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  1. Article: Hypoxia-induced and stress-specific changes in chromatin structure and function.

    Johnson, Amber Buescher / Barton, Michelle Craig

    Mutation research

    2007  Volume 618, Issue 1-2, Page(s) 149–162

    Abstract: Cellular adaptation to stress relies on specific, regulated responses to evoke changes in gene expression. Stresses such as hypoxia, heat shock, oxidative stress and DNA-damage activate signaling cascades that ultimately lead to either induction or ... ...

    Abstract Cellular adaptation to stress relies on specific, regulated responses to evoke changes in gene expression. Stresses such as hypoxia, heat shock, oxidative stress and DNA-damage activate signaling cascades that ultimately lead to either induction or repression of stress-responsive genes. In this review, we concentrate on the mechanisms by which stress-induced signaling promotes alterations in chromatin structure, whether the read-out is activation or repression of transcription. Specific alterations in chromatin are highly regulated and dictated by the type of imposed stress. Our primary focus is on the types of chromatin alterations that occur under hypoxic conditions, which exist within a majority of tumors, and to compare these to changes in chromatin structure that occur in response to a wide variety of cellular stresses.
    MeSH term(s) Animals ; Chromatin/chemistry ; Chromatin Assembly and Disassembly ; DNA Damage ; Gene Expression Regulation ; Heat-Shock Response ; Histone Acetyltransferases/metabolism ; Histones/chemistry ; Humans ; Hypoxia ; Oxidative Stress ; Phosphorylation ; Protein Binding ; Transcription, Genetic
    Chemical Substances Chromatin ; Histones ; Histone Acetyltransferases (EC 2.3.1.48)
    Language English
    Publishing date 2007-05-01
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 206607-5
    ISSN 1873-135X ; 0027-5107 ; 1383-5718 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
    ISSN (online) 1873-135X
    ISSN 0027-5107 ; 1383-5718 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
    DOI 10.1016/j.mrfmmm.2006.10.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1316: Show issues Location:
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  2. Article: Hypoxia induces a novel signature of chromatin modifications and global repression of transcription.

    Johnson, Amber Buescher / Denko, Nicholas / Barton, Michelle Craig

    Mutation research

    2008  Volume 640, Issue 1-2, Page(s) 174–179

    Abstract: Tumor cells respond to the harsh hypoxic microenvironment, in part, by transcriptional regulation of specific target genes. We found that hypoxia-mediated activation of selected genes occurs amidst widespread repression of transcription that is neither ... ...

    Abstract Tumor cells respond to the harsh hypoxic microenvironment, in part, by transcriptional regulation of specific target genes. We found that hypoxia-mediated activation of selected genes occurs amidst widespread repression of transcription that is neither cell type-specific nor HIF-1-dependent. Despite overall repression, hypoxia induces a pool of histone modifications typically associated with transcriptional activation or repression. Chromatin immunoprecipitation analyses showed that this global mixture of hypoxia-modified histones is sorted in a gene-specific manner to correlate with transcriptional response to hypoxia. Exceptions to this were unexpected increases in H3K4me3 levels, typically associated with transcriptional activation, and decreased H3K27me3 levels, generally a marker of transcriptional silencing, at core promoters of both hypoxia-activated and -repressed genes. These data suggest that a novel signature of chromatin modifications is induced under hypoxic stress, which may play a role in gene regulatory switches active in proliferating tumor cells undergoing cycles of hypoxia and reoxygenation.
    MeSH term(s) Animals ; Cell Hypoxia/genetics ; Cell Line, Tumor ; Chromatin Assembly and Disassembly ; Gene Expression Regulation, Neoplastic ; Histones/metabolism ; Hypoxia-Inducible Factor 1/metabolism ; Mice ; RNA/biosynthesis ; RNA, Messenger/biosynthesis ; Transcription, Genetic
    Chemical Substances Histones ; Hypoxia-Inducible Factor 1 ; RNA, Messenger ; RNA (63231-63-0)
    Language English
    Publishing date 2008-01-16
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 206607-5
    ISSN 1873-135X ; 0027-5107 ; 1383-5718 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
    ISSN (online) 1873-135X
    ISSN 0027-5107 ; 1383-5718 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
    DOI 10.1016/j.mrfmmm.2008.01.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1316: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article: Hypoxia actively represses transcription by inducing negative cofactor 2 (Dr1/DrAP1) and blocking preinitiation complex assembly.

    Denko, Nicholas / Wernke-Dollries, Kara / Johnson, Amber Buescher / Hammond, Ester / Chiang, Cheng-Ming / Barton, Michelle Craig

    The Journal of biological chemistry

    2002  Volume 278, Issue 8, Page(s) 5744–5749

    Abstract: Hypoxia is a growth inhibitory stress associated with multiple disease states. We find that hypoxic stress actively regulates transcription not only by activation of specific genes but also by selective repression. We reconstituted this bimodal response ... ...

    Abstract Hypoxia is a growth inhibitory stress associated with multiple disease states. We find that hypoxic stress actively regulates transcription not only by activation of specific genes but also by selective repression. We reconstituted this bimodal response to hypoxia in vitro and determined a mechanism for hypoxia-mediated repression of transcription. Hypoxic cell extracts are competent for transcript elongation, but cannot assemble a functional preinitiation complex (PIC) at a subset of promoters. PIC assembly and RNA polymerase II C-terminal domain (CTD) phosphorylation were blocked by hypoxic induction and core promoter binding of negative cofactor 2 protein (NC2 alpha/beta, Dr1/DrAP1). Immunodepletion of NC2 beta/Dr1 protein complexes rescued hypoxic-repressed transcription without alteration of normoxic transcription. Physiological regulation of NC2 activity may represent an active means of conserving energy in response to hypoxic stress.
    MeSH term(s) Carcinoma, Hepatocellular ; Cell Hypoxia/physiology ; Cells, Cultured ; Fibroblasts/physiology ; Humans ; Peptide Chain Initiation, Translational/physiology ; Phosphorylation ; Promoter Regions, Genetic ; RNA Polymerase II/metabolism ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Transcription, Genetic/physiology ; Tumor Cells, Cultured
    Chemical Substances DRAP1 protein, human ; Repressor Proteins ; RNA Polymerase II (EC 2.7.7.-)
    Language English
    Publishing date 2002-12-10
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M212534200
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: GMP Manufacturing and IND-Enabling Studies of a Recombinant Hyperimmune Globulin Targeting SARS-CoV-2.

    Mizrahi, Rena A / Lin, Wendy Y / Gras, Ashley / Niedecken, Ariel R / Wagner, Ellen K / Keating, Sheila M / Ikon, Nikita / Manickam, Vishal A / Asensio, Michael A / Leong, Jackson / Medina-Cucurella, Angelica V / Benzie, Emily / Carter, Kyle P / Chiang, Yao / Edgar, Robert C / Leong, Renee / Lim, Yoong Wearn / Simons, Jan Fredrik / Spindler, Matthew J /
    Stadtmiller, Kacy / Wayham, Nicholas / Büscher, Dirk / Terencio, Jose Vicente / Germanio, Clara Di / Chamow, Steven M / Olson, Charles / Pino, Paula A / Park, Jun-Gyu / Hicks, Amberlee / Ye, Chengjin / Garcia-Vilanova, Andreu / Martinez-Sobrido, Luis / Torrelles, Jordi B / Johnson, David S / Adler, Adam S

    Pathogens (Basel, Switzerland)

    2022  Volume 11, Issue 7

    Abstract: Conventionally, hyperimmune globulin drugs manufactured from pooled immunoglobulins from vaccinated or convalescent donors have been used in treating infections where no treatment is available. This is especially important where multi-epitope ... ...

    Abstract Conventionally, hyperimmune globulin drugs manufactured from pooled immunoglobulins from vaccinated or convalescent donors have been used in treating infections where no treatment is available. This is especially important where multi-epitope neutralization is required to prevent the development of immune-evading viral mutants that can emerge upon treatment with monoclonal antibodies. Using microfluidics, flow sorting, and a targeted integration cell line, a first-in-class recombinant hyperimmune globulin therapeutic against SARS-CoV-2 (GIGA-2050) was generated. Using processes similar to conventional monoclonal antibody manufacturing, GIGA-2050, comprising 12,500 antibodies, was scaled-up for clinical manufacturing and multiple development/tox lots were assessed for consistency. Antibody sequence diversity, cell growth, productivity, and product quality were assessed across different manufacturing sites and production scales. GIGA-2050 was purified and tested for good laboratory procedures (GLP) toxicology, pharmacokinetics, and in vivo efficacy against natural SARS-CoV-2 infection in mice. The GIGA-2050 master cell bank was highly stable, producing material at consistent yield and product quality up to >70 generations. Good manufacturing practices (GMP) and development batches of GIGA-2050 showed consistent product quality, impurity clearance, potency, and protection in an in vivo efficacy model. Nonhuman primate toxicology and pharmacokinetics studies suggest that GIGA-2050 is safe and has a half-life similar to other recombinant human IgG1 antibodies. These results supported a successful investigational new drug application for GIGA-2050. This study demonstrates that a new class of drugs, recombinant hyperimmune globulins, can be manufactured consistently at the clinical scale and presents a new approach to treating infectious diseases that targets multiple epitopes of a virus.
    Language English
    Publishing date 2022-07-19
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2695572-6
    ISSN 2076-0817
    ISSN 2076-0817
    DOI 10.3390/pathogens11070806
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: GMP Manufacturing and IND-Enabling Studies of a Recombinant Hyperimmune Globulin Targeting SARS-CoV-2

    Mizrahi, Rena A. / Lin, Wendy Y. / Gras, Ashley / Niedecken, Ariel R. / Wagner, Ellen K. / Keating, Sheila M. / Ikon, Nikita / Manickam, Vishal A. / Asensio, Michael A. / Leong, Jackson / Medina-Cucurella, Angelica V. / Benzie, Emily / Carter, Kyle P. / Chiang, Yao / Edgar, Robert C. / Leong, Renee / Lim, Yoong Wearn / Simons, Jan Fredrik / Spindler, Matthew J. /
    Stadtmiller, Kacy / Wayham, Nicholas / Büscher, Dirk / Terencio, Jose Vicente / Germanio, Clara Di / Chamow, Steven M. / Olson, Charles / Pino, Paula A. / Park, Jun-Gyu / Hicks, Amberlee / Ye, Chengjin / Garcia-Vilanova, Andreu / Martinez-Sobrido, Luis / Torrelles, Jordi B. / Johnson, David S. / Adler, Adam S.

    Pathogens. 2022 July 19, v. 11, no. 7

    2022  

    Abstract: Conventionally, hyperimmune globulin drugs manufactured from pooled immunoglobulins from vaccinated or convalescent donors have been used in treating infections where no treatment is available. This is especially important where multi-epitope ... ...

    Abstract Conventionally, hyperimmune globulin drugs manufactured from pooled immunoglobulins from vaccinated or convalescent donors have been used in treating infections where no treatment is available. This is especially important where multi-epitope neutralization is required to prevent the development of immune-evading viral mutants that can emerge upon treatment with monoclonal antibodies. Using microfluidics, flow sorting, and a targeted integration cell line, a first-in-class recombinant hyperimmune globulin therapeutic against SARS-CoV-2 (GIGA-2050) was generated. Using processes similar to conventional monoclonal antibody manufacturing, GIGA-2050, comprising 12,500 antibodies, was scaled-up for clinical manufacturing and multiple development/tox lots were assessed for consistency. Antibody sequence diversity, cell growth, productivity, and product quality were assessed across different manufacturing sites and production scales. GIGA-2050 was purified and tested for good laboratory procedures (GLP) toxicology, pharmacokinetics, and in vivo efficacy against natural SARS-CoV-2 infection in mice. The GIGA-2050 master cell bank was highly stable, producing material at consistent yield and product quality up to >70 generations. Good manufacturing practices (GMP) and development batches of GIGA-2050 showed consistent product quality, impurity clearance, potency, and protection in an in vivo efficacy model. Nonhuman primate toxicology and pharmacokinetics studies suggest that GIGA-2050 is safe and has a half-life similar to other recombinant human IgG1 antibodies. These results supported a successful investigational new drug application for GIGA-2050. This study demonstrates that a new class of drugs, recombinant hyperimmune globulins, can be manufactured consistently at the clinical scale and presents a new approach to treating infectious diseases that targets multiple epitopes of a virus.
    Keywords Severe acute respiratory syndrome coronavirus 2 ; cell growth ; cell lines ; drugs ; epitopes ; half life ; humans ; immunoglobulin G ; microfluidic technology ; models ; monoclonal antibodies ; neutralization ; pharmacokinetics ; product quality ; sequence diversity ; therapeutics ; toxicology ; viruses
    Language English
    Dates of publication 2022-0719
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article
    ZDB-ID 2695572-6
    ISSN 2076-0817
    ISSN 2076-0817
    DOI 10.3390/pathogens11070806
    Database NAL-Catalogue (AGRICOLA)

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  6. Article ; Online: GMP Manufacturing and IND-Enabling Studies of a Recombinant Hyperimmune Globulin Targeting SARS-CoV-2

    Rena A. Mizrahi / Wendy Y. Lin / Ashley Gras / Ariel R. Niedecken / Ellen K. Wagner / Sheila M. Keating / Nikita Ikon / Vishal A. Manickam / Michael A. Asensio / Jackson Leong / Angelica V. Medina-Cucurella / Emily Benzie / Kyle P. Carter / Yao Chiang / Robert C. Edgar / Renee Leong / Yoong Wearn Lim / Jan Fredrik Simons / Matthew J. Spindler /
    Kacy Stadtmiller / Nicholas Wayham / Dirk Büscher / Jose Vicente Terencio / Clara Di Germanio / Steven M. Chamow / Charles Olson / Paula A. Pino / Jun-Gyu Park / Amberlee Hicks / Chengjin Ye / Andreu Garcia-Vilanova / Luis Martinez-Sobrido / Jordi B. Torrelles / David S. Johnson / Adam S. Adler

    Pathogens, Vol 11, Iss 806, p

    2022  Volume 806

    Abstract: Conventionally, hyperimmune globulin drugs manufactured from pooled immunoglobulins from vaccinated or convalescent donors have been used in treating infections where no treatment is available. This is especially important where multi-epitope ... ...

    Abstract Conventionally, hyperimmune globulin drugs manufactured from pooled immunoglobulins from vaccinated or convalescent donors have been used in treating infections where no treatment is available. This is especially important where multi-epitope neutralization is required to prevent the development of immune-evading viral mutants that can emerge upon treatment with monoclonal antibodies. Using microfluidics, flow sorting, and a targeted integration cell line, a first-in-class recombinant hyperimmune globulin therapeutic against SARS-CoV-2 (GIGA-2050) was generated. Using processes similar to conventional monoclonal antibody manufacturing, GIGA-2050, comprising 12,500 antibodies, was scaled-up for clinical manufacturing and multiple development/tox lots were assessed for consistency. Antibody sequence diversity, cell growth, productivity, and product quality were assessed across different manufacturing sites and production scales. GIGA-2050 was purified and tested for good laboratory procedures (GLP) toxicology, pharmacokinetics, and in vivo efficacy against natural SARS-CoV-2 infection in mice. The GIGA-2050 master cell bank was highly stable, producing material at consistent yield and product quality up to >70 generations. Good manufacturing practices (GMP) and development batches of GIGA-2050 showed consistent product quality, impurity clearance, potency, and protection in an in vivo efficacy model. Nonhuman primate toxicology and pharmacokinetics studies suggest that GIGA-2050 is safe and has a half-life similar to other recombinant human IgG1 antibodies. These results supported a successful investigational new drug application for GIGA-2050. This study demonstrates that a new class of drugs, recombinant hyperimmune globulins, can be manufactured consistently at the clinical scale and presents a new approach to treating infectious diseases that targets multiple epitopes of a virus.
    Keywords recombinant hyperimmune ; GMP manufacturing ; SARS-CoV-2 ; Medicine ; R
    Language English
    Publishing date 2022-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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