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  • 1
    Abstract: As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to approximately 100 x shows benefits, as long as the tumour:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.
    Type of Publication: Journal article published
    PubMed ID: 26647970
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  • 2
    Publication Date: 2014-08-15
    Description: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in western countries, with a median survival of 6 months and an extremely low percentage of long-term surviving patients. KRAS mutations are known to be a driver event of PDAC, but targeting mutant KRAS has proved challenging. Targeting oncogene-driven signalling pathways is a clinically validated approach for several devastating diseases. Still, despite marked tumour shrinkage, the frequency of relapse indicates that a fraction of tumour cells survives shut down of oncogenic signalling. Here we explore the role of mutant KRAS in PDAC maintenance using a recently developed inducible mouse model of mutated Kras (Kras(G12D), herein KRas) in a p53(LoxP/WT) background. We demonstrate that a subpopulation of dormant tumour cells surviving oncogene ablation (surviving cells) and responsible for tumour relapse has features of cancer stem cells and relies on oxidative phosphorylation for survival. Transcriptomic and metabolic analyses of surviving cells reveal prominent expression of genes governing mitochondrial function, autophagy and lysosome activity, as well as a strong reliance on mitochondrial respiration and a decreased dependence on glycolysis for cellular energetics. Accordingly, surviving cells show high sensitivity to oxidative phosphorylation inhibitors, which can inhibit tumour recurrence. Our integrated analyses illuminate a therapeutic strategy of combined targeting of the KRAS pathway and mitochondrial respiration to manage pancreatic cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376130/" 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/PMC4376130/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Viale, Andrea -- Pettazzoni, Piergiorgio -- Lyssiotis, Costas A -- Ying, Haoqiang -- Sanchez, Nora -- Marchesini, Matteo -- Carugo, Alessandro -- Green, Tessa -- Seth, Sahil -- Giuliani, Virginia -- Kost-Alimova, Maria -- Muller, Florian -- Colla, Simona -- Nezi, Luigi -- Genovese, Giannicola -- Deem, Angela K -- Kapoor, Avnish -- Yao, Wantong -- Brunetto, Emanuela -- Kang, Ya'an -- Yuan, Min -- Asara, John M -- Wang, Y Alan -- Heffernan, Timothy P -- Kimmelman, Alec C -- Wang, Huamin -- Fleming, Jason B -- Cantley, Lewis C -- DePinho, Ronald A -- Draetta, Giulio F -- CA016672/CA/NCI NIH HHS/ -- CA16672/CA/NCI NIH HHS/ -- P01 CA117969/CA/NCI NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P01CA117969/CA/NCI NIH HHS/ -- P01CA120964/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P30CA16672/CA/NCI NIH HHS/ -- P50 CA127003/CA/NCI NIH HHS/ -- England -- Nature. 2014 Oct 30;514(7524):628-32. doi: 10.1038/nature13611. Epub 2014 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3]. ; Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA. ; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3] Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy. ; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; Pathology Unit, San Raffaele Scientific Institute, Milan 20132, Italy. ; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA. ; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119024" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autophagy ; Carcinoma, Pancreatic Ductal/drug therapy/genetics/*metabolism/*pathology ; Cell Respiration/drug effects ; Cell Survival/drug effects ; Disease Models, Animal ; Female ; Gene Expression Regulation, Neoplastic ; Genes, p53/genetics ; Glycolysis ; Lysosomes/metabolism ; Mice ; Mitochondria/drug effects/*metabolism ; Mutation/genetics ; Neoplasm Recurrence, Local/prevention & control ; Neoplastic Stem Cells/drug effects/metabolism/pathology ; Oxidative Phosphorylation/drug effects ; Pancreatic Neoplasms/drug therapy/genetics/*metabolism/*pathology ; Proto-Oncogene Proteins p21(ras)/*genetics/metabolism ; Recurrence ; Signal Transduction
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2014-10-11
    Description: Cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed intratumor heterogeneity (ITH). ITH in lung cancers has not been well studied. We applied multiregion whole-exome sequencing (WES) on 11 localized lung adenocarcinomas. All tumors showed clear evidence of ITH. On average, 76% of all mutations and 20 out of 21 known cancer gene mutations were identified in all regions of individual tumors, which suggested that single-region sequencing may be adequate to identify the majority of known cancer gene mutations in localized lung adenocarcinomas. With a median follow-up of 21 months after surgery, three patients have relapsed, and all three patients had significantly larger fractions of subclonal mutations in their primary tumors than patients without relapse. These data indicate that a larger subclonal mutation fraction may be associated with increased likelihood of postsurgical relapse in patients with localized lung adenocarcinomas.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354858/" 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/PMC4354858/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Jianjun -- Fujimoto, Junya -- Zhang, Jianhua -- Wedge, David C -- Song, Xingzhi -- Zhang, Jiexin -- Seth, Sahil -- Chow, Chi-Wan -- Cao, Yu -- Gumbs, Curtis -- Gold, Kathryn A -- Kalhor, Neda -- Little, Latasha -- Mahadeshwar, Harshad -- Moran, Cesar -- Protopopov, Alexei -- Sun, Huandong -- Tang, Jiabin -- Wu, Xifeng -- Ye, Yuanqing -- William, William N -- Lee, J Jack -- Heymach, John V -- Hong, Waun Ki -- Swisher, Stephen -- Wistuba, Ignacio I -- Futreal, P Andrew -- CA016672/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P50 CA070907/CA/NCI NIH HHS/ -- P50CA70907/CA/NCI NIH HHS/ -- T32 CA-009666/CA/NCI NIH HHS/ -- T32 CA009666/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2014 Oct 10;346(6206):256-9. doi: 10.1126/science.1256930.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. ; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. ; Applied Cancer Science Institute, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. ; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK. ; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. ; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. ; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. ; Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. ; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. ; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. ; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. ; Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. ; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Honorary Faculty, Wellcome Trust Sanger Institute, Hinxton, UK CB10 1SA. afutreal@mdanderson.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25301631" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/*genetics/pathology ; DNA Mutational Analysis ; Exome/genetics ; Genes, Neoplasm ; *Genetic Heterogeneity ; Humans ; Lung Neoplasms/*genetics/pathology ; Mutation ; Neoplasm Recurrence, Local/*genetics/pathology
    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
    ISSN: 1432-1106
    Keywords: Weaver mutant mouse ; Dopamine ; Neural transplantation ; Uptake radioautography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A recently introduced quantitative radioautographic technique was used to characterize the striatal dopaminergic deficit in weaver mutant mice and to evaluate the extent of DA reinnervation resulting from cell suspension grafts of fetal ventral mesencephalic tissue. Brain slices from normal mice and unilaterally grafted weaver mice were incubated in [3H]DA, in the presence of desipramine and pargyline, 3–5 months after graft surgery. Semi-thin sections from the fixed and resin-embedded slices were subsequently exposed on tritium sensitive film and afterwards dipped in nuclear emulsion for light microscope radioautography. Alternate slices were embedded in Epon for post-embedding tyrosine hydroxylase (TH) immunocytochemistry. The grain density of the film radioautographs matched well the distribution of TH positive fibers. Both methods revealed an almost complete absence of DA axons in the dorsomedial quadrant of the weaver neostriatum and an increasing density of DA innervation towards the ventrolateral areas. In the light microscope radioautographs, only the ventral striatum (i.e. nucleus accumbens and olfactory tubercle) and a narrow ventral and periventricular zone of the caudate-putamen were covered by silver grain clusters typical of DA varicosity labeling. Such labeled varicosities were nevertheless found in reduced numbers in the lateral portion of both nucleus accumbens and the olfactory tubercle. The remaining neostriatum was overlaid by diffuse silver grains, suggesting a deficient DA uptake and storage mechanism in the residual DA fibers in this region. Immunocytochemistry using antibodies specific for DA or TH provided further evidence that the residual DA innervation in the weaver neostriatum was biochemically defective. Weaver mice with grafts of ventral mesencephalic tissue in the right neostriatum showed an amphetamine-induced rotational bias to the contralateral side, which was not seen in the sham-operated animals. In contrast to the intrinsic weaver neostriatal DA innervation, DA fibers of graft origin exhibited the normal, clustered type of varicosity labeling. The computerized image analysis of silver grain density in film radioautographs was calibrated by counting these labeled varicosities in selected areas of light microscope radioautographs from the same sections. Results showed a mean DA reinnervation of neostriatal tissue surrounding the graft of about 20%, in some cases up to 80%, of the density seen in wild type mice, with a gradual decrease with distance up to 1–1.4 mm from the graft. The ventral parts of the neostriatum, which contained higher numbers of residual intrinsic DA fibers, were much more sparsely reinnervated than the dorsal and dorsomedial areas. These data show that a quantitatively significant DA reinnervation of the weaver neostriatum can be provided by fetal mesencephalic cell suspension grafts and that these DA fibers become functional, at least with respect to their DA uptake and storage mechanisms, in a neostriatal environment where intrinsic weaver DA axons are strongly deficient. However, observations in long-term weaver mice (9 months after transplantation) suggested that the graft-derived DA fiber outgrowth was reduced with time in the affected striatum, in spite of good survival of the grafted neurones.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Description / Table of Contents: Zusammenfassung Mit Hilfe der horizontalen Stärkegel-Elektrophorese und eines diskontinuierlichen Puffer-Systems wurden die Haptoglobin- und Transferrin-Typen bei 200 Khatris und Aroras aus dem Punjab untersucht. In dieser Serie fand sich ein Khatri-Individuum mit einer Hp1-P-Variante und ein anderes Khatri-Individuum mit einer noch unklassifizierten Hp2-1(m)-Variante. Beide Bevölkerungen sind durch das ausschließliche Vorkommen des häufigen Transferrin CC-Typs charakterisiert.
    Notes: Summary Using horizontal starch gel electrophoresis along with the discontinuous buffer system, resolution of haptoglobin and transferrin bands has been obtained for 200 Khatris and Aroras of Punjab. One Khatri individual possessing Hp1-P variant and another Khatri individual possessing, as yet unclassified, Hp2-1(m) was found in this series. Common CC type transferrin bands characterise Khatris and Aroras.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Human genetics 〈Berlin〉 28 (1975), S. 329-330 
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The group-specific component in 17 Macaca mulatta was examined. All the individuals reveal the same Gc1-1 pattern.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Human genetics 〈Berlin〉 29 (1975), S. 341-348 
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Blood and serum from 17 Macaca mulatta were analysed for haptoglobins, transferrins, 6-phosphogluconate dehydrogenase, adenylate kinase, adenosine deaminase, phosphoglucomutase, acid phosphatase, glucose-6-phosphate dehydrogenase and phosphohexose isomerase. Compared to the human pattern, the AcPh and the ADA components of macaques are fast moving; AK, PGM, 6-PGD and G-6-PD have almost uniform and similar electrophoretic mobilities; and the Hp, Tf and PHI show differential mobilities. All these macaques possess similar karyotypes.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Human genetics 〈Berlin〉 33 (1976), S. 201-211 
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Results obtained so far on the C3 polymorphism suggest that the system should be a valuable marker in population studies. The instability of the complement component C3 may, however, cause some practical problems in population genetic fieldwork, since a certain fraction of serum samples may be difficult to type with certainty due to storage alterations. Studies of the conversion rate and the concentration of C3 have shown that there is no significant difference between the phenotypes. And furthermore, the fact that there is good agreement with the Hardy-Weinberg distribution indicates that the conversion has had no appreciable selective effect on the phenotype distribution (Brönnestam et al., 1971).
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1420-908X
    Keywords: Myocardial ischemia ; Reperfusion ; Aspirin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The role of low-dose aspirin (3 mg/kg, i.v.) in attenuating ischemic reperfusion injury was studied in a canine model. Regional ischemia for 40 min was produced by temporary occlusion of the left anterior descending coronary artery and thereafter reperfusion instituted for 3 h. Mean arterial pressure (MAP), heart rate (HR), left ventricular end diastolic pressure (LVEDP), positive (+) LV dP/dt max and negative (−) LV dP/dt max were monitored alongwith myocardial adenosine triphosphate (ATP), creatine phosphate (CP), glycogen and lactate. Following reperfusion, there was a significant fall in (i) MAP, (ii) (+) LV dP/dt max and (iii) (−) LV dP/dt max. LVEDP was corrected after about 2h of reperfusion. Replenishment of only myocardial CP occurred, without any change in ATP and glycogen, although lactate accumulation was corrected. Aspirin administered 15 min before reperfusion (posttreatment) caused normalisation of LVEDP within 15 min and prevented any deterioration in (−) LV dP/dt max, although it had no effect on MAP and (+) LV dP/dt max. After 3h of reperfusion (post-treatment), myocardial ATP, CP, glycogen and lactate contents became normal. The number of premature ventricular complexes was significantly reduced after aspirin treatment. The present study indicates that low-dose aspirin post-treatment can ameliorate at least some of the deleterious consequences of reperfusion injury of the myocardium.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Group
    Nature 315 (1985), S. 406-409 
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Fig. 1 Sensory neurones of a wing at 2 h after pupariation (a), or after having been removed at 2 h after pupariation and cultured for an additional 8 h (b) or 22 h (c). The earliest-arising neurones are those of the anterior cross vein campaniform sensillum (ACV), the second dorsal campaniform ...
    Type of Medium: Electronic Resource
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