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Melanoma brain colonization involves the emergence of a brain-adaptive phenotype

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Melanoma brain colonization involves the emergence of a brain-adaptive phenotype ABSTRACT The brain offers a unique microenvironment that plays an important role in the establishment and progression of metastasis. However, the molecular determinants that promote development of melanoma brain metastases are largely unknown. Utilizing two species of immune-compromised animals, with  in vivo  cultivated metastatic tissues along with their corresponding host tissues in a metastasis model, we here identify molecular events associated with melanoma brain metastases. We find that the transcriptional changes in the melanoma cells, as induced by the brain-microenvironment in both host species, reveal the opportunistic nature of melanoma in this biological context in rewiring the molecular framework of key molecular players with their associated biological processes. Specifically, we identify the existence of a neuron-like melanoma phenotype, which includes synaptic characteristics and a neurotr
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Origins of cancer symposium 2016: exploring tumor complexity

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Origins of cancer symposium 2016: exploring tumor complexity ABSTRACT Cancer has challenged researchers with its immense complexity, from initiation to progression and on to therapeutic resistance. The seventh Origins of Cancer Symposium, held on July 22, 2016, at Van Andel Research Institute, was organized around the theme “Exploring Tumor Complexity”, and the latest advances under that theme from seven leading cancer research laboratories were discussed. Here we summarize highlights from the meeting and their implications. oncotarget impact factor Misha Blagosklonny Mikhail (Misha) V. Blagosklonny graduated with an MD and PhD from First Pavlov State Medical University of St. Petersburg, Russia. Dr. Mikhail V. Blagosklonny has then immigrated to the United States, where he received the prestigious Fogarty Fellowship from the National Institutes of Health. During his fellowship in Leonard Neckers’ lab at the National Cancer Institute (NCI), he was a co-author of 18 publications on var
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Pharmacological induction of Hsp70 protects apoptosis-prone cells from doxorubicin: Comparison with caspase-inhibitor- and cycle-arrest-mediated cytoprotection

Pharmacological induction of Hsp70 protects apoptosis-prone cells from doxorubicin: Comparison with caspase-inhibitor- and cycle-arrest-mediated cytoprotection Abstract Selective modulation of cell death is important for rational chemotherapy. By depleting Hsp90-client oncoproteins, geldanamycin (GA) and 17-allylamino-17-demethoxy-GA (17-AAG) (heat-shock protein-90-active drugs) render certain oncoprotein-addictive cancer cells sensitive to chemotherapy. Here we investigated effects of GA and 17-AAG in apoptosis-prone cells such as HL60 and U937. In these cells, doxorubicin (DOX) caused rapid apoptosis, whereas GA-induced heat-shock protein-70 (Hsp70) (a potent inhibitor of apoptosis) and G1 arrest without significant apoptosis. GA blocked caspase activation and apoptosis and delayed cell death caused by DOX. Inhibitors of translation and transcription and siRNA Hsp70 abrogated cytoprotective effects of GA. Also GA failed to protect HL60 cells from cytotoxicity of actinomycin D and fla
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Rapamycin decelerates cellular senescence. Zoya N Demidenko

Rapamycin decelerates cellular senescence Abstract When the cell cycle is arrested but cellular growth is not, then cells senesce, permanently losing proliferative potential. Here we demonstrated that the duration of cell cycle arrest determines a progressive loss of proliferative capacity. In human and rodent cell lines, rapamycin (an inhibitor of mTOR) dramatically decelerated loss of proliferative potential caused by ectopic p21, p16 and sodium butyrate-induced p21. Thus, when the cell cycle was arrested by these factors in the presence of rapamycin, cells retained the capacity to resume proliferation, once p21, p16 or sodium butyrate were removed. While rapamycin prevented the permanent loss of proliferative potential in arrested cells, it did not force the arrested cells into proliferation. During cell cycle arrest, rapamycin transformed the irreversible arrest into a reversible condition. Our data demonstrate that senescence can be pharmacologically suppressed.  https://www.resea
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Pharmacologic inhibition of MEK and PI-3K converges on the mTOR/S6 pathway to decelerate cellular senescence

Pharmacologic inhibition of MEK and PI-3K converges on the mTOR/S6 pathway to decelerate cellular senescence Abstract Inhibition of mTOR by rapamycin prevents cellular senescence. Here we investigated the effects of MEK and PI-3K on cellular senescence. Unlike LY294002 (PI-3K inhibitor), both U0126 and PD98059 (MEK inhibitors) did not significantly decrease beta-Gal staining in aging human fibroblasts and fibrosarcoma cells. However, using a sensitive, functional method, we identified that not only LY294002 but also U0126 prevented irreversible loss of proliferative potential associated with cellular senescence. At concentrations that blocked S6 phosphorylation, rapamycin, U0126 and LY294002 equally prevented senescence. Furthermore, there was no additive effect by combining of rapamycin with either U0126 or LY294002. Taken together this suggests that (a) simultaneous activation of PI-3K and MEK is required to ensure cellular senescence and (b) U0126 and LY294002 suppress senescence vi
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At concentrations that inhibit mTOR, resveratrol suppresses cellular senescence. Zoya N Demidenko

At concentrations that inhibit mTOR, resveratrol suppresses cellular senescence Abstract Here we demonstrated that, at cytostatic, near-toxic concentrations, resveratrol inhibited S6 phosphorylation and prevented the senescence morphology in human cells. Using a sensitive functional assay, we found that resveratrol partially prevented loss of the proliferative potential associated with cellular senescence. Resveratrol was less effective than rapamycin, because aging-suppression by resveratrol was limited by its toxicity at high concentrations. We discuss whether concentrations of resveratrol that inhibit mTOR (target of rapamycin) and suppress cellular senescence are clinically achievable and whether partial inhibition of mTOR by resveratrol might be sufficient to affect organismal aging.  https://www.researchgate.net/scientific-contributions/39445053_Zoya_N_Demidenko oncotarget research Zoya Demidenko Dr. Zoya N. Demidenko Zoya N. Demidenko , Ph.D. is Executive Manager of the Oncota
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Cellular quiescence caused by the Mdm2 inhibitor Nutlin-3A. Zoya N Demidenko

Cellular quiescence caused by the Mdm2 inhibitor Nutlin-3A Abstract Cellular senescence is characterized by irreversible loss of proliferative potential and a large, flat cell morphology. Ectopic p21 and doxorubicin induced cellular senescence in HT1080 and WI-38-tert cell lines. In the same cell lines, the Mdm2 inhibitor nutlin-3a induced p53 but, unexpectedly, caused quiescence (reversible arrest) with a small cell morphology. We discuss that Mdm antagonists could be used in combination with chemotherapy to reversibly arrest normal cells, thus protecting them during chemotherapy of cancer (cyclotherapy).  https://www.researchgate.net/scientific-contributions/39445053_Zoya_N_Demidenko oncotarget impact Zoya Demidenko Dr. Zoya N. Demidenko Zoya N. Demidenko , Ph.D. is Executive Manager of the Oncotarget journal . Oncotarget publishes high-impact research papers of general interest and outstanding significance and novelty in all areas of biology and medicine: in translational, basic a
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