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Sender's message: Sepsis or genomics or altitude: JKB_daily1

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Items 1 - 7 of 7

1.	Lancet. 2014 Mar 1;383(9919):775. doi: 10.1016/S0140-6736(14)60393-7. James Watson: thinking outside the genome. Watts G.
	PMID: 24581658 [PubMed - indexed for MEDLINE]
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2.	Nature. 2014 Feb 27;506(7489):445-50. doi: 10.1038/nature13108. Epub 2014 Feb 19. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Mack SC1, Witt H2, Piro RM3, Gu L4, Zuyderduyn S5, Stütz AM6, Wang X7, Gallo M8, Garzia L8, Zayne K8, Zhang X9, Ramaswamy V7, Jäger N4, Jones DT10, Sill M11, Pugh TJ12, Ryzhova M10, Wani KM13, Shih DJ7, Head R8, Remke M7, Bailey SD14, Zichner T6, Faria CC8, Barszczyk M7, Stark S10, Seker-Cin H10, Hutter S10, Johann P10, Bender S10, Hovestadt V3, Tzaridis T10, Dubuc AM7, Northcott PA10, Peacock J7, Bertrand KC7, Agnihotri S8, Cavalli FM8, Clarke I8, Nethery-Brokx K8, Creasy CL15, Verma SK15, Koster J16, Wu X8, Yao Y7, Milde T17, Sin-Chan P8, Zuccaro J8, Lau L8, Pereira S8, Castelo-Branco P8, Hirst M18, Marra MA19, Roberts SS20, Fults D21, Massimi L22, Cho YJ23, Van Meter T24, Grajkowska W25, Lach B26, Kulozik AE27, von Deimling A28, Witt O17, Scherer SW8, Fan X29, Muraszko KM30, Kool M10, Pomeroy SL12, Gupta N31, Phillips J32, Huang A33, Tabori U33, Hawkins C7, Malkin D34, Kongkham PN35, Weiss WA32, Jabado N36, Rutka JT35, Bouffet E37, Korbel JO38, Lupien M39, Aldape KD13, Bader GD5, Eils R4, Lichter P3, Dirks PB40, Pfister SM41, Korshunov A42, Taylor MD35. Author information: 11] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada [3] Division of Neurosurgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada [4]. 21] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [3] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [4]. 31] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. 41] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. 5Department of Molecular Genetics, Banting and Best Department of Medical Research, The Donnelly Centre, University of Toronto, Toronto, Ontario M4N 1X8, Canada. 61] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Genome Biology, European Molecular Biology, Laboratory Meyerhofstr. 1, Heidelberg 69117, Germany. 71] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. 8Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada. 9Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA. 101] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK), Heidelberg 69120, Germany. 111] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Division of Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. 12Department of Neurology, Harvard Medical School, Children's Hospital Boston, MIT, Boston, Massachusetts 02115, USA. 13Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. 141] Ontario Cancer Institute, Princess Margaret Cancer Centre-University Health Network, Toronto, Ontario M5G 1L7, Canada [2] Ontario Institute for Cancer Research, Toronto, Ontario M5G 1L7, Canada. 15Cancer Epigenetics Discovery Performance Unit, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426, USA. 16Department of Oncogenomics, Academic Medical Center, Amsterdam 1105, The Netherlands. 171] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [2] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [3] CCU Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. 181] Centre for High-Throughput Biology, Department of Microbiology & Immunology, University of British Columbia, Vancouver, V6T 1Z4 British Columbia, Canada [2] Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada. 191] Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada. 20Department of Pediatrics and National Capital Consortium, Uniformed Services University, Bethesda, Maryland 20814, USA. 21Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA. 22Pediatric Neurosurgery, Catholic University Medical School, Gemelli Hospital, Rome 00168, Italy. 23Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA. 24Department of Pediatrics, Virginia Commonwealth, Richmond, Virginia 23298-0646, USA. 25Department of Pathology, University of Warsaw, Children's Memorial Health Institute University of Warsaw, Warsaw 04-730, Poland. 26Division of Anatomical Pathology, Department of Pathology and Molecular Medicine, McMaster University, Hamilton General Hospital, Hamilton, Ontario L8S 4K1, Canada. 271] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [2] German Cancer Consortium (DKTK), Heidelberg 69120, Germany. 281] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Department of Neuropathology Ruprecht-Karls-University Heidelberg, Institute of Pathology, Heidelberg 69120, Germany. 291] University of Michigan Cell and Developmental Biology, Ann Arbor, Michigan 48109-2200, USA [2] Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. 30Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. 31Department of Neurosurgery, University of California San Francisco, San Francisco, California 94143-0112, USA. 32Departments of Neurology, Pediatrics, and Neurosurgery, University of California, San Francisco, The Helen Diller Family Cancer Research Building, San Francisco, California 94158, USA. 331] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Department of Neuro-oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada. 34Department of Haematology and Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada. 351] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada [3] Division of Neurosurgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada. 36Departments of Pediatrics and Human Genetics, McGill University and the McGill University Health Center Research Institute, Montreal, Quebec H3Z 2Z3, Canada. 37Department of Neuro-oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada. 38Genome Biology, European Molecular Biology, Laboratory Meyerhofstr. 1, Heidelberg 69117, Germany. 391] Ontario Cancer Institute, Princess Margaret Cancer Centre-University Health Network, Toronto, Ontario M5G 1L7, Canada [2] Ontario Institute for Cancer Research, Toronto, Ontario M5G 1L7, Canada [3] Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1X8, Canada. 401] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada [3] Division of Neurosurgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada [4] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. 411] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [3] German Cancer Consortium (DKTK), Heidelberg 69120, Germany. 421] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] University of Michigan Cell and Developmental Biology, Ann Arbor, Michigan 48109-2200, USA [3] CCU Neuropathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. Comment in Cancer: Tumours outside the mutation box. [Nature. 2014] Cancer: Tumours outside the mutation box.Versteeg R. Nature. 2014 Feb 27; 506(7489):438-9. Epub 2014 Feb 19. Abstract Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.
	PMID: 24553142 [PubMed - indexed for MEDLINE]
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3.	Nature. 2014 Feb 27;506(7489):456-62. doi: 10.1038/nature13044. Epub 2014 Feb 19. A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3. Murthy A1, Li Y1, Peng I1, Reichelt M2, Katakam AK2, Noubade R1, Roose-Girma M3, DeVoss J1, Diehl L2, Graham RR4, van Lookeren Campagne M1. Author information: 1Department of Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. 2Department of Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. 3Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. 4ITGR Human Genetics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. Comment in Cell biology: Stressful genetics in Crohn's disease. [Nature. 2014] Cell biology: Stressful genetics in Crohn's disease.Kaser A, Blumberg RS. Nature. 2014 Feb 27; 506(7489):441-2. Epub 2014 Feb 19. Abstract Crohn's disease is a debilitating inflammatory bowel disease (IBD) that can involve the entire digestive tract. A single-nucleotide polymorphism (SNP) encoding a missense variant in the autophagy gene ATG16L1 (rs2241880, Thr300Ala) is strongly associated with the incidence of Crohn's disease. Numerous studies have demonstrated the effect of ATG16L1 deletion or deficiency; however, the molecular consequences of the Thr300Ala (T300A) variant remains unknown. Here we show that amino acids 296-299 constitute a caspase cleavage motif in ATG16L1 and that the T300A variant (T316A in mice) significantly increases ATG16L1 sensitization to caspase-3-mediated processing. We observed that death-receptor activation or starvation-induced metabolic stress in human and murine macrophages increased degradation of the T300A or T316A variants of ATG16L1, respectively, resulting in diminished autophagy. Knock-in mice harbouring the T316A variant showed defective clearance of the ileal pathogen Yersinia enterocolitica and an elevated inflammatory cytokine response. In turn, deletion of the caspase-3-encoding gene, Casp3, or elimination of the caspase cleavage site by site-directed mutagenesis rescued starvation-induced autophagy and pathogen clearance, respectively. These findings demonstrate that caspase 3 activation in the presence of a common risk allele leads to accelerated degradation of ATG16L1, placing cellular stress, apoptotic stimuli and impaired autophagy in a unified pathway that predisposes to Crohn's disease.
	PMID: 24553140 [PubMed - indexed for MEDLINE]
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4.	Nature. 2014 Feb 27;506(7489):503-6. doi: 10.1038/nature12902. Epub 2014 Jan 19. Sessile alveolar macrophages communicate with alveolar epithelium to modulate immunity. Westphalen K1, Gusarova GA1, Islam MN1, Subramanian M2, Cohen TS3, Prince AS3, Bhattacharya J4. Author information: 1Lung Biology Laboratory, Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Columbia University Medical Center, New York, New York 10032, USA. 2Department of Medicine, Division of Molecular Medicine, Columbia University Medical Center, New York, New York 10032, USA. 3Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA. 41] Lung Biology Laboratory, Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Columbia University Medical Center, New York, New York 10032, USA [2] Department of Physiology & Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York 10032, USA. Abstract The tissue-resident macrophages of barrier organs constitute the first line of defence against pathogens at the systemic interface with the ambient environment. In the lung, resident alveolar macrophages (AMs) provide a sentinel function against inhaled pathogens. Bacterial constituents ligate Toll-like receptors (TLRs) on AMs, causing AMs to secrete proinflammatory cytokines that activate alveolar epithelial receptors, leading to recruitment of neutrophils that engulf pathogens. Because the AM-induced response could itself cause tissue injury, it is unclear how AMs modulate the response to prevent injury. Here, using real-time alveolar imaging in situ, we show that a subset of AMs attached to the alveolar wall form connexin 43 (Cx43)-containing gap junction channels with the epithelium. During lipopolysaccharide-induced inflammation, the AMs remained sessile and attached to the alveoli, and they established intercommunication through synchronized Ca(2+) waves, using the epithelium as the conducting pathway. The intercommunication was immunosuppressive, involving Ca(2+)-dependent activation of Akt, because AM-specific knockout of Cx43 enhanced alveolar neutrophil recruitment and secretion of proinflammatory cytokines in the bronchoalveolar lavage. A picture emerges of a novel immunomodulatory process in which a subset of alveolus-attached AMs intercommunicates immunosuppressive signals to reduce endotoxin-induced lung inflammation.
	PMID: 24463523 [PubMed - indexed for MEDLINE]
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5.	Nature. 2014 Feb 27;506(7489):494-7. doi: 10.1038/nature12904. Epub 2014 Jan 8. Genetics of single-cell protein abundance variation in large yeast populations. Albert FW1, Treusch S2, Shockley AH3, Bloom JS4, Kruglyak L5. Author information: 11] Department of Human Genetics, University of California, Los Angeles, California 90095, USA [2] Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA. 2Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA. 3Synthetic Genomics, 11149 North Torrey Pines Road, La Jolla, California 92037, USA. 41] Department of Human Genetics, University of California, Los Angeles, California 90095, USA [2] Howard Hughes Medical Institute, University of California, Los Angeles, California 90095, USA. 51] Department of Human Genetics, University of California, Los Angeles, California 90095, USA [2] Howard Hughes Medical Institute, University of California, Los Angeles, California 90095, USA [3] Department of Biological Chemistry, University of California, Los Angeles, California 90095, USA. Abstract Variation among individuals arises in part from differences in DNA sequences, but the genetic basis for variation in most traits, including common diseases, remains only partly understood. Many DNA variants influence phenotypes by altering the expression level of one or several genes. The effects of such variants can be detected as expression quantitative trait loci (eQTL). Traditional eQTL mapping requires large-scale genotype and gene expression data for each individual in the study sample, which limits sample sizes to hundreds of individuals in both humans and model organisms and reduces statistical power. Consequently, many eQTL are probably missed, especially those with smaller effects. Furthermore, most studies use messenger RNA rather than protein abundance as the measure of gene expression. Studies that have used mass-spectrometry proteomics reported unexpected differences between eQTL and protein QTL (pQTL) for the same genes, but these studies have been even more limited in scope. Here we introduce a powerful method for identifying genetic loci that influence protein expression in the yeast Saccharomyces cerevisiae. We measure single-cell protein abundance through the use of green fluorescent protein tags in very large populations of genetically variable cells, and use pooled sequencing to compare allele frequencies across the genome in thousands of individuals with high versus low protein abundance. We applied this method to 160 genes and detected many more loci per gene than previous studies. We also observed closer correspondence between loci that influence protein abundance and loci that influence mRNA abundance of a given gene. Most loci that we detected were clustered in 'hotspots' that influence multiple proteins, and some hotspots were found to influence more than half of the proteins that we examined. The variants that underlie these hotspots have profound effects on the gene regulatory network and provide insights into genetic variation in cell physiology between yeast strains.
	PMID: 24402228 [PubMed - indexed for MEDLINE]
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6.	Nature. 2014 Feb 20;506(7488):371-5. doi: 10.1038/nature12881. Epub 2013 Dec 25. Landscape of genomic alterations in cervical carcinomas. Ojesina AI1, Lichtenstein L2, Freeman SS3, Pedamallu CS4, Imaz-Rosshandler I5, Pugh TJ4, Cherniack AD3, Ambrogio L3, Cibulskis K3, Bertelsen B6, Romero-Cordoba S5, Treviño V7, Vazquez-Santillan K5, Guadarrama AS5, Wright AA8, Rosenberg MW 3, Duke F9, Kaplan B4, Wang R10, Nickerson E3, Walline HM11, Lawrence MS3, Stewart C3, Carter SL3, McKenna A3, Rodriguez-Sanchez IP12, Espinosa-Castilla M5, Woie K13, Bjorge L14, Wik E14, Halle MK14, Hoivik EA14, Krakstad C14, Gabiño NB5, Gómez-Macías GS12, Valdez-Chapa LD12, Garza-Rodríguez ML12, Maytorena G15, Vazquez J15, Rodea C15, Cravioto A15, Cortes ML3, Greulich H16, Crum CP17, Neuberg DS18, Hidalgo-Miranda A 5, Escareno CR19, Akslen LA20, Carey TE21, Vintermyr OK20, Gabriel SB3, Barrera-Saldaña HA 12, Melendez-Zajgla J5, Getz G22, Salvesen HB23, Meyerson M24. Author information: 11] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [3]. 21] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [2]. 3The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. 41] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. 5Instituto Nacional de Medicina Genomica, Mexico City 14610, Mexico. 6Department of Pathology, Haukeland University Hospital, N5021 Bergen, Norway. 7Tecnológico de Monterrey, Monterrey 64849, Mexico. 81] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. 9Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. 101] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. 11Cancer Biology Program, Program in the Biomedical Sciences, Rackham Graduate School, University of Michigan, Ann Arbor, Michigan 48109, USA. 12Facultad de Medicina y Hospital Universitario 'Dr. José Eluterio González' de la Universidad Autónoma de Nuevo León, Monterrey, Nuevo León 64460, México. 13Department of Obstetrics and Gynecology, Haukeland University Hospital, N5021 Bergen, Norway. 141] Department of Obstetrics and Gynecology, Haukeland University Hospital, N5021 Bergen, Norway [2] Department of Clinical Science, Centre for Cancer Biomarkers, University of Bergen, N5020 Bergen, Norway. 15Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico. 161] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [3] Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. 17Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. 18Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. 191] Instituto Nacional de Medicina Genomica, Mexico City 14610, Mexico [2] Claremont Graduate University, Claremont, California 91711, USA. 201] Department of Pathology, Haukeland University Hospital, N5021 Bergen, Norway [2] Centre for Cancer Biomarkers, Department of Clinical Medicine, University of Bergen, N5020 Bergen, Norway. 21Head and Neck Oncology Program and Department of Otolaryngology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 38109, USA. 221] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [2] Massachusetts General Hospital Cancer Center and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. 231] Department of Obstetrics and Gynecology, Haukeland University Hospital, N5021 Bergen, Norway [2] Department of Clinical Science, Centre for Cancer Biomarkers, University of Bergen, N5020 Bergen, Norway [3]. 241] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [3] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [4]. Abstract Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy-number alterations in the pathogenesis of cervical carcinomas. Here we report whole-exome sequencing analysis of 115 cervical carcinoma-normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour-normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%) and ERBB2 (6%). We also observe somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines (Tp*C sites) than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease.
	PMID: 24390348 [PubMed - indexed for MEDLINE]
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7.	Lancet. 2014 Mar 1;383(9919):828-40. doi: 10.1016/S0140-6736(13)60630-3. Epub 2013 Aug 6. Genetics of dementia. Loy CT1, Schofield PR2, Turner AM3, Kwok JB4. Author information: 1School of Public Health, University of Sydney, Sydney, NSW, Australia; Neuroscience Research Australia, Randwick, NSW, Australia; Huntington Disease Service, Westmead Hospital, Westmead, NSW, Australia. 2Neuroscience Research Australia, Randwick, NSW, Australia; University of New South Wales, Kensington, NSW, Australia. 3Department of Medical Genetics, Sydney Children's Hospital, Randwick, NSW, Australia. 4Neuroscience Research Australia, Randwick, NSW, Australia; University of New South Wales, Kensington, NSW, Australia. Electronic address: j.kwok@neura.edu.au. Abstract 25% of all people aged 55 years and older have a family history of dementia. For most, the family history is due to genetically complex disease, where many genetic variations of small effect interact to increase risk of dementia. The lifetime risk of dementia for these families is about 20%, compared with 10% in the general population. A small proportion of families have an autosomal dominant family history of early-onset dementia, which is often due to mendelian disease, caused by a mutation in one of the dementia genes. Each family member has a 50% chance of inheriting the mutation, which confers a lifetime dementia risk of over 95%. In this Review, we focus on the evidence for, and the approach to, genetic testing in Alzheimer's disease (APP, PSEN1, and PSEN2 genes), frontotemporal dementia (MAPT, GRN, C9ORF72, and other genes), and other familial dementias. We conclude by discussing the practical aspects of genetic counselling. Copyright © 2014 Elsevier Ltd. All rights reserved.
	PMID: 23927914 [PubMed - indexed for MEDLINE]
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