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  • 1
    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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  • 2
    Publication Date: 2013-11-16
    Description: Cytochrome P450 enzymes activate oxygen at heme iron centers to oxidize relatively inert substrate carbon-hydrogen bonds. Cysteine thiolate coordination to iron is posited to increase the pK(a) (where K(a) is the acid dissociation constant) of compound II, an iron(IV)hydroxide complex, correspondingly lowering the one-electron reduction potential of compound I, the active catalytic intermediate, and decreasing the driving force for deleterious auto-oxidation of tyrosine and tryptophan residues in the enzyme's framework. Here, we report on the preparation of an iron(IV)hydroxide complex in a P450 enzyme (CYP158) in 〉/=90% yield. Using rapid mixing technologies in conjunction with Mossbauer, ultraviolet/visible, and x-ray absorption spectroscopies, we determine a pK(a) value for this compound of 11.9. Marcus theory analysis indicates that this elevated pK(a) results in a 〉10,000-fold reduction in the rate constant for oxidations of the protein framework, making these processes noncompetitive with substrate oxidation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4299822/" 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/PMC4299822/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yosca, Timothy H -- Rittle, Jonathan -- Krest, Courtney M -- Onderko, Elizabeth L -- Silakov, Alexey -- Calixto, Julio C -- Behan, Rachel K -- Green, Michael T -- P41GM103393/GM/NIGMS NIH HHS/ -- R01 GM101390/GM/NIGMS NIH HHS/ -- R01-GM101390/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Nov 15;342(6160):825-9. doi: 10.1126/science.1244373.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24233717" target="_blank"〉PubMed〈/a〉
    Keywords: Carbon/chemistry ; Catalysis ; Cysteine/*analogs & derivatives/chemistry ; Cytochrome P-450 Enzyme System/*chemistry ; Enzyme Activation ; Hydrogen Bonding ; Hydroxides/*chemistry ; Oxidation-Reduction ; Tryptophan/chemistry ; Tyrosine/chemistry
    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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  • 3
    Publication Date: 2016-03-17
    Description: Microbial viruses can control host abundances via density-dependent lytic predator-prey dynamics. Less clear is how temperate viruses, which coexist and replicate with their host, influence microbial communities. Here we show that virus-like particles are relatively less abundant at high host densities. This suggests suppressed lysis where established models predict lytic dynamics are favoured. Meta-analysis of published viral and microbial densities showed that this trend was widespread in diverse ecosystems ranging from soil to freshwater to human lungs. Experimental manipulations showed viral densities more consistent with temperate than lytic life cycles at increasing microbial abundance. An analysis of 24 coral reef viromes showed a relative increase in the abundance of hallmark genes encoded by temperate viruses with increased microbial abundance. Based on these four lines of evidence, we propose the Piggyback-the-Winner model wherein temperate dynamics become increasingly important in ecosystems with high microbial densities; thus 'more microbes, fewer viruses'.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Knowles, B -- Silveira, C B -- Bailey, B A -- Barott, K -- Cantu, V A -- Cobian-Guemes, A G -- Coutinho, F H -- Dinsdale, E A -- Felts, B -- Furby, K A -- George, E E -- Green, K T -- Gregoracci, G B -- Haas, A F -- Haggerty, J M -- Hester, E R -- Hisakawa, N -- Kelly, L W -- Lim, Y W -- Little, M -- Luque, A -- McDole-Somera, T -- McNair, K -- de Oliveira, L S -- Quistad, S D -- Robinett, N L -- Sala, E -- Salamon, P -- Sanchez, S E -- Sandin, S -- Silva, G G Z -- Smith, J -- Sullivan, C -- Thompson, C -- Vermeij, M J A -- Youle, M -- Young, C -- Zgliczynski, B -- Brainard, R -- Edwards, R A -- Nulton, J -- Thompson, F -- Rohwer, F -- England -- Nature. 2016 Mar 24;531(7595):466-70. doi: 10.1038/nature17193. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, San Diego State University, 5500 Campanile Drive, San Diego, California 92182, USA. ; Biology Institute, Rio de Janeiro Federal University, Av. Carlos Chagas Filho 373, Rio de Janeiro, Rio de Janeiro 21941-599, Brazil. ; Department of Mathematics and Statistics, San Diego State University, 5500 Campanile Drive, San Diego, California 92182, USA. ; Hawaii Institute of Marine Biology, University of Hawaii at Manoa, 46-007 Lilipuna Road, Kaneohe, Hawaii 96744, USA. ; Computational Science Research Center, San Diego State University, 5500 Campanile Drive, San Diego, California 92182, USA. ; Rainbow Rock, Ocean View, Hawaii 96737, USA. ; Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences, Centre for Molecular and Biomolecular Informatics, 6525HP Nijmegen, The Netherlands. ; Viral Information Institute, San Diego State University, 5500 Campanile Drive, San Diego, California 92182, USA. ; Scripps Institution of Oceanography, 8622 Kennel Way, La Jolla, California 92037, USA. ; Department of Biology, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. ; Marine Sciences Department, Sao Paulo Federal University - Baixada Santista, Av. Alm. Saldanha da Gama, 89, Santos, Sao Paulo 11030-400, Brazil. ; National Geographic Society, 1145 17th St NW, Washington D.C. 20036, USA. ; CARMABI Foundation, Piscaderabaai z/n, Willemstad, Curacao, Netherlands Antilles. ; Aquatic Microbiology, Institute for Biodiversity and Ecosystem Dynamics, University of Amsterdam, 1098XH Amsterdam, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982729" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anthozoa/physiology/*virology ; Bacteriophages/pathogenicity/physiology ; Coral Reefs ; *Ecosystem ; Genes, Viral/genetics ; *Host-Pathogen Interactions ; Lysogeny ; Models, Biological ; Virulence/genetics ; Viruses/genetics/isolation & purification/*pathogenicity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Keywords: POPULATION ; GENOME ; ASSOCIATION ; FREQUENCY ; BREAST-CANCER ; GENETIC-VARIATION ; SIGNATURES ; POSITIVE SELECTION ; JEWS ; TAY-SACHS DISEASE
    Abstract: Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews
    Type of Publication: Journal article published
    PubMed ID: 21597964
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  • 5
  • 6
    Abstract: The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (, 40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (lambda) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values, 10 25 and 39 SNPs had p-values〈10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p = 3: 8 x 10(-5)) and for rs311499 was 0.72 (95% CI 0.61-0.85, p = 6: 6 x 10(-5)). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p = 1: 2 x 10(-8)). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer
    Type of Publication: Journal article published
    PubMed ID: 21060860
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  • 7
    ISSN: 0920-9964
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-1041
    Keywords: diuretics ; antihypertensive agents ; renal disease ; dispositon ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacodynamic actions and disposition of diuretic and antihypertensive agents may be significantly modified in subjects with renal disease. Most studies on this question have dealt with alterations in the elimination kinetics of these drugs and, while they generate descriptive data, minimal insight about changes in dose-response relationships or mechanisms of drug action are provided by such investigations. Several basic principles which may serve as useful guidelines in determining how renal failure will influence the response to drugs have been considered. They include the following: degree of renal malfunction, intrinsic toxicity of the drug, alternative pathways for drug metabolism and elimination, elimination pharmacokinetics and dose-response characteristics. Several classes of diuretic agents (thiazides, furosemide) and antihypertensive drugs (hydralazine, methyldopa, propranolol, prazosin, and clonidine) have been used as models to define how basic knowledge of renal and non-renal pathways for elimination of drugs and their pharmacodynamic actions may assist in establishing rational therapeutic regimens for these agents in patients with renal failure.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: β-endorphin is an endogenous opioid peptide that has been hypothesized to be involved in the behavioral effects of drugs of abuse including psychostimulants. Using microdialysis, we studied the effect of cocaine on extracellular levels of β-endorphin in the nucleus accumbens, a brain region involved in the reinforcing effects of psychostimulant drugs. Experimenter-delivered cocaine (2 mg/kg, i.v.) increased extracellular β-endorphin immunoreactive levels in the nucleus accumbens, an effect attenuated by 6-hydroxy-dopamine lesions or systemic administration of the D1-like receptor antagonist, SCH-23390 (0.25 mg/kg, i.p.). The effect of cocaine on β-endorphin release in the nucleus accumbens was mimicked by a local perfusion of dopamine (5 µm) and was blocked by coadministration of SCH-23390 (10 µm). Self-administered cocaine (1 mg/kg/infusion, i.v.) also increased extracellular β-endorphin levels in the nucleus accumbens. In addition, using functional magnetic resonance imaging, we found that cocaine (1 mg/kg, i.v.) increases regional brain activity in the nucleus accumbens and arcuate nucleus. We demonstrate an increase in β-endorphin release in the nucleus accumbens following experimenter-delivered and self-administered cocaine mediated by the local dopaminergic system. These findings suggest that activation of the β-endorphin neurons within the arcuate nucleus–nucleus accumbens pathway may be important in the neurobiological mechanisms underlying the behavioral effects of cocaine.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    ISSN: 1365-2230
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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