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  • 1
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    Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-10-04
    Description: Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC and the polymerase-associated factor complex (PAFc), are associated with the BET family of acetyl-lysine recognizing, chromatin 'adaptor' proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679520/" 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/PMC3679520/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dawson, Mark A -- Prinjha, Rab K -- Dittmann, Antje -- Giotopoulos, George -- Bantscheff, Marcus -- Chan, Wai-In -- Robson, Samuel C -- Chung, Chun-wa -- Hopf, Carsten -- Savitski, Mikhail M -- Huthmacher, Carola -- Gudgin, Emma -- Lugo, Dave -- Beinke, Soren -- Chapman, Trevor D -- Roberts, Emma J -- Soden, Peter E -- Auger, Kurt R -- Mirguet, Olivier -- Doehner, Konstanze -- Delwel, Ruud -- Burnett, Alan K -- Jeffrey, Phillip -- Drewes, Gerard -- Lee, Kevin -- Huntly, Brian J P -- Kouzarides, Tony -- 092096/Wellcome Trust/United Kingdom -- G0800784/Medical Research Council/United Kingdom -- G116/187/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2011 Oct 2;478(7370):529-33. doi: 10.1038/nature10509.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge CB2 0XY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21964340" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Chromatin/genetics/*metabolism ; Chromatin Immunoprecipitation ; Disease Models, Animal ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects ; Heterocyclic Compounds with 4 or More Rings/pharmacology/therapeutic use ; Humans ; Leukemia, Myeloid, Acute/*drug therapy/genetics/*metabolism/pathology ; Mice ; Models, Molecular ; Multiprotein Complexes/chemistry/metabolism ; Myeloid-Lymphoid Leukemia Protein/*metabolism ; Oncogene Proteins, Fusion/*metabolism ; Protein Binding/drug effects ; Proteomics ; Transcription Factors/*antagonists & inhibitors/*metabolism ; Transcription, Genetic/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    BET inhibitor resistance emerges from leukaemia stem cells (2015)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2015-09-15
    Description: Bromodomain and extra terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic opportunity by directly targeting bromodomain proteins that bind acetylated chromatin marks. Early clinical trials have shown promise, especially in acute myeloid leukaemia, and therefore the evaluation of resistance mechanisms is crucial to optimize the clinical efficacy of these drugs. Here we use primary mouse haematopoietic stem and progenitor cells immortalized with the fusion protein MLL-AF9 to generate several single-cell clones that demonstrate resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism, but is shown to emerge from leukaemia stem cells both ex vivo and in vivo. Chromatin-bound BRD4 is globally reduced in resistant cells, whereas the expression of key target genes such as Myc remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors, in human and mouse leukaemia cells, is in part a consequence of increased Wnt/beta-catenin signalling, and negative regulation of this pathway results in restoration of sensitivity to I-BET in vitro and in vivo. Together, these findings provide new insights into the biology of acute myeloid leukaemia, highlight potential therapeutic limitations of BET inhibitors, and identify strategies that may enhance the clinical utility of these unique targeted therapies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fong, Chun Yew -- Gilan, Omer -- Lam, Enid Y N -- Rubin, Alan F -- Ftouni, Sarah -- Tyler, Dean -- Stanley, Kym -- Sinha, Devbarna -- Yeh, Paul -- Morison, Jessica -- Giotopoulos, George -- Lugo, Dave -- Jeffrey, Philip -- Lee, Stanley Chun-Wei -- Carpenter, Christopher -- Gregory, Richard -- Ramsay, Robert G -- Lane, Steven W -- Abdel-Wahab, Omar -- Kouzarides, Tony -- Johnstone, Ricky W -- Dawson, Sarah-Jane -- Huntly, Brian J P -- Prinjha, Rab K -- Papenfuss, Anthony T -- Dawson, Mark A -- England -- Nature. 2015 Sep 24;525(7570):538-42. doi: 10.1038/nature14888. Epub 2015 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. ; Sir Peter MacCallum Department of Oncology, The University of Melbourne, East Melbourne, Victoria 3002, Australia. ; Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. ; Bioinformatics Division, The Walter &Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia. ; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia. ; Department of Haematology, Cambridge Institute for Medical Research and Wellcome Trust-MRC Stem Cell Institute, Cambridge CB2 0XY, UK. ; Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK. ; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA. ; QIMR Berghofer Medical Research Institute, University of Queensland, Brisbane, Queensland 4029, Australia. ; Gurdon Institute and Department of Pathology, Tennis Court Road, Cambridge CB2 1QN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26367796" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Azepines/pharmacology ; Benzodiazepines/*pharmacology ; Cell Line, Tumor ; Cells, Cultured ; Chromatin/metabolism ; Clone Cells/drug effects/metabolism/pathology ; Drug Resistance, Neoplasm/*drug effects/genetics ; Epigenesis, Genetic ; Gene Expression Regulation, Neoplastic/drug effects ; Genes, myc/genetics ; Hematopoietic Stem Cells/cytology/drug effects/metabolism ; Humans ; Leukemia, Myeloid, Acute/*drug therapy/genetics/*metabolism/pathology ; Mice ; Molecular Targeted Therapy ; Neoplastic Stem Cells/*drug effects/metabolism/*pathology ; Nuclear Proteins/*antagonists & inhibitors/metabolism ; Transcription Factors/*antagonists & inhibitors/metabolism ; Transcription, Genetic/drug effects ; Triazoles/pharmacology ; Wnt Signaling Pathway/drug effects ; beta Catenin/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Time-resolved structural evolution during the collapse of responsive hydrogels: The microgel-to-particle transition (2018)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2018-04-07
    Description: Adaptive hydrogels, often termed smart materials, are macromolecules whose structure adjusts to external stimuli. Responsive micro- and nanogels are particularly interesting because the small length scale enables very fast response times. Chemical cross-links provide topological constraints and define the three-dimensional structure of the microgels, whereas their porous structure permits fast mass transfer, enabling very rapid structural adaption of the microgel to the environment. The change of microgel structure involves a unique transition from a flexible, swollen finite-size macromolecular network, characterized by a fuzzy surface, to a colloidal particle with homogeneous density and a sharp surface. In this contribution, we determine, for the first time, the structural evolution during the microgel-to-particle transition. Time-resolved small-angle x-ray scattering experiments and computer simulations unambiguously reveal a two-stage process: In a first, very fast process, collapsed clusters form at the periphery, leading to an intermediate, hollowish core-shell structure that slowly transforms to a globule. This structural evolution is independent of the type of stimulus and thus applies to instantaneous transitions as in a temperature jump or to slower stimuli that rely on the uptake of active molecules from and/or exchange with the environment. The fast transitions of size and shape provide unique opportunities for various applications as, for example, in uptake and release, catalysis, or sensing.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    Mars Thermosphere as seen in MAVEN Accelerometer Data (2017)
    Wiley
    Details
    Publication Date: 2017-02-15
    Description: The Mars thermosphere (above approximately 120 km) has been probed in situ for one Mars year using accelerometers onboard the Mars Atmosphere and Volatile Evolution (MAVEN) spacecraft. This region is affected by radiation and energy deposition from the Sun and by energy and momentum from the lower atmosphere. Densities derived from measurements made during the nominal science orbits (periapsis 〉 140 km) show consistent trends with solar zenith angle and Sun-Mars distance, reflecting direct and indirect heating of the thermosphere, although orbit-to-orbit variability is still significant. The six Deep Dip campaigns that MAVEN has conducted (with periapsis dropping below ~135 km) significantly extend the vertical profiles of the densities derived from accelerometer data. These show complex structure and high variability, both dependent on season, local time, location, and lower atmosphere activity, including dust storms and wave propagation from a dynamic lower atmosphere. In particular, the terminators are a region of convoluted structure and high variability, which may be greatest in the post mid-night, pre-dawn hours of the sol. This space-time regime was not sampled by previous orbiters at Mars. While initial comparisons with thermospheric general circulation modes show broad areas of agreement, these terminator transition regions are not simulated well by current models. Judicious choice of the timing of these Deep Dip campaigns during the remaining MAVEN mission, as periapsis continues to precess through local time, latitude, and longitude in both hemispheres and in different seasons, should help clarify the processes at work in this complicated region.
    Print ISSN: 0148-0227
    Topics: Geosciences , Physics
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 5
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    Click chemistry enables preclinical evaluation of targeted epigenetic therapies (2017)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2017-06-30
    Description: The success of new therapies hinges on our ability to understand their molecular and cellular mechanisms of action. We modified BET bromodomain inhibitors, an epigenetic-based therapy, to create functionally conserved compounds that are amenable to click chemistry and can be used as molecular probes in vitro and in vivo. We used click proteomics and click sequencing to explore the gene regulatory function of BRD4 (bromodomain containing protein 4) and the transcriptional changes induced by BET inhibitors. In our studies of mouse models of acute leukemia, we used high-resolution microscopy and flow cytometry to highlight the heterogeneity of drug activity within tumor cells located in different tissue compartments. We also demonstrate the differential distribution and effects of BET inhibitors in normal and malignant cells in vivo. This study provides a potential framework for the preclinical assessment of a wide range of drugs.
    Keywords: Medicine, Diseases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 6
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    Development of Large-Format Lithium-Ion Cells with Silicon Anode and Low Flammable Electrolyte (2014)
    In:  CASI
    Details
    Publication Date: 2019-07-13
    Description: NASA is developing safe, high energy and high capacity lithium-ion cell designs and batteries for future missions under NASAs Advanced Space Power System (ASPS) project. Advanced cell components, such as high specific capacity silicon anodes and low-flammable electrolytes have been developed for improving the cell specific energy and enhancing safety. To advance the technology readiness level, we have developed large-format flight-type hermetically sealed battery cells by incorporating high capacity silicon anodes, commercially available lithium nickel, cobalt, aluminum oxide (NCA) cathodes, and low-flammable electrolytes. In this report, we will present the performance results of these various battery cells. In addition, we will also discuss the post-test cell analysis results as well.
    Keywords: Composite Materials; Atomic and Molecular Physics; Energy Production and Conversion
    Type: GRC-E-DAA-TN19064 , Annual Lithium Battery Power Conference 2014; Nov 11, 2014 - Nov 12, 2014; Washington, DC; United States
    Format: application/pdf
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    NASA TECHNICAL REPORTS
  • 7
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    Análisis de contaminantes inorgánicos tóxicos en las aguas del Rio Almendares, Cuba (2008)
    CONyMA
    Details
    Publication Date: 2021-05-19
    Description: The Almendares River constitutes the most important superficial stream in Cuban capital, that finishes in the Metropolitan Park of Havana, which is an entertaining centre. The objective of this work is to determine the presence of toxic inorganic pollutants in the Almendares River water. 10 samplings were carried out from June 2003 to May 2004 in 14 stations established along the last 10 km of the river and 3 tributaries. The quantification of nitrates, nitrites and ammonium was done by spectrophotometric methods The concentration of heavy metals in the dissolved and particulate phase was determined by atomic emission spectrometry. The total microbial charge was determined by epifluorescency. Were found high levels of ammonium and nitrites, as well as high values of Cd, Co, Ni and Pb. The total microbial charge were high in the 14 stations in spite of the presence of toxic metals.
    Description: Published
    Keywords: Rivers ; Heavy metals ; Rivers ; Freshwater pollution ; Heavy metals
    Repository Name: AquaDocs
    Type: Proceedings Paper
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