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  1. Article ; Online: PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal influenza vaccine.

    Herati, Ramin Sedaghat / Knorr, David A / Vella, Laura A / Silva, Luisa Victoria / Chilukuri, Lakshmi / Apostolidis, Sokratis A / Huang, Alexander C / Muselman, Alexander / Manne, Sasikanth / Kuthuru, Oliva / Staupe, Ryan P / Adamski, Sharon A / Kannan, Senthil / Kurupati, Raj K / Ertl, Hildegund C J / Wong, Jeffrey L / Bournazos, Stylianos / McGettigan, Suzanne / Schuchter, Lynn M /
    Kotecha, Ritesh R / Funt, Samuel A / Voss, Martin H / Motzer, Robert J / Lee, Chung-Han / Bajorin, Dean F / Mitchell, Tara C / Ravetch, Jeffrey V / Wherry, E John

    Nature immunology

    2022  Volume 23, Issue 8, Page(s) 1183–1192

    Abstract: Anti-programmed death-1 (anti-PD-1) immunotherapy reinvigorates CD8 T cell responses in patients with cancer but PD-1 is also expressed by other immune cells, including follicular helper CD4 T cells (Tfh) which are involved in germinal centre responses. ... ...

    Abstract Anti-programmed death-1 (anti-PD-1) immunotherapy reinvigorates CD8 T cell responses in patients with cancer but PD-1 is also expressed by other immune cells, including follicular helper CD4 T cells (Tfh) which are involved in germinal centre responses. Little is known, however, about the effects of anti-PD-1 immunotherapy on noncancer immune responses in humans. To investigate this question, we examined the impact of anti-PD-1 immunotherapy on the Tfh-B cell axis responding to unrelated viral antigens. Following influenza vaccination, a subset of adults receiving anti-PD-1 had more robust circulating Tfh responses than adults not receiving immunotherapy. PD-1 pathway blockade resulted in transcriptional signatures of increased cellular proliferation in circulating Tfh and responding B cells compared with controls. These latter observations suggest an underlying change in the Tfh-B cell and germinal centre axis in a subset of immunotherapy patients. Together, these results demonstrate dynamic effects of anti-PD-1 therapy on influenza vaccine responses and highlight analytical vaccination as an approach that may reveal underlying immune predisposition to adverse events.
    MeSH term(s) Adult ; Humans ; Immunity, Humoral ; Influenza Vaccines ; Seasons ; T-Lymphocytes, Helper-Inducer ; Vaccination
    Chemical Substances Influenza Vaccines
    Language English
    Publishing date 2022-07-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2016987-5
    ISSN 1529-2916 ; 1529-2908
    ISSN (online) 1529-2916
    ISSN 1529-2908
    DOI 10.1038/s41590-022-01274-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Discovery of the Selective Androgen Receptor Modulator MK-0773 Using a Rational Development Strategy Based on Differential Transcriptional Requirements for Androgenic Anabolism Versus Reproductive Physiology

    Schmidt, Azriel / Kimmel, Donald B / Bai, Chang / Scafonas, Angela / Rutledge, SuJane / Vogel, Robert L / McElwee-Witmer, Sheila / Chen, Fang / Nantermet, Pascale V / Kasparcova, Viera / Leu, Chih-tai / Zhang, Hai-Zhuan / Duggan, Mark E / Gentile, Michael A / Hodor, Paul / Pennypacker, Brenda / Masarachia, Patricia / Opas, Evan E / Adamski, Sharon A /
    Cusick, Tara E / Wang, Jiabing / Mitchell, Helen J / Kim, Yuntae / Prueksaritanont, Thomayant / Perkins, James J / Meissner, Robert S / Hartman, George D / Freedman, Leonard P / Harada, Shun-ichi / Ray, William J

    Journal of biological chemistry. 2010 May 28, v. 285, no. 22

    2010  

    Abstract: Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize ... ...

    Abstract Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated a model promoter 40-80% of an agonist, recruited the coactivator GRIP-1 <15%, and stabilized the N-/C-terminal interdomain interaction <7% induced bone formation with reduced effects in the uterus and in sebaceous glands. Using these criteria, multiple SARMs were synthesized including MK-0773, a 4-aza-steroid that exhibited tissue selectivity in humans. Thus, AR activated to moderate levels due to reduced cofactor recruitment, and N-/C-terminal interactions produce a fully anabolic response, whereas more complete receptor activation is required for reproductive effects. This bimodal activation provides a molecular basis for the development of SARMs.
    Language English
    Dates of publication 2010-0528
    Size p. 17054-17064.
    Publishing place American Society for Biochemistry and Molecular Biology
    Document type Article
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    Database NAL-Catalogue (AGRICOLA)

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  3. Article ; Online: Discovery of the selective androgen receptor modulator MK-0773 using a rational development strategy based on differential transcriptional requirements for androgenic anabolism versus reproductive physiology.

    Schmidt, Azriel / Kimmel, Donald B / Bai, Chang / Scafonas, Angela / Rutledge, Sujane / Vogel, Robert L / McElwee-Witmer, Sheila / Chen, Fang / Nantermet, Pascale V / Kasparcova, Viera / Leu, Chih-Tai / Zhang, Hai-Zhuan / Duggan, Mark E / Gentile, Michael A / Hodor, Paul / Pennypacker, Brenda / Masarachia, Patricia / Opas, Evan E / Adamski, Sharon A /
    Cusick, Tara E / Wang, Jiabing / Mitchell, Helen J / Kim, Yuntae / Prueksaritanont, Thomayant / Perkins, James J / Meissner, Robert S / Hartman, George D / Freedman, Leonard P / Harada, Shun-ichi / Ray, William J

    The Journal of biological chemistry

    2010  Volume 285, Issue 22, Page(s) 17054–17064

    Abstract: Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize ... ...

    Abstract Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated a model promoter 40-80% of an agonist, recruited the coactivator GRIP-1 <15%, and stabilized the N-/C-terminal interdomain interaction <7% induced bone formation with reduced effects in the uterus and in sebaceous glands. Using these criteria, multiple SARMs were synthesized including MK-0773, a 4-aza-steroid that exhibited tissue selectivity in humans. Thus, AR activated to moderate levels due to reduced cofactor recruitment, and N-/C-terminal interactions produce a fully anabolic response, whereas more complete receptor activation is required for reproductive effects. This bimodal activation provides a molecular basis for the development of SARMs.
    MeSH term(s) Androgens/metabolism ; Animals ; Azasteroids/chemistry ; Azasteroids/pharmacology ; COS Cells ; Cell Line, Tumor ; Chemistry, Pharmaceutical/methods ; Chlorocebus aethiops ; Drug Design ; Female ; Hormone Antagonists/pharmacology ; Humans ; Ligands ; Male ; Models, Biological ; Protein Structure, Tertiary ; Rats ; Receptors, Androgen/chemistry ; Receptors, Cytoplasmic and Nuclear/metabolism ; Steroids/metabolism ; Transcription, Genetic ; Transcriptional Activation
    Chemical Substances 3-fluoro-N-(3H-imidazo(4,5-b)pyridin-2-ylmethyl)-1,4a,6a-trimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno(5,4-f)quinoline-7-carboxamide ; Androgens ; Azasteroids ; Hormone Antagonists ; Ligands ; Receptors, Androgen ; Receptors, Cytoplasmic and Nuclear ; Steroids
    Language English
    Publishing date 2010-03-31
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M109.099002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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