Showing papers by "University of California, San Francisco published in 2014"
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TL;DR: Associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses.
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
6,809 citations
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TL;DR: The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues, and the convergence of signalling pathways is essential for EMT.
Abstract: The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial-mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.
6,036 citations
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TL;DR: A comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project is described and a molecular classification dividing gastric cancer into four subtypes is proposed.
Abstract: Gastric cancer was the world’s third leading cause of cancer mortality in 2012, responsible for 723,000 deaths1. The vast majority of gastric cancers are adenocarcinomas, which can be further subdivided into intestinal and diffuse types according to the Lauren classification2. An alternative system, proposed by the World Health Organization, divides gastric cancer into papillary, tubular, mucinous (colloid) and poorly cohesive carcinomas3. These classification systems have little clinical utility, making the development of robust classifiers that can guide patient therapy an urgent priority.
The majority of gastric cancers are associated with infectious agents, including the bacterium Helicobacter pylori4 and Epstein–Barr virus (EBV). The distribution of histological subtypes of gastric cancer and the frequencies of H. pylori and EBV associated gastric cancer vary across the globe5. A small minority of gastric cancer cases are associated with germline mutation in E-cadherin (CDH1)6 or mismatch repair genes7 (Lynch syndrome), whereas sporadic mismatch repair-deficient gastric cancers have epigenetic silencing of MLH1 in the context of a CpG island methylator phenotype (CIMP)8. Molecular profiling of gastric cancer has been performed using gene expression or DNA sequencing9–12, but has not led to a clear biologic classification scheme. The goals of this study by The Cancer Genome Atlas (TCGA) were to develop a robust molecular classification of gastric cancer and to identify dysregulated pathways and candidate drivers of distinct classes of gastric cancer.
4,583 citations
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TL;DR: In this paper, the authors formulate and define standards for reporting qualitative research while preserving the requisite flexibility for the broad spectrum of qualitative research, and present a set of guidelines for reporting such research.
Abstract: PurposeStandards for reporting exist for many types of quantitative research, but currently none exist for the broad spectrum of qualitative research. The purpose of the present study was to formulate and define standards for reporting qualitative research while preserving the requisite flexibility
4,506 citations
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Eric A. Collisson1, Joshua D. Campbell2, Angela N. Brooks3, Angela N. Brooks2 +315 more•Institutions (41)
TL;DR: In this paper, the authors report molecular profiling of 230 resected lung adnocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses.
Abstract: Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.
4,104 citations
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TL;DR: The authors' data provide clues as to how neurons and astrocytes differ in their ability to dynamically regulate glycolytic flux and lactate generation attributable to unique splicing of PKM2, the gene encoding the glycoleytic enzyme pyruvate kinase.
Abstract: The major cell classes of the brain differ in their developmental processes, metabolism, signaling, and function To better understand the functions and interactions of the cell types that comprise these classes, we acutely purified representative populations of neurons, astrocytes, oligodendrocyte precursor cells, newly formed oligodendrocytes, myelinating oligodendrocytes, microglia, endothelial cells, and pericytes from mouse cerebral cortex We generated a transcriptome database for these eight cell types by RNA sequencing and used a sensitive algorithm to detect alternative splicing events in each cell type Bioinformatic analyses identified thousands of new cell type-enriched genes and splicing isoforms that will provide novel markers for cell identification, tools for genetic manipulation, and insights into the biology of the brain For example, our data provide clues as to how neurons and astrocytes differ in their ability to dynamically regulate glycolytic flux and lactate generation attributable to unique splicing of PKM2, the gene encoding the glycolytic enzyme pyruvate kinase This dataset will provide a powerful new resource for understanding the development and function of the brain To ensure the widespread distribution of these datasets, we have created a user-friendly website (http://webstanfordedu/group/barres_lab/brain_rnaseqhtml) that provides a platform for analyzing and comparing transciption and alternative splicing profiles for various cell classes in the brain
3,891 citations
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Emory University1, University of California, San Francisco2, University of California, San Diego3, Baylor College of Medicine4, University of Minnesota5, Virginia Commonwealth University6, Rush University Medical Center7, Texas Tech University8, Duke University9, University of Texas Health Science Center at Houston10, National Institutes of Health11
TL;DR: In this article, Anderson et al. discuss the FAHA chair election process and discuss the state of the art in the field of cancer research. But they do not discuss the role of women in this process.
3,218 citations
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University of Southampton1, Imperial College London2, University of Washington3, Nippon Medical School4, University of Colorado Denver5, University of Duisburg-Essen6, University of Lyon7, University of Ulsan8, McMaster University9, Cedars-Sinai Medical Center10, Boehringer Ingelheim11, University of California, San Francisco12
TL;DR: In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintinganib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients.
Abstract: Background Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. Methods We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George’s Respiratory Questionnaire, both assessed over a 52-week period. Results A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was −114.7 ml with nintedanib versus −239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and −113.6 ml with nintedanib versus −207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P = 0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P = 0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2. Conclusions In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.)
2,936 citations
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TL;DR: The extracellular matrix is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands, and its regulation contributes to several pathological conditions, such as fibrosis and invasive cancer.
Abstract: The extracellular matrix (ECM) is a highly dynamic structure that is present in all tissues and continuously undergoes controlled remodelling. This process involves quantitative and qualitative changes in the ECM, mediated by specific enzymes that are responsible for ECM degradation, such as metalloproteinases. The ECM interacts with cells to regulate diverse functions, including proliferation, migration and differentiation. ECM remodelling is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands. Dysregulation of ECM composition, structure, stiffness and abundance contributes to several pathological conditions, such as fibrosis and invasive cancer. A better understanding of how the ECM regulates organ structure and function and of how ECM remodelling affects disease progression will contribute to the development of new therapeutics.
2,854 citations
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French Institute of Health and Medical Research1, Pierre-and-Marie-Curie University2, University of British Columbia3, UBC Hospital4, Beta5, Sahlgrenska University Hospital6, University of Virginia7, McGill University8, Brigham and Women's Hospital9, Washington University in St. Louis10, Vita-Salute San Raffaele University11, University College London12, University of Antwerp13, University of Geneva14, University of California, San Diego15, University of Kentucky16, Karolinska University Hospital17, university of lille18, University of California, San Francisco19, University of Nice Sophia Antipolis20, Brown University21, University of Paris22, Universidade Federal de Minas Gerais23, Maastricht University Medical Centre24, University of Southern California25, NewYork–Presbyterian Hospital26, VU University Amsterdam27, Lou Ruvo Brain Institute28
TL;DR: It is proposed that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease.
Abstract: In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.
2,581 citations
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European Bioinformatics Institute1, Institute for Systems Biology2, University of California, San Diego3, Swiss Institute of Bioinformatics4, Ruhr University Bochum5, University of Cambridge6, University of California, San Francisco7, Wiley-VCH8, Spanish National Research Council9, Ghent University10, University of Liverpool11
TL;DR: The PX submission tool simplifies the process of submitting data to PRIDE by automating the very labor-intensive and therefore time-heavy and expensive process of manually downloading and editing files.
Abstract: 5. Tools available and ways to submit data to PX ............................................................. 11 5.1. MS/MS data submissions to PRIDE .................................................................................... 11 5.1.1. Creation of supported files for “Complete” submissions .................................................. 11 5.1.1.1. PRIDE XML .................................................................................................................................. 11 5.1.1.2. mzIdentML ................................................................................................................................. 13 5.1.2. Checking the files before submission (initial quality assessment) ..................................... 14 5.1.3. File submission to PRIDE: the PX submission tool ............................................................. 15 5.1.3.1. General Information ................................................................................................................... 15 5.1.3.2. Functionality, Design and Implementation Details .................................................................... 15 5.1.3.3. New open source libraries made available with PX submission tool ......................................... 18 5.1.3.4. PX Submission Tool Java Web Start ............................................................................................ 18 5.1.4. File submission to PRIDE: Command line support using Aspera ........................................ 19 5.1.5. Examples of Partial submissions to PRIDE ......................................................................... 19 5.2. SRM data submissions via PASSEL ..................................................................................... 20
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Broad Institute1, Emory University2, Cincinnati Children's Hospital Medical Center3, University of Colorado Boulder4, Harvard University5, University of Minnesota6, University of Toronto7, Women & Children's Hospital of Buffalo8, Boston Children's Hospital9, Mayo Clinic10, University of California, San Francisco11, Long Island Jewish Medical Center12, Children's Hospital of Philadelphia13, Children's Hospital of Eastern Ontario14, Nationwide Children's Hospital15, Howard Hughes Medical Institute16
TL;DR: Comparing the microbial signatures between the ileum, the rectum, and fecal samples indicates that at this early stage of disease, assessing the rectal mucosal-associated microbiome offers unique potential for convenient and early diagnosis of CD.
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TL;DR: Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis.
Abstract: Background In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients. Methods In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis. Results In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P = 0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P = 0.16) or in rates of death from any cause (P = 0.10) or from idiopathic pulmonary fibrosis (P = 0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P = 0.01) and from idiopathic pulmonary fibrosis (P = 0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation. Conclusions Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable sideeffect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.)
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TL;DR: It is recommended that the Triple Aim be expanded to a Quadruple Aim, adding the goal of improving the work life of health care providers, including clinicians and staff.
Abstract: The Triple Aim—enhancing patient experience, improving population health, and reducing costs—is widely accepted as a compass to optimize health system per- formance. Yet physicians and other members of the health care workforce report widespread burnout and dissatisfaction. Burnout is associated with lower patient satisfaction, reduced health outcomes, and it may increase costs. Burnout thus imperils the Triple Aim. This article recommends that the Triple Aim be expanded to a Quadruple Aim, adding the goal of improving the work life of health care providers, including clinicians and staff.
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TL;DR: Ch Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.
Abstract: Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. To date, no molecularly targeted agents have been approved for the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#termsThis paper is distributed under the terms of the Creative Commons. Attribution-Non-Commercial-Share Alike license, and the online version of the paper is freely available to all readers.
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TL;DR: This work presents PLUMED 2 here—a complete rewrite of the code in an object-oriented programming language (C++), which introduces greater flexibility and greater modularity, which both extends its core capabilities and makes it far easier to add new methods and CVs.
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Icahn School of Medicine at Mount Sinai1, Carnegie Mellon University2, Harvard University3, University of Toronto4, Wellcome Trust Sanger Institute5, University of Pittsburgh6, Nagoya University7, University of Freiburg8, King's College London9, Vanderbilt University10, University of Santiago de Compostela11, King Abdulaziz University12, University of Utah13, Duke University14, Memorial University of Newfoundland15, Trinity College, Dublin16, University of Pennsylvania17, University of Illinois at Chicago18, Boston Children's Hospital19, Columbia University20, German Cancer Research Center21, University College London22, Kaiser Permanente23, Broad Institute24, Cardiff University25, Complutense University of Madrid26, Newcastle University27, Baylor College of Medicine28, University of California, San Francisco29, RWTH Aachen University30, National Health Service31, McMaster University32, Saarland University33, Karolinska Institutet34, National Institutes of Health35, University of Helsinki36, Emory University37
TL;DR: Using exome sequencing, it is shown that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate of < 0.05, plus a set of 107 genes strongly enriched for those likely to affect risk (FDR < 0.30).
Abstract: The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.
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Icahn School of Medicine at Mount Sinai1, Cleveland Clinic2, University of Alabama at Birmingham3, University of Copenhagen4, University College London5, University of Texas Health Science Center at Houston6, New York University7, University of Pennsylvania8, VU University Amsterdam9, National Multiple Sclerosis Society10, Johns Hopkins University11, Vita-Salute San Raffaele University12, University of Ottawa13, University of Rochester14, University of Basel15, University of Düsseldorf16, Pierre-and-Marie-Curie University17, Autonomous University of Barcelona18, University of Toronto19, University of British Columbia20, Sapienza University of Rome21, University of Texas Southwestern Medical Center22, University of California, San Francisco23
TL;DR: Refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression are proposed and strategies for future research to better define phenotypes are outlined.
Abstract: Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.
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TL;DR: It is estimated that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation.
Abstract: Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.
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TL;DR: This work identifies rules for specific targeting of transcriptional repressors (CRISPRi), typically achieving 90%-99% knockdown with minimal off-target effects, and activators to endogenous genes via endonuclease-deficient Cas9, which enable modulation of gene expression over a ∼1,000-fold range.
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Broad Institute1, Harvard University2, Monash University3, Kyoto University4, Genentech5, Vanderbilt University6, New York University7, NewYork–Presbyterian Hospital8, Second Military Medical University9, University of Queensland10, University of Toronto11, University of Groningen12, University of Tartu13, Beijing Jiaotong University14, Icahn School of Medicine at Mount Sinai15, Radboud University Nijmegen16, Medisch Spectrum Twente17, Leiden University18, University of Paris19, French Institute of Health and Medical Research20, University of Alabama at Birmingham21, University of Amsterdam22, GlaxoSmithKline23, University of Cambridge24, Hanyang University25, Spanish National Research Council26, Complutense University of Madrid27, Umeå University28, Boston University29, Council on Education for Public Health30, McGill University31, National Health Service32, University of Manchester33, University of Pittsburgh34, University of California, San Francisco35, Karolinska Institutet36, North Shore-LIJ Health System37, University of Chicago38, University of Tokyo39
TL;DR: A genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries provides empirical evidence that the genetics of RA can provide important information for drug discovery, and sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis.
Abstract: A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7, 8, 9—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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TL;DR: This evidence-based guideline recommends minimally invasive adrenalectomy for most pheochromocytomas with open resection for most paragangliomas and suggests personalized management with evaluation and treatment by multidisciplinary teams with appropriate expertise to ensure favorable outcomes.
Abstract: Objective: The aim was to formulate clinical practice guidelines for pheochromocytoma and paraganglioma (PPGL). Participants: The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), seven experts in the field, and a methodologist. The authors received no corporate funding or remuneration. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews. Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, European Society of Endocrinology, and Americal Association for Clinical Chemistry reviewed drafts of the guidelines. Conclusions: The Task Force recommends that initial biochemical testing for PPGLs shou...
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TL;DR: Evidence has accumulated pointing to socioeconomic factors such as income, wealth, and education as the fundamental causes of a wide range of health outcomes, and plausible pathways and biological mechanisms that may explain their effects are reviewed.
Abstract: During the past two decades, the public health community’s attention has been drawn increasingly to the social determinants of health (SDH)—the factors apart from medical care that can be influenced by social policies and shape health in powerful ways. We use “medical care” rather than “health care” to refer to clinical services, to avoid potential confusion between “health” and “health care.” The World Health Organization’s Commission on the Social Determinants of Health has defined SDH as “the conditions in which people are born, grow, live, work and age” and “the fundamental drivers of these conditions.” The term “social determinants” often evokes factors such as health-related features of neighborhoods (e.g., walkability, recreational areas, and accessibility of healthful foods), which can influence health-related behaviors. Evidence has accumulated, however, pointing to socioeconomic factors such as income, wealth, and education as the fundamental causes of a wide range of health outcomes. This article broadly reviews some of the knowledge accumulated to date that highlights the importance of social—and particularly socioeconomic— factors in shaping health, and plausible pathways and biological mechanisms that may explain their effects. We also discuss challenges to advancing this knowledge and how they might be overcome.
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TL;DR: Around a third of Alzheimer's diseases cases worldwide might be attributable to potentially modifiable risk factors, and Alzheimer's disease incidence might be reduced through improved access to education and use of effective methods targeted at reducing the prevalence of vascular risk factors.
Abstract: Summary Background Recent estimates suggesting that over half of Alzheimer's disease burden worldwide might be attributed to potentially modifiable risk factors do not take into account risk-factor non-independence. We aimed to provide specific estimates of preventive potential by accounting for the association between risk factors. Methods Using relative risks from existing meta-analyses, we estimated the population-attributable risk (PAR) of Alzheimer's disease worldwide and in the USA, Europe, and the UK for seven potentially modifiable risk factors that have consistent evidence of an association with the disease (diabetes, midlife hypertension, midlife obesity, physical inactivity, depression, smoking, and low educational attainment). The combined PAR associated with the risk factors was calculated using data from the Health Survey for England 2006 to estimate and adjust for the association between risk factors. The potential of risk factor reduction was assessed by examining the combined effect of relative reductions of 10% and 20% per decade for each of the seven risk factors on projections for Alzheimer's disease cases to 2050. Findings Worldwide, the highest estimated PAR was for low educational attainment (19·1%, 95% CI 12·3–25·6). The highest estimated PAR was for physical inactivity in the USA (21·0%, 95% CI 5·8–36·6), Europe (20·3%, 5·6–35·6), and the UK (21·8%, 6·1–37·7). Assuming independence, the combined worldwide PAR for the seven risk factors was 49·4% (95% CI 25·7–68·4), which equates to 16·8 million attributable cases (95% CI 8·7–23·2 million) of 33·9 million cases. However, after adjustment for the association between the risk factors, the estimate reduced to 28·2% (95% CI 14·2–41·5), which equates to 9·6 million attributable cases (95% CI 4·8–14·1 million) of 33·9 million cases. Combined PAR estimates were about 30% for the USA, Europe, and the UK. Assuming a causal relation and intervention at the correct age for prevention, relative reductions of 10% per decade in the prevalence of each of the seven risk factors could reduce the prevalence of Alzheimer's disease in 2050 by 8·3% worldwide. Interpretation After accounting for non-independence between risk factors, around a third of Alzheimer's diseases cases worldwide might be attributable to potentially modifiable risk factors. Alzheimer's disease incidence might be reduced through improved access to education and use of effective methods targeted at reducing the prevalence of vascular risk factors (eg, physical inactivity, smoking, midlife hypertension, midlife obesity, and diabetes) and depression. Funding National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care for Cambridgeshire and Peterborough.
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TL;DR: Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival, and underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.
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Duke University1, University of Texas at Austin2, Heidelberg Institute for Theoretical Studies3, Xi'an Jiaotong University4, Beijing Genomics Institute5, American Museum of Natural History6, New Mexico State University7, University of Sydney8, University of California9, Uppsala University10, University of Copenhagen11, Okinawa Institute of Science and Technology12, University of Georgia13, Griffith University14, Catalan Institution for Research and Advanced Studies15, Oak Ridge National Laboratory16, Joint Institute for Nuclear Research17, Aarhus University18, Washington University in St. Louis19, University of California, Santa Cruz20, Cardiff University21, Kunming Institute of Zoology22, China Agricultural University23, Louisiana State University24, Tulane University25, Copenhagen Zoo26, Oregon Health & Science University27, Federal University of Pará28, Technical University of Denmark29, Canterbury Museum30, Curtin University31, Novosibirsk State University32, Smithsonian Institution33, National University of Singapore34, National Museum of Natural History35, Nova Southeastern University36, Occidental College37, University of Edinburgh38, Harvard University39, University of California, San Francisco40, University of Florida41, University of Illinois at Urbana–Champaign42
TL;DR: A genome-scale phylogenetic analysis of 48 species representing all orders of Neoaves recovered a highly resolved tree that confirms previously controversial sister or close relationships and identifies the first divergence in Neoaves, two groups the authors named Passerea and Columbea.
Abstract: To better determine the history of modern birds, we performed a genome-scale phylogenetic analysis of 48 species representing all orders of Neoaves using phylogenomic methods created to handle genome-scale data. We recovered a highly resolved tree that confirms previously controversial sister or close relationships. We identified the first divergence in Neoaves, two groups we named Passerea and Columbea, representing independent lineages of diverse and convergently evolved land and water bird species. Among Passerea, we infer the common ancestor of core landbirds to have been an apex predator and confirm independent gains of vocal learning. Among Columbea, we identify pigeons and flamingoes as belonging to sister clades. Even with whole genomes, some of the earliest branches in Neoaves proved challenging to resolve, which was best explained by massive protein-coding sequence convergence and high levels of incomplete lineage sorting that occurred during a rapid radiation after the Cretaceous-Paleogene mass extinction event about 66 million years ago.
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Howard Hughes Medical Institute1, Florida State University2, University of the Sciences3, National Institutes of Health4, University of Minnesota5, University of Cambridge6, University of California, San Francisco7, University of Tennessee8, Max Planck Society9, Johns Hopkins University10, Duke University11
TL;DR: A new microscope using ultrathin light sheets derived from two-dimensional optical lattices is developed, demonstrating the performance advantages of lattice light-sheet microscopy compared with previous techniques and highlighted phenomena that, when seen at increased spatiotemporal detail, may hint at previously unknown biological mechanisms.
Abstract: Although fluorescence microscopy provides a crucial window into the physiology of living specimens, many biological processes are too fragile, are too small, or occur too rapidly to see clearly with existing tools. We crafted ultrathin light sheets from two-dimensional optical lattices that allowed us to image three-dimensional (3D) dynamics for hundreds of volumes, often at subsecond intervals, at the diffraction limit and beyond. We applied this to systems spanning four orders of magnitude in space and time, including the diffusion of single transcription factor molecules in stem cell spheroids, the dynamic instability of mitotic microtubules, the immunological synapse, neutrophil motility in a 3D matrix, and embryogenesis in Caenorhabditis elegans and Drosophila melanogaster. The results provide a visceral reminder of the beauty and the complexity of living systems.
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Institut Gustave Roussy1, University of California, Los Angeles2, Memorial Sloan Kettering Cancer Center3, Harvard University4, Westmead Hospital5, University of Sydney6, Princess Margaret Cancer Centre7, University of Texas MD Anderson Cancer Center8, University of Pennsylvania9, Mayo Clinic10, University of Pittsburgh11, Merck & Co.12, University of California, San Francisco13
TL;DR: The results suggest that pembrolizumab at a dose of 2mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options.
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07 Nov 2014TL;DR: A guide to using some of the recently added advanced μManager features, including hardware synchronization, simultaneous use of multiple cameras, projection of patterned light onto a specimen, live slide mapping, imaging with multi-well plates, particle localization and tracking, and high-speed imaging.
Abstract: μManager is an open-source, cross-platform desktop application, to control a wide variety of motorized microscopes, scientific cameras, stages, illuminators, and other microscope accessories. Since its inception in 2005, μManager has grown to support a wide range of microscopy hardware and is now used by thousands of researchers around the world. The application provides a mature graphical user interface and offers open programming interfaces to facilitate plugins and scripts. Here, we present a guide to using some of the recently added advanced μManager features, including hardware synchronization, simultaneous use of multiple cameras, projection of patterned light onto a specimen, live slide mapping, imaging with multi-well plates, particle localization and tracking, and high-speed imaging.
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TL;DR: A “state of the science” review of current research into causes and risk factors for gliomas in adults is provided.
Abstract: Gliomas are the most common primary intracranial tumor, representing 81% of malignant brain tumors Although relatively rare, they cause significant mortality and morbidity Glioblastoma, the most common glioma histology (∼45% of all gliomas), has a 5-year relative survival of ∼5% A small portion of these tumors are caused by Mendelian disorders, including neurofibromatosis, tuberous sclerosis, and Li-Fraumeni syndrome Genomic analyses of glioma have also produced new evidence about risk and prognosis Recently discovered biomarkers that indicate improved survival include O⁶-methylguanine-DNA methyltransferase methylation, isocitrate dehydrogenase mutation, and a glioma cytosine-phosphate-guanine island methylator phenotype Genome-wide association studies have identified heritable risk alleles within 7 genes that are associated with increased risk of glioma Many risk factors have been examined as potential contributors to glioma risk Most significantly, these include an increase in risk by exposure to ionizing radiation and a decrease in risk by history of allergies or atopic disease(s) The potential influence of occupational exposures and cellular phones has also been examined, with inconclusive results We provide a “state of the science” review of current research into causes and risk factors for gliomas in adults