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  1. Article ; Online: MLL3 regulates the

    Zhu, Changyu / Soto-Feliciano, Yadira M / Morris, John P / Huang, Chun-Hao / Koche, Richard P / Ho, Yu-Jui / Banito, Ana / Chen, Chun-Wei / Shroff, Aditya / Tian, Sha / Livshits, Geulah / Chen, Chi-Chao / Fennell, Myles / Armstrong, Scott A / Allis, C David / Tschaharganeh, Darjus F / Lowe, Scott W

    eLife

    2023  Volume 12

    Abstract: Mutations in genes encoding components of chromatin modifying and remodeling complexes are among the most frequently observed somatic events in human cancers. For example, missense and nonsense mutations targeting the mixed lineage leukemia family member ...

    Abstract Mutations in genes encoding components of chromatin modifying and remodeling complexes are among the most frequently observed somatic events in human cancers. For example, missense and nonsense mutations targeting the mixed lineage leukemia family member 3 (MLL3, encoded by
    MeSH term(s) Humans ; Animals ; Mice ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; Tumor Suppressor Protein p14ARF/genetics ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/pathology ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Chromatin ; Carcinogenesis
    Chemical Substances Tumor Suppressor Protein p14ARF ; Cyclin-Dependent Kinase Inhibitor p16 ; Chromatin ; CDKN2A protein, human
    Language English
    Publishing date 2023-06-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.80854
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Oral haloperidol or olanzapine intake produces distinct and region-specific increase in cannabinoid receptor levels that is prevented by high fat diet.

    Delis, Foteini / Rosko, Lauren / Shroff, Aditya / Leonard, Kenneth E / Thanos, Panayotis K

    Progress in neuro-psychopharmacology & biological psychiatry

    2017  Volume 79, Issue Pt B, Page(s) 268–280

    Abstract: Clinical studies show higher levels of cannabinoid CB1 receptors (CB1R) in the brain of schizophrenic patients while preclinical studies report a significant functional interaction between dopamine D2 receptors and CB1Rs as well as an upregulation of ... ...

    Abstract Clinical studies show higher levels of cannabinoid CB1 receptors (CB1R) in the brain of schizophrenic patients while preclinical studies report a significant functional interaction between dopamine D2 receptors and CB1Rs as well as an upregulation of CB1Rs after antipsychotic treatment. These findings prompted us to study the effects of chronic oral intake of a first and a second generation antipsychotic, haloperidol and olanzapine, on the levels and distribution of CB1Rs in the rat brain. Rats consumed either regular chow or high-fat food and drank water, haloperidol drinking solution (1.5mg/kg), or olanzapine drinking solution (10mg/kg) for four weeks. Motor and cognitive functions were tested at the end of treatment week 3 and upon drug discontinuation. Two days after drug discontinuation, rats were euthanized and brains were processed for in vitro receptor autoradiography. In chow-fed animals, haloperidol and olanzapine increased CB1R levels in the basal ganglia and the hippocampus, in a similar, but not identical pattern. In addition, olanzapine had unique effects in CB1R upregulation in higher order cognitive areas, in the secondary somatosensory cortex, in the visual and auditory cortices and the geniculate nuclei, as well as in the hypothalamus. High fat food consumption prevented antipsychotic-induced increase in CB1R levels in all regions examined, with one exception, the globus pallidus, in which they were higher in haloperidol-treated rats. The results point towards the hypothesis that increased CB1R levels could be a confounding effect of antipsychotic medication in schizophrenia that is circumveneted by high fat feeding.
    MeSH term(s) Administration, Oral ; Animals ; Antipsychotic Agents/administration & dosage ; Autoradiography ; Benzodiazepines/administration & dosage ; Brain/drug effects ; Brain/metabolism ; Brain/pathology ; Diet, High-Fat/adverse effects ; Drinking Water ; Exploratory Behavior/drug effects ; Exploratory Behavior/physiology ; Haloperidol/administration & dosage ; Male ; Motor Activity/drug effects ; Motor Activity/physiology ; Olanzapine ; Random Allocation ; Rats, Sprague-Dawley ; Receptor, Cannabinoid, CB1/metabolism ; Recognition, Psychology/drug effects ; Recognition, Psychology/physiology ; Up-Regulation/drug effects ; Up-Regulation/physiology
    Chemical Substances Antipsychotic Agents ; Cnr1 protein, rat ; Drinking Water ; Receptor, Cannabinoid, CB1 ; Benzodiazepines (12794-10-4) ; Haloperidol (J6292F8L3D) ; Olanzapine (N7U69T4SZR)
    Language English
    Publishing date 2017-06-13
    Publishing country England
    Document type Comparative Study ; Journal Article
    ZDB-ID 781181-0
    ISSN 1878-4216 ; 0278-5846
    ISSN (online) 1878-4216
    ISSN 0278-5846
    DOI 10.1016/j.pnpbp.2017.06.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1342: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition.

    Chen, Chong / Liu, Yu / Lu, Chao / Cross, Justin R / Morris, John P / Shroff, Aditya S / Ward, Patrick S / Bradner, James E / Thompson, Craig / Lowe, Scott W

    Genes & development

    2013  Volume 27, Issue 18, Page(s) 1974–1985

    Abstract: Somatic mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 occur frequently in acute myeloid leukemia (AML) and other cancers. These genes encode neomorphic proteins that produce the presumed oncometabolite 2-hydroxyglutarate (2-HG). ... ...

    Abstract Somatic mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 occur frequently in acute myeloid leukemia (AML) and other cancers. These genes encode neomorphic proteins that produce the presumed oncometabolite 2-hydroxyglutarate (2-HG). Despite the prospect of treating AML and other cancers by targeting IDH mutant proteins, it remains unclear how these mutants affect tumor development and maintenance in vivo, and no cancer models exist to study the action of IDH2 mutants in vivo. We show that IDH2 mutants can cooperate with oncogenic Flt3 or Nras alleles to drive leukemia in mice by impairing the differentiation of cells of the myeloid lineage. Pharmacologic or genetic inhibition of IDH2 triggers the differentiation and death of AML cells, albeit only with prolonged IDH2 inhibition. In contrast, inhibition of the bromodomain-containing protein Brd4 triggers rapid differentiation and death of IDH2 mutant AML. Our results establish a critical role for mutant IDH2 in leukemogenesis and tumor maintenance and identify an IDH-independent strategy to target these cancers therapeutically.
    MeSH term(s) Animals ; Cell Differentiation/genetics ; Cell Transformation, Neoplastic ; Cells, Cultured ; DNA Methylation/genetics ; Disease Models, Animal ; GTP Phosphohydrolases/metabolism ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/enzymology ; Hematopoietic Stem Cells/pathology ; Humans ; Isocitrate Dehydrogenase/genetics ; Isocitrate Dehydrogenase/metabolism ; Leukemia, Myeloid, Acute/enzymology ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/physiopathology ; Mice ; Mice, Inbred C57BL ; Mutation ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism ; fms-Like Tyrosine Kinase 3/metabolism
    Chemical Substances Brd4 protein, mouse ; Nuclear Proteins ; Transcription Factors ; Isocitrate Dehydrogenase (EC 1.1.1.41) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1) ; GTP Phosphohydrolases (EC 3.6.1.-)
    Language English
    Publishing date 2013-09-21
    Publishing country United States
    Document type Journal Article
    ZDB-ID 806684-x
    ISSN 1549-5477 ; 0890-9369
    ISSN (online) 1549-5477
    ISSN 0890-9369
    DOI 10.1101/gad.226613.113
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2292: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 54: Show issues

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  4. Article ; Online: MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia.

    Chen, Chong / Liu, Yu / Rappaport, Amy R / Kitzing, Thomas / Schultz, Nikolaus / Zhao, Zhen / Shroff, Aditya S / Dickins, Ross A / Vakoc, Christopher R / Bradner, James E / Stock, Wendy / LeBeau, Michelle M / Shannon, Kevin M / Kogan, Scott / Zuber, Johannes / Lowe, Scott W

    Cancer cell

    2014  Volume 25, Issue 5, Page(s) 652–665

    Abstract: Recurring deletions of chromosome 7 and 7q [-7/del(7q)] occur in myelodysplastic syndromes and acute myeloid leukemia (AML) and are associated with poor prognosis. However, the identity of functionally relevant tumor suppressors on 7q remains unclear. ... ...

    Abstract Recurring deletions of chromosome 7 and 7q [-7/del(7q)] occur in myelodysplastic syndromes and acute myeloid leukemia (AML) and are associated with poor prognosis. However, the identity of functionally relevant tumor suppressors on 7q remains unclear. Using RNAi and CRISPR/Cas9 approaches, we show that an ∼50% reduction in gene dosage of the mixed lineage leukemia 3 (MLL3) gene, located on 7q36.1, cooperates with other events occurring in -7/del(7q) AMLs to promote leukemogenesis. Mll3 suppression impairs the differentiation of HSPC. Interestingly, Mll3-suppressed leukemias, like human -7/del(7q) AMLs, are refractory to conventional chemotherapy but sensitive to the BET inhibitor JQ1. Thus, our mouse model functionally validates MLL3 as a haploinsufficient 7q tumor suppressor and suggests a therapeutic option for this aggressive disease.
    MeSH term(s) Animals ; Azepines/pharmacology ; Cell Differentiation/genetics ; Cell Transformation, Neoplastic/genetics ; Chromosome Deletion ; Chromosomes, Human, Pair 7/genetics ; Clustered Regularly Interspaced Short Palindromic Repeats ; Drug Resistance, Neoplasm/genetics ; Gene Dosage ; Haploinsufficiency/genetics ; Histone-Lysine N-Methyltransferase/antagonists & inhibitors ; Histone-Lysine N-Methyltransferase/genetics ; Humans ; Leukemia, Myeloid, Acute/genetics ; Mice ; Mice, Inbred C57BL ; Myeloid-Lymphoid Leukemia Protein/genetics ; RNA Interference ; RNA, Small Interfering ; Triazoles/pharmacology ; Tumor Suppressor Proteins/genetics
    Chemical Substances (+)-JQ1 compound ; Azepines ; RNA, Small Interfering ; Triazoles ; Tumor Suppressor Proteins ; Myeloid-Lymphoid Leukemia Protein (149025-06-9) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; MLL3 protein, mouse (EC 2.1.1.43)
    Language English
    Publishing date 2014-05-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2078448-X
    ISSN 1878-3686 ; 1535-6108
    ISSN (online) 1878-3686
    ISSN 1535-6108
    DOI 10.1016/j.ccr.2014.03.016
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5650: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 104: Show issues

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