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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: 2010-11-30
    Description: An ageing world population has fuelled interest in regenerative remedies that may stem declining organ function and maintain fitness. Unanswered is whether elimination of intrinsic instigators driving age-associated degeneration can reverse, as opposed to simply arrest, various afflictions of the aged. Such instigators include progressively damaged genomes. Telomerase-deficient mice have served as a model system to study the adverse cellular and organismal consequences of wide-spread endogenous DNA damage signalling activation in vivo. Telomere loss and uncapping provokes progressive tissue atrophy, stem cell depletion, organ system failure and impaired tissue injury responses. Here, we sought to determine whether entrenched multi-system degeneration in adult mice with severe telomere dysfunction can be halted or possibly reversed by reactivation of endogenous telomerase activity. To this end, we engineered a knock-in allele encoding a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase-oestrogen receptor (TERT-ER) under transcriptional control of the endogenous TERT promoter. Homozygous TERT-ER mice have short dysfunctional telomeres and sustain increased DNA damage signalling and classical degenerative phenotypes upon successive generational matings and advancing age. Telomerase reactivation in such late generation TERT-ER mice extends telomeres, reduces DNA damage signalling and associated cellular checkpoint responses, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines. Notably, somatic telomerase reactivation reversed neurodegeneration with restoration of proliferating Sox2(+) neural progenitors, Dcx(+) newborn neurons, and Olig2(+) oligodendrocyte populations. Consistent with the integral role of subventricular zone neural progenitors in generation and maintenance of olfactory bulb interneurons, this wave of telomerase-dependent neurogenesis resulted in alleviation of hyposmia and recovery of innate olfactory avoidance responses. Accumulating evidence implicating telomere damage as a driver of age-associated organ decline and disease risk and the marked reversal of systemic degenerative phenotypes in adult mice observed here support the development of regenerative strategies designed to restore telomere integrity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057569/" 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/PMC3057569/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jaskelioff, Mariela -- Muller, Florian L -- Paik, Ji-Hye -- Thomas, Emily -- Jiang, Shan -- Adams, Andrew C -- Sahin, Ergun -- Kost-Alimova, Maria -- Protopopov, Alexei -- Cadinanos, Juan -- Horner, James W -- Maratos-Flier, Eleftheria -- Depinho, Ronald A -- R01 CA084628/CA/NCI NIH HHS/ -- R01 CA084628-19/CA/NCI NIH HHS/ -- R01CA84628/CA/NCI NIH HHS/ -- U01 CA141508/CA/NCI NIH HHS/ -- U01 CA141508-01/CA/NCI NIH HHS/ -- U01CA141508/CA/NCI NIH HHS/ -- England -- Nature. 2011 Jan 6;469(7328):102-6. doi: 10.1038/nature09603. Epub 2010 Nov 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Belfer Institute for Applied Cancer Science and Departments of Medical Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21113150" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/drug effects/*metabolism/*pathology ; Animals ; Avoidance Learning/drug effects ; Brain/anatomy & histology/cytology/drug effects/pathology ; Cell Differentiation/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; DNA Damage/drug effects ; Enzyme Activation/drug effects ; Enzyme Reactivators/pharmacology ; Mice ; Mice, Inbred C57BL ; Models, Animal ; Myelin Sheath/metabolism ; Neural Stem Cells/cytology/drug effects/enzymology/pathology ; Organ Size/drug effects ; Phenotype ; Receptors, Estrogen/genetics/metabolism ; Recombinant Fusion Proteins/genetics/metabolism ; Regenerative Medicine ; Smell/drug effects/physiology ; Tamoxifen/analogs & derivatives/pharmacology ; Telomerase/*deficiency/genetics/*metabolism ; Telomere/drug effects/metabolism/pathology
    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: 2011-02-11
    Description: Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1alpha and PGC-1beta, also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1alpha expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1alpha and PGC-1beta promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741661/" 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/PMC3741661/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sahin, Ergun -- Colla, Simona -- Liesa, Marc -- Moslehi, Javid -- Muller, Florian L -- Guo, Mira -- Cooper, Marcus -- Kotton, Darrell -- Fabian, Attila J -- Walkey, Carl -- Maser, Richard S -- Tonon, Giovanni -- Foerster, Friedrich -- Xiong, Robert -- Wang, Y Alan -- Shukla, Sachet A -- Jaskelioff, Mariela -- Martin, Eric S -- Heffernan, Timothy P -- Protopopov, Alexei -- Ivanova, Elena -- Mahoney, John E -- Kost-Alimova, Maria -- Perry, Samuel R -- Bronson, Roderick -- Liao, Ronglih -- Mulligan, Richard -- Shirihai, Orian S -- Chin, Lynda -- DePinho, Ronald A -- P30 DK046200/DK/NIDDK NIH HHS/ -- P30DK079638/DK/NIDDK NIH HHS/ -- R01 CA084628/CA/NCI NIH HHS/ -- R01 DK035914/DK/NIDDK NIH HHS/ -- R01 DK056690/DK/NIDDK NIH HHS/ -- R01 DK063356/DK/NIDDK NIH HHS/ -- R01 DK089185/DK/NIDDK NIH HHS/ -- U24 DK-59635/DK/NIDDK NIH HHS/ -- England -- Nature. 2011 Feb 17;470(7334):359-65. doi: 10.1038/nature09787. Epub 2011 Feb 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21307849" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/biosynthesis ; Aging/metabolism/pathology ; Animals ; Cardiomyopathies/chemically induced/metabolism/pathology/physiopathology ; Cell Proliferation ; DNA, Mitochondrial/analysis ; Doxorubicin/toxicity ; Gluconeogenesis ; Hematopoietic Stem Cells/metabolism/pathology ; Liver/cytology/metabolism ; Mice ; Mitochondria/*metabolism/*pathology ; Myocardium/cytology/metabolism ; RNA/genetics ; Reactive Oxygen Species/metabolism ; Telomerase/deficiency/genetics ; Telomere/enzymology/genetics/*metabolism/*pathology ; Transcription Factors/antagonists & inhibitors/metabolism ; Tumor Suppressor Protein p53/deficiency/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Advances in Space Research 14 (1994), S. 125-130 
    ISSN: 0273-1177
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1573-935X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1573-935X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1573-8647
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1573-8647
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Radiation and environmental biophysics 29 (1990), S. 103-107 
    ISSN: 1432-2099
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Physics
    Notes: Summary Dry eggs of Artemia salina were exposed to 80 KV-X-rays and Kr-Ions (energy: 11.75 MeV/u; LET: 3500 KeV/µm). Emergence, hatching and survival were determined. The results demonstrate a very high resistance both to sparsely and ionizing radiation.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1573-9171
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Conclusions 1. In the interaction of tantalum halides with lithium aluminum hydride, regardless of the ratio of the initial components, tantalum tetraaluminum hydride Ta(AlH4)4 is formed; during the reaction it already decomposes, eliminating aluminum hydride and forming products of variable composition TaHn(AlH4)4−n. 2. The solubility of tantalum and lithium chlorides at room temperature and that of their bromides in the interval −70 to +25° were determined. When tantalum pentabromide is treated with ether, it is reduced.
    Type of Medium: Electronic Resource
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