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  • 1
    Publication Date: 2018-07-20
    Description: Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor B activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.
    Keywords: Cell Biology, Medicine, Diseases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Keywords: COLORECTAL-CANCER ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; STEM-CELLS ; medulloblastoma ; GLIOBLASTOMA ; GENE-EXPRESSION SIGNATURE ; DISTINCT SUBGROUPS ; ISLAND METHYLATOR PHENOTYPE ; DRIVER MUTATIONS ; GENOMIC COMPLEXITY
    Abstract: Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.
    Type of Publication: Journal article published
    PubMed ID: 24553142
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  • 3
    Publication Date: 2014-04-11
    Description: The BRAF kinase is mutated, typically Val 600--〉Glu (V600E), to induce an active oncogenic state in a large fraction of melanomas, thyroid cancers, hairy cell leukaemias and, to a smaller extent, a wide spectrum of other cancers. BRAF(V600E) phosphorylates and activates the MEK1 and MEK2 kinases, which in turn phosphorylate and activate the ERK1 and ERK2 kinases, stimulating the mitogen-activated protein kinase (MAPK) pathway to promote cancer. Targeting MEK1/2 is proving to be an important therapeutic strategy, given that a MEK1/2 inhibitor provides a survival advantage in metastatic melanoma, an effect that is increased when administered together with a BRAF(V600E) inhibitor. We previously found that copper (Cu) influx enhances MEK1 phosphorylation of ERK1/2 through a Cu-MEK1 interaction. Here we show decreasing the levels of CTR1 (Cu transporter 1), or mutations in MEK1 that disrupt Cu binding, decreased BRAF(V600E)-driven signalling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 chimaera that phosphorylated ERK1/2 independently of Cu or an active ERK2 restored the tumour growth of murine cells lacking Ctr1. Cu chelators used in the treatment of Wilson disease decreased tumour growth of human or murine cells transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Taken together, these results suggest that Cu-chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138975/" 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/PMC4138975/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brady, Donita C -- Crowe, Matthew S -- Turski, Michelle L -- Hobbs, G Aaron -- Yao, Xiaojie -- Chaikuad, Apirat -- Knapp, Stefan -- Xiao, Kunhong -- Campbell, Sharon L -- Thiele, Dennis J -- Counter, Christopher M -- 092809/Wellcome Trust/United Kingdom -- 092809/Z/10/Z/Wellcome Trust/United Kingdom -- CA094184/CA/NCI NIH HHS/ -- CA172104/CA/NCI NIH HHS/ -- CA178145/CA/NCI NIH HHS/ -- DK074192/DK/NIDDK NIH HHS/ -- HL075443/HL/NHLBI NIH HHS/ -- K01 CA178145/CA/NCI NIH HHS/ -- P01 HL075443/HL/NHLBI NIH HHS/ -- P30 CA014236/CA/NCI NIH HHS/ -- P30 CA016086/CA/NCI NIH HHS/ -- R01 CA089614/CA/NCI NIH HHS/ -- R01 CA094184/CA/NCI NIH HHS/ -- R01 DK074192/DK/NIDDK NIH HHS/ -- R21 CA172104/CA/NCI NIH HHS/ -- T32 GM007184/GM/NIGMS NIH HHS/ -- T32 GM008570/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 May 22;509(7501):492-6. doi: 10.1038/nature13180. Epub 2014 Apr 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. ; Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Nuffield Department of Clinical Medicine, Target Discovery Institute and Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. ; 1] Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24717435" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cation Transport Proteins/deficiency/genetics ; Cell Line, Tumor ; *Cell Transformation, Neoplastic/drug effects ; Chelating Agents/pharmacology/therapeutic use ; Copper/*metabolism/pharmacology ; Disease Models, Animal ; Drug Repositioning ; Drug Resistance, Neoplasm/drug effects ; Female ; Hepatolenticular Degeneration/drug therapy ; Humans ; Indoles/pharmacology ; Lung Neoplasms/drug therapy/genetics/metabolism/pathology ; *MAP Kinase Signaling System/drug effects ; Mice ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Mitogen-Activated Protein Kinase Kinases/antagonists & ; inhibitors/genetics/metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors/genetics/*metabolism ; Sulfonamides/pharmacology ; Survival Analysis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2018-11-02
    Description: Purpose: The prognosis for patients with refractory soft-tissue sarcoma (STS) is dismal. Anlotinib has previously shown antitumor activity on STS in preclinical and phase I studies. Patients and Methods: Patients 18 years and older, progressing after anthracycline-based chemotherapy, naïve from angiogenesis inhibitors, with at least one measurable lesion according to RECIST 1.1, were enrolled. The main subtypes eligible were undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), leiomyosarcoma (LMS), synovial sarcoma (SS), fibrosarcoma (FS), alveolar soft-part sarcoma (ASPS), and clear cell sarcoma (CCS). Participants were treated with anlotinib. The primary endpoint was progression-free rate at 12 weeks (PFR 12 weeks ). Results: A total of 166 patients were included in the final analysis. Overall, the PFR 12 weeks was 68%, and objective response rate was 13% (95% confidence interval, 7.6%–18%). The median progression-free survival (PFS) and overall survival (OS) were 5.6 and 12 months, respectively. The PFR 12 weeks , median PFS and OS were: 58%, 4.1 and 11 months for UPS ( n = 19); 63%, 5.6 and 13 months for LPS ( n = 13); 75%, 11 and 15 months for LMS ( n = 26); 75%, 7.7 and 12 months for SS ( n = 47); 81%, 5.6 and 12 months for FS ( n = 18); 77%, 21 and not reached for ASPS ( n = 13); 54%, 11 and 16 months for CCS ( n = 7); and 44%, 2.8 and 8.8 months for other sarcoma ( n = 23), respectively. The most common clinically significant grade 3 or higher adverse events were hypertension (4.8%), triglyceride elevation (3.6%), and pneumothorax (2.4%). No treatment-related death occurred. Conclusions: Anlotinib showed antitumor activity in several STS entities. The toxicity was manageable. Clin Cancer Res; 24(21); 5233–8. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 5
    Publication Date: 2018-03-29
    Description: Respiratory syncytial virus (RSV) is the main cause of acute lower respiratory tract infection (ALRI) in children worldwide. Virus-host interactions affect the progression and prognosis of the infection. Autophagy plays important roles in virus-host interactions. Respiratory epithelial cells serve as the front line of host defense during RSV infection, However, it is still unclear how they interact with RSV. In this study, we found that RSV induced autophagy that favored RSV replication and exacerbated lung pathology in vivo . Mechanistically, RSV induced complete autophagy flux through reactive oxygen species (ROS) generation and activation of the AMP-activated protein kinase/mammalian target of rapamycin (AMPK-MTOR) signaling pathway in HEp-2 cells. Furthermore, we evaluated the functions of autophagy in RSV replication and found that RSV replication was increased in HEp-2 cells treated with rapamycin but decreased remarkably in cells treated with 3-methylademine (3-MA) or wortmannin. Knockdown key molecules in the autophagy pathway with short hairpinp RNA (shRNA) against autophagy-related gene 5 ( ATG5 ), autophagy-related gene 7 ( ATG7 ), or BECN1/Beclin 1 or treatment with ROS scavenger N-acetyl- l -cysteine (NAC) and AMPK inhibitor (compound C) suppressed RSV replication. 3-MA or sh ATG5/BECN1 significantly decreased cell viability and increased cell apoptosis at 48 hours postinfection (hpi). Blocking apoptosis with Z-VAD-FMK partially restored virus replication at 48 hpi. Those results provide strong evidence that autophagy may function as a proviral mechanism in a cell-intrinsic manner during RSV infection. IMPORTANCE An understanding of the mechanisms that respiratory syncytial virus utilizes to interact with respiratory epithelial cells is critical to the development of novel antiviral strategies. In this study, we found that RSV induces autophagy through a ROS-AMPK signaling axis, which in turn promotes viral infection. Autophagy favors RSV replication through blocking cell apoptosis at 48 hpi. Mechanistically, RSV induces mitophagy, which maintains mitochondrial homeostasis and therefore decreases cytochrome c release and apoptosis induction. This study provides a novel insight into this virus-host interaction, which may help to exploit new antiviral treatments targeting autophagy processes.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
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  • 6
    Publication Date: 2015-10-17
    Description: Neural stem cells show age-dependent developmental potentials, as evidenced by their production of distinct neuron types at different developmental times. Drosophila neuroblasts produce long, stereotyped lineages of neurons. We searched for factors that could regulate neural temporal fate by RNA-sequencing lineage-specific neuroblasts at various developmental times. We found that two RNA-binding proteins, IGF-II mRNA-binding protein (Imp) and Syncrip (Syp), display opposing high-to-low and low-to-high temporal gradients with lineage-specific temporal dynamics. Imp and Syp promote early and late fates, respectively, in both a slowly progressing and a rapidly changing lineage. Imp and Syp control neuronal fates in the mushroom body lineages by regulating the temporal transcription factor Chinmo translation. Together, the opposing Imp/Syp gradients encode stem cell age, specifying multiple cell fates within a lineage.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Zhiyong -- Yang, Ching-Po -- Sugino, Ken -- Fu, Chi-Cheng -- Liu, Ling-Yu -- Yao, Xiaohao -- Lee, Luke P -- Lee, Tzumin -- R01-GM084947/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Oct 16;350(6258):317-20. doi: 10.1126/science.aad1886.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Janelia Research Campus, 19700 Helix Drive, Ashburn, VA, USA. ; Howard Hughes Medical Institute, Janelia Research Campus, 19700 Helix Drive, Ashburn, VA, USA. Departments of Bioengineering, Electrical Engineering, and Computer Science, and Biophysics Graduate Program, University of California Berkeley, 408C Stanley Hall, Berkeley, CA, USA. ; Departments of Bioengineering, Electrical Engineering, and Computer Science, and Biophysics Graduate Program, University of California Berkeley, 408C Stanley Hall, Berkeley, CA, USA. ; Howard Hughes Medical Institute, Janelia Research Campus, 19700 Helix Drive, Ashburn, VA, USA. leet@janelia.hhmi.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26472907" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Lineage ; Drosophila Proteins/genetics/metabolism/*physiology ; Drosophila melanogaster/genetics/*growth & development ; Mushroom Bodies/cytology/growth & development ; Nerve Tissue Proteins/metabolism ; Neural Stem Cells/*cytology ; Neurogenesis/genetics/*physiology ; Neurons/*cytology ; RNA-Binding Proteins/genetics/*physiology ; Sequence Analysis, RNA
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    ISSN: 0168-9002
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 0277-5387
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 0277-5387
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 0304-3991
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Electrical Engineering, Measurement and Control Technology , Natural Sciences in General , Physics
    Type of Medium: Electronic Resource
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