articles+ search results

United Kingdom

Summary Background Treatment of dysplastic Barrett's oesophagus prevents progression to adenocarcinoma; however, the optimal diagnostic strategy for Barrett's oesophagus is unclear. The Cytosponge-trefoil factor 3 (TFF3) is a non-endoscopic test for Barrett's oesophagus. The aim of this study was to investigate whether offering this test to patients on medication for gastro-oesophageal reflux would increase the detection of Barrett's oesophagus compared with standard management. Methods This multicentre, pragmatic, randomised controlled trial was done in 109 socio-demographically diverse general practice clinics in England. Randomisation was done both at the general practice clinic level (cluster randomisation) and at the individual patient level, and the results for each type of randomisation were analysed separately before being combined. Patients were eligible if they were aged 50 years or older, had been taking acid-suppressants for symptoms of gastro-oesophageal reflux for more than 6 months, and had not undergone an endoscopy procedure within the past 5 years. General practice clinics were selected by the local clinical research network and invited to participate in the trial. For cluster randomisation, clinics were randomly assigned (1:1) by the trial statistician using a computer-generated randomisation sequence; for individual patient-level randomisation, patients were randomly assigned (1:1) by the general practice clinics using a centrally prepared computer-generated randomisation sequence. After randomisation, participants received either standard management of gastro-oesophageal reflux (usual care group), in which participants only received an endoscopy if required by their general practitioner, or usual care plus an offer of the Cytosponge-TFF3 procedure, with a subsequent endoscopy if the procedure identified TFF3-positive cells (intervention group). The primary outcome was the diagnosis of Barrett's oesophagus at 12 months after enrolment, expressed as a rate per 1000 person-years, in all participants in the intervention group (regardless of whether they had accepted the offer of the Cytosponge-TFF3 procedure) compared with all participants in the usual care group. Analyses were intention-to-treat. The trial is registered with the ISRCTN registry, ISRCTN68382401, and is completed. Findings Between March 20, 2017, and March 21, 2019, 113 general practice clinics were enrolled, but four clinics dropped out shortly after randomisation. Using an automated search of the electronic prescribing records of the remaining 109 clinics, we identified 13,657 eligible patients who were sent an introductory letter with 14 days to opt out. 13,514 of these patients were randomly assigned (per practice or at the individual patient level) to the usual care group (n=6531) or the intervention group (n=6983). Following randomisation, 149 (2%) of 6983 participants in the intervention group and 143 (2%) of 6531 participants in the usual care group, on further scrutiny, did not meet all eligibility criteria or withdrew from the study. Of the remaining 6834 participants in the intervention group, 2679 (39%) expressed an interest in undergoing the Cytosponge-TFF3 procedure. Of these, 1750 (65%) met all of the eligibility criteria on telephone screening and underwent the procedure. Most of these participants (1654 [95%]; median age 69 years) swallowed the Cytosponge successfully and produced a sample. 231 (3%) of 6834 participants had a positive Cytosponge-TFF3 result and were referred for an endoscopy. Patients who declined the offer of the Cytosponge-TFF3 procedure and all participants in the usual care group only had an endoscopy if deemed necessary by their general practitioner. During an average of 12 months of follow-up, 140 (2%) of 6834 participants in the intervention group and 13 (<1%) of 6388 participants in the usual care group were diagnosed with Barrett's oesophagus (absolute difference 18*3 per 1000 person-years [95% CI 14*8--21*8]; rate ratio adjusted for cluster randomisation 10*6 [95% CI 6*0--18*8], p<0*0001). Nine (<1%) of 6834 participants were diagnosed with dysplastic Barrett's oesophagus (n=4) or stage I oesophago-gastric cancer (n=5) in the intervention group, whereas no participants were diagnosed with dysplastic Barrett's oesophagus or stage I gastro-oesophageal junction cancer in the usual care group. Among 1654 participants in the intervention group who swallowed the Cytosponge device successfully, 221 (13%) underwent endoscopy after testing positive for TFF3 and 131 (8%, corresponding to 59% of those having an endoscopy) were diagnosed with Barrett's oesophagus or cancer. One patient had a detachment of the Cytosponge from the thread requiring endoscopic removal, and the most common side-effect was a sore throat in 63 (4%) of 1654 participants. Interpretation In patients with gastro-oesophageal reflux, the offer of Cytosponge-TFF3 testing results in improved detection of Barrett's oesophagus. Cytosponge-TFF3 testing could also lead to the diagnosis of treatable dysplasia and early cancer. This strategy will lead to additional endoscopies with some false positive results. Funding Cancer Research UK, National Institute for Health Research, the UK National Health Service, Medtronic, and the Medical Research Council. Author Affiliation: (a) MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK (b) The Primary Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK (c) Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK (d) Cancer Research UK and King's College London Cancer Prevention Trials Unit, School of Cancer and Pharmaceutical Sciences, King's College London, London, UK (e) Cancer Prevention Group, School of Cancer and Pharmaceutical Sciences, King's College London, London, UK (f) Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK (g) Leeds Institute of Health Sciences, University of Leeds, Leeds, UK (h) Institute of Population Health Sciences, Newcastle University, Sir James Spence Institute, Royal Victoria Infirmary, Newcastle upon Tyne, UK * Correspondence to: Prof Rebecca C Fitzgerald, MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge CB2 0XZ, UK (footnote)[Dagger] Members of the BEST3 trial team are listed in the Byline: Prof Rebecca C Fitzgerald, MD [rcf29@mrc-cu.cam.ac.uk] (a,c), Massimiliano di Pietro, MD (a,c), Maria O'Donovan, MD (a,c), Roberta Maroni, MSc (d), Beth Muldrew, MA (d), Irene Debiram-Beecham, RN (a), Marcel Gehrung, MSc (f), Judith Offman, PhD (e), Monika Tripathi, MD (a,c), Samuel G Smith, PhD (g), Benoit Aigret, MSc (d), Fiona M Walter, MD (b), Prof Greg Rubin, FRCGP (h), Abhay Bagewadi, Abigail Patrick, Achuth Shenoy, Aisling Redmond, Ajay Muddu, Alex Northrop, Alice Groves, Alice Shiner, Amardeep Heer, Amrit Takhar, Amy Bowles, Andrea Jarman, Angela Wong, Angie Lucas, Anita Gibbons, Anjan Dhar, Anji Curry, Anna Lalonde, Anna Swinburn, Anne Turner, Anne-Marie Lydon, Anthony Gunstone, Arlene Lee, Arul Nambi, Arun Ariyarathenam, Ashley Elden, Ashley Wilson, Balaji Donepudi, Barbara Campbell, Basia Uszycka, Ben Bowers, Ben Coghill, Bruno de Quadros, Calvin Cheah, Carla Bratten, Carly Brown, Chantelle Moorbey, Charles Clisby, Charles Gordon, Chris Schramm, Chris Castle, Chris Newark, Chrissie Norris, Christine A'Court, Claire Graham, Clare Fletcher, Clare Grocott, Colin Rees, Corinne Bakker, Costas Paschalides, Craig Vickery, Damian Schembri, Danielle Morris, Daryl Hagan, David Cronk, David Goddard, David Graham, Dean Phillips, Deeksha Prabhu, Deepak Kejariwal, Dhirendra Garg, Diane Lonsdale, Dianne Butterworth, Donna Clements, Drew Bradman, Duncan Blake, Elizabeth Mather, Ewan O'Farrell, Florian Markowetz, Fran Adams, Francesca Pesola, Gareth Forbes, Gary Taylor, Glenn Collins, Gordon Irvine, Gysbert Fourie, Harriet Doyle, Heather Barnes, Helen Bowyer, Helen Whiting, Ian Beales, Ian Binnian, Ian Bremner, Ian Jennings, Ilona Troiceanu, Ines Modelell, Ingrid Emmerson, Jacobo Ortiz, Jacqueline Lilley, Jacquelyn Harvey, Jacqui Vicars, Jagjit Takhar, James Larcombe, Jan Bornschein, Jehad Aldegather, Jenny Johnson, Jill Ducker, Jo Skinner, Joanne Dash, Joanne Walsh, Jose Miralles, Josephine Ridgway, Julia Ince, Julie Kennedy, Kat Hampson, Kate Milne, Katherine Ellerby, Katherine Priddis, Kathy Rainsbury, Kelly Powell, Kerry Gunner, Krish Ragunath, Kyle Knox, Laura Baseley, Lauren White, Laurence Lovat, Lee Berney, Lindsay Crockett, Lisa Murray, Lisa Westwood, Lisa Chalkley, Loraine Leggett, Louise Dale, Louise Scovell, Lucy Brooks, Lucy Saunders, Lydia Owen, Maria Dilwershah, Marie Baldry, Marie Corcoran, Marie Roy, Mario Macedo, Mark Attah, Mary-Jo Anson, Matt Rutter, Matthew Wallard, Matthew Gaw, Matthew Hunt, Megan Lea-Hagerty, Melchizedek Penacerrada, Michele Bianchi, Michelle Baker-Moffatt, Michelle Czajkowski, Michelle Sleeth, Nick Brewer, Nick Wooding, Nicky Todd, Nicola Millen, Olga Zolle, Orla Whitehead, Patrick Ojechi, Patrick Moore, Paul Banim, Paula Spellar, Pradeep Bhandari, Prashant Kant, Rachel Nixon, Rebecca Russell, Rebekah Roberts, Rene Skule, Richard West, Robin Fox, Ruth Beesley, Ruth Gibbins, Ruth Osborne, S Thiagarajan, Sally Bastiman, Samantha Warburton, Samir Pai, Sarah Leith-Russell, Sarah Utting, Sarah Watson, Sarah Wytrykowski, Satish Singh, Shalini Malhotra, Sharon Woods, Shaun Conway, Sherrie Mateer, Shona Macrae, Shruti Singh, Simona Fourie, Siobhan Campbell, Siobhan Parslow-Williams, Sonica Goel, Stephen Dellar, Stephen Jones, Steve Knight, Stuart Mackay-Thomas, Stuti Mukherjee, Sue Allen, Suzanne Henry, Tara Evans, Theresa Leighton, Tim Bray, Tom Shackleton, Vanaja Santosh, Vicki Glover, Vijay Chandraraj, Will Elson, William Briggs, Zoe Barron, Zohrah Khan

Cellular signal transduction -- Research, Lungs -- Health aspects, and Carcinogenesis -- Research

Introduction Human cancers are characterized by recurrent somatic copy number alterations (SCNAs), which include both focal and broad arm-level amplifications and deletions (1). How these alterations contribute to tumorigenesis remains [...]
Recurrent broad-scale heterozygous deletions are frequently observed in human cancer. Here we tested the hypothesis that compound haploinsufficiency of neighboring genes at chromosome 8p promotes tumorigenesis. By targeting the mouse orthologs of human DOK2 and DUSP4 genes, which were co-deleted in approximately half of human lung adenocarcinomas, we found that compound-heterozygous deletion of Dok2 and Dusp4 in mice resulted in lung tumorigenesis with short latency and high incidence, and that their co-deletion synergistically activated MAPK signaling and promoted cell proliferation. Conversely, restoration of DOK2 and DUSP4 in lung cancer cells suppressed MAPK activation and cell proliferation. Importantly, in contrast to downregulation of DOK2 or DUSP4 alone, concomitant downregulation of DOK2 and DUSP4 was associated with poor survival in human lung adenocarcinoma. Therefore, our findings lend in vivo experimental support to the notion that compound haploinsufficiency, due to broad-scale chromosome deletions, constitutes a driving force in tumorigenesis.

Ethnicity -- Analysis, Genome-wide association studies -- Analysis, and Racism -- Analysis

Keywords trans-ethnic GWAS; genetic ancestry; multi-ethnic cohort; biobank; ethnicity-specific trait loci; self-reported race/ethnicity; stratified analysis Large-scale multi-ethnic cohorts offer unprecedented opportunities to elucidate the genetic factors influencing complex traits related to health and disease among minority populations. At the same time, the genetic diversity in these cohorts presents new challenges for analysis and interpretation. We consider the utility of race and/or ethnicity categories in genome-wide association studies (GWASs) of multi-ethnic cohorts. We demonstrate that race/ethnicity information enhances the ability to understand population-specific genetic architecture. To address the practical issue that self-identified racial/ethnic information may be incomplete, we propose a machine learning algorithm that produces a surrogate variable, termed HARE. We use height as a model trait to demonstrate the utility of HARE and ethnicity-specific GWASs. Author Affiliation: (1) Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA (2) VA Palo Alto Epidemiology Research and Information Center for Genomics, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA (3) Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA 30322, USA (4) Atlanta VA Medical Center, Atlanta, GA 30033, USA (5) Edith Norse Rogers Memorial VA Medical Center, Bedford, MA 01730, USA (6) University of Massachusetts College of Nursing & Health Sciences, Boston, MA 02125, USA (7) Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA 02130, USA (8) Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA (9) Cardiovascular Medicine Division, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA (10) Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104, USA (11) Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA (12) Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA (13) Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA (14) VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT 84148, USA (15) University of Utah School of Medicine, Salt Lake City, UT 84132, USA (16) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA (17) Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA (18) Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA 30322, USA * Corresponding author Article History: Received 7 April 2019; Accepted 28 August 2019 (miscellaneous) Published: September 26, 2019 (footnote)19 Present address: Department of Global Health, School of Public Health, Peking University, Beijing 100191, China Byline: Huaying Fang (1,2), Qin Hui (3,4), Julie Lynch (5,6,14), Jacqueline Honerlaw (7), Themistocles L. Assimes (2,8), Jie Huang (7,9,19), Marijana Vujkovic (10,11), Scott M. Damrauer (10,12), Saiju Pyarajan (7,13), J. Michael Gaziano (7,13), Scott L. DuVall (14,15), Christopher J. O'Donnell (7,9), Kelly Cho (7,13), Kyong-Mi Chang (10,16), Peter W.F. Wilson (4,17), Philip S. Tsao (2,8), J. Michael Gaziano, Rachel Ramoni, Jim Breeling, Kyong-Mi Chang, Grant Huang, Sumitra Muralidhar, Christopher J. O'Donnell, Philip S. Tsao, Sumitra Muralidhar, Jennifer Moser, Stacey B. Whitbourne, Jessica V. Brewer, John Concato, Stuart Warren, Dean P. Argyres, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Nhan Do, Shahpoor Shayan, Xuan-Mai T. Nguyen, Saiju Pyarajan, Kelly Cho, Elizabeth Hauser, Yan Sun, Hongyu Zhao, Peter Wilson, Rachel McArdle, Louis Dellitalia, John Harley, Jeffrey Whittle, Jean Beckham, John Wells, Salvador Gutierrez, Gretchen Gibson, Laurence Kaminsky, Gerardo Villareal, Scott Kinlay, Junzhe Xu, Mark Hamner, Kathlyn Sue Haddock, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair Ballas, Malcolm Buford, Stephen Mastorides, Jon Klein, Nora Ratcliffe, Hermes Florez, Alan Swann, Maureen Murdoch, Peruvemba Sriram, Shing Shing Yeh, Ronald Washburn, Darshana Jhala, Samuel Aguayo, David Cohen, Satish Sharma, John Callaghan, Kris Ann Oursler, Mary Whooley, Sunil Ahuja, Amparo Gutierrez, Ronald Schifman, Jennifer Greco, Michael Rauchman, Richard Servatius, Mary Oehlert, Agnes Wallbom, Ronald Fernando, Timothy Morgan, Todd Stapley, Scott Sherman, Gwenevere Anderson, Elif Sonel, Edward Boyko, Laurence Meyer, Samir Gupta, Joseph Fayad, Adriana Hung, Jack Lichy, Robin Hurley, Brooks Robey, Robert Striker

T cells, Genetic research, Genomics, and Multiple sclerosis

Highlights * Almost 20% of MS risk heritability can be attributed to common genetic variants * We show that nearly 5% of heritability is explained by coding low-frequency variants * We identify four novel genes driving risk independently of common-variant signals * These genes would not have been found by common-variant studies Summary Multiple sclerosis is a complex neurological disease, with ~20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFN[gamma] biology, and NF[kappa]B signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS. * Corresponding author Article History: Received 21 March 2018; Revised 8 August 2018; Accepted 24 September 2018 (miscellaneous) Published: October 18, 2018; corrected online June 20, 2019 (footnote)1 Lead Contact (Chris Cotsapas) Byline: Mitja Mitrovic, Nikolaos A. Patsopoulos, Ashley H. Beecham, Theresa Dankowski, An Goris, Benedicte Dubois, Marie B. D'hooghe, Robin Lemmens, Philip Van Damme, Helle Bach Sondergaard, Finn Sellebjerg, Per Soelberg Sorensen, Henrik Ullum, Lise W. Thorner, Thomas Werge, Janna Saarela, Isabelle Cournu-Rebeix, Vincent Damotte, Bertrand Fontaine, Lena Guillot-Noel, Mark Lathrop, Sandra Vukusik, Pierre-Antoine Gourraud, Till F.M. Andlauer, Viola Pongratz, Dorothea Buck, Christiane Gasperi, Antonios Bayas, Christoph Heesen, Tania Kumpfel, Ralf Linker, Friedemann Paul, Martin Stangel, Bjorn Tackenberg, Florian Then Bergh, Clemens Warnke, Heinz Wiendl, Brigitte Wildemann, Uwe Zettl, Ulf Ziemann, Hayrettin Tumani, Ralf Gold, Verena Grummel, Bernhard Hemmer, Benjamin Knier, Christina M. Lill, Felix Luessi, Efthimios Dardiotis, Cristina Agliardi, Nadia Barizzone, Elisabetta Mascia, Luisa Bernardinelli, Giancarlo Comi, Daniele Cusi, Federica Esposito, Laura Ferre, Cristoforo Comi, Daniela Galimberti, Maurizio A. Leone, Melissa Sorosina, Julia Mescheriakova, Rogier Hintzen, Cornelia van Duijn, Charlotte E. Teunissen, Steffan D. Bos, Kjell-Morten Myhr, Elisabeth G. Celius, Benedicte A. Lie, Anne Spurkland, Manuel Comabella, Xavier Montalban, Lars Alfredsson, Pernilla Stridh, Jan Hillert, Maja Jagodic, Fredrik Piehl, Ilijas Jelcic, Roland Martin, Mireia Sospedra, Maria Ban, Clive Hawkins, Pirro Hysi, Seema Kalra, Fredrik Karpe, Jyoti Khadake, Genevieve Lachance, Matthew Neville, Adam Santaniello, Stacy J. Caillier, Peter A. Calabresi, Bruce A.C. Cree, Anne Cross, Mary F. Davis, Jonathan L. Haines, Paul I.W. de Bakker, Silvia Delgado, Marieme Dembele, Keith Edwards, Kathryn C. Fitzgerald, Hakon Hakonarson, Ioanna Konidari, Ellen Lathi, Clara P. Manrique, Margaret A. Pericak-Vance, Laura Piccio, Cathy Schaefer, Cristin McCabe, Howard Weiner, Jacqueline Goldstein, Tomas Olsson, Georgios Hadjigeorgiou, Bruce Taylor, Lotti Tajouri, Jac Charlesworth, David R. Booth, Hanne F. Harbo, Adrian J. Ivinson, Stephen L. Hauser, Alastair Compston, Graeme Stewart, Frauke Zipp, Lisa F. Barcellos, Sergio E. Baranzini, Filippo Martinelli-Boneschi, Sandra D'Alfonso, Andreas Ziegler, Annette Oturai, Jacob L. McCauley, Stephen J. Sawcer, Jorge R. Oksenberg, Philip L. De Jager, Ingrid Kockum, David A. Hafler, Chris Cotsapas

Linkage (Genetics) -- Physiological aspects, Linkage (Genetics) -- Research, Population genetics -- Research, Single nucleotide polymorphisms -- Physiological aspects, and Single nucleotide polymorphisms -- Research

Schizophrenia Working Group of the Psychiatric Genomics Consortium Keywords linkage disequilibrium score regression; genomic restricted maximum likelihood; genetic correlation; schizophrenia; body mass index; height; SNP heritability; accuracy; biasedness; genome-wide SNPs Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC. When there is genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the accuracy of LDSC decreases further. In real data analyses estimating the genetic correlation between schizophrenia (SCZ) and body mass index, we show that GREML estimates based on ~150,000 individuals give a higher accuracy than LDSC estimates based on ~400,000 individuals (from combined meta-data). A GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which whole genome or LDSC approach has less power to detect. We conclude that LDSC estimates should be carefully interpreted as there can be uncertainty about homogeneity among combined meta-datasets. We suggest that any interesting findings from massive LDSC analysis for a large number of complex traits should be followed up, where possible, with more detailed analyses with GREML methods, even if sample sizes are lesser. Author Affiliation: (1) Centre for Population Health Research, School of Health Sciences and Sansom Institute of Health Research, University of South Australia, Adelaide, SA 5000, Australia (2) School of Environmental and Rural Science, University of New England, Armidale, NSW 2351, Australia (3) Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia (4) Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia * Corresponding author Article History: Received 4 October 2017; Accepted 20 March 2018 (miscellaneous) Published: May 10, 2018 Byline: Guiyan Ni (1,2), Gerhard Moser (1,2), Stephan Ripke, Benjamin M. Neale, Aiden Corvin, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau Jr., Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Ina Giegling, Paola Giusti-Rodriguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, Masashi Ikeda, Inge Joa, Antonio Julia, Rene S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kahler, Claudine Laurent, Jimmy Lee Chee Keong, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lonnqvist, Milan Macek Jr., Patrik K.E. Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsda, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Ole Mors, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Bertram Muller-Myhsok, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O'Callaghan, Colm O'Dushlaine, F. Anthony O'Neill, Sang-Yun Oh, Ann Olinc, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papio, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietilainenl, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Alan R. Sanders, Ulrich Schall, Christian R. Schubert, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Jordan W. Smoller, Hon-Cheong So, Chris C.A. Spencer, Eli A. Stah, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Soderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Kari Stefansson, Peter M. Visscher, Rolf Adolfsson, Ole A. Andreassen, Douglas H.R. Blackwood, Elvira Bramon, Joseph D. Buxbaum, Anders D. Borglum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tonu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jonsson, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Steven A. McCarrol, Andrew McQuillin, Jennifer L. Moran, Preben B. Mortensen, Bryan J. Mowry, Markus M. Nothen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Danielle Posthuma, Marcella Rietsche, Brien P. Riley, Dan Rujescu, Pak C. Sham, Pamela Sklar, David St Clair, Daniel R. Weinberger, Jens R. Wendland, Thomas Werge, Mark J. Daly, Patrick F. Sullivan, Michael C. O'Donovan

Nursing homes -- Management and Nursing homes -- Care and treatment

Government regulation, United States. Food and Drug Administration -- Laws, regulations and rules, College students -- Health aspects, Epidemics -- Research, and Epidemics -- United States

Australia. National Health and Medical Research Council -- Standards, Drinking of alcoholic beverages -- Surveys, and Drinking of alcoholic beverages -- Standards

Objective: To examine self-reported alcohol consumption and relationships between consumption, awareness of the 2009 NHMRC guidelines of no more than two standard drinks per day, drinking in excess of the guideline threshold and perceptions of alcohol as a risk factor for cancer. Methods: Questions were included in annual, cross-sectional surveys of approximately 2,700 South Australians aged 18 years and over from 2004 to 2012. Consumption data for 2011 and 2012 were merged for the majority of analyses. Results: In 2011 and 2012, 21.6% of adults drank in excess of the guideline threshold (33.0% males; 10.7% females). While 53.5% correctly identified the NHMRC consumption threshold for women, only 20.3% did so for men (39.0% nominated a higher amount). A large minority said they did not know the consumption threshold for women (39.2%) or men (40.4%). In 2012, only 36.6% saw alcohol as an important risk factor for cancer. Important predictors of excess consumption for men were: higher household income; and not perceiving alcohol as an important risk factor for cancer. Predictors for women were similar but the role of household income was even more prominent. Conclusions: Men were nearly three times as likely to drink in excess of the guidelines as women. The majority of the population did not see an important link between alcohol and cancer. Awareness of the latest NHMRC guidelines consumption threshold is still low, particularly for men. Implications: A strategy to raise awareness of the NHMRC guidelines and the link between alcohol and cancer is warranted. Key words: alcohol consumption, NHMRC guidelines, income, cancer risk doi: 10.1111/1753-6405.12159

Hepatoma -- Analysis, DNA sequencing -- Analysis, Nucleotide sequencing -- Analysis, Tumor proteins -- Analysis, Methylation -- Analysis, Stem cells -- Analysis, Mortality -- Analysis, Genes -- Analysis, Gene expression -- Analysis, RNA -- Analysis, Gene mutations -- Analysis, Cancer -- Genetic aspects, and Cancer -- Analysis

To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1016/j.cell.2017.05.046 Byline: Adrian Ally, Miruna Balasundaram, Rebecca Carlsen, Eric Chuah, Amanda Clarke, Noreen Dhalla, Robert A. Holt, Steven J.M. Jones, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Dorothy Cheung, Tina Wong, Denise Brooks, A. Gordon Robertson, Reanne Bowlby, Karen Mungall, Sara Sadeghi, Liu Xi, Kyle Covington, Eve Shinbrot, David A. Wheeler, Richard A. Gibbs, Lawrence A. Donehower, Linghua Wang, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Carmen Helsel, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Stacey B. Gabriel, Matthew Meyerson, Carrie Cibulskis, Bradley A. Murray, Juliann Shih, Rameen Beroukhim, Andrew D. Cherniack, Steven E. Schumacher, Gordon Saksena, Chandra Sekhar Pedamallu, Lynda Chin, Gad Getz, Michael Noble, Hailei Zhang, David Heiman, Juok Cho, Nils Gehlenborg, Gordon Saksena, Douglas Voet, Pei Lin, Scott Frazer, Timothy Defreitas, Sam Meier, Michael Lawrence, Jaegil Kim, Chad J. Creighton, Donna Muzny, HarshaVardhan Doddapaneni, Jianhong Hu, Min Wang, Donna Morton, Viktoriya Korchina, Yi Han, Huyen Dinh, Lora Lewis, Michelle Bellair, Xiuping Liu, Jireh Santibanez, Robert Glenn, Sandra Lee, Walker Hale, Joel S. Parker, Matthew D. Wilkerson, D. Neil Hayes, Sheila M. Reynolds, Ilya Shmulevich, Wei Zhang, Yuexin Liu, Lisa Iype, Hala Makhlouf, Michael S. Torbenson, Sanjay Kakar, Matthew M. Yeh, Dhanpat Jain, David E. Kleiner, Dhanpat Jain, Renumathy Dhanasekaran, Hashem B. El-Serag, Sun Young Yim, John N. Weinstein, Lopa Mishra, Jianping Zhang, Rehan Akbani, Shiyun Ling, Zhenlin Ju, Xiaoping Su, Apurva M. Hegde, Gordon B. Mills, Yiling Lu, Jian Chen, Ju-Seog Lee, Bo Hwa Sohn, Jae Jun Shim, Pan Tong, Hiroyuki Aburatani, Shogo Yamamoto, Kenji Tatsuno, Wei Li, Zheng Xia, Nicolas Stransky, Eric Seiser, Federico Innocenti, Jianjiong Gao, Ritika Kundra, Hongxin Zhang, Zachary Heins, Angelica Ochoa, Chris Sander, Marc Ladanyi, Ronglai Shen, Arshi Arora, Francisco Sanchez-Vega, Nikolaus Schultz, Katayoon Kasaian, Amie Radenbaugh, Karl-Dimiter Bissig, David D. Moore, Yasushi Totoki, Hiromi Nakamura, Tatsuhiro Shibata, Christina Yau, Kiley Graim, Josh Stuart, David Haussler, Betty L. Slagle, Akinyemi I. Ojesina, Panagiotis Katsonis, Amanda Koire, Olivier Lichtarge, Teng-Kuei Hsu, Martin L. Ferguson, John A. Demchok, Ina Felau, Margi Sheth, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan Zhang, Carolyn M. Hutter, Heidi J. Sofia, Roel G.W. Verhaak, Siyuan Zheng, Frederick Lang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Ye Wu, Rashi Naresh, Todd Pihl, Charlie Sun, Yunhu Wan, Christopher Benz, Amy H. Perou, Leigh B. Thorne, Lori Boice, Mei Huang, W. Kimryn Rathmell, Houtan Noushmehr, Fabiano Pinto Saggioro, Daniela Pretti da Cunha Tirapelli, Carlos Gilberto Carlotti Junior, Enio David Mente, Orlando de Castro Silva Jr., Felipe Amstalden Trevisan, Koo Jeong Kang, Keun Soo Ahn, Nasra H. Giama, Catherine D. Moser, Thomas J. Giordano, Michelle Vinco, Theodore H. Welling, Daniel Crain, Erin Curley, Johanna Gardner, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Robin Kelley, Joong-Won Park, Vishal S. Chandan, Lewis R. Roberts, Oliver F. Bathe, Curt H. Hagedorn, J. Todd Auman, Daniel R. O'Brien, Jean-Pierre A. Kocher, Corbin D. Jones, Piotr A. Mieczkowski, Charles M. Perou, Tara Skelly, Donghui Tan, Umadevi Veluvolu, Saianand Balu, Tom Bodenheimer, Alan P. Hoyle, Stuart R. Jefferys, Shaowu Meng, Lisle E. Mose, Yan Shi, Janae V. Simons, Matthew G. Soloway, Jeffrey Roach, Katherine A. Hoadley, Stephen B. Baylin, Hui Shen, Toshinori Hinoue, Moiz S. Bootwalla, David J. Van Den Berg, Daniel J. Weisenberger, Phillip H. Lai, Andrea Holbrook, Mario Berrios, Peter W. Laird Keywords hepatocellular carcinoma; promoter hypermethylation; cancer subtyping; significantly mutated genes; expression profile; sonic hedgehog signaling; metabolic reprogramming; stem cell phenotype; TP53; IDH1/2 Highlights * Analysis of hepatocellular carcinomas integrates data of multiple genomic platforms * Mutated genes reveal oncogenic processes altering hepatocyte energy balance * Multiplex analyses suggest a key role for Sonic hedgehog signaling in HCC * IDH mutations point to a HCC subgroup molecularly similar to cholangiocarcinoma Summary Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1. * Corresponding author Article History: Received 9 November 2016; Revised 2 April 2017; Accepted 26 May 2017 (miscellaneous) Published: June 15, 2017 (footnote)1 Lead Contact (David A. Wheeler)

Cancer -- Care and treatment, Membrane proteins -- Research, and Urothelium -- Research

Author(s): Alexandra Snyder 1,2,*, Tavi Nathanson 3, Samuel A. Funt 1,2, Arun Ahuja 3, Jacqueline Buros Novik 3, Matthew D. Hellmann 1,2, Eliza Chang 3, Bulent Arman Aksoy 3, Hikmat [...]
Background Inhibition of programmed death-ligand 1 (PD-L1) with atezolizumab can induce durable clinical benefit (DCB) in patients with metastatic urothelial cancers, including complete remissions in patients with chemotherapy refractory disease. Although mutation load and PD-L1 immune cell (IC) staining have been associated with response, they lack sufficient sensitivity and specificity for clinical use. Thus, there is a need to evaluate the peripheral blood immune environment and to conduct detailed analyses of mutation load, predicted neoantigens, and immune cellular infiltration in tumors to enhance our understanding of the biologic underpinnings of response and resistance. Methods and findings The goals of this study were to (1) evaluate the association of mutation load and predicted neoantigen load with therapeutic benefit and (2) determine whether intratumoral and peripheral blood T cell receptor (TCR) clonality inform clinical outcomes in urothelial carcinoma treated with atezolizumab. We hypothesized that an elevated mutation load in combination with T cell clonal dominance among intratumoral lymphocytes prior to treatment or among peripheral T cells after treatment would be associated with effective tumor control upon treatment with anti-PD-L1 therapy. We performed whole exome sequencing (WES), RNA sequencing (RNA-seq), and T cell receptor sequencing (TCR-seq) of pretreatment tumor samples as well as TCR-seq of matched, serially collected peripheral blood, collected before and after treatment with atezolizumab. These parameters were assessed for correlation with DCB (defined as progression-free survival [PFS] >6 months), PFS, and overall survival (OS), both alone and in the context of clinical and intratumoral parameters known to be predictive of survival in this disease state. Patients with DCB displayed a higher proportion of tumor-infiltrating T lymphocytes (TIL) (n = 24, Mann-Whitney p = 0.047). Pretreatment peripheral blood TCR clonality below the median was associated with improved PFS (n = 29, log-rank p = 0.048) and OS (n = 29, log-rank p = 0.011). Patients with DCB also demonstrated more substantial expansion of tumor-associated TCR clones in the peripheral blood 3 weeks after starting treatment (n = 22, Mann-Whitney p = 0.022). The combination of high pretreatment peripheral blood TCR clonality with elevated PD-L1 IC staining in tumor tissue was strongly associated with poor clinical outcomes (n = 10, hazard ratio (HR) (mean) = 89.88, HR (median) = 23.41, 95% CI [2.43, 506.94], p(HR > 1) = 0.0014). Marked variations in mutation loads were seen with different somatic variant calling methodologies, which, in turn, impacted associations with clinical outcomes. Missense mutation load, predicted neoantigen load, and expressed neoantigen load did not demonstrate significant association with DCB (n = 25, Mann-Whitney p = 0.22, n = 25, Mann-Whitney p = 0.55, and n = 25, Mann-Whitney p = 0.29, respectively). Instead, we found evidence of time-varying effects of somatic mutation load on PFS in this cohort (n = 25, p = 0.044). A limitation of our study is its small sample size (n = 29), a subset of the patients treated on IMvigor 210 (NCT02108652). Given the number of exploratory analyses performed, we intend for these results to be hypothesis-generating. Conclusions These results demonstrate the complex nature of immune response to checkpoint blockade and the compelling need for greater interrogation and data integration of both host and tumor factors. Incorporating these variables in prospective studies will facilitate identification and treatment of resistant patients.

Drug discovery -- Research, Biological products -- Research, Biological assay -- Usage, and Cell lines -- Research

Sex (Biology) -- Genetic aspects, Sex (Biology) -- Research, Gene expression -- Research, Sex chromosomes -- Physiological aspects, and Sex chromosomes -- Research

Introduction Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and XX females) and at the phenotypic level by the [...]
Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and XX females). The Y chromosome-linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sry-related HMG box-containing gene 9 (SOX9). Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis. Indeed, loss-of-function mutations in SOX3 do not affect sex determination in mice or humans. To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3. Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal. Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry. Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal. Together, these data suggest that SOX3 and SRY are functionally interchangeable in sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.

Swine influenza -- Patient outcomes, Swine influenza -- Reports, and Epidemiology -- Research

Hospital patients -- Health aspects, Epidemics -- United States, Epidemics -- Reports, Swine influenza -- Reports, Swine influenza -- Diagnosis, Swine influenza -- Prognosis, and Polymerase chain reaction -- Usage

Air pollution -- Health aspects and Respiratory tract diseases -- Risk factors

BACKGROUND: Individuals involved in rescue, recovery, demolition, and cleanup at the World Trade Center (WTC) site were exposed to a complex mixture of airborne smoke, dust, combustion gases, acid mists, [...]

Nanotubes -- Usage, Lung diseases -- Risk factors, Lung diseases -- Diagnosis, Lung diseases -- Case studies, and Smoke -- Health aspects

CONTEXT: After the collapse of the World Trade Center (WTC) on 11 September 2001, a dense cloud of dust containing high levels of airborne pollutants covered Manhattan and parts of [...]

Falls (Accidents) -- Prevention, Falls (Accidents) -- Risk factors, Falls (Accidents) -- Economic aspects, and Falls (Accidents) -- Research

Falls (Accidents) -- Risk factors, Falls (Accidents) -- Economic aspects, Falls (Accidents) -- Research, and Medical care, Cost of -- Research

Schizophrenia -- Research, Schizophrenia -- Health aspects, and Genetic research -- Analysis

Author(s): Schizophrenia Working Group of the Psychiatric Genomics Consortium; Stephan Ripke [1, 2]; Benjamin M. Neale [1, 2, 3, 4]; Aiden Corvin [5]; James T. R. Walters [6]; Kai-How Farh [...]
Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.