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  • 1
    Abstract: Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
    Type of Publication: Journal article published
    PubMed ID: 27252175
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  • 2
    Abstract: Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
    Type of Publication: Journal article published
    PubMed ID: 27252175
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  • 3
    Publication Date: 2013-02-02
    Description: The geographic origins of breeds and the genetic basis of variation within the widely distributed and phenotypically diverse domestic rock pigeon (Columba livia) remain largely unknown. We generated a rock pigeon reference genome and additional genome sequences representing domestic and feral populations. We found evidence for the origins of major breed groups in the Middle East and contributions from a racing breed to North American feral populations. We identified the gene EphB2 as a strong candidate for the derived head crest phenotype shared by numerous breeds, an important trait in mate selection in many avian species. We also found evidence that this trait evolved just once and spread throughout the species, and that the crest originates early in development by the localized molecular reversal of feather bud polarity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778192/" 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/PMC3778192/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shapiro, Michael D -- Kronenberg, Zev -- Li, Cai -- Domyan, Eric T -- Pan, Hailin -- Campbell, Michael -- Tan, Hao -- Huff, Chad D -- Hu, Haofu -- Vickrey, Anna I -- Nielsen, Sandra C A -- Stringham, Sydney A -- Hu, Hao -- Willerslev, Eske -- Gilbert, M Thomas P -- Yandell, Mark -- Zhang, Guojie -- Wang, Jun -- GO RC2HG005619/HG/NHGRI NIH HHS/ -- R01 GM104390/GM/NIGMS NIH HHS/ -- R01 HG004694/HG/NHGRI NIH HHS/ -- R01HG004694/HG/NHGRI NIH HHS/ -- R44 HG006579/HG/NHGRI NIH HHS/ -- RC2 HG005619/HG/NHGRI NIH HHS/ -- T32 GM007464/GM/NIGMS NIH HHS/ -- T32 HD007491/HD/NICHD NIH HHS/ -- T32GM007464/GM/NIGMS NIH HHS/ -- T32HD07491/HD/NICHD NIH HHS/ -- New York, N.Y. -- Science. 2013 Mar 1;339(6123):1063-7. doi: 10.1126/science.1230422. Epub 2013 Jan 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, University of Utah, Salt Lake City, UT 84112, USA. mike.shapiro@utah.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23371554" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Animals, Domestic/anatomy & histology/classification/genetics ; Animals, Wild/anatomy & histology/classification/genetics ; Breeding ; Columbidae/anatomy & histology/*classification/*genetics ; *Evolution, Molecular ; Feathers/anatomy & histology ; *Genetic Variation ; Genome ; Head/*anatomy & histology ; Models, Genetic ; Molecular Sequence Data ; Phylogeny ; Polymorphism, Single Nucleotide ; *Quantitative Trait, Heritable ; Receptor, EphB2/genetics ; Sequence Analysis, DNA
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2012-07-18
    Description: Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS), it has been difficult to demonstrate which variants are causal and what role they have in disease. Moreover, the modest contribution that these variants make to disease risk has raised questions regarding their medical relevance. Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS), but not with other autoimmune conditions such as rheumatoid arthritis, psoriasis and Crohn's disease. By analysing MS GWAS data in conjunction with the 1000 Genomes Project data we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF-blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268493/" 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/PMC4268493/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gregory, Adam P -- Dendrou, Calliope A -- Attfield, Kathrine E -- Haghikia, Aiden -- Xifara, Dionysia K -- Butter, Falk -- Poschmann, Gereon -- Kaur, Gurman -- Lambert, Lydia -- Leach, Oliver A -- Promel, Simone -- Punwani, Divya -- Felce, James H -- Davis, Simon J -- Gold, Ralf -- Nielsen, Finn C -- Siegel, Richard M -- Mann, Matthias -- Bell, John I -- McVean, Gil -- Fugger, Lars -- 086084/Wellcome Trust/United Kingdom -- 086084/Z/08/Z/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 090532/Z/09/Z/Wellcome Trust/United Kingdom -- 098274/Wellcome Trust/United Kingdom -- G0800500/Medical Research Council/United Kingdom -- G1000800I/Medical Research Council/United Kingdom -- MC_U137881016/Medical Research Council/United Kingdom -- MC_UU_12010/3/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2012 Aug 23;488(7412):508-11. doi: 10.1038/nature11307.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22801493" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Exons/genetics ; Genetic Predisposition to Disease/*genetics ; Genome, Human/genetics ; Genome-Wide Association Study ; Genomics ; Genotype ; Great Britain ; Humans ; Multiple Sclerosis/*chemically induced/drug therapy/*genetics ; Polymorphism, Single Nucleotide/*genetics ; RNA Splicing/genetics ; Receptors, Tumor Necrosis Factor, Type I/analysis/*genetics/metabolism ; Solubility ; Tumor Necrosis Factor-alpha/*antagonists & inhibitors/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2014-12-04
    Description: Human cancers, including breast cancers, comprise clones differing in mutation content. Clones evolve dynamically in space and time following principles of Darwinian evolution, underpinning important emergent features such as drug resistance and metastasis. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours. However, the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours have not been systematically examined at single-cell resolution. Here we show, using deep-genome and single-cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all 15 cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (〈5% of starting population) clones to moderate, polyclonal engraftment. Furthermore, ongoing clonal dynamics during serial passaging is a feature of tumours experiencing modest initial selection. Through single-cell sequencing, we show that major mutation clusters estimated from tumour population sequencing relate predictably to the most abundant clonal genotypes, even in clonally complex and rapidly evolving cases. Finally, we show that similar clonal expansion patterns can emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. Our results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies using patient-derived breast cancer xenoengraftment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Eirew, Peter -- Steif, Adi -- Khattra, Jaswinder -- Ha, Gavin -- Yap, Damian -- Farahani, Hossein -- Gelmon, Karen -- Chia, Stephen -- Mar, Colin -- Wan, Adrian -- Laks, Emma -- Biele, Justina -- Shumansky, Karey -- Rosner, Jamie -- McPherson, Andrew -- Nielsen, Cydney -- Roth, Andrew J L -- Lefebvre, Calvin -- Bashashati, Ali -- de Souza, Camila -- Siu, Celia -- Aniba, Radhouane -- Brimhall, Jazmine -- Oloumi, Arusha -- Osako, Tomo -- Bruna, Alejandra -- Sandoval, Jose L -- Algara, Teresa -- Greenwood, Wendy -- Leung, Kaston -- Cheng, Hongwei -- Xue, Hui -- Wang, Yuzhuo -- Lin, Dong -- Mungall, Andrew J -- Moore, Richard -- Zhao, Yongjun -- Lorette, Julie -- Nguyen, Long -- Huntsman, David -- Eaves, Connie J -- Hansen, Carl -- Marra, Marco A -- Caldas, Carlos -- Shah, Sohrab P -- Aparicio, Samuel -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2015 Feb 19;518(7539):422-6. doi: 10.1038/nature13952. Epub 2014 Nov 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada. ; Department of Medical Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada. ; Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada. ; 1] Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK [2] Cancer Research UK Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK. ; 1] Centre for High-Throughput Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada [2] Department of Physics and Astronomy, University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada. ; 1] Department of Experimental Therapeutics, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada. ; Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada. ; Centre for Translational and Applied Genomics, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada. ; 1] Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada [2] Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada. ; 1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada [2] Centre for Translational and Applied Genomics, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada. ; 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada [3] Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada. ; 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada [3] Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada [4] Centre for Translational and Applied Genomics, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470049" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/*genetics/*pathology/secondary ; Clone Cells/*metabolism/*pathology ; DNA Mutational Analysis ; Genome, Human/*genetics ; Genomics ; Genotype ; High-Throughput Nucleotide Sequencing ; Humans ; Mice ; Neoplasm Transplantation ; *Single-Cell Analysis ; Time Factors ; Transplantation, Heterologous ; *Xenograft Model Antitumor Assays/methods
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    Yingchang Lu, Alicia Beeghly–Fadiel, Lang Wu, Xingyi Guo, Bingshan Li, Joellen M. Schildkraut, Hae Kyung Im, Yian A. Chen, Jennifer B. Permuth, Brett M. Reid, Jamie K. Teer, Kirsten B. Moysich, Irene L. Andrulis, Hoda Anton–Culver, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Javier Benitez, Line Bȷorge, James Brenton, Ralf Butzow, Trinidad Caldes, Maria A. Caligo, Ian Campbell, Jenny Chang–Claude, Kathleen B.M. Claes, Fergus J. Couch, Daniel W. Cramer, Mary B. Daly, Anna de; Fazio, Joe Dennis, Orland Diez, Susan M. Domchek, Thilo Dork, Douglas F. Easton, Diana M. Eccles, Peter A. Fasching, Renee T. Fortner, George Fountzilas, Eitan Friedman, Patricia A. Ganz, Judy Garber, Graham G. Giles, Andrew K. Godwin, David E. Goldgar, Marc T. Goodman, Mark H. Greene, Jacek Gronwald, Ute Hamann, Florian Heitz, Michelle A.T. Hildebrandt, Claus K. Hogdall, Antoinette Hollestelle, Peter J. Hulick, David G. Huntsman, Evgeny N. Imyanitov, Claudine Isaacs, Anna Jakubowska, Paul James, Beth Y. Karlan, Linda E. Kelemen, Lambertus A. Kiemeney, Susanne K. Kȷaer, Ava Kwong, Nhu D. Le, Goska Leslie, Fabienne Lesueur, Douglas A. Levine, Amalia Mattiello, Taymaa May, Lesley McGuffog, Iain A. McNeish, Melissa A. Merritt, Francesmary Modugno, Marco Montagna, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Liene Nikitina–Zake, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Sara H. Olson, Hakan Olsson, Ana Osorio, Sue K. Park, Michael T. Parsons, Petra H.M. Peeters, Tanȷa Peȷovic, Paolo Peterlongo, Catherine M. Phelan, Miquel Angel Puȷana, Susan J. Ramus, Gad Rennert, Harvey Risch, Gustavo C. Rodriguez, Cristina Rodriguez–Antona, Isabelle Romieu, Matti A. Rookus, Mary Anne Rossing, Iwona K. Rzepecka, Dale P. Sandler, Rita K. Schmutzler, Veronica W. Setiawan, Priyanka Sharma, Weiva Sieh, Jacques Simard, Christian F. Singer, Honglin Song, Melissa C. Southey, Amanda B. Spurdle, Rebecca Sutphen, Anthony J. Swerdlow, Manuel R. Teixeira, Soo H. Teo, Mads Thomassen, Marc Tischkowitz, Amanda E. Toland, Antonia Trichopoulou, Nadine Tung, Shelley S. Tworoger, Elizabeth J. van Rensburg, Adriaan Vanderstichele, Ana Vega, Digna Velez Edwards, Penelope M. Webb, Jeffrey N. Weitzel, Nicolas Wentzensen, Emily White, Alicȷa Wolk, Anna H. Wu, Drakoulis Yannoukakos, Kristin K. Zorn, Simon A. Gayther, Antonis C. Antoniou, Andrew Berchuck, Ellen L. Goode, Georgia Chenevix–Trench, Thomas A. Sellers, Paul D.P. Pharoah, Wei Zheng, Jirong Long
    The American Association for Cancer Research (AACR)
    Publication Date: 2018-09-15
    Description: Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P 〈 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P 〈 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.
    Print ISSN: 0008-5472
    Electronic ISSN: 1538-7445
    Topics: Medicine
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  • 7
    Publication Date: 2014-08-30
    Description: The New World Arctic, the last region of the Americas to be populated by humans, has a relatively well-researched archaeology, but an understanding of its genetic history is lacking. We present genome-wide sequence data from ancient and present-day humans from Greenland, Arctic Canada, Alaska, Aleutian Islands, and Siberia. We show that Paleo-Eskimos (~3000 BCE to 1300 CE) represent a migration pulse into the Americas independent of both Native American and Inuit expansions. Furthermore, the genetic continuity characterizing the Paleo-Eskimo period was interrupted by the arrival of a new population, representing the ancestors of present-day Inuit, with evidence of past gene flow between these lineages. Despite periodic abandonment of major Arctic regions, a single Paleo-Eskimo metapopulation likely survived in near-isolation for more than 4000 years, only to vanish around 700 years ago.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Raghavan, Maanasa -- DeGiorgio, Michael -- Albrechtsen, Anders -- Moltke, Ida -- Skoglund, Pontus -- Korneliussen, Thorfinn S -- Gronnow, Bjarne -- Appelt, Martin -- Gullov, Hans Christian -- Friesen, T Max -- Fitzhugh, William -- Malmstrom, Helena -- Rasmussen, Simon -- Olsen, Jesper -- Melchior, Linea -- Fuller, Benjamin T -- Fahrni, Simon M -- Stafford, Thomas Jr -- Grimes, Vaughan -- Renouf, M A Priscilla -- Cybulski, Jerome -- Lynnerup, Niels -- Lahr, Marta Mirazon -- Britton, Kate -- Knecht, Rick -- Arneborg, Jette -- Metspalu, Mait -- Cornejo, Omar E -- Malaspinas, Anna-Sapfo -- Wang, Yong -- Rasmussen, Morten -- Raghavan, Vibha -- Hansen, Thomas V O -- Khusnutdinova, Elza -- Pierre, Tracey -- Dneprovsky, Kirill -- Andreasen, Claus -- Lange, Hans -- Hayes, M Geoffrey -- Coltrain, Joan -- Spitsyn, Victor A -- Gotherstrom, Anders -- Orlando, Ludovic -- Kivisild, Toomas -- Villems, Richard -- Crawford, Michael H -- Nielsen, Finn C -- Dissing, Jorgen -- Heinemeier, Jan -- Meldgaard, Morten -- Bustamante, Carlos -- O'Rourke, Dennis H -- Jakobsson, Mattias -- Gilbert, M Thomas P -- Nielsen, Rasmus -- Willerslev, Eske -- New York, N.Y. -- Science. 2014 Aug 29;345(6200):1255832. doi: 10.1126/science.1255832.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Oster Voldgade 5-7, 1350 Copenhagen, Denmark. ; Department of Biology, Pennsylvania State University, 502 Wartik Laboratory, University Park, PA 16802, USA. ; Bioinformatics Centre, Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark. ; Bioinformatics Centre, Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark. Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA. ; Department of Evolutionary Biology, Uppsala University, Norbyvagen 18D, 75236 Uppsala, Sweden. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. ; Arctic Centre at the Ethnographic Collections (SILA), National Museum of Denmark, Frederiksholms Kanal 12, 1220 Copenhagen, Denmark. ; Department of Anthropology, University of Toronto, Toronto, Ontario M5S 2S2, Canada. ; Arctic Studies Center, Post Office Box 37012, Department of Anthropology, MRC 112, National Museum of Natural History, Smithsonian Institution, Washington, DC 20013-7012, USA. ; Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Oster Voldgade 5-7, 1350 Copenhagen, Denmark. Department of Evolutionary Biology, Uppsala University, Norbyvagen 18D, 75236 Uppsala, Sweden. ; Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet, 2800 Kongens Lyngby, Denmark. ; AMS 14C Dating Centre, Department of Physics and Astronomy, Aarhus University, Ny Munkegade 120, 8000 Aarhus C, Denmark. ; Anthropological Laboratory, Institute of Forensic Medicine, Faculty of Health Sciences, University of Copenhagen, Frederik V's Vej 11, 2100 Copenhagen, Denmark. ; Department of Earth System Science, University of California, Irvine, CA 92697, USA. ; Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Oster Voldgade 5-7, 1350 Copenhagen, Denmark. AMS 14C Dating Centre, Department of Physics and Astronomy, Aarhus University, Ny Munkegade 120, 8000 Aarhus C, Denmark. ; Department of Archaeology, Memorial University, Queen's College, 210 Prince Philip Drive, St. John's, Newfoundland, A1C 5S7, Canada. Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany. ; Department of Archaeology, Memorial University, Queen's College, 210 Prince Philip Drive, St. John's, Newfoundland, A1C 5S7, Canada. ; Canadian Museum of History, 100 Rue Laurier, Gatineau, Quebec K1A 0M8, Canada. Department of Anthropology, University of Western Ontario, 1151 Richmond Street North, London N6A 5C2, Canada. ; Leverhulme Centre for Human Evolutionary Studies, Department of Archaeology and Anthropology, University of Cambridge, Cambridge CB2 1QH, UK. ; Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany. Department of Archaeology, University of Aberdeen, St. Mary's Building, Elphinstone Road, Aberdeen AB24 3UF, Scotland, UK. ; Department of Archaeology, University of Aberdeen, St. Mary's Building, Elphinstone Road, Aberdeen AB24 3UF, Scotland, UK. ; National Museum of Denmark, Frederiksholms kanal 12, 1220 Copenhagen, Denmark. School of Geosciences, University of Edinburgh, Edinburgh EH8 9XP, UK. ; Estonian Biocentre, Evolutionary Biology Group, Tartu 51010, Estonia. Department of Evolutionary Biology, University of Tartu, Tartu 51010, Estonia. ; Department of Genetics, School of Medicine, Stanford University, Stanford, CA 94305, USA. School of Biological Sciences, Washington State University, Post Office Box 644236, Pullman, WA 99164, USA. ; Department of Integrative Biology, University of California, Berkeley, CA 94720, USA. Ancestry.com DNA LLC, San Francisco, CA 94107, USA. ; Informatics and Bio-computing, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, Ontario, M5G 0A3, Canada. ; Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark. ; Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russia. Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Bashkortostan 450074, Russia. ; State Museum for Oriental Art, 12a, Nikitsky Boulevard, Moscow 119019, Russia. ; Greenland National Museum and Archives, Post Office Box 145, 3900 Nuuk, Greenland. ; Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Department of Anthropology, Weinberg College of Arts and Sciences, Northwestern University, Evanston, IL 60208, USA. Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. ; Department of Anthropology, University of Utah, Salt Lake City, UT 84112, USA. ; Research Centre for Medical Genetics of Russian Academy of Medical Sciences, 1 Moskvorechie, Moscow 115478, Russia. ; Department of Archaeology and Classical Studies, Stockholm University, Stockholm, Sweden. ; Estonian Biocentre, Evolutionary Biology Group, Tartu 51010, Estonia. Department of Archaeology and Anthropology, University of Cambridge, Cambridge CB2 1QH, UK. ; Laboratory of Biological Anthropology, University of Kansas, Lawrence, KS 66045, USA. ; Department of Genetics, School of Medicine, Stanford University, Stanford, CA 94305, USA. ; Department of Evolutionary Biology, Uppsala University, Norbyvagen 18D, 75236 Uppsala, Sweden. ; Department of Integrative Biology, University of California, Berkeley, CA 94720, USA. ; Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Oster Voldgade 5-7, 1350 Copenhagen, Denmark. ewillerslev@snm.ku.dk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25170159" target="_blank"〉PubMed〈/a〉
    Keywords: Alaska/ethnology ; Arctic Regions/ethnology ; Base Sequence ; Bone and Bones ; Canada/ethnology ; DNA, Mitochondrial/genetics ; Genome, Human/*genetics ; Greenland/ethnology ; Hair ; History, Ancient ; *Human Migration ; Humans ; Inuits/ethnology/*genetics/history ; Molecular Sequence Data ; Siberia/ethnology ; Survivors/history ; Tooth
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2018-06-16
    Description: Purpose: Insulin-like growth factor receptor 1 (IGF-1R) is critically involved in pancreatic cancer pathophysiology, promoting cancer cell survival and therapeutic resistance. Assessment of IGF-1R inhibitors in combination with standard-of-care chemotherapy, however, failed to demonstrate significant clinical benefit. The aim of this work is to unravel mechanisms of resistance to IGF-1R inhibition in pancreatic cancer and develop novel strategies to improve the activity of standard-of-care therapies. Experimental Design: Growth factor screening in pancreatic cancer cell lines was performed to identify activators of prosurvival PI3K/AKT signaling. The prevalence of activating growth factors and their receptors was assessed in pancreatic cancer patient samples. Effects of a bispecific IGF-1R and ErbB3 targeting antibody on receptor expression, signaling, cancer cell viability and apoptosis, spheroid growth, and in vivo chemotherapy activity in pancreatic cancer xenograft models were determined. Results: Growth factor screening in pancreatic cancer cells revealed insulin-like growth factor 1 (IGF-1) and heregulin (HRG) as the most potent AKT activators. Both growth factors reduced pancreatic cancer cell sensitivity to gemcitabine or paclitaxel in spheroid growth assays. Istiratumab (MM-141), a novel bispecific antibody that blocks IGF-1R and ErbB3, restored the activity of paclitaxel and gemcitabine in the presence of IGF-1 and HRG in vitro . Dual IGF-1R/ErbB3 blocking enhanced chemosensitivity through inhibition of AKT phosphorylation and promotion of IGF-1R and ErbB3 degradation. Addition of istiratumab to gemcitabine and nab-paclitaxel improved chemotherapy activity in vivo . Conclusions: Our findings suggest a critical role for the HRG/ErbB3 axis and support the clinical exploration of dual IGF-1R/ErbB3 blocking in pancreatic cancer. Clin Cancer Res; 24(12); 2873–85. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 9
  • 10
    ISSN: 0890-8508
    Keywords: Polymerase chain reaction ; biotin labelled probe ; human immunodeficiency virus ; nested primers
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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