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  1. Article ; Online: With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage.

    Altinok, Selin / Sanchez-Hodge, Rebekah / Stewart, Mariah / Smith, Kaitlan / Schisler, Jonathan C

    Cells

    2021  Volume 10, Issue 11

    Abstract: Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintain protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these ... ...

    Abstract Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintain protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these interactions impact the outcome of protein triage, impacting everything from structural proteins to cell signaling mediators. The chaperone/co-chaperone machinery protects against various stressors to ensure cellular function in the face of stress. However, coding mutations, expression changes, and post-translational modifications of the chaperone/co-chaperone machinery can alter the cellular stress response. Importantly, these dysfunctions appear to contribute to numerous human diseases. Therapeutic targeting of chaperones is an attractive but challenging approach due to the vast functions of HSPs, likely contributing to the off-target effects of these therapies. Current efforts focus on targeting co-chaperones to develop precise treatments for numerous diseases caused by defects in protein quality control. This review focuses on the recent developments regarding selected HSP70/HSP90 co-chaperones, with a concentration on cardioprotection, neuroprotection, cancer, and autoimmune diseases. We also discuss therapeutic approaches that highlight both the utility and challenges of targeting co-chaperones.
    MeSH term(s) Disease ; Health ; Humans ; Models, Biological ; Molecular Chaperones/metabolism ; Small Molecule Libraries/pharmacology
    Chemical Substances Molecular Chaperones ; Small Molecule Libraries
    Language English
    Publishing date 2021-11-11
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells10113121
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Reply to Pisan et al.: Pathogenicity of inherited TRAF7 mutations in congenital heart disease.

    Mishra-Gorur, Ketu / Barak, Tanyeri / Kaulen, Leon D / Henegariu, Octavian / Jin, Sheng Chih / Aguilera, Stephanie Marie / Yalbir, Ezgi / Goles, Gizem / Nishimura, Sayoko / Miyagishima, Danielle / Djenoune, Lydia / Altinok, Selin / Rai, Devendra K / Viviano, Stephen / Prendergast, Andrew / Zerillo, Cynthia / Ozcan, Kent / Baran, Burcin / Sencar, Leman /
    Goc, Nukte / Yarman, Yanki / Ercan-Encicek, A Gulhan / Bilguvar, Kaya / Lifton, Richard P / Moliterno, Jennifer / Louvi, Angeliki / Yuan, Shiaulou / Deniz, Engin / Brueckner, Martina / Gunel, Murat

    Proceedings of the National Academy of Sciences of the United States of America

    2024  Volume 121, Issue 12, Page(s) e2319578121

    MeSH term(s) Humans ; Virulence ; Germ-Line Mutation ; Heart Defects, Congenital/genetics ; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
    Chemical Substances TRAF7 protein, human ; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
    Language English
    Publishing date 2024-03-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2319578121
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Ubiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling.

    Apriamashvili, Georgi / Vredevoogd, David W / Krijgsman, Oscar / Bleijerveld, Onno B / Ligtenberg, Maarten A / de Bruijn, Beaunelle / Boshuizen, Julia / Traets, Joleen J H / D'Empaire Altimari, Daniela / van Vliet, Alex / Lin, Chun-Pu / Visser, Nils L / Londino, James D / Sanchez-Hodge, Rebekah / Oswalt, Leah E / Altinok, Selin / Schisler, Jonathan C / Altelaar, Maarten / Peeper, Daniel S

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 1923

    Abstract: The cytokine IFNγ differentially impacts on tumors upon immune checkpoint blockade (ICB). Despite our understanding of downstream signaling events, less is known about regulation of its receptor (IFNγ-R1). With an unbiased genome-wide CRISPR/Cas9 screen ... ...

    Abstract The cytokine IFNγ differentially impacts on tumors upon immune checkpoint blockade (ICB). Despite our understanding of downstream signaling events, less is known about regulation of its receptor (IFNγ-R1). With an unbiased genome-wide CRISPR/Cas9 screen for critical regulators of IFNγ-R1 cell surface abundance, we identify STUB1 as an E3 ubiquitin ligase for IFNγ-R1 in complex with its signal-relaying kinase JAK1. STUB1 mediates ubiquitination-dependent proteasomal degradation of IFNγ-R1/JAK1 complex through IFNγ-R1
    MeSH term(s) Humans ; Immune Checkpoint Inhibitors ; Interferon-gamma/metabolism ; Neoplasms/immunology ; Receptors, Interferon/metabolism ; Signal Transduction ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination ; Interferon gamma Receptor
    Chemical Substances IFNG protein, human ; Immune Checkpoint Inhibitors ; Receptors, Interferon ; Interferon-gamma (82115-62-6) ; STUB1 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2022-04-08
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-29442-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.

    Mishra-Gorur, Ketu / Barak, Tanyeri / Kaulen, Leon D / Henegariu, Octavian / Jin, Sheng Chih / Aguilera, Stephanie Marie / Yalbir, Ezgi / Goles, Gizem / Nishimura, Sayoko / Miyagishima, Danielle / Djenoune, Lydia / Altinok, Selin / Rai, Devendra K / Viviano, Stephen / Prendergast, Andrew / Zerillo, Cynthia / Ozcan, Kent / Baran, Burcin / Sencar, Leman /
    Goc, Nukte / Yarman, Yanki / Ercan-Sencicek, A Gulhan / Bilguvar, Kaya / Lifton, Richard P / Moliterno, Jennifer / Louvi, Angeliki / Yuan, Shiaulou / Deniz, Engin / Brueckner, Martina / Gunel, Murat

    Proceedings of the National Academy of Sciences of the United States of America

    2023  Volume 120, Issue 16, Page(s) e2214997120

    Abstract: While somatic variants ... ...

    Abstract While somatic variants of
    MeSH term(s) Animals ; Adaptor Proteins, Signal Transducing/metabolism ; Heart Defects, Congenital/genetics ; Meningeal Neoplasms/genetics ; Meningioma/genetics ; Meningioma/pathology ; Mutation ; Skull/metabolism ; Zebrafish/genetics ; Zebrafish/metabolism ; Zebrafish Proteins/genetics ; Humans ; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
    Chemical Substances Adaptor Proteins, Signal Transducing ; IFT57 protein, zebrafish ; Zebrafish Proteins ; TRAF7 protein, human ; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
    Language English
    Publishing date 2023-04-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2214997120
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. McDonald, J Tyson / Enguita, Francisco Javier / Taylor, Deanne / Griffin, Robert J / Priebe, Waldemar / Emmett, Mark R / Sajadi, Mohammad M / Harris, Anthony D / Clement, Jean / Dybas, Joseph M / Aykin-Burns, Nukhet / Guarnieri, Joseph W / Singh, Larry N / Grabham, Peter / Baylin, Stephen B / Yousey, Aliza / Pearson, Andrea N / Corry, Peter M / Saravia-Butler, Amanda /
    Aunins, Thomas R / Sharma, Sadhana / Nagpal, Prashant / Meydan, Cem / Foox, Jonathan / Mozsary, Christopher / Cerqueira, Bianca / Zaksas, Viktorija / Singh, Urminder / Wurtele, Eve Syrkin / Costes, Sylvain V / Davanzo, Gustavo Gastão / Galeano, Diego / Paccanaro, Alberto / Meinig, Suzanne L / Hagan, Robert S / Bowman, Natalie M / Wolfgang, Matthew C / Altinok, Selin / Sapoval, Nicolae / Treangen, Todd J / Moraes-Vieira, Pedro M / Vanderburg, Charles / Wallace, Douglas C / Schisler, Jonathan / Mason, Christopher E / Chatterjee, Anushree / Meller, Robert / Beheshti, Afshin

    bioRxiv : the preprint server for biology

    2021  

    Abstract: MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provides an exciting avenue towards antiviral therapeutics. From patient transcriptomic data, we have discovered a ...

    Abstract MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provides an exciting avenue towards antiviral therapeutics. From patient transcriptomic data, we have discovered a circulating miRNA, miR-2392, that is directly involved with SARS-CoV-2 machinery during host infection. Specifically, we show that miR-2392 is key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia as well as promoting many symptoms associated with COVID-19 infection. We demonstrate miR-2392 is present in the blood and urine of COVID-19 positive patients, but not detected in COVID-19 negative patients. These findings indicate the potential for developing a novel, minimally invasive, COVID-19 detection method. Lastly, using
    Language English
    Publishing date 2021-08-18
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2021.04.23.441024
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Role of miR-2392 in driving SARS-CoV-2 infection.

    McDonald, J Tyson / Enguita, Francisco J / Taylor, Deanne / Griffin, Robert J / Priebe, Waldemar / Emmett, Mark R / Sajadi, Mohammad M / Harris, Anthony D / Clement, Jean / Dybas, Joseph M / Aykin-Burns, Nukhet / Guarnieri, Joseph W / Singh, Larry N / Grabham, Peter / Baylin, Stephen B / Yousey, Aliza / Pearson, Andrea N / Corry, Peter M / Saravia-Butler, Amanda /
    Aunins, Thomas R / Sharma, Sadhana / Nagpal, Prashant / Meydan, Cem / Foox, Jonathan / Mozsary, Christopher / Cerqueira, Bianca / Zaksas, Viktorija / Singh, Urminder / Wurtele, Eve Syrkin / Costes, Sylvain V / Davanzo, Gustavo Gastão / Galeano, Diego / Paccanaro, Alberto / Meinig, Suzanne L / Hagan, Robert S / Bowman, Natalie M / Wolfgang, Matthew C / Altinok, Selin / Sapoval, Nicolae / Treangen, Todd J / Moraes-Vieira, Pedro M / Vanderburg, Charles / Wallace, Douglas C / Schisler, Jonathan C / Mason, Christopher E / Chatterjee, Anushree / Meller, Robert / Beheshti, Afshin

    Cell reports

    2021  Volume 37, Issue 3, Page(s) 109839

    Abstract: MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provide an exciting avenue toward antiviral therapeutics. From patient transcriptomic data, we determined that a ... ...

    Abstract MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provide an exciting avenue toward antiviral therapeutics. From patient transcriptomic data, we determined that a circulating miRNA, miR-2392, is directly involved with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) machinery during host infection. Specifically, we show that miR-2392 is key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia, as well as promoting many symptoms associated with coronavirus disease 2019 (COVID-19) infection. We demonstrate that miR-2392 is present in the blood and urine of patients positive for COVID-19 but is not present in patients negative for COVID-19. These findings indicate the potential for developing a minimally invasive COVID-19 detection method. Lastly, using in vitro human and in vivo hamster models, we design a miRNA-based antiviral therapeutic that targets miR-2392, significantly reduces SARS-CoV-2 viability in hamsters, and may potentially inhibit a COVID-19 disease state in humans.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Animals ; Antiviral Agents/pharmacology ; Biomarkers/metabolism ; COVID-19/genetics ; COVID-19/immunology ; Cricetinae ; Female ; Ferrets ; Gene Expression Regulation ; Glycolysis ; Healthy Volunteers ; Humans ; Hypoxia ; Inflammation ; Male ; Mice ; MicroRNAs/genetics ; Middle Aged ; Proteomics/methods ; ROC Curve ; Rats ; SARS-CoV-2/genetics ; COVID-19 Drug Treatment
    Chemical Substances Antiviral Agents ; Biomarkers ; MIRN2392 microRNA, human ; MicroRNAs
    Language English
    Publishing date 2021-09-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2021.109839
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: PPIL4 is essential for brain angiogenesis and implicated in intracranial aneurysms in humans.

    Barak, Tanyeri / Ristori, Emma / Ercan-Sencicek, A Gulhan / Miyagishima, Danielle F / Nelson-Williams, Carol / Dong, Weilai / Jin, Sheng Chih / Prendergast, Andrew / Armero, William / Henegariu, Octavian / Erson-Omay, E Zeynep / Harmancı, Akdes Serin / Guy, Mikhael / Gültekin, Batur / Kilic, Deniz / Rai, Devendra K / Goc, Nükte / Aguilera, Stephanie Marie / Gülez, Burcu /
    Altinok, Selin / Ozcan, Kent / Yarman, Yanki / Coskun, Süleyman / Sempou, Emily / Deniz, Engin / Hintzen, Jared / Cox, Andrew / Fomchenko, Elena / Jung, Su Woong / Ozturk, Ali Kemal / Louvi, Angeliki / Bilgüvar, Kaya / Connolly, E Sander / Khokha, Mustafa K / Kahle, Kristopher T / Yasuno, Katsuhito / Lifton, Richard P / Mishra-Gorur, Ketu / Nicoli, Stefania / Günel, Murat

    Nature medicine

    2021  Volume 27, Issue 12, Page(s) 2165–2175

    Abstract: Intracranial aneurysm (IA) rupture leads to subarachnoid hemorrhage, a sudden-onset disease that often causes death or severe disability. Although genome-wide association studies have identified common genetic variants that increase IA risk moderately, ... ...

    Abstract Intracranial aneurysm (IA) rupture leads to subarachnoid hemorrhage, a sudden-onset disease that often causes death or severe disability. Although genome-wide association studies have identified common genetic variants that increase IA risk moderately, the contribution of variants with large effect remains poorly defined. Using whole-exome sequencing, we identified significant enrichment of rare, deleterious mutations in PPIL4, encoding peptidyl-prolyl cis-trans isomerase-like 4, in both familial and index IA cases. Ppil4 depletion in vertebrate models causes intracerebral hemorrhage, defects in cerebrovascular morphology and impaired Wnt signaling. Wild-type, but not IA-mutant, PPIL4 potentiates Wnt signaling by binding JMJD6, a known angiogenesis regulator and Wnt activator. These findings identify a novel PPIL4-dependent Wnt signaling mechanism involved in brain-specific angiogenesis and maintenance of cerebrovascular integrity and implicate PPIL4 gene mutations in the pathogenesis of IA.
    MeSH term(s) Brain/blood supply ; Cyclophilins/genetics ; Cyclophilins/physiology ; Humans ; Intracranial Aneurysm/genetics ; Mutation ; Neovascularization, Pathologic/genetics ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/physiology ; Exome Sequencing ; Wnt Signaling Pathway/physiology
    Chemical Substances RNA-Binding Proteins ; Cyclophilins (EC 5.2.1.-) ; PPIL4 protein, human (EC 5.2.1.8)
    Language English
    Publishing date 2021-12-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/s41591-021-01572-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. McDonald, J. Tyson / Enguita, Francisco Javier / Taylor, Deanne / Bowen, Richard A / Griffin, Robert J / Priebe, Waldemar / Emmett, Mark R / McGrath, Marisa / Sajadi, Mohammad / Harris, Anthony D / Clement, Jean / Dybas, Joseph M / Aykin-Burns, Nukhet / Guarnieri, Joseph W / Singh, Larry N / Grabham, Peter / Baylin, Stephen / Yousey, Aliza / Pearson, Andrea N /
    Corry, Peter M / Saravia-Butler, Amanda / Aunins, Thomas R / Nagpal, Prashant / Meydan, Cem / Foox, Jonathan / Mozsary, Christopher / Cerqueira, Bianca / Zaksas, Viktorija / Singh, Urminder / Wurtele, Eve Syrkin / Costes, Sylvain V / Galeano, Diego / Paccanaro, Alberto / Meinig, Suzanne L / Hagan, Robert S / Bowman, Natalie M / UNC COVID-19 Pathobiology Consortium / Wolfgang, Matthew C / Altinok, Selin / Sapoval, Nicolae / Treangen, Todd J / Frieman, Matthew / Vanderburg, Charles / Schisler, Jonathan C / Mason, Christopher / Chatterjee, Anushree / Meller, Robert / Beheshti, Afshin

    bioRxiv

    Abstract: MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provides an exciting avenue towards antiviral therapeutics. From patient transcriptomic data, we have discovered a ...

    Abstract MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provides an exciting avenue towards antiviral therapeutics. From patient transcriptomic data, we have discovered a circulating miRNA, miR-2392, that is directly involved with SARS-CoV-2 machinery during host infection. Specifically, we found that miR-2392 was key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia as well as promoting many symptoms associated with COVID-19 infection. We demonstrate miR-2392 is present in the blood and urine of COVID-19 patients tested, but not detected in COVID-19 negative patients. These findings indicate the potential for developing a novel, minimally invasive, COVID-19 detection method. Lastly, using both in vitro human and in vivo hamster models, we have developed a novel miRNA-based antiviral therapeutic targeting miR-2392 that significantly reduces SARS-CoV-2 viability and may potentially inhibit a COVID-19 disease state in the host.
    Keywords covid19
    Language English
    Publishing date 2021-04-23
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2021.04.23.441024
    Database COVID19

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  9. Article ; Online: The Great Deceiver: miR-2392’s Hidden Role in Driving SARS-CoV-2 Infection

    McDonald, J. Tyson / Enguita, Francisco Javier / Taylor, Deanne / Bowen, Richard A. / Griffin, Robert J. / Priebe, Waldemar / Emmett, Mark R. / McGrath, Marisa / Sajadi, Mohammad M. / Harris, Anthony D. / Clement, Jean / Dybas, Joseph M. / Aykin-Burns, Nukhet / Guarnieri, Joseph W. / Singh, Larry N. / Grabham, Peter / Baylin, Stephen B. / Yousey, Aliza / Pearson, Andrea N. /
    Corry, Peter M. / Saravia-Butler, Amanda / Aunins, Thomas R. / Nagpal, Prashant / Meydan, Cem / Foox, Jonathan / Mozsary, Christopher / Cerqueira, Bianca / Zaksas, Viktorija / Singh, Urminder / Wurtele, Eve Syrkin / Costes, Sylvain V. / Galeano, Diego / Paccanaro, Alberto / Meinig, Suzanne L. / Hagan, Robert S. / Bowman, Natalie M / UNC COVID-19 Pathobiology Consortium / Wolfgang, Matthew C. / Altinok, Selin / Sapoval, Nicolae / Treangen, Todd J. / Frieman, Matthew / Vanderburg, Charles / Wallace, Douglas C. / Schisler, Jonathan / Mason, Christopher E. / Chatterjee, Anushree / Meller, Robert / Beheshti, Afshin

    bioRxiv

    Abstract: MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provides an exciting avenue towards antiviral therapeutics. From patient transcriptomic data, we have discovered a ...

    Abstract MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provides an exciting avenue towards antiviral therapeutics. From patient transcriptomic data, we have discovered a circulating miRNA, miR-2392, that is directly involved with SARS-CoV-2 machinery during host infection. Specifically, we found that miR-2392 was key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia as well as promoting many symptoms associated with COVID-19 infection. We demonstrate miR-2392 is present in the blood and urine of COVID-19 patients tested, but not detected in COVID-19 negative patients. These findings indicate the potential for developing a novel, minimally invasive, COVID-19 detection method. Lastly, using both in vitro human and in vivo hamster models, we have developed a novel miRNA-based antiviral therapeutic targeting miR-2392 that significantly reduces SARS-CoV-2 viability and may potentially inhibit a COVID-19 disease state in the host.
    Keywords covid19
    Language English
    Publishing date 2021-04-23
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2021.04.23.441024
    Database COVID19

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  10. Article ; Online: Integrated genomic characterization of IDH1-mutant glioma malignant progression.

    Bai, Hanwen / Harmancı, Akdes Serin / Erson-Omay, E Zeynep / Li, Jie / Coşkun, Süleyman / Simon, Matthias / Krischek, Boris / Özduman, Koray / Omay, S Bülent / Sorensen, Eric A / Turcan, Şevin / Bakırcığlu, Mehmet / Carrión-Grant, Geneive / Murray, Phillip B / Clark, Victoria E / Ercan-Sencicek, A Gulhan / Knight, James / Sencar, Leman / Altınok, Selin /
    Kaulen, Leon D / Gülez, Burcu / Timmer, Marco / Schramm, Johannes / Mishra-Gorur, Ketu / Henegariu, Octavian / Moliterno, Jennifer / Louvi, Angeliki / Chan, Timothy A / Tannheimer, Stacey L / Pamir, M Necmettin / Vortmeyer, Alexander O / Bilguvar, Kaya / Yasuno, Katsuhito / Günel, Murat

    Nature genetics

    2016  Volume 48, Issue 1, Page(s) 59–66

    Abstract: Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate ... ...

    Abstract Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.
    MeSH term(s) Central Nervous System Neoplasms/genetics ; Central Nervous System Neoplasms/pathology ; DNA Methylation ; Embryonic Stem Cells/metabolism ; Forkhead Box Protein M1 ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; Gene Dosage ; Gene Expression Regulation, Neoplastic ; Genes, myc ; Glioma/genetics ; Glioma/pathology ; Humans ; Isocitrate Dehydrogenase/genetics ; Isocitrate Dehydrogenase/metabolism ; Mutation ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Receptor, Notch1/genetics ; Receptor, Notch1/metabolism
    Chemical Substances FOXM1 protein, human ; Forkhead Box Protein M1 ; Forkhead Transcription Factors ; NOTCH1 protein, human ; Receptor, Notch1 ; Isocitrate Dehydrogenase (EC 1.1.1.41) ; IDH1 protein, human (EC 1.1.1.42.) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-)
    Language English
    Publishing date 2016-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/ng.3457
    Database MEDical Literature Analysis and Retrieval System OnLINE

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