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  1. Article: Cellular senescence in musculoskeletal homeostasis, diseases, and regeneration.

    Wan, Mei / Gray-Gaillard, Elise F / Elisseeff, Jennifer H

    Bone research

    2021  Volume 9, Issue 1, Page(s) 41

    Abstract: Emerging insights into cellular senescence highlight the relevance of senescence in musculoskeletal disorders, which represent the leading global cause of disability. Cellular senescence was initially described by Hayflick et al. in 1961 as an ... ...

    Abstract Emerging insights into cellular senescence highlight the relevance of senescence in musculoskeletal disorders, which represent the leading global cause of disability. Cellular senescence was initially described by Hayflick et al. in 1961 as an irreversible nondividing state in in vitro cell culture studies. We now know that cellular senescence can occur in vivo in response to various stressors as a heterogeneous and tissue-specific cell state with a secretome phenotype acquired after the initial growth arrest. In the past two decades, compelling evidence from preclinical models and human data show an accumulation of senescent cells in many components of the musculoskeletal system. Cellular senescence is therefore a defining feature of age-related musculoskeletal disorders, and targeted elimination of these cells has emerged recently as a promising therapeutic approach to ameliorate tissue damage and promote repair and regeneration of the skeleton and skeletal muscles. In this review, we summarize evidence of the role of senescent cells in the maintenance of bone homeostasis during childhood and their contribution to the pathogenesis of chronic musculoskeletal disorders, including osteoporosis, osteoarthritis, and sarcopenia. We highlight the diversity of the senescent cells in the microenvironment of bone, joint, and skeletal muscle tissue, as well as the mechanisms by which these senescent cells are involved in musculoskeletal diseases. In addition, we discuss how identifying and targeting senescent cells might positively affect pathologic progression and musculoskeletal system regeneration.
    Language English
    Publishing date 2021-09-10
    Publishing country China
    Document type Journal Article ; Review
    ZDB-ID 2803313-9
    ISSN 2095-6231 ; 2095-4700
    ISSN (online) 2095-6231
    ISSN 2095-4700
    DOI 10.1038/s41413-021-00164-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Modeling the complete kinetics of coxsackievirus B3 reveals human determinants of host-cell feedback.

    Lopacinski, Aaron B / Sweatt, Andrew J / Smolko, Christian M / Gray-Gaillard, Elise / Borgman, Cheryl A / Shah, Millie / Janes, Kevin A

    Cell systems

    2021  Volume 12, Issue 4, Page(s) 304–323.e13

    Abstract: Complete kinetic models are pervasive in chemistry but lacking in biological systems. We encoded the complete kinetics of infection for coxsackievirus B3 (CVB3), a compact and fast-acting RNA virus. The model consists of separable, detailed modules ... ...

    Abstract Complete kinetic models are pervasive in chemistry but lacking in biological systems. We encoded the complete kinetics of infection for coxsackievirus B3 (CVB3), a compact and fast-acting RNA virus. The model consists of separable, detailed modules describing viral binding-delivery, translation-replication, and encapsidation. Specific module activities are dampened by the type I interferon response to viral double-stranded RNAs (dsRNAs), which is itself disrupted by viral proteinases. The experimentally validated kinetics uncovered that cleavability of the dsRNA transducer mitochondrial antiviral signaling protein (MAVS) becomes a stronger determinant of viral outcomes when cells receive supplemental interferon after infection. Cleavability is naturally altered in humans by a common MAVS polymorphism, which removes a proteinase-targeted site but paradoxically elevates CVB3 infectivity. These observations are reconciled with a simple nonlinear model of MAVS regulation. Modeling complete kinetics is an attainable goal for small, rapidly infecting viruses and perhaps viral pathogens more broadly. A record of this paper's transparent peer review process is included in the Supplemental information.
    MeSH term(s) Enterovirus B, Human/genetics ; Host-Pathogen Interactions/genetics ; Humans ; Kinetics
    Language English
    Publishing date 2021-03-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2854138-8
    ISSN 2405-4720 ; 2405-4712
    ISSN (online) 2405-4720
    ISSN 2405-4712
    DOI 10.1016/j.cels.2021.02.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Age-associated Senescent - T Cell Signaling Promotes Type 3 Immunity that Inhibits the Biomaterial Regenerative Response.

    Han, Jin / Cherry, Christopher / Mejías, Joscelyn C / Krishnan, Kavita / Ruta, Anna / Maestas, David R / Peña, Alexis N / Nguyen, Helen Hieu / Nagaraj, Sushma / Yang, Brenda / Gray-Gaillard, Elise F / Rutkowski, Natalie / Browne, Maria / Tam, Ada J / Fertig, Elana J / Housseau, Franck / Ganguly, Sudipto / Moore, Erika M / Pardoll, Drew M /
    Elisseeff, Jennifer H

    Advanced materials (Deerfield Beach, Fla.)

    2023  , Page(s) e2310476

    Abstract: Aging is associated with immunological changes that compromise response to infections and vaccines, exacerbate inflammatory diseases and can potentially mitigate tissue repair. Even so, age-related changes to the immune response to tissue damage and ... ...

    Abstract Aging is associated with immunological changes that compromise response to infections and vaccines, exacerbate inflammatory diseases and can potentially mitigate tissue repair. Even so, age-related changes to the immune response to tissue damage and regenerative medicine therapies remain unknown. Here, it is characterized how aging induces changes in immunological signatures that inhibit tissue repair and therapeutic response to a clinical regenerative biological scaffold derived from extracellular matrix. Signatures of inflammation and interleukin (IL)-17 signaling increased with injury and treatment both locally and regionally in aged animals, and computational analysis uncovered age-associated senescent-T cell communication that promotes type 3 immunity in T cells. Local inhibition of type 3 immune activation using IL17-neutralizing antibodies improves healing and restores therapeutic response to the regenerative biomaterial, promoting muscle repair in older animals. These results provide insights into tissue immune dysregulation that occurs with aging that can be targeted to rejuvenate repair.
    Language English
    Publishing date 2023-12-12
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 1474949-X
    ISSN 1521-4095 ; 0935-9648
    ISSN (online) 1521-4095
    ISSN 0935-9648
    DOI 10.1002/adma.202310476
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Transfer learning in a biomaterial fibrosis model identifies in vivo senescence heterogeneity and contributions to vascularization and matrix production across species and diverse pathologies.

    Cherry, Christopher / Andorko, James I / Krishnan, Kavita / Mejías, Joscelyn C / Nguyen, Helen Hieu / Stivers, Katlin B / Gray-Gaillard, Elise F / Ruta, Anna / Han, Jin / Hamada, Naomi / Hamada, Masakazu / Sturmlechner, Ines / Trewartha, Shawn / Michel, John H / Davenport Huyer, Locke / Wolf, Matthew T / Tam, Ada J / Peña, Alexis N / Keerthivasan, Shilpa /
    Le Saux, Claude Jordan / Fertig, Elana J / Baker, Darren J / Housseau, Franck / van Deursen, Jan M / Pardoll, Drew M / Elisseeff, Jennifer H

    GeroScience

    2023  Volume 45, Issue 4, Page(s) 2559–2587

    Abstract: Cellular senescence is a state of permanent growth arrest that plays an important role in wound healing, tissue fibrosis, and tumor suppression. Despite senescent cells' (SnCs) pathological role and therapeutic interest, their phenotype in vivo remains ... ...

    Abstract Cellular senescence is a state of permanent growth arrest that plays an important role in wound healing, tissue fibrosis, and tumor suppression. Despite senescent cells' (SnCs) pathological role and therapeutic interest, their phenotype in vivo remains poorly defined. Here, we developed an in vivo-derived senescence signature (SenSig) using a foreign body response-driven fibrosis model in a p16-CreER
    MeSH term(s) Humans ; Mice ; Animals ; Cellular Senescence/genetics ; Aging/genetics ; Phenotype ; Fibroblasts ; Machine Learning
    Language English
    Publishing date 2023-04-20
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2886586-8
    ISSN 2509-2723 ; 2509-2715
    ISSN (online) 2509-2723
    ISSN 2509-2715
    DOI 10.1007/s11357-023-00785-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Author Correction: A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy.

    Giordano-Attianese, Greta / Gainza, Pablo / Gray-Gaillard, Elise / Cribioli, Elisabetta / Shui, Sailan / Kim, Seonghoon / Kwak, Mi-Jeong / Vollers, Sabrina / Corria Osorio, Angel De Jesus / Reichenbach, Patrick / Bonet, Jaume / Oh, Byung-Ha / Irving, Melita / Coukos, George / Correia, Bruno E

    Nature biotechnology

    2020  Volume 38, Issue 4, Page(s) 503

    Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...

    Abstract An amendment to this paper has been published and can be accessed via a link at the top of the paper.
    Language English
    Publishing date 2020-03-04
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 1311932-1
    ISSN 1546-1696 ; 1087-0156
    ISSN (online) 1546-1696
    ISSN 1087-0156
    DOI 10.1038/s41587-020-0461-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy.

    Giordano-Attianese, Greta / Gainza, Pablo / Gray-Gaillard, Elise / Cribioli, Elisabetta / Shui, Sailan / Kim, Seonghoon / Kwak, Mi-Jeong / Vollers, Sabrina / Corria Osorio, Angel De Jesus / Reichenbach, Patrick / Bonet, Jaume / Oh, Byung-Ha / Irving, Melita / Coukos, George / Correia, Bruno E

    Nature biotechnology

    2020  Volume 38, Issue 4, Page(s) 426–432

    Abstract: Approaches to increase the activity of chimeric antigen receptor (CAR)-T cells against solid tumors may also increase the risk of toxicity and other side effects. To improve the safety of CAR-T-cell therapy, we computationally designed a chemically ... ...

    Abstract Approaches to increase the activity of chimeric antigen receptor (CAR)-T cells against solid tumors may also increase the risk of toxicity and other side effects. To improve the safety of CAR-T-cell therapy, we computationally designed a chemically disruptable heterodimer (CDH) based on the binding of two human proteins. The CDH self-assembles, can be disrupted by a small-molecule drug and has a high-affinity protein interface with minimal amino acid deviation from wild-type human proteins. We incorporated the CDH into a synthetic heterodimeric CAR, called STOP-CAR, that has an antigen-recognition chain and a CD3ζ- and CD28-containing endodomain signaling chain. We tested STOP-CAR-T cells specific for two antigens in vitro and in vivo and found similar antitumor activity compared to second-generation (2G) CAR-T cells. Timed administration of the small-molecule drug dynamically inactivated the activity of STOP-CAR-T cells. Our work highlights the potential for structure-based design to add controllable elements to synthetic cellular therapies.
    MeSH term(s) Cell Engineering ; Cells, Cultured ; Humans ; Immunotherapy, Adoptive ; Jurkat Cells ; Lymphocyte Activation/drug effects ; PC-3 Cells ; Protein Binding ; Protein Engineering ; Protein Multimerization ; Receptors, Antigen, T-Cell/antagonists & inhibitors ; Receptors, Antigen, T-Cell/chemistry ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Chimeric Antigen/antagonists & inhibitors ; Receptors, Chimeric Antigen/chemistry ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/metabolism ; Signal Transduction ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
    Chemical Substances Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen ; Small Molecule Libraries
    Language English
    Publishing date 2020-02-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1311932-1
    ISSN 1546-1696 ; 1087-0156
    ISSN (online) 1546-1696
    ISSN 1087-0156
    DOI 10.1038/s41587-019-0403-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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