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  • 1
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; INHIBITION ; PATHWAY ; MIGRATION ; HEPATOCYTE GROWTH-FACTOR ; C-MET ; PEDIATRIC MEDULLOBLASTOMA ; GENETIC PROFILES
    Abstract: Medulloblastoma is the most common malignant pediatric brain tumor, with metastases present at diagnosis conferring a poor prognosis. Mechanisms of dissemination are poorly understood and metastatic lesions are genetically divergent from the matched primary tumor. Effective and less toxic therapies that target both compartments have yet to be identified. Here we report that the analysis of several large non-overlapping cohorts of medulloblastoma patients reveal MET kinase as a marker of sonic hedgehog (SHH) driven medulloblastoma. Immunohistochemical analysis of phosphorylated, active MET kinase in an independent patient cohort confirmed its correlation with increased tumor relapse and poor survival, suggesting that SHH medulloblastoma patients may benefit from MET-targeted therapy. In support of this hypothesis, we found that the approved MET inhibitor foretinib could suppress MET activation, decrease tumor cell proliferation and induce apoptosis in SHH medulloblastomas in vitro and in vivo. Foretinib penetrated the blood-brain barrier and was effective in both the primary and metastatic tumor compartments. In established mouse xenograft or transgenic models of metastatic SHH medulloblastoma, foretinib administration reduced the growth of the primary tumor, decreased the incidence of metastases and increased host survival. Taken together, our results provide a strong rationale to clinically evaluate foretinib as an effective therapy for patients with SHH-driven medulloblastoma.
    Type of Publication: Journal article published
    PubMed ID: 25391241
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  • 2
  • 3
    ISSN: 0003-2697
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1434-6052
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract. A modification of perturbation theory, known as the delta expansion (variationally improved perturbation), gave rigorously convergent series in some D=1 models (oscillator energy levels) with factorially divergent ordinary perturbative expansions. In a generalization of the variationally improved perturbation technique appropriate to renormalizable asymptotically free theories, we show that the large expansion orders of certain physical quantities are similarly improved, and prove the Borel convergence of the corresponding series for $m_{\mathrm {v}} \lessim 0$ , with $m_{\mathrm {v}}$ the new (arbitrary) mass perturbation parameter. We argue that non-ambiguous estimates of quantities relevant to dynamical (chiral) symmetry breaking in QCD are possible in this resummation framework.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    ISSN: 0006-291X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 6
    Publication Date: 2018-02-10
    Description: Obesity is a chronic organismal stress that disrupts multiple systemic and tissue-specific functions. In this study, we describe the impact of obesity on the activity of the hematopoietic stem cell (HSC) compartment. We show that obesity alters the composition of the HSC compartment and its activity in response to hematopoietic stress. The impact of obesity on HSC function is progressively acquired but persists after weight loss or transplantation into a normal environment. Mechanistically, we establish that the oxidative stress induced by obesity dysregulates the expression of the transcription factor Gfi1 and that increased Gfi1 expression is required for the abnormal HSC function induced by obesity. These results demonstrate that obesity produces durable changes in HSC function and phenotype and that elevation of Gfi1 expression in response to the oxidative environment is a key driver of the altered HSC properties observed in obesity. Altogether, these data provide phenotypic and mechanistic insight into durable hematopoietic dysregulations resulting from obesity.
    Keywords: Stem Cells & Regeneration, Hematopoiesis
    Print ISSN: 0022-1007
    Electronic ISSN: 1540-9538
    Topics: Medicine
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  • 7
    Publication Date: 2013-02-08
    Description: Blood production is ensured by rare, self-renewing haematopoietic stem cells (HSCs). How HSCs accommodate the diverse cellular stresses associated with their life-long activity remains elusive. Here we identify autophagy as an essential mechanism protecting HSCs from metabolic stress. We show that mouse HSCs, in contrast to their short-lived myeloid progeny, robustly induce autophagy after ex vivo cytokine withdrawal and in vivo calorie restriction. We demonstrate that FOXO3A is critical to maintain a gene expression program that poises HSCs for rapid induction of autophagy upon starvation. Notably, we find that old HSCs retain an intact FOXO3A-driven pro-autophagy gene program, and that ongoing autophagy is needed to mitigate an energy crisis and allow their survival. Our results demonstrate that autophagy is essential for the life-long maintenance of the HSC compartment and for supporting an old, failing blood system.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579002/" 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/PMC3579002/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Warr, Matthew R -- Binnewies, Mikhail -- Flach, Johanna -- Reynaud, Damien -- Garg, Trit -- Malhotra, Ritu -- Debnath, Jayanta -- Passegue, Emmanuelle -- CA126792/CA/NCI NIH HHS/ -- HL092471/HL/NHLBI NIH HHS/ -- R01 CA126792/CA/NCI NIH HHS/ -- R01 CA184014/CA/NCI NIH HHS/ -- R01 HL111266/HL/NHLBI NIH HHS/ -- England -- Nature. 2013 Feb 21;494(7437):323-7. doi: 10.1038/nature11895. Epub 2013 Feb 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23389440" target="_blank"〉PubMed〈/a〉
    Keywords: Aging ; Animals ; Apoptosis ; Autophagy/*genetics ; Caloric Restriction ; Cell Aging ; Cell Survival/genetics ; Cytokines/deficiency/metabolism ; Energy Metabolism/*genetics ; Food Deprivation ; Forkhead Transcription Factors/*metabolism ; *Gene Expression Regulation ; Hematopoietic Stem Cells/*cytology/*metabolism ; Homeostasis ; Mice ; Mice, Inbred C57BL ; Stress, Physiological/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2014-08-01
    Description: Haematopoietic stem cells (HSCs) self-renew for life, thereby making them one of the few blood cells that truly age. Paradoxically, although HSCs numerically expand with age, their functional activity declines over time, resulting in degraded blood production and impaired engraftment following transplantation. While many drivers of HSC ageing have been proposed, the reason why HSC function degrades with age remains unknown. Here we show that cycling old HSCs in mice have heightened levels of replication stress associated with cell cycle defects and chromosome gaps or breaks, which are due to decreased expression of mini-chromosome maintenance (MCM) helicase components and altered dynamics of DNA replication forks. Nonetheless, old HSCs survive replication unless confronted with a strong replication challenge, such as transplantation. Moreover, once old HSCs re-establish quiescence, residual replication stress on ribosomal DNA (rDNA) genes leads to the formation of nucleolar-associated gammaH2AX signals, which persist owing to ineffective H2AX dephosphorylation by mislocalized PP4c phosphatase rather than ongoing DNA damage. Persistent nucleolar gammaH2AX also acts as a histone modification marking the transcriptional silencing of rDNA genes and decreased ribosome biogenesis in quiescent old HSCs. Our results identify replication stress as a potent driver of functional decline in old HSCs, and highlight the MCM DNA helicase as a potential molecular target for rejuvenation therapies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456040/" 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/PMC4456040/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Flach, Johanna -- Bakker, Sietske T -- Mohrin, Mary -- Conroy, Pauline C -- Pietras, Eric M -- Reynaud, Damien -- Alvarez, Silvia -- Diolaiti, Morgan E -- Ugarte, Fernando -- Forsberg, E Camilla -- Le Beau, Michelle M -- Stohr, Bradley A -- Mendez, Juan -- Morrison, Ciaran G -- Passegue, Emmanuelle -- F32 HL106989/HL/NHLBI NIH HHS/ -- R01 CA184014/CA/NCI NIH HHS/ -- R01 HL092471/HL/NHLBI NIH HHS/ -- R01 HL115158/HL/NHLBI NIH HHS/ -- T32 AI007334/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Aug 14;512(7513):198-202. doi: 10.1038/nature13619. Epub 2014 Jul 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Hem/Onc Division, University of California San Francisco, San Francisco, California 94143, USA [2] Institute of Experimental Cancer Research, Comprehensive Cancer Center, 89081 Ulm, Germany. ; The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Hem/Onc Division, University of California San Francisco, San Francisco, California 94143, USA. ; Center for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland. ; Spanish National Cancer Research Centre (CNIO), E-28049 Madrid, Spain. ; Department of Pathology, University of California San Francisco, San Francisco, California 94143, USA. ; Institute for the Biology of Stem Cells, Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California 95064, USA. ; Section of Hematology/Oncology and the Comprehensive Cancer Center, University of Chicago, Chicago, Illinois 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25079315" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Aging/genetics/*physiology ; Cell Proliferation ; DNA Damage/genetics ; DNA Replication/*physiology ; DNA, Ribosomal/genetics ; Female ; Gene Expression Regulation ; Hematopoietic Stem Cells/cytology/*pathology ; Histones/genetics/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Minichromosome Maintenance Proteins/genetics ; *Stress, Physiological
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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