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  1. Article ; Online: After 62 years of regulating immunity, dexamethasone meets COVID-19.

    Cain, Derek W / Cidlowski, John A

    Nature reviews. Immunology

    2020  Volume 20, Issue 10, Page(s) 587–588

    MeSH term(s) Alarmins/antagonists & inhibitors ; Alarmins/genetics ; Alarmins/immunology ; Anti-Inflammatory Agents/therapeutic use ; Betacoronavirus/immunology ; Betacoronavirus/pathogenicity ; COVID-19 ; Coronavirus Infections/drug therapy ; Coronavirus Infections/immunology ; Coronavirus Infections/pathology ; Coronavirus Infections/virology ; Cytokine Release Syndrome/immunology ; Cytokine Release Syndrome/pathology ; Cytokine Release Syndrome/prevention & control ; Cytokine Release Syndrome/virology ; Dexamethasone/therapeutic use ; Drug Administration Schedule ; Humans ; Immunity, Innate/drug effects ; Immunosuppressive Agents/therapeutic use ; Pandemics ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/immunology ; Pneumonia, Viral/pathology ; Pneumonia, Viral/virology ; Randomized Controlled Trials as Topic ; Receptors, Glucocorticoid/antagonists & inhibitors ; Receptors, Glucocorticoid/genetics ; Receptors, Glucocorticoid/immunology ; SARS-CoV-2 ; Severity of Illness Index ; Time Factors
    Chemical Substances Alarmins ; Anti-Inflammatory Agents ; Immunosuppressive Agents ; Receptors, Glucocorticoid ; Dexamethasone (7S5I7G3JQL)
    Keywords covid19
    Language English
    Publishing date 2020-12-21
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 2062776-2
    ISSN 1474-1741 ; 1474-1733
    ISSN (online) 1474-1741
    ISSN 1474-1733
    DOI 10.1038/s41577-020-00421-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: HIV mRNA Vaccines-Progress and Future Paths.

    Mu, Zekun / Haynes, Barton F / Cain, Derek W

    Vaccines

    2021  Volume 9, Issue 2

    Abstract: The SARS-CoV-2 pandemic introduced the world to a new type of vaccine based on mRNA encapsulated in lipid nanoparticles (LNPs). Instead of delivering antigenic proteins directly, an mRNA-based vaccine relies on the host's cells to manufacture protein ... ...

    Abstract The SARS-CoV-2 pandemic introduced the world to a new type of vaccine based on mRNA encapsulated in lipid nanoparticles (LNPs). Instead of delivering antigenic proteins directly, an mRNA-based vaccine relies on the host's cells to manufacture protein immunogens which, in turn, are targets for antibody and cytotoxic T cell responses. mRNA-based vaccines have been the subject of research for over three decades as a platform to protect against or treat a variety of cancers, amyloidosis and infectious diseases. In this review, we discuss mRNA-based approaches for the generation of prophylactic and therapeutic vaccines to HIV. We examine the special immunological hurdles for a vaccine to elicit broadly neutralizing antibodies and effective T cell responses to HIV. Lastly, we outline an mRNA-based HIV vaccination strategy based on the immunobiology of broadly neutralizing antibody development.
    Language English
    Publishing date 2021-02-07
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2703319-3
    ISSN 2076-393X
    ISSN 2076-393X
    DOI 10.3390/vaccines9020134
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  3. Article ; Online: Strategies for eliciting multiple lineages of broadly neutralizing antibodies to HIV by vaccination.

    Mu, Zekun / Haynes, Barton F / Cain, Derek W

    Current opinion in virology

    2021  Volume 51, Page(s) 172–178

    Abstract: A prophylactic vaccine would be a powerful tool in the fight against HIV. Passive immunization of animals with broadly neutralizing antibodies (bnAbs) affords protection against viral challenge, and recent data from the Antibody Mediated Prevention ... ...

    Abstract A prophylactic vaccine would be a powerful tool in the fight against HIV. Passive immunization of animals with broadly neutralizing antibodies (bnAbs) affords protection against viral challenge, and recent data from the Antibody Mediated Prevention clinical trials support the concept of bnAbs providing protection against HIV in humans, albeit only at broad and potent neutralizing antibody titers. Moreover, it is now clear that a successful vaccine will also need to induce bnAbs against multiple neutralizing epitopes on the HIV envelope (Env) glycoprotein. Here, we review recent clinical trials evaluating bnAb-based vaccines, and discuss key issues in the development of an HIV vaccine capable of targeting multiple Env neutralizing epitopes.
    MeSH term(s) AIDS Vaccines/immunology ; Animals ; Broadly Neutralizing Antibodies/immunology ; Epitopes/chemistry ; Epitopes/immunology ; HIV/chemistry ; HIV/immunology ; HIV Antibodies/immunology ; HIV Infections/immunology ; HIV Infections/prevention & control ; Humans ; Vaccination
    Chemical Substances AIDS Vaccines ; Broadly Neutralizing Antibodies ; Epitopes ; HIV Antibodies
    Language English
    Publishing date 2021-11-04
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2611378-8
    ISSN 1879-6265 ; 1879-6257
    ISSN (online) 1879-6265
    ISSN 1879-6257
    DOI 10.1016/j.coviro.2021.09.015
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: After 62 years of regulating immunity, dexamethasone meets COVID-19

    Cain, Derek W. / Cidlowski, John A.

    Nature Reviews Immunology

    2020  Volume 20, Issue 10, Page(s) 587–588

    Keywords Immunology ; covid19
    Language English
    Publisher Springer Science and Business Media LLC
    Publishing country us
    Document type Article ; Online
    ZDB-ID 2062776-2
    ISSN 1474-1741 ; 1474-1733
    ISSN (online) 1474-1741
    ISSN 1474-1733
    DOI 10.1038/s41577-020-00421-x
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: HIV mRNA Vaccines—Progress and Future Paths

    Zekun Mu / Barton F. Haynes / Derek W. Cain

    Vaccines, Vol 9, Iss 2, p

    2021  Volume 134

    Abstract: The SARS-CoV-2 pandemic introduced the world to a new type of vaccine based on mRNA encapsulated in lipid nanoparticles (LNPs). Instead of delivering antigenic proteins directly, an mRNA-based vaccine relies on the host’s cells to manufacture protein ... ...

    Abstract The SARS-CoV-2 pandemic introduced the world to a new type of vaccine based on mRNA encapsulated in lipid nanoparticles (LNPs). Instead of delivering antigenic proteins directly, an mRNA-based vaccine relies on the host’s cells to manufacture protein immunogens which, in turn, are targets for antibody and cytotoxic T cell responses. mRNA-based vaccines have been the subject of research for over three decades as a platform to protect against or treat a variety of cancers, amyloidosis and infectious diseases. In this review, we discuss mRNA-based approaches for the generation of prophylactic and therapeutic vaccines to HIV. We examine the special immunological hurdles for a vaccine to elicit broadly neutralizing antibodies and effective T cell responses to HIV. Lastly, we outline an mRNA-based HIV vaccination strategy based on the immunobiology of broadly neutralizing antibody development.
    Keywords HIV ; vaccine ; messenger RNA ; Medicine ; R
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Immune regulation by glucocorticoids.

    Cain, Derek W / Cidlowski, John A

    Nature reviews. Immunology

    2017  Volume 17, Issue 4, Page(s) 233–247

    Abstract: Endogenous glucocorticoids are crucial to various physiological processes, including metabolism, development and inflammation. Since 1948, synthetic glucocorticoids have been used to treat various immune-related disorders. The mechanisms that underlie ... ...

    Abstract Endogenous glucocorticoids are crucial to various physiological processes, including metabolism, development and inflammation. Since 1948, synthetic glucocorticoids have been used to treat various immune-related disorders. The mechanisms that underlie the immunosuppressive properties of these hormones have been intensely scrutinized, and it is widely appreciated that glucocorticoids have pleiotropic effects on the immune system. However, a clear picture of the cellular and molecular basis of glucocorticoid action has remained elusive. In this Review, we distil several decades of intense (and often conflicting) research that defines the interface between the endocrine stress response and the immune system.
    MeSH term(s) Animals ; Glucocorticoids/immunology ; Glucocorticoids/pharmacology ; Humans ; Immune System/drug effects ; Immune System/physiology ; Immunosuppressive Agents/immunology ; Immunosuppressive Agents/pharmacology ; Inflammation/drug therapy
    Chemical Substances Glucocorticoids ; Immunosuppressive Agents
    Language English
    Publishing date 2017-04
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2062776-2
    ISSN 1474-1741 ; 1474-1733
    ISSN (online) 1474-1741
    ISSN 1474-1733
    DOI 10.1038/nri.2017.1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Specificity and sensitivity of glucocorticoid signaling in health and disease.

    Cain, Derek W / Cidlowski, John A

    Best practice & research. Clinical endocrinology & metabolism

    2015  Volume 29, Issue 4, Page(s) 545–556

    Abstract: Endogenous glucocorticoids regulate a variety of physiologic processes and are crucial to the systemic stress response. Glucocorticoid receptors are expressed throughout the body, but there is considerable heterogeneity in glucocorticoid sensitivity and ... ...

    Abstract Endogenous glucocorticoids regulate a variety of physiologic processes and are crucial to the systemic stress response. Glucocorticoid receptors are expressed throughout the body, but there is considerable heterogeneity in glucocorticoid sensitivity and induced biological responses across tissues. The immunoregulatory properties of glucocorticoids are exploited in the clinic for the treatment of inflammatory and autoimmune disorders as well as certain hematological malignancies, but adverse side effects hamper prolonged use. Fully understanding the molecular events that shape the physiologic effects of glucocorticoid treatment will provide insight into optimal glucocorticoid therapies, reliable assessment of glucocorticoid sensitivity in patients, and may advance the development of novel GR agonists that exert immunosuppressive effects while avoiding harmful side effects. In this review, we provide an overview of mechanisms that affect glucocorticoid specificity and sensitivity in health and disease, focusing on the distinct isoforms of the glucocorticoid receptor and their unique regulatory and functional properties.
    MeSH term(s) Animals ; Anti-Inflammatory Agents/pharmacology ; Anti-Inflammatory Agents/therapeutic use ; Glucocorticoids/pharmacology ; Glucocorticoids/therapeutic use ; Humans ; Immunologic Factors/pharmacology ; Immunologic Factors/therapeutic use ; Receptors, Glucocorticoid/agonists ; Receptors, Glucocorticoid/metabolism ; Signal Transduction
    Chemical Substances Anti-Inflammatory Agents ; Glucocorticoids ; Immunologic Factors ; Receptors, Glucocorticoid
    Language English
    Publishing date 2015-04-25
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Review
    ZDB-ID 2052339-7
    ISSN 1878-1594 ; 1532-1908 ; 1521-690X
    ISSN (online) 1878-1594 ; 1532-1908
    ISSN 1521-690X
    DOI 10.1016/j.beem.2015.04.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: c-Rel-dependent Chk2 signaling regulates the DNA damage response limiting hepatocarcinogenesis.

    Leslie, Jack / Hunter, Jill E / Collins, Amy / Rushton, Amelia / Russell, Lauren G / Ramon-Gil, Erik / Laszczewska, Maja / McCain, Misti / Zaki, Marco Y W / Knox, Amber / Seow, Yixin / Sabater, Laura / Geh, Daniel / Perkins, Neil D / Reeves, Helen L / Tiniakos, Dina / Mann, Derek A / Oakley, Fiona

    Hepatology (Baltimore, Md.)

    2023  Volume 78, Issue 4, Page(s) 1050–1063

    Abstract: Background and aims: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. The NF-κB transcription factor family subunit c-Rel is typically protumorigenic; however, it has recently been reported as a tumor suppressor. Here, we ... ...

    Abstract Background and aims: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. The NF-κB transcription factor family subunit c-Rel is typically protumorigenic; however, it has recently been reported as a tumor suppressor. Here, we investigated the role of c-Rel in HCC.
    Approach and results: Histological and transcriptional studies confirmed expression of c-Rel in human patients with HCC, but low c-Rel expression correlated with increased tumor cell proliferation and mutational burden and was associated with advanced disease. In vivo , global ( Rel-/- ) and epithelial specific ( RelAlb ) c-Rel knockout mice develop more tumors, with a higher proliferative rate and increased DNA damage, than wild-type (WT) controls 30 weeks after N-diethylnitrosamine injury. However, tumor burden was comparable when c-Rel was deleted in hepatocytes once tumors were established, suggesting c-Rel signaling is important for preventing HCC initiation after genotoxic injury, rather than for HCC progression. In vitro , Rel-/- hepatocytes were more susceptible to genotoxic injury than WT controls. ATM-CHK2 DNA damage response pathway proteins were suppressed in Rel-/- hepatocytes following genotoxic injury, suggesting that c-Rel is required for effective DNA repair. To determine if c-Rel inhibition sensitizes cancer cells to chemotherapy, by preventing repair of chemotherapy-induced DNA damage, thus increasing tumor cell death, we administered single or combination doxorubicin and IT-603 (c-Rel inhibitor) therapy in an orthotopic HCC model. Indeed, combination therapy was more efficacious than doxorubicin alone.
    Conclusion: Hepatocyte c-Rel signaling limits genotoxic injury and subsequent HCC burden. Inhibiting c-Rel as an adjuvant therapy increased the effectiveness of DNA damaging agents and reduced HCC growth.
    MeSH term(s) Animals ; Humans ; Mice ; Carcinogenesis/genetics ; Carcinoma, Hepatocellular/pathology ; DNA Damage ; Doxorubicin/pharmacology ; Hepatocytes/metabolism ; Liver Neoplasms/metabolism ; Mice, Knockout ; NF-kappa B/metabolism ; Proto-Oncogene Proteins c-rel/metabolism
    Chemical Substances Doxorubicin (80168379AG) ; NF-kappa B ; Proto-Oncogene Proteins c-rel
    Language English
    Publishing date 2023-09-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604603-4
    ISSN 1527-3350 ; 0270-9139
    ISSN (online) 1527-3350
    ISSN 0270-9139
    DOI 10.1002/hep.32781
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  10. Article ; Online: Mutation-guided vaccine design: A process for developing boosting immunogens for HIV broadly neutralizing antibody induction.

    Wiehe, Kevin / Saunders, Kevin O / Stalls, Victoria / Cain, Derek W / Venkatayogi, Sravani / Martin Beem, Joshua S / Berry, Madison / Evangelous, Tyler / Henderson, Rory / Hora, Bhavna / Xia, Shi-Mao / Jiang, Chuancang / Newman, Amanda / Bowman, Cindy / Lu, Xiaozhi / Bryan, Mary E / Bal, Joena / Sanzone, Aja / Chen, Haiyan /
    Eaton, Amanda / Tomai, Mark A / Fox, Christopher B / Tam, Ying K / Barbosa, Christopher / Bonsignori, Mattia / Muramatsu, Hiromi / Alam, S Munir / Montefiori, David C / Williams, Wilton B / Pardi, Norbert / Tian, Ming / Weissman, Drew / Alt, Frederick W / Acharya, Priyamvada / Haynes, Barton F

    Cell host & microbe

    2024  

    Abstract: A major goal of HIV-1 vaccine development is the induction of broadly neutralizing antibodies (bnAbs). Although success has been achieved in initiating bnAb B cell lineages, design of boosting immunogens that select for bnAb B cell receptors with ... ...

    Abstract A major goal of HIV-1 vaccine development is the induction of broadly neutralizing antibodies (bnAbs). Although success has been achieved in initiating bnAb B cell lineages, design of boosting immunogens that select for bnAb B cell receptors with improbable mutations required for bnAb affinity maturation remains difficult. Here, we demonstrate a process for designing boosting immunogens for a V3-glycan bnAb B cell lineage. The immunogens induced affinity-matured antibodies by selecting for functional improbable mutations in bnAb precursor knockin mice. Moreover, we show similar success in prime and boosting with nucleoside-modified mRNA-encoded HIV-1 envelope trimer immunogens, with improved selection by mRNA immunogens of improbable mutations required for bnAb binding to key envelope glycans. These results demonstrate the ability of both protein and mRNA prime-boost immunogens for selection of rare B cell lineage intermediates with neutralizing breadth after bnAb precursor expansion, a key proof of concept and milestone toward development of an HIV-1 vaccine.
    Language English
    Publishing date 2024-04-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2278004-X
    ISSN 1934-6069 ; 1931-3128
    ISSN (online) 1934-6069
    ISSN 1931-3128
    DOI 10.1016/j.chom.2024.04.006
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