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  • 1
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    Genomic analyses identify molecular subtypes of pancreatic cancer (2016)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2016-02-26
    Description: Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-beta, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bailey, Peter -- Chang, David K -- Nones, Katia -- Johns, Amber L -- Patch, Ann-Marie -- Gingras, Marie-Claude -- Miller, David K -- Christ, Angelika N -- Bruxner, Tim J C -- Quinn, Michael C -- Nourse, Craig -- Murtaugh, L Charles -- Harliwong, Ivon -- Idrisoglu, Senel -- Manning, Suzanne -- Nourbakhsh, Ehsan -- Wani, Shivangi -- Fink, Lynn -- Holmes, Oliver -- Chin, Venessa -- Anderson, Matthew J -- Kazakoff, Stephen -- Leonard, Conrad -- Newell, Felicity -- Waddell, Nick -- Wood, Scott -- Xu, Qinying -- Wilson, Peter J -- Cloonan, Nicole -- Kassahn, Karin S -- Taylor, Darrin -- Quek, Kelly -- Robertson, Alan -- Pantano, Lorena -- Mincarelli, Laura -- Sanchez, Luis N -- Evers, Lisa -- Wu, Jianmin -- Pinese, Mark -- Cowley, Mark J -- Jones, Marc D -- Colvin, Emily K -- Nagrial, Adnan M -- Humphrey, Emily S -- Chantrill, Lorraine A -- Mawson, Amanda -- Humphris, Jeremy -- Chou, Angela -- Pajic, Marina -- Scarlett, Christopher J -- Pinho, Andreia V -- Giry-Laterriere, Marc -- Rooman, Ilse -- Samra, Jaswinder S -- Kench, James G -- Lovell, Jessica A -- Merrett, Neil D -- Toon, Christopher W -- Epari, Krishna -- Nguyen, Nam Q -- Barbour, Andrew -- Zeps, Nikolajs -- Moran-Jones, Kim -- Jamieson, Nigel B -- Graham, Janet S -- Duthie, Fraser -- Oien, Karin -- Hair, Jane -- Grutzmann, Robert -- Maitra, Anirban -- Iacobuzio-Donahue, Christine A -- Wolfgang, Christopher L -- Morgan, Richard A -- Lawlor, Rita T -- Corbo, Vincenzo -- Bassi, Claudio -- Rusev, Borislav -- Capelli, Paola -- Salvia, Roberto -- Tortora, Giampaolo -- Mukhopadhyay, Debabrata -- Petersen, Gloria M -- Australian Pancreatic Cancer Genome Initiative -- Munzy, Donna M -- Fisher, William E -- Karim, Saadia A -- Eshleman, James R -- Hruban, Ralph H -- Pilarsky, Christian -- Morton, Jennifer P -- Sansom, Owen J -- Scarpa, Aldo -- Musgrove, Elizabeth A -- Bailey, Ulla-Maja Hagbo -- Hofmann, Oliver -- Sutherland, Robert L -- Wheeler, David A -- Gill, Anthony J -- Gibbs, Richard A -- Pearson, John V -- Waddell, Nicola -- Biankin, Andrew V -- Grimmond, Sean M -- 103721/Z/14/Z/Wellcome Trust/United Kingdom -- A12481/Cancer Research UK/United Kingdom -- A18076/Cancer Research UK/United Kingdom -- C29717/A17263/Cancer Research UK/United Kingdom -- England -- Nature. 2016 Mar 3;531(7592):47-52. doi: 10.1038/nature16965. Epub 2016 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia. ; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. ; The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia. ; Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia. ; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia. ; QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia. ; Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA. ; Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA. ; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA. ; Genetic and Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia. ; School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5000, Australia. ; Harvard Chan Bioinformatics Core, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA. ; Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales 2560, Australia. ; Department of Pathology. SydPath, St Vincent's Hospital, Sydney, NSW 2010, Australia. ; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2052, Australia. ; School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia. ; Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia. ; University of Sydney, Sydney, New South Wales 2006, Australia. ; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown New South Wales 2050, Australia. ; School of Medicine, University of Western Sydney, Penrith, New South Wales 2175, Australia. ; Fiona Stanley Hospital, Robin Warren Drive, Murdoch, Western Australia 6150, Australia. ; Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. ; Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia. ; School of Surgery M507, University of Western Australia, 35 Stirling Hwy, Nedlands 6009, Australia and St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia. ; Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK. ; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. ; Department of Medical Oncology, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK. ; Department of Pathology, Southern General Hospital, Greater Glasgow &Clyde NHS, Glasgow G51 4TF, UK. ; GGC Bio-repository, Pathology Department, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TY, UK. ; Department of Surgery, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany. ; Departments of Pathology and Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston Texas 77030, USA. ; The David M. Rubenstein Pancreatic Cancer Research Center and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. ; Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. ; ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy. ; Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy. ; Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy. ; Department of Medical Oncology, Comprehensive Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy. ; Mayo Clinic, Rochester, Minnesota 55905, USA. ; Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA. ; Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. ; Institute for Cancer Science, University of Glasgow, Glasgow G12 8QQ, UK. ; University of Melbourne, Parkville, Victoria 3010, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26909576" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Carcinoma, Pancreatic ; Ductal/classification/genetics/immunology/metabolism/pathology ; Cell Line, Tumor ; DNA Methylation ; DNA-Binding Proteins/genetics ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks ; Genes, Neoplasm/*genetics ; Genome, Human/*genetics ; *Genomics ; Hepatocyte Nuclear Factor 3-beta/genetics ; Hepatocyte Nuclear Factor 3-gamma/genetics ; Histone Demethylases/genetics ; Homeodomain Proteins/genetics ; Humans ; Mice ; Mutation/*genetics ; Nuclear Proteins/genetics ; Pancreatic Neoplasms/*classification/*genetics/immunology/metabolism/pathology ; Prognosis ; Receptors, Cytoplasmic and Nuclear/genetics ; Survival Analysis ; Trans-Activators/genetics ; Transcription Factors/genetics ; Transcription, Genetic ; Transcriptome ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Proteins/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-03-12
    Description: Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zanoni, Paolo -- Khetarpal, Sumeet A -- Larach, Daniel B -- Hancock-Cerutti, William F -- Millar, John S -- Cuchel, Marina -- DerOhannessian, Stephanie -- Kontush, Anatol -- Surendran, Praveen -- Saleheen, Danish -- Trompet, Stella -- Jukema, J Wouter -- De Craen, Anton -- Deloukas, Panos -- Sattar, Naveed -- Ford, Ian -- Packard, Chris -- Majumder, Abdullah al Shafi -- Alam, Dewan S -- Di Angelantonio, Emanuele -- Abecasis, Goncalo -- Chowdhury, Rajiv -- Erdmann, Jeanette -- Nordestgaard, Borge G -- Nielsen, Sune F -- Tybjaerg-Hansen, Anne -- Schmidt, Ruth Frikke -- Kuulasmaa, Kari -- Liu, Dajiang J -- Perola, Markus -- Blankenberg, Stefan -- Salomaa, Veikko -- Mannisto, Satu -- Amouyel, Philippe -- Arveiler, Dominique -- Ferrieres, Jean -- Muller-Nurasyid, Martina -- Ferrario, Marco -- Kee, Frank -- Willer, Cristen J -- Samani, Nilesh -- Schunkert, Heribert -- Butterworth, Adam S -- Howson, Joanna M M -- Peloso, Gina M -- Stitziel, Nathan O -- Danesh, John -- Kathiresan, Sekar -- Rader, Daniel J -- CHD Exome+ Consortium -- CARDIoGRAM Exome Consortium -- Global Lipids Genetics Consortium -- R01 DK089256/DK/NIDDK NIH HHS/ -- R01 HL117078/HL/NHLBI NIH HHS/ -- TL1 RR024133/RR/NCRR NIH HHS/ -- TL1R000138/PHS HHS/ -- TL1RR024133/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1166-71. doi: 10.1126/science.aad3517.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. ; Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. INSERM UMR 1166 ICAN, Universite Pierre et Marie Curie Paris 6, Hopital de la Pitie, Paris, France. ; INSERM UMR 1166 ICAN, Universite Pierre et Marie Curie Paris 6, Hopital de la Pitie, Paris, France. ; Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. ; Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Centre for Non-Communicable Diseases, Karachi, Pakistan. ; Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands. Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands. ; Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands. The Interuniversity Cardiology Institute of the Netherlands, Utrecht, Netherlands. ; Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands. ; Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK. ; Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK. ; Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK. ; Glasgow Clinical Research Facility, Western Infirmary, Glasgow, UK. ; National Institute of Cardiovascular Diseases, Sher-e-Bangla Nagar, Dhaka, Bangladesh. ; International Centre for Diarrhoeal Disease Research, Mohakhali, Dhaka, Bangladesh. ; Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA. ; Institute for Integrative and Experimental Genomics, University of Lubeck, Lubeck 23562, Germany. ; Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark. ; Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark. ; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospitals, Copenhagen, Denmark. ; Department of Health, National Institute for Health and Welfare, Helsinki, Finland. ; Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA. ; Department of Health, National Institute for Health and Welfare, Helsinki, Finland. Institute of Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland. ; Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany. University Medical Center Hamburg-Eppendorf, Hamburg, Germany. ; Department of Epidemiology and Public Health, Institut Pasteur de Lille, Lille, France. ; Department of Epidemiology and Public Health, University of Strasbourg, Strasbourg, France. ; Department of Epidemiology, Toulouse University-CHU Toulouse, Toulouse, France. ; Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen-German Research Center for Environmental Health, Neuherberg, Germany. Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany. ; Research Centre in Epidemiology and Preventive Medicine, Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy. ; UKCRC Centre of Excellence for Public Health, Queens University, Belfast, Northern Ireland. ; Department of Computational Medicine and Bioinformatics, Department of Human Genetics, and Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. ; Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hotel, Leicester, UK. ; Deutsches Herzzentrum Munchen, Technische Universitat Munchen, Munich, Germany. ; Broad Institute and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA. ; Department of Medicine, Division of Cardiology, Department of Genetics, and the McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, USA. ; Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK. ; Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. rader@mail.med.upenn.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26965621" target="_blank"〉PubMed〈/a〉
    Keywords: Aged ; Amino Acid Substitution ; Animals ; Cholesterol, HDL/*blood ; Coronary Disease/*blood/*genetics ; DNA Mutational Analysis ; Female ; Genetic Variation ; Heterozygote ; Homozygote ; Humans ; Leucine/genetics ; Male ; Mice ; Middle Aged ; Proline/genetics ; Protein Processing, Post-Translational ; Risk ; Scavenger Receptors, Class B/*genetics/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    The phenotypic legacy of admixture between modern humans and Neandertals (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-26
    Description: Many modern human genomes retain DNA inherited from interbreeding with archaic hominins, such as Neandertals, yet the influence of this admixture on human traits is largely unknown. We analyzed the contribution of common Neandertal variants to over 1000 electronic health record (EHR)-derived phenotypes in ~28,000 adults of European ancestry. We discovered and replicated associations of Neandertal alleles with neurological, psychiatric, immunological, and dermatological phenotypes. Neandertal alleles together explained a significant fraction of the variation in risk for depression and skin lesions resulting from sun exposure (actinic keratosis), and individual Neandertal alleles were significantly associated with specific human phenotypes, including hypercoagulation and tobacco use. Our results establish that archaic admixture influences disease risk in modern humans, provide hypotheses about the effects of hundreds of Neandertal haplotypes, and demonstrate the utility of EHR data in evolutionary analyses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Simonti, Corinne N -- Vernot, Benjamin -- Bastarache, Lisa -- Bottinger, Erwin -- Carrell, David S -- Chisholm, Rex L -- Crosslin, David R -- Hebbring, Scott J -- Jarvik, Gail P -- Kullo, Iftikhar J -- Li, Rongling -- Pathak, Jyotishman -- Ritchie, Marylyn D -- Roden, Dan M -- Verma, Shefali S -- Tromp, Gerard -- Prato, Jeffrey D -- Bush, William S -- Akey, Joshua M -- Denny, Joshua C -- Capra, John A -- 1K22LM011938/LM/NLM NIH HHS/ -- 1R01GM114128/GM/NIGMS NIH HHS/ -- 5T32EY021453/EY/NEI NIH HHS/ -- R01GM110068/GM/NIGMS NIH HHS/ -- R01LM010685/LM/NLM NIH HHS/ -- U01HG004438/HG/NHGRI NIH HHS/ -- U01HG004608/HG/NHGRI NIH HHS/ -- U01HG004609/HG/NHGRI NIH HHS/ -- U01HG004610/HG/NHGRI NIH HHS/ -- U01HG006378/HG/NHGRI NIH HHS/ -- U01HG006379/HG/NHGRI NIH HHS/ -- U01HG006380/HG/NHGRI NIH HHS/ -- U01HG006382/HG/NHGRI NIH HHS/ -- U01HG006385/HG/NHGRI NIH HHS/ -- U01HG006388/HG/NHGRI NIH HHS/ -- U01HG006389/HG/NHGRI NIH HHS/ -- U01HG008657/HG/NHGRI NIH HHS/ -- U01HG04599/HG/NHGRI NIH HHS/ -- U01HG04603/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2016 Feb 12;351(6274):737-41. doi: 10.1126/science.aad2149.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA. ; Department of Genome Sciences, University of Washington, Seattle, WA, USA. ; Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA. ; Mount Sinai School of Medicine, New York, NY, USA. ; Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, WA, USA. ; Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. ; Department of Genome Sciences, University of Washington, Seattle, WA, USA. Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, WA, USA. ; Center for Human Genetics, Marshfield Clinic, Marshfield, WI, USA. ; Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA. ; Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. ; Division of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. ; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA. Biomedical and Translational Informatics, Geisinger Health System, Danville, PA, USA. ; Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA. Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA. Department of Medicine, Vanderbilt University, Nashville, TN, USA. Department of Pharmacology, Vanderbilt University, Nashville, TN, USA. ; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA. ; Weis Center for Research, Geisinger Health System, Danville, PA, USA. Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Health Science, Stellenbosch University, Tygerberg, South Africa. ; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA. ; Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA. Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA. Department of Medicine, Vanderbilt University, Nashville, TN, USA. ; Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA. Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA. Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA. Center for Quantitative Sciences, Vanderbilt University, Nashville, TN, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912863" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Depression/genetics ; Disease/*genetics ; European Continental Ancestry Group/genetics ; Evolution, Molecular ; Genetic Variation ; Genome, Human ; Haplotypes ; Humans ; Keratosis, Actinic/genetics ; Neanderthals/*genetics ; Phenotype
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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    The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-04-02
    Description: Host responses against metazoan parasites or an array of environmental substances elicit type 2 immunity. Despite its protective function, type 2 immunity also drives allergic diseases. The mechanisms that regulate the magnitude of the type 2 response remain largely unknown. Here, we show that genetic ablation of a receptor tyrosine kinase encoded byTyro3in mice or the functional neutralization of its ortholog in human dendritic cells resulted in enhanced type 2 immunity. Furthermore, the TYRO3 agonist PROS1 was induced in T cells by the quintessential type 2 cytokine, interleukin-4. T cell-specificPros1knockouts phenocopied the loss ofTyro3 Thus, a PROS1-mediated feedback from adaptive immunity engages a rheostat, TYRO3, on innate immune cells to limit the intensity of type 2 responses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chan, Pamela Y -- Carrera Silva, Eugenio A -- De Kouchkovsky, Dimitri -- Joannas, Leonel D -- Hao, Liming -- Hu, Donglei -- Huntsman, Scott -- Eng, Celeste -- Licona-Limon, Paula -- Weinstein, Jason S -- Herbert, De'Broski R -- Craft, Joseph E -- Flavell, Richard A -- Repetto, Silvia -- Correale, Jorge -- Burchard, Esteban G -- Torgerson, Dara G -- Ghosh, Sourav -- Rothlin, Carla V -- HL004464/HL/NHLBI NIH HHS/ -- HL078885/HL/NHLBI NIH HHS/ -- HL088133/HL/NHLBI NIH HHS/ -- HL104608/HL/NHLBI NIH HHS/ -- HL117004/HL/NHLBI NIH HHS/ -- MD006902/MD/NIMHD NIH HHS/ -- R01 AI089824/AI/NIAID NIH HHS/ -- T32 AI007019/AI/NIAID NIH HHS/ -- T32 GM007205/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Apr 1;352(6281):99-103. doi: 10.1126/science.aaf1358.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA. ; Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA. Laboratorio de Trombosis Experimental, Instituto de Medicina Experimental, Academia Nacional de Medicina-CONICET, Buenos Aires, 1425, Argentina. ; Department of Pathology, School of Medicine, Yale University, New Haven, CT 06520, USA. ; Department of Medicine, University of California San Francisco, CA 94158, USA. ; Department of Experimental Medicine, University of California San Francisco, CA 94158, USA. ; Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA. Department of Internal Medicine (Rheumatology), School of Medicine, Yale University, New Haven, CT 06520, USA. ; Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA. Howard Hughes Medical Institute, School of Medicine, Yale University, New Haven, CT 06520, USA. ; Instituto de Investigaciones en Microbiologia y Parasitologia Medica, University of Buenos Aires-CONICET, Buenos Aires, 1121, Argentina. Hospital de Clinicas Jose de San Martin, University of Buenos Aires, 1120, Argentina. ; Center for Research on Neuroimmunological Diseases, Raul Carrea Institute for Neurological Research (FLENI), Buenos Aires 1428, Argentina. ; Department of Medicine, University of California San Francisco, CA 94158, USA. Department of Bioengineering, School of Pharmacy, University of California San Francisco, CA 94158, USA. ; Department of Neurology, School of Medicine, Yale University, New Haven, CT 06520, USA. ; Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA. carla.rothlin@yale.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27034374" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptive Immunity/*genetics ; Animals ; Asthma/genetics/*immunology ; Blood Proteins/antagonists & inhibitors/genetics/metabolism ; Dendritic Cells/immunology ; Disease Models, Animal ; Gene Knockout Techniques ; Host-Parasite Interactions/genetics/*immunology ; Humans ; Immunity, Innate/*genetics ; Interleukin-4/immunology/pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nippostrongylus/immunology ; Pyroglyphidae/immunology ; Receptor Protein-Tyrosine Kinases/genetics/*physiology ; Strongylida Infections/immunology ; T-Lymphocytes/immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
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    Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys (2016)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2016-03-05
    Description: The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg(-1) GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Warren, Travis K -- Jordan, Robert -- Lo, Michael K -- Ray, Adrian S -- Mackman, Richard L -- Soloveva, Veronica -- Siegel, Dustin -- Perron, Michel -- Bannister, Roy -- Hui, Hon C -- Larson, Nate -- Strickley, Robert -- Wells, Jay -- Stuthman, Kelly S -- Van Tongeren, Sean A -- Garza, Nicole L -- Donnelly, Ginger -- Shurtleff, Amy C -- Retterer, Cary J -- Gharaibeh, Dima -- Zamani, Rouzbeh -- Kenny, Tara -- Eaton, Brett P -- Grimes, Elizabeth -- Welch, Lisa S -- Gomba, Laura -- Wilhelmsen, Catherine L -- Nichols, Donald K -- Nuss, Jonathan E -- Nagle, Elyse R -- Kugelman, Jeffrey R -- Palacios, Gustavo -- Doerffler, Edward -- Neville, Sean -- Carra, Ernest -- Clarke, Michael O -- Zhang, Lijun -- Lew, Willard -- Ross, Bruce -- Wang, Queenie -- Chun, Kwon -- Wolfe, Lydia -- Babusis, Darius -- Park, Yeojin -- Stray, Kirsten M -- Trancheva, Iva -- Feng, Joy Y -- Barauskas, Ona -- Xu, Yili -- Wong, Pamela -- Braun, Molly R -- Flint, Mike -- McMullan, Laura K -- Chen, Shan-Shan -- Fearns, Rachel -- Swaminathan, Swami -- Mayers, Douglas L -- Spiropoulou, Christina F -- Lee, William A -- Nichol, Stuart T -- Cihlar, Tomas -- Bavari, Sina -- R01 AI113321/AI/NIAID NIH HHS/ -- R01AI113321/AI/NIAID NIH HHS/ -- England -- Nature. 2016 Mar 17;531(7594):381-5. doi: 10.1038/nature17180. Epub 2016 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA. ; United States Army Medical Research Institute of Infectious Diseases, Therapeutic Development Center, Frederick, Maryland 21702, USA. ; Gilead Sciences, Foster City, California 94404, USA. ; Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA. ; Boston University School of Medicine, Boston, Massachusetts 02118, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26934220" target="_blank"〉PubMed〈/a〉
    Keywords: Alanine/*analogs & derivatives/pharmacokinetics/pharmacology/therapeutic use ; Amino Acid Sequence ; Animals ; Antiviral Agents/pharmacokinetics/pharmacology/*therapeutic use ; Cell Line, Tumor ; Ebolavirus/drug effects ; Female ; HeLa Cells ; Hemorrhagic Fever, Ebola/*drug therapy/prevention & control ; Humans ; Macaca mulatta/*virology ; Male ; Molecular Sequence Data ; Organ Specificity ; Prodrugs/pharmacokinetics/pharmacology/therapeutic use ; Ribonucleotides/pharmacokinetics/pharmacology/*therapeutic use
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    Real-time, portable genome sequencing for Ebola surveillance (2016)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2016-02-04
    Description: The Ebola virus disease epidemic in West Africa is the largest on record, responsible for over 28,599 cases and more than 11,299 deaths. Genome sequencing in viral outbreaks is desirable to characterize the infectious agent and determine its evolutionary rate. Genome sequencing also allows the identification of signatures of host adaptation, identification and monitoring of diagnostic targets, and characterization of responses to vaccines and treatments. The Ebola virus (EBOV) genome substitution rate in the Makona strain has been estimated at between 0.87 x 10(-3) and 1.42 x 10(-3) mutations per site per year. This is equivalent to 16-27 mutations in each genome, meaning that sequences diverge rapidly enough to identify distinct sub-lineages during a prolonged epidemic. Genome sequencing provides a high-resolution view of pathogen evolution and is increasingly sought after for outbreak surveillance. Sequence data may be used to guide control measures, but only if the results are generated quickly enough to inform interventions. Genomic surveillance during the epidemic has been sporadic owing to a lack of local sequencing capacity coupled with practical difficulties transporting samples to remote sequencing facilities. To address this problem, here we devise a genomic surveillance system that utilizes a novel nanopore DNA sequencing instrument. In April 2015 this system was transported in standard airline luggage to Guinea and used for real-time genomic surveillance of the ongoing epidemic. We present sequence data and analysis of 142 EBOV samples collected during the period March to October 2015. We were able to generate results less than 24 h after receiving an Ebola-positive sample, with the sequencing process taking as little as 15-60 min. We show that real-time genomic surveillance is possible in resource-limited settings and can be established rapidly to monitor outbreaks.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Quick, Joshua -- Loman, Nicholas J -- Duraffour, Sophie -- Simpson, Jared T -- Severi, Ettore -- Cowley, Lauren -- Bore, Joseph Akoi -- Koundouno, Raymond -- Dudas, Gytis -- Mikhail, Amy -- Ouedraogo, Nobila -- Afrough, Babak -- Bah, Amadou -- Baum, Jonathan H J -- Becker-Ziaja, Beate -- Boettcher, Jan Peter -- Cabeza-Cabrerizo, Mar -- Camino-Sanchez, Alvaro -- Carter, Lisa L -- Doerrbecker, Juliane -- Enkirch, Theresa -- Garcia-Dorival, Isabel -- Hetzelt, Nicole -- Hinzmann, Julia -- Holm, Tobias -- Kafetzopoulou, Liana Eleni -- Koropogui, Michel -- Kosgey, Abigael -- Kuisma, Eeva -- Logue, Christopher H -- Mazzarelli, Antonio -- Meisel, Sarah -- Mertens, Marc -- Michel, Janine -- Ngabo, Didier -- Nitzsche, Katja -- Pallasch, Elisa -- Patrono, Livia Victoria -- Portmann, Jasmine -- Repits, Johanna Gabriella -- Rickett, Natasha Y -- Sachse, Andreas -- Singethan, Katrin -- Vitoriano, Ines -- Yemanaberhan, Rahel L -- Zekeng, Elsa G -- Racine, Trina -- Bello, Alexander -- Sall, Amadou Alpha -- Faye, Ousmane -- Faye, Oumar -- Magassouba, N'Faly -- Williams, Cecelia V -- Amburgey, Victoria -- Winona, Linda -- Davis, Emily -- Gerlach, Jon -- Washington, Frank -- Monteil, Vanessa -- Jourdain, Marine -- Bererd, Marion -- Camara, Alimou -- Somlare, Hermann -- Camara, Abdoulaye -- Gerard, Marianne -- Bado, Guillaume -- Baillet, Bernard -- Delaune, Deborah -- Nebie, Koumpingnin Yacouba -- Diarra, Abdoulaye -- Savane, Yacouba -- Pallawo, Raymond Bernard -- Gutierrez, Giovanna Jaramillo -- Milhano, Natacha -- Roger, Isabelle -- Williams, Christopher J -- Yattara, Facinet -- Lewandowski, Kuiama -- Taylor, James -- Rachwal, Phillip -- Turner, Daniel J -- Pollakis, Georgios -- Hiscox, Julian A -- Matthews, David A -- O'Shea, Matthew K -- Johnston, Andrew McD -- Wilson, Duncan -- Hutley, Emma -- Smit, Erasmus -- Di Caro, Antonino -- Wolfel, Roman -- Stoecker, Kilian -- Fleischmann, Erna -- Gabriel, Martin -- Weller, Simon A -- Koivogui, Lamine -- Diallo, Boubacar -- Keita, Sakoba -- Rambaut, Andrew -- Formenty, Pierre -- Gunther, Stephan -- Carroll, Miles W -- Medical Research Council/United Kingdom -- England -- Nature. 2016 Feb 11;530(7589):228-32. doi: 10.1038/nature16996. Epub 2016 Feb 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Microbiology and Infection, University of Birmingham, Birmingham B15 2TT, UK. ; The European Mobile Laboratory Consortium, Bernhard-Nocht-Institute for Tropical Medicine, D-20359 Hamburg, Germany. ; Bernhard-Nocht-Institute for Tropical Medicine, D-20359 Hamburg, Germany. ; Ontario Institute for Cancer Research, Toronto M5G 0A3, Canada. ; Department of Computer Science, University of Toronto, Toronto M5S 3G4, Canada. ; European Centre for Disease Prevention and Control (ECDC), 171 65 Solna, Sweden. ; National Infection Service, Public Health England, London NW9 5EQ, UK. ; Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 2FL, UK. ; Postgraduate Training for Applied Epidemiology (PAE, German FETP), Robert Koch Institute, D-13302 Berlin, Germany. ; National Infection Service, Public Health England, Porton Down, Wiltshire SP4 0JG, UK. ; Swiss Tropical and Public Health Institute, 4002 Basel, Switzerland. ; Robert Koch Institute, D-13302 Berlin, Germany. ; University College London, London WC1E 6BT, UK. ; Paul-Ehrlich-Institut, Division of Veterinary Medicine, D-63225 Langen, Germany. ; Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, UK. ; Laboratory for Clinical and Epidemiological Virology, Department of Microbiology and Immunology, KU Leuven, Leuven B-3000, Belgium. ; Ministry of Health Guinea, Conakry BP 585, Guinea. ; Kenya Medical Research Institute, Nairobi P.O. BOX 54840 - 00200, Kenya. ; National Institute for Infectious Diseases L. Spallanzani, 00149 Rome, Italy. ; Friedrich-Loeffler-Institute, D-17493 Greifswald, Germany. ; Federal Office for Civil Protection, Spiez Laboratory, 3700 Spiez, Switzerland. ; Janssen-Cilag, Stockholm, Box 7073 - 19207, Sweden. ; NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool L69 7BE, UK. ; Institute of Virology, Technische Universitat Munchen, D-81675 Munich, Germany. ; Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada. ; Institut Pasteur Dakar, Dakar, DP 220 Senegal. ; Laboratoire de Fievres Hemorragiques de Guinee, Conakry BP 5680, Guinea. ; Sandia National Laboratories, PO Box 5800 MS1363, Albuquerque, New Mexico 87185-1363, USA. ; Ratoma Ebola Diagnostic Center, Conakry, Guinea. ; MRIGlobal, Kansas City, Missouri 64110-2241, USA. ; Expertise France, Laboratoire K-plan de Forecariah en Guinee, 75006 Paris, France. ; Federation des Laboratoires - HIA Begin, 94163 Saint-Mande cedex, France. ; Laboratoire de Biologie - Centre de Traitement des Soignants, Conakry, Guinea. ; World Health Organization, Conakry BP 817, Guinea. ; London School of Hygiene and Tropical Medicine, London EC1E 7HT, UK. ; Norwegian Institute of Public Health, PO Box 4404 Nydalen, 0403 Oslo, Norway. ; Public Health Wales, Cardiff CF11 9LJ, UK. ; Defence Science and Technology Laboratory (Dstl) Porton Down, Salisbury SP4 0JQ, UK. ; Oxford Nanopore Technologies, Oxford OX4 4GA, UK. ; Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK. ; Academic Department of Military Medicine, Royal Centre for Defence Medicine, Birmingham B15 2TH, UK. ; Centre of Defence Pathology, Royal Centre for Defence Medicine, Birmingham B15 2TH, UK. ; Queen Elizabeth Hospital, Birmingham B12 2TH, UK. ; Bundeswehr Institute of Microbiology, D-80937 Munich, Germany. ; Institut National de Sante Publique, Conakry BP 1147, Guinea. ; Fogarty International Center, National Institutes of Health, Bethesda, MD 20892-2220, USA. ; Centre for Immunology, Infection and Evolution, University of Edinburgh, Edinburgh EH9 2FL, UK. ; University of Southampton, South General Hospital, Southampton SO16 6YD, UK. ; NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, PHE Porton Down, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26840485" target="_blank"〉PubMed〈/a〉
    Keywords: Aircraft ; Disease Outbreaks/statistics & numerical data ; Ebolavirus/classification/*genetics/pathogenicity ; *Epidemiological Monitoring ; Genome, Viral/*genetics ; Guinea/epidemiology ; Hemorrhagic Fever, Ebola/*epidemiology/*virology ; Humans ; Mutagenesis/genetics ; Mutation Rate ; Sequence Analysis, DNA/*instrumentation/*methods ; Time Factors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
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    Basic science: Bedrock of progress (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-03-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Collins, Francis S -- Anderson, James M -- Austin, Christopher P -- Battey, James F -- Birnbaum, Linda S -- Briggs, Josephine P -- Clayton, Janine A -- Cuthbert, Bruce -- Eisinger, Robert W -- Fauci, Anthony S -- Gallin, John I -- Gibbons, Gary H -- Glass, Roger I -- Gottesman, Michael M -- Gray, Patricia A -- Green, Eric D -- Greider, Franziska B -- Hodes, Richard -- Hudson, Kathy L -- Humphreys, Betsy -- Katz, Stephen I -- Koob, George F -- Koroshetz, Walter J -- Lauer, Michael S -- Lorsch, Jon R -- Lowy, Douglas R -- McGowan, John J -- Murray, David M -- Nakamura, Richard -- Norris, Andrea -- Perez-Stable, Eliseo J -- Pettigrew, Roderic I -- Riley, William T -- Rodgers, Griffin P -- Sieving, Paul A -- Somerman, Martha J -- Spong, Catherine Y -- Tabak, Lawrence A -- Volkow, Nora D -- Wilder, Elizabeth L -- New York, N.Y. -- Science. 2016 Mar 25;351(6280):1405. doi: 10.1126/science.351.6280.1405-a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Office of the Director, NIH, Bethesda, MD 20892, USA. collinsf@mail.nih.gov. ; Division of Program Coordination, Planning, and Strategic Initiatives, NIH, Bethesda, MD 20892, USA. ; National Center for Advancing Translational Science, NIH, Rockville, MD 20850, USA. ; National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA. ; National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA. ; National Center for Complementary and Integrative Health, NIH, Bethesda, MD 20892, USA. ; Office of Research on Women's Health, NIH, Bethesda, MD 20892, USA. ; National Institute of Mental Health, NIH, Bethesda, MD 20892, USA. ; Office of AIDS Research, NIH, Bethesda, MD 20892, USA. ; National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. ; Clinical Center, NIH, Bethesda, MD 20892, USA. ; National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA. ; Fogarty International Center, NIH, Bethesda, MD 20892, USA. ; Office of Intramural Research, NIH, Bethesda, MD 20892, USA. ; National Institute of Nursing Research, NIH, Bethesda, MD 20892, USA. ; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. ; Office of Research Infrastructure Programs, NIH, Bethesda, MD 20892, USA. ; National Institute on Aging, NIH, Bethesda, MD 20892, USA. ; Office of the Director, NIH, Bethesda, MD 20892, USA. ; National Library of Medicine, NIH, Bethesda, MD 20892, USA. ; National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA. ; National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA. ; NINDS, NIH, Bethesda, MD 20892, USA. ; Office of Extramural Research, NIH, Bethesda, MD 20892, USA. ; National Institute of General Medical Sciences, NIH, Bethesda, MD 20892, USA. ; National Cancer Institute, NIH, Bethesda, MD 20892, USA. ; Office of Management, NIH, Bethesda, MD 20892, USA. ; Office of Disease Prevention, NIH, Bethesda, MD 20892, USA. ; Center for Scientific Review, NIH, Bethesda, MD 20892, USA. ; Center for Information Technology, NIH, Bethesda, MD 20892, USA. ; National Institute on Minority Health and Health Disparities, NIH, Bethesda, MD 20892, USA. ; National Institute of Biomedical Imaging and Bioengineering, NIH, Bethesda, MD 20892, USA. ; Office of Behavioral and Social Sciences Research, NIH, Bethesda, MD 20892, USA. ; National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA. ; National Eye Institute, NIH, Bethesda, MD 20892, USA. ; National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 20892, USA. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA. ; National Institute on Drug Abuse, NIH, Bethesda, MD 20892, USA. ; Office of Strategic Coordination, NIH, Bethesda, MD 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27013720" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biomedical Research/*economics ; Humans ; National Institutes of Health (U.S.)/*economics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
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    Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-03-05
    Description: As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8(+)tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non-small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy-induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McGranahan, Nicholas -- Furness, Andrew J S -- Rosenthal, Rachel -- Ramskov, Sofie -- Lyngaa, Rikke -- Saini, Sunil Kumar -- Jamal-Hanjani, Mariam -- Wilson, Gareth A -- Birkbak, Nicolai J -- Hiley, Crispin T -- Watkins, Thomas B K -- Shafi, Seema -- Murugaesu, Nirupa -- Mitter, Richard -- Akarca, Ayse U -- Linares, Joseph -- Marafioti, Teresa -- Henry, Jake Y -- Van Allen, Eliezer M -- Miao, Diana -- Schilling, Bastian -- Schadendorf, Dirk -- Garraway, Levi A -- Makarov, Vladimir -- Rizvi, Naiyer A -- Snyder, Alexandra -- Hellmann, Matthew D -- Merghoub, Taha -- Wolchok, Jedd D -- Shukla, Sachet A -- Wu, Catherine J -- Peggs, Karl S -- Chan, Timothy A -- Hadrup, Sine R -- Quezada, Sergio A -- Swanton, Charles -- 12100/Cancer Research UK/United Kingdom -- 1R01CA155010-02/CA/NCI NIH HHS/ -- 1R01CA182461-01/CA/NCI NIH HHS/ -- 1R01CA184922-01/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- New York, N.Y. -- Science. 2016 Mar 25;351(6280):1463-9. doi: 10.1126/science.aaf1490. Epub 2016 Mar 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Francis Crick Institute, London WC2A 3LY, UK. Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London (UCL), London WC1E 6BT, UK. Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. ; Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. Cancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UK. ; Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. ; Section for Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, 1970 Frederiksberg C, Denmark. ; The Francis Crick Institute, London WC2A 3LY, UK. Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. ; The Francis Crick Institute, London WC2A 3LY, UK. ; Cancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UK. Department of Cellular Pathology, UCL, London WC1E 6BT, UK. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany. German Cancer Consortium (DKTK), 69121 Heidelberg, Germany. ; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Hematology/Oncology Division, 177 Fort Washington Avenue, Columbia University, New York, NY 10032, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Department of Internal Medicine, Brigham and Woman's Hospital, Boston, MA 02115, USA. ; Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. Cancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UK. s.quezada@ucl.ac.uk charles.swanton@crick.ac.uk. ; The Francis Crick Institute, London WC2A 3LY, UK. Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. s.quezada@ucl.ac.uk charles.swanton@crick.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26940869" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/drug therapy/genetics/*immunology ; Aged ; Aged, 80 and over ; Antigens, Neoplasm/genetics/*immunology ; Antineoplastic Agents/therapeutic use ; CD4-Positive T-Lymphocytes/*immunology ; CTLA-4 Antigen/immunology ; Carcinoma, Non-Small-Cell Lung/genetics/immunology ; Cell Cycle Checkpoints/immunology ; Female ; Humans ; *Immunologic Surveillance ; Lung Neoplasms/drug therapy/genetics/*immunology ; Lymphocytes, Tumor-Infiltrating/immunology ; Male ; Melanoma/immunology ; Middle Aged ; Mutation ; Programmed Cell Death 1 Receptor/immunology ; Skin Neoplasms/immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
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    Zika virus in the Americas: Early epidemiological and genetic findings (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-03-26
    Description: Brazil has experienced an unprecedented epidemic of Zika virus (ZIKV), with ~30,000 cases reported to date. ZIKV was first detected in Brazil in May 2015, and cases of microcephaly potentially associated with ZIKV infection were identified in November 2015. We performed next-generation sequencing to generate seven Brazilian ZIKV genomes sampled from four self-limited cases, one blood donor, one fatal adult case, and one newborn with microcephaly and congenital malformations. Results of phylogenetic and molecular clock analyses show a single introduction of ZIKV into the Americas, which we estimated to have occurred between May and December 2013, more than 12 months before the detection of ZIKV in Brazil. The estimated date of origin coincides with an increase in air passengers to Brazil from ZIKV-endemic areas, as well as with reported outbreaks in the Pacific Islands. ZIKV genomes from Brazil are phylogenetically interspersed with those from other South American and Caribbean countries. Mapping mutations onto existing structural models revealed the context of viral amino acid changes present in the outbreak lineage; however, no shared amino acid changes were found among the three currently available virus genomes from microcephaly cases. Municipality-level incidence data indicate that reports of suspected microcephaly in Brazil best correlate with ZIKV incidence around week 17 of pregnancy, although this correlation does not demonstrate causation. Our genetic description and analysis of ZIKV isolates in Brazil provide a baseline for future studies of the evolution and molecular epidemiology of this emerging virus in the Americas.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Faria, Nuno Rodrigues -- Azevedo, Raimunda do Socorro da Silva -- Kraemer, Moritz U G -- Souza, Renato -- Cunha, Mariana Sequetin -- Hill, Sarah C -- Theze, Julien -- Bonsall, Michael B -- Bowden, Thomas A -- Rissanen, Ilona -- Rocco, Iray Maria -- Nogueira, Juliana Silva -- Maeda, Adriana Yurika -- Vasami, Fernanda Giseli da Silva -- Macedo, Fernando Luiz de Lima -- Suzuki, Akemi -- Rodrigues, Sueli Guerreiro -- Cruz, Ana Cecilia Ribeiro -- Nunes, Bruno Tardeli -- Medeiros, Daniele Barbosa de Almeida -- Rodrigues, Daniela Sueli Guerreiro -- Nunes Queiroz, Alice Louize -- da Silva, Eliana Vieira Pinto -- Henriques, Daniele Freitas -- Travassos da Rosa, Elisabeth Salbe -- de Oliveira, Consuelo Silva -- Martins, Livia Caricio -- Vasconcelos, Helena Baldez -- Casseb, Livia Medeiros Neves -- Simith, Darlene de Brito -- Messina, Jane P -- Abade, Leandro -- Lourenco, Jose -- Carlos Junior Alcantara, Luiz -- de Lima, Maricelia Maia -- Giovanetti, Marta -- Hay, Simon I -- de Oliveira, Rodrigo Santos -- Lemos, Poliana da Silva -- de Oliveira, Layanna Freitas -- de Lima, Clayton Pereira Silva -- da Silva, Sandro Patroca -- de Vasconcelos, Janaina Mota -- Franco, Luciano -- Cardoso, Jedson Ferreira -- Vianez-Junior, Joao Lidio da Silva Goncalves -- Mir, Daiana -- Bello, Gonzalo -- Delatorre, Edson -- Khan, Kamran -- Creatore, Marisa -- Coelho, Giovanini Evelim -- de Oliveira, Wanderson Kleber -- Tesh, Robert -- Pybus, Oliver G -- Nunes, Marcio R T -- Vasconcelos, Pedro F C -- 090532/Z/09/Z/Wellcome Trust/United Kingdom -- 095066/Wellcome Trust/United Kingdom -- 102427/Wellcome Trust/United Kingdom -- MR/L009528/1/Medical Research Council/United Kingdom -- R24 AT 120942/AT/NCCIH NIH HHS/ -- New York, N.Y. -- Science. 2016 Apr 15;352(6283):345-9. doi: 10.1126/science.aaf5036. Epub 2016 Mar 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Technological Innovation, Evandro Chagas Institute, Ministry of Health, Ananindeua, PA 67030-000, Brazil. Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK. ; Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Para State, Brazil. ; Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK. ; Instituto Adolfo Lutz, University of Sao Paulo, Sao Paulo, Brazil. ; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. ; Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK. Metabiota, San Francisco, CA 94104, USA. ; Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia, Brazil. ; Centre of Post Graduation in Collective Health, Department of Health, Universidade Estadual de Feira de Santana, Feira de Santana, Bahia, Brazil. ; Institute for Health Metrics and Evaluation, University of Washington, Seattle, WA 98121, USA. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. ; Center for Technological Innovation, Evandro Chagas Institute, Ministry of Health, Ananindeua, PA 67030-000, Brazil. ; Laboratorio de AIDS and Imunologia Molecular, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil. ; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada. Department of Medicine, Division of Infectious Diseases, University of Toronto, Toronto, Ontario, Canada. ; Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. ; Brazilian Ministry of Health, Brasilia, Brazil. ; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA. ; Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK. Metabiota, San Francisco, CA 94104, USA. oliver.pybus@zoo.ox.ac.uk marcionunesbrasil@yahoo.com.br pedrovasconcelos@iec.pa.gov.br. ; Center for Technological Innovation, Evandro Chagas Institute, Ministry of Health, Ananindeua, PA 67030-000, Brazil. Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA. oliver.pybus@zoo.ox.ac.uk marcionunesbrasil@yahoo.com.br pedrovasconcelos@iec.pa.gov.br. ; Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Para State, Brazil. oliver.pybus@zoo.ox.ac.uk marcionunesbrasil@yahoo.com.br pedrovasconcelos@iec.pa.gov.br.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27013429" target="_blank"〉PubMed〈/a〉
    Keywords: Aedes/virology ; Americas/epidemiology ; Animals ; *Disease Outbreaks ; Female ; Genome, Viral/genetics ; Humans ; Incidence ; Insect Vectors/virology ; Microcephaly/*epidemiology/virology ; Molecular Epidemiology ; Molecular Sequence Data ; Mutation ; Pacific Islands/epidemiology ; Phylogeny ; Pregnancy ; RNA, Viral/genetics ; Sequence Analysis, RNA ; Travel ; Zika Virus/classification/*genetics/isolation & purification ; Zika Virus Infection/*epidemiology/transmission/*virology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 10
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    High-fat diet enhances stemness and tumorigenicity of intestinal progenitors (2016)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2016-03-05
    Description: Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we show that high-fat diet (HFD)-induced obesity augments the numbers and function of Lgr5(+) intestinal stem cells of the mammalian intestine. Mechanistically, a HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-delta) signature in intestinal stem cells and progenitor cells (non-intestinal stem cells), and pharmacological activation of PPAR-delta recapitulates the effects of a HFD on these cells. Like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhances the self-renewal potential of these organoid bodies in a PPAR-delta-dependent manner. Notably, HFD- and agonist-activated PPAR-delta signalling endow organoid-initiating capacity to progenitors, and enforced PPAR-delta signalling permits these progenitors to form in vivo tumours after loss of the tumour suppressor Apc. These findings highlight how diet-modulated PPAR-delta activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumours.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846772/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846772/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Beyaz, Semir -- Mana, Miyeko D -- Roper, Jatin -- Kedrin, Dmitriy -- Saadatpour, Assieh -- Hong, Sue-Jean -- Bauer-Rowe, Khristian E -- Xifaras, Michael E -- Akkad, Adam -- Arias, Erika -- Pinello, Luca -- Katz, Yarden -- Shinagare, Shweta -- Abu-Remaileh, Monther -- Mihaylova, Maria M -- Lamming, Dudley W -- Dogum, Rizkullah -- Guo, Guoji -- Bell, George W -- Selig, Martin -- Nielsen, G Petur -- Gupta, Nitin -- Ferrone, Cristina R -- Deshpande, Vikram -- Yuan, Guo-Cheng -- Orkin, Stuart H -- Sabatini, David M -- Yilmaz, Omer H -- AI47389/AI/NIAID NIH HHS/ -- DK043351/DK/NIDDK NIH HHS/ -- K08 CA198002/CA/NCI NIH HHS/ -- K99 AG041765/AG/NIA NIH HHS/ -- K99 AG045144/AG/NIA NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R00 AG041765/AG/NIA NIH HHS/ -- R00 AG045144/AG/NIA NIH HHS/ -- R01 AI047389/AI/NIAID NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R37 AI047389/AI/NIAID NIH HHS/ -- T32DK007191/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 3;531(7592):53-8. doi: 10.1038/nature17173.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA. ; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Division of Gastroenterology and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111, USA. ; Departments of Pathology, Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA. ; Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, Massachusetts 02142, USA. ; Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA. ; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA. ; Division of Digestive Diseases, University of Mississippi Medical Center, Jackson, Missisippi 39216, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26935695" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Count ; Cell Self Renewal/drug effects ; Cell Transformation, Neoplastic/*drug effects ; Colonic Neoplasms/*pathology ; Diet, High-Fat/*adverse effects ; Female ; Genes, APC ; Humans ; Intestines/*pathology ; Male ; Mice ; Obesity/chemically induced/pathology ; Organoids/drug effects/metabolism/pathology ; PPAR delta/metabolism ; Signal Transduction/drug effects ; Stem Cell Niche/drug effects ; Stem Cells/*drug effects/metabolism/*pathology ; beta Catenin/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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