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  1. Article ; Online: Control of T lymphocyte fate decisions by PI3K signaling.

    Murter, Benjamin / Kane, Lawrence P

    F1000Research

    2020  Volume 9

    Abstract: Virtually all aspects of T and B lymphocyte development, homeostasis, activation, and effector function are impacted by the interaction of their clonally distributed antigen receptors with antigens encountered in their respective environments. Antigen ... ...

    Abstract Virtually all aspects of T and B lymphocyte development, homeostasis, activation, and effector function are impacted by the interaction of their clonally distributed antigen receptors with antigens encountered in their respective environments. Antigen receptors mediate their effects by modulating intracellular signaling pathways that ultimately impinge on the cytoskeleton, bioenergetic pathways, transcription, and translation. Although these signaling pathways are rather well described at this point, especially those steps that are most receptor-proximal, how such pathways contribute to more quantitative aspects of lymphocyte function is still being elucidated. One of the signaling pathways that appears to be involved in this "tuning" process is controlled by the lipid kinase PI3K. Here we review recent key findings regarding both the triggering/enhancement of PI3K signals (via BCAP and ICOS) as well as their regulation (via PIK3IP1 and PHLPP) and how these signals integrate and determine cellular processes. Lymphocytes display tremendous functional plasticity, adjusting their metabolism and gene expression programs to specific conditions depending on their tissue of residence and the nature of the infectious threat to which they are responding. We give an overview of recent findings that have contributed to this model, with a focus on T cells, including what has been learned from patients with gain-of-function mutations in PI3K as well as lessons from cancer immunotherapy approaches.
    MeSH term(s) Cell Differentiation ; Humans ; Phosphatidylinositol 3-Kinases/metabolism ; Signal Transduction ; T-Lymphocytes/cytology ; T-Lymphocytes/enzymology
    Language English
    Publishing date 2020-09-25
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2699932-8
    ISSN 2046-1402 ; 2046-1402
    ISSN (online) 2046-1402
    ISSN 2046-1402
    DOI 10.12688/f1000research.26928.1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Excyt: a graphical user interface for streamlining analysis of high-dimensional cytometry data

    Sidhom, John-William / Theodros, Debebe / Murter, Benjamin / Zarif, Jelani C / Ganguly, Sudipto / Pardoll, Drew M / Baras, Alexander

    Journal of visualized experiments. 2019 Jan. 16, , no. 143

    2019  

    Abstract: With the advent of flow cytometers capable of measuring an increasing number of parameters, scientists continue to develop larger panels to phenotypically explore characteristics of their cellular samples. However, these technological advancements yield ... ...

    Abstract With the advent of flow cytometers capable of measuring an increasing number of parameters, scientists continue to develop larger panels to phenotypically explore characteristics of their cellular samples. However, these technological advancements yield high-dimensional data sets that have become increasingly difficult to analyze objectively within traditional manual-based gating programs. In order to better analyze and present data, scientists partner with bioinformaticians with expertise in analyzing high-dimensional data to parse their flow cytometry data. While these methods have been shown to be highly valuable in studying flow cytometry, they have yet to be incorporated in a straightforward and easy-to-use package for scientists who lack computational or programming expertise. To address this need, we have developed ExCYT, a MATLAB-based Graphical User Interface (GUI) that streamlines the analysis of high-dimensional flow cytometry data by implementing commonly employed analytical techniques for high-dimensional data including dimensionality reduction by t-SNE, a variety of automated and manual clustering methods, heatmaps, and novel high-dimensional flow plots. Additionally, ExCYT provides traditional gating options of select populations of interest for further t-SNE and clustering analysis as well as the ability to apply gates directly on t-SNE plots. The software provides the additional advantage of working with either compensated or uncompensated FCS files. In the event that post-acquisition compensation is required, the user can choose to provide the program a directory of single stains and an unstained sample. The program detects positive events in all channels and uses this select data to more objectively calculate the compensation matrix. In summary, ExCYT provides a comprehensive analysis pipeline to take flow cytometry data in the form of FCS files and allow any individual, regardless of computational training, to use the latest algorithmic approaches in understanding their data.
    Keywords automation ; cluster analysis ; computer software ; data collection ; flow cytometry ; user interface
    Language English
    Dates of publication 2019-0116
    Size p. e57473.
    Publishing place Journal of Visualized Experiments
    Document type Article
    ISSN 1940-087X
    DOI 10.3791/57473
    Database NAL-Catalogue (AGRICOLA)

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  3. Article ; Online: Expression of Tim-3 drives phenotypic and functional changes in Treg cells in secondary lymphoid organs and the tumor microenvironment.

    Banerjee, Hridesh / Nieves-Rosado, Hector / Kulkarni, Aditi / Murter, Benjamin / McGrath, Kyle V / Chandran, Uma R / Chang, Alexander / Szymczak-Workman, Andrea L / Vujanovic, Lazar / Delgoffe, Greg M / Ferris, Robert L / Kane, Lawrence P

    Cell reports

    2021  Volume 36, Issue 11, Page(s) 109699

    Abstract: Regulatory T cells (Treg cells) are critical mediators of self-tolerance, but they can also limit effective anti-tumor immunity. Although under homeostasis a small fraction of Treg cells in lymphoid organs express the putative checkpoint molecule Tim-3, ... ...

    Abstract Regulatory T cells (Treg cells) are critical mediators of self-tolerance, but they can also limit effective anti-tumor immunity. Although under homeostasis a small fraction of Treg cells in lymphoid organs express the putative checkpoint molecule Tim-3, this protein is expressed by a much larger proportion of tumor-infiltrating Treg cells. Using a mouse model that drives cell-type-specific inducible Tim-3 expression, we show that expression of Tim-3 by Treg cells is sufficient to drive Treg cells to a more effector-like phenotype, resulting in increases in suppressive activity, effector T cell exhaustion, and tumor growth. We also show that T-reg-cell-specific inducible deletion of Tim-3 enhances anti-tumor immunity. Enhancement of Treg cell function by Tim-3 is strongly correlated with increased expression of interleukin-10 (IL-10) and a shift to a more glycolytic metabolic phenotype. Our data demonstrate that Tim-3
    Language English
    Publishing date 2021-09-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2021.109699
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: ExCYT: A Graphical User Interface for Streamlining Analysis of High-Dimensional Cytometry Data.

    Sidhom, John-William / Theodros, Debebe / Murter, Benjamin / Zarif, Jelani C / Ganguly, Sudipto / Pardoll, Drew M / Baras, Alexander

    Journal of visualized experiments : JoVE

    2019  , Issue 143

    Abstract: With the advent of flow cytometers capable of measuring an increasing number of parameters, scientists continue to develop larger panels to phenotypically explore characteristics of their cellular samples. However, these technological advancements yield ... ...

    Abstract With the advent of flow cytometers capable of measuring an increasing number of parameters, scientists continue to develop larger panels to phenotypically explore characteristics of their cellular samples. However, these technological advancements yield high-dimensional data sets that have become increasingly difficult to analyze objectively within traditional manual-based gating programs. In order to better analyze and present data, scientists partner with bioinformaticians with expertise in analyzing high-dimensional data to parse their flow cytometry data. While these methods have been shown to be highly valuable in studying flow cytometry, they have yet to be incorporated in a straightforward and easy-to-use package for scientists who lack computational or programming expertise. To address this need, we have developed ExCYT, a MATLAB-based Graphical User Interface (GUI) that streamlines the analysis of high-dimensional flow cytometry data by implementing commonly employed analytical techniques for high-dimensional data including dimensionality reduction by t-SNE, a variety of automated and manual clustering methods, heatmaps, and novel high-dimensional flow plots. Additionally, ExCYT provides traditional gating options of select populations of interest for further t-SNE and clustering analysis as well as the ability to apply gates directly on t-SNE plots. The software provides the additional advantage of working with either compensated or uncompensated FCS files. In the event that post-acquisition compensation is required, the user can choose to provide the program a directory of single stains and an unstained sample. The program detects positive events in all channels and uses this select data to more objectively calculate the compensation matrix. In summary, ExCYT provides a comprehensive analysis pipeline to take flow cytometry data in the form of FCS files and allow any individual, regardless of computational training, to use the latest algorithmic approaches in understanding their data.
    MeSH term(s) Algorithms ; Flow Cytometry/methods ; Humans ; Lymphocytes/metabolism ; Myeloid Cells/metabolism ; Phenotype ; Software ; Staining and Labeling ; User-Computer Interface
    Language English
    Publishing date 2019-01-16
    Publishing country United States
    Document type Journal Article ; Video-Audio Media
    ZDB-ID 2259946-0
    ISSN 1940-087X ; 1940-087X
    ISSN (online) 1940-087X
    ISSN 1940-087X
    DOI 10.3791/57473
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: High-dimensional Cytometry (ExCYT) and Mass Spectrometry of Myeloid Infiltrate in Clinically Localized Clear Cell Renal Cell Carcinoma Identifies Novel Potential Myeloid Targets for Immunotherapy.

    Theodros, Debebe / Murter, Benjamin M / Sidhom, John-William / Nirschl, Thomas R / Clark, David J / Chen, LiJun / Tam, Ada J / Blosser, Richard L / Schwen, Zeyad R / Johnson, Michael H / Pierorazio, Phillip M / Zhang, Hui / Ganguly, Sudipto / Pardoll, Drew M / Zarif, Jelani C

    Molecular & cellular proteomics : MCP

    2020  Volume 19, Issue 11, Page(s) 1850–1859

    Abstract: Renal Cell Carcinoma (RCC) is one of the most commonly diagnosed cancers worldwide with research efforts dramatically improving understanding of the biology of the disease. To investigate the role of the immune system in treatment-naïve clear cell Renal ... ...

    Abstract Renal Cell Carcinoma (RCC) is one of the most commonly diagnosed cancers worldwide with research efforts dramatically improving understanding of the biology of the disease. To investigate the role of the immune system in treatment-naïve clear cell Renal Cell Carcinoma (ccRCC), we interrogated the immune infiltrate in patient-matched ccRCC tumor samples, benign normal adjacent tissue (NAT) and peripheral blood mononuclear cells (PBMCs isolated from whole blood, focusing our attention on the myeloid cell infiltrate. Using flow cytometric, MS, and ExCYT analysis, we discovered unique myeloid populations in PBMCs across patient samples. Furthermore, normal adjacent tissues and ccRCC tissues contained numerous myeloid populations with a unique signature for both tissues. Enrichment of the immune cell (CD45
    MeSH term(s) Biomarkers, Tumor/analysis ; Biomarkers, Tumor/blood ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/immunology ; Carcinoma, Renal Cell/genetics ; Carcinoma, Renal Cell/immunology ; Carcinoma, Renal Cell/metabolism ; Flow Cytometry ; Gene Expression Regulation, Neoplastic/immunology ; Genomics ; Humans ; Immunotherapy/methods ; Kidney Neoplasms/genetics ; Kidney Neoplasms/immunology ; Kidney Neoplasms/metabolism ; Leukocyte Common Antigens/blood ; Leukocytes, Mononuclear/cytology ; Leukocytes, Mononuclear/metabolism ; Mass Spectrometry ; Prognosis ; Signal Transduction ; Tandem Mass Spectrometry ; Tumor Microenvironment/immunology
    Chemical Substances Biomarkers, Tumor ; Leukocyte Common Antigens (EC 3.1.3.48) ; PTPRC protein, human (EC 3.1.3.48)
    Language English
    Publishing date 2020-07-31
    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, Non-P.H.S.
    ZDB-ID 2075924-1
    ISSN 1535-9484 ; 1535-9476
    ISSN (online) 1535-9484
    ISSN 1535-9476
    DOI 10.1074/mcp.RA120.002049
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5599: Show issues Location:
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  6. Article ; Online: Mouse PVRIG Has CD8

    Murter, Benjamin / Pan, Xiaoyu / Ophir, Eran / Alteber, Zoya / Azulay, Meir / Sen, Rupashree / Levy, Ofer / Dassa, Liat / Vaknin, Ilan / Fridman-Kfir, Tal / Salomon, Ran / Ravet, Achinoam / Tam, Ada / Levin, Doron / Vaknin, Yakir / Tatirovsky, Evgeny / Machlenkin, Arthur / Pardoll, Drew / Ganguly, Sudipto

    Cancer immunology research

    2019  Volume 7, Issue 2, Page(s) 244–256

    Abstract: A limitation to antitumor immunity is the dysfunction of T cells in the tumor microenvironment, in part due to upregulation of coinhibitory receptors such as PD-1. Here, we describe that poliovirus receptor-related immunoglobulin domain protein (PVRIG) ... ...

    Abstract A limitation to antitumor immunity is the dysfunction of T cells in the tumor microenvironment, in part due to upregulation of coinhibitory receptors such as PD-1. Here, we describe that poliovirus receptor-related immunoglobulin domain protein (PVRIG) acts as a coinhibitory receptor in mice. Murine PVRIG interacted weakly with poliovirus receptor (PVR) but bound poliovirus receptor-like 2 (PVRL2) strongly, making the latter its principal ligand. As in humans, murine NK and NKT cells constitutively expressed PVRIG. However, when compared with humans, less PVRIG transcript and surface protein was detected in murine CD8
    MeSH term(s) Animals ; B7-H1 Antigen/antagonists & inhibitors ; Biomarkers ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Cell Line, Tumor ; Disease Models, Animal ; Female ; Humans ; Lymphocyte Activation/genetics ; Lymphocyte Activation/immunology ; Lymphocytes, Tumor-Infiltrating/immunology ; Lymphocytes, Tumor-Infiltrating/metabolism ; Mice ; Mice, Knockout ; Neoplasms/immunology ; Neoplasms/metabolism ; Neoplasms/pathology ; RNA Interference ; Receptors, Cell Surface/metabolism ; T-Cell Antigen Receptor Specificity/immunology ; Tumor Burden ; Tumor Microenvironment/immunology ; Xenograft Model Antitumor Assays
    Chemical Substances B7-H1 Antigen ; Biomarkers ; CD274 protein, human ; Receptors, Cell Surface
    Language English
    Publishing date 2019-01-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2732489-8
    ISSN 2326-6074 ; 2326-6066
    ISSN (online) 2326-6074
    ISSN 2326-6066
    DOI 10.1158/2326-6066.CIR-18-0460
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 7022: Show issues Location:
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  7. Article ; Online: PVRIG and PVRL2 Are Induced in Cancer and Inhibit CD8

    Whelan, Sarah / Ophir, Eran / Kotturi, Maya F / Levy, Ofer / Ganguly, Sudipto / Leung, Ling / Vaknin, Ilan / Kumar, Sandeep / Dassa, Liat / Hansen, Kyle / Bernados, David / Murter, Benjamin / Soni, Abha / Taube, Janis M / Fader, Amanda Nickles / Wang, Tian-Li / Shih, Ie-Ming / White, Mark / Pardoll, Drew M /
    Liang, Spencer C

    Cancer immunology research

    2019  Volume 7, Issue 2, Page(s) 257–268

    Abstract: Although checkpoint inhibitors that block CTLA-4 and PD-1 have improved cancer immunotherapies, targeting additional checkpoint receptors may be required to broaden patient response to immunotherapy. PVRIG is a coinhibitory receptor of the DNAM/TIGIT/ ... ...

    Abstract Although checkpoint inhibitors that block CTLA-4 and PD-1 have improved cancer immunotherapies, targeting additional checkpoint receptors may be required to broaden patient response to immunotherapy. PVRIG is a coinhibitory receptor of the DNAM/TIGIT/CD96 nectin family that binds to PVRL2. We report that antagonism of PVRIG and TIGIT, but not CD96, increased CD8
    MeSH term(s) Animals ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Lymphocyte Activation/immunology ; Lymphocytes, Tumor-Infiltrating/immunology ; Lymphocytes, Tumor-Infiltrating/metabolism ; Lymphocytes, Tumor-Infiltrating/pathology ; Mice ; Nectins/metabolism ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/metabolism ; Neoplasms/pathology ; Programmed Cell Death 1 Receptor/genetics ; Programmed Cell Death 1 Receptor/metabolism ; Protein Binding ; Receptors, Cell Surface/metabolism ; Receptors, Immunologic/genetics ; Receptors, Immunologic/metabolism ; Signal Transduction
    Chemical Substances NECTIN2 protein, human ; Nectins ; PDCD1 protein, human ; PVRIG protein, human ; Programmed Cell Death 1 Receptor ; Receptors, Cell Surface ; Receptors, Immunologic ; TIGIT protein, human
    Language English
    Publishing date 2019-01-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2732489-8
    ISSN 2326-6074 ; 2326-6066
    ISSN (online) 2326-6074
    ISSN 2326-6066
    DOI 10.1158/2326-6066.CIR-18-0442
    Database MEDical Literature Analysis and Retrieval System OnLINE

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