently, novel KRAS G12C inhibitors, such as sotorasib and adagrasib, are being developed in clinical trials and have revealed promising results in metastatic NSCLC. Nevertheless, it is strongly anticipated that acquired resistance will limit their clinical use. In this study, we developed in vitro models of the KRAS G12C cancer, derived from resistant clones against sotorasib and adagrasib, and searched for secondary KRAS mutations as on-target resistance mechanisms to develop possible strategies to overcome such resistance.METHODS: We chronically exposed Ba/F3 cells transduced with KRASG12C to sotorasib or adagrasib in the presence of N-ethyl-N-nitrosourea and searched for secondary KRAS mutations. Strategies to overcome resistance were also investigated.RESULTS: We generated 142 Ba/F3 clones resistant to either sotorasib or adagrasib, of which 124 (87%) harbored secondary KRAS mutations. There were 12 different secondary KRAS mutations. Y96D and Y96S were resistant to both inhibitors. A combination of novel SOS1 inhibitor, BI-3406, and trametinib had potent activity against this resistance. Although G13D, R68M, A59S and A59T, which were highly resistant to sotorasib, remained sensitive to adagrasib, Q99L was resistant to adagrasib but sensitive to sotorasib.CONCLUSIONS: We identified many secondary KRAS mutations causing resistance to sotorasib, adagrasib, or both, in vitro. The differential activities of these two inhibitors depending on the secondary mutations suggest sequential use in some cases. In addition, switching to BI-3406 plus trametinib might be a useful strategy to overcome acquired resistance owing to the secondary Y96D and Y96S mutations." ]

[ "A right adrenal tumor was found incidentally by renal echography in a 25-year-old man, who had been on hemodialysis for 4 years. Inquiry and clinical examination suggested pheochromocytoma, which was confirmed by plasma catecholamine measurements. Subsequent adrenalectomy was uneventful. Although hypertension, headache, and diaphoresis are common symptoms in a dialyzed patient, pheochromocytoma has to be eliminated in the presence of this clinical triad.", "Prions are self-propagating infectious protein isoforms. A growing number of prions have been identified in yeast, each resulting from the conversion of soluble proteins into an insoluble amyloid form. These yeast prions have served as a powerful model system for studying the causes and consequences of prion aggregation. Remarkably, a number of human proteins containing prion-like domains, defined as domains with compositional similarity to yeast prion domains, have recently been linked to various human degenerative diseases, including amyotrophic lateral sclerosis. This suggests that the lessons learned from yeast prions may help in understanding these human diseases. In this review, we examine what has been learned about the amino acid sequence basis for prion aggregation in yeast, and how this information has been used to develop methods to predict aggregation propensity. We then discuss how this information is being applied to understand human disease, and the challenges involved in applying yeast prediction methods to higher organisms.", "The start of the new year signals that it is time for mAbs' annual review of the therapeutic monoclonal antibodies (mAbs) in active Phase 2/3 or Phase 3 clinical studies. The entire clinical pipeline currently includes ~350 mAbs, but most of these are in early development. As of the beginning of 2013, our \"Antibodies to watch\" list includes 28 single mAbs and one mAb mixture that are undergoing evaluation in Phase 3 studies for inflammatory or immunological disorders, cancers, high cholesterol, osteoporosis, Alzheimer disease and infectious disease. In alphabetical order, the 28 mabs are alirocumab, AMG 145, elotuzumab, epratuzumab, farletuzumab, gantenerumab, gevokizumab, inotuzumab ozogamicin, itolizumab, ixekizumab, lebrikizumab, mepolizumab, naptumomab estafenatox, necitumumab, nivolumab, obinutuzumab, ocrelizumab, onartuzumab, racotumomab, ramucirumab, reslizumab, romosozumab, sarilumab, secukinumab, sirukumab, solanezumab, tabalumab, and vedolizumab. The mixture of actoxumab and bezlotoxumab is being evaluated in two Phase 3 studies as a treatment for Clostridium difficile infection.", "Modern humans have occupied almost all possible environments globally since exiting Africa about 100,000 years ago. Both behavioral and biological adaptations have contributed to their success in surviving the rigors of climatic extremes, including cold, strong ultraviolet radiation, and high altitude. Among these environmental stresses, high-altitude hypoxia is the only condition in which traditional technology is incapable of mediating its effects. Inhabiting at >3,000-m high plateau, the Tibetan population provides a widely studied example of high-altitude adaptation. Yet, the genetic mechanisms underpinning long-term survival in this environmental extreme remain unknown. We performed an analysis of genome-wide sequence variations in Tibetans. In combination with the reported data, we identified strong signals of selective sweep in two hypoxia-related genes, EPAS1 and EGLN1. For these two genes, Tibetans show unusually high divergence from the non-Tibetan lowlanders (Han Chinese and Japanese) and possess high frequencies of many linked sequence variations as reflected by the Tibetan-specific haplotypes. Further analysis in seven Tibetan populations (1,334 individuals) indicates the prevalence of selective sweep across the Himalayan region. The observed indicators of natural selection on EPAS1 and EGLN1 suggest that during the long-term occupation of high-altitude areas, the functional sequence variations for acquiring biological adaptation to high-altitude hypoxia have been enriched in Tibetan populations.", "Author information:(1)Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. hcm@sanger.ac.uk jeff.barrett@genomicsplc.com.(2)Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.(3)Great Ormond Street Hospital for Children, National Health Service (NHS) Foundation Trust, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK.(4)European Molecular Biology Laboratory-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.(5)Department of Paediatrics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.(6)Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.(7)Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, OPD2, Northern General Hospital, Herries Rd., Sheffield, S5 7AU, UK.(8)Department of Genetics, Aberdeen Royal Infirmary, Aberdeen, UK.(9)Wessex Clinical Genetics Service, G Level, Princess Anne Hospital, Coxford Road, Southampton SO16 5YA, UK.(10)Cheshire and Merseyside Clinical Genetic Service, Liverpool Women's NHS Foundation Trust, Crown Street, Liverpool L8 7SS, UK.(11)Department of Clinical Genetics, City Hospital Campus, Hucknall Road, Nottingham NG5 1PB, UK.(12)Institute of Cancer and Genetics, University Hospital of Wales, Cardiff, UK.(13)Temple Street Children's Hospital, Dublin, Ireland.(14)Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.(15)Clinical Genetics Unit, Birmingham Women's Hospital, Edgbaston, Birmingham B15 2TG, UK.(16)Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH, UK.(17)Northern Genetics Service, Newcastle upon Tyne Hospitals, NHS Foundation Trust, Newcastle upon Tyne, UK.(18)Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.(19)Department of Clinical Genetics, University Hospitals of Leicester NHS Trust, Leicester Royal Infirmary, Leicester LE1 5WW, UK.(20)University of Exeter Medical School, Institute of Biomedical and Clinical Science, Research, Innovation, Learning and Development (RILD), Royal Devon and Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.(21)Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.", "The IFAP syndrome is characterized by the congenital onset of ichthyosis follicularis, absence of hair, and photophobia. A limited number of patients with the disorder have been described, and X-linked recessive inheritance has been proposed. Two unrelated female patients with a complete IFAP syndrome are reported. Both patients show a diffuse distribution of the disorder without linear arrangement. Because the suggested X-linked recessive pattern of inheritance is unlikely in these patients, a different way of transmission or, alternatively, genetic heterogeneity of the disorder has to be considered.", "Mal de Debarquement Syndrome (MDS) is a rare, understudied, underdiagnosed, and self-limiting condition. Etiology and incidence are unknown. It is characterized by abnormal sensation of motion/balance reported after travel by air, land, and sea; being reexposed to motion/activity relieves it. Symptoms may last from minutes to years. Workup though required reveals no findings; it is a diagnosis of exclusion. While no efficacious treatment exists, amitriptyline and benzodiazepines as well as supportive therapy have proved to be useful. We have described a 40-year-old Caucasian female who presented for the evaluation of persistent rocking and swaying sensation after a ship cruise which lasted for one week. Patient was treated with benzodiazepines after extensive workup and is now stable. A high index of suspicion is required to make a diagnosis." ]

[ "Miller Fisher syndrome (MFS), a variant of Guillain-Barré syndrome, is a rare disorder typically characterized by a triad of ataxia, areflexia, and ophthalmoplegia, which may have a highly variable clinical presentation. We report a case of MFS in a 45-year-old female presenting with sphenoid sinusitis and sixth nerve palsy. She underwent endoscopic sphenoid sinusotomy without improvement, had postoperative deterioration, was diagnosed with MFS, and was treated with intravenous immunoglobulin with complete response. Because of the potential severity of Guillain-Barré syndrome, great vigilance should be taken when examining sixth nerve palsies to prevent misdiagnosis and delay in treatment of the MFS variant of this disease.", "Ankylosing spondylitis (AS) and axial spondyloarthritis (ax SpA) are chronic inflammatory diseases mainly involving the axial skeleton. Pharmacological treatments for AS and ax SpA usually include local glucocorticoid injections, NSAIDs and anti-TNFα agents. Since around 30% to 40% of patients are non responders or intolerant to anti-TNFα agents, we need new therapeutic options for AS and ax SpA. Areas covered: This review describes the new biological agents that can be used or are in development for AS or ax SpA as well as emerging synthetic targeted drugs. Expert opinion: Based on the rationale of the involvement of the IL-23/Th17 axis in AS, novel biological agents have been developed and include secukinumab, an anti-IL-17A agent and ustekinumab, an anti-IL-23 antibody. New compounds in the class of synthetic drugs are apremilast, a PDE4 inhibitor, and inhibitors of kinase pathways. Secukinumab gave positive results in the treatment of AS. Ustekinumab yielded promising results in AS in an open labeled study. Apremilast is not effective in AS while results with kinase inhibitors are preliminary. Future studies will clarify the place of secukinumab in the therapeutic management of AS, its influence on radiographic progression and its effects on the non radiographic form of the disease.", "PURPOSE OF REVIEW: Prevention of stroke and systemic emboli is paramount in the management of atrial fibrillation. Although warfarin is the predominant anticoagulant used in patients with atrial fibrillation, it has significant limitations that have impeded appropriate use of stroke prophylaxis in eligible patients with atrial fibrillation. Consequently, much research has been focused on finding an alternative to warfarin. We review the potential alternatives in development and evaluate the current evidence concerning their safety and efficacy.RECENT FINDINGS: Oral direct factor Xa inhibitors are potentially well tolerated and effective replacements for warfarin. These agents do not require cofactors and offer selective inhibition at a critical step of amplification in the coagulation cascade. Multiple direct anti-factor Xa agents are currently undergoing evaluation in phase I, II, and III trials. Early results suggest that these novel anticoagulants have favorable pharmacokinetic and pharmacodynamic profiles with minimal-to-no requirements for therapeutic monitoring. Two direct factor Xa inhibitors are emerging from phase II trials (betrixaban and YM150) and three are being evaluated in phase III trials (apixaban, edoxaban, and rivaroxaban) for the prevention of stroke and systemic emboli in patients with atrial fibrillation. The phase III trials of apixaban and rivaroxaban have completed enrollment and are in the follow-up phase.SUMMARY: Given the growing population of patients with atrial fibrillation, there is a great interest in finding new therapies for oral anticoagulation. The direct factor Xa inhibitors may offer several promising alternatives to warfarin therapy.", "Formation of mRNA 3' termini involves cleavage of an mRNA precursor and polyadenylation of the newly formed end. Cleavage of simian virus 40 late pre-mRNA in a crude nuclear extract generated two RNAs, 5' and 3' half-molecules. These RNAs were unmodified and linear. The 5' half-molecule contained sequences upstream but not downstream of the poly(A) site and ended in a 3'-terminal hydroxyl. The 3' half-molecules comprised a family of RNAs, each of which contains only sequences downstream of the poly(A) site, and ends in a 5'-terminal phosphate. These RNAs differed only in the locations of their 5' terminus. The 3' terminus of the 5' half-molecule was the adenosine 10 nucleotides downstream of AAUAAA, at the +1 position. The 5' terminus of the longest 3' half-molecule was at +2. Thus, these two RNAs contain every nucleoside and phosphate of the precursor. The existence of these half-molecules demonstrates that endonucleolytic cleavage occurs near the poly(A) site. 5' half-molecules generated in the presence of EDTA (which blocks polyadenylation, but not cleavage) ended at the adenosine at position +1 of the precursor. When incubated in the extract under suitable conditions, they became polyadenylated. 5' half-molecules formed in 3'-dATP-containing reactions contained a single 3'-deoxyadenosine (cordycepin) residue added onto the +1 adenosine and were poor polyadenylation substrates. We infer that the +1 adenosine of the precursor becomes the first A of the poly(A) tract and provides a 3' hydroxyl group to which poly(A) is added posttranscriptionally.", "A 40-year-old woman was admitted for investigation of weakness and angina pectoris. She had generalised weakness of muscles, cold intolerance and a reduced physical performance. A previous neurological examination had already revealed a carpal-tunnel syndrome of the right hand. This syndrome, combined with a rough, cool skin and a periorbital edema, lead to the assumption of hypothyroidism. The diagnosis was confirmed by a combination of very high concentrations of TSH and decreased concentrations of the thyroid hormones. Replacement therapy by oral administration of L-thyroxin resulted in a gradual improvement of the patient's state.", "Alemtuzumab is a humanized monoclonal antibody against CD52, an antigen found on the surface of normal and malignant lymphocytes. It is approved for the treatment of B-cell chronic lymphocytic leukaemia and is undergoing Phase III clinical trials for the treatment of multiple sclerosis. The exact mechanism by which alemtuzumab mediates its biological effects in vivo is not clearly defined and mechanism of action studies have been hampered by the lack of cross-reactivity between human and mouse CD52. To address this issue, a transgenic mouse expressing human CD52 (hCD52) was created. Transgenic mice did not display any phenotypic abnormalities and were able to mount normal immune responses. The tissue distribution of hCD52 and the level of expression by various immune cell populations were comparable to those seen in humans. Treatment with alemtuzumab replicated the transient increase in serum cytokines and depletion of peripheral blood lymphocytes observed in humans. Lymphocyte depletion was not as profound in lymphoid organs, providing a possible explanation for the relatively low incidence of infection in alemtuzumab-treated patients. Interestingly, both lymphocyte depletion and cytokine induction by alemtuzumab were largely independent of complement and appeared to be mediated by neutrophils and natural killer cells because removal of these populations with antibodies to Gr-1 or asialo-GM-1, respectively, strongly inhibited the activity of alemtuzumab whereas removal of complement by treatment with cobra venom factor had no impact. The hCD52 transgenic mouse appears to be a useful model and has provided evidence for the previously uncharacterized involvement of neutrophils in the activity of alemtuzumab.", "BACKGROUND: Facing a growing workload and dwindling resources, the US National Library of Medicine (NLM) created the Indexing Initiative project in 1996. This cross-library team's mission is to explore indexing methodologies for ensuring quality and currency of NLM document collections. The NLM Medical Text Indexer (MTI) is the main product of this project and has been providing automated indexing recommendations since 2002. After all of this time, the questions arise whether MTI is still useful and relevant.METHODS: To answer the question about MTI usefulness, we track a wide variety of statistics related to how frequently MEDLINE indexers refer to MTI recommendations, how well MTI performs against human indexing, and how often MTI is used. To answer the question of MTI relevancy compared to other available tools, we have participated in the 2013 and 2014 BioASQ Challenges. The BioASQ Challenges have provided us with an unbiased comparison between the MTI system and other systems performing the same task.RESULTS: Indexers have continually increased their use of MTI recommendations over the years from 15.75% of the articles they index in 2002 to 62.44% in 2014 showing that the indexers find MTI to be increasingly useful. The MTI performance statistics show significant improvement in Precision (+0.2992) and F1 (+0.1997) with modest gains in Recall (+0.0454) over the years. MTI consistency is comparable to the available indexer consistency studies. MTI performed well in both of the BioASQ Challenges ranking within the top tier teams.CONCLUSIONS: Based on our findings, yes, MTI is still relevant and useful, and needs to be improved and expanded. The BioASQ Challenge results have shown that we need to incorporate more machine learning into MTI while still retaining the indexing rules that have earned MTI the indexers' trust over the years. We also need to expand MTI through the use of full text, when and where it is available, to provide coverage of indexing terms that are typically only found in the full text. The role of MTI at NLM is also expanding into new areas, further reinforcing the idea that MTI is increasingly useful and relevant." ]

[ "The present study provides a survey of the immunolocalization of ionotropic glutamate receptor subunits throughout the rat and cat cerebellar cortex, with emphasis on the unipolar brush cell (UBC), a hitherto neglected cerebellar cell that is densely concentrated in the granular layer of the vestibulocerebellum and that forms giant synapses with mossy fibers. An array of nine previously characterized antibodies has been used, each of which stained a characteristic profile of cerebellar cells. The UBCs of both rat and cat were strongly immunostained by an antibody against the alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) receptor subunits, GluR2 and GluR3; were moderately immunostained by a monoclonal antibody to kainate receptor subunits, GluR5/6/7; were weakly immunostained by antibodies to NR1 subunits; and were not stained by antibodies to GluR1, GluR4, GluR6/7, KA-2, and NR2A/B. Postsynaptic densities of the giant mossy fiber-UBC synapses were GluR2/3, GluR5/6/7, and NR1 immunoreactive. The other cerebellar neurons were all immunolabeled to some extent with the GluR2/3 and NR1 antibodies. In addition, Purkinje cells were immunopositive for GluR1 and GluR5/6/7; granule cells were immunopositive for GluR5/6/7, GluR6/7, KA-2, and NR2A/B. The Golgi-Bergmann glia was densely stained by GluR1 and GluR4 antibodies, whereas astrocytes of the granular layer were stained by the GluR4 antiserum. Data provided herein may guide further electrophysiological and pharmacological studies of cerebellar cells in general and the UBCs in particular.", "A total of 875 nymphal and adult Ixodes ricinus ticks and 148 adult Dermacentor reticulatus ticks were collected by flagging lower vegetation in the Lublin region (eastern Poland) and examined for the presence of RNA of tick-borne encephalitis virus (TBEV) by nested RT-PCR. The minimum infection rate of I. ricinus ticks with TBEV amounted to 1.6% while the infection rate of D. reticulatus ticks was 10.8%. The results suggest that D. reticulatus may be a potential vector of TBEV in Central Europe.", "BACKGROUND: The purpose of this study was to investigate the long-term effects of adalimumab, a tumor necrosis factor alpha antagonist, in the treatment of uveitis associated with juvenile idiopathic arthritis.METHODS: Adalimumab was initiated in 94 patients with juvenile idiopathic arthritis to treat active arthritis and/or active associated uveitis. In 18 patients, therapy was discontinued after a short period because of inefficacy or side effects. The activity of uveitis (using Standardized Uveitis Nomenclature [SUN] criteria and clinical examination) and arthritis (number of swollen or active joints) was evaluated at the start and at end of the study.RESULTS: At the end of the study, uveitis was under good clinical control in two thirds of 54 patients (31% did not need any local treatment and 35% used only 1-2 corticosteroid drops a day), and one third had active uveitis (at least three corticosteroid drops a day). According to SUN criteria, adalimumab treatment for uveitis showed improved activity (a two-fold decrease in uveitis activity) in 28% of patients, with a moderate response in 16 patients, no change in a further 16 patients, and worsening activity (a two-fold increase in uveitis activity) in 13% of patients. The overall proportion of patients with active arthritis decreased. At the beginning of the study, 69% of patients with uveitis had more than two active joints, and at the end of the study only 27% had active joint disease. In 27 patients with juvenile idiopathic arthritis without uveitis on adalimumab, the number of active joints decreased from 93% to 59%. Systemic corticosteroid treatment could be stopped in 22% of patients with uveitis and in 11% of those without uveitis. Most of the patients had received methotrexate, other immunosuppressive therapy, or other biological drugs before initiating adalimumab.CONCLUSION: Adalimumab is a valuable option in the treatment of uveitis associated with active juvenile idiopathic arthritis.", "A device for measuring human breath ammonia was developed based on a single use, disposable, inkjet printed ammonia sensor fabricated using polyaniline nanoparticles. The device was optimized for sampling ammonia in human breath samples by addressing issues such as variations in breath sample volume, flow rate, sources of oral ammonia, temperature and humidity. The resulting system was capable of measuring ammonia in breath from 40 to 2993 ppbv (r(2 )= 0.99, n = 3) as correlated with photoacoustic laser spectroscopy and correlation in normal human breath samples yielded a slope of 0.93 and a Pearson correlation coefficient of 0.9705 (p < 0.05, n = 11). Measurement of ammonia in the breath of patients with end-stage kidney disease demonstrated its significant reduction following dialysis, while also correlating well with blood urea nitrogen (BUN) (r = 0.61, p < 0.01, n = 96). Excellent intraindividual correlations were demonstrated between breath ammonia and BUN (0.86 to 0.96), which demonstrates the possibility of using low cost point of care breath ammonia systems as a noninvasive means of monitoring kidney dysfunction and treatment.", "BACKGROUND: Mirabegron is the first β3-adrenoceptor agonist that is clinically effective for overactive bladder.OBJECTIVE: The effects of mirabegron on primary bladder mechanosensitive single-unit afferent activities (SAAs) and bladder microcontractions were evaluated and compared with the effects of oxybutynin.DESIGN, SETTING, AND PARTICIPANTS: Female Sprague-Dawley rats were anesthetized. The SAAs generated from left L6 dorsal roots were identified by electrical stimulation of the left pelvic nerve and bladder distension. Nerves with conduction velocities (CVs) >2.5 m/s were designated as Aδ-fibers, and nerves with CVs<2.5 m/s were designated as C-fibers.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Two measurements were performed in separate animals. First, after measuring the baselines of SAA during constant filling cystometry, the procedure was repeated with each intravenous administration of mirabegron at three doses-0.1, 0.3, and 1.0mg/kg-cumulatively. Second, the bladder was filled with saline until the intravesical pressure reached 30 cm H(2)O and was kept under an isovolumetric condition; then the recording was performed for 5 min with vehicle and mirabegron or oxybutynin administrated intravenously.RESULTS AND LIMITATIONS: A total of 74 single-unit afferent fibers were isolated from 55 rats (Aδ-fibers: n=34; C-fibers: n=40). SAAs of both Aδ-fibers and C-fibers in response to bladder filling significantly decreased after mirabegron administration in a dose-dependent manner, which was more remarkable for Aδ-fibers. During an isovolumetric condition of the bladder, the mean bladder pressure and the number of microcontractions decreased after mirabegron administration, whereas these parameters did not change with oxybutynin administration. SAAs of Aδ-fibers were significantly decreased by mirabegron administration at both 0.3 and 1mg/kg, whereas SAAs of C-fibers decreased only at 1mg/kg. In contrast, oxybutynin (1mg/kg) did not alter either type of SAA.CONCLUSIONS: The present study demonstrates that mirabegron can inhibit mechanosensitive bladder afferent activity, especially of Aδ-fibers, which may be related to suppression of bladder microcontractions.", "BACKGROUND: Strimvelis (autologous CD34+ cells transduced to express adenosine deaminase [ADA]) is the first ex vivo stem cell gene therapy approved by the European Medicines Agency (EMA), indicated as a single treatment for patients with ADA-severe combined immunodeficiency (ADA-SCID) who lack a suitable matched related bone marrow donor. Existing primary immunodeficiency registries are tailored to transplantation outcomes and do not capture the breadth of safety and efficacy endpoints required by the EMA for the long-term monitoring of gene therapies. Furthermore, for extended monitoring of Strimvelis, the young age of children treated, small patient numbers, and broad geographic distribution of patients all increase the risk of loss to follow-up before sufficient data have been collected. Establishing individual investigator sites would be impractical and uneconomical owing to the small number of patients from each location receiving Strimvelis.RESULTS: An observational registry has been established to monitor the safety and effectiveness of Strimvelis in up to 50 patients over a minimum of 15 years. To address the potential challenges highlighted above, data will be collected by a single investigator site at Ospedale San Raffaele (OSR), Milan, Italy, and entered into the registry via a central electronic platform. Patients/families and the patient's local physician will also be able to submit healthcare information directly to the registry using a uniquely designed electronic platform. Data entry will be monitored by a Gene Therapy Registry Centre (funded by GlaxoSmithKline) who will ensure that necessary information is collected and flows between OSR, the patient/family and the patient's local healthcare provider.CONCLUSION: The Strimvelis registry sets a precedent for the safety monitoring of future gene therapies. A unique, patient-focused design has been implemented to address the challenges of long-term follow-up of patients treated with gene therapy for a rare disease. Strategies to ensure data completeness and patient retention in the registry will help fulfil pharmacovigilance requirements. Collaboration with partners is being sought to expand from a treatment registry into a disease registry. Using practical and cost-efficient approaches, the Strimvelis registry is hoped to encourage further innovation in registry design within orphan drug development.", "During the past decade, DNA sequencing output has been mostly dominated by the second generation sequencing platforms which are characterized by low cost, high throughput and shorter read lengths for example, Illumina. The emergence and development of so called third generation sequencing platforms such as PacBio has permitted exceptionally long reads (over 20 kb) to be generated. Due to read length increases, algorithm improvements and hybrid assembly approaches, the concept of one chromosome, one contig and automated finishing of microbial genomes is now a realistic and achievable task for many microbial laboratories. In this paper, we describe high quality sequence datasets which span three generations of sequencing technologies, containing six types of data from four NGS platforms and originating from a single microorganism, Clostridium autoethanogenum. The dataset reported here will be useful for the scientific community to evaluate upcoming NGS platforms, enabling comparison of existing and novel bioinformatics approaches and will encourage interest in the development of innovative experimental and computational methods for NGS data." ]

[ "There is no single test that is diagnostic of MS, including MRI. The lesions detected with MRI are pathologically nonspecific. The principles of MS diagnosis are based on showing dissemination of white matter lesions in space and time. MRI is the most sensitive method for revealing asymptomatic dissemination of lesions in space and time. The pattern and evolution of MRI lesions, in the appropriate clinical setting, has made MRI abnormalities invaluable criteria for the early diagnosis of MS. The first important role for MRI in the diagnosis of MS allows for an early diagnosis of MS for CIS patients using the IP diagnostic criteria, including MRI for dissemination in space (DIS) and time (DIT). The sensitivity of diagnosing MS within the first year after a single attack is 94%, with a specificity of 83%. The MRI evidence required to support the diagnosis varies, depending on the strength of the clinical findings. Allowing a new MRI lesion to substitute for a clinical attack doubles the number of CIS patients who can be diagnosed as having MS within 1 year of symptom onset. Increasing the sensitivity of the test with more lenient criteria, as recommended by the AAN subcommittee, can result in decreased specificity. The second important role for MRI in the diagnostic work-up of suspected MS patients is to rule out alternative diagnoses obvious on MRI, such as spinal stenosis and most brain tumors. Characteristic lesions that favor MS include Dawson Fingers, ovoid lesions, corpus callosum lesions, and asymptomatic spinal cord lesions. However, other white matter diseases can have similar appearances on MRI. Persistent gadolinium enhancement greater than three months, lesions with mass effect, and meningeal enhancement suggest other disorders. A standardized MRI protocol for brain and spinal cord is crucial for comparing across studies or between centers. T2W MRI cannot distinguish between acute and chronic lesions. Gadolinium provides useful information about new lesion activity and is helpful in ruling out alternative diagnoses such as neoplasm, vascular malformations, and leptomeningeal disease. A single gadolinium-enhanced MRI can potentially provide evidence for dissemination in space and time. Spinal cord imaging is equally valuable to rule out spinal stenosis or tumor, and for detecting asymptomatic lesions when brain imaging is nondiagnostic in patients suspected of having MS. Precise criteria may be too suggestive that MS can be diagnosed by MRI and a negative MRI at the time of CIS does not rule out MS. MRI evidence plays a supportive role in what is ultimately a clinical diagnosis of MS, in the appropriate clinical situation, and always at the exclusion of alternative diagnoses.", "Cerliponase alfa (Brineura™) is a recombinant human tripeptidyl peptidase-1 (TPP1) being developed by BioMarin Pharmaceutical Inc. for use in patients with neuronal ceroid lipofuscinosis type 2 (CLN2), a paediatric neurodegenerative disease caused by a deficiency in TPP1. CLN2 is characterised by progressive impairment of motor function, language deficiencies, seizures, ataxia, blindness and early death, and intracerebroventricular infusion of cerliponase alfa has been shown to reduce the progression of functional decline. This article summarizes the milestones in the development of cerliponase alfa leading to its first global approval in the USA for the treatment of motor function loss in paediatric patients ≥3 years of age with CLN2, and subsequent approval in the EU for CLN2 in all ages.", "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.", "Recurrences of Clostridium difficile infections lead to hospital readmissions and high costs, in addition to the suffering and frustration for the patients. Fidaxomicin has recently been introduced as a new antibiotic that has been shown to significantly reduce the recurrence of this infection. Despite this superiority, its high cost has led to very restrictive policies in its use, as such that many institutions only use it in patients with multiple recurrences. While waiting for new predictive clinical tools, we propose the development of scoring systems that allow the more high-risk patients to be treated earlier.", "Since its discovery 40 years ago, rotavirus (RV) is considered to be a major cause of infant and childhood morbidity and mortality particularly in developing countries. Nearly every child in the world under 5 years of age is at the risk of RV infection. It is estimated that 90% of RV-associated mortalities occur in developing countries of Africa and Asia. Two live oral vaccines, RotaTeq (RV5, Merck) and Rotarix (RV1, GlaxoSmithKline) have been successfully deployed to scale down the disease burden in Europe and America, but they are less effective in Africa and Asia. In April 2009, the World Health Organization recommended the inclusion of RV vaccination in national immunization programs of all countries with great emphasis in developing countries. To date, 86 countries have included RV vaccines into their national immunization programs including 41 Global Alliance for Vaccines and Immunization eligible countries. The predominant RV genotypes circulating all over the world are G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8], while G12[P6] and G12[P8] are emerging genotypes. On account of the segmented genome, RV shows an enormous genetic diversity that leads to the evolution of new genotypes that can influence the efficacy of current vaccines. The current need is for a global RV surveillance program to monitor the prevalence and antigenic variability of new genotypes to formulate future vaccine development planning. In this review, we will summarize the previous and recent insights into RV structure, classification, and epidemiology and current status of RV vaccination around the globe and will also cover the status of RV research and vaccine policy in Pakistan.", "BACKGROUND AND GOALS: Fidaxomicin is a new antibiotic used to treat Clostridium difficile infection (CDI). Given limited clinical experience with fidaxomicin, we assessed outcomes in a diverse cohort of patients with CDI treated with fidaxomicin.STUDY: All CDI cases treated with fidaxomicin at 3 referral centers over a 4-year period were included. Response was defined as resolution of diarrhea and recurrence was defined by recurrence of CDI within 8 weeks of the end of treatment.RESULTS: Overall, 81 patients (median age 55.9 y; 53% female; 26% with inflammatory bowel disease) were included. Response occurred in 90%. Responders had fewer prior CDI episodes [median 1 (range, 0 to 8)] than nonresponders [median 2.5 (range, 1 to 8)], P=0.01. Response after a first CDI episode was 100%, 96% after 1 prior episode, and 82% after 2 or more, P=0.02. Recurrence occurred in 19%. Patients without recurrence had fewer prior episodes of CDI [median 1 (range, 0 to 6)] than patients who recurred [median 2 (range, 1 to 8)], P=0.005. Recurrence after a first episode was 0%, 23% after 1 prior episode, and 29% after 2 or more, P=0.005. All patients with inflammatory bowel disease responded either with improvement of symptoms or a negative C. difficile test; 19% recurred.CONCLUSIONS: All patients with a first CDI episode treated with fidaxomicin responded with no recurrences. Patients with prior CDI episodes were less likely to respond (especially with more than 1 prior episode) and more likely to recur, suggesting a greater clinical benefit of fidaxomicin earlier in the course of CDI.", "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.", "Selenocysteine (Sec), a rare genetically encoded amino acid with unusual chemical properties, is of great interest for protein engineering. Sec is synthesized on its cognate tRNA (tRNASec) by the concerted action of several enzymes. While all other aminoacyl-tRNAs are delivered to the ribosome by the elongation factor Tu (EF-Tu), Sec-tRNASec requires a dedicated factor, SelB. Incorporation of Sec into protein requires recoding of the stop codon UGA aided by a specific mRNA structure, the SECIS element. This unusual biogenesis restricts the use of Sec in recombinant proteins, limiting our ability to study the properties of selenoproteins. Several methods are currently available for the synthesis selenoproteins. Here we focus on strategies for in vivo Sec insertion at any position(s) within a recombinant protein in a SECIS-independent manner: (i) engineering of tRNASec for use by EF-Tu without the SECIS requirement, and (ii) design of a SECIS-independent SelB route." ]

[ "Polycomb group (PcG) proteins are essential to maintain gene expression patterns during development. Transcriptional repression by PcG proteins involves trimethylation of H3K27 (H3K27me3) by Polycomb Repressive Complex 2 (PRC2) in animals and plants. PRC1 binds to H3K27me3 and is required for transcriptional repression in animals, but in plants PRC1-like activities have remained elusive. One candidate protein that could be involved in PRC1-like functions in plants is LIKE HETEROCHROMATIN PROTEIN 1 (LHP1), because LHP1 associates with genes marked by H3K27me3 in vivo and has a chromodomain that binds H3K27me3 in vitro. Here, we show that disruption of the chromodomain of Arabidopsis thaliana LHP1 abolishes H3K27me3 recognition, releases gene silencing and causes similar phenotypic alterations as transcriptional lhp1 null mutants. Therefore, binding to H3K27me3 is essential for LHP1 protein function.", "AIMS: To assess safety, pharmacokinetics (PK) and clinical efficacy of bimekizumab (formerly UCB4940), a novel humanized monoclonal antibody and dual inhibitor of interleukin (IL)-17A and IL-17F, in subjects with mild plaque psoriasis.METHODS: Randomized, double-blind, first-in-human study of bimekizumab in 39 subjects who received single-dose intravenous bimekizumab (8-640 mg) or placebo (NCT02529956).RESULTS: Bimekizumab demonstrated dose-proportional linear PK and was tolerated across the dose range assessed. No subject discontinued due to treatment-emergent adverse events and no severe adverse events were reported. Bimekizumab demonstrated fast onset of clinically-meaningful effects on skin of patients with mild psoriasis as early as Week 2. Maximal improvements (100% or near 100% reductions from baseline) in all measures of disease activity were observed between Weeks 8-12 in subjects receiving 160-640 mg bimekizumab. The duration of effect at doses ≥160 mg was evident up to Weeks 12-20 after a single intravenous dose, dependent on endpoint.CONCLUSIONS: This is the first study to demonstrate the safety, tolerability and clinical efficacy of a dual IL-17A and IL-17F inhibitor, in subjects with mild psoriasis. Bimekizumab showed fast onset of clinically-meaningful efficacy by Week 2, with a maximal or near-maximal magnitude of response that was maintained up to study Weeks 12-20. These findings support the continued clinical development of bimekizumab for diseases mediated by both IL-17A and IL-17F, including psoriasis.", "The expression of selenoproteins requires the translational recoding of the UGA stop codon to selenocysteine. In eukaryotes, this requires an RNA stem loop structure in the 3'-untranslated region, termed a selenocysteine insertion sequence (SECIS), and SECIS-binding protein 2 (SBP2). This study implicates SBP2 in dictating the hierarchy of selenoprotein expression, because it is the first to show that SBP2 distinguishes between SECIS elements in vitro. Using RNA electrophoretic mobility shift assays, we demonstrate that a naturally occurring mutation in SBP2, which correlates with abnormal thyroid hormone function in humans, lies within a novel, bipartite RNA-binding domain. This mutation alters the RNA binding affinity of SBP2 such that it no longer stably interacts with a subset of SECIS elements. Assays performed under competitive conditions to mimic intracellular conditions suggest that the differential affinity of SBP2 for various SECIS elements will determine the expression pattern of the selenoproteome. We hypothesize that the selective loss of a subset of selenoproteins, including some involved in thyroid hormone homeostasis, is responsible for the abnormal thyroid hormone metabolism previously observed in the affected individuals.", "MLN4924 is an investigational small-molecule inhibitor of the Nedd8-activating enzyme currently in phase I clinical trials. MLN4924 induces DNA damage via rereplication in most cell lines. This distinct mechanism of DNA damage may affect its ability to combine with standard-of-care agents and may affect the clinical development of MLN4924. As such, we studied its interaction with other DNA-damaging agents. Mitomycin C, cisplatin, cytarabine, UV radiation, SN-38, and gemcitabine demonstrated synergy in combination with MLN4924 in vitro. The combination of mitomycin C and MLN4924 was shown to be synergistic in a mouse xenograft model. Importantly, depletion of genes within the ataxia telangiectasia and Rad3 related (ATR) and BRCA1/BRCA2 pathways, chromatin modification, and transcription-coupled repair reduced the synergy between mitomycin C and MLN4924. In addition, comet assay demonstrated increased DNA strand breaks with the combination of MLN4924 and mitomycin C. Our data suggest that mitomycin C causes stalled replication forks, which when combined with rereplication induced by MLN4924 results in frequent replication fork collisions, leading to cell death. This study provides a straightforward approach to understand the mechanism of synergy, which may provide useful information for the clinical development of these combinations.", "The multiunit Cullin (CUL)-RING E3 ligase (CRL) controls diverse biological processes by targeting a mass of substrates for ubiquitination and degradation, whereas its dysfunction causes carcinogenesis. Post-translational neddylation of CUL, a process triggered by the NEDD8-activating enzyme E1 subunit 1 (NAE1), is required for CRL activation. Recently, MLN4924 was discovered via a high-throughput screen as a specific NAE1 inhibitor and first-in-class anticancer drug. By blocking CUL neddylation, MLN4924 inactivates CRL and causes the accumulation of CRL substrates that trigger cell cycle arrest, senescence and/or apoptosis to suppress the growth of cancer cells in vitro and in vivo. Recently, we found that MLN4924 also triggers protective autophagy in response to CRL inactivation. MLN4924-induced autophagy is attributed partially to the inhibition of mechanistic target of rapamycin (also known as mammalian target of rapamycin, MTOR) activity by the accumulation of the MTOR inhibitory protein DEPTOR, as well as reactive oxygen species (ROS)-induced stress. Moreover, the blockage of autophagy response enhances apoptosis in MLN4924-treated cells. Together, our findings not only reveal autophagy as a novel cellular response to CRL inactivation by MLN4924, but also provide a piece of proof-of-concept evidence for the combination of MLN4924 with autophagy inhibitors to enhance therapeutic efficacy.", "Author information:(1)Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China.(2)Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.(3)Department of Medical Biochemistry and Cell Biology, University of Gothenburg, PO Box 440, Gothenburg 405 30, Sweden.(4)Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden.(5)Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27514, USA.(6)Proteomics Core Facility, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.(7)Harry Perkins Institute of Medical Research and ARC Centre of Excellence in Synthetic Biology, Nedlands, WA 6009, Australia.(8)Telethon Kids Institute, Northern Entrance, Perth Children's Hospital, 15 Hospital Avenue, Nedlands, WA, Australia.(9)Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.(10)IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy.(11)Wellcome Centre for Mitochondrial Research, Biosciences Institute, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.(12)Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden. nils-goran.larsson@ki.se maria.falkenberg@medkem.gu.se.(13)Department of Medical Biochemistry and Cell Biology, University of Gothenburg, PO Box 440, Gothenburg 405 30, Sweden. nils-goran.larsson@ki.se maria.falkenberg@medkem.gu.se.", "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.", "Etanercept is a dimeric genetic recombinant glycoprotein consisting of Fc domain of human Immunoglobulin G1 and the extracellular domain of human tumor necrosis factor (TNF) receptor type II. Etanercept exerts therapeutic effects on inflammatory diseases such as rheumatoid arthritis and juvenile idiopathic arthritis by neutralizing biological activities of TNFα/Lymphotoxin (LT) α. Mochida Pharmaceutical and LG Chem have developed syringe, pen, and vial products of Etanercept BS (biosimilar) as the first biosimilar of Enbrel in Japan. The active ingredient of those products \"Etanercept biosimilar 1\" has the identical primary structure to that of Enbrel. The development of the Etanercept BS, including evaluations of quality attributes, nonclinical and clinical studies was performed in accordance with \"Policies on Assurance of Quality, Safety and Efficacy of Biosimilars\". The quality attributes of Etanercept BS were similar to those of Enbrel, and the binding affinities to TNFα/LTα, TNFα neutralizing activity, nonclinical pharmacokinetics and toxicological profiles of Etanercept BS were comparable to Enbrel. Additionally, the pharmacokinetic profile and efficacy of Etanercept BS were equivalent to those of Enbrel and there was no clinically significant difference in safety profiles between them in Phase I and Phase III clinical studies. The marketing approval application of the Etanercept BS with the same indications as Enbrel filed by Mochida Pharmaceutical was approved in January 2018 and the products will be launched by Ayumi Pharmaceutical in the near future. The Etanercept BS, which is as highly effective as Enbrel is expected to make beneficial therapies more easily accessible to patients.", "BACKGROUND: Metastatic castration-resistant prostate cancer is enriched in DNA damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively validate the association between DDR gene aberrations and response to olaparib in metastatic castration-resistant prostate cancer.METHODS: In this open-label, investigator-initiated, randomised phase 2 trial following a selection (or pick-the-winner) design, we recruited participants from 17 UK hospitals. Men aged 18 years or older with progressing metastatic castration-resistant prostate cancer previously treated with one or two taxane chemotherapy regimens and with an Eastern Cooperative Oncology Group performance status of 2 or less had tumour biopsies tested with targeted sequencing. Patients with DDR gene aberrations were randomly assigned (1:1) by a computer-generated minimisation method, with balancing for circulating tumour cell count at screening, to receive 400 mg or 300 mg olaparib twice daily, given continuously in 4-week cycles until disease progression or unacceptable toxicity. Neither participants nor investigators were masked to dose allocation. The primary endpoint of confirmed response was defined as a composite of all patients presenting with any of the following outcomes: radiological objective response (as assessed by Response Evaluation Criteria in Solid Tumors 1.1), a decrease in prostate-specific antigen (PSA) of 50% or more (PSA50) from baseline, or conversion of circulating tumour cell count (from ≥5 cells per 7·5 mL blood at baseline to <5 cells per 7·5 mL blood). A confirmed response in a consecutive assessment after at least 4 weeks was required for each component. The primary analysis was done in the evaluable population. If at least 19 (43%) of 44 evaluable patients in a dose cohort responded, then the dose cohort would be considered successful. Safety was assessed in all patients who received at least one dose of olaparib. This trial is registered at ClinicalTrials.gov, NCT01682772. Recruitment for the trial has completed and follow-up is ongoing.FINDINGS: 711 patients consented for targeted screening between April 1, 2015, and Aug 30, 2018. 161 patients had DDR gene aberrations, 98 of whom were randomly assigned and treated (49 patients for each olaparib dose), with 92 evaluable for the primary endpoint (46 patients for each olaparib dose). Median follow-up was 24·8 months (IQR 16·7-35·9). Confirmed composite response was achieved in 25 (54·3%; 95% CI 39·0-69·1) of 46 evaluable patients in the 400 mg cohort, and 18 (39·1%; 25·1-54·6) of 46 evaluable patients in the 300 mg cohort. Radiological response was achieved in eight (24·2%; 11·1-42·3) of 33 evaluable patients in the 400 mg cohort and six (16·2%; 6·2-32·0) of 37 in the 300 mg cohort; PSA50 response was achieved in 17 (37·0%; 23·2-52·5) of 46 and 13 (30·2%; 17·2-46·1) of 43; and circulating tumour cell count conversion was achieved in 15 (53·6%; 33·9-72·5) of 28 and 13 (48·1%; 28·7-68·1) of 27. The most common grade 3-4 adverse event in both cohorts was anaemia (15 [31%] of 49 patients in the 300 mg cohort and 18 [37%] of 49 in the 400 mg cohort). 19 serious adverse reactions were reported in 13 patients. One death possibly related to treatment (myocardial infarction) occurred after 11 days of treatment in the 300 mg cohort.INTERPRETATION: Olaparib has antitumour activity against metastatic castration-resistant prostate cancer with DDR gene aberrations, supporting the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice.FUNDING: Cancer Research UK, AstraZeneca, Prostate Cancer UK, the Prostate Cancer Foundation, the Experimental Cancer Medicine Centres Network, and the National Institute for Health Research Biomedical Research Centres.", "Cisplatin-like chemotherapeutics cause vomiting via calcium (Ca2+)-dependent release of multiple neurotransmitters (dopamine, serotonin, substance P, etc.) from the gastrointestinal enterochromaffin cells and/or the brainstem. Intracellular Ca2+ signaling is triggered by activation of diverse emetic receptors (including tachykininergic NK1, serotonergic 5-HT3, dopaminergic D2, cholinergic M1, or histaminergic H1), whose activation in vomit-competent species can evoke emesis. Other emetogens such as cisplatin, rotavirus NSP4 protein and bacterial toxins can also induce intracellular Ca2+ elevation. Netupitant is a highly selective neurokinin NK1 receptor (NK1R) antagonist and palonosetron is a selective second-generation serotonin 5-HT3 receptor (5-HT3R) antagonist with a distinct pharmacological profile. An oral fixed combination of netupitant/palonosetron (NEPA; Akynzeo(®)) with >85% antiemetic efficacy is available for use in the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Cannabinoid CB1 receptor agonists possess broad-spectrum antiemetic activity since they prevent vomiting caused by a variety of emetic stimuli including the chemotherapeutic agent cisplatin, 5-HT3R agonists, and D2R agonists. Our findings demonstrate that application of the L-type Ca2+ channel (LTCC) agonist FPL 64176 and the intracellular Ca2+ mobilizing agent thapsigargin (a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor) cause vomiting in the least shrew. On the other hand, blockade of LTCCs by corresponding antagonists (nifedipine or amlodipine) not only provide broad-spectrum antiemetic efficacy against diverse agents that specifically activate emetogenic receptors such as 5-HT3, NK1, D2, and M1 receptors, but can also potentiate the antiemetic efficacy of palonosetron against the non-specific emetogen, cisplatin. In this review, we will provide an overview of Ca2+ involvement in the emetic process; discuss the relationship between Ca2+ signaling and the prevailing therapeutics in control of vomiting; highlight the evidence for Ca2+-signaling blockers/inhibitors in suppressing emetic behavior in the least shrew model of emesis as well as in the clinical setting; and also draw attention to the clinical benefits of Ca2+-signaling blockers/inhibitors in the treatment of nausea and vomiting.", "An oral fixed combination of netupitant/palonosetron (NEPA; Akynzeo(®)) is available for use in the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Netupitant is a highly selective neurokinin-1 receptor antagonist and palonosetron is a serotonin 5-HT3 receptor antagonist with a distinct pharmacological profile. Complete response rates during the delayed, acute and overall phases were significantly higher with single-dose netupitant 300 mg plus palonosetron 0.5 mg than with single-dose palonosetron 0.5 mg in cycle 1 of cisplatin-based highly emetogenic chemotherapy (HEC) in a phase II trial and with single-dose netupitant/palonosetron 300/0.5 mg than with single-dose palonosetron 0.5 mg in cycle 1 of anthracycline-cyclophosphamide (AC) moderately emetogenic chemotherapy (MEC) in a phase III trial; the greater efficacy of netupitant/palonosetron was maintained over repeated cycles of AC MEC in the phase III trial. In another phase III trial, netupitant/palonosetron 300/0.5 mg was effective over repeated cycles of non-AC MEC or HEC. Netupitant/palonosetron was well tolerated, with no cardiac safety concerns. The convenience of administering netupitant/palonosetron as a single dose in a fixed combination has the potential to improve adherence to CINV prevention guidelines. In conclusion, netupitant/palonosetron is an important option to consider in the prevention of acute and delayed CINV in patients receiving MEC or HEC.", "The monoamine oxidase A (MAOA) gene has been suggested as a prime candidate in the pathogenesis of panic disorder. In the present study, DNA methylation patterns in the MAOA regulatory and exon 1/intron 1 region were investigated for association with panic disorder with particular attention to possible effects of gender and environmental factors. Sixty-five patients with panic disorder (44 females, 21 males) and 65 healthy controls were analysed for DNA methylation status at 42 MAOA CpG sites via direct sequencing of sodium bisulfate treated DNA extracted from blood cells. The occurrence of recent positive and negative life events was ascertained. Male subjects showed no or only very minor methylation with some evidence for relative hypomethylation at one CpG site in intron 1 in patients compared to controls. Female patients exhibited significantly lower methylation than healthy controls at 10 MAOA CpG sites in the promoter as well as in exon/intron 1, with significance surviving correction for multiple testing at four CpG sites (p≤0.001). Furthermore, in female subjects the occurrence of negative life events was associated with relatively decreased methylation, while positive life events were associated with increased methylation. The present pilot data suggest a potential role of MAOA gene hypomethylation in the pathogenesis of panic disorder particularly in female patients, possibly mediating a detrimental influence of negative life events. Future studies are warranted to replicate the present finding in independent samples, preferably in a longitudinal design.", "Ledipasvir/sofosbuvir (Harvoni) for hepatitis C virus genotype 1 infection; dulaglutide (Trulicity) for glycemic control in type-2 diabetes; netupitant/palonosetron (Akynzeo) for prevention of nausea and vomiting related to chemotherapy; and naloxegol (Movantik) for opioid-induced constipation in patients with chronic noncancer pain.", "Mass spectrometry based proteomics technologies have allowed for a great progress in identifying disease biomarkers for clinical diagnosis and prognosis. However, they face acute challenges from a data reproducibility standpoint, in that no two independent studies have been found to produce the same proteomic patterns. Such reproducibility issues cause the identified biomarker patterns to lose repeatability and prevent real clinical usage. In this work, we propose a profile biomarker approach to overcome this problem from a machine-learning viewpoint by developing a novel derivative component analysis (DCA). As an implicit feature selection algorithm, derivative component analysis enables the separation of true signals from red herrings by capturing subtle data behaviors and removing system noises from a proteomic profile. We further demonstrate its advantages in disease diagnosis by viewing input data as a profile biomarker. The results from our profile biomarker diagnosis suggest an effective solution to overcoming proteomics data's reproducibility problem, present an alternative method for biomarker discovery in proteomics, and provide a good candidate for clinical proteomic diagnosis.", "Levodopa (LD), in combination with a decarboxylase inhibitor, is a mainstay and the most effective therapeutic agent in the treatment of Parkinson's disease (PD). Unfortunately, during chronic treatment with this agent, ON-OFF phenomena and dyskinesia appear. Despite the many medical treatment options available, unpredictable OFF episodes can still occur and be severe and disabling. A rescue therapy that provides a rapid and predictable ON response for patients with OFF periods would be of great value for such patients. Areas covered: CVT-301 is a self-administered dry powder aerosol inhaled formulation of LD that is being developed as a self-administered treatment for OFF periods. The PK profile of CVT-301, the efficacy, and the safety highlighted in randomized clinical trials will be reviewed. Expert opinion: CVT-301 may offer several potential advantages including increased systemic bioavailability through pulmonary absorption, rapid onset of action, avoidance of first-pass drug metabolism and less plasma-level variability. List of Abbreviations: PD: Parkinson's disease; LD: Levodopa; CD: Carbidopa; AADC: aromatic L-amino acid decarboxylase; IR: immediate-release; FPD: fine particle dose; GI: gastrointestinal; PK: pharmacokinetic; CVs: coefficient of variation; UPDRS: Unified Parkinson's Disease Rating Scale; AEs: adverse events; FEV: forced expiratory volume; FVC: forced vital capacity; DLCO: diffuse lung CO ; tmax: time to maximum concentration.", "CONTEXT: Six transmembrane protein of prostate 2 (STAMP2) is a counterregulator of adipose inflammation and insulin resistance in mice. Our hypothesis was that STAMP2 could be involved in human obesity and insulin resistance.OBJECTIVE: The objective of the study was to elucidate the role of adipose STAMP2 expression in human obesity and insulin resistance.DESIGN: The design was to quantify STAMP2 in human abdominal sc and omental white adipose tissue (WAT), isolated adipocytes, and stroma and in vitro differentiated preadipocytes and relate levels of STAMP2 in sc WAT to clinical and adipocyte phenotypes involved in insulin resistance.PARTICIPANTS: Nonobese and obese women and men (n = 236) recruited from an obesity clinic or through local advertisement.MAIN OUTCOME MEASUREMENT: Clinical measures included body mass index, body fat, total adiponectin, and homeostasis model assessment as measure of overall insulin resistance. In adipocytes we determined cell size, sensitivity of lipolysis and lipogenesis to insulin, adiponectin secretion, and inflammatory gene expression.RESULTS: STAMP2 levels in sc and visceral WAT and adipocytes were increased in obesity (P = 0.0008-0.05) but not influenced by weight loss. Increased WAT STAMP2 levels associated with a high amount of body fat (P = 0.04), high homeostasis model assessment (P = 0.01), and large adipocytes (P = 0.02). Subjects with high STAMP2 levels displayed reduced sensitivity of adipocyte lipogenesis (P = 0.04) and lipolysis (P = 0.03) to insulin but had normal adiponectin levels. WAT STAMP2 levels correlated with expression of the macrophage marker CD68 (P = 0.0006).CONCLUSION: Human WAT STAMP2 associates with obesity and insulin resistance independently of adiponectin, but the role of STAMP2 in obesity and its complications seems different from that in mice." ]

[ "Left ventricular systolic dysfunction is the hallmark pathology in heart failure with reduced ejection fraction. Increasing left ventricular contractility with beta-adrenergic receptor agonists, phosphodiesterase-3 inhibitors, or levosimendan has failed to improve clinical outcomes and, in some situations, increased the risk of sudden cardiac death. Beta-adrenergic receptor agonists and phosphodiesterase-3 inhibitors retain an important role in advanced heart failure. Thus, there remains an unmet need for safe and effective therapies to improve left ventricular systolic function. Two novel cardiac myotropes, omecamtiv mecarbil and danicamtiv, target cardiac myosin to increase left ventricular systolic performance. Neither omecamtiv mecarbil nor danicamtiv affects cardiomyocyte calcium handling, the proposed mechanism underlying the life-threatening arrhythmias associated with cardiac calcitropes and calcium sensitizers. Phase 2 clinical trials have demonstrated that these cardiac myosin activators prolong left ventricular systolic ejection time and promote left ventricular and atrial reverse remodeling. At higher plasma concentrations, these agents may be associated with myocardial ischemia and impaired diastolic function. An ongoing phase 3 clinical trial will estimate the clinical efficacy and safety of omecamtiv mecarbil. An additional study of these agents, which have minimal hemodynamic and renal effects, is warranted in patients with advanced heart failure refractory to guideline-directed neurohormonal blockers.", "Guillain-Barré syndrome (GBS) and its variant, Miller Fisher syndrome (MFS), exist as several clinical subtypes with different neurological features and presentations. Although the typical clinical features of GBS and MFS are well recognized, current classification systems do not comprehensively describe the full spectrum of either syndrome. In this Perspectives article, GBS and MFS are classified on the basis of current understanding of the common pathophysiological profiles of each disease phenotype. GBS is subclassified into classic and localized forms (for example, pharyngeal-cervical-brachial weakness and bifacial weakness with paraesthesias), and MFS is divided into incomplete (for example, acute ophthalmoparesis, acute ataxic neuropathy) and CNS subtypes (Bickerstaff brainstem encephalitis). Diagnostic criteria based on clinical characteristics are suggested for each condition. We believe this approach to be more inclusive than existing systems, and argue that it could facilitate early clinical diagnosis and initiation of appropriate immunotherapy.", "The direct factor Xa inhibitor apixaban (Eliquis(®)) has predictable pharmacodynamics and pharmacokinetics and does not require routine anticoagulation monitoring. This article reviews the efficacy and tolerability of oral apixaban to reduce the risk of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (AF). In the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial in patients with AF and at least one additional risk factor for stroke, apixaban recipients were significantly less likely than warfarin recipients to experience stroke or systemic embolism, major bleeding or death; the beneficial effects of treatment with apixaban versus warfarin were generally maintained across various patient subgroups. Apixaban recipients also had a significantly lower risk of intracranial haemorrhage than warfarin recipients. In the AVERROES (Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients who have Failed or are Unsuitable for Vitamin K Antagonist Therapy) trial in patients with AF and at least one additional risk factor for stroke for whom vitamin K antagonist therapy was unsuitable, apixaban was associated with a significantly lower risk of stroke or systemic embolism than aspirin, without an increase in the risk of major bleeding. In conclusion, although longer-term efficacy and safety data are needed, apixaban is an important new option for use in patients with nonvalvular AF to reduce the risk of stroke or systemic embolism.", "CONTEXT: Although vitamin deficiency is encountered infrequently in developed countries, inadequate intake of several vitamins is associated with chronic disease.OBJECTIVE: To review the clinically important vitamins with regard to their biological effects, food sources, deficiency syndromes, potential for toxicity, and relationship to chronic disease.DATA SOURCES AND STUDY SELECTION: We searched MEDLINE for English-language articles about vitamins in relation to chronic diseases and their references published from 1966 through January 11, 2002.DATA EXTRACTION: We reviewed articles jointly for the most clinically important information, emphasizing randomized trials where available.DATA SYNTHESIS: Our review of 9 vitamins showed that elderly people, vegans, alcohol-dependent individuals, and patients with malabsorption are at higher risk of inadequate intake or absorption of several vitamins. Excessive doses of vitamin A during early pregnancy and fat-soluble vitamins taken anytime may result in adverse outcomes. Inadequate folate status is associated with neural tube defect and some cancers. Folate and vitamins B(6) and B(12) are required for homocysteine metabolism and are associated with coronary heart disease risk. Vitamin E and lycopene may decrease the risk of prostate cancer. Vitamin D is associated with decreased occurrence of fractures when taken with calcium.CONCLUSIONS: Some groups of patients are at higher risk for vitamin deficiency and suboptimal vitamin status. Many physicians may be unaware of common food sources of vitamins or unsure which vitamins they should recommend for their patients. Vitamin excess is possible with supplementation, particularly for fat-soluble vitamins. Inadequate intake of several vitamins has been linked to chronic diseases, including coronary heart disease, cancer, and osteoporosis", "Sequence-dependent DNA flexibility is an important structural property originating from the DNA 3D structure. In this paper, we investigate the DNA flexibility of the budding yeast (S. Cerevisiae) replication origins on a genome-wide scale using flexibility parameters from two different models, the trinucleotide and the tetranucleotide models. Based on analyzing average flexibility profiles of 270 replication origins, we find that yeast replication origins are significantly rigid compared with their surrounding genomic regions. To further understand the highly distinctive property of replication origins, we compare the flexibility patterns between yeast replication origins and promoters, and find that they both contain significantly rigid DNAs. Our results suggest that DNA flexibility is an important factor that helps proteins recognize and bind the target sites in order to initiate DNA replication. Inspired by the role of the rigid region in promoters, we speculate that the rigid replication origins may facilitate binding of proteins, including the origin recognition complex (ORC), Cdc6, Cdt1 and the MCM2-7 complex.", "CONTEXT: The iodothyronine deiodinases D1, D2, and D3 enable tissue-specific adaptation of thyroid hormone levels in response to various conditions, such as hypothyroidism or fasting. The possible expression of D2 mRNA in skeletal muscle is intriguing because this enzyme could play a role in systemic as well as local T3 production.OBJECTIVE: We determined D2 activity and D2 mRNA expression in human skeletal muscle biopsies under control conditions and during hypothyroidism, fasting, and hyperinsulinemia.DESIGN: This was a prospective study.SETTING: The study was conducted at a university hospital.PATIENTS: We studied 11 thyroidectomized patients with differentiated thyroid carcinoma (DTC) on and after 4 wk off T4( replacement and six healthy lean subjects in the fasting state and during hyperinsulinemia after both 14 and 62 h of fasting.MEAN OUTCOME MEASURES: D2 activity and D2 mRNA levels were measured in skeletal muscle samples.RESULTS: No differences were observed in muscle D2 mRNA levels in DTC patients on and off T4 replacement therapy. In healthy subjects, muscle D2 mRNA levels were lower after 62 h compared to 14 h of fasting. Insulin increased mRNA expression after 62 h, but not after 14 h of fasting. Skeletal muscle D2 activities were very low and not influenced by hypothyroidism and fasting.CONCLUSION: Human skeletal muscle D2 mRNA expression is modulated by fasting and insulin, but not by hypothyroidism. The lack of a clear effect of D2 mRNA modulation on the observed low D2 activities questions the physiological relevance of D2 activity in human skeletal muscle.", "PURPOSE: Hodgkin lymphoma (HL) survivors have an increased risk of cardiovascular disease (CD), lung cancer, and breast cancer. We investigated the risk for the development of CD and secondary lung, breast, and thyroid cancer after radiation therapy (RT) delivered with deep inspiration breath-hold (DIBH) compared with free-breathing (FB) using 3-dimensional conformal RT (3DCRT) and intensity modulated RT (IMRT). The aim of this study was to determine which treatment modality best reduced the combined risk of life-threatening late effects in patients with mediastinal HL.METHODS AND MATERIALS: Twenty-two patients with early-stage mediastinal HL were eligible for the study. Treatment plans were calculated with both 3DCRT and IMRT on both DIBH and FB planning computed tomographic scans. We reported the estimated dose to the heart, lung, female breasts, and thyroid and calculated the estimated life years lost attributable to CD and to lung, breast, and thyroid cancer.RESULTS: DIBH lowered the estimated dose to heart and lung regardless of delivery technique (P<.001). There was no significant difference between IMRT-FB and 3DCRT-DIBH in mean heart dose, heart V20Gy, and lung V20Gy. The mean breast dose was increased with IMRT regardless of breathing technique. Life years lost was lowest with DIBH and highest with FB.CONCLUSIONS: In this cohort, 3DCRT-DIBH resulted in lower estimated doses and lower lifetime excess risks than did IMRT-FB. Combining IMRT and DIBH could be beneficial for a subgroup of patients." ]

[ "MOTIVATION: Gene regulation is inherently stochastic. In many applications concerning Systems and Synthetic Biology such as the reverse engineering and the de novo design of genetic circuits, stochastic effects (yet potentially crucial) are often neglected due to the high computational cost of stochastic simulations. With advances in these fields there is an increasing need of tools providing accurate approximations of the stochastic dynamics of gene regulatory networks (GRNs) with reduced computational effort.RESULTS: This work presents SELANSI (SEmi-LAgrangian SImulation of GRNs), a software toolbox for the simulation of stochastic multidimensional gene regulatory networks. SELANSI exploits intrinsic structural properties of gene regulatory networks to accurately approximate the corresponding Chemical Master Equation with a partial integral differential equation that is solved by a semi-lagrangian method with high efficiency. Networks under consideration might involve multiple genes with self and cross regulations, in which genes can be regulated by different transcription factors. Moreover, the validity of the method is not restricted to a particular type of kinetics. The tool offers total flexibility regarding network topology, kinetics and parameterization, as well as simulation options.AVAILABILITY AND IMPLEMENTATION: SELANSI runs under the MATLAB environment, and is available under GPLv3 license at https://sites.google.com/view/selansi.CONTACT: antonio@iim.csic.es.", "Genomic disorders contribute significantly to genetic disease and, as detection methods improve, greater numbers are being defined. Paralogous low copy repeats (LCRs) mediate many of the chromosomal rearrangements that underlie these disorders, predisposing chromosomes to recombination errors. Deletions of proximal 22q11.2 comprise the most frequently occurring microdeletion syndrome, DiGeorge/Velocardiofacial syndrome (DGS/VCFS), in which most breakpoints have been localized to a 3 Mb region containing four large LCRs. Immediately distal to this region, there are another four related but smaller LCRs that have not been characterized extensively. We used paralog-specific primers and long-range PCR to clone, sequence, and examine the distal deletion breakpoints from two patients with de novo deletions mapping to these distal LCRs. Our results present definitive evidence of the direct involvement of LCRs in 22q11 deletions and map both breakpoints to the BCRL module, common to most 22q11 LCRs, suggesting a potential region for LCR-mediated rearrangement both in the distal LCRs and in the DGS interval. These are the first reported cases of distal 22q11 deletions in which breakpoints have been characterized at the nucleotide level within LCRs, confirming that distal 22q11 LCRs can and do mediate rearrangements leading to genomic disorders.", "We report a case of Prader-Willi syndrome (PWS) complicated with juvenile stroke. The patient is a 19-year-old man with right hemiplegia, who has had a history of non-insulin-dependent diabetes mellitus (NIDDM) for ten years. The diagnosis of PWS was confirmed genetically by the method of fluorescence in situ hybridization which showed the deletion of chromosome 15. His brain MRI revealed abnormal signal intensities in the left basal ganglia and around the right trigone of the lateral ventricle. Angiographic examination showed occlusions of bilateral proximal middle cerebral arteries with basal moyamoya vessels. The left vertebral artery was also occluded at its origin. Only a few cases of PWS complicated with stroke have been reported before and, to date, there has been no case with arterial occlusion similar to our case. Though the cause of these arterial occlusions is unknown, it may be related to arteriosclerosis following NIDDM.", "Publisher: Chronisch nierenkranke Patienten weisen eine erhöhte kardiovaskuläre Morbidität und Sterblichkeit auf. Im letzten Jahr sind einige wichtige Studien zur Herz-Nieren-Interaktion veröffentlicht worden, die im Folgenden zusammengefasst und diskutiert werden. In der DAPA-CKD-Studie sowie in der SCORED-Studie konnten 2 unterschiedliche SGLT2(„sodium-glucose linked transporter 2“)-Inhibitoren (Dapagliflozin und Sotagliflozin) die Prognose von chronisch nierenkranken Patienten mit und ohne Diabetes nachweislich verbessern. Auch die Ergebnisse der randomisierten Studie zum neuen Mineralokortikoidrezeptorantagonisten Finerenon – FIDELIO-DKD – liefern einen vielversprechenden neuen Therapieansatz für Patienten mit diabetischer Nephropathie. Die veröffentlichten Daten der ISCHEMIA-CKD-Studie bei Patienten mit koronarer Herzkrankheit und Untersuchungen zum Einfluss einer TAVI („transcatheter aortic valve implantation“) auf die Nierenfunktion sowie eine weitere Studie zum akuten Nierenversagen nach MitraClip®-Implantation (Abbott, Chicago, IL, USA) geben wichtige Hinweise zu zukünftigen Handlungsempfehlungen. Der optimale Zeitpunkt der Einleitung einer Nierenersatztherapie bei Patienten mit akuter Nierenschädigung in der Intensivmedizin wurde in 2 randomisierten Studien untersucht, die entsprechend diskutiert werden.", "The Escherichia coli DNA Mismatch Repair (MMR) protein MutS exist as dimers and tetramers in solution, and the identification of its functional oligomeric state has been matter of extensive study. In the present work, we have analyzed the oligomerization state of MutS from Pseudomonas aeruginosa a bacterial species devoid of Dam methylation and MutH homologue. By analyzing native MutS and different mutated versions of the protein, we determined that P. aeruginosa MutS is mainly tetrameric in solution and that its oligomerization capacity is conducted as in E. coli, by the C-terminal region of the protein. The analysis of mismatch oligonucleotide binding activity showed that wild-type MutS binds to DNA as tetramer. The DNA binding activity decreased when the C-terminal region was deleted (MutSDelta798) or when a full-length MutS with tetramerization defects (MutSR842E) was tested. The ATPase activity of MutSDelta798 was similar to MutSR842E and diminished respect to the wild-type protein. Experiments carried out on a P. aeruginosa mutS strain to test the proficiency of different oligomeric versions of MutS to function in vivo showed that MutSDelta798 is not functional and that full-length dimeric version MutSR842E, is not capable of completely restoring the MMR activity of the mutant strain. Additional experiments carried out in conditions of high mutation rate induced by the base analogue 2-AP confirm that the dimeric version of MutS is not as efficient as the tetrameric wild-type protein to prevent mutations. Therefore, it is concluded that although dimeric MutS is sufficient for MMR activity, optimal activity is obtained with the tetrameric version of the protein and therefore it should be considered as the active form of MutS in P. aeruginosa.", "Chronic gastrointestinal symptoms are commonly reported in autistic patients. Dysphagia is often present, and it is generally related to behavioral eating disorders. The association between autism and esophageal achalasia has not been described in literature yet. We report our experience with three cases of autistic children we recently treated for esophageal achalasia. In the first case (a 14-year-old male), achalasia was diagnosed with barium swallow and esophageal manometry and was successfully treated with three pneumatic endoscopic dilatations (follow-up: 3 years). In the second case (a 12-year-old female), achalasia was diagnosed with barium swallow and esophageal manometry and was treated with Heller myotomy after two unsuccessful pneumatic endoscopic attempts (follow-up: 3 months). In the last case, a 15-year-old male underwent barium swallow and endoscopy that confirmed achalasia. He was treated with Heller myotomy, and he is asymptomatic at a 6-month follow-up. To our knowledge, this is the first report of a possible association between autism and esophageal achalasia. Because of the rarity of both diseases, their association in the same patient is unlikely to be casual even if speculation on their common etiology is impossible at present. This finding needs further confirmation, but it is sufficient, in our opinion, to indicate proper evaluation with barium swallow and/or manometry in any autistic children with eating difficulty.", "In Saccharomyces cerevisiae, G1/S transcription factors MBF and SBF regulate a large family of genes important for entry to the cell cycle and DNA replication and repair. Their regulation is crucial for cell viability, and it is conserved throughout evolution. MBF and SBF consist of a common component, Swi6, and a DNA-specific binding protein, Mbp1 and Swi4, respectively. Transcriptional repressors bind to and regulate the activity of both transcription factors. Whi5 binds to SBF and represses its activity at the beginning of the G1 phase to prevent early activation. Nrm1 binds to MBF to repress transcription as cells progress through S phase. Here, we describe a protein motif, the GTB motif (for G1/S transcription factor binding), in Nrm1 and Whi5 that is required to bind to the transcription factors. We also identify a region of the carboxy terminus of Swi6 that is required for Nrm1 and Whi5 binding to their target transcription factors and show that mutation of this region overrides the repression of MBF- and SBF-regulated genes by Nrm1 and Whi5. Finally, we show that the GTB motif is the core of a functional module that is necessary and sufficient for targeting of the transcription factors by their cognate repressors." ]

[ "MOTIVATION: RNA-Seq technology is promising to uncover many novel alternative splicing events, gene fusions and other variations in RNA transcripts. For an accurate detection and quantification of transcripts, it is important to resolve the mapping ambiguity for those RNA-Seq reads that can be mapped to multiple loci: >17% of the reads from mouse RNA-Seq data and 50% of the reads from some plant RNA-Seq data have multiple mapping loci. In this study, we show how to resolve the mapping ambiguity in the presence of novel transcriptomic events such as exon skipping and novel indels towards accurate downstream analysis. We introduce ORMAN ( O ptimal R esolution of M ultimapping A mbiguity of R N A-Seq Reads), which aims to compute the minimum number of potential transcript products for each gene and to assign each multimapping read to one of these transcripts based on the estimated distribution of the region covering the read. ORMAN achieves this objective through a combinatorial optimization formulation, which is solved through well-known approximation algorithms, integer linear programs and heuristics.RESULTS: On a simulated RNA-Seq dataset including a random subset of transcripts from the UCSC database, the performance of several state-of-the-art methods for identifying and quantifying novel transcripts, such as Cufflinks, IsoLasso and CLIIQ, is significantly improved through the use of ORMAN. Furthermore, in an experiment using real RNA-Seq reads, we show that ORMAN is able to resolve multimapping to produce coverage values that are similar to the original distribution, even in genes with highly non-uniform coverage.AVAILABILITY: ORMAN is available at http://orman.sf.net", "OBJECTIVE: To conduct a descriptive analysis of the sweat test (ST), associating ST results with epidemiological data, CFTR (cystic fibrosis transmembrane conductance regulator) mutations and reasons to indicate the ST, as well as correlating sweat sodium and sweat chloride concentrations in subjects.METHODS: Retrospective survey and descriptive analysis of 5,721 ST at a university referral center.RESULTS: The inclusion of the subjects was based on clinical data related with cystic fibrosis (CF) phenotype. The samples were grouped by (i) sweat chloride concentrations (mEq/L): <30: 3,249/5,277 (61.6%); ≥30 to <60: 1,326/5,277 (25.1%); ≥60: 702/5,277 (13.3%) and (ii) age: (Group A--GA) 0 to <6 months; (Group B--GB) ≥6 months to <18 years; (Group C--GC) ≥18 years. Digestive symptoms showed higher prevalence ratio for the CF diagnosis as well as association between younger age and higher values of sweat chloride, sweat sodium, and chloride/sodium ratio. The indication of ST due to respiratory symptoms was higher in GB and associated with greater age, lower values of sweat chloride, sweat sodium, and chloride/sodium ratio. There was higher prevalence of ST with sweat chloride levels <30 mEq/L in GB, ≥60 mEq/L in GC, and with borderline level in GB. There was positive correlation between sweat sodium and sweat chloride. Sweat chloride/sweat sodium and sweat sodium-sweat chloride indexes showed association with sex, reason for ST indication, and CFTR mutations. Sex alters some values presented in the ST. The number of ST/year performed before and after the newborn screening implementation was the same; however, we observed a higher number of borderlines values. A wide spectrum of CFTR mutation was found. Severe CFTR mutations and F508del/F508del genotype were associated with highest probability of ST chloride levels ≥60 mEq/L, and the absence of CFTR mutations identified was associated with borderline ST and respiratory symptoms.CONCLUSIONS: ST data showed wide variability dependent on age, sex, reason for examination indication, CFTR mutations, and weight of the collected sweat sample. Sweat sodium concentration is directly correlated with sweat chloride levels and it could be used as a quality parameter.", "OBJECTIVE: Mal de debarquement syndrome (MdDS) is a chronic disorder of imbalance characterized by a feeling of rocking and swaying. The disorder starts after prolonged exposure to passive motion such as from a boat or plane. All medical treatment is palliative and symptoms that persist beyond 6 months show low likelihood of remission. This pilot study explored the feasibility and tolerability of repetitive transcranial magnetic stimulation (rTMS) as potential treatment for MdDS.PATIENTS/INTERVENTION: Ten subjects (8 women) with persistent MdDS lasting from 10 to 91 months were given 1 session each of 4 counterbalanced protocols: left 10 Hz (high frequency), left 1 Hz (low frequency), right 10 Hz, and right 1 Hz rTMS over the dorsolateral prefrontal cortex (DLPFC).MAIN OUTCOME MEASURE: Reduction of rocking sensation reported on a visual analogue scale.RESULTS: 1) Right-handers improved most with 10-Hz stimulation over the left DLPFC while left-handers improved most with 10 Hz stimulation over the right DLPFC; 2) low-frequency DLPFC stimulation was associated with symptom worsening in some subjects; 3) duration of symptoms was negatively correlated with treatment response; 4) rTMS was well tolerated in MdDS subjects, showing similar rates of headache (10 of 40 sessions) as for other studies; and 5) fatigue occurred after 6 sessions usually with low-frequency stimulation.CONCLUSION: rTMS was well tolerated in subjects with MdDS with promising short-term symptom improvement. Future studies of rTMS in MdDS may consider sequential days of stimulation, longer post-rTMS observation periods, formal measurement of post-TMS fatigue, and randomization with a sham condition.", "Introduction. Amyloid-beta-related angiitis (ABRA) is a form of CNS vasculitis in which perivascular beta-amyloid in the intracerebral vessels is thought to act as a trigger for inflammation mediated by CD68+ macrophages and CD3+ T lymphocytes. Patients with severe ABRA may develop coma responsive to immunosuppressive treatment. Case Presentation. A 57-year-old man presented to the neurological intensive care unit febrile, obtunded, and with a left hemiparesis. He had suffered from intermittent left arm weakness and numbness for several months prior. Serum and cerebrospinal fluid studies showed a lymphocytic leukocytosis in the cerebrospinal fluid (CSF), but no other evidence of infection, and the patient underwent a brain biopsy. Histopathological examination demonstrated amyloid angiopathy, with an extensive perivascular lymphocytic infiltrate, indicative of ABRA. The patient was started on cyclophosphamide and steroids. Following a week of treatment he awakened and over several weeks made a significant neurological recovery. Conclusions. ABRA can have a variety of clinical presentations, including impairments in consciousness and coma. Accurate pathological diagnosis, followed by aggressive immunosuppression, can lead to impressive neurological improvements. This diagnosis should be considered in patients with paroxysmal recurrent neurological symptoms and an accelerated progression.", "Author information:(1)Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. pardis@broadinstitute.org cmyhrvol@broadinstitute.org cfreije@broadinstitute.org.(2)Center for Systems Biology, Department of Organismal and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.(3)Ph.D. Program in Virology, Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.(4)Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA.(5)Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.(6)McGovern Institute for Brain Research, MIT, Cambridge, MA 02139, USA.(7)Department of Brain and Cognitive Science, MIT, Cambridge, MA 02139, USA.(8)Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.(9)Department of Health Sciences and Technology, MIT, Cambridge, MA 02139, USA.(10)Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA 02139, USA.(11)Institute for Medical Engineering and Science, MIT, Cambridge, MA 02139, USA.(12)Department of Biological Sciences, Florida Gulf Coast University, Fort Myers, FL 33965, USA.(13)Centro de Investigaciones Genética, Instituto de Investigacion en Microbiologia, Universidad Nacional Autónoma de Honduras, Tegucigalpa, Honduras.(14)Department of Immunology and Infectious Disease, Harvard School of Public Health, Boston, MA 02115, USA.(15)Araraquara Laboratory of Public Health, School of Pharmaceutical Sciences, São Paulo State University, São Paulo, Brazil.(16)Laboratorio de Pesquisas em Virologia, Faculdade de Medicina de Sao Jose do Rio Preto, São Paulo, Brazil.(17)Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.(18)Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.(19)Howard Hughes Medical Institute (HHMI), Chevy Chase, MD 20815, USA.", "PURPOSE: Studies suggest that aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), and statins may reduce risk of some cancers. However, findings have been conflicting as to whether these agents reduce the risk of pancreatic cancer.METHODS: We used data from the Queensland Pancreatic Cancer Study, a population-based case-control study. In total, 704 cases and 711 age- and sex-matched controls were recruited. Participants completed an interview in which they were asked about history of NSAID and statin use. We included 522 cases and 653 controls who had completed the medication section of the interview in this analysis. Unconditional multivariable logistic regression was used to estimate associations between medication use and pancreatic cancer.RESULTS: We found no consistent evidence of an association between use of NSAIDs or statins and risk of pancreatic cancer. There was some suggestion of a protective effect in infrequent users of selective COX-2 inhibitors, but no association in more frequent users. We did not find evidence of protective effects in analyses stratified by sex, smoking status, time between diagnosis and interview, or presence/absence of metastases.CONCLUSIONS: Overall, our results do support the hypothesis that use of NSAIDs or statins may reduce the odds of developing pancreatic cancer.", "Adaptive (stationary-phase) mutagenesis occurs in the gram-positive bacterium Bacillus subtilis. Furthermore, taking advantage of B. subtilis as a paradigm for the study of prokaryotic differentiation and development, we have shown that this type of mutagenesis is subject to regulation involving at least two of the genes that are involved in the regulation of post-exponential phase prokaryotic differentiation, i.e., comA and comK. On the other hand, a functional RecA protein was not required for this type of mutagenesis. The results seem to suggest that a small subpopulation(s) of the culture is involved in adaptive mutagenesis and that this subpopulation(s) is hypermutable. The existence of such a hypermutable subpopulation(s) raises important considerations with respect to evolution, the development of specific mutations, the nature of bacterial populations, and the level of communication among bacteria in an ecological niche." ]

[ "Receptor tyrosine kinases (RTKs) are cell surface proteins that tightly regulate a variety of downstream intra-cellular processes; ligand-receptor interactions result in cascades of signaling events leading to growth, proliferation, differentiation and migration. There are 58 described RTKs, which are further categorized into 20 different RTK families. When dysregulated or overexpressed, these RTKs are implicated in disordered growth, development, and oncogenesis. The TAM family of RTKs, consisting of Tyro3, Axl, and MerTK, is prominently expressed during the development and function of the central nervous system (CNS). Aberrant expression and dysregulated activation of TAM family members has been demonstrated in a variety of CNS-related disorders and diseases, including the most common but least treatable brain cancer in children and adults: glioblastoma multiforme.", "INTRODUCTION: Intestinal endometriosis is considered the most severe form of deep endometriosis, the rectosigmoid being involved in about 90% of cases of bowel infiltration. Transvaginal sonography (TVS) and magnetic resonance imaging (MRI) have been used for noninvasive diagnosis and preoperative mapping of rectosigmoid endometriosis (RE), but no consensus has been reached so far regarding which method is the most accurate in this setting.OBJECTIVE: We aimed at performing a systematic review and meta-analysis to compare the accuracy of TVS versus MRI in the diagnosis of RE in a same population.METHODS: A systematic review was conducted in accordance with the PRISMA guidelines. Studies were identified by searching the MEDLINE, Embase, and LILACS databases, as well the reference lists of retrieved articles, through February 2019. We included all cross-sectional studies that evaluated the accuracy of TVS versus MRI in the diagnosis of RE within a same sample of subjects and that used surgical findings with histological confirmation as the gold standard. The QUADAS-2 instrument was used to evaluate study quality. Sensitivity, specificity, positive likelihood ratios (LR+), and negative likelihood ratios (LR-) for the diagnosis of RE were calculated. This study is registered with PROSPERO, number CRD42017064378.RESULTS: Eight studies (n = 1132) were included in the meta-analysis. The pooled sensitivity, specificity, LR+, and LR- values of MRI for RE were 90% (95% CI, 87-92%), 96% (95% CI, 94-97%), 17.26 (95% CI, 3.57-83.50), and 0.15 (95% CI, 0.10-0.23); values of TVS were 90% [95% CI, 87-92%], 96% (95% CI, 94-97%), 20.66 (95% CI, 8.71-49.00) and 0.12 (95% CI, 0.08-0.20), respectively. Areas under the S-ROC curves (AUC) showed no statistically significant differences between MRI (AUC = 0.948) and TVS (AUC = 0.930) in the diagnosis of RE (P = 0.13). Moreover, considering the average prevalence among the studies of 47.3%, both methods demonstrated similarly high positive post-test probabilities (93.9% for TVS and 94.8% for MRI), and the combined use of them yielded a post-test probability of 99.6%.CONCLUSION: MRI and TVS have similarly high accuracy and positive post-test probabilities in the noninvasive diagnosis of RE. Combination of MRI and TVS may increase even further the positive post-test probabilities to near 100%.", "BACKGROUND: Baricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor.METHODS: In this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3.RESULTS: More patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein.CONCLUSIONS: In patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage.TRIAL REGISTRATION NUMBER: NCT01721057; Results.", "CRISPR-Cas12a (Cpf1) proteins are RNA-guided enzymes that bind and cut DNA as components of bacterial adaptive immune systems. Like CRISPR-Cas9, Cas12a has been harnessed for genome editing on the basis of its ability to generate targeted, double-stranded DNA breaks. Here we show that RNA-guided DNA binding unleashes indiscriminate single-stranded DNA (ssDNA) cleavage activity by Cas12a that completely degrades ssDNA molecules. We find that target-activated, nonspecific single-stranded deoxyribonuclease (ssDNase) cleavage is also a property of other type V CRISPR-Cas12 enzymes. By combining Cas12a ssDNase activation with isothermal amplification, we create a method termed DNA endonuclease-targeted CRISPR trans reporter (DETECTR), which achieves attomolar sensitivity for DNA detection. DETECTR enables rapid and specific detection of human papillomavirus in patient samples, thereby providing a simple platform for molecular diagnostics.", "A new vaccine (the 4CMenB 4-component protein vaccine [Bexsero], which includes PorA, factor H-binding protein [fHbp], neisserial heparin-binding antigen [NHBA], and Neisseria adhesin A [NadA]) against serogroup B meningococci has recently been approved for use in people older than age 2 months in Europe, Australia, and Canada. Preapproval clinical efficacy studies are not feasible for invasive meningococcal disease because its incidence is low/very low, and the serum bactericidal antibody (SBA) titer (or the human SBA [hSBA] titer when human complement is used in the assay) has been used as a surrogate marker of protection. However, the hSBA assay cannot be used on a large scale, and therefore, a meningococcal antigen typing system (MATS) was developed. MATS combines conventional PorA genotyping with an enzyme-linked immunosorbent assay (ELISA) that quantifies both the expression and the cross-reactivity of antigenic variants. The assay has been used to evaluate the potential of the 4CMenB meningococcal group B vaccine to cover group B strains in several countries. Some recent data suggest that MATS is a conservative predictor of strain coverage. We used pooled sera from adolescents and infants to test by the hSBA assay 10 meningococcal group B strains isolated in Spain that were negative for the 3 antigens (n = 9) or that had very low levels of the 3 antigens (n = 1) by MATS. We found that all strains were killed by sera from adolescents and that 5 of the 10 strains were also killed, although at a low titer, by sera from infants. Our data confirm that MATS underestimates vaccine coverage.", "Three-dimensional genome structure plays an important role in gene regulation. Globally, chromosomes are organized into active and inactive compartments while, at the gene level, looping interactions connect promoters to regulatory elements. Topologically associating domains (TADs), typically several hundred kilobases in size, form an intermediate level of organization. Major questions include how TADs are formed and how they are related to looping interactions between genes and regulatory elements. Here we performed a focused 5C analysis of a 2.8 Mb chromosome 7 region surrounding CFTR in a panel of cell types. We find that the same TAD boundaries are present in all cell types, indicating that TADs represent a universal chromosome architecture. Furthermore, we find that these TAD boundaries are present irrespective of the expression and looping of genes located between them. In contrast, looping interactions between promoters and regulatory elements are cell-type specific and occur mostly within TADs. This is exemplified by the CFTR promoter that in different cell types interacts with distinct sets of distal cell-type-specific regulatory elements that are all located within the same TAD. Finally, we find that long-range associations between loci located in different TADs are also detected, but these display much lower interaction frequencies than looping interactions within TADs. Interestingly, interactions between TADs are also highly cell-type-specific and often involve loci clustered around TAD boundaries. These data point to key roles of invariant TAD boundaries in constraining as well as mediating cell-type-specific long-range interactions and gene regulation.", "Parkin mutations are responsible for the pathogenesis of autosomal-recessive juvenile parkinsonism (AR-JP). On initial screening of Japanese patients with AR-JP, we had found that approximately half of the parkin mutations are deletions occurring between exons 2 and 5, forming a deletion hot spot. In this study, we investigated the deletion breakpoints of the parkin mutations in 22 families with AR-JP and examined the possible association between these deletion events and meiotic recombinations. We identified 18 deletion breakpoints at the DNA nucleotide sequence level. Almost all these deletions were different, indicating that the deletion hot spot was generated by recurrent but independent events. We found no association between the deletions and specific DNA elements. Recent copy number variation (CNV) data from various ethnic groups showed that the deletion hot spot is overlapped by a highly polymorphic CNV region, indicating that the recurrent deletion mutation or CNV is observable worldwide. By comparing Marshfield and deCODE linkage maps, we found that the parkin deletion hot spot may be associated with a meiotic recombination hot spot, although such association was not found on comparison with recent high-resolution genetic maps generated from the International HapMap project. Here, we discuss the possible mechanisms for deletion hot spot formation and its effects on human genomes." ]

[ "Dihydroorotate dehydrogenase (DHODH) mediates the fourth step of de novo pyrimidine biosynthesis and is a proven drug target for inducing immunosuppression in therapy of human disease as well as a rapidly emerging drug target for treatment of malaria. In Toxoplasma gondii, disruption of the first, fifth, or sixth step of de novo pyrimidine biosynthesis induced uracil auxotrophy. However, previous attempts to generate uracil auxotrophy by genetically deleting the mitochondrion-associated DHODH of T. gondii (TgDHODH) failed. To further address the essentiality of TgDHODH, mutant gene alleles deficient in TgDHODH activity were designed to ablate the enzyme activity. Replacement of the endogenous DHODH gene with catalytically deficient DHODH gene alleles induced uracil auxotrophy. Catalytically deficient TgDHODH localized to the mitochondria, and parasites retained mitochondrial membrane potential. These results show that TgDHODH is essential for the synthesis of pyrimidines and suggest that TgDHODH is required for a second essential function independent of its role in pyrimidine biosynthesis.", "BACKGROUND: Through transcription and alternative splicing, a gene can be transcribed into different RNA sequences (isoforms), depending on the individual, on the tissue the cell is in, or in response to some stimuli. Recent RNA-Seq technology allows for new high-throughput ways for isoform identification and quantification based on short reads, and various methods have been put forward for this non-trivial problem.RESULTS: In this paper we propose a novel radically different method based on minimum-cost network flows. This has a two-fold advantage: on the one hand, it translates the problem as an established one in the field of network flows, which can be solved in polynomial time, with different existing solvers; on the other hand, it is general enough to encompass many of the previous proposals under the least sum of squares model. Our method works as follows: in order to find the transcripts which best explain, under a given fitness model, a splicing graph resulting from an RNA-Seq experiment, we find a min-cost flow in an offset flow network, under an equivalent cost model. Under very weak assumptions on the fitness model, the optimal flow can be computed in polynomial time. Parsimoniously splitting the flow back into few path transcripts can be done with any of the heuristics and approximations available from the theory of network flows. In the present implementation, we choose the simple strategy of repeatedly removing the heaviest path.CONCLUSIONS: We proposed a new very general method based on network flows for a multiassembly problem arising from isoform identification and quantification with RNA-Seq. Experimental results on prediction accuracy show that our method is very competitive with popular tools such as Cufflinks and IsoLasso. Our tool, called Traph (Transcrips in gRAPHs), is available at: http://www.cs.helsinki.fi/gsa/traph/.", "Patients with chronic pain may have difficulties estimating their own physical activity level in daily life. Pain-related factors such as depression and pain intensity may affect a patients' ability to estimate their own daily life activity level. This study evaluates whether patients with Chronic Low Back Pain (CLBP) who are more depressed and/or report more pain indeed have a lower objectively assessed daily life activity level or whether they only perceive their activity level as lower. Patients with CLBP were included in a cross-sectional study. During 14days physical activity in daily life was measured, with both an electronic diary and an accelerometer. Multilevel analyses were performed to evaluate whether a higher level of depression and/or pain intensity was associated with a lower objectively assessed activity level or the discrepancy between the self-reported and objectively assessed daily life activity levels. Results, based on 66 patients with CLBP (mean RDQ score 11.8), showed that the objectively assessed daily life activity level is not associated with depression or pain intensity. There was a moderate association between the self-reported and objectively assessed activity levels (beta=0.39, p<0.01). The discrepancy between the two was significantly and negatively related to depression (beta=-0.19, p=0.01), indicating that patients who had higher levels of depression judged their own activity level to be relatively low compared to their objectively assessed activity level. Pain intensity was not associated with the perception of a patient's activity level (beta=0.12, ns).", "Anoïkis is defined as programmed cell death induced by the loss of cell/matrix interactions. Adhesion to structural glycoproteins of the extracellular matrix is necessary for survival of the differentiated adherent cells in the cardiovascular system, including endothelial cells, smooth muscle cells, fibroblasts, and cardiac myocytes. Adhesion is also a key factor for the differentiation of mesenchymal stem cells. In particular, fibronectin is considered a factor of survival and differentiation for many adherent cells. Adhesion generates cell tensional integrity (tensegrity) and repression of apoptotic signals, whereas detachment has the opposite effect. Anoïkis plays a physiological role by regulating cell homeostasis in tissues. However, anoïkis can also be involved in pathological processes, as illustrated by the resistance to anoïkis in cancer and its enhancement in degenerative tissue remodeling. Extracellular mediators of anoïkis include matrix retraction, leading to loss of tensegrity in fibroblasts, pharmacological disengagement of integrins by RGD-like peptides and fragments of fibronectin, and focal adhesion disassembly by fragments of thrombospondin, plasminogen activator-1, and high-molecular-weight kininogen. In addition to binding of the RGD peptide by integrins, the engagement of the heparin binding sites of adhesive glycoproteins with glycosaminoglycans on the cell surface is also involved in the prevention of cell detachment-induced apoptosis. Proteases able to degrade adhesive glycoproteins, such as fibronectin, induce anoïkis of vascular adherent cells. Active proteases can either be secreted directly by inflammatory cells, as elastase and cathepsin G by polymorphonuclear leukocytes, chymase and tryptase by mast cells, and granzymes by lymphocytes, or generated from circulating zymogens by activation in close contact with the cells. This is the case for the pericellular conversion of plasminogen to plasmin, which degrades fibronectin and induces anoïkis of smooth muscle cells. Involvement of proteases has also been proposed in the apoptotic response of cultured adherent cells to serum starvation. Anoïkis is probably involved in pathological remodeling of cardiovascular tissues, including cardiac myocyte detachment in heart failure, deendothelialization and plaque rupture in atherosclerosis, and smooth muscle cell disappearance in aneurysms and varicose veins. The absence of cell adhesion and growth resulting from cleavage of adhesive proteins also represents a major impediment to cellular healing, including the absence of cell recolonization of proteolytically injured tissue and the low efficacy of cell transplantation. However, the exact role of anoïkis in cardiovascular pathologies remains to be further defined.", "Application of the bacterial CRISPR/Cas systems to eukaryotes is revolutionizing biology. Cas9 and Cas12 (previously called Cpf1) are widely used as DNA nucleases for inducing site-specific DNA breaks for different kinds of genome engineering applications, and in their mutated forms as DNA-binding proteins to modify gene expression. Moreover, histone modifications, as well as cytosine methylation or base editing, were achieved with these systems in plants. Recently, with the discovery of the nuclease Cas13a (previously called C2c2), molecular biologists have obtained a system that enables sequence-specific cleavage of single-stranded RNA molecules. The latest experiments with this and also the alternative Cas13b system demonstrate that these proteins can be used in a similar manner in eukaryotes for RNA manipulation as Cas9 and Cas12 for DNA manipulations. The first application of Cas13a for post-transcriptional regulation of gene expression in plants has been reported. Recent results show that the system is also applicable for combating viral infection in plants. As single-stranded RNA viruses are by far the most abundant class of viruses in plants, the application of this system is of special promise for crops. More interesting applications are imminent for plant biologists, with nuclease dead versions of Cas13 enabling the ability to visualize RNA molecules in vivo, as well as to edit different kinds of RNA molecules at specific bases by deamination or to modify them by conjugation. Moreover, by combining DNA- and RNA-directed systems, the most complex of changes in plant metabolism might be achievable.", "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.", "PURPOSE: STXBP1 (MUNC18-1) mutations have been associated with various types of epilepsies, mostly beginning early in life. To refine the phenotype associated with STXBP1 aberrations in early onset epileptic syndromes, we studied this gene in a cohort of patients with early onset epileptic encephalopathy.METHODS: STXBP1 was screened in a multicenter cohort of 52 patients with early onset epilepsy (first seizure observed before the age of 3 months), no cortical malformation on brain magnetic resonance imaging (MRI), and negative metabolic screening. Three groups of patients could be distinguished in this cohort: (1) Ohtahara syndromes (n = 38); (2) early myoclonic encephalopathies (n = 7); and (3) early onset epileptic encephalopathies that did not match any familiar syndrome (n = 7). None of the patients displayed any cortical malformation on brain MRI and all were screened through multiple video-electroencephalography (EEG) recordings for a time period spanning from birth to their sixth postnatal month. Subsequently, patients had standard EEG or video-EEG recordings.KEY FINDINGS: We found five novel STXBP1 mutations in patients for whom video-EEG recordings could be sampled from the beginning of the disease. All patients with a mutation displayed Ohtahara syndrome, since most early seizures could be classified as epileptic spasms and since the silent EEG periods were on average shorter than bursts. However, each patient in addition displayed a particular clinical and EEG feature: In two patients, early seizures were clonic, with very early EEG studies exhibiting relatively low amplitude bursts of activity before progressing into a typical suppression-burst pattern, whereas the three other patients displayed epileptic spasms associated with typical suppression-burst patterns starting from the early recordings. Epilepsy dramatically improved after 6 months and finally disappeared before the end of the first year of life for four patients; the remaining one patient had few seizures until 18 months of age. In parallel, EEG paroxysmal abnormalities disappeared in three patients and decreased in two, giving place to continuous activity with fast rhythms. Each patient displayed frequent nonepileptic movement disorders that could easily be mistaken for epileptic seizures. These movements could be observed as early as the neonatal period and, unlike seizures, persisted during all the follow-up period.SIGNIFICANCE: We confirm that STXBP1 is a major gene to screen in cases of Ohtahara syndrome, since it is mutated in >10% of the Ohtahara patients within our cohort. This gene should particularly be tested in the case of a surprising evolution of the patient condition if epileptic seizures and EEG paroxysmal activity disappear and are replaced by fast rhythms after the end of the first postnatal year." ]

[ "Mutations in the transcriptional regulator, Aire, cause APECED, a polyglandular autoimmune disease with monogenic transmission. Animal models of APECED have revealed that Aire plays an important role in T cell tolerance induction in the thymus, mainly by promoting ectopic expression of a large repertoire of transcripts encoding proteins normally restricted to differentiated organs residing in the periphery. The absence of Aire results in impaired clonal deletion of self-reactive thymocytes, which escape into the periphery and attack a variety of organs. In addition, Aire is a proapoptotic factor, expressed at the final maturation stage of thymic medullary epithelial cells, a function that may promote cross-presentation of the antigens encoded by Aire-induced transcripts in these cells. Transcriptional regulation by Aire is unusual in being very broad, context-dependent, probabilistic, and noisy. Structure/function analyses and identification of its interaction partners suggest that Aire may impact transcription at several levels, including nucleosome displacement during elongation and transcript splicing or other aspects of maturation.", "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.", "Thyroid hormone (TH) is known to have many beneficial effects on vital organs, but its extrapolation to be used therapeutically has been restricted by the fact that it does have concurrent adverse effects. Recent finding of various thyroid hormone receptors (TR) isoforms and their differential pattern of tissue distribution has regained interest in possible use of TH analogues in therapeutics. These findings were followed by search of compounds with isoform-specific or tissue-specific action on TR. Studying the structure-activity relationship of TR led to the development of compounds like GC1 and KB141, which preferentially act on the β1 isoform of TR. More recently, eprotirome was developed and has been studied in humans. It has shown to be effective in dyslipidemia by the lipid-lowering action of TH in the liver and also in obesity. Another compound, 3,5-diiodothyropropionic acid (DITPA), binds to both α- and β-type TRs with relatively low affinity and has been shown to be effective in heart failure (HF). In postinfarction models of HF and in a pilot clinical study, DITPA increased cardiac performance without affecting the heart rate. TR antagonists like NH3 can be used in thyrotoxicosis and cardiac arrhythmias. However, further larger clinical trials on some of these promising compounds and development of newer compounds with increased selectivity is required to achieve higher precision of action and avoid adverse effects seen with TH.", "Pannexins (Panx) are proteins with a similar membrane topology to connexins, the integral membrane protein of gap junctions. Panx1 channels are generally of major importance in a large number of system and cellular processes and their function has been thoroughly characterized. In contrast, little is known about channel structure and subcellular distribution. We therefore determine the subcellular localization of Panx1 channels in cultured cells and aim at the identification of channel morphology in vitro. Using freeze-fracture replica immunolabeling on EYFP-Panx1-overexpressing HEK 293 cells, large particles were identified in plasma membranes, which were immunogold-labeled using either GFP or Panx1 antibodies. There was no labeling or particles in the nuclear membranes of these cells, pointing to plasma membrane localization of Panx1-EYFP channels. The assembly of particles was irregular, this being in contrast to the regular pattern of gap junctions. The fact that no counterparts were identified on apposing cells, which would have been indicative of intercellular signaling, supported the idea of Panx1 channels within one membrane. Control cells (transfected with EYFP only, non-transfected) were devoid of both particles and immunogold labeling. Altogether, this study provides the first demonstration of Panx1 channel morphology and assembly in intact cells. The identification of Panx1 channels as large particles within the plasma membrane provides the knowledge required to enable recognition of Panx1 channels in tissues in future studies. Thus, these results open up new avenues for the detailed analysis of the subcellular localization of Panx1 and of its nearest neighbors such as purinergic receptors in vivo.", "Pannexins (Panxs) are a multifaceted family of ion and metabolite channels that play key roles in a number of physiological and pathophysiological settings. These single membrane large-pore channels exhibit a variety of tissue, cell type, and subcellular distributions. The lifecycles of Panxs are complex, yet must be understood to accurately target these proteins for future therapeutic use. Here we review the basics of Panx function and localization, and then analyze the recent advances in knowledge regarding Panx trafficking. We examine several intrinsic features of Panxs including specific post-translational modifications, the divergent C-termini, and oligomerization, all of which contribute to Panx anterograde transport pathways. Further, we examine the potential influence of extrinsic factors, such as protein-protein interactions, on Panx trafficking. Finally, we highlight what is currently known with respect to Panx internalization and retrograde transport, and present new data illustrating Panx1 internalization following an activating stimulus.", "C-Phycocyanin (C-PC), the major light harvesting biliprotein from Spirulina platensis is of greater importance because of its various biological and pharmacological properties. It is a water soluble, non-toxic fluorescent protein pigment with potent anti-oxidant, anti-inflammatory and anti-cancer properties. In the present study the effect of highly purified C-PC was tested on growth and multiplication of human chronic myeloid leukemia cell line (K562). The results indicate significant decrease (49%) in the proliferation of K562 cells treated with 50 microM C-PC up to 48 h. Further studies involving fluorescence and electron microscope revealed characteristic apoptotic features like cell shrinkage, membrane blebbing and nuclear condensation. Agarose electrophoresis of genomic DNA of cells treated with C-PC showed fragmentation pattern typical for apoptotic cells. Flow cytometric analysis of cells treated with 25 and 50 microM C-PC for 48 h showed 14.11 and 20.93% cells in sub-G0/G1 phase, respectively. C-PC treatment of K562 cells also resulted in release of cytochrome c into the cytosol and poly(ADP) ribose polymerase (PARP) cleavage. These studies also showed down regulation of anti-apoptotic Bcl-2 but without any changes in pro-apoptotic Bax and thereby tilting the Bcl-2/Bax ratio towards apoptosis. These effects of C-PC appear to be mediated through entry of C-PC into the cytosol by an unknown mechanism. The present study thus demonstrates that C-PC induces apoptosis in K562 cells by cytochrome c release from mitochondria into the cytosol, PARP cleavage and down regulation of Bcl-2.", "Neisseria meningitidis serogroup B is the most prevalent cause of invasive meningococcal disease in Europe and members of laboratories working on meningococci are at risk due to frequent handling. Recommendation for anti-meningococcal vaccination among these workers has been recently updated upon the licensure in Europe of Bexsero® vaccine. We tested the immunogenicity and safety of this vaccine among adults laboratory staff using the recommended schedule of 2 doses at 5 weeks interval. The vaccine was well tolerated in spite of frequent local side effects and all participants reported at least one side effect after each dose. Immunogenicity was evaluated 6 weeks and one year after the second dose. All participants showed increase in their bactericidal titers against the components of the vaccine 6 weeks after the second dose, however titers declined significantly one year later.", "Collaborators: Sklar P, Ripke S, Scott LJ, Andreassen OA, Cichon S, Craddock N, Edenberg HJ Jr, Nurnberger JI, Rietschel M, Blackwood D, Corvin A, Flickinger M, Guan W, Mattingsdal M, McQuillen A, Kwan P, Wienker TF, Daly M, Dudbridge F, Holmans PA, Lin D, Burmeister M, Greenwood TA, Hamshere ML, Muglia P, Smith EN, Zandi PP, Nievergelt CM, McKinney R, Shilling PD, Schork NJ, Bloss CS, Foroud T, Koller DL, Gershon ES, Liu C, Badner JA, Scheftner WA, Lawson WB, Nwulia EA, Hipolito M, Coryell W, Rice J, Byerley W, McMahon FJ, Schulze TG, Berrettini W, Lohoff FW, Potash JB, Mahon PB, McInnis MG, Zöllner S, Zhang P, Craig DW, Szelinger S, Barrett TB, Breuer R, Meier S, Strohmaier J, Witt SH, Tozzi F, Farmer A, McGuffin P, Strauss J, Xu W, Kennedy JL, Vincent JB, Matthews K, Day R, Ferreira MA, O'Dushlaine C, Perlis R, Raychaudhuri S, Ruderfer D, Lee PH, Smoller JW, Li J, Absher D, Bunny WE, Barchas JD, Schatzberg AF, Jones EG, Meng F, Thompson RC, Watson SJ, Myers RM, Akil H, Boehnke M, Chambert K, Moran J, Scolnick E, Djurovic S, Melle I, Morken G, Gill M, Morris D, Quinn E, Mühleisen TW, Degenhardt FA, Mattheisen M, Schumacher J, Maier W, Steffans M, Propping P, Nöthen MM, Anjorin A, Bass N, Gurling H, Kandaswamy R, Lawrence J, McGhee K, McIntosh A, McLean AW, Muir WJ, Pickard BS, Breen G, St Clair D, Caesar S, Gordon-Smith K, Jones L, Fraser C, Green EK, Frozeva D, Jones IR, Kirov G, Moskvina V, Nikolov I, O'Donovan MC, Owen MJ, Collier DA, Elkin A, Williamson R, Young AH, Ferrier IN, Stefansson K, Stefansson H, Porgeirsson P, Steinberg S, Gustafsson Ó, Bergen SE, Nimgaonkar V, Hultman C, Landén M, Lichtenstein P, Sullivan P, Schalling M, Osby U, Backlund L, Frisén L, Langstrom N, Jamain S, Leboyer M, Etain B, Bellivier F, Petursson H, Sigurđsson E, Müller-Mysok B, Lucae S, Schwarz M, Fullerton JM, Schofield PR, Martin N, Montgomery GW, Lathrop M, Óskarsson H, Bauer M, Wright A, Mitchell PB, Hautzinger M, Reif A, Kelsoe JR, Purcell SM.", "Novel oral anticoagulants (NOACs) that directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, edoxaban) are effective therapies for the prevention and treatment of thromboembolism with reduced bleeding complications compared with warfarin for some indications. However, specific antidotes to reverse the anticoagulant activity of NOACs in the event of major bleeding are not available. Evidence supporting non-specific prohemostatic therapies (prothrombin complex concentrate [PCC], activated prothrombin complex concentrate [aPCC], recombinant factor VIIa) in this setting is limited to healthy human volunteers, animal models, and in vitro studies. Clinical outcome data are lacking. Administration of PCC or aPCC may be considered in addition to supportive measures for patients with severe or life-threatening bleeding. Clinical studies are needed to establish the efficacy and safety of these treatments. Target-specific antidotes are in development and hold promise for NOAC reversal, but require further investigation.", "Pannexins are a family of integral membrane proteins with distinct post-translational modifications, sub-cellular localization and tissue distribution. Panx1 is the most studied and best-characterized isoform of this gene family. The ubiquitous expression, as well as its function as a major ATP release and nucleotide permeation channel, makes Panx1 a primary candidate for participating in the pathophysiology of CNS disorders. While many investigations revolve around Panx1 functions in health and disease, more recently, details started emerging about mechanisms that control Panx1 channel activity. These advancements in Panx1 biology have revealed that beyond its classical role as an unopposed plasma membrane channel, it participates in alternative pathways involving multiple intracellular compartments, protein complexes and a myriad of extracellular participants. Here, we review recent progress in our understanding of Panx1 at the center of these pathways, highlighting its modulation in a context specific manner. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.", "A girl with Williams syndrome (WS) presented with elevated thyrotropin (TSH) levels (7.0 microU/ml), normal free thyroid hormone concentrations, and absent antithyroid autoantibodies. Thyroid ultrasonography and scintigraphy showed hemiagenesis of the left lobe and no evidence of ectopic tissue. TSH response to thyrotropin-releasing hormone (TRH) injection (200 microg/mq, i.v.) was exaggerated and prolonged, suggesting subclinical hypothyroidism. The biological activity of circulating TSH was slightly below the normal range [TSH bioactivity (B) to immunoreactivity (I) ratio (TSH B/I) = 0.4, normal: 0.6-2.2]. These abnormalities are similar to those seen in patients with hypothalamic hypothyroidism. Thyroid function is not a recognized manifestation of WS and is not routinely investigated. However, abnormalities of the hypothalamic-pituitary-thyroid (HPT) axis and thyroid dysgenesis have been found in other WS cases. Genes mapping at 7q11.23, contiguous to the chromosomal region deleted in most WS patients, may be involved in the development of the thyroid gland, contributing to the complex phenotype of WS.", "AIMS: Familial dilated cardiomyopathy (FDCM) is associated with mutations in more than 10 genes, but genes mutation frequencies and associated clinical features remain largely unknown. Here, we performed a mutation analysis of four genes involved in FDCM in a population of idiopathic DCM.METHODS AND RESULTS: A SSCP and sequencing mutation screening of all the exons coding for beta myosin heavy chain (MYH7 gene), cardiac T troponin (TNNT2 gene), phospholamban (PLN gene), and the cardio-specific exon of metavinculin (VCL gene) were performed in 96 independent patients (54 familial and 42 sporadic). It led to the identification of eight heterozygous mutations, seven new ones in MYH7, and the already described R141W mutation in TNNT2. MYH7 mutations (in five familial and two sporadic cases) substitute residues located either in the head (I201T, T412N, A550V) or tail domains (T1019N, R1193S, E1426K, R1634S) of the protein. DCM was not associated with skeletal myopathy or conduction defects in any patients. Contrasting clinical features were observed between MYH7 and TNNT2 mutations carriers. In MYH7 vs. TNNT2, mean age at diagnosis was late (P<0.03), penetrance was incomplete in adults (56 vs. 100%), and mean age at major cardiac event was higher (P<0.04).CONCLUSION: We have identified seven mutations in MYH7, one in TNNT2, and none in PLN or in the VCL cardio-specific exon. MYH7 appears as the most frequently mutated gene in our FDCM population (approximately 10%), and mutation carriers present with delayed onset, in contrast to TNNT2.", "In mammalian embryonic stem cells, the acquisition of pluripotency is dependent on Nanog, but the in vivo analysis of Nanog has been hampered by its requirement for early mouse development. In an effort to examine the role of Nanog in vivo, we identified a zebrafish Nanog ortholog and found that its knockdown impaired endoderm formation. Genome-wide transcription analysis revealed that nanog-like morphants fail to develop the extraembryonic yolk syncytial layer (YSL), which produces Nodal, required for endoderm induction. We examined the genes that were regulated by Nanog-like and identified the homeobox gene mxtx2, which is both necessary and sufficient for YSL induction. Chromatin immunoprecipitation assays and genetic studies indicated that Nanog-like directly activates mxtx2, which, in turn, specifies the YSL lineage by directly activating YSL genes. Our study identifies a Nanog-like-Mxtx2-Nodal pathway and establishes a role for Nanog-like in regulating the formation of the extraembryonic tissue required for endoderm induction.", "A macroscopic and microscopic study of the mandibular organ of the silky anteater (Cyclopes didactylus) was carried out. The organ extends from below the zygomatic bone line to the middle of the mandible body, between the skin and the masseter muscle, on both sides of the animal. It has an average length of 11.7 mm and a width of 6.3 mm. In the mesoscopic analysis, it was observed that the organ presents in yellowish color due to the high amount of sebaceous content. In the histological analysis, the mandibular organ was observed to be composed of innumerable alveoli of the specialized sebaceous gland, surrounded by a layer of adventitia tunica. Scanning electron microscopy (SEM), revealed an apparent alveolar division with what appeared to be a sulcus at its center. The information here presented regarding the constitution and location of this structure has not been previously explored for other species and differs with respect to other descriptions for anteaters. Based on the present study, it is suggested that the mandibular organ is involved in social interaction in this species.", "Sinodielide A (SA) is a naturally occurring guaianolide, which is isolated from the root of Sinodielsia yunnanensis. This root, commonly found in Yunnan province, is used in traditional Chinese medicine as an antipyretic, analgesic and diaphoretic agent. A number of studies have reported that agents isolated from a species of Umbelliferae (Apiaceae) have antitumor activities. We previously reported, using combined treatments with this medicinal herb and hyperthermia at various temperatures, an enhanced cytotoxicity in the human prostate cancer androgen‑independent cell lines, PC3 and DU145, and analyzed the related mechanisms. In the present study, we investigated the effects of treatment with SA prior to hyperthermia on the thermosensitivity of DU145 cells, and the mechanisms related to the induction of apoptosis and G(2)/M cell cycle arrest via the activation of extracellular-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) signaling pathways, as well as the phosphoinositide 3-kinase (PI3K)/Akt signaling pathways. Cells were exposed to hyperthermia alone (40-44˚C) or hyperthermia in combination with SA. Lethal damage to cells treated with mild hyperthermia (40 or 42˚C) for up to 6 h was slight; however, hyperthermia in combination with SA synergistically enhanced thermosensivity. Lethal damage to cells treated with acute hyperthermia (43 or 44˚C) was more severe, but these effects were also enhanced and were more significant by the combined treatment with SA. The kinetics of apoptosis induction and cell cycle distribution were analyzed by flow cytometry. In addition, the levels of ERK1/2, JNK and Akt were determined by western blot analysis. The incidence of apoptotic cells after treatment with SA (20.0 µM) at 37˚C for 4 h, hyperthermia (44˚C) alone for 30 min, and the combination in sequence were examined. The sub-G1 division (%) in the diagram obtained by flow cytometry was applied to that assay. The percentage of apoptotic cells (10.53±5.02%) was higher at 48 h as compared to 0, 12 and 24 h after treatment. The distribution of DU145 cells in the G2/M cell cycle phase was markedly increased after 24 h of heating at 44˚C and after the combined treatment with heating and SA. The phosphorylation of ERK1/2 was reduced following treatment with heating and SA, while the levels of phosphorylated JNK (p-JNK) were markedly increased immediately after heating at 44˚C and when heating was combined with SA. By contrast, the levels of phosphorylated Akt (p-Akt) were immediately increased only after heating at 44˚C. Thus, we concluded that SA exerts its thermosensitizing effects on DU145 cells by inhibiting the activation of the MAPK/ERK1/2 and PI3K/Akt signaling pathways.", "Epidemiological data suggests suicide is uncommon in childhood but becomes an extremely serious issue among adolescents.Several risk factors have been identified and include the presence of psychiatric illness, a previous suicide attempt, family factors, substance abuse, sexual and physical abuse, disorders in gender identity or bullying. Pediatricians have a primary role in searching for these risk factors, recognizing them and acting synergistically with other specialists to prevent and treat suicidal behavior.Pediatricians should also be able to identify the \"warning signs\" for suicide since their presence implies a need for immediate action, as attempted suicide may occur in a few hours or days.The use of antidepressant drugs and its association with suicidal risk in pediatric age is another topic of ongoing debate. Food and Drug Administration has recently introduced the so-called \"black box\" on antidepressants' packages with the aim of gaining attention to the possible risk of suicide among adolescents who are treated with antidepressants, with a warning that the risk of suicide is higher when starting a therapy or while adjusting its dosage.", "The clinical association between multiple endocrine neoplasia type 2 (MEN2) and Hirschsprung disease (HSCR) is infrequent. Germline mutations of the ret protooncogene are the underlying cause of the MEN2 syndromes and a proportion of cases of HSCR. In this report, we describe a new kindred in which the MEN2 and HSCR phenotypes are associated with a single C620S point mutation at one of the cysteine codons of the extracellular domain of the ret protooncogene. We also speculate about the role of a silent mutation in exon 2 of this same gene (A45A), present in a homozygous state in the patient with both MEN2A and HSCR. To investigate the contribution of GDNF to the phenotype observed in this kindred, we scanned the coding region of GDNF in the patient with MEN2/HSCR, but no mutation was found.", "Pannexins (Panx) are proteins homologous to the invertebrate gap junction proteins called innexins (Inx) and are traditionally described as transmembrane channels connecting the intracellular and extracellular compartments. Three distinct Panx paralogs (Panx1, Panx2 and Panx3) have been identified in vertebrates but previous reports on Panx expression and functionality focused primarily on Panx1 and Panx3 proteins. Several gene expression studies reported that Panx2 transcript is largely restricted to the central nervous system (CNS) hence suggesting that Panx2 might serve an important role in the CNS. However, the lack of suitable antibodies prevented the creation of a comprehensive map of Panx2 protein expression and Panx2 protein localization profile is currently mostly inferred from the distribution of its transcript. In this study, we characterized novel commercial monoclonal antibodies and surveyed Panx2 expression and distribution at the mRNA and protein level by real-time qPCR, Western blotting and immunofluorescence. Panx2 protein levels were readily detected in every tissue examined, even when transcriptional analysis predicted very low Panx2 protein expression. Furthermore, our results indicate that Panx2 transcriptional activity is a poor predictor of Panx2 protein abundance and does not correlate with Panx2 protein levels. Despite showing disproportionately high transcript levels, the CNS expressed less Panx2 protein than any other tissues analyzed. Additionally, we showed that Panx2 protein does not localize at the plasma membrane like other gap junction proteins but remains confined within cytoplasmic compartments. Overall, our results demonstrate that the endogenous expression of Panx2 protein is not restricted to the CNS and is more ubiquitous than initially predicted.", "In order to propose a reliable model for Brucella porin topology, several structure prediction methods were evaluated in their ability to predict porin topology. Four porins of known structure were selected as test-cases and their secondary structure delineated. The specificity and sensitivity of 11 methods were separately evaluated. Our critical assessment shows that some secondary structure prediction methods (PHD, Dsc, Sopma) originally designed to predict globular protein structure are useful on porin topology prediction. The overall best prediction is obtained by combining these three \"generalist\" methods with a transmembrane beta strand prediction technique. This \"consensus\" method was applied to Brucella porins Omp2b and Omp2a, sharing no sequence homology with any other porin. The predicted topology is a 16-stranded antiparallel beta barrel with Omp2a showing a higher number of negatively charged residue in the exposed loops than Omp2b. Experiments are in progress to validate the proposed topology and the functional hypotheses. The ability of the proposed consensus method to predict topology of complex outer membrane protein is briefly discussed.", "Pannexins (Panx1, 2, 3) are channel-forming glycoproteins expressed in mammalian tissues. We previously reported that N-glycosylation acts as a regulator of the localization and intermixing of Panx1 and Panx3, but its effects on Panx2 are currently unknown. Panx1 and Panx2 intermixing can regulate channel properties, and both pannexins have been implicated in neuronal cell death after ischemia. Our objectives were to validate the predicted N-glycosylation site of Panx2 and to study the effects of Panx2 glycosylation on localization and its capacity to interact with Panx1. We used site-directed mutagenesis, enzymatic de-glycosylation, cell-surface biotinylation, co-immunoprecipitation, and confocal microscopy. Our results showed that N86 is the only N-glycosylation site of Panx2. Panx2 and the N86Q mutant are predominantly localized to the endoplasmic reticulum (ER) and cis-Golgi matrix with limited cell surface localization was seen only in the presence of Panx1. The Panx2 N86Q mutant is glycosylation-deficient and tends to aggregate in the ER reducing its cell surface trafficking but it can still interact with Panx1. Our study indicates that N-glycosylation may be important for folding and trafficking of Panx2. We found that the un-glycosylated forms of Panx1 and 2 can readily interact, regulating their localization and potentially their channel function in cells where they are co-expressed." ]

[ "MOTIVATION: Genome plotting is performed using a wide range of visualizations tools each with emphasis on a different informative dimension of the genome. These tools can provide a deeper insight into the genomic structure of the organism.RESULTS: Here, we announce a new visualization tool that is specifically designed for chloroplast genomes. It allows the users to depict the genetic architecture of up to ten chloroplast genomes in the vicinity of the sites connecting the inverted repeats to the short and long single copy regions. The software and its dependent libraries are fully coded in R and the reflected plot is scaled up to realistic size of nucleotide base pairs in the vicinity of the junction sites. We introduce a website for easier use of the program and R source code of the software to be used in case of preferences to be changed and integrated into personal pipelines. The input of the program is an annotation GenBank (.gb) file, the accession or GI number of the sequence or a DOGMA output file. The software was tested using over a 100 embryophyte chloroplast genomes and in all cases a reliable output was obtained.AVAILABILITY AND IMPLEMENTATION: Source codes and the online suit available at https://irscope.shinyapps.io/irapp/ or https://github.com/Limpfrog/irscope.", "Exome sequencing studies have identified multiple genes harboring de novo loss-of-function (LoF) variants in individuals with autism spectrum disorders (ASD), including TBR1, a master regulator of cortical development. We performed ChIP-seq for TBR1 during mouse cortical neurogenesis and show that TBR1-bound regions are enriched adjacent to ASD genes. ASD genes were also enriched among genes that are differentially expressed in Tbr1 knockouts, which together with the ChIP-seq data, suggests direct transcriptional regulation. Of the nine ASD genes examined, seven were misexpressed in the cortices of Tbr1 knockout mice, including six with increased expression in the deep cortical layers. ASD genes with adjacent cortical TBR1 ChIP-seq peaks also showed unusually low levels of LoF mutations in a reference human population and among Icelanders. We then leveraged TBR1 binding to identify an appealing subset of candidate ASD genes. Our findings highlight a TBR1-regulated network of ASD genes in the developing neocortex that are relatively intolerant to LoF mutations, indicating that these genes may play critical roles in normal cortical development.", "Chronic wasting disease (CWD) is an emergent, rapidly spreading prion disease of cervids. Shedding of infectious prions in saliva and urine is thought to be an important factor in CWD transmission. To help to elucidate this issue, we applied an in vitro amplification assay to determine the onset, duration, and magnitude of prion shedding in longitudinally collected saliva and urine samples from CWD-exposed white-tailed deer. We detected prion shedding as early as 3 months after CWD exposure and sustained shedding throughout the disease course. We estimated that the 50% lethal dose (LD50) for cervidized transgenic mice would be contained in 1 ml of infected deer saliva or 10 ml of urine. Given the average course of infection and daily production of these body fluids, an infected deer would shed thousands of prion infectious doses over the course of CWD infection. The direct and indirect environmental impacts of this magnitude of prion shedding on cervid and noncervid species are surely significant.IMPORTANCE: Chronic wasting disease (CWD) is an emerging and uniformly fatal prion disease affecting free-ranging deer and elk and is now recognized in 22 U.S. states and 2 Canadian provinces. It is unique among prion diseases in that it is transmitted naturally through wild populations. A major hypothesis to explain CWD's florid spread is that prions are shed in excreta and transmitted via direct or indirect environmental contact. Here we use a rapid in vitro assay to show that infectious doses of CWD prions are in fact shed throughout the multiyear disease course in deer. This finding is an important advance in assessing the risks posed by shed CWD prions to animals as well as humans.", "The packaging of the eukaryotic genome into chromatin is likely to have a profound influence on transcription from the underlying genes. We have previously shown that the disassembly of promoter nucleosomes is obligatory for activation of the yeast PHO5 and PHO8 genes. Here, we show that the PHO5 promoter nucleosomes are reassembled concomitant with transcriptional repression and displacement of the TATA binding protein and RNA polymerase II (RNA Pol II). We identify the histone H3-H4 chaperone Spt6 as the factor that mediates nucleosome reassembly onto the PHO5, PHO8, ADH2, ADY2, and SUC2 promoters during transcriptional repression. Furthermore, promoter nucleosome reassembly is essential for transcriptional repression. In the absence of Spt6-mediated nucleosome reassembly, the activators Pho4 and Pho2 are displaced from the PHO5 promoter in repressing conditions, yet transcription is sustained. As such, these studies demonstrate that activators are not required for transcription in the absence of competing chromatin reassembly.", "BACKGROUND: Recently, mutations affecting different domains of dynamin-2 (DNM2) were associated alternatively with autosomal dominant centronuclear myopathy or dominant intermediate (demyelinating and axonal) Charcot-Marie-Tooth disease (CMT) type B.OBJECTIVE: To assess the etiologic role of DNM2 in CMT.METHODS: We performed a mutational screening of DNM2 exons 13 through 16 encoding the pleckstrin homology domain in a large series of CMT patients with a broad range of nerve conduction velocities and without mutations in more common genes.RESULTS: We identified two novel DNM2 mutations that cosegregated with purely axonal CMT in two pedigrees without clinical evidence of primary myopathy.CONCLUSION: Patients with axonal Charcot-Marie-Tooth disease type 2 neuropathy without mutations in more common genes should undergo investigation for DNM2 pleckstrin homology.", "The potential of the HER2-targeting antibody trastuzumab as a radioimmunoconjugate useful for both imaging and therapy was investigated. Conjugation of trastuzumab with the acyclic bifunctional chelator CHX-A\"-DTPA yielded a chelate:protein ratio of 3.4 ± 0.3; the immunoreactivity of the antibody unaffected. Radiolabeling was efficient, routinely yielding a product with high specific activity. Tumor targeting was evaluated in mice bearing subcutaneous (s.c.) xenografts of colorectal, pancreatic, ovarian, and prostate carcinomas. High uptake of the radioimmunoconjugate, injected intravenously (i.v.), was observed in each of the models, and the highest tumor %ID/g (51.18 ± 13.58) was obtained with the ovarian (SKOV-3) tumor xenograft. Specificity was demonstrated by the absence of uptake of 111In-trastuzumab by melanoma (A375) s.c. xenografts and 111In-HuIgG by s.c. LS-174T xenografts. Minimal uptake of i.v. injected 111In-trastuzumab in normal organs was confirmed in non-tumor-bearing mice. The in vivo behavior of 111In-trastuzumab in mice bearing intraperitoneal (i.p.) LS-174T tumors resulted in a tumor %ID/g of 130.85 ± 273.34 at 24 h. Visualization of tumor, s.c. and i.p. xenografts, was achieved by γ-scintigraphy and PET imaging. Blood pool was evident as expected, but cleared over time. The blood pharmacokinetics of i.v. and i.p. injected 111In-trastuzumab was determined in mice with and without tumors. The data from these in vitro and in vivo studies supported advancement of radiolabeled trastuzumab into two clinical studies, a Phase 0 imaging study in the Molecular Imaging Program of the National Cancer Institute and a Phase 1 radioimmunotherapy study at the University of Alabama.", "Gaucher's disease (GD) results from a deficiency of the lysosomal enzyme glucocerebrosidase and, in very rare occasions, a deficiency of its activator, the saposin C. The complexity of identification and characterization of mutations in the gene of glucocerebrosidase (GBA1) is caused by a great amount of mutated alleles, the existence of a highly homologous pseudogene and its location in a very rich zone in genes, which promotes the presence of complex alleles. Although genotype-phenotype correlations in EG are not completely established, there are a series of generalities, as the mutation c.1226A>G (N370S) is often associated with a certain degree of neuroprotection and the homozygosity for the c.1448T>C (L444P) mutation presents with neurological symptoms." ]

[ "Grafting of cell lines and primary tumours is a crucial step in the drug development process between cell line studies and clinical trials. Disambiguate is a program for computationally separating the sequencing reads of two species derived from grafted samples. Disambiguate operates on DNA or RNA-seq alignments to the two species and separates the components at very high sensitivity and specificity as illustrated in artificially mixed human-mouse samples. This allows for maximum recovery of data from target tumours for more accurate variant calling and gene expression quantification. Given that no general use open source algorithm accessible to the bioinformatics community exists for the purposes of separating the two species data, the proposed Disambiguate tool presents a novel approach and improvement to performing sequence analysis of grafted samples. Both Python and C++ implementations are available and they are integrated into several open and closed source pipelines. Disambiguate is open source and is freely available at https://github.com/AstraZeneca-NGS/disambiguate.", "OBJECTIVE: Review available data on adjunctive therapies for type 1 diabetes (T1D), with a special focus on newer antihyperglycemic agents.METHODS: Published data on hypoglycemia, obesity, mortality, and goal attainment in T1D were reviewed to determine unmet therapeutic needs. PubMed databases and abstracts from recent diabetes meetings were searched using the term \"type 1 diabetes\" and the available and investigational sodium-glucose cotransporter (SGLT) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 inhibitors, and metformin.RESULTS: The majority of patients with T1D do not meet glycated hemoglobin (A1C) goals established by major diabetes organizations. Hypoglycemia risks and a rising incidence of obesity and metabolic syndrome featured in the T1D population limit optimal use of intensive insulin therapy. Noninsulin antihyperglycemic agents may enable T1D patients to achieve target A1C levels using lower insulin doses, which may reduce the risk of hypoglycemia. In pilot studies, the SGLT2 inhibitor dapagliflozin and the GLP-1 receptor agonist liraglutide reduced blood glucose, weight, and insulin dose in patients with T1D. Phase 2 studies with the SGLT2 inhibitor empagliflozin and the dual SGLT1 and SGLT2 inhibitor sotagliflozin, which acts in the gut and the kidney, have demonstrated reductions in A1C, weight, and glucose variability without an increased incidence of hypoglycemia.CONCLUSION: Newer antihyperglycemic agents, particularly GLP-1 agonists, SGLT2 inhibitors, and dual SGLT1 and SGLT2 inhibitors, show promise as adjunctive treatment for T1D that may help patients achieve better glucose control without weight gain or increased hypoglycemia.", "Eukaryotic histones serve as prototypical examples of posttranslational complexity with diverse modifications (PTMs) on many different residues that comprise a \"Histone Code\". To help crack this code more efficiently, we demonstrate a new strategy for protein characterization wherein complete PTM descriptions are obtained by database retrieval instead of manual interpretation of information-rich data from high-resolution tandem mass spectrometry (MS/MS). A database of nearly 50 000 modified histone H4 sequences was created and queried with 91 fragment ions from electron capture dissociation of a histone form +112 Da (versus unmodified mass) selectively accumulated in a quadrupole Fourier transform hybrid mass spectrometer. The correct form atop the retrieval list indicated dimethylation at Lys20, acetylation at the N terminus, and acetylation at Lys16 (resolved from trimethylation, Deltam = 0.036 Da). A statistical evaluation reveals the critical role of mass accuracy and that PTM \"isomers\" are retrieved as next-best matches. The applicability of shotgun annotation to forms of H4 with up to six PTMs is demonstrated, with extensibility to other histones (e.g., H2A, H2B, H3) and other protein classes projected.", "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.", "INTRODUCTION: Advanced understanding of the pathogenesis of renal cell carcinoma (RCC) has led to development and approval of several molecularly targeted therapies since 2005. Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. In the randomized Phase III AXIS trial, axitinib significantly prolonged progression-free survival compared with sorafenib, respectively (6.7 vs 4.7 months; p < 0.0001), and improved objective response rate (19 vs 9%; p = 0.0001), resulting in its approval for advanced or metastatic RCC after failure of one systemic therapy. However, overall survival was similar with axitinib and sorafenib. Common adverse events associated with axitinib include diarrhea, hypertension and fatigue.AREAS COVERED: The properties, clinical efficacy, adverse events, pharmacokinetics and pharmacodynamics of axitinib are summarized and its position in the overall therapeutic landscape for metastatic RCC among several targeted therapies is described.EXPERT OPINION: Axitinib is generally well-tolerated and provides definitive clinical benefits in patients with advanced or metastatic RCC as second-line therapy. However, as with other tyrosine kinase inhibitors of the same class, axitinib does not prolong overall survival; therefore, selection of second-line tyrosine kinase inhibitor therapy, including axitinib, must be carefully considered to maximize outcomes for each patient.", "BACKGROUND: Familial history of obesity (FHO) and certain dietary habits are risk factors for obesity. The objectives of this cross-sectional study were 1) to derive dietary patterns using factor analysis in a population of men and women with and without FHO; 2) to compare mean factor scores for each dietary pattern between individuals with and without FHO; and 3) to examine the association between these patterns and anthropometric, lifestyle and sociodemographic variables.METHODS: A total of 197 women and 129 men with a body mass index <30 kg/m2 were recruited. A positive FHO (FHO+) was defined as having at least one obese first-degree relative and a negative FHO (FHO-) as no obese first-degree relative. Dietary data were collected from a food frequency questionnaire. Factor analysis was performed to derive dietary patterns. Mean factor scores were compared using general linear model among men and women according to FHO. Regression analyses were performed to study the relationship between anthropometric, lifestyle and sociodemographic variables, and each dietary pattern.RESULTS: Two dietary patterns were identified in both men and women : the Western pattern characterized by a higher consumption of red meats, poultry, processed meats, refined grains as well as desserts, and the Prudent pattern characterized by greater intakes of vegetables, fruits, non-hydrogenated fat, and fish and seafood. Similar Western and Prudent factor scores were observed in individual with and without FHO. In men with FHO+, the Western pattern is negatively associated with age and positively associated with physical activity, smoking, and personal income. In women with FHO-, the Prudent pattern is negatively associated with BMI and smoking and these pattern is positively associated with age and physical activity.CONCLUSION: Two dietary patterns have been identified among men and women with and without FHO. Although that FHO does not seem to influence the adherence to dietary patterns, results of this study suggest that anthropometric, lifestyle and sociodemographic variables associated with dietary patterns differ according to FHO and gender.", "CONTEXT: Elagolix is an oral gonadotropin-releasing hormone (GnRH) antagonist recently approved for the treatment of endometriosis-associated pain and being developed for heavy menstrual bleeding associated with uterine fibroids.OBJECTIVE: The objective was to evaluate the effects of elagolix on ovulation and ovarian sex hormones.DESIGN AND SETTING: This was a randomized, open-label, multicenter study.PARTICIPANTS: Participants were healthy ovulatory women aged 18 to 40 years.INTERVENTIONS: Elagolix was administered orally for 3 continuous 28-day dosing intervals at 100 to 200 mg once daily (QD), 100 to 300 mg twice daily (BID), and 300 mg BID plus estradiol/norethindrone acetate (E2/NETA) 1/0.5 mg QD.MAIN OUTCOME MEASURES: The main outcomes measures were ovulation rates measured by transvaginal ultrasound, progesterone concentrations, and hormone suppression.RESULTS: Elagolix suppressed ovulation in a dose-dependent manner. The percentage of women who ovulated was highest at 100 mg QD (78%), intermediate at 150 and 200 mg QD and 100 mg BID (47%-57%), and lowest at 200 and 300 mg BID (32% and 27%, respectively). Addition of E2/NETA to elagolix 300 mg BID further suppressed the ovulation rate to 10%. Elagolix also suppressed luteinizing hormone and follicle stimulating hormone in a dose-dependent manner, leading to dose-dependent suppression of estradiol and progesterone. Elagolix had no effect on serum biomarker of ovarian reserve, and reduced endometrial thickness compared to the screening cycle.CONCLUSION: Women being treated with elagolix may ovulate and should use effective methods of contraception. The rate of ovulation was lowest with elagolix 300 mg BID plus E2/NETA 1/0.5 mg QD.", "Huntington's disease is an inherited disorder caused by expansion of a CAG trinucleotide repeat in the IT15 gene, which leads to expansion of a polyglutamine tract within the protein called huntingtin. Despite the characterization of the IT15 gene and the mutation involved in the disease, the normal function of huntingtin and the effects of the mutation on its function and on its neuronal location remain unknown. To study whether mutated huntingtin has the same neuronal distribution and intracellular location as normal huntingtin, we analyzed immunohistochemically both forms of this protein in the brain of 5 controls and 5 patients with Huntington's disease. We show that the distribution of mutated huntingtin is, like that of the normal form, heterogeneous throughout the brain, but is not limited to vulnerable neurons in Huntington's disease, supporting the hypothesis that the presence of the mutated huntingtin in a neuron is not in itself sufficient to lead to neuronal death. Moreover, whereas normal huntingtin is detected in some neuronal perikarya, nerve fibers, and nerve endings, the mutated form is observed in some neuronal perikarya and proximal nerve processes but is not detectable in nerve endings. Our results suggest that the expression or processing of the mutated huntingtin in perikarya and nerve endings differs quantitatively or qualitatively from the expression of the normal form in the same neuronal compartments.", "Gaucher disease is a heterogeneous disease characterized by impaired activity of the lysosomal enzyme glucocerebrosidase. This heterogeneity is attributed to a large number of mutations in the corresponding gene. In order to test the biochemical properties of some mutations prevalent among Israeli populations, the normal human glucocerebrosidase cDNA and cDNAs carrying mutations N370S, L444P, D409H, recTL, recNcil, P415R and 84GG were coupled to the T7 RNA polymerase promoter in a vaccinia virus-derived expression vector (pTM-1). Recombinant viruses were produced and used to infect human tissue culture cells. RNA and protein stability, recognition by anti-glucocerebrosidase monoclonal antibodies and intracellular enzymatic activity were measured. The results demonstrated that the D409H allele directed synthesis of cytoplasmic RNA with decreased stability compared with its normal counterpart or other mutated forms. The D409H and L444P mutated proteins had lower stability than that of their normal counterpart, while the recNcil-mutated protein was more stable. Only glucocerebrosidase forms harboring leucine at position 444 were recognized by the anti-glucocerebrosidase monoclonal antibodies used (8E4 and 2C7). Measurements of enzymatic activity of the recombinant proteins in cells loaded with a fluorescent glucosylceramide demonstrated that the N370S mutated enzyme had activity similar to that of the normal enzyme. The other mutated enzymes exhibited varying degrees of activities, generally corresponding to the phenotypes with which they are associated. The results presented demonstrate the use of the vaccinia virus-derived expression system and of loading living cells with fluorescent substrate as efficient tools for studying mutants in Gaucher disease and in other lysosomal diseases.", "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.", "The incidence of migraine is higher among women than men and peaks during the reproductive years, when contraceptive medication use is common. Atogepant, a potent, selective antagonist of the calcitonin gene-related peptide receptor-in development for migraine prevention-is thus likely to be used by women taking oral contraceptives. This phase 1, open-label, single-center, 2-period, fixed-sequence study examined the effect of multiple-dose atogepant 60 mg once daily on the single-dose pharmacokinetics of a combination oral contraceptive, ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg (EE/LNG), in healthy postmenopausal or oophorectomized women. For participants in period 1, a single dose of EE/LNG was followed by a 7-day washout. In period 2, atogepant was given once daily on days 1-17; an oral dose of EE/LNG was coadministered with atogepant on day 14. Plasma pharmacokinetic parameters for EE and LNG were assessed following administration with and without atogepant. Twenty-six participants aged 45-64 years enrolled; 22 completed the study in accordance with the protocol. The area under the concentration-time curve extrapolated to infinity (AUC0-∞ ) of LNG was increased by 19% when administered with atogepant. Coadministration of atogepant and a single dose of EE/LNG did not substantially alter the pharmacokinetics of EE; the ∼19% increase in plasma AUC0-∞ of LNG is not anticipated to be clinically significant. Overall, atogepant alone and in combination with EE/LNG was generally well tolerated, with no new safety signals identified.", "BACKGROUND: Duchenne muscular dystrophy is caused by dystrophin deficiency and muscle deterioration and preferentially affects boys. Antisense-oligonucleotide-induced exon skipping allows synthesis of partially functional dystrophin. We investigated the efficacy and safety of drisapersen, a 2'-O-methyl-phosphorothioate antisense oligonucleotide, given for 48 weeks.METHODS: In this exploratory, double-blind, placebo-controlled study we recruited male patients (≥5 years of age; time to rise from floor ≤7 s) with Duchenne muscular dystrophy from 13 specialist centres in nine countries between Sept 1, 2010, and Sept 12, 2012. By use of a computer-generated randomisation sequence, we randomly allocated patients (2:2:1:1; block size of six; no stratification) to drisapersen 6 mg/kg or placebo, each given subcutaneously and either continuously (once weekly) or intermittently (nine doses over 10 weeks). The primary endpoint was change in 6-min walk distance (6MWD) at week 25 in patients in the intention-to-treat population for whom data were available. Safety assessments included renal, hepatic, and haematological monitoring and recording of adverse events. This trial is registered with ClinicalTrials.gov, number NCT01153932.FINDINGS: We recruited 53 patients: 18 were given continuous drisapersen, 17 were given intermittent drisapersen, and 18 were given placebo (continuous and intermittent groups combined). At week 25, mean 6MWD had increased by 31·5 m (SE 9·8) from baseline for continuous drisapersen, with a mean difference in change from baseline of 35·09 m (95% CI 7·59 to 62·60; p=0·014) versus placebo. We recorded no difference in 6MWD changes from baseline between intermittent drisapersen (mean change -0·1 [SE 10·3]) and placebo (mean difference 3·51 m [-24·34 to 31·35]) at week 25. The most common adverse events in drisapersen-treated patients were injection-site reactions (14 patients given continuous drisapersen, 15 patients given intermittent drisapersen, and six given placebo) and renal events (13 for continuous drisapersen, 12 for intermittent drisapersen, and seven for placebo), most of which were subclinical proteinuria. None of the serious adverse events reported (one for continuous, two for intermittent, and two for placebo) resulted in withdrawal from the study.INTERPRETATION: Continuous drisapersen resulted in some benefit in 6MWD versus placebo at week 25. The safety findings are similar to those from previous studies. Ambulation improvements in this young population with early-stage Duchenne muscular dystrophy are encouraging but need to be confirmed in larger studies.FUNDING: GlaxoSmithKline, Prosensa Therapeutics BV (a subsidiary of Prosensa Holding NV)." ]

[ "Bacteriophage T4 initiates DNA replication from specialized structures that form in its genome. Immediately after infection, RNA-DNA hybrids (R-loops) occur on (at least some) replication origins, with the annealed RNA serving as a primer for leading-strand synthesis in one direction. As the infection progresses, replication initiation becomes dependent on recombination proteins in a process called recombination-dependent replication (RDR). RDR occurs when the replication machinery is assembled onto D-loop recombination intermediates, and in this case, the invading 3' DNA end is used as a primer for leading strand synthesis. Over the last 15 years, these two modes of T4 DNA replication initiation have been studied in vivo using a variety of approaches, including replication of plasmids with segments of the T4 genome, analysis of replication intermediates by two-dimensional gel electrophoresis, and genomic approaches that measure DNA copy number as the infection progresses. In addition, biochemical approaches have reconstituted replication from origin R-loop structures and have clarified some detailed roles of both replication and recombination proteins in the process of RDR and related pathways. We will also discuss the parallels between T4 DNA replication modes and similar events in cellular and eukaryotic organelle DNA replication, and close with some current questions of interest concerning the mechanisms of replication, recombination and repair in phage T4.", "The different types of cells in the lung, from the conducting airway epithelium to the alveolar epithelium and the pulmonary vasculature, are interconnected by gap junctions. The specific profile of gap junction proteins, the connexins, expressed in these different cell types forms compartments of intercellular communication that can be further shaped by the release of extracellular nucleotides via pannexin1 channels. In this review, we focus on the physiology of connexins and pannexins and describe how this lung communication network modulates lung function and host defenses in conductive and respiratory airways.", "BACKGROUND/PURPOSE: Hirschsprung disease (HSCR) is a congenital disorder characterized by the absence of intramural ganglion cells along with variable lengths of the gastrointestinal tract. Recent studies have indicated the potential function of neuregulin-1 (NRG1) in HSCR, which encodes the heregulins and other mitogenic ligands for the ErbB family. The purpose of this study was to further clarify the role of NRG1 in the pathogenesis of HSCR.METHODS: We examined the NRG1 messenger RNA (messenger RNA) and protein expression levels in gut tissues of 63 patients with sporadic HSCR (both stenotic and dilated gut tissues) and 35 controls. Moreover, using the methylation-specific polymerase chain reaction, we examined the methylation pattern of exon 1 of the NRG1 gene.RESULTS: The mRNA expression levels of NRG1 were significantly higher in tissues of HSCR than those in controls, and the increased NRG1 protein levels in HSCR were consistent with the mRNA levels. However, no methylation pattern change was observed in exon 1 of the gene among different groups.CONCLUSIONS: Our study demonstrates that the aberrant expression of NRG1 may play an important role in the pathology of HSCR. DNA methylation of the gene seems not to be involved in the mechanism of such aberrant expression, and other factors should be explored.", "Netherton syndrome is a severe autosomal recessive skin disorder characterized by congenital erythroderma, a specific hair-shaft abnormality, and atopic manifestations with high IgE levels. Recently, we identified SPINK5, which encodes the serine protease inhibitor Kazal-type 5 protein (LEKTI), as the defective gene in Netherton syndrome. Here we describe the intron-exon organization of the gene and characterize the SPINK5 mutations in patients from 21 families of different geographic origin, using denaturing high performance liquid chromatography and direct sequencing. We identified 18 mutations, of which 13 were novel and seven (39%) were recurrent. The majority of the mutations were clustered between exons 1-8 and exons 21-26. They comprised four nonsense mutations (22%), eight frameshift insertions or deletions (44%), and six splice-site defects (33%). All mutations predict the formation of premature termination codons. Northern blot analysis showed variable reduction of SPINK5 mutant transcript levels, suggesting variable efficiency of nonsense-mediated mRNA decay. Seven patients were homozygotes, eight were compound heterozygotes, and five were heterozygotes with only one identifiable SPINK5 mutation. Five mutations, one of which resulted in perinatal lethal disease in three families, were associated with certain ethnic groups. We also describe 45 intragenic polymorphisms in the patients studied. The clinical features of erythroderma, trichorrhexis invaginata, and atopic manifestations were present in the majority of affected individuals and ichthyosis linearis circumflexa was seen in 12 out of 24 patients. Interfamilial and intrafamilial variation in disease severity was observed, with no clear correlation between mutations and phenotype, suggesting that the degree of severity may be affected by other factors.", "The muscle LIM protein (MLP) and cofilin 2 (CFL2) are important regulators of striated myocyte function. Mutations in the corresponding genes have been directly associated with severe human cardiac and skeletal myopathies, and aberrant expression patterns have often been observed in affected muscles. Herein, we have investigated whether MLP and CFL2 are involved in common molecular mechanisms, which would promote our understanding of disease pathogenesis. We have shown for the first time, using a range of biochemical and immunohistochemical methods, that MLP binds directly to CFL2 in human cardiac and skeletal muscles. The interaction involves the inter-LIM domain, amino acids 94 to 105, of MLP and the amino-terminal domain, amino acids 1 to 105, of CFL2, which includes part of the actin depolymerization domain. The MLP/CFL2 complex is stronger in moderately acidic (pH 6.8) environments and upon CFL2 phosphorylation, while it is independent of Ca(2+) levels. This interaction has direct implications in actin cytoskeleton dynamics in regulating CFL2-dependent F-actin depolymerization, with maximal depolymerization enhancement at an MLP/CFL2 molecular ratio of 2:1. Deregulation of this interaction by intracellular pH variations, CFL2 phosphorylation, MLP or CFL2 gene mutations, or expression changes, as observed in a range of cardiac and skeletal myopathies, could impair F-actin depolymerization, leading to sarcomere dysfunction and disease.", "DNA methylation is widespread in most species, from bacteria to mammals, and is crucial for genomic imprinting, gene expression, and embryogenesis. DNA methylation occurs via two major classes of enzymatic reactions: maintenance-type methylation catalyzed by DNA (cytosine-5-)-methyltransferase (DNMT) 1, and de novo methylation catalyzed by DNMT 3 alpha (DNMT3A) and -beta (DNMT3B). The expression pattern and regulation of DNMT genes in primordial germ cells (PGCs) and germ line cells has not been sufficiently established in birds. Therefore, we employed bioinformatics, RT-PCR, real-time PCR, and in situ hybridization analyses to examine the structural conservation and conserved expression patterns of chicken DNMT family genes. We further examined the regulation of a candidate de novo DNA methyltransferase gene, cDNMT3B by cotransfection of cDNMT3B 3'UTR- and cDNMT3B 3'UTR-specific miRNAs through a dual fluorescence reporter assay. All cDNMT family members were differentially detected during early embryonic development. Of interest, cDNMT3B expression was highly detected in early embryos and in PGCs. During germ line development and sexual maturation, cDNMT3B expression was reestablished in a female germ cell-specific manner. In the dual fluorescence reporter assay, cDNMT3B expression was significantly downregulated by four miRNAs: gga-miR-15c (25.82%), gga-miR-29b (30.01%), gga-miR-383 (30.0%), and gga-miR-222 (31.28%). Our data highlight the structural conservation and conserved expression patterns of chicken DNMTs. The miRNAs investigated in this study may induce downregulation of gene expression in chicken PGCs and germ cells.", "The human T-cell leukemia virus type I Tax protein transforms T cells through induced expression of many cellular genes, including those encoding the growth-related proteins interleukin 2 and the alpha chain of its receptor. Induction of these genes is mediated, at least in part, through Tax-dependent posttranslational activation of NF-kappa B, typically heterodimers of p50 (NF-kappa B1) and p65 (RelA). The preexisting NF-kappa B proteins are retained in the cytoplasm of cells by association with inhibitory ankyrin-motif-containing I kappa B proteins, primarily I kappa B-alpha but also including the precursor proteins p105 (NF-kappa B1) and p100 (NF-kappa B2). Here we demonstrate the existence of a previously undescribed multimeric cytoplasmic complex in which NF-kappa B dimers are associated with the p100 inhibitor in a manner dependent on the precursor protein's ankyrin domain. We also demonstrate an antagonistic effect of the Tax protein on the cytoplasmic sequestration function of p100; this in turn leads to nuclear translocation of NF-kappa B dimers liberated from multimeric complexes. Tax may exert these effects through the physical association with p100. Tax also relieves the p100-mediated inhibition of DNA binding by p50-p65 heterodimers in vitro. The results demonstrate a mechanism by which Tax may activate NF-kappa B in T cells." ]

[ "An essentially full-length cDNA clone for the human enzyme monoamine oxidase type A (MAO-A) has been used to determine the chromosomal location of a gene encoding it. This enzyme is important in the degradative metabolism of biogenic amines throughout the body and is located in the outer mitochondrial membrane of many cell types. Southern blot analysis of PstI-digested human DNA revealed multiple fragments that hybridized to this probe. Using rodent-human somatic cell hybrids containing all or part of the human X chromosome, we have mapped these fragments to the region Xp21-p11. A restriction fragment length polymorphism (RFLP) for this MAOA gene was identified and used to evaluate linkage distances between this locus and several other loci on Xp. The MAOA locus lies between DXS14 and OTC, about 29 cM from the former.", "Lactotransferrin (LTF) has been shown to regulate tumorogenesis. However, little is known about the role of LTF in regulating the development of human nasopharyngeal carcinoma (NPC). The aim of our study was to investigate whether LTF could regulate the development of NPC by characterizing the pattern of LTF expression in human NPC tissues using cDNA and tissue microarrays. Loss of LTF expression was observed in a significantly higher frequency of NPC tissues compared to that in nontumor nasopharyngeal epithelial tissues. While 61.25% of NPC tissues at the T1/T2 stage were positive for LTF expression, only 40.82% of NPC at the T3/T4 stage were stained by anti-LTF. Similarly, 41.58% of NPC with local lymph node metastasis displayed LTF expression, a value significantly lower than the 46.36% in primary tumors (p < 0.05). These findings suggest that LTF may negatively regulate the development and metastasis of NPC in vivo. Furthermore, overexpression of or treatment with LTF inhibited the proliferation of NPC cells and promoted cell cycle arrest at the G(0)/G(1) phase in vitro. While LTF treatment downregulated expression of cyclin D1 and phosphorylation of retinoblastoma protein (Rb), expression of p21 and p27 in 5-8F NPC cells was enhanced. Moreover, LTF treatment modulated the mitogen-activated protein kinase (MAPK) pathway, but did not affect p53 and STAT3 expression in 5-8F NPC cells. Thus LTF is likely to be a candidate tumor suppressor and downregulates the development of NPC by inhibiting NPC proliferation through induction of cell cycle arrest and modulation of the MAPK signaling pathway. Therefore, our findings provide new insights in understanding the mechanism(s) underlying the action of LTF in regulating the development of human NPC.", "Brooke-Spiegler syndrome, familial cylindromatosis, and familial trichoepithelioma are autosomal-dominant genetic predispositions for benign tumors of skin appendages caused by mutations in the CYLD gene localized on chromosome 16q12-q13. The encoded protein functions as ubiquitin-specific protease (UBP), which negatively regulates NF-kappaB and c-Jun N-terminal kinase (JNK) signaling. We investigated five families affected with these skin neoplasms and identified four premature stop codons and the novel missense mutation D681G in a family in which 11 of 12 investigated tumors were trichoepitheliomas. CYLD protein harboring this missense mutation had a significant reduced ability to inhibit TNF receptor-associated factor (TRAF)2- and TRAF6-mediated NF-kappaB activation, tumor necrosis factor-alpha (TNFalpha)-induced JNK signaling, and to deubiquitinate TRAF2. CYLD-D681G was coimmunoprecipitated by TRAF2, but was unable to cleave K63-linked polyubiquitin chains. Aspartic acid 681 is highly conserved in CYLD homologues and other members of the UBP family, but does not belong to the Cys and His boxes providing the CYLD catalytic triad (Cys601, His871, and Asp889). As reported previously, the homologous residue D295 of HAUSP/USP-7 forms a hydrogen bond with the C-terminal end of ubiquitin and is important for the enzymatic activity. These results underline that D681 in CYLD is required for cleavage of K63-linked polyubiquitin chains.", "LTF (lactotransferrin, also known as lactoferrin) is a key component of innate immune defense. It has recently been found to have anti-tumor and anti-metastatic activity in different cancers. We previously reported LTF to be the most significantly downregulated gene in nasopharyngeal carcinoma (NPC) specimens relative to normal nasopharyngeal epithelial tissues, and it was also negatively associated with the progression and metastasis of NPC. However, the mechanism underlying this remains unclear. In the current study, we revealed that LTF can suppress 3-phosphoinositide-dependent protein kinase 1 expression via the mitogen-activated protein kinase/c-Jun pathway and thus repress AKT signaling. We also showed that LTF interacts with keratin 18 (K18) and so blocks the formation of the K18-14-3-3 complex, leading to downregulation of K18-mediated AKT activation. Thus, LTF suppresses AKT signaling by two separate mechanisms, leading to inhibition of NPC tumorigenesis. This is the first report on the tumor suppressive effects of LTF through repression of AKT signaling in NPC. It suggests that both LTF and AKT signaling merit further study in the field of NPC research.", "Gastric cancer (GC) is the second leading cause of cancer-associated mortality worldwide. In advanced and metastatic GC, conventional chemotherapy results in limited efficacy and the average survival rate is currently approximately 10 months. Dysregulated activation of numerous genes, including zinc finger, DHHC-type containing 14; caspase-associated recruitment domain-containing protein; and Ras association domain family member 10, have been implicated in GC. The tumor suppressor function of lactotransferrin (LTF) has been reported in a variety of tumors, including GC, nasopharyngeal carcinoma (NPC) and prostate cancer. However, the mechanism of the tumor suppressor function of LTF in GC remains unclear. In the present study, the expression levels of LTF in patient GC tissue samples were investigated using reverse transcription-quantitative polymerase chain reaction, and it was demonstrated that the LTF mRNA expression level in GC tissue samples was reduced by ~20-fold compared with the adjacent non-cancerous tissues (t=4.56, P<0.01). A similar trend in LTF protein expression was observed by western blot analysis. Furthermore, the present study demonstrated that the mitogen-activated protein kinase (MAPK) signaling pathway intermediates p38, c-Jun N-terminal kinase (JNK) and c-Jun were highly expressed in GC tissue samples, and indicated that LTF downregulation may be associated with the dysregulation of the MAPK signaling pathway in GC tissues. In addition, the present study indicated that LTF overexpression reduced the expression of p38, JNK2 and c-Jun in the GC cell line, SGC7901. The present study demonstrates that LTF expression is downregulated in GC tissues and that LTF may serve an important role in the dysregulation of the MAPK signaling pathway.", "1. ", "OBJECTIVES: The aim of this study was to evaluate the efficacy of aloe vera (AV) applied in combination with a tongue protector, comparing this with a placebo.METHODS: A total of 75 patients with burning mouth syndrome (BMS) were divided into three groups randomly: Group I (tongue protector three times a day), Group II (tongue protector and 0.5 ml AV at 70% three times a day) and Group III (tongue protector and 0.5 ml placebo three times a day). Symptoms were evaluated by visual analogue scale (VAS), while patient psychological profiles were assessed using the Hospital Anxiety-Depression scale and their quality of life using the Oral Health Impact Profile 49 (OHIP-49). Treatment continued for 3 months.RESULTS: Visual analogue scale pain values improved for all three study groups but without statistically significant differences between the groups (P = 0.210). Regarding quality of life, no significant differences were found between groups with the exception of the OHIP-49 score for handicap. The overall clinical improvement was greater for Group II, with a difference almost reaching significance.CONCLUSIONS: The concomitant prescription of tongue protector and AV is effective for treating patients with BMS.", "LTF (lactotransferrin, or lactoferrin) plays important role in innate immunity, and its anti-tumor function has also been reported in multiple cancers. We previously reported that LTF is significantly down-regulated in nasopharyngeal carcinoma (NPC) and acts as a tumor suppressor by suppressing AKT signaling. However, the exact mechanism of the down-regulation of LTF in NPC has not been revealed. In the current study, we screened and identified LTF is a bona fide target of miR-214 in NPC cells. miR-214 mimics significantly suppressed LTF mRNA and protein expression levels in NPC cells. miR-214 not only can promote NPC cell proliferation and invasion abilities in vitro, but also can accelerate tumor formation and lung metastasis in a mouse xenograft model. The pro-tumor function of miR-214 was depended on LTF suppression since LTF re-expression can reverse it. miR-214 can also activate AKT signaling by suppressing LTF expression. Furthermore, miR-214 expression level was up-regulated in NPC especially in metastasis-prone NPC tumor tissues compared with normal nasopharyngeal epithelial tissues, while the LTF expression level was negatively correlated with miR-214, suggesting that miR-214 targeting is partly responsible for LTF down-regulation in NPC specimens.", "BACKGROUND: Lactotransferrin (LTF) has been confirmed to act as a tumor suppressor in multiple cancers; however, its roles in oral squamous cell carcinoma (OSCC), one of malignant head and neck carcinomas, has not been explored.METHODS: Here, the expression of LTF in OSCC tissues and TCA8113 cells was detected with RT-PCR, qPCR, and IHC. And the correlation between LTF expression and OSCC metastasis was assessed. MS-PCR was performed to reveal the methylation status in promoter regions of LTF both in OSCC tissue samples and cells. The influences of 5-Aza-Cdc treatment to the methylation status and expression levels of LTF were also analyzed. At last, the functions of LTF in OSCC progression were demonstrated by MTT analysis, clone formation assay, and cell cycle analysis in TCA8113 cells with forced ectopic expression of LTF.RESULTS: LTF showed a low or null expression pattern in OSCC tissues and cells, at least partially, due to the hypermethylated status in promoter regions for 5-Aza-Cdc, a methyltransferase inhibitor, could restore the expression of LTF in TCA8113 cells. And the expression level of LTF exhibited a negative correlation with OSCC metastasis.CONCLUSIONS: Re-expression of LTF inhibited the growth, proliferation, as well as cell cycle progression of TCA8113 cells. In conclusion, hypermethylation contributes much to LTF inactivation in OSCC. And LTF can partially reverse the malignant phenotypes of OSCC cells and may be served as a potential target for diagnosis and therapy of OSCC in future.", "Frailty syndrome is frequently encountered in elderly populations. Frailty has been defined as a geriatric syndrome of increased vulnerability to environmental factors. Although knowledge of this syndrome continues to develop, there are still many areas of uncertainty. The pathophysiological pathways, role of biomarkers in the early identification of this syndrome and best management strategies are still under investigation. This study is a literature review of articles published on frailty syndrome in English, French and Spanish. Frailty and aging are similar processes with some differences. Multiple pathophysiological models of frailty have been studied. Factors associated with frailty include hormonal adjustments, sarcopenia and vitamin deficiencies among others. Biomarkers have been studied, but they are not specific. Phenotypes have been developed, but early recognition and prevention of this syndrome are still difficult. In conclusion, early recognition of this syndrome is of paramount importance. Preventative strategies need to be studied. The role of specific biomarkers in early detection of frailty needs to be defined. Clinical trials are needed to find better interventions for this syndrome.", "PURPOSE: Orteronel (TAK-700) is an investigational, nonsteroidal, oral, inhibitor of androgen synthesis with greater specificity for 17,20-lyase than for 17α-hydroxylase. We investigated orteronel without steroids in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC; M0).EXPERIMENTAL DESIGN: Patients with nmCRPC and rising prostate-specific antigen (PSA) received orteronel 300 mg twice daily until PSA progression, metastases, or unacceptable toxicity. The primary endpoint was percentage of patients achieving PSA ≤0.2 ng/mL (undetectable levels) at 3 months. Secondary endpoints included safety, PSA response, time to metastases, and correlated endpoints.RESULTS: Thirty-nine patients with a median baseline PSA doubling time of 2.4 months (range, 0.9-9.2) received a median of fourteen 28-day treatment cycles. PSA decreased >30% in 35 patients and 6 (16%) achieved PSA ≤ 0.2 ng/mL at 3 months. Median times to PSA progression and metastasis were 13.8 and 25.4 months, respectively. Kaplan-Meier estimates of freedom from PSA progression were 57% and 42% at 12 and 24 months, and of freedom from metastasis were 94% and 62% at 12 and 24 months, respectively. At 3 months, median testosterone declined by 89% from baseline. Adverse events led to therapy discontinuation in 12 patients and grade ≥3/4 adverse events occurred in 22 patients. Most frequent all-cause adverse events included fatigue (64%), hypertension (44%), diarrhea (38%), and nausea (33%), which were primarily grade 1/2.CONCLUSIONS: Single-agent orteronel produced marked and durable declines in PSA in patients with nmCRPC. Orteronel has moderate but manageable toxicities and its chronic administration without steroids appears feasible.", "Restless legs syndrome is common in patients with multiple sclerosis but has not been reported as occurring due to an acute, inflammatory, demyelinating attack. Restless legs syndrome is known to be related to low brain iron levels. Multiple sclerosis has been associated with the abnormal accumulation of iron in the chronic, progressive phase of axonal degeneration. Iron deficiency may play a role in demyelination. This suggests that restless legs syndrome may be caused by the inflammatory, demyelinating component of multiple sclerosis rather than axonal degeneration. The author presents a case of self-limited restless legs syndrome occurring as an acute attack of multiple sclerosis, supporting the notion that inflammatory demyelination is the underlying pathophysiology of restless legs syndrome in multiple sclerosis.", "Scleroderma (progressive systemic sclerosis) is a systemic autoimmune disorder characterised by skin sclerosis, calcinosis and changes in microvasculature. The etiology of the disease is unknown but both genetic and environmental factors have been implicated. Telangiectasia (macroscopically visible dilated skin vessels) occurring primarily on the hands and face, are a prominent feature in scleroderma and are present in the majority of patients. Similarly, telangiectasia are found in patients with hereditary hemorrhagic telangiectasia (HHT), a mutational disorder of the germline genes endoglin and ALK-1, members of the TGFbeta receptor family, expressed on endothelial cells. Our study investigated the number, distribution and microscopic characteristics of telangiectasia in both limited (n = 29) and diffuse scleroderma (n = 9) and compared findings with 3 patients with HHT. In limited scleroderma, the mean number of telangiectasia (hand and face) was 36 (0-150) compared with 23 (0-135) in diffuse scieroderma. A significant correlation was observed between the number of telangiectasia on the face and on the hands (p = 0.014). The total number of telangiectasia correlated significantly with the disease duration (p = 0.009). The spatial distribution of the telangiectasia appeared to be random on both hands and foreface in contrast with the distribution of subcutaneous calcification of the hands which occurred predominantly on the distal and flexor surfaces of the first, second and fifth digits. Nailfold microscopic capillaroscopy was performed on 12 patients. No significant correlation was observed between capillary diameter or density and with total number of telangiectasia observed macroscopically. The distribution and microscopic appearance of telangiectasia in scleroderma appeared very similar to those observed in HHT. In view of these similarities we therefore conclude that telangiectactic development in scleroderma may be associated with disorders of the TGFb receptor family proteins found on the microvasculature.", "The prevalence of obesity has led to a surge of interest in understanding the detailed mechanisms underlying adipocyte development. Many protein-coding genes, mRNAs, and microRNAs have been implicated in adipocyte development, but the global expression patterns and functional contributions of long noncoding RNA (lncRNA) during adipogenesis have not been explored. Here we profiled the transcriptome of primary brown and white adipocytes, preadipocytes, and cultured adipocytes and identified 175 lncRNAs that are specifically regulated during adipogenesis. Many lncRNAs are adipose-enriched, strongly induced during adipogenesis, and bound at their promoters by key transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα). RNAi-mediated loss of function screens identified functional lncRNAs with varying impact on adipogenesis. Collectively, we have identified numerous lncRNAs that are functionally required for proper adipogenesis.", "Cytokine storm is an immune reaction to an acute or chronic injury and may be caused by a disease itself or by treatment directed at an underlying disease. The result is an overwhelming release of cytokines which can cause a sepsis-like response and may lead to multi-system organ failure and even death. Because it occurs in various settings, oncology nurses need to be aware of this process when assessing the pediatric oncology patient. Early recognition and treatment initiation is imperative and may lead to better outcomes for the patient.", "Klotho is a recently discovered anti-aging gene and is primarily expressed in kidneys. In humans, the klotho level decreases with age whereas the prevalence of chronic kidney disease (CKD) increases with age. Diabetic nephropathy is the most common form of CKD, which leads to end-stage renal disease. A decrease in klotho has been found in kidneys of patients with diabetic nephropathy. The purpose of this study is to assess whether klotho gene deficiency affects early diabetic nephropathy in a mouse of model of type 1 diabetes induced by streptozotocin (STZ). Male KL(+/-) mutant and wild-type mice (6-8 weeks) were injected with multiple low doses of STZ. Renal functions and renal blood flow were assessed. Kidneys were collected for histological examination and molecular assays of TGFβ1 and mammalian targets of rapamycin (mTOR) signaling. Klotho deficiency in KL(+/-) mutant mice exacerbated STZ-induced increases in urine albumin, blood urea nitrogen, expansion of mesangial matrix in renal glomeruli, and kidney hypertrophy, suggesting a protective role of klotho in kidney function and structure. Klotho deficiency did not affect renal blood flow. Notably, klotho deficiency significantly increased phosphorylation of Smad2, indicating enhanced TGFβ1 signaling in kidneys. Klotho deficiency also increased phosphorylation of mTOR and S6 (a downstream effector of mTOR), indicating enhanced mTOR signaling in kidneys of early diabetic mice. Thus, klotho gene deficiency may make kidneys more susceptible to diabetic injury. Klotho gene deficiency exacerbated early diabetic nephropathy via enhancing both TGFβ1 and mTOR signaling in kidneys.", "Alu elements are the most abundant repetitive elements in the human genome; they have amplified by retrotransposition to reach the present number of more than one million copies. Alu elements can be transcribed in two different ways, by two independent polymerases. 'Free Alu RNAs' are transcribed by Pol III from their own promoter, while 'embedded Alu RNAs' are transcribed by Pol II as part of protein- and non-protein-coding RNAs. Recent studies have demonstrated that both free and embedded Alu RNAs play a major role in post transcriptional regulation of gene expression, for example by affecting protein translation, alternative splicing and mRNA stability. These discoveries illustrate how a part of the 'junk DNA' content of the human genome has been recruited to important functions in regulation of gene expression.", "Circular RNAs (circRNA) have been reported as regulators involved in hepatocellular carcinoma (HCC), but their mechanism of activity remains unknown. This study performed quantitative reverse-transcription polymerase chain reaction to determine if circNFATC3 was downregulated in 46 paired HCC tissues and cell lines. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, apoptotic, and transwell assay proved that circNFATC3 can inhibit hepatoma cell proliferation, apoptosis, and migration/invasion in vitro. Mouse xenograft assay demonstrated that circNFATC3 suppressed tumor size and weight and reduced lung metastasis in vivo, and vice versa. The RNA-seq results showed that NFATC3 itself was the most significantly differentially expressed gene when circNFATC3 was manipulated, and bioinformatics and luciferase reporter assays verified circNFATC3 regulated the expression of NFATC3 by interacting with the hsa-miR-548I. Additionally, it was also indicated that the level of NFATC3 was downregulated in HCC patients also and was significantly correlated with the staging and prognosis of HCC. Moreover, both circNFATC3 and NFATC3 were shown to inhibit the phosphorylation of JNK, c-Jun, AKT, and mTOR signaling pathways. Overall, the circNFATC3 can sponge miR-548I to protect NFATC3 itself, then it regulates hepatoma cell function via the JNK, c-Jun, AKT, and mTOR signaling pathways, and the circNFATC3 can be a tumor-repressor on HCC.", "In the present study, we investigated the 3' untranslated region (UTR) of the mouse core clock gene cryptochrome 1 (Cry1) at the post-transcriptional level, particularly its translational regulation. Interestingly, the 3'UTR of Cry1 mRNA decreased its mRNA levels but increased protein amounts. The 3'UTR is widely known to function as a cis-acting element of mRNA degradation. The 3'UTR also provides a binding site for microRNA and mainly suppresses translation of target mRNAs. We found that AU-rich element RNA binding protein 1 (AUF1) directly binds to the Cry1 3'UTR and regulates translation of Cry1 mRNA. AUF1 interacted with eukaryotic translation initiation factor 3 subunit B and also directly associated with ribosomal protein S3 or ribosomal protein S14, resulting in translation of Cry1 mRNA in a 3'UTR-dependent manner. Expression of cytoplasmic AUF1 and binding of AUF1 to the Cry1 3'UTR were parallel to the circadian CRY1 protein profile. Our results suggest that the 3'UTR of Cry1 is important for its rhythmic translation, and AUF1 bound to the 3'UTR facilitates interaction with the 5' end of mRNA by interacting with translation initiation factors and recruiting the 40S ribosomal subunit to initiate translation of Cry1 mRNA.", "The RNA-binding protein, HuR, associates with the HuR mRNA, but the consequences of this interaction are unknown. Here, we use human diploid fibroblasts (HDFs) and cervical carcinoma cells to study this regulatory paradigm. Ectopic overexpression of HuR potently enhanced the translation and cytoplasmic levels of endogenous HuR, but did not affect HuR mRNA levels. Inhibition of CRM1 function by Lemptomycin B or by knockdown of CRM1 greatly diminished the cytoplasmic levels of endogenous HuR mRNA and hence blocked the induction of endogenous HuR by exogenous HuR. Further studies showed that HuR interacted with the 3'-untranslated region (UTR) of HuR and that overexpression of HuR increased the cytoplasmic levels of a chimeric luciferase-HuR 3'-UTR reporter transcript, as well as luciferase activity; conversely, HuR knockdown reduced both parameters. Moreover, the loss of HuR in senescent, late-passage HDFs was accompanied by a reduced cytoplasmic presence of endogenous HuR mRNA, ectopic Luc-HuR-3'UTR reporter transcript, and luciferase activity relative to what was observed in young, early-passage cells. Our results reveal a positive feedback mechanism for the regulation of HuR, which may play an important role in the regulation of HuR during replicative senescence." ]

[ "Understanding of frontotemporal lobar degeneration, the underlying pathology most often linked to the clinical diagnosis of frontotemporal dementia, is rapidly increasing. Mutations in 7 known genes (MAPT, GRN, C9orf72, VCP, CHMP2B, and, rarely, TARDBP and FUS) are associated with frontotemporal dementia, and the pathologic classification of frontotemporal lobar degeneration has recently been modified to reflect these discoveries. Mutations in one of these genes (GRN), which encodes progranulin, have been implicated in up to a quarter of cases of frontotemporal lobar degeneration with TDP-43 (TAR DNA-binding protein 43)-positive inclusions; currently, there are more than 60 known pathogenic mutations of the gene. We present the clinical, pathologic, and genetic findings on 6 cases from 4 families, 5 of which were shown to have a novel GRN c.708+6_+9delTGAG mutation.", "BACKGROUND: Necrobiosis lipoidica is a rare complication of diabetes mellitus.It is said to occur more often in people with diabetes,a family history of diabetes,tendency to develop diabetes mellitus and those with insulin dependent diabetes.METHOD: We report an evaluated case of necrobiosis lipoidica diabeticorum residing in the northern part of Nigeria.RESULT: The patient was treated for 3 weeks in the hospital on admission and was followed up in the general-out-patient department (GOPD) and has been in good health.AIM AND OBJECTIVE: To bring to the fore of clinicians this dermal complication of diabetes mellitus, the different medical treatments available and the medical treatment employed in our index patient.CONCLUSION: That necrobiosis lipoidica diabeticorum does exist in our environment and requires a high index of suspicion and scrupplelousness in making the diagnosis and treating the patient.", "CTCF is a highly conserved, ubiquitously expressed DNA-binding protein that has widespread capabilities in gene regulation. CTCF plays important roles in cell growth regulatory processes and epigenetic functions. Ectopic expression of CTCF results in severe cell growth inhibition at multiple points within the cell cycle, indicating that CTCF levels must be stringently monitored. We have investigated the subcellular localization of CTCF in detail. Interestingly, we observe that CTCF shows a dynamic cell cycle-dependent distribution. Immunofluorescent staining reveals that in interphase CTCF is a nuclear protein, which is mainly excluded from the nucleolus. Strikingly, CTCF is associated with the centrosome during mitosis, especially from metaphase to anaphase. At telophase, CTCF dissociates from the centrosome and localizes to the midbody and the reformed nuclei. The association of CTCF with centrosomes and the midbody is further confirmed by biochemical fractionation. Moreover, subcellular fractions of CTCF show cell cycle and organelle-specific posttranslational modifications, suggesting different roles for CTCF at different stages of the cell cycle.", "Human beings are constantly exposed to pathogens. The innate immune system is the first line of defense against microbes. It has evolved to recognize conserved microbial motifs (PAMP or pathogen-associated molecular patterns) thanks to a limited array of receptors termed pattern recognition receptors (PRR). Upon activation, most PRR trigger a transcriptional response leading to neosynthesis of hundreds of genes. In contrast, engagement of various PRR in the recently identified inflammasome complexes lead to activation of a cysteine protease, caspase-1. This inflammatory caspase has a dual activity: it triggers the release of very potent proinflammatory cytokines IL-1β and IL-18 and, an hyperinflammatory cell death termed pyroptosis. In this review, we describe the inflammasome receptors and their ligands, the molecular mechanisms leading to the assembly of this innate immune platform and the role of the inflammasome during viral and bacterial infections.", "BACKGROUND: Although levodopa is the most effective oral PD therapy, many patients experience motor fluctuations, including sudden loss of dose effect and delayed benefit. CVT-301 is a levodopa inhalation powder with the potential for rapid onset of action. The objective of this study was to evaluate CVT-301 self-administered by PD patients to relieve OFF episodes.METHODS: PD patients with ≥2 hours per day of OFF time despite oral levodopa ≥4 times per day were randomized to CVT-301 or placebo for 4 weeks, to be used up to 3 times per day for OFF episodes. After 2 weeks, the study-drug dose was escalated from 35 to 50 mg. The primary end point was mean change in UPDRS Part III score from a predose OFF state to the average of postdose scores obtained at 10, 20, 30, and 60 minutes, as assessed in-clinic at the end of week 4. Home diaries were recorded.RESULTS: Eighty-six patients used the study drug at an average frequency of 2.1 times per day for CVT-301 and for placebo. At 4 weeks, least-squares mean change in UPDRS Part III score favored CVT-301 by 7.0 points (P < 0.001). A treatment effect was evident at 10 minutes. At 4 weeks, least-squares mean OFF-time change from baseline favored CVT-301 by 0.9 hours per day (P = 0.045). The most frequently reported adverse events in the CVT-301 group were dizziness, cough, and nausea, each in 7% (3 of 43 patients).CONCLUSIONS: CVT-301 self-administered during OFF episodes provided rapid improvement of motor function, and daily OFF time was significantly reduced at the higher dose. CVT-301 was generally safe and well-tolerated. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.", "In forensic analysis predictive tests for external visible characteristics (or EVCs), including inference of iris color, represent a potentially useful tool to guide criminal investigations. Two recent studies, both focused on forensic testing, have analyzed single nucleotide polymorphism (SNP) genotypes underlying common eye color variation (Mengel-From et al., Forensic Sci. Int. Genet. 4:323 and Walsh et al., Forensic Sci. Int. Genet. 5:170). Each study arrived at different recommendations for eye color predictive tests aiming to type the most closely associated SNPs, although both confirmed rs12913832 in HERC2 as the key predictor, widely recognized as the most strongly associated marker with blue and brown iris colors. Differences between these two studies in identification of other eye color predictors may partly arise from varying approaches to assigning phenotypes, notably those not unequivocally blue or dark brown and therefore occupying an intermediate iris color continuum. We have developed two single base extension assays typing 37 SNPs in pigmentation-associated genes to study SNP-genotype based prediction of eye, skin, and hair color variation. These assays were used to test the performance of different sets of eye color predictors in 416 subjects from six populations of north and south Europe. The presence of a complex and continuous range of intermediate phenotypes distinct from blue and brown eye colors was confirmed by establishing eye color populations compared to genetic clusters defined using Structure software. Our study explored the effect of an expanded SNP combination beyond six markers has on the ability to predict eye color in a forensic test without extending the SNP assay excessively - thus maintaining a balance between the test's predictive value and an ability to reliably type challenging DNA with a multiplex of manageable size. Our evaluation used AUC analysis (area under the receiver operating characteristic curves) and naïve Bayesian likelihood-based classification approaches. To provide flexibility in SNP-based eye color predictive tests in forensic applications we modified an online Bayesian classifier, originally developed for genetic ancestry analysis, to provide a straightforward system to assign eye color likelihoods from a SNP profile combining additional informative markers from the predictors analyzed by our study plus those of Walsh and Mengel-From. Two advantages of the online classifier is the ability to submit incomplete SNP profiles, a common occurrence when typing challenging DNA, and the ability to handle physically linked SNPs showing independent effect, by allowing the user to input frequencies from SNP pairs or larger combinations. This system was used to include the submission of frequency data for the SNP pair rs12913832 and rs1129038: indicated by our study to be the two SNPs most closely associated to eye color.", "Radiation therapy represents an alternative treatment to radical prostatectomy in the management of clinically localized prostate cancer. Radiation-induced second neoplasms are defined by a latency period of at least 5 years, location within the field of radiation therapy, and a histology which differs from the primary tumor. Based on the data in the literature, there is a consistently increased risk of bladder cancer (HR: 1.67, 95% CI 1.55-1.80), rectal cancer (HR: 1.79, 95% CI 1.34-2.38), and colorectal cancer (HR: 1.79, 95% CI 1.34-23.8) following percutaneous radiation therapy. Following brachytherapy only an increased for the development of bladder cancer (HR: 2.14, 95% CI 1.03-3.94) has been observed. The incidence of second neoplasms increases significantly and continuously with the posttreatment time interval. Although bladder cancers following RT of the prostate are usually more locally advanced and of high grade, no negative impact in terms of overall survival and cancer-specific survival has been observed. Symptoms or findings of microhematuria need to be examined thoroughly after radiation therapy to identify bladder cancer quite early.", "OBJECTIVES AND BACKGROUND: Rivaroxaban, an oral direct factor Xa-inhibitor was non-inferior to adjusted dose warfarin in the prevention of stroke and embolism among patients with atrial fibrillation (AF) in the ROCKET-AF trial and has been approved for stroke prevention in AF.CASE REPORT: A 88-years-old female (body-mass-index = 19.95) with AF, hypertension and diabetes mellitus, hospitalized because of heart failure and a non-convulsive epileptic state, was treated by valproate, mirtazepin, nebivolol, digitoxin, lisinopril, gliclazide and amlodipine. Irrespective of renal insufficiency, rivaroxaban 15 mg/d was started. After 3 days rivaroxaban was stopped because of concerns about the bleeding risk. Coagulation tests 28 h after rivaroxaban-intake showed INR 2.26, PT 35%, aPTT 38.3 s and anti-Factor Xa-activity 2.00 U/ml. Explanations for the prolonged anticoagulant activity of rivaroxaban comprise renal failure, the low body-mass-index, the advanced age and drug-drug interactions of rivaroxaban with mirtazepin, valproate and amlodipine.CONCLUSION: Health care providers should consider renal function, concomitant medication, polymorbidity and age prior to prescribing rivaroxaban. Care has to be taken when prescribing rivaroxaban to patients who are different from those included in the ROCKET AF trial.", "De novo assembly of the genome of a species is essential in the absence of a reference genome sequence. Many scalable assembly algorithms use the de Bruijn graph (DBG) paradigm to reconstruct genomes, where a table of subsequences of a certain length is derived from the reads, and their overlaps are analyzed to assemble sequences. Despite longer subsequences unlocking longer genomic features for assembly, associated increase in compute resources limits the practicability of DBG over other assembly archetypes already designed for longer reads. Here, we revisit the DBG paradigm to adapt it to the changing sequencing technology landscape and introduce three data structure designs for spaced seeds in the form of paired subsequences. These data structures address memory and run time constraints imposed by longer reads. We observe that when a fixed distance separates seed pairs, it provides increased sequence specificity with increased gap length. Further, we note that Bloom filters would be suitable to implicitly store spaced seeds and be tolerant to sequencing errors. Building on this concept, we describe a data structure for tracking the frequencies of observed spaced seeds. These data structure designs will have applications in genome, transcriptome and metagenome assemblies, and read error correction.", "INTRODUCTION: Recent outbreaks of brodifacoum-induced coagulopathy resulting from the use of synthetic cannabinoids represents a growing public health concern. Brodifacoum is a commonly used and commercially available rodenticide that has anticoagulant properties. As new, unregulated synthetic cannabinoids enter the market, the potential for further outbreaks continues to rise.CASE PRESENTATION: We report a case of severe bleeding secondary to inhalation of synthetic cannabinoids contaminated with brodifacoum. The patient had been evaluated for several months of ongoing, unexplained vaginal bleeding and developed hematemesis and rectal bleeding 2 weeks after her last reported use.DISCUSSION: There have been previous reports of hemorrhage after exposure to synthetic marijuana in rare cases, including an outbreak of severe bleeding and reported synthetic marijuana use in the Midwestern region of the United States in 2018.CONCLUSION: While hemorrhaging after exposure to synthetic cannabinoids has been reported previously, we use this case to increase awareness of the potentially deadly exposures to brodifacoum from synthetic cannabinoids use in Wisconsin. By increasing awareness, emergency department physicians and state agencies can collaborate more effectively when responding in these cases.", "Gilteritinib is a potent and selective FLT3 kinase inhibitor with single-agent clinical efficacy in relapsed/refractory FLT3-mutated acute myeloid leukemia (AML). In this context, however, gilteritinib is not curative, and response duration is limited by the development of secondary resistance. To evaluate resistance mechanisms, we analyzed baseline and progression samples from patients treated on clinical trials of gilteritinib. Targeted next-generation sequencing at the time of AML progression on gilteritinib identified treatment-emergent mutations that activate RAS/MAPK pathway signaling, most commonly in NRAS or KRAS. Less frequently, secondary FLT3-F691L gatekeeper mutations or BCR-ABL1 fusions were identified at progression. Single-cell targeted DNA sequencing revealed diverse patterns of clonal selection and evolution in response to FLT3 inhibition, including the emergence of RAS mutations in FLT3-mutated subclones, the expansion of alternative wild-type FLT3 subclones, or both patterns simultaneously. These data illustrate dynamic and complex changes in clonal architecture underlying response and resistance to mutation-selective tyrosine kinase inhibitor therapy in AML. SIGNIFICANCE: Comprehensive serial genotyping of AML specimens from patients treated with the selective FLT3 inhibitor gilteritinib demonstrates that complex, heterogeneous patterns of clonal selection and evolution mediate clinical resistance to tyrosine kinase inhibition in FLT3-mutated AML. Our data support the development of combinatorial targeted therapeutic approaches for advanced AML.See related commentary by Wei and Roberts, p. 998.This article is highlighted in the In This Issue feature, p. 983.", "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.", "Tamoxifen was approved for breast cancer prevention in October 1998. Thus, for the first time, we as gynecologists are being asked to prescribe this drug to healthy women. In the past each one of us has cared for women with breast cancer who have been treated with tamoxifen by oncologists or breast surgeons for the malignancy. Effects of tamoxifen on the uterus resulting in carcinomas, hyperplasia, and polyps are well known. Furthermore, tamoxifen has estrogenic properties in the venous system, increasing the incidence of deep vein thrombosis and pulmonary emboli. A new SERM (selective estrogen receptor modulator), raloxifene, has been approved for prevention and treatment of osteoporosis in postmenopausal women. It does not have stimulatory effects on the endometrium; however, it is estrogenic in the venous system. Preclinical data, as well as the breast cancer incidence reported in studies of the skeleton, seem to indicate that its effects in the breast are similar to those of tamoxifen. This article reviews tamoxifen and the new SERM, raloxifene, in an attempt to help gynecologists better understand each compound and what data are currently known, what we hope to learn from future studies, and what currently makes sense for clinical practice.", "Levodopa (LD), in combination with a decarboxylase inhibitor, is a mainstay and the most effective therapeutic agent in the treatment of Parkinson's disease (PD). Unfortunately, during chronic treatment with this agent, ON-OFF phenomena and dyskinesia appear. Despite the many medical treatment options available, unpredictable OFF episodes can still occur and be severe and disabling. A rescue therapy that provides a rapid and predictable ON response for patients with OFF periods would be of great value for such patients. Areas covered: CVT-301 is a self-administered dry powder aerosol inhaled formulation of LD that is being developed as a self-administered treatment for OFF periods. The PK profile of CVT-301, the efficacy, and the safety highlighted in randomized clinical trials will be reviewed. Expert opinion: CVT-301 may offer several potential advantages including increased systemic bioavailability through pulmonary absorption, rapid onset of action, avoidance of first-pass drug metabolism and less plasma-level variability. List of Abbreviations: PD: Parkinson's disease; LD: Levodopa; CD: Carbidopa; AADC: aromatic L-amino acid decarboxylase; IR: immediate-release; FPD: fine particle dose; GI: gastrointestinal; PK: pharmacokinetic; CVs: coefficient of variation; UPDRS: Unified Parkinson's Disease Rating Scale; AEs: adverse events; FEV: forced expiratory volume; FVC: forced vital capacity; DLCO: diffuse lung CO ; tmax: time to maximum concentration.", "Deficiency of propionyl-CoA carboxylase (PCC; alpha 4 beta 4) results in the rare, autosomal recessive disease propionic acidemia. Cell fusion experiments have revealed two complementation groups, pccA and pccB, corresponding to defects of the PCCA (alpha-subunit) and PCCB (beta-subunit) genes, respectively. The pccBCC group includes subgroups, pccB and pccC, which are thought to reflect interallelic complementation between certain mutations of the PCCB gene. In this study, we have identified the mutations in two pccB, one pccC, and two pccBC cell lines and have deduced those alleles participating in interallelic complementation. One pccB line was a compound heterozygote of Pro228Leu and Asn536Asp. The latter mutation was also detected in a noncomplementing pccBC line. This leaves Pro228Leu responsible for complementation in the pccB cells. The second pccB line contained an insertional duplication, dupKICK140-143, and a splice mutation IVS + 1 G-->T, located after Lys466. We suggest that the dupKICK mutation is the complementing allele, since the second allele is incompatible with normal splicing. The pccC line studied was homozygous for Arg410Trp, which is necessarily the complementing allele in that line. For a second pccC line, we previously had proposed that delta Ile408 was the complementing allele. We now show that its second allele, \"Ins.Del,\" a 14-bp deletion replaced by a 12-bp insertion beginning at codon 407, fails to complement in homozygous form. We conclude that the interallelic complementation results from mutations in domains that can interact between beta-subunits in the PCC heteromer to restore enzymatic function. On the basis of sequence homology with the Propionibacterium shermanii transcarboxylase 12S subunit, we suggest that the pccC domain, defined by Ile408 and Arg410, may involve the propionyl-CoA binding site.", "Clozapine reduces L-3,4-dihydroxyphenylalanine (L-Dopa)-induced dyskinesias in parkinsonian patients. To test if the antidyskinetic effect of clozapine is related to antagonism at the dopamine D(4) receptor, we investigated the effect of 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1, 4]benzodiazepine (JL-18), a structural analog of clozapine which is more selective for this receptor. Four 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias to L-Dopa were used in this study. They were injected subcutaneously (s.c.) with L-Dopa methyl ester (125 mg per animal) plus benserazide (50 mg per animal; L-Dopa/benserazide) alone or in combination with JL-18 (at the doses of 0.1, 0.3, or 0.9 mg/kg, s.c.). Subcutaneous injection of sterile saline was used as control. L-Dopa/benserazide increased locomotion and improved parkinsonism but also induced dyskinesias. Co-administration of JL-18, at low doses (0.1, 0.3 mg/kg) with L-Dopa/benserazide, produced a dose-dependent reduction in L-Dopa-induced dyskinesias without a parallel return to parkinsonism. The present results suggest that novel selective dopamine D(4) receptor antagonists may represent a useful tool to reduce L-Dopa-induced dyskinesias.", "Fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSCs) by the application of Yamanaka factors (OSKM), but the mechanisms underlying this reprogramming remain poorly understood. Here, we report that Sox2 directly regulates endogenous microRNA-29b (miR-29b) expression during iPSC generation and that miR-29b expression is required for OSKM- and OSK-mediated reprogramming. Mechanistic studies show that Dnmt3a and Dnmt3b are in vivo targets of miR-29b and that Dnmt3a and Dnmt3b expression is inversely correlated with miR-29b expression during reprogramming. Moreover, the effect of miR-29b on reprogramming can be blocked by Dnmt3a or Dnmt3b overexpression. Further experiments indicate that miR-29b-DNMT signaling is significantly involved in the regulation of DNA methylation-related reprogramming events, such as mesenchymal-to-epithelial transition (MET) and Dlk1-Dio3 region transcription. Thus, our studies not only reveal that miR-29b is a novel mediator of reprogramming factor Sox2 but also provide evidence for a multistep mechanism in which Sox2 drives a miR-29b-DNMT signaling axis that regulates DNA methylation-related events during reprogramming.", "Uncovering new therapeutic targets for renal fibrosis holds promise for the treatment of chronic kidney diseases. Bromodomain and extra-terminal (BET) protein inhibitors have been shown to effectively ameliorate pathological fibrotic responses. However, the pharmacological effects and underlying mechanisms of these inhibitors in renal fibrosis remain elusive. In this study, we determined that the inhibition of Brd4, a BET family member, with a selective potent chemical inhibitor, JQ1, could prevent the development of renal fibrosis and block the progression of fibrosis in rats that have undergone unilateral ureteral obstruction (UUO). Inhibiting Brd4 with either JQ1 or genetic knockdown resulted in decreased expression of fibrotic genes such as α-smooth muscle actin, collagen IV and fibronectin both in UUO-induced fibrosis and upon TGF-β1 stimulation in HK-2 cells. Brd4 inhibition also suppressed the oxidative stress induced by UUO in vivo or by TGF-β1 in HK-2 cells. Moreover, Nox4, which is constitutively active in renal cells and is involved in the generation of hydrogen peroxide, was up-regulated during UUO-mediated fibrosis and induced by TGF-β1 in HK-2 cells, and this up-regulation could be blunted by Brd4 inhibition. Consistently, Nox4-mediated ROS generation and fibrotic gene expression were attenuated upon Brd4 inhibition. Further, the transcriptional activity of Nox4 was suppressed by JQ1 or siRNA against Brd4. Additionally, Smad3 and ERK1/2 phosphorylation, which are upstream signals of Nox4 expression, were inhibited both in JQ1-administered UUO rats and Brd4-inhibited HK-2 cells. In conclusion, these results indicated that the inhibition of Brd4 might protect against renal fibrosis by blocking the TGF-β-Nox4-ROS-fibrosis axis, suggesting that Brd4 could be a promising therapeutic target.", "BACKGROUND: Platinum-based doublet chemotherapy regimens, preferentially gemcitabine plus cisplatin, are generally considered the first-line standard of care for patients with recurrent or metastatic nasopharyngeal carcinoma. However, no consensus has been reached regarding treatment following progression after first-line therapy. Camrelizumab (SHR-1210) is a humanised anti-programmed death-1 (anti PD-1) antibody. We present safety and preliminary antitumour activity of camrelizumab alone as second-line therapy in patients with recurrent or metastatic nasopharyngeal carcinoma and combined with gemcitabine and cisplatin as first-line therapy in this patient population.METHODS: We report the results from two single-arm, phase 1 trials. Both trials included patients aged 18-70 years with histologically or cytologically confirmed nasopharyngeal carcinoma and confirmed metastatic disease or locoreginal recurrence, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients who received at least one previous line of treatment were enrolled at five academic hospitals in China into the dose-escalation and expansion trial to receive camrelizumab monotherapy intravenously at escalating doses of 1 mg/kg, 3 mg/kg, and 10 mg/kg, and a bridging dose of 200 mg per dose once every 2 weeks (monotherapy trial). Treatment-naive patients were enrolled from a single centre in China to receive six cycles of camrelizumab 200 mg (day 1), gemcitabine 1 g/m2 (days 1 and 8), and cisplatin 80 mg/m2 (day 1) every 3 weeks followed by camrelizumab 200 mg maintenance once every 3 weeks (combination trial). The primary endpoint of both trials was the safety and tolerability of the study treatment. Analyses were done per protocol. Both trials are registered with ClinicalTrials.gov, number NCT02721589 (camrelizumab monotherapy trial) and NCT03121716 (camrelizumab combination trial). Both trials are ongoing, but are no longer enrolling patients.FINDINGS: In the camrelizumab monotherapy trial, between March 31, 2016, and Sept 20, 2017, 121 patients were assessed for eligibility, of whom 93 patients were enrolled across the dose-escalation and expansion cohorts and received at least one dose of camrelizumab (safety population). 15 (16%) of 93 patients had treatment-related adverse events of grade 3 or 4, the most common of which were elevated conjugated bilirubin concentration (three [3%] of 93 patients), stomatitis, anaemia, and increased concentrations of aspartate aminotransferase, alanine aminotransferase, and total bilirubin, each of which occurred in two (2%) patients. Eight (9%) patients had a treatment-related serious adverse event. No dose-limiting toxic effects were observed during the dose-escalation phase. 31 (34%; 95% CI 24-44) of 91 evaluable patients on camrelizumab monotherapy had an overall response with a median follow-up of 9·9 months (IQR 8·1-11·7). In the camrelizumab combination trial, between April 18, 2017, and Aug 15, 2017, 24 patients were assessed for eligibility, of whom 23 patients were enrolled and treated (safety population). 20 (87%) of 23 patients had grade 3 or 4 treatment-related adverse events: neutropenia (13 [57%] of 23 patients), anaemia (11 [48%] patients), leucopenia (11 [48%] patients), thrombocytopenia (seven [30%] patients), oedema (two [9%] patients), hyponatraemia (two [9%] patients), hypochloraemia (one [4%] patients), and rash (one [4%] patient). Two patients had treatment-related serious adverse events. No treatment-related deaths occurred in these trials. 20 (91% [95% CI 72-97]) of 22 evaluable patients had an overall response with a median follow-up time of 10·2 months (IQR 9·7-10·8).INTERPRETATION: Camrelizumab is a well tolerated, potential treatment option for patients with recurrent or metastatic nasopharyngeal carcinoma. The combination of camrelizumab plus gemcitabine and cisplatin has a manageable toxicity profile and promising preliminary antitumour activity for this disease in treatment-naive patients. Randomised controlled trials are needed to further establish the role of immune checkpoint inhibition for nasopharyngeal carcinomas.FUNDING: Hengrui Medicine Co, Chinese National Natural Science Foundation project, Science and Technology Program of Guangdong, Pearl River Nova Program of Guangzhou.", "BACKGROUND: CVT-301, an inhaled levodopa (LD) formulation, is under development for relief of OFF periods in Parkinson's disease (PD). Previously, we reported that CVT-301 improved OFF symptoms relative to placebo. In this study, we evaluate pulmonary function in patients treated with a single dose of CVT-301 or placebo for 3 hours, or received multiple doses/day for 4 weeks.METHODS: As part of two phase 2 studies, pulmonary safety and tolerability of CVT-301 were evaluated in PD patients experiencing motor fluctuations (≥2 hours OFF/day), Hoehn and Yahr stage 1-3, and forced expiratory volume in 1 second/forced vital capacity ratio ≥75% of predicted (in ON state). In study A, patients received single doses of oral carbidopa/LD and each of the following via the inhaled route: placebo and 25 and 50 mg LD fine particle dose (FPD) CVT-301. In study B, patients received up to 3 inhaled doses/day of 35 mg (weeks 1-2) and 50 mg LD FPD CVT-301 (weeks 3-4) versus placebo. Assessments included spirometry and treatment-emergent adverse events (TEAEs).RESULTS: In study A, (n = 24) mean age ± standard deviation was 61.3 ± 7.4 years, mean time since diagnosis was 10.5 ± 4.6 years, and mean duration of LD treatment 8.4 ± 3.7 years. Assessment of pulmonary function (predose to 3 hours postdose) showed that spirometry findings were within normal ranges, regardless of treatment groups, or motor status at screening. In study B, (n = 86) mean age was 62.4 ± 8.7 years, time since PD diagnosis was 9.4 ± 3.9 years, and duration of LD treatment 7.8 ± 3.9 years. Longitudinal assessment of pulmonary function over 4 weeks showed no significant difference in spirometry between CVT-301 versus placebo groups. In both studies, the most common CVT-301 TEAE was mild-to-moderate cough (study A: 21%; study B: 7% vs. 2% in placebo). Other common TEAEs in study B were dizziness and nausea.CONCLUSION: Acute and longitudinal assessment of pulmonary function showed that CVT-301 treatment was not associated with acute airflow obstruction in this population. CVT-301 was generally safe and well tolerated.", "BACKGROUND: Spirometry patterns suggesting restrictive and obstructive pulmonary dysfunction have been reported in Parkinson's disease (PD). However, the patterns' precise relation to PD pathophysiology remains unclear. Purpose/Aim. To assess ON- versus OFF-state pulmonary function, the quality of its spirometric evaluation, and the quality of longitudinal spirometric findings in a large sample of PD patients with motor fluctuations.METHODS: During a placebo-controlled trial of an inhaled levodopa formulation, CVT-301, in PD patients with ≥2 h/d of OFF time, spirometry was performed by American Thoracic Society (ATS) guidelines at screening and throughout the 4-week treatment period.RESULTS: Among 86 patients, mean motor impairment during an OFF state at screening was moderately severe. However, mean spirometry results at screening were within normal ranges, and in a mixed model for repeated measures (MMRM), the results at screening were not dependent on motor state (ON vs. OFF). In the placebo group (n = 43), 76% of ON-state and 81% of OFF-state examinations throughout the study met ATS quality metrics, and in an MMRM analysis, mean findings at these patients' arrivals for treatment-period visits showed no significant 4-week change. Across all 86 patients, flow-volume curves prior to any study-drug administration showed only a 3% incidence of \"sawtooth\" morphology.CONCLUSIONS: In PD patients with motor fluctuations, longitudinal spirometry of acceptable quality was generally obtained. Although mean findings were normal, about a quarter of spirograms did not meet ATS quality criteria. Spirogram morphology may be less indicative of various forms of respiratory dysfunction than has previously been reported in PD.", "Inhaled drugs offer advantages, such as rapid onset of action, but require formulations and delivery systems that reproducibly and conveniently administer the drug. CVT-301 is a powder formulation of levodopa delivered by a breath-actuated inhaler that has been developed for treating OFF episodes (motor fluctuations between doses of standard oral levodopa) in patients with Parkinson's disease (PD). We present preclinical, phase 1, and phase 2 results for CVT-301. In dogs insufflated with a levodopa powder, plasma levodopa peaked in all animals 2.5 min after administration; in contrast, in dogs dosed orally with levodopa plus carbidopa, plasma levodopa was not detected until 30 min after administration. In 18 healthy persons, comparisons between inhaled CVT-301 and oral carbidopa/levodopa showed analogous differences in pharmacokinetics. Among 24 PD patients inhaling CVT-301 as a single 50-mg dose during an OFF episode, 77% showed an increase in plasma levodopa (>400 ng/ml) within 10 min versus 27% for oral dosing with carbidopa/levodopa at a 25-mg/100-mg dose. Improvements in timed finger tapping and overall motor function (Part III of the Unified Parkinson's Disease Rating Scale) were seen 5 and 15 min after administration, the earliest assessment time points. For average and best change, the improvements were statistically significant compared to placebo. The most common adverse event was cough; all cough events were mild to moderate, occurred at the time of inhalation, resolved rapidly, and became less frequent after initial dosing. These results support further development of CVT-301 for better management of PD.", "A patient with the phenotype of trisomy 21 (Down syndrome) was found to have a normal karyotype in blood lymphocytes and fibroblasts. Assessment of the chromosome 21 markers SOD1, CBS, ETS2, D21S11, and BCEI showed partial trisomy by duplication of a chromosome segment carrying the SOD1, CBS, and ETS2 loci and flanked by the BCEI and D21S11 loci, which are not duplicated. This submicroscopic duplication at the interface of 21q21 and 21q22.1 reduces to about 2000-3000 kb the critical segment the trisomy of which is responsible for the phenotype of trisomy 21.", "BACKGROUND: Ever since the pioneering reports in the 60s, L-3,4-Dioxyphenylalanine (levodopa) has represented the gold standard for the treatment of Parkinson's Disease (PD). However, long-term levodopa (LD) treatment is frequently associated with fluctuations in motor response with serious impact on patient quality of life. The pharmacokinetic and pharmacodynamic properties of LD are pivotal to such motor fluctuations: discontinuous drug delivery, short half-life, poor bioavailability, and narrow therapeutic window are all crucial for such fluctuations. During the last 60 years, several attempts have been made to improve LD treatment and avoid long-term complications.METHODS: Research and trials to improve the LD pharmacokinetic since 1960s are reviewed, summarizing the progressive improvements of LD treatment.RESULTS: Inhibitors of peripheral amino acid decarboxylase (AADC) have been introduced to achieve proper LD concentration in the central nervous system reducing systemic adverse events. Inhibitors of catechol-O-methyltransferase (COMT) increased LD half-life and bioavailability. Efforts are still being made to achieve a continuous dopaminergic stimulation, with the combination of oral LD with an AADC inhibitor and a COMT inhibitor, or the intra-duodenal water-based LD/ carbidopa gel. Further approaches to enhance LD efficacy are focused on new non-oral administration routes, including nasal, intra-duodenal, intrapulmonary (CVT-301) and subcutaneous (ND0612), as well as on novel ER formulations, including IPX066, which recently concluded phase III trial.CONCLUSION: New LD formulations, oral compounds as well as routes have been tested in the last years, with two main targets: achieve continuous dopaminergic stimulation and find an instant deliver route for LD.", "Levodopa remains the most effective treatment for Parkinson's disease and is considered the gold standard therapy. However, disease progression and changes in the gastrointestinal tract result in a declining window of treatment response in a majority of patients. Efforts have been made recently to improve levodopa bioavailability either by developing more effective oral formulations or by innovating routes of administration (intestinal infusion, transcutaneous or inhaled levodopa). IPX066 is a novel levodopa-carbidopa (LD/CD) oral formulation combining immediate-release (IR) and extended-release (ER) LD/CD recently approved in the USA and the EU. Levodopa-carbidopa intestinal gel (LCIG) is an approved therapy consisting of a suspension of levodopa and carbidopa infused directly into the proximal jejunum via a percutaneous endoscopic gastrojejunostomy (PEG-J) tube through a portable infusion pump. Ongoing studies are evaluating the 'accordion pill' (AP09004), an ER LD/CD formulation with gastroretentive properties. ND0612 is a proprietary liquid formulation of LD/CD that enables subcutaneous administration via a small patch-pump device, and CVT-301 is a levodopa inhalation powder with rapid onset of action; both are currently in active studies. Other novel formulations have been discontinued, including DM-1992, which is a bilayer formulation containing an IR LD/CD layer and an ER LD/CD layer with gastroretentive properties, and XP21279, a novel oral levodopa prodrug that is absorbed from the small and large intestine by high-capacity nutrient transporters expressed throughout the gastrointestinal system. ODM-101 is a new oral formulation of levodopa/carbidopa/entacapone that contains a higher amount of carbidopa (65 or 105 mg), but no active studies are underway. The current review aims to summarize the pharmacokinetic aspects, clinical efficacy, and potential adverse events of novel levodopa formulations currently available or under development.", "Sudden cardiac death (SCD) in young athletes is generally caused by inherited cardiac disorders. While these events are relatively few compared to other cardiac deaths, they are tragic in that death occurs in a young, otherwise healthy person. The genetic abnormalities most associated with SCD are hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. As a result of growing awareness that these deaths can be prevented, guidelines have been issued in both Europe and the United States to help screen and determine qualification for young persons who want to participate in competitive athletics. There remains debate on the how extensive screening should be, in particular over the use of the 12-lead electrocardiogram (ECG), with European guidelines mandating ECG and United States guidelines not recommending routine use of the ECG.", "OBJECTIVES: The aim of this study was to test the effects of treatment with ivabradine on exercise capacity and left ventricular filling in patients with heart failure with preserved ejection fraction (HFpEF).BACKGROUND: Because symptoms of HFpEF are typically exertional, optimization of diastolic filling time by controlling heart rate may delay the onset of symptoms.METHODS: Sixty-one patients with HFpEF were randomly assigned to ivabradine 5 mg twice daily (n = 30) or placebo (n = 31) for 7 days in this double-blind trial. Cardiopulmonary exercise testing with echocardiographic assessment of myocardial function and left ventricular filling were undertaken at rest and after exercise.RESULTS: The ivabradine group demonstrated significant improvement between baseline and follow-up exercise capacity (4.2 ± 1.8 METs vs. 5.7 ± 1.9 METs, p = 0.001) and peak oxygen uptake (14.0 ± 6.1 ml/min/kg vs. 17.0 ± 3.3 ml/min/kg, p = 0.001), with simultaneous reduction in exercise-induced increase in the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity (3.1 ± 2.7 vs. 1.3 ± 2.0, p = 0.004). Work load-corrected chronotropic response (the difference in heart rate at the same exercise time at the baseline and follow-up tests) showed a slower increase in heart rate during exercise than in the placebo-treated group. Therapy with ivabradine (β = 0.34, p = 0.04) and change with treatment in exertional increase in the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity (β = -0.30, p = 0.02) were independent correlates of increase in exercise capacity, and therapy with ivabradine (β = 0.32, p = 0.007) was independently correlated with increase in peak oxygen uptake.CONCLUSIONS: In patients with HFpEF, short-term treatment with ivabradine increased exercise capacity, with a contribution from improved left ventricular filling pressure response to exercise as reflected by the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity. Because this patient population is symptomatic on exertion, therapeutic treatments targeting abnormal exercise hemodynamic status may prove useful. (Use of Exercise and Medical Therapies to Improve Cardiac Function Among Patients With Exertional Shortness of Breath Due to Lung Congestion; ACTRN12610001087044).", "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." ]

[ "BACKGROUND: Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase.METHODS: After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy.RESULTS: Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects.CONCLUSIONS: The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).", "BAX protein plays a key role in the mitochondria-mediated apoptosis. However, it remains unclear by what mechanism BAX is triggered to initiate apoptosis. Here, we reveal the mechanism using electron spin resonance (ESR) techniques. An inactive BAX monomer was found to exhibit conformational heterogeneity and exist at equilibrium in two conformations, one of which has never been reported. We show that upon apoptotic stimulus by BH3-only peptides, BAX can be induced to convert into either a ligand-bound monomer or an oligomer through a conformational selection mechanism. The kinetics of reaction is studied by means of time-resolved ESR, allowing a direct in situ observation for the transformation of BAX from the native to the bound states. In vitro mitochondrial assays provide further discrimination between the proposed BAX states, thereby revealing a population-shift allosteric mechanism in the process. BAX's apoptotic function is shown to critically depend on excursions between different structural conformations.", "The coronavirus disease 2019 (COVID-19) pandemic has impacted the health of children worldwide. Although overall mortality from COVID-19 in children remains low, an associated multisystem inflammatory disorder has emerged. The disorder has been recognized and named multisystem inflammatory syndrome in children (MIS-C) by the World Health Organization and the Centers for Disease Control and Prevention. This comprehensive review describes the epidemiology, pathophysiology, signs and symptoms, other potential diagnoses, and treatments relevant to MIS-C. The review also includes patient and family education and anticipatory guidance, and discusses nursing implications for nurses working in various roles and settings, including direct care, research, and public health.", "CONTEXT: Alemtuzumab, an anti-CD52 monoclonal antibody, increased the risk of thyroid dysfunction in CAMMS223, a phase 2 trial in relapsing-remitting multiple sclerosis.OBJECTIVE: The objective of the study was a detailed description of thyroid dysfunction in CAMMS223.DESIGN: Relapsing-remitting multiple sclerosis patients (n=334) were randomized 1:1:1 to 44 μg sc interferon-β-1a (SC IFNB-1a, Rebif) or annual courses of 12 or 24 mg iv alemtuzumab. Thyroid function tests (TSH, free T3, free T4) and thyrotropin-binding inhibitory immunoglobulin (TBII) were assessed at screening, month 1, and quarterly thereafter; antithyroid peroxidase antibodies were assessed at screening and every 6 months. Thyroid dysfunction episodes were categorized post hoc by an endocrinologist.RESULTS: During a median follow-up of 57.3 months, 34% of alemtuzumab and 6.5% of SC IFNB-1a patients had thyroid dysfunction (P<.0001). Ten percent of alemtuzumab and 3% of SC IFNB-1a patients had more than one episode of thyroid dysfunction. With alemtuzumab, Graves' hyperthyroidism occurred in 22%, hypothyroidism in 7%, and subacute thyroiditis in 4%. Of patients with overt Graves' hyperthyroidism, 23% spontaneously became euthyroid and an additional 15% spontaneously developed hypothyroidism. Of patients with overt hypothyroidism, 74% were TBII positive. The annual incidence of a first episode of thyroid dysfunction increased each year through year 3 and then decreased each subsequent study year.CONCLUSIONS: Thyroid dysfunction was more common with alemtuzumab than with SC IFNB-1a. There were few serious episodes. Regular monitoring facilitated early detection. Unique features of this population included high prevalence of Graves' hyperthyroidism, multiple episodes of thyroid dysfunction in individual patients, spontaneous hypothyroidism after overt Graves' hyperthyroidism, and a high prevalence of TBII-positive overt hypothyroidism.", "BACKGROUND: Krabbe disease is a rare neurodegenerative genetic disorder caused by deficiency of galactocerebrosidase. Patients with the infantile form of Krabbe disease can be treated at a presymptomatic stage with human stem cell transplantation which improves survival and clinical outcomes. However, without a family history, most cases of infantile Krabbe disease present after onset of symptoms and are ineligible for transplantation. In 2006, New York began screening newborns for Krabbe disease to identify presymptomatic cases. To ensure that those identified with infantile disease received timely treatment, New York public health and medical systems took steps to accurately diagnose and rapidly refer infants for human stem cell transplantation within the first few weeks of life. After 11 years of active screening in New York and the introduction of Krabbe disease newborn screening in other states, new information has been gained which can inform the design of newborn screening programs to improve infantile Krabbe disease outcomes.FINDINGS: Recent information relevant to Krabbe disease screening, diagnosis, and treatment were assessed by a diverse group of public health, medical, and advocacy professionals. Outcomes after newborn screening may improve if treatment for infantile disease is initiated before 30 days of life. Newer laboratory screening and diagnostic tools can improve the speed and specificity of diagnosis and help facilitate this early referral. Given the rarity of Krabbe disease, most recommendations were based on case series or expert opinion.CONCLUSION: This report updates recommendations for Krabbe disease newborn screening to improve the timeliness of diagnosis and treatment of infantile Krabbe disease. In the United States, several states have begun or are considering Krabbe disease newborn screening. These recommendations can guide public health laboratories on methodologies for screening and inform clinicians about the need to promptly diagnose and treat infantile Krabbe disease. The timing of the initial referral after newborn screening, the speed of diagnostic confirmation of infantile disease, and the transplantation center's experience and ability to rapidly respond to a suspected patient with newly diagnosed infantile Krabbe disease are critical for optimal outcomes.", "Aim: To investigate whether plasma C-MYC level could be an indicator in clinical progression of breast cancer. Materials & methods: Plasma level of C-MYC expression was detected by quantitative real time PCR and the level of c-myc protein in breast cancer tissues was detected by immunohistochemistry. The expression level of C-MYC mRNA in supernatant of cancer cells culture was measured compared with the nonbreast cancer cells. Results: Plasma C-MYC level was significantly higher in patients with breast cancer than that in the controls, which associated with clinical stages, lymph node status, etc. Receiver operating characteristic curve analysis showed the sensitivity and specificity of plasma C-MYC level for diagnosis of breast cancer were 63.6 and 81.8%, respectively. The expression of c-myc protein in breast cancer tissues was associated with plasma C-MYC level, even C-MYC level in supernatant of cancer cells was elevated. Conclusion: Plasma C-MYC level might be a potential indicator in progression of breast cancer.", "SUMMARY: Here we describe NanoPack, a set of tools developed for visualization and processing of long-read sequencing data from Oxford Nanopore Technologies and Pacific Biosciences.AVAILABILITY AND IMPLEMENTATION: The NanoPack tools are written in Python3 and released under the GNU GPL3.0 License. The source code can be found at https://github.com/wdecoster/nanopack, together with links to separate scripts and their documentation. The scripts are compatible with Linux, Mac OS and the MS Windows 10 subsystem for Linux and are available as a graphical user interface, a web service at http://nanoplot.bioinf.be and command line tools.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online." ]

[ "Mutations in superoxide dismutase 1 (SOD1) are a major cause of familial amyotrophic lateral sclerosis (ALS), whereby the mutant proteins misfold and aggregate to form intracellular inclusions. We report that both small ubiquitin-like modifier (SUMO) 1 and SUMO2/3 modify ALS-linked SOD1 mutant proteins at lysine 75 in a motoneuronal cell line, the cell type affected in ALS. In these cells, SUMO1 modification occurred on both lysine 75 and lysine 9 of SOD1, and modification of ALS-linked SOD1 mutant proteins by SUMO3, rather than by SUMO1, significantly increased the stability of the proteins and accelerated intracellular aggregate formation. These findings suggest the contribution of sumoylation, particularly by SUMO3, to the protein aggregation process underlying the pathogenesis of ALS.", "Warfarin and other coumarin anticoagulants are widely used clinically, but currently dosing is determined individually on the basis of patient response. There is increasing evidence that genetic factors, together with several non-genetic patient-specific factors, are important determinants of stable dose requirement for these compounds. Genotype for CYP2C9, which encodes the main cytochrome P450 enzyme that metabolizes warfarin, and VKORC1, the gene encoding the warfarin target vitamin K epoxide reductase, together account for approximately 30% of the variability in dose requirement. The past two years have seen several advances in the area of genetic factors affecting coumarin anticoagulant response. In particular, prospective studies have taken place to analyze whether earlier small retrospective studies can be confirmed, and the question of whether genes other than CYP2C9 and VKORC1 are important in determining dose requirement has been examined. So far, no strong evidence that other genes contribute to dose requirement has been found, apart from a minor but novel role for another cytochrome P450 gene, CYP4F2. A recently published whole genome association study confirms that the main genes important in warfarin response are CYP2C9 and VKORC1. Clinical trials comparing genotype-guided and conventional warfarin initiation have suggested that genotyping may be of value, but larger studies are still needed to show clear clinical benefit. Current knowledge of genetic factors affecting other coumarin anticoagulants is more limited and this area requires further study, as does the impact of ethnic variation in genes relevant to coumarin responses. Here we review recent advances in the area of coumarin anticoagulant genetics and its potential clinical application.", "Ubiquitination is a posttranslational modification of proteins that involves the covalent attachment of ubiquitin, either as a single moiety or as polymers. This process controls almost every cellular metabolic pathway through a variety of combinations of linkages. Mass spectrometry now allows high throughput approaches for the identification of the thousands of ubiquitinated proteins and of their ubiquitination sites. Despite major technological improvements in mass spectrometry in terms of sensitivity, resolution and acquisition speed, the use of efficient purification methods of ubiquitinated proteins prior to mass spectrometry analysis is critical to achieve an efficient characterization of the ubiquitome. This critical step is achieved using different approaches that possess advantages and pitfalls. Here, we discuss the limits that can be encountered when deciphering the ubiquitome. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.", "Genetic and epigenetic factors are of great importance in cardiovascular biology and disease. Tobacco-smoking, one of the most important cardiovascular risk factors, is itself partially determined by genetic background and is associated with altered epigenetic patterns. This could render the genetics and epigenetics of smoking-related cardiovascular disease a textbook example of environmental epigenetics and modern approaches to multimodal data analysis. A pronounced association of smoking-related methylation patterns in the F2RL3 gene with prognosis in patients with stable coronary heart disease has recently been described. Nonetheless, surprisingly little concrete knowledge on the role of specific genetic variants and epigenetic modifications in the development of cardiovascular diseases in people who smoke has been accumulated. Beyond the current knowledge, the present review briefly outlines some chief challenges and priorities for moving forward in this field.", "Ten years after Fire and Melo's Nobel Prize for discovery of gene silencing by double-stranded RNA, a remarkable progress was achieved in RNA interference (RNAi). Changes in the chemical structure of synthetic oligonucleotides make them more stable and specific, and new delivery strategies became progressively available. The attention of pharmaceutical industry rapidly turned to RNAi, as an opportunity to explore new drug targets. This review addresses nine small-interfering RNAs (siRNAs) and one unique microRNA (miRNA) inhibitor, which entered the phase 2-3 clinical trials. The siRNAs in focus are PF-04523655, TKM-080301, Atu027, SYL040012, SYL1001, siG12D-LODER (phase 2), QPI-1002, QPI-1007, and patisiran (phase 3). Regarding miRNAs, their content can be down- or up-regulated, by using miRNA inhibitors (AntimiRs) or miRNA mimics. Miravirsen is an AntimiR-122 for hepatitis C virus infection. The flexibility of RNAi technology is easily understood taking into account: (i) the different drug targets (i.e. p53, caspase 2, PKN3, β2-adrenergic receptor, mutated KRAS, microRNAs); (ii) therapeutic conditions, including ophthalmic diseases, kidney injury, amyloidosis, pancreatic cancer, viral hepatitis; and (iii) routes of administration (ocular, intravenous, subcutaneous, intratumoral). Although some issues are still matters of concern (delivery, toxicity, cost, and biological barriers), RNAi definitively opens a wide avenue for drug development.", "Ibudilast (IBD) is a non‑selective (3, 4, 10, 11) phosphodiesterase (PDE) inhibitor, used mainly as a bronchodilator for the treatment of bronchial asthma. PDE play a central role in cellular function (e.g. differentiation, synaptic plasticity and inflammatory response) by metabolizing cyclic nucleotides. The results from preclinical and clinical studies indicate that IBD has a broader range of action through suppression of pro‑inflammatory cytokines (IL‑6, IL‑1β, TNF‑α), toll‑like receptor 4 blockade (TLR‑4), inhibition of a macrophage migration inhibitory factor (MIF), up‑regulation the anti‑inflammatory cytokine (IL‑10), and promotion of neurotrophic factors (GDNF, NGF, NT‑4). Recent data indicate that the efficacy of IBD appears to be independent from PDE inhibition activity and rather linked to glial activity attenuation. Additional advantages of IBD, such as crossing the blood-brain barrier, good tolerance and activity by oral administration, makes it a promising therapeutic candidate for treating neuroinflammatory conditions, where the currently available treatment remains unsatisfying due to poor tolerability and/or sub‑optimal efficacy. IBD has no direct receptor affinity with exemption of some undefined effect on adenosine receptors that makes the drug devoid of its receptors‑mediated adverse effects. Current article provides an overview of the pharmacology of IBD with a focus on preclinical and clinical data supporting its potential neuroprotective benefits for neurological conditions, including multiple sclerosis, neuropathic pain, medication overuse headache, stroke, opioid, alcohol and methamphetamine abuse.", "Dronedarone (Dron), without iodine, was developed as an alternative to the iodine-containing antiarrhythmic drug amiodarone (AM). AM acts, via its major metabolite desethylamiodarone, in vitro and in vivo as a thyroid hormone receptor alpha(1) (TRalpha(1)) and TRbeta(1) antagonist. Here we investigate whether Dron and/or its metabolite debutyldronedarone inhibit T(3) binding to TRalpha(1) and TRbeta(1) in vitro and whether dronedarone behaves similarly to amiodarone in vivo. In vitro, Dron had a inhibitory effect of 14% on the binding of T(3) to TRalpha(1), but not on TRbeta(1). Desethylamiodarone inhibited T(3) binding to TRalpha(1) and TRbeta(1) equally. Debutyldronedarone inhibited T(3) binding to TRalpha(1) by 77%, but to TRbeta(1) by only 25%. In vivo, AM increased plasma TSH and rT(3), and decreased T(3). Dron decreased T(4) and T(3), rT(3) did not change, and TSH fell slightly. Plasma total cholesterol was increased by AM, but remained unchanged in Dron-treated animals. TRbeta(1)-dependent liver low density lipoprotein receptor protein and type 1 deiodinase activities decreased in AM-treated, but not in Dron-treated, animals. TRalpha(1)-mediated lengthening of the QTc interval was present in both AM- and Dron-treated animals. The in vitro and in vivo findings suggest that dronedarone via its metabolite debutyldronedarone acts as a TRalpha(1)-selective inhibitor." ]

[ "BACKGROUND Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive genetic condition that was first described in 1983. Since its original description, approximately 50 cases have been reported with various clinical signs and symptoms. Characteristics include progressive neurologic deterioration with extrapyramidal involvement and polyendocrinopathy most notable for hypogonadism starting in early adolescence. Clinical presentation is variable, and a subset of patients may have additional features, such as premature aging, alopecia, distinctive facial features, cognitive impairment, or deafness. CASE REPORT We illustrate the phenotypic variability of 5 patients with WSS due to the previously reported homozygous single nucleotide deletion c.436delC in the DCAF17 gene, identified in 2008. Despite identical genetic alteration, our 5 patients had various clinical features among them and compared with previously reported cases with the same pathogenic mutation. CONCLUSIONS The phenotypic variability of WSS due to c.436delC founder mutation may have a wider range than previously recognized.", "First described in 1983, Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive genetic disorder that leads to a spectrum of hypogonadal symptoms in adolescence. The responsible gene, DCAF17 located on chromosome 2q31.1, was discovered in 2008 and to date nine mutations have been reported in the literature. The aim of the study was to review WSS descriptively in the light of new case reports with focus on endocrine features. Phenotypic description of three patients (two females, one male) with WSS followed in the Endocrinology Department of the University Hospital of Nancy, France, and exhaustive review of the literature using the PUBMED database were performed. Of 72 patients from 29 families with documented WSS who were identified, 39 had undergone genetic testing. WSS was invariably associated with hypogonadism, decreased IGF1 and frontotemporal alopecia starting in childhood. In addition to this triad, some patients exhibited intellectual disabilities of varying severity (87 %), bilateral deafness (76 %), cervicofacial dystonia and limb pain (42 % of cases, rising to 89 % after 25 years) and diabetes (66 %, rising to 96 % after 25 years). The pathophysiology of WSS remains unclear.", "The pancreas arises from Pdx1-expressing progenitors in developing foregut endoderm in early embryo. Expression of Ngn3 and NeuroD1 commits the cells to form endocrine pancreas, and to differentiate into subsets of cells that constitute islets of Langerhans. β-cells in the islets transcribe gene-encoding insulin, and subsequently process and secrete insulin, in response to circulating glucose. Dysfunction of β-cells has profound metabolic consequences leading to hyperglycemia and diabetes mellitus. β-cells are destroyed via autoimmune reaction in type 1 diabetes (T1D). Type 2 diabetes (T2D), characterized by impaired β-cell functions and reduced insulin sensitivity, accounts for 90% of all diabetic patients. Islet transplantation is a promising treatment for T1D. Pluripotent stem cells provide an unlimited cell source to generate new β-cells for patients with T1D. Furthermore, derivation of induced pluripotent stem cells (iPSCs) from patients captures \"disease-in-a-dish\" for autologous cell replacement therapy, disease modeling, and drug screening for both types of diabetes. This review highlights essential steps in pancreas development, and potential stem cell applications in cell regeneration therapy for diabetes mellitus.", "OBJECTIVE: Negative symptoms are core features of schizophrenia that are functionally debilitating, associated with poor outcomes, and resistant to existing pharmacotherapies. We performed a randomized, double-blind, placebo-controlled study of modafinil, a medication approved for the treatment of excessive daytime sleepiness, to explore its efficacy as an adjunctive therapy for negative symptoms in schizophrenia.METHOD: Twenty subjects with DSM-IV schizophrenia or schizoaffective disorder were randomly assigned to double-blind treatment with modafinil or placebo for 8 weeks. The study ran from March 2002 through March 2006. Outcome measures included the Scale for the Assessment of Negative Symptoms (SANS), Brief Psychiatric Rating Scale (BPRS), Clinical Global Impressions (CGI) scale, Quality of Life Interview, neurocognitive assessments (California Verbal Learning Test, Degraded Performance-Continuous Performance Test, Trail-Making Test B), and somatic measures (sleep, weight, side effects).RESULTS: Modafinil treatment was associated with a greater rate (CGI-Improvement [CGI-I] score < or = 3, 7/10 vs. 1/10) and degree (mean CGI-I score, 3.2 vs. 4.1) of global improvement at study endpoint compared with placebo. However, modafinil did not significantly improve global negative symptoms as measured by the total SANS or SANS individual global items. Modafinil did not significantly worsen psycho-pathology (according to the BPRS), compared with placebo, and was well tolerated.CONCLUSIONS: Although no effect on negative symptoms was found, adjunctive therapy with modafinil may result in global improvements in patients with schizophrenia who have prominent negative symptoms.", "Pax genes encode DNA binding proteins that play pivotal roles in the determination of complex tissues. Members of one subclass, Pax6, function as selector genes and play key roles in the retinal development of all seeing animals. Mutations within the Pax6 homologs including fly eyeless, mouse Small eye and human Pax6 lead to severe retinal defects in their respective systems. In Drosophila eyeless and twin of eyeless, play non-redundant roles in the developing retina. One particularly interesting characteristic of these genes is that, although expression of either gene can induce ectopic eye formation in non-retinal tissues, there are differences in the location and frequencies at which the eyes develop. eyeless induces much larger ectopic eyes, at higher frequencies, and in a broader range of tissues than twin of eyeless. In this report we describe a series of experiments conducted in both yeast and flies that has identified protein modules that are responsible for the differences in tissue transformation. These domains appear to contain transcriptional activator and repressor activity of distinct strengths. We propose a model in which the selective presence of these activities and their relative strengths accounts, in part, for the disparity to which ectopic eyes are induced in response to the forced expression of eyeless and twin of eyeless. The identification of both transcriptional activator and repressor activity within the Pax6 protein furthers our understanding of how this gene family regulates tissue determination.", "BACKGROUND: Improvisation of the nanosized vesicular systems has led to a series of useful developments including the deformable vesicles namely transfersomes, ethosomes and invasomes. The former two have been explored extensively, however, literature on invasomes is relatively scanty.METHOD: Invasomal formulations researched for various applications have been reviewed using search engine \"Scopus\". The present review focuses on the update of the research activity on effectiveness and permeation enhancing effects of invasomes for dermal and topical delivery.RESULT: Many research reports could be found on invasomes in the literature but scarce patent citations were found. The present write up elaborates the mechanism of penetration, and compiles literature dental applications of the invasomes, the detection ability, use in photodynamic therapy, pilosebaceous targeting, and for delivery of macromolecules. The use of massage and microneedles for penetration enhancement is the newer element in this area. Interestingly, the majority of research has been reported on temoporfin molecule but scarce literature is available for other molecules, so the area provides ample research opportunities. The review also highlights toxicity fact sheet of commonly used terpenes for invasome formulation.CONCLUSION: Though invasomes present an advantageous system for enhanced topical delivery but it needs to be assessed for dermatopharmacokinetics; safety and toxicity issues on long term usage.", "Cytogenetic re-evaluation of a fibroblast cell line from a female Hunter's syndrome case with a balanced X;autosome translocation, which had previously been reported to have a breakpoint in Xq26 to Xq27, showed the breakpoint to be either between Xq27 and Xq28 or within Xq28. The normal X chromosome was preferentially inactivated, supporting the view that the translocation had disrupted the Hunter gene. The new localisation is now in full agreement with our previous linkage work and other published data. Results of further linkage studies using probes defining the loci DXS86, DXS144, DXS100, DXS102, DXS105, F8C, and DXS134 are also consistent with our original conclusion that the Hunter locus lies within the distal region of the X chromosome long arm.", "OBJECTIVE: Long non-coding RNAs (lncRNAs) are emerging as key molecules in cancers, yet their potential molecular mechanisms are not well understood. The objective of this study is to examine the expression and functions of lncRNAs in the development of colorectal cancer (CRC).METHODS: LncRNA expression profiling of CRC, adenoma and normal colorectal tissues was performed to identify tumour-related lncRNAs involved in colorectal malignant transformation. Then, we used quantitative reverse transcription PCR assays to measure the tumour-related lncRNA and to assess its association with survival and response to adjuvant chemotherapy in 252 patients with CRC. The mechanisms of CCAL function and regulation in CRC were examined using molecular biological methods.RESULTS: We identified colorectal cancer-associated lncRNA (CCAL) as a key regulator of CRC progression. Patients whose tumours had high CCAL expression had a shorter overall survival and a worse response to adjuvant chemotherapy than patients whose tumours had low CCAL expression. CCAL promoted CRC progression by targeting activator protein 2α (AP-2α), which in turn activated Wnt/β-catenin pathway. CCAL induced multidrug resistance (MDR) through activating Wnt/β-catenin signalling by suppressing AP-2α and further upregulating MDR1/P-gp expression. In addition, we found that histone H3 methylation and deacetylases contributed to the upregulation of CCAL in CRC.CONCLUSIONS: Our results suggest that CCAL is a crucial oncogenic regulator involved in CRC tumorigenesis and progression.", "The three-dimensional organization of a genome plays a critical role in regulating gene expression, yet little is known about the machinery and mechanisms that determine higher-order chromosome structure. Here we perform genome-wide chromosome conformation capture analysis, fluorescent in situ hybridization (FISH), and RNA-seq to obtain comprehensive three-dimensional (3D) maps of the Caenorhabditis elegans genome and to dissect X chromosome dosage compensation, which balances gene expression between XX hermaphrodites and XO males. The dosage compensation complex (DCC), a condensin complex, binds to both hermaphrodite X chromosomes via sequence-specific recruitment elements on X (rex sites) to reduce chromosome-wide gene expression by half. Most DCC condensin subunits also act in other condensin complexes to control the compaction and resolution of all mitotic and meiotic chromosomes. By comparing chromosome structure in wild-type and DCC-defective embryos, we show that the DCC remodels hermaphrodite X chromosomes into a sex-specific spatial conformation distinct from autosomes. Dosage-compensated X chromosomes consist of self-interacting domains (∼1 Mb) resembling mammalian topologically associating domains (TADs). TADs on X chromosomes have stronger boundaries and more regular spacing than on autosomes. Many TAD boundaries on X chromosomes coincide with the highest-affinity rex sites and become diminished or lost in DCC-defective mutants, thereby converting the topology of X to a conformation resembling autosomes. rex sites engage in DCC-dependent long-range interactions, with the most frequent interactions occurring between rex sites at DCC-dependent TAD boundaries. These results imply that the DCC reshapes the topology of X chromosomes by forming new TAD boundaries and reinforcing weak boundaries through interactions between its highest-affinity binding sites. As this model predicts, deletion of an endogenous rex site at a DCC-dependent TAD boundary using CRISPR/Cas9 greatly diminished the boundary. Thus, the DCC imposes a distinct higher-order structure onto X chromosomes while regulating gene expression chromosome-wide.", "BACKGROUND: The major genetic cause of Currarino syndrome (CS), a congenital malformation syndrome typically characterized by sacral agenesis, anorectal malformation, and presence of a pre-sacral mass, is known to be pathogenic variants in motor neuron and pancreas homeobox 1 (MNX1), which exist in almost all familial cases and 30% of sporadic cases. Less commonly, a large deletion or a complex rearrangement involving the 7q36 region is associated with CS. We investigated the spectrum of MNX1 pathogenic variants and associated clinical features in the Korean patients with CS.METHODS: We enrolled 25 patients with CS, including 24 sporadic cases and one familial case. Direct sequencing of MNX1 and multiplex ligation-dependent probe amplification were performed. We also analyzed clinical phenotypes and evaluated genotype-phenotype correlations.RESULTS: We identified six novel variants amongst a total of six null variants, one missense variant, and one large deletion. The null variants included four frameshift variants (p.Gly98Alafs* 124, p.Gly145Alafs*77, p.Gly151Leufs*67, and p.Ala216Profs*5) and two nonsense variants (p.Tyr186* and p.Gln212*). The missense variant, p.Lys295Gln, was located in the highly-conserved homeobox domain and was predicted to be deleterious. A large deletion involving the 7q36 region was detected in one patient. Pathogenic variants in MNX1 were detected in 28% of all CS cases and 25% of sporadic cases. The clinical phenotype was variable in patients with and without pathogenic variants; no significant genotype-phenotype correlation was observed.CONCLUSIONS: This study revealed the spectrum and phenotypic variability of MNX1 pathogenic variants in the Korean population.", "Conflict of interest statement: Conflict of interest statement Dr Jones reported receiving grants from MSD; and personal fees from Adaptimmune, Athenex, Blueprint Medicines Corporation, Clinigen, Eisai, Eli Lilly, Epizyme, Daichii Sankyo, Deciphera Pharmaceuticals, Helsinn, Immunedesign, Merck, PharmaMar, Tracon and UptoDate outside the submitted work. Dr Serrano reported receiving other support from Bayer, Blueprint Medicines Corporation, Deciphera Pharmaceuticals, Eli Lilly, Novartis, Pfizer and PharmaMar; and grants from Bayer, Deciphera Pharmaceuticals and Pfizer outside the submitted work. Dr von Mehren reported receiving other support from Blueprint Medicines Corporation during the conduct of the study; and other support from Arog Pharmaceuticals, Deciphera Pharmaceuticals, Exelixis and Novartis outside the submitted work. Dr George reported receiving research support to her institution from Ariad, Bayer, Blueprint Medicines Corporation, Daiichi Sankyo, Deciphera Pharmaceuticals, Novartis and Pfizer; and advisory board/consulting fees from AstraZeneca, Blueprint Medicines Corporation, Daiichi Sankyo, Deciphera Pharmaceuticals and Eli Lilly. Dr Heinrich reported receiving grants and personal fees from Blueprint Medicines Corporation; and personal fees and other support from Molecular MD during the conduct of the study; personal fees and other from Novartis; and grants and personal fees from Deciphera Pharmaceuticals outside the submitted work. Dr Heinrich also has a patent “Treatment of Gastrointestinal Stromal Tumors” licenced to Novartis, and a patent “Activating Mutations of PDGFRA” issued. Dr Kang reported receiving personal fees from ALX Oncology, Amgen, Bristol Myers Squibb, Daehwa Pharmaceutical, MacroGenics, Novartis, Surface Oncology and Zymeworks outside the submitted work. Dr Schöffski reported receiving personal fees from Deciphera Pharmaceuticals; other support from Adaptimmune, Blueprint Medicines Corporation, Deciphera Pharmaceuticals, Exelixis, Eisai, Eli Lilly, Ellipses Pharma, Genmab, Intellisphere, Loxo Oncology, Merck, Plexxikon, Servier and Transgene; and grants from Ipsen and MSD outside the submitted work. Dr Cassier reported receiving personal fees from Blueprint Medicines Corporation during the conduct of the study; other support from AbbVie, Bayer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck Serono, MSD, Novartis and Roche/Genentech; personal fees from Amgen, Bristol Myers Squibb, MSD, Novartis and Roche/Genentech; non-financial support from MSD and Novartis; and grants from Novartis outside the submitted work. Dr Mir reported receiving consulting fees from Eli Lilly, Janssen, Lundbeck, Pfizer, Roche, Servier and Vifor Pharma; and owns stock options from Amplitude Surgical, Transgene and Ipsen. Dr Chawla reported receiving funding from ADI, Amgen, GlaxoSmithKline, Ignyta, Immix Bopharma, Inhibrx, Janssen, Karyopharm Therapeutics, Roche, SARC and Tracon outside the submitted work. Dr Eskens has nothing to disclose. Dr Rutkowski reported receiving personal fees from Blueprint Medicines Corporation, Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Pfizer, Roche and Sanofi outside the submitted work. Dr Tap reported receiving other support from Blueprint Medicines Corporation during the conduct of the study; receiving personal fees from Agios Pharmaceuticals, Blueprint Medicines Corporation, Daiichi Sankyo, Deciphera Pharmaceuticals, Eli Lilly, EMD Serono, Eisai, GlaxoSmithKline, Janssen, Immune Design, Loxo Oncology and NanoCarrier outside the submitted work; having a patent Companion Diagnostic for CDK4 inhibitors – 14/854,329 pending to MSKCC/SKI; attending scientific advisory boards for Atropos Therapeutics and Certis Oncology Solutions; being a consultant for Daiichi Sankyo; having stock ownership in Atropos Therapeutics and Daiichi Sankyo; and having involvement in an FDA ODAC meeting for pexidartinib. Dr Zhou is a former employee of Blueprint Medicines Corporation. Dr Roche reported receiving other support from Epizyme outside the submitted work; and being a current employee and shareholder of Blueprint Medicines Corporation. Dr Bauer reported receiving grants from Blueprint Medicines Corporation, Incyte and Novartis; personal fees from Bayer, Blueprint Medicines Corporation, Deciphera Pharmaceuticals, Exelixis and Novartis during the conduct of the study; and personal fees from ADC Therapeutics, Daiichi Sankyo, Eli Lilly, Exelixis, Janssen-Cilag, Nanobiotix, PharmaMar and Plexxikon outside the submitted work.", "The use of cardiovascular magnetic resonance in patients with hypertrophic cardiomyopathy over the last decade has helped elucidate the diagnosis, prognosis, pathophysiology, and management of this disease. Studies have shown that the use of magnetic resonance imaging in a patient with a permanent pacemaker and implantable cardioverter defibrillator is safe.", "A total of 875 nymphal and adult Ixodes ricinus ticks and 148 adult Dermacentor reticulatus ticks were collected by flagging lower vegetation in the Lublin region (eastern Poland) and examined for the presence of RNA of tick-borne encephalitis virus (TBEV) by nested RT-PCR. The minimum infection rate of I. ricinus ticks with TBEV amounted to 1.6% while the infection rate of D. reticulatus ticks was 10.8%. The results suggest that D. reticulatus may be a potential vector of TBEV in Central Europe.", "The mammalian nucleus is a highly complex structure that carries out a diverse range of functions such as DNA replication, cell division, RNA processing, and nuclear export/import. Many of these activities occur at discrete subcompartments that intersect with specific regions of the genome. Over the past few decades, evidence has accumulated to suggest that RNA transcription also occurs in specialized sites, called transcription factories, that may influence how the genome is organized. There may be certain efficiency benefits to cluster transcriptional activity in this way. However, the clustering of genes at transcription factories may have consequences for genome stability, and increase the susceptibility to recurrent chromosomal translocations that lead to cancer. The relationships between genome organization, transcription, and chromosomal translocation formation will have important implications in understanding the causes of therapy-related cancers.", "MicroRNAs (miRNA) participate in regulating diverse biological pathways by translational repression in animals. They have attracted increasing attention recently. However, little work has been done on the miRNA genes in agriculturally important pests. Because the transcripts of most miRNA genes are the products of type-II RNA polymerase, pri-miRNA has a poly(A) tail and appears in expressed sequence tags (EST). We developed a computational pipeline to identify miRNA genes from insect ESTs. First, 980,697 ESTs from 63 insects were collected and used to search the nr database. The ESTs which did not share significant similarities with any known protein-coding genes were treated as non-coding ESTs. Next, known mature miRNAs were used to align with non-coding ESTs. The ESTs which contain the sequence of mature miRNA were treated as candidate ESTs. Finally, putative precursors were extracted flanking the mature miRNA region in candidate ESTs and evaluated by the Triplet-SVM algorithm. As a result, 86 miRNAs from 30 insect species were found based on a strict criterion while 330 miRNAs from 51 species were found based on a loose criterion. Evolution analysis indicated that mir-467, mir-297 and mir-466 were the highest conserved miRNA families in insects. To confirm the reliability of putative insect miRNAs, the expression profile of nine predicted miRNAs in Locusta migratoria was investigated. Eight miRNAs were successfully detected by RT-PCR. Most miRNAs were expressed ubiquitously at all examined tissues and developmental stages whereas Lmi-mir-509 was specifically expressed in the thorax of the 2nd, 4th and 5th instars and adult locust. In all, our work reported an efficient computational strategy for predicting miRNA genes from insect ESTs and presented tens of miRNAs in diverse insect species which are expected to participate in many important physiological processes.", "BACKGROUND AND PURPOSE: Woodhouse-Sakati syndrome is a rare autosomal recessive disorder characterized by hypogonadism, alopecia, diabetes mellitus, and progressive extrapyramidal signs. The disease is caused by biallelic pathogenic variants in the DCAF17 gene. The purpose of this study was to describe the spectrum of brain MR imaging abnormalities in Woodhouse-Sakati syndrome.MATERIALS AND METHODS: We reviewed brain MR images of 26 patients with a clinical and genetic diagnosis of Woodhouse-Sakati syndrome (12 males, 14 females; age range, 16-45 years; mean age, 26.6 years). Follow-up studies were conducted for 6 patients.RESULTS: All patients had abnormal MR imaging findings. The most common abnormalities were a small pituitary gland (76.9%), pronounced basal ganglia iron deposition (73%), and white matter lesions in 69.2%. White matter lesions showed frontoparietal and periventricular predominance. All white matter lesions spared subcortical U-fibers and were nonenhanced. Prominent perivascular spaces (15.3%) and restricted diffusion in the splenium of the corpus callosum (7.6%) were less frequent findings. Follow-up studies showed expansion of white matter lesions with iron deposition further involving the red nucleus and substantia nigra. Older age was associated with a more severe degree of white matter lesions (P < .001).CONCLUSIONS: Small pituitary gland, accentuated iron deposition in the globus pallidus, and nonenhancing frontoparietal/periventricular white matter lesions were the most noted abnormalities seen in our cohort. The pattern and extent of these findings were observed to correlate with older age, reflecting a possible progressive myelin destruction and/or axonal loss. The presence of pituitary hypoplasia and white matter lesions can further distinguish Woodhouse-Sakati syndrome from other neurodegenerative diseases with brain iron accumulation subtypes.", "Two consanguineous Qatari siblings presented for evaluation: a 17-4/12-year-old male with hypogonadotropic hypogonadism, alopecia, intellectual disability, and microcephaly and his 19-year-old sister with primary amenorrhea, alopecia, and normal cognition. Both required hormone treatment to produce secondary sex characteristics and pubertal development beyond Tanner 1. SNP array analysis of both probands was performed to detect shared regions of homozygosity which may harbor homozygous mutations in a gene causing their common features of abnormal pubertal development, alopecia, and variable cognitive delay. Our patients shared multiple homozygous genomic regions; ten shared regions were >1 Mb in length and constituted 0.99% of the genome. DCAF17, encoding a transmembrane nuclear protein of uncertain function, was the only gene identified in a homozygous region known to cause hypogonadotropic hypogonadism. DCAF17 mutations are associated with Woodhouse-Sakati syndrome, a rare disorder characterized by alopecia, hypogonadotropic hypogonadism, sensorineural hearing loss, diabetes mellitus, and extrapyramidal movements. Sequencing of the coding exons and flanking intronic regions of DCAF17 in the proband revealed homozygosity for a previously described founder mutation (c.436delC). Targeted DCAF17 sequencing of his affected sibling revealed the same homozygous mutation. This family illustrates the utility of SNP array testing in consanguineous families to efficiently and inexpensively identify regions of genomic homozygosity in which genetic candidates for recessive conditions can be identified.", "Woodhouse Sakati syndrome (WSS, MIM 241080) is a rare autosomal recessive genetic condition characterized by alopecia, hypogonadism, hearing impairment, diabetes mellitus, learning disabilities and extrapydamidal manifestations. Sequence variants in the gene DCAF17, encoding nucleolar substrate receptor, were identified as the underlying cause of inherited WSS. Considerable phenotypic heterogeneity exists in WSS with regard to severity, organs involvement and age of onset, both in inter-familial and intra-familial cases. In this study, the genetic characterization of a consanguineous pedigree showing mild features of WSS was performed, followed by structural analysis of truncated protein. Exome sequencing identified a novel single base deletion variant (c.270delA; K90Nfs8*) in third exon of the gene DCAF17 (RefSeq; NM_025000), resulting in a truncated protein. Structural analysis of truncated DCAF17 revealed absence of amino acid residues crucial for interaction with DDB1. Taken together, the data confirmed the single base pair deletion as the underlying cause of this second report of WSS from Pakistan. This signifies the vital yet unexplored role of DCAF17 both in development and maintenance of adult tissues homeostasis.", "OBJECTIVES: The goal of this study was to evaluate the relationship between various suicide screening tools and clinical impression with subsequent patient psychiatric admission and near-term adverse emergency department (ED) events.METHODS: We performed a prospective observational study of 50 patients with suicidal ideation in the ED. Subjects completed a series of depression/suicide screening tools: the Columbia Suicide Severity Scale, SAD PERSONS scale, Patient Health Questionnaire 9, and Beck Scale for Suicidal Ideation. Clinicians were also asked about their impression on likelihood of patient admission. Outcome measures were as follows: need for psychiatric hospital admission, prolonged stay at psychiatric facility, and any adverse events during ED stay including need for unscheduled psychiatric or sedating medications, need for physical restraints, and need for intervention by security staff.RESULTS: The Beck Scale for Suicidal Ideation, Patient Health Questionnaire 9, and Columbia Suicide Severity Scale did not significantly predict within-ED adverse events or admissions to psychiatric facilities. Wald test for individual parameters at an α of .10 level found that patients who were screened positive by their nurse had 3.37 times the odds of adverse within-ED events; patients with a positive SAD PERSONS score had 8.18 times the odds of psychiatric admission greater than 5 days. However, at the α of .05 level, no screening tools correlated with patient ED course or likelihood of psychiatric admission.CONCLUSION: Clinical impression alone and the suicide screening tools showed poor predictive value for near-term events. Data from this study highlight the need for the development of ED-based suicide screening instruments capable of identifying those patients with suicidal ideation at greatest risk.", "Selective macroautophagy uses double-membrane vesicles, termed autophagosomes, to transport cytoplasmic pathogens, organelles and protein complexes to the vacuole for degradation. Autophagosomes are formed de novo by membrane fusion events at the phagophore assembly site (PAS). Therefore, precursor membrane material must be targeted and transported to the PAS. While some autophagy-related (Atg) proteins, such as Atg9 and Atg11, are known to be involved in this process, most of the mechanistic details are not understood. Previous work has also implicated the small Rab-family GTPase Ypt1 in the process, identifying Trs85 as a unique subunit of the TRAPPIII targeting complex and showing that it plays a macroautophagy-specific role; however, the relationship between Ypt1, Atg9 and Atg11 was not clear. Now, a recent report shows that Atg11 is a Trs85-specific effector of the Rab Ypt1, and may act as a classic coiled-coil membrane tether that targets Atg9-containing membranes to the PAS. Here, we review this finding in the context of what is known about Atg11, other Rab-dependent coiled-coil tethers, and other tethering complexes involved in autophagosome formation." ]

[ "A comprehensive phylogenetic classification of the kingdom Fungi is proposed, with reference to recent molecular phylogenetic analyses, and with input from diverse members of the fungal taxonomic community. The classification includes 195 taxa, down to the level of order, of which 16 are described or validated here: Dikarya subkingdom nov.; Chytridiomycota, Neocallimastigomycota phyla nov.; Monoblepharidomycetes, Neocallimastigomycetes class. nov.; Eurotiomycetidae, Lecanoromycetidae, Mycocaliciomycetidae subclass. nov.; Acarosporales, Corticiales, Baeomycetales, Candelariales, Gloeophyllales, Melanosporales, Trechisporales, Umbilicariales ords. nov. The clade containing Ascomycota and Basidiomycota is classified as subkingdom Dikarya, reflecting the putative synapomorphy of dikaryotic hyphae. The most dramatic shifts in the classification relative to previous works concern the groups that have traditionally been included in the Chytridiomycota and Zygomycota. The Chytridiomycota is retained in a restricted sense, with Blastocladiomycota and Neocallimastigomycota representing segregate phyla of flagellated Fungi. Taxa traditionally placed in Zygomycota are distributed among Glomeromycota and several subphyla incertae sedis, including Mucoromycotina, Entomophthoromycotina, Kickxellomycotina, and Zoopagomycotina. Microsporidia are included in the Fungi, but no further subdivision of the group is proposed. Several genera of 'basal' Fungi of uncertain position are not placed in any higher taxa, including Basidiobolus, Caulochytrium, Olpidium, and Rozella.", "A genome must locate its coding genes on the chromosomes in a meaningful manner with the help of natural selection, but the mechanism of gene order evolution is poorly understood. To explore the role of selection in shaping the current order of coding genes and their cis-regulatory elements, a comparative genomic approach was applied to the baker's yeast Saccharomyces cerevisiae and its close relatives. S. cerevisiae have experienced a whole-genome duplication followed by an extensive reorganization process of gene order, during which a number of new adjacent gene pairs appeared. We found that the proportion of new adjacent gene pairs in divergent orientation is significantly reduced, suggesting that such new divergent gene pairs may be disfavored most likely because their coregulation may be deleterious. It is also found that such new divergent gene pairs have particularly long intergenic regions. These observations suggest that selection specifically worked against deletions in intergenic regions of new divergent gene pairs, perhaps because they should be physically kept away so that they are not coregulated. It is indicated that gene regulation would be one of the major factors to determine the order of coding genes.", "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.", "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.", "The human protein kinome comprises 535 proteins that, with the exception of approximately 50 pseudokinases, control intracellular signaling networks by catalyzing the phosphorylation of multiple protein substrates. While a major research focus of the last 30 years has been cancer-associated Tyr and Ser/Thr kinases, over 85% of the kinome has been identified to be dysregulated in at least one disease or developmental disorder. Despite this remarkable statistic, for the majority of protein kinases and pseudokinases, there are currently no inhibitors progressing toward the clinic, and in most cases, details of their physiologic and pathologic mechanisms remain at least partially obscure. By curating and annotating data from the literature and major public databases of phosphorylation sites, kinases, and disease associations, we generate an unbiased resource that highlights areas of unmet need within the kinome. We discuss strategies and challenges associated with characterizing catalytic and noncatalytic outputs in cells, and describe successes and new frontiers that will support more comprehensive cancer-targeting and therapeutic evaluation in the future. Cancer Res; 78(1); 15-29. ©2017 AACR.", "Metabolites in islets of Langerhans and Escherichia coli strain DH5-alpha were analyzed using negative-mode, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). For analysis of anionic metabolites by MALDI, 9-aminoacridine as the matrix yielded a far superior signal in comparison to alpha-cyano-4-hydroxycinnamic acid, 2,5-dihydrobenzoic acid, 2,4,6,-trihydroxyacetophenone, and 3-hydroxypicolinic acid. Limits of detection for metabolite standards were as low as 15 nM for GDP, GTP, ADP, and ATP and as high as 1 muM for succinate in 1-muL samples. Analysis of islet extracts allowed detection of 44 metabolites, 29 of which were tentatively identified by matching molecular weight to compounds in METLIN and KEGG databases. Relative quantification was demonstrated by comparing the ratio of selected di- and triphosphorylated nucleotides for islets incubated with different concentrations of glucose. For islets at 3 mM glucose, concentration ratios of ATP/ADP, GTP/GDP, and UTP/UDP were 1.9 +/- 1.39, 1.12 +/- 0.50, and 0.79 +/- 0.35 respectively, and at 20 mM glucose stimulation, the ratios increased to 4.13 +/- 1.89, 5.62 +/-4.48, and 4.30 +/- 4.07 (n = 3). Analysis was also performed by placing individual, intact islets on a MALDI target plate with matrix and impinging the laser directly on the dried islet. Direct analysis of single islets allowed detection of 43 metabolites, 28 of which were database identifiable. A total of 43% of detected metabolites from direct islet analysis were different from those detected in islet extracts. The method was extended to prokaryotic cells by analysis of extracts from E. coli. Sixty metabolites were detected, 39 of which matched compounds in the MetaCyc database. A total of 27% of the metabolites detected from prokaryotes overlapped those found in islets. These results show that MALDI can be used for detection of metabolites in complex biological samples.", "Evidence continues to grow that KRAS, once considered an \"undruggable\" target, can be targeted successfully in non-small cell lung cancer. In a phase I trial, the KRASG12C inhibitor sotorasib elicited responses in about a third of patients with the disease and was generally well tolerated." ]

[ "Traditional technologies to investigate system biology are limited by the detection of parameters resulting from the averages of large populations of cells, missing cells produced in small numbers, and attempting to uniform the heterogeneity. The advent of proteomics and genomics at a single-cell level has set the basis for an outstanding improvement in analytical technology and data acquisition. It has been well demonstrated that cellular heterogeneity is closely related to numerous stochastic transcriptional events leading to variations in patterns of expression among single genetically identical cells. The new-generation technology of single-cell analysis is able to better characterize a cell's population, identifying and differentiating outlier cells, in order to provide both a single-cell experiment and a corresponding bulk measurement, through the identification, quantification and characterization of all system biology aspects (genomics, transcriptomics, proteomics, metabolomics, degradomics and fluxomics). The movement of omics into single-cell analysis represents a significant and outstanding shift.", "The Paramyxoviridae family includes many viruses that are pathogenic in humans, including parainfluenza viruses, measles virus, respiratory syncytial virus, and the emerging zoonotic Henipaviruses. No effective treatments are currently available for these viruses, and there is a need for efficient antiviral therapies. Paramyxoviruses enter the target cell by binding to a cell surface receptor and then fusing the viral envelope with the target cell membrane, allowing the release of the viral genome into the cytoplasm. Blockage of these crucial steps prevents infection and disease. Binding and fusion are driven by two virus-encoded glycoproteins, the receptor-binding protein and the fusion protein, that together form the viral \"fusion machinery.\" The development of efficient antiviral drugs requires a deeper understanding of the mechanism of action of the Paramyxoviridae fusion machinery, which is still controversial. Here, we review recent structural and functional data on these proteins and the current understanding of the mechanism of the paramyxovirus cell entry process.", "Aberrant PRC2 activity produces gene repressive epigenetic marks in multiple diseases and led to identification of Ezh2 as a drug target. Recent studies have shown that the epigenetic reader protein EED, associated with Ezh2 in PRC2, has an additional function to stimulate the PRC2 activity after binding to H3K27me3. Optimizing a compound known to block the H3K27me3 site in EED discovered by in-house screening, Novartis scientists have now produced a compound that shows durable tumor regression in a lymphoma xenograft model.", "Nickel is a very common metal contained in many everyday objects and is the leading cause of ACD (Allergic Contact Dermatitis). Nickel is present in most of the constituents of a normal diet, but some food groups are usually considered to be richer. However, the nickel content of specific food can vary widely, depending on many factors. Thus, the daily intake of nickel is also highly variable both among different populations and in a single individual, in different seasons and even in different days. Measuring precisely the daily intake of nickel from food and drinks is extremely difficult, if not impossible. The relationship between ACD and contact with nickel is undisputed and widely confirmed in literature. The situation is different for systemic nickel allergy syndrome (SNAS). The SNAS can have cutaneous signs and symptoms (Systemic Contact Dermatitis or SCD) or extracutaneous signs and symptoms (gastrointestinal, respiratory, neurological, etc.).The occurrence of SCD as a systemic reaction to the nickel normally assumed in the daily diet is very controversial. A rigorous demonstration of the relationship between SCD and nickel is extremely difficult. In particular, further and larger studies are needed to assess the reality and the prevalence of nickel urticaria. With respect to nickel-related gastrointestinal symptoms, as well as chronic fatigue syndrome, fibromyalgia, headache, recurring cold sores and recurrent infections in general, the data available in literature are not conclusive and the studies lack the support of clear, first-hand evidence. With respect to respiratory disorders, the role of food nickel and the effectiveness of a dietary treatment have been assumed but not proven. In fact, the usefullness of a therapeutic low-nickel diet is controversial: rare, if not exceptional, and limited to very sporadic cases of SCD. Additionally, the quantitative and qualitative composition of a low-nickel diet presents few certainties and many uncertainties. The low-nickel diets suggested in literature are highly variable, both in the extension of the restrictions and in their details--and the differences are not marginal.CONCLUSION: an evaluation of the data presented by medical literature about SNAS and its relationship with oral nickel does not allow to draw final conclusions. In the absence of genuine certainty we can only conclude that further and broader studies, more rigorously conducted, are needed.", "On December 22, 2014, the FDA granted accelerated approval to nivolumab (OPDIVO; Bristol-Myers Squibb) for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on a clinically meaningful, durable objective response rate (ORR) in a non-comparative analysis of 120 patients who received 3 mg/kg of nivolumab intravenously every 2 weeks with at least 6-month follow-up in an ongoing, randomized, open-label, active-controlled clinical trial. The ORR as assessed by a blinded independent review committee per RECIST v1.1 was 31.7% (95% confidence interval, 23.5-40.8). Ongoing responses were observed in 87% of responding patients, ranging from 2.6+ to 10+ months. In 13 patients, the response duration was 6 months or longer. The risks of nivolumab, including clinically significant immune-mediated adverse reactions (imARs), were assessed in 268 patients who received at least one dose of nivolumab. The FDA review considered whether the ORR and durations of responses were reasonably likely to predict clinical benefit, the adequacy of the safety database, and systematic approaches to the identification, description, and patient management for imARs in product labeling. Clin Cancer Res; 23(14); 3484-8. ©2017 AACR.", "BACKGROUND: T-type Ca(2+) channels (TCC) are important for pain transmission, especially the Ca(V)3.2 subtype. In this study, we examined the effects of intrathecal TCC blockers in the L5/6 spinal nerve ligation pain rat model.METHODS: Under isoflurane anaesthesia, rats received right L5/6 spinal nerve ligation and intrathecal catheters (attached to an infusion pump) were sited. After surgery, saline, mibefradil, ethosuximide or NiCl2 were given intrathecally for seven days. The right hindpaw withdrawal thresholds to von Frey hair stimuli and withdrawal latencies to radiant heat were measured before and once daily for seven days after surgery. Double immunofluorescence and western blotting were used to examine the expression of Ca(V)3.2 in dorsal root ganglion (DRG) and spinal cord.RESULTS: On post-ligation day seven, rats receiving mibefradil, ethosuximide or NiCl2 had significant higher median withdrawal thresholds (15.0, 10.2, and 10.9 g) and latencies (8.0, 7.6 and 7.6 s) than saline-treated rats (1.6 g and 4.3 s, respectively). Ca(V)3.2 was expressed in parvalbumin(+), IB4(+), CGRP(+) and VR1(+) neurones in DRG and most neurones in spinal dorsal horn. Ca(V)3.2 was up-regulated in the right L5/6 DRG and spinal cord seven days after nerve ligation.CONCLUSIONS: In this study, we demonstrated that intrathecal TCC blockers attenuate the development of nerve injury-induced mechanical allodynia and thermal hyperalgesia. Our data suggest that continuous intrathecal infusion of TCC or Ca(V)3.2 blockers may be a promising alternative for the management of nerve injury-induced pain.", "OBJECTIVE: History, clinical examination and throat culture may be inadequate to rule in or out the presence of group A streptococci (GAS) infection in patients with sore throat in a remote location. We correlated the diagnostic accuracy for guiding antibiotic prescription of clinical decision and physiological scoring systems to a rapid diagnostic point of care (POC) test result in paediatric patients presenting with sore throat.METHODS: Prospective diagnostic accuracy study conducted between 30 June 2014 and 27 February 2015 in a remote Australian ED using a convenience sample. Among paediatric patients presenting with sore throat, the Centor criteria and clinical decision were documented. Simultaneously, patients without sore throat or respiratory tract infection were tested to determine the number of carriers. A throat swab on all patients was tested using a POC test (Alere TestPack +Plus Strep A with on board control), considered as reference standard to detect GAS infection.RESULTS: A total of 101 patients with sore throat were tested with 26 (25.7%) positive for GAS. One hundred and forty-seven patients without sore throat were tested with one positive POC test result (specificity 99%; 95% CI 96-100). Positive predictive value for clinician decision-making for a positive GAS swab (bacterial infection) was 29% (95% CI 17-43), negative predictive value 78% (95% CI 63-88). Area under ROC for the Centor score was 0.70 (95% CI 0.58-0.81).CONCLUSION: Clinician judgement and Centor score are inadequate tools for clinical decision-making for children presenting with sore throat. Adjunctive POC testing provides sufficient accuracy to guide antibiotic prescription on first presentation." ]

[ "AIMS: Erythropoietin (EPO) improves cardiac function and induces neovascularization in chronic heart failure (CHF), although the exact mechanism has not been elucidated. We studied the effects of EPO on homing and incorporation of endothelial progenitor cells (EPC) into the myocardial microvasculature and myocardial expression of angiogenic factors.METHODS AND RESULTS: CHF was induced in rats by coronary artery ligation resulting in myocardial infarction (MI) after bone marrow had been replaced by human placental alkaline phosphatase (hPAP) transgenic cells. We studied the effects of darbepoetin alfa treatment (EPO, 40 microg/kg, every 3 weeks, starting 3 weeks after MI) on longitudinal changes in left ventricular (LV) function, circulating EPC, myocardial histology, and expression of vascular endothelial growth factor (VEGF) determined 9 weeks after MI. EPO prevented LV-dilatation and improved cardiac function (all P < 0.05), which was associated with 42% increased capillary growth (P < 0.01). EPO-induced mobilization of EPC from the bone marrow (P < 0.01), which resulted in a three-fold increased homing of EPC into the cardiac microvasculature. The percentage of the endothelium that consisted of bone marrow derived cells was significantly increased (3.9 +/- 0.5 vs. 11.4 +/- 1%, P < 0.001) comprising 30% of the newly formed capillaries. In addition, EPO treatment resulted in a 4.5-fold increased myocardial expression of VEGF, which correlated strongly with neovascularization (r = 0.67; P < 0.001). VEGF was equally expressed by endothelial cells of myocardial and bone marrow origin.CONCLUSION: EPO-induced neovascularization in post-MI heart failure is mediated through a combination of EPC recruitment from the bone marrow and increased myocardial expression of VEGF.", "CONTEXT: A polymerase chain reaction-based companion diagnostic (cobas 4800 BRAF V600 Mutation Test) was recently approved by the US Food and Drug Administration to select patients with BRAF-mutant metastatic melanoma for treatment with the BRAF inhibitor vemurafenib.OBJECTIVES: (1) To compare the analytic performance of the cobas test to Sanger sequencing by using screening specimens from phase II and phase III trials of vemurafenib, and (2) to assess the reproducibility of the cobas test at different testing sites.DESIGN: Specimens from 477 patients were used to determine positive and negative percent agreements between the cobas test and Sanger sequencing for detecting V600E (1799T>A) mutations. Specimens were evaluated with a massively parallel pyrosequencing method (454) to resolve discordances between polymerase chain reaction and Sanger results. Reproducibility of the cobas test was assessed at 3 sites by using 3 reagent lots and an 8-member panel of melanoma samples.RESULTS: A valid cobas result was obtained for all eligible patients. Sanger sequencing had a failure rate of 9.2% (44 of 477). For the remaining 433 specimens, positive percent agreement was 96.4% (215 of 223) and negative percent agreement, 80% (168 of 210). Among 42 cobas mutation-positive/Sanger V600E-negative specimens, 17 were V600E positive and 24 were V600K positive by 454. The cobas test detected 70% of V600K mutations. In the reproducibility study, a correct interpretation was made for 100% of wild-type specimens and specimens with greater than 5% mutant alleles; V600E mutations were detected in 90% of specimens with less than 5% mutant alleles.CONCLUSIONS: The cobas test (1) had a lower assay failure rate than that of Sanger, (2) was more sensitive in detecting V600E mutations, (3) detected most V600K mutations, and (4) was highly reproducible.", "BACKGROUND: Amyloid-β (Aβ) peptides derive from the amyloid precursor protein (APP) and play a pivotal role in Alzheimer's disease (AD) pathogenesis. Our previous work showed that the APP intracellular domain (AICD), which is produced simultaneously with Aβ, also contributes to the development of AD-like features. Studies show that administration of apolipoprotein E (apoE) and apoE-derived small peptide mimetics protect AD mouse models against these AD-like features. However, the effects of apoE-mimetic treatment on AICD-mediated AD-like pathologies remain to be elucidated.OBJECTIVE: To study the effects of an apoE mimetic (COG112) on neuroinflammation, hyperphosphorylation of tau and defects in adult neurogenesis in AICD- overexpressing transgenic mice (FeCγ25 line).METHODS: Beginning at 1 month of age, animals were administered subcutaneous COG112 3 times per week for 3 months, followed by immunohistochemical analysis for neuroinflammation, neurogenesis and phosphorylated tau.RESULTS: Treatment with COG112 significantly reduced neuroinflammation in AICD mice and protected against impaired adult hippocampal neurogenesis. We also found that COG112 treatment reduced hyperphosphorylation and somatodendritic accumulation of tau in the hippocampus and cerebral cortex of AICD mice.CONCLUSIONS: Reduction of neuroinflammation by the apoE-mimetic COG112 protects against impaired neurogenesis and tau pathology in AICD transgenic mice. These data suggest that neuroinflammation plays an important role in AICD-induced AD-like pathologies.", "MicroRNAs (miRNAs), small noncoding RNAs, are negative regulators of gene expression and play important roles in gene regulation in the heart. To examine the role of miRNAs in the expression of the two isoforms of the cardiac myosin heavy chain (MHC) gene, α- and β-MHC, which regulate cardiac contractility, endogenous miRNAs were downregulated in neonatal rat ventricular myocytes (NRVMs) using lentivirus-mediated small interfering RNA (siRNA) against Dicer, an essential enzyme for miRNA biosynthesis, and MHC expression levels were examined. As a result, Dicer siRNA could downregulate endogenous miRNAs simultaneously and the β-MHC gene but not α-MHC, which implied that specific miRNAs could upregulate the β-MHC gene. Among 19 selected miRNAs, miR-27a was found to most strongly upregulate the β-MHC gene but not α-MHC. Moreover, β-MHC protein was downregulated by silencing of endogenous miR-27a. Through a bioinformatics screening using TargetScan, we identified thyroid hormone receptor β1 (TRβ1), which negatively regulates β-MHC transcription, as a target of miR-27a. Moreover, miR-27a was demonstrated to modulate β-MHC gene regulation via thyroid hormone signaling and to be upregulated during the differentiation of mouse embryonic stem (ES) cells or in hypertrophic hearts in association with β-MHC gene upregulation. These findings suggested that miR-27a regulates β-MHC gene expression by targeting TRβ1 in cardiomyocytes.", "Author information:(1)Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California, USA.(2)Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA.(3)Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.(4)Department of Bioengineering, Stanford University School of Medicine and School of Engineering, Stanford, California, USA.(5)Program in Cancer Biology, Stanford University School of Medicine, Stanford, California, USA.(6)Program in Biomedical Informatics, Stanford University School of Medicine, Stanford, California, USA.(7)Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.(8)Department of Otolaryngology Head and Neck Surgery, Stanford University School of Medicine, Stanford, California, USA.(9)Department of Computer Science, Stanford University, Stanford, California, USA.(10)Chan Zuckerberg Biohub, San Francisco, California, USA.", "BACKGROUND: The malaria vaccine candidate antigen RTS,S includes parts of the pre-erythrocytic stage circumsporozoite protein fused to the Hepatitis B surface antigen. Two Adjuvant Systems are in development for this vaccine, an oil-in water emulsion--based formulation (AS02) and a formulation based on liposomes (AS01).METHODS & PRINCIPAL FINDINGS: In this Phase II, double-blind study (NCT00307021), 180 healthy Gabonese children aged 18 months to 4 years were randomized to receive either RTS,S/AS01(E) or RTS,S/AS02(D), on a 0-1-2 month vaccination schedule. The children were followed-up daily for six days after each vaccination and monthly for 14 months. Blood samples were collected at 4 time-points. Both vaccines were well tolerated. Safety parameters were distributed similarly between the two groups. Both vaccines elicited a strong specific immune response after Doses 2 and 3 with a ratio of anti-CS GMT titers (AS02(D)/AS01(E)) of 0.88 (95% CI: 0.68-1.15) post-Dose 3. After Doses 2 and 3 of experimental vaccines, anti-CS and anti-HBs antibody GMTs were higher in children who had been previously vaccinated with at least one dose of hepatitis B vaccine compared to those not previously vaccinated.CONCLUSIONS: RTS,S/AS01(E) proved similarly as well tolerated and immunogenic as RTS,S/AS02(D), completing an essential step in the age de-escalation process within the RTS,S clinical development plan.TRIAL REGISTRATION: ClinicalTrials.gov. NCT00307021.", "BACKGROUND: Gastroesophageal reflux disease (GERD) is a common chronic disease requiring adequate treatment since it represents one major cause of development of Barrett's esophagus and eventually carcinoma. Novel laparoscopic magnetic sphincter augmentation for GERD was evaluated prospectively.PATIENTS AND METHODS: A total of 23 patients with GERD underwent minimally invasive implantation of LINX™ Reflux Management System. Primary outcome measures were overall feasibility, short-term procedure safety and efficacy. Secondary GERD-related quality of life was assessed.RESULTS: All implantations were performed without serious adverse events. A significant decrease in all major GERD complaints were found: heartburn: 96%-22% (p<0.001); bloating: 70%-30% (p=0.006); respiratory complaints: 57%-17% (p=0.039); sleep disturbance: 65%-4% (p<0.001). A four-week follow-up reduction of ≥50% of proton pump inhibitor (PPI) dose was achieved in over 80% of patients. Self-limiting difficulty in swallowing was found in 70% within four weeks. One patient required for endoscopic dilation. GERD-related quality of life improved significantly.CONCLUSION: LINX™ implantation is a standardized, technically simple, safe and well-tolerated expeditious procedure." ]

[ "Intrinsically disordered proteins and regions are involved in a wide range of cellular functions, and they often facilitate protein-protein interactions. Molecular recognition features (MoRFs) are segments of intrinsically disordered regions that bind to partner proteins, where binding is concomitant with a transition to a structured conformation. MoRFs facilitate translation, transport, signaling, and regulatory processes and are found across all domains of life. A popular computational tool, MoRFpred, accurately predicts MoRFs in protein sequences. MoRFpred is implemented as a user-friendly web server that is freely available at http://biomine.cs.vcu.edu/servers/MoRFpred/ . We describe this predictor, explain how to run the web server, and show how to interpret the results it generates. We also demonstrate the utility of this web server based on two case studies, focusing on the relevance of evolutionary conservation of MoRF regions.", "BACKGROUND: The unique radiobiological properties of protons have been understood for many years. In addition, many of the clinical benefits of radiotherapy were first noted in tumors involving the skull base. More public attention has been given to proton beam therapy due to the increasing number of centers now in operation or in the planning stages for offering this treatment option.METHODS: We reviewed the physical properties of protons and the clinical studies performed to justify their use in the management of skull-base tumors and determine the benefits of proton beam therapy.RESULTS: Published reports suggest a benefit to proton beam therapy for use in tumors of the skull base, including craniopharyngiomas, chordomas, skull-base sarcomas, and unresectable meningiomas.CONCLUSIONS: Use of proton beam therapy may be beneficial in select patients. Surgical and medical oncologists should have a general understanding of such cases to facilitate their appropriate referral.", "MOTIVATION: Intrinsically disordered regions of proteins play an essential role in the regulation of various biological processes. Key to their regulatory function is often the binding to globular protein domains via sequence elements known as molecular recognition features (MoRFs). Development of computational tools for the identification of candidate MoRF locations in amino acid sequences is an important task and an area of growing interest. Given the relative sparseness of MoRFs in protein sequences, the accuracy of the available MoRF predictors is often inadequate for practical usage, which leaves a significant need and room for improvement. In this work, we introduce MoRFCHiBi_Web, which predicts MoRF locations in protein sequences with higher accuracy compared to current MoRF predictors.METHODS: Three distinct and largely independent property scores are computed with component predictors and then combined to generate the final MoRF propensity scores. The first score reflects the likelihood of sequence windows to harbour MoRFs and is based on amino acid composition and sequence similarity information. It is generated by MoRFCHiBi using small windows of up to 40 residues in size. The second score identifies long stretches of protein disorder and is generated by ESpritz with the DisProt option. Lastly, the third score reflects residue conservation and is assembled from PSSM files generated by PSI-BLAST. These propensity scores are processed and then hierarchically combined using Bayes rule to generate the final MoRFCHiBi_Web predictions.RESULTS: MoRFCHiBi_Web was tested on three datasets. Results show that MoRFCHiBi_Web outperforms previously developed predictors by generating less than half the false positive rate for the same true positive rate at practical threshold values. This level of accuracy paired with its relatively high processing speed makes MoRFCHiBi_Web a practical tool for MoRF prediction.AVAILABILITY: http://morf.chibi.ubc.ca:8080/morf/.", "Histone methylation was first described more than 35 years ago, but its role has remained enigmatic. Proposed functions range from transcriptional regulation to the higher-order packaging of chromatin in preparation for mitotic condensation. Histone methylation can occur on Arg or Lys residues, with an exquisite site selectivity for Lys methylation at specific positions in the N-termini of histones H3 and H4. Thus, Lys methylation joins acetylation and phosphorylation as a third component of a 'histone code' that modifies the underlying chromatin structure of the genetic information. Notably, in contrast to acetylation and phosphorylation, Lys methylation appears to be a relatively stable histone modification, thereby providing an ideal epigenetic mark for more long-term maintenance of chromatin states. The recent discovery of the first histone Lys methyltransferase has allowed the identification of a molecular mechanism in which the specific methylation of histone H3 at Lys9 generates a binding site for heterochromatin-associated proteins. These findings have broad implications for the overall functional organization of chromosome structure at constitutive heterochromatin (e.g. centromeres) and for chromatin-dependent inheritance of gene expression patterns. This review discusses how understanding this methylation system should address some of the long-standing mysteries of heterochromatin.", "MOTIVATION: Intrinsically disordered regions of proteins play an essential role in the regulation of various biological processes. Key to their regulatory function is the binding of molecular recognition features (MoRFs) to globular protein domains in a process known as a disorder-to-order transition. Predicting the location of MoRFs in protein sequences with high accuracy remains an important computational challenge.METHOD: In this study, we introduce MoRFCHiBi, a new computational approach for fast and accurate prediction of MoRFs in protein sequences. MoRFCHiBi combines the outcomes of two support vector machine (SVM) models that take advantage of two different kernels with high noise tolerance. The first, SVMS, is designed to extract maximal information from the general contrast in amino acid compositions between MoRFs, their surrounding regions (Flanks), and the remainders of the sequences. The second, SVMT, is used to identify similarities between regions in a query sequence and MoRFs of the training set.RESULTS: We evaluated the performance of our predictor by comparing its results with those of two currently available MoRF predictors, MoRFpred and ANCHOR. Using three test sets that have previously been collected and used to evaluate MoRFpred and ANCHOR, we demonstrate that MoRFCHiBi outperforms the other predictors with respect to different evaluation metrics. In addition, MoRFCHiBi is downloadable and fast, which makes it useful as a component in other computational prediction tools.AVAILABILITY AND IMPLEMENTATION: http://www.chibi.ubc.ca/morf/.", "Intrinsically disordered proteins (IDPs) contain long unstructured regions, which play an important role in their function. These intrinsically disordered regions (IDRs) participate in binding events through regions called molecular recognition features (MoRFs). Computational prediction of MoRFs helps identify the potentially functional regions in IDRs. In this study, OPAL+, a novel MoRF predictor, is presented. OPAL+ uses separate models to predict MoRFs of varying lengths along with incorporating the hidden Markov model (HMM) profiles and physicochemical properties of MoRFs and their flanking regions. Together, these features help OPAL+ achieve a marginal performance improvement of 0.4-0.7% over its predecessor for diverse MoRF test sets. This performance improvement comes at the expense of increased run time as a result of the requirement of HMM profiles. OPAL+ is available for download at https://github.com/roneshsharma/OPAL-plus/wiki/OPAL-plus-Download.", "Accruing evidence suggests that prion-like behavior of fibrillar forms of α-synuclein, β-amyloid peptide and mutant huntingtin are responsible for the spread of the lesions that characterize Parkinson disease, Alzheimer disease and Huntington disease, respectively. It is unknown whether these distinct protein assemblies are transported within and between neurons by similar or distinct mechanisms. It is also unclear if neuronal death or injury is required for neuron-to-neuron transfer. To address these questions, we used mouse primary cortical neurons grown in microfluidic devices to measure the amounts of α-synuclein, Aβ42 and HTTExon1 fibrils transported by axons in both directions (anterograde and retrograde), as well as to examine the mechanism of their release from axons after anterograde transport. We observed that the three fibrils were transported in both anterograde and retrograde directions but with strikingly different efficiencies. The amount of Aβ42 fibrils transported was ten times higher than that of the other two fibrils. HTTExon1 was efficiently transported in the retrograde direction but only marginally in the anterograde direction. Finally, using neurons from two distinct mutant mouse strains whose axons are highly resistant to neurodegeneration (Wld(S) and Sarm1(-/-)), we found that the three different fibrils were secreted by axons after anterograde transport, in the absence of axonal lysis, indicating that trans-neuronal spread can occur in intact healthy neurons. In summary, fibrils of α-synuclein, Aβ42 and HTTExon1 are all transported in axons but in directions and amounts that are specific of each fibril. After anterograde transport, the three fibrils were secreted in the medium in the absence of axon lysis. Continuous secretion could play an important role in the spread of pathology between neurons but may be amenable to pharmacological intervention.", "BACKGROUND: Bow Hunter's Syndrome is a mechanical occlusion of the vertebral artery which leads to a reduction in blood flow in posterior cerebral circulation resulting in transient reversible symptomatic vertebrobasilar insufficiency.CASE DESCRIPTION: We present a case of Bow Hunter's syndrome in a 53-year-old male that occurred after the patient underwent surgical correction of a proximal left subclavian artery aneurysm. Shortly after the surgery, the patient began to complain of transient visual changes, presyncopal spells, and dizziness upon turning his head to the left. A transcranial doppler ultrasound confirmed the diagnosis of Bow Hunter's syndrome.SYSTEMIC REVIEW: We analyzed the data on 153 patients with Bow Hunter's syndrome from the literature. An osteophyte was the most common cause of vertebral artery occlusion, and left vertebral artery was more commonly involved in patients with Bow Hunter's syndrome. Dynamic angiography was the definitive imaging modality to confirm the diagnosis, and surgery was most successful in alleviating symptoms.CONCLUSION: We believe that this is the first case of iatrogenic Bow Hunter's syndrome after surgical intervention for an aneurysm repair, and the largest review of literature of Bow Hunter's syndrome. Dynamic angiography is the gold standard for the diagnosis of Bow Hunter's syndrome. Surgery should be considered as the primary treatment approach in these patients, especially those who have bony compression as the etiology.", "The genetic identity of Ixodes granulatus ticks was determined for the first time in Taiwan. The phylogenetic relationships were analyzed by comparing the sequences of mitochondrial 16S ribosomal DNA gene obtained from 19 strains of ticks representing seven species of Ixodes and two outgroup species (Rhipicephalus sanguineus and Haemaphysalis inermis). Four major clades could be easily distinguished by neighbour-joining analysis and were congruent by maximum-parsimony method. All these I. granulatus ticks of Taiwan were genetically affiliated to a monophyletic group with highly homogeneous sequences (92.2-99.3% similarity), and can be discriminated from other Ixodes species and other genera of ticks with a sequence divergence ranging from 11.7 to 30.8%. Moreover, intraspecific analysis revealed that two distinct lineages are evident between the same species of I. granulatus ticks collected from Taiwan and Malaysia. Our results demonstrate that all these I. granulatus ticks of Taiwan represent a unique lineage distinct from the common vector ticks (I. ricinus complex) for Borrelia burgdorferi spirochetes.", "Cardiac magnetic resonance (MR) imaging has grown over the past several decades into a validated, noninvasive diagnostic imaging tool with a pivotal role in cardiac morphologic and functional assessment and tissue characterization. With traditional cardiac MR imaging sequences, assessment of various pathologic conditions ranging from ischemic and nonischemic cardiomyopathy to cardiac involvement in systemic diseases (eg, amyloidosis and sarcoidosis) is possible; however, these sequences are most useful in focal myocardial disease, and image interpretation relies on subjective qualitative analysis of signal intensity. Newer T1 and T2 myocardial mapping techniques offer a quantitative assessment of the myocardium (by using T1 and T2 relaxation times), which can be helpful in focal disease, and demonstrate special utility in the evaluation of diffuse myocardial disease (eg, edema and fibrosis). Altered T1 and T2 relaxation times in disease states can be compared with published ranges of normal relaxation times in healthy patients. In conjunction with traditional cardiac MR imaging sequences, T1 and T2 mapping can limit the interpatient and interstudy variability that are common with qualitative analysis and may provide clinical markers for long-term follow-up.", "Alemtuzumab is an immunosuppressive antibody that depletes normal T cells and B cells. Prophylaxis for herpes virus and Pneumocystis carinii is standard with this agent. Approximately 20% to 25% of patients will experience cytomegalovirus (CMV) reactivation. We conducted a randomized trial wherein patients being treated with an alemtuzumab-containing regimen received prophylaxis with either valaciclovir 500 mg orally daily or valganciclovir 450 mg orally twice daily. The study design planned to enroll 128 patients, but stopping rules for early termination were met. Forty patients were evaluable. Median age was 58 years (range, 25-83 years); median number of prior therapies was 2 (range, 0-10). Diagnoses included chronic lymphocytic leukemia (29), T-cell prolymphocytic leukemia (3), hairy cell leukemia (1), adult T-cell leukemia/lymphoma (ATLL) (1), marginal zone leukemia (1), large granular lymphocyte leukemia (2), acute lymphoblastic leukemia (1), and T-cell lymphoma (2). Patients received various alemtuzumab-containing regimens, including single agent (5) or combined with: rituximab (2), pentostatin (6), fludarabine, cyclophosphamide, and rituximab (23), or fractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone (hyper-CVAD) (4). Seven of 20 patients enrolled on the valaciclovir arm experienced CMV reactivation. None of the 20 patients randomized to valganciclovir experienced CMV reactivation (P = .004). In conclusion, this agent was highly effective for prophylaxis of CMV reactivation in patients receiving alemtuzumab. This trial was registered at www.ClinicalTrials.gov as #NCT00562770.", "Amyotrophic lateral sclerosis (ALS) remains a clinical diagnosis without validated biomarkers. To increase diagnostic sensitivity, an expert group modified the Airlie House diagnostic criteria and formulated new recommendations at a meeting on Awaji Island. Our retrospective analysis of patients referred over a 6-month period to the electromyography (EMG) laboratory for suspected motor neuron disease (MND) showed a higher agreement of the Awaji modifications than the Airlie House criteria with the clinical diagnosis of ALS.", "MOTIVATION: Intrinsically disordered proteins lack stable 3-dimensional structure and play a crucial role in performing various biological functions. Key to their biological function are the molecular recognition features (MoRFs) located within long disordered regions. Computationally identifying these MoRFs from disordered protein sequences is a challenging task. In this study, we present a new MoRF predictor, OPAL, to identify MoRFs in disordered protein sequences. OPAL utilizes two independent sources of information computed using different component predictors. The scores are processed and combined using common averaging method. The first score is computed using a component MoRF predictor which utilizes composition and sequence similarity of MoRF and non-MoRF regions to detect MoRFs. The second score is calculated using half-sphere exposure (HSE), solvent accessible surface area (ASA) and backbone angle information of the disordered protein sequence, using information from the amino acid properties of flanks surrounding the MoRFs to distinguish MoRF and non-MoRF residues.RESULTS: OPAL is evaluated using test sets that were previously used to evaluate MoRF predictors, MoRFpred, MoRFchibi and MoRFchibi-web. The results demonstrate that OPAL outperforms all the available MoRF predictors and is the most accurate predictor available for MoRF prediction. It is available at http://www.alok-ai-lab.com/tools/opal/.CONTACT: ashwini@hgc.jp or alok.sharma@griffith.edu.au.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "We report two observations of significant left heart involvement in patients with the carcinoid syndrome assessed by transthoracic and transoesophageal echocardiography. Echocardiographic lesions of this kind have only been reported twice. In the present cases, there was mitral involvement with mitral regurgitation in one case and a mitro-aortic involvement with mitral and aortic regurgitation in the other. The mechanism of left heart lesions is unclear since in both cases no right-to-left cardiac shunt was present, as attested by colour Doppler and saline contrast transoesophageal echocardiography. The location of the primary tumour was unknown in one case and ileal in the other; no pulmonary metastasis was detected. The use of transoesophageal echocardiography might make it possible to detect left-sided cardiac lesions more frequently since they were found in anatomical series, in 30% of patients with carcinoid syndrome.", "There is current debate concerning the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers (ARBs), for hypertension management, during COVID-19 infection. Specifically, the suggestion has been made that ACE inhibitors or ARBs could theoretically contribute to infection via increasing ACE2 receptor expression and hence increase viral load. The ACE2 receptor is responsible for binding the SAR-CoV2 viral spike and causing COVID-19 infection. What makes the argument somewhat obtuse for ACE inhibitors or ARBs is that ACE2 receptor expression can be increased by compounds that activate or increase the expression of SIRT1. Henceforth common dietary interventions, vitamins and nutrients may directly or indirectly influence the cellular expression of the ACE2 receptor. There are many common compounds that can increase the expression of the ACE2 receptor including Vitamin C, Metformin, Resveratrol, Vitamin B3 and Vitamin D. It is important to acknowledge that down-regulation or blocking the cellular ACE2 receptor will likely be pro-inflammatory and may contribute to end organ pathology and mortality in COVID-19. In conclusion from the perspective of the ACE2 receptor, COVID-19 prevention and treatment are distinctly different. This letter reflects on this current debate and suggests angiotensin-converting enzyme inhibitors and ARBs are likely beneficial during COVID-19 infection for hypertensive and normotensive patients.", "Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist in late-stage clinical development for the treatment of bipolar disorder (manic/mixed and depressive episodes), as well as for schizophrenia, and as an adjunctive agent for the treatment of major depressive disorder. Three phase 2 or 3, 3-week, randomized controlled trials in bipolar mania or mixed episodes have been completed and reported as poster presentations or in press releases by the manufacturer. Superiority over placebo on the Young Mania Rating Scale total score was evidenced for daily doses of cariprazine 3-12 mg/day. In short-term randomized controlled trials, cariprazine does not appear to adversely impact metabolic variables, prolactin, or the electrocardiogram (ECG) QT interval. The most commonly encountered adverse events in the mania trials were extrapyramidal disorder, akathisia, insomnia, vomiting, restlessness, sedation, vision blurred, and pain in extremity in the phase 2 trial where this was presented in a poster, and akathisia, extrapyramidal disorder, tremor, dyspepsia, vomiting, dizziness, diarrhea, somnolence, restlessness, and pyrexia for the phase 3 trial where this was presented in a poster. With the exception of akathisia and extrapyramidal disorder, the differences in incidence versus placebo for these events were generally small. If approved by regulatory authorities, cariprazine would join aripiprazole as the second dopamine receptor partial agonist antipsychotic available for clinical use in persons with bipolar mania or mixed episodes. Cariprazine differs from aripiprazole in terms of dopamine D3 receptor selectivity. Further studies would be helpful to discern the distinguishing features of cariprazine from other antimanic agents.", "BACKGROUND: There is much uncertainty about the risks of leukaemia and lymphoma after repeated or protracted low-dose radiation exposure typical of occupational, environmental, and diagnostic medical settings. We quantified associations between protracted low-dose radiation exposures and leukaemia, lymphoma, and multiple myeloma mortality among radiation-monitored adults employed in France, the UK, and the USA.METHODS: We assembled a cohort of 308,297 radiation-monitored workers employed for at least 1 year by the Atomic Energy Commission, AREVA Nuclear Cycle, or the National Electricity Company in France, the Departments of Energy and Defence in the USA, and nuclear industry employers included in the National Registry for Radiation Workers in the UK. The cohort was followed up for a total of 8.22 million person-years. We ascertained deaths caused by leukaemia, lymphoma, and multiple myeloma. We used Poisson regression to quantify associations between estimated red bone marrow absorbed dose and leukaemia and lymphoma mortality.FINDINGS: Doses were accrued at very low rates (mean 1.1 mGy per year, SD 2.6). The excess relative risk of leukaemia mortality (excluding chronic lymphocytic leukaemia) was 2.96 per Gy (90% CI 1.17-5.21; lagged 2 years), most notably because of an association between radiation dose and mortality from chronic myeloid leukaemia (excess relative risk per Gy 10.45, 90% CI 4.48-19.65).INTERPRETATION: This study provides strong evidence of positive associations between protracted low-dose radiation exposure and leukaemia.FUNDING: Centers for Disease Control and Prevention, Ministry of Health, Labour and Welfare of Japan, Institut de Radioprotection et de Sûreté Nucléaire, AREVA, Electricité de France, National Institute for Occupational Safety and Health, US Department of Energy, US Department of Health and Human Services, University of North Carolina, Public Health England.", "DNA methylation, methylation of histone H3 at Lys9 (H3K9me3) and hypoacetylated histones are common molecular features of heterochromatin. Important details of their functions and inter-relationships remain unclear, however. In Neurospora crassa, H3K9me3 directs DNA methylation through a complex containing heterochromatin protein 1 (HP1) and the DNA methyltransferase DIM-2. We identified a distinct HP1 complex, HP1, CDP-2, HDA-1 and CHAP (HCHC), and found that it is responsible for silencing independently of DNA methylation. HCHC defects cause hyperacetylation of centromeric histones, greater accessibility of DIM-2 and hypermethylation of centromeric DNA. Loss of HCHC also causes mislocalization of the DIM-5 H3K9 methyltransferase at a subset of interstitial methylated regions, leading to selective DNA hypomethylation. We demonstrate that HP1 forms distinct DNA methylation and histone deacetylation complexes that work in parallel to assemble silent chromatin in N. crassa.", "This multicenter, randomized, double-blind, placebo-controlled, ascending-dose study investigated the pharmacokinetics, pharmacodynamic effects, safety, and tolerability of aleglitazar, a novel peroxisome proliferator-activated receptor alpha/gamma (PPARalpha/gamma) dual agonist. After a 3-week washout period, 71 patients with type 2 diabetes received either a single oral dose of aleglitazar (20, 50, 100, 300, 600, or 900 microg) or placebo, followed by once-daily dosing for 6 weeks. Few adverse events were reported, with no apparent relationship between the rate of incidence or severity of the adverse events and the dose of aleglitazar administered. Aleglitazar exposure increased in a dose-proportional manner both after a single dose and at steady state, with no accumulation. Aleglitazar produced dose-dependent improvements in levels of fasting and postprandial glucose, insulin resistance, and lipid parameters. Dose-dependent decreases from baseline in creatinine clearance exceeded 10% at doses >300 microg. The PPARalpha- and PPARgamma-related effects occurred over similar dose ranges, indicating that aleglitazar is a balanced agonist of the two receptor subtypes.", "Tick-borne flaviviruses are maintained in nature in an enzootic cycle involving a tick vector and a vertebrate host. Thus, the virus replicates in two disparate hosts, each providing selective pressures that can influence virus replication and pathogenicity. To identify viral determinants associated with replication in the individual hosts, plaque purified Langat virus (TP21pp) was adapted to growth in mouse or tick cell lines to generate two virus variants, MNBp20 and ISEp20, respectively. Virus adaptation to mouse cells resulted in four amino acid changes in MNBp20 relative to TP21pp, occurring in E, NS4A and NS4B. A comparison between TP21pp and ISEp20 revealed three amino acid modifications in M, NS3 and NS4A of ISEp20. ISEp20, but not MNBp20, was attenuated following intraperitoneal inoculation of mice. Following isolation from mice brains, additional mutations reproducibly emerged in E and NS3 of ISEp20 that were possibly compensatory for the initial adaptation to tick cells. Thus, our data implicate a role for E, M, NS3, NS4A and NS4B in host adaptation and pathogenicity of tick-borne flaviviruses.", "Zyxin is a focal adhesion protein that has been implicated in the modulation of cell adhesion and motility, and is hypothesized to be a mechano-sensor in integrin-mediated responses to mechanical force. To test the functional role of zyxin in the mechanotransduction of microvascular smooth muscle cells (VSMC), we utilized atomic force microscopy (AFM) to apply localized pulling forces to VSMC through a fibronectin (FN) focal adhesion induced by a FN-coated bead on cell surface. Application of force with the AFM induced an increase of zyxin accumulation at the site of the FN-bead focal adhesion that accompanied the VSMC contractile response. Whereas, reduction of zyxin expression by using a zyxin-shRNA construct abolished the VSMC contractile response to AFM pulling forces, even though the zyxin-silenced VSMCs displayed increased adhesion to FN in both AFM adhesion assays and cell adhesion assays. The reduced zyxin expression significantly impaired cell spreading and reorganization of the actin cytoskeleton that could indicate a possible underlying reason for the loss of a contractile response to mechanical force. Consistent with these observations, in zyxin-silenced VSMC, we also observed a reduced expression of Rac1, which plays an important role in the actin reorganization in VSMC, but increased thyroid receptor-interacting proteins (TRIP6) and FAK expression, the latter being a major protein that promote cell adhesion. In conclusion, these data support an important enabling role for zyxin in VSMCs ability to mechanically respond to applied force.", "MOTIVATION: Intrinsically Disordered Proteins (IDPs) lack stable tertiary structure and they actively participate in performing various biological functions. These IDPs expose short binding regions called Molecular Recognition Features (MoRFs) that permit interaction with structured protein regions. Upon interaction they undergo a disorder-to-order transition as a result of which their functionality arises. Predicting these MoRFs in disordered protein sequences is a challenging task.METHOD: In this study, we present MoRFpred-plus, an improved predictor over our previous proposed predictor to identify MoRFs in disordered protein sequences. Two separate independent propensity scores are computed via incorporating physicochemical properties and HMM profiles, these scores are combined to predict final MoRF propensity score for a given residue. The first score reflects the characteristics of a query residue to be part of MoRF region based on the composition and similarity of assumed MoRF and flank regions. The second score reflects the characteristics of a query residue to be part of MoRF region based on the properties of flanks associated around the given residue in the query protein sequence. The propensity scores are processed and common averaging is applied to generate the final prediction score of MoRFpred-plus.RESULTS: Performance of the proposed predictor is compared with available MoRF predictors, MoRFchibi, MoRFpred, and ANCHOR. Using previously collected training and test sets used to evaluate the mentioned predictors, the proposed predictor outperforms these predictors and generates lower false positive rate. In addition, MoRFpred-plus is a downloadable predictor, which makes it useful as it can be used as input to other computational tools.AVAILABILITY: https://github.com/roneshsharma/MoRFpred-plus/wiki/MoRFpred-plus:-Download.", "The molecular organization of the yeast transcriptional coactivator Spt-Ada-Gcn5 acetyltransferase (SAGA) was analyzed by single-particle electron microscopy. Complete or partial deletion of the Sgf73 subunit disconnects the deubiquitination (DUB) module from SAGA and favors in our conditions the cleavage of the C-terminal ends of the Spt7 subunit and the loss of the Spt8 subunit. The structural comparison of the wild-type SAGA with two deletion mutants positioned the DUB module and enabled the fitting of the available atomic models. The localization of the DUB module close to Gcn5 defines a chromatin-binding interface within SAGA, which could be demonstrated by the binding of nucleosome core particles. The TATA-box binding protein (TBP)-interacting subunit Spt8 was found to be located close to the DUB but in a different domain than Spt3, also known to contact TBP. A flexible protein arm brings both subunits close enough to interact simultaneously with TBP.", "Author information:(1)Service de réanimation médicale, hôpital Saint-Louis, AP-HP, 1, avenue Claude-Vellefaux, 75010 Paris, France. Electronic address: dumas.guillaume1@gmail.com.(2)Service de réanimation médicale, hôpital Saint-Louis, AP-HP, 1, avenue Claude-Vellefaux, 75010 Paris, France. Electronic address: sybille07@gmail.com.(3)Service de réanimation médicale, hôpital Saint-Louis, AP-HP, 1, avenue Claude-Vellefaux, 75010 Paris, France. Electronic address: larazafrani@hotmail.com.(4)Service de réanimation médicale, hôpital Saint-Louis, AP-HP, 1, avenue Claude-Vellefaux, 75010 Paris, France. Electronic address: emmanuel.canet@sls.aphp.fr.(5)Service de réanimation médicale, hôpital Saint-Louis, AP-HP, 1, avenue Claude-Vellefaux, 75010 Paris, France. Electronic address: virginie.lemiale@sls.aphp.fr.(6)Service de réanimation médicale, CHU d'Angers, 4, rue Larrey, 49100 Angers, France. Electronic address: ackouatchet@chu-angers.fr.(7)Service de réanimation médicale, hôpital Saint-Louis, AP-HP, 1, avenue Claude-Vellefaux, 75010 Paris, France. Electronic address: elie.azoulay@sls.aphp.fr." ]

[ "The 13-valent pneumococcal conjugate vaccine (Prevenar 13(®), Prevnar 13(®)) [PCV13] consists of 13 serotype-specific polysaccharides of Streptococcus pneumoniae (pneumococcus), each covalently conjugated to a non-toxic immunogenic carrier protein. PCV13 has a well established immunogenicity and tolerability profile in adults, particularly those ≥50 years of age. Results of CAPiTA, a randomized, double-blind, placebo-controlled trial in >84,000 older adults aged ≥65 years, showed that PCV13 was effective in preventing vaccine-type pneumococcal community-acquired pneumonia (CAP), vaccine-type pneumococcal nonbacteraemic (noninvasive) CAP and vaccine-type invasive pneumococcal disease (IPD). These findings, along with changes in pneumococcal serotype distribution and epidemiology of pneumococcal disease, prompted the US Advisory Committee on Immunization Practices (ACIP) to recommend PCV13 in series with 23-valent pneumococcal polysaccharide vaccine (PPVS23) for all adults aged ≥65 years. PCV13 also has a role in preventing pneumococcal disease (pneumonia and IPD) in younger adults with immunocompromising conditions and potentially in those with other underlying medical conditions that increase the risk of pneumococcal disease.", "Dengue and West Nile viruses are enveloped RNA viruses that belong to genus Flavivirus (family Flaviviridae) and are considered important mosquito-borne viral pathogenic agents worldwide. A potential target for intervention strategies is the virus cell entry mechanism. Previous studies of flavivirus entry have focused on the effects of biochemical and molecular inhibitors on viral entry leading to controversial conclusions suggesting that the process is dependent upon endocytosis and low pH mediated membrane fusion. In this study we analyzed the early events in the infection process by means of electron microscopy and immuno-gold labeling of viral particles during cell entry, and used as a new approach for infecting cells with viruses obtained directly from mosquitoes. The results show that Dengue and West Nile viruses may infect cells by a mechanism that involves direct penetration of the host cell plasma membrane as proposed for alphaviruses.", "With 2 million deaths per year, TB remains the most significant bacterial killer. The long duration of chemotherapy and the large pool of latently infected people represent challenges in disease control. To develop drugs that effectively eradicate latent infection and shorten treatment duration, the pathophysiology of the causative agent Mycobacterium tuberculosis needs to be understood. The discovery that the tubercle bacillus can develop a drug-tolerant dormant form and the identification of the underlying genetic program 10 years ago paved the way for a deeper understanding of the life of the parasite inside human lesions and for new approaches to antimycobacterial drug discovery. Here, we summarize what we have learnt since the discovery of the master regulator of dormancy, DosR, and the key gaps in our knowledge that remain. Furthermore, we discuss a possible wider clinical relevance of DosR for 'nontuberculous mycobacteria'.", "Author information:(1)From Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College (A.D., E.R.) and New York University Langone Medical Center (V.V.), New York, and Roswell Park Comprehensive Cancer Center, Buffalo (G.K.D.) - all in New York; Dana-Farber Cancer Institute (G.R.O.) and Massachusetts General Hospital (J.G.), Boston; National Cancer Centre Singapore, Singapore (D.S.W.T.); the Chinese University of Hong Kong, Hong Kong, China (H.H.F.L.); Sarah Cannon Research Institute, Nashville (M.J.); University of California, San Francisco-Helen Diller Family Comprehensive Cancer Center, San Francisco (C.E.M.), University of California, San Diego, Moores Cancer Center, La Jolla (L.B.), and City of Hope Comprehensive Cancer Center, Duarte (K.L.R.) - all in California; University of Bern, Bern, and Cantonal Hospital of Lucerne, Lucerne - both in Switzerland (O.G.); Institut Gustave Roussy, Villejuif (B.B.), Hospital La Timone, Marseille (F.B.), and Centre Léon Bérard, Lyon (P.A.C.) - all in France; Severance Hospital, Yonsei University Health System (B.C.C.), and Samsung Medical Center, Sungkyunkwan University School of Medicine (K.P.), Seoul, and Seoul National University Bundang Hospital, Seongnam (Y.J.K.) - all in South Korea; Soroka University Medical Center, Beer-Sheva, Israel (N.P.); University of North Carolina-Chapel Hill, Chapel Hill (J. Weiss); National Cancer Center Hospital (Y.O.) and Cancer Institute Hospital of the Japanese Foundation for Cancer Research (M. Nishio), Tokyo, National Hospital Organization Kyushu Cancer Center, Fukuoka (T. Seto), Tottori University Hospital, Tottori (T. Sakamoto), Hyogo Cancer Center, Akashi (M.S.), Okayama University Hospital, Okayama (K.O.), and National Cancer Center Hospital East, Chiba (K.G.) - all in Japan; University of Chicago, Chicago (J.P.); the Ohio State University Comprehensive Cancer Center, Columbus (M.H.S.), and Cleveland Clinic, Cleveland (N.A.P.); Istituto Nazionale Tumori-National Cancer Institute, Università degli Studi di Milano, Milan (F.D.B.); Vall d'Hebron Institute of Oncology, Hospital Universitario Vall d'Hebron, Barcelona (E.G.); Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany (J. Wolf); Peter MacCallum Cancer Institute, Melbourne, VIC, Australia (B.S.); Sarah Cannon Research Institute at HealthONE, Denver (G.F.); Loxo Oncology, Stamford, CT (K.E., M. Nguyen, B.N., E.Y.Z., L.Y., X.H., E.O., S.M.R.); and the University of Texas M.D. Anderson Cancer Center, Houston (V.S.).", "Acquired resistance to anticancer treatments is a substantial barrier to reducing the morbidity and mortality that is attributable to malignant tumors. Components of tissue microenvironments are recognized to profoundly influence cellular phenotypes, including susceptibilities to toxic insults. Using a genome-wide analysis of transcriptional responses to genotoxic stress induced by cancer therapeutics, we identified a spectrum of secreted proteins derived from the tumor microenvironment that includes the Wnt family member wingless-type MMTV integration site family member 16B (WNT16B). We determined that WNT16B expression is regulated by nuclear factor of κ light polypeptide gene enhancer in B cells 1 (NF-κB) after DNA damage and subsequently signals in a paracrine manner to activate the canonical Wnt program in tumor cells. The expression of WNT16B in the prostate tumor microenvironment attenuated the effects of cytotoxic chemotherapy in vivo, promoting tumor cell survival and disease progression. These results delineate a mechanism by which genotoxic therapies given in a cyclical manner can enhance subsequent treatment resistance through cell nonautonomous effects that are contributed by the tumor microenvironment.", "1. ", "Tirbanibulin is a novel tubulin polymerization and Src kinase signaling inhibitor. This study was designed to fully characterize tirbanibulin pharmacokinetics (PK) when applied topically under maximal use conditions. This was an open-label, parallel-group PK safety study of tirbanibulin ointment 1% applied to 25 cm2 of the face or balding scalp in adults with actinic keratosis (AK). Eligible subjects self-applied tirbanibulin once-daily for 5 days. PK sampling occurred on days 1, 3 and 4 at 0 hour (before dosing), and on day 5 at prespecified time points up to 24 hours after application. Safety assessments included adverse events and local skin reactions were evaluated up to day 29. Eighteen subjects (face or scalp, n = 9 each) completed the study. Subjects were White (100%), of mean [range] age 66.4 [43-83] years, predominantly men (83.3%) with Fitzpatrick skin type I to III (94.4%); baseline AK lesion count, mean [range] 8.2 [6-14]. All subjects had quantifiable but low plasma concentrations of tirbanibulin. On day 5, overall mean (standard deviation) maximum concentration (Cmax ) was 0.26 (0.23) ng/mL (or 0.60 nM), median time to maximum concentration was 6.91 hours, and mean (standard deviation) area under the plasma concentration-time curve from time 0 to 24 hours was 4.09 (3.15) ng ∙ h/mL. Four subjects experienced a total of 5 treatment-emergent adverse events that resolved. Mild to moderate erythema, flaking, or scaling in the treatment area peaked around day 8 before resolving or returning to baseline by day 29. In conclusion, under maximal use conditions, tirbanibulin ointment 1% for 5 days in the treatment of AK on the face or scalp was well tolerated and resulted in low systemic exposure with subnanomolar plasma concentrations." ]

[ "Pitolisant (Wakix™) is an inverse agonist of the histamine H3 receptor that is being developed by Bioproject. Oral pitolisant is approved in the EU for the treatment of narcolepsy with or without cataplexy in adults. Pitolisant has received a Temporary Authorization of Use in France for this indication in case of treatment failure, intolerance or contraindication to currently available treatment. Pitolisant has orphan drug designation in the EU and the USA. In the pivotal HARMONY I trial, pitolisant significantly decreased excessive daytime sleepiness versus placebo in adults with narcolepsy with or without cataplexy (primary endpoint). Pitolisant also significantly decreased cataplexy rate versus placebo in these patients. This article summarizes the milestones in the development of pitolisant leading to this first approval for narcolepsy.", "BACKGROUND: Non-islet cell tumor induced hypoglycemia (NICTH) is a very rare phenomenon, but even more so in gastrointestinal stromal tumors. It tends to present in large or metastatic tumors, and can appear at any time in the progression of the disease. We present herein a case of NICTH in a GIST tumor and report an exon 9 mutation associated to it.CASE PRESENTATION: A thirty nine year-old man with a recurrent, metastatic gastrointestinal stromal tumor presented to the hospital with nausea, dizziness, loss of consciousness, and profound hypoglycemia (20 mg/dL). There was no evidence of factitious hypoglycemia. He was stabilized with a continuous glucose infusion and following selective vascular embolization, the patient underwent debulking of a multicentric 40 cm x 25 cm x 10 cm gastrointestinal stromal tumor. After resection, the patient became euglycemic and returned to his normal activities. Tumor analysis confirmed excessive production of insulin-like growth factor II m-RNA and the precursor protein, \"big\" insulin-like growth factor II. Mutational analysis also identified a rare, 6 bp tandem repeat insert (gcctat) at position 1530 in exon 9 of KIT.CONCLUSION: Optimal management of gastrointestinal stromal tumor-induced hypoglycemia requires a multidisciplinary approach, and surgical debulking is the treatment of choice to obtain immediate symptom relief. Imatinib or combinations of glucocorticoids and growth hormone are alternative palliative strategies for symptomatic hypoglycemia. In addition, mutations in exon 9 of the tyrosine kinase receptor KIT occur in 11-20% of GIST and are often associated with poor patient outcomes. The association of this KIT mutation with non-islet cell tumor induced hypoglycemia has yet to be established.", "CYLD is a deubiquitination enzyme that regulates different cellular processes, such as cell proliferation and cell survival. Mutation and loss of heterozygosity of the CYLD gene causes development of cylindromatosis, a benign tumour originating from the skin. Our study shows that CYLD expression is dramatically downregulated in basal cell carcinoma (BCC), the most common cancer in humans. Reduced CYLD expression in basal cell carcinoma was mediated by GLI1-dependent activation of the transcriptional repressor Snail. Inhibition of GLI1 restored the CYLD expression-mediated Snail signaling pathway, and caused a significant delay in the G1 to S phase transition, as well as proliferation. Our data suggest that GLI1-mediated suppression of CYLD has a significant role in basal cell carcinoma progression.", "Split networks are a type of phylogenetic network that allow visualization of conflict in evolutionary data. We present a new method for constructing such networks called FlatNetJoining (FlatNJ). A key feature of FlatNJ is that it produces networks that can be drawn in the plane in which labels may appear inside of the network. For complex data sets that involve, for example, non-neutral molecular markers, this can allow additional detail to be visualized as compared to previous methods such as split decomposition and NeighborNet. We illustrate the application of FlatNJ by applying it to whole HIV genome sequences, where recombination has taken place, fluorescent proteins in corals, where ancestral sequences are present, and mitochondrial DNA sequences from gall wasps, where biogeographical relationships are of interest. We find that the networks generated by FlatNJ can facilitate the study of genetic variation in the underlying molecular sequence data and, in particular, may help to investigate processes such as intra-locus recombination. FlatNJ has been implemented in Java and is freely available at www.uea.ac.uk/computing/software/flatnj.", "Glutamic acid decarboxylase (GAD) is the enzyme responsible for synthesis of the neurotransmitter gamma-aminobutyric acid in neurons and pancreatic beta cells. It is represented by two isoforms, GAD-65 and GAD-67, which are the products of two different genes and differ substantially only at their N-terminal regions. GAD-65 is a dominant autoantigen in stiff-man syndrome and insulin-dependent diabetes mellitus. In neurons and beta cells, GAD is concentrated around synaptic vesicles and synaptic-like microvesicles, respectively, as well as in the area of the Golgi complex. The mechanisms responsible for specific targeting of GAD to these organelles are not yet understood. The elucidation of the mechanism of subcellular targeting of GAD may be relevant to understanding its role as an autoantigen. In this study, the cloned genes for GAD-65 and GAD-67 were expressed separately in Chinese hamster ovary (CHO) cells and COS cells. While GAD-67 had a diffuse cytoplasmic localization, GAD-65 had a punctate distribution, with most of the immunoreactivity being concentrated in the area of the Golgi complex. A chimeric protein in which the 88 N-terminal amino acids of GAD-67 were replaced by the 83 N-terminal amino acids of GAD-65 was targeted to the Golgi complex, indicating that the N-terminal region of GAD-65 contains a targeting signal sufficient for directing the remaining portion of the molecule, highly similar in GAD-65 and GAD-67, to the Golgi complex-associated structures.", "We present QNet, a method for constructing split networks from weighted quartet trees. QNet can be viewed as a quartet analogue of the distance-based Neighbor-Net (NNet) method for network construction. Just as NNet, QNet works by agglomeratively computing a collection of circular weighted splits of the taxa set which is subsequently represented by a planar split network. To illustrate the applicability of QNet, we apply it to a previously published Salmonella data set. We conclude that QNet can provide a useful alternative to NNet if distance data are not available or a character-based approach is preferred. Moreover, it can be used as an aid for determining when a quartet-based tree-building method may or may not be appropriate for a given data set. QNet is freely available for download.", "The piggyBac transposon system is naturally active, originally derived from the cabbage looper moth. This non-viral system is plasmid based, most commonly utilizing two plasmids with one expressing the piggyBac transposase enzyme and a transposon plasmid harboring the gene(s) of interest between inverted repeat elements which are required for gene transfer activity. PiggyBac mediates gene transfer through a \"cut and paste\" mechanism whereby the transposase integrates the transposon segment into the genome of the target cell(s) of interest. PiggyBac has demonstrated efficient gene delivery activity in a wide variety of insect, mammalian, and human cells6 including primary human T cells. Recently, a hyperactive piggyBac transposase was generated improving gene transfer efficiency. Human T lymphocytes are of clinical interest for adoptive immunotherapy of cancer. Of note, the first clinical trial involving transposon modification of human T cells using the Sleeping beauty transposon system has been approved. We have previously evaluated the utility of piggyBac as a non-viral methodology for genetic modification of human T cells. We found piggyBac to be efficient in genetic modification of human T cells with a reporter gene and a non-immunogenic inducible suicide gene. Analysis of genomic integration sites revealed a lack of preference for integration into or near known proto-oncogenes. We used piggyBac to gene-modify cytotoxic T lymphocytes to carry a chimeric antigen receptor directed against the tumor antigen HER2, and found that gene-modified T cells mediated targeted killing of HER2-positive tumor cells in vitro and in vivo in an orthotopic mouse model. We have also used piggyBac to generate human T cells resistant to rapamycin, which should be useful in cancer therapies where rapamycin is utilized. Herein, we describe a method for using piggyBac to genetically modify primary human T cells. This includes isolation of peripheral blood mononuclear cells (PBMCs) from human blood followed by culture, gene modification, and activation of T cells. For the purpose of this report, T cells were modified with a reporter gene (eGFP) for analysis and quantification of gene expression by flow cytometry. PiggyBac can be used to modify human T cells with a variety of genes of interest. Although we have used piggyBac to direct T cells to tumor antigens, we have also used piggyBac to add an inducible safety switch in order to eliminate gene modified cells if needed. The large cargo capacity of piggyBac has also enabled gene transfer of a large rapamycin resistant mTOR molecule (15 kb). Therefore, we present a non-viral methodology for stable gene-modification of primary human T cells for a wide variety of purposes.", "In testis mRNA stability and translation initiation are extensively under the control of poly(A)-binding proteins (PABP). Here we have cloned a new human testis-specific PABP (PABP3) of 631 amino acids (70.1 kDa) with 92.5% identical residues to the ubiquitous PABP1. A northern blot of multiple human tissues hybridised with PABP3- and PABP1-specific oligonucleotide probes revealed two PABP3 mRNAs (2.1 and 2.5 kb) detected only in testis, whereas PABP1 mRNA (3.2 kb) was present in all tested tissues. In human adult testis, PABP3 mRNA expression was restricted to round spermatids, whereas PABP1 was expressed in these cells as well as in pachytene spermatocytes. PABP3-specific antibodies identified a protein of 70 kDa in human testis extracts. This protein binds poly(A) with a slightly lower affinity as compared to PABP1. The human PABP3 gene is intronless with a transcription start site 61 nt upstream from the initiation codon. A sequence of 256 bp upstream from the transcription start site drives the promoter activity of PABP3 and its tissue-specific expression. The expression of PABP3 might be a way to bypass PABP1 translational repression and to produce the amount of PABP needed for active mRNA translation in spermatids.", "Since the 2013 Supreme Court ruling on BRCA1/BRCA2 patenting, hereditary cancer gene panels now include BRCA1 and BRCA2, making these panels an option for first-tier testing. However, questions remain about the clinical utility and implications of these panels for medical management with inclusion of genes of unknown to moderate penetrance. To better understand how use of these panels affected our practice, we reviewed patients who underwent testing in our clinic from July 1, 2013 through May 23, 2014. Indications for testing included personal and/or family history of breast and/or ovarian cancer. A total of 136 patients underwent panel testing via a single commercial laboratory; 12 (8.8 %) patients were positive for a pathogenic or likely pathogenic mutation (four BRCA2 mutations, two TP53 mutations, one CDH1 mutation, two ATM mutations, and one patient each with a CHEK2, NBN, or PALB2 mutation). Of these positive patients, 100 % met the National Comprehensive Cancer Network (NCCN) guidelines for Hereditary Breast and Ovarian Cancer genetic testing (2.2014). Mutations in seven of twelve (58 %) patients led to changes in medical management; three of seven (43 %) had a non-BRCA1 or BRCA2 gene mutation. Our findings suggest that there is clinical utility of panels that include genes of unknown to moderate penetrance.", "SUMMARY: Split-networks are a generalization of phylogenetic trees that have proven to be a powerful tool in phylogenetics. Various ways have been developed for computing such networks, including split-decomposition, NeighborNet, QNet and FlatNJ. Some of these approaches are implemented in the user-friendly SplitsTree software package. However, to give the user the option to adjust and extend these approaches and to facilitate their integration into analysis pipelines, there is a need for robust, open-source implementations of associated data structures and algorithms. Here, we present SPECTRE, a readily available, open-source library of data structures written in Java, that comes complete with new implementations of several pre-published algorithms and a basic interactive graphical interface for visualizing planar split networks. SPECTRE also supports the use of longer running algorithms by providing command line interfaces, which can be executed on servers or in High Performance Computing environments.AVAILABILITY AND IMPLEMENTATION: Full source code is available under the GPLv3 license at: https://github.com/maplesond/SPECTRE. SPECTRE's core library is available from Maven Central at: https://mvnrepository.com/artifact/uk.ac.uea.cmp.spectre/core. Documentation is available at: http://spectre-suite-of-phylogenetic-tools-for-reticulate-evolution.readthedocs.io/en/latest/.CONTACT: sarah.bastkowski@earlham.ac.uk.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "As a barrier to metastasis of cancer, cells that lost contact with the neighbouring cells or extracellular matrix(Extracellular matrix, ECM) will be subjected to apoptosis. This cell death process has been termed \"anoikis\". When normal epithelial cells or solid tumor cells without metastatic potential detach from the primary site, and then enter into the circulatory system, the anoikis mechanism will be activated. The significance of anoikis is to prevent the shedding cells from growing and implanting into other inappropriate sites. Tumor cells, especially several malignant cells that is prone to transfer to distant sites, have properties of anti-anoikis, which facilitates metastasis as well as invasion of tumor cells. The studies found that tumor cells can resist anoikis through multiple mechanisms: the pro-survival pathways are activated by cells autocrine growth factors and paracrine factors derived from neighboring cells; cells change the pattern of integrin expression so that they can receive survival signals from new environment; reactive oxygen species (ROS) activates growth factor receptors in a ligand-independent way to avoid apoptosis; and epithelial-mesenchymal transformation(EMT) is activated etc.. All of these mechanisms lead to activation of survival signals and inhibition of apoptotic pathways, and ultimately cause resistance to anoikis as well as metastasis. This paper summarizes the key mechanisms of the current studies on metastasis, which also suggest important targets for cancer therapy.", "Author information:(1)Department of Biostatistics and Health Informatics, King's College London, London, UK; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK; National Institute for Health Research Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and King's College London, London, UK. Electronic address: alfredo.iacoangeli@kcl.ac.uk.(2)Institute for Molecular Bioscience, The University of Queensland, Brisbane, Brisbane QLD 4072, Australia.(3)Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK.(4)National Institute for Health Research Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and King's College London, London, UK; Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.(5)Centre for Motor Neuron Disease Research, Macquarie University, Sidney NSW 2109, Australia.(6)Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney NSW, Australia; Neuroscience Research Australia, Randwick NSW, Australia.(7)Fiona Stanley Hospital, 11 Robin Warren Drive, Murdoch Perth WA 6150, Australia; Notre Dame University, 32 Mouat Street, Fremantle WA 6160, Australia; Murdoch University, 90 South Street, Murdoch WA 6150, Australia.(8)Calvary Health Care Bethlehem, Parkdale VIC 3195, Australia.(9)ANZAC Research Institute, Concord Repatriation General Hospital, Sydney NSW 2139, Australia.(10)Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.(11)Centre for Clinical Research, The University of Queensland, Brisbane QLD, Australia; Queensland Brain Institute, The University of Queensland, Brisbane QLD, Australia.(12)Centre for Clinical Research, The University of Queensland, Brisbane QLD, Australia; Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane QLD, Australia.(13)Brain and Mind Centre, The University of Sydney, Sydney NSW, Australia.(14)Flinders Medical Centre, Bedford Park SA 5042, Australia.(15)Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney NSW, Australia; Neuropsychiatric Institute, Prince of Wales Hospital, Sydney NSW Australia.(16)Department of Biostatistics and Health Informatics, King's College London, London, UK; National Institute for Health Research Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and King's College London, London, UK; Institute of Health Informatics, University College London, London, UK.(17)Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK; Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.(18)Centre for Clinical Research, The University of Queensland, Brisbane QLD, Australia; Queensland Brain Institute, The University of Queensland, Brisbane QLD, Australia; Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane QLD, Australia; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane QLD, Australia.(19)Institute for Molecular Bioscience, The University of Queensland, Brisbane, Brisbane QLD 4072, Australia; Queensland Brain Institute, The University of Queensland, Brisbane QLD, Australia.(20)Centre for Clinical Research, The University of Queensland, Brisbane QLD, Australia; Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane QLD, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane QLD, Australia.(21)Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK; King's College Hospital, Bessemer Road, London SE5 9RS, UK." ]

[ "Malaria parasites are known to invade and develop in erythrocytes and reticulocytes, but little is known about their infection of nucleated erythroid precursors. We used an in vitro cell system that progressed through basophilic, polychromatic, orthochromatic, and reticulocyte stages to mature erythrocytes. We show that orthochromatic cells are the earliest stages that may be invaded by Plasmodium falciparum, the causative agent of fatal human malaria. Susceptibility to invasion is distinct from intracellular survival and occurs at a time of extensive erythroid remodeling. Together these data suggest that the potential for complexity of host interactions involved in infection may be vastly greater than hitherto realized.", "Keratin is a protein in the intermediate filament family and the key component of hair, nail, and skin. Here we report a bottom-up atomistic model of the keratin dimer, using the complete human keratin type k35 and k85 amino acid sequence. A detailed analysis of geometric and mechanical properties through full-atomistic simulation with validation against experimental results is presented. We introduce disulfide cross-links in a keratin tetramer and compare the mechanical behavior of the disulfide bonded systems with a system without disulfide bonds. Disulfide bond results in a higher strength (20% increase) and toughness (49% increase), but the system loses α-helical structures under loading, suggesting that disulfide bonds play a significant role in achieving the characteristic mechanical properties of trichocyte α-keratin. Our study provides general insight into the effect of disulfide cross-link on mechanical properties. Moreover, the availability of an atomistic model of this protein opens the possibility to study the mechanical properties of hair fibrils and other fibers from a bottom-up perspective.", "A young woman with humeroperoneal muscular dystrophy and contractures received a heart transplant for a severe dilated cardiomyopathy. Cardiac histopathology consisted of myocyte hypertrophy, interstitial fibrosis, and nuclear hyperchromaticity without mitochondrial abnormalities. Myopathy and heart disease were not clinically evident in her family, although three relatives had unexplained shortened Achilles tendons without weakness. Tendon contractures may be a partial expression of this myopathic disorder, suggesting an autosomal dominant inheritance with variable penetrance. A muscular dystrophy clinically similar to that of the Emery-Dreifuss (EDMD) type can thus occur in women. Rather than the cardiac arrhythmias typical of EDMD, a dilated cardiomyopathy may occur and present with severe congestive heart failure. This is the first report of cardiac transplantation in such a case.", "BACKGROUND: Non-invasive methods to assess the foetal genome during pregnancy will provide new opportunities to offer pregnant women a more comprehensive genetic diagnosis of their established foetus. The aim of this study was to determine the presence and frequency of foetal cells in transcervical cell (TCC) mucus samples from pregnant women and determine their suitability for early prenatal diagnosis.METHODS: Syncytiotrophoblasts in aspirated TCC mucus samples were identified by immunostaining with the foetal-specific antibody NDOG1. Genetic analysis of foetal cells was performed by laser capture microdissection and quantitative fluorescent PCR (QF-PCR).RESULTS: In 116 of 207 (56%) TCC samples, abundant syncytiotrophoblasts were retrieved. However, when TCC samples were stratified for the presence of chorionic villous fragments, syncytiotrophoblasts were identified in 85 of 109 (78%) samples. Significant numbers of syncytiotrophoblasts were found in TCC samples collected between 6 and 9weeks of gestation (mean 741, range 25-2884). QF-PCR analysis of NDOG1 positive syncytiotrophoblasts and matching maternal DNA confirmed their foetal origin and correct foetal cell sexing was achieved in 97% of TCC samples. The one discordant sex diagnosis was associated with a dizygotic dichorionic twin pregnancy resulting from the implantation of a female T21 embryo and a normal male embryo, where the female T21 foetus had succumbed at 6weeks of gestation and was vanishing.CONCLUSIONS: Syncytiotrophoblasts can be successfully isolated from TCC samples and represent a suitable source of cells for genetic analysis of the established foetus in early pregnancy. The study highlights a vanishing twin as a potential cause for discordant non-invasive prenatal test results.", "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.", "BACKGROUND: Macrophages are major targets for HIV-1, contribute to viral propagation in vivo, and are instrumental in the pathogenesis of HAND. While it is known that host sex affects HIV-1 viremia and influences the severity of HIV-1-associated neurocognitive disease, a cellular or molecular basis for these findings remains elusive.METHODS: We explored whether sex affects HIV-1 infectivity of primary human macrophages and CD4+ T cells in vitro.RESULTS: Macrophages derived from female donors were less susceptible to HIV-1 infection than those derived from males. This sex-dependent difference in macrophage infectivity was independent of the requirement for CD4/CCR5-mediated virus entry and was not observed in CD4+ T cells. Investigations into the mechanism governing these sex-dependent differences revealed that the host restriction factor SAMHD1 exists in a hyperphosphorylated, less active state in male-derived macrophages. In addition, the major kinase responsible for SAMHD1 phosphorylation, CDK1, exhibited lower levels of expression in female-derived macrophages in all tested donor pairs. The sex-dependent differences in viral restriction imposed by SAMHD1 were abrogated upon its depletion.CONCLUSIONS: We conclude that SAMHD1 is an essential modulator of infectivity in a sex-dependent manner in macrophages, constituting a novel component of sex differences in innate immune control of HIV-1.", "DNA vaccines have demonstrated antitumor efficacy in multiple preclinical models, but low immunogenicity has been observed in several human clinical trials. This has led to many approaches seeking to improve the immunogenicity of DNA vaccines. We previously reported that a DNA vaccine encoding the cancer-testis antigen SSX2, modified to encode altered epitopes with increased MHC class I affinity, elicited a greater frequency of cytolytic, multifunctional CD8(+) T cells in non-tumor-bearing mice. We sought to test whether this optimized vaccine resulted in increased antitumor activity in mice bearing an HLA-A2-expressing tumor engineered to express SSX2. We found that immunization of tumor-bearing mice with the optimized vaccine elicited a surprisingly inferior antitumor effect relative to the native vaccine. Both native and optimized vaccines led to increased expression of PD-L1 on tumor cells, but antigen-specific CD8(+) T cells from mice immunized with the optimized construct expressed higher PD-1. Splenocytes from immunized animals induced PD-L1 expression on tumor cells in vitro. Antitumor activity of the optimized vaccine could be increased when combined with antibodies blocking PD-1 or PD-L1, or by targeting a tumor line not expressing PD-L1. These findings suggest that vaccines aimed at eliciting effector CD8(+) T cells, and DNA vaccines in particular, might best be combined with PD-1 pathway inhibitors in clinical trials. This strategy may be particularly advantageous for vaccines targeting prostate cancer, a disease for which antitumor vaccines have demonstrated clinical benefit and yet PD-1 pathway inhibitors alone have shown little efficacy to date." ]

[ "BACKGROUND: Resistin is an immunometabolic mediator that is elevated in several inflammatory disorders. A ligand for Toll-like receptor 4, resistin modulates the recruitment and activation of myeloid cells, notably neutrophils. Neutrophils are major drivers of cystic fibrosis (CF) lung disease, in part due to the release of human neutrophil elastase- and myeloperoxidase-rich primary granules, leading to tissue damage. Here we assessed the relationship of resistin to CF lung disease.METHODS: Resistin levels were measured in plasma and sputum from three retrospective CF cohorts spanning a wide range of disease. We also assessed the ability of neutrophils to secrete resistin upon activation in vitro. Finally, we constructed a multivariate model assessing the relationship between resistin levels and lung function.RESULTS: Plasma resistin levels were only marginally higher in CF than in healthy control subjects. By contrast, sputum resistin levels were very high in CF, reaching 50-100 fold higher levels than in plasma. Among CF patients, higher plasma resistin levels were associated with allergic bronchopulmonary aspergillosis, and higher sputum resistin levels were associated with CF-related diabetes. Mechanistically, in vitro release of neutrophil primary granules was concomitant with resistin secretion. Overall, sputum resistin levels were negatively correlated with CF lung function, independently of other variables (age, sex, and genotype).CONCLUSIONS: Our data establish relationships between resistin levels in the plasma and sputum of CF patients that correlate with disease status, and identify resistin as a novel mechanistic link between neutrophilic inflammation and lung disease in CF.", "1. ", "According to current models, once the cell has reached terminal differentiation, the enhancer repertoire is completely established and maintained by cooperatively acting lineage-specific transcription factors (TFs). TFs activated by extracellular stimuli operate within this predetermined repertoire, landing close to where master regulators are constitutively bound. Here, we describe latent enhancers, defined as regions of the genome that in terminally differentiated cells are unbound by TFs and lack the histone marks characteristic of enhancers but acquire these features in response to stimulation. Macrophage stimulation caused sequential binding of stimulus-activated and lineage-determining TFs to these regions, enabling deposition of enhancer marks. Once unveiled, many of these enhancers did not return to a latent state when stimulation ceased; instead, they persisted and mediated a faster and stronger response upon restimulation. We suggest that stimulus-specific expansion of the cis-regulatory repertoire provides an epigenomic memory of the exposure to environmental agents.", "Anxiety disorders are prevalent and associated with an increase in morbidity and mortality, particularly when present with additional psychiatric disorders. They represent a public health and economic burden, yet they are commonly underrecognized and undertreated. Benzodiazepines are effective anxiolytics, but they primarily treat the somatic symptoms of generalized anxiety disorder (GAD), and are not effective in treating the depressive symptoms that are often comorbid in chronic anxiety disorders like GAD. Some antidepressants may therefore offer the best choice of therapy. Their benefit in the treatment of GAD has been demonstrated using the tricyclic antidepressant, imipramine, and some selective serotonin reuptake inhibitors. The serotonin and norepinephrine reuptake inhibitor venlafaxine extended release (XR), has been indicated for GAD and has proven to be effective in both the short- and long-term treatment of patients with this disorder. Many patients treated with venlafaxine XR achieve and sustain remission from the symptoms of GAD, which is the goal of treatment.", "Enzymes of the tubulin tyrosine ligase-like (TTLL) family posttranslationally modify and thereby mark microtubules by glutamylation, generating specific recognition sites for microtubule-interacting proteins. Garnham et al. report the first structure of a TTLL protein alone and in complex with microtubules, elucidating their mechanism of action.", "The pathogenesis of nonalcoholic steatohepatitis (NASH) is still unclear, where involvement of circRNA is considered for its active role as \"miRNA sponge\". Therefore, we aimed to investigate the circRNA expression pattern in NASH and further construct the circRNA-miRNA-mRNA network for in-depth mechanism exploration. Briefly, NASH mice model was established by Methionine and choline deficiency (MCD) diet feeding. Liver circRNA and mRNA profile was initially screened by microarray and ensuing qRT-PCR verification was carried out. The overlapped predicted miRNAs as downstream targets of circRNAs and upstream regulators of mRNAs were verified by qRT-PCR and final circRNA-miRNA-mRNA network was constructed. Gene Ontology (GO) and KEGG pathway analysis were further applied to enrich the huge mRNA microarray data. To sum up, there were 69 up and 63 down regulated circRNAs as well as 2760 up and 2465 down regulated mRNAs in NASH group, comparing with control group. Randomly selected 13 of 14 mRNAs and 2 of 8 circRNAs were successfully verified by qRT-PCR. Through predicted overlapped miRNA verification, four circRNA-miRNA-mRNA pathways were constructed, including circRNA_002581-miR-122-Slc1a5, circRNA_002581- miR-122-Plp2, circRNA_002581-miR-122-Cpeb1 and circRNA_007585-miR-326- UCP2. GO and KEGG pathway analysis also enriched specific mRNAs. Therefore, circRNA profile may serve as candidate for NASH diagnosis and circRNA-miRNA -mRNA pathway may provide novel mechanism for NASH.", "This review article is written so as to present the pathophysiology, the symptomatology and the ways of diagnosis and treatment of a rather rare aortic disease called Intra-Mural Haematoma (IMH). Intramural haematoma is a quite uncommon but potentially lethal aortic disease that can strike as a primary occurrence in hypertensive and atherosclerotic patients to whom there is spontaneous bleeding from vasa vasorum into the aortic wall (media) or less frequently, as the evolution of a penetrating atherosclerotic ulcer (PAU). IMH displays a typical of dissection progress, and could be considered as a precursor of classic aortic dissection. IMH enfeebles the aortic wall and may progress to either outward rupture of the aorta or inward disruption of the intima layer, which ultimately results in aortic dissection. Chest and back acute penetrating pain is the most commonly noticed symptom at patients with IMH. Apart from a transesophageal echocardiography (TEE), a tomographic imaging such as a chest computed tomography (CT), a magnetic resonance (MRI) and most lately a multy detector computed tomography (MDCT) can ensure a quick and accurate diagnosis of IMH. Similar to type A and B aortic dissection, surgery is indicated at patients with type-A IMH, as well as at patients with a persistent and/or recurrent pain. For any other patient (with type-B IMH without an incessant pain and/or without complications), medical treatment is suggested, as applied in the case of aortic dissection. The outcome of IMH in ascending aorta (type A) appears favourable after immediate (emergent or urgent) surgical intervention, but according to international bibliography patients with IMH of the descending aorta (type B) show similar mortality rates to those being subjected to conservative medical or surgical treatment. Endovascular surgery and stent-graft placement is currently indicated in type B IMH." ]

[ "Pancreatic cancer is an aggressive malignancy that is unresponsive to conventional radiation and chemotherapy. Therefore, development of novel immune therapeutic strategies is urgently needed. L-4F, an Apolipoprotein A-I (ApoA-I) mimetic peptide, is engineered to mimic the anti-inflammatory and anti-oxidative functionalities of ApoA-I. In this work, H7 cells were orthotopically implanted in C57BL/6 mice and treated with L-4F. Then, pancreatic cancer progression and the inflammatory microenvironment were investigated in vivo. The cytotoxicity of L-4F toward H7 cells was assessed in vitro. Furthermore, we investigated the effects of L-4F on macrophage polarization by analyzing the polarization and genes of mouse bone marrow-derived macrophages in vitro. The results show that L-4F substantially reduced the tumorigenicity of H7 cells. L-4F inhibited inflammation by reducing the accumulation of inflammatory cells, such as IL-17A-, IL-4-, GM-CSF-, IL-1β-, and IL-6-producing cells and Th1 and Th17. Notably, L-4F also decreased the percentage of macrophages in tumor tissues, especially M2 macrophages (CD11b+F4/80+CD206+), which was also confirmed in vitro. Additionally, the expression of the M2 marker genes Arg1, MRC1, and CCL22 and the inflammatory genes IL-6, iNOS, and IL-12 was decreased by L-4F, indicating that L-4F prevents M2 type macrophage polarization. However, L-4F could not directly attenuate H7 cell invasion or proliferation and did not induce apoptosis. In addition, L-4F potently down-regulated STAT3, JNK and ERK signaling pathways but not affects the phosphorylation of p38 in RAW 264.7 cells. These results suggest that L-4F exhibits an effective therapeutic effect on pancreatic cancer progression by inhibiting tumor-associated macrophages and inflammation.", "Both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), its animal model, involve inflammatory attack on central nervous system (CNS) white matter, leading to demyelination and axonal damage. Changes in astrocytic morphology and function are also prominent features of MS and EAE. Resting astrocytes form a network that is interconnected through gap junctions, composed mainly of connexin43 (Cx43) protein. Although astrocytic gap junctional connectivity is known to be altered in many CNS pathologies, little is known about Cx43 expression in inflammatory demyelinating disease. Therefore, we evaluated the expression of Cx43 in spinal cords of EAE mice compared with healthy controls. Lumbar ventral white matter areas were heavily infiltrated with CD11beta-immunoreactive monocytes, and within these infiltrated regions loss of Cx43 immunoreactivity was evident. These regions also showed axonal dystrophy, demonstrated by the abnormally dephosphorylated heavy-chain neurofilament proteins. Astrocytes in these Cx43-depleted lesions were strongly glial fibrillary acidic protein reactive. Significant loss (38%) of Cx43 protein in EAE mouse at the lumbar portion of spinal cords was confirmed by Western blot analysis. Decreased Cx43 transcript level was also observed on cDNA microarray analysis. In addition to changes in Cx43 expression, numerous other genes were altered, including those encoding adhesion and extracellular matrix proteins. Our data support the notion that, in addition to damage of myelinating glia, altered astrocyte connectivity is a prominent feature of inflammatory demyelination.", "Spinal motoneurons (MNs) in the chick embryo undergo programmed cell death coincident with the establishment of nerve-muscle connections and the onset of synaptic transmission at the neuromuscular junction. Chronic treatment of embryos during this period with nicotinic acetylcholine receptor (nAChR)-blocking agents [e.g., curare or alpha-bungarotoxin (alpha-BTX)] prevents the death of MNs. Although this rescue effect has been attributed previously to a peripheral site of action of the nAChR-blocking agents at the neuromuscular junction (NMJ), because nAChRs are expressed in both muscle and spinal cord, it has been suggested that the rescue effect may, in fact, be mediated by a direct central action of nAChR antagonists. By using a variety of different nAChR-blocking agents that target specific muscle or neuronal nAChR subunits, we find that only those agents that act on muscle-type receptors block neuromuscular activity and rescue MNs. However, paralytic, muscular dysgenic mutant chick embryos also exhibit significant increases in MN survival that can be further enhanced by treatment with curare or alpha-BTX, suggesting that muscle paralysis may not be the sole factor involved in MN survival. Taken together, the data presented here support the argument that, in vivo, nAChR antagonists promote the survival of spinal MNs primarily by acting peripherally at the NMJ to inhibit synaptic transmission and reduce or block muscle activity. Although a central action of these agents involving direct perturbations of MN activity may also play a contributory role, further studies are needed to determine more precisely the relative roles of central versus peripheral sites of action in MN rescue.", "The polypeptide composition of the phycobilisome, the major light-harvesting complex of prokaryotic cyanobacteria and certain eukaryotic algae, can be modulated by different light qualities in cyanobacteria exhibiting chromatic adaptation. We have identified genomic fragments encoding a cluster of phycobilisome polypeptides (phycobiliproteins) from the chromatically adapting cyanobacterium Fremyella diplosiphon using previously characterized DNA fragments of phycobiliprotein genes from the eukaryotic alga Cyanophora paradoxa and from F. diplosiphon. Characterization of two lambda-EMBL3 clones containing overlapping genomic fragments indicates that three sets of phycobiliprotein genes--the alpha- and beta-allophycocyanin genes plus two sets of alpha- and beta-phycocyanin genes--are clustered within 13 kilobases on the cyanobacterial genome and transcribed off the same strand. The gene order (alpha-allophycocyanin followed by beta-allophycocyanin and beta-phycocyanin followed by alpha-phycocyanin) appears to be a conserved arrangement found previously in a eukaryotic alga and another cyanobacterium. We have reported that one set of phycocyanin genes is transcribed as two abundant red light-induced mRNAs (1600 and 3800 bases). We now present data showing that the allophycocyanin genes and a second set of phycocyanin genes are transcribed into major mRNAs of 1400 and 1600 bases, respectively. These transcripts are present in RNA isolated from cultures grown in red and green light, although lower levels of the 1600-base phycocyanin transcript are present in cells grown in green light. Furthermore, a larger transcript of 1750 bases hybridizes to the allophycocyanin genes and may be a precursor to the 1400-base species.", "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.", "In spite of introduction of combination antiretroviral therapy (cART) against human immunodeficiency virus (HIV) infection; inaccessibility and poor adherence to oral cART costs 10 in 100,000 death worldwide. Failure in adherence leads to viral rebound, emergence of drug resistance and anticipated HIV infection in high risk individuals. Various Long-acting antiretroviral (LA ARV) nanoformulations including nano-prodrug, solid drug nanoparticles (SDN), nanocrystals, aspherical nanoparticles, polymeric and lipidic nanoparticles have shown plasma/tissue drug concentration in the therapeutic range for several weeks during pre-clinical evaluation. LA ARV nanoformulations therefore have replaced cART as better alternative for the treatment of HIV infection. Cabenuva™ is recently approved by Health Canada containing LA cabotegravir+LA rilpivirine nanocrystals (ViiV healthcare) for once monthly administration by intramuscular route. The LA nanoformulation due to its nanosize insist on better stability, delivery to lymphatic, slow release into systemic circulation via lymphatic-circulatory system conjoint and secondary drug depot within infiltered immune cells at site of administration and systemic circulation in contrast to conventional drugs. However, the pharmacokinetic, biodistribution and efficacy of LA nanoformulations hinge onto physicochemical properties of the drugs and route of administration. Therefore, current review emphasizes on these contradistinctive factors that affects the reproducibility, safety, efficacy and toxicity of LA anti-HIV nanoformulations. Moreover, it expatiates on application of profuse nanoformulations for long-acting effect with promising preclinical discoveries and two clinical leads. To add on, utilization of physiology-based and mechanism-based pharmacokinetic modelling and in vivo animal models which could lead to enhanced safety and efficacy of LA ARV nanoformulations in humans have been included.", "BACKGROUND: Although thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly (TAFRO) syndrome was first described as a variant of idiopathic multicentric Castleman disease (CD), patients with TAFRO syndrome demonstrate more aggressive clinical features. Because these patients may present with fever of unknown origin, general physicians need to recognise its characteristic laboratory data and clinical features during hospitalisation.AIMS: to describe the features, symptoms and characteristics of TAFRO syndrome and to compare them to those of idiopathic CD.METHODS: This was a retrospective study of patients with histopathologically confirmed TAFRO syndrome and idiopathic multicentric CD who were diagnosed and managed between April 2012 and June 2018 in a Japanese university hospital's General Medicine Department.RESULTS: We found that the hospitalisations were significantly longer among patients with TAFRO syndrome compared to those with idiopathic CD (median: 87 days; range: 34-236 days vs median: 30 days; range: 13-59 days; P < 0.01). Patients with TAFRO syndrome were more likely to present with fever, abdominal pain and elevated inflammatory markers and be misdiagnosed with an infectious disease during the first hospital visit. Approximately 40% of patients with TAFRO syndrome had no radiographically enlarged lymph nodes.CONCLUSIONS: TAFRO syndrome may present as an infectious disease with an aggressive clinical course. Our study highlights the importance of giving significance to chief complaints and laboratory data. Physicians need to recognise the clinical and laboratory features of this disease to avoid missing this potentially fatal disorder." ]

[ "Considerable effort has been expended to identify genes that account for myeloid lineage commitment and development. However, currently available non-invasive mouse models utilize myeloid-specific reporters that are significantly expressed in hematopoietic stem cells as well as lymphoid compartments. Here, we describe a myeloid-specific marker that is not shared by any other lineage. We show that lactotransferrin mRNA is expressed by Gr-1(+)/CD11b(+) cells in the bone marrow, as opposed to hematopoietic stem cells or any peripheral cell population. To follow the progeny of lactotransferrin-expressing bone marrow cells, we generated a mouse model in which a reporter gene is irreversibly activated from the lactotransferrin-promoter. We found that lactotransferrin-reporter labels a majority of neutrophils, monocytes, macrophages and distinct subtypes of dendritic cells, while excluding T, B, natural killer cells, interferon-producing killer dendritic cells, plasmacytoid dendritic cells, erythrocytes and eosinophils. Lactotransferrin-reporter(-) bone marrow cells retain lymphoid, erythroid and long-term repopulating potential, while lactotransferrin-reporter(+) bone marrow cells confer only myeloid, but not lymphoid potential. We conclude that lactotransferrin represents a late stage differentiation marker of neutrophils, macrophages and distinct subtypes of dendritic cells.", "Human psoriasin (S100A7) has originally been described as a member of the family of S100 calcium-binding proteins which is overexpressed in patients suffering from psoriasis. The bovine homolog was first identified as a cow-derived respiratory allergen. As Escherichia coli mastitis is a common problem in dairy cattle, and human psoriasin was found to exhibit antimicrobial activity preferentially against E. coli, we examined whether the bovine mRNA is expressed in the mammary gland. To demonstrate the antimicrobial activity of bovine psoriasin, we isolated cDNA from the udder, cloned the bovine psoriasin gene in a bacterial expression vector, and the recombinant protein was expressed in BL21 cells. The in vitro antibacterial activity was tested by performing microdilution susceptibility tests and radial diffusion assays with eight different bacterial strains, thereof three different E. coli strains, and one yeast. The antimicrobial activity of the recombinant bovine psoriasin is comparable with human psoriasin and also limited to E. coli. Psoriasin appears to be a part of the local host defense mechanism in the udder, is a putative candidate for a cow-specific factor influencing mastitis susceptibility, and a possible alternative to conventional antibiotics.", "Argonaute proteins are effectors of RNA interference that function in the context of cytoplasmic ribonucleoprotein complexes to regulate gene expression. Processing bodies (PBs) and stress granules (SGs) are the two main types of ribonucleoprotein complexes with which Argonautes are associated. Targeting of Argonautes to these structures seems to be regulated by different factors. In the present study, we show that heat-shock protein (Hsp) 90 activity is required for efficient targeting of hAgo2 to PBs and SGs. Furthermore, pharmacological inhibition of Hsp90 was associated with reduced microRNA- and short interfering RNA-dependent gene silencing. Neither Dicer nor its cofactor TAR RNA binding protein (TRBP) associates with PBs or SGs, but interestingly, protein activator of the double-stranded RNA-activated protein kinase (PACT), another Dicer cofactor, is recruited to SGs. Formation of PBs and recruitment of hAgo2 to SGs were not dependent upon PACT (or TRBP) expression. Together, our data suggest that Hsp90 is a critical modulator of Argonaute function. Moreover, we propose that Ago2 and PACT form a complex that functions at the level of SGs.", "Skin side effects following XRT take place more often in patients with skin disorders. In this study six patients with psoriatic lesions were evaluated. The total/daily XRT dose to the tumor site was 50-70/1.8-2.0 Gy. No debilitating effect of XRT was observed in both the psoriatic lesions and in the surrounding normal skin.", "Recent studies in patients with disorders of consciousness (DOC) tend to support the view that awareness is not related to activity in a single brain region but to thalamo-cortical connectivity in the frontoparietal network. Functional neuroimaging studies have shown preserved albeit disconnected low-level cortical activation in response to external stimulation in patients in a \"vegetative state\" or unresponsive wakefulness syndrome. While activation of these \"primary\" sensory cortices does not necessarily reflect conscious awareness, activation in higher-order associative cortices in minimally conscious state patients seems to herald some residual perceptual awareness. PET studies have identified a metabolic dysfunction in a widespread frontoparietal \"global neuronal workspace\" in DOC patients including the midline default mode network (\"intrinsic\" system) and the lateral frontoparietal cortices or \"extrinsic system.\" Recent studies have investigated the relation of awareness to the functional connectivity within intrinsic and extrinsic networks, and with the thalami in both pathological and pharmacological coma. In brain damaged patients, connectivity in all default network areas was found to be non-linearly correlated with the degree of clinical consciousness impairment, ranging from healthy controls and locked-in syndrome to minimally conscious, vegetative, coma, and brain dead patients. Anesthesia-induced loss of consciousness was also shown to correlate with a global decrease in cortico-cortical and thalamo-cortical connectivity in both intrinsic and extrinsic networks, but not in auditory, or visual networks. In anesthesia, unconsciousness was also associated with a loss of cross-modal interactions between networks. These results suggest that conscious awareness critically depends on the functional integrity of thalamo-cortical and cortico-cortical frontoparietal connectivity within and between \"intrinsic\" and \"extrinsic\" brain networks.", "Substance-related disorders (SRD) are common psychiatric morbidities among adolescents within youth correctional systems. Identification and treatment of SRDs is critical for successful reformation and reintegration. Lack of simple, structured, valid, brief screening instruments that can be easily administered and scored by lay workers militates against screening for SRDs. We present the results of the reliability and concurrent validity of the CRAFFT (acronym for Car, Relax, Alone, Forget, Friends, and Trouble) substance abuse screening instrument among residents of youth correctional facilities in Lagos, Nigeria. Adolescents who screened positive on CRAFFT were further assessed with the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) to determine whether they met diagnostic criteria for SRDs. The mean CRAFFT scores for all the adolescents (n = 178) was 0.66 (SD ± 1.45). A total of 23 (12.9%) had CRAFFT scores of >1.00. The CRAFFT instrument has good internal consistency (Cronbach's α = 0.85) and 2-week test reliability (Spearman correlation = 0.979; p < .001). At a cutoff point of >1.00, CRAFFT had the best sensitivity and specificity (area under the curve = 0.889; 95% confidence interval 0.765-1.000) among the participants. As validated, the CRAFFT is a reliable instrument for screening for SRDs in incarcerated youth.", "Telomerase is a cellular ribonucleoprotein reverse transcriptase that plays a crucial role in telomere maintenance. This enzyme is expressed in approximately 90% of human tumors, but not in the majority of normal somatic cells. imetelstat sodium (GRN163L), is a 13-mer oligonucleotide N3'→P5' thio-phosphoramidate lipid conjugate, which represents the latest generation of telomerase inhibitors targeting the template region of the human functional telomerase RNA (hTR) subunit. In preclinical trials, this compound has been found to inhibit telomerase activity in multiple cancer cell lines, as well as in vivo xenograft mouse models. Currently, GRN163L is being investigated in several clinical trials, including a phase II human non‑small cell lung cancer clinical trial, in a maintenance setting following standard doublet chemotherapy. In addition to the inhibition of telomerase activity in cancer cell lines, GRN163L causes morphological cell rounding changes, independent of hTR expression or telomere length. This leads to the loss of cell adhesion properties; however, the mechanism underlying this effect is not yet fully understood. In the present study, we observed that GRN163L treatment leads to the loss of adhesion in A549 lung cancer cells, due to decreased E-cadherin expression, leading to the disruption of the cytoskeleton through the alteration of actin, tubulin and intermediate filament organization. Consequently, the less adherent cancer cells initially cease to proliferate and are arrested in the G1 phase of the cell cycle, accompanied by decreased matrix metalloproteinase-2 (MMP-2) expression. These effects of GRN163L are independent of its telomerase catalytic activity and may increase the therapeutic efficacy of GRN163L by decreasing the adhesion, proliferation and metastatic potential of cancer cells in vivo." ]

[ "PURPOSE: We compared proton beam therapy (PBT) with intensity modulated radiation therapy (IMRT) for pediatric craniopharyngioma in terms of disease control, cyst dynamics, and toxicity.METHODS AND MATERIALS: We reviewed records from 52 children treated with PBT (n=21) or IMRT (n=31) at 2 institutions from 1996-2012. Endpoints were overall survival (OS), disease control, cyst dynamics, and toxicity.RESULTS: At 59.6 months' median follow-up (PBT 33 mo vs IMRT 106 mo; P<.001), the 3-year outcomes were 96% for OS, 95% for nodular failure-free survival and 76% for cystic failure-free survival. Neither OS nor disease control differed between treatment groups (OS P=.742; nodular failure-free survival P=.546; cystic failure-free survival P=.994). During therapy, 40% of patients had cyst growth (20% requiring intervention); immediately after therapy, 17 patients (33%) had cyst growth (transient in 14), more commonly in the IMRT group (42% vs 19% PBT; P=.082); and 27% experienced late cyst growth (32% IMRT, 19% PBT; P=.353), with intervention required in 40%. Toxicity did not differ between groups. On multivariate analysis, cyst growth was related to visual and hypothalamic toxicity (P=.009 and .04, respectively). Patients given radiation as salvage therapy (for recurrence) rather than adjuvant therapy had higher rates of visual and endocrine (P=.017 and .024, respectively) dysfunction.CONCLUSIONS: Survival and disease-control outcomes were equivalent for PBT and IMRT. Cyst growth is common, unpredictable, and should be followed during and after therapy, because it contributes to late toxicity. Delaying radiation therapy until recurrence may result in worse visual and endocrine function.", "Sporadic inclusion body myositis (sIBM) and polymyositis (PM) are characterized by muscle inflammation, with sIBM showing additional degenerative alterations. In this study we investigated human beta defensins and associated TLRs to elucidate the role of the innate immune system in idiopathic inflammatory myopathies (IIM), and its association with inflammatory and degenerative alterations. Expression levels of human beta-defensin (HBD)-1, HBD-2, HBD-3 and TLR2, 3, 4, 7 and 9 were analysed by quantitative real-time PCR in skeletal muscle tissue. Localization of HBD-3, collagen 6, dystrophin, CD8-positive T-cells, CD-68-positive macrophages, β-amyloid, the autophagy marker LC3, and TLR3 were detected by immunofluorescence and co-localization was quantified. HBD-3 and all TLRs except for TLR9 were overexpressed in both IIM with significant overexpression of TLR3 in sIBM. HBD-3 showed characteristic intracellular accumulations near deposits of β-amyloid, LC3 and TLR3 in sIBM, and was detected in inflammatory infiltrations and macrophages invading necrotic muscle fibres in both IIM. The characteristic intracellular localization of HBD-3 near markers of degeneration and autophagy, and overexpression of endosomal TLR3 in sIBM hint at different pathogenetic mechanisms in sIBM compared with PM. This descriptive study serves as a first approach to the role of the innate immune system in sIBM and PM.", "Several multiple, large-scale, genetic studies on autoimmune-disease-associated SNPs have been reported recently: peptidylarginine deiminase type 4 (PADI4) in rheumatoid arthritis (RA); solute carrier family 22 members 4 and 5 (SLC22A4 and 5) in RA and Crohn's disease (CD); programmed cell death 1 (PDCD1) in systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), and RA; and protein tyrosine phosphatase nonreceptor type 22 (PTPN22) in T1D, RA, and SLE. Because these reports on association were not always evaluated in multiple ethnic groups and because ethnic difference in allele frequency of the variants has been also reported, we investigated allele frequencies of nine SNPs in four autoimmune-disease-associated loci in Caucasian, African-descent, and Japanese populations. Although SNPs in PADI4 had similar allele frequency among three groups [maximal difference 11%; (P >0.05)], the other three loci revealed statistically significant allele frequency differences (maximal difference 39% (P <0.00001), 13% (P <0.00001), and 8% (P <0.00001) in SLC22A4, PDCD1, and PTPN22, respectively). Of note, three SNPs in the three loci that had allele frequency more than 8% in the Caucasian population were either not polymorphic at all or extremely rare in the Japanese population. Our data suggest that ethnic variations of polymorphisms should be evaluated in detail, and differences should be incorporated into investigations of susceptibility variants for common diseases.", "1. ", "Olive leaves are rich in polyphenolic compounds that are known to have antioxidant, antimicrobial, and anti-inflammatory activities. Therefore, olive leaf extract (OLE) is considered as a natural supplement. In this study we evaluated the antibacterial and the anti-inflammatory effect of OLE and its individual phenolic components in vitro. Polymorphonuclear cells (PMNCs) were isolated from the whole blood using Histopaque solution and cultured in RPMI-enriched medium. Tumor necrosis factor α (TNFα) level was determined by ELISA after 24 h of lipopolysaccharide stimulation. The antibacterial activity of OLE was determined by well diffusion assay. We found a significant decrease in TNFα secretion level in PMNCs culture treated with OLE. Oleuropein is the only OLE component that has shown anti-inflammatory effects at a concentration of 20 μg/mL. Furthermore, OLE exhibited antibacterial activity against some gram positive bacterial strains; however, gram negative bacterial strains were resistant to OLE. Downregulation of TNFα secretion in PMNCs culture in response to OLE treatment indicates that this polyphenol-rich extract has an anti-inflammatory effect, and oleuropein is the major OLE component responsible for this effect. The antibacterial activity of OLE is limited to gram positive bacteria.", "BACKGROUND: Overweight and obesity are risk factors for cardiovascular disease. There is also an association between body mass index (BMI) and cognitive ability. Since low birth weight is associated with adult metabolic disease, particularly in obese subjects, the question emerges whether obesity has an additional negative effect on cognitive function in subjects with low birth weight.OBJECTIVES: The aim was to analyse whether overweight or obesity influence intellectual performance in young adults with particular focus on those with a low birth weight.METHODS: Data were collected from the Swedish Medical Birth Register on 620,834 males born between 1973 and 1988 and matched to results on intellectual performance and BMI at conscription.RESULTS: The risk for low intellectual performance was higher for those with high BMI compared to those with normal. The highest risk was found among subjects with low birth weight and overweight or obesity in young adulthood (odds ratios, 1.98 [1.73-2.22] and 2.59 [2.00-3.34], respectively). However, subjects with further high birth weight and a high BMI at conscription had no further increased risk.CONCLUSIONS: Overweight and obesity are associated with an increased risk of subnormal intellectual performance in young adult males. Subjects with low birth weight and adolescent overweight/obesity are at particular risk of subnormal performance. A high birth weight increases the risk for obesity, but a high adult BMI does not further increase the risk for subnormal performance.", "Introduction: Familial hypercholesterolemia (FH) is characterized by lifelong elevation of low-density lipoprotein cholesterol (LDL-C), early onset coronary atherosclerosis, and premature death. FH is underdiagnosed and undertreated, but requires aggressive LDL-C-lowering to prevent complications. Current treatment strategies such as lifestyle modification and numerous LDL-C-lowering medications are often insufficient to achieve lipid goals in FH.Areas covered: Angiopoietin-like 3 protein (ANGPTL3) is intricately involved in lipid metabolism. Loss-of-function mutations in ANGPTL3 are associated with panhypolipidemia and reduced coronary atherosclerosis. Evinacumab, a fully human monoclonal antibody, inhibits ANGPTL3 and reduces multiple lipoprotein fractions ~50%, including LDL-C. The use of evinacumab within the FH population is described as well as its regulatory journey to an approved therapeutic.Expert opinion: Evinacumab, with its capacity to lower multiple lipoprotein fractions, particularly LDL-C, independently of LDLR function has potential to revolutionize treatment for FH patients. Current FDA-approval is only for homozygous FH (HoFH), arguably the most impactful indication, but use in other lipid disorders is under investigation. The short-term tolerability of evinacumab is very good, with infrequent, mild, and transient adverse events; however, long-term safety data are needed. The high cost and requirement for intravenous administration may limit adoption of evinacumab, but dramatic LDL-C-lowering and need for new therapeutic options for HoFH will drive interest." ]

[ "Author information:(1)Department of Biomedical, Experimental and Clinical Sciences 'Mario Serio', University of Florence, Viale Morgagni, 50 50134 Florence, Italy; Department of Neuroscience, Psychology, Area of Medicine and Health of the Child of the University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy.(2)Department of Physics, University of Genova, via Dodecaneso 33, 16146, Genova, Italy.(3)Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, Viale Taramelli 3/B, 27100 Pavia, Italy.(4)Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, Viale Taramelli 3/B, 27100 Pavia, Italy; Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine Royal Free Campus, University College London, NW3 2PF London, UK.(5)Department of Biomedical, Experimental and Clinical Sciences 'Mario Serio', University of Florence, Viale Morgagni, 50 50134 Florence, Italy.(6)Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, Viale Taramelli 3/B, 27100 Pavia, Italy; Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine Royal Free Campus, University College London, NW3 2PF London, UK; Interuniversity Center for the Study of Neurodegenerative Diseases (CIMN), Florence, Italy.(7)Department of Biomedical, Experimental and Clinical Sciences 'Mario Serio', University of Florence, Viale Morgagni, 50 50134 Florence, Italy; Interuniversity Center for the Study of Neurodegenerative Diseases (CIMN), Florence, Italy.(8)Department of Biomedical, Experimental and Clinical Sciences 'Mario Serio', University of Florence, Viale Morgagni, 50 50134 Florence, Italy; Interuniversity Center for the Study of Neurodegenerative Diseases (CIMN), Florence, Italy. Electronic address: monica.bucciantini@unifi.it.", "New oral anticoagulants which specifically inhibit factor Xa (FXa) or thrombin (FIIa) do not require routine laboratory monitoring. However, they induce a state of hypocoagulation and increase the risk of bleeding. In some clinical situations, such as emergency surgery, hemorrhagic episodes, or recurrent stroke, coagulation monitoring may be useful. A significant number of publications have reported uncontrollable hemorrhagic complications and deaths in patients treated with these new anticoagulants. The selection of the most appropriate clotting assay is based on the drug used and the availability of the test. The new anticoagulants influence all global clot-based tests. Prothrombin time and partial thromboplastin time measured before and after treatment are considered as qualitative tests since they are not specific. Specific anti-Xa and anti-IIa assays are available and results can be expressed in nanogram per milliliter of plasma using calibrated plasmas containing well-established amounts of drug. The fact that there is no specific antidote to reverse the anticoagulant action of the new anticoagulants can impair management of hemorrhagic complications; clinical experience is still limited. Pro-hemostatic treatment with non-activated or activated prothrombin complexes (FEIBA(®)), or as a last recourse with FVIIa concentrates (NovoSeven(®)), has been used with variable results. Some suggestions for the management of patients with bleeding have been published but there is still little clinical evidence for these interventions.", "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.", "BACKGROUND: Mutations in the ribosomal protein S19 gene (RPS19) have been found in 25% of patients with Diamond-Blackfan anemia, a rare syndrome of congenital bone marrow failure characterized by erythroblastopenia and various malformations. Mechanistic understanding of the role of RPS19 in normal erythropoiesis and in the Diamond-Blackfan anemia defect is still poor. However, defective ribosome biogenesis and, in particular, impaired 18S ribosomal RNA maturation have been documented in association with various identified RPS19 mutations. Recently, new genes, all encoding ribosomal proteins, have been found to be mutated in Diamond-Blackfan anemia, adding further support to the concept that ribosome biogenesis plays an important role in regulating erythropoiesis. We previously showed variability in the levels of expression and subcellular localization of a subset of RPS19 mutant proteins.DESIGN AND METHODS: To define the mechanistic basis for this variability better, we studied a large number of mutant proteins and characterized both RPS19 expression level using a specific antibody against RPS19 and RPS19 subcellular localization after transfection of Cos-7 cells with various green fluorescent protein-RPS19 mutants. To investigate the role of the proteasome in RPS19 degradation, we examined the effect of various proteasome inhibitors, namely lactacystin, MG132, and bortezomib on RPS19 expression and subcellular localizationRESULTS: We found two distinct classes of RPS19 protein defects in Diamond-Blackfan anemia based on the stability of the mutant proteins: (i) slightly decreased to normal levels of expression and normal nucleolar localization and (ii) markedly deficient expression and failure to localize to the nucleolus. All the proteasome inhibitors tested were able to restore the expression levels and normal subcellular localization of several unstable mutant proteins.CONCLUSIONS: Our findings demonstrate an important role for the proteasomal degradation pathway in regulating the expression levels and nucleolar localization of certain mutant RPS19 proteins in Diamond-Blackfan anemia.", "AIMS: Up to 50% of patients with heart failure (HF) may suffer from severe cognitive impairment (SCI), but longitudinal studies are sparse, and effects of changes in HF severity on cognitive function are unknown. Therefore, we assessed the prevalence of SCI in HF patients, its relationship with HF severity, its effects on morbidity and mortality, and the relationship between changes in HF severity and cognitive function.METHODS AND RESULTS: We included 611 patients from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) and assessed cognitive function [Hodkinson Abbreviated Mental Test (AMT)] in relation to severity of HF (NYHA class, NT-proBNP) at baseline and 18 months (n = 382) and effects on hospitalization-free survival and mortality. SCI (i.e. AMT score ≤ 7) was present in 9.2% of patients at baseline, but only 20% of them had a diagnosis of dementia. Prevalence of SCI remained stable during follow-up. SCI was present at baseline more often in NYHA IV patients compared with NYHA II [odds ratio 2.94; 95% confidence interval (CI) 1.15-7.51, P = 0.025], but it was not related to NT-proBNP levels. SCI was related to higher mortality (hazard ratio 1.53, 95% CI 1.02-2.30, P = 0.04), but not hospitalization-free survival. Changes in HF severity were not significantly related to changes in cognitive function.CONCLUSION: SCI is a frequent, but often unrecognized finding in HF patients, but the influence of HF severity and its changes on cognitive function were less than hypothesized. Trial registration ISRCTN43596477.", "Shone's complex is a rare congenital cardiac malformation characterized by serial obstructive lesions of the left heart at multiple levels. Presently described is an unusual case of an adult male patient who presented with palpitations and worsening dyspnea. An echocardiographic evaluation revealed Shone's complex associated with left ventricular non-compaction cardiomyopathy (NCC). To our knowledge, an association between NCC and Shone's complex has not been previously described.", "Confident characterization of the microheterogeneity of protein glycosylation through identification of intact glycopeptides remains one of the toughest analytical challenges for glycoproteomics. Recently proposed mass spectrometry (MS)-based methods still have some defects such as lack of the false discovery rate (FDR) analysis for the glycan identification and lack of sufficient fragmentation information for the peptide identification. Here we proposed pGlyco, a novel pipeline for the identification of intact glycopeptides by using complementary MS techniques: 1) HCD-MS/MS followed by product-dependent CID-MS/MS was used to provide complementary fragments to identify the glycans, and a novel target-decoy method was developed to estimate the false discovery rate of the glycan identification; 2) data-dependent acquisition of MS3 for some most intense peaks of HCD-MS/MS was used to provide fragments to identify the peptide backbones. By integrating HCD-MS/MS, CID-MS/MS and MS3, intact glycopeptides could be confidently identified. With pGlyco, a standard glycoprotein mixture was analyzed in the Orbitrap Fusion, and 309 non-redundant intact glycopeptides were identified with detailed spectral information of both glycans and peptides." ]

[ "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.", "Chronic low-grade inflammation in adipose tissue often accompanies obesity, leading to insulin resistance and increasing the risk for metabolic diseases. MAP3K8 (TPL2/COT) is an important signal transductor and activator of pro-inflammatory pathways that has been linked to obesity-induced adipose tissue inflammation. We used human adipose tissue biopsies to study the relationship of MAP3K8 expression with markers of obesity and expression of pro-inflammatory cytokines (IL-1β, IL-6 and IL-8). Moreover, we evaluated obesity-induced adipose tissue inflammation and insulin resistance in mice lacking MAP3K8 and WT mice on a high-fat diet (HFD) for 16 weeks. Individuals with a BMI >30 displayed a higher mRNA expression of MAP3K8 in adipose tissue compared to individuals with a normal BMI. Additionally, high mRNA expression levels of IL-1β, IL-6 and IL-8, but not TNF -α, in human adipose tissue were associated with higher expression of MAP3K8. Moreover, high plasma SAA and CRP did not associate with increased MAP3K8 expression in adipose tissue. Similarly, no association was found for MAP3K8 expression with plasma insulin or glucose levels. Mice lacking MAP3K8 had similar bodyweight gain as WT mice, yet displayed lower mRNA expression levels of IL-1β, IL-6 and CXCL1 in adipose tissue in response to the HFD as compared to WT animals. However, MAP3K8 deficient mice were not protected against HFD-induced adipose tissue macrophage infiltration or the development of insulin resistance. Together, the data in both human and mouse show that MAP3K8 is involved in local adipose tissue inflammation, specifically for IL-1β and its responsive cytokines IL-6 and IL-8, but does not seem to have systemic effects on insulin resistance.", "The highly structured (64% GC) covalently closed circular (CCC) RNA (220 nt) of the virusoid associated with rice yellow mottle virus codes for a 16-kDa highly basic protein using novel modalities for coding, translation, and gene expression. This CCC RNA is the smallest among all known viroids and virusoids and the only one that codes proteins. Its sequence possesses an internal ribosome entry site and is directly translated through two (or three) completely overlapping ORFs (shifting to a new reading frame at the end of each round). The initiation and termination codons overlap UGAUGA (underline highlights the initiation codon AUG within the combined initiation-termination sequence). Termination codons can be ignored to obtain larger read-through proteins. This circular RNA with no noncoding sequences is a unique natural supercompact \"nanogenome.\"", "The transcriptional co-activator p300 is a histone acetyltransferase (HAT) that is typically recruited to transcriptional enhancers and regulates gene expression by acetylating chromatin. Here we show that the activation of p300 directly depends on the activation and oligomerization status of transcription factor ligands. Using two model transcription factors, IRF3 and STAT1, we demonstrate that transcription factor dimerization enables the trans-autoacetylation of p300 in a highly conserved and intrinsically disordered autoinhibitory lysine-rich loop, resulting in p300 activation. We describe a crystal structure of p300 in which the autoinhibitory loop invades the active site of a neighbouring HAT domain, revealing a snapshot of a trans-autoacetylation reaction intermediate. Substrate access to the active site involves the rearrangement of an autoinhibitory RING domain. Our data explain how cellular signalling and the activation and dimerization of transcription factors control the activation of p300, and therefore explain why gene transcription is associated with chromatin acetylation.", "The mammalian INO80 remodelling complex facilitates homologous recombination (HR), but the mechanism by which it does this is unclear. Budding yeast INO80 can remove H2A.Z/H2B dimers from chromatin and replace them with H2A/H2B dimers. H2A.Z is actively incorporated at sites of damage in mammalian cells, raising the possibility that H2A.Z may need to be subsequently removed for resolution of repair. Here, we show that H2A.Z in human cells is indeed rapidly removed from chromatin flanking DNA damage by INO80. We also report that the histone chaperone ANP32E, which is implicated in removing H2AZ from chromatin, similarly promotes HR and appears to work on the same pathway as INO80 in these assays. Importantly, we demonstrate that the HR defect in cells depleted of INO80 or ANP32E can be rescued by H2A.Z co-depletion, suggesting that H2A.Z removal from chromatin is the primary function of INO80 and ANP32E in promoting homologous recombination.", "An online metal-free weak cation exchange-hydrophilic interaction LC/RPLC system has been developed for sensitive, high-throughput top-down MS. Here, we report results for analyzing PTMs of core histones, with a focus on histone H4, using this system. With just ∼24 μg on-column of core histones (H4, H2B, H2A, and H3) purified from human fibroblasts, 41 H4 isoforms were identified, with the type and location of PTMs unambiguously mapped for 20 of these variants. Compared to corresponding offline studies reported previously, the online weak cation exchange-hydrophilic interaction LC/RPLC platform offers significant improvement in sensitivity, with several orders of magnitude reduction in sample requirements and a reduction in the overall analysis time. To the best of our knowledge, this study represents the first online 2-D LC-MS/MS characterization of core histone mixture at the intact protein level.", "Acute annular ligament interposition into the radiocapitellar joint (\"nursemaid's elbow\") is a common injury in children younger than 5 years. The injury occurs when axial traction is applied to an extended, pronated arm. There are no abnormal radiographic findings associated with this condition. We recommend that children with a classic history and clinical presentation of an acute annular ligament interposition into the radiocapitellar joint be treated without obtaining radiographs.", "Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motoneuron degeneration, resulting in muscle paralysis and death, typically within 1-5 years of diagnosis. Although the pathogenesis of ALS remains unclear, there is evidence for the involvement of proteasome dysfunction and heat shock proteins in the disease. We have previously shown that treatment with a co-inducer of the heat shock response called arimoclomol is effective in the SOD(G93A) mouse model of ALS, delaying disease progression and extending the lifespan of SOD(G93A) mice (Kieran et al. 2004). However, this previous study only examined the effects arimoclomol when treatment was initiated in pre- or early symptomatic stages of the disease. Clearly, to be of benefit to the majority of ALS patients, any therapy must be effective after symptom onset. In order to establish whether post-symptomatic treatment with arimoclomol is effective, in this study we carried out a systematic assessment of different treatment regimes in SOD(G93A) mice. Treatment with arimoclomol from early (75 days) or late (90 days) symptomatic stages significantly improved muscle function. Treatment from 75 days also significantly increased the lifespan of SOD(G93A) mice, although treatment from 90 days has no significant effect on lifespan. The mechanism of action of arimoclomol involves potentiation of the heat shock response, and treatment with arimoclomol increased Hsp70 expression. Interestingly, this up-regulation in Hsp70 was accompanied by a decrease in the number of ubiquitin-positive aggregates in the spinal cord of treated SOD(G93A) mice, suggesting that arimoclomol directly effects protein aggregation and degradation." ]

[ "PURPOSE: We investigated the correlations between ultrasonographic bladder wall thickness and urodynamic parameters, and estimated the diagnostic accuracy of bladder wall thickness for predicting unfavorable urodynamic patterns in children with myelodysplasia.MATERIALS AND METHODS: A total of 57 children (median age 5.1 years) with myelodysplasia were enrolled in the study. All children underwent ultrasonography to measure bladder wall thickness. Videourodynamic evaluation was also performed within 3 months of ultrasound assessment. Bladder wall thickness was compared to urodynamic data. A urodynamic risk of upper urinary tract deterioration was defined as maximum detrusor pressure greater than 40 cm H(2)O during filling or at leakage, or sphincter dyssynergia during voiding.RESULTS: Bladder wall thickness was significantly correlated to detrusor leak point pressure, maximum amplitude of detrusor overactivity and maximum detrusor pressure during storage phase. In 16 children who had unfavorable urodynamic risk patterns the mean bladder wall thickness was 3.9 +/- 1.0 mm, compared to 2.4 +/- 0.7 mm in 41 patients with favorable urodynamic patterns. There was a significant difference between bladder wall thickness in children with and those without urodynamic risk factors (p <0.001). For a diagnosis of unfavorable urodynamic patterns bladder wall thickness greater than 3.3 mm had a positive predictive value of 85.7%, a negative predictive value of 90.7%, specificity of 75.0% and sensitivity of 95.1%. Receiver operator characteristic analysis revealed that bladder wall thickness had a high predictive value for unfavorable urodynamic patterns, with an area under the curve of 0.908.CONCLUSIONS: Ultrasonographic assessment of bladder wall thickness is a sensitive screening tool for the diagnosis of urodynamic risk factors for upper urinary tract deterioration in children with myelodysplasia.", "BACKGROUND: Uropathogenic Escherichia coli (UPEC) is a major cause of Urinary Tract Infections (UTIs). Due to increasing antibiotic-resistance among UPEC bacteria, new treatment options for UTIs are urgently needed.OBJECTIVE: To identify new agents targeting growing bacteria that may be used for the treatment of antibiotic-resistant UTIs.METHODS: We screened a clinical compound library consisting of 1,524 compounds using a high throughput 96-well plate assay and ranked the activities of the selected agents according to their MICs against the UPEC strain UTI89.RESULTS: We identified 33 antibiotics which were active against log-phase clinical UPEC strain UTI89. Among the selected antibiotics, there were 12 fluoroquinolone antibiotics (tosufloxacin, levofloxacin, sparfloxacin, clinafloxacin, pazufloxacin, gatifloxacin, enrofloxacin, lomefloxacin, norfloxacin, fleroxacin, flumequine, ciprofloxacin), 15 beta-lactam or cephalosporin antibiotics (cefmenoxime, cefotaxime, ceftizoxime, cefotiam, cefdinir, cefoperazone, cefpiramide, cefamandole, cefixime, ceftibuten, cefmetazole, cephalosporin C, aztreonam, piperacillintazobactam, mezlocillin), 3 tetracycline antibiotics (meclocycline, doxycycline, tetracycline), 2 membrane-acting agents (colistin and clofoctol), and 1 protein synthesis inhibitor (amikacin). Among them, the top 7 hits were colistin, tosufloxacin, levofloxacin, sparfloxacin, clinafloxacin, cefmenoxime and pazufloxacin, where clinafloxacin and pazufloxacin were the newly identified agents active against UPEC strain UTI89. We validated the key results obtained with UTI89 on two other UTI strains CFT073 and KTE181 and found that they all had comparable MICs for fluoroquinolones while CFT073 and KTE181 were more susceptible to cephalosporin antibiotics and tetracycline antibiotics but were less susceptible to colistin than UTI89.CONCLUSION: Our findings provide possible effective drug candidates for the more effective treatment of antibiotic-resistant UTIs.", "Ledipasvir/sofosbuvir (Harvoni) for hepatitis C virus genotype 1 infection; dulaglutide (Trulicity) for glycemic control in type-2 diabetes; netupitant/palonosetron (Akynzeo) for prevention of nausea and vomiting related to chemotherapy; and naloxegol (Movantik) for opioid-induced constipation in patients with chronic noncancer pain.", "BACKGROUND: Pompe disease is an autosomal recessive disorder of glycogen metabolism that is characterized by a deficiency of the lysosomal acid alpha-glucosidase. Enzyme replacement therapy for the infantile and juvenile forms of Pompe disease currently is undergoing clinical trials. Early diagnosis before the onset of irreversible pathology is thought to be critical for maximum efficacy of current and proposed therapies. In the absence of a family history, the presymptomatic detection of these disorders ideally can be achieved through a newborn-screening program. Currently, the clinical diagnosis of Pompe disease is confirmed by the virtual absence, in infantile onset, or a marked reduction, in juvenile and adult onset, of acid alpha-glucosidase activity in muscle biopsies and cultured fibroblasts. These assays are invasive and not suited to large-scale screening.METHODS: A sensitive immune-capture enzyme activity assay for the measurement of acid alpha-glucosidase protein was developed and used to determine the activity of this enzyme in dried-blood spots from newborn and adult controls, Pompe-affected individuals, and obligate heterozygotes.RESULTS: Pompe-affected individuals showed an almost total absence of acid alpha-glucosidase activity in blood spots. The assay showed a sensitivity and specificity of 100% for the identification of Pompe-affected individuals.CONCLUSIONS: The determination of acid alpha-glucosidase activity in dried-blood spots is a useful, noninvasive diagnostic assay for the identification of Pompe disease. With further validation, this procedure could be adapted for use with blood spots collected in newborn-screening programs.", "The epidermal growth factor receptor (EGFR) is frequently expressed in triple-negative breast cancer (TNBC) and is a marker of poor prognosis in this patient population. Because activating mutations in this kinase are very rare events in breast cancer, we screened breast tumor gene expression profiles to examine the distribution of EGFR ligand expression. Of the six known EGFR ligands, transforming growth factor alpha (TGFα) was expressed more highly in triple-negative breast tumors than in tumors of other subtypes. TGFα is synthesized as a transmembrane precursor requiring tumor necrosis factor alpha converting enzyme (TACE)/ADAM17-dependent proteolytic release to activate its receptor. In our study, we show that an inhibitor of this proteolytic release blocks invasion, migration and colony formation by several TNBC cell lines. Each of the effects of the drug was reversed upon expression of a soluble TGFα mutant that does not require TACE activity, implicating this growth factor as a key metalloproteinase substrate for these phenotypes. Together, these data demonstrate that TACE-dependent TGFα shedding is a key process driving EGFR activation and subsequent proliferation and invasion in TNBC cell lines.", "The transcriptional regulation of genes determines the fate of animal cell differentiation and subsequent organ development. With the recent progress in genome-wide technologies, the genomic landscapes of enhancers have been broadly explored in mammalian genomes, which led to the discovery of novel specific subsets of enhancers, termed super-enhancers. Super-enhancers are large clusters of enhancers covering the long region of regulatory DNA and are densely occupied by transcription factors, active histone marks, and co-activators. Accumulating evidence points to the critical role that super-enhancers play in cell type-specific development and differentiation, as well as in the development of various diseases. Here, I provide a comprehensive description of the optimal approach for identifying functional units of super-enhancers and their unique chromatin features in normal development and in diseases, including cancers. I also review the recent updated knowledge on novel approaches of targeting super-enhancers for the treatment of specific diseases, such as small-molecule inhibitors and potential gene therapy. This review will provide perspectives on using super-enhancers as biomarkers to develop novel disease diagnostic tools and establish new directions in clinical therapeutic strategies.", "The Ewing family of tumors (EFT) is characterized by high MIC2/CD99 expression and specific EWS/ETS gene rearrangements, resulting in different chimeric transcripts. Further division into peripheral primitive neuroectodermal tumors and Ewing's sarcoma is still debated and, in the absence of distinct morphological parameters, has been based on the reactivity with neuroglial markers (NgM). We investigated 44 EFT in terms of a possible correlation between the type of EWS chimeric transcripts and reactivity with the following NgM: polyclonal and monoclonal neuron-specific enolase (NSE), S-100, chromogranin A, synaptophysin, Leu-7, glial fibrillary acid protein, and neurofilament. EWS/Fli1 fusion type 1 was detected in 30 of 44 and type 2 in 11 of 44 tumors. Three tumors, presenting with an uncommon morphology, carried rare chimeric transcripts. Our results indicate an association of lack of NgM staining with type 1 EWS/Fli1 translocations, found in 16 of 18 tumors with no NgM expression as detectable by any of the antibodies we applied. Using the monoclonal NSE antibody, 21 of 26 tumors without NgM staining expressed type 1 EWS/FLI1chimeric RNA, whereas in the groups with 1 or more and 2 or more NgM, only 9 of 17 and 1 of 5 tumors, respectively, carried type 1 EWS/Fli1 fusion transcripts. Despite this association of increased NgM expression with a non-type 1 EWS/Fli1 gene fusion, a strict correlation between the extent of NgM expression and certain EWS fusion types was not evident. This fortifies the concept to consider EFT as a spectrum of tumors and suggests the type of EWS fusion transcripts as one, but not the only parameter influencing the extent of differentiation." ]

[ "Muenke syndrome is an autosomal dominant craniosynostosis syndrome resulting from a defining point mutation in the Fibroblast Growth Factor Receptor3 (FGFR3) gene. Muenke syndrome is characterized by coronal craniosynostosis (bilateral more often than unilateral), hearing loss, developmental delay, and carpal and/or tarsal bone coalition. Tarsal coalition is a distinct feature of Muenke syndrome and has been reported since the initial description of the disorder in the 1990s. Although talocalcaneal coalition is the most common tarsal coalition in the general population, it has never previously been reported in a patient with Muenke syndrome. We present a 7-year-old female patient with Muenke syndrome and symptomatic talocalcaneal coalition. She presented at the age of 7 with limping, tenderness and pain in her right foot following a fall and strain of her right foot. She was treated with ibuprofen, shoe inserts, a CAM walker boot, and stretching exercises without much improvement in symptoms. A computed tomography (CT) scan revealed bilateral talocalcaneal coalitions involving the middle facet. She underwent resection of the talocalcaneal coalitions, remaining pain-free post-operatively with an improvement in her range of motion, gait, and mobility. This report expands the phenotype of tarsal coalition in Muenke syndrome to include talocalcaneal coalition. A literature review revealed a high incidence of tarsal coalition in all FGFR related craniosynostosis syndromes when compared to the general population, a difference that is statistically significant. The most common articulation involved in all syndromic craniosynostoses associated with FGFR mutations is the calcaneocuboid articulation.", "BACKGROUND: Neither the presence nor prevalence of enteric hyperoxaluria has been recognized after Roux-en-Y gastric bypass (RYGBP). We have noted a high rate of oxalate nephrolithiasis and even 2 patients with oxalate nephropathy in this patient population postoperatively. Our aim was to determine the frequency of the occurrence and effects of enteric hyperoxaluria after RYGBP.METHODS: Retrospective review of all patients at our institution diagnosed with calcium oxalate nephrolithiasis or oxalate nephropathy after standard (n = 14) or distal (n = 9) RYGBP. The mean postoperative follow-up was 55 months.RESULTS: A total of 23 patients (14 men and 9 women; mean age 45 years; mean preoperative body mass index 55 kg/m(2)) developed enteric hyperoxaluria after RYGBP, defined by the presence of oxalate nephropathy (n = 2) or calcium oxalate nephrolithiasis (n = 21) and increased 24-hour excretion of urinary oxalate and/or calcium oxalate supersaturation. Enteric hyperoxaluria was recognized after a mean weight loss of 46 kg at 29 months (range 2-85) after RYGBP. Two patients developed renal failure and required chronic hemodialysis. Of the 21 patients with nephrolithiasis, 14 had no history of nephrolithiasis preoperatively, and 19 of 21 required lithotripsy or other intervention. Of the 23 patients, 20 tested had increased oxalate excretion, and 14 of 15 tested had high urine calcium oxalate supersaturation.CONCLUSION: Enteric hyperoxaluria, nephrolithiasis, and oxalate nephropathy must be considered with the other risks of RYGBP. Efforts should be made to identify factors that predispose patients to developing hyperoxaluria.", "DNA damage response and repair pathways are important barriers to carcinogenesis. Here, we show that promyelocytic leukaemia (PML, also known as TRIM19), involved in sensing DNA damage and executing homologous recombination repair, is down-regulated in non-tumour liver cells surrounding hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). No PML mutation or deletion was found in HBV-infected liver or HCC cells. Immunohistochemical analysis of liver biopsies from patients with breast or liver cancer and HBV reactivation after chemotherapy revealed PML up-regulation and HBV exacerbation in normal liver tissue in response to DNA damage (functional PML), PML down-regulation in HCC peritumour cells associated with high HBsAg accumulation and low HBV replication activity (suppressive PML), and heterogeneous nuclear PML expression in HCC cells that lost HBV DNA and HBsAg and were non-reactive to DNA damage (dysregulated PML). Loss of PML in HBsAg-transgenic mice promoted chromosome breaks in liver cells and accelerated the accumulation of body and liver fat and the development of a liver steatosis-dysplasia-adenoma-carcinoma sequence in an inflammation-independent and male-predominant manner, compared to PML knock-out or HBsAg-transgenic mice during the same time period. These results indicate that PML deficiency facilitates genomic instability and promotes HBsAg-related hepatocarcinogenesis, which also involves androgen and lipid metabolism. These findings uncover a novel PML link between HBV-related tumourigenesis, DNA repair, and metabolism.", "DNA methyltransferase 1 (DNMT1) is an emerging target for the treatment of cancer, brain disorders, and other diseases. Currently, there are only a few DNMT1 inhibitors with potential application as therapeutic agents or research tools. 5,5-Methylenedisalicylic acid is a novel scaffold previously identified by virtual screening with detectable although weak inhibitory activity of DNMT1 in biochemical assays. Herein, we report enzyme inhibition of a structurally related compound, trimethylaurintricarboxylic acid (NSC97317) that showed a low micromolar inhibition of DNMT1 (IC(50) = 4.79 μM). Docking studies of the new inhibitor with the catalytic domain of DNMT1 suggest that NSC97317 can bind into the catalytic site. Interactions with amino acid residues that participate in the mechanism of DNA methylation contribute to the binding recognition. In addition, NSC97317 had a good match with a structure-based pharmacophore model recently developed for inhibitors of DNMT1. Trimethylaurintricarboxylic acid can be a valuable biochemical tool to study DNMT1 inhibition in cancer and other diseases related to DNA methylation.", "A system for growing Geobacter sulfurreducens under anaerobic conditions in chemostats was developed in order to study the physiology of this organism under conditions that might more closely approximate those found in the subsurface than batch cultures. Geobacter sulfurreducens could be cultured under acetate-limiting conditions with fumarate or Fe(III)-citrate as the electron acceptor at growth rates between 0.04 and 0.09 h(-1). The molar growth yield was threefold higher with fumarate as the electron acceptor than with Fe(III), despite the lower mid-point potential of the fumarate/succinate redox couple. When growth was limited by availability of fumarate, high steady-state concentrations were detected, suggesting that fumarate is unlikely to be an important electron acceptor in sedimentary environments. The half-saturation constant, Ks, for acetate in Fe(III)-grown cultures (10 microM) suggested that the growth of Geobacter species is likely to be acetate limited in most subsurface sediments, but that when millimolar quantities of acetate are added to the subsurface in order to promote the growth of Geobacter for bioremediation applications, this should be enough to overcome any acetate limitations. When the availability of electron acceptors, rather than acetate, limited growth, G. sulfurreducens was less efficient in incorporating acetate into biomass but had higher respiration rates, a desirable physiological characteristic when adding acetate to stimulate the activity of Geobacter species during in situ uranium bioremediation. These results demonstrate that the ability to study the growth of G. sulfurreducens under steady-state conditions can provide insights into its physiological characteristics that have relevance for its activity in a diversity of sedimentary environments.", "OBJECTIVE: Dravet syndrome or severe myoclonic epilepsy of infancy (SMEI) is a baleful epileptic encephalopathy that begins in the first year of life. This syndrome specified by febrile seizures followed by intractable epilepsy, disturbed psychomotor development, and ataxia. Clinical similarities between Dravet syndrome and generalized epilepsy with febrile seizure plus (GEFS+) includes occurrence of febrile seizures and joint molecular genetic etiology. Shared features of these two diseases support the idea that these two disorders represent a severity spectrum of the same illness. Nowadays, more than 60 heterozygous pattern SCN1A mutations, which many are de novo mutations, have been detected in Dravet syndrome.MATERIALS & METHODS: From May 2008 to August 2012, 35 patients who referred to Pediatric Neurology Clinic of Mofid Children Hospital in Tehran were enrolled in this study. Entrance criterion of this study was having equal or more than four criteria for Dravet syndrome. We compared clinical features and genetic findings of the patients diagnosed as Dravet syndrome or GEFS+.RESULTS: 35 patients (15 girls and 20 boys) underwent genetic testing. Mean age of them was 7.7 years (a range of 13 months to 15 years). Three criteria that were best evident in SCN1A mutation positive patients are as follows: \"Normal development before the onset of seizures, onset of seizure before age of one year, and psychomotor retardation after onset of seizures. Our genetic testing showed that 1 of 3 (33.3%) patients with clinical Dravet syndrome and 3 of 20 (15%) patients that diagnosed as GEFS+, had SCN1A mutation.CONCLUSION: In this study, normal development before seizure onset, seizures beginning before age of one year and psychomotor retardation after age of two years are the most significant criteria in SCN1A mutation positive patients.", "Chimeric antigen receptor (CAR) T cells represent a medical and scientific breakthrough that may represent a paradigm for the future of personalized medicine in the age of cancer immunotherapy. As with many new cancer agents, such novel and incredible results come with a high price. At the time of the writing of this article, there are two CAR T cells available, Kymriah, produced by Novrtis with a price tag of US$475,000 and Yescarta produced by Gilead Pharmaceuticals with a price tag of US$373,000, neither price including the required hospital admission in order to administer the agent in addition to potential treatment of side effects. There are several issues that are imperative to recognize when understanding the high cost, however the two more pertinent issues are low availability of the agent and no billing code. While only approved for less than a year, there are thoughts about how to bring the price down with more approved CAR T cells and more center with the ability to administer this therapy, however results may be years away before they are realized. In the short term, insurance companies are grappling over how to pay for CAR T therapy, with one of the biggest voids concerning the absence of a billing code for CAR T cells. Regardless, its high price tag highlights moral issues underlying value-based payments and whether the treatment is worth the cost while evaluating the juxtaposition of life years and monetary values. As CAR T cells expand the boundaries of immunotherapy with extraordinary results, the need for a lower price in combination for more availability of CAR T cells will grow until some of these fundamental issues are addressed." ]

[ "Mitochondria can be isolated from skeletal muscle in a manner that preserves tightly coupled bioenergetic function in vitro. The purpose of this study was to characterize the composition of such preparations using a proteomics approach. Mitochondria isolated from human vastus lateralis biopsies were functional as evidenced by their response to carbohydrate and fat-derived fuels. Using one-dimensional gel electrophoresis and HPLC-ESI-MS/MS, 823 unique proteins were detected, and 487 of these were assigned to the mitochondrion, including the newly characterized SIRT5, MitoNEET and RDH13. Proteins detected included 9 of the 13 mitochondrial DNA-encoded proteins and 86 of 104 electron transport chain (ETC) and ETC-related proteins. In addition, 59 of 78 proteins of the 55S mitoribosome, several TIM and TOM proteins and cell death proteins were present. This study presents an efficient method for future qualitative assessments of proteins from functional isolated mitochondria from small samples of healthy and diseased skeletal muscle.", "While actin was discovered in the nucleus over 50 years ago, research lagged for decades due to strong skepticism. The revitalization of research into nuclear actin occurred after it was found that cellular stresses induce the nuclear localization and alter the structure of actin. These studies provided the first hints that actin has a nuclear function. Subsequently, it was established that the nuclear import and export of actin is highly regulated. While the structures of nuclear actin remain unclear, it can function as monomers, polymers, and even rods. Furthermore, even within a given structure, distinct pools of nuclear actin that can be differentially labeled have been identified. Numerous mechanistic studies have uncovered an array of functions for nuclear actin. It regulates the activity of RNA polymerases, as well as specific transcription factors. Actin also modulates the activity of several chromatin remodeling complexes and histone deacetylases, to ultimately impinge on transcriptional programing and DNA damage repair. Further, nuclear actin mediates chromatin movement and organization. It has roles in meiosis and mitosis, and these functions may be functionally conserved from ancient bacterial actin homologs. The structure and integrity of the nuclear envelope and sub-nuclear compartments are also regulated by nuclear actin. Furthermore, nuclear actin contributes to human diseases like cancer, neurodegeneration, and myopathies. Here, we explore the early discovery of actin in the nucleus and discuss the forms and functions of nuclear actin in both normal and disease contexts. Anat Rec, 301:1999-2013, 2018. © 2018 Wiley Periodicals, Inc.", "DNA double-strand breaks repaired by non-homologous end joining display limited DNA end-processing and chromosomal mobility. By contrast, double-strand breaks undergoing homology-directed repair exhibit extensive processing and enhanced motion. The molecular basis of this movement is unknown. Here, using Xenopus laevis cell-free extracts and mammalian cells, we establish that nuclear actin, WASP, and the actin-nucleating ARP2/3 complex are recruited to damaged chromatin undergoing homology-directed repair. We demonstrate that nuclear actin polymerization is required for the migration of a subset of double-strand breaks into discrete sub-nuclear clusters. Actin-driven movements specifically affect double-strand breaks repaired by homology-directed repair in G2 cell cycle phase; inhibition of actin nucleation impairs DNA end-processing and homology-directed repair. By contrast, ARP2/3 is not enriched at double-strand breaks repaired by non-homologous end joining and does not regulate non-homologous end joining. Our findings establish that nuclear actin-based mobility shapes chromatin organization by generating repair domains that are essential for homology-directed repair in eukaryotic cells.", "Until recently it was widely accepted that the dynamic cytoskeletal matrix is exclusive to the cytoplasm of eukaryotes, evolving before the emergence of the cell nucleus to enable phagocytosis, cell motility and the sophisticated functioning of the endomembrane system within the cytosol. The discovery of the existence of a prokaryotic cytoskeleton has changed this picture significantly. As a result, the idea has taken shape that the appearance of actin occurred in the very first cell; therefore, the emergence of microfilaments precedes that of the eukaryotic cytoskeleton. The discovery of nuclear actin opened new perspective on the field, suggesting that the nuclear activities of actin reflect the functions of primordial actin-like proteins. In this paper, we review the recent literature to explore the evolutionary origin of nuclear actin. We conclude that both ancient and eukaryotic features of the actin world can be detected in the nucleus today, which supports the idea that the cytoskeleton attained significant eukaryotic innovations before the tandem evolution of the cytoskeleton and nucleus occurred.", "We provide evidence for a mechanism of DNA repair that requires nuclear myosin/actin-dependent contact between homologous chromosomes to prevent formation of chromosomal rearrangement in human cells. We recently showed that DNA double strand breaks (DSBs) induced by γ-rays or endonucleases cause ATM-dependent contact formation between homologous chromosomes at damaged sites of transcriptionally active chromatin in G0/G1-phase cells. Here, we report that the mechanism of contact generation between homologous chromosomes also requires homology-directed repair proteins, including BRCA1, RAD51 and RAD52, and nuclear myosin/actin-motors. Moreover, inhibition of ATM kinase or deficiency in nuclear actin polymerization causes carcinogenic RET/PTC chromosome rearrangements after DSBs induction in human cells. These data suggest that DSBs in transcriptionally active euchromatin in G0/G1-phase cells are repaired through a mechanism that requires contact formation between homologous chromosomes and that this mechanism is mediated by HDR proteins and nuclear myosin/actin motors.", "The Grg gene encodes a 197 amino acid protein homologous to the amino-terminal domain of the product of the groucho gene of the Drosophila Enhancer of split complex. Analysis with a polyclonal antisera specific for the Grg protein revealed that Grg is a 25 kd nuclear protein that can participate in specific protein-protein interactions. A null mutation of the Grg gene was constructed by gene targeting. Mice homozygous for this mutation completed embryogenesis and were born, but exhibited varying degrees of post-natal growth deficiency. No dosage-sensitive genetic interaction was detected between the Notch1 and Grg genes in mice heterozygous for a Notch1 mutant allele and homozygous for the Grg null mutation.", "Background: Roflumilast cream (ARQ-151) is a highly potent, selective phosphodiesterase-4 inhibitor in development for once-daily topical treatment of chronic plaque psoriasis. Objectives: To assess the safety and efficacy of once-daily roflumilast cream 0.5% and 0.15% in patients with chronic plaque psoriasis. Methods: This phase 1/2a study enrolled a single-dose, open-label cohort (Cohort 1: 0.5% cream applied to 25 cm² psoriatic plaques), and a 28-day, double-blinded cohort (Cohort 2: 1:1:1 randomization to roflumilast cream 0.5%, 0.15%, or vehicle). Patients had chronic plaque psoriasis of >6 months' duration with ≤5% body surface area involvement. Outcomes included safety (adverse events) and efficacy (percentage change in the Target Plaque Severity Score [TPSS] × Target Plaque Area [TPA]) at week 4. Results: For Cohorts 1 (n=8) and 2 (n=89), adverse events (all mild/moderate; none severe or serious) were similar between active arms and vehicle. Treatment-related events were confined to the application site, without differences between drug and vehicle. No patient discontinued treatment due to adverse events. The primary efficacy endpoint was met for both roflumilast cream doses: TPSS×TPA improvement at week 4 was statistically significant for roflumilast 0.5% (P=0.0007) and 0.15% (P=0.0011) versus vehicle; significance was reached as early as 2 weeks. For both roflumilast cream doses, 66%-67% improvement from baseline was observed at week 4, without reaching a plateau, versus 38% improvement for vehicle. Conclusion: Roflumilast cream was safe and highly effective at doses of 0.5% and 0.15% and represents a potential novel once-daily topical therapy for the treatment of chronic plaque psoriasis. ClinicalTrials.gov NCT03392168. J Drugs Dermatol. 2020;19(8): doi:10.36849/JDD.2020.5370.", "Central to most hypotheses of the mechanism of idiosyncratic drug-induced blood dyscrasias is the involvement of reactive metabolites. In view of the reactive nature of the majority of such metabolites, it is likely that they are formed by, or in close proximity to the blood cells affected. The major oxidative system of neutrophils generates hypochlorous acid. We have demonstrated that the drugs associated with the highest incidence of agranulocytosis are oxidized to reactive metabolites by hypochlorous acid and/or activated neutrophils. There are many mechanisms by which such reactive metabolites could induce agranulocytosis. In the case of aminopyrine-induced agranulocytosis, most cases appear to involve drug-dependent anti-neutrophil antibodies, and these are likely to be induced by cell membrane antigens modified by the reactive metabolite of aminopyrine. The target of agranulocytosis associated with many other drugs is usually neutrophil precursors and may involve cytotoxicity or a cell-mediated immune reaction induced by a reactive metabolite. In the case of aplastic anaemia, there is evidence in some cases for involvement of cytotoxic T cells, which could either be induced by metabolites generated by neutrophils, or more likely, by reactive metabolites generated by stem cells.", "While it is long known that actin is part of the nuclear proteome, its properties and functions as regulated, functional and dynamically assembled actin filaments are only recently emerging. Thus, newly uncovered roles for intranuclear actin filaments are opening new perspectives on how the nucleus and its genomic content may be organized in particular with regard to a given stage of the cell cycle. Here, we summarize recent studies on actin filament polymerization and turnover within the nuclear compartment of mammalian cells. We emphasize and discuss novel findings, in which transient and dynamic nuclear actin filaments have been visualized in physiological contexts, and focus on aspects of signalling mechanisms, chromatin reorganization and DNA repair. Further, a better understanding of the spatiotemporal control of nuclear actin-regulating factors in mammalian cells will ultimately provide a more detailed view on how the nuclear F-actin cytoskeleton contributes to genome organization and nuclear architecture.", "This randomized, placebo-controlled within dose groups, double-blind, single rising dose study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of 1 mg to 100 mg doses of empagliflozin in 48 healthy Japanese male subjects. Empagliflozin was rapidly absorbed, reaching peak levels in 1.25 to 2.50 h; thereafter, plasma concentrations declined in a biphasic fashion, with mean terminal elimination half-life ranging from 7.76 to 11.7 h. Increase in empagliflozin exposure was proportional to dose. Oral clearance was dose independent and ranged from 140 to 172 mL/min. In the 24 h following 100 mg empagliflozin administration, the mean (%CV) amount of glucose excreted in urine was 74.3 (17.1) g. The amount and the maximum rate of glucose excreted via urine increased with dose of empagliflozin. Nine adverse events, all of mild intensity, were reported by 8 subjects (7 with empagliflozin and 1 with the placebo). No hypoglycemia was reported. In conclusion, 1 mg to 100 mg doses of empagliflozin had a good safety and tolerability profile in healthy Japanese male subjects. Exposure to empagliflozin was dose proportional. The amount and rate of urinary glucose excretion were higher with empagliflozin than with the placebo, and increased with empagliflozin dose.", "Cancer cells do not exist as pure homogeneous populations in vivo. Instead they are embedded in \"cancer cell nests\" that are surrounded by stromal cells, especially cancer associated fibroblasts. Thus, it is not unreasonable to suspect that stromal fibroblasts could influence the metabolism of adjacent cancer cells, and visa versa. In accordance with this idea, we have recently proposed that the Warburg effect in cancer cells may be due to culturing cancer cells by themselves, out of their normal stromal context or tumor microenvironment. In fact, when cancer cells are co-cultured with fibroblasts, then cancer cells increase their mitochondrial mass, while fibroblasts lose their mitochondria. An in depth analysis of this phenomenon reveals that aggressive cancer cells are \"parasites\" that use oxidative stress as a \"weapon\" to extract nutrients from surrounding stromal cells. Oxidative stress in fibroblasts induces the autophagic destruction of mitochondria, by mitophagy. Then, stromal cells are forced to undergo aerobic glycolysis, and produce energy-rich nutrients (such as lactate and ketones) to \"feed\" cancer cells. This mechanism would allow cancer cells to seed anywhere, without blood vessels as a food source, as they could simply induce oxidative stress wherever they go, explaining how cancer cells survive during metastasis. We suggest that stromal catabolism, via autophagy and mitophagy, fuels the anabolic growth of tumor cells, promoting tumor progression and metastasis. We have previously termed this new paradigm \"The Autophagic Tumor Stroma Model of Cancer Metabolism\", or the \"Reverse Warburg Effect\". We also discuss how glutamine addiction (glutaminolysis) in cancer cells fits well with this new model, by promoting oxidative mitochondrial metabolism in aggressive cancer cells.", "Macropinocytosis has emerged as an important nutrient supply pathway that sustains cell growth of cancer cells within the nutrient-poor tumor microenvironment. By internalizing extracellular fluid through this bulk endocytic pathway, albumin is supplied to the cancer cells, which, after degradation, serves as an amino acid source to meet the high nutrient demands of these highly proliferating cells. Here, we describe a streamlined protocol for visualization and quantitation of macropinosomes in adherent cancer cells grown in vitro. The determination of the \"macropinocytic index\" provides a tool for measuring the extent to which this internalization pathway is utilized within the cancer cells and allows for comparison between different cell lines and treatments. The protocol provided herein has been optimized for reproducibility and is readily adaptable to multiple conditions and settings.", "STUDY OBJECTIVE: To evaluate the diagnostic contribution of the computed tomography (CT) enema and magnetic resonance imaging (MRI) for multifocal (multiple lesions affecting the same segment) and multicentric (multiple lesions affecting several digestive segments) bowel endometriosis.DESIGN: Prospective cohort study (Canadian Task Force classification II-2).PATIENTS: Eighty-five patients.SETTING: Tenon University Hospital, Paris, France.INTERVENTION: All patients received a preoperative CT enema and underwent MRI interpreted by 2 radiologists.MEASUREMENTS AND MAIN RESULTS: Patients underwent colorectal resection for colorectal endometriosis from February 2009 to November 2012. Nineteen patients (22%) had multifocal lesions, and 11 patients (13%) had multicentric lesions. Six patients (7%) had both multifocal and multicentric lesions. The sensitivity, specificity, and positive and negative likelihood ratios (LRs) of MRI for the diagnosis of multifocal lesions were 0.58, 0.84, 3.55, and 0.5, respectively. The sensitivity, specificity, and positive and negative LRs of the CT enema for the diagnosis of multifocal lesions were 0.64, 0.86, 4.56, and 0.4, respectively. The sensitivity, specificity, and positive LR of MRI for the diagnosis of multicentric lesions were 1, 0.88, and 8.4, respectively. The sensitivity, specificity, and positive and negative LRs of MRI for the diagnosis of multicentric lesions were 0.46, 0.92, 5.6, and 0.59, respectively. No difference was observed between MRI and the CT enema for the diagnosis of multifocal and multicentric colorectal endometriosis. The interobserver agreement was good for MRI and the CT enema (κ = 0.45 and 0.45) for multifocality, and it was poor for both MRI and the CT enema (κ = 0.32 and 0.34) for multicentricity.CONCLUSIONS: Both MRI and the CT enema were able to diagnose multifocal and multicentric bowel endometriosis with similar accuracy.", "If patients with hyperlipoproteinemia type IIa are treated with diet and additionally over a period of two weeks with 2 grams of Clofibrate daily, the cholesterol-level in the serum decreases. This decrease is caused mainly by a reduction of the apolipoprotein B and the LDL-cholesterol in serum. If elevated cholesterol-levels in the serum are reduced through a \"prudent\" diet, the concentration of apolipoprotein B in serum remains the same. It is not fully understood which influence a diet, which is rich in poly-unsaturated fatty acids and has a low content of saturated fatty acids and carbohydrates, has upon the lipoproteins in the serum. The mode of action of this diet and its significance for the concentration of HDL need further investigation.", "Given the current SARS-CoV-2 (COVID-19) pandemic, the availability of reliable information for clinicians and patients is paramount. There have been a number of reports stating that non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids may exacerbate symptoms in COVID-19 patients. Therefore, this review aimed to collate information available in published articles to identify any evidence behind these claims with the aim of advising clinicians on how best to treat patients. This review found no published evidence for or against the use of NSAIDs in COVID-19 patients. Meanwhile, there appeared to be some evidence that corticosteroids may be beneficial if utilised in the early acute phase of infection, however, conflicting evidence from the World Health Organisation surrounding corticosteroid use in certain viral infections means this evidence is not conclusive. Given the current availability of literature, caution should be exercised until further evidence emerges surrounding the use of NSAIDs and corticosteroids in COVID-19 patients.", "Identifying genomic variants is a fundamental first step toward the understanding of the role of inherited and acquired variation in disease. The accelerating growth in the corpus of sequencing data that underpins such analysis is making the data-download bottleneck more evident, placing substantial burdens on the research community to keep pace. As a result, the search for alternative approaches to the traditional \"download and analyze\" paradigm on local computing resources has led to a rapidly growing demand for cloud-computing solutions for genomics analysis. Here, we introduce the Genome Variant Investigation Platform (GenomeVIP), an open-source framework for performing genomics variant discovery and annotation using cloud- or local high-performance computing infrastructure. GenomeVIP orchestrates the analysis of whole-genome and exome sequence data using a set of robust and popular task-specific tools, including VarScan, GATK, Pindel, BreakDancer, Strelka, and Genome STRiP, through a web interface. GenomeVIP has been used for genomic analysis in large-data projects such as the TCGA PanCanAtlas and in other projects, such as the ICGC Pilots, CPTAC, ICGC-TCGA DREAM Challenges, and the 1000 Genomes SV Project. Here, we demonstrate GenomeVIP's ability to provide high-confidence annotated somatic, germline, and de novo variants of potential biological significance using publicly available data sets.", "PURPOSE OF REVIEW: This article critically reviews the advances in medical management of giant cell arteritis (GCA) and Takayasu arteritis (TAK) with a focus on recent developments in targeted biologic therapy.RECENT FINDINGS: The role of biologics in the treatment of large vessel vasculitis (LVV) is expanding. TNFα inhibitors appear to be effective in the treatment of TAK but have little benefit in GCA. Preliminary clinical trial data suggest that abatacept and tocilizumab reduce the risk of relapse in GCA. Increasing observational evidence supports the use of interleukin-6 inhibitors in TAK. Based on a small open-label study, ustekinumab appears safe and potentially effective for refractory GCA. A possible role of B cell dysregulation may contribute to pathogenic mechanisms in LVV, but support for the use of B cell depleting therapy is limited.SUMMARY: Interleukin-6 inhibitors appear efficacious in the treatment of refractory cases of LVV; however, utility in newly diagnosed immunosuppressive-naïve patients is less well established. Abatacept and ustekinumab are promising targets for therapy in LVV but further investigation is needed before routine use is considered.", "INTRODUCTION: The workup of lymphoproliferative disorders (LPDs) involves the combined use of flow cytometry (FC) and immunohistochemistry (IHC). This often results in duplicate immunophenotypic testing and adds costs that may not be eligible for reimbursement based on the Medicare National Correct Coding Initiative. We aimed to establish a cost-effective diagnostic algorithm based on initial FC categorization to reduce repetitive immunophenotyping.METHODS: We retrospectively reviewed 242 cases of suspected LPDs with concurrent FC and IHC testing over a 12-month period. We correlated FC with surgical diagnoses and evaluated the frequency of repeat IHC testing.RESULTS: Repetitive immunophenotyping was common; overall, 85% of cases had at least one marker repeated. Concordant cases were significantly less likely to have markers repeated than discordant cases. Of concordant B cell malignancies, 57% represented recurrent disease; however, repeat marker usage was not decreased as compared to new diagnoses. The most frequently repeated markers were CD3, CD5, CD10, and CD20.CONCLUSIONS: We propose that in concordant cases, CD5 and CD10 should not be repeated by IHC; this would decrease the use of these markers by 80% and 76%, respectively. We developed an algorithmic approach to IHC usage that has improved incorporation of FC data at our institution and may reduce healthcare costs.", "In Russia, an intradermal Diaskintest® drug has been designed, which is a recombinant tuberculosis allergen based on M. tuberculosis-- specific proteins: ESAT-6 and CFP-10 produced by a genetically modified Escherichia coli culture. Diaskintest® test and Mantoux test with 2TE PPD-L were concurrently carried out in 300 children and adolescents with tuberculosis and followed up in risk groups at a tuberculosis dispensary to determine the sensitivity of the new skin test in active tuberculosis infection. Diaskintest® showed a high sensitivity not only in active tuberculosis, but also in occult, the so-called latent, tuberculosis infection. This is suggested by the following evidence. The high percentage (83.8%) of positive responses to Diaskintest® is noted in children and adolescents with tuberculosis, receiving an intensive course of chemotherapy. Negative tests were observed only in minor forms at the resolution stage. In the children who had completed treatment, positive tests were seen in 78.3%, moreover in those with prior tuberculosis of intrathoracic lymph nodes; negative tests were observed not earlier than 18 months after start of treatment. The highest sensitivity of Diaskintest® was shown in children with early primary tuberculosis infection and through family contact with bacteria-excreting subjects (91.7%). These children may be judged with the highest assurance to have latent tuberculosis infection, the population of which is in an active state at the moment of the study. The children with early primary tuberculosis infection, but in no family contact with bacteria-excreting individuals, showed a lower percentage of positive responses to Diaskintest® both before (37.5%) and after (10%) treatment, which suggests that there must be a lower bacterial burden in the child. A high percentage of positive responses to Diaskintest® (76.2%) were found in subjects with hyperergic reactions to tuberculin. These were in only 16.7% in the group of patients receiving preventive therapy. In children and adolescents with a persistent positive Mantoux test (for more than 3 years), the response to Diaskintest® was negative in most cases since in early infection when mycobacteria propagated, the reaction to the drug was positive, but as 3 years pass the probability of the infection transition to the persistence stage is high--at that time the response to Diaskintest® becomes negative. Diaskintest® induces no delayed hypersensitivity associated with BCG vaccination, suggesting its high specificity. There were no positive reactions in patients with nonspecific lung diseases.", "Collaborators: Kong XZ, Mathias SR, Guadalupe T, Abé C, Agartz I, Akudjedu TN, Aleman A, Alhusaini S, Allen NB, Ames D, Andreassen OA, Vasquez AA, Armstrong NJ, Bergo F, Bastin ME, Batalla A, Bauer J, Baune BT, Baur-Streubel R, Biederman J, Blaine SK, Boedhoe P, Bøen E, Bose A, Bralten J, Brandeis D, Brem S, Brodaty H, Yüksel D, Brooks SJ, Buitelaar J, Bürger C, Bülow R, Calhoun V, Calvo A, Canales-Rodríguez EJ, Canive JM, Cannon DM, Caparelli EC, Castellanos FX, Cavalleri GL, Cendes F, Chaim-Avancini TM, Chantiluke K, Chen QL, Chen X, Cheng Y, Christakou A, Clark VP, Coghill D, Connolly CG, Conzelmann A, Córdova-Palomera A, Cousijn J, Crow T, Cubillo A, Dale A, Dannlowski U, Ambrosino de Bruttopilo S, de Zeeuw P, Deary IJ, Delanty N, Demeter DV, Di Martino A, Dickie EW, Dietsche B, Doan NT, Doherty CP, Doyle A, Durston S, Earl E, Ehrlich S, Ekman CJ, Elvsåshagen T, Epstein JN, Fair DA, Faraone SV, Fernández G, Filho GB, Förster K, Fouche JP, Foxe JJ, Frodl T, Fuentes-Claramonte P, Fullerton J, Garavan H, Garcia DDS, Gotlib IH, Goudriaan AE, Grabe HJ, Groenewold NA, Grotegerd D, Gruber O, Gurholt T, Haavik J, Hahn T, Hansell NK, Harris MA, Hartman CA, Hernández MDCV, Heslenfeld D, Hester R, Hibar DP, Ho BC, Ho TC, Hoekstra PJ, van Holst RJ, Hoogman M, Høvik MF, Howells FM, Hugdahl K, Huyser C, Ingvar M, Irwin L, Ishikawa A, James A, Jahanshad N, Jernigan TL, Jönsson EG, Kähler C, Kaleda V, Kelly C, Kerich M, Keshavan MS, Khadka S, Kircher T, Kohls G, Konrad K, Korucuoglu O, Krämer B, Krug A, Kwon JS, Lambregts-Rommelse N, Landén M, Lázaro L, Lebedeva I, Lenroot R, Lesch KP, Li Q, Lim KO, Liu J, Lochner C, London ED, Lonning V, Lorenzetti V, Luciano M, Luijten M, Lundervold AJ, Mackey S, MacMaster FP, Maingault S, Malpas CB, Malt UF, Mataix-Cols D, Martin-Santos R, Mayer AR, McCarthy H, Mitchell PB, Mueller BA, Maniega SM, Mazoyer B, McDonald C, McLellan Q, McMahon KL, McPhilemy G, Momenan R, Morales AM, Narayanaswamy JC, Moreira JCV, Nerland S, Nestor L, Newman E, Nigg JT, Nordvik JE, Novotny S, Weiss EO, O'Gorman RL, Oosterlaan J, Oranje B, Orr C, Overs B, Pauli P, Paulus M, Plessen KJ, von Polier GG, Pomarol-Clotet E, Portella MJ, Qiu J, Radua J, Ramos-Quiroga JA, Reddy YCJ, Reif A, Roberts G, Rosa P, Rubia K, Sacchet MD, Sachdev PS, Salvador R, Schmaal L, Schulte-Rüther M, Schweren L, Seidman L, Seitz J, Serpa MH, Shaw P, Shumskaya E, Silk TJ, Simmons AN, Simulionyte E, Sinha R, Sjoerds Z, Smelror RE, Soliva JC, Solowij N, Souza-Duran FL, Sponheim SR, Stein DJ, Stein EA, Stevens M, Strike LT, Sudre G, Sui J, Tamm L, Temmingh HS, Thoma RJ, Tomyshev A, Tronchin G, Turner J, Uhlmann A, van Erp TGM, van den Heuvel OA, van der Meer D, van Eijk L, Vance A, Veer IM, Veltman DJ, Venkatasubramanian G, Vilarroya O, Vives-Gilabert Y, Voineskos AN, Völzke H, Vuletic D, Walitza S, Walter H, Walton E, Wardlaw JM, Wen W, Westlye LT, Whelan CD, White T, Wiers RW, Wright MJ, Wittfeld K, Yang TT, Yasuda CL, Yoncheva Y, Yücel M, Yun JY, Zanetti MV, Zhen Z, Zhu XX, Ziegler GC, Zierhut K, de Zubicaray GI, Zwiers M, Glahn DC, Franke B, Crivello F, Tzourio-Mazoyer N, Fisher SE, Thompson PM, Francks C, Farde L, Flyckt L, Engberg G, Erhardt S, Fatouros-Bergman H, Cervenka S, Schwieler L, Piehl F, Agartz I, Collste K, Victorsson P, Malmqvist A, Hedberg M, Orhan F." ]

[ "Thermoesthesia-and-algesthesia disorders have been registered in the dermatomes of cauda equina roots of patients with lumbar spine osteochondrosis in all the cases. Negative changes in the sensitivity of this type are manifested themselves as follows: 1) 2-8-degree increases of thresholds; 2) 3-6-degree decreases of thresholds; 3) absence of thermal sense. In the presence of reflex syndromes (lumbalgia and lumbar ischialgia) the disorders in L4, L5, S1 dermatomes have been determined to the greatest degree. Thermoesthesia-and-algesthesia disorders are more pronounced in patients with the radicular syndrome than in those with the reflex syndromes. The most improvement ofthermoesthesia-and-algesthesia values is observed in L5 dermatome of patients with lumbalgia and lumbar ischialgia after complex conservative therapy. The treatment performed does not result in significant thermoesthesia-and-algesthesia improvement for the limb with radiculopathy events and in the dermatome of the root compressed in patients with the radicular syndrome. Positive changes in contralateral limb are more pronounced.", "BACKGROUND: The role of brain natriuretic peptide (BNP) after traumatic brain injury (TBI) remains unclear, and its relationship with hyponatremia is still controversial. The aim of this study is to investigate the secretion pattern of N-terminal (NT)-proBNP in patients with TBI and to assess the relationship between NT-proBNP, sodium balance, and intracranial pressure (ICP).METHODS: We measured serum NT-proBNP levels of 84 patients with isolated TBI on a daily basis from day 1 to day 14 after injury.RESULTS: In average, the peak of BNP level was measured at 703.9 pg/mL±179.1 pg/mL on day 3 after injury, which was correlated to the severity of TBI. Among patients with severe TBI, plasma NT-proBNP concentrations in patients with hyponatremia were statistically higher than those without hyponatremia (p<0.05). In the hyponatremic group, the plasma NT-proBNP increased to a peak of 1001.16 pg/mL±131.52 pg/mL within 48 hours after injury and maintained at a high level for 3 days. In the normonatremic group, the plasma NT-proBNP reached a peak of 826.43 pg/mL±337.43 pg/mL on day 5 and quickly decreased thereafter. In addition, we found plasma NT-proBNP concentrations in patients with ICP>15 mm Hg were significantly higher than those in patients with ICP≤15 mm Hg (p<0.01).CONCLUSIONS: This study provides evidence that BNP plasma concentrations increase rapidly after TBI. Plasma BNP concentrations are correlated with hyponatremia in severe TBI patients but not in mild and moderate TBI patients. Furthermore, patients with elevated ICP have a higher serum BNP level in first 4 days after injury.", "PURPOSE: This study examines the relationship between low back pain, disability and fatigue and overt physical activity with respect to fear-avoidance and endurance-related subgroups.METHOD: 49 patients completed questionnaires (Pain, Disability, Fatigue, Depression, Pain-responses pattern) 6 months after lumbar disc surgery and underwent an 8-hour accelerometer assessment measuring overall physical activity (PAL), constant strain postures (CSP), standing time (ST) and lying time (LT). Four subgroups, representing patterns of distress-endurance (DER), eustress-endurance (EER), fear-avoidance (FAR) and adaptive responses (AR) due to the avoidance-endurance model of pain-regulation were investigated.RESULTS: Multivariate analyses of covariance revealed significantly higher pain, disability and fatigue in FAR compared to AR patients and, as expected lower PAL and CSP in FAR than in endurance patients. Both endurance groups revealed higher pain accompanied by higher accelerometer-based physical activity (PAL, CSP) than AR and FAR patients. Most of the subgroup differences displayed moderate to high effect sizes.CONCLUSIONS: The results indicate different pathways to chronic pain and disability with physical underuse in FAR patients and overuse/overload in endurance patients suggesting the need for individually targeted cognitive-behavioral treatments in the maladaptive groups. Implications for Rehabilitation Improving the return to a normal physical activity level is an important goal for the rehabilitation of patients after lumbar disc surgery. Different pathways to chronic pain and disability with physical underuse in fear-avoidance patients and overuse in endurance patients should be considered. Different pain-related pain response pattern, based on the avoidance-endurance model, indicate the need for individual targeting of rehabilitation programs.", "Two autologous chimeric antigen receptor (CAR) T cell therapies (Kymriah™ and Yescarta™) were recently approved by the FDA. Kymriah™ is for the treatment of pediatric patients and young adults with refractory or relapse (R/R) B cell precursor acute lymphoblastic leukemia and Yescarta™ is for the treatment of adult patients with R/R large B cell lymphoma. In common, both are CD19-specific CAR T cell therapies lysing CD19-positive targets. Their dramatic efficacy in the short term has been highlighted by many media reports. By contrast, their glaring safety gaps behind the miracles remain much less addressed. Here, we focus on addressing the crucial challenges in relation to the gaps.", "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).", "Infectious complications are frequent and often lethal in patients with uremia. Serious alterations in neutrophil function, e.g., phagocytosis, mononuclear cell activation, cytokine production, complement activation, T-cell function, and adhesion molecule expression, have been documented in uremic patients. Uremia per se is a cause of some of these derangements, but much evidence now exists that blood-membrane interaction during dialysis is responsible for many of these abnormalities. This is particularly true when bio-incompatible cellulose-based membranes are used. In many of these patients, newly described granulocyte inhibitory proteins (GIP) can be demonstrated. These two proteins, GIP I and II (28 kD and 9.5 kD, respectively, in molecular weight), block effective bacterial killing, chemotaxis, and oxygen metabolism. It appears that GIP I is a member of the lightchain family, and GIP II is the advanced glycosilation end product of beta 2-microglobulin. Another inhibitory protein, degranulation inhibitory protein (DIP), has been isolated. This protein is 14 kD in molecular weight, and is identical to the angioplastic factor angiogenin. DIP levels are significantly elevated in patients undergoing dialysis. Much still needs to be learned about the interactions of these inhibitory proteins with other soluble inflammatory mediators and, in particular, cytokines. It is clear, however, that profound derangements in immune function take place during uremia and dialytic therapy. Such derangements are likely to play an important role in determining the rate of recovery of renal function and the patient's ability to respond to septic insults. Further insights into the pathogenesis of uremic-dialytic immune dysfunction are already yielding improved patient management and decreased infection rates.", "AIMS: Familial hypertrophic cardiomyopathy (HCM) is one the most common heart disorders, with gene mutations in the cardiac sarcomere. Studying HCM with patient-specific induced pluripotent stem-cell (iPSC)-derived cardiomyocytes (CMs) would benefit the understanding of HCM mechanism, as well as the development of personalized therapeutic strategies.METHODS AND RESULTS: To investigate the molecular mechanism underlying the abnormal CM functions in HCM, we derived iPSCs from an HCM patient with a single missense mutation (Arginine442Glycine) in the MYH7 gene. CMs were next enriched from HCM and healthy iPSCs, followed with whole transcriptome sequencing and pathway enrichment analysis. A widespread increase of genes responsible for 'Cell Proliferation' was observed in HCM iPSC-CMs when compared with control iPSC-CMs. Additionally, HCM iPSC-CMs exhibited disorganized sarcomeres and electrophysiological irregularities. Furthermore, disease phenotypes of HCM iPSC-CMs were attenuated with pharmaceutical treatments.CONCLUSION: Overall, this study explored the possible patient-specific and mutation-specific disease mechanism of HCM, and demonstrates the potential of using HCM iPSC-CMs for future development of therapeutic strategies. Additionally, the whole methodology established in this study could be utilized to study mechanisms of other human-inherited heart diseases." ]

[ "L-3, 4-dihydroxyphenylalanine (L-dopa) is the gold standard for symptomatic treatment of Parkinson's disease (PD), but long-term therapy is associated with the emergence of L-dopa-induced dyskinesia (LID). In the present study, L-dopa and benserazide were loaded by poly (lactic-co-glycolic acid) microspheres (LBM), which can release levodopa and benserazide in a sustained manner in order to continuous stimulate dopaminergic receptors. We investigated the role of striatal DR1/PKA/P-tau signal transduction in the molecular event underlying LID in the 6-OHDA-lesioned rat model of PD. We found that animals rendered dyskinetic by L-dopa treatment, administration of LBM prevented the severity of AIM score, as well as improvement in motor function. Moreover, we also showed L-dopa elicits profound alterations in the activity of three LID molecular markers, namely DR1/PKA/P-tau (ser396). These modifications are totally prevented by LBM treatment, a similar way to achieve continuous dopaminergic delivery (CDD). In conclusion, our experiments provided evidence that intermittent administration of L-dopa, but not continuous delivery, and DR1/PKA/p-tau (ser396) activation played a critical role in the molecular and behavioural induction of LID in 6-OHDA-lesioned rats. In addition, LBM treatment prevented the development of LID by inhibiting the expression of DR1/PKA/p-tau, as well as PPEB mRNA in dyskintic rats.", "We report a Japanese infant with Horner syndrome whose clinical examination and testing suggested the location of the causative lesion. A 4-year-old Japanese girl had an acquired right ocular ptosis and unequal pupils presenting shortly after birth. She also exhibited left hemifacial flushing and loss of sweating on the contralateral side (harlequin sign). Physical examination demonstrated 2.0 mm of ptosis of the right upper lid with normal elevator function. The diameters of the pupils were 4 mm on the left and 2.5 mm on the right. No sweating was induced in the right frontal region at 40 degrees C for 15 minutes of sweat challenge test. Otherwise, no abnormalities were found by the neurophysiologic examinations or magnetic resonance imaging of the brain. Based on the clinical examination, we speculated that the responsible lesion might be in the preganglionic areas. Harlequin sign was informative for making the diagnosis of Horner syndrome.", "OBJECTIVES: To describe the development of an interactive, web-based self-management intervention for opioid-treated, chronic pain patients with aberrant drug-related behavior.METHODS: Fifty-three chronic pain patients participated in either focus groups (N = 23) or individual feedback sessions (N = 30). Focus groups probed interest in and relevance of the planned content and structure of the program. Individual session participants reviewed draft program modules and provided feedback on acceptability, ease of use, and usefulness. Focus group transcripts were thematically analyzed, and summary statistics were performed on feedback data.RESULTS: Focus group participants stressed the need for additional pain management strategies and emphasized themes consistent with planned program content related to: 1) ambivalence about opioids; 2) reciprocal relationships among cognition, mood, and pain; 3) importance of recognizing physical limitations; and 4) effectiveness of goal setting for increasing motivation and functioning. Participants also offered insights on: 5) the loss of identity due to chronic pain; and 6) the desire to connect with pain peers to share strategies for managing daily life. Feedback session data demonstrate that participants believed that a web-based tool would be potentially useful and acceptable, and that exposure to program sections significantly increased participants' knowledge of key topics related to self-management of chronic pain.CONCLUSIONS: Results suggest the potential value of self-management for chronic pain patients and the potential acceptability of web-based delivery of intervention content. Focus group and feedback methodologies highlight the usefulness of including potential program users in intervention development.", "The TET family of FE(II) and 2-oxoglutarate-dependent enzymes (Tet1/2/3) promote DNA demethylation by converting 5-methylcytosine to 5-hydroxymethylcytosine (5hmC), which they further oxidize into 5-formylcytosine and 5-carboxylcytosine. Tet1 is robustly expressed in mouse embryonic stem cells (mESCs) and has been implicated in mESC maintenance. Here we demonstrate that, unlike genetic deletion, RNAi-mediated depletion of Tet1 in mESCs led to a significant reduction in 5hmC and loss of mESC identity. The differentiation phenotype due to Tet1 depletion positively correlated with the extent of 5hmC loss. Meta-analyses of genomic data sets suggested interaction between Tet1 and leukemia inhibitory factor (LIF) signaling. LIF signaling is known to promote self-renewal and pluripotency in mESCs partly by opposing MAPK/ERK-mediated differentiation. Withdrawal of LIF leads to differentiation of mESCs. We discovered that Tet1 depletion impaired LIF-dependent Stat3-mediated gene activation by affecting Stat3's ability to bind to its target sites on chromatin. Nanog overexpression or inhibition of MAPK/ERK signaling, both known to maintain mESCs in the absence of LIF, rescued Tet1 depletion, further supporting the dependence of LIF/Stat3 signaling on Tet1. These data support the conclusion that analysis of mESCs in the hours/days immediately following efficient Tet1 depletion reveals Tet1's normal physiological role in maintaining the pluripotent state that may be subject to homeostatic compensation in genetic models.", "Author information:(1)Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University Mainz, 55128 Mainz, Germany.(2)Institute of Molecular Biology (IMB), 55128 Mainz, Germany.(3)Institute of Molecular Biology (IMB), 55128 Mainz, Germany; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.(4)Instituto Cajal, CSIC, Madrid, Spain.(5)Institute of Molecular Biology (IMB), 55128 Mainz, Germany; Focus Program Translational Neuroscience, Johannes Gutenberg University Mainz, 55131 Mainz, Germany. Electronic address: vijay.tiwari@yahoo.com.(6)Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University Mainz, 55128 Mainz, Germany; Focus Program Translational Neuroscience, Johannes Gutenberg University Mainz, 55131 Mainz, Germany; Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE1 1UL, UK; MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE1 1UL, UK. Electronic address: benedikt.berninger@kcl.ac.uk.", "The purpose of this study was to establish the frequency and pattern of depressive disorders after surgery for acoustic neuroma, and to look for associations. Twenty seven patients with acoustic neuroma underwent thorough psychiatric assessment before surgery and at three and 12 months after surgery. Three patients had a depressive disorder in the preoperative assessment. Of the remaining 24 patients, nine (38%) had a depressive disorder at the three month check up. Deterioration of hearing was the only postoperative detriment associated with a depressive disorder (P = 0·024). All nine patients with a depressive disorder were women (P = 0·001), giving them a 69% incidence. None of the patients without preoperative depression required inpatient treatment for depressive disorder, but three patients out of nine still had a depressive disorder 12 months after surgery.", "A pharmacophore is a model which represents the key physico-chemical interactions that mediate biological activity. There is a long history of using pharmacophore modeling methods to select subsets of compounds, focused towards a specific target of interest. This paper will review existing computational methods for deriving and comparing pharmacophore models. We outline a new classification of pharmacophore methods based on the abstraction of the underlying chemical interactions which embody a pharmacophore, and the methods available to quantitatively compare them. Within the context of this classification, example studies, using specific pharmacophore modeling methods for focused library selection, will be discussed." ]

[ "IMPORTANCE: In phase 2 studies, evolocumab, a fully human monoclonal antibody to PCSK9, reduced LDL-C levels in patients receiving statin therapy.OBJECTIVE: To evaluate the efficacy and tolerability of evolocumab when used in combination with a moderate- vs high-intensity statin.DESIGN, SETTING, AND PATIENTS: Phase 3, 12-week, randomized, double-blind, placebo- and ezetimibe-controlled study conducted between January and December of 2013 in patients with primary hypercholesterolemia and mixed dyslipidemia at 198 sites in 17 countries.INTERVENTIONS: Patients (n = 2067) were randomized to 1 of 24 treatment groups in 2 steps. Patients were initially randomized to a daily, moderate-intensity (atorvastatin [10 mg], simvastatin [40 mg], or rosuvastatin [5 mg]) or high-intensity (atorvastatin [80 mg], rosuvastatin [40 mg]) statin. After a 4-week lipid-stabilization period, patients (n = 1899) were randomized to compare evolocumab (140 mg every 2 weeks or 420 mg monthly) with placebo (every 2 weeks or monthly) or ezetimibe (10 mg or placebo daily; atorvastatin patients only) when added to statin therapies.MAIN OUTCOMES AND MEASURES: Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) level at the mean of weeks 10 and 12 and at week 12.RESULTS: Evolocumab reduced LDL-C levels by 66% (95% CI, 58% to 73%) to 75% (95% CI, 65% to 84%) (every 2 weeks) and by 63% (95% CI, 54% to 71%) to 75% (95% CI, 67% to 83%) (monthly) vs placebo at the mean of weeks 10 and 12 in the moderate- and high-intensity statin-treated groups; the LDL-C reductions at week 12 were comparable. For moderate-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 115 to 124 mg/dL to an on-treatment mean of 39 to 49 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 123 to 126 mg/dL to an on-treatment mean of 43 to 48 mg/dL. For high-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 35 to 38 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 33 to 35 mg/dL. Adverse events were reported in 36%, 40%, and 39% of evolocumab-, ezetimibe-, and placebo-treated patients, respectively. The most common adverse events in evolocumab-treated patients were back pain, arthralgia, headache, muscle spasms, and pain in extremity (all <2%).CONCLUSIONS AND RELEVANCE: In this 12-week trial conducted among patients with primary hypercholesterolemia and mixed dyslipidemia, evolocumab added to moderate- or high-intensity statin therapy resulted in additional LDL-C lowering. Further studies are needed to evaluate the longer-term clinical outcomes and safety of this approach for LDL-C lowering.TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01763866.", "The forkhead O (FoxO) family of transcription factors participates in diverse physiologic processes, including induction of cell-cycle arrest, stress resistance, differentiation, apoptosis, and metabolism. Several recent studies indicate that FoxO-dependent signaling is required for long-term regenerative potential of the hematopoietic stem cell (HSC) compartment through regulation of HSC response to physiologic oxidative stress, quiescence, and survival. These observations link FoxO function in mammalian systems with the evolutionarily conserved role of FoxO in promotion of stress resistance and longevity in lower phylogenetic systems. Furthermore, these findings have implications for aging in higher organisms and in malignant stem cell biology, and suggest that FoxOs may play an important role in the maintenance and integrity of stem cell compartments in a broad spectrum of tissues.", "Recent studies have revealed the scientific basis for the use of intravenous (i.v.) vitamin C or ascorbic acid (ascorbate) in treating cancers, and raised the possibility of using i.v. ascorbate as a prooxidant anticancer therapy. Through the production of H2O2, pharmacologic ascorbate can induce some cancer cell death in vitro and inhibit a number of types of tumor growth in animal models. However, the mechanism of cell death triggered by ascorbate is not well understood. In this study, we investigated the cytotoxicity of pharmacological concentrations of ascorbate to human prostate cancer cells and the mechanisms involved. The results showed that ascorbate in the millimolar range induced cytotoxicity in five of the six tested prostate cancer cell lines. The IC50 values in the sensitive prostate cancer cells ranged from 1.9 to 3.5 mmol/l, concentrations clinically achievable with i.v. ascorbate use. All tested androgen-independent cells were sensitive to ascorbate treatment. The ascorbate-insensitive cell line LaPC4 is hormonally dependent. Whereas the reasons for sensitivity/resistance to ascorbate treatment need to be investigated further, cell death in sensitive cells was dependent on H2O2. Ascorbate treatment depleted ATP and induced autophagy in sensitive prostate cancer cells, resulting in cell death. Taken together with previous studies, high-dose ascorbate has the potential to be a novel treatment option to hormone-refractory prostate cancer.", "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: MicroRNAs (miRNAs) are involved in the pathogenesis of human cancers, including medullary thyroid carcinoma (MTC). The aim of this study was to test the hypothesis that different miRNA profiles are related to RET status and prognosis in patients with hereditary MTC (hMTC) and sporadic MTC (sMTC).METHODS: We analyzed the expression of nine miRNAs (miR-21, miR-127, miR-154, miR-224, miR-323, miR-370, miR-9*, miR-183, and miR-375) by quantitative real-time-polymerase chain reaction in 34 cases of sMTC, 6 cases of hMTC, and 2 cases of C-cell hyperplasia (CCH). We also analyzed the immunohistochemical expression of PDCD4, an miR-21 gene target. sMTC (n=34) was genotyped for somatic RET and RAS mutations. Disease status was defined on the basis of the concentration of serum calcitonin at the latest follow-up and other parameters as indicated in the results.RESULTS: MTC and CCH were both characterized by a significant overexpression of the whole set of miRNAs (the increase being 4.2-fold for miR-21, 6.7-fold for miR-127, 8.8-fold for miR-154, 6.6-fold for miR-224, 5.8-fold for miR-323, 6.1-fold for miR-370, 13-fold for miR-9*, 6.7-fold for miR-183, and 10.1 for miR-375, p<0.0001). PDCD4 expression was significantly downregulated in MTC samples, consistent with miR-21 upregulation. Significantly lower miR-127 levels were observed in sMTC carrying somatic RET mutations in comparison to sMTC carrying a wild-type RET. In sMTC and familial MTC, the miR-224 upregulation correlated with the absence of node metastases, lower stages at diagnosis, and with biochemical cure during follow-up.CONCLUSIONS: miRNAs are significantly dysregulated in MTC, and this dysregulation is probably an early event in C-cell carcinogenesis. miR-224 upregulation could represent a prognostic biomarker associated with a better outcome in MTC patients.", "OBJECTIVE: To determine the frequency, risk factors, clinical features, and management of amiodarone-induced thyroid dysfunctions.DESIGN: Retrospective study.SETTING: A regional hospital in Hong Kong.PATIENTS: Patients who had been prescribed amiodarone for at least 6 months from 1 October 2005 to 30 September 2007.RESULTS: A total of 390 patients (mean age, 70 years; standard deviation, 9 years; 54% male) with a median follow-up of 43 (interquartile range, 25-69) months were studied. Hypothyroidism developed in 87 (22%) of the patients (mean age, 72 years; standard deviation, 7 years; 56% male) and thyrotoxicosis in 24 (6%) of the patients (65 years; 11 years; 54% male). Increased baseline thyrotropin (thyroid-stimulating hormone) level appeared to be predictive of amiodarone-induced hypothyroidism, in which a thyroid-stimulating hormone level of 4 mIU/L or above was associated with a 4.7-fold increase in the risk (95% confidence interval, 1.9-11.7; P<0.001). Compared with those who remained euthyroid on amiodarone, thyrotoxicosis developed in younger patients. In these patients, the classical symptoms of thyroid dysfunction were frequently absent, although worsening of underlying arrhythmias, their cardiac condition, weight loss, and over-warfarinisation were suggestive of amiodarone-induced thyrotoxicosis. In both amiodarone-induced thyrotoxicosis and hypothyroidism, the disease course was benign. Patients with the former showed a good response to anti-thyroid drugs and steroid therapy.CONCLUSIONS: Amiodarone-induced thyroid dysfunction is common among our population. As the clinical presentations are usually vague and atypical, regular biochemical monitoring of thyroid function is warranted, particularly in patients with elevated baseline thyroid-stimulating hormone level. The disease course of amiodarone-induced thyrotoxicosis is usually benign and remits with timely administration of anti-thyroid medications, with or without corticosteroids.", "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.", "Protein kinase casein kinase 1 (CK1) phosphorylates Ser-45 of beta-catenin, \"priming\" the subsequent phosphorylation by glycogen synthase-3 of residues 41, 37, and 33. This concerted phosphorylation of beta-catenin signals its degradation and prevents its function in triggering cell division. The sequence around Ser-45 does not conform to the canonical consensus for CK1 substrates, which prescribes either phosphoamino acids or acidic residues in position n-3 from the target serine. However, the beta-catenin sequence downstream from Ser-45 is very similar to a sequence recognized by CK1 in nuclear factor for activated T cells 4. The common features include an SLS motif followed two to five residues downstream by a cluster of acidic residues. Synthetic peptides reproducing residues 38-65 of beta-catenin were assayed with purified rat liver CK1 or recombinant CK1 alpha and CK1 alpha L from zebrafish. The results demonstrate that SLS and acidic cluster motifs are crucial for CK1 recognition. Pro-44 and Pro-52 are also important for efficient phosphorylation. Similar results were obtained with the different isoforms of CK1. Phosphorylation of mutants of full-length recombinant beta-catenin from zebrafish confirmed the importance of the SLS and acidic cluster motifs. A search for proteins with similar motifs yielded, among other proteins, adenomatous polyposis coli, previously found to be phosphorylated by CK1. There is a strong correlation of beta-catenin mutations found in thyroid tumors with the motifs recognized by CK1 in this protein.", "Pancreatic cholesterol esterase (CEase) is a serine hydrolase involved in the hydrolysis of variety of lipids and transport of free cholesterol. In this study, pharmacophore hypotheses based on known inhibitors were generated using common feature pharmacophore generation protocol available in Discovery Studio program. The best pharmacophore model containing two hydrogen bond acceptor and three hydrophobic features was selected and validated. It was further used in screening three diverse chemical databases. Hit compounds were subjected to drug-likeness and molecular docking studies. Four hits, namely SEW00846, NCI0040784, GK03167, and CD10645, were selected based on the GOLD fitness score and interaction with active site amino acids. All hit compounds were further optimized to improve their binding in the active site. The optimized compounds were found to have improved binding at the active site. Strongly binding optimized hits at the active site can act as virtual leads in potent CEase inhibitor designing.", "The continuous itaconic acid production from sucrose with Aspergillus terreus TKK 200-5-3 mycelium immobilized on polyurethane foam cubes was optimized in column bioreactors using statistical experimental design and empirical modelling. The highest itaconic acid product concentration calculated on the basis of the obtained model was 15.8 g l-1 in the investigated experimental area, when sucrose concentration was 13.5%, aeration rate 150 ml min-1 and residence time 178 h. From sucrose with immobilized A. terreus TKK 200-5-3 mycelium itaconic acid production was stable for at least 4.5 months in continuous column bioreactors. In comparison, using glucose as substrate and immobilized A. terreus TKK 200-5-1 mycelium as biocatalyst similar stability was obtained with higher product concentration. The omission of copper sulphate from the production medium gave the highest itaconic acid product concentration (26 g l-1) from 9% glucose with 0.25% ammonium nitrate and 0.095% magnesium sulphate.", "Interleukin (IL)-6 has a variety of biological functions. For example, it stimulates the production of acute-phase reactants (C-reactive protein and serum amyloid A) and hepcidin which interferes with iron recycling and absorption, causing iron-deficient anemia, and augments expression of vascular endothelial growth factor and receptor activator of nuclear factor-κB ligand in synovial cells, leading to neovascularization and osteoclast formation. IL-6 also acts on lymphocytes, not only on B cells to stimulate autoantibody production, but also on naïve T helper cells to promote Th17 cell differentiation. Thus, an imbalance between T cell subsets possibly contributes to development of rheumatoid arthritis. Several clinical studies have demonstrated that a humanized anti-IL-6 receptor antibody, tocilizumab, improves clinical symptoms in rheumatoid arthritis. Tocilizumab prevented radiographic progression of joint destruction by inhibiting cartilage/bone resorption. Tocilizumab also improved hematological abnormalities, including hypergammaglobulinemia, high levels of autoantibodies, and elevation of erythrocyte sedimentation rate and acute-phase proteins. Importantly, tocilizumab improved quality of life by reducing systemic symptoms, including fatigue, anemia, anorexia, and fever. These findings have confirmed that hyperproduction of IL-6 is responsible for the above clinical symptoms, including joint destruction. Many patients treated with tocilizumab achieved clinical remission associated with decreased serum IL-6, suggesting that IL-6 enhances autoimmunity. Tocilizumab is a new therapeutic option for rheumatoid arthritis.", "To examine the RNA polymerase (EC 2.7.7.6) specificity of RNA maturation/utilization and transcriptional enhancement, we constructed a chimeric plasmid (pPolI-CAT) in which a promoter for mouse rRNA gene transcription was placed adjacent the coding sequences for chloramphenicol acetyltransferase (CAT; EC 2.3.1.28). A number of other constructs, including plasmids also containing a murine sarcoma virus enhancer or lacking any natural eukaryotic promoter sequences, were also prepared. In apparent agreement with earlier conclusions that an RNA polymerase I transcript can act as a messenger RNA, transient transfection of mouse L cells with pPolI-CAT yielded both high levels of transcription from the RNA polymerase I promoter and enzymatically active CAT protein. However, further examination revealed that CAT protein is not translated from RNA that begins at the normal rRNA transcription initiation site. Polysomal RNA is devoid of such RNA and instead consists of CAT-encoding transcripts that begin elsewhere in the mouse ribosomal DNA (rDNA) region. Since transcription of these aberrant RNAs is stimulated by the addition of a murine sarcoma virus enhancer segment, they are probably transcribed by RNA polymerase II. Transcripts that map to the authentic rRNA start site are not similarly enhanced. Moreover, unlike the RNAs deriving from the rRNA initiation site, these aberrant RNAs are more stable and the level of translatable CAT transcripts is suppressed by inclusion of larger segments of the rDNA promoter regions. Fortuitously initiated mRNAs are also formed in the absence of any natural eukaryotic promoter sequence. From these data we conclude that there is no evidence that normal RNA polymerase I transcription yields functional mRNA and that transcriptional enhancement appears to be RNA polymerase specific." ]

[ "Repeated predictions that vector-borne disease prevalence will increase with global warming are usually based on univariate models. To accommodate the full range of constraints, the present-day distribution of tick-borne encephalitis virus (TBEv) was matched statistically to current climatic variables, to provide a multivariate description of present-day areas of disease risk. This was then applied to outputs of a general circulation model that predicts how climatic variables may change in the future, and future distributions of TBEv were predicted for them. The expected summer rise in temperature and decrease in moisture appears to drive the distribution of TBEv into higher-latitude and higher-altitude regions progressively through the 2020s, 2050s and 2080s. The final toe-hold in the 2080s may be confined to a small part of Scandinavia, including new foci in southern Finland. The reason for this apparent contraction of the range of TBEv is that its transmission cycles depend on a particular pattern of tick seasonal dynamics, which may be disrupted by climate change. The observed marked increase in incidence of tick-borne encephalitis in most parts of Europe since 1993 may be due to non-biological causes, such as political and sociological changes.", "A 12 year old, 38 kg, mix-breed, intact male dog presented with a 20 day history of clinical signs consistent with hyperviscosity syndrome secondary to multiple myeloma. The dog received three double filtration plasmapheresis treatments on day 0, 7 and 22 after presentation. A significant (p<0.05) reduction in serum total protein, alpha-2 and gamma globulins was found following each treatment. These reductions were accompanied by a complete resolution, although temporary, of the clinical signs of hyperviscosity syndrome. The present study reported for the first time the use of double filtration plasmapheresis to reduce clinical signs of hyperviscosity syndrome in a dog with multiple myeloma.", "In ciliates, only one of the alternative forms of the immunodominant membrane glycoprotein usually coats the external surface of the cell. Such mutual exclusion is regulated at the pretranslational level by mechanisms that result in the expression of a single protein gene. In the holotrich Tetrahymena thermophila five alternative cell surface immobilization proteins (i-antigens) are expressed under different conditions of temperature (L, H, T) and culture media (I, S). Using polyclonal and monoclonal antibodies to these proteins and a cDNA probe derived from the SerH3 gene, we have reinvestigated expression of i-antigens in media supplemented with 0.2 M NaCl. We find that in addition to S, the H and L antigens are also present on the cell surface. While all three i-antigens may be simultaneously present on the cell surface, the combinations S/L and S/H are more frequent. Compared to cells expressing H and L singly, the level of H3 mRNA is diminished, and a subset of the L family of polypeptides is variably expressed. The expression of S begins within 30 min after transfer to NaCl-supplemented medium, while the expression of L begins three days to several weeks after transfer. When cells are transferred out of NaCl-supplemented medium, S is turned off within 24 h, and L is expressed for at least 1 wk prior to the return of full H expression. Although these differences in kinetics suggest differences in control mechanism(s), the absence of I and T on the surface of NaCl-grown cells suggests that there is also a common regulatory link among H, S and L.(ABSTRACT TRUNCATED AT 250 WORDS)", "The autoimmune regulator gene (AIRE) is a transcription factor expressed both in the thymus, by medullary thymic epithelial cells, and in secondary lymphoid organs. AIRE controls the local transcription of organ- specific proteins typically expressed in peripheral tissues, thus allowing the negative selection of self- reactive T cells. The crucial role played by AIRE in central immune tolerance emerged in the studies on the pathogenesis of Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy, a rare inherited polyendocrine/autoimmune disease. Thereafter, several studies found evidences indicating that AIRE impairment might be pathogenically involved in several autoimmune diseases and in tumorigenesis. In this review, we focus on recent advances relative to AIRE's effect on T cell development in physiology and disease. In particular, we address the following issues: 1) AIRE function and mTECs biology, 2) the impact of AIRE gene mutations in autoimmune diseases, and 3) the role of AIRE gene in anti-tumor immune response.", "OBJECTIVE: Accumulating evidence has suggested that microRNAs play critical roles in the development and progression of human glioma. The role of miR-122 in glioma tumorigenesis has been poorly defined. The current study is designed to investigate whether and how miR-122 affects proliferation and apoptosis of human glioma cells.PATIENTS AND METHODS: 8 normal brain tissues and 19 glioma tissues (7 for low grade and 12 for high grade) were collected. The expressions of miR-122 and runt-related transcription factors (RUNX2) in normal brain/glioma tissues and normal astrocytes (NHA)/multiple glioma cell lines (U87, U251, and U118) were analyzed by Real-time polymerase chain reaction (PCR). Western blot and luciferase activity assays were performed to validate the predicted relationship between miR-122 and RUNX2. The effects of miR-122 on cell proliferation and apoptosis were assessed by cell counting kit-8 (CCK-8), colony forming, and Annexin V-FITC/PI apoptosis assays using both gain- and loss-of-function approaches.RESULTS: MiR-122 expression is downregulated in glioma tissues compared with normal brain tissues, and is negatively correlated with the WHO grade. In contrast, the RUNX2 expression is upregulated in glioma tissues, and is positively correlated with the WHO grade. In glioma cell lines, the miR-122 expression is also constantly downregulated. MiR-122 functions as a tumor suppressor by inhibiting proliferation and inducing apoptosis, which is achieved by directly targeting RUNX2. Overexpression of RUNX2 can partially abrogate the effect of miR-122 on glioma cells.CONCLUSIONS: These results demonstrate a crucial role of miR-122 in regulating cell proliferation and apoptosis. Identifying the miR-122/RUNX2 signaling provides novel insights into the development of therapeutic targets for glioma.", "Botulism is a serious foodborne neuroparalytic disease, caused by botulinum neurotoxin (BoNT), produced by the anaerobic bacterium Clostridium botulinum. Seven toxin serotypes (A-H) have been described. The majority of human cases of botulism are caused by serotypes A and B followed by E and F. We report here a group of serotype B specific monoclonal antibodies (mAbs) capable of binding toxin under physiological conditions. Thus, they serve as capture antibodies for a sandwich (capture) ELISA. The antibodies were generated using recombinant peptide fragments corresponding to the receptor-binding domain of the toxin heavy chain as immunogen. Their binding properties suggest that they bind a complex epitope with dissociation constants (KD's) for individual antibodies ranging from 10 to 48 × 10-11 M. Assay performance for all possible combinations of capture-detector antibody pairs was evaluated and the antibody pair resulting in the lowest level of detection (L.O.D.), ~20 pg/mL was determined. Toxin was detected in spiked dairy samples with good recoveries at concentrations as low as 0.5 pg/mL and in ground beef samples at levels as low as 2 ng/g. Thus, the sandwich ELISA described here uses mAb for both the capture and detector antibodies (binding different epitopes on the toxin molecule) and readily detects toxin in those food samples tested.", "Hirschsprung disease (HSCR) is a frequent congenital disorder (1 in 5,000 newborns) of unknown origin characterized by the absence of parasympathetic intrinsic ganglion cells of the hindgut. Taking advantage of a proximal deletion of chromosome 10q (del 10q11.2-q21.2) in a patient with total colonic aganglionosis, and of a high-density genetic map of microsatellite DNA markers, we performed genetic linkage analysis in 15 non-syndromic long-segment and short-segment HSCR families. Multipoint linkage analysis indicated that the most likely location for a HSCR locus is between loci D10S208 and D10S196, suggesting that a dominant gene for HSCR maps to 10q11.2, a region to which other neural crest defects have been mapped." ]

[ "Stroke is a major cause of mortality and morbidity, and thrombolysis has served as a catalyst for major changes in the management of acute ischaemic stroke. Intravenous alteplase (recombinant tissue plasminogen activator) is the only approved thrombolytic agent at present indicated for acute ischaemic stoke. While the licensed time window extends to 3h from symptom onset, recent data suggest that the trial window can be extended up to 4.5 h with overall benefit. Nonetheless, 'time is brain' and every effort must be made to reduce the time delay to thrombolysis. Intracranial haemorrhage is the major complication associated with thrombolysis, and key factors increasing risk of haemorrhage include increasing age, high blood pressure, diabetes and stroke severity. Currently, there is no direct evidence to support thrombolysis in patients >80 years of age, with a few case series indicating no overt harm. Identification of viable penumbra based on computed tomography/magnetic resonance imaging may allow future extension of the time window. Adjuvant transcranial Doppler ultrasound has the potential to improve reperfusion rates. While intra-arterial thrombolysis has been in vogue for a few decades, there is no clear advantage over intravenous thrombolysis. The evidence base for thrombolysis in specific situations (e.g. dissection, pregnancy) is inadequate, and individualized decisions are needed, with a clear indication to the patient/carer about the lack of direct evidence, and the risk-benefit balance. Patient-friendly information leaflets may facilitate the process of consent for thrombolysis. This article summarizes the recent advances in thrombolysis for acute ischaemic stroke. Key questions faced by clinicians during the decision-making process are answered based on the evidence available.", "The axon/dendrite specification collapsin response mediator protein 2 (CRMP2) bidirectionally modulates N-type voltage-gated Ca ( 2+) channels (CaV2.2). Here we demonstrate that small ubiquitin-like modifier (SUMO) protein modifies CRMP2 via the SUMO E2-conjugating enzyme Ubc9 in vivo. Removal of a SUMO conjugation site KMD in CRMP2 (K374A/M375A/D376A; CRMP2AAA) resulted in loss of SUMOylated CRMP2 without compromising neurite branching, a canonical hallmark of CRMP2 function. Increasing SUMOylation levels correlated inversely with calcium influx in sensory neurons. CRMP2 deSUMOylation by SUMO proteases SENP1 and SENP2 normalized calcium influx to those in the CRMP2AAA mutant. Thus, our results identify a novel role for SUMO modification in CRMP2/CaV2.2 signaling pathway.", "This article reviews the relationship between metabolic syndrome (MetS) and nephrolithiasis, as well as the clinical implications for patients with this dual diagnosis. MetS, estimated to affect 25% of adults in the United States, is associated with a fivefold increase in the risk of developing diabetes, a doubling of the risk of acquiring cardiovascular disease, and an increase in overall mortality. Defined as a syndrome, MetS is recognized clinically by numerous constitutive traits, including abdominal obesity, hypertension, dyslipidemia (elevated triglycerides, low high-density lipoprotein cholesterol), and hyperglycemia. Urologic complications of MetS include a 30% higher risk of nephrolithiasis, with an increased percentage of uric acid nephrolithiasis in the setting of hyperuricemia, hyperuricosuria, low urine pH, and low urinary volume. Current American Urological Association and European Association of Urology guidelines suggest investigating the etiology of nephrolithiasis in affected individuals; however, there is no specific goal of treating MetS as part of the medical management. Weight loss and exercise, the main lifestyle treatments of MetS, counter abdominal obesity and insulin resistance and reduce the incidence of cardiovascular events and the development of diabetes. These recommendations may offer a beneficial adjunctive treatment option for nephrolithiasis complicated by MetS. Although definitive therapeutic recommendations must await further studies, it seems both reasonable and justifiable for the urologist, as part of a multidisciplinary team, to recommend these important lifestyle changes to patients with both conditions. These recommendations should accompany the currently accepted management of nephrolithiasis.", "Heyde's syndrome was first proposed in 1958. It refers to gastrointestinal haemorrhage resulting from a combination of aortic stenosis with angiodysplasia. This report explores the case of a 93-year-old lady who was admitted to hospital following a neck of femur fracture. She suffered from multiple comorbidities including renal failure and congestive heart failure secondary to critical aortic stenosis. As an inpatient she suffered an exacerbation of both her heart and renal failure postoperatively. A week later she suffered from heavy upper gastro-intestinal bleeding, which failed to respond to pharmacological and endoscopic therapies as well as angiographic embolisation. The pathophysiology of Heyde's syndrome: an acquired von Willebrand deficiency syndrome has a much wider impact than was commonly thought, both in terms of how common it is and in how the association may be extrapolated to a wide range of bleeding disorders, rather than simply angiodysplasia associated gastrointestinal haemorrhage.", "As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Bristol-Myers Squibb) of nivolumab (Opdivo®) to submit evidence of its clinical and cost effectiveness for metastatic or unresectable urothelial cancer. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG), which produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company's submission to NICE. Nivolumab was compared with docetaxel, paclitaxel, best supportive care and retreatment with platinum-based chemotherapy (cisplatin plus gemcitabine, but only for patients whose disease has had an adequate response in first-line treatment). Two ongoing, phase I/II, single-arm studies for nivolumab were identified, but no studies directly compared nivolumab with any specified comparator. Evidence from directly examining the single arms of the trial data indicated little difference between the outcomes measured from the nivolumab and comparator studies. A simulated treatment comparison (STC) analysis was used in an attempt to reduce the bias induced by naïve comparison, but there was no clear evidence that risk of bias was reduced. Multiple limitations in the STC were identified and remained. The effect of an analysis based on different combinations of covariates in the prediction model remains unknown. The ERG's concerns regarding the economic analysis included the use of a non-established response-based survival analysis method, which introduced additional uncertainty. The use of time-dependent hazard ratios produced overfitting and was not represented in the probabilistic sensitivity analysis. The use of a treatment stopping rule to cap treatment cost left treatment effectiveness unaltered. A relevant comparator was excluded from the base-case analysis. The revised ERG deterministic base-case incremental cost-effectiveness ratios based on the company's Appraisal Consultation Document response were £58,791, £78,869 and £62,352 per quality-adjusted life-year gained versus paclitaxel, docetaxel and best supportive care, respectively. Nivolumab was dominated by cisplatin plus gemcitabine in the ERG base case. Substantial uncertainties about the relative treatment effectiveness comparing nivolumab against all comparators remained. NICE did not recommend nivolumab, within its marketing authorisation, as an option for treating locally advanced, unresectable or metastatic urothelial carcinoma in adults who have had platinum-containing therapy, and considered that nivolumab was not suitable for use within the Cancer Drugs Fund.", "Cortisol is a classical biomarker for the stress levels of human beings. We fabricated highly sensitive bioluminescent probes for salivary cortisol. The following strategies were contrived in the molecular design. Gaussia princeps luciferase (GLuc) was dissected into two fragments, between which an N-terminal-extended ligand binding domain of glucocorticoid receptor (GR HLBD), named Simgr4, was inserted. First, this unique single-chain probe was then situated downstream of a glucocorticoid response element (GRE) promoter in a reporter-gene system for constructing two ON-OFF switches for cortisol. Second, a circularly permutated (CP) variant of Simgr4 was formulated. The reporter-gene system exerted an improved signal-to-background (S/B) ratio of 8.5 to cortisol. Furthermore, a circularly permutated (CP) variant of Simgr4 exerted a 10× enhanced detection limit to cortisol and a long dynamic range from 10(-9) to 10(-6) M cortisol, covering all of the normal clinical ranges of serum, urine, and saliva. This optimized probe successfully determined daily fluctuations of salivary cortisol and the correlations with those by ELISA. This study is the first to investigate the contribution of the HLBD of a nuclear receptor and multiple ON-OFF switches for molecular probes and salivary cortisols.", "Induced pluripotent stem (iPS) cells were originally generated from mouse fibroblasts by enforced expression of Yamanaka factors (Oct3/4, Sox2, Klf4, and c-Myc). The technique was quickly reproduced with human fibroblasts or mesenchymal stem cells. Although having been showed therapeutic potential in animal models of sickle cell anemia and Parkinson's disease, iPS cells generated by viral methods do not suit all the clinical applications. Various non-viral methods have appeared in recent years for application of iPS cells in cell transplantation therapy. These methods mainly include DNA vector-based approaches, transfection of mRNA, and transduction of reprogramming proteins. This review summarized these non-viral methods and compare the advantages, disadvantages, efficiency, and safety of these methods." ]

[ "OBJECTIVE: To review the immunogenicity, efficacy, and safety of the 13-valent pneumococcal conjugate vaccine (PCV13) for use in pediatric patients.DATA SOURCES: A MEDLINE search (2000-September 2011) was conducted using the key words Streptococcus pneumoniae and pneumococcal conjugate vaccine for clinical trials, limited to studies conducted in humans and published in English.STUDY SELECTION AND DATA EXTRACTION: Randomized, controlled, multicenter trials were reviewed and included to evaluate the safety and efficacy of PCV13. Literature on the epidemiology and pathology of pneumococcal infections and recommendations from the Advisory Committee on Immunization Practices (ACIP) were also reviewed.DATA SYNTHESIS: PCV13 is approved for routine vaccination of all infants as a 4-dose series at age 2, 4, 6, and 12-15 months for children who previously received 1 or more doses of the 7-valent pneumococcal conjugate vaccine (PCV7), and for children with underlying medical conditions that increase their risk for pneumococcal disease or its complications. PCV13 has comparable immunogenicity to the serotypes common with PCV7 and also provides protection against 6 additional pneumococcal serotypes. PCV13 has also been shown to have a comparable adverse reaction profile to PCV7.CONCLUSIONS: Based on published immunogenicity and safety data, as well as the recent recommendations by the ACIP for routine use in infants and indications for high-risk pediatric patients, PCV13 is a revised formulation of pneumococcal vaccine that should be included on pharmacy formularies.", "BACKGROUND: Abnormal laboratory findings are common in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The aim of this systematic review was to investigate the effect of the level of some laboratory factors (C-reactive protein (CRP), creatinine, leukocyte count, hemoglobin, and platelet count) on the severity and outcome of coronavirus disease 2019 (COVID-19).METHODS: We searched PubMed, Web of Science, Scopus, and Google Scholar. We collected the articles published before May 26, 2020. We gathered the laboratory factors in groups of patients with COVID-19, and studied the relation between level of these factors with severity and outcome of the disease.RESULTS: Mean CRP level, creatinine, hemoglobin, and the leukocytes count in the critically ill patients were significantly higher than those of the other groups (non-critical patients); mean CRP = 54.81 mg/l, mean creatinine = 86.82 μmol/l, mean hemoglobin = 144.05 g/l, and mean leukocyte count = 7.41 × 109. The lymphocyte count was higher in patients with mild/moderate disease (mean: 1.32 × 109) and in the invasive ventilation group (mean value of 0.72 × 109), but it was considerably lower than those of the other two groups. The results showed that the platelet count was higher in critically ill patients (mean value of 205.96 × 109). However, the amount was lower in the invasive ventilation group compared with the other groups (mean level = 185.67 × 109).CONCLUSION: With increasing disease severity, the leukocyte count and the level of CRP increase significantly and the lymphocyte count decreases. There seems to be a significant relation between platelet level, hemoglobin, and creatinine level with severity of the disease. However, more studies are required to confirm this.", "AIMS: Mutations in the cardiac ryanodine receptor Ca(2+) release channel, RyR2, underlie catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited life-threatening arrhythmia. CPVT is triggered by spontaneous RyR2-mediated sarcoplasmic reticulum (SR) Ca(2+) release in response to SR Ca(2+) overload during beta-adrenergic stimulation. However, whether elevated SR Ca(2+) content--in the absence of protein kinase A activation--affects RyR2 function and arrhythmogenesis in CPVT remains elusive.METHODS AND RESULTS: Isolated murine ventricular myocytes harbouring a human RyR2 mutation (RyR2(R4496C+/-)) associated with CPVT were investigated in the absence and presence of 1 micromol/L JTV-519 (RyR2 stabilizer) followed by 100 micromol/L ouabain intervention to increase cytosolic [Na(+)] and SR Ca(2+) load. Changes in membrane potential and intracellular [Ca(2+)] were monitored with whole-cell patch-clamping and confocal Ca(2+) imaging, respectively. At baseline, action potentials (APs), Ca(2+) transients, fractional SR Ca(2+) release, and SR Ca(2+) load were comparable in wild-type (WT) and RyR2(R4496C+/-) myocytes. Ouabain evoked significant increases in diastolic [Ca(2+)], peak systolic [Ca(2+)], fractional SR Ca(2+) release, and SR Ca(2+) content that were quantitatively similar in WT and RyR2(R4496C+/-) myocytes. Ouabain also induced arrhythmogenic events, i.e. spontaneous Ca(2+) waves, delayed afterdepolarizations and spontaneous APs, in both groups. However, the ouabain-induced increase in the frequency of arrhythmogenic events was dramatically larger in RyR2(R4496C+/-) when compared with WT myocytes. JTV-519 greatly reduced the frequency of ouabain-induced arrhythmogenic events.CONCLUSION: The elevation of SR Ca(2+) load--in the absence of beta-adrenergic stimulation--is sufficient to increase the propensity for triggered arrhythmias in RyR2(R4496C+/-) cardiomyocytes. Stabilization of RyR2 by JTV-519 effectively reduces these triggered arrhythmias.", "Tourette syndrome is a neurologic disorder characterized by both motor and vocal tics. Recently, two variants, including a single-base deletion resulting in a truncated protein and a 3'-untranslated-region variant altering a binding site for micro-RNA in the Slit and Trk-like 1 gene, were found to be a genetic cause of Tourette syndrome. The Slit and Trk-like 1 family was identified as neuronal transmembrane proteins that control neurite outgrowth. This study aimed to determine whether mutations in the gene can be found in Taiwanese patients with Tourette syndrome. In total, 160 patients were included. All children underwent peripheral blood sampling for genotype analyses. We sequenced the whole Slit and Trk-like 1 gene, including the promoter, the 3'-untranslated region, the 5'-untranslated region, and the whole coding region. We found that none of the 160 samples revealed any mutation in the whole gene sequence. In addition, there was only one polymorphism, c.3225 T>C, detected in 10 individuals. We conclude that in rare variants, it may be difficult to establish an association with disorder. Therefore, genetic screening in the Slit and Trk-like 1 gene for the recently identified mutations does not appear to be of utility in the diagnosis of Tourette syndrome.", "OBJECTIVE: To assess the added prognostic value of the aggregated clinical and electrodiagnostic data, which define a given diagnostic category according to the Awaji or revised El Escorial criteria at time of diagnosis in patients with amyotrophic lateral sclerosis (ALS).METHODS: Clinical signs and electrodiagnostic test results were collected at time of diagnosis in 396 patients with ALS between January 2009 and January 2016. Significant predictors of prognosis were identified using a univariate model, and later combined in a multivariate Cox regression model.RESULTS: Known factors associated with reduced survival included older age at onset, shorter diagnostic delay, higher ALSFRS-R slope and presence of C9orf72 mutation (all p < 0.05). Diagnostic category according to Awaji (p < 0.0001) or to revised El Escorial (p = 0.0177) criteria, definite ALS according to Awaji (p < 0.0001) or to revised El Escorial (p = 0.0343) and number of regions with LMN involvement (p < 0.0001) were all associated with shorter survival.DISCUSSION: Clinical and electrodiagnostic data at time of diagnosis provide additional prognostic information compared to other known prognostic factors. Diagnostic category according to Awaji and the extensiveness of LMN involvement contain the most additional value.", "Cancer bears a poisoning threat to human society. Melanoma, the skin cancer, originates from skin layers and penetrates deep into subcutaneous layers. There exists an extensive research in melanoma diagnosis using dermatoscopic images captured through a dermatoscope. While designing a diagnostic model for general handheld imaging systems is an emerging trend, this article proposes a computer-aided decision support system for macro images captured by a general-purpose camera. General imaging conditions are adversely affected by nonuniform illumination, which further affects the extraction of relevant information. To mitigate it, we process an image to define a smooth illumination surface using the multistage illumination compensation approach, and the infected region is extracted using the proposed multimode segmentation method. The lesion information is numerated as a feature set comprising geometry, photometry, border series, and texture measures. The redundancy in feature set is reduced using information theory methods, and a classification boundary is modeled to distinguish benign and malignant samples using support vector machine, random forest, neural network, and fast discriminative mixed-membership-based naive Bayesian classifiers. Moreover, the experimental outcome is supported by hypothesis testing and boxplot representation for classification losses. The simulation results prove the significance of the proposed model that shows an improved performance as compared with competing arts.", "The mammalian master clock driving circadian rhythmicity in physiology, metabolism, and behaviour resides within the suprachiasmatic nuclei (SCN) of the anterior hypothalamus and is composed of intertwined negative and positive autoregulatory transcription-translation feedback loops. The Cryptochrome 1 and 2 gene products act in the negative feedback loop and are indispensable for molecular core oscillator function, as evident from the arrhythmic wheel running behaviour and absence of cyclic clock gene expression in mCry1/mCry2 double mutant mice in constant darkness. Recently, we have measured real-time multi-unit electrode activity recordings in hypothalamic slices from mCry-deficient mice kept in constant darkness and observed a complete lack of circadian oscillations in firing patterns. This proves that CRY proteins, and thus an intact circadian clock, are prerequisite for circadian rhythmicity in membrane excitability in SCN neurons. Strikingly, when mCry-deficient mice are housed in normal light-dark cycles, a single non-circadian peak in neuronal activity can be detected in SCN slices prepared two hours after the beginning of the day. This light-induced increase in electric activity of the SCN suggests that deletion of the mCry genes converts the core oscillator in an hour-glass-like timekeeper and may explain why in normal day-night cycles mCry-deficient mice show apparently normal behaviour." ]

[ "BACKGROUND: It is common for the results of a microarray study to be analyzed in the context of biologically-motivated groups of genes such as pathways or Gene Ontology categories. The most common method for such analysis uses the hypergeometric distribution (or a related technique) to look for \"over-representation\" of groups among genes selected as being differentially expressed or otherwise of interest based on a gene-by-gene analysis. However, this method suffers from some limitations, and biologist-friendly tools that implement alternatives have not been reported.RESULTS: We introduce ErmineJ, a multiplatform user-friendly stand-alone software tool for the analysis of functionally-relevant sets of genes in the context of microarray gene expression data. ErmineJ implements multiple algorithms for gene set analysis, including over-representation and resampling-based methods that focus on gene scores or correlation of gene expression profiles. In addition to a graphical user interface, ErmineJ has a command line interface and an application programming interface that can be used to automate analyses. The graphical user interface includes tools for creating and modifying gene sets, visualizing the Gene Ontology as a table or tree, and visualizing gene expression data. ErmineJ comes with a complete user manual, and is open-source software licensed under the Gnu Public License.CONCLUSION: The availability of multiple analysis algorithms, together with a rich feature set and simple graphical interface, should make ErmineJ a useful addition to the biologist's informatics toolbox. ErmineJ is available from http://microarray.cu.genome.org.", "BACKGROUND: Several biologic therapies are approved by the National Institute for Health and Care Excellence (NICE) for psoriatic arthritis (PsA) patients who have had an inadequate response to two or more synthetic disease-modifying antirheumatic drugs (DMARDs). NICE does not specifically recommend switching from one biologic to another, and only ustekinumab (UST; STELARA®, Janssen Pharmaceuticals, Inc., Horsham, PA, USA) is recommended after anti-tumour necrosis factor failure. Secukinumab (SEC; COSENTYX®, Novartis International AG, Basel, Switzerland) and certolizumab pegol (CZP; CIMZIA®, UCB Pharma, Brussels, Belgium) have not previously been appraised by NICE.OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of CZP and SEC for treating active PsA in adults in whom DMARDs have been inadequately effective.DESIGN: Systematic review and economic model.DATA SOURCES: Fourteen databases (including MEDLINE and EMBASE) were searched for relevant studies from inception to April 2016 for CZP and SEC studies; update searches were run to identify new comparator studies.REVIEW METHODS: Clinical effectiveness data from randomised controlled trials (RCTs) were synthesised using Bayesian network meta-analysis (NMA) methods to investigate the relative efficacy of SEC and CZP compared with comparator therapies. A de novo model was developed to assess the cost-effectiveness of SEC and CZP compared with the other relevant comparators. The model was specified for three subpopulations, in accordance with the NICE scope (patients who have taken one prior DMARD, patients who have taken two or more prior DMARDs and biologic-experienced patients). The models were further classified according to the level of concomitant psoriasis.RESULTS: Nineteen eligible RCTs were included in the systematic review of short-term efficacy. Most studies were well conducted and were rated as being at low risk of bias. Trials of SEC and CZP demonstrated clinically important efficacy in all key clinical outcomes. At 3 months, patients taking 150 mg of SEC [relative risk (RR) 6.27, 95% confidence interval (CI) 2.55 to 15.43] or CZP (RR 3.29, 95% CI 1.94 to 5.56) were more likely to be responders than patients taking placebo. The NMA results for the biologic-naive subpopulations indicated that the effectiveness of SEC and CZP relative to other biologics and each other was uncertain. Limited data were available for the biologic-experienced subpopulation. Longer-term evidence suggested that these newer biologics reduced disease progression, with the benefits being similar to those seen for older biologics. The de novo model generated incremental cost-effectiveness ratios (ICERs) for three subpopulations and three psoriasis subgroups. In subpopulation 1 (biologic-naive patients who had taken one prior DMARD), CZP was the optimal treatment in the moderate-severe psoriasis subgroup and 150 mg of SEC was optimal in the subgroups of patients with mild-moderate psoriasis or no concomitant psoriasis. In subpopulation 2 (biologic-naive patients who had taken two or more prior DMARDs), etanercept (ETN; ENBREL®, Pfizer Inc., New York City, NY, USA) is likely to be the optimal treatment in all subgroups. The ICERs for SEC and CZP versus best supportive care are in the region of £20,000-30,000 per quality-adjusted life-year (QALY). In subpopulation 3 (biologic-experienced patients or patients in whom biologics are contraindicated), UST is likely to be the optimal treatment (ICERs are in the region of £21,000-27,000 per QALY). The optimal treatment in subpopulation 2 was sensitive to the choice of evidence synthesis model. In subpopulations 2 and 3, results were sensitive to the algorithm for Health Assessment Questionnaire-Disability Index costs. The optimal treatment is not sensitive to the use of biosimilar prices for ETN and infliximab (REMICADE®, Merck Sharp & Dohme, Kenilworth, NJ, USA).CONCLUSIONS: SEC and CZP may be an effective use of NHS resources, depending on the subpopulation and subgroup of psoriasis severity. There are a number of limitations to this assessment, driven mainly by data availability.FUTURE WORK: Trials are needed to inform effectiveness of biologics in biologic-experienced populations.STUDY REGISTRATION: This study is registered as PROSPERO CRD42016033357.FUNDING: The National Institute for Health Research Health Technology Assessment programme.", "BACKGROUND: Septins are a highly conserved family of GTP-binding proteins involved in multiple cellular functions, including cell division and morphogenesis. Studies of septins in fungal cells underpin a clear correlation between septin-based structures and fungal morphology, providing clues to understand the molecular frame behind the varied morphologies found in fungal world.METHODOLOGY/PRINCIPAL FINDINGS: Ustilago maydis genome has the ability to encode four septins. Here, using loss-of-function as well as GFP-tagged alleles of these septin genes, we investigated the roles of septins in the morphogenesis of this basidiomycete fungus. We described that septins in U. maydis could assemble into at least three different structures coexisting in the same cell: bud neck collars, band-like structures at the growing tip, and long septin fibers that run from pole to pole near the cell cortex. We also found that in the absence of septins, U. maydis cells lost their elongated shape, became wider at the central region and ended up losing their polarity, pointing to an important role of septins in the morphogenesis of this fungus. These morphological defects were alleviated in the presence of an osmotic stabilizer suggesting that absence of septins affected the proper formation of the cell wall, which was coherent with a higher sensitivity of septin defective cells to drugs that affect cell wall construction as well as exocytosis. As U. maydis is a phytopathogen, we analyzed the role of septins in virulence and found that in spite of the described morphological defects, septin mutants were virulent in corn plants.CONCLUSIONS/SIGNIFICANCE: Our results indicated a major role of septins in morphogenesis in U. maydis. However, in contrast to studies in other fungal pathogens, in which septins were reported to be necessary during the infection process, we found a minor role of septins during corn infection by U. maydis.", "Dairy cows mobilise body tissues to support milk production and, because glucose supplies are limited, lipids are used preferentially for energy production. Lipogenic activity is switched off and lipolytic mechanisms in adipose tissue increase through changes in the expression of several key enzymes. This results in a loss of body condition, together with high circulating concentrations of non-esterified fatty acids. Changes in the synthesis, secretion and signalling pathways of somatotrophic hormones (insulin, growth hormone, insulin-like growth factor 1) and adipokines (e.g. leptin) are central to the regulation of these processes. A high reliance on fatty acids as an energy source in the peripartum period causes oxidative damage to mitochondria in metabolically active tissues, including the liver and reproductive tract. The expression of genes involved in insulin resistance (PDK4, AHSG) is increased, together with expression of TIEG1, a transcription factor that can induce apoptosis via the mitochondrial pathway. Polymorphisms in TFAM and UCP2, two autosomal mitochondrial genes, have been associated with longevity in dairy cows. Polymorphisms in many other genes that affect lipid metabolism also show some associations with fertility traits. These include DGAT1, SCD1, DECR1, CRH, CBFA2T1, GH, LEP and NPY. Excess lipid accumulation in oocytes and the regenerating endometrium reduces fertility via reductions in embryo survival and increased inflammatory changes, respectively.", "Fanconi anaemia (FA) is a rare, predominantly autosomal recessive syndrome (with one X-linked form) that results in congenital defects, abnormal haematopoiesis and a greatly increased risk of solid tumours in humans. Mutations in at least 14 different genes have been shown to cause FA, and several of these genes, including FANCJ/BRIP1, FANCD1/BRCA2 and FANCN/PALB2, also predispose to breast cancer in heterozygote carriers. The FA genes code for proteins that act in complexes to coordinate the repair of damaged DNA, and thus the FA repair network is intimately linked with hereditary breast cancer. Much remains to be learnt about the functions and interactions of the FA proteins and one experimental approach involves the generation of mice that are deficient in various FA genes. Mouse models for FANCN/PALB2 have recently been generated, including one reported in a recent issue of The Journal of Pathology. Given the pivotal role of the PALB2 protein, which interacts with both BRCA1 and BRCA2, these mice provide valuable insights into the FA phenotype and mechanisms of tumourigenesis caused by disruption of the FA protein network.", "A live attenuated vaccine to prevent herpes zoster, or shingles (Zostavax; Merck & Co Inc, Whitehouse Station, NJ), is approved by the US Food and Drug Administration (FDA) for use in adults aged 50 years or older. Studies show that this vaccine is safe when administered to immunocompetent adults. Investigations are being conducted to evaluate the long-term safety and efficacy of the vaccine in immunocompromised populations, including patients who are dependent on steroids. The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention recommends that this vaccine be routinely administered only to patients aged 60 years or older. As more data regarding duration of immunity after vaccination become available and as concerns regarding supply of this vaccine are adequately addressed, the ACIP plans to reconsider its recommendations regarding its use in patients aged 50 to 59 years. The author provides an overview of the herpes zoster vaccine, focusing on the latest extension in use approved by the FDA and the recommendations of the ACIP.", "Mineralocorticoid receptor (MR) antagonists, for example, spironolactone and eplerenone, are in clinical use to treat hypertension. Increasing evidence suggests that mineralocorticoid receptor activation causes the pathogenesis and progression of chronic kidney disease. Aldosterone-induced MR activation increases inflammation, fibrosis, and oxidative stress in the kidney. MR antagonists (MRAs) have demonstrated therapeutic actions in chronic kidney disease (CKD), diabetic nephropathy (DN), renal fibrosis, and drug-induced renal injury in preclinical and clinical studies. We have summarized and discussed these studies in this review. The nonsteroidal MRA, esaxerenone, recently received approval for the treatment of hypertension. It has also shown a positive therapeutic effect in phase 3 clinical trials in patients with DN. Other nonsteroidal MRA such as apararenone, finerenone, AZD9977, and LY2623091 are in different clinical trials in patients with hypertension suffering from renal or hepatic fibrotic diseases. Hyperkalemia associated with MRA therapy has frequently led to the discontinuation of the treatment. The new generation nonsteroidal MRAs like esaxerenone are less likely to cause hyperkalemia at therapeutic doses. It appears that the nonsteroidal MRAs can provide optimum therapeutic benefit for patients suffering from kidney diseases." ]

[ "Granulocyte colony-stimulating factor (G-CSF) mediates \"emergency\" granulopoiesis during infection, a process that is mimicked by clinical G-CSF use, yet we understand little about the intracellular signaling cascades that control demand-driven neutrophil production. Using a murine model with conditional deletion of signal transducer and activator of transcription 3 (STAT3) in bone marrow, we investigated the cellular and molecular mechanisms of STAT3 function in the emergency granulopoiesis response to G-CSF administration or infection with Listeria monocytogenes, a pathogen that is restrained by G-CSF signaling in vivo. Our results show that STAT3 deficiency renders hematopoietic progenitor cells and myeloid precursors refractory to the growth-promoting functions of G-CSF or L monocytogenes infection. STAT3 is necessary for accelerating granulocyte cell-cycle progression and maturation in response to G-CSF. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. These results place STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion.", "Propionic acidemia results from mutations in either of the two genes, PCCA or PCCB, that encode the two subunits of the propionyl-CoA carboxylase (PCC) enzyme. In this study, we report the identification and analysis of seven novel splicing mutations involving consensus donor and acceptor splice sites. Most of them were identified in patients with a Central Asian origin, and some present in several alleles, probably reflecting founder effects. The functional consequences of the splicing mutations were analyzed in patients' fibroblasts, as well as transcript quantification using real-time PCR methods. In the PCCA gene, two mutations were demonstrated to affect 5' splice sites (c.231+1G>C and c.1209+3A>G) and two 3' acceptor splice sites (c.1210delG and c.1430G>T), all causing skipping of the exons involved, with no detectable levels of normally spliced transcript. In the PCCB gene, all three mutations involved 5' donor splice sites-two affected exon 1 splicing (c.154_183+17del46 and c.183+2T>C), the latter activating a cryptic splice site in intron 1, and the remaining mutation (c.1498+2T>C) resulted in exon 14 skipping. The results highlight the necessity to perform transcript analysis in addition to genomic DNA sequencing to characterize the effect of splicing mutations and add relevant information on the genetic epidemiology of the disease.", "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.", "AIM: To determine a possible relationship between migraine and body mass index.METHODS: Migraine shows a wide spectrum of comorbidities, including cardiocerebral, vascular, psychiatric, metabolic, neurological as well as other pathologies. Recent researches suggest that obesity was significantly correlated with migraine frequency and disability in children, as well as in adult population studies. We reviewed data from the literature to clarify this possible relationship.RESULTS: Translational and basic science research shows multiple areas of overlap between migraine pathophysiology and the central and peripheral pathways regulating feeding. Specifically, neurotransmittors such as serotonin, peptides such as orexin, and adipocytokines such as adiponectin and leptin have been suggested to have roles in both feeding and migraine. A relationship between migraine and body mass index exists, and therefore, interventions to modify body mass index may provide a useful treatment model for investigating whether modest weight loss reduces headache frequency and severity in obese migraineurs.CONCLUSION: The effect of obesity and weight change on headache outcomes may have important implications for clinical care.", "BACKGROUND: Lysosomal acid lipase deficiency is an autosomal recessive metabolic disease with a wide range of severity from Wolman Disease to Cholesterol Ester Storage Disease. Recently enzyme replacement therapy with sebelipase alpha has been approved by drug agencies for treatment of this lysosomal disease. Ezetimibe is an azetidine derivative which blocks Niemann Pick C1-Like 1 Protein; as its consequence, plasmatic concentration of low density lipoproteins and other apoB-containing lipoproteins, that are the substrate of lysosomal acid lipase, are decreased. Furthermore, ezetimibe acts by blocking inflammasome activation which is the cause of liver fibrosis in steatohepatitis and in lysosomal storage diseases.RESULTS: Two patients with Cholesterol Ester Storage Disease were treated with ezetimibe for 9 years and a third patients for 10 years. Treatment was supplemented with low dose of atorvastatin in the first two patients during the last 6 years. All patients showed a significant reduction of alanine aminotransferase, cholesterol and triglyceride. Furthermore, no progression of liver fibrosis was demonstrated.CONCLUSION: In this observational case series, ezetimibe is effective, safe, and sustainable treatment for lysosomal acid lipase deficiency. Further studies are warranted to demonstrate that ezetimibe is an alternative therapy to enzyme replacement therapy.", "Epidemiologic studies have shown a correlation between antioxidant intake and coronary artery disease (CAD); however, the results of clinical trials have been inconsistent. We evaluated the effect of combined antioxidant supplementation on endothelial function and its correlation with change in low-density lipoprotein cholesterol (LDLC) oxidation in patients with established CAD. In a double-blind, placebo-controlled 12-week trial, 18 nonsmoking, nondiabetic patients (mean age 62.4 +/- 8.1 years) were randomized to receive placebo or antioxidant supplementation consisting of (a) 400 IU of vitamin E, 500 mg of vitamin C, and 12 mg of beta-carotene; or (b) 800 IU of vitamin E, 1000 mg of vitamin C, and 24 mg of beta-carotene daily. Endothelial function was evaluated on the basis of percent and absolute changes in brachial artery diameter in response to reactive hyperemia induced by occlusion-release. Baseline and 12-week values of LDL oxidation (measured on the basis of lag phase), endothelial function, dietary composition, serum antioxidants, and lipids were measured. We noted a significant between-group difference at 12 weeks for change in plasma concentrations of alpha-tocopherol, vitamin C, and beta-carotene between the placebo and antioxidant groups (p <.05). Both placebo and treatment groups demonstrated a significant improvement in lag phase; however, the treatment group achieved a greater, although nonsignificant, magnitude of change compared with the placebo group (181.3 +/- 177.8 minutes vs 80.6 +/- 63.0 minutes, P =.06). Within-group change in brachial reactivity from baseline to follow-up in the treatment group did not reach statistical significance (1.7% +/- 3.2% and 0.07 mm +/- 0.13 mm, P =.08 and P =.09, respectively), whereas an improved change in brachial reactivity was observed in the placebo group (2.2% +/- 1.9%, 0.09 mm +/- 0.06 mm, P <.05). No significant correlation was found between change in lag phase and change in endothelial function. On adjustment for confounders, antioxidant supplementation was found not to be a significant predictor of brachial reactivity. We conclude that antioxidant supplementation did not significantly alter brachial reactivity, despite significantly increased plasma levels of antioxidants and improved lag phase. These data should be confirmed in larger-scale trials and examined in studies evaluating individual dietary antioxidant supplementation.", "Globoid cell leukodystrophy (GLD), or Krabbe disease, is an inherited, neurologic disorder that results from deficiency of a lysosomal enzyme, galactosylceramidase. Most commonly, deficits of galactosylceramidase result in widespread central and peripheral nervous system demyelination and death in affected infants typically by 2 years of age. Hematopoietic stem-cell transplantation is the current standard of care in children diagnosed prior to symptom onset. However, disease correction is incomplete. Herein, the first adeno-associated virus (AAV) gene therapy experiments are presented in a naturally occurring canine model of GLD that closely recapitulates the clinical disease progression, neuropathological alterations, and biochemical abnormalities observed in human patients. Adapted from studies in twitcher mice, GLD dogs were treated by combination intravenous and intracerebroventricular injections of AAVrh10 to target both the peripheral and central nervous systems. Combination of intravenous and intracerebroventricular AAV gene therapy had a clear dose response and resulted in delayed onset of clinical signs, extended life-span, correction of biochemical defects, and attenuation of neuropathology. For the first time, therapeutic effect has been established in the canine model of GLD by targeting both peripheral and central nervous system impairments with potential clinical implications for GLD patients.", "Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, affecting up to 10 million people worldwide. Current treatment primarily involves symptom management with dopaminergic replacement therapy. Levodopa remains the most effective oral treatment, although long-term use is associated with complications such as wearing off, dyskinesias, and on-off fluctuations. Non-dopaminergic medications that improve PD symptoms and motor fluctuations are in demand. Adenosine A2A receptors are abundantly expressed within the basal ganglia and offer a unique target to modify abnormal striatal signaling associated with PD. Preclinical animal models have shown the ability of adenosine A2A receptor antagonists to improve PD motor symptoms, reduce motor fluctuations and dyskinesia, as well as protect against toxin-induced neuronal degeneration. Both istradefylline and preladenant have demonstrated moderate efficacy in reducing off time in PD patients with motor fluctuations. The safety and efficacy of this class of compounds continues to be defined and future studies should focus on non-motor symptoms, dyskinesias, and neuroprotection.", "Dupuytren's contracture is a common hand problem that affects the palmar fascia. Several treatment options exist, but none are curative and recurrence is common. Bacterial collagenase has recently been proven beneficial for treating Dupuytren's disease, cleaving the collagen fibers at different sites, with weakening and eventually rupture of the fibrous cords after manipulation. An independent prospective follow-up study was organized on 87 patients, treated with one or more collagenase injections. Inclusion criteria were a contracture of at least 20° at the metacarpophalangeal (MCP) or the proximal interphalangeal (PIP) joint. The most diseased joint was taken into consideration for follow-up evaluation. The resulting extension deficit was measured at 1 month, 1 year and 2 years and was graded as \"clinical success\", \"clinical improvement\" or \"clinical failure\". The mean contracture improved from 45° (39° for MCP and 54° for PIP joints) before treatment to 5° (2° for MCP and 9° for PIP joints) 4 weeks after treatment. No serious complications occurred. After 2 years, 68 joints were evaluated; 61.5% of the MCP joints and 34.5% of the PIP joints had a contracture of ≤20°. When compared with the 4-week evaluation, 28.2% of MCP joints and 62.1% of PIP joints had a recurrence (20° or greater worsening) or had received additional treatment. Collagenase injection is a safe and effective treatment option for Dupuytren disease, but recurrence is common especially for the PIP joint.", "BACKGROUND: Krabbe disease is a rare neurodegenerative genetic disorder caused by deficiency of galactocerebrosidase. Patients with the infantile form of Krabbe disease can be treated at a presymptomatic stage with human stem cell transplantation which improves survival and clinical outcomes. However, without a family history, most cases of infantile Krabbe disease present after onset of symptoms and are ineligible for transplantation. In 2006, New York began screening newborns for Krabbe disease to identify presymptomatic cases. To ensure that those identified with infantile disease received timely treatment, New York public health and medical systems took steps to accurately diagnose and rapidly refer infants for human stem cell transplantation within the first few weeks of life. After 11 years of active screening in New York and the introduction of Krabbe disease newborn screening in other states, new information has been gained which can inform the design of newborn screening programs to improve infantile Krabbe disease outcomes.FINDINGS: Recent information relevant to Krabbe disease screening, diagnosis, and treatment were assessed by a diverse group of public health, medical, and advocacy professionals. Outcomes after newborn screening may improve if treatment for infantile disease is initiated before 30 days of life. Newer laboratory screening and diagnostic tools can improve the speed and specificity of diagnosis and help facilitate this early referral. Given the rarity of Krabbe disease, most recommendations were based on case series or expert opinion.CONCLUSION: This report updates recommendations for Krabbe disease newborn screening to improve the timeliness of diagnosis and treatment of infantile Krabbe disease. In the United States, several states have begun or are considering Krabbe disease newborn screening. These recommendations can guide public health laboratories on methodologies for screening and inform clinicians about the need to promptly diagnose and treat infantile Krabbe disease. The timing of the initial referral after newborn screening, the speed of diagnostic confirmation of infantile disease, and the transplantation center's experience and ability to rapidly respond to a suspected patient with newly diagnosed infantile Krabbe disease are critical for optimal outcomes.", "Phospholamban (PLN), a homopentameric, integral membrane protein, reversibly inhibits cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity through intramembrane interactions. Here, alanine-scanning mutagenesis of the PLN transmembrane sequence was used to identify two functional domains on opposite faces of the transmembrane helix. Mutations in one face diminish inhibitory interactions with transmembrane sequences of SERCA2a, but have relatively little effect on the pentameric state, while mutations in the other face activate inhibitory interactions and enhance monomer formation. Double mutants are monomeric, but loss of inhibitory function is dominant over activation of inhibitory function. These observations support the proposal that the SERCA2a interaction site lies on the helical face which is not involved in pentamer formation. Four highly inhibitory mutants are effectively devoid of pentamer, suggesting that pentameric PLN represents a less active or inactive reservoir that dissociates to provide inhibitory monomeric PLN subunits. A model is presented in which the degree of PLN inhibition of SERCA2a activity is ultimately determined by the concentration of the inhibited PLN monomer.SERCA2a heterodimeric complex. The concentration of this inhibited complex is determined by the dissociation constant for the PLN pentamer (which is mutation-sensitive) and by the dissociation constant for the PLN/SERCA2a heterodimer (which is likely to be mutation-sensitive).", "Exosomes are extracellular vesicles released by the vast majority of cell types both in vivo and ex vivo, upon the fusion of multivesicular bodies (MVBs) with the cellular plasma membrane. Two main functions have been attributed to exosomes: their capacity to transport proteins, lipids and nucleic acids between cells and organs, as well as their potential to act as natural intercellular communicators in normal biological processes and in pathologies. From a clinical perspective, the majority of applications use exosomes as biomarkers of disease. A new approach uses exosomes as biologically active carriers to provide a platform for the enhanced delivery of cargo in vivo. One of the major limitations in developing exosome-based therapies is the difficulty of producing sufficient amounts of safe and efficient exosomes. The identification of potential proteins involved in exosome biogenesis is expected to directly cause a deliberate increase in exosome production. In this review, we summarize the current state of knowledge regarding exosomes, with particular emphasis on their structural features, biosynthesis pathways, production techniques and potential clinical applications." ]

[ "CCR4, an evolutionarily conserved member of the CCR4-NOT complex, is the main cytoplasmic deadenylase. It contains a C-terminal nuclease domain with homology to the endonuclease-exonuclease-phosphatase (EEP) family of enzymes. We have determined the high-resolution three-dimensional structure of the nuclease domain of CNOT6L, a human homologue of CCR4, by X-ray crystallography using the single-wavelength anomalous dispersion method. This first structure of a deadenylase belonging to the EEP family adopts a complete alpha/beta sandwich fold typical of hydrolases with highly conserved active site residues similar to APE1. The active site of CNOT6L should recognize the RNA substrate through its negatively charged surface. In vitro deadenylase assays confirm the critical active site residues and show that the nuclease domain of CNOT6L exhibits full Mg(2+)-dependent deadenylase activity with strict poly(A) RNA substrate specificity. To understand the structural basis for poly(A) RNA substrate binding, crystal structures of the CNOT6L nuclease domain have also been determined in complex with AMP and poly(A) DNA. The resulting structures suggest a molecular deadenylase mechanism involving a pentacovalent phosphate transition.", "Plantar fascia (PF) disorders commonly cause heel pain and disability in the general population. Imaging is often required to confirm diagnosis. This review article aims to provide simple and systematic guidelines for imaging assessment of PF disease, focussing on key findings detectable on plain radiography, ultrasound and magnetic resonance imaging (MRI). Sonographic characteristics of plantar fasciitis include PF thickening, loss of fibrillar structure, perifascial collections, calcifications and hyperaemia on Doppler imaging. Thickening and signal changes in the PF as well as oedema of adjacent soft tissues and bone marrow can be assessed on MRI. Radiographic findings of plantar fasciitis include PF thickening, cortical irregularities and abnormalities in the fat pad located deep below the PF. Plantar fibromatosis appears as well-demarcated, nodular thickenings that are iso-hypoechoic on ultrasound and show low-signal intensity on MRI. PF tears present with partial or complete fibre interruption on both ultrasound and MRI. Imaging description of further PF disorders, including xanthoma, diabetic fascial disease, foreign-body reactions and plantar infections, is detailed in the main text. Ultrasound and MRI should be considered as first- and second-line modalities for assessment of PF disorders, respectively. Indirect findings of PF disease can be ruled out on plain radiography. Teaching Points • PF disorders commonly cause heel pain and disability in the general population.• Imaging is often required to confirm diagnosis or reveal concomitant injuries.• Ultrasound and MRI respectively represent the first- and second-line modalities for diagnosis.• Indirect findings of PF disease can be ruled out on plain radiography.", "Nemaline myopathy and myofibrillar myopathy are heterogeneous myopathies that both comprise early-onset forms. We present two sisters from a consanguineous Iraqi Kurdish family with predominant axial and limb girdle weakness. Muscle biopsies showed features of both nemaline myopathy and myofibrillar myopathy. We performed homozygosity mapping in both siblings using an Affymetrix 250K Nspl SNP array. One of the overlapping homozygous regions harbored the gene CFL2. Because a mutation in CFL2 was identified in a family with nemaline myopathy, we performed sequence analysis of the gene and a novel homozygous missense mutation in exon 2 (c.19G>A, p.Val7Met) of CFL2 was identified in both siblings. CFL2 encodes the protein cofilin-2, which plays an important role in regulation of sarcomeric actin filaments. To our knowledge, this is the second family in which a mutation in CFL2 causes an autosomal recessive form of congenital myopathy with features of both nemaline and myofibrillar myopathy. Given the clinical variability and the multitude of histological features of congenital myopathies, CFL2 sequence analysis should be considered in patients presenting with an autosomal recessive form of congenital myopathy.", "Addition of wortmannin to normal rat kidney cells caused a redistribution of the lysosomal type I integral membrane proteins Igp110 and Igp120 to a swollen vacuolar compartment. This compartment did not contain the cation independent mannose 6-phosphate receptor and was depleted in acid hydrolases. It was distinct from another swollen vacuolar compartment containing the cation independent mannose 6-phosphate receptor. The swollen Igp110-positive compartment was accessible to a monoclonal antibody against Igp120 added extracellularly, showing that it had the characteristics of an endosomal compartment. Wortmannin had no gross morphological effect on the trans-Golgi network or lysosomes nor any effect on the delivery to the trans-Golgi network of endocytosed antibodies against the type I membrane protein TGN38. We propose that the observed effects of wortmannin were due to inhibition of membrane traffic between cation independent mannose 6-phosphate receptor-positive late endosomes and the trans-Golgi network and to inhibition of membrane traffic between a novel Igp120-positive, cation independent mannose 6-phosphate receptor-negative late endosomal compartment and lysosomes. The effects of wortmannin suggest a function for a phosphatidylinositol 3-kinase(s) in regulating membrane traffic in the late endocytic pathway.", "Rational peptide design and large-scale prediction of peptide structure from sequence remain a challenge for chemical biologists. We present PEP-FOLD, an online service, aimed at de novo modelling of 3D conformations for peptides between 9 and 25 amino acids in aqueous solution. Using a hidden Markov model-derived structural alphabet (SA) of 27 four-residue letters, PEP-FOLD first predicts the SA letter profiles from the amino acid sequence and then assembles the predicted fragments by a greedy procedure driven by a modified version of the OPEP coarse-grained force field. Starting from an amino acid sequence, PEP-FOLD performs series of 50 simulations and returns the most representative conformations identified in terms of energy and population. Using a benchmark of 25 peptides with 9-23 amino acids, and considering the reproducibility of the runs, we find that, on average, PEP-FOLD locates lowest energy conformations differing by 2.6 A Calpha root mean square deviation from the full NMR structures. PEP-FOLD can be accessed at http://bioserv.rpbs.univ-paris-diderot.fr/PEP-FOLD.", "A central goal of evolutionary biology is to understand the genetic origin of morphological novelties-i.e. anatomical structures unique to a taxonomic group. Elaboration of morphology during development depends on networks of regulatory genes that activate patterned gene expression through transcriptional enhancer regions. We summarize recent case studies and genome-wide investigations that have uncovered diverse mechanisms though which new enhancers arise. We also discuss how these enhancer-originating mechanisms have clarified the history of genetic networks underlying diversification of genital structures in flies, limbs and neural crest in chordates, and plant leaves. These studies have identified enhancers that were pivotal for morphological divergence and highlighted how novel genetic networks shaping form emerged from pre-existing ones.", "The androgen receptor (AR) is a key factor that regulates the behavior and fate of prostate cancer cells. The AR-regulated network is activated when AR binds enhancer elements and modulates specific enhancer-promoter looping. Kallikrein-related peptidase 3 (KLK3), which codes for prostate-specific antigen (PSA), is a well-known AR-regulated gene and its upstream enhancers produce bidirectional enhancer RNAs (eRNAs), termed KLK3e. Here, we demonstrate that KLK3e facilitates the spatial interaction of the KLK3 enhancer and the KLK2 promoter and enhances long-distance KLK2 transcriptional activation. KLK3e carries the core enhancer element derived from the androgen response element III (ARE III), which is required for the interaction of AR and Mediator 1 (Med1). Furthermore, we show that KLK3e processes RNA-dependent enhancer activity depending on the integrity of core enhancer elements. The transcription of KLK3e was detectable and its expression is significantly correlated with KLK3 (R(2) = 0.6213, P < 5 × 10(-11)) and KLK2 (R(2) = 0.5893, P < 5 × 10(-10)) in human prostate tissues. Interestingly, RNAi silencing of KLK3e resulted in a modest negative effect on prostate cancer cell proliferation. Accordingly, we report that an androgen-induced eRNA scaffolds the AR-associated protein complex that modulates chromosomal architecture and selectively enhances AR-dependent gene expression." ]

[ "Progressive accumulation of amyloid-β peptide (Aβ) in the brain is implicated as the central event in the development of Alzheimer's disease (AD). It is thought that extracellular Aβ triggers toxic signals leading to neurodegeneration. The events downstream of Aβ however are not entirely clear. Clusterin (Apo J) is one of the major risk factors for sporadic form of AD. Clusterin binds to Aβ and prevents Aβ aggregation. In addition, clusterin promotes Aβ degradation and accelerates Aβ clearance from the brain. Clusterin thus protects neurons from Aβ and loss of clusterin level in the brain is implicated as promoting AD pathology. In this study, we found that the level of clusterin protein but not mRNA is reduced in the brains of 3xTg-AD mice. When rat hippocampal primary neurons were treated with Aβ1-42, level of clusterin protein but not mRNA was downregulated. Aβ1-42-induced downregulation of clusterin was blocked by lysosome inhibitors bafilomycin A1 and ammonium chloride. In neurons, Aβ1-42 induced expression of sortilin, a lysosomal sorting protein that targets proteins to lysosome for degradation. In BE(2) M17 human neuroblastoma cells, clusterin bound to sortilin and when sortilin expression was silenced, Aβ1-42-induced clusterin downregulation was almost completely blocked. Our data demonstrate that in neurons, Aβ1-42 promotes lysosomal degradation of clusterin by inducing expression of sortilin and provide a novel mechanism by which Aβ promotes AD pathogenesis.", "The present study determined the changes in appetite and appetite-regulating gut hormones during and following bouts of both rope skipping exercise (weight-bearing) and bicycle ergometer exercise (non-weight-bearing). After a 12-h fast, 15 young men (mean ± SD, age 24.4 ± 1.7 yrs, maximal oxygen uptake 47.0 ± 6.5 mL/kg/min) participated in three 160 min trials: (1) rope skipping exercise (295 ± 40 kcal, 3 sets × 10 min with 5-min interval, then rested for 120 min); (2) bicycle ergometer exercise (288 ± 36 kcal, 3 sets × 10 min with 5-min interval, then rested for 120 min); (3) control (rested for 160 min). Ratings of perceived hunger and acylated ghrelin were suppressed and total peptide YY (PYY) were increased during and immediately after exercise in both exercise trials, but glucagon liked peptide-1 was not changed. Furthermore, suppressed hunger during rope skipping exercise was greater than that during bicycle ergometer exercise, but there were no differences in acylated ghrelin and total PYY. These results indicate that weight-bearing exercise has a greater exercise-induced appetite suppressive effect compared with non-weight-bearing exercise, and both forms of exercise lowered acylated ghrelin and increased total PYY, but the changes did not differ significantly between exercise modes.", "Because advances in therapy have increased long-term survival for women with cervical cancer, it is important to study the risk of secondary primary malignancies in high-dose organ areas. From the 1973-2009 National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program, we studied the risk of developing cancer of the colon and rectum in 64,507 cervical cancer patients over 35 years after initial radiation treatment. We also assessed change in risk over time. Kaplan-Meier estimator for survival curve and Cox proportional hazards models was used. More than half (52.6%) of the cervical cancer patients received radiation treatment. In the analyses adjusted for race/ethnicity, age, marital status, surgery status, stage and grade, the risk of colon cancer between those both with and without XRT diverged beginning at approximately 8 years. After 8 years, the hazard ratio for developing colon cancer was 2.00 (95% CI 1.43-2.80) for women with radiation versus those without radiation treatment. The risk of rectal cancer diverged after 15 years of follow-up (HR 4.04, 95% CI 2.08-7.86). After 35 years of follow-up, the absolute risk of developing colon cancer was 6.5% for those who received radiation versus 2.5% for those without, and 3.7 versus 0.8% for rectum. The risk of colon and rectum cancer over 20 years of follow-up after radiation remained the same across three eras (1973-1980, 1981-1990, and 1991-2000). Radiation-induced second cancers of the colon and rectum may occur 8 years after radiation treatment for cervical cancer.", "In mammals, most of the selenium contained in the body is present as an unusual amino acid, selenocysteine (Sec), whose codon is UGA. Because the UGA codon is typically recognized as a translation stop signal, it is intriguing how a cell recognizes and distinguishes a UGA Sec codon from a UGA stop codon. For eukaryotic selenoprotein mRNAs, it has been proposed that a conserved stem-loop structure designated the Sec insertion sequence (SECIS) in the 3'-untranslated (3'-UTR) region is required for recognition of UGA as a Sec codon. Some proteins which bind to SECIS (SBP) have been reported. However, it is not clear how the SECIS element in the 3'-UTR can mediate Sec insertion far at the in-frame UGA Sec codons. The idea that there must be a signal near the UGA Sec codon is still considered. Therefore, we searched for a protein which binds to an RNA sequence surrounding the UGA Sec codon on human glutathione peroxidase (GPx) mRNA. We found a protein which strongly bound to the RNA fragment upstream of the UGA Sec codon. However, this protein did not bind to the RNA sequence downstream of the UGA codon. This protein also bound to the SECIS sequence in the 3'-UTR of human GPx, and this binding to SECIS was competed with the RNA fragment upstream of the UGA Sec codon. Comparison of the RNA fragment with the SECIS fragment identified the conserved regions, which appeared in the region upstream of the in-frame UGA Sec codon of Se-protein mRNAs. Thus, this study proposes a novel model to understand the mechanisms of Sec incorporation at the UGA Sec codon, especially the regions upstream of the UGA codon of mRNAs of mammalian selenoproteins. This model explains that the stem-loop structure covering the UGA codon is recognized by SBP and how the UGA Sec codon escapes from attack by eRF of the peptide releasing factor.", "Protamines are nuclear proteins which are specifically expressed in haploid male germ cells. Their replacement of histones and binding to DNA is followed by chromatin hypercondensation that protects DNA from negative influences by environmental factors. Mammalian sperm contain two types of protamines: PRM1 and PRM2. While the proportion of the two protamines is highly variable between different species, abnormal ratios within a species are known to be associated with male subfertility. Therefore, it is more than likely that correct protamine expression represents a kind of chromatin checkpoint during sperm development rendering protamines as suitable biomarkers for the estimation of sperm quality. This review presents an overview of our current knowledge on protamines comparing gene and protein structures between different mammalian species with particular consideration given to man, mouse and stallion. At last, recent insights into the possible role of inherited sperm histones for early embryo development are provided.", "Meningioangiomatosis is a rare, benign, developmental, or hamartomatous lesion which may involve the leptomeninges and underlying brain parenchyma. Histologically, meningioangiomatosis is marked by a proliferation of blood vessels in the parenchyma, rimmed by collars of spindled meningothelial cells. There are anecdotal reports of an association of meningioangiomatosis with focal cortical dysplasia. We retrospectively analyzed the clinical, histopathologic, and treatment outcomes of 16 patients with a diagnosis of meningioangiomatosis, specifically investigating these cases for evidence of adjacent focal cortical dysplasia. Patients ranged in age from 1 to 34 years (median 18), 12 of whom had medically-intractable epilepsy as their presenting symptom. No patients in this study had a confirmed diagnosis of neurofibromatosis type II. Four patients (25%) were found to have fibrous meningiomas associated with the meningioangiomatosis. Ten of the 12 patients (83%) who had adequate tissue excised adjacent to the meningioangiomatosis demonstrated evidence of focal cortical dysplasia, with 6 of those (60%) classified as Palmini type IA, and 4 patients (40%) classified as Palmini type IIA. Seven of the patients (44%) had no post-operative seizures, and were off anti-epileptic drugs, while 2 patients relapsed, and required pharmacologic treatment for seizure control. This study therefore presents evidence to support inclusion of meningioangiomatosis as a focal cortical dysplasia-associated entity, as suggested by the ILAE classification (type IIIc). As focal cortical dysplasia is a developmental malformation, its association with meningioangiomatosis supports a developmental etiology of sporadic meningioangiomatosis.", "INTRODUCTION: Advanced understanding of the pathogenesis of renal cell carcinoma (RCC) has led to development and approval of several molecularly targeted therapies since 2005. Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. In the randomized Phase III AXIS trial, axitinib significantly prolonged progression-free survival compared with sorafenib, respectively (6.7 vs 4.7 months; p < 0.0001), and improved objective response rate (19 vs 9%; p = 0.0001), resulting in its approval for advanced or metastatic RCC after failure of one systemic therapy. However, overall survival was similar with axitinib and sorafenib. Common adverse events associated with axitinib include diarrhea, hypertension and fatigue.AREAS COVERED: The properties, clinical efficacy, adverse events, pharmacokinetics and pharmacodynamics of axitinib are summarized and its position in the overall therapeutic landscape for metastatic RCC among several targeted therapies is described.EXPERT OPINION: Axitinib is generally well-tolerated and provides definitive clinical benefits in patients with advanced or metastatic RCC as second-line therapy. However, as with other tyrosine kinase inhibitors of the same class, axitinib does not prolong overall survival; therefore, selection of second-line tyrosine kinase inhibitor therapy, including axitinib, must be carefully considered to maximize outcomes for each patient." ]

[ "BACKGROUND: Calcific aortic valve disease is characterized by an abnormal mineralization of the aortic valve. Osteogenic activity in the aortic valve is under the control of NOTCH1, which regulates the expression of key pro-osteogenic genes such as RUNX2 and BMP2. Long noncoding RNAs (lncRNAs) may reprogram cells by altering the gene expression pattern.METHODS: Multidimensional genomic profiling was performed in human aortic valves to document the expression of lncRNAs and the DNA methylation pattern in calcific aortic valve disease. In-depth functional assays were carried out to document the impact of lncRNA on the mineralization of the aortic valve.RESULTS: We documented that lncRNA H19 (H19) was increased in calcific aortic valve disease. Hypomethylation of the promoter region was observed in mineralized aortic valves and was inversely associated with H19 expression. Knockdown and overexpression experiments showed that H19 induces a strong osteogenic phenotype by altering the NOTCH1 pathway. Gene promoter analyses showed that H19 silenced NOTCH1 by preventing the recruitment of p53 to its promoter. A knockdown of H19 in valve interstitial cells (VICs) increased the expression of NOTCH1 and decreased the level of RUNX2 and BMP2, 2 downstream targets repressed by NOTCH1. In rescue experiments, the transfection of a vector encoding for the active Notch intracellular domain prevented H19-induced mineralization of valve interstitial cells.CONCLUSIONS: These findings indicate that a dysregulation of DNA methylation in the promoter of H19 during calcific aortic valve disease is associated with a higher expression of this lncRNA, which promotes an osteogenic program by interfering with the expression of NOTCH1.", "Nemaline myopathy (NM) is the most common congenital myopathy and is caused by mutations in various genes including NEB (nebulin), TPM2 (beta-tropomyosin), TPM3 (gamma-tropomyosin), and ACTA1 (skeletal alpha-actin). 20-25% of NM cases carry ACTA1 defects and these particular mutations usually induce substitutions of single residues in the actin protein. Despite increasing clinical and scientific interest, the contractile consequences of these subtle amino acid substitutions remain obscure. To decipher them, in the present study, we originally recorded and analysed the mechanics as well as the X-ray diffraction patterns of human membrane-permeabilized single muscle fibres with a particular peptide substitution in actin, i.e. p.Phe352Ser. Results unravelled an unexpected cascade of molecular and cellular events. During contraction, p.Phe352Ser greatly enhances the strain of individual cross-bridges. Paradoxically, p.Phe352Ser also slightly lowers the number of cross-bridges by altering the rate of myosin head attachment to actin monomers. Overall, at the cell level, these divergent mechanisms conduct to an improved steady-state force production. Such results provide new surprising scientific insights and crucial information for future therapeutic strategies.", "The DNA replication (or origin) licensing system ensures precise duplication of the genome in each cell cycle and is a powerful regulator of cell proliferation in metazoa. Studies in yeast, Drosophila melanogaster and Xenopus laevis have characterised the molecular machinery that constitutes the licensing system, but it remains to be determined how this important evolutionary conserved pathway is regulated in Homo sapiens. We have investigated regulation of the origin licensing factors Cdc6, Cdt1, Mcm2 and Geminin in human somatic and germ cells. Cdc6 and Cdt1 play an essential role in DNA replication initiation by loading the Mcm2-7 complex, which is required for unwinding the DNA helix, onto chromosomal origins. Geminin is a repressor of origin licensing that blocks Mcm2-7 loading onto origins. Our studies demonstrate that Cdc6, Cdt1 and Mcm2 play a central role in coordinating growth during the proliferation-differentiation switch in somatic self-renewing systems and that Cdc6 expression is rate-limiting for acquisition of replication competence in primary oocytes. In striking contrast, we show that proliferation control during male gametogenesis is not linked to Cdc6 or Mcm2, but appears to be coordinated by the negative regulator Geminin with Cdt1 becoming rate-limiting in late prophase. Our data demonstrate a striking sexual dimorphism in the mechanisms repressing origin licensing and preventing untimely DNA synthesis during meiosis I, implicating a pivotal role for Geminin in maintaining integrity of the male germline genome.", "PURPOSE: To develop polymeric films containing dual combinations of anti-HIV drug candidate tenofovir, maraviroc and dapivirine for vaginal application as topical microbicides.METHODS: A solvent casting method was used to manufacture the films. Solid phase solubility was used to identify potential polymers for use in the film formulation. Physical and chemical properties (such as water content, puncture strength and in vitro release) and product stability were determined. The bioactivity of the film products against HIV was assessed using the TZM-bl assay and a cervical explant model.RESULTS: Polymers identified from the solid phase solubility study maintained tenofovir and maraviroc in an amorphous state and prevented drug crystallization. Three combination film products were developed using cellulose polymers and polyvinyl alcohol. The residual water content in all films was <10% (w/w). All films delivered the active agents with release of >50% of film drug content within 30 min. Stability testing confirmed that the combination film products were stable for 12 months at ambient temperature and 6 months under stressed conditions. Antiviral activity was confirmed in TZM-bl and cervical explant models.CONCLUSIONS: Polymeric films can be used as a stable dosage form for the delivery of antiretroviral combinations as microbicides.", "Crocus sativus, commonly known as saffron or Kesar, is used in Ayurveda and other folk medicines for various purposes as an aphrodisiac, antispasmodic, and expectorant. Previous evidence suggested that Crocus sativus is linked to improving cognitive function in Alzheimer's disease (AD) patients. The aim of this study was to in vitro and in vivo investigate the mechanism(s) by which Crocus sativus exerts its positive effect against AD. The effect of Crocus sativus extract on Aβ load and related toxicity was evaluated. In vitro results showed that Crocus sativus extract increases the tightness of a cell-based blood-brain barrier (BBB) model and enhances transport of Aβ. Further in vivo studies confirmed the effect of Crocus sativus extract (50 mg/kg/day, added to mice diet) on the BBB tightness and function that was associated with reduced Aβ load and related pathological changes in 5XFAD mice used as an AD model. Reduced Aβ load could be explained, at least in part, by Crocus sativus extract effect to enhance Aβ clearance pathways including BBB clearance, enzymatic degradation and ApoE clearance pathway. Furthermore, Crocus sativus extract upregulated synaptic proteins and reduced neuroinflammation associated with Aβ pathology in the brains of 5XFAD mice. Crocin, a major active constituent of Crocus sativus and known for its antioxidant and anti-inflammatory effect, was also tested separately in vivo in 5XFAD mice. Crocin (10 mg/kg/day) was able to reduce Aβ load but to a lesser extent when compared to Crocus sativus extract. Collectively, findings from this study support the positive effect of Crocus sativus against AD by reducing Aβ pathological manifestations.", "OBJECTIVE: To investigate the influence of occupational stress on salivary cortisol concentration in employees.METHODS: In September 2014, occupational stress evaluation was performed for 186 employees in a solar photovoltaic company, and enzyme-linked immunosorbent assay was used to measure the salivary cortisol concentration.RESULTS: The salivary cortisol concentration showed no significant differences between groups with different demographic features(P>0.05). The group with a high score of job control had a significantly lower salivary cortisol concentration than that with a low score(74.62±15.34 μg/L vs 79.95±12.99 μg/L, P<0.05). The groups with high scores of job danger and job responsibility and burden had significantly higher salivary cortisol concentrations than those with low scores(80.29±9.45 μg/L vs 75.60±16.41, P<0.05; 80.94±10.87 μg/L vs 74.05±16.35 μg/L, P<0.05). The salivary cortisol concentration was positively correlated with the scores of job danger and job responsibility and burden(r=0.176 and 0.252, P<0.05) and negatively correlated with the score of job control(r=-0.208, P<0.05).CONCLUSION: Salivary cortisol concentration is positively correlated with occupational stress and increases with the increasing degree of occupational stress, and can be used as an objective biomarker for the identification and evaluation of occupational stress.", "The hepatic expression of the cell death-inducing DNA fragmentation factor A-like effector family (CIDEA, CIDEB, and CIDEC) genes is markedly upregulated in mouse models of obesity. We evaluated the expression of CIDE genes in liver of obese human subjects undergoing gastric bypass surgery (GBS), at the time of surgery and again 1 year later when subjects had lost 37.6 +/- 1.4% of their initial body weight. At the time of GBS, the expression of CIDEA (r(2) = 0.20, P = 0.04) and CIDEC (r(2) = 0.32, P = 0.01) was strongly correlated with BMI, whereas CIDEB was not (r(2) = 0.01, P = 0.81). One year after surgery, CIDEC expression had declined over 60% (P = 0.02), whereas CIDEA expression did not change (P = 0.20). These data demonstrate that, consistent with previous studies conducted in rodents, hepatic expression of CIDEA and CIDEC, but not CIDEB, is increased in obese humans. Moreover, the hepatic expression of CIDEC is downregulated by marked weight loss." ]

[ "Crocus sativus, commonly known as saffron or Kesar, is used in Ayurveda and other folk medicines for various purposes as an aphrodisiac, antispasmodic, and expectorant. Previous evidence suggested that Crocus sativus is linked to improving cognitive function in Alzheimer's disease (AD) patients. The aim of this study was to in vitro and in vivo investigate the mechanism(s) by which Crocus sativus exerts its positive effect against AD. The effect of Crocus sativus extract on Aβ load and related toxicity was evaluated. In vitro results showed that Crocus sativus extract increases the tightness of a cell-based blood-brain barrier (BBB) model and enhances transport of Aβ. Further in vivo studies confirmed the effect of Crocus sativus extract (50 mg/kg/day, added to mice diet) on the BBB tightness and function that was associated with reduced Aβ load and related pathological changes in 5XFAD mice used as an AD model. Reduced Aβ load could be explained, at least in part, by Crocus sativus extract effect to enhance Aβ clearance pathways including BBB clearance, enzymatic degradation and ApoE clearance pathway. Furthermore, Crocus sativus extract upregulated synaptic proteins and reduced neuroinflammation associated with Aβ pathology in the brains of 5XFAD mice. Crocin, a major active constituent of Crocus sativus and known for its antioxidant and anti-inflammatory effect, was also tested separately in vivo in 5XFAD mice. Crocin (10 mg/kg/day) was able to reduce Aβ load but to a lesser extent when compared to Crocus sativus extract. Collectively, findings from this study support the positive effect of Crocus sativus against AD by reducing Aβ pathological manifestations.", "The dynamin-related protein Opa1 is localized to the mitochondrial intermembrane space, where it facilitates fusion between mitochondria. Apoptosis causes Opa1 release into the cytosol and causes mitochondria to fragment. Loss of mitochondrial membrane potential also causes mitochondrial fragmentation but not Opa1 release into the cytosol. Both conditions induce the proteolytic cleavage of Opa1, suggesting that mitochondrial fragmentation is triggered by Opa1 inactivation. The opposite effect was observed with knockdown of the mitochondrial intermembrane space protease Yme1. Knockdown of Yme1 prevents the constitutive cleavage of a subset of Opa1 splice variants but does not affect carbonyl cyanide m-chlorophenyl hydrazone or apoptosis-induced cleavage. Knockdown of Yme1 also increases mitochondrial connectivity, but this effect is independent of Opa1 because it also occurs in Opa1 knockdown cells. We conclude that Yme1 constitutively regulates a subset of Opa1 isoforms and an unknown mitochondrial morphology protein, whereas the loss of membrane potential induces the further proteolysis of Opa1.", "We have investigated the molecular basis of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency in a patient who presented with the Lesch-Nyhan syndrome. A catalytically incompetent form of HPRT has been isolated from this patient's erythrocytes and lymphoblasts. This enzyme variant, which we have termed HPRTKinston, is indistinguishable from the normal enzyme in terms of its intracellular concentration and maximal velocity, but differs with respect to its isoelectric point (more basic) and Michaelis constants for both substrates (markedly elevated). The tryptic peptides of HPRTKinston were mapped by reverse-phase high pressure liquid chromatography in an attempt to define the precise abnormality in its primary structure. Sequence analysis of the single aberrant tryptic peptide in HPRTKinston revealed an aspartic acid to asparagine amino acid substitution at position 193. Electrophoretic analysis of the CNBr peptides of HPRTKinston confirmed the location of the proposed mutation. This amino acid substitution can be explained by a single nucleotide change in the codon for aspartic acid 193 (GAC leads to AAC). This is the first specific mutation described at the molecular level in a patient with the Lesch-Nyhan syndrome.", "Several key transcription factors and coregulators important to peripheral nerve myelination have been identified, but the contributions of specific chromatin remodeling complexes to peripheral nerve myelination have not been analyzed. Chromodomain helicase DNA-binding protein 4 (Chd4) is the core catalytic subunit of the nucleosome remodeling and deacetylase (NuRD) chromatin remodeling complex. Previous studies have shown Chd4 interacts with Nab (NGFI-A/Egr-binding) corepressors, which are required for early growth response 2 (Egr2/Krox20), to direct peripheral nerve myelination by Schwann cells. In this study, we examined the developmental importance of the NuRD complex in peripheral nerve myelination through the generation of conditional Chd4 knock-out mice in Schwann cells (Chd4(loxP/loxP); P0-cre). Chd4 conditional null mice were found to have delayed myelination, radial sorting defects, hypomyelination, and the persistence of promyelinating Schwann cells. Loss of Chd4 leads to elevated expression of immature Schwann cell genes (Id2, c-Jun, and p75), and sustained expression of the promyelinating Schwann cell gene, Oct6/Scip, without affecting the levels of Egr2/Krox20. Furthermore, Schwann cell proliferation is upregulated in Chd4-null sciatic nerve. In vivo chromatin immunoprecipitation studies reveal recruitment of Chd4 and another NuRD component, Mta2, to genes that are positively and negatively regulated by Egr2 during myelination. Together, these results underscore the necessity of Chd4 function to guide proper terminal differentiation of Schwann cells and implicate the NuRD chromatin remodeling complex as a requisite factor in timely and stable peripheral nerve myelination.", "BACKGROUND: Carcinosarcomas of the gynecologic tract, also known as malignant mixed Müllerian tumors, are aggressive neoplasms with a high recurrence rate and poor prognosis. Despite advances in adjuvant therapies in recent years, the prognosis of these tumors has not improved. In fact, there are currently no consensus guidelines for the treatment of these neoplasms and the search for targetable biomarkers has not been successful so far. Programmed death-ligand 1 (PD-L1) has emerged as a potential target for therapeutics in a number of malignant tumors, including melanoma, lung, and colorectal cancer. In normal conditions, PD-L1 is thought to promote immune homeostasis via a number of pathways, but mainly through downregulation of cytotoxic T cells. In some human neoplasms, however, overexpression of PD-L1 by tumor cells has been observed, which can modulate the immune system to allow cancer cells to evade host response. As this marker could potentially be a therapeutic target for these tumors, the immunohistochemical expression of PD-L1 in a group of carcinosarcomas was evaluated in the present study.MATERIAL AND METHODS: Twenty-nine cases of gynecologic carcinosarcomas were analyzed, corresponding to tumors originating from the uterus (25), ovary (2), fallopian tube (1), and pelvic epithelium (1). Immunohistochemistry for PD-L1 was performed on paraffin sections and the staining results were assessed semiquantitatively in both epithelial and mesenchymal components of each tumor.RESULTS: Positive membranous staining for PD-L1 was detected in 25/29 tumors (86%). The epithelial components were strongly positive in 19/29 (65%) and weakly positive in 6/29 tumors (21%). The mesenchymal elements were strongly positive in 8/29 (27%) and weakly positive in 3/29 tumors (10%). With exception of 1, all tumors with positive sarcomatous components had staining of the carcinomatous element. Four tumors were negative for PD-L1 in both components.CONCLUSIONS: This study shows that PD-L1 is expressed by the majority of carcinosarcomas, predominantly in the epithelial components. This is particularly important as most locoregional recurrences and distant metastases are of epithelial origin. This finding may serve as a basis for possible therapeutic approaches using antibodies that have already shown significant value in a number of other malignant tumors.", "BACKGROUND: Current chemotherapy in platinum-resistant ovarian cancer patients has demonstrated minimal to no improvements in survival. Despite the lack of benefit, significant resources are utilized with such therapies. Therefore, the objective in the current study was to assess the cost-effectiveness of salvage chemotherapy for patients with platinum-resistant epithelial ovarian cancer (EOC).METHODS: A decision analysis model evaluated a hypothetical cohort of 4000 platinum-resistant patients with recurrent EOC. Several chemotherapy strategies were analyzed: 1) best supportive care (BSC); 2) second-line chemotherapy-monotherapy; 3) second-line chemotherapy-combination therapy; 4) third-line chemotherapy after disease progression on second-line monotherapy; and 5) third-line chemotherapy after disease progression on second-line combination therapy. Sensitivity analyses were performed on all pertinent uncertainties.RESULTS: Using costs alone, BSC was the only definitive cost-effective treatment for platinum-resistant recurrent ovarian cancer patients, and second-line monotherapy was a reasonable cost-effective strategy with an incremental cost-effectiveness ratio (ICER) of 64,104 dollars. The cost-effectiveness ranged from 4,065 dollars per month of overall survival (OS) for BSC to 12,927 dollars for third-line previous combination therapy. Compared with BSC, second-line monotherapy gained an additional 3 months of OS, with a cost-effectiveness of 4,703 dollars per month of OS. Second-line combination therapy and third-line therapies exhibited unfavorable ICER.CONCLUSIONS: The current decision analysis was intended to be thought-provoking and bring awareness to the high costs of subsequent chemotherapy with limited effectiveness in patients with recurrent platinum-resistant EOC. Although actual patients may receive multiple lines of chemotherapy, from the perspective of costs alone this model using a hypothetical cohort demonstrated that best supportive care was the only cost-effective strategy, with second-line monotherapy appearing to be a reasonable cost-effective strategy given current chemotherapeutic options.", "AIM: Chromodomain helicase DNA-binding protein 5 (CHD5) plays a role in normal neural development and in tumorigenesis of various human cancers. However, its role in primary gallbladder carcinoma (PGC) is still unclear. The aim of this study was to investigate CHD5 expression in PGC and its clinical significance.METHODS: CHD5 mRNA and protein expression in 120 PGC and 20 normal gallbladder specimens was determined by quantitative reverse transcription-polymerase chain reaction (QRT-PCR) and Western blotting analysis, respectively.RESULTS: The expression levels of CHD5 mRNA and protein in PGC tissues were both significantly lower than those in the normal epithelium of the gallbladder (mRNA: P = 0.006; protein: P = 0.01). CHD5 mRNA expression was closely correlated with its protein expression (r = 0.8; P < 0.001). Additionally, the low expression of CHD5 protein was significantly associated with high pathologic T stage (P = 0.01) and clinical stage (P = 0.008), and advanced histologic grade (P = 0.009). The expression levels of CHD5 protein in PGC tissues with positive nodal metastasis were also significantly lower than those without (P = 0.01). Survival analysis showed that low CHD5 expression was associated with shorter disease-free (P = 0.01) and overall survival (P = 0.008) compared to those with high CHD5 expression in PGC patients. Furthermore, multivariate analyses showed that the decreased expression of CHD5 was an independent prognostic marker for both unfavorable disease-free (P = 0.01) and overall survival (P = 0.006).CONCLUSION: CHD5 may be involved in carcinogenesis of PGC and its down-regulation may be significantly correlated with unfavorable clinicopathologic features including poor overall and disease-free survival in patients." ]

[ "Author information:(1)From the Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, University of Texas M.D. Anderson Cancer Center, Houston (D.S.H., F.M.-B.); the Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte (M.G.F.), the University of California, San Francisco, San Francisco (P.N.M.), and Amgen, Thousand Oaks (H.H., J.N., G.N., J.K., B.E.H., J.C., J.R.L., G.F.) - all in California; Duke University Medical Center, Durham, NC (J.H.S.); Royal Melbourne Hospital/Peter MacCallum Cancer Centre, Melbourne, VIC (J.D.), Queen Elizabeth Hospital and University of Adelaide, Woodville South, SA (T.J.P.), and Scientia Clinical Research, Randwick, NSW (J.C. Kuo) - all in Australia; the Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis (G.A.D.); Dana-Farber Cancer Institute, Harvard Medical School, Boston (G.I.S.); the Sarah Cannon Research Institute at HealthONE, Denver (G.S.F.); Princess Margaret Cancer Centre, University Health Network, Toronto (A.S.); Fox Chase Cancer Center, Philadelphia (C.S.D.); the University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh, Pittsburgh (T.F.B.); Seoul National University College of Medicine (Y.-J.B.), Samsung Medical Center, Sungkyunkwan University School of Medicine (K.P.), and the Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine (T.W.K.) - all in Seoul, South Korea; Roswell Park Cancer Institute, Buffalo (G.K.D.), and Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York (P.L., B.T.L.) - all in New York; the University of Michigan, Ann Arbor (J.C. Krauss); the Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan (Y.K.); the Department of Medicine, Division of Oncology, University of Washington, Seattle (A.L.C.); Aix Marseille University, Centre National de la Recherche Scientifique, INSERM, Centre de Recherche en Cancérologie de Marseille, Assistance Publique-Hôpitaux de Marseille, Marseille, France (F.B.); Winship Cancer Institute of Emory University, Atlanta (S.S.R.); and the Alvin J. Siteman Cancer Center at Washington University School of Medicine, St. Louis (R.G.).", "OBJECTIVES: To investigate upper urinary tract stone composition rates in Australia To investigate changes in stone composition in Australia over the past 30 yearsPATIENTS AND METHODS: The Institute for Clinical Pathology and Medical Research (ICPMR) database was used to obtain - stone composition statistics from 2009-2011 Historical comparisons of stone composition rates were obtained from previous Australian studies; Rofe; 1981, and Baker; 1993 for epidemiological data from the 1970s and 1980s respectively. Stone composition data was separated into gender and age-groupsRESULTS: From the 791 stones analysed between 2009 and 2011, calcium oxalate remains the dominant type accounting for 64% of stones in our dataset, which compares to 68% from both the 1970s and 1980s. Uric acid stones contributed 16% of contemporary stone compositions, comparable to 16% in the 1970s and 17% in the 1980s. Struvite stones showed a decreasing trend from 14% in the 1970s, to 12% in the 1980s and 7% in the current data. For struvite stones, while the female 21-30 age-group was the most prolific for struvite stone formation in the 1980s, the peak group in contemporaneous records is 61-70 year-old men.CONCLUSION: Stone composition in Australia has remained relatively static over the past 30 years. Modifications in diet and body habitus have not resulted in significant changes in the proportion of uric acid and calcium oxalate stones detected. The decreasing trend in the proportion of struvite stones most likely reflects improved management of urinary tract infections within the Australian population.", "Author information:(1)Department of Medical Oncology, Hematology Section, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar. yassinmoha@gmail.com.(2)Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, Doha, Qatar. yassinmoha@gmail.com.(3)Department of Medical Education, Internal Medicine Section, Hamad Medical Corporation, Doha, Qatar. yassinmoha@gmail.com.(4)Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, Doha, Qatar;. yassinmoha@gmail.com.(5)Clinical Pathology Department, Faculty of Medicine, AlAzhar University, Cairo, Egypt. yassinmoha@gmail.com.", "Chronic myeloid leukemia (CML) is a hematologic malignancy associated with increased circulating myeloid cells and platelets in the peripheral blood, with accompanying bone marrow hyperplasia. The Philadelphia chromosome, t(9;22)(q34;q11), is present in 95% of CML patients, resulting in constitutive tyrosine kinase activity; however, ~5% of CML patients possess a Philadelphia variant. A novel three-way Philadelphia translocation variant, t(9;22;17)(q34;q11.2;q11.2), was identified in a 54-year old man who presented with leukocytosis, anemia and thrombocytosis that was diagnosed with chronic myeloid leukemia, chronic phase. Cytogenetic analysis by G-banding revealed the presence of a three-way translocation involving the long arms of chromosomes 9, 22 and 17. Fluorescence is situ hybridization utilizing a dual-color fusion probe confirmed the presence of the Bcr-Abl fusion gene.", "Chronic myeloid leukemia is a stem cell disease with the presence of Philadelphia chromosome generated through reciprocal translocation of chromosome 9 and 22. The use of first- and second-generation tyrosine kinase inhibitors has been successful to an extent. However, resistance against such drugs is an emerging problem. Apart from several drug-resistant mechanisms, drug influx/efflux ratio appears to be one of the key determinants of therapeutic outcomes. In addition, intracellular accumulation of drug critically depends on cell membrane fluidity and lipid raft dynamics. Previously, we reported two novel cell-penetrating peptides (CPPs), namely, cationic IR15 and anionic SR11 present in tryptic digest of Abrus agglutinin. Here, the potential of IR15 and SR11 to influence intracellular concentration of imatinib has been evaluated. Fluorescent correlation spectroscopy and lifetime imaging were employed to map membrane fluidity and lipid raft distribution following peptide-drug co-administration. Results show that IR15 and SR11 are the two CPPs which can modulate membrane fluidity and lipid raft distribution in K562 cells. Both IR15 and SR11 significantly reduce the viability of CML cells in the presence of imatinib by increasing the intracellular accumulation of the drug.", "PURPOSE: Our objective was to compare open and endovascular aortic aneurysm repair with respect to postoperative delirium.METHODS: After Institutional Ethics Review Board approval, we conducted a retrospective review of all patients who underwent abdominal and thoraco-abdominal aortic aneurysm repair surgery at Toronto General Hospital during June 2006 to December 2007. Patients were classed into either the OPEN or the endovascular (EVAR) group based on the type of surgery and were assessed for the presence of delirium after surgery. The NEECHAM Confusion Scale and the validated chart review instrument were used for diagnosis of delirium. Patients with dementia and/or abnormal levels of consciousness preoperatively were excluded.RESULTS: There were 256 patients included in the study, 149 (58%) in the OPEN group and 107 (42%) in the EVAR group. Patients in the EVAR group were considerably older, 74 (10) yr vs 68 (9) yr, and they had shorter duration of surgery, 150 [119, 180] min vs 200 [165, 260] min, respectively, P < 0.0001. Postoperative delirium was present in 43 (29%) patients in the OPEN group and 14 (13%) patients in the EVAR group (95% confidence interval [CI], 22 to 36 vs 95% CI, 7 to 19, respectively; P = 0.003). Hospital length of stay was 8.3 [6.6, 13.4] days in the OPEN group and 4.5 [3.1, 6.4] days in the EVAR group, P < 0.0001.CONCLUSIONS: Perioperative management of patients undergoing endovascular aortic aneurysm repair was associated with lower rates of delirium after surgery than that of patients undergoing open aortic aneurysm repair.", "BACKGROUND: Prognosis of patients affected by metastatic esophageal-gastric junction (EGJ) or gastric cancer (GC) remains dismal. Trastuzumab, an anti-HER2 monoclonal antibody, is the only targeted agent approved for the first-line treatment of patients with HER2-overexpressing advanced EGJ or GC in combination with chemotherapy. However, patients invariably become resistant during this treatment. We recently identified the overexpression of fibroblast growth factor (FGF) receptor 3 (FGFR3) as a molecular mechanism responsible for trastuzumab resistance in GC models, providing the rationale for the inhibition of this receptor as a potential second-line strategy in this disease. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3.METHODS: The FiGhTeR trial is a phase II, single-arm, open-label study to assess safety and activity of the FGFR inhibitor pemigatinib as second-line treatment strategy in metastatic EGJ/GC patients progressing under trastuzumab-containing therapies. The primary endpoint is the 12-week progression-free survival rate. Plasma and tumor tissue samples will be collected for translational research analyses at baseline, during treatment, and at progression on pemigatinib.DISCUSSION: Co-alterations in genes coding for different tyrosine-kinase receptors are emerging as relevant mechanisms of acquired resistance to anti-HER2 therapeutic strategies in GC. In particular, our group has recently identified that in GC models the overexpression of FGFR3 sustains the acquired resistance to trastuzumab. This trial aims to assess the safety, tolerability and activity of the FGFR inhibitor pemigatinib as a second-line treatment in metastatic EGJ/GC patients refractory to first-line trastuzumab-containing therapies. Furthermore, this study offers the opportunity to prospectively study mechanisms and pathways involved in trastuzumab resistance.PROTOCOL NUMBER: CRC2017_02.EUDRACT NUMBER: 2017-004522-14.", "Cardiovascular disease remains the leading cause of morbidity and mortality in the developed countries. This review summarizes current pre-clinical and clinical evidence for the potential role and mechanisms of action of stem and progenitor cells in vascular and cardiac repair and regeneration. Apart from cell transplantation strategies, approaches to maintain stem cell niche function and targeting mobilization/recruitment of specific stem/progenitor cell populations may aid in preserving vascular and cardiac function. Moreover, with the use of patient-derived induced pluripotent stem cells, the field of regenerative medicine is entering a new era. Potential applications of induced pluripotent stem cells and direct reprogrammed cells as well as recent developments in tissue engineering are discussed.", "Precursor B-cell lymphoblastic lymphomas (B-LBLs) are rare and most often involve the skin in the head and neck region. Histologically, cutaneous B-LBLs may be confused with other small round-cell neoplasms. Moreover, half of B-LBL patients are negative for CD45 (leucocyte common antigen, LCA), a widely used marker for the diagnosis of lymphoma, and a significant portion express CD99, a marker for Ewing's sarcoma (ES) or primitive neuroectodermal tumor (PNET). Therefore, an extranodal B-LBL may be misinterpreted as PNET or ES. Here, we report on 2 boys, aged 10 and 5 years, with primary cutaneous B-LBL of the scalp. PNET was initially misdiagnosed because the tumor cells were negative for CD45 but strongly positive for CD99. Advanced stage of acute lymphoblastic leukemia (ALL) developed later and both patients died during the course of treatment for ALL. In retrospective analyses, tumor cells in the initial biopsy specimens of both patients were found to be reactive to terminal deoxynucleotidyl transferase (TdT), CD43 and CD10. Thus, the diagnosis of B-LBL was confirmed. These cases illustrate the possibility that primary cutaneous B-LBL may mimic ES or PNET immunophenotypically, and that correct diagnosis in doubtful cases may be facilitated by analysis using a complete panel of antibodies, particularly including TdT and CD43.", "People with epilepsy may die unexpectedly without a clear structural or pathologic cause. This condition is called sudden unexpected death in epilepsy (SUDEP), and it accounts for a large proportion of deaths among people with epilepsy. SUDEP incidence rates vary with the cohort studied, ranging from 0.35 per 1,000 person-years of follow-up in population-based studies to 9.3 per 1,000 person-years in patients with refractory epilepsy. Although many studies have been performed, the causes of SUDEP are not understood. However, even without precise knowledge of the underlying pathogenic mechanism(s), SUDEP prevention could start with the identification of the most prominent risk factors. SUDEP seems to occur more commonly during sleep and it preferentially affects young adults with medically intractable epilepsy (especially tonic-clonic seizures), individuals who also have neurologic comorbidity, and patients receiving antiepileptic drug polytherapy. This article reviews the clinical features associated with SUDEP and suggests preventive measures for this condition.", "BACKGROUND/OBJECTIVES: Selenium was thought to have a role in cardiovascular disease (CVD) owing to its antioxidant properties; however, evidence from observational studies and randomized controlled trials (RCTs) has been inconsistent and controversial. We thus conducted a meta-analysis to assess the discrepancies between observational and randomized trial evidence.SUBJECTS/METHODS: We searched MEDLINE and EMBASE for eligible prospective studies regarding the relationship between selenium and CVD up to 15 December 2013 and finally included 16 prospective observational studies and 16 RCTs. Random effects model was used to estimate the pooled relative risk (RR). Generalized least-squares trend test and restricted cubic spline model were performed to assess a linear and a nonlinear dose-response relationship.RESULTS: Our meta-analysis of prospective studies showed a nonlinear relationship of CVD risk with blood selenium concentrations across a range of 30-165 μg/l and a significant benefit of CVD within a narrow selenium range of 55-145 μg/l. Our meta-analyses of RCTs showed that oral selenium supplements (median dose: 200 μg/day) for 2 weeks to 144 months significantly raised the blood selenium concentrations by 56.4 μg/l (95% confidence interval (CI): 40.9, 72.0 μg/l), whereas oral selenium supplements (median: 100 μg/day) for 6 to 114 months caused no effect on CVD (RR=0.91; 95% CI: 0.74, 1.10).CONCLUSIONS: Our meta-analysis in prospective studies demonstrated a significant inverse association between selenium status and CVD risk within a narrow selenium range and a null effect of selenium supplementation on CVD was observed in RCTs. These findings indicate the importance of considering selenium status, dose and safety in health assessment and future study design.", "BACKGROUND: Head injuries in children are responsible for a large number of emergency department visits. Failure to identify a clinically significant intracranial injury in a timely fashion may result in long term neurodisability and death. Whilst cranial computed tomography (CT) provides rapid and definitive identification of intracranial injuries, it is resource intensive and associated with radiation induced cancer. Evidence based head injury clinical decision rules have been derived to aid physicians in identifying patients at risk of having a clinically significant intracranial injury. Three rules have been identified as being of high quality and accuracy: the Canadian Assessment of Tomography for Childhood Head Injury (CATCH) from Canada, the Children's Head Injury Algorithm for the Prediction of Important Clinical Events (CHALICE) from the UK, and the prediction rule for the identification of children at very low risk of clinically important traumatic brain injury developed by the Pediatric Emergency Care Applied Research Network (PECARN) from the USA. This study aims to prospectively validate and compare the performance accuracy of these three clinical decision rules when applied outside the derivation setting.METHODS/DESIGN: This study is a prospective observational study of children aged 0 to less than 18 years presenting to 10 emergency departments within the Paediatric Research in Emergency Departments International Collaborative (PREDICT) research network in Australia and New Zealand after head injuries of any severity. Predictor variables identified in CATCH, CHALICE and PECARN clinical decision rules will be collected. Patients will be managed as per the treating clinicians at the participating hospitals. All patients not undergoing cranial CT will receive a follow up call 14 to 90 days after the injury. Outcome data collected will include results of cranial CTs (if performed) and details of admission, intubation, neurosurgery and death. The performance accuracy of each of the rules will be assessed using rule specific outcomes and inclusion and exclusion criteria.DISCUSSION: This study will allow the simultaneous comparative application and validation of three major paediatric head injury clinical decision rules outside their derivation setting.TRIAL REGISTRATION: The study is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR)- ACTRN12614000463673 (registered 2 May 2014)." ]

[ "BACKGROUND: Recently, several studies have demonstrated that two long non-coding RNAs (lncRNAs), HULC and MALAT1, may participate in hepatocellular carcinoma (HCC) development and progression. However, genetic variations in the two lncRNAs and their associations with HCC susceptibility have not been reported. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) in HULC and MALAT1 may contribute to HCC risk.METHODS: We conducted a case-control study and genotyped two SNPs, rs7763881 in HULC and rs619586 in MALAT1, in 1300 HBV positive HCC patients, 1344 HBV persistent carriers and 1344 subjects with HBV natural clearance to test the associations between the two SNPs and susceptibility to HCC and HBV chronic infection.RESULTS: The variant genotypes of rs7763881 were significantly associated with decreased HCC risk in a dominant genetic model [AC/CC vs. AA: adjusted odds ration (OR)  =  0.81, 95% confidence intervals (CIs)  =  0.68-0.97, P  =  0.022]. Furthermore, the variant genotypes of rs619586 was associated with decreased HCC risk with a borderline significance (AG/GG vs. AA: adjusted OR  =  0.81, 95% CIs  =  0.65-1.01, P  =  0.057). However, no significant association was found between the two SNPs and HBV clearance.CONCLUSIONS: The variant genotypes of rs7763881 in HULC may contribute to decreased susceptibility to HCC in HBV persistent carriers.", "OBJECTIVE: Resistin is a secreted factor that is elevated in rheumatoid arthritis (RA) and believed to drive joint inflammation in vivo. This study was undertaken to determine if resistin is present in the joint following joint injury and to elucidate the role of resistin in cartilage degradation.METHODS: The level of resistin was measured in paired synovial fluid (SF) and serum samples from patients following joint injury (anterior cruciate ligament, ACL or meniscus tear). Localization of resistin was visualized by immunohistochemistry of synovial tissue and cartilage from healthy and OA donors. Mouse and human cartilage cultures were used to assess the effect of resistin on cartilage metabolism.RESULTS: In trauma patients, resistin levels declined with increasing time post injury. The resistin levels were highest in samples collected up to 1 week following traumatic injury (SF: 2980 pg/ml, serum: 7901 pg/ml) and lowest in samples collected 6-26 years post injury (SF: 686 pg/ml, serum: 5682 pg/ml). Resistin was shown to be expressed in macrophage-like cells in both healthy and OA synovial tissue. Treatment of mouse cartilage cultures with recombinant resistin led to a dose dependent loss of proteoglycan and induction of inflammatory cytokine and PGE(2) production. Recombinant resistin inhibited proteoglycan synthesis in human cartilage explants.CONCLUSION: Resistin is elevated both systemically and locally in the weeks immediately following joint injury and has a direct effect on cartilage matrix turnover and cytokine production. Resistin may play a role in the early stages of trauma-induced OA and may represent a new therapeutic target to slow joint destruction in OA.", "Two autologous chimeric antigen receptor (CAR) T cell therapies (Kymriah™ and Yescarta™) were recently approved by the FDA. Kymriah™ is for the treatment of pediatric patients and young adults with refractory or relapse (R/R) B cell precursor acute lymphoblastic leukemia and Yescarta™ is for the treatment of adult patients with R/R large B cell lymphoma. In common, both are CD19-specific CAR T cell therapies lysing CD19-positive targets. Their dramatic efficacy in the short term has been highlighted by many media reports. By contrast, their glaring safety gaps behind the miracles remain much less addressed. Here, we focus on addressing the crucial challenges in relation to the gaps.", "BACKGROUND: The use of imatinib combined with chemotherapy has demonstrated improved outcome in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). However, a substantial proportion of patients continue to die as a result of disease progression.PATIENTS AND METHODS: We assessed the minimal residual disease (MRD)-based effect and long-term outcome of first-line incorporation of dasatinib (100 mg once daily) into chemotherapy alternatively for adults with Ph-positive ALL. The primary end point was the major molecular response (MMR) rate by the end of the second dasatinib cycle. Patients with a donor proceeded to allogeneic stem cell transplantation (SCT) as early as possible. MRD monitoring was centrally evaluated by real-time quantitative polymerase chain reaction (4.5-log sensitivity) using bone marrow samples.RESULTS: Fifty-one patients (median age, 46 years) were enrolled and treated with this strategy. After the first dasatinib cycle, 50 patients (98.0%) achieved complete remission (CR). By the end of the second dasatinib cycle, 46 (93.9%) of 49 assessable patients had persistent CR, and 38 (77.6%) had MMR (32.7%) or undetectable MRD (44.9%). On the basis of the MRD kinetics by this time point, the numbers of early-stable, late, and poor molecular responders were 23 (46.9%), 15 (30.7%), and 11 (22.4%), respectively. Thirty-nine patients (76.5%) underwent allogeneic SCT in CR1. After a median follow-up of 54 months, the 4-year cumulative incidence of relapse and disease-free survival (DFS) rate for all patients were 30.0% and 52.0%, respectively, and the corresponding outcomes among those receiving allogeneic SCT in CR1 were 20.5% and 64.1%, respectively. Poor molecular responders had a higher risk of relapse and DFS than those of early-stable molecular responders.CONCLUSION: This dasatinib-based protocol was effective for achieving a good quality molecular response and durable DFS in adults with Ph-positive ALL.TRIAL REGISTRATION: clinicaltrials.gov, NCT01004497.", "We have recently reported that topoisomerase 1 (Top1) cooperates with ASF/SF2, a splicing factor of the SR family, to prevent unscheduled replication fork arrest and genomic instability in human cells. Our results suggest that Top1 execute this function by suppressing the formation of DNA-RNA hybrids during transcription, these so-called R-loops interfering with the progression of replication forks. Using ChIP-chip, we have shown that γ-H2AX, a marker of DNA damage, accumulates at gene-rich regions of the genome in Top1-deficient cells. This is best illustrated at histone genes, which are highly expressed during S phase and display discrete γ-H2AX peaks on ChIP-chip profiles. Here, we show that these γ-H2AX domains are different from those induced by camptothecin, a Top1 inhibitor inducing double-strand DNA breaks throughout the genome. These data support the view that R-loops promote genomic instability at specific sites by blocking fork progression and inducing chromosome breaks. Whether this type of transcription-dependent fork arrest contributes to the replication stress observed in precancerous lesions is an important question that deserves further attention.", "Alpha thalassemia retardation associated with chromosome16 (ATR-16 syndrome) is defined as a contiguous gene syndrome resulting from haploinsufficiency of the alpha-globin gene cluster and genes involved in mental retardation (MR). To date, only few cases have been described which result from pure monosomy for a deletion of 16p. In most of these cases the deletion was identified by densitometric analysis of Southern blot results or by Fluorescent In Situ Hybridization analysis, and these alterations have not been mapped in detail. In this study, we have fine mapped deletions causing alpha-thalassemia within 2 Mb from the telomere of 16p by multiplex ligation-dependent probe amplification (MLPA). We have developed a rapid and simple test for high resolution mapping of rearrangements involving the tip of the short arm of chromosome 16 by incorporating 62 MLPA probes spaced approximately 10-200 kb over a region of 2 Mb from the telomere. One deletion of approximately 900 kb without MR was identified in addition to three de novo deletions varying between 1.5 and 2 Mb causing ATR-16 in three patients having mild MR and alpha-thalassemia. Two were found by chance to be ATR-16 because they were included in a study to search for telomeric loss in MR and not by hematological analysis. This would plead for more alertness when a persistent microcytic hypochromic anemia at normal ferritin levels is observed as suggestive for the ATR-16 syndrome. The region on chromosome 16p for which haploinsufficiency leads to the dysmorphic features and MR typical for ATR-16, has been narrowed down to a 800 kb region localized between 0.9 and 1.7 Mb from the telomere.", "Proteins are essential to life, and understanding their structure can facilitate a mechanistic understanding of their function. Through an enormous experimental effort1-4, the structures of around 100,000 unique proteins have been determined5, but this represents a small fraction of the billions of known protein sequences6,7. Structural coverage is bottlenecked by the months to years of painstaking effort required to determine a single protein structure. Accurate computational approaches are needed to address this gap and to enable large-scale structural bioinformatics. Predicting the three-dimensional structure that a protein will adopt based solely on its amino acid sequence-the structure prediction component of the 'protein folding problem'8-has been an important open research problem for more than 50 years9. Despite recent progress10-14, existing methods fall far short of atomic accuracy, especially when no homologous structure is available. Here we provide the first computational method that can regularly predict protein structures with atomic accuracy even in cases in which no similar structure is known. We validated an entirely redesigned version of our neural network-based model, AlphaFold, in the challenging 14th Critical Assessment of protein Structure Prediction (CASP14)15, demonstrating accuracy competitive with experimental structures in a majority of cases and greatly outperforming other methods. Underpinning the latest version of AlphaFold is a novel machine learning approach that incorporates physical and biological knowledge about protein structure, leveraging multi-sequence alignments, into the design of the deep learning algorithm." ]

[ "Intensive efforts have been spent to discover therapeutic, non-peptide and orally effective hypertensive drugs. One drug that emerged from this effort is aliskiren, a direct human renin inhibitor that blocks the conversion of angiotensinogen to angiotensin I (Ang I). In contrast to other antihypertensive agents, aliskiren decreases plasma renin activity (PRA). In healthy human subjects, doses of between 40 and 640 mg of aliskiren exert a dose-dependent reduction in PRA and Ang I and Ang II levels. The bioavailability of aliskiren is low (2%), peak plasma concentrations are reached within one to three hours and the binding with plasma proteins achieves approximately 47-51%. Aliskiren is slightly metabolized (20%) by CYP3A4. The most common adverse events include diarrhea, headache, back pain and gastrointestinal disorders. Aliskiren is well tolerated, and may be used alone or in combination with other antihypertensive agents. Aliskiren belongs to a new class of agents that effectively and specifically inhibit the RAS. This drug functions through a novel mechanism of action and has the potential to become a true alternative to angiotensin converting enzyme inhibitors and angiotensin receptor blockers in the therapy of hypertension and other cardiovascular and renal disorders.", "Spinocerebellar ataxia type 3 is a neurodegenerative disorder caused by the expansion of the polyglutamine repeat region within the ataxin-3 protein. The mutant protein forms intracellular aggregates in the brain. However, the cellular mechanisms causing toxicity are still poorly understood and there are currently no effective treatments. In this study we show that administration of a rapamycin ester (cell cycle inhibitor-779, temsirolimus) improves motor performance in a transgenic mouse model of spinocerebellar ataxia type 3. Temsirolimus inhibits mammalian target of rapamycin and hence upregulates protein degradation by autophagy. Temsirolimus reduces the number of aggregates seen in the brains of transgenic mice and decreases levels of cytosolic soluble mutant ataxin-3, while endogenous wild-type protein levels remain unaffected. Temsirolimus is designed for long-term use in patients and therefore represents a possible therapeutic strategy for the treatment of spinocerebellar ataxia type 3. Using this disease model and treatment paradigm, we employed a microarray approach to investigate transcriptional changes that might be important in the pathogenesis of spinocerebellar ataxia type 3. This identified ubiquitin specific peptidase-15, which showed expression changes at both the messenger ribonucleic acid and protein level. Ubiquitin specific peptidase-15 levels were also changed in mice expressing another mutant polyglutamine protein, huntingtin. In total we identified 16 transcripts that were decreased in transgenic ataxin-3 mice that were normalized following temsirolimus treatment. In this mouse model with relatively mild disease progression, the number of transcripts changed was low and the magnitude of these changes was small. However, the importance of these transcriptional alterations in the pathogenesis of spinocerebellar ataxia type 3 remains unclear.", "Although it is debated whether chronic cerebro-spinal venous insufficiency (CCSVI) plays a role in multiple sclerosis (MS) development, many patients undergo endovascular treatment (ET) of CCSVI. A study is ongoing in Italy to evaluate the clinical outcome of ET. Severe adverse events (AEs) occurred in 15/462 subjects at a variable interval after ET: jugular thrombosis in seven patients, tetraventricular hydrocephalus, stroke, paroxysmal atrial fibrillation, status epilepticus, aspiration pneumonia, hypertension with tachicardia, or bleeding of bedsore in the remaining seven cases. One patient died because of myocardial infarction 10 weeks after ET. The risk of severe AEs related to ET for CCSVI must be carefully considered.", "In previous years, identification of fetal cells in maternal blood circulation has caused a new revolution in non-invasive method of prenatal diagnosis. Low number of fetal cells in maternal blood and long-term survival after pregnancy limited the use of fetal cells in diagnostic and clinical applications. With the discovery of cell-free fetal DNA (cffDNA) in plasma of pregnant women, access to genetic material of the fetus had become possible to determine early gender of a fetus in pregnancies at the risk of X-linked genetic conditions instead of applying invasive methods. Therefore in this study, the probability of detecting sequences on the Y chromosome in pregnant women has been evaluated to identify the gender of fetuses. Peripheral blood samples were obtained from 80 pregnant women at 6(th) to 10(th) weeks of gestation and then the fetal DNA was extracted from the plasma. Nested PCR was applied to detect the sequences of single copy SRY gene and multi copy DYS14 & DAZ genes on the Y chromosome of the male fetuses. At the end, all the obtained results were compared with the actual gender of the newborns. In 40 out of 42 born baby boys, the relevant gene sequences were identified and 95.2% sensitivity was obtained. Non-invasive early determination of fetal gender using cffDNA could be employed as a pre-test in the shortest possible time and with a high reliability to avoid applying invasive methods in cases where a fetus is at the risk of genetic diseases.", "Susceptibility to autoimmune disorders results from the interaction of multiple genetic factors that regulate the threshold of autoreactivity. Genome-wide microsatellite screens and large-scale single nucleotide polymorphism (SNP) association studies have identified chromosomal loci that are associated with specific disorders including systemic lupus erythematosus, rheumatoid arthritis, juvenile arthritis, multiple sclerosis, and diabetes. Numerous candidate gene association studies have in turn investigated the association of specific genes within these chromosomal regions, with susceptibility to autoimmune diseases (e.g. FcgammaReceptors, TYK2 and systemic lupus). More recently, large-scale differential gene expression studies performed on selected tissues from patients with autoimmune disorders, have led to the identification of gene signatures associated with the activation of specific pathways in these diseases (e.g. interferon signature in lupus). In the future, integrated analyses of gene (and protein) expression together with SNP data will allow us to sketch an intelligible picture of the genesis of autoimmunity in humans. This review sets out to illustrate how the most recent advances in the field of systemic lupus erythematosus, rheumatoid arthritis and juvenile arthritis have led to a better understanding of these disorders.", "BACKGROUND: When feeding preterm infants, donor milk is preferred if the mother's own milk is unavailable. Pasteurization may have detrimental effects on bioactivity, but more information is needed about its effects on the immunological compounds. Research aim: This work has two main aims: evaluate the antibody profile of colostrum and study the quantitative variations in the antibodies' level and specific reactivity after undergoing Holder pasteurization. The authors focused on immunoregulatory components of colostrum (antidietary antibodies and TGF-β2) in the neonatal gut.METHODS: This is a descriptive cross-sectional study of a convenience sample of 67 donated colostrum samples at different days after delivery, both raw and pasteurized. Antibody profiles were analyzed at different times during breastfeeding, and total and specific antibodies (IgM, IgA, and IgG subclasses) were compared with tetanus toxoid and ovalbumin using enzyme-linked immunosorbent assay. The processing effect on total and specific antibodies, as well as TGF-β2, was evaluated by paired analyses.RESULTS: No variations in immunological compounds were observed throughout the colostrum stage. The TGF-β2, antibodies' concentrations, and antibodies' specific reactivity after pasteurization did not vary significantly as days of lactation varied. Changes in antibody levels were dependent on isotype and IgG subclass, and IgG4 showed remarkable resistance to heating. Moreover, the effect of the pasteurization on specific reactivity was antigen dependent.CONCLUSION: The supply of relevant immunological components is stable throughout the colostrum stage. The effects of pasteurization on antibodies depend on isotype, subclass, and specificity. This information is relevant to improving the immunological quality of colostrum, especially for preterm newborns.", "MWS is a multiple congenital anomaly syndrome, first clinically delineated by Mowat et al in 1998. Over 45 cases have now been reported. All patients have typical dysmorphic features in association with severe intellectual disability, and nearly all have microcephaly and seizures. Congenital anomalies, including Hirschsprung disease (HSCR), congenital heart disease, hypospadias, genitourinary anomalies, agenesis of the corpus callosum, and short stature are common. The syndrome is the result of heterozygous deletions or truncating mutations of the ZFHX1B (SIP1) gene on chromosome 2q22." ]

[ "BACKGROUND: Anticitrullinated protein antibodies (ACPAs) are serological biomarkers associated with early, rapidly progressing rheumatoid arthritis (RA), including more severe disease and joint damage. ACPA testing has become a routine tool for RA diagnosis and prognosis. Furthermore, treatment efficacy has been shown to vary by ACPA-positive status. However, it is not clear if the economic burden of patients with RA varies by ACPA status.OBJECTIVE: To determine if the economic burden of RA varies by patient ACPA status.METHODS: IMS PharMetrics Plus health insurance claims and electronic medical record (EMR) data from 2010-2015 were used to identify patients with incident RA. Patients were aged ≥ 18 years, had ≥ 1 inpatient or ≥ 2 outpatient claims reporting an RA diagnosis code (ICD-9-CM code 714.0), and had an anticyclic citrullinated peptide (anti-CCP; a surrogate of ACPA) antibody test within 6 months of diagnosis. Incident patients were defined as those who had no claims with an RA diagnosis code in the 6 months before the first observed RA diagnosis. The primary outcome of interest was RA-related medical expenditures, defined as the sum of payer- and patient-paid amounts for all claims with an RA diagnosis code. Secondary outcomes included health care utilization metrics such as treatment with a disease-modifying antirheumatic drug (DMARD) and physician visits. Generalized linear regression models were used for each outcome, controlling for ACPA-positive status (defined as anti-CCP ≥ 20 AU/mL), age, sex, and Charlson Comorbidity Index score as explanatory variables.RESULTS: Of 647,171 patients diagnosed with RA, 89,296 were incident cases, and 47% (n = 42,285) had an anti-CCP test. After restricting this sample to patients with a linked EMR and reported anti-CCP test result, 859 remained, with 24.7% (n = 212) being ACPA-positive. Compared with ACPA-negative patients, adjusted results showed that ACPA-positive patients were more likely to use either conventional (71.2% vs. 49.6%; P < 0.001) or biologic (20.3% vs. 11.8%; P < 0.001) DMARDs during the first year after diagnosis and had more physician visits (5.58 vs. 3.91 times per year; P < 0.001). Annual RA-associated total expenditures were $7,941 for ACPA-positive and $5,243 for ACPA-negative patients (Δ = $2,698; P = 0.002). RA-associated medical expenditures were $4,380 for ACPA-positive and $3,427 for ACPA-negative patients (Δ = $954; P = 0.168), whereas DMARD expenditures were $3,560 and $1,817, respectively (Δ = $1,743; P = 0.001).CONCLUSIONS: RA-related economic burden is higher for patients who are ACPA-positive compared with those who are ACPA-negative. Providers may wish to inform patients diagnosed with ACPA-positive RA about the likely future disease and economic burden in hopes that both stakeholders can be more proactive in addressing them.DISCLOSURES: Funding for this research was contributed by Bristol-Myers Squibb. Patel and Price are employees and stockholders of Bristol-Myers Squibb. Shafrin and Tebeka are employees of Precision Health Economics, a health care consulting firm that received funding from Bristol-Myers Squibb to conduct this study. Michaud has received a grant from Pfizer and is employed by the National Data Bank for Rheumatic Diseases, which has received funds from Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer, and Regeneron. Study concept and design were contributed by Shafrin, Price, Patel, and Michaud. Shafrin, Price, and Patel collected the data, and all authors contributed equally to data analysis. The manuscript was written by Shafrin and Tebeka and revised by Shafrin, Price, Patel, and Michaud.", "Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect almost any organ in the human body. Despite significant advancements in our understanding of SLE over the recent years, its exact mode of onset and disease progression remains elusive. Low concordance rates among monozygotic twins with SLE (as low as 24%), clustering of disease prevalence around polluted regions and an urban-rural difference in prevalence all highlight the importance of environmental influences in SLE. Experimental data strongly suggests a complex interaction between the exposome (or environmental influences) and genome (genetic material) to produce epigenetic changes (epigenome) that can alter the expression of genetic material and lead to development of disease in the susceptible individual. In this review, we focus on the available literature to explore the role of environmental factors in SLE disease onset and progression and to better understand the role of exposome-epigenome-genome interactions in this dreaded disease.", "Like that of many protein-coding genes, expression of the p21(CIP1) cell cycle inhibitor is regulated at the level of transcription elongation. While many transcriptional activators have been shown to stimulate elongation, the mechanisms by which promoter-specific repressors regulate pausing and elongation by RNA polymerase II (RNA PolII) are not well described. Here we report that the transcription factor Sp3 inhibits basal p21(CIP1) gene expression by promoter-bound RNA PolII. Knockdown of Sp3 led to increased p21(CIP1) mRNA levels and reduced occupancy of the negative elongation factor (NELF) at the p21(CIP1) promoter, although the level of binding of the positive transcription elongation factor b (P-TEFb) kinase was not increased. Sp3 depletion correlated with increased H3K36me3 and H2Bub1, two histone modifications associated with transcription elongation. Further, Sp3 was shown to promote the binding of protein phosphatase 1 (PP1) to the p21(CIP1) promoter, leading to reduced H3S10 phosphorylation, a finding consistent with Sp3-dependent regulation of the local balance between kinase and phosphatase activities. Analysis of other targets of Sp3-mediated repression suggests that, in addition to previously described SUMO modification-dependent chromatin-silencing mechanisms, inhibition of the transition of paused RNA PolII to productive elongation, described here for p21(CIP1), is a general mechanism by which transcription factor Sp3 fine-tunes gene expression.", "BACKGROUND: Upon infection of a mammalian host, Bacillus anthracis responds to host cues, and particularly to elevated temperature (37°C) and bicarbonate/CO2 concentrations, with increased expression of virulence factors that include the anthrax toxins and extracellular capsular layer. This response requires the presence of the pXO1 virulence plasmid-encoded pleiotropic regulator AtxA. To better understand the genetic basis of this response, we utilized a controlled in vitro system and Next Generation sequencing to determine and compare RNA expression profiles of the parental strain and an isogenic AtxA-deficient strain in a 2 × 2 factorial design with growth environments containing or lacking carbon dioxide.RESULTS: We found 15 pXO1-encoded genes and 3 chromosomal genes that were strongly regulated by the separate or synergistic actions of AtxA and carbon dioxide. The majority of the regulated genes responded to both AtxA and carbon dioxide rather than to just one of these factors. Interestingly, we identified two previously unrecognized small RNAs that are highly expressed under physiological carbon dioxide concentrations in an AtxA-dependent manner. Expression levels of the two small RNAs were found to be higher than that of any other gene differentially expressed in response to these conditions. Secondary structure and small RNA-mRNA binding predictions for the two small RNAs suggest that they may perform important functions in regulating B. anthracis virulence.CONCLUSIONS: A majority of genes on the virulence plasmid pXO1 that are regulated by the presence of either CO2 or AtxA separately are also regulated synergistically in the presence of both. These results also elucidate novel pXO1-encoded small RNAs that are associated with virulence conditions.", "Macropinocytosis has emerged as an important nutrient supply pathway that sustains cell growth of cancer cells within the nutrient-poor tumor microenvironment. By internalizing extracellular fluid through this bulk endocytic pathway, albumin is supplied to the cancer cells, which, after degradation, serves as an amino acid source to meet the high nutrient demands of these highly proliferating cells. Here, we describe a streamlined protocol for visualization and quantitation of macropinosomes in adherent cancer cells grown in vitro. The determination of the \"macropinocytic index\" provides a tool for measuring the extent to which this internalization pathway is utilized within the cancer cells and allows for comparison between different cell lines and treatments. The protocol provided herein has been optimized for reproducibility and is readily adaptable to multiple conditions and settings.", "1. ", "Previous analysis of the hsp26 gene of Drosophila melanogaster has shown that in addition to the TATA box and the proximal and distal heat shock elements (HSEs) (centered at -59 and -340, relative to the start site of transcription), a segment of (CT)n repeats at -135 to -85 is required for full heat shock inducibility (R.L. Glaser, G.H. Thomas, E.S. Siegfried, S.C.R. Elgin, and J.T. Lis, J. Mol. Biol. 211:751-761, 1990). This (CT)n element appears to contribute to formation of the wild-type chromatin structure of hsp26, an organized nucleosome array that leaves the HSEs in nucleosome-free, DNase I-hypersensitive (DH) sites (Q. Lu, L.L. Wallrath, B.D. Allan, R.L. Glaser, J.T. Lis, and S.C.R. Elgin, J. Mol. Biol. 225:985-998, 1992). Inspection of the sequences upstream of hsp26 has revealed an additional (CT)n element at -347 to -341, adjacent to the distal HSE. We have analyzed the contribution of this distal (CT)n element (-347 to -341), the proximal (CT)n element (-135 to -85), and the two HSEs both to the formation of the chromatin structure and to heat shock inducibility. hsp26 constructs containing site-directed mutations, deletions, substitutions, or rearrangements of these sequence elements have been fused in frame to the Escherichia coli lacZ gene and reintroduced into the D. melanogaster genome by P-element-mediated germ line transformation. Chromatin structure of the transgenes was analyzed (prior to gene activation) by DNase I or restriction enzyme treatment of isolated nuclei, and heat-inducible expression was monitored by measuring beta-galactosidase activity. The results indicate that mutations, deletions, or substitutions of either the distal or the proximal (CT)n element affect the chromatin structure and heat-inducible expression of the transgenes. These (CT)n repeats are associated with a nonhistone protein(s) in vivo and are bound by a purified Drosophila protein, the GAGA factor, in vitro. In contrast, the HSEs are required for heat-inducible expression but play only a minor role in establishing the chromatin structure of the transgenes. Previous analysis indicates that prior to heat shock, these HSEs appear to be free of protein. Our results suggest that GAGA factor, an abundant protein factor required for normal expression of many Drosophila genes, and heat shock factor, a specific transcription factor activated upon heat shock, play distinct roles in gene regulation: the GAGA factor establishes and/or maintains the DH sites prior to heat shock induction, while the activated heat shock factor recognizes and binds HSEs located within the DH sites to trigger transcription.", "BACKGROUND: The role and impact of systemic inflammatory response after aneurysmal subarachnoid hemorrhage remain to be elucidated.OBJECTIVE: To assess the time course and correlation of systemic inflammatory parameters with outcome and the occurrence of delayed ischemic neurological deficits (DINDs) after subarachnoid hemorrhage.METHODS: Besides the baseline characteristics, daily interleukin-6 (IL-6), procalcitonin, C-reactive protein levels, and leukocyte counts were prospectively measured until day 14 after subarachnoid hemorrhage. Occurrence of infectious complications and application of therapeutic hypothermia were assessed as confounding factors. The primary end point was outcome after 3 months, assessed by Glasgow outcome scale; the secondary end point was the occurrence of DINDs.RESULTS: During a 3-year period, a total of 138 patients were included. All inflammatory parameters measured were higher in patients with unfavorable outcome (Glasgow outcome scale score, 1-3). After adjustment for confounding factors, elevated IL-6 and leukocyte counts remained significant risk factors for unfavorable outcome. The odds ratio for log IL-6 was 4.07 (95% confidence interval, 1.18 to 14.03; P = .03) and for leukocyte counts was 1.24 (95% confidence interval, 1.06-1.46, P = .008). The analysis of the time course established that IL-6 was the only significantly elevated parameter in the early phase in patients with unfavorable outcome. Higher IL-6 levels in the early phase (days 3-7) were associated with the occurrence of DINDs. The adjusted odds ratio for log IL-6 was 4.03 (95% confidence interval, 1.21-13.40; P = .02).CONCLUSION: Higher IL-6 levels are associated with worse clinical outcome and the occurrence of DINDs. Because IL-6 levels were significantly elevated in the early phase, they might be a useful parameter to monitor.", "In addition to their role as oncogenes, Ras GTPases are key regulators of cell function. There is a proven relationship between the signaling pathways of transforming growth factor-β1 (TGF- β1) and Ras GTPases. Each of the Ras isoforms (H, N and K) exhibits specific modulatory activity on different cellular pathways. Our purpose has been to study some of the mechanisms involved in the development of renal fibrosis, assessing the individual role of N-Ras in basal and TGF-β1-mediated extracellular matrix (ECM) synthesis, proliferation, and migration in immortalized N-Ras deficient fibroblasts (N-ras(-/-)). Compared to normal counterparts, fibroblasts deficient for N-Ras exhibited higher basal activity levels of phosphatidylinositol-3-kinase (PI3K)/Akt and MEK/Erk, accompanied by upregulated collagen synthesis and diminished proliferation and migration rates. We found that the absence of N-Ras did not affect TGF-β1-induced proliferation and migration, which required PI3K/Akt but not Erk1/2 activation. Similar effector pathway dependence was found for fibronectin and collagen type I expression. Our results indicate that N-Ras might contribute to renal fibrosis through the down-regulation of ECM synthesis and up-regulation proliferation and migration modulating Akt activation. N-Ras also regulates TGF-β1-induced collagen I and fibronectin expression through Erk-independent pathways.", "Six persons with the classical Angelman syndrome (AS) phenotype and de novo deletions of chromosome 15q11-q13 were studied to determine the parental origin of the chromosome deletion. Four of the 6 patients had informative cytogenetic studies and all demonstrated maternal inheritance of the deletion. These findings, together with other reported cases of the origin of the chromosome 15 deletion in AS, suggest that deletion of the maternally contributed chromosome leads to the AS phenotype. This contrasts with the Prader-Willi syndrome (PWS) in which a similar deletion of the paternally contributed chromosome 15 is observed. In deletion cases, a parental gamete effect such as genomic imprinting may be the best model to explain why apparently identical 15q11-q13 deletions may develop the different phenotypes of AS or PWS.", "OBJECTIVE: To study the protective effect of edaravone on severe traumatic brain injury (TBI) and its potential mechanism.METHODS: Two hundred and seventy-three male Sprague-Dawley (SD) rats were divided randomly into four groups: control group (n=45), model group (n=88), low-dose edaravone treatment group (n=72), high-dose edaravone treatment group (n=68). TBI rat model was reproduced by weight-dropping injury. One, 6, 24, 48 and 72 hours after injury, changes in brain tissue were observed with light and electron microscopy. The expression of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) was determined by Western blotting. The rate of neuron apoptosis was observed with immunohistochemistry and terminal-deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) method. Learning and memory function assessments were performed with Morris water maze from 7th day to 10th day after injury.RESULTS: Compared with control group, a part of neurons in hippocampus displayed histopathologic changes denoting necrosis 6, 24, 48 and 72 hours after injury. The p-ERK1/2 expression level (pg/unit) increased 1, 6, 24, 48 hours after injury (2.05 + or - 0.40, 4.40 + or - 0.96, 6.70 + or - 0.87, 3.67 + or - 0.28 vs. 0.40 + or - 0.04, 0.41 + or - 0.05, 0.43 + or - 0.06, 0.40 + or - 0.03), and the number of apoptotic cells increased 6, 24, 48, 72 hours after injury (9.60 + or - 2.69, 12.68 + or - 2.99, 16.94 + or - 3.92, 25.82 + or - 4.61 vs. 2.42 + or - 0.38, 2.58 + or - 0.57, 2.74 + or - 0.56, 2.61 + or - 0.58); latent period to find the safety platform (s) was significantly prolonged (119.8 + or - 25.0, 105.6 + or - 24.5, 98.5 + or - 21.8, 92.0 + or - 19.5 vs. 49.5 + or - 7.5, 32.7 + or - 6.3, 25.8 + or - 6.5, 24.8 + or - 5.5, all P<0.05). After treatment with edaravone, the degree of morphological injury, p-ERK1/2 level and number of apoptotic neurons decreased, latent period to find the safety platform was significantly shortened (in low-dose edaravone treatment group, p-ERK1/2 expression level at 6, 24, 48 hours was 2.46 + or - 0.22, 4.00 + or - 0.84, 2.38 + or - 0.32, and in high-dose edaravone treatment group was 1.67 + or - 0.15, 1.86 + or - 0.38, 1.27 + or - 0.28; in low-dose edaravone treatment group, the apoptotic cells at 6, 24, 48, 72 hours was 5.20 + or - 1.23, 7.10 + or - 1.72, 9.54 + or - 1.36, 14.12 + or - 3.19, and in high-dose edaravone treatment group was 3.40 + or - 0.49 , 4.39 + or - 0.73, 5.02 + or - 1.12, 8.78 + or - 2.16; in low-dose edaravone treatment group, latent period to find the safety platform at 7-10 days was 94.8 + or - 22.8, 65.2 + or - 19.0, 62.0 + or - 16.7, 59.5 + or - 15.6, and in high-dose edaravone treatment group it was 81.5 + or - 20.7, 55.4 + or - 18.5, 40.0 + or - 12.3, 32.2 + or - 11.0, all P<0.05). High-dose edaravone showed a better effect (all P<0.05).CONCLUSION: Edaravone gives good therapeutic effect on severe TBI, and the molecular mechanism is related to attenuation of ERK1/2 pathway and neuronal apoptosis following severe brain trauma.", "We report a 72-year-old woman with overlapping Miller Fisher syndrome (MFS), Guillain-Barré syndrome (GBS) and Bickerstaff's brainstem encephalitis (BBE). She developed diplopia and unsteady gait a week after an upper respiratory infection on day 1. She had weakness of both upper limbs on day 3 and became drowsy, and her respiratory status worsened on day 5. Neurologic examination revealed ophthalmoplegia, ataxia, symmetrical weakness, areflexia, and consciousness disturbance. We diagnosed her with MFS on day 1, GBS on day 3 and overlapping BBE on day 5. She underwent immunoadsorption therapy and two courses of intravenous immunoglobulin therapy. Ten months after onset, her symptoms had fully recovered. Anti-GM1 IgG, GD1a IgG, GQ1b IgG, and GT1a IgG antibodies were positive. Our case supports the notion that MFS, GBS, and BBE are all part of a continuous clinical spectrum, which is an antibody-mediated process.", "Biological agents targeting on pro-inflammatory cytokines are developed, and provide a great impact on the medical management of rheumatoid arthritis (RA). Particularly, biologics against tumor necrosis factor(TNF) can not only induce great clinical improvement, but also halt structural damage on the joints. Now chimeric anti-TNFalpha monoclonal antibody, infliximab, full human anti-TNFalpha monoclonal antibody, adalimumab, and TNF receptor II (p75) -IgGFc fusion protein, etanercept, are widely used in the inflammatory disorders including RA. This review article shows the characteristics of these anti-TNF biologics on RA, and summarizes the efficacy as well as the safety of the agents.", "BACKGROUND AND OBJECTIVES: The non-depolarizing muscle relaxant vecuronium inhibits contraction by competitive inhibition of postsynaptic acetylcholine receptors (AchRs), which decreases the number of quanta released per impulse in response to 50 Hz stimulation. The specific role of calcium influx through L-type calcium channels is the promotion of endocytosis and vesicle recycling during high-frequency stimulation. Vecuronium also induces four pulse tetanic fade, a proxy measure of decreased quanta release. We examined whether vecuronium suppresses neuromuscular transmission during high-frequency stimulation by inhibiting presynaptic L-type calcium channels.METHODS: Fifty male Sprague-Dawley rats were divided into five treatment groups: unstimulated control group, α-bungarotoxin (BTX) group, nifedipine group, vecuronium group, and nifedipine plus vecuronium group. Rat phrenic nerve-diaphragm neuromuscular juctions were stimulated at 50 Hz and field excitatory post-synaptic potentials (fEPSPs) were recorded. Expression levels of the presynaptic Ca(2+)-binding, protein synaptotagmin 1, and the presynaptic plasma membrane protein, syntaxin 1, were measured by Western blots.RESULTS: The fEPSPs evoked by 50 Hz stimulus trains were decreased by vecuronium, nifedipine, and by vecuronium plus nifedipine. Nifedipine, an L-type calcium channel blocker, reduced the expression of synaptogamin and syntaxin and blocked the suppressive effect of vecuronium, suggesting that both agents inhibit presynaptic L-type calcium channels.CONCLUSIONS: Vecuronium which blocked L-type calcium channels may suppress activity of the α(3)β(2) nAChR subunit, which exists in the presynaptic membrane and enhances quantal release. This α(3)β(2) nAChR-mediated positive feedback effect may be facilitated by L-type Ca(2+) channel activity under high-frequency stimulation. Vecuronium may disrupt this positive feedback cycle, leading to suppression of fEPSPs. Vercuronium may reduce neuromuscular transmission through presynaptic and postsynaptic mechanisms.", "OBJECTIVE: Impulse control disorders (ICDs) in Parkinson disease (PD) are common and can be difficult to manage. The objective of this study was to determine the efficacy and tolerability of naltrexone, an opioid antagonist, for the treatment of ICDs in PD.METHODS: Patients with PD (n = 50) and an ICD were enrolled in an 8-week, randomized (1:1), double-blind, placebo-controlled study of naltrexone 50-100 mg/d (flexible dosing). The primary outcome measure was response based on the Clinical Global Impression-Change score, and the secondary outcome measure was change in symptom severity using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) ICD score.RESULTS: Forty-five patients (90%) completed the study. The Clinical Global Impression-Change response rate difference favoring naltrexone in completers was 19.8% (95% confidence interval [CI] -8.7% to 44.2%). While this difference was not significant (odds ratio=1.6, 95% CI 0.5-5.2, Wald χ2 [df]=0.5 [1], p=0.5), naltrexone treatment led to a significantly greater decrease in QUIP-RS ICD score over time compared with placebo (regression coefficient for interaction term in linear mixed-effects model=-7.37, F[df]=4.3 [1, 49], p=0.04). The estimated changes in QUIP-RS ICD scores from baseline to week 8 were 14.9 points (95% CI 9.9-19.9) for naltrexone and 7.5 points (95% CI 2.5-12.6) for placebo.CONCLUSIONS: Naltrexone treatment was not efficacious for the treatment of ICDs in PD using a global assessment of response, but findings using a PD-specific ICD rating scale support further evaluation of opioid antagonists for the treatment of ICD symptoms in PD.CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with PD and an ICD, naltrexone does not significantly increase the probability of achieving response. However, the study lacked the precision to exclude an important difference in response rates.", "BACKGROUND: Acne vulgaris is one of the main reasons for dermatological consultations. Severity and response to treatment may be impacted by various external factors or exposome.AIM: To assess the impact of environmental factors on acne and to provide a comprehensive overview of the acne exposome.METHODS: Two consensus meetings of five European dermatologists and a comprehensive literature search on exposome factors triggering acne served as a basis for this review.RESULTS: Acne exposome was defined as the sum of all environmental factors influencing the occurrence, duration and severity of acne. Exposome factors impact on the response and the frequency of relapse to treatments by interacting with the skin barrier, sebaceous gland, innate immunity and cutaneous microbiota. They may be classified into the following six main categories: nutrition, psychological and lifestyle factors, occupational factors including cosmetics, as well as pollutants, medication and climatic factors. Moreover, practical considerations for the dermatologist's clinical practice are proposed.CONCLUSION: Exposome factors including nutrition, medication, occupational factors, pollutants, climatic factors, and psychosocial and lifestyle factors may impact on the course and severity of acne and on treatment efficacy. Identifying and reducing the impact of exposome is important for an adequate acne disease management.", "SIGNIFICANCE: The environment can elicit biological responses such as oxidative stress (OS) and inflammation as a consequence of chemical, physical, or psychological changes. As population studies are essential for establishing these environment-organism interactions, biomarkers of OS or inflammation are critical in formulating mechanistic hypotheses. Recent Advances: By using examples of stress induced by various mechanisms, we focus on the biomarkers that have been used to assess OS and inflammation in these conditions. We discuss the difference between biomarkers that are the result of a chemical reaction (such as lipid peroxides or oxidized proteins that are a result of the reaction of molecules with reactive oxygen species) and those that represent the biological response to stress, such as the transcription factor NRF2 or inflammation and inflammatory cytokines.CRITICAL ISSUES: The high-throughput and holistic approaches to biomarker discovery used extensively in large-scale molecular epidemiological exposome are also discussed in the context of human exposure to environmental stressors.FUTURE DIRECTIONS: We propose to consider the role of biomarkers as signs and to distinguish between signs that are just indicators of biological processes and proxies that one can interact with and modify the disease process. Antioxid. Redox Signal. 28, 852-872.", "BACKGROUND: The CYP2C19 G681A single polymorphism has been proven to affect clopidogrel responsiveness. However, the effect of coexisting polymorphisms of other genes has not yet been reported in the Chinese population. This study investigated the effect of coexisting polymorphisms of CYP2C19 and P2Y12 on clopidogrel responsiveness and adverse clinical events in Chinese patients.METHODS: In 577 Han Chinese patients undergoing stent placement because of acute coronary syndrome had platelet reactivity assessed by thromboelastography, and the CYP2C19 G681A and P2Y12 C34T polymorphisms were detected by the ligase detection reaction. Primary clinical endpoints included cardiovascular death, nonfatal myocardial infarction, target vessel revascularization, and stent thrombosis. The secondary clinical endpoints were thrombolysis in myocardial infarction bleeding. The follow-up period was 12 months.RESULTS: Genotyping revealed 194 carriers of the wild type GG genotype of CYP2C19 and the wild type CC genotype of P2Y12 (group 1), 102 carriers of the wild type GG genotype of CYP2C19 and the mutational T allele of P2Y12 (group 2), 163 carriers of the mutational A allele of CYP2C19 and the wild type CC genotype of P2Y12 (group 3), and 118 carriers of the mutational A allele of CYP2C19 and the mutational T allele of P2Y12 (group 4). Group 4 had the lowest ADP-inhibition (49.74 ± 32.61) and the highest prevalence of clopidogrel low response (29.7%) of the four groups. The rate of the composite of primary clinical endpoints increased more in group 4 (8.5%) than in the other three groups; the rate of composite primary endpoints in group 2 (2.9%) and group 3 (3.7%) were not significantly different than that of group 1 (1.5%).CONCLUSION: Coexisting polymorphisms of different genes affected clopidogrel responsiveness and clinical outcome more than single polymorphism in Chinese patients with acute coronary syndrome undergoing percutaneous coronary intervention.", "OBJECTIVE: Pediatric Index of Mortality 2 (PIM2) is an up-to-date mortality prediction model in the public domain that has not yet been widely validated. We aimed to evaluate this score in the population of patients admitted to our pediatric intensive care unit.DESIGN: Prospective cohort study.SETTING: Multidisciplinary pediatric intensive care unit in a general university hospital in Buenos Aires, Argentina.PATIENTS: All consecutive patients admitted between January 1, 2004, and December 31, 2005.INTERVENTIONS: None.MEASUREMENTS AND MAIN RESULTS: There were 1,574 patients included in the study. We observed 41 (2.6%) deaths, and PIM2 estimated 48.1 (3.06) deaths. Discrimination assessed by the area under the receiver operating characteristic curve was 0.9 (95% confidence interval, 0.89-0.92). Calibration across five conventional mortality risk intervals assessed by the Hosmer-Lemeshow goodness-of-fit test showed chi5 = 12.2 (p = .0348). The standardized mortality ratio for the whole population was 0.85 (95% confidence interval, 0.6-1.1).CONCLUSIONS: PIM2 showed an adequate discrimination between death and survival and a poor calibration assessed by the Hosmer-Lemeshow goodness-of-fit test. The standardized mortality ratio and clinical analysis of the Hosmer-Lemeshow table make us consider that PIM2 reasonably predicted the outcome of our patients.", "Author information:(1)International Agency for Research on Cancer (IARC), 150 Cours Albert-Thomas, Lyon, 69008, France.(2)Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.(3)School of Pharmacy and Life Sciences, The Robert Gordon University, Aberdeen, United Kingdom.(4)Gillings School of Global Public Health, UNC, Chapel Hill, NC.(5)Fels Institute for Cancer Research & Molecular Biology, Philadelphia, PA.(6)Texas Children's Hospital, Baylor College of Medicine, TX.(7)University of Arkansas for Medical Sciences, AR.(8)Aichi Cancer Center Research Institute, Nagoya, Japan.(9)INSERM, Albert Bonniot Institute, Grenoble, France.(10)National Cancer Institute (INCA), Rio de Janeiro, Brazil.(11)Emory University, Atlanta, GA.(12)Centre for Genomics and Child Health, Blizard Institute, London, United Kingdom.(13)Murdoch Childrens Research Institute, Melbourne, Australia.(14)National Institute of Health, NC.(15)Statistical Cancer Genomics, UCL Cancer Institute & Dept. of Woman's Cancer, University College London, United Kingdom.(16)CAS-MPG Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, Shanghai, 200031, China.(17)National Cancer Center Research Institute, Tokyo, Japan.(18)MRC/PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.(19)Departments of Molecular & Cellular Biology and Medicine, Baylor College of Medicine, Houston, TX.(20)Baylor College of Medicine, USDA/ARS Children's Nutrition Research Center, Houston, TX.(21)UCSF School of Medicine, Epidemiology & Biostatistics, San Francisco, CA." ]

[ "BACKGROUND: Strimvelis (autologous CD34+ cells transduced to express adenosine deaminase [ADA]) is the first ex vivo stem cell gene therapy approved by the European Medicines Agency (EMA), indicated as a single treatment for patients with ADA-severe combined immunodeficiency (ADA-SCID) who lack a suitable matched related bone marrow donor. Existing primary immunodeficiency registries are tailored to transplantation outcomes and do not capture the breadth of safety and efficacy endpoints required by the EMA for the long-term monitoring of gene therapies. Furthermore, for extended monitoring of Strimvelis, the young age of children treated, small patient numbers, and broad geographic distribution of patients all increase the risk of loss to follow-up before sufficient data have been collected. Establishing individual investigator sites would be impractical and uneconomical owing to the small number of patients from each location receiving Strimvelis.RESULTS: An observational registry has been established to monitor the safety and effectiveness of Strimvelis in up to 50 patients over a minimum of 15 years. To address the potential challenges highlighted above, data will be collected by a single investigator site at Ospedale San Raffaele (OSR), Milan, Italy, and entered into the registry via a central electronic platform. Patients/families and the patient's local physician will also be able to submit healthcare information directly to the registry using a uniquely designed electronic platform. Data entry will be monitored by a Gene Therapy Registry Centre (funded by GlaxoSmithKline) who will ensure that necessary information is collected and flows between OSR, the patient/family and the patient's local healthcare provider.CONCLUSION: The Strimvelis registry sets a precedent for the safety monitoring of future gene therapies. A unique, patient-focused design has been implemented to address the challenges of long-term follow-up of patients treated with gene therapy for a rare disease. Strategies to ensure data completeness and patient retention in the registry will help fulfil pharmacovigilance requirements. Collaboration with partners is being sought to expand from a treatment registry into a disease registry. Using practical and cost-efficient approaches, the Strimvelis registry is hoped to encourage further innovation in registry design within orphan drug development.", "Moyamoya disease is a specific chronic cerebrovascular occlusive disease first reported by Japanese surgeons in 1957. The disease is characterized by stenosis or occlusion of the terminal portions of the bilateral internal carotid arteries and abnormal vascular network in the vicinity of the arterial occlusion. It may cause ischemic attacks or cerebral infarction, which is more frequent in children than in adults. In adults, cerebral hemorrhage may occur. The disease is distributed in all age groups, but the highest peak is in childhood at less than 10 years of age. The characteristic histopathologic features of the steno-occlusive arteries are fibrocellular thickening of the intima containing proliferated smooth muscle cells and prominently tortuous and often duplicated internal elastic lamina. There is usually no atheromatous plaque in the arterial wall. Etiology of the disease is still unknown; however, multifactorial inheritance is considered possible because of a higher incidence of the disease in Japanese and Koreans and approximately 10% of familial occurrence among the Japanese. Recent genetic studies suggest some responsible genetic foci in chromosomes 3, 6 and 17.", "To examine the significance of chemokine activation of CXCR2 in wound healing after chemical burn, cutaneous injury was created by topical application of nitrogen mustard on CXCR2 wild type (+/+), heterozygous (+/-), and knockout (-/-) mice. Wounds were analyzed histologically for neutrophil and monocyte infiltration and for reepithelialization at postwound days 4, 7, and 10. Neutrophil recruitment to the wound site was reduced through postwound day 7 in CXCR2 -/- mice as indicated by myeloperoxidase assay and by visual quantitation. Because there is always concern that mice with targeted deletion of a specific receptor may undergo developmental adaptations to offset the loss of the receptor, we also accessed chemical wound repair in the presence of a small molecule antagonist of CXCR2. Dietary supplementation with a CXCR2 antagonist (SB-265610) during the wound repair process also markedly delayed healing parameters in CXCR2 +/+ mice, even greater than treatment with glucocorticoids. These parallel studies further establish that mice deficient in CXCR2 function exhibit delayed cutaneous wound healing that may be primarily linked to impaired neutrophil recruitment after chemical burn with nitrogen mustard. Thus, there may be a potential therapeutic benefit of treating nitrogen mustard-induced skin lesions with agonists of CXCR2 to facilitate the wound repair process.", "The Radiation Therapy Oncology Group (RTOG) initiated the single-arm, phase II study 9806 to determine the safety and efficacy of daily thalidomide with radiation therapy in patients with newly diagnosed glioblastoma. Patients were treated with thalidomide (200 mg daily) from day one of radiation therapy, increasing by 100-200 to 1,200 mg every 1-2 weeks until tumor progression or unacceptable toxicity. The median survival time (MST) of all 89 evaluable patients was 10 months. When compared with the historical database stratified by recursive partitioning analysis (RPA) class, this end point was not different [hazard ratio (HR) = 1.18; 95 % CI: 0.95-1.46; P = 0.93]. The MST of RPA class III and IV patients was 13.9 versus 12.5 months in controls (HR = 0.99; 95 % CI: 0.73-1.36; P = 0.48), and 4.3 versus 8.6 months in RPA class V controls (HR = 1.63, 95 % CI: 1.17-2.27; P = 0.99). In all, 34 % of patients discontinued thalidomide because of adverse events or refusal. The most common grade 3-4 toxicities were venous thrombosis, fatigue, skin reactions, encephalopathy, and neuropathy. In conclusion, thalidomide given simultaneously with radiation therapy was safe, but did not improve survival in patients with newly diagnosed glioblastoma.", "The myotubularin-related genes define a large family of eukaryotic proteins, most of them initially characterized by the presence of a ten-amino acid consensus sequence related to the active sites of tyrosine phosphatases, dual-specificity protein phosphatases and the lipid phosphatase PTEN. Myotubularin (hMTM1), the founder member, is mutated in myotubular myopathy, and a close homolog (hMTMR2) was recently found mutated in a recessive form of Charcot-Marie-Tooth neuropathy. Although myotubularin was thought to be a dual-specificity protein phosphatase, recent results indicate that it is primarily a lipid phosphatase, acting on phosphatidylinositol 3-monophosphate, and might be involved in the regulation of phosphatidylinositol 3-kinase (PI 3-kinase) pathway and membrane trafficking.", "The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is a phosphatase that antagonizes the phosphoinositol-3-kinase/AKT signaling pathway and suppresses cell survival as well as cell proliferation. PTEN is the second most frequently mutated gene in human cancer after p53. Germline mutations of PTEN have been found in cancer susceptibility syndromes, such as Cowden syndrome, in which over 80% of patients have mutations of PTEN. Homozygous deletion of Pten causes embryonic lethality, suggesting that PTEN is essential for embryonic development. Mice heterozygous for Pten develop spontaneous tumors in a variety of organs comparable with the spectrum of its mutations in human cancer. The mechanisms of PTEN functions in tumor suppression are currently under intense investigation. Recent studies demonstrate that PTEN plays an essential role in the maintenance of chromosomal stability and that loss of PTEN leads to massive alterations of chromosomes. The tumor suppressor p53 is known as a guardian of the genome that mediates the cellular response to environmental stress, leading to cell cycle arrest or cell death. Through completely different mechanisms, PTEN also protects the genome from instability. Thus, we propose that PTEN is a new guardian of the genome. In this review, we will discuss new discoveries on the role of PTEN in tumor suppression and explore mechanisms by which PTEN maintains genomic stability.", "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." ]

[ "Recent clinical trials have demonstrated the potential of adeno-associated virus (AAV)-based vectors for treating rare diseases. However, significant barriers remain for the translation of these vectors into widely available therapies. In particular, exposure to the AAV capsid can generate an immune response of neutralizing antibodies. One approach to overcome this response is to map the AAV-specific neutralizing epitopes and rationally design an AAV capsid able to evade neutralization. To accomplish this, we isolated a monoclonal antibody against AAV9 following immunization of BALB/c mice and hybridoma screening. This antibody, PAV9.1, is specific for intact AAV9 capsids and has a high neutralizing titer of >1:160,000. We used cryo-electron microscopy to reconstruct PAV9.1 in complex with AAV9. We then mapped its epitope to the 3-fold axis of symmetry on the capsid, specifically to residues 496-NNN-498 and 588-QAQAQT-592. Capsid mutagenesis demonstrated that even a single amino acid substitution within this epitope markedly reduced binding and neutralization by PAV9.1. In addition, in vivo studies showed that mutations in the PAV9.1 epitope conferred a \"liver-detargeting\" phenotype to the mutant vectors, unlike AAV9, indicating that the residues involved in PAV9.1 interactions are also responsible for AAV9 tropism. However, we observed minimal changes in binding and neutralizing titer when we tested these mutant vectors for evasion of polyclonal sera from mice, macaques, or humans previously exposed to AAV. Taken together, these studies demonstrate the complexity of incorporating mapped neutralizing epitopes and previously identified functional motifs into the design of novel capsids able to evade immune response.IMPORTANCE Gene therapy utilizing viral vectors has experienced recent success, culminating in U.S. Food and Drug Administration approval of the first adeno-associated virus vector gene therapy product in the United States: Luxturna for inherited retinal dystrophy. However, application of this approach to other tissues faces significant barriers. One challenge is the immune response to viral infection or vector administration, precluding patients from receiving an initial or readministered dose of vector, respectively. Here, we mapped the epitope of a novel neutralizing antibody generated in response to this viral vector to design a next-generation capsid to evade immune responses. Epitope-based mutations in the capsid interfered with the binding and neutralizing ability of the antibody but not when tested against polyclonal samples from various sources. Our results suggest that targeted mutation of a greater breadth of neutralizing epitopes will be required to evade the repertoire of neutralizing antibodies responsible for blocking viral vector transduction.", "Titin is the largest polypeptide yet described (relative molecular mass approximately 3 x 10(6); refs 1, 2) and an abundant protein of striated muscle. Its molecules are string-like and in vivo span from the M to Z-lines. I-band regions of titin are thought to make elastic connections between the thick filament and the Z-line, thereby forming a third type of sarcomere filament. These would centre the A-band in the sarcomere and provide structural continuity in relaxed myofibrils. The A-band region of titin seems to be bound to the thick filament, where it has been proposed to act as a 'molecular ruler' regulating filament length and assembly. Here, we show that partial titin complementary DNAs encode a regular pattern of two types of 100-residue motif, each of which probably folds into a separate domain type. Such motifs are present in several evolutionarily divergent muscle proteins, all of which are likely to interact with myosin. One or both of the domain types is therefore likely to bind to myosin.", "BACKGROUND: Biologic agents offer a range of new therapeutic options for patients with psoriasis; however, the relative benefit-risk profiles of such therapies are not well known. We compared two biologic agents, ustekinumab (an interleukin-12 and interleukin-23 blocker) and etanercept (an inhibitor of tumor necrosis factor alpha), for the treatment of psoriasis.METHODS: We randomly assigned 903 patients with moderate-to-severe psoriasis to receive subcutaneous injections of either 45 or 90 mg of ustekinumab (at weeks 0 and 4) or high-dose etanercept (50 mg twice weekly for 12 weeks). The primary end point was the proportion of patients with at least 75% improvement in the psoriasis area-and-severity index (PASI) at week 12; a secondary end point was the proportion with cleared or minimal disease on the basis of the physician's global assessment. Assessors were unaware of the treatment assignments. The efficacy and safety of a crossover from etanercept to ustekinumab were evaluated after week 12.RESULTS: There was at least 75% improvement in the PASI at week 12 in 67.5% of patients who received 45 mg of ustekinumab and 73.8% of patients who received 90 mg, as compared with 56.8% of those who received etanercept (P=0.01 and P<0.001, respectively). Similarly, 65.1% of patients who received 45 mg of ustekinumab and 70.6% of patients who received 90 mg of ustekinumab had cleared or minimal disease according to the physician's global assessment, as compared with 49.0% of those who received etanercept (P<0.001 for both comparisons). Among patients who did not have a response to etanercept, 48.9% had at least 75% improvement in the PASI within 12 weeks after crossover to ustekinumab. One or more adverse events occurred through week 12 in 66.0% of patients who received 45 mg of ustekinumab and 69.2% of patients who received 90 mg of ustekinumab and in 70.0% who received etanercept; 1.9%, 1.2%, and 1.2%, respectively, had serious adverse events. Safety patterns were similar before and after crossover from etanercept to ustekinumab.CONCLUSIONS: The efficacy of ustekinumab at a dose of 45 or 90 mg was superior to that of high-dose etanercept over a 12-week period in patients with psoriasis. (ClinicalTrials.gov number, NCT00454584.)", "The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non-small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. In the present study, lung cancer cell lines, HCC78 harboring SLC34A2-ROS1 and ABC-20 harboring CD74-ROS1, were used as cell line-based resistance models. Crizotinib-resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor-receptor tyrosine kinase array and RNA sequence analysis by next-generation sequencing. HCC78R cells showed upregulation of HB-EGF and activation of epidermal growth factor receptor (EGFR) phosphorylation and the EGFR signaling pathway. Recombinant HB-EGF or EGF rendered HCC78 cells or ABC-20 cells resistant to crizotinib. RNA sequence analysis by next-generation sequencing revealed the upregulation of AXL in HCC78R cells. HCC78R cells showed marked sensitivity to EGFR-TKI or anti-EGFR antibody treatment in vitro. Combinations of an AXL inhibitor, cabozantinib or gilteritinib, and an EGFR-TKI were more effective against HCC78R cells than monotherapy with an EGFR-TKI or AXL inhibitor. The combination of cabozantinib and gefitinib effectively inhibited the growth of HCC78R tumors in an in vivo xenograft model of NOG mice. The results of this study indicated that HB-EGF/EGFR and AXL play roles in crizotinib resistance in lung cancers harboring ROS1 fusions. The combination of cabozantinib and EGFR-TKI may represent a useful alternative treatment strategy for patients with advanced NSCLC harboring ROS1 fusion genes.", "BACKGROUND: It is estimated that 30% of adults in the United States experience daily chronic pain. This results in a significant burden on the health care system, in particular primary care, and on the workplace. Chronic pain management with cognitive-behavioral psychological treatment is effective in reducing pain intensity and interference, health-related quality of life, mood, and return to work. However, the population of individuals with chronic pain far exceeds the population of therapists that can provide this care face-to-face. The use of tailored, Web-based interventions for the management of chronic pain could address limitations to access by virtue of its unlimited scalability.OBJECTIVE: To examine the effects of a tailored Web-based chronic pain management program on subjective pain, activity and work interference, quality of life and health, and stress.METHODS: Eligible participants accessed the online pain management program and informed consent via participating employer or health care benefit systems; program participants who completed baseline, 1-, and 6-month assessments were included in the study. Of the 645 participants, the mean age was 56.16 years (SD 12.83), most were female (447/645, 69.3%), and white (505/641, 78.8%). Frequent pain complaints were joint (249/645, 38.6%), back (218/645, 33.8%), and osteoarthritis (174/654, 27.0%). The online pain management program used evidence-based theories of cognitive behavioral intervention, motivational enhancement, and health behavior change to address self-management, coping, medical adherence, social support, comorbidities, and productivity. The program content was individually tailored on several relevant participant variables.RESULTS: Both pain intensity (mean 5.30, SD 2.46), and unpleasantness (mean 5.43, SD 2.52) decreased significantly from baseline to 1-month (mean 4.16, SD 2.69 and mean 4.24, 2.81, respectively) and 6-month (mean 3.78, SD 2.79 and mean 3.78, SD 2.79, respectively) assessments (P<.001). The magnitude of the 6-month effects were large. Trends for decreases in pain interference (36.8% reported moderate or enormous interference) reached significance at 6 months (28.9%, P<.001). The percentage of the sample reporting fair or poor quality of life decreased significantly from 20.6% at baseline to 16.5% at 6 months (P=.006).CONCLUSIONS: Results suggest that the tailored online chronic pain management program showed promising effects on pain at 1 and 6 months posttreatment and quality of life at 6 months posttreatment in this naturalistic study. Further research is warranted to determine the significance and magnitude of the intervention's effects in a randomized controlled trial.", "PURPOSE: The purpose of this study is to determine the sensibility of each imaging tool in identifying focal cortical dysplasia (FCD) in children and adolescents with epilepsy and to define the prognostic factors of pediatric and adolescent epilepsy surgery.METHODS: We identified 48 children with FCD who underwent resective surgery and analyzed their preoperative data. The results of various anatomic and functional neuroimaging studies were compared for accuracy in locating the lesion. We also investigated clinical factors that affected the outcome of surgical treatment.KEY FINDINGS: Brain magnetic resonance imaging (MRI) was able to localize FCD in 30 patients and fluorodeoxyglucose positron emission tomography (FDG-PET) and/or subtraction ictal single photon emission computed tomography (SPECT) coregistered with MRI provided additional information that helped to define the lesion in 13 patients. When comparing the pathologic results between a mild malformation of cortical development (MCD) and FCD type I and II, we noted a strong tendency for patients with FCD to have MRI abnormalities (p = 0.005). In addition, severe pathologic features (Palmini's classification, FCD type II) (p = 0.025) showed significant correlation with a better surgical outcome. To define the primary epileptogenic area, various interictal epileptiform discharges and the results of multimodal neuroimaging studies were helpful, and younger age at the time of operation could aid in more favorable surgical outcomes (p = 0.048).SIGNIFICANCE: Our study showed a significant relationship between pathologic grade and the detectability of FCD by brain MRI. In addition, early surgery can be justified by showing that advanced neuroimaging studies in children with FCD and even with extensive epileptiform discharges have a higher rate of success.", "OBJECTIVE: To evaluate the prevalence, disease course, and survival of patients with systemic lupus erythematosus (SLE) in a population of over 120,000 North American Indians (NAI), and contrast the results to those in the non-Indian population.METHODS: The regional arthritis center database and the medical records of all rheumatologists, hematologists, nephrologists, and general internists with > 1 patient with SLE were searched for cases of SLE diagnosed between 1980 and 1996. A random survey of 20% of family physicians serving this population suggested that > 85% of all SLE cases were identified. Demographics, SLE Disease Activity Index (SLEDAI) scores, Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage scores. clinical manifestations, and therapy for NAI were contrasted with the results in Caucasians (CAUC).RESULTS: We identified 257 cases meeting the ACR criteria for SLE diagnosed between 1980 and 1996. There were 49 NAI cases, resulting in a prevalence of 42.3/100,000, compared to a prevalence of 20.6/100,000 for the remainder of the population. NAI patients were younger at diagnosis, had higher SLEDAI scores at diagnosis, and had more frequent vasculitis, proteinuria and cellular casts. There were no treatment differences at diagnosis or at 2 years, but NAI patients were significantly more likely to receive treatment with prednisone or immunosuppressives at the last clinic visit. The NAI patients had similar damage scores at diagnosis, but significantly higher scores at 2 years and at the last clinic visit. NAI ethnicity increased the likelihood of death more than 4-fold.CONCLUSION: The prevalence of SLE was increased 2-fold in the NAI population. NAI patients had higher SLEDAI scores at diagnosis and more frequent vasculitis and renal involvement, required more treatment later in the disease course, accumulated more damage following diagnosis, and had increased fatality." ]

[ "SWItchMiner (SWIM) is a wizard-like software implementation of a procedure, previously described, able to extract information contained in complex networks. Specifically, SWIM allows unearthing the existence of a new class of hubs, called \"fight-club hubs\", characterized by a marked negative correlation with their first nearest neighbors. Among them, a special subset of genes, called \"switch genes\", appears to be characterized by an unusual pattern of intra- and inter-module connections that confers them a crucial topological role, interestingly mirrored by the evidence of their clinic-biological relevance. Here, we applied SWIM to a large panel of cancer datasets from The Cancer Genome Atlas, in order to highlight switch genes that could be critically associated with the drastic changes in the physiological state of cells or tissues induced by the cancer development. We discovered that switch genes are found in all cancers we studied and they encompass protein coding genes and non-coding RNAs, recovering many known key cancer players but also many new potential biomarkers not yet characterized in cancer context. Furthermore, SWIM is amenable to detect switch genes in different organisms and cell conditions, with the potential to uncover important players in biologically relevant scenarios, including but not limited to human cancer.", "S100A7 (psoriasin) and S100A15 (koebnerisin) were first identified in inflamed psoriatic skin. They are of major interest because of their putative functional roles in innate immunity, epidermal cell maturation, and epithelial tumorigenesis. Human S100A7 and S100A15 have lately evolved by gene duplications within the epidermal differentiation complex (chromosome 1q21) during primate evolution forming a novel S100 subfamily. Therefore, S100A7 and S100A15 are almost identical in sequence (>90%) and are difficult to discriminate. Despite their high homology, S100A7 and S100A15 are distinct in tissue distribution, regulation, and function, and thus, exemplary for the diversity within the S100 family. Their different properties are compelling reasons to discriminate S100A7 (psoriasin) and S100A15 (koebnerisin) in epithelial homeostasis, inflammation, and cancer.", "Age-related accumulation of ploidy changes is associated with decreased expression of genes controlling chromosome segregation and cohesin functions. To determine the consequences of whole chromosome instability (W-CIN) we down-regulated the spindle assembly checkpoint component BUB1 and the mitotic cohesin SMC1A, and used four-color-interphase-FISH coupled with BrdU incorporation and analyses of senescence features to reveal the fate of W-CIN cells. We observed significant correlations between levels of not-diploid cells and senescence-associated features (SAFs). W-CIN induced DNA double strand breaks and elevated oxidative stress, but caused low apoptosis. SAFs of W-CIN cells were remarkably similar to those induced by replicative senescence but occurred in only 13 days versus 4 months. Cultures enriched with not-diploid cells acquired a senescence-associated secretory phenotype (SASP) characterized by IL1B, CXCL8, CCL2, TNF, CCL27 and other pro-inflammatory factors including a novel SASP component CLEC11A. These findings suggest that W-CIN triggers premature senescence, presumably to prevent the propagation of cells with an abnormal DNA content. Cells deviating from diploidy have the ability to communicate with their microenvironment by secretion of an array of signaling factors. Our results suggest that aneuploid cells that accumulate during aging in some mammalian tissues potentially contribute to age-related pathologies and inflammation through SASP secretion.", "The natural phytoalexin resveratrol, found in grapes and red wine, recently rose to public fame for its positive effects on longevity in yeasts, worms and flies. Resveratrol anti-cancer and anti-inflammatory in vitro action on mammalian cell cultures also suggest a possible positive effect on human health and life-expectancy. To study the effects of resveratrol on vertebrate aging is obviously a particularly relevant question. We have studied resveratrol effects in a very short-lived vertebrate: the annual fish Nothobranchius furzeri. Resveratrol treatment prolonged lifespan and delayed the onset of age-related dysfunctions in this fish. This result identifies resveratrol as the first molecule which consistently retards aging in organisms as diverse as yeast, worm, fly and fish, but it also reveals the potential of this short-lived fish as an animal model for pharmacological research. Moreover, being related to stickleback (Gasterosteus aculeatus) the \"pufferfishes\" Takifugu and Tetraodon, and even more closely related to medaka (Oryzias latipes), it can greatly beneficiate from the recent development of genomic resources for these fish models and in the future become a complete model system for the aging research community.", "Recent clinical trials have demonstrated the potential of adeno-associated virus (AAV)-based vectors for treating rare diseases. However, significant barriers remain for the translation of these vectors into widely available therapies. In particular, exposure to the AAV capsid can generate an immune response of neutralizing antibodies. One approach to overcome this response is to map the AAV-specific neutralizing epitopes and rationally design an AAV capsid able to evade neutralization. To accomplish this, we isolated a monoclonal antibody against AAV9 following immunization of BALB/c mice and hybridoma screening. This antibody, PAV9.1, is specific for intact AAV9 capsids and has a high neutralizing titer of >1:160,000. We used cryo-electron microscopy to reconstruct PAV9.1 in complex with AAV9. We then mapped its epitope to the 3-fold axis of symmetry on the capsid, specifically to residues 496-NNN-498 and 588-QAQAQT-592. Capsid mutagenesis demonstrated that even a single amino acid substitution within this epitope markedly reduced binding and neutralization by PAV9.1. In addition, in vivo studies showed that mutations in the PAV9.1 epitope conferred a \"liver-detargeting\" phenotype to the mutant vectors, unlike AAV9, indicating that the residues involved in PAV9.1 interactions are also responsible for AAV9 tropism. However, we observed minimal changes in binding and neutralizing titer when we tested these mutant vectors for evasion of polyclonal sera from mice, macaques, or humans previously exposed to AAV. Taken together, these studies demonstrate the complexity of incorporating mapped neutralizing epitopes and previously identified functional motifs into the design of novel capsids able to evade immune response.IMPORTANCE Gene therapy utilizing viral vectors has experienced recent success, culminating in U.S. Food and Drug Administration approval of the first adeno-associated virus vector gene therapy product in the United States: Luxturna for inherited retinal dystrophy. However, application of this approach to other tissues faces significant barriers. One challenge is the immune response to viral infection or vector administration, precluding patients from receiving an initial or readministered dose of vector, respectively. Here, we mapped the epitope of a novel neutralizing antibody generated in response to this viral vector to design a next-generation capsid to evade immune responses. Epitope-based mutations in the capsid interfered with the binding and neutralizing ability of the antibody but not when tested against polyclonal samples from various sources. Our results suggest that targeted mutation of a greater breadth of neutralizing epitopes will be required to evade the repertoire of neutralizing antibodies responsible for blocking viral vector transduction.", "Psoriatic arthritis is a complex and heterogeneous disease with potential significant disability and impaired quality of life. Although in the last decades new treatment options have led to a better management of this disease, there are still significant unmet therapeutic needs. Dual inhibitor antibodies target two different cytokines simultaneously, potentially offering a better disease control. In psoriatic arthritis, there is evidence for a pathogenic role not only of IL-17A but also the structurally homologous IL-17F. It is postulated that differential expression of both in several targets of PsA could account for disparities in clinical response to IL-17A inhibition alone (such as with secukinumab or ixekizumab). Here we review the evidence so far for the use in psoriatic arthritis of bimekizumab, the first humanized monoclonal IgG1 antibody that selectively neutralizes both IL-17A and IL-17F. A Phase 2b trial reports better outcomes over both placebo and IL-17A inhibition alone. Very recently encouraging results from open-label extensions with regards to both safety and maintenance of response were presented. Phase III trials are ongoing with the first results awaited in 2021.", "BACKGROUND: Ischaemic stroke and coronary heart disease are important contributors to the global disease burden and share atherosclerosis as the main underlying cause. Recent evidence from a genome-wide association study (GWAS) suggested that single nucleotide polymorphisms (SNP) near the MMP12 gene at chromosome 11q22.3 were associated with large-vessel ischaemic stroke. Here, we evaluated and extended these results by examining the relationship between MMP12 and atherosclerosis in clinical and experimental studies.METHODS AND RESULTS: Plasma concentrations of MMP12 were measured at baseline in 3394 subjects with high-risk for cardiovascular disease (CVD) using the Olink ProSeek CVD I array. The plasma MMP12 concentration showed association with incident cardiovascular and cerebrovascular events (130 and 67 events, respectively, over 36 months) and carotid intima-media thickness progression (P = 3.6 × 10-5 ). A GWAS of plasma MMP12 concentrations revealed that SNPs rs499459, rs613084 and rs1892971 at chr11q22.3 were independently associated with plasma MMP12 (P < 5 × 10-8 ). The lead SNPs showed associations with mRNA levels of MMP12 and adjacent MMPs in atherosclerotic plaques. MMP12 transcriptomic and proteomic levels were strongly significantly increased in carotid plaques compared with control arterial tissue and in plaques from symptomatic versus asymptomatic patients. By combining immunohistochemistry and proximity ligation assay, we demonstrated that MMP12 localizes to CD68 + macrophages and interacts with elastin in plaques. MMP12 silencing in human THP-1-derived macrophages resulted in reduced macrophage migration.CONCLUSIONS: Our study supports the notion that MMP12 is implicated in large-artery atherosclerotic stroke, functionally by enhancing elastin degradation and macrophage invasion in plaques." ]

[ "Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.", "PURPOSE: Androgenetic alopecia (AGA), or male pattern hair loss, affects up to 96% of Caucasian men. Characterized by gradual thinning and eventual loss of hair along frontotemporal, parietal, and vertex areas of the scalp, AGA is associated with low self-esteem, depression, and dissatisfaction with body appearance.DATA SOURCES: In this systematic review of the literature, six primary research studies conducted in the United States are evaluated for their clinical application to primary care provider practice.CONCLUSIONS: Topical minoxidil 2%-5% 1 mL twice daily or finasteride 1 mg daily are recommended as first line treatments, followed by the use of Food and Drug Administration-cleared HairMax LaserComb® in patients who do not respond to first line modalities.IMPLICATIONS FOR PRACTICE: Further research in novel and established treatments is recommended, along with an evidence-based clinical practice guideline for practitioners in the United States.", "Erythropoietin (EPO) has been suggested to have a cardioprotective effect against ischemia. The purpose of this study was to examine the effects of EPO on cardiac remodeling after myocardial infarction (MI). MI was induced by ligation of the coronary artery in Wistar rats. The rats with MI were randomly divided into untreated MI and two EPO-treated MI groups. EPO was administered subcutaneously by injection once a day for 4 days after MI at 5000 U/kg or 3 times a week for 4 weeks at 1000 U/kg. Five days after MI, EPO prevented the increase in activated caspase 3, matrix metalloproteinase-2, and transcriptional activation of activator protein-1 in non-infarcted myocardium. Four weeks after MI, left ventricular weight, left ventricular end-diastolic pressure, and left ventricular dimension were increased, and ejection fraction and E wave deceleration time were decreased. EPO significantly attenuated this ventricular remodeling and systolic and diastolic dysfunction. In addition, EPO significantly attenuated the interstitial fibrosis and remodeling-related gene expression in non-infarcted myocardium. Furthermore, EPO significantly enhanced angiogenesis and reduced apoptotic cell death in peri-infarcted myocardium. In conclusion, when administered after MI, EPO prevents cardiac remodeling and improves ventricular function with enhanced angiogenesis and reduced apoptosis.", "The Oncotype DX assay is one of the molecular tests that provide predictive and prognostic information to breast cancer patients with estrogen receptor (ER)-positive and node-negative disease. This study evaluates the association of Forkhead-box protein A1 (FOXA1) and GATA-binding protein 3 (GATA3) expressions with Oncotype DX recurrences scores in 77 cases of patients with ER-positive node-negative breast carcinomas diagnosed at Indiana University. The data were correlated with patient age, tumor size, histologic type, Scarff-Bloom-Richardson score, histologic grade, and progesterone receptor status. The median FOXA1 and GATA3 scores were 240 and 200, respectively. The Oncotype DX recurrence scores were low in 57%, intermediate in 30%, and high in 13% of cases. FOXA1 expression correlated negatively with Oncotype DX recurrence scores (P=0.004), and histologic type (P=0.0004). Oncotype DX recurrences score also correlated negatively with progesterone receptor (P=0.035) with 100% of progesterone receptor-negative cases having high or intermediate Oncotype DX scores. FOXA1 and GATA3 expressions correlated positively (P=0.014). The correlation between FOXA1 expression and Oncotype DX recurrence scores remained significant after adjusting for multiple comparisons and controlling for confounders such as histological type, grade, and progesterone receptor. A statistically significant correlation between the Oncotype DX recurrence scores and FOXA1 expression in our diverse cohort of ER-positive breast cancer patients was observed. We propose that this may represent a more cost-effective strategy to further risk stratify patients with good prognosis in whom chemotherapy may be omitted. To confirm these findings, further studies in a larger cohort of patients are warranted.", "PURPOSE OF REVIEW: von Hippel-Lindau disease is an inherited, multisystemic cancer syndrome often involving the retina. This review will provide an update for the clinical characterization and treatment of ocular von Hippel-Lindau disease.RECENT FINDINGS: A comprehensive and quantitative clinical characterization of ocular von Hippel-Lindau disease has been limited by small patient numbers and nonrepresentative sampling. Recently, a large population of patients with clinically and genetically defined von Hippel-Lindau disease was systemically characterized in a single center, enabling a quantitative evaluation of the ocular involvement of this syndrome. Correlations between the nature of von Hippel-Lindau gene mutations and the ocular phenotype were also examined, providing clues as to how disruptions in von Hippel-Lindau protein function may result in eye disease. This understanding may be relevant to the development of new therapies targeting the molecular biology of von Hippel-Lindau disease, some of which are presently being investigated.SUMMARY: Quantitative studies enable a full characterization of the impact of von Hippel-Lindau disease on eye health and visual function. Establishing correlations between the genotype of the von Hippel-Lindau mutation and the phenotype of eye disease may inform us as to how ocular von Hippel-Lindau disease arises, and help guide molecular interventions in ocular von Hippel-Lindau disease.", "Hereditary hemochromatosis is an inherited disorder of iron metabolism in the Caucasian population with an autosomal recessive inheritance and a prevalence between 1 in 200 and 1 in 500. Until the discovery of HFE gene the diagnosis of hemochromatosis required documentation of iron overload or family linkage using HLA testing. The discovery of HFE gene has established the foundation for a better understanding of iron homeostasis and has changed hemochromatosis management: liver biopsy, gold standard diagnostic, was replaced by genetic test and it was suggested that population screening using genetic testing might be ideal for HFE related hemochromatosis. Considered for long time a unitary disease, a monogenic disorder characterized by excess tissue deposits of iron and subsequently organ damage, hemochromatosis is in fact a polygenic disease with many faces. The Online Mendelian Inheritance in Man database has lists four types of hereditary hemochromatosis, each of them caused by a different gene mutation (hepcidine, hemojuvelin, transferring receptor 2, ferroportin). The basic features shared by iron overload disorders associated with mutation in HFE, hepcidine, hemojuvelin, transferring receptor 2, ferroportin gene indicate that they are genetic variation of the same syndrome. Hereditary hemochromatosis must be distinguished from the other syndrome of iron overload and the classic term hereditary hemochromatosis should be reserved only for HFE related hemochromatosis.", "Identification of cell-fate determinants for directing stem cell differentiation remains a challenge. Moreover, little is known about how cell-fate determinants are regulated in functionally important subnetworks in large gene-regulatory networks (i.e., GRN motifs). Here we propose a model of stem cell differentiation in which cell-fate determinants work synergistically to determine different cellular identities, and reside in a class of GRN motifs known as feedback loops. Based on this model, we develop a computational method that can systematically predict cell-fate determinants and their GRN motifs. The method was able to recapitulate experimentally validated cell-fate determinants, and validation of two predicted cell-fate determinants confirmed that overexpression of ESR1 and RUNX2 in mouse neural stem cells induces neuronal and astrocyte differentiation, respectively. Thus, the presented GRN-based model of stem cell differentiation and computational method can guide differentiation experiments in stem cell research and regenerative medicine." ]

[ "Tc toxins from pathogenic bacteria use a special syringe-like mechanism to perforate the host cell membrane and inject a deadly enzyme into the host cytosol. The molecular mechanism of this unusual injection system is poorly understood. Using electron cryomicroscopy, we determined the structure of TcdA1 from Photorhabdus luminescens embedded in lipid nanodiscs. In our structure, compared with the previous structure of TcdA1 in the prepore state, the transmembrane helices rearrange in the membrane and open the initially closed pore. However, the helices do not span the complete membrane; instead, the loops connecting the helices form the rim of the funnel. Lipid head groups reach into the space between the loops and consequently stabilize the pore conformation. The linker domain is folded and packed into a pocket formed by the other domains of the toxin, thereby considerably contributing to stabilization of the pore state.", "OBJECTIVE: To identify specific premorbid personality traits in patients with Alzheimer's disease (AD).DESIGN: A prospective case-control study.SETTING: A memory clinic of a department of geriatric medicine in a teaching hospital.PATIENTS: Fifty-six consecutive patients with probable AD. Sixty-five controls with Parkinson's disease (PD).MEASURES: Premorbid personality traits were assessed using the relative rating version of the Munich Personality Test (MPT).RESULTS: The AD patients showed higher neuroticism than the controls with PD (p=0.013). In comparison with MPT normative values for psychiatric inpatients, the AD patients scored significantly (p<0.05) lower on neuroticism and higher on frustration tolerance and rigidity.CONCLUSION: Our results support the assumption of specific premorbid characteristics in AD patients, ie increased neuroticism and rigidity. More research is needed to confirm the existence of typical premorbid personality traits in AD.", "In Arabidopsis a SWI2/SNF2 chromatin remodeling factor-related protein DDM1 and a cytosine methyltransferase MET1 are required for maintenance of genomic cytosine methylation. Mutations in either gene cause global demethylation. In this work we have assessed the effects of these mutations on the PAI tryptophan biosynthetic gene family, which consists of four densely methylated genes arranged as a tail-to-tail inverted repeat plus two unlinked singlet genes. The methylation mutations caused only partial demethylation of the PAI loci: ddm1 had a strong effect on the singlet genes but a weaker effect on the inverted repeat, whereas met1 had a stronger effect on the inverted repeat than on the singlet genes. The double ddm1 met1 mutant also displayed partial demethylation of the PAI genes, with a pattern similar to the ddm1 single mutant. To determine the relationship between partial methylation and expression for the singlet PAI2 gene we constructed a novel reporter strain of Arabidopsis in which PAI2 silencing could be monitored by a blue fluorescent plant phenotype diagnostic of tryptophan pathway defects. This reporter strain revealed that intermediate levels of methylation correlate with intermediate suppression of the fluorescent phenotype.", "Employing a combination of reverse transcription-polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE) techniques, the complete coding sequence of cDNA for the equine SRY gene was determined. We also attempted to make clear whether the equine SRY gene transcript is expressed in the adult testis, and whether the type of transcript is expressed as linear or circular RNA. As a result, in total a 1420 bp cDNA sequence was determined. Accomplishment of 3' RACE infers that equine SRY gene was expressed as a linear RNA transcript in testicular tissue just after puberty, in contrast to the situation in mice.", "Diffuse intrinsic pontine gliomas (DIPG) are the most aggressive brain tumors in children with 5-year survival rates of only 2%. About 85% of all DIPG are characterized by a lysine-to-methionine substitution in histone 3, which leads to global H3K27 hypomethylation accompanied by H3K27 hyperacetylation. Hyperacetylation in DIPG favors the action of the Bromodomain and Extra-Terminal (BET) protein BRD4, and leads to the reprogramming of the enhancer landscape contributing to the activation of DIPG super enhancer-driven oncogenes. The activity of the acetyltransferase CREB-binding protein (CBP) is enhanced by BRD4 and associated with acetylation of nucleosomes at super enhancers (SE). In addition, CBP contributes to transcriptional activation through its function as a scaffold and protein bridge. Monotherapy with either a CBP (ICG-001) or BET inhibitor (JQ1) led to the reduction of tumor-related characteristics. Interestingly, combined treatment induced strong cytotoxic effects in H3.3K27M-mutated DIPG cell lines. RNA sequencing and chromatin immunoprecipitation revealed that these effects were caused by the inactivation of DIPG SE-controlled tumor-related genes. However, single treatment with ICG-001 or JQ1, respectively, led to activation of a subgroup of detrimental super enhancers. Combinatorial treatment reversed the inadvertent activation of these super enhancers and rescued the effect of ICG-001 and JQ1 single treatment on enhancer-driven oncogenes in H3K27M-mutated DIPG, but not in H3 wild-type pedHGG cells. In conclusion, combinatorial treatment with CBP and BET inhibitors is highly efficient in H3K27M-mutant DIPG due to reversal of inadvertent activation of detrimental SE programs in comparison with monotherapy.", "Tc toxins secrete toxic enzymes into host cells using a unique syringe-like injection mechanism. They are composed of three subunits, TcA, TcB and TcC. TcA forms the translocation channel and the TcB-TcC heterodimer functions as a cocoon that shields the toxic enzyme. Binding of the cocoon to the channel triggers opening of the cocoon and translocation of the toxic enzyme into the channel. Here we show in atomic detail how the assembly of the three components activates the toxin. We find that part of the cocoon completely unfolds and refolds into an alternative conformation upon binding. The presence of the toxic enzyme inside the cocoon is essential for its subnanomolar binding affinity for the TcA subunit. The enzyme passes through a narrow negatively charged constriction site inside the cocoon, probably acting as an extruder that releases the unfolded protein with its C terminus first into the translocation channel.", "The human protein kinome comprises 535 proteins that, with the exception of approximately 50 pseudokinases, control intracellular signaling networks by catalyzing the phosphorylation of multiple protein substrates. While a major research focus of the last 30 years has been cancer-associated Tyr and Ser/Thr kinases, over 85% of the kinome has been identified to be dysregulated in at least one disease or developmental disorder. Despite this remarkable statistic, for the majority of protein kinases and pseudokinases, there are currently no inhibitors progressing toward the clinic, and in most cases, details of their physiologic and pathologic mechanisms remain at least partially obscure. By curating and annotating data from the literature and major public databases of phosphorylation sites, kinases, and disease associations, we generate an unbiased resource that highlights areas of unmet need within the kinome. We discuss strategies and challenges associated with characterizing catalytic and noncatalytic outputs in cells, and describe successes and new frontiers that will support more comprehensive cancer-targeting and therapeutic evaluation in the future. Cancer Res; 78(1); 15-29. ©2017 AACR.", "Nucleosomal core histones (H2A, H2B, H3 and H4) must be assembled, replaced or exchanged to preserve or modify chromatin organization and function according to cellular needs. Histone chaperones escort histones, and play key functions during nucleosome assembly/disassembly and in nucleosome structure configuration. Because of their location at the periphery of nucleosome, histone H2A-H2B dimers are remarkably dynamic. Here we focus on plant histone H2A/H2B chaperones, particularly members of the NUCLEOSOME ASSEMBLY PROTEIN-1 (NAP1) and FACILITATES CHROMATIN TRANSCRIPTION (FACT) families, discussing their molecular features, properties, regulation and function. Covalent histone modifications (e.g. ubiquitination, phosphorylation, methylation, acetylation) and H2A variants (H2A.Z, H2A.X and H2A.W) are also discussed in view of their crucial importance in modulating nucleosome organization and function. We further discuss roles of NAP1 and FACT in chromatin-based processes, such as transcription, DNA replication and repair. Specific functions of NAP1 and FACT are evident when their roles are considered with respect to regulation of plant growth and development and in plant responses to environmental stresses. Future major challenges remain in order to define in more detail the overlapping and specific roles of various members of the NAP1 family as well as differences and similarities between NAP1 and FACT family members, and to identify and characterize their partners as well as new families of chaperones to understand histone variant incorporation and chromatin target specificity.", "HbVar (http://globin.bx.psu.edu/hbvar) is one of the oldest and most appreciated locus-specific databases launched in 2001 by a multi-center academic effort to provide timely information on the genomic alterations leading to hemoglobin variants and all types of thalassemia and hemoglobinopathies. Database records include extensive phenotypic descriptions, biochemical and hematological effects, associated pathology and ethnic occurrence, accompanied by mutation frequencies and references. Here, we report updates to >600 HbVar entries, inclusion of population-specific data for 28 populations and 27 ethnic groups for α-, and β-thalassemias and additional querying options in the HbVar query page. HbVar content was also inter-connected with two other established genetic databases, namely FINDbase (http://www.findbase.org) and Leiden Open-Access Variation database (http://www.lovd.nl), which allows comparative data querying and analysis. HbVar data content has contributed to the realization of two collaborative projects to identify genomic variants that lie on different globin paralogs. Most importantly, HbVar data content has contributed to demonstrate the microattribution concept in practice. These updates significantly enriched the database content and querying potential, enhanced the database profile and data quality and broadened the inter-relation of HbVar with other databases, which should increase the already high impact of this resource to the globin and genetic database community.", "Studies in primary and tumor cells suggest that MYC plays an important role in regulating cellular senescence, thereby impacting on tumor development. Here we describe different common methods to measure senescence in cell cultures and in tissues. These include measurement of senescence-associated β-galactosidase activity (SA-β-gal), senescence-associated heterochromatin foci (SAHFs), proliferative arrest, morphological changes, and expression and activity of proteins involved in the senescence process, such as p53 and Rb pathway proteins and secretory proteins. It is important to note that there is no unique marker that unambiguously defines a senescent state, and it is therefore necessary to combine measurements of several different markers that together determine whether cells are senescent or not. Measurement of senescence is an important aspect of studies of MYC biology and will improve our understanding of MYC function and regulation both in preclinical and clinical settings. This may form the basis for new concepts of pro-senescence therapy to combat MYC in cancer.", "In Gaucher disease (GD), the inherited deficiency of glucocerebrosidase results in the accumulation of glucocerebroside within lysosomes. Although almost 300 mutations in the glucocerebrosidase gene (GBA) have been identified, the ability to predict phenotype from genotype is quite limited. In this study, we sought to examine potential GBA transcriptional regulatory elements for variants that contribute to phenotypic diversity. Specifically, we generated the genomic sequence for the orthologous genomic region ( approximately 39.4kb) encompassing GBA in eight non-human mammals. Computational comparisons of the resulting sequences, using human sequence as the reference, allowed the identification of multi-species conserved sequences (MCSs). Further analyses predicted the presence of two putative clusters of transcriptional regulatory elements upstream and downstream of GBA, containing five and three transcription factor-binding sites (TFBSs), respectively. A firefly luciferase (Fluc) reporter construct containing sequence flanking the GBA gene was used to test the functional consequences of altering these conserved sequences. The predicted TFBSs were individually altered by targeted mutagenesis, resulting in enhanced Fluc expression for one site and decreased expression for seven others sites. Gel-shift assays confirmed the loss of nuclear-protein binding for several of the mutated constructs. These identified conserved non-coding sequences flanking GBA could play a role in the transcriptional regulation of the gene contributing to the complexity underlying the phenotypic diversity seen in GD.", "Various bacterial toxins have potent insecticidal activity. Recently, the Toxin complexes (Tc's) of Photorhabdus and Xenorhabdus species have become an increased focus of current research. These large tripartite toxins with molecular masses >1.4 megadaltons consist of three components termed A, B, and C (or TcA, TcB, and TcC). While TcA is involved in receptor binding and toxin translocation, TcC possesses the specific toxin enzyme activity and TcB is a linker between components TcA and TcC. Here, a structure function analysis of the toxins is described and the application of Tc toxins as potential insecticides is discussed.", "A 61-year-old male patient presented with petechiae on the arms and legs due to a thrombocytopenia of 3 Gpt/l (3000/microl). A butterfly rash on the patient's face suggested a diagnosis of systemic lupus erythematosus (SLE). The thrombocytopenia was due to autoimmune thrombocytopenia. The diagnosis of SLE could be excluded and the butterfly rash attributed to a laminar hemorrhage, an ecchymosis due to the autoimmune thrombocytopenia.", "Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites produced by cytochrome P450 epoxygenases which are highly expressed in hepatocytes. The functions of EETs in hepatocytes are not well understood. In this study, we investigated the effects of 14,15-EETs treatment on the insulin signal transduction pathway in hepatocytes. We report that chronic treatment, not acute treatment, with 30 μM 14,15-EETs prevents palmitate induced insulin resistance and potentiates insulin action in cultured HepG2 hepatocytes. 14,15-EETs increase Akt phosphorylation at S473, activating Akt, in an insulin dependent manner in HepG2 cells. Under insulin resistant conditions induced by palmitate, 14,15-EETs restore the insulin response by increasing S473-phosphorylated Akt. 8,9-EETs and 11,12-EETs demonstrated similar effects to 14,15-EETs. Furthermore, 14,15-EETs potentiate insulin-suppression of gluconeogenesis in cultured H4IIE hepatocytes. To elucidate the mechanism of EETs function, we analyzed the insulin signaling factors upstream of Akt. Inhibition of phosphatidylinositol 3-kinase (PI3K) with LY294002 attenuated the 14,15-EETs-induced activating phosphorylation of Akt. 14,15-EETs reduced palmitate-stimulated phosphorylation of IRS-1 on S312 and phosphorylation of c-Jun N-terminal kinase (JNK) at threonine 183 and tyrosine 185 residues. The regulation of insulin sensitivity in cultured hepatocytes by chronic 14,15-EETs treatment appears to involve the JNK-IRS-PI3K pathway. The requirement of chronic treatment with EETs suggests that the effects of EETs on insulin response may be indirect.", "Methylation of lysine residues in the N-terminal tails of histones is thought to represent an important component of the mechanism that regulates chromatin structure. The evolutionarily conserved SET domain occurs in most proteins known to possess histone lysine methyltransferase activity. We present here the crystal structure of a large fragment of human SET7/9 that contains a N-terminal beta-sheet domain as well as the conserved SET domain. Mutagenesis identifies two residues in the C terminus of the protein that appear essential for catalytic activity toward lysine-4 of histone H3. Furthermore, we show how the cofactor AdoMet binds to this domain and present biochemical data supporting the role of invariant residues in catalysis, binding of AdoMet, and interactions with the peptide substrate.", "Tripartite Tc toxin complexes of bacterial pathogens perforate the host membrane and translocate toxic enzymes into the host cell, including in humans. The underlying mechanism is complex but poorly understood. Here we report the first, to our knowledge, high-resolution structures of a TcA subunit in its prepore and pore state and of a complete 1.7 megadalton Tc complex. The structures reveal that, in addition to a translocation channel, TcA forms four receptor-binding sites and a neuraminidase-like region, which are important for its host specificity. pH-induced opening of the shell releases an entropic spring that drives the injection of the TcA channel into the membrane. Binding of TcB/TcC to TcA opens a gate formed by a six-bladed β-propeller and results in a continuous protein translocation channel, whose architecture and properties suggest a novel mode of protein unfolding and translocation. Our results allow us to understand key steps of infections involving Tc toxins at the molecular level.", "PURPOSE OF REVIEW: The purpose of this study is to highlight the pathological features and clinical aspects of progressive multiple sclerosis (PMS) and also the results of clinical trial experience to date and review ongoing clinical trials and prospective new treatment options. This study will explain the challenges of clinical trial design in PMS.RECENT FINDINGS: Multiple sclerosis (MS) has been identified as a chronic immune mediated disease, and the progressive phase of the disease appears to have significant neurodegenerative mechanisms. The classification of the course of PMS has been reorganized into categories of active vs. inactive inflammatory disease and the presence vs. absence of gradual disease progression. This differentiation allows clearer conceptualization of PMS and possibly even more efficient recruitment of PMS patients into clinical trials. Clinical trial experience to date in PMS has been negative with anti-inflammatory medications used in relapsing MS. Simvastatin was recently tested in a phase II trial and showed a 43% reduction of annualized atrophy progression in secondary progressive MS. Ongoing PMS trials are currently being conducted with the phosphodiesterase inhibitor ibudilast, S1P modulator siponimod and anti-B-cell therapy ocrelizumab. Several efforts for development of outcome measures in PMS are ongoing.SUMMARY: PMS represents a significant challenge, as the pathogenesis of the disease is not well understood, no validated outcome metrics have been established and clinical trial experience to date has been disappointing. Advances in the understanding of the disease and lessons learned in previous clinical trials are paving the way for successful development of disease-modifying agents for this disease.", "Abacavir hypersensitivity (ABC HSR) is a treatment-limiting adverse event associated with the use of the antiretroviral medicine, abacavir. The objective of the ABC HSR pharmacogenetics program was to identify clinically useful genetic risk factors to predict an individual patient's risk for ABC HSR. The major histocompatibility complex allele, HLA-B*5701, was identified retrospectively and confirmed with independent sample sets. The clinical utility of prospective HLA-B*5701 screening was demonstrated in a blinded randomized clinical trial and in open-label cohorts. Screening has been incorporated into clinical practice and the ABC HSR pharmacogenetics program has been highlighted as a success by pharmacogenetics researchers. Important lessons from this pharmacogenetics program will be discussed in this paper.", "Bexsero, a new vaccine against Neisseria meningitidis serogroup B (MenB), is composed of 3 main recombinant proteins and an outer membrane vesicle component. One of the main bactericidal antigens, neisseria heparin binding antigen (NHBA), is present as a fusion protein with the accessory protein genome-derived neisserial antigen (GNA) 1030 to further increase its immunogenicity. The gene encoding for GNA1030 is present and highly conserved in all Neisseria strains, and although orthologs are present in numerous species, its biologic function is unknown. Native mass spectrometry was used to demonstrate that GNA1030 forms a homodimer associated with 2 molecules of ubiquinone-8 (Ub8), a cofactor mainly involved in the electron transport chain and with antioxidant properties. Disc diffusion assays on the wild-type and knockout mutant of GNA1030, in the presence of various compounds, suggested that GNA1030 is not involved in oxidative stress or electron chain transport per se, although it contributes to constitutive refilling of the inner membrane with Ub8. These studies shed light on an accessory protein present in Bexsero and reveal functional insights into the family of related proteins. On the basis of our findings, we propose to name the protein neisseria ubiquinone binding protein (NUbp).", "BACKGROUND: Neurofibromatosis type 1 (NF1) is a common disorder of dysregulated tissue growth secondary to mutations in the tumor suppressor gene NF1. Pulmonary arterial hypertension (PAH) in patients with NF1 is hypothesized to be secondary to an underlying vasculopathy.METHODS: We describe the entity we term NF1-associated PAH (NF1-PAH) in four new patients and update the data on four previously published reports of patients with PAH and NF1. We performed genetic testing of the bone morphogenic protein receptor 2 (BMPR2) gene, which mutated in 70% of patients with familial PAH and approximately 25% of patients with idiopathic PAH. We report, for the first time, pathologic findings in the autopsy-obtained lung of one patient with NF1-PAH.RESULTS: Patients with NF1-PAH have a generally poor long-term prognosis. In four patients, we observed the mosaic pattern of lung attenuation on a CT scan of the chest, a radiographic finding that can be consistent with an underlying vasculopathy. No mutations or rearrangements in the BMPR2 gene were found. We observed complex plexiform lesions in the one available autopsy specimen. Similar lesions are a hallmark of plexogenic pulmonary arteriopathy and are associated with several severe types of PAH. (Plexiform lesions should not be confused with plexiform neurofibromas, which are distinctive tumors seen in NF1.)CONCLUSIONS: Our findings suggest that NF1 should be considered as being \"associated with PAH as outlined in the Revised Clinical Classification of Pulmonary Hypertension. Understanding the mechanism of PAH in NF1 may inform the pathogenesis of PAH, NF1-PAH itself, and other NF1-associated vasculopathies. The pulmonary vasculature should now be included among the arterial beds affected by NF1 vasculopathy.", "Reverse vaccinology (RV), the first application of genomic technologies in vaccine research, represented a major revolution in the process of discovering novel vaccines. By determining their entire antigenic repertoire, researchers could identify protective targets and design efficacious vaccines for pathogens where conventional approaches had failed. Bexsero, the first vaccine developed using RV, has recently received positive opinion from the European Medicines Agency. The use of RV initiated a cascade of changes that affected the entire vaccine development process, shifting the focus from the identification of a list of vaccine candidates to the definition of a set of high throughput screens to reduce the need for costly and labor intensive tests in animal models. It is now clear that a deep understanding of the epidemiology of vaccine candidates, and their regulation and role in host-pathogen interactions, must become an integral component of the screening workflow. Far from being outdated by technological advancements, RV still represents a paradigm of how high-throughput technologies and scientific insight can be integrated into biotechnology research.", "Tc toxins are widely distributed among different gram-negative and gram-positive bacteria, where they act as pathogenicity factors. The toxins are composed of different components that form oligomers for biological activity. Lipid bilayer experiments were performed with the TcdA1 component of the Tc toxin from Photorhabdus luminescens, which preferentially kills insects by actin polymerization. TcdA1 was able to increase the specific conductance of artificial lipid bilayer membranes by the formation of ion-permeable channels. The channels had on average a single-channel conductance of 125 pS in 150 mM KCl and were found to be cation selective. The single-channel conductance of the TcdA1-channels was only moderately dependent on the bulk aqueous KCl concentration, which indicated point-charge effects on the channel properties. Experiments to study the voltage dependence of the TcdA1 channel demonstrated that it is reconstituted in a fully oriented way when it is added to only one side of the lipid bilayer membrane. A combination of biologically active components (TccC3) and a possible chaperone (TcdB2) blocked the TcdA1-mediated conductance efficiently in a dose-dependent manner when they were added to the cis side of the membrane. The half-saturation constant for binding of TcdB2-TccC3 to TcdA1 is in the low nanomolar range.", "The toxin complex (tc) genes of bacteria comprise a large and growing family whose mode of action remains obscure. In the insect pathogen Photorhabdus, tc genes encode high molecular weight insecticidal toxins with oral activity against caterpillar pests. One protein, TcdA, has recently been expressed in transgenic plants and shown to confer insect resistance. These toxins therefore represent alternatives to toxins from Bacillus thuringiensis (Bt) for deployment in transgenic crops. Levels of TcdA expression in transgenic plants were, however, low and the full toxicity associated with the native toxin was not reconstituted. Here we show that increased activity of the toxin TcdA1 requires potentiation by either of two pairs of gene products, TcdB1 and TccC1 or TcdB2 and TccC3. Moreover, these same pairs of proteins can also cross-potentiate a second toxin, TcaA1B1. To elucidate the likely functional domains present in these large proteins, we expressed fragments of each 'toxin' or 'potentiator' gene within mammalian cells. Several domains produced abnormal cellular morphologies leading to cell death, while others showed specific phenotypes such as nuclear translocation. Our results prove that the Tc toxins are complex proteins with multiple functional domains. They also show that both toxin genes and their potentiator pairs will need to be expressed to reconstitute full activity in insect-resistant transgenic plants. Moreover, they suggest that the same potentiator pair will be able to cross-potentiate more than one toxin in a single plant.", "The toxin complex (tc) genes of Photorhabdus encode insecticidal, high molecular weight Tc toxins. These toxins have been suggested as useful alternatives to those derived from Bacillus thuringiensis for expression in insect-resistant transgenic plants. Although Photorhabdus luminescens is symbiotic with nematodes that kill insects, tc genes have recently been described from other insect-associated bacteria such as Serratia entomophila, an insect pathogen, and Yersinia pestis, the causative agent of bubonic plague, which has a flea vector. Here, recent advances in our understanding of the tc gene family are reviewed in view of their potential development as insect-control agents.", "BACKGROUND: Kabuki syndrome is a haploinsufficient congenital multi-organ malformation syndrome, which frequently includes severe heart defects. Mutations in the histone H3K4 methyltransferase KMT2D have been identified as the main cause of Kabuki syndrome, however, the role of KMT2D in heart development remains to be characterized.RESULTS: Here we analyze the function of Kmt2d at different stages of Xenopus heart development. Xenopus Kmt2d is ubiquitously expressed at early stages of cardiogenesis, with enrichment in the anterior region including the cardiac precursor cells. Morpholino-mediated knockdown of Kmt2d led to hypoplastic hearts lacking the three-chambered structure. Analyzing different stages of cardiogenesis revealed that development of the first and second heart fields as well as cardiac differentiation were severely affected by loss of Kmt2d function.CONCLUSION: Kmt2d loss of function in Xenopus recapitulates the hypoplastic heart defects observed in Kabuki syndrome patients and shows that Kmt2d function is required for the establishment of the primary and secondary heart fields. Thus, Xenopus Kmt2d morphants can be a valuable tool to elucidate the etiology of the congenital heart defects associated with Kabuki syndrome.", "Small ubiquitin-like modifier (SUMO) participates in a reversible posttranslational modification process (SUMOylation) that regulates a wide variety of cellular processes and plays important roles for numerous viruses during infection. However, the roles of viral protein SUMOylation in dengue virus (DENV) infection have not been elucidated. In this study, we found that the SUMOylation pathway was involved in the DENV life cycle, since DENV replication was reduced by silencing the cellular gene Ubc9, which encodes the sole E2-conjugating enzyme required for SUMOylation. By in vivo and in vitro SUMOylation assays, the DENV NS5 protein was identified as an authentic SUMO-targeted protein. By expressing various NS5 mutants, we found that the SUMO acceptor sites are located in the N-terminal domain of NS5 and that a putative SUMO-interacting motif (SIM) of this domain is crucial for its SUMOylation. A DENV replicon harboring the SUMOylation-defective SIM mutant showed a severe defect in viral RNA replication, supporting the notion that NS5 SUMOylation is required for DENV replication. SUMOylation-defective mutants also failed to suppress the induction of STAT2-mediated host antiviral interferon signaling. Furthermore, the SUMOylation of NS5 significantly increased the stability of NS5 protein, which could account for most of the biological functions of SUMOylated NS5. Collectively, these findings suggest that the SUMOylation of DENV NS5 is one of the mechanisms regulating DENV replication.IMPORTANCE: SUMOylation is a common posttranslational modification that regulates cellular protein functions but has not been reported in the proteins of dengue virus. Here, we found that the replicase of DENV, nonstructural protein 5 (NS5), can be SUMOylated. It is well known that providing RNA-dependent RNA polymerase activity and antagonizing host antiviral IFN signaling are a \"double indemnity\" of NS5 to support DENV replication. Without SUMOylation, NS5 fails to maintain its protein stability, which consequently disrupts its function in viral RNA replication and innate immunity antagonism. DENV threatens billions of people worldwide, but no licensed vaccine or specific therapeutics are currently available. Thus, our findings suggest that rather than specifically targeting NS5 enzyme activity, NS5 protein stability is a novel drug target on the growing list of anti-DENV strategies.", "MLN4924 is a first-in-class experimental cancer drug that inhibits the NEDD8-activating enzyme, thereby inhibiting cullin-RING E3 ubiquitin ligases and stabilizing many cullin substrates. The mechanism by which MLN4924 inhibits cancer cell proliferation has not been defined, although it is accompanied by DNA rereplication and attendant DNA damage. Here we show that stabilization of the DNA replication factor Cdt1, a substrate of cullins 1 and 4, is critical for MLN4924 to trigger DNA rereplication and inhibit cell proliferation. Even only 1 hour of exposure to MLN4924, which was sufficient to elevate Cdt1 for 4-5 hours, was found to be sufficient to induce DNA rereplication and to activate apoptosis and senescence pathways. Cells in S phase were most susceptible, suggesting that MLN4924 will be most toxic on highly proliferating cancers. Although MLN4924-induced cell senescence seems to be dependent on induction of p53 and its downstream effector p21(Waf1), we found that p53(-/-) and p21(-/-) cells were even more susceptible than wild-type cells to MLN4924. Our results suggested that apoptosis, not senescence, might be more important for the antiproliferative effect of MLN4924. Furthermore, our findings show that transient exposure to this new investigational drug should be useful for controlling p53-negative cancer cells, which often pose significant clinical challenge.", "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." ]

[ "Exosomes are extracellular vesicles of endosomal origin which have emerged as key mediators of intercellular communication. All major cardiac cell types-including cardiomyocytes, endothelial cells, and fibroblasts-release exosomes that modulate cellular functions. Exosomes released from human cardiac progenitor cells (CPCs) are cardioprotective and improve cardiac function after myocardial infarction to an extent comparable with that achieved by their parent cells. Cardiac progenitor cell-derived exosomes are enriched in cardioprotective microRNAs, particularly miR-146a-3p. Circulating exosomes mediate remote ischaemic preconditioning. Moreover, they currently are being investigated as diagnostic markers. The discovery that cell-derived extracellular signalling organelles mediate the paracrine effects of stem cells suggests that cell-free strategies could supplant cell transplantation. This review discusses emerging roles of exosomes in cardiovascular physiology, with a focus on cardioprotective activities of CPC-derived exosomes.", "Genetic and biological studies provide evidence that the production and deposition of amyloid-beta peptides (Abeta) contribute to the etiology of Alzheimer's disease. beta- and gamma-secretases, which are responsible for the generation of Abeta, are plausible molecular targets for Alzheimer's disease treatment. gamma-Secretase is an unusual aspartic protease that cleaves the scissile bond within the transmembrane domain. This unusual enzyme is composed of a high molecular weight membrane protein complex containing presenilin, nicastrin, Aph-1 and Pen-2. Drugs that regulate the production of Abeta by inhibiting or modulating gamma-secretase activity could provide a disease-modifying effect on Alzheimer's disease, although recent studies suggest that gamma-secretase plays important roles in cellular signaling including Notch. Thus, understanding the molecular mechanism whereby gamma-secretase recognizes and cleaves its substrate is a critical issue for the development of compounds that specifically regulate Abeta-generating gamma-secretase activity. This review focuses on the structure and function relationship of gamma-secretase complex and the mode of action of the gamma-secretase inhibitors.", "Anemia in chronic kidney disease is a prevalent and expensive problem in the United States, and it is well documented that anemia worsens as glomerular filtration rates decline. The complications of severe anemia in this patient population contribute significantly to their overall morbidity with increased cardiovascular complications, decreased quality of life, and increased dependence on transfusions to maintain adequate hemoglobin levels. Erythropoietin-stimulating agents (ESAs) have revolutionized the treatment of anemia in this population, but there has been a great deal of controversy surrounding the quest for the ideal hemoglobin target. In addition, there are economic and practice management implications where anemia treatment is concerned, with ongoing refinement of Centers for Medicare and Medicaid Services-bundled payments. One of the newest additions to the arsenal used to fight anemia in end-stage renal disease patients is peginesatide (Omontys), a synthetic, PEGylated, peptide-based ESA that acts by stimulating the erythropoietin receptor. The role of peginesatide in the future treatment of anemia in chronic kidney disease remains uncertain, with new safety concerns being brought to attention as it emerges on the market, prompting a national recall.", "BACKGROUND: Dislocated metatarsophalangeal joints from clawed or hammer toes can be a disabling consequence of several conditions. The Cobb-Stainsby forefoot arthroplasty combines partial phalangectomy (Stainsby) with extensor tendon transfer to the metatarsal head (Cobb). We present a retrospective, three surgeon case series of 215 toes in 126 patients.METHODS: Early results and complications were gathered from the medical charts of 126 patients who met the inclusion criteria. Seventy-five patients were contactable by phone with a follow up range of 12-82 months (median follow up 45 months). Primary outcome measures were improvement of pain and function, reduction in plantar callosities and cosmetic improvement of the deformity.RESULTS: Pre-operatively all patients presented with pain and shoe wear problems. Post-operatively seventy-two patients (96%) were satisfied, 72 (96%) reported pain relief, 55 (73%) were happy with toe control, 61 (81%) were pleased with cosmesis and 56 (75%) reported unlimited daily activities. Superficial wound infections were observed in 13 of the 126 patients (10%) and two in 75 patients (2%) developed recurrent clawing.CONCLUSION: Our case series demonstrates improved outcomes over alternatives such as the Weil's osteotomy.", "Capnocytophaga canimorsus has been recognized as an opportunistic pathogen causing systemic infections in immunocompromised individuals. It is part of the normal oral flora of the dog, and can be responsible for localized wound infections in humans in consequence of bites. This microorganism causes also septicemia, meningitis, endocarditis, ocular infections and rarely brain abscess. We describe the case of an immunocompetent 28-year-old male with temporal brain abscess from Capnocytophaga canimorsus secondary to dog's bite.", "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.", "Results in 136 hyperprolactinaemic women who presented with infertility, amenorrhoea, menstrual irregularities and/or galactorrhoea are reported. There was radiographic evidence of pituitary microadenoma in 21 (15.4%) patients and 5 (3.7%) had macroadenoma. Four patients were taking antidepressants, 2 antihypertensive drugs and 7 had taken oral contraceptives for a period of 6 months to 5 years. The remaining patients had no obvious cause for elevated prolactin levels. Patients with pituitary adenoma had a significantly higher (p less than 0.001) baseline serum prolactin level (182 +/- 4.6 ng/ml) than those with no adenoma (59.2 +/- 4.2 ng/ml). All patients in the study were treated with bromocriptine (2.5-10 mg) to normalize serum prolactin or to achieve a pregnancy. The patients without an adenoma required a significantly smaller dose of bromocriptine (2.5-5.0 mg) (p less than 0.005) than those with an adenoma. Galactorrhoea disappeared in all 64 patients within 2-4 months of treatment, sixty-six (71%) of the 93 patients who desired pregnancy achieved it within 3 to 8 months of bromocriptine therapy; 32 of these patients received additional treatment with clomiphene and human chorionic gonadotrophins for induction of ovulation. In the remaining 70 patients menstruation became regular and ovulation was evident in 40% of them. There was no significant difference in the pregnancy rate between the patients with or without pituitary adenoma. Similarly, presence of galactorrhoea or a high level of prolactin did not influence the pregnancy rate. No complications were observed during pregnancy related to pituitary adenomas; 8 (12%) pregnancies ended in first trimester abortion. No lethal congenital fetal abnormalities were observed in the patients treated with bromocriptine.(ABSTRACT TRUNCATED AT 250 WORDS)" ]

[ "The 26S proteasome complex engages in an ATP-dependent proteolytic degradation of a variety of oncoproteins, transcription factors, cell cycle specific cyclins, cyclin-dependent kinase inhibitors, ornithine decarboxylase, and other key regulatory cellular proteins. Thus, the proteasome regulates either directly or indirectly many important cellular processes. Altered regulation of these cellular events is linked to the development of cancer. Therefore, the proteasome has become an attractive target for the treatment of numerous cancers. Several proteasome inhibitors that target the proteolytic active sites of the 26S proteasome complex have been developed and tested for anti-tumor activities. These proteasome inhibitors have displayed impressive anti-tumor functions by inducing apoptosis in different tumor types. Further, the proteasome inhibitors have been shown to induce cell cycle arrest, and inhibit angiogenesis, cell-cell adhesion, cell migration, immune and inflammatory responses, and DNA repair response. A number of proteasome inhibitors are now in clinical trials to treat multiple myeloma and solid tumors. Many other proteasome inhibitors with different efficiencies are being developed and tested for anti-tumor activities. Several proteasome inhibitors currently in clinical trials have shown significantly improved anti-tumor activities when combined with other drugs such as histone deacetylase (HDAC) inhibitors, Akt (protein kinase B) inhibitors, DNA damaging agents, Hsp90 (heat shock protein 90) inhibitors, and lenalidomide. The proteasome inhibitor bortezomib is now in the clinic to treat multiple myeloma and mantle cell lymphoma. Here, we discuss the 26S proteasome complex in carcinogenesis and different proteasome inhibitors with their potential therapeutic applications in treatment of numerous cancers.", "Lenalidomide was approved by the US Food and Drug Administration (FDA) for treatment of transfusion-dependent lower-risk myelodysplastic syndrome patients with deletion (del) (5q) alone or with additional karyotype abnormalities. The approval was based on high rates of prolonged transfusion independence and complete cytogenetic response in this subset. In lower-risk non-del(5q) patients, meaningful erythroid responses also were reported with a low frequency of cytogenetic improvement, although inferior to that observed in the del(5q) patients. There is now a better understanding of the mechanism of the karyotype-dependent drug action, explaining the disparate response rates and frequency of myelosuppression. In del(5q) patients, lenalidomide suppresses the clone by inhibiting the nuclear sequestration of the haplodeficient cell cycle regulatory protein cdc25c, thereby promoting selective G2 arrest and apoptosis. In non-del(5q) patients, lenalidomide enhances erythropoietin receptor signaling. Future directions include use of biologic and molecular markers as predictive tools to select patients and use of combination strategies to overcome resistance to lenalidomide in del(5q) patients or enhance erythropoiesis in non-del 5 patients.", "Emanuel syndrome (ES) is the most frequent type of recurrent non‑Robertsonian translocation that is characterized by numerous anomalies. Over 100 patients with ES have been described in the literature. The phenotype of this syndrome varies but often consists of facial dysmorphism, microcephaly, severe intellectual disability, developmental retardation, congenital heart disease and genital anomalies. The present study describes a 2‑year‑old boy with multiple malformations, including facial dysmorphism, severe intellectual disability, growth retardation, congenital heart disease, cleft lip and palate, genital malformation (micropenis), amblyopia, thymic dysplasia and hearing impairment. The karyotype of the patient was 47,XY,+del(22)(q13), and the maternal karyotype was 46,XX,t(11;22)(q25;q13),9qh‑,15p+. Single‑nucleotide polymorphism‑array analysis of the proband indicated a partial duplication of chromosomes 22 and 11 at 22q11.1‑q11.21 and 11q23.3‑q25, respectively, which confirmed the diagnosis of ES. To date, no cases of ES have been reported in mainland China. The present case further emphasizes the necessity and importance of high‑resolution techniques for genetic diagnosis and for subsequent genetic counseling. The present study contributed to the phenotypic delineation of ES and confirmed the first ES patient in mainland China.", "OBJECTIVE: To characterize the pharmacokinetics of the oral, non-estrogen agent ospemifene, an estrogen agonist/antagonist with tissue-selective effects (also called a selective estrogen receptor modulator) that was recently approved for the treatment of dyspareunia associated with vulvar and vaginal atrophy in postmenopausal women.METHODS: Two open-label, Phase 1 studies were conducted to determine the pharmacokinetics of ospemifene in healthy postmenopausal women. In the single-dose study, 60 mg of [3H]-ospemifene was orally administered to 6 subjects. Blood, urine, and fecal samples were collected predose and serially up to 240 hours postdose. In the multiple-dose study, 12 subjects received 60 mg of ospemifene once daily for 9 days. Blood samples were collected predose and serially postdose on Day 1, predose on Days 7 and 8, and predose and serially postdose on Day 9.RESULTS: Ospemifene exhibited high plasma protein binding and was extensively metabolized, predominantly to 4-hydroxyospemifene and 4'-hydroxyospemifene. In the single-dose study, ospemifene was rapidly absorbed, with a median tmax of 1.50 hours and geometric mean Cmax of 612 ng/ml. The geometric mean (CV%) t1/2 was 24.5 (21.3) hours and 29.0 (18.0) hours for ospemifene and 4-hydroxyospemifene, respectively. Fecal elimination accounted for 75% of the administered [3H]-ospemifene dose in 240 hours. In the multiple dosing study, steady state was reached by Day 7. The mean t1/2 at steady state for ospemifene was 29.1 hours. High values for volume of distribution and total clearance suggested extensive tissue distribution and efficient elimination of ospemifene.CONCLUSIONS: In healthy postmenopausal women, ospemifene 60 mg/day reached steady state concentrations by Day 7 and showed minimal accumulation of parent drug or its two main metabolites, indicating that once daily dosing is appropriate.", "Phospholemman (FXYD1) is a single-transmembrane protein regulator of Na,K-ATPase, expressed strongly in heart, skeletal muscle, and brain and phosphorylated by protein kinases A and C at Ser-68 and Ser-63, respectively. Binding of FXYD1 reduces Na,K-ATPase activity, and phosphorylation at Ser-68 or Ser-63 relieves the inhibition. Despite the accumulated information on physiological effects, whole cell studies provide only limited information on molecular mechanisms. As a complementary approach, we utilized purified human Na,K-ATPase (α1β1 and α2β1) reconstituted with FXYD1 or mutants S63E, S68E, and S63E,S68E that mimic phosphorylation at Ser-63 and Ser-68. Compared with control α1β1, FXYD1 reduces Vmax and turnover rate and raises K0.5Na. The phosphomimetic mutants reverse these effects and reduce K0.5Na below control K0.5Na. Effects on α2β1 are similar but smaller. Experiments in proteoliposomes reconstituted with α1β1 show analogous effects of FXYD1 on K0.5Na, which are abolished by phosphomimetic mutants and also by increasing mole fractions of DOPS in the proteoliposomes. Stopped-flow experiments using the dye RH421 show that FXYD1 slows the conformational transition E2(2K)ATP → E1(3Na)ATP but does not affect 3NaE1P → E2P3Na. This regulatory effect is explained simply by molecular modeling, which indicates that a cytoplasmic helix (residues 60-70) docks between the αN and αP domains in the E2 conformation, but docking is weaker in E1 (also for phosphomimetic mutants). Taken together with previous work showing that FXYD1 also raises binding affinity for the Na(+)-selective site III, these results provide a rather comprehensive picture of the regulatory mechanism of FXYD1 that complements the physiological studies.", "Due to high volatility and environmental mobility, radioactive isotopes of iodine pose a serious risk in the acute phases of a nuclear accident. The critical organ for iodine is the thyroid. A number of studies dealing with thyroid protection from exposure to radioiodine have shown that radioiodine uptake by the thyroid can be effectively blocked by administration of stable iodine, usually in the form of potassium iodide (KI) pills. However, unless perfectly timed, this protective action may be counterproductive. The International Atomic Energy Agency recommends potassium iodide prophylaxis in cases when an avertable thyroid dose by protective action exceeds 100 mGy. This paper reviews experiences and practices with potassium iodide in the thyroid protection. This kind of information should serve as the basis for discussion and decision making on KI prophylactic programmes in nuclear emergency situations in Croatia. If Croatia adopts such programme, it will still have to develop the most effective way of KI stockpiling and distribution or predistribution.", "Lowering mutant Huntingtin is a consensus therapeutic strategy for Huntington's disease. In this issue of Neuron, Kordasiewicz et al. (2012) show the benefit of transient antisense oligonucleotide (ASO) therapy to degrade Huntingtin mRNA and elicit sustained therapeutic benefit in HD mice." ]

[ "INTRODUCTION: Listeria monocytogenes is a gram-positive bacillus which causes sporadic infections in immunocompromised humans, with a special propensity for the central nervous system, in the form of acute, subacute or chronic meningitis, rhombencephalitis or abscesses in the brain or spinal cord. The final diagnosis is established by germ culture in blood or in cerebrospinal fluid (CSF). Preferred treatment is ampicillin in association with aminoglycosides.CASE REPORT: We report the case of a 70-year-old male patient with a history of arterial hypertension and chronic lymphatic leukaemia with no specific treatment, who suffered meningoencephalitis and brain abscesses caused by L. monocytogenes. Symptoms were a 48-hour history of headache and a febrile condition. The CSF showed lymphocytic pleocytosis with hypoglycorrhachia. Magnetic resonance scans of the brain revealed areas of cerebritis and multiple brain abscesses in the right frontal lobe. Specific treatment was established with ampicillin for 13 weeks, associated with gentamicin and vancomycin during the first few weeks, until x-rays showed the lesions to be resolved.CONCLUSIONS: L. monocytogenes infections must be investigated in all patients with cellular immunosuppression who present febrile symptoms. The central nervous system may be the only area of the body infected. Moreover, this site will need studying in patients who present neurological focus data or an alteration in the state of consciousness and bacteraemia due to L. monocytogenes. Establishing suitable treatment as early as possible can improve the prognosis.", "OBJECTIVES: To investigate and analyze the BRCA mutations in Korean ovarian cancer patients with or without family history and to find founder mutations in this group.METHODS/MATERIALS: One hundred two patients who underwent a staging operation for pathologically proven epithelial cancer between January 2013 and December 2014 were enrolled. Thirty-two patients declined to analyze BRCA1/2 gene alterations after genetic counseling and pedigree analysis. Lymphocyte specimens from peripheral blood were assessed for BRCA1/2 by direct sequencing.RESULTS: BRCA genetic test results of 70 patients were available. Eighteen BRCA1/2 mutations and 17 unclassified variations (UVs) were found. Five of the BRCA1/2 mutations and 4 of the UVs were not reported in the Breast Cancer Information Core database. One BRCA2 UV (8665_8667delGGA) was strongly suspicious to be a deleterious mutation. BRCA1/2 mutations were identified in 11 (61.1%) of 18 patients with a family history and in 7 (13.5%) of 52 patients without a family history.Candidates for founder mutations in Korean ovarian cancer patients were assessed among 39 BRCA1/2 mutations from the present study and from literature reviews. The analysis showed that 1041_1043delAGCinsT (n = 4; 10.2%) and 3746insA (n = 4; 10.2%) were possible BRCA1 founder mutations. Only one of the BRCA2 mutations (5804_5807delTTAA) was repeated twice (n = 2; 5.1%).CONCLUSIONS: The prevalence of BRCA1/2 mutations in Korean ovarian cancer patients irrespective of the family history was significantly higher than previously reported. Possible founder mutations in Korean ovarian cancer patients were identified.", "Alternative splicing affects more than 90% of human genes. Coupling between transcription and splicing has become crucial in the complex network underlying alternative splicing regulation. Because chromatin is the real template for nuclear transcription, changes in its structure, but also in the \"reading\" and \"writing\" of the histone code, could modulate splicing choices. Here, we discuss the evidence supporting these ideas, from the first proposal of chromatin affecting alternative splicing, performed 20 years ago, to the latest findings including genome-wide evidence that nucleosomes are preferentially positioned in exons. We focus on two recent reports from our laboratories that add new evidence to this field. The first report shows that a physiological stimulus such as neuron depolarization promotes intragenic histone acetylation (H3K9ac) and chromatin relaxation, causing the skipping of exon 18 of the neural cell adhesion molecule gene. In the second report, we show how specific histone modifications can be created at targeted gene regions as a way to affect alternative splicing: Using small interfering RNAs (siRNAs), we increased the levels of H3K9me2 and H3K27me3 in the proximity of alternative exon 33 of the human fibronectin gene, favoring its inclusion into mature messenger RNA (mRNA) through a mechanism that recalls RNA-mediated transcriptional gene silencing.", "The mammalian microbiome has many important roles in health and disease, and genetic engineering is enabling the development of microbial therapeutics and diagnostics. A key determinant of the activity of both natural and engineered microorganisms in vivo is their location within the host organism. However, existing methods for imaging cellular location and function, primarily based on optical reporter genes, have limited deep tissue performance owing to light scattering or require radioactive tracers. Here we introduce acoustic reporter genes, which are genetic constructs that allow bacterial gene expression to be visualized in vivo using ultrasound, a widely available inexpensive technique with deep tissue penetration and high spatial resolution. These constructs are based on gas vesicles, a unique class of gas-filled protein nanostructures that are expressed primarily in water-dwelling photosynthetic organisms as a means to regulate buoyancy. Heterologous expression of engineered gene clusters encoding gas vesicles allows Escherichia coli and Salmonella typhimurium to be imaged noninvasively at volumetric densities below 0.01% with a resolution of less than 100 μm. We demonstrate the imaging of engineered cells in vivo in proof-of-concept models of gastrointestinal and tumour localization, and develop acoustically distinct reporters that enable multiplexed imaging of cellular populations. This technology equips microbial cells with a means to be visualized deep inside mammalian hosts, facilitating the study of the mammalian microbiome and the development of diagnostic and therapeutic cellular agents.", "Morgellons disease (MD) is a dermopathy characterized by multicolored filaments that lie under, are embedded in, or project from skin. Although MD was initially considered to be a delusional disorder, recent studies have demonstrated that the dermopathy is associated with tickborne infection, that the filaments are composed of keratin and collagen, and that they result from proliferation of keratinocytes and fibroblasts in epithelial tissue. Culture, histopathological and molecular evidence of spirochetal infection associated with MD has been presented in several published studies using a variety of techniques. Spirochetes genetically identified as Borrelia burgdorferi sensu stricto predominate as the infective agent in most of the Morgellons skin specimens studied so far. Other species of Borrelia including Borrelia garinii, Borrelia miyamotoi, and Borrelia hermsii have also been detected in skin specimens taken from MD patients. The optimal treatment for MD remains to be determined.", "A typical eukaryotic genome harbors a rich variety of repetitive elements. The most abundant are retrotransposons, mobile retroelements that utilize reverse transcriptase and an RNA intermediate to relocate to a new location within the cellular genomes. A vast majority of the repetitive mammalian genome content has originated from the retrotransposition of SINE (100-300 bp short interspersed nuclear elements that are derived from the structural 7SL RNA or tRNA), LINE (7kb long interspersed nuclear element), and LTR (2-3 kb long terminal repeats) transposable element superfamilies. Broadly labeled as \"evolutionary junkyard\" or \"fossils\", this enigmatic \"dark matter\" of the genome possesses many yet to be discovered properties.", "Stem cells persist throughout life by self-renewing in numerous tissues including the central and peripheral nervous systems. This raises the issue of whether there is a conserved mechanism to effect self-renewing divisions. Deficiency in the polycomb family transcriptional repressor Bmi-1 leads to progressive postnatal growth retardation and neurological defects. Here we show that Bmi-1 is required for the self-renewal of stem cells in the peripheral and central nervous systems but not for their survival or differentiation. The reduced self-renewal of Bmi-1-deficient neural stem cells leads to their postnatal depletion. In the absence of Bmi-1, the cyclin-dependent kinase inhibitor gene p16Ink4a is upregulated in neural stem cells, reducing the rate of proliferation. p16Ink4a deficiency partially reverses the self-renewal defect in Bmi-1-/- neural stem cells. This conserved requirement for Bmi-1 to promote self-renewal and to repress p16Ink4a expression suggests that a common mechanism regulates the self-renewal and postnatal persistence of diverse types of stem cell. Restricted neural progenitors from the gut and forebrain proliferate normally in the absence of Bmi-1. Thus, Bmi-1 dependence distinguishes stem cell self-renewal from restricted progenitor proliferation in these tissues." ]

[ "Most tubes have seams (intercellular or autocellular junctions that seal membranes together into a tube), but \"seamless\" tubes also exist. In Drosophila, stellate-shaped tracheal terminal cells make seamless tubes, with single branches running through each of dozens of cellular extensions. We find that mutations in braided impair terminal cell branching and cause formation of seamless tube cysts. We show that braided encodes Syntaxin7 and that cysts also form in cells deficient for other genes required either for membrane scission (shibire) or for early endosome formation (Rab5, Vps45, and Rabenosyn-5). These data define a requirement for early endocytosis in shaping seamless tube lumens. Importantly, apical proteins Crumbs and phospho-Moesin accumulate to aberrantly high levels in braided terminal cells. Overexpression of either Crumbs or phosphomimetic Moesin induced lumenal cysts and decreased terminal branching. Conversely, the braided seamless tube cyst phenotype was suppressed by mutations in crumbs or Moesin. Indeed, mutations in Moesin dominantly suppressed seamless tube cyst formation and restored terminal branching. We propose that early endocytosis maintains normal steady-state levels of Crumbs, which recruits apical phosphorylated (active) Moe, which in turn regulates seamless tube shape through modulation of cortical actin filaments.", "BACKGROUND: Animal-derived, protein-containing surfactants seem to be superior to protein-free surfactants. Lucinactant, a synthetic surfactant containing a surfactant protein-B peptide analog, has been shown to be effective in animal models and phase II clinical trials. To date, lucinactant has not been compared with an animal-derived surfactant in a premature animal model.OBJECTIVE: The objective was to compare the acute and sustained effects of lucinactant among premature lambs with respiratory distress syndrome (RDS) with the effects of a natural porcine surfactant (poractant-alpha).METHODS: After 5 minutes of mechanical ventilation twin premature lambs were assigned randomly to the lucinactant group (30 mg/mL, 5.8 mL/kg) or the poractant-alpha group (80 mg/mL, 2.2 mL/kg). Heart rate, systemic arterial pressure, arterial pH, blood gas values, and lung mechanics were recorded for 12 hours.RESULTS: Baseline fetal pH values were similar for the 2 groups (pH 7.27). After 5 minutes of mechanical ventilation, severe RDS developed (pH: <7.08; Paco2: >80 mm Hg; Pao2: <40 mm Hg; dynamic compliance: <0.08 mL/cm H2O per kg). After surfactant instillation, similar improvements in gas exchange and lung mechanics were observed for the lucinactant and poractant-alpha groups at 1 hour (pH: 7.3 +/- 0.1 vs 7.4 +/- 0.1; Paco2: 8 +/- 18 mm Hg vs 40 +/- 8 mm Hg; Pao2: 167 +/- 52 mm Hg vs 259 +/- 51 mm Hg; dynamic compliance: 0.3 +/- 0.1 mL/cm H2O per kg vs 0.3 +/- 0.1 mL/cm H2O per kg). The improvements in lung function were sustained, with no differences between groups. Cardiovascular profiles remained stable in both groups.CONCLUSIONS: Among preterm lambs with severe RDS, lucinactant produced improvements in gas exchange and lung mechanics similar to those observed with a porcine-derived surfactant.", "Many epithelial tissues undergo extensive remodelling during morphogenesis. How their epithelial features, such as apicobasal polarity or adhesion, are maintained and remodelled and how adhesion and polarity proteins contribute to morphogenesis are two important questions in development. Here, we approach these issues by investigating the role of the apical determinant protein Crumbs (Crb) during the morphogenesis of the embryonic Drosophila tracheal system. Crb accumulates differentially throughout tracheal development and is required for different tracheal events. The earliest requirement for Crb is for tracheal invagination, which is preceded by an enhanced accumulation of Crb in the invagination domain. There, Crb, acting in parallel with the epidermal growth factor receptor (Egfr) pathway, is required for tracheal cell apical constriction and for organising an actomyosin complex, which we propose is mediated by Crb recruitment of moesin (Moe). The ability of a Crb isoform unable to rescue polarity in crb mutants to otherwise rescue their invagination phenotype, and the converse inability of a FERM-binding domain mutant Crb to rescue faulty invagination, support our hypothesis that it is the absence of Crb-dependent Moe enrichment, and not the polarity defect, that mainly underlies the crb invagination phenotype. This hypothesis is supported by the phenotype of lethal giant larvae (lgl); crb double mutants. These results unveil a link between Crb and the organisation of the actin cytoskeleton during morphogenesis.", "The sarco-endoplasmic reticulum calcium ATPase 2a (SERCA2a) is critical for sequestering cytosolic calcium into the sarco-endoplasmic reticulum (SR) and regulating cardiac muscle relaxation. Protein-protein interactions indicated that it exists in complex with Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and its anchoring protein alphaKAP. Confocal imaging of isolated cardiomyocytes revealed the colocalization of CAMKII and alphaKAP with SERCA2a at the SR. Deletion analysis indicated that SERCA2a and CaMKII bind to different regions in the association domain of alphaKAP but not with each other. Although deletion of the putative N-terminal hydrophobic amino acid stretch in alphaKAP prevented its membrane targeting, it did not influence binding to SERCA2a or CaMKII. Both CaMKIIdelta(C) and the novel CaMKIIbeta(4) isoforms were found to exist in complex with alphaKAP and SERCA2a at the SR and were able to phosphorylate Thr-17 on phospholamban (PLN), an accessory subunit and known regulator of SERCA2a activity. Interestingly, the presence of alphaKAP was also found to significantly modulate the Ca(2+)/calmodulin-dependent phosphorylation of Thr-17 on PLN. These data demonstrate that alphaKAP exhibits a novel interaction with SERCA2a and may serve to spatially position CaMKII isoforms at the SR and to uniquely modulate the phosphorylation of PLN.", "Vortioxetine is a novel antidepressant with effects on multiple 5-HT receptors and on the serotonin transporter. This paper reviews preclinical and clinical evidence regarding its mechanism of action, its tolerability, and its efficacy in treating major depression. Clinical studies indicate that vortioxetine is effective in the treatment of major depression, though there is no suggestion of superiority over active comparators. There may be a clinically meaningful advantage in terms of tolerability.", "Chaperonins are a subclass of molecular chaperones that assist cellular proteins to fold and assemble into their native shape. Much work has been done on Type I chaperonins, which has elucidated their elegant mechanism. Some debate remains about the details in these mechanisms, but nonetheless the roles of these in helping protein folding have been understood in great depth. In this review we discuss the known functions of atypical Type I chaperonins, highlighting evolutionary aspects that might lead chaperonins to perform alternate functions.", "PURPOSE: Disturbances of the autonomic nervous system are common in patients with Parkinson's disease (PD) but the effect of deep brain stimulation of the subthalamic nucleus on cerebrovascular reactivity is not entirely known.METHODS: Seven patients in an advanced stage of the disease and seven healthy age-matched controls participated in the study, which took place after one night of drug withdrawal. Cerebral blood flow velocity was continuously monitored on both sides with transcranial Doppler ultrasound, and cerebrovascular reactivity (CR) was evaluated with the cold pressure test. The measurements were repeated and compared during the stimulation-on and -off phases.RESULTS: The PD patients had significantly higher CR values in the stimulation-on than -off conditions (15.1% ± 6.9 versus 9.4% ± 6.2; p = 0.03). CR values were higher in controls than in patients in the stimulation-off condition (20.4% ± 12.5 versus 9.4% ± 6.2; p = 0.007) without a significant difference with the stimulation-on phase.CONCLUSIONS: CR, evaluated by the response to the cold pressure test, is impaired in patients with advanced PD and improved by subthalamic nucleus.", "Recently developed molecular prognostic tests in patients with early Binet stage chronic lymphocytic leukemia (B-CLL) are costly and often require a high level of technologic expertise. Recent data give evidence for the prognostic relevance of the percentage of smudge cells in B-CLL. In our study we analysed the prognostic potential of this novel marker in a cohort of 100 CLL patients. The percentage of smudge cells ranged from 0% to 70% (median 21%). Patients with <or=20% smudge cells (according to ROC analysis) had a significantly shorter time to first treatment and overall survival than patients with >20% smudge cells. Multivariate Cox regression analysis identified percentages of smudge cells, stage according to Binet and CD38 expression as independent prognostic markers. The percentage of smudge cells was significantly lower in CD38+, ZAP-70+ and unmutated IgVH patients. Combined analysis of smudge cell percentages with CD38 expression provided complementary prognostic information identifying three patient subgroups with good, intermediate and poor prognosis. Comparing gene expression profiles in a subset of 12 patients we identified eight differentially expressed genes in groups with high vs. low percentage of smudge cells suggesting a role of these differentially expressed genes, especially for Tribbles homolog 2 (Trib2), in the disease progression of high risk CLL patients. In conclusion, our data confirm previous studies showing that the simple and inexpensive microscopic detection of smudge cells on blood smears prepared for routine diagnostic purposes is a novel independent factor predicting overall survival in CLL." ]

[ "Poly(A)-binding protein 1 (PABP1) has a fundamental role in the regulation of mRNA translation and stability, both of which are crucial for a wide variety of cellular processes. Although generally a diffuse cytoplasmic protein, it can be found in discrete foci such as stress and neuronal granules. Mammals encode several additional cytoplasmic PABPs that remain poorly characterised, and with the exception of PABP4, appear to be restricted in their expression to a small number of cell types. We have found that PABP4, similarly to PABP1, is a diffusely cytoplasmic protein that can be localised to stress granules. However, UV exposure unexpectedly relocalised both proteins to the nucleus. Nuclear relocalisation of PABPs was accompanied by a reduction in protein synthesis but was not linked to apoptosis. In examining the mechanism of PABP relocalisation, we found that it was related to a change in the distribution of poly(A) RNA within cells. Further investigation revealed that this change in RNA distribution was not affected by PABP knockdown but that perturbations that block mRNA export recapitulate PABP relocalisation. Our results support a model in which nuclear export of PABPs is dependent on ongoing mRNA export, and that a block in this process following UV exposure leads to accumulation of cytoplasmic PABPs in the nucleus. These data also provide mechanistic insight into reports that transcriptional inhibitors and expression of certain viral proteins cause relocation of PABP to the nucleus.", "The Wnt inhibitor Dickkopf-1 (DKK-1) has been associated with the occurrence of bone metastases in osteotropic prostate cancer by inhibiting osteoblastogenesis. P38 mitogen-activated protein kinase (MAPK) activity is also dysregulated in advanced prostate cancer. However, the impact of p38 MAPK signaling on DKK-1 remains unknown. Inhibition of p38 MAPK signaling in osteolytic PC3 cells by small molecule inhibitors (doramapimod, LY2228820 and SB202190) suppressed DKK-1 expression, whereas activation of p38 MAPK by anisomycin increased DKK-1. Further dissection by targeting individual p38 MAPK isoforms with siRNA revealed a stronger role for MAPK11 than MAPK14 and MAPK12 in the regulation of DKK-1. Moreover, prostate cancer cells with a predominantly osteolytic phenotype produced sufficient amounts of DKK-1 to inhibit Wnt3a-induced osteoblastic differentiation in C2C12 cells. This inhibition was blocked directly by neutralizing DKK-1 using a specific antibody and also indirectly by blocking p38 MAPK. Furthermore, tissue expression in human prostate cancer revealed a correlation between p38 MAPK and DKK-1 expression with higher expression in tumor compared with normal tissues. These results reveal that p38 MAPK regulates DKK-1 in prostate cancer and may present a potential target in osteolytic prostate cancers.", "The short QT syndrome constitutes a new clinical entity that is associated with a high incidence of sudden cardiac death, syncope, and/or atrial fibrillation even in young patients and newborns. Patients with this congenital electrical abnormality are characterized by rate-corrected QT intervals<320 ms. Missense mutations in KCNH2 (HERG) linked to a gain-of-function of the rapidly activating delayed-rectifier current I(Kr) have been identified in the first two reported families with familial sudden cardiac death. Recently, two further gain-of-function mutations in the KCNQ1 gene encoding the alpha-subunit of the KvLQT1 (I(Ks)) channel and in the KCNJ2 gene encoding the strong inwardly rectifying channel protein Kir2.1 confirmed a genetically heterogeneous disease. The possible substrate for the development of ventricular tachyarrhythmias may be a significant transmural dispersion of the repolarisation due to a heterogeneous abbreviation of the action potential duration. The implantable cardioverter defibrillator is the therapy of choice in patients with syncope and a positive family history of sudden cardiac death. However, ICD therapy in patients with a short QT syndrome has an increased risk for inappropriate shock therapies due to possible T wave oversensing. The impact of sotalol, ibutilide, flecainide, and quinidine on QT prolongation has been evaluated, but only quinidine effectively suppressed gain-of-function in I(Kr) with prolongation of the QT interval. In patients with a mutation in HERG, it rendered ventricular tachycardias/ventricular fibrillation non-inducible and restored the QT interval/heart rate relationship towards a normal range. It may serve as an adjunct to ICD therapy or as a possible alternative treatment, especially for children and newborns.", "AIM: Ustekinumab, a human monoclonal IgG1 antibody targeting the p40-subunit shared by interleukin (IL)12 and IL-23, represents a potential treatment for atopic dermatitis (AD). We evaluated the efficacy and safety of ustekinumab in the treatment of AD.METHODS: We reviewed the published literature by searching from PubMed, EMBASE, Web of Science and ClinicalTrial.gov then retrieved and analyzed several variables from patients records.RESULTS: Ten studies including eight cases and two RCT, comprising 107 patients, were included in the systematic review. Analysis all studies, a total of 58 patients (54.2%) gained an effective treatment with little adverse events.CONCLUSIONS: Ustekinumab is a well-tolerated and safe treatment with no significant difference in effect from placebo in patients with AD. Further, larger randomized controlled trials need to be conducted to identify a suitable regimen for AD and provide more evidence for clinical application.", "Chronic myeloid leukemia (CML) is a pluripotent hematopoietic disorder that is currently considered incurable. The tyrosine kinase product of the Philadelphia chromosome, P210 BCR-ABL, provided a pathogenetic explanation for the initiation of the CML chronic phase and is the molecular therapeutic target for the disease. Imatinib mesylate, an orally available BCR-ABL kinase inhibitor, can induce haematologic and cytogenetic remission of CML. However, imatinib resistance occurs frequently, resulting in relapse. New treatment strategies are focusing on resistant CML stem cells and the bone marrow stroma. The identification of novel pathways and mechanisms in the bone marrow microenvironment could significantly contribute to the development of such strategies. In this work, we used a high-resolution label-free MS(E) proteomic approach to identify differential protein expression in the CML bone marrow plasma of responsive and resistant patients. Oxidative lipid metabolism and regulation of the switch from canonical to noncanonical WNT signaling may contribute to CML resistance in the bone marrow compartment.", "In mature B cells of mice and most mammals, cellular release of single H chain Abs without L chains is prevented by H chain association with Ig-specific chaperons in the endoplasmic reticulum. In precursor B cells, however, surface expression of mu-H chain in the absence of surrogate and conventional L chain has been identified. Despite this, Ag-specific single H chain Ig repertoires, using mu-, gamma-, epsilon-, or alpha-H chains found in conventional Abs, are not produced. Moreover, removal of H chain or, separately, L chain (kappa/lambda) locus core sequences by gene targeting has prevented B cell development. In contrast, H chain-only Abs are produced abundantly in Camelidae as H2 IgG without the C(H)1 domain. To test whether H chain Abs can be produced in mice, and to investigate how their expression affects B cell development, we introduced a rearranged dromedary gamma2a H chain into the mouse germline. The dromedary transgene was expressed as a naturally occurring Ag-specific disulphide-linked homodimer, which showed that B cell development can be instigated by expression of single H chains without L chains. Lymphocyte development and B cell proliferation was accomplished despite the absence of L chain from the BCR complex. Endogenous Ig could not be detected, although V(D)J recombination and IgH/L transcription was unaltered. Furthermore, crossing the dromedary H chain mice with mice devoid of all C genes demonstrated without a doubt that a H chain-only Ab can facilitate B cell development independent of endogenous Ig expression, such as mu- or delta-H chain, at early developmental stages.", "Castration-refractory prostate cancer (CRPC) is treated with taxane-based chemotherapy, but eventually becomes drug resistant. It is thus essential to identify novel therapeutic targets for taxane resistance in CRPC patients. We investigated the role of the chemokine (C-C motif) receptor 1 (CCR1) and its ligand, chemokine (C-C motif) ligand 5 (CCL5), in taxane-resistant CRPC using paclitaxel-resistant prostate cancer cells (PC3PR) established from PC3 cells. We found that the expression levels of CCR1 mRNA and protein were up-regulated in PC3PR cells compared to PC3 cells. In order to investigate the role of increased CCR1 in PC3PR cells, we stimulated cells with CCL5, one of the chemokine ligands of CCR1. In CCL5-stimulated PC3PR cells, siRNA-mediated knockdown of CCR1 expression reduced phosphorylation of ERK1/2 and Rac1/cdc42. Furthermore, CCR1 knockdown and MEK1/2 inhibition decreased CCL5-stimulated secretion of MMPs 2 and 9, which play important roles in cancer cell invasion and metastasis. In the Matrigel invasion assay, knockdown of CCR1 and inhibition of the ERK and Rac signaling pathways significantly decreased the number of invading cells. Finally, the serum CCL5 protein level as measured by ELISA was not different among the three groups of patients: those with negative prostate biopsy, those at initial diagnosis of prostate cancer, and those with taxane-resistant prostate cancer. These results demonstrated for the first time that the interaction of CCR1 with CCL5 caused by increased expression of CCR1 promotes invasion of PC3PR cells by increasing secretion of MMPs 2 and 9 and by activating ERK and Rac signaling. Our findings suggest that CCR1 could be a novel therapeutic target for taxane-resistant CRPC." ]

[ "Toripalimab, a humanized IgG4 monoclonal antibody (mAb) against programmed death receptor-1, is being extensively studied to treat various malignancies. At present, there is no complete methodology reported for quantifying toripalimab, except for an electrochemiluminescence immunoassay (ECLIA) mentioned in several clinical studies. Therefore, a sensitive and robust ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed to accurately detect toripalimab levels, compared with the ECLIA. Plasma samples were pretreated by a five-step process, encompassing denaturation, reduction, alkylation, enzymatic hydrolysis and quenching. And a unique, sensitive and stable enzymatic peptide (ASGYTFTDYEMHWVR) selected as surrogate of toripalimab was eluted and monitored by UPLC-MS/MS system with the linear range of 5.0375-201.5 μg/mL. After fully validated, the UPLC-MS/MS method was applied to determine 77 plasma samples from 29 patients in a phase I clinical trial, and compared with ECLIA based on 56 samples. Wilcoxon paired samples test showed toripalimab levels by UPLC-MS/MS were significantly higher than that by ECLIA (p < 0.001), though a strong correlation was observed (r = 0.96). Moreover, Passing-Bablok regression analysis exhibited constant and proportional biases: UPLC-MS/MS = 2.25 + 1.21 * ECLIA. This discrepancy could be mainly attributed to different forms determined: total mAb for UPLC-MS/MS and free mAb for ECLIA, respectively. As a result, this UPLC-MS/MS method may be complementary to ECLIA to monitor different forms of toripalimab. Beyond that, it can be easily modified to simultaneously quantitate multiple-analyte with a small volume of plasma.", "OBJECTIVE: To examine the association between the circadian locomotor output cycles kaput (CLOCK) gene rs1554483 G/C polymorphism and susceptibility to Alzheimer's disease in Chinese people.METHODS: This case-control study determined apolipoprotein E (APOE) and CLOCK rs1554483 G/C genotypes using polymerase chain reaction restriction fragment length polymorphism.RESULTS: Unrelated patients with Alzheimer's disease (n = 130) and healthy controls (n = 188) were analysed for an association between the CLOCK gene rs1554483 G/C polymorphism and susceptibility to Alzheimer's disease. In the whole sample and in APOE ε4 isoform noncarriers, the prevalence of CLOCK gene rs1554483 G allele carriers was significantly higher in patients with Alzheimer's disease than in controls. Among APOE ε4 carriers, the prevalence of CLOCK rs1554483 G allele carriers was not significantly different between patients with Alzheimer's disease and controls.CONCLUSION: Among APOE ε4 noncarriers, but not APOE ε4 carriers, the CLOCK rs1554483 G allele was associated with increased susceptibility to Alzheimer's disease.", "We examined the relation between the use of hormone replacement therapy (HRT) and the incidence of central nervous system (CNS) tumours in a large prospective study of 1,147,894 postmenopausal women. Women were aged 56.6 years on average at entry, and HRT use was recorded at recruitment and updated, where possible, about 3 years later. During a mean follow-up of 5.3 years per woman, 1,266 CNS tumours were diagnosed, including 557 gliomas, 311 meningiomas and 117 acoustic neuromas. Compared with never users of HRT, the relative risks (RRs) for all incident CNS tumours, gliomas, meningiomas and acoustic neuromas in current users of HRT were 1.20 (95% CI: 1.05-1.36), 1.09 (95% CI: 0.89-1.32), 1.34 (95% CI: 1.03-1.75) and 1.58 (95% CI: 1.02-2.45), respectively, and there was no significant difference in the relative risks by tumour type (heterogeneity p = 0.2). In past users of HRT the relative risk was 1.07 (95% CI: 0.93-1.24) for all CNS tumours. Among current users of HRT, there was significant heterogeneity by the type of HRT with the users of oestrogen-only HRT at higher risk of all CNS tumours than users of oestrogen-progestagen HRT (RR = 1.42, 95% CI: 1.21-1.67 versus RR = 0.97, 95% CI: 0.82-1.16) (heterogeneity p < 0.001). Among current users of oestrogen-only and oestrogen-progestagen HRT, there was no significant heterogeneity by duration of use, hormonal constituent or mode of administration of HRT.", "Inflammatory caspases drive a lytic form of cell death called pyroptosis in response to microbial infection and endogenous damage-associated signals. Two studies now demonstrate that cleavage of the substrate gasdermin D by inflammatory caspases necessitates eventual pyroptotic demise of a cell.", "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 metastasis-associated lung adenocarcinoma transcript 1, MALAT1, is a long non-coding RNA (lncRNA) that has been discovered as a marker for lung cancer metastasis. It is highly abundant, its expression is strongly regulated in many tumor entities including lung adenocarcinoma and hepatocellular carcinoma as well as physiological processes, and it is associated with many RNA binding proteins and highly conserved throughout evolution. The nuclear transcript MALAT-1 has been functionally associated with gene regulation and alternative splicing and its regulation has been shown to impact proliferation, apoptosis, migration and invasion.   Here, we have developed a human and a mouse knockout system to study the loss-of-function phenotypes of this important ncRNA. In human tumor cells, MALAT1 expression was abrogated using Zinc Finger Nucleases. Unexpectedly, the quantitative loss of MALAT1 did neither affect proliferation nor cell cycle progression nor nuclear architecture in human lung or liver cancer cells. Moreover, genetic loss of Malat1 in a knockout mouse model did not give rise to any obvious phenotype or histological abnormalities in Malat1-null compared with wild-type animals. Thus, loss of the abundant nuclear long ncRNA MALAT1 is compatible with cell viability and normal development.", "BACKGROUND: Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients.METHODS: The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3-21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549-BRAF fusion or the BRAFV600E [Val600Glu] mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m2 twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101.FINDINGS: Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% [95% CI 18-57]) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14-51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]). No treatment-realted deaths were reported.INTERPRETATION: Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1.FUNDING: National Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca." ]

[ "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.", "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.", "INTRODUCTION: The Pediatric Index of Mortality 2 (PIM2) is one of the most commonly used scoring systems to predict mortality in patients admitted to pediatric intensive care units (PICU) in Argentina. The objective of this study was to validate the PIM2 score in PICUs participating in the Quality of Care Program promoted by the Argentine Society of Intensive Care.POPULATION AND METHODS: Multicenter, prospective, observational, cross-sectional study. All patients between 1 month and 16 years old admitted to participating PICUs between January 1st, 2009 and December 31st, 2009 were included. The discrimination and calibration of the PIM2 score were assessed in the entire population and in different subgroups (risk of mortality, age, diagnoses on admission).RESULTS: Two thousand, eight hundred and thirty-two patients were included. PIM2 predicted 246 deaths; however, 297 patients died (p < 0.01). The standardized mortality ratio was 1.20 (95% confidence interval [CI]: 1.01-1.43). The area under the ROC curve was 0.84 (95% CI: 0.82-0.86). Statistically significant differences were detected between the observed and the predicted mortality for the entire population and for the different risk intervals (χ2: 71.02, df: 8, p < 0.001). Statistically significant differences were also found between observed and predicted mortality in adolescent patients (37/22, p = 0.03) and in those hospitalized due to respiratory disease (105/81, p = 0.03).CONCLUSIONS: The PIM2 score adequately discriminates survivors from non-survivors. However, it underscores the overall risk of death, especially in adolescent patients and those hospitalized due to respiratory disease. It is critical to take such differences into account when interpreting results.", "Calsarcin-1 deficient mice develop dilated cardiomyopathy (DCM) phenotype in pure C57BL/6 genetic background (Cs1-ko) despite severe contractile dysfunction and robust activation of fetal gene program. Here we performed a microRNA microarray to identify the molecular causes of this cardiac phenotype that revealed the dysregulation of several microRNAs including miR-301a, which was highly downregulated in Cs1-ko mice compared to the wild-type littermates. Cofilin-2 (Cfl2) was identified as one of the potential targets of miR-301a using prediction databases, which we validated by luciferase assay and mutation of predicted binding sites. Furthermore, expression of miR-301a contrastingly regulated Cfl2 expression levels in neonatal rat ventricular cardiomyocytes (NRVCM). Along these lines, Cfl2 was significantly upregulated in Cs1-ko mice, indicating the physiological association between miR-301a and Cfl2 in vivo. Mechanistically, we found that Cfl2 activated serum response factor response element (SRF-RE) driven luciferase activity in neonatal rat cardiomyocytes and in C2C12 cells. Similarly, knockdown of miR301a activated, whereas, its overexpression inhibited the SRF-RE driven luciferase activity, further strengthening physiological interaction between miR-301a and Cfl2. Interestingly, the expression of SRF and its target genes was strikingly increased in Cs1-ko suggesting a possible in vivo correlation between expression levels of Cfl2/miR-301a and SRF activation, which needs to be independently validated. In summary, our data demonstrates that miR-301a regulates Cofilin-2 in vitro in NRVCM, and in vivo in Cs1-ko mice. Our findings provide an additional and important layer of Cfl2 regulation, which we believe has an extended role in cardiac signal transduction and dilated cardiomyopathy presumably due to the reported involvement of Cfl2 in these mechanisms.", "The Na+ and Ca(2+)-permeable melastatin related transient receptor potential 2 (TRPM2) channels can be gated either by ADP-ribose (ADPR) in concert with Ca(2+) or by hydrogen peroxide (H(2)O(2)), an experimental model for oxidative stress, binding to the channel's enzymatic Nudix domain. Since the mechanisms that lead to TRPM2 gating in response to ADPR and H(2)O(2) are not understood in neuronal cells, I summarized previous findings and important recent advances in the understanding of Ca(2+) influx via TRPM2 channels in different neuronal cell types and disease processes. Considering that TRPM2 is activated by oxidative stress, mediated cell death and inflammation, and is highly expressed in brain, the channel has been investigated in the context of central nervous system. TRPM2 plays a role in H(2)O(2) and amyloid β-peptide induced striatal cell death. Genetic variants of the TRPM2 gene confer a risk of developing Western Pacific amyotropic lateral sclerosis and parkinsonism-dementia complex and bipolar disorders. TRPM2 also contributes to traumatic brain injury processes such as oxidative stress, inflammation and neuronal death. There are a limited number of TRPM2 channel blockers and they seem to be cell specific. For example, ADPR-induced Ca(2+) influx in rat hippocampal cells was not blocked by N-(p-amylcinnomoyl)anthralic acid (ACA), the IP(3) receptor inhibitor 2-aminoethoxydiphenyl borate or PLC inhibitor flufenamic acid (FFA). However, the Ca(2+) entry in rat primary striatal cells was blocked by ACA and FFA. In conclusion TRPM2 channels in neuronal cells can be gated by either ADPR or H(2)O(2). It seems to that the exact relationship between TRPM2 channels activation and neuronal cell death still remains to be determined.", "ADF/cofilins drive cytoskeletal dynamics by promoting the disassembly of \"aged\" ADP-actin filaments. Mammals express several ADF/cofilin isoforms, but their specific biochemical activities and cellular functions have not been studied in detail. Here, we demonstrate that the muscle-specific isoform cofilin-2 promotes actin filament disassembly in sarcomeres to control the precise length of thin filaments in the contractile apparatus. In contrast to other isoforms, cofilin-2 efficiently binds and disassembles both ADP- and ATP/ADP-Pi-actin filaments. We mapped surface-exposed cofilin-2-specific residues required for ATP-actin binding and propose that these residues function as an \"actin nucleotide-state sensor\" among ADF/cofilins. The results suggest that cofilin-2 evolved specific biochemical and cellular properties that allow it to control actin dynamics in sarcomeres, where filament pointed ends may contain a mixture of ADP- and ATP/ADP-Pi-actin subunits. Our findings also offer a rationale for why cofilin-2 mutations in humans lead to myopathies.", "BACKGROUND: Interactive and mobile technologies (i.e., smartphones such as Blackberries, iPhones, and palm-top computers) show promise as an efficacious and cost-effective means of communicating health-behavior risks, improving public health outcomes, and accelerating behavior change. The present study was conducted as a \"needs assessment\" to examine the current available mobile smartphone applications (e.g., apps) that utilize principles of ecological momentary assessment (EMA)-daily self-monitoring or near real-time self-assessment of alcohol-use behavior-to promote positive behavior change, alcohol harm reduction, psycho-education about alcohol use, or abstinence from alcohol.METHODS: Data were collected and analyzed from iTunes for Apple iPhone(©) . An inventory assessed the number of available apps that directly addressed alcohol use and consumption, alcohol treatment, or recovery, and whether these apps incorporated empirically based components of alcohol treatment.RESULTS: Findings showed that few apps addressed alcohol-use behavior change or recovery. Aside from tracking drinking consumption, a minority utilized empirically based components of alcohol treatment. Some apps claimed they could serve as an intervention; however, no empirical evidence was provided.CONCLUSIONS: More studies are needed to examine the efficacy of mobile technology in alcohol intervention studies. The large gap between availability of mobile apps and their use in alcohol treatment programs indicates several important future directions for research.", "The muscle LIM protein (MLP) and cofilin 2 (CFL2) are important regulators of striated myocyte function. Mutations in the corresponding genes have been directly associated with severe human cardiac and skeletal myopathies, and aberrant expression patterns have often been observed in affected muscles. Herein, we have investigated whether MLP and CFL2 are involved in common molecular mechanisms, which would promote our understanding of disease pathogenesis. We have shown for the first time, using a range of biochemical and immunohistochemical methods, that MLP binds directly to CFL2 in human cardiac and skeletal muscles. The interaction involves the inter-LIM domain, amino acids 94 to 105, of MLP and the amino-terminal domain, amino acids 1 to 105, of CFL2, which includes part of the actin depolymerization domain. The MLP/CFL2 complex is stronger in moderately acidic (pH 6.8) environments and upon CFL2 phosphorylation, while it is independent of Ca(2+) levels. This interaction has direct implications in actin cytoskeleton dynamics in regulating CFL2-dependent F-actin depolymerization, with maximal depolymerization enhancement at an MLP/CFL2 molecular ratio of 2:1. Deregulation of this interaction by intracellular pH variations, CFL2 phosphorylation, MLP or CFL2 gene mutations, or expression changes, as observed in a range of cardiac and skeletal myopathies, could impair F-actin depolymerization, leading to sarcomere dysfunction and disease.", "Many inborn errors of metabolism (IEMs) are amenable to treatment, therefore early diagnosis is imperative. Whole-exome sequencing (WES) variant prioritization coupled with phenotype-guided clinical and bioinformatics expertise is typically used to identify disease-causing variants; however, it can be challenging to identify the causal candidate gene when a large number of rare and potentially pathogenic variants are detected. Here, we present a network-based approach, metPropagate, that uses untargeted metabolomics (UM) data from a single patient and a group of controls to prioritize candidate genes in patients with suspected IEMs. We validate metPropagate on 107 patients with IEMs diagnosed in Miller et al. (2015) and 11 patients with both CNS and metabolic abnormalities. The metPropagate method ranks candidate genes by label propagation, a graph-smoothing algorithm that considers each gene's metabolic perturbation in addition to the network of interactions between neighbors. metPropagate was able to prioritize at least one causative gene in the top 20th percentile of candidate genes for 92% of patients with known IEMs. Applied to patients with suspected neurometabolic disease, metPropagate placed at least one causative gene in the top 20th percentile in 9/11 patients, and ranked the causative gene more highly than Exomiser's phenotype-based ranking in 6/11 patients. Interestingly, ranking by a weighted combination of metPropagate and Exomiser scores resulted in improved prioritization. The results of this study indicate that network-based analysis of UM data can provide an additional mode of evidence to prioritize causal genes in patients with suspected IEMs.", "NicVAX, a nicotine vaccine (3'AmNic-rEPA), has been clinically evaluated to determine whether higher antibody (Ab) concentrations are associated with higher smoking abstinence rates and whether dosages and frequency of administration are associated with increased Ab response. This randomized, double-blinded, placebo-controlled multicenter clinical trial (N = 301 smokers) tested the results of 200- and 400-µg doses administered four or five times over a period of 6 months, as compared with placebo. 3'AmNic-rEPA recipients with the highest serum antinicotine Ab response (top 30% by area under the curve (AUC)) were significantly more likely than the placebo recipients (24.6% vs. 12.0%, P = 0.024, odds ratio (OR) = 2.69, 95% confidence interval (CI), 1.14-6.37) to attain 8 weeks of continuous abstinence from weeks 19 through 26. The five-injection, 400-µg dose regimen elicited the greatest Ab response and resulted in significantly higher abstinence rates than placebo. This study demonstrates, as proof of concept, that 3'AmNic-rEPA elicits Abs to nicotine and is associated with higher continuous abstinence rates (CAR). Its further development as a treatment for nicotine dependence is therefore justified.", "The NHPX protein is a nucleolar factor that binds directly to a conserved RNA target sequence found in nucleolar box C/D snoRNAs and in U4 snRNA. Using enhanced yellow fluorescent protein (EYFP)- and enhanced cyan fluorescent protein-NHPX fusions, we show here that NHPX is specifically accumulated in both nucleoli and Cajal bodies (CBs) in vivo. The fusion proteins display identical localization patterns and RNA binding specificities to the endogenous NHPX. Analysis of a HeLa cell line stably expressing EYFP-NHPX showed that the nucleolar accumulation of NHPX was preceded by its transient accumulation in splicing speckles. Only newly expressed NHPX accumulated in speckles, and the nucleolar pool of NHPX did not interchange with the pool in speckles, consistent with a unidirectional pathway. The transient accumulation of NHPX in speckles prior to nucleoli was observed in multiple cell lines, including primary cells that lack CBs. Inhibitor studies indicated that progression of newly expressed NHPX from speckles to nucleoli was dependent on RNA polymerase II transcription, but not on RNA polymerase I activity. The data show a specific temporal pathway involving the sequential and directed accumulation of NHPX in distinct subnuclear compartments, and define a novel mechanism for nucleolar localization.", "OBJECTIVE: Hereditary long QT syndrome (LQTS) is a cardiac disorder characterized by prolongation of QT interval on electrocardiograms (ECGs) and syncope and sudden death caused by a specific multi-polymorphic ventricular tachyarrhythmia known as torsade de pointes. LQTS is caused by mutations in cardiac sodium channel gene SCN5A; potassium channel subunit genes KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2; calcium channel gene Cav2.1. and ankyrin-B gene ANK2.METHODS: We characterized 77 Chinese LQTS patients with clinical manifestations and mutations in the main LQTS genes, KCNQ1 and KCNH2 using PCR and sequence analysis.RESULTS: The spectrum of ST-T-wave patterns of 24 (31.2%) probands were considered as LQT1, 42 (54.5%) as LQT2 and 3 (3.9%) as LQT3. The remaining 8 (10.3%) could not be characterized. The average age for this population of LQTS patients was (27.6 +/- 16.4) years and the average QTc (561 +/- 70) ms, and the age of the first syncopal attack was (17.6 +/- 14.7) years. The triggering factors for cardiac events happening in these mutation carriers included physical exercise, emotional excitement and auditory irritation. We identified 4 KCNQ1 mutations and 7 KCNH2 mutations. Six of them were first identified with some data already shown. In this paper we showed the data of 6 other mutations.CONCLUSIONS: LQT2 is the most common type of LQTS in Chinese; 2 mutations of KCNQ1 and KCNH2 were first identified in this report; there are some differences between Chinese and North American or European LQTS patients in clinical characters and ECG." ]

[ "BACKGROUND: Juvenile polyposis syndrome is a dominant GI polyposis syndrome defined by ≥ 5 GI juvenile polyps or ≥ 1 juvenile polyps with a family history of juvenile polyposis. Mutations in BMPR1A or SMAD4 are found in 50% of individuals. Hereditary hemorrhagic telangiectasia is a dominant disorder characterized by epistaxis, visceral arteriovenous malformations, and telangiectasias. Hereditary hemorrhagic telangiectasia is diagnosed when ≥ 3 criteria including clinical manifestations or a family history, are present. A juvenile polyposis-hereditary hemorrhagic telangiectasia overlap syndrome has previously been reported in 22% of patients with juvenile polyposis due to a SMAD4 mutation.OBJECTIVE: Our objective was to determine the prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia by Curacao criteria in our juvenile polyposis SMAD4 patients.DESIGN, PATIENTS, AND SETTING: This was a cohort study of juvenile polyposis patients in our inherited colon cancer registries. Hereditary hemorrhagic telangiectasia manifestations were obtained from medical records, patient contact, and/or prospective hereditary hemorrhagic telangiectasia screening. The Curacao criteria was used for diagnosis of hereditary hemorrhagic telangiectasia (≥ 3 criteria diagnostic; 2 criteria suspect of).MAIN OUTCOME MEASURES: Prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia in juvenile polyposis SMAD4 patients.RESULTS: Forty-one juvenile polyposis families were identified. Genetic testing was available for individuals within 18 families. SMAD4 mutations were found in 21 relatives in 9 families. Eighty-one percent of SMAD4 patients had hereditary hemorrhagic telangiectasia and 14% were suspected of having hereditary hemorrhagic telangiectasia. Epistaxis and asthma are the most common symptoms in our overlap patients. Symptomatic and subclinical arteriovenous malformations were noted near universally.LIMITATIONS: There was a single, tertiary referral center.CONCLUSIONS: Nearly all juvenile polyposis SMAD4 patients have the overlap syndrome. The clinical implications and need for hereditary hemorrhagic telangiectasia screening are important factors for genetic testing in juvenile polyposis. Health care providers must be cognizant of the juvenile polyposis-hereditary hemorrhagic telangiectasia overlap syndrome and the implications for management of these patients.", "Hutchinson-Gilford progeria is a rare genetic disorder resulting from mutations in the LMNA gene encoding lamin A/C. In addition to the classical phenotype usually caused by the 1824C>T mutation of LMNA, a number of atypical progeroid syndromes have been described. They have some distinct features, such as skeletal deformities or scleroderma-like skin changes. The underlying defect is usually a homozygous mutation of LMNA, or a combined defect of LMNA and another gene, for example, ZMPSTE-24. We present a 2-year-old girl born to consanguineous parents affected by progeroid syndrome with scleroderma-like skin changes. Genetic analysis revealed the homozygous LMNA mutation 1303C>T (R435C). The same heterozygous mutation was found in the patient's parents and 11 other family members. The progeroid syndrome in our patient shares the signs of two laminopathies: progeria and restrictive dermatopathy. Two other children in the family died at the age of 2 due to a disease similar to that in the proposita. On the basis of the family pedigree we presume that these children probably had the same homozygous LMNA mutation. Scleroderma-like skin changes in infants, associated with growth retardation and dysmorphic features, suggest premature aging syndrome, requiring genetic testing and counseling of asymptomatic carriers of LMNA mutations.", "Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a primary immunodeficiency caused by mutations in the autoimmune regulator gene (AIRE). Patients with AIRE mutations are susceptible to Candida albicans infection and present with autoimmune disorders. We previously demonstrated that cytoplasmic AIRE regulates the Syk-dependent Dectin-1 pathway. In this study, we further evaluated direct contact with fungal elements, synapse formation, and the response of macrophage-like THP-1 cells to C. albicans hyphae to determine the role of AIRE upon Dectin receptors function and signaling. We examined the fungal synapse (FS) formation in wild-type and AIRE-knockdown THP-1 cells differentiated to macrophages, as well as monocyte-derived macrophages from APECED patients. We evaluated Dectin-2 receptor signaling, phagocytosis, and cytokine secretion upon hyphal stimulation. AIRE co-localized with Dectin-2 and Syk at the FS upon hyphal stimulation of macrophage-like THP-1 cells. AIRE-knockdown macrophage-like THP-1 cells exhibited less Dectin-1 and Dectin-2 receptors accumulation, decreased signaling pathway activity at the FS, lower C. albicans phagocytosis, and less lysosome formation. Furthermore, IL-1β, IL-6, or TNF-α secretion by AIRE-knockdown macrophage-like THP-1 cells and AIRE-deficient patient macrophages was decreased compared to control cells. Our results suggest that AIRE modulates the FS formation and hyphal recognition and help to orchestrate an effective immune response against C. albicans.", "The gene encoding ribosomal protein S19 (RPS19) has been shown to be mutated in 25% of the patients affected by Diamond-Blackfan anemia (DBA), a congenital erythroblastopenia. As the role of RPS19 in erythropoiesis is still to be defined, we performed studies on RPS19 expression during terminal erythroid differentiation. Comparative analysis of the genomic sequences of human and mouse RPS19 genes enabled the identification of 4 conserved sequence elements in the 5' region. Characterization of transcriptional elements allowed the identification of the promoter in the human RPS19 gene and the localization of a strong regulatory element in the third conserved sequence element. By Northern blot and Western blot analyses of murine splenic erythroblasts infected with the anemia-inducing strain Friend virus (FAV cells), RPS19 mRNA and protein expression were shown to decrease during terminal erythroid differentiation. We anticipate that these findings will contribute to further development of our understanding of the contribution of RPS19 to erythropoiesis.", "The autoimmune regulator gene (AIRE) is a transcription factor expressed both in the thymus, by medullary thymic epithelial cells, and in secondary lymphoid organs. AIRE controls the local transcription of organ- specific proteins typically expressed in peripheral tissues, thus allowing the negative selection of self- reactive T cells. The crucial role played by AIRE in central immune tolerance emerged in the studies on the pathogenesis of Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy, a rare inherited polyendocrine/autoimmune disease. Thereafter, several studies found evidences indicating that AIRE impairment might be pathogenically involved in several autoimmune diseases and in tumorigenesis. In this review, we focus on recent advances relative to AIRE's effect on T cell development in physiology and disease. In particular, we address the following issues: 1) AIRE function and mTECs biology, 2) the impact of AIRE gene mutations in autoimmune diseases, and 3) the role of AIRE gene in anti-tumor immune response.", "Protection against mucocutaneous candidiasis depends on the T helper (Th)17 pathway, as gene defects affecting its integrity result in inability to clear Candida albicans infection on body surfaces. Moreover, autoantibodies neutralizing Th17 cytokines have been related to chronic candidiasis in a rare inherited disorder called autoimmune polyendocriopathy candidiasis ectodermal dystrophy (APECED) caused by mutations in autoimmune regulator (AIRE) gene. However, the direct pathogenicity of these autoantibodies has not yet been addressed. Here we show that the level of anti-IL17A autoantibodies that develop in aged Aire-deficient mice is not sufficient for conferring susceptibility to oropharyngeal candidiasis. However, patient-derived monoclonal antibodies that cross-react with murine IL-22 increase the fungal burden on C. albicans infected mucosa. Nevertheless, the lack of macroscopically evident infectious pathology on the oral mucosa of infected mice suggests that additional susceptibility factors are needed to precipitate a clinical disease.", "Autoimmune polyendocrine syndrome type 1 (APS-1; OMIM #240300), also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. APS-1 is classically characterized by a triad of chronic mucocutaneous candidiasis, autoimmune hypoparathyroidism, and autoimmune adrenocortical insufficiency. We report a 5-yr-old female who presented with symptoms of tetany due to hypocalcemia and was subsequently found to be secondary to hypoparathyroidism. Rapid trio whole-genome sequencing revealed compound heterozygous variants in AIRE in the proband, with a paternally inherited, pathogenic, frameshift variant (c.1265delC; p.Pro422LeufsTer58) and a novel, likely pathogenic, maternally inherited missense variant (c.268T>C; p.Tyr90His).", "A mutation in the huntingtin (Htt) gene produces mutant Htt and Huntington's disease (HD), a neurodegenerative disorder. HD patients have oxidative damage in the brain, but the causes are unclear. Compared with controls, we found brain levels of NADPH oxidase (NOX) activity, which produces reactive oxygen species (ROS), elevated in human HD postmortem cortex and striatum and highest in striatum of presymptomatic individuals. Synaptosome fractions from cortex and striatum of HD(140Q/140Q) mice had elevated NOX activity at 3 months of age and a further rise at 6 and 12 months compared with synaptosomes of age-matched wild-type (WT) mice. High NOX activity in primary cortical and striatal neurons of HD(140Q/140Q) mice correlated with more ROS and neurite swellings. These features and neuronal cell death were markedly reduced by treatment with NOX inhibitors such as diphenyleneiodonium (DPI), apocynin (APO) and VAS2870. The rise in ROS levels in mitochondria of HD(140Q/140Q) neurons followed the rise in NOX activity and inhibiting only mitochondrial ROS was not neuroprotective. Mutant Htt colocalized at plasma membrane lipid rafts with gp91-phox, a catalytic subunit for the NOX2 isoform. Assembly of NOX2 components at lipid rafts requires activation of Rac1 which was also elevated in HD(140Q/140Q) neurons. HD(140Q/140Q) mice bred to gp91-phox knock-out mice had lower NOX activity in the brain and in primary neurons, and neurons had normal ROS levels and significantly improved survival. These findings suggest that increased NOX2 activity at lipid rafts is an early and major source of oxidative stress and cell death in HD(140Q/140Q) neurons.", "Contrave(®) is a combination of naltrexone hydrochloride extended release and bupropion hydrochloride extended release for the treatment of obesity, and is used with lifestyle modification. Its safety and efficacy were assessed in four randomized, double-blind, placebo-controlled, 56-week Phase III clinical trials in 4536 adult subjects: COR-1, COR-II, COR-BMOD and COR-DM. All four studies demonstrated statistically significant and clinically meaningful weight loss following up to 52 weeks of treatment with naltrexone/bupropion compared with placebo. The average weight loss from baseline across the four studies was approximately 11-22 lbs (5-9 kg). Results show the efficacy of Contrave for weight loss, as well as significant improvements in cardiometabolic markers. This review focuses on the four studies, their outcomes and the mechanism of action of Contrave.", "Rituximab is increasingly used off label for difficult-to-treat auto-immune diseases. We reviewed the main case series or clinical studies to identify the best indications of rituximab and the situations at substantial risks for adverse events. Refractory immune thrombocytopenic purpura was the main indication. However, the long term benefit-to-risk ratio of rituximab treatment before or after splenectomy is unknown. A single 375 mg/m2 infusion may be as efficacious as the classical four infusions cycle. Rituximab is the best treatment for cold agglutinin disease. In warm agglutinin auto-immune anaemia, its efficacy has essentially been reported in chronic lymphocytic leukemia (CLL) patients and in children. In CLL patients, lethal adverse events occurred in patients also receiving cyclophosphamide. Rituximab seems to have an interesting benefit-to-risk ratio in Wegener granulomatosis (excepted in granulomatous lesions), HCV-associated symptomatic cryoglobulinemia in patients unresponsive to anti-viral therapy, pemphigus and thrombotic thrombocytopenic purpura. Efficacy and safety data in lupus are difficult to interpret. Serum sickness disease is not exceptional in immune thrombocytopenic purpura (ITP), lupus and sicca syndrome patients. A substantial infectious risk has been reported in pemphigus patients and in post-renal transplant cryoglobulinemia. Double-blind randomised controlled trials and phase IV studies are mandatory in most clinical settings to confirm the overall favourable perception of rituximab benefit to risk ratio.", "Interferon-gamma (IFN-γ) plays a key role in the pathophysiology of hemophagocytic lymphohistiocytosis (HLH), and available evidence also points to a role in other conditions, including aplastic anemia (AA) and graft failure following allogeneic hematopoietic stem cell transplantation. Recently, the therapeutic potential of IFN-γ inhibition has been documented; emapalumab, an anti-IFN-γ monoclonal antibody, has been approved in the United States for treatment of primary HLH that is refractory, recurrent or progressive, or in patients with intolerance to conventional therapy. Moreover, ruxolitinib, an inhibitor of JAK/STAT intracellular signaling, is currently being investigated for treating HLH. In AA, IFN-γ inhibits hematopoiesis by disrupting the interaction between thrombopoietin and its receptor, c-MPL. Eltrombopag, a small-molecule agonist of c-MPL, acts at a different binding site to IFN-γ and is thus able to circumvent its inhibitory effects. Ongoing trials will elucidate the role of IFN-γ neutralization in secondary HLH and future studies could explore this strategy in controlling hyperinflammation due to CAR T cells.", "Migraine and obesity are associated in several ways. First, both are prevalent and disabling disorders influenced by genetic and environmental risk factors. Second, migraine with aura, as obesity, seems to be a risk factor for cardiovascular events. Finally, large population-based studies suggest that obesity is a risk factor for chronic migraine after adjusting for comorbidities. In this article, we discuss plausible mechanisms that may account for this association. Several of the inflammatory mediators that are increased in obese individuals are important in migraine pathophysiology, including interleukins and calcitonin gene-related peptide (CGRP). These mediators may increase the frequency, severity, and duration of migraine attacks per se, which in turn would cause central sensitization. Repeated central sensitization may be associated with permanent neuronal damage close to the periaqueductal gray area, with poor modulation to pain. Obesity is also a state of sympathetic activation, which may contribute to increase in headache frequency. Furthermore, the levels of adiponectin are decreased in obesity. At low but not normal levels, adiponectin is nociceptive. Shared biologic predisposition may also play a major role. Orexins modulate both pain and metabolism. Dysfunction in the orexins pathways seems to be a risk factor for both conditions. Finally, conditions that are comorbid to both states (e.g., depression, sleep apnea) may also make the relationship between both diseases more complex.", "Measles can persist in the central nervous system and cause subacute sclerosing panencephalitis (SSPE), a progressive disease that is almost always fatal. The clinical findings of SSPE include behavioral changes, ataxia, seizures, and mental-motor deterioration that begins several years after natural infection with the virus. Measles antibody is found in the spinal fluid, and its presence is particularly useful in establishing the diagnosis. The mechanisms of pathogenesis of SSPE apparently involves the selection of clones of virus, which do not replicate to become complete virus particles. These \"suppressed\" viruses are able to multiply and spread from cell to cell. The immune system of the patient is unable to clear this infection. Several hypotheses are advanced to explain these events. Further studies are needed, however, to develop a complete understanding of the pathogenesis of these diseases. Fortunately, SSPE is disappearing in the United States. This apparently is related to the widespread use of measles vaccines and to the resulting low frequency of natural measles infections.", "Honey bees provision glandular secretions in the form of royal jelly as larval nourishment to developing queens. Exposure to chemicals and nutritional conditions can influence queen development and thus impact colony fitness. Previous research reports that royal jelly remains pesticide-free during colony-level exposure and that chemical residues are buffered by the nurse bees. However, the impacts of pesticides can also manifest in quality and quantity of royal jelly produced by nurse bees. Here, we tested how colony exposure to a multi-pesticide pollen treatment influences the amount of royal jelly provisioned per queen and the additional impacts on royal jelly nutritional quality. We observed differences in the metabolome, proteome, and phytosterol compositions of royal jelly synthesized by nurse bees from multi-pesticide exposed colonies, including significant reductions of key nutrients such as 24-methylenecholesterol, major royal jelly proteins, and 10-hydroxy-2-decenoic acid. Additionally, quantity of royal jelly provisioned per queen was lower in colonies exposed to pesticides, but this effect was colony-dependent. Pesticide treatment had a greater impact on royal jelly nutritional composition than the weight of royal jelly provisioned per queen cell. These novel findings highlight the indirect effects of pesticide exposure on queen developmental nutrition and allude to social consequences of nurse bee glandular degeneration.", "PURPOSE: To assess the maximum tolerated dose (MTD)/dose-limiting toxicities (DLT), safety, pharmacokinetics, and pharmacodynamics of tivozanib, a potent and selective oral VEGF receptor (VEGFR) tyrosine kinase inhibitor.EXPERIMENTAL DESIGN: Dose levels of 1.0, 1.5, and 2.0 mg/d tivozanib for 28 days followed by 14 days of medication were explored in patients with advanced solid tumors.RESULTS: Forty-one patients were enrolled. Animal data incorrectly predicted toxicity, resulting in DLTs at the starting dose (2.0 mg) consisting of grade 3 proteinuria and hypertension and grade 3 ataxia. At 1.0 mg, no DLT was observed. At an intermediate dose (1.5 mg), 1 patient experienced DLT consisting of grade 3 hypertension. This dose was determined as the MTD. Of 10 additional patients treated at 1.5 mg, 1 patient each experienced grade 3 hypertension and grade 3 fatigue, and 2 patients experienced grade 3 and 4 transaminase elevation. In 12 additional patients treated at 1.0 mg, no DLT was observed. Pharmacokinetics displayed long absorption time, dose proportional exposure, and a half-life of 4.7 days. Plasma levels of VEGF-A and soluble VEGFR-2 showed dose-dependent increases and decreases, respectively. Dynamic contrast-enhanced MRI indicated reduction in tumor perfusion. Clinical activity was observed in renal cell cancer, colorectal cancer, and other tumors.CONCLUSION: Tivozanib was well tolerated with manageable side effects. The pharmacokinetics profile revealed that tivozanib was suitable for once-daily dosing. Encouraging and durable clinical activity was observed. The recommended daily dose of tivozanib in a 4-week-on and 2-week-off dosing regimen is 1.5 mg.", "Marfan syndrome is an inherited multisystemic connective-tissue disease that is caused by a mutation of the fibrillin-1 gene. The syndrome is characterized by a wide range of clinical manifestations. Common cardiovascular manifestations, most of which are substantial contributors to mortality, include annuloaortic ectasia with or without aortic valve insufficiency, aortic dissection, aortic aneurysm, pulmonary artery dilatation, and mitral valve prolapse. Scoliosis, pectus excavatum and carinatum, arachnodactyly, and acetabular protrusion are common musculoskeletal manifestations. Dural ectasia is a characteristic central nervous system manifestation. In some patients with Marfan syndrome, there is also pulmonary and ocular involvement. Early identification and treatment of these conditions contribute to an improved quality of life and a life expectancy close to the average for the general population in the United States. Radiologists play a key role in the diagnosis of Marfan syndrome. Knowledge about the various manifestations of Marfan syndrome and awareness of their radiologic appearances permit a comprehensive diagnostic approach that allows better patient care." ]

[ "Prolactinomas are the most common secretory pituitary adenoma. They typically occur in women in the 3rd-6th decade of life and rarely in the pediatric population or after menopause. Most women present with irregular menses and/or infertility. Dopamine (DA) agonists, used in their treatment, are safe during pregnancy, but in most cases are discontinued at conception with close monitoring for signs or symptoms of tumor growth. Breastfeeding is safe postpartum, provided there was no significant growth during pregnancy. Some women will experience normalization of prolactin levels postpartum. Menopause may also decrease prolactin levels and even those with macroprolactinomas may consider discontinuing their DA agonist with close follow-up. Prolactinomas may be associated with decreased quality of life scores in women, and play a role in bone health and cardiovascular risk factors. This review discusses the current literature and clinical understanding of prolactinomas throughout the entirety of the female life cycle.", "Human granulocytic anaplasmosis (HGA), an increasingly recognized febrile tick-borne illness, is caused by a gram-negative obligate intracellular bacterium Anaplasma phagocytophilum. Because of nonspecific clinical manifestations, diagnosis of HGA highly depends on laboratory tests. Identification of immunoreactive proteins is prerequisite for development of specific and sensitive immunoassays for HGA. In this study, we identified novel immunoreactive proteins of A. phagocytophilum. Previous studies indicated that secreted proteins of A. phagocytophilum and other bacteria can be immunoreactive antigens. Here we in silico screened A. phagocytophilum genome for encoding proteins which bear features of type IV secretion system substrates. Among seventy seven predicted proteins, fourteen proteins were determined for antigenicity and nine proteins were showed to be immunoreactive antigens. In addition, an APH1384 peptide harboring a B cell epitope predicted by bioinformatics was found specifically reacting with anti-A. phagocytophilum sera. Hereby, we identified novel immunoreactive proteins and delineated a specific epitope of A. phagocytophilum, which might be employed for HGA diagnosis.", "The genus Anaplasma belonging to the Anaplasmataceae family (order Rickettsiales) comprises obligate intracellular Gram-negative bacteria of veterinary and public health importance. Six species and five types of strains genetically related are currently assigned to the genus Anaplasma including Anaplasma marginale, A. centrale, A. bovis, A. phagocytophilum, A. ovis and A. platys as classified species, and \"A. capra\", A. odocolei sp. nov., A. phagocytophilum-like 1 (Anaplasma sp.-Japan), A. phagocytophilum-like 2 (Anaplasma sp.-China) and A. platys-like (also named Candidatus Anaplasma camelii) as unclassified strains. Most of these Anaplasma species and strains have been molecularly identified in several animal and/or tick species in the north of Africa. The aim of this review is to summarize the current knowledge about molecular epidemiology, associated risk factors and genetic diversity of Anaplasma species and related strains infecting animals and/or their incriminated tick vectors in North Africa. All these data should be considered when establishing of common management and control programs for anaplasmosis infecting humans and different animal species in North African countries.", "BACKGROUND: Model violations constitute the major limitation in inferring accurate phylogenies. Characterizing properties of the data that are not being correctly handled by current models is therefore of prime importance. One of the properties of protein evolution is the variation of the relative rate of substitutions across sites and over time, the latter is the phenomenon called heterotachy. Its effect on phylogenetic inference has recently obtained considerable attention, which led to the development of new models of sequence evolution. However, thus far focus has been on the quantitative heterogeneity of the evolutionary process, thereby overlooking more qualitative variations.RESULTS: We studied the importance of variation of the site-specific amino-acid substitution process over time and its possible impact on phylogenetic inference. We used the CAT model to define an infinite mixture of substitution processes characterized by equilibrium frequencies over the twenty amino acids, a useful proxy for qualitatively estimating the evolutionary process. Using two large datasets, we show that qualitative changes in site-specific substitution properties over time occurred significantly. To test whether this unaccounted qualitative variation can lead to an erroneous phylogenetic tree, we analyzed a concatenation of mitochondrial proteins in which Cnidaria and Porifera were erroneously grouped. The progressive removal of the sites with the most heterogeneous CAT profiles across clades led to the recovery of the monophyly of Eumetazoa (Cnidaria+Bilateria), suggesting that this heterogeneity can negatively influence phylogenetic inference.CONCLUSION: The time-heterogeneity of the amino-acid replacement process is therefore an important evolutionary aspect that should be incorporated in future models of sequence change.", "The HAT-B enzyme complex is responsible for acetylating newly synthesized histone H4 on lysines K5 and K12. HAT-B is a multisubunit complex composed of the histone acetyltransferase 1 (Hat1) catalytic subunit and the Hat2 (rbap46) histone chaperone. Hat1 is predominantly localized in the nucleus as a member of a trimeric NuB4 complex containing Hat1, Hat2, and a histone H3-H4 specific histone chaperone called Hif1 (NASP). In addition to Hif1 and Hat2, Hat1 interacts with Asf1 (anti-silencing function 1), a histone chaperone that has been reported to be involved in both replication-dependent and -independent chromatin assembly. To elucidate the molecular roles of the Hif1 and Asf1 histone chaperones in HAT-B histone binding and acetyltransferase activity, we have characterized the stoichiometry and binding mode of Hif1 and Asf1 to HAT-B and the effect of this binding on the enzymatic activity of HAT-B. We find that Hif1 and Asf1 bind through different modes and independently to HAT-B, whereby Hif1 binds directly to Hat2, and Asf1 is only capable of interactions with HAT-B through contacts with histones H3-H4. We also demonstrate that HAT-B is significantly more active against an intact H3-H4 heterodimer over a histone H4 peptide, independent of either Hif1 or Asf1 binding. Mutational studies further demonstrate that HAT-B binding to the histone tail regions is not sufficient for this enhanced activity. Based on these data, we propose a model for HAT-B/histone chaperone assembly and acetylation of H3-H4 complexes.", "Th2 cells produce Th2 cytokines such as IL-4, IL-5 and IL-13, but repress Th1 cytokine IFNγ. Recent studies have revealed various distinct memory-type Th2 cell subsets, one of which produces a substantial amount of IFNγ in addition to Th2 cytokines, however it remains unclear precisely how these Th2 cells produce IFNγ. We herein show that phosphorylation of Gata3 at Ser308, Thr315 and Ser316 induces dissociation of a histone deacetylase Hdac2 from the Gata3/Chd4 repressive complex in Th2 cells. We also identify Akt1 as a Gata3-phosphorylating kinase, and the activation of Akt1 induces derepression of Tbx21 and Ifng expression in Th2 cells. Moreover, T-bet-dependent IFNγ expression in IFNγ-producing memory Th2 cells appears to be controlled by the phosphorylation status of Gata3 in human and murine systems. Thus, this study highlights the molecular basis for posttranslational modifications of Gata3 that control the regulation of IFNγ expression in memory Th2 cells.", "MOTIVATION: Major tumor sequencing projects have been conducted in the past few years to identify genes that contain 'driver' somatic mutations in tumor samples. These genes have been defined as those for which the non-silent mutation rate is significantly greater than a background mutation rate estimated from silent mutations. Several methods have been used for estimating the background mutation rate.RESULTS: We propose a new method for identifying cancer driver genes, which we believe provides improved accuracy. The new method accounts for the functional impact of mutations on proteins, variation in background mutation rate among tumors and the redundancy of the genetic code. We reanalyzed sequence data for 623 candidate genes in 188 non-small cell lung tumors using the new method. We found several important genes like PTEN, which were not deemed significant by the previous method. At the same time, we determined that some genes previously reported as drivers were not significant by the new analysis because mutations in these genes occurred mainly in tumors with large background mutation rates.AVAILABILITY: The software is available at: http://linus.nci.nih.gov/Data/YounA/software.zip.", "Ehlers-Danlos syndrome (EDS) type I (the classical variety) is a dominantly inherited, genetically heterogeneous connective-tissue disorder. Mutations in the COL5A1 and COL5A2 genes, which encode type V collagen, have been identified in several individuals. Most mutations affect either the triple-helical domain of the protein or the expression of one COL5A1 allele. We identified a novel splice-acceptor mutation (IVS4-2A-->G) in the N-propeptide-encoding region of COL5A1, in one patient with EDS type I. The outcome of this mutation was complex: In the major product, both exons 5 and 6 were skipped; other products included a small amount in which only exon 5 was skipped and an even smaller amount in which cryptic acceptor sites within exon 5 were used. All products were in frame. Pro-alpha1(V) chains with abnormal N-propeptides were secreted and were incorporated into extracellular matrix, and the mutation resulted in dramatic alterations in collagen fibril structure. The two-exon skip occurred in transcripts in which intron 5 was removed rapidly relative to introns 4 and 6, leaving a large (270 nt) composite exon that can be skipped in its entirety. The transcripts in which only exon 5 was skipped were derived from those in which intron 6 was removed prior to intron 5. The use of cryptic acceptor sites in exon 5 occurred in transcripts in which intron 4 was removed subsequent to introns 5 and 6. These findings suggest that the order of intron removal plays an important role in the outcome of splice-site mutations and provide a model that explains why multiple products derive from a mutation at a single splice site." ]

[ "Cardiac arrhythmias are a major problem in elderly persons, because of the high prevalence of underlying heart disease and hypertension, arrhythmias are associated with significant morbidity and mortality in this age group. Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. Its incidence increases with age and the presence of structural heart disease. It is a major cause of stroke, especially in the elderly. Although the established principles of evaluation and management of cardiac arrhythmias apply to all age groups, management in the elderly patient is especially challenging because of increased risk of interventional and pharmacologic therapies, altered pharmacokinetics of drugs, and sometimes unclear long-term benefits in the older patient.", "In HLH-94, the first prospective international treatment study for hemophagocytic lymphohistiocytosis (HLH), diagnosis was based on five criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). In HLH-2004 three additional criteria are introduced; low/absent NK-cell-activity, hyperferritinemia, and high-soluble interleukin-2-receptor levels. Altogether five of these eight criteria must be fulfilled, unless family history or molecular diagnosis is consistent with HLH. HLH-2004 chemo-immunotherapy includes etoposide, dexamethasone, cyclosporine A upfront and, in selected patients, intrathecal therapy with methotrexate and corticosteroids. Subsequent hematopoietic stem cell transplantation (HSCT) is recommended for patients with familial disease or molecular diagnosis, and patients with severe and persistent, or reactivated, disease. In order to hopefully further improve diagnosis, therapy and biological understanding, participation in HLH studies is encouraged.", "OBJECTIVES AND BACKGROUND: Rivaroxaban, an oral direct factor Xa-inhibitor was non-inferior to adjusted dose warfarin in the prevention of stroke and embolism among patients with atrial fibrillation (AF) in the ROCKET-AF trial and has been approved for stroke prevention in AF.CASE REPORT: A 88-years-old female (body-mass-index = 19.95) with AF, hypertension and diabetes mellitus, hospitalized because of heart failure and a non-convulsive epileptic state, was treated by valproate, mirtazepin, nebivolol, digitoxin, lisinopril, gliclazide and amlodipine. Irrespective of renal insufficiency, rivaroxaban 15 mg/d was started. After 3 days rivaroxaban was stopped because of concerns about the bleeding risk. Coagulation tests 28 h after rivaroxaban-intake showed INR 2.26, PT 35%, aPTT 38.3 s and anti-Factor Xa-activity 2.00 U/ml. Explanations for the prolonged anticoagulant activity of rivaroxaban comprise renal failure, the low body-mass-index, the advanced age and drug-drug interactions of rivaroxaban with mirtazepin, valproate and amlodipine.CONCLUSION: Health care providers should consider renal function, concomitant medication, polymorbidity and age prior to prescribing rivaroxaban. Care has to be taken when prescribing rivaroxaban to patients who are different from those included in the ROCKET AF trial.", "Malignant glioma, ie, anaplastic astrocytoma and glioblastoma, is the most common type of primary malignant brain tumor in the People's Republic of China, and is particularly aggressive. The median survival of patients with newly diagnosed glioblastoma is only 12-14 months despite advanced therapeutic strategies. Treatment of malignant glioma consists mainly of surgical resection followed by adjuvant radiation and chemotherapy. Temozolomide (TMZ), a second-generation oral alkylating agent, is playing an increasingly important role in the treatment of malignant glioma in Chinese patients. Since the publication of a study by Stupp et al in 2005, which used a protocol of conventional fractionated irradiation with concomitant TMZ followed by standard TMZ for six cycles, many clinical studies in the People's Republic of China have demonstrated that such a treatment strategy has significantly improved efficacy with limited side effects for newly diagnosed glioblastoma after surgery as compared with strategies that do not contain TMZ. However, as a relatively new agent, the history and development of TMZ for malignant glioma is not well documented in Chinese patients. Multicenter, randomized controlled trials including appropriately sized patient populations investigating multiple aspects of TMZ therapy and related combination therapies are warranted in patients with malignant glioma. This review provides an update on the efficacy, mechanism of action, adverse reactions, and clinical role of TMZ in the treatment of malignant glioma in Chinese patients.", "The methyl-cytosine binding domain 2 (MBD2)-nucleosome remodeling and deacetylase (NuRD) complex recognizes methylated DNA and silences expression of associated genes through histone deacetylase and nucleosome remodeling functions. Our previous structural work demonstrated that a coiled-coil interaction between MBD2 and GATA zinc finger domain containing 2A (GATAD2A/p66α) proteins recruits the chromodomain helicase DNA-binding protein (CHD4/Mi2β) to the NuRD complex and is necessary for MBD2-mediated DNA methylation-dependent gene silencing in vivo (Gnanapragasam, M. N., Scarsdale, J. N., Amaya, M. L., Webb, H. D., Desai, M. A., Walavalkar, N. M., Wang, S. Z., Zu Zhu, S., Ginder, G. D., and Williams, D. C., Jr. (2011) p66α-MBD2 coiled-coil interaction and recruitment of Mi-2 are critical for globin gene silencing by the MBD2-NuRD complex. Proc. Natl. Acad. Sci. U.S.A. 108, 7487-7492). The p66α-MBD2 interaction differs from most coiled-coils studied to date by forming an anti-parallel heterodimeric complex between two peptides that are largely monomeric in isolation. To further characterize unique features of this complex that drive heterodimeric specificity and high affinity binding, we carried out biophysical analyses of MBD2 and the related homologues MBD3, MBD3-like protein 1 (MBD3L1), and MBD3-like protein 2 (MBD3L2) as well as specific mutations that modify charge-charge interactions and helical propensity of the coiled-coil domains. Analytical ultracentrifugation analyses show that the individual peptides remain monomeric in isolation even at 300 μM in concentration for MBD2. Circular dichroism analyses demonstrate a direct correlation between helical content of the coiled-coil domains in isolation and binding affinity for p66α. Furthermore, complementary electrostatic surface potentials and inherent helical content of each peptide are necessary to maintain high-affinity association. These factors lead to a binding affinity hierarchy of p66α for the different MBD2 homologues (MBD2 ≈ MBD3 > MBD3L1 ≈ MBD3L2) and suggest a hierarchical regulatory model in tissue and life cycle stage-specific silencing by NuRD complexes.", "There are several reports of a closer-than-random colocalization of homologous chromosomes in the vegetative nuclei of diploid budding yeast. Here, we studied by fluorescence in situ hybridization (FISH) the nuclear distribution of chromosomes and found a slight tendency toward closer proximity between homologous (allelic) loci than between any nonhomologous chromosomal regions. We show that most of this preferential association is not due to vegetative (also known as somatic) pairing but is caused by the polar orientation of interphase chromosomes (Rabl orientation). We quantified the occasional loss of detectable fluorescence signals that is inherent to the FISH method. Signal loss leads to the occurrence of a single signal that may be misinterpreted as the close association of two homologous chromosomal sites. The nuclear distribution of homologous loci, when corrected for the influence of nuclear architecture and methodological faults, was not different or was only marginally different from a random relative positioning as predicted by computer simulation. We discuss here several possibilities for the residual homologous proximity that do not invoke homology-dependent vegetative pairing, and we conclude that, in diploid budding yeast, constitutive vegetative pairing is a negligible factor for the organization of the interphase nucleus.", "AIMS: Glioblastomas are highly aggressive and treatment resistant. Increasing evidence suggests that tumour-associated macrophages/microglia (TAMs) facilitate tumour progression by acquiring a M2-like phenotype. Our objective was to investigate the prognostic value of TAMs in gliomas using automated quantitative double immunofluorescence.METHODS: Samples from 240 patients with primary glioma were stained with antibodies against ionized calcium-binding adaptor molecule-1 (IBA-1) and cluster of differentiation 204 (CD204) to detect TAMs and M2-like TAMs. The expression levels were quantified by software-based classifiers. The associations between TAMs, gemistocytic cells and glioblastoma subtype were examined with immuno- and haematoxylin-eosin stainings. Three tissue arrays containing glioblastoma specimens were included to study IBA-1/CD204 levels in central tumour and tumour periphery and to characterize CD204+ cells.RESULTS: Our data revealed that the amount of especially CD204+ TAMs increases with malignancy grade. In grade III-IV, high CD204 expression was associated with shorter survival, while high IBA-1 intensity correlated with a longer survival. In grade IV, CD204 showed independent prognostic value when adjusting for clinical data and the methylation status of O6-methylguanine-DNA methyltransferase. Our findings were confirmed in two bioinformatics databases. TAMs were more abundant in central tumour tissue, mesenchymal glioblastomas and gliomas with many gemistocytic cells. CD204+ TAMs co-expressed proteins related to tumour aggressiveness including matrix metallopeptidase-14 and hypoxia-inducible factor-1α.CONCLUSIONS: This is the first study to use automated quantitative immunofluorescence to determine the prognostic impact of TAMs. Our results suggest that M2-like TAMs hold an unfavourable prognostic value in high-grade gliomas and may contribute to a pro-tumourigenic microenvironment." ]

[ "INTRODUCTION: Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is characterised by abnormal sensations in the legs as well as dysaesthesia. Although the aetiology of RLS has not yet been determined, it may be associated with systemic inflammation. The neutrophil-to-lymphocyte ratio (NLR) is a new and simple marker indicating systemic inflammation. The present study aimed to investigate the relationship between systemic inflammation and RLS through the use of the NLR.METHODS: A total of 75 newly diagnosed patients with RLS and 56 healthy control subjects were included in the study. Baseline NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. The NLRs of the two groups were compared.RESULTS: There were no significant differences in gender and age between the two groups. The NLR was 1.96 ± 0.66 in the patient group and 1.67 ± 0.68 in the control group (p = 0.005). Receiver operating characteristic analysis was performed to determine the cut-off value of NLR to predict RLS. The NLR was predictive at 1.58 with a 64% sensitivity and 50% specificity (95% confidence interval 0.55-0.74, area under curve 0.648 ± 0.05). The NLR was found to be statistically higher in patients with RLS and may be used to predict RLS.CONCLUSION: The aetiology of RLS remains undetermined. The present study showed that systemic inflammation may play a role in RLS. However, RLS could also be associated with systemic inflammatory diseases. This relationship is supported by high NLR values, which are related to chronic systemic inflammation.", "INTRODUCTION: An intradermal version of Fluzone® split-virion inactivated trivalent influenza vaccine, containing 9 µg hemagglutinin per strain of A/H1N1, A/H3N2, and one B lineage virus (Fluzone Intradermal, Sanofi Pasteur), became available in the US during the 2011-2012 influenza season for adults 18-64 years of age. In advance of the 2015-2016 season, Fluzone Intradermal was replaced with Fluzone Intradermal Quadrivalent vaccine, which contains 9 µg hemagglutinin per strain of the two A-strain viruses and both B-strain lineage viruses (Victoria and Yamagata).AREAS COVERED: This literature review summarizes the history and mechanism of intradermal vaccination, discusses the clinical trial results supporting the immunogenicity and safety of Fluzone Intradermal Quadrivalent vaccine, and describes the unique microinjection system used to deliver Fluzone Intradermal Quadrivalent. Expert commentary: Fluzone Intradermal Quadrivalent may boost confidence in influenza vaccination with the addition of a second B-lineage strain. By using an innovative microinjection system, the vaccine is also designed to address some of the logistic challenges faced by healthcare providers administering immunizations.", "It is generally assumed that squamous cell carcinoma develops in a stepwise manner from normal bronchial epithelium towards cancer by the accumulation of (epi)genetic alterations. Several mechanisms including mutations and homozygous deletions or hypermethylation of the p16(INK4a) promoter region can cause loss of p16 expression. Recent studies suggest overexpression of the polycomb-group gene BMI-1 might also down-regulate p16 expression. In this study, we analyzed the p16 expression in relation to the methylation status of the p16 promoter region of the p16(INK4a) gene and the expression of BMI-1 in bronchial squamous cell carcinomas (SCC) and its premalignant lesions. Nine (69%) SCC showed loss of p16 expression and 10 (77%) showed expression of BMI-1. Of four p16 positive samples two (50%) were BMI-1 positive, whereas among nine p16 negative samples, eight (89%) revealed BMI-1 staining. Four (44%) p16 negative samples were hypermethylated at the p16(INK4a) promoter region; the other p16 negative tumors that showed no hypermethylation revealed BMI-1 staining. Only two premalignant lesions showed absence of p16 expression, of which one (carcinoma in situ) was hypermethylated at the p16(INK4a) promoter region and the other (severe dysplasia) showed BMI-1 expression. In total, 11 precursor lesions (48%) revealed BMI-1 expression. In conclusion, the results of this study suggest that loss of p16 expression by promoter hypermethylation is inconsistently and occurs late in the carcinogenic process at the level of severe dysplasia. To what extent overexpression of the polycomb-group protein BMI-1 attributes to down regulating of p16 expression remains unclear.", "Because of high stability and slow unfolding rates of G-quadruplexes (G4), cells have evolved specialized helicases that disrupt these non-canonical DNA and RNA structures in an ATP-dependent manner. One example is DHX36, a DEAH-box helicase, which participates in gene expression and replication by recognizing and unwinding parallel G4s. Here, we studied the molecular basis for the high affinity and specificity of DHX36 for parallel-type G4s using all-atom molecular dynamics simulations. By computing binding free energies, we found that the two main G4-interacting subdomains of DHX36, DSM and OB, separately exhibit high G4 affinity but they act cooperatively to recognize two distinctive features of parallel G4s: the exposed planar face of a guanine tetrad and the unique backbone conformation of a continuous guanine tract, respectively. Our results also show that DSM-mediated interactions are the main contributor to the binding free energy and rely on making extensive van der Waals contacts between the GXXXG motifs and hydrophobic residues of DSM and a flat guanine plane. Accordingly, the sterically more accessible 5'-G-tetrad allows for more favorable van der Waals and hydrophobic interactions which leads to the preferential binding of DSM to the 5'-side. In contrast to DSM, OB binds to G4 mostly through polar interactions by flexibly adapting to the 5'-terminal guanine tract to form a number of strong hydrogen bonds with the backbone phosphate groups. We also identified a third DHX36/G4 interaction site formed by the flexible loop missing in the crystal structure.", "Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aβ levels in rats and nonhuman primates and CSF Aβ levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization.", "BACKGROUND: Site-1 protease (S1P) is the key enzyme required for activation of the sterol regulatory element binding proteins (SREBPs) that govern lipid synthesis. While S1P has been speculated to influence plasma apoB-containing lipoprotein (Blp) metabolism, there has been little investigative work. LDL receptor (LDLR) is the major receptor for clearing plasma LDL cholesterol (LDL-c). Proprotein convertase subtilisin kexin type 9 (PCSK9) modulates LDL-c through post-translational degradation of the LDLR.METHODS: A hepatic-specific knockdown (KD) of S1P was achieved using floxed S1P mouse models (S1P(f/f) and LDLR(-/-)S1P(f/f)) and hepatic expression of Cre recombinase. Lipids were measured in total plasma and size fractionated plasma using colorimetric assays. Realtime polymerase chain reaction, western blotting and ELISA were used to determine hepatic expression of key genes/protein. Plasmid mediated overexpression and siRNA mediated knockdown of genes were performed in mouse primary hepatocytes to determine the mechanistic basis of PCSK9 gene regulation.RESULTS: A hepatic-specific KD of S1P resulted in a 45 % and 38 % reduction in plasma total cholesterol and triglyceride levels, respectively. Hepatic S1P KD had a minimal effect on plasma Blp cholesterol (Blp-c) in S1P(f/f) mice, despite significantly reducing VLDL secretion. Notably, hepatic S1P KD decreased the LDL receptor (LDLR) mRNA expression by 50 %. However, the reduction in LDLR protein levels was less than that of mRNA expression, especially under fed conditions. Further assessment of hepatic S1P deficiency revealed that it increased LDLR protein stability in vivo. Mechanistically, hepatic S1P KD was shown to decrease the liver and plasma levels of the protein proprotein convertase subtilisin/kexin type 9 (PCSK9), which degrades LDLR protein. This effect was more prominent in the fed condition and sufficient to account for the discordance in LDLR mRNA and protein levels. Furthermore, hepatic S1P was shown to regulate PCSK9 expression through activation of the SREBPs. In the LDLR(-/-) background, hepatic S1P KD significantly reduced Blp-c levels.CONCLUSION: Hepatic S1P is a physiological modulator of plasma Blp metabolism through its regulation of LDLR and PCSK9. Hepatic S1P is a valid target for lowering plasma Blp-c levels in the situation where LDLR function is compromised.", "The congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome (OMIM 604168) is a recently described autosomal recessive developmental disorder. It is almost completely restricted to an endogamous group of the European Vlax Roma population, called the Rudari. The CCFDN syndrome is a complex phenotype involving multiple systems, characterized by facial dysmorphism, congenital cataracts, microcorneae, delayed early motor and intellectual development, hypogonadotrop hypogonadism, hypomyelination of the peripheral nervous system, and serious complications related to general anaesthesia. This disorder is caused by a homozygous mutation of the carboxy-terminal domain phosphatase 1 (CTDP1) gene, localized to the 18q23 region. Authors present one genetically identified case in a large Roma family. The case documents that the CCFDN mutation is present also in the Hungarian Roma population. Underlie of antropomorphological data the authors presume that the CCFDN mutation reached Hungary as a result of emigration of Vlax Gypsies in the 18th century. The paper calls attention to the fact that molecular genetic diagnostics can replace invasive methods and makes possible the identification of heterozygotes without clinical symptoms. The introduction of the genetic screening enables us to perform genetic counselling and prevention in this high-risk population." ]

[ "BACKGROUND: Rectovaginal endometriosis is a severe form of pelvic endometriosis in which pharmacological treatment is relatively ineffective (Vercellini et al., Fertil Steril. 2005;84:1375-87). Laparoscopic surgical treatment is effective, but has the potential risks of bowel perforation and colostomy formation (Darai et al., Am J Obstet Gynecol. 2005;192:394-400). Transrectal ultrasound scanning can be applied as a preoperative tool to predict the presence of rectovaginal endometriosis and bowel wall involvement (Abrao et al., J Am Assoc Gynecol Laparosc. 2004;11:50-4).METHODS: Thirty-two women underwent transrectal ultrasound followed by therapeutic laparoscopy. Likelihood ratios and post-test prevalences were calculated with Fagan's normogram. This was then extrapolated with the aid of a mathematical model to a low-risk population.RESULTS: A positive likelihood ratio was found to be 10.89 (95% confidence ratio (CI): 1.62-73.15) and a negative likelihood ratio was found to be 0.24 (95% CI: 0.1-0.57). The pre-test prevalence of rectovaginal endometriosis was 56%. The positive post-test prevalence probability was 93%, and the negative post-test prevalence probability was 23%.CONCLUSION: Preoperative transrectal ultrasound scanning for rectovaginal endometriosis is an extremely accurate predictive test, and strongly predicts the need for extensive laparoscopic dissection and potential bowel resection.", "JASPAR (http://jaspar.genereg.net) is an open-access database storing curated, non-redundant transcription factor (TF) binding profiles representing transcription factor binding preferences as position frequency matrices for multiple species in six taxonomic groups. For this 2016 release, we expanded the JASPAR CORE collection with 494 new TF binding profiles (315 in vertebrates, 11 in nematodes, 3 in insects, 1 in fungi and 164 in plants) and updated 59 profiles (58 in vertebrates and 1 in fungi). The introduced profiles represent an 83% expansion and 10% update when compared to the previous release. We updated the structural annotation of the TF DNA binding domains (DBDs) following a published hierarchical structural classification. In addition, we introduced 130 transcription factor flexible models trained on ChIP-seq data for vertebrates, which capture dinucleotide dependencies within TF binding sites. This new JASPAR release is accompanied by a new web tool to infer JASPAR TF binding profiles recognized by a given TF protein sequence. Moreover, we provide the users with a Ruby module complementing the JASPAR API to ease programmatic access and use of the JASPAR collection of profiles. Finally, we provide the JASPAR2016 R/Bioconductor data package with the data of this release.", "An estimated 4.2 million seasonal and migrant farmworkers and their dependents live in the U.S. Most of these farmworkers are Latino. These workers are exposed to numerous occupational and environmental risk factors that can result in skin disease. Few data exist on the prevalence of skin disease in this population. The purpose of this study was to estimate the prevalence and predictors of skin disease in a sample of Latino farmworkers in North Carolina. A sample of 59 farmworkers was recruited and interviewed at two camps during the 2004 agricultural season. A dermatologist completed a skin exam of each worker and recorded any skin disease present. Forty-two (77.7%) of the 54 men, and all five of the women examined had a diagnosed skin disease. For the men, onychomycosis (nail fungus, 31.5%), tinea pedis (foot fungus, 27.8%), and acne (24.1 %) were the most commonly diagnosed skin diseases, with contact dermatitis diagnosed in 5.6% of the sample. Other diagnoses included scars, sunburn, and atopic dermatitis. Among the women, diagnoses included melasma (dark patches on the face, 2 cases), xerosis (excessively dry skin, 1 case), tinea pedis (2 cases), onychomycosis (1 case), acne (1 case), and insect bites (1 case). There were no statistically significant differences between workers in the two camps despite different growing seasons and different crops harvested. Skin disease is prevalent among the North Carolina Latino farmworkers who participated in this study, with fungal disease being the most prevalent.", "The current review was designed to compare between the insulin inhalation systems Exubera and Afrezza and to investigate the reasons why Exubera was unsuccessful, when Afrezza maker is expecting their product to be felicitous. In January 2006, Pfizer secured FDA and EC approval for the first of its kind, regular insulin through Exubera inhaler device for the management of types 1 and 2 diabetes mellitus (DM) in adults. The product was no longer available to the market after less than two years from its approval triggering a setback for competitive new inhalable insulins that were already in various clinical development phases. In contrary, MannKind Corporation started developing its ultra-rapid-acting insulin Afrezza in a bold bid, probably by managing the issues in which Exubera was not successful. Afrezza has been marketed since February, 2015 by Sanofi after getting FDA approval in June 2014. The results from this systematic review indicate the effectiveness of insulin inhalation products, particularly for patients initiating insulin therapy. Pharmaceutical companies should capitalize on the information available from insulin inhalation to produce competitive products that are able to match the bioavailability of subcutaneous (SC) insulin injection and to deal with the single insulin unit increments and basal insulin requirements in some diabetic patients or extending the horizon to inhalable drug products with completely different drug entities for other indications.", "The epigenetic mechanisms in regulation of genes' expression seem to be another field of research that gains land in genetic association studies of rheumatoid arthritis (RA) susceptibility factors. Recently, a new class of molecules has been discovered, the microRNAs (miRNAs). miRNAs are related to post-transcriptional regulation of genes' expression. Different expression patterns of mir-146a, miRNA-155, miRNA-124a, mir-203, mir-223, mir-346, mir-132, mir-363, mir-498, mir-15a, and mir-16 were documented in several tissue sample types of RA patients. The polymorphisms of these miRNAs and their gene targets, which previously have been associated with RA or other autoimmune diseases, are also reviewed. Finally, using web-based tools we propose polymorphisms of the discussed miRNAs and their gene-targets that worth to be studied for their role in RA predisposition.", "Novel protein-coding genes can arise either through re-organization of pre-existing genes or de novo. Processes involving re-organization of pre-existing genes, notably after gene duplication, have been extensively described. In contrast, de novo gene birth remains poorly understood, mainly because translation of sequences devoid of genes, or 'non-genic' sequences, is expected to produce insignificant polypeptides rather than proteins with specific biological functions. Here we formalize an evolutionary model according to which functional genes evolve de novo through transitory proto-genes generated by widespread translational activity in non-genic sequences. Testing this model at the genome scale in Saccharomyces cerevisiae, we detect translation of hundreds of short species-specific open reading frames (ORFs) located in non-genic sequences. These translation events seem to provide adaptive potential, as suggested by their differential regulation upon stress and by signatures of retention by natural selection. In line with our model, we establish that S. cerevisiae ORFs can be placed within an evolutionary continuum ranging from non-genic sequences to genes. We identify ~1,900 candidate proto-genes among S. cerevisiae ORFs and find that de novo gene birth from such a reservoir may be more prevalent than sporadic gene duplication. Our work illustrates that evolution exploits seemingly dispensable sequences to generate adaptive functional innovation.", "The dynamin-related GTPase protein OPA1, localized in the intermembrane space and tethered to the inner membrane of mitochondria, participates in the fusion of these organelles. Its mutation is the most prevalent cause of Autosomal Dominant Optic Atrophy. OPA1 controls the diameter of the junctions between the boundary part of the inner membrane and the membrane of cristae and reduces the diffusibility of cytochrome c through these junctions. We postulated that if significant Ca²⁺ uptake into the matrix occurs from the lumen of the cristae, reduced expression of OPA1 would increase the access of Ca²⁺ to the transporters in the crista membrane and thus would enhance Ca²⁺ uptake. In intact H295R adrenocortical and HeLa cells cytosolic Ca²⁺ signals evoked with K⁺ and histamine, respectively, were transferred into the mitochondria. The rate and amplitude of mitochondrial [Ca²⁺] rise (followed with confocal laser scanning microscopy and FRET measurements with fluorescent wide-field microscopy) were increased after knockdown of OPA1, as compared with cells transfected with control RNA or mitofusin1 siRNA. Ca²⁺ uptake was enhanced despite reduced mitochondrial membrane potential. In permeabilized cells the rate of Ca²⁺ uptake by depolarized mitochondria was also increased in OPA1-silenced cells. The participation of Na⁺/Ca²⁺ and Ca²⁺/H⁺ antiporters in this transport process is indicated by pharmacological data. Altogether, our observations reveal the significance of OPA1 in the control of mitochondrial Ca²⁺ metabolism." ]

[ "RATIONALE: Atrial fibrillation (AF) is the most common cardiac arrhythmia, however the mechanism(s) causing AF remain poorly understood and therapy is suboptimal. The ryanodine receptor (RyR2) is the major calcium (Ca2+) release channel on the sarcoplasmic reticulum (SR) required for excitation-contraction coupling in cardiac muscle.OBJECTIVE: In the present study, we sought to determine whether intracellular diastolic SR Ca2+ leak via RyR2 plays a role in triggering AF and whether inhibiting this leak can prevent AF.METHODS AND RESULTS: We generated 3 knock-in mice with mutations introduced into RyR2 that result in leaky channels and cause exercise induced polymorphic ventricular tachycardia in humans [catecholaminergic polymorphic ventricular tachycardia (CPVT)]. We examined AF susceptibility in these three CPVT mouse models harboring RyR2 mutations to explore the role of diastolic SR Ca2+ leak in AF. AF was stimulated with an intra-esophageal burst pacing protocol in the 3 CPVT mouse models (RyR2-R2474S+/-, 70%; RyR2-N2386I+/-, 60%; RyR2-L433P+/-, 35.71%) but not in wild-type (WT) mice (P<0.05). Consistent with these in vivo results, there was a significant diastolic SR Ca2+ leak in atrial myocytes isolated from the CPVT mouse models. Calstabin2 (FKBP12.6) is an RyR2 subunit that stabilizes the closed state of RyR2 and prevents a Ca2+ leak through the channel. Atrial RyR2 from RyR2-R2474S+/- mice were oxidized, and the RyR2 macromolecular complex was depleted of calstabin2. The Rycal drug S107 stabilizes the closed state of RyR2 by inhibiting the oxidation/phosphorylation induced dissociation of calstabin2 from the channel. S107 reduced the diastolic SR Ca2+ leak in atrial myocytes and decreased burst pacing-induced AF in vivo. S107 did not reduce the increased prevalence of burst pacing-induced AF in calstabin2-deficient mice, confirming that calstabin2 is required for the mechanism of action of the drug.CONCLUSIONS: The present study demonstrates that RyR2-mediated diastolic SR Ca2+ leak in atrial myocytes is associated with AF in CPVT mice. Moreover, the Rycal S107 inhibited diastolic SR Ca2+ leak through RyR2 and pacing-induced AF associated with CPVT mutations.", "Hansen's disease is a chronic granulomatous disease of infectious origin. It has a worldwide distribution and a variety of clinical manifestations often involving the skin, nasal mucosa, and peripheral nerves. Lepromatous leprosy characterizes the condition of a large group of patients with little or no resistence to the infection. Several forms of lepromatous leprosy are recognized, including macular, nodular, and diffuse. Lucio's phenomenon is a rare but distinctive skin eruption seen in patients with diffuse lepromatous leprosy. The diffuse lesions of Lucio's phenomenon have a predilection for the extremities, can include nodules, and heal with atrophic stellate scars; histologically, a necrotizing vasculitis accompanied by a nonspecific inflammatory reaction may be seen. We describe two patients with Lucio's phenomenon who presented with nontender, painless, skin lesions with nodules in part perceptible only by palpation. Both patients were treated with multidrug therapy, and immunosuppressive doses of steroids as the suggested optimal treatment for this reactional state. However, Lucio's phenomenon is frequently fatal as a result of bacterial infection or sepsis, and both patients reported here died. We call attention to this particular and unusual skin manifestation of lepromatous leprosy, which can mimic rheumatic disease and other causes of vasculitis. This is especially likely to be unrecognized in nonendemic countries but cases will occasionally be seen in this age of extensive international travel.", "Author information:(1)Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) S.r.l., IRCCS, Gene Therapy Unit, 47014, Meldola (FC), Italy.(2)Departments of Pediatrics and Molecular Microbiology & Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Children's Center for Cancer and Blood Diseases and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA.(3)Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198, USA.(4)Department of Internal Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Ohio State University, Columbus, OH, 43210, USA.(5)Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, 40126, Bologna, Italy.(6)Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.(7)The Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA.(8)Departments of Preventive Medicine and Neurological Surgery, Northwestern University-Feinberg School of Medicine, Chicago, IL, 60611, USA.(9)Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.(10)Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.(11)Integrated Molecular Discovery Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.(12)Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH, 43210, USA.(13)Department of Biochemistry and Molecular Biology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.(14)Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) S.r.l., IRCCS, Biosciences Laboratory Unit, 47014, Meldola (FC), Italy.(15)Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.(16)Departments of Surgery and Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.(17)Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA.(18)Department of Morphology, Surgery and Experimental Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121, Ferrara, Italy.(19)Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.(20)Department of Oncology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) S.r.l., IRCCS, 47014, Meldola (FC), Italy.(21)Institute of Genetics and Biophysics, National Research Council, 80131, Naples, Italy.(22)Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. gcalin@mdanderson.org.(23)The Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA. gcalin@mdanderson.org.(24)Departments of Pediatrics and Molecular Microbiology & Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Children's Center for Cancer and Blood Diseases and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA. mfabbri@chla.usc.edu.", "Topaz1 (Testis and Ovary-specific PAZ domain gene 1) is a germ cell specific gene highly conserved in vertebrates. The putative protein TOPAZ1 contains a PAZ domain, specifically found in PIWI, Argonaute and Zwille proteins. Consequently, Topaz1 is supposed to have a role during gametogenesis and may be involved in the piRNA pathway and contribute to silencing of transposable elements and maintenance of genome integrity. Here we report Topaz1 inactivation in mouse. Female fertility was not affected, but male sterility appeared exclusively in homozygous mutants in accordance with the high expression of Topaz1 in male germ cells. Pachytene Topaz1--deficient spermatocytes progress through meiosis without either derepression of retrotransposons or MSCI dysfunction, but become arrested before the post-meiotic round spermatid stage with extensive apoptosis. Consequently, an absence of spermatids and spermatozoa was observed in Topaz1(-/-) testis. Histological analysis also revealed that disturbances of spermatogenesis take place between post natal days 15 and 20, during the first wave of male meiosis and before the generation of haploid germ cells. Transcriptomic analysis at these two stages showed that TOPAZ1 influences the expression of one hundred transcripts, most of which are up-regulated in mutant testis at post natal day 20. Our results also showed that 10% of these transcripts are long non-coding RNA. This suggests that a highly regulated balance of lncRNAs seems to be essential during spermatogenesis for induction of appropriate male gamete production.", "Transcribed ultraconserved regions (T-UCRs) classified as long non-coding RNAs (Lnc-RNAs) are transcripts longer than 200-nt RNA with no protein-coding capacity. Previous studies showed that T-UCRs serve as novel oncogenes, or tumor suppressors are involved in tumorigenesis and cancer progressive. Nevertheless, the clinicopathologic significance and regulatory mechanism of T-UCRs in lung cancer (LC) remain largely unknown. We found that uc.454 was downregulated in both non-small-cell LC (NSCLC) tissues and LC cell lines, and the downregulated uc.454 is associated with tumor size and tumors with more advanced stages. Transfection with uc.454 markedly induced apoptosis and inhibited cell proliferation in SPC-A-1 and NCI-H2170 LC cell lines. Above results suggested that uc.454 played a suppressive role in LC. Heat shock protein family A member 12B (HSPA12B) protein was negatively regulated by uc.454 at the posttranscriptional level by dual-luciferase reporter assay and affected the expressions of Bcl-2 family members, which finally induced LC apoptosis. The uc.454/HSPA12B axis furthers our understanding of the molecular mechanisms involved in tumor apoptosis, which may potentially serve as a therapeutic target for lung carcinoma.", "PURPOSE: Wnt signaling was demonstrated to be activated in chronic lymphocytic leukemia (CLL). It is thought to be responsible for the extended survival of CLL cells in vivo. Dickkopf1 (DKK1) is known to antagonize Wnt signaling by direct high-affinity binding to the extracellular domain of WNT coreceptor lipoprotein receptor-related protein 6 (LRP6). The purpose of this study was to investigate the effect of DKK1 in B-CLL cells in vitro.METHODS: Expression of DKK1 was estimated by Western blot and real-time PCR. B cells from patients with CLL and healthy donors were incubated with recombinant DKK1. Survival was measured by flow cytometry. Primers for real-time PCR were designed for extracellular domain of LRP6, responsible for DKK1 binding, and the intracellular region, essential for inhibiting GSK3 β.RESULTS: Healthy and CLL cells express equivalent mRNA levels of DKK1 and LRP6. After treatment of CLL cells with recombinant DKK1 (1 μg/mL) for 3 h, there was no change in the levels of phosphorylated β-catenin and total β-catenin. Healthy B cells proved to have significantly higher levels of extracellular, DKK1 binding domain of LRP6. We estimated that in CLL cells every 6th LRP6 receptor is lacking the extracellular domain.DISCUSSION: For the first time we show the expression of DKK1 in CLL cells. Unlike in similar tumors, the addition of DKK1 to culture of CLL cells does not inactivate WNT pathway. The reason for this could be the absence of the binding domain of LRP6. On the other hand, a truncated LRP6 without extracellular DKK1 binding domain could lead to an uncontrollable activation of WNT signaling.", "BACKGROUND: Discovering novel disease genes is still challenging for diseases for which no prior knowledge--such as known disease genes or disease-related pathways--is available. Performing genetic studies frequently results in large lists of candidate genes of which only few can be followed up for further investigation. We have recently developed a computational method for constitutional genetic disorders that identifies the most promising candidate genes by replacing prior knowledge by experimental data of differential gene expression between affected and healthy individuals.To improve the performance of our prioritization strategy, we have extended our previous work by applying different machine learning approaches that identify promising candidate genes by determining whether a gene is surrounded by highly differentially expressed genes in a functional association or protein-protein interaction network.RESULTS: We have proposed three strategies scoring disease candidate genes relying on network-based machine learning approaches, such as kernel ridge regression, heat kernel, and Arnoldi kernel approximation. For comparison purposes, a local measure based on the expression of the direct neighbors is also computed. We have benchmarked these strategies on 40 publicly available knockout experiments in mice, and performance was assessed against results obtained using a standard procedure in genetics that ranks candidate genes based solely on their differential expression levels (Simple Expression Ranking). Our results showed that our four strategies could outperform this standard procedure and that the best results were obtained using the Heat Kernel Diffusion Ranking leading to an average ranking position of 8 out of 100 genes, an AUC value of 92.3% and an error reduction of 52.8% relative to the standard procedure approach which ranked the knockout gene on average at position 17 with an AUC value of 83.7%.CONCLUSION: In this study we could identify promising candidate genes using network based machine learning approaches even if no knowledge is available about the disease or phenotype.", "The effects of thyroxine-stimulated hypertrophy (TSH) were studied in the porcine left ventricular myocardium. Hypertrophy was produced in six adult pigs by administration of triiodothyronine (1 mg/kg; i.v.) for eight days. Six pigs served as controls. The degree of hypertrophy, determined by left ventricular-to-body weight ratio, was 47%. With hypertrophy there was a significant increase in heart rate, blood pressure and myocardial blood flows. Minimal coronary resistance measured during adenosine infusion was lower in the TSH group compared with the control group. Anatomic studies revealed a balanced proliferative response of mitochondria, myofibrils and the t-tubular system during TSH. Analysis of the microvasculature indicated that the capillary and arteriolar beds both experienced growth which paralleled myocyte growth during TSH. These results suggest that thyroxine administration promotes angiogenesis in the microvascular bed which provides a partial anatomic rationale for the lowered minimal coronary resistance." ]

[ "BACKGROUND: The programmed death-1 (PD-1) pathway negatively regulates T-cell activation and has an important role in regulating antitumor host immunity. Monoclonal antibodies directed against PD-1 or the PD-1 ligand (PD-L1) have shown activity in several tumor types with preliminary data suggesting a relationship between PD-L1 expression and response. The aim of this study was to establish the frequency of PD-L1 expression in muscle-invasive bladder cancer and associated lymph node metastasis using immunohistochemistry and to investigate the feasibility of using PD-L1 expression as a biomarker to select patients for PD-1-directed therapy.PATIENTS AND METHODS: Cases of radical cystectomy for muscle-invasive bladder cancer with no exposure to previous chemotherapy were identified and representative slides from archived paraffin-embedded blocks stained with anti-PD-L1 antibody (5H1 clone) were identified. PD-L1 positivity was defined by a 5% expression threshold.RESULTS: Fifty-two radical cystectomy specimens were reviewed. PD-L1 was overexpressed in the tumor cells of 5/52 (9.6%) of cystectomy specimens in this cohort with 17/52 (32.7%) of cases showing PD-L1 overexpression in tumor-infiltrating immune cells. Discordance was observed between PD-L1 expression in lymph node metastasis and the primary tumor.CONCLUSION: Standard assays for PD-L1 expression have yet to be established. The observation of discordance between PD-L1 expression in metastatic sites and primary tumors suggests that prospective biomarker studies should aim to acquire material immediately before treatment initiation rather than archived tissue from resected specimens that might not reflect the current immune-active microenvironment.", "OBJECTIVE/PATIENTS: Rabson-Mendenhall syndrome (RMS) is a rare, recessively inherited disorder of extreme insulin resistance due to mutations in the insulin receptor gene. We have identified a pair of siblings with RMS attributable to compound heterozygosity for two insulin receptor mutations, one previously unreported, and have characterized the novel receptor mutation functionally.MEASUREMENTS: Insulin receptor sequencing was performed to identify the mutations. Expression levels of the mature receptor were determined in lymphoblastoid cells from the affected subjects. Further studies of immortalized cell lines transfected with mutant and wild type (WT) receptors were undertaken to characterize the effects of the novel mutation on [(125)I]-labelled insulin binding, proreceptor processing and insulin-stimulated receptor autophosphorylation.RESULTS: Sequencing of the insulin proreceptor coding sequence revealed both siblings to be compound heterozygotes for the missense mutations Arg209His and Gly359Ser in the mature insulin receptor. The former mutation has been described in homozygous form in Donohue syndrome, while the latter is novel. Insulin receptor expression in lymphoblastoid cell lines was present at only 10-30% of that in control cells; studies of immortalized cells transfected with mutant and WT receptors confirmed the reduced expression of the mutant. The degree of impairment of insulin binding and insulin-stimulated receptor autophosphorylation were commensurate with the decrease in expression of the mature receptor.CONCLUSIONS: Loss of function of the novel insulin receptor (INSR) G359S variant is largely accounted for by aberrant proreceptor processing rather than intrinsically impaired signal transduction by the mutant receptor.", "INTRODUCTION: An intradermal version of Fluzone® split-virion inactivated trivalent influenza vaccine, containing 9 µg hemagglutinin per strain of A/H1N1, A/H3N2, and one B lineage virus (Fluzone Intradermal, Sanofi Pasteur), became available in the US during the 2011-2012 influenza season for adults 18-64 years of age. In advance of the 2015-2016 season, Fluzone Intradermal was replaced with Fluzone Intradermal Quadrivalent vaccine, which contains 9 µg hemagglutinin per strain of the two A-strain viruses and both B-strain lineage viruses (Victoria and Yamagata).AREAS COVERED: This literature review summarizes the history and mechanism of intradermal vaccination, discusses the clinical trial results supporting the immunogenicity and safety of Fluzone Intradermal Quadrivalent vaccine, and describes the unique microinjection system used to deliver Fluzone Intradermal Quadrivalent. Expert commentary: Fluzone Intradermal Quadrivalent may boost confidence in influenza vaccination with the addition of a second B-lineage strain. By using an innovative microinjection system, the vaccine is also designed to address some of the logistic challenges faced by healthcare providers administering immunizations.", "Narcolepsy is a chronic sleep disorder characterized by a pentad of excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and disturbed nocturnal sleep. While non-pharmacological treatments are sometimes helpful, more than 90% of narcoleptic patients require a pharmacological treatment. Areas covered: The present review is based on an extensive Internet and PubMed search from 1994 to 2017. It is focused on drugs currently in development for the treatment of narcolepsy. Expert opinion: Currently there is no cure for narcolepsy, with treatment focusing on symptoms control. However, these symptomatic treatments are often unsatisfactory. The research is leading to a better understanding of narcolepsy and its symptoms. New classes of compounds with possible applications in the development of novel stimulant/anticataplectic medications are described. H3 receptor antagonists represent a new therapeutic option for EDS in narcolepsy. JZP-110, with its distinct mechanism of action, would be a new therapeutic option for the treatment of EDS in the coming years. In the future, hypocretin-based therapies and immune-based therapies, could modify the clinical course of the disease. However, more information would be necessary to completely understand the autoimmune process and also how this process can be altered for therapeutic benefits.", "OBJECTIVE: Subacute thyroiditis (SAT) is a transient inflammatory disease of the thyroid. We evaluated the clinical characteristics based on laboratory and imaging studies in patients with SAT before treatment.PATIENTS: We reviewed the medical records of 852 patients (107 men and 745 women) with SAT who visited our thyroid clinic at Kuma Hospital from 1996 through 2004.RESULTS: SAT developed most often in female patients aged 40 to 50 years, with significant seasonal clusters during summer to early autumn. While the rates of any virus infections and diseases did not differ from those in the general population, recurrent episodes of SAT at intervals of 13.6+/-5.6 years accounted for 1.6% of all cases. At the onset of SAT, 28.2% of patients had temperatures greater than 38 degrees C and typical symptoms associated with thyrotoxicosis developed in more than 60% of patients. Before treatment, most of the abnormal laboratory findings associated with thyrotoxicosis, inflammation, and liver dysfunction reached peak levels within 1 week after onset. Ultrasound examination showed that half of the patients with unilateral thyroid pain presented with bilateral hypoechogenic area in the thyroid and the rate of bilateral hypoechogenic area tended to increase 2 months after onset.CONCLUSION: Laboratory studies of thyroid dysfunction and inflammation related to SAT presented peak levels within 1 week after onset.", "Abnormalities in DNA copy number are frequently found in patients with multiple anomaly syndromes and mental retardation. Array-based comparative genomic hybridization (array-CGH) is a high-resolution, whole-genome technology that improves detection of submicroscopic aberrations underlying these syndromes. Eight patients with mental disability, multiple congenital anomalies, and dysmorphic features were screened for submicroscopic chromosomal imbalances using the GenoSensor Array 300 Chip. Subtelomeric aberrations previously detected by fluorescence in situ hybridization (FISH) analysis were confirmed in two patients, and accurate diagnosis was provided in two previously undiagnosed complex cases. Microdeletions at 15q11.2-q13 in a newborn with hypotonia, cryptorchidism, and hypopigmentation were detected with few discrepancies between the array results and FISH analysis. Contiguous microdeletion of GSCL, HIRA and TBX1 genes at 22q11.2 was identified in a previously undiagnosed boy with an unusual presentation of the VCF/DiGeorge spectrum. In a newborn with aniridia, a borderline false-negative WT1 deletion was observed, most probably because of differences between the size of the genomic deletion and the microarray probe. A false-positive rate of 0.2% was calculated for clone-by-clone analysis, whereas the per patient false-positive rate was 20%. Array-CGH is a powerful tool for the rapid and accurate detection of genetic disorders associated with copy number abnormalities and can significantly improve clinical genetic diagnosis and care.", "Conflict of interest statement: Conflict of Interest Disclosures: Dr. Takeshita receives a research grant (to the Trusteees of the University of Pennyslvania) from Pfizer and payment for continuing medical education work related to psoriasis. Dr. Mehta is a full time U.S. Government employee. Dr. Ogdie receives research grants from AbbVie (to the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis [GRAPPA]), Celgene (to GRAPPA), and Pfizer Inc. (to the Trustees of the University of Pennsylvania and GRAPPA), and has served as a consultant for Novartis, receiving honoraria. Dr. Van Voorhees has served as a consultant for AbbVie, Amgen, Aqua, Astra Zeneca, Celgene, Corrona, Dermira, Janssen, Leo, Novartis, and Pfizer, receiving honoraria; received a research grant from AbbVie; and has other relationship with Merck. Dr. Gelfand has served as a consultant for AbbVie, AstraZeneca, Celgene Corp, Coherus, Eli Lilly, Janssen Biologics (formerly Centocor), Sanofi, Merck, Novartis Corp, Endo, and Pfizer Inc., receiving honoraria; and receives research grants (to the Trustees of the University of Pennsylvania) from AbbVie, Amgen, Eli Lilly, Janssen, Novartis Corp, Regeneron, and Pfizer Inc.; and received payment for continuing medical education work related to psoriasis. Dr. Gelfand is a co-patent holder of resiquimod for treatment of cutaneous T cell lymphoma." ]

[ "INTRODUCTION: A recent randomized controlled trial (RCT), the Multicenter Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN), demonstrated better outcomes with endovascular treatment compared with medical therapy for acute ischemic stroke (AIS). However, previous trials have provided mixed results regarding the efficacy of endovascular treatment for AIS. A meta-analysis of all available trial data was performed to summarize the available evidence.METHODS: A literature search was performed to identify all prospective RCTs comparing endovascular therapies with medical management for AIS. Two datasets were created: (1) all patients randomized after confirmation of large vessel occlusion (LVO) (consistent with the contemporary standard of practice at the majority of centers); and (2) all patients with outcome data who underwent randomization regardless of qualifying vascular imaging. The pre-specified primary outcome measure was modified Rankin Scale score of 0-2 at 90 days. A fixed-effect model was used to determine significance.RESULTS: Five prospective RCTs comparing endovascular therapies with medical management were included in dataset 1 (1183 patients) and six were included in dataset 2 (1903 total patients). Endovascular therapies were associated with significantly improved outcomes compared with medical management (OR 1.67, 95% CI 1.29 to 1.16, p=0.0001) for patients with LVO (dataset 1). This benefit persisted when patients from all six RCTs were included, even in the absence of confirmation of LVO (OR 1.27, 95% CI 1.05 to 1.54, p=0.019; dataset 2).CONCLUSIONS: A meta-analysis of prospective RCTs comparing endovascular therapies with medical management demonstrates superior outcomes in patients randomized to endovascular therapy.", "The ameloblastoma is a benign but aggressive neoplasm of odontogenic origin. However, no enamel or hard tissue is formed by the tumor cells. Ameloblastomas are infamous for their invasive growth and their tendency to recur. Robinson (1937) as a benign tumor that is 'usually unicentric, nonfunctional, intermittent in growth, anatomically benign and clinically persistent.' They may occur at any age, even though nearly half of the tumors do occur between the ages of 20 and 40 years. This is the most common neoplasm affecting the jaws, yet only accounts for 1% of all tumors of the maxilla and mandible and 11% of all odontogenic tumors. This report presents a case of ameloblastoma involving entire ramus and part of body of mandible with resorption of the mesial and distal root apices of second molar and distal root of mandibular first molar. The lesion extending till the base of mandible surrounding the crown of the unerupted third molar resembling the dentigerous cyst. This was surgically resected followed by harvesting the contralateral sixth costochondral rib graft. How to cite this article: Celur S, Babu KS. Plexiform Ameloblastoma. Int J Clin Pediatr Dent 2012;5(1):78-83.", "INTRODUCTION: We investigated the health-related quality of life (HRQoL) of long-term prostate cancer patients who received leuprorelin acetate in microcapsules (LAM) for androgen-deprivation therapy (ADT).METHODS: The observational study was carried out by 30 office-based German urologists in 536 prostate cancer (PCa) patients treated for ≥5 years with LAM and in 116 patients of an age-matched control group (CG). Data on HRQoL and health status was collected prospectively using validated questionnaires QLQ-C30, QLQ-PR25 and Karnofsky Index. Data on effectiveness (clinical response, prostate specific antigen [PSA], testosterone) and safety was collected retrospectively from patients' health records. We used descriptive statistics to analyze the data.RESULTS: The mean treatment duration was 8.6 years (range 4.5-19.8 years). General health status (QLQ-C30) was comparable for both groups. Differences were observed regarding physical - and role functioning. ADT patients rated single items slightly worse than CG. Karnofsky-Index showed comparable high values (median of 90%). QLQ-PR25 revealed more PCa-related symptoms for ADT patients. Within 6 months, median PSA level declined >90% and median testosterone levels declined below castration level from 4.0 to 0.2 ng/mL. Clinical response (European Organisation for Research and Treatment of Cancer criteria) was observed in at least 90% of ADT patients.CONCLUSIONS: Long-term ADT with LAM is a well-accepted, tolerated, effective, and low-burden treatment option for patients with advanced, hormone-sensitive PCa.", "Histamine-N-methyltransferase (HMT) inactivates the neurotransmitter histamine. Central histaminergic deficits may contribute to the cognitive impairment of neurodegenerative disorders including Alzheimer's disease (AD) and Down syndrome (DS). However, there is no evidence for histaminergic deficits in Pick's disease (PiD). HMT levels were measured in the frontal cortex and cerebellum of brains of patients with AD, DS, and PiD, and normal aged subjects using proteomics techniques. In frontal cortex, HMT was significantly decreased in DS, but significantly increased in PiD compared with controls. HMT levels were comparable in cerebellum of all groups. Elevated HMT in PiD could lead to increased histamine degradation that in turn would be in agreement with impaired cognitive functions of PiD. Decreased HMT in DS would be compatible with findings of decreased histamine synthesis, thus reflecting a compensation mechanism to antagonize reduced synthesis by decreased degradation.", "Neutrophil extracellular traps (NETs) represent an important defense mechanism against microorganisms. Clearance of NETs is impaired in a subset of patients with systemic lupus erythematosus, and NETosis is increased in neutrophils and, particularly, in low-density granulocytes derived from lupus patients. NETs are toxic to the endothelium, expose immunostimulatory molecules, activate plasmacytoid dendritic cells, and may participate in organ damage through incompletely characterized pathways. To better understand the role of NETs in fostering dysregulated inflammation, we examined inflammasome activation in response to NETs or to LL-37, an antibacterial protein externalized on NETs. Both NETs and LL-37 activate caspase-1, the central enzyme of the inflammasome, in both human and murine macrophages, resulting in release of active IL-1β and IL-18. LL-37 activation of the NLRP3 inflammasome utilizes P2X7 receptor-mediated potassium efflux. NET and LL-37-mediated activation of the inflammasome is enhanced in macrophages derived from lupus patients. In turn, IL-18 is able to stimulate NETosis in human neutrophils. These results suggest that enhanced formation of NETs in lupus patients can lead to increased inflammasome activation in adjacent macrophages. This leads to release of inflammatory cytokines that further stimulate NETosis, resulting in a feed-forward inflammatory loop that could potentially lead to disease flares and/or organ damage.", "The aim of this study was to evaluate the effect of Lactobacillus rhamnosus IMC 501 and Lactobacillus paracasei IMC 502 on oxidative stress in athletes during a four-week period of intense physical activity. Two groups of twelve subjects each were selected for this analysis. The first group consumed a daily dose of a mixture of the two probiotic strains (1:1 L. rhamnosus IMC 501 and L. paracasei IMC 502; ~10(9) cells/day) for 4 weeks. The second group (control) did not consume any supplements during the 4 weeks. Blood samples collected immediately before and after the supplementation were analyzed, and plasma levels of reactive oxygen metabolites and biological antioxidant potential were determined. Faeces were also collected and analyzed before and at the end of the probiotic supplementation. Antioxidative activity and oxidative stress resistance of the two strains were determined in vitro. Results demonstrated that intense physical activity induced oxidative stress and that probiotic supplementation increased plasma antioxidant levels, thus neutralizing reactive oxygen species. The two strains, L. rhamnosus IMC 501(®) and L. paracasei IMC 502(®), exert strong antioxidant activity. Athletes and all those exposed to oxidative stress may benefit from the ability of these probiotics to increase antioxidant levels and neutralize the effects of reactive oxygen species.", "In patients with active rheumatoid arthritis despite therapy with DMARDS, treatment with a spleen tyrosine kinase inhibitor has achieved similar response rates to those achieved in clinical trials of other drugs, including biologic agents. Where might these agents fit in the current armamentarium against this disease?" ]

[ "High levels of serum unconjugated bilirubin (UCB) in newborns are associated with axonal damage and glial reactivity that may contribute to subsequent neurologic injury and encephalopathy (kernicterus). Impairments in myelination and white matter damage were observed at autopsy in kernicteric infants. We have recently reported that UCB reduces oligodendrocyte progenitor cell (OPC) survival in a pure OPC in vitro proliferative culture. Here, we hypothesized that neonatal hyperbilirubinemia may also impair oligodendrocyte (OL) maturation and myelination. We used an experimental model of hyperbilirubinemia that has been shown to mimic the pathophysiological conditions leading to brain dysfunction by unbound (free) UCB. Using primary cultures of OL, we demonstrated that UCB delays cell differentiation by increasing the OPC number and reducing the number of mature OL. This finding was combined with a downregulation of Olig1 mRNA levels and upregulation of Olig2 mRNA levels. Addition of UCB, prior to or during differentiation, impaired OL morphological maturation, extension of processes and cell diameter. Both conditions reduced active guanosine triphosphate (GTP)-bound Rac1 fraction. In myelinating co-cultures of dorsal root ganglia neurons and OL, UCB treatment prior to the onset of myelination decreased oligodendroglial differentiation and the number of myelinating OL, also observed when UCB was added after the onset of myelination. In both circumstances, UCB decreased the number of myelin internodes per OL, as well as the myelin internode length. Our studies demonstrate that increased concentrations of UCB compromise myelinogenesis, thereby elucidating a potential deleterious consequence of elevated UCB.", "Background. A common research goal in transcriptome projects is to find genes that are differentially expressed in different phenotype classes. Biologists might wish to validate such gene candidates experimentally, or use them for downstream systems biology analysis. Producing a coherent differential gene expression analysis from RNA-seq count data requires an understanding of how numerous sources of variation such as the replicate size, the hypothesized biological effect size, and the specific method for making differential expression calls interact. We believe an explicit demonstration of such interactions in real RNA-seq data sets is of practical interest to biologists. Results. Using two large public RNA-seq data sets-one representing strong, and another mild, biological effect size-we simulated different replicate size scenarios, and tested the performance of several commonly-used methods for calling differentially expressed genes in each of them. We found that, when biological effect size was mild, RNA-seq experiments should focus on experimental validation of differentially expressed gene candidates. Importantly, at least triplicates must be used, and the differentially expressed genes should be called using methods with high positive predictive value (PPV), such as NOISeq or GFOLD. In contrast, when biological effect size was strong, differentially expressed genes mined from unreplicated experiments using NOISeq, ASC and GFOLD had between 30 to 50% mean PPV, an increase of more than 30-fold compared to the cases of mild biological effect size. Among methods with good PPV performance, having triplicates or more substantially improved mean PPV to over 90% for GFOLD, 60% for DESeq2, 50% for NOISeq, and 30% for edgeR. At a replicate size of six, we found DESeq2 and edgeR to be reasonable methods for calling differentially expressed genes at systems level analysis, as their PPV and sensitivity trade-off were superior to the other methods'. Conclusion. When biological effect size is weak, systems level investigation is not possible using RNAseq data, and no meaningful result can be obtained in unreplicated experiments. Nonetheless, NOISeq or GFOLD may yield limited numbers of gene candidates with good validation potential, when triplicates or more are available. When biological effect size is strong, NOISeq and GFOLD are effective tools for detecting differentially expressed genes in unreplicated RNA-seq experiments for qPCR validation. When triplicates or more are available, GFOLD is a sharp tool for identifying high confidence differentially expressed genes for targeted qPCR validation; for downstream systems level analysis, combined results from DESeq2 and edgeR are useful.", "AIM: International HIV treatment guidelines recommend HLA-B*57:01 typing before abacavir administration, in order to reduce the incidence of abacavir hypersensitivity reactions, the major cause of early therapy discontinuation. A fast, sensitive and specific test for HLA-B*57:01 detection has been developed in the present study.MATERIALS & METHODS: Two sets of sequence-specific primers were designed, and amplification rapidly detected by real-time PCR.RESULTS: A total of 108 samples were analyzed in a single-blind fashion, and 41 samples were identified as positive. Complete agreement, with κ = 1 (standard error = 0.0962, p < 0.0001), was found, with a validated methodology used in the EPI109367 clinical trial funded by GlaxoSmithKline, and consisting of low-resolution sequence-specific oligonucleotide PCR, followed by high-resolution sequence-specific oligonucleotide PCR carried out on the HLA-B*57-positive samples.CONCLUSION: We provided a detailed characterization of a novel HLA-B*57:01 screening test, which can be easily implemented by those laboratories already involved in the detection of viral load and virus genotyping. Original submitted 26 October 2010; Revision submitted 13 December 2010.", "Upadacitinib is a Janus kinase 1 inhibitor under development for the treatment of several inflammatory disorders including rheumatoid arthritis (RA). Upadacitinib was administered in the phase 2 RA trials primarily as twice-daily regimens of an immediate-release (IR) formulation. The upadacitinib extended-release (ER) formulation was developed to enable once-daily dosing. In the present study, upadacitinib pharmacokinetics were characterized after the administration of single and multiple once-daily doses of the ER formulation in healthy subjects relative to single and multiple twice-daily doses of the IR formulation. Increase in upadacitinib exposure was dose-proportional over the evaluated 15- to 30-mg ER dose range. Single 15- and 30-mg ER doses provided equivalent AUC0-inf compared with single 12- and 24-mg IR doses, respectively. A high-fat breakfast increased upadacitinib ER Cmax and AUC0-inf by only 20% and 17%, respectively, relative to fasting conditions. The median time to peak plasma concentrations was 2 to 4 hours for the ER formulation, and steady state was achieved by day 4 of once-daily dosing. Doses of 15 and 30 mg once daily using the ER formulation provided equivalent AUC0-24 , comparable Cmax and Cmin , and a fluctuation index over a 24-hour period at steady state similar to 6 and 12 mg twice daily, respectively, using the IR formulation. These results supported the use of upadacitinib 15- and 30-mg doses of the ER formulation in the phase 3 trials in RA.", "Canagliflozin (Invokana) is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor that was first introduced in 2013 for the treatment of type 2 diabetes mellitus (DM). Though not FDA approved yet, its use in type 1 DM has been justified by the fact that its mechanism of action is independent of insulin secretion or action. However, some serious side effects, including severe anion gap metabolic acidosis and euglycemic diabetic ketoacidosis (DKA), have been reported. Prompt identification of the causal association and initiation of appropriate therapy should be instituted for this life threatening condition.", "BACKGROUND: Although many clinical prediction rules (CPRs) for appendicitis exist, none have been developed for a New Zealand population presenting with right iliac fossa (RIF) pain. The aim of this study was to derive and validate an appendicitis CPR for our population.METHOD: This is a retrospective review of all patients from December 2010 to February 2012 of at least 15 years of age presenting to the general surgery service with RIF pain. Patient data were divided into derivation and validation groups. Univariate and multiple regression analyses identified significant predictors of appendicitis which were used to construct a CPR. A retrospective validation study was then performed and the CPR was refined accordingly. Finally, the accuracy of the CPR was tested.RESULTS: The final components of the new CPR, the APPEND score, were Anorexia, migratory Pain, local Peritonism, Elevated C-reactive protein, Neutrophilia and male gender (Dude). This CPR has an area under the receiver operating characteristic curve of 0.84. The CPR can stratify patients into low, intermediate and high-risk groups which may standardize patient care and reduce the negative appendicectomy rate.CONCLUSION: A new CPR for predicting appendicitis, in patients presenting with RIF pain, has been derived and validated for use in our population. A prospective study to further evaluate its performance is required.", "Mammalian selenium-containing proteins identified thus far contain selenium in the form of a selenocysteine residue encoded by UGA. These proteins lack common amino acid sequence motifs, but 3'-untranslated regions of selenoprotein genes contain a common stem-loop structure, selenocysteine insertion sequence (SECIS) element, that is necessary for decoding UGA as selenocysteine rather than a stop signal. We describe here a computer program, SECISearch, that identifies mammalian selenoprotein genes by recognizing SECIS elements on the basis of their primary and secondary structures and free energy requirements. When SECISearch was applied to search human dbEST, two new mammalian selenoproteins, designated SelT and SelR, were identified. We determined their cDNA sequences and expressed them in a monkey cell line as fusion proteins with a green fluorescent protein. Incorporation of selenium into new proteins was confirmed by metabolic labeling with (75)Se, and expression of SelT was additionally documented in immunoblot assays. SelT and SelR did not have homology to previously characterized proteins, but their putative homologs were detected in various organisms. SelR homologs were present in every organism characterized by complete genome sequencing. The data suggest applicability of SECISearch for identification of new selenoprotein genes in nucleotide data bases." ]

[ "OBJECTIVE: Several secreted phospholipases A2 (sPLA2s), including group IIA, III, V, and X, have been linked to the development of atherosclerosis, which led to the clinical testing of A-002 (varespladib), a broad sPLA2 inhibitor for the treatment of coronary artery disease. Group X sPLA2 (PLA2G10) has the most potent hydrolyzing activity toward phosphatidylcholine and is believed to play a proatherogenic role.METHODS AND RESULTS: Here, we show that Ldlr(-/-) mice reconstituted with bone marrow from mouse group X-deficient mice (Pla2g10(-/-)) unexpectedly display a doubling of plaque size compared with Pla2g10(+/+) chimeric mice. Macrophages of Pla2g10(-/-) mice are more susceptible to apoptosis in vitro, which is associated with a 4-fold increase of plaque necrotic core in vivo. In addition, chimeric Pla2g10(-/-) mice show exaggerated T lymphocyte (Th)1 immune response, associated with enhanced T-cell infiltration in atherosclerotic plaques. Interestingly, overexpression of human PLA2G10 in murine bone marrow cells leads to significant reduction of Th1 response and to 50% reduction of lesion size.CONCLUSIONS: PLA2G10 expression in bone marrow cells controls a proatherogenic Th1 response and limits the development of atherosclerosis. The results may provide an explanation for the recently reported inefficacy of A-002 (varespladib) to treat patients with coronary artery disease. Indeed, A-002 is a nonselective sPLA2 inhibitor that inhibits both proatherogenic (groups IIA and V) and antiatherogenic (group X) sPLA2s. Our results suggest that selective targeting of individual sPLA2 enzymes may be a better strategy to treat cardiovascular diseases.", "Adolescent idiopathic scoliosis (AIS) is a condition characterized by a three-dimensional structural deformity of the spine. It is the most common type of spine deformity occurring in children aged 10 to maturity. Although the etiology of AIS still remains unknown, the role of genetic factors in the development of idiopathic scoliosis is widely accepted. However, to date no causative genes of AIS have been identified. Recently, the semicircular canals, which are part of the inner ear, were found to be morphologically abnormal in idiopathic scoliosis patients. Here we hypothesized that genetic predisposition to inner ear anomalies in AIS patients may be a strong factor in the generation of idiopathic scoliosis. The proposed idea is that gene defects could impair the development of the semicircular canals. A malformation of semicircular canals might affect the transmission of sensory signal about rotational movement of the body to the central nervous system; leading to an alteration in the neuronal circuit of balance. This will in turn affect body posture and results in the initiation of the curvature of the spine. This hypothesis may provide new insights in the understanding of the pathophysiologic mechanisms of idiopathic scoliosis. It can also offer hopes for potential early prediction of scoliosis.", "8-Oxo-dGTP (8-oxo-7,8-dihydrodeoxyguanosine triphosphate) is a potent mutagenic substrate for DNA synthesis. The accumulation of 8-oxo-dGTP in the nucleotide pool induces G:C-->T:A transversion as well as A:T-->C:G transversion, and Escherichia coli cells possess mechanisms for preventing such mutations. The mutT gene product specifically hydrolyzes 8-oxo-dGTP to the monophosphate form while the mutM and the mutY gene products function to correct mispairs caused by incorporation of 8-oxoguanine into DNA. From analyses of forward mutations induced in cells lacking 8-oxo-dGTPase (MutT protein) and/or repair enzymes that suppress mutations caused by 8-oxoguanine in DNA (MutM and MutY proteins), cooperative functions of these proteins in control of the spontaneous mutagenesis became evident. In mutator strains lacking MutT and/or MutM proteins, 8-oxoguanine of DNA increased to a concentration expected from the increased rate of mutation.", "Shigellosis is a leading cause of diarrhea worldwide prompting vaccine development. The Shigella flexneri Invaplex 50 is a macromolecular complex containing IpaB, IpaC, and LPS, formulated from an aqueous extract of virulent Shigella delivered via nasal administration. Preclinical vaccine testing demonstrated safety, immunogenicity and efficacy. An open-label dose-escalating phase 1 study evaluated a 3-dose (2-week intervals) regimen via nasal pipette delivery. Thirty-two subjects were enrolled into one of four vaccine dose groups (10, 50, 240, or 480 microg). The vaccine was well tolerated with minor short-lived nasal symptoms without evidence of dose effect. Antibody-secreting cell (ASC) responses were elicited at doses > or =50 microg with the highest IgG ASC, Invaplex 50 (100%) and S. flexneri 2a LPS (71%), as well as, serologic responses (43%) occurring with the 240 microg dose. Fecal IgA responses, Invaplex 50 (38.5%) and LPS (30.8%), were observed at doses > or =240 microg. The Invaplex 50 nasal vaccine was safe with encouraging mucosal immune responses. Follow-on studies will optimize dose, delivery mechanism and assess efficacy in a S. flexneri 2a challenge study.", "Alemtuzumab, formally known as Campath-1H, is a humanized monoclonal antibody directed against CD52, a protein on the surface of lymphocytes and monocytes with unknown function. A single dose of alemtuzumab leads to a rapid, profound and prolonged lymphopenia. A Phase II trial has shown that alemtuzumab reduces the risk of relapse and accumulation of disability by over 70% compared with interferon beta in patients with early relapsing-remitting multiple sclerosis (MS). Alemtuzumab has been used in Cambridge as an experimental treatment for MS since 1991. In this review we summarize our experience; describing how this prototypical, \"bench-to-bedside\" therapy continues to inform basic science, revealing aspects of the pathogenesis of MS and lymphopeniaassociated autoimmunity.", "The theoretical possibility of applying gene transfer methodologies to the human germline is explored. Transgenic methods for genetically manipulating embryos may in principle be applied to humans. In particular, microinjection of retroviral vector appears to hold the greatest promise, with transgenic primates already obtained from this approach. Sperm-mediated gene transfer offers potentially the easiest route to the human germline, however the requisite methodology is presently underdeveloped. Nuclear transfer (cloning) offers an alternative approach to germline genetic modification, however there are major health concerns associated with current nuclear transfer methods. It is concluded that human germline gene therapy remains for all practical purposes a future possibility that must await significant and important advances in gene transfer technology.", "Heart rate, respiratory rate, systolic and diastolic blood pressure, and oral and skin temperature changes following intravenous administration of TRH occur at lower infusion rates in patients with ALS and bulbar involvement than in patients with ALS without bulbar involvement. This autonomic sensitivity to TRH infusion is characteristic of a more advanced stage of ALS with difficulties in speaking and swallowing. Patients who will be receiving neuropeptides, such as TRH, must be carefully studied to determine whether subclinical bulbar involvement is present. Such patients may require a lower initial dose or dose rate adjustment as well as continual monitoring during neuropeptide administration." ]

[ "The KH-type RNA binding protein Sam68 is required for adipogenesis. We have previously shown that Sam68-deficient mice have a lean phenotype and are protected against dietary-induced obesity due to defects in mTOR and S6K1 alternative splicing. Herein we profiled the transcriptome of Sam68 wild type and deficient 3T3-L1 mouse preadipocytes. We identified 652 protein-coding genes and 9 ncRNAs that were significantly altered with the loss of Sam68. As expected, downregulated genes were significantly associated with GO terms linked to cell migration, motility, and fat cell differentiation, while upregulated genes were mostly associated with GO terms linked to neurogenesis. Of the lncRNAs, we identified Hotair, Mir155hg, as well as two new lncRNAs (SR-lncRNA-1 and SR-lncRNA-2) that were regulated by Sam68, and contained consensus Sam68 binding sites. RNA stability assays showed that Sam68-deficiency decreased the half-life of Hotair, and increased the half-lives of Mir155hg and SR-lncRNA-2, while the stability of SR-lncRNA-1 was unaffected. Depletion of Hotair and SR-lncRNA-1 in wild type 3T3-L1 cells led to defects in adipogenesis, whereas depletion of SR-lncRNA-2 in Sam68-deficient 3T3-L1 cells partially rescued the adipogenesis defect observed in these cells. Collectively, our findings define a new role for Sam68 as a regulator of lncRNAs during adipogenic differentiation.", "Author information:(1)Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.(2)Universidad Católica de Murcia (UCAM), Campus de los Jerónimos, 135, Guadalupe 30107, Spain.(3)Research Center for Tumor Medical Science, Graduate Institute of Cancer Biology, China Medical University, Taichung 40402, Taiwan.(4)Department of Dental Hygiene, China Medical University, Taichung 40402, Taiwan.(5)Department of Pathology, National Defense Medical Centre and Tri-Service General Hospital, Taipei 114, Taiwan.(6)Flow Cytometry Core Facility, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.(7)Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.(8)Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.(9)Division of Biological Sciences, University of California, San Diego, La Jolla, California 92037, USA.(10)Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, California 92037, USA.(11)Department of Otolaryngology-Head and Neck Surgery, National Defense Medical Centre and Tri-Service General Hospital, Taipei 114, Taiwan.(12)Department of Otolaryngology-Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan.(13)Moores Cancer Center, University of California, San Diego, La Jolla, California 92037, USA.(14)Center for Microbiome Innovation, University of California, San Diego, La Jolla, California 92037, USA.", "Commotio cordis is a term used for cases of sudden cardiac death due to nonpenetrating chest trauma without evidence of underlying myocardial disease or injury. Contusio cordis has been reserved for cases of chest trauma where there is cardiac bruising. Three deaths due to blunt cardiac and chest trauma after vehicle accidents are presented where the only significant injuries were contusions of the heart and fractures of the sternum and ribs. One case had moderate coronary artery atherosclerosis and another had a blood alcohol level of 0.218%. Given that individuals with cardiac bruising, chest trauma, coronary atherosclerosis, and alcohol intoxication may still die of the same mechanisms as in classic commotio cordis, and that these entities represent a spectrum of findings after chest impact, it may be more useful to separate cases into related subcategories: (A) those with no evidence of injury or underlying cardiovascular disease, (B) those with chest wall fractures, chest wall contusions and/or cardiac contusions, and (C) those with underlying cardiovascular disease or the presence of substances such as alcohol or drugs that may reduce the threshold for cardiac arrhythmias. As there may be cases with a number of these factors, a fourth category (D) includes those with a combination of injuries and predisposing factors (ie, categories B and C). Including cases such as these under the diagnostic umbrella of commotio cordis may demonstrate that a wider range of individuals are at risk for death from blunt cardiac trauma than sports-playing adolescents.", "BACKGROUND: The 22-item Sino-Nasal Outcome Test (SNOT-22) is a commonly utilized outcome measure for chronic rhinosinusitis (CRS). However, what constitutes a normal score remains poorly defined. The goal of this study was to evaluate SNOT-22 scores in a control population without CRS and perform a systematic review and meta-analysis of \"normal\" values.METHODS: Ninety-nine subjects without CRS were enrolled, with 95 fully completing the SNOT-22 questionnaire. Multivariable linear regression was used to determine whether demographic factors or medical comorbidities influence SNOT-22 scores in a population without CRS. A systematic literature search was performed, identifying studies that evaluated the SNOT-22 in a non-CRS population and estimates for SNOT-22 values were pooled.RESULTS: Thirty-six males and 59 females were included in the primary analysis with a mean age of 53.4 ± 17.3 years (range, 18-88 years). The mean SNOT-22 score was 16.4 ± 15.2. Asthma (p = 0.003) and depression (p = 0.002) were found to be independent predictors of higher SNOT-22 scores. Thirteen articles were identified in the literature search and 1 was provided via author correspondence, with 10 reporting sufficient data to be included in the meta-analysis. Weighted mean SNOT-22 score was 11 ± 9.4 (n = 1517). Our data differed significantly from published data (mean difference = 5.4; 95% confidence interval [CI], 3.4 to 7.5; p < 0.0001) likely owing to differences in comorbidities.CONCLUSION: SNOT-22 scores vary in non-CRS populations depending upon the group queried. Asthma and depression are associated with higher SNOT-22 scores and should be considered when determining what constitutes a normal value.", "We have shown that intracellular superoxide (O(2)(*-)) production in CNS neurons plays a key role in the pressor, bradycardic, and dipsogenic actions of Ang II in the brain. In this study, we tested the hypothesis that a Rac1-dependent NADPH oxidase is a key source of O(2)(*-) in Ang II-sensitive neurons and is involved in these central Ang II-dependent effects. We performed both in vitro and in vivo studies using adenoviral (Ad)-mediated expression of dominant-negative Rac1 (AdN17Rac1) to inhibit Ang II-stimulated Rac1 activation, an obligatory step in NADPH oxidase activation. Ang II induced a time-dependent increase in Rac1 activation and O(2)(*-) production in Neuro-2A cells, and this was abolished by pretreatment with AdN17Rac1 or the NADPH oxidase inhibitors apocynin or diphenylene iodonium. AdN17Rac1 also inhibited Ang II-induced increases in NADPH oxidase activity in primary neurons cultured from central cardiovascular control regions. In contrast, overexpression of wild-type Rac1 (AdwtRac1) caused more robust NADPH oxidase-dependent O(2)(*-) production to Ang II. To extend the in vitro studies, the pressor, bradycardic, and drinking responses to intracerebroventricularly (ICV) injected Ang II were measured in mice that had undergone gene transfer of AdN17Rac1 or AdwtRac1 to the brain. AdN17Rac1 abolished the increase in blood pressure, decrease in heart rate, and drinking response induced by ICV injection of Ang II, whereas AdwtRac1 enhanced these physiological effects. The exaggerated physiological responses in AdwtRac1-treated mice were abolished by O(2)(*-) scavenging. These results, for the first time, identify a Rac1-dependent NADPH oxidase as the source of central Ang II-induced O(2)(*-) production, and implicate this oxidase in cardiovascular diseases associated with dysregulation of brain Ang II signaling, including hypertension.", "INTRODUCTION: Septo-optic dysplasia (De Morsier syndrome) is defined as the association between optic nerve hypoplasia, midline central nervous system malformations and pituitary dysfunction.CASE REPORT: Third child born to nonconsanguineous parents, female, adequate pre-natal medical care, cesarean term delivery due to breech presentation, Apgar score 3 at the first minute and 8 at 5 minutes, symptomatic hypoglycemia at 18 hours. Neurological follow-up identified a delay in acquisition of motor and language developmental milestones. Epileptic generalized seizures began at 12 months and were controlled with phenobarbital. EEG was normal. MRI revealed agenesis of the pituitary stalk, hypoplasia of the optic chiasm and periventricular nodular heterotopia. Ophthalmologic evaluation showed bilateral optic disk hypoplasia. Endocrine function laboratory tests revealed primary hypothyroidism and hyperprolactinemia.CONCLUSION: The relevance of this case report relies on its uniqueness, since periventricular heterotopia had not been described in association with septo-optic dysplasia until 2006.", "Millions of children are affected by different neurodevelopmental disorders, out of which autism spectrum disorder (ASD) poses a major hurdle to normal life style due to associated behavioral abnormalities. Several studies have shown an increased expression/release of Th17 related cytokine, IL-17A in ASD. IL-17A may enhance neuroinflammation via its IL-17A receptor, i.e. IL-17RA expressed in immune cells (such as monocytes) of autistic children. Increased oxidative stress has been implicated in a number of neuropsychiatric disorders including ASD. However, whether IL-17A/IL-17RA signaling contributes to oxidative inflammation in monocytes of autistic children has not been explored previously. With this background, we performed this study in peripheral monocytes of ASD patients and age-matched typically developing children. Our study shows that ASD individuals have increased IL-17RA expression in monocytes which is associated with increased nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway and inducible nitric oxide synthase (iNOS)/nitrotyrosine expression as compared to typically developing children. Moreover, in vitro activation of IL-17 receptor by IL-17A in monocytes isolated from ASD individuals leads to enhanced iNOS expression via NFκB pathway. IL-17RA antibody treatment in vitro reversed IL-17A-induced increase in NFκB and iNOS/nitrotyrosine expression in monocytes isolated from ASD subjects. These data connect increased IL-17A/IL-17RA signaling in ASD patients with enhanced oxidative inflammation in monocytes. Therefore, IL-17 receptor signaling in monocytes may potentiate the effects of IL-17A released by other immune cells and may aggravate neuroinflammation in ASD. Our study further suggests that blockade of IL-17A/IL-17 receptor signaling may be beneficial in the children with ASD." ]

[ "Psychiatric symptoms and motor impairment are major contributions to the poor quality of life in patients with Parkinson's disease (PD). Here, we applied a novel diffusion-weighted imaging approach, diffusion MRI connectometry, to investigate the correlation of quality of life, evaluated by Parkinson's Disease Questionnaire (PDQ39) with the white matter structural connectivity in 27 non-demented PD patients (disease duration of 5.3 ± 2.9 years, H and Y stage = 1.5 ± 0.6, UPDRS-III = 13.7 ± 6.5, indicating unilateral and mild motor involvement). The connectometry analysis demonstrated bilateral posterior limbs of the internal capsule (PLIC) with increased connectivity related to the higher quality of life (FDR = 0.027) in a multiple regression model. The present study suggests for the first time a neural basis of the quality of life in PD in the light of major determinants of poor quality of life in these patients: anxiety, depression, apathy and motor impairment. Results in our sample of non-demented PD patients with relatively mild motor impairment and no apparent sign of depression/anxiety also identify a unique and inexplicable association of the PLIC to the quality of life in PD patients.", "Polyadenylate polymerase (PAP) catalyzes the synthesis of 3'-polyadenylate tails onto mRNA. A comprehensive steady-state kinetic analysis of PAP was conducted which included initial velocity studies of the forward and reverse reactions, inhibition studies, and the use of alternative substrates. The reaction (A(n) + ATP <--> A(n+1) + PP(i)) is adequately described by a rapid equilibrium random mechanism. Several thermodynamic parameters for the reaction were determined or calculated, including the overall equilibrium constant (K(eq) = 84) and the apparent equilibrium constant of the internal step (K(int) = 4) which involves the rate-determining interconversion of central complexes. A large (100-fold) difference in Vmax accounts for nucleotide specificity (ATP vs CTP), despite an only 3-fold difference in Km. Comparison of the sulfur elemental effect on Vmax for ATP and CTP suggests that the chemical step is rate-determining for both reactions. Comparison of the sulfur elemental effect on Vmax/Km revealed differences in the mechanism by which either nucleotide is incorporated. Consistent with these data, an induced fit mechanism for nucleotide specificity is proposed whereby PAP couples a uniform binding mechanism, which selects for ATP, with a ground-state destabilization mechanism, which serves to accelerate the velocity for the correct substrate.", "Eukaryotic histones serve as prototypical examples of posttranslational complexity with diverse modifications (PTMs) on many different residues that comprise a \"Histone Code\". To help crack this code more efficiently, we demonstrate a new strategy for protein characterization wherein complete PTM descriptions are obtained by database retrieval instead of manual interpretation of information-rich data from high-resolution tandem mass spectrometry (MS/MS). A database of nearly 50 000 modified histone H4 sequences was created and queried with 91 fragment ions from electron capture dissociation of a histone form +112 Da (versus unmodified mass) selectively accumulated in a quadrupole Fourier transform hybrid mass spectrometer. The correct form atop the retrieval list indicated dimethylation at Lys20, acetylation at the N terminus, and acetylation at Lys16 (resolved from trimethylation, Deltam = 0.036 Da). A statistical evaluation reveals the critical role of mass accuracy and that PTM \"isomers\" are retrieved as next-best matches. The applicability of shotgun annotation to forms of H4 with up to six PTMs is demonstrated, with extensibility to other histones (e.g., H2A, H2B, H3) and other protein classes projected.", "BACKGROUND: Various different mucocutaneous symptoms may affect up to 80 % of systemic lupus erythematosus (SLE) patients.OBJECTIVES: To investigate, various unspecific, but otherwise typical clinical symptoms of skin and mucous membranes that arise in SLE patients other than those defined as SLE criteria such as butterfly rash, chronic cutaneous lupus erythematosus, oral ulcers, and increased photosensitivity.MATERIALS AND METHODS: Extensive search of peer-reviewed scientific articles was performed, medical histories of several SLE patients seen in our department were analyzed, and the rare disease courses in three SLE patients are presented.RESULTS: Here we present a variety of unspecific but typical mucocutaneous manifestations in SLE patients: periungual erythema, periungual telangiectasia and periungual splinter hemorrhage, papules on the dorsum of the hands, scaling erythema, sometimes associated with necrosis, especially of the ears, along with complement deficiency, and the bizarre necroses of antiphospholipid syndrome. Furthermore, we show the typical clinico-histological features of neutrophilic urticarial dermatosis, as well as those of bullous SLE and finally a severe course of bacterial sepsis with Neisseria flavescens/macacae.CONCLUSIONS: Here we show several unspecific but rather typical mucocutaneous symptoms in lupus patients that are indicative of SLE and thus may lead to an early diagnosis. Also, life-threatening bacterial sepsis may occur with microorganisms that are commonly considered \"apathogenic\", such as Neisseria flavescens/macacae, which exclusively affect immunosuppressed patients.", "Costello syndrome (CS) is a rare congenital disorder characterized by failure to thrive, craniofacial dysmorphisms, cardiac and skin abnormalities, mental retardation, and predisposition to malignancies. CS is caused by heterozygous gain-of-function mutations in HRAS that also occur as somatic alterations in human tumors. HRAS is one of the three classical RAS proteins and cycles between an active, GTP- and an inactive, GDP-bound conformation. We used primary human skin fibroblasts from patients with CS as a model system to study the functional consequences of HRAS mutations on endogenous signaling pathways. The GTP-bound form of HRAS was significantly enriched in CS compared with normal fibroblasts. Active HRAS is known to stimulate both the RAF-MEK-ERK and the PI3K-AKT signaling cascade. Phosphorylation of MEK and ERK was normal in CS fibroblasts under basal conditions and slightly prolonged after epidermal growth factor (EGF) stimulation. Interestingly, basal phosphorylation of AKT was increased yet more in CS fibroblasts. Moreover, AKT phosphorylation was diminished in the early and enhanced in the late phase of EGF stimulation. Taken together, these results document that CS-associated HRAS mutations result in prolonged signal flux in a ligand-dependent manner. Our data suggest that altered cellular response to growth factors rather than constitutive activation of HRAS downstream signaling molecules may contribute to some of the clinical features in patients with CS.", "Multifocal tumor recurrence of glioblastomas occurs in up to 14% of patients. In a parallel phase-II-study investigating post-operative treatment with tamoxifen (TAM), carboplatin and radiation therapy for glioblastomas, 16 of 49 patients (33%) showed multifocal recurrence, which developed after a mean of 46 weeks, raising the question of an association with therapy. We studied the interrelation of proliferation and migration in the presence of different protein-kinase-C(PKC) inhibitors (TAM, staurosporine, hypericin) in 2 glioma cell lines. In addition, 3 cell lines were selected for TAM resistance by repeated cycles of treatment with sub-lethal concentrations of TAM. The proliferative capacity and the invasive potential of selected sub-populations were assessed using growth-curve experiments, monolayer migration, and cell-adhesion assays. Treatment with all PKC inhibitors tested resulted in a dose-dependent decrease of proliferation, while motility was altered only at significantly higher doses. Resistance to TAM occurred in all 3 selected cell lines. The TAM-resistant sub-populations showed significantly increased proliferation, migration and adhesion as compared with the parental (non-selected) cell line. The higher incidence of multifocal disease after TAM treatment was paralleled by increased migratory potential of TAM-treated cells in vitro.", "Proteins perform essential cellular functions as part of protein complexes, often in conjunction with RNA, DNA, metabolites and other small molecules. The genome encodes thousands of proteins but not all of them are expressed in every cell type; and expressed proteins are not active at all times. Such diversity of protein expression and function accounts for the level of biological intricacy seen in nature. Defining protein-protein interactions in protein complexes, and establishing the when, what and where of potential interactions, is therefore crucial to understanding the cellular function of any protein-especially those that have not been well studied by traditional molecular genetic approaches. We generated a large-scale resource of affinity-tagged expression-ready clones and used co-affinity purification combined with tandem mass-spectrometry to identify protein partners of nearly 5,000 Drosophila melanogaster proteins. The resulting protein complex \"map\" provided a blueprint of metazoan protein complex organization. Here we describe how the map has provided valuable insights into protein function in addition to generating hundreds of testable hypotheses. We also discuss recent technological advancements that will be critical in addressing the next generation of questions arising from the map." ]

[ "Histone modification plays important roles in many biological processes such as development and carcinogenesis. Methylation of histone H3 lysine 4 (H3K4) is commonly associated with transcriptional activation of genes. H3K4 methylation in mammalian cells is carried out by COMPASS (complex of proteins associated with Set1)-like complexes that are composed of catalytic subunits such as MLL1 (mixed-lineage leukaemia 1) and multiple regulatory subunits in which WDR5 (WD40 repeat-containing protein 5), RBBP5 (retinoblastoma-binding protein 5), ASH2 (absent, small or homoeotic discs 2) and DPY30 [constituting the WRAD sub-complex (WDR5-ASH2-RBBP5-DPY30 complex)] are the major ones shared from yeast to metazoans. We report, in the present paper, a new mode of spatial regulation of H3K4 methyltransferase complexes. PAQR3 (progestin and adipoQ receptors member 3), a tumour suppressor specifically localized in the Golgi apparatus, negatively regulates H3K4 trimethylation (H3K4me3) in mammalian cells. Consistently, HOXC8 and HOXA9 gene expression was negatively regulated by PAQR3 expression levels. Hypoxia-induced H3K4me3 was augmented by PAQR3 knockdown and suppressed by PAQR3 overexpression in AGS gastric cancer cells. PAQR3 was able to interact directly or indirectly with the four members of the WRAD sub-complex and tether them to the Golgi apparatus, accompanied by reduction in histone methyltransferase activity in the nucleus. PAQR3 also interfered with the interaction of WDR5 with the C-terminus of MLL1 (C-ter). Collectively, our study indicates that PAQR3 negatively modulates H3K4 methylation via altering the subcellular compartmentalization of the core regulatory subunits of the COMPASS-like complexes in mammalian cells.", "Although it is still debated whether chronic cerebro-spinal venous insufficiency (CCSVI) plays a role in multiple sclerosis (MS) development, many patients underwent endovascular treatment (ET) of CCSVI. The objective of the study is to evaluate the outcome and safety of ET in Italian MS patients. Italian MS centers that are part of the Italian MS Study Group were all invited to participate to this retrospective study. A structured questionnaire was used to collect detailed clinical data before and after the ET. Data from 462 patients were collected in 33 centers. ET consisted of balloon dilatation (93 % of cases) or stent application. The mean follow-up duration after ET was 31 weeks. Mean EDSS remained unchanged after ET (5.2 vs. 4.9), 144 relapses occurred in 98/462 cases (21 %), mainly in RR-MS patients. Fifteen severe adverse events were recorded in 3.2 % of cases. Given the risk of severe adverse events and the lack of objective beneficial effects, our findings confirm that at present ET should not be recommended to patients with MS.", "Chronic inflammation underscores the pathogenesis of a range of human diseases. Lipopolysaccharide (LPS) elicits strong pro-inflammatory responses in macrophages through the transcription factor NF-κB. The epigenetic mechanism underlying LPS-induced pro-inflammatory transcription is not fully understood. Herein, we describe a role for myocardin-related transcription factor A (MRTF-A, also known as MKL1) in this process. MRTF-A overexpression enhanced NF-κB-dependent pro-inflammatory transcription, whereas MRTF-A silencing inhibited this process. MRTF-A deficiency also reduced the synthesis of pro-inflammatory mediators in a mouse model of colitis. LPS promoted the recruitment of MRTF-A to the promoters of pro-inflammatory genes in an NF-κB-dependent manner. Reciprocally, MRTF-A influenced the nuclear enrichment and target binding of NF-κB. Mechanistically, MRTF-A was necessary for the accumulation of active histone modifications on NF-κB target promoters by communicating with the histone H3K4 methyltransferase complex (COMPASS). Silencing of individual members of COMPASS, including ASH2, WDR5 and SET1 (also known as SETD1A), downregulated the production of pro-inflammatory mediators and impaired the NF-κB kinetics. In summary, our work has uncovered a previously unknown function for MRTF-A and provided insights into the rationalized development of anti-inflammatory therapeutic strategies.", "This is the case of a 79-year-old man with chronic lymphocytic leukemia who presented with Guillain-Barré syndrome with features overlapping with the Miller Fisher syndrome and Bickerstaff brainstem encephalitis and positive antiganglioside GQ1b antibody about 6 months after treatment with bendamustine and rituximab. His clinical and neurologic condition continued to deteriorate despite sequential treatment with corticosteroids, intravenous immunoglobulin and plasmapheresis, but in the end, he had a complete and durable response to treatment with alemtuzumab.", "CTCF is a ubiquitous 11 zinc finger (ZF) protein with highly versatile functions: in addition to transcriptional silencing or activating in a context-dependent fashion, it organizes epigenetically controlled chromatin insulators that regulate imprinted genes in soma. Recently, we have identified a CTCF paralogue, termed BORIS for Brother of the Regulator of Imprinted Sites, that is expressed only in the testis. BORIS has the same exons encoding the 11 ZF domain as mammalian CTCF genes, and hence interacts with similar cis elements, but encodes amino and carboxy termini distinct from those in CTCF. Normally, CTCF and BORIS are expressed in a mutually exclusive pattern that correlates with re-setting of methylation marks during male germ cell differentiation. The antagonistic features of these two gene siblings are underscored by showing that while CTCF overexpression blocks cell proliferation, expression of BORIS in normally BORIS-negative cells promotes cell growth which can lead to transformation. The suggestion that BORIS directs epigenetic reprogramming at CTCF target sites impinges on the observations that human BORIS is not only abnormally activated in a wide range of human cancers, but also maps to the cancer-associated amplification region at 20q13. The sibling rivalry occasioned by aberrant expression of BORIS in cancer may interfere with normal functions of CTCF including growth suppression, and contribute to epigenetic dysregulation which is a common feature in human cancer.", "The newer and emerging treatments for atopic dermatitis (AD) focus on blockade of inflammatory cytokines, especially those that derive from T helper cell type 2 (TH2) and are associated with a pathway of immunoglobulin E (IgE) sensitization. Among the proinflammatory cytokines that have been identified as promising therapeutic targets are chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2), IgE, thymic stromal lymphopoietin (TSLP), and several monoclonal antibodies that block key cytokine pathways in the innate immune response. Two agents that have been studied in phase III clinical trials are the boronbased phosphodiesterase-4 (PDE-4) inhibitor, crisaborole, and dupilumab, an antibody that inhibits the interleukin-4/ IL-13 receptor α chain. Semin Cutan Med Surg 35(supp5):S92-S96.", "Two human demethylases, the fat mass and obesity-associated (FTO) enzyme and ALKBH5, oxidatively demethylate abundant N(6)-methyladenosine (m(6)A) residues in mRNA. Achieving a method for selective inhibition of FTO over ALKBH5 remains a challenge, however. Here, we have identified meclofenamic acid (MA) as a highly selective inhibitor of FTO. MA is a non-steroidal, anti-inflammatory drug that mechanistic studies indicate competes with FTO binding for the m(6)A-containing nucleic acid. The structure of FTO/MA has revealed much about the inhibitory function of FTO. Our newfound understanding, revealed herein, of the part of the nucleotide recognition lid (NRL) in FTO, for example, has helped elucidate the principles behind the selectivity of FTO over ALKBH5. Treatment of HeLa cells with the ethyl ester form of MA (MA2) has led to elevated levels of m(6)A modification in mRNA. Our collective results highlight the development of functional probes of the FTO enzyme that will (i) enable future biological studies and (ii) pave the way for the rational design of potent and specific inhibitors of FTO for use in medicine.", "Bruck syndrome (BS) is an autosomal recessive syndromic form of osteogenesis imperfecta (OI) that is characterized by the additional presence of pterygium formation. We have recently shown that FKBP10 previously reported as a novel autosomal recessive OI gene also defines a novel Bruck syndrome locus (BKS3). In this manuscript, we extend our analysis to describe a mutation previously described in isolated OI patients and show that it results in BS phenotype in a Saudi family. More interestingly, we describe a novel FKBP10 mutation that results in isolated OI as well as BS phenotype in the same family. These results, combined with recently published work, confirm that FKBP10 is a bonafide BS locus and lay the foundation for future research into modifiers that underlie the phenotypic heterogeneity of FKBP10 mutations.", "BACKGROUND: Dipyrithione (PTS2) is widely used as a bactericide and fungicide. Here, we investigated whether PTS2 has broad-spectrum antitumor activity by studying its cytotoxicity and proapoptotic effects in four cancer cell lines.METHODS: We used MTT assays and trypan blue staining to test the viability of cancer cell lines. Hoechst 33258 and DAPI staining were used to observe cell apoptosis. Cell-cycle percentages were analyzed by flow cytometry. Apoptosis was assayed using caspase-3 and poly (ADP-ribose) polymerase (PARP) combined with Western blotting. Student's t-test was used for statistical analysis.RESULTS: PTS2 inhibited proliferation in four cancer cell lines in a dose-dependent manner. Treated cells showed shrinkage, irregular fragments, condensed and dispersed blue fluorescent particles compared with control cells. PTS2 induced cycle-arrest and death. Cleavage of caspase-9, caspase-3, and PARP were detected in PTS2-treated cells. Antitumor activity of PTS2 was more effective against widely used cancer drugs and its precursor.CONCLUSIONS: PTS2 appears to have novel cytotoxicity and potent broad-spectrum antitumor activity, which suggests its potential as the basis of an anticancer drug.", "The clinical efficacy of different doses of the specific benzodiazepine antagonist flumazenil was studied in a total of 72 patients with benzodiazepine or ethanol overdose. In a randomized double-blind study, 18 patients (group 1) and eight patients (group 2) with suspected benzodiazepine overdose received 5 mg (group 1) or 1 mg (group 2) flumazenil or placebo, respectively. The stage of coma, heart rate, blood pressure and respiratory rate were monitored within the following 15 min. If no change in the stage of coma was observed, 5 mg (group 1) or 1 mg (group 2) flumazenil were given, and the stage of coma, heart rate and blood pressure were again monitored. In a similar way, the effect of 5 and 1 mg flumazenil was investigated in 13 patients (group 3) and four patients (group 4) with ethanol intoxication. In an open trial, the clinical efficacy of flumazenil for the diagnosis of benzodiazepine or ethanol overdose was studied in 29 patients (group 5). In all patients, a toxicological screening confirmed benzodiazepine or ethanol overdose. None of the patients receiving placebo showed effects on stage of coma, heart rate, blood pressure or respiratory rate. Patients with benzodiazepine overdose who received 5 mg flumazenil regained consciousness about 1-2 min after the end of injection. The effect of 1 mg flumazenil (group 2) on benzodiazepine-induced coma was less pronounced. In patients with ethanol overdose (group 3), ethanol-induced coma was reversed after 5 mg flumazenil more slowly than in patients of group 1. No effect of flumazenil on ethanol-induced coma was observed in group 4. In group 5, flumazenil proved to be useful for diagnosing benzodiazepine or ethanol intoxication. In one patient with coma due to carbamazepine overdose, flumazenil was also found to be effective. Additionally, a possible analytical interference of flumazenil and its metabolites with the identification of other benzodiazepines by a toxicological screening procedure was studied. Even after an oral dose of 200 mg flumazenil, no interference with immunological benzodiazepine assays (EMIT, TDX, and RIA) was found. A metabolite and an artifact of flumazenil could be identified in urine by gas chromatography/mass spectrometry.", "The purpose of these case reports is to describe treatment of three consecutive patients with post-herpetic neuralgia using a bioelectronical device (SCENAR). The instrument is approved as a Class II device in the United States. The electrode of the device was stroked gently over the involved skin area for up to 15 minutes per session. No more than 5 sessions over a 3-week period was required. All patients experienced substantial relief of pain from the first treatment. One patient required only 1 treatment lasting 10 minutes. The other 2 patients required 4 to 5 treatments over a 3-week period. One patient required a treatment for skin itch after one year with a follow up period of 6 months to 24 months. An electronic biofeedback device (SCENAR) may be successfully utilized in the management of post-herpetic neuralgia.", "Recent advances in optogenetic methods demonstrate the feasibility of selective photoactivation at the soma of neurons that express channelrhodopsin-2 (ChR2), but a comprehensive evaluation of different methods to selectively evoke transmitter release from distant synapses using optogenetic approaches is needed. Here we compared different lentiviral vectors, with sub-population-specific and strong promoters, and transgenic methods to express and photostimulate ChR2 in the long-range projections of paraventricular nucleus of the hypothalamus (PVN) neurons to brain stem cardiac vagal neurons (CVNs). Using PVN subpopulation-specific promoters for vasopressin and oxytocin, we were able to depolarize the soma of these neurons upon photostimulation, but these promoters were not strong enough to drive sufficient expression for optogenetic stimulation and synaptic release from the distal axons. However, utilizing the synapsin promoter photostimulation of distal PVN axons successfully evoked glutamatergic excitatory post-synaptic currents in CVNs. Employing the Cre/loxP system, using the Sim-1 Cre-driver mouse line, we found that the Rosa-CAG-LSL-ChR2-EYFP Cre-responder mice expressed higher levels of ChR2 than the Rosa-CAG-LSL-ChR2-tdTomato line in the PVN, judged by photo-evoked currents at the soma. However, neither was able to drive sufficient expression to observe and photostimulate the long-range projections to brainstem autonomic regions. We conclude that a viral vector approach with a strong promoter is required for successful optogenetic stimulation of distal axons to evoke transmitter release in pre-autonomic PVN neurons. This approach can be very useful to study important hypothalamus-brainstem connections, and can be easily modified to selectively activate other long-range projections within the brain.", "Chromatin regulators control cellular differentiation by orchestrating dynamic developmental gene expression programs, and hence, malfunctions in the regulation of chromatin state contribute to both developmental disorders and disease state. Mll4 (Kmt2d), a member of the COMPASS (COMplex of Proteins ASsociated with Set1) protein family that implements histone H3 lysine 4 monomethylation (H3K4me1) at enhancers, is essential for embryonic development and functions as a pancancer tumor suppressor. We define the roles of Mll4/COMPASS and its catalytic activity in the maintenance and exit of ground-state pluripotency in murine embryonic stem cells (ESCs). Mll4 is required for ESC to exit the naive pluripotent state; however, its intrinsic catalytic activity is dispensable for this process. The depletion of the H3K4 demethylase Lsd1 (Kdm1a) restores the ability of Mll4 null ESCs to transition from naive to primed pluripotency. Thus, we define an opposing regulatory axis, wherein Lsd1 and associated co-repressors directly repress Mll4-activated gene targets. This finding has broad reaching implications for human developmental syndromes and the treatment of tumors carrying Mll4 mutations.", "INTRODUCTION: Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency) is the most common red blood cell (RBC) enzyme disorder. The decrease as well as the absence of the enzyme increase RBC vulnerability to oxidative stress caused by exposure to certain medications or intake of fava beans. Among the most common clinical manifestations of this condition, acute hemolysis, chronic hemolysis, neonatal hyperbilirubinemia, and an asymptomatic form are observed.OBJECTIVE: To analyze the case of a child who presented hemolytic crisis due to favism.CASE REPORT: A 2 year and 7 month old boy with a history of hyperbilirubinemia during the newborn period with no apparent cause, no family history of hemolytic anemia or parental consanguinity. He presented a prolonged neonatal jaundice and severe anemia requiring RBC transfusion. An intake of fava beans 48 h prior to onset of symptoms was reported. G6PD qualitative determination was compatible with this enzyme deficiency.CONCLUSION: G6PD deficiency can be highly variable in its clinical presentation, so it is necessary to keep it in mind during the diagnosis of hemolytic anemia at any age.", "Heart failure (HF) is one of the leading causes of morbidity, mortality, and health care expenditures in the US and worldwide. For three decades, the pillars of treatment of HF with reduced ejection fraction (HFrEF) were medications that targeted the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS). Prior attempts to augment the natriuretic peptide system (NPS) for the management of HF failed either due to lack of significant clinical benefit or due to the unacceptable side effect profile. This review article will discuss the NPS, the failure of early drugs which targeted the NPS as therapies for HF, and the sequence of events which led to the development of sacubitril plus valsartan (Entresto; LCZ696; Novartis). LCZ696 has been shown to be superior to the standard of care available for treatment of HFrEF in several substantial hard endpoints including heart failure hospitalizations, cardiovascular mortality, and all-cause mortality.", "The lysine methyltransferase KMT2C (also known as MLL3), a subunit of the COMPASS complex, implements monomethylation of Lys4 on histone H3 (H3K4) at gene enhancers. KMT2C (hereafter referred to as MLL3) frequently incurs point mutations across a range of human tumor types, but precisely how these lesions alter MLL3 function and contribute to oncogenesis is unclear. Here we report a cancer mutational hotspot in MLL3 within the region encoding its plant homeodomain (PHD) repeats and demonstrate that this domain mediates association of MLL3 with the histone H2A deubiquitinase and tumor suppressor BAP1. Cancer-associated mutations in the sequence encoding the MLL3 PHD repeats disrupt the interaction between MLL3 and BAP1 and correlate with poor patient survival. Cancer cells that had PHD-associated MLL3 mutations or lacked BAP1 showed reduced recruitment of MLL3 and the H3K27 demethylase KDM6A (also known as UTX) to gene enhancers. As a result, inhibition of the H3K27 methyltransferase activity of the Polycomb repressive complex 2 (PRC2) in tumor cells harboring BAP1 or MLL3 mutations restored normal gene expression patterns and impaired cell proliferation in vivo. This study provides mechanistic insight into the oncogenic effects of PHD-associated mutations in MLL3 and suggests that restoration of a balanced state of Polycomb-COMPASS activity may have therapeutic efficacy in tumors that bear mutations in the genes encoding these epigenetic factors." ]

[ "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.", "We report in the present study the effect of intrathecal treatment with antisense oligonucleotides complementary to thyrotropin releasing hormone (TRH) receptor mRNA on the pressor response to intrathecal administration of TRH and on resting arterial blood pressure in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). In 16-week-old male WKY rats, 18-base phosphodiester antisense or mismatch oligonucleotides to TRH receptor mRNA (100 micrograms per day) were injected intrathecally for 3 days. Twenty-four hours after the last injection, the magnitude of the pressor response to intrathecal TRH (10 micrograms) was significantly smaller in the antisense-treated group (n = 7) compared with mismatch-treated controls (n = 7) (change in mean arterial pressure, +20.3 +/- 3.0 versus +32.6 +/- 2.5 mm Hg, P < .01). No differences were observed in the pressor responses to injection of N-methyl-D-aspartic acid. Resting arterial blood pressure was unaffected by antisense treatment in WKY rats. In separate experiments, 16-week-old male SHR were treated with antisense (n = 7) or mismatch (n = 6) oligonucleotides for 3 days. Mean resting arterial blood pressure was significantly reduced by treatment with antisense oligonucleotides (from 157 +/- 4.8 to 119 +/- 8.8 mm Hg, P < .01), but no significant changes were observed in mismatch-treated animals. Our results suggest that the expression of TRH receptors in spinal sympathetic preganglionic neurons can be selectively reduced by intrathecal treatment with antisense oligonucleotides and that TRH projections to sympathetic preganglionic neurons play an important role in the elevation of arterial blood pressure in SHR.", "Fanconi anemia (FA) is an autosomal recessive disorder that is defined by cellular hypersensitivity to DNA cross-linking agents, and is characterized clinically by developmental abnormalities, progressive bone-marrow failure, and predisposition to leukemia and solid tumors. There is extensive genetic heterogeneity, with at least 11 different FA complementation groups. FA-A is the most common group, accounting for approximately 65% of all affected individuals. The mutation spectrum of the FANCA gene, located on chromosome 16q24.3, is highly heterogeneous. Here we summarize all sequence variations (mutations and polymorphisms) in FANCA described in the literature and listed in the Fanconi Anemia Mutation Database as of March 2004, and report 61 novel FANCA mutations identified in FA patients registered in the International Fanconi Anemia Registry (IFAR). Thirty-eight novel SNPs, previously unreported in the literature or in dbSNP, were also identified. We studied the segregation of common FANCA SNPs in FA families to generate haplotypes. We found that FANCA SNP data are highly useful for carrier testing, prenatal diagnosis, and preimplantation genetic diagnosis, particularly when the disease-causing mutations are unknown. Twenty-two large genomic deletions were identified by detection of apparent homozygosity for rare SNPs. In addition, a conserved SNP haplotype block spanning at least 60 kb of the FANCA gene was identified in individuals from various ethnic groups.", "The current review was designed to compare between the insulin inhalation systems Exubera and Afrezza and to investigate the reasons why Exubera was unsuccessful, when Afrezza maker is expecting their product to be felicitous. In January 2006, Pfizer secured FDA and EC approval for the first of its kind, regular insulin through Exubera inhaler device for the management of types 1 and 2 diabetes mellitus (DM) in adults. The product was no longer available to the market after less than two years from its approval triggering a setback for competitive new inhalable insulins that were already in various clinical development phases. In contrary, MannKind Corporation started developing its ultra-rapid-acting insulin Afrezza in a bold bid, probably by managing the issues in which Exubera was not successful. Afrezza has been marketed since February, 2015 by Sanofi after getting FDA approval in June 2014. The results from this systematic review indicate the effectiveness of insulin inhalation products, particularly for patients initiating insulin therapy. Pharmaceutical companies should capitalize on the information available from insulin inhalation to produce competitive products that are able to match the bioavailability of subcutaneous (SC) insulin injection and to deal with the single insulin unit increments and basal insulin requirements in some diabetic patients or extending the horizon to inhalable drug products with completely different drug entities for other indications.", "Burning mouth syndrome (BMS) is a distinct clinical entity characterized by a chief complaint of unremitting oral burning concomitant with no oral mucosal clinically observable lesions. Numerous causes of this condition have been suggested, including local factors, systemic factors, and psychogenic disorders. A total of 36 consecutive subjects, 32 women and 4 men, complaining of BMS, who had attended the Dental Clinic of the University of Ferrara during a period of 2 years, was studied. The method of assessment followed closely a strictly co-ordinated management protocol based on conventional guidelines, namely history, clinical examination and special investigations. A detailed history was taken of duration of the condition, site affected, and pattern of burning. The severity and the response to treatment were assessed with a Visual Linear Analogue Scale (VLAS). A full medical history was taken, with regard to xerostomia-inducing drug assumption. The presence and the severity of menopausal symptoms were explored. Inquiries were made on use of mouthwashes. For the denture-wearers, specific questioning was directed to the length of denture-wearing experience, temporal association of the symptom with the wearing of dentures, relationship to burning sensation of any relines or repairs, denture cleaning technique, and use of fixatives. A complete routine intraoral and extraoral examination was performed. The presence of parafunctional habits, such as tongue thrusting, clenching, grinding, lip and cheek biting, was investigated. If dentures were worn, their design and condition were examined. In particular, the relation between the vertical and horizontal components of the jaw and the denture base extension was assessed and the freeway space measured.(ABSTRACT TRUNCATED AT 250 WORDS)", "PURPOSE: L612, a human IgM monoclonal antibody produced by an EBV-transformed human B-cell line, binds to ganglioside GM3 and kills GM3-positive human melanoma cells in the presence of complement. It has been shown to be effective in some patients with late-stage melanoma. L612 consists of hexameric IgM (about 20%), pentameric IgM (about 74%), and other minor IgM molecules. Because hexameric IgM activates complement more effectively than pentameric IgM, we developed and evaluated a hexamer-dominant recombinant IgM for clinical applications.EXPERIMENTAL DESIGN: Chinese hamster ovary (CHO) cells were transfected with heavy- and light-chain genes of L612, with or without the joining-chain gene. Antitumor effects of the recombinant IgM secreted from CHO cells were evaluated in vitro and in vivo.RESULTS: Recombinant IgM secreted from CHO cells without the joining chain (designated CA19) was approximately 80% hexameric, whereas recombinant IgM from CHO cells transfected with heavy-, light-, and joining-chain genes (designated CJ45) was about 90% pentameric. Both CA19 and CJ45 recombinant IgMs caused complement-dependent cytotoxicity against human and mouse melanoma cell lines, but the amount of CA19 required for 50% specific cytotoxicity was 5 to 10 times smaller. I.v. injection of CA19 compared with CJ45 or native L612 elicited more profound antitumor activity in nude rats bearing a GM3-positive mouse melanoma xenograft.CONCLUSIONS: A hexamer-dominant human IgM against GM3 may provide a more potent treatment option for patients with GM3-positive melanoma.", "BACKGROUND: Eosinophilic gastritis and duodenitis are characterized by gastrointestinal mucosal eosinophilia, chronic symptoms, impaired quality of life, and a lack of adequate treatments. Mast-cell activity may contribute to the pathogenesis of the conditions. AK002 (lirentelimab) is an anti-Siglec-8 antibody that depletes eosinophils and inhibits mast cells and that has shown potential in animal models as a treatment for eosinophilic gastritis and duodenitis.METHODS: In this phase 2 trial, we randomly assigned adults who had symptomatic eosinophilic gastritis, eosinophilic duodenitis, or both conditions in a 1:1:1 ratio to receive four monthly infusions of low-dose AK002, high-dose AK002, or placebo. The primary end point was the change in gastrointestinal eosinophil count from baseline to 2 weeks after the final dose; to maximize statistical power, we evaluated this end point in the placebo group as compared with the combined AK002 group. Secondary end points were treatment response (>30% reduction in total symptom score and >75% reduction in gastrointestinal eosinophil count) and the change in total symptom score.RESULTS: Of the 65 patients who underwent randomization, 43 were assigned to receive AK002 and 22 were assigned to receive placebo. The mean percentage change in gastrointestinal eosinophil count was -86% in the combined AK002 group, as compared with 9% in the placebo group (least-squares mean difference, -98 percentage points; 95% confidence interval [CI], -121 to -76; P<0.001). Treatment response occurred in 63% of the patients who received AK002 and in 5% of the patients who received placebo (difference, 58 percentage points; 95% CI, 36 to 74; P<0.001). The mean change in total symptom score was -48% with AK002 and -22% with placebo (least-squares mean difference, -26 percentage points; 95% CI, -44 to -9; P = 0.004). Adverse events associated with AK002 were similar to those with placebo, with the exception of higher percentages of patients having mild-to-moderate infusion-related reactions with AK002 (60% in the combined AK002 group and 23% in the placebo group).CONCLUSIONS: In patients with eosinophilic gastritis or duodenitis, AK002 reduced gastrointestinal eosinophils and symptoms. Infusion-related reactions were more common with AK002 than with placebo. (Funded by Allakos; ENIGMA ClinicalTrials.gov number, NCT03496571.)." ]

[ "It is well established that testicular differentiation of the human embryonic gonad depends on the action of the Y-chromosomal gene SRY. However, exceptional cases such as SRY-negative cases of 46,XX testicular disorder of sexual development (DSD), and of 46,XX ovotesticular DSD document that testicular tissue can develop in the absence of the SRY gene. These SRY-negative XX sex reversal cases are very rare and usually sporadic, but a few familial cases have been reported. We present a large, consanguineous family with nine affected individuals with phenotypes ranging from 46,XX testicular DSD to 46,XX ovotesticular DSD, with predominance of male characteristics. Absence of SRY in peripheral blood was documented by fluorescence in situ hybridization (FISH) and PCR analysis in all nine affected individuals, and by FISH analysis on gonadal sections with testicular tissue in four affected individuals. By quantitative PCR, a duplication of the SOX9 gene was excluded. In addition, as linkage analysis showed that the nine affected members of the family do not share a common SOX9 haplotype, any mutation at the SOX9 locus could be ruled out. Together, these findings implicate a mutation at a sex-determining locus other than SRY and SOX9 as the cause for the XX sex reversal trait in this family.", "Several reports from mammals indicate that an increase in the mutation rate in late-replicating regions may, in part, be responsible for the observed genomic heterogeneity in neutral substitution rates and levels of diversity, although the mechanisms for this remain poorly understood. Recent evidence also suggests that late replication is associated with high mutability in yeast. This then raises the question as to whether a similar effect is operating across all eukaryotes. Limited evidence from one chromosome arm in Drosophila melanogaster suggests the opposite pattern, with regions overlapping early-firing origins showing increased levels of diversity and divergence. Given the availability of genome-wide replication timing profiles for D. melanogaster, we now return to this issue. Consistent with what is seen in other taxa, we find that divergence at synonymous sites in exon cores, as well as divergence at putatively unconstrained intronic sites, is elevated in late-replicating regions. Analysis of genes with low codon usage bias suggests a ∼30% difference in mutation rate between the earliest and the latest replicating sequence. Intronic sequence suggests a more modest difference. We additionally show that an increase in diversity in late-replicating sequences is not owing to replication timing covarying with the local recombination rate. If anything, the effects of recombination mask the impact of replication timing. We conclude that, contrary to prior reports and consistent with what is seen in mammals and yeast, there is indeed a relationship between rates of nucleotide divergence and diversity and replication timing that is consistent with an increase in the mutation rate during late S-phase in D. melanogaster. It is therefore plausible that such an effect might be common among eukaryotes. The result may have implications for the inference of positive selection.", "Author information:(1)Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.(2)Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA.(3)Department of Pediatric Hematology and Oncology, Center for Pediatrics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.(4)Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.(5)US Fish and Wildlife Service, Private John Allen National Fish Hatchery, Tupelo, MS, USA.(6)Department of Biology, Stanford University, Stanford, CA, USA.(7)US Geological Survey, Great Lakes Science Center, Hammond Bay Biological Station, Millersburg, MI, USA.(8)Molecular Cell Biology, University of California, Merced, CA, USA.(9)Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.(10)Department of Dermatology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.(11)Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.(12)Developmental Biology, Faculty of Biology, Centre for Biological Signalling Studies (BIOSS), Albert-Ludwigs-University of Freiburg, Freiburg, Germany.(13)Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. zon@enders.tch.harvard.edu.(14)Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA. zon@enders.tch.harvard.edu.", "Carboxyl-terminal modulator protein (CTMP) is a tumor suppressor-like binding partner of Protein kinase B (PKB/Akt) that negative regulates this kinase. In the course of our recent work, we identified that CTMP is consistently associated with leucine zipper/EF-hand-containing transmembrane-1 (LETM1). Here, we report that adenovirus-LETM1 increased the sensitivity of HeLa cells to apoptosis, induced by either staurosporine or actinomycin D. As shown previously, LETM1 localized to the inner mitochondrial membrane. Electron-microscopy analysis of adenovirus-LETM1 transduced cells revealed that mitochondrial cristae were swollen in these cells, a phenotype similar to that observed in optic atrophy type-1 (OPA1)-ablated cells. OPA1 cleavage was increased in LETM1-overexpressing cells, and this phenotype was reversed by overexpression of OPA1 variant-7, a cleavage resistant form of OPA1. Taken together, these data suggest that LETM1 is a novel binding partner for CTMP that may play an important role in mitochondrial fragmentation via OPA1-cleavage.", "PREMISE OF THE STUDY: Pachypodium (Apocynaceae) is a genus of iconic stem-succulent and poisonous plants endemic to Madagascar and southern Africa. We tested hypotheses about the mode of action and macroevolution of toxicity in this group. We further hypothesized that while monarch butterflies are highly resistant to cardenolide toxins (a type of cardiac glycoside) from American Asclepias, they may be negatively affected by Pachypodium defenses, which evolved independently.METHODS: We grew 16 of 21 known Pachypodium spp. and quantified putative cardenolides by HPLC and also by inhibition of animal Na+ /K+ -ATPase (the physiological target of cardiac glycosides) using an in vitro assay. Pachypodium extracts were tested against monarch caterpillars in a feeding bioassay. We also tested four Asclepias spp. and five Pachypodium spp. extracts, contrasting inhibition of the cardenolide-sensitive porcine Na+ /K+ -ATPase to the monarch's resistant form.KEY RESULTS: We found evidence for low cardenolides by HPLC, but substantial toxicity when extracts were assayed on Na+ /K+ -ATPases. Toxicity showed phylogenetic signal, and taller species showed greater toxicity (this was marginal after phylogenetic correction). Application of Pachypodium extracts to milkweed leaves reduced monarch growth, and this was predicted by inhibition of the sensitive Na+ /K+ -ATPase in phylogenetic analyses. Asclepias extracts were 100-fold less potent against the monarch compared to the porcine Na+ /K+ -ATPase, but this difference was absent for Pachypodium extracts.CONCLUSIONS: Pachypodium contains potent toxicity capable of inhibiting sensitive and cardenolide-adapted Na+ /K+ -ATPases. Given the monarch's sensitivity to Pachypodium, we suggest that these plants contain novel cardiac glycosides or other compounds that facilitate toxicity by binding to Na+ /K+ -ATPases.", "Multiple sclerosis (MS) is the most common disabling neurological disease in young adults characterized by recurrent relapses and / or progression that are attributable to multifocal inflammation, demyelination and axonal pathology within the central nervous system. Currently approved disease-modifying treatments achieve their effects primarily by blocking the proinflammatory response in a nonspecific manner. Their limited clinical efficacy urges a more differentiated and specific therapeutic approach. Advances in understanding the pathophysiology of MS and appreciation of the contribution of neurodegenerative processes to disease pathology have led to promising therapeutic approaches at different points along the MS disease pathway: (i) monoclonal antibody therapy has provided the opportunity to rationally direct the therapeutic intervention by specifically targeting mechanisms of the immune system such as CD52 (alemtuzumab), CD25 (daclizumab), VLA-4 (natalizumab) and CD20 (rituximab); (ii) novel oral immunomodulating agents have shown to prevent lymphocyte recirculation from lymphoid organs such as fingolimod (FTY720); (iii) blocking of intracellular signaling cascades or ion channels at the cell-surface can protect axons from degeneration and restore axonal function in experimental settings; (iv) neuroprotective agents and stem cell therapy are able to promote remyelination and axonal regeneration in vitro. Despite the tremendous efforts undertaken, a better understanding of the sequential evolution of the MS lesion and the development of clinical surrogate markers, which allow to define subsets of patients with different forms of underlying pathogenesis, is necessary. This will pave the way for an optimized treatment approach, which will likely need both to target inflammation and to focus on promotion of neuroprotection and repair.", "The pathogenesis of stroke involves inflammation, apoptosis, and excitotoxicity, which is mediated in part by neuronal NO synthase (nNOS) activation. Ghrelin, an endogenous 28-amino acid peptide, is shown to exert antiapoptotic and anti-inflammatory properties. However, the effect of ghrelin in permanent focal cerebral ischemia and the role of the vagus nerve in its action remain unknown. To study this, male adult Sprague-Dawley rats underwent right-sided permanent middle cerebral artery occlusion (MCAO) with or without prior bilateral truncal vagotomy. This was followed by infusion of 4 nmol human ghrelin as treatment or saline as vehicle. Neurological deficit was assessed at 24 h after MCAO. Rats were killed thereafter, and brains were rapidly removed and analyzed for infarct size, markers of inflammation, excitotoxicity, and apoptosis. Compared with vehicle treatment, human ghrelin treatment in vagus nerve-intact rats after MCAO showed marked reduction in neurological deficit by 57% and infarct size by 25%. Middle cerebral artery occlusion resulted in increases in cerebral TNF-α, IL-6, neutrophil trafficking, matrix metalloproteinase 9 and nNOS gene expression, nitrotyrosine, and apoptosis. Human ghrelin treatment in vagus nerve-intact rats significantly decreased the above measurements. Human ghrelin treatment also improved 7-day survival and significantly decreased neurological deficit over the entire 7 days after MCAO in vagus nerve-intact rats compared with vehicle. Prior vagotomy, however, blunted human ghrelin's neuroprotective effects on neurological deficit, infarct size, TNF-α, neutrophil trafficking, nitrotyrosine, and apoptosis. Human ghrelin is thus a neuroprotective agent that inhibits inflammation, nNOS activity, and apoptosis in focal cerebral ischemia through a vagal pathway." ]

[ "OBJECTIVE: To review trials evaluating the efficacy and safety of Vaxchora, a reformulated, single-dose, oral, lyophilized Vibrio cholerae CVD 103-HgR vaccine for the prevention of travel-related cholera caused by V cholerae serogroup O1.DATA SOURCES: A literature search was conducted using MEDLINE (1946 to January week 3, 2017) and EMBASE (1996 to 2017 week 3). Keywords included oral cholera vaccine, single-dose, Vaxchora, and CVD 103-HgR. Limits included human, clinical trials published in English since 2010. ClinicalTrials.gov was used as a source for unpublished data. Additional data sources were obtained through bibliographic review of selected articles.STUDY SELECTION AND DATA EXTRACTION: Studies that addressed the safety and efficacy of Vaxchora, the reformulated, single-dose oral CVD 103-HgR cholera vaccine, were selected for analysis.DATA SYNTHESIS: Approval of Vaxchora, was based on efficacy of the vaccine in human trials demonstrating 90.3% protection among those challenged with V cholerae 10 days after vaccination and in immunogenicity studies with 90% systemic vibriocidal antibody conversion at 6 months after a single-dose of vaccine. Tolerability was acceptable, with the most common adverse effects reported to be fatigue, headache, and abdominal pain.CONCLUSION: Vaxchora is the only FDA-approved, single-dose oral vaccine for the prevention of cholera caused by V cholerae serogroup O1 in adult travelers from the United States going to cholera-affected areas. Safety and efficacy has not been established in children, immunocompromised persons, and pregnant or breastfeeding women or those living in cholera-endemic areas.", "Chromodomain helicase DNA binding protein 5 (CHD5) is a potent tumor suppressor that serves as a master regulator of a tumor-suppressive network. Examination of the role played by CHD5 in a wide range of human cancers is warranted. In this study, we focused on the epigenetic modification and tumor-suppressive role of CHD5 in lung cancer. We measured CHD5 mRNA and protein expression in lung cancer cells, lung cancer tissues, and their corresponding noncancerous lung tissues using real-time PCR and Western blot analysis. We then determined the methylation status of the CHD5 promoter in these samples using methylation-specific sequencing and analyzed CHD5 re-expression in lung cancer cells treated with or without 5-aza-2-deoxycytidine, an inhibitor of DNA methylation. Next, the lung cancer cell clones stably expressing EGFP-CHD5 protein or EGFP protein, respectively, were obtained and the effects of restored CHD5 expression on cell proliferation, colony formation, and tumorigenicity were assessed. CHD5 expression ranged from low to absent in the lung cancer cell lines and tissues examined; the CHD5 promoter was hyperethylated in these samples. Treatment with 5-aza-dC resulted in a localized decrease in methylation density and an increase in CHD5 expression. Clonogenicity and tumor growth were abrogated in A549 and H1299 cells upon restoration of CHD5 expression. A significant reduction in clonogenicity was observed; an average of 47.83 ± 4.6% reduction for A549-EGFP-CHD5 was observed compared to A549-EGFP, and an average of 56.39 ± 5.3% reduction for H1299-EGFP-CHD5 was observed compared to H1299-EGFP. A549-EGFP exhibited an average tumor size of 452.3 ± 36.5 mm(3), whereas A549-EGFP-CHD5 exhibited an average tumor size of only 57.7 ± 18.5 mm(3). Thus, our findings indicate that CHD5 is a potential tumor suppressor gene that is inactivated via an epigenetic mechanism in lung cancer.", "Signal transduction networks allow cells to recognize and respond to changes in the extracellular environment. All eukaryotic cells have MAPK (mitogen-activated protein kinase) pathways that participate in diverse cellular functions, including differentiation, survival, transformation and movement. Five distinct groups of MAPKs have been characterized in mammals, the most extensively studied of which is the Ras/Raf/MEK [MAPK/ERK (extracellular-signal-regulated kinase) kinase]/ERK cascade. Numerous stimuli, including growth factors and phorbol esters, activate MEK/ERK signalling. How disparate extracellular signals are translated by MEK/ERK into different cellular functions remains obscure. Originally identified in yeast, scaffold proteins are now recognized to contribute to the specificity of MEK/ERK pathways in mammalian cells. These scaffolds include KSR (kinase suppressor of Ras), beta-arrestin, MEK partner-1, Sef and IQGAP1. Scaffolds organize multiprotein signalling complexes. This targets MEK/ERK to specific substrates and facilitates communication with other pathways, thereby mediating diverse functions. The adaptor proteins regulate the kinetics, amplitude and localization of MEK/ERK signalling, providing an efficient mechanism that enables an individual extracellular stimulus to promote a specific biological response.", "Variegate porphyria (VP) is an autosomal-dominant disorder that is caused by inheritance of a partial deficiency of the enzyme protoporphyrinogen oxidase (EC 1.3.3.4). It is characterized by cutaneous photosensitivity and/or various neurological manifestations. Protoporphyrinogen oxidase catalyses the penultimate step of haem biosynthesis, and mutations in the PPOX gene have been coupled to VP. In the present study, sequencing analysis revealed 10 different mutations in the PPOX gene in 14 out of 17 apparently unrelated Swedish VP families. Six of the identified mutations, 3G > A (exon 2), 454C > T (exon 5), 472G > C (exon 6), 614C > T (exon 6), 988G > C (exon 10) and IVS12 + 2T > G (intron 12), are single nucleotide substitutions, while 604delC (exon 6), 916-17delCT (exon 9) and 1330-31delCT (exon 13) are small deletions, and IVS12 + 2-3insT (intron 12) is a small insertion. Only one of these 10 mutations has been reported previously. Three of the mutations were each identified in two or more families, while the remaining mutations were specific for an individual family. In addition to the 10 mutations, one previously unreported single nucleotide polymorphism was identified. Mutation analysis of family members revealed two adults and four children who were silent carriers of the VP trait. Genetic analysis can now be added to the conventional biochemical analyses and used in investigation of putative carriers of a VP trait in these families.", "Ability to reproduce is one of the hallmark features of all life forms by which new organisms are produced from their progenitors. During this process each cell duplicates its genome and passes a copy of its genome to the daughter cells along with the cellular matrix. Unlike bacteria, in eukaryotes there is a definite time gap between when the genome is duplicated and when it is physically separated. Therefore, for precise halving of the duplicated genome into two, it is required that each pair of duplicated chromosomes, termed sister chromatids, should be paired together in a binary fashion from the moment they are generated. This pairing function between the duplicated genome is primarily provided by a multimeric protein complex, called cohesin. Thus, genome integrity largely depends on cohesin as it ensures faithful chromosome segregation by holding the sister chromatids glued together from S phase to anaphase. In this review, we have discussed the life cycle of cohesin during both mitotic and meiotic cell divisions including the structure and architecture of cohesin complex, relevance of cohesin associated proteins, mechanism of cohesin loading onto the chromatin, cohesion establishment and the mechanism of cohesin disassembly during anaphase to separate the sister chromatids. We have also focused on the role of posttranslational modifications in cohesin biology. For better understanding of the complexity of the cohesin regulatory network to the readers, we have presented an interactome profiling of cohesin core subunits in budding yeast during mitosis and meiosis.", "Helicobacter pylori is the major causal factor in chronic gastritis. Its acquisition leads to a chronic, usually lifelong, inflammation of the gastric mucosa, which may gradually progress to atrophy (with intestinal metaplasia) in a significant proportion of infected individuals. This progression is probably multifactorial, being influenced by genetic or environmental factors in addition to H. pylori infection. The pathogenesis of peptic ulcer and gastric cancer is closely associated with H. pylori gastritis and its subsequent atrophic sequelae (atrophic gastritis). H. pylori-induced gastritis is an important risk factor in the multifactorial aetiology of these diseases. It causes a cascade of reactions that damage the gastric mucosa and epithelium in various ways. The specific mechanisms involved are largely unknown. Some are probably bacterium-related reactions, which are influenced by various virulence factors, and others are consequences of the mucosal inflammation and atrophy. The risk of peptic ulcer and gastric cancer in patients with H. pylori gastritis can be summarized as follows: i) the risk of both peptic ulcer and gastric cancer is low in individuals with a normal stomach; ii) the risk of peptic ulcer is approximately ten times higher and the risk of gastric cancer approximately twice as high in patients with non-atrophic H. pylori-positive gastritis as in those with a normal stomach; iii) these risks are further increased (twofold to threefold) when there is antral atrophy; whereas iv) in the presence of corpus atrophy the risk of gastric cancer remains high, but that of peptic ulcer decreases gradually to zero with increasing severity of corpus atrophy.", "Medicinal plant extracts of five plants; Adhatoda vasica, Eucalyptus globulus, Lantana camara, Nerium oleander and Ocimum basilicum collected from Cairo, Egypt were evaluated against Fusarium oxysporum f. sp. lycopersici race 3 in vitro conditions using water and certain organic solvents. The results revealed that cold distilled water extracts of O. basilicum and E. globulus were the most effective ones for inhibiting the growth of F. oxysporum f. sp. lycopersici. Butanolic and ethanolic extracts of the tested plants inhibited the pathogen growth to a higher extent than water extracts. Butanolic extract of O. basilicum completely inhibited the growth of F. oxysporum f. sp. lycopersici at concentrations 1.5 and 2.0% (v/v). Butanolic extracts (2.0%) of tested plants had a strong inhibitory effect on hydrolytic enzymes; β-glucosidase, pectin lyase and protease of F. oxysporum f. sp. lycopersici. This study has confirmed that the application of plant extracts, especially from O. basilicum for controlling F. oxysporum f. sp. lycopersici is environmentally safe, cost effective and does not disturb ecological balance. Investigations are in progress to test the efficacy of O. basilicum extract under in vivo conditions." ]

[ "BACKGROUND: Chromosomal replication is the central event in the bacterial cell cycle. Identification of replication origins (oriCs) is necessary for almost all newly sequenced bacterial genomes. Given the increasing pace of genome sequencing, the current available software for predicting oriCs, however, still leaves much to be desired. Therefore, the increasing availability of genome sequences calls for improved software to identify oriCs in newly sequenced and unannotated bacterial genomes.RESULTS: We have developed Ori-Finder, an online system for finding oriCs in bacterial genomes based on an integrated method comprising the analysis of base composition asymmetry using the Z-curve method, distribution of DnaA boxes, and the occurrence of genes frequently close to oriCs. The program can also deal with unannotated genome sequences by integrating the gene-finding program ZCURVE 1.02. Output of the predicted results is exported to an HTML report, which offers convenient views on the results in both graphical and tabular formats.CONCLUSION: A web-based system to predict replication origins of bacterial genomes has been presented here. Based on this system, oriC regions have been predicted for the bacterial genomes available in GenBank currently. It is hoped that Ori-Finder will become a useful tool for the identification and analysis of oriCs in both bacterial and archaeal genomes.", "Teriparatide (recombinant human parathyroid hormone ) is an anabolic agent approved for the treatment of patients at high risk for fracture. The Fracture Prevention Trial administered teriparatide to treatment-naïve patients, leading to its US Food and Drug Administration approval in 2002. Clinical trial data using antiresorptive agents administered before, during, and after any parathyroid hormone (PTH) therapy, as well as alternative PTH dosing, have provided additional insight yet raise fundamental questions about the most appropriate use of teriparatide. This article provides an update on teriparatide, focusing on its mechanism of action compared with other antiresorptive agents, indications, adverse effects, therapy duration, combination therapy, contraindications, and cost effectiveness.", "Diamond-Blackfan anemia (DBA) is a congenital red blood cell aplasia that is usually diagnosed during early infancy. Apart from defects in red blood cell maturation, the disorder is also associated with various physical anomalies in 40% of patients. Mutations in the ribosomal protein (RP) S19 are found in 25% of patients, while mutations in other proteins of the small ribosomal subunit--RPS17 and RPS24--have been found in a fraction of patients. Recently, mutations in RPL5, RPL11, and RPL35a of the large ribosomal subunit have also been reported in several DBA patients. Here, we present the identification of mutations in the RPL5 and RPL11 genes in patients from the Czech DBA Registry. Mutations in RPL5 were identified in eight patients from 6 out of 28 families (21.4%), and mutations in RPL11 in two patients from 2 out of 28 families (7.1%). Interestingly, all 10 patients with either an RPL5 or RPL11 mutation exhibited one or more physical anomalies; specifically, thumb anomalies (flat thenar) were always present, while no such anomaly was observed in seven patients with an RPS19 mutation. Moreover, 9 out of 10 patients with either an RPL5 or RPL11 mutation were born small for gestational age (SGA) compared to 3 out of 7 patients from the RPS19-mutated group. These observations may suggest that mutations, at least in RPL5, seem to generally have more profound impact on fetal development than mutations in RPS19. Since RPL5 and RPL11, together with RPL23, are also involved in the MDM2-mediated p53 pathway regulation, we also screened the RPL23 gene for mutations; however, no mutations were identified.", "The diterpenoid ester ingenol mebutate (IngMeb) is the active ingredient in the topical drug Picato, a first-in-class treatment for the precancerous skin condition actinic keratosis. IngMeb is proposed to exert its therapeutic effects through a dual mode of action involving (i) induction of cell death that is associated with mitochondrial dysfunction followed by (ii) stimulation of a local inflammatory response, at least partially driven by protein kinase C (PKC) activation. Although this therapeutic model has been well characterized, the complete set of molecular targets responsible for mediating IngMeb activity remains ill-defined. Here, we have synthesized a photoreactive, clickable analogue of IngMeb and used this probe in quantitative proteomic experiments to map several protein targets of IngMeb in human cancer cell lines and primary human keratinocytes. Prominent among these targets was the mitochondrial carnitine-acylcarnitine translocase SLC25A20, which we show is inhibited in cells by IngMeb and the more stable analogue ingenol disoxate (IngDsx), but not by the canonical PKC agonist 12-O-tetradecanoylphorbol-13-acetate (TPA). SLC25A20 blockade by IngMeb and IngDsx leads to a buildup of cellular acylcarnitines and blockade of fatty acid oxidation (FAO), pointing to a possible mechanism for IngMeb-mediated perturbations in mitochondrial function.", "High CO2 retention, or hypercapnia, is associated with worse outcomes in patients with chronic pulmonary diseases. Skeletal muscle wasting is also an independent predictor of poor outcomes in patients with acute and chronic pulmonary diseases. Although previous evidence indicates that high CO2 accelerates skeletal muscle catabolism via AMPK (AMP-activated protein kinase)-FoxO3a-MuRF1 (E3-ubiquitin ligase muscle RING finger protein 1), little is known about the role of high CO2 in regulating skeletal muscle anabolism. In the present study, we investigated the potential role of high CO2 in attenuating skeletal muscle protein synthesis. We found that locomotor muscles from patients with chronic CO2 retention demonstrated depressed ribosomal gene expression in comparison with locomotor muscles from non-CO2-retaining individuals, and analysis of the muscle proteome of normo- and hypercapnic mice indicates reduction of important components of ribosomal structure and function. Indeed, mice chronically kept under a high-CO2 environment show evidence of skeletal muscle downregulation of ribosomal biogenesis and decreased protein synthesis as measured by the incorporation of puromycin into skeletal muscle. Hypercapnia did not regulate the mTOR pathway, and rapamycin-induced deactivation of mTOR did not cause a decrease in ribosomal gene expression. Loss-of-function studies in cultured myotubes showed that AMPKα2 regulates CO2-mediated reductions in ribosomal gene expression and protein synthesis. Although previous evidence has implicated TIF1A (transcription initiation factor-1α) and KDM2A (lysine-specific demethylase 2A) in AMPK-driven regulation of ribosomal gene expression, we found that these mediators were not required in the high CO2-induced depressed protein anabolism. Our research supports future studies targeting ribosomal biogenesis and protein synthesis to alleviate the effects of high CO2 on skeletal muscle turnover.", "Cardiac metabolism is highly adaptive in response to changes in substrate availability, as occur during fasting. This metabolic flexibility is essential to the maintenance of contractile function and is under the control of a group of select transcriptional regulators, notably the nuclear receptor family of factors member PPARα. However, the diversity of physiologic and pathologic states through which the heart must sustain function suggests the possible existence of additional transcriptional regulators that play a role in matching cardiac metabolism to energetic demand. Here we show that cardiac KLF15 is required for the normal cardiac response to fasting. Specifically, we find that cardiac function is impaired upon fasting in systemic and cardiac specific Klf15-null mice. Further, cardiac specific Klf15-null mice display a fasting-dependent accumulation of long chain acylcarnitine species along with a decrease in expression of the carnitine translocase Slc25a20. Treatment with a diet high in short chain fatty acids relieves the KLF15-dependent long chain acylcarnitine accumulation and impaired cardiac function in response to fasting. Our observations establish KLF15 as a critical mediator of the cardiac adaptive response to fasting through its regulation of myocardial lipid utilization.", "The Morel-Lavallée lesion (MLL) is a posttraumatic close degloving injury, which is often underdiagnosed at first. Patients with MLLs usually present with tender and enlarging soft tissue swelling with fluctuation, decreased skin sensation, ecchymosis, or even skin necrosis hours to days after the inciting injury. The lesion can lead to intractable morbidity if it remains untreated. There is no consensus regarding the treatment for MLL at present. Here, we report an MLL in the pretibial region of a 43-year-old woman who experienced a low-energy contusion in a motorbike accident. The pretibial lesion was diagnosed using sonography and fine-needle aspiration. We successfully treated the patient by performing percutaneous debridement via a small incision and injections of fibrin after conservative treatment failed. The method we herein propose achieved the goal of open surgical debridement, providing faster recovery and a high degree of patient comfort. We reviewed the available pertinent literature and propose our own treatment protocol with the aim to establish common therapies ofMLL.", "The carnitine/acylcarnitine transporter (CACT; SLC25A20) mediates an antiport reaction allowing entry of acyl moieties in the form of acylcarnitines into the mitochondrial matrix and exit of free carnitine. The transport function of CACT is crucial for the β-oxidation pathway. In this work, it has been found that CACT is partially acetylated in rat liver mitochondria as demonstrated by anti-acetyl-lys antibody immunostaining. Acetylation was reversed by the deacetylase Sirtuin 3 in the presence of NAD+. After treatment of the mitochondrial extract with the deacetylase, the CACT activity, assayed in proteoliposomes, increased. The half-saturation constant of the CACT was not influenced, while the V max was increased by deacetylation. Sirtuin 3 was not able to deacetylate the CACT when incubation was performed in intact mitoplasts, indicating that the acetylation sites are located in the mitochondrial matrix. Prediction on the localization of acetylated residues by bioinformatics correlates well with the experimental data. Recombinant CACT treated with acetyl-CoA was partially acetylated by non-enzymatic mechanism with a corresponding decrease of transport activity. The experimental data indicate that acetylation of CACT inhibits its transport activity, and thus may contribute to the regulation of the mitochondrial β-oxidation pathway.", "Activating transcription factor 4 (ATF4), an endoplasmic reticulum stress-inducible transcription factor, plays important roles in cancer progression and resistance to therapy. However, no report is available about its roles in endometrial cancer (EC). In this study, we found that ATF4 is commonly expressed in EC cell lines. Loss-of-function studies in two EC cell lines showed that ATF4 knockdown suppresses tumor growth of EC in vivo without influencing cell proliferation in vitro. And xenograft tumors derived from ATF4-knockdown cells had reduced M2 macrophage infiltration. In clinical specimens, ATF4-high expressing tumors indeed contained more macrophage infiltration compared to those with lower ATF4 expression. Moreover, we identified that ATF4-mediated chemokine CCL2 expression ultimately results in macrophage infiltration and tumor growth of EC. Taken together, our findings suggest that ATF4 contributes to tumor growth of EC by promoting CCL2 and subsequent recruitment of macrophage, and that ATF4/CCL2 axis might be a potential therapeutic target for EC.", "Anti-angiogenic agents have played crucial roles in the treatment of ovarian cancer in recent years, but potential benefits of endostatin have been largely unexplored. The present retrospective study evaluated its efficacy and toxicity with two cohorts of patients with platinum-resistant recurrent ovarian cancer. One cohort received gemcitabine plus endostar (rh-endostatin), and the second cohort received gemcitabine regimen alone, with totals of 31 and 27 patients, respectively. The main endpoints were disease control rate (DCR), PFS, overall survival (OS) and safety. There were statistically significant differences in DCR (70.9% vs. 40.7%; P = 0.02) and PFS (6.3 months vs. 3.2 months, P = 0.001) between the two cohorts. Though the endostar cohort also improved median OS by 2.1 months, there was no statistically significant difference compared with gemcitabine alone cohort in this case (12.5 months vs. 10.4 months, P = 0.201). Treatment was well tolerated for most patients, and toxicity of endostar was negligible. Gemcitabine plus endostar significantly improved the prognosis in patients with platinum-resistant recurrent ovarian cancer, especially in those with malignant effusion. The endostar- containing regimen is recommended in this setting.", "OBJECTIVE: MicroRNAs (miRNA) have recently emerged as a new class of modulators of gene expression. In this study we investigated the expression, regulation, and function of miR-155 and miR-146a in rheumatoid arthritis (RA) synovial fibroblasts (RASFs) and RA synovial tissue.METHODS: Locked nucleic acid microarray was used to screen for differentially expressed miRNA in RASFs treated with tumor necrosis factor alpha (TNFalpha). TaqMan-based real-time polymerase chain reaction was applied to measure the levels of miR-155 and miR-146a. Enforced overexpression of miR-155 was used to investigate the function of miR-155 in RASFs.RESULTS: Microarray analysis of miRNA expressed in RASFs treated with TNFalpha revealed a prominent up-regulation of miR-155. Constitutive expression of both miR-155 and miR-146a was higher in RASFs than in those from patients with osteoarthritis (OA), and expression of miR-155 could be further induced by TNFalpha, interleukin-1beta, lipopolysaccharide, poly(I-C), and bacterial lipoprotein. The expression of miR-155 in RA synovial tissue was higher than in OA synovial tissue. Enforced expression of miR-155 in RASFs was found to repress the levels of matrix metalloproteinase 3 (MMP-3) and reduce the induction of MMPs 3 and 1 by Toll-like receptor ligands and cytokines. Moreover, compared with monocytes from RA peripheral blood, RA synovial fluid monocytes displayed higher levels of miR-155.CONCLUSION: This study provides the first description of increased expression of miRNA miR-155 and miR-146a in RA. Based on these findings, we postulate that the inflammatory milieu may alter miRNA expression profiles in resident cells of the rheumatoid joints. Considering the repressive effect of miR-155 on the expression of MMPs 3 and 1 in RASFs, we hypothesize that miR-155 may be involved in modulation of the destructive properties of RASFs.", "BACKGROUND: Given the slow and variable clinical course of Alzheimer disease, very large and extended clinical trials are needed to identify a beneficial clinical effect of disease-modifying treatments. Therefore, biomarkers are essential to prove that an anti-β-amyloid (Aβ) drug candidate affects both Aβ metabolism and plaque load as well as downstream pathogenic mechanisms.OBJECTIVE: To evaluate the effect of the anti-Aβ monoclonal antibody bapineuzumab on cerebrospinal fluid (CSF) biomarkers reflecting Aβ homeostasis, neuronal degeneration, and tau-related pathology in patients with Alzheimer disease.DESIGN: Two phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trials of 12-month duration.SETTING: Academic centers in the United States (Study 201) and England and Finland (Study 202).PATIENTS: Forty-six patients with mild to moderate Alzheimer disease.INTERVENTIONS: Patients received either placebo (n = 19) or bapineuzumab (n = 27) in 3 or 4 ascending dose groups.MAIN OUTCOME MEASURES: Changes between end of study and baseline in the exploratory CSF biomarkers Aβ1-42, AβX-42, AβX-40; total tau (T-tau); and phosphorylated tau (P-tau).RESULTS: Within the bapineuzumab group, a decrease at end of study compared with baseline was found both for CSF T-tau (-72.3 pg/mL) and P-tau (-9.9 pg/mL). When comparing the treatment and placebo groups, this difference was statistically significant for P-tau (P = .03), while a similar trend for a decrease was found for T-tau (P = .09). No clear-cut differences were observed for CSF Aβ.CONCLUSIONS: To our knowledge, this study is the first to show that passive Aβ immunotherapy with bapineuzumab results in decreases in CSF T-tau and P-tau, which may indicate downstream effects on the degenerative process. Cerebrospinal fluid biomarkers may be useful to monitor the effects of novel disease-modifying anti-Aβ drugs in clinical trials. TRIAL REGISTRATIONS clinicaltrials.gov Identifier: NCT00112073, EudraCT Identifier: 2004-004120-12, and isrctn.org Identifier: ISRCTN17517446." ]

[ "Microalbuminuria was originally considered to be an important new risk factor for diabetic nephropathy. More recently, it has been convincingly shown that microalbuminuria is also an independent risk factor for cardiovascular morbidity and mortality in Type 1 and Type 2 diabetic patients. Even in the non-diabetic background population, microalbuminuria is a risk factor for cardiovascular mortality. What is the link between increased loss of albumin in urine and cardiovascular disease and mortality? As microalbuminuria is apparently associated with increased universal vascular sieving of albumin in terms of the transcapillary escape rate of albumin (TER-alb), microalbuminuria may reflect this universal sieving. The pathophysiology of increased TER-alb is unknown, but could be caused by haemodynamics or damage to the functional properties of the vascular wall. A number of studies have provided evidence of endothelial dysfunction in patients with microalbuminuria, which may be the common link accounting for the associations mentioned above. In this context, a number of markers of endothelial cell dysfunction have been found to be increased in patients with microalbuminuria. In addition, a number of functional in vivo tests of endothelial dysfunction have been performed in Type 1 and Type 2 diabetic patients as well as in normal controls. Overall, these studies indicate the existence of a functional vascular dysfunction in Type 1 diabetic patients and normal controls with microalbuminuria, which may be related to dysfunction of endothelial cells.", "The amniotic band syndrome (ABS) refers to the infrequent occurrence of congenital deformities presumably due to fetal entanglement in strands of ruptured amniotic sac. The most commonly associated anomalies include amputations, constriction bands, syndactyly, craniofacial defects, club feet, and cleft lip. We present a typical case and short literature review of ABS. The infant reported also had a connective tissue nevus and a cutaneous striated muscle hamartoma.", "Recent evidence suggests that abnormal activation of cyclin-dependent kinase 5 (cdk5) is a critical prodeath signal in stroke. However, the mechanism(s) by which cdk5 promotes death is unclear. Complicating the role of cdk5 are the observations that cdk5 can exist in multiple cellular regions and possess both prosurvival and prodeath characteristics. In particular, the critical role of cytoplasmic or nuclear cdk5 in neuronal jury, in vivo, is unclear. Therefore, we determined where cdk5 was activated in models of ischemia and how manipulation of cdk5 in differing compartments may affect neuronal death. Here, we show a critical function for cytoplasmic cdk5 in both focal and global models of stroke, in vivo. Cdk5 is activated in the cytoplasm and expression of DNcdk5 localized to the cytoplasm is protective. Importantly, we also demonstrate the antioxidant enzyme Prx2 (peroxiredoxin 2) as a critical cytoplasmic target of cdk5. In contrast, the role of cdk5 in the nucleus is context-dependent. Following focal ischemia, nuclear cdk5 is activated and functionally relevant while there is no evidence for such activation following global ischemia. Importantly, myocyte enhancer factor 2D (MEF2D), a previously described nuclear target of cdk5 in vitro, is also phosphorylated by cdk5 following focal ischemia. In addition, MEF2D expression in this paradigm ameliorates death. Together, our results address the critical issue of cdk5 activity compartmentalization, as well as define critical substrates for both cytoplasmic and nuclear cdk5 activity in adult models of stroke.", "Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death in young people, including trained athletes. The implantable cardioverter-defibrillator (ICD), although initially designed as a treatment for older patients with coronary artery disease, has more recently proved to be a safe and effective therapeutic intervention in young patients with HCM, both for primary or secondary prevention of sudden death. The largest such report of >500 patients showed that the ICD intervened appropriately to abort ventricular tachycardia/fibrillation (VT/VF) in 20% of patients over an average follow-up period of only 3.7 years, at a rate of about 4% per year in those patients implanted prophylactically, and often with considerable delays of up to 10 years. Extensive experience with high-risk HCM patients showed that appropriate device discharges for VT/VF occur with similar frequency in patients with 1, 2, or > or = 3 noninvasive risk markers. Despite the extreme morphology characteristic of HCM, often with massive degrees of left ventricular (LV) hypertrophy and/or LV outflow tract obstruction, ICDs performed in a highly effective fashion, with failure to convert life-threatening arrhythmias extraordinarily rare. In conclusion, in a large high-risk HCM cohort, ICD interventions for life-threatening ventricular tachyarrhythmias were frequent and highly effective in restoring normal rhythm. An important proportion of ICD discharges occurred in primary prevention patients with only one risk factor. Therefore, a single marker of high risk may represent sufficient evidence to justify the recommendation for a prophylactic ICD in selected patients with HCM.", "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is a cerebrovasuclar disease caused by NOTCH3 mutations, usually localized to exons 3 and 4. This report describes the clinical and neuroradiological findings of 2 subjects of two unrelated Japanese families who shared a common p.Arg332Cys mutation. The subject from family A presented syncope attacks as the sole clinical presentation at the beginning of his disease course. The subject from family B showed recurrent ischemic attacks, followed by a large intracranial hemorrhage. This is the first report to describe the detailed phenotypes of patients with a rare p.Arg332Cys mutation in Japan.", "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.", "Skin lesions are a severe disease globally. Early detection of melanoma in dermoscopy images significantly increases the survival rate. However, the accurate recognition of melanoma is extremely challenging due to the following reasons: low contrast between lesions and skin, visual similarity between melanoma and non-melanoma lesions, etc. Hence, reliable automatic detection of skin tumors is very useful to increase the accuracy and efficiency of pathologists. In this paper, we proposed two deep learning methods to address three main tasks emerging in the area of skin lesion image processing, i.e., lesion segmentation (task 1), lesion dermoscopic feature extraction (task 2) and lesion classification (task 3). A deep learning framework consisting of two fully convolutional residual networks (FCRN) is proposed to simultaneously produce the segmentation result and the coarse classification result. A lesion index calculation unit (LICU) is developed to refine the coarse classification results by calculating the distance heat-map. A straight-forward CNN is proposed for the dermoscopic feature extraction task. The proposed deep learning frameworks were evaluated on the ISIC 2017 dataset. Experimental results show the promising accuracies of our frameworks, i.e., 0.753 for task 1, 0.848 for task 2 and 0.912 for task 3 were achieved." ]