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  • 1
    Publication Date: 2014-10-11
    Description: Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636050/" 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/PMC4636050/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉de Bruin, Elza C -- McGranahan, Nicholas -- Mitter, Richard -- Salm, Max -- Wedge, David C -- Yates, Lucy -- Jamal-Hanjani, Mariam -- Shafi, Seema -- Murugaesu, Nirupa -- Rowan, Andrew J -- Gronroos, Eva -- Muhammad, Madiha A -- Horswell, Stuart -- Gerlinger, Marco -- Varela, Ignacio -- Jones, David -- Marshall, John -- Voet, Thierry -- Van Loo, Peter -- Rassl, Doris M -- Rintoul, Robert C -- Janes, Sam M -- Lee, Siow-Ming -- Forster, Martin -- Ahmad, Tanya -- Lawrence, David -- Falzon, Mary -- Capitanio, Arrigo -- Harkins, Timothy T -- Lee, Clarence C -- Tom, Warren -- Teefe, Enock -- Chen, Shann-Ching -- Begum, Sharmin -- Rabinowitz, Adam -- Phillimore, Benjamin -- Spencer-Dene, Bradley -- Stamp, Gordon -- Szallasi, Zoltan -- Matthews, Nik -- Stewart, Aengus -- Campbell, Peter -- Swanton, Charles -- 088340/Wellcome Trust/United Kingdom -- 091730/Wellcome Trust/United Kingdom -- 105104/Wellcome Trust/United Kingdom -- A11590/Cancer Research UK/United Kingdom -- A17786/Cancer Research UK/United Kingdom -- A19310/Cancer Research UK/United Kingdom -- A4688/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Oct 10;346(6206):251-6. doi: 10.1126/science.1253462.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK. ; Cancer Research UK London Research Institute, London WC2A 3LY, UK. Centre for Mathematics and Physics in the Life Science and Experimental Biology (CoMPLEX), University College London, London WC1E 6BT, UK. ; Cancer Research UK London Research Institute, London WC2A 3LY, UK. ; Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. ; Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. University of Cambridge, Cambridge CB2 1TN, UK. ; Instituto de Biomedicina y Biotecnologia de Cantabria (CSIC-UC-Sodercan), Departamento de Biologia Molecular, Universidad de Cantabria, Santander, Spain. ; Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium. ; Papworth Hospital NHS Foundation Trust, Cambridge CB23 3RE, UK. ; Lungs for Living Research Centre, University College London, London WC1E 6BT, UK. ; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK. University College London Hospitals, London NW1 2BU, UK. ; University College London Hospitals, London NW1 2BU, UK. ; Thermo Fisher Scientific, Carlsbad, CA 92008, USA. ; Technical University of Denmark, 2800 Kongens Lyngby, Denmark. Children's Hospital Informatics Program, Harvard Medical School, Boston, MA 02115, USA. ; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK. Cancer Research UK London Research Institute, London WC2A 3LY, UK. charles.swanton@cancer.org.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25301630" target="_blank"〉PubMed〈/a〉
    Keywords: Carcinogens/toxicity ; Carcinoma, Non-Small-Cell Lung/chemically induced/*diagnosis/*genetics ; Cytidine Deaminase/genetics ; Evolution, Molecular ; Gene Dosage ; *Genetic Heterogeneity ; *Genomic Instability ; Humans ; Lung Neoplasms/chemically induced/*diagnosis/*genetics ; Mutation ; Neoplasm Recurrence, Local/genetics ; Prognosis ; Smoking/adverse effects ; Translocation, Genetic ; Tumor Cells, Cultured
    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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  • 2
    ISSN: 1432-1440
    Keywords: liver disease ; phospholipids ; lecithin ; lysolecithin ; phosphatidylethanolamine ; Lebererkrankungen ; Phospholipide ; Lecithin ; Lysolecithin ; Colamin-Kephalin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Bei 30 leber-und stoffwechselgesunden Probanden, 10 Patienten mit einer Fettleber, 37 Patienten mit einer Lebercirrhose und 18 Patienten mit einer akuten Hepatitis wurden mit Hilfe der Dünnschichtchromatographie die Gesamtphosphatide sowie die Phosphatidfraktionen Lysolecithin, Sphingomyelin, Lecithin und Colamin-Kephalin im Plasma bestimmt. Bei den Patienten mit einer Fettleber ergeben sich im Phosphatidmuster — abgesehen von einer Erhöhung des mittleren Colamin-Kephalinspiegels — keine Abweichungen von der Normalsituation. Die Mittelwerte der Gesamtphosphatidkonzentration bei kompensierter und dekompensierter Lebercirrhose sind trotz großer Streuung der Einzeldaten weder untereinander noch von dem Mittelwert des Normalkollektivs verschieden. Die Analyse der einzelnen Phosphatidfraktionen ergibt lediglich einen signifikanten Abfall des mittleren Lysolecithinspiegels und einen eindeutigen Anstieg des Colamin-Kephalinspiegels. Bei den Patienten mit einer akuten Hepatitis sind die Mittelwerte der Gesamtphosphatide und auch die der Phosphatidfraktionen Sphingomyelin, Lecithin und Colamin-Kephalin erhöht. Der mittlere Lysolecithinspiegel ist dagegen eindeutig erniedrigt. Beziehungen zwischen den Änderungen der Plasmaphosphatidspiegel und den Leberfunktionsproben konnten nicht hergestellt werden. Der Lysolecithin/Lecithin-Quotient ist bei Patienten mit einer Hepatitis und einer Lebercirrhose eindeutig niedriger als bei den Normalpersonen. Das diskordante Verhalten von Lysolecithin und Lecithin wird als Folge einer verminderten LCAT-Aktivität interpretiert.
    Notes: Summary Plasma concentrations of total phospholipids and the phospholipid fractions lysolecithin, sphingomyelin, lecithin and phosphatidylethanolamine were determined by means of thin-layer chromatography in 30 subjects without liver or metabolic diseases, in 10 patients with fatty liver, 37 patients with liver cirrhosis, and in 18 patients with acute hepatitis. In patients with fatty liver there were no alterations in the phospholipid pattern except for an increase in the mean levels of phosphatidylethanolamine. In spite of the large scatter of the single data the mean values of the total phospholipid concentrations in patients with liver cirrhosis were not different from the control group. The analysis of the phospholipid fractions showed a statistically significant decrease of the mean level of lysolecithin and a marked elevation of the phosphatidylethanolamine level. In patients with acute hepatitis the mean concentration of the total phospholipids as well as the phospholipid fractions sphingomyelin, lecithin and phosphatidylethanolamine were increased. However the mean level of lysolecithin was significantly decreased. No correlation between changes in phospholipid levels and liver function could be observed. The lysolecithin/lecithin ratio is markedly lower in patients with hepatitis and liver cirrhosis than in normal subjects. The discordant alterations of lysolecithin and lecithin were interpreted as the consequence of a decreased LCAT-activity.
    Type of Medium: Electronic Resource
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