ALBERT

Description: Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Patch, Ann-Marie -- Christie, Elizabeth L -- Etemadmoghadam, Dariush -- Garsed, Dale W -- George, Joshy -- Fereday, Sian -- Nones, Katia -- Cowin, Prue -- Alsop, Kathryn -- Bailey, Peter J -- Kassahn, Karin S -- Newell, Felicity -- Quinn, Michael C J -- Kazakoff, Stephen -- Quek, Kelly -- Wilhelm-Benartzi, Charlotte -- Curry, Ed -- Leong, Huei San -- Australian Ovarian Cancer Study Group -- Hamilton, Anne -- Mileshkin, Linda -- Au-Yeung, George -- Kennedy, Catherine -- Hung, Jillian -- Chiew, Yoke-Eng -- Harnett, Paul -- Friedlander, Michael -- Quinn, Michael -- Pyman, Jan -- Cordner, Stephen -- O'Brien, Patricia -- Leditschke, Jodie -- Young, Greg -- Strachan, Kate -- Waring, Paul -- Azar, Walid -- Mitchell, Chris -- Traficante, Nadia -- Hendley, Joy -- Thorne, Heather -- Shackleton, Mark -- Miller, David K -- Arnau, Gisela Mir -- Tothill, Richard W -- Holloway, Timothy P -- Semple, Timothy -- Harliwong, Ivon -- Nourse, Craig -- Nourbakhsh, Ehsan -- Manning, Suzanne -- Idrisoglu, Senel -- Bruxner, Timothy J C -- Christ, Angelika N -- Poudel, Barsha -- Holmes, Oliver -- Anderson, Matthew -- Leonard, Conrad -- Lonie, Andrew -- Hall, Nathan -- Wood, Scott -- Taylor, Darrin F -- Xu, Qinying -- Fink, J Lynn -- Waddell, Nick -- Drapkin, Ronny -- Stronach, Euan -- Gabra, Hani -- Brown, Robert -- Jewell, Andrea -- Nagaraj, Shivashankar H -- Markham, Emma -- Wilson, Peter J -- Ellul, Jason -- McNally, Orla -- Doyle, Maria A -- Vedururu, Ravikiran -- Stewart, Collin -- Lengyel, Ernst -- Pearson, John V -- Waddell, Nicola -- deFazio, Anna -- Grimmond, Sean M -- Bowtell, David D L -- 13086/Cancer Research UK/United Kingdom -- England -- Nature. 2015 May 28;521(7553):489-94. doi: 10.1038/nature14410.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia. ; Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. ; 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia [3] Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia. ; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06030, USA. ; 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] WolfsonWohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. ; 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] Technology Advancement Unit, Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia. ; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia. ; Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK. ; 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Department of Medicine, University of Melbourne, Parkville, Victoria 3052, Australia [3] The Royal Women's Hospital, Parkville, Victoria 3052, Australia. ; 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia. ; Centre for Cancer Research, University of Sydney at Westmead Millennium Institute, and Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales 2145, Australia. ; Crown Princess Mary Cancer Centre and University of Sydney at Westmead Hospital, Westmead, Sydney, New South Wales 2145, Australia. ; Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2031, Australia. ; The Royal Women's Hospital, Parkville, Victoria 3052, Australia. ; Victorian Institute of Forensic Medicine, Southbank, Victoria 3006, Australia. ; Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia. ; Victorian Life Sciences Computation Initiative, Carlton, Victoria 3053, Australia. ; La Trobe Institute for Molecular Science, Bundoora, Victoria 3083, Australia. ; Dana-Farber Cancer Institute, Boston, Massachusetts 02115-5450, USA. ; University of Chicago, Chicago, Illinois 60637, USA. ; The University of Western Australia, Crawley, Western Australia 6009, Australia. ; 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia [3] Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia [4] Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK [5] Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3052, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26017449" target="_blank"〉PubMed〈/a〉

Description: The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene Slc39a12 as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter ZIP12. Here we report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This new and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Lan -- Oliver, Eduardo -- Maratou, Klio -- Atanur, Santosh S -- Dubois, Olivier D -- Cotroneo, Emanuele -- Chen, Chien-Nien -- Wang, Lei -- Arce, Cristina -- Chabosseau, Pauline L -- Ponsa-Cobas, Joan -- Frid, Maria G -- Moyon, Benjamin -- Webster, Zoe -- Aldashev, Almaz -- Ferrer, Jorge -- Rutter, Guy A -- Stenmark, Kurt R -- Aitman, Timothy J -- Wilkins, Martin R -- 098424/Wellcome Trust/United Kingdom -- 101033/Wellcome Trust/United Kingdom -- MR/J0003042/1/Medical Research Council/United Kingdom -- P01 HL014985/HL/NHLBI NIH HHS/ -- PG/04/035/16912/British Heart Foundation/United Kingdom -- PG/10/59/28478/British Heart Foundation/United Kingdom -- PG/12/61/29818/British Heart Foundation/United Kingdom -- PG/2000137/British Heart Foundation/United Kingdom -- PG/95170/British Heart Foundation/United Kingdom -- PG/98018/British Heart Foundation/United Kingdom -- RG/10/16/28575/British Heart Foundation/United Kingdom -- WT098424AIA/Wellcome Trust/United Kingdom -- England -- Nature. 2015 Aug 20;524(7565):356-60. doi: 10.1038/nature14620. Epub 2015 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. ; Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK. ; Section of Epigenomics and Disease, Department of Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. ; Department of Pediatrics and Medicine, Division of Critical Care Medicine and Cardiovascular Pulmonary Research Laboratories, University of Colorado Denver, Denver, Colorado 80045, USA. ; Transgenics and Embryonic Stem Cell Laboratory, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK. ; Institute of Molecular Biology and Medicine, 3 Togolok Moldo Street, Bishkek 720040, Kyrgyzstan. ; Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26258299" target="_blank"〉PubMed〈/a〉

Description: Understanding the diversity of human tissues is fundamental to disease and requires linking genetic information, which is identical in most of an individual's cells, with epigenetic mechanisms that could have tissue-specific roles. Surveys of DNA methylation in human tissues have established a complex landscape including both tissue-specific and invariant methylation patterns. Here we report high coverage methylomes that catalogue cytosine methylation in all contexts for the major human organ systems, integrated with matched transcriptomes and genomic sequence. By combining these diverse data types with each individuals' phased genome, we identified widespread tissue-specific differential CG methylation (mCG), partially methylated domains, allele-specific methylation and transcription, and the unexpected presence of non-CG methylation (mCH) in almost all human tissues. mCH correlated with tissue-specific functions, and using this mark, we made novel predictions of genes that escape X-chromosome inactivation in specific tissues. Overall, DNA methylation in several genomic contexts varies substantially among human tissues.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499021/" 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/PMC4499021/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schultz, Matthew D -- He, Yupeng -- Whitaker, John W -- Hariharan, Manoj -- Mukamel, Eran A -- Leung, Danny -- Rajagopal, Nisha -- Nery, Joseph R -- Urich, Mark A -- Chen, Huaming -- Lin, Shin -- Lin, Yiing -- Jung, Inkyung -- Schmitt, Anthony D -- Selvaraj, Siddarth -- Ren, Bing -- Sejnowski, Terrence J -- Wang, Wei -- Ecker, Joseph R -- F32 HL110473/HL/NHLBI NIH HHS/ -- F32HL110473/HL/NHLBI NIH HHS/ -- K99 HL119617/HL/NHLBI NIH HHS/ -- K99 NS080911/NS/NINDS NIH HHS/ -- K99HL119617/HL/NHLBI NIH HHS/ -- R00 NS080911/NS/NINDS NIH HHS/ -- R00NS080911/NS/NINDS NIH HHS/ -- R01 ES024984/ES/NIEHS NIH HHS/ -- T32 GM008666/GM/NIGMS NIH HHS/ -- U01 ES017166/ES/NIEHS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jul 9;523(7559):212-6. doi: 10.1038/nature14465. Epub 2015 Jun 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Bioinformatics Program, University of California, San Diego, La Jolla, California 92093, USA [2] Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA. ; Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; 1] Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] Department of Cognitive Science, University of California, San Diego, La Jolla, California 92037, USA. ; Ludwig Institute for Cancer Research, La Jolla, California 92093, USA. ; Department of Genetics, Stanford University, 300 Pasteur Drive, M-344 Stanford, California 94305, USA. ; Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8109, St Louis, Missouri 63110, USA. ; Bioinformatics Program, University of California, San Diego, La Jolla, California 92093, USA. ; 1] Ludwig Institute for Cancer Research, La Jolla, California 92093, USA [2] University of California, San Diego School of Medicine, Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, La Jolla, California 92093, USA. ; 1] Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] Division of Biological Sciences, University of California at San Diego, La Jolla, California 92037, USA [3] Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA. ; 1] Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA [2] Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, USA. ; 1] Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26030523" target="_blank"〉PubMed〈/a〉

Description: Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC-BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioural regulation pathway.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Adhikari, Avishek -- Lerner, Talia N -- Finkelstein, Joel -- Pak, Sally -- Jennings, Joshua H -- Davidson, Thomas J -- Ferenczi, Emily -- Gunaydin, Lisa A -- Mirzabekov, Julie J -- Ye, Li -- Kim, Sung-Yon -- Lei, Anna -- Deisseroth, Karl -- 1F32MH105053-01/MH/NIMH NIH HHS/ -- K99 MH106649/MH/NIMH NIH HHS/ -- K99MH106649/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Nov 12;527(7577):179-85. doi: 10.1038/nature15698. Epub 2015 Nov 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Bioengineering, Stanford University, Stanford, California 94305, USA. ; CNC Program, Stanford University, Stanford, California 94304, USA. ; Neurosciences Program, Stanford University, Stanford, California 94305, USA. ; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305, USA. ; Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26536109" target="_blank"〉PubMed〈/a〉

Description: At least 120 non-olfactory G-protein-coupled receptors in the human genome are 'orphans' for which endogenous ligands are unknown, and many have no selective ligands, hindering the determination of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Using yeast-based screens against GPR68, here we identify the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. More than 3,000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators, many of which were confirmed in functional assays. One potent GPR68 modulator, ogerin, suppressed recall in fear conditioning in wild-type but not in GPR68-knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Xi-Ping -- Karpiak, Joel -- Kroeze, Wesley K -- Zhu, Hu -- Chen, Xin -- Moy, Sheryl S -- Saddoris, Kara A -- Nikolova, Viktoriya D -- Farrell, Martilias S -- Wang, Sheng -- Mangano, Thomas J -- Deshpande, Deepak A -- Jiang, Alice -- Penn, Raymond B -- Jin, Jian -- Koller, Beverly H -- Kenakin, Terry -- Shoichet, Brian K -- Roth, Bryan L -- GM59957/GM/NIGMS NIH HHS/ -- GM71896/GM/NIGMS NIH HHS/ -- P01 HL114471/HL/NHLBI NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 DA027170/DA/NIDA NIH HHS/ -- U01 MH104974/MH/NIMH NIH HHS/ -- U19MH082441/MH/NIMH NIH HHS/ -- U54 HD079124/HD/NICHD NIH HHS/ -- England -- Nature. 2015 Nov 26;527(7579):477-83. doi: 10.1038/nature15699. Epub 2015 Nov 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-7365, USA. ; National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365, USA. ; Department of Pharmaceutical Chemistry, University of California at San Francisco, Byers Hall, 1700 4th Street, San Francisco, California 94158-2550, USA. ; Center for Integrative Chemical Biology and Drug Discovery (CICBDD), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7363, USA. ; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7360, USA. ; Department of Psychiatry and Carolina Institute for Developmental Disabilities (CIDD), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7146, USA. ; Center for Translational Medicine and Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. ; Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7264, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26550826" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Florence, T J -- Reiser, Michael B -- England -- Nature. 2015 Mar 19;519(7543):296-7. doi: 10.1038/nature14209. Epub 2015 Mar 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Janelia Research Campus, Ashburn, Virginia 20147, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25739498" target="_blank"〉PubMed〈/a〉

Description: Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523082/" 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/PMC4523082/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Waddell, Nicola -- Pajic, Marina -- Patch, Ann-Marie -- Chang, David K -- Kassahn, Karin S -- Bailey, Peter -- Johns, Amber L -- Miller, David -- Nones, Katia -- Quek, Kelly -- Quinn, Michael C J -- Robertson, Alan J -- Fadlullah, Muhammad Z H -- Bruxner, Tim J C -- Christ, Angelika N -- Harliwong, Ivon -- Idrisoglu, Senel -- Manning, Suzanne -- Nourse, Craig -- Nourbakhsh, Ehsan -- Wani, Shivangi -- Wilson, Peter J -- Markham, Emma -- Cloonan, Nicole -- Anderson, Matthew J -- Fink, J Lynn -- Holmes, Oliver -- Kazakoff, Stephen H -- Leonard, Conrad -- Newell, Felicity -- Poudel, Barsha -- Song, Sarah -- Taylor, Darrin -- Waddell, Nick -- Wood, Scott -- Xu, Qinying -- Wu, Jianmin -- Pinese, Mark -- Cowley, Mark J -- Lee, Hong C -- Jones, Marc D -- Nagrial, Adnan M -- Humphris, Jeremy -- Chantrill, Lorraine A -- Chin, Venessa -- Steinmann, Angela M -- Mawson, Amanda -- Humphrey, Emily S -- Colvin, Emily K -- Chou, Angela -- Scarlett, Christopher J -- Pinho, Andreia V -- Giry-Laterriere, Marc -- Rooman, Ilse -- Samra, Jaswinder S -- Kench, James G -- Pettitt, Jessica A -- Merrett, Neil D -- Toon, Christopher -- Epari, Krishna -- Nguyen, Nam Q -- Barbour, Andrew -- Zeps, Nikolajs -- Jamieson, Nigel B -- Graham, Janet S -- Niclou, Simone P -- Bjerkvig, Rolf -- Grutzmann, Robert -- Aust, Daniela -- Hruban, Ralph H -- Maitra, Anirban -- Iacobuzio-Donahue, Christine A -- Wolfgang, Christopher L -- Morgan, Richard A -- Lawlor, Rita T -- Corbo, Vincenzo -- Bassi, Claudio -- Falconi, Massimo -- Zamboni, Giuseppe -- Tortora, Giampaolo -- Tempero, Margaret A -- Australian Pancreatic Cancer Genome Initiative -- Gill, Anthony J -- Eshleman, James R -- Pilarsky, Christian -- Scarpa, Aldo -- Musgrove, Elizabeth A -- Pearson, John V -- Biankin, Andrew V -- Grimmond, Sean M -- 103721/Wellcome Trust/United Kingdom -- C29717/A17263/Cancer Research UK/United Kingdom -- C596/A18076/Cancer Research UK/United Kingdom -- P30 CA006973/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P50 CA062924/CA/NCI NIH HHS/ -- P50 CA62924/CA/NCI NIH HHS/ -- England -- Nature. 2015 Feb 26;518(7540):495-501. doi: 10.1038/nature14169.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia [2] QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia. ; 1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2010, Australia. ; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia. ; 1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia [3] South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia [4] Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. ; 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia [2] 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, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia. ; 1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. ; 1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] Department of Anatomical Pathology, St Vincent's Hospital, Sydney, New South Wales 2010, Australia. ; 1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia. ; 1] Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia [2] University of Sydney, Sydney, New South Wales 2006, Australia. ; 1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] University of Sydney, Sydney, New South Wales 2006, Australia [3] Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia. ; 1] Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia [2] School of Medicine, University of Western Sydney, Penrith, New South Wales 2175, Australia. ; Department of Surgery, Fremantle Hospital, Alma Street, Fremantle, Western Australia 6160, 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. ; 1] School of Surgery M507, University of Western Australia, 35 Stirling Highway, Nedlands 6009, Australia [2] St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia [3] Bendat Family Comprehensive Cancer Centre, St John of God Subiaco Hospital, Subiaco, Western Australia 6008, Australia. ; 1] Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK [2] Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK [3] West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. ; 1] Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK [2] Department of Medical Oncology, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK. ; Norlux Neuro-Oncology Laboratory, CRP-Sante Luxembourg, 84 Val Fleuri, L-1526, Luxembourg. ; Norlux Neuro-Oncology, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, N-5019 Bergen, Norway. ; Departments of Surgery and Pathology, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany. ; Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. ; Departments of Pathology and Translational Molecular Pathology, University of Texas 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 Surgery, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. ; 1] ARC-NET Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy [2] Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy. ; ARC-NET Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy. ; Department of Surgery and Oncology, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy. ; 1] Department of Surgery and Oncology, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy [2] Departments of Surgery and Pathology, Ospedale Sacro Cuore Don Calabria Negrar, Verona 37024, Italy. ; 1] Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy [2] Departments of Surgery and Pathology, Ospedale Sacro Cuore Don Calabria Negrar, Verona 37024, Italy. ; Department of Oncology, University and Hospital Trust of Verona, Verona 37134, Italy. ; Division of Hematology and Oncology, University of California, San Francisco, California 94122, USA. ; 1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] University of Sydney, Sydney, New South Wales 2006, Australia. ; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25719666" target="_blank"〉PubMed〈/a〉

Description: Transcriptional regulation and posttranscriptional processing underlie many cellular and organismal phenotypes. We used RNA sequence data generated by Genotype-Tissue Expression (GTEx) project to investigate the patterns of transcriptome variation across individuals and tissues. Tissues exhibit characteristic transcriptional signatures that show stability in postmortem samples. These signatures are dominated by a relatively small number of genes-which is most clearly seen in blood-though few are exclusive to a particular tissue and vary more across tissues than individuals. Genes exhibiting high interindividual expression variation include disease candidates associated with sex, ethnicity, and age. Primary transcription is the major driver of cellular specificity, with splicing playing mostly a complementary role; except for the brain, which exhibits a more divergent splicing program. Variation in splicing, despite its stochasticity, may play in contrast a comparatively greater role in defining individual phenotypes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4547472/" 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/PMC4547472/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mele, Marta -- Ferreira, Pedro G -- Reverter, Ferran -- DeLuca, David S -- Monlong, Jean -- Sammeth, Michael -- Young, Taylor R -- Goldmann, Jakob M -- Pervouchine, Dmitri D -- Sullivan, Timothy J -- Johnson, Rory -- Segre, Ayellet V -- Djebali, Sarah -- Niarchou, Anastasia -- GTEx Consortium -- Wright, Fred A -- Lappalainen, Tuuli -- Calvo, Miquel -- Getz, Gad -- Dermitzakis, Emmanouil T -- Ardlie, Kristin G -- Guigo, Roderic -- HHSN261200800001E/PHS HHS/ -- HHSN268201000029C/HL/NHLBI NIH HHS/ -- HHSN268201000029C/PHS HHS/ -- R01 DA006227-17/DA/NIDA NIH HHS/ -- R01 MH090936/MH/NIMH NIH HHS/ -- R01 MH090941/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2015 May 8;348(6235):660-5. doi: 10.1126/science.aaa0355.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Harvard Department of stem cell and regenerative biology, Harvard University, Cambridge, MA, USA. ; Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switzerland. ; Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Catalonia, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. ; Broad Institute of MIT and Harvard, Cambridge, MA, USA. ; Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. McGill University, Montreal, Canada. ; Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. National Institute for Scientific Computing (LNCC), Petropolis, Rio de Janeiro, Brazil. ; Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. Radboud University, Nijmegen, Netherlands. ; Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. Faculty of Bioengineering and Bioinformatics, Moscow State University, Leninskie Gory 1-73, 119992 Moscow, Russia. ; Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. ; Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switzerland. ; Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Harvard Department of stem cell and regenerative biology, Harvard University, Cambridge, MA, USA. Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switzerland. Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Catalonia, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. Broad Institute of MIT and Harvard, Cambridge, MA, USA. McGill University, Montreal, Canada. National Institute for Scientific Computing (LNCC), Petropolis, Rio de Janeiro, Brazil. Radboud University, Nijmegen, Netherlands. Faculty of Bioengineering and Bioinformatics, Moscow State University, Leninskie Gory 1-73, 119992 Moscow, Russia. North Carolina State University, Raleigh, NC, USA. New York Genome Center, New York, NY, USA. Department of Systems Biology, Columbia University, New York, NY, USA. Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Institut Hospital del Mar d'Investigacions Mediques (IMIM), Barcelona, Catalonia, Spain. Joint CRG-Barcelona Super Computing Center (BSC)-Institut de Recerca Biomedica (IRB) Program in Computational Biology, Barcelona, Catalonia, Spain. ; North Carolina State University, Raleigh, NC, USA. ; Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switzerland. New York Genome Center, New York, NY, USA. Department of Systems Biology, Columbia University, New York, NY, USA. ; Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Catalonia, Spain. ; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. ; Broad Institute of MIT and Harvard, Cambridge, MA, USA. kardlie@broadinstitute.org roderic.guigo@crg.cat. ; Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. Institut Hospital del Mar d'Investigacions Mediques (IMIM), Barcelona, Catalonia, Spain. Joint CRG-Barcelona Super Computing Center (BSC)-Institut de Recerca Biomedica (IRB) Program in Computational Biology, Barcelona, Catalonia, Spain. kardlie@broadinstitute.org roderic.guigo@crg.cat.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25954002" target="_blank"〉PubMed〈/a〉

Description: During flexible behavior, multiple brain regions encode sensory inputs, the current task, and choices. It remains unclear how these signals evolve. We simultaneously recorded neuronal activity from six cortical regions [middle temporal area (MT), visual area four (V4), inferior temporal cortex (IT), lateral intraparietal area (LIP), prefrontal cortex (PFC), and frontal eye fields (FEF)] of monkeys reporting the color or motion of stimuli. After a transient bottom-up sweep, there was a top-down flow of sustained task information from frontoparietal to visual cortex. Sensory information flowed from visual to parietal and prefrontal cortex. Choice signals developed simultaneously in frontoparietal regions and travelled to FEF and sensory cortex. This suggests that flexible sensorimotor choices emerge in a frontoparietal network from the integration of opposite flows of sensory and task information.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721574/" 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/PMC4721574/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Siegel, Markus -- Buschman, Timothy J -- Miller, Earl K -- 5R37MH087027/MH/NIMH NIH HHS/ -- R00 MH092715/MH/NIMH NIH HHS/ -- R37 MH087027/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2015 Jun 19;348(6241):1352-5. doi: 10.1126/science.aab0551.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Integrative Neuroscience and MEG Center, University of Tubingen, Tubingen, Germany. Picower Institute for Learning and Memory and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. markus.siegel@uni-tuebingen.de. ; Picower Institute for Learning and Memory and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Princeton Neuroscience Institute and Department of Psychology, Princeton University, Princeton, NJ 08544, USA. ; Picower Institute for Learning and Memory and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26089513" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pugh, Trevor J -- Banerji, Shantanu -- Meyerson, Matthew -- England -- Nature. 2015 Apr 16;520(7547):E12-4. doi: 10.1038/nature14266.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Princess Margaret Cancer Centre, University Health Network; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada. ; Department of Internal Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R3E 0V9, Canada. ; 1] Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Cancer Program, Broad Institute, Cambridge, Massachusetts, 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25877207" target="_blank"〉PubMed〈/a〉