ALBERT

Description: The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering approximately 4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for approximately 60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3207357/" 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/PMC3207357/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lindblad-Toh, Kerstin -- Garber, Manuel -- Zuk, Or -- Lin, Michael F -- Parker, Brian J -- Washietl, Stefan -- Kheradpour, Pouya -- Ernst, Jason -- Jordan, Gregory -- Mauceli, Evan -- Ward, Lucas D -- Lowe, Craig B -- Holloway, Alisha K -- Clamp, Michele -- Gnerre, Sante -- Alfoldi, Jessica -- Beal, Kathryn -- Chang, Jean -- Clawson, Hiram -- Cuff, James -- Di Palma, Federica -- Fitzgerald, Stephen -- Flicek, Paul -- Guttman, Mitchell -- Hubisz, Melissa J -- Jaffe, David B -- Jungreis, Irwin -- Kent, W James -- Kostka, Dennis -- Lara, Marcia -- Martins, Andre L -- Massingham, Tim -- Moltke, Ida -- Raney, Brian J -- Rasmussen, Matthew D -- Robinson, Jim -- Stark, Alexander -- Vilella, Albert J -- Wen, Jiayu -- Xie, Xiaohui -- Zody, Michael C -- Broad Institute Sequencing Platform and Whole Genome Assembly Team -- Baldwin, Jen -- Bloom, Toby -- Chin, Chee Whye -- Heiman, Dave -- Nicol, Robert -- Nusbaum, Chad -- Young, Sarah -- Wilkinson, Jane -- Worley, Kim C -- Kovar, Christie L -- Muzny, Donna M -- Gibbs, Richard A -- Baylor College of Medicine Human Genome Sequencing Center Sequencing Team -- Cree, Andrew -- Dihn, Huyen H -- Fowler, Gerald -- Jhangiani, Shalili -- Joshi, Vandita -- Lee, Sandra -- Lewis, Lora R -- Nazareth, Lynne V -- Okwuonu, Geoffrey -- Santibanez, Jireh -- Warren, Wesley C -- Mardis, Elaine R -- Weinstock, George M -- Wilson, Richard K -- Genome Institute at Washington University -- Delehaunty, Kim -- Dooling, David -- Fronik, Catrina -- Fulton, Lucinda -- Fulton, Bob -- Graves, Tina -- Minx, Patrick -- Sodergren, Erica -- Birney, Ewan -- Margulies, Elliott H -- Herrero, Javier -- Green, Eric D -- Haussler, David -- Siepel, Adam -- Goldman, Nick -- Pollard, Katherine S -- Pedersen, Jakob S -- Lander, Eric S -- Kellis, Manolis -- 095908/Wellcome Trust/United Kingdom -- GM82901/GM/NIGMS NIH HHS/ -- R01 HG003474/HG/NHGRI NIH HHS/ -- R01 HG004037/HG/NHGRI NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54 HG003067-09/HG/NHGRI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Oct 12;478(7370):476-82. doi: 10.1038/nature10530.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. kersli@broadinstitute.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21993624" target="_blank"〉PubMed〈/a〉

Description: Defects in the availability of haem substrates or the catalytic activity of the terminal enzyme in haem biosynthesis, ferrochelatase (Fech), impair haem synthesis and thus cause human congenital anaemias. The interdependent functions of regulators of mitochondrial homeostasis and enzymes responsible for haem synthesis are largely unknown. To investigate this we used zebrafish genetic screens and cloned mitochondrial ATPase inhibitory factor 1 (atpif1) from a zebrafish mutant with profound anaemia, pinotage (pnt (tq209)). Here we describe a direct mechanism establishing that Atpif1 regulates the catalytic efficiency of vertebrate Fech to synthesize haem. The loss of Atpif1 impairs haemoglobin synthesis in zebrafish, mouse and human haematopoietic models as a consequence of diminished Fech activity and elevated mitochondrial pH. To understand the relationship between mitochondrial pH, redox potential, [2Fe-2S] clusters and Fech activity, we used genetic complementation studies of Fech constructs with or without [2Fe-2S] clusters in pnt, as well as pharmacological agents modulating mitochondrial pH and redox potential. The presence of [2Fe-2S] cluster renders vertebrate Fech vulnerable to perturbations in Atpif1-regulated mitochondrial pH and redox potential. Therefore, Atpif1 deficiency reduces the efficiency of vertebrate Fech to synthesize haem, resulting in anaemia. The identification of mitochondrial Atpif1 as a regulator of haem synthesis advances our understanding of the mechanisms regulating mitochondrial haem homeostasis and red blood cell development. An ATPIF1 deficiency may contribute to important human diseases, such as congenital sideroblastic anaemias and mitochondriopathies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504625/" 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/PMC3504625/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shah, Dhvanit I -- Takahashi-Makise, Naoko -- Cooney, Jeffrey D -- Li, Liangtao -- Schultz, Iman J -- Pierce, Eric L -- Narla, Anupama -- Seguin, Alexandra -- Hattangadi, Shilpa M -- Medlock, Amy E -- Langer, Nathaniel B -- Dailey, Tamara A -- Hurst, Slater N -- Faccenda, Danilo -- Wiwczar, Jessica M -- Heggers, Spencer K -- Vogin, Guillaume -- Chen, Wen -- Chen, Caiyong -- Campagna, Dean R -- Brugnara, Carlo -- Zhou, Yi -- Ebert, Benjamin L -- Danial, Nika N -- Fleming, Mark D -- Ward, Diane M -- Campanella, Michelangelo -- Dailey, Harry A -- Kaplan, Jerry -- Paw, Barry H -- K01 DK085217/DK/NIDDK NIH HHS/ -- P01 HL032262/HL/NHLBI NIH HHS/ -- P30 DK072437/DK/NIDDK NIH HHS/ -- R01 DK052380/DK/NIDDK NIH HHS/ -- R01 DK070838/DK/NIDDK NIH HHS/ -- R01 DK096051/DK/NIDDK NIH HHS/ -- R01 HL082945/HL/NHLBI NIH HHS/ -- T32 GM007223/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Nov 22;491(7425):608-12. doi: 10.1038/nature11536. Epub 2012 Nov 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23135403" target="_blank"〉PubMed〈/a〉

Description: The basal ganglia are subcortical nuclei that control voluntary actions, and they are affected by a number of debilitating neurological disorders. The prevailing model of basal ganglia function proposes that two orthogonal projection circuits originating from distinct populations of spiny projection neurons (SPNs) in the striatum--the so-called direct and indirect pathways--have opposing effects on movement: activity of direct-pathway SPNs is thought to facilitate movement, whereas activity of indirect-pathway SPNs is presumed to inhibit movement. This model has been difficult to test owing to the lack of methods to selectively measure the activity of direct- and indirect-pathway SPNs in freely moving animals. Here we develop a novel in vivo method to specifically measure direct- and indirect-pathway SPN activity, using Cre-dependent viral expression of the genetically encoded calcium indicator (GECI) GCaMP3 in the dorsal striatum of D1-Cre (direct-pathway-specific) and A2A-Cre (indirect-pathway-specific) mice. Using fibre optics and time-correlated single-photon counting (TCSPC) in mice performing an operant task, we observed transient increases in neural activity in both direct- and indirect-pathway SPNs when animals initiated actions, but not when they were inactive. Concurrent activation of SPNs from both pathways in one hemisphere preceded the initiation of contraversive movements and predicted the occurrence of specific movements within 500 ms. These observations challenge the classical view of basal ganglia function and may have implications for understanding the origin of motor symptoms in basal ganglia disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039389/" 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/PMC4039389/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cui, Guohong -- Jun, Sang Beom -- Jin, Xin -- Pham, Michael D -- Vogel, Steven S -- Lovinger, David M -- Costa, Rui M -- 243393/European Research Council/International -- ZIA AA000407-12/Intramural NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Feb 14;494(7436):238-42. doi: 10.1038/nature11846. Epub 2013 Jan 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section on In Vivo Neural Function, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892-9412, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23354054" target="_blank"〉PubMed〈/a〉

Description: Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530898/" 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/PMC3530898/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Biankin, Andrew V -- Waddell, Nicola -- Kassahn, Karin S -- Gingras, Marie-Claude -- Muthuswamy, Lakshmi B -- Johns, Amber L -- Miller, David K -- Wilson, Peter J -- Patch, Ann-Marie -- Wu, Jianmin -- Chang, David K -- Cowley, Mark J -- Gardiner, Brooke B -- Song, Sarah -- Harliwong, Ivon -- Idrisoglu, Senel -- Nourse, Craig -- Nourbakhsh, Ehsan -- Manning, Suzanne -- Wani, Shivangi -- Gongora, Milena -- Pajic, Marina -- Scarlett, Christopher J -- Gill, Anthony J -- Pinho, Andreia V -- Rooman, Ilse -- Anderson, Matthew -- Holmes, Oliver -- Leonard, Conrad -- Taylor, Darrin -- Wood, Scott -- Xu, Qinying -- Nones, Katia -- Fink, J Lynn -- Christ, Angelika -- Bruxner, Tim -- Cloonan, Nicole -- Kolle, Gabriel -- Newell, Felicity -- Pinese, Mark -- Mead, R Scott -- Humphris, Jeremy L -- Kaplan, Warren -- Jones, Marc D -- Colvin, Emily K -- Nagrial, Adnan M -- Humphrey, Emily S -- Chou, Angela -- Chin, Venessa T -- Chantrill, Lorraine A -- Mawson, Amanda -- Samra, Jaswinder S -- Kench, James G -- Lovell, Jessica A -- Daly, Roger J -- Merrett, Neil D -- Toon, Christopher -- Epari, Krishna -- Nguyen, Nam Q -- Barbour, Andrew -- Zeps, Nikolajs -- Australian Pancreatic Cancer Genome Initiative -- Kakkar, Nipun -- Zhao, Fengmei -- Wu, Yuan Qing -- Wang, Min -- Muzny, Donna M -- Fisher, William E -- Brunicardi, F Charles -- Hodges, Sally E -- Reid, Jeffrey G -- Drummond, Jennifer -- Chang, Kyle -- Han, Yi -- Lewis, Lora R -- Dinh, Huyen -- Buhay, Christian J -- Beck, Timothy -- Timms, Lee -- Sam, Michelle -- Begley, Kimberly -- Brown, Andrew -- Pai, Deepa -- Panchal, Ami -- Buchner, Nicholas -- De Borja, Richard -- Denroche, Robert E -- Yung, Christina K -- Serra, Stefano -- Onetto, Nicole -- Mukhopadhyay, Debabrata -- Tsao, Ming-Sound -- Shaw, Patricia A -- Petersen, Gloria M -- Gallinger, Steven -- Hruban, Ralph H -- Maitra, Anirban -- Iacobuzio-Donahue, Christine A -- Schulick, Richard D -- Wolfgang, Christopher L -- Morgan, Richard A -- Lawlor, Rita T -- Capelli, Paola -- Corbo, Vincenzo -- Scardoni, Maria -- Tortora, Giampaolo -- Tempero, Margaret A -- Mann, Karen M -- Jenkins, Nancy A -- Perez-Mancera, Pedro A -- Adams, David J -- Largaespada, David A -- Wessels, Lodewyk F A -- Rust, Alistair G -- Stein, Lincoln D -- Tuveson, David A -- Copeland, Neal G -- Musgrove, Elizabeth A -- Scarpa, Aldo -- Eshleman, James R -- Hudson, Thomas J -- Sutherland, Robert L -- Wheeler, David A -- Pearson, John V -- McPherson, John D -- Gibbs, Richard A -- Grimmond, Sean M -- 13031/Cancer Research UK/United Kingdom -- 2P50CA101955/CA/NCI NIH HHS/ -- P01CA134292/CA/NCI NIH HHS/ -- P50 CA101955/CA/NCI NIH HHS/ -- P50 CA102701/CA/NCI NIH HHS/ -- P50CA062924/CA/NCI NIH HHS/ -- R01 CA097075/CA/NCI NIH HHS/ -- R01 CA97075/CA/NCI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- Cancer Research UK/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2012 Nov 15;491(7424):399-405. doi: 10.1038/nature11547. Epub 2012 Oct 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23103869" target="_blank"〉PubMed〈/a〉

Description: The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266106/" 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/PMC4266106/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yue, Feng -- Cheng, Yong -- Breschi, Alessandra -- Vierstra, Jeff -- Wu, Weisheng -- Ryba, Tyrone -- Sandstrom, Richard -- Ma, Zhihai -- Davis, Carrie -- Pope, Benjamin D -- Shen, Yin -- Pervouchine, Dmitri D -- Djebali, Sarah -- Thurman, Robert E -- Kaul, Rajinder -- Rynes, Eric -- Kirilusha, Anthony -- Marinov, Georgi K -- Williams, Brian A -- Trout, Diane -- Amrhein, Henry -- Fisher-Aylor, Katherine -- Antoshechkin, Igor -- DeSalvo, Gilberto -- See, Lei-Hoon -- Fastuca, Meagan -- Drenkow, Jorg -- Zaleski, Chris -- Dobin, Alex -- Prieto, Pablo -- Lagarde, Julien -- Bussotti, Giovanni -- Tanzer, Andrea -- Denas, Olgert -- Li, Kanwei -- Bender, M A -- Zhang, Miaohua -- Byron, Rachel -- Groudine, Mark T -- McCleary, David -- Pham, Long -- Ye, Zhen -- Kuan, Samantha -- Edsall, Lee -- Wu, Yi-Chieh -- Rasmussen, Matthew D -- Bansal, Mukul S -- Kellis, Manolis -- Keller, Cheryl A -- Morrissey, Christapher S -- Mishra, Tejaswini -- Jain, Deepti -- Dogan, Nergiz -- Harris, Robert S -- Cayting, Philip -- Kawli, Trupti -- Boyle, Alan P -- Euskirchen, Ghia -- Kundaje, Anshul -- Lin, Shin -- Lin, Yiing -- Jansen, Camden -- Malladi, Venkat S -- Cline, Melissa S -- Erickson, Drew T -- Kirkup, Vanessa M -- Learned, Katrina -- Sloan, Cricket A -- Rosenbloom, Kate R -- Lacerda de Sousa, Beatriz -- Beal, Kathryn -- Pignatelli, Miguel -- Flicek, Paul -- Lian, Jin -- Kahveci, Tamer -- Lee, Dongwon -- Kent, W James -- Ramalho Santos, Miguel -- Herrero, Javier -- Notredame, Cedric -- Johnson, Audra -- Vong, Shinny -- Lee, Kristen -- Bates, Daniel -- Neri, Fidencio -- Diegel, Morgan -- Canfield, Theresa -- Sabo, Peter J -- Wilken, Matthew S -- Reh, Thomas A -- Giste, Erika -- Shafer, Anthony -- Kutyavin, Tanya -- Haugen, Eric -- Dunn, Douglas -- Reynolds, Alex P -- Neph, Shane -- Humbert, Richard -- Hansen, R Scott -- De Bruijn, Marella -- Selleri, Licia -- Rudensky, Alexander -- Josefowicz, Steven -- Samstein, Robert -- Eichler, Evan E -- Orkin, Stuart H -- Levasseur, Dana -- Papayannopoulou, Thalia -- Chang, Kai-Hsin -- Skoultchi, Arthur -- Gosh, Srikanta -- Disteche, Christine -- Treuting, Piper -- Wang, Yanli -- Weiss, Mitchell J -- Blobel, Gerd A -- Cao, Xiaoyi -- Zhong, Sheng -- Wang, Ting -- Good, Peter J -- Lowdon, Rebecca F -- Adams, Leslie B -- Zhou, Xiao-Qiao -- Pazin, Michael J -- Feingold, Elise A -- Wold, Barbara -- Taylor, James -- Mortazavi, Ali -- Weissman, Sherman M -- Stamatoyannopoulos, John A -- Snyder, Michael P -- Guigo, Roderic -- Gingeras, Thomas R -- Gilbert, David M -- Hardison, Ross C -- Beer, Michael A -- Ren, Bing -- Mouse ENCODE Consortium -- 095908/Wellcome Trust/United Kingdom -- 1U54HG007004/HG/NHGRI NIH HHS/ -- 3RC2HG005602/HG/NHGRI NIH HHS/ -- F31CA165863/CA/NCI NIH HHS/ -- F32HL110473/HL/NHLBI NIH HHS/ -- GM083337/GM/NIGMS NIH HHS/ -- GM085354/GM/NIGMS NIH HHS/ -- K99HL119617/HL/NHLBI NIH HHS/ -- P01 GM085354/GM/NIGMS NIH HHS/ -- P01 HL064190/HL/NHLBI NIH HHS/ -- P01 HL110860/HL/NHLBI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- P30 CA045508/CA/NCI NIH HHS/ -- R01 DK065806/DK/NIDDK NIH HHS/ -- R01 DK096266/DK/NIDDK NIH HHS/ -- R01 ES024992/ES/NIEHS NIH HHS/ -- R01 EY021482/EY/NEI NIH HHS/ -- R01 GM083337/GM/NIGMS NIH HHS/ -- R01 HG004037/HG/NHGRI NIH HHS/ -- R01 HG007175/HG/NHGRI NIH HHS/ -- R01 HG007348/HG/NHGRI NIH HHS/ -- R01 HG007354/HG/NHGRI NIH HHS/ -- R01DK065806/DK/NIDDK NIH HHS/ -- R01HD043997-09/HD/NICHD NIH HHS/ -- R01HG003991/HG/NHGRI NIH HHS/ -- R37 DK044746/DK/NIDDK NIH HHS/ -- R56 DK065806/DK/NIDDK NIH HHS/ -- RC2 HG005573/HG/NHGRI NIH HHS/ -- RC2HG005573/HG/NHGRI NIH HHS/ -- T32 GM081739/GM/NIGMS NIH HHS/ -- U01 HL099656/HL/NHLBI NIH HHS/ -- U01 HL099993/HL/NHLBI NIH HHS/ -- U54 HG006997/HG/NHGRI NIH HHS/ -- U54 HG006998/HG/NHGRI NIH HHS/ -- U54 HG007004/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Nov 20;515(7527):355-64. doi: 10.1038/nature13992.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Ludwig Institute for Cancer Research and University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093, USA. [2] Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania 17033, USA. ; Department of Genetics, Stanford University, 300 Pasteur Drive, MC-5477 Stanford, California 94305, USA. ; Bioinformatics and Genomics, Centre for Genomic Regulation (CRG) and UPF, Doctor Aiguader, 88, 08003 Barcelona, Catalonia, Spain. ; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. ; Center for Comparative Genomics and Bioinformatics, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; Department of Biological Science, 319 Stadium Drive, Florida State University, Tallahassee, Florida 32306-4295, USA. ; Functional Genomics, Cold Spring Harbor Laboratory, Bungtown Road, Cold Spring Harbor, New York 11724, USA. ; Ludwig Institute for Cancer Research and University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093, USA. ; Division of Biology, California Institute of Technology, Pasadena, California 91125, USA. ; 1] Bioinformatics and Genomics, Centre for Genomic Regulation (CRG) and UPF, Doctor Aiguader, 88, 08003 Barcelona, Catalonia, Spain. [2] Department of Theoretical Chemistry, Faculty of Chemistry, University of Vienna, Waehringerstrasse 17/3/303, A-1090 Vienna, Austria. ; Departments of Biology and Mathematics and Computer Science, Emory University, O. Wayne Rollins Research Center, 1510 Clifton Road NE, Atlanta, Georgia 30322, USA. ; 1] Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA. [2] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; 1] Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. [2] Department of Radiation Oncology, University of Washington, Seattle, Washington 98195, USA. ; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA. ; 1] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California 92697, USA. ; Center for Biomolecular Science and Engineering, School of Engineering, University of California Santa Cruz (UCSC), Santa Cruz, California 95064, USA. ; Departments of Obstetrics/Gynecology and Pathology, and Center for Reproductive Sciences, University of California San Francisco, San Francisco, California 94143, USA. ; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. ; Yale University, Department of Genetics, PO Box 208005, 333 Cedar Street, New Haven, Connecticut 06520-8005, USA. ; Computer &Information Sciences &Engineering, University of Florida, Gainesville, Florida 32611, USA. ; McKusick-Nathans Institute of Genetic Medicine and Department of Biomedical Engineering, Johns Hopkins University, 733 N. Broadway, BRB 573 Baltimore, Maryland 21205, USA. ; 1] European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. [2] Bill Lyons Informatics Centre, UCL Cancer Institute, University College London, London WC1E 6DD, UK. ; Department of Biological Structure, University of Washington, HSB I-516, 1959 NE Pacific Street, Seattle, Washington 98195, USA. ; MRC Molecular Haemotology Unit, University of Oxford, Oxford OX3 9DS, UK. ; Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA. ; HHMI and Ludwig Center at Memorial Sloan Kettering Cancer Center, Immunology Program, Memorial Sloan Kettering Cancer Canter, New York, New York 10065, USA. ; Dana Farber Cancer Institute, Harvard Medical School, Cambridge, Massachusetts 02138, USA. ; University of Iowa Carver College of Medicine, Department of Internal Medicine, Iowa City, Iowa 52242, USA. ; Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA. ; Department of Pathology, University of Washington, Seattle, Washington 98195, USA. ; Department of Comparative Medicine, University of Washington, Seattle, Washington 98195, USA. ; Bioinformatics and Genomics program, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; Department of Hematology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. [2] Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. ; Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63108, USA. ; NHGRI, National Institutes of Health, 5635 Fishers Lane, Bethesda, Maryland 20892-9307, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409824" target="_blank"〉PubMed〈/a〉

Description: Ecological differences often evolve early in speciation as divergent natural selection drives adaptation to distinct ecological niches, leading ultimately to reproductive isolation. Although this process is a major generator of biodiversity, its genetic basis is still poorly understood. Here we investigate the genetic architecture of niche differentiation in a sympatric species pair of threespine stickleback fish by mapping the environment-dependent effects of phenotypic traits on hybrid feeding and performance under semi-natural conditions. We show that multiple, unlinked loci act largely additively to determine position along the major niche axis separating these recently diverged species. We also find that functional mismatch between phenotypic traits reduces the growth of some stickleback hybrids beyond that expected from an intermediate phenotype, suggesting a role for epistasis between the underlying genes. This functional mismatch might lead to hybrid incompatibilities that are analogous to those underlying intrinsic reproductive isolation but depend on the ecological context.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149549/" 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/PMC4149549/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arnegard, Matthew E -- McGee, Matthew D -- Matthews, Blake -- Marchinko, Kerry B -- Conte, Gina L -- Kabir, Sahriar -- Bedford, Nicole -- Bergek, Sara -- Chan, Yingguang Frank -- Jones, Felicity C -- Kingsley, David M -- Peichel, Catherine L -- Schluter, Dolph -- F32 GM086125/GM/NIGMS NIH HHS/ -- F32GM086125/GM/NIGMS NIH HHS/ -- P30 CA015704/CA/NCI NIH HHS/ -- P50 HG002568/HG/NHGRI NIH HHS/ -- R01 GM089733/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Jul 17;511(7509):307-11. doi: 10.1038/nature13301. Epub 2014 Jun 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Fred Hutchinson Cancer Research Center, Human Biology and Basic Sciences Divisions, 1100 Fairview Avenue North, Seattle, Washington 98109, USA [2] University of British Columbia, Biodiversity Research Centre and Zoology Department, 6270 University Boulevard, Vancouver, British Columbia V6T 1Z4, Canada. ; University of California at Davis, Department of Evolution and Ecology, One Shields Avenue, Davis, California 95616, USA. ; EAWAG, Department of Aquatic Ecology, Center for Ecology, Evolution, and Biogeochemistry, Seestrasse 79, 6047 Kastanienbaum, Switzerland. ; University of British Columbia, Biodiversity Research Centre and Zoology Department, 6270 University Boulevard, Vancouver, British Columbia V6T 1Z4, Canada. ; 1] Uppsala University, Department of Animal Ecology, Evolutionary Biology Centre (EBC), Norbyvagen 18D, SE-75236 Uppsala, Sweden [2] Swedish University of Agricultural Sciences, Department of Aquatic Resources, Stangholmsvagen 2, SE-17893 Drottningholm, Sweden. ; Stanford University School of Medicine, Department of Developmental Biology and Howard Hughes Medical Institute, 279 Campus Drive, Stanford, California 94305, USA. ; Fred Hutchinson Cancer Research Center, Human Biology and Basic Sciences Divisions, 1100 Fairview Avenue North, Seattle, Washington 98109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24909991" target="_blank"〉PubMed〈/a〉

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〉

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〉

Description: Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385933/" 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/PMC3385933/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Zhao -- Cheng, Katherine -- Walton, Zandra -- Wang, Yuchuan -- Ebi, Hiromichi -- Shimamura, Takeshi -- Liu, Yan -- Tupper, Tanya -- Ouyang, Jing -- Li, Jie -- Gao, Peng -- Woo, Michele S -- Xu, Chunxiao -- Yanagita, Masahiko -- Altabef, Abigail -- Wang, Shumei -- Lee, Charles -- Nakada, Yuji -- Pena, Christopher G -- Sun, Yanping -- Franchetti, Yoko -- Yao, Catherine -- Saur, Amy -- Cameron, Michael D -- Nishino, Mizuki -- Hayes, D Neil -- Wilkerson, Matthew D -- Roberts, Patrick J -- Lee, Carrie B -- Bardeesy, Nabeel -- Butaney, Mohit -- Chirieac, Lucian R -- Costa, Daniel B -- Jackman, David -- Sharpless, Norman E -- Castrillon, Diego H -- Demetri, George D -- Janne, Pasi A -- Pandolfi, Pier Paolo -- Cantley, Lewis C -- Kung, Andrew L -- Engelman, Jeffrey A -- Wong, Kwok-Kin -- 1U01CA141576/CA/NCI NIH HHS/ -- CA122794/CA/NCI NIH HHS/ -- CA137008/CA/NCI NIH HHS/ -- CA137008-01/CA/NCI NIH HHS/ -- CA137181/CA/NCI NIH HHS/ -- CA140594/CA/NCI NIH HHS/ -- CA147940/CA/NCI NIH HHS/ -- K23 CA157631/CA/NCI NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P30 CA016086/CA/NCI NIH HHS/ -- P50 CA090578/CA/NCI NIH HHS/ -- P50 CA090578-06/CA/NCI NIH HHS/ -- P50CA090578/CA/NCI NIH HHS/ -- R01 CA122794/CA/NCI NIH HHS/ -- R01 CA122794-01/CA/NCI NIH HHS/ -- R01 CA137008/CA/NCI NIH HHS/ -- R01 CA137008-01/CA/NCI NIH HHS/ -- R01 CA137181/CA/NCI NIH HHS/ -- R01 CA137181-01A2/CA/NCI NIH HHS/ -- R01 CA140594/CA/NCI NIH HHS/ -- R01 CA140594-01/CA/NCI NIH HHS/ -- R01 CA163896/CA/NCI NIH HHS/ -- RC2 CA147940/CA/NCI NIH HHS/ -- RC2 CA147940-01/CA/NCI NIH HHS/ -- U01 CA141576/CA/NCI NIH HHS/ -- U01 CA141576-01/CA/NCI NIH HHS/ -- England -- Nature. 2012 Mar 18;483(7391):613-7. doi: 10.1038/nature10937.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22425996" target="_blank"〉PubMed〈/a〉

Description: Fossil crocodyliforms discovered in recent years have revealed a level of morphological and ecological diversity not exhibited by extant members of the group. This diversity is particularly notable among taxa of the Cretaceous Period (144-65 million years ago) recovered from former Gondwanan landmasses. Here we report the discovery of a new species of Cretaceous notosuchian crocodyliform from the Rukwa Rift Basin of southwestern Tanzania. This small-bodied form deviates significantly from more typical crocodyliform craniodental morphologies, having a short, broad skull, robust lower jaw, and a dentition with relatively few teeth that nonetheless show marked heterodonty. The presence of morphologically complex, complementary upper and lower molariform teeth suggests a degree of crown-crown contact during jaw adduction that is unmatched among known crocodyliforms, paralleling the level of occlusal complexity seen in mammals and their extinct relatives. The presence of another small-bodied mammal-like crocodyliform in the Cretaceous of Gondwana indicates that notosuchians probably filled niches and inhabited ecomorphospace that were otherwise occupied by mammals on northern continents.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉O'Connor, Patrick M -- Sertich, Joseph J W -- Stevens, Nancy J -- Roberts, Eric M -- Gottfried, Michael D -- Hieronymus, Tobin L -- Jinnah, Zubair A -- Ridgely, Ryan -- Ngasala, Sifa E -- Temba, Jesuit -- England -- Nature. 2010 Aug 5;466(7307):748-51. doi: 10.1038/nature09061.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biomedical Sciences, Ohio University College of Osteopathic Medicine, 228 Irvine Hall, Athens, Ohio 45701, USA. oconnorp@ohio.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20686573" target="_blank"〉PubMed〈/a〉