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  1. Article: Astragalus

    Yakubogullari, Nilgun / Cagir, Ali / Bedir, Erdal / Sag, Duygu

    Vaccines

    2023  Volume 11, Issue 3

    Abstract: Astragaloside VII (AST VII), a triterpenic saponin isolated ... ...

    Abstract Astragaloside VII (AST VII), a triterpenic saponin isolated from
    Language English
    Publishing date 2023-02-21
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2703319-3
    ISSN 2076-393X
    ISSN 2076-393X
    DOI 10.3390/vaccines11030495
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype and is associated with increased survival in cancer patients with high tumor macrophage content.

    Gunalp, Sinem / Helvaci, Derya Goksu / Oner, Aysenur / Bursalı, Ahmet / Conforte, Alessandra / Güner, Hüseyin / Karakülah, Gökhan / Szegezdi, Eva / Sag, Duygu

    Frontiers in immunology

    2023  Volume 14, Page(s) 1209249

    Abstract: Background: TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that can either induce cell death or activate survival pathways after binding to death receptors (DRs) DR4 or DR5. TRAIL is investigated as a therapeutic agent ... ...

    Abstract Background: TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that can either induce cell death or activate survival pathways after binding to death receptors (DRs) DR4 or DR5. TRAIL is investigated as a therapeutic agent in clinical trials due to its selective toxicity to transformed cells. Macrophages can be polarized into pro-inflammatory/tumor-fighting M1 macrophages or anti-inflammatory/tumor-supportive M2 macrophages and an imbalance between M1 and M2 macrophages can promote diseases. Therefore, identifying modulators that regulate macrophage polarization is important to design effective macrophage-targeted immunotherapies. The impact of TRAIL on macrophage polarization is not known.
    Methods: Primary human monocyte-derived macrophages were pre-treated with either TRAIL or with DR4 or DR5-specific ligands and then polarized into M1, M2a, or M2c phenotypes
    Results: TRAIL increased the expression of M1 markers at both mRNA and protein levels while decreasing the expression of M2 markers at the mRNA level in human macrophages. TRAIL also shifted M2 macrophages towards an M1 phenotype. Our data showed that both DR4 and DR5 death receptors play a role in macrophage polarization. Furthermore, TRAIL enhanced the cytotoxicity of macrophages against the AML cancer cells
    Conclusions: TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype via both DR4 and DR5. Our study defines TRAIL as a new regulator of macrophage polarization and suggests that targeting DRs can enhance the anti-tumorigenic response of macrophages in the tumor microenvironment by increasing M1 polarization.
    MeSH term(s) Humans ; TNF-Related Apoptosis-Inducing Ligand/metabolism ; Macrophages/metabolism ; Phenotype ; RNA, Messenger/metabolism ; Receptors, Death Domain/metabolism ; Leukemia, Myeloid, Acute/metabolism ; Tumor Microenvironment
    Chemical Substances TNF-Related Apoptosis-Inducing Ligand ; RNA, Messenger ; Receptors, Death Domain
    Language English
    Publishing date 2023-09-21
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1209249
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The Ca2+ concentration impacts the cytokine production of mouse and human lymphoid cells and the polarization of human macrophages in vitro.

    Eskiocak, Yusuf Cem / Ayyildiz, Zeynep Ozge / Gunalp, Sinem / Korkmaz, Asli / Helvaci, Derya Goksu / Dogan, Yavuz / Sag, Duygu / Wingender, Gerhard

    PloS one

    2023  Volume 18, Issue 2, Page(s) e0282037

    Abstract: Various aspects of the in vitro culture conditions can impact the functional response of immune cells. For example, it was shown that a Ca2+ concentration of at least 1.5 mM during in vitro stimulation is needed for optimal cytokine production by ... ...

    Abstract Various aspects of the in vitro culture conditions can impact the functional response of immune cells. For example, it was shown that a Ca2+ concentration of at least 1.5 mM during in vitro stimulation is needed for optimal cytokine production by conventional αβ T cells. Here we extend these findings by showing that also unconventional T cells (invariant Natural Killer T cells, mucosal-associated invariant T cells, γδ T cells), as well as B cells, show an increased cytokine response following in vitro stimulation in the presence of elevated Ca2+ concentrations. This effect appeared more pronounced with mouse than with human lymphoid cells and did not influence their survival. A similarly increased cytokine response due to elevated Ca2+ levels was observed with primary human monocytes. In contrast, primary human monocyte-derived macrophages, either unpolarized (M0) or polarized into M1 or M2 macrophages, displayed increased cell death in the presence of elevated Ca2+ concentrations. Furthermore, elevated Ca2+ concentrations promoted phenotypic M1 differentiation by increasing M1 markers on M1 and M2 macrophages and decreasing M2 markers on M2 macrophages. However, the cytokine production of macrophages, again in contrast to the lymphoid cells, was unaltered by the Ca2+ concentration. In summary, our data demonstrate that the Ca2+ concentration during in vitro cultures is an important variable to be considered for functional experiments and that elevated Ca2+ levels can boost cytokine production by both mouse and human lymphoid cells.
    MeSH term(s) Humans ; Calcium/metabolism ; Macrophages/metabolism ; Cytokines/metabolism ; Monocytes/metabolism ; Cell Differentiation ; Lymphocytes/metabolism
    Chemical Substances Calcium (SY7Q814VUP) ; Cytokines
    Language English
    Publishing date 2023-02-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0282037
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  4. Article ; Online: Sudarshan Kriya Yoga Breathing and a Meditation Program for Burnout Among Physicians: A Randomized Clinical Trial.

    Korkmaz, Asli / Bernhardsen, Guro Pauck / Cirit, Burcu / Koprucu Suzer, Gayem / Kayan, Hale / Biçmen, Hülya / Tahra, Muratcan / Suner, Asli / Lehto, Soili Marianne / Sag, Duygu / Saatcioglu, Fahri

    JAMA network open

    2024  Volume 7, Issue 1, Page(s) e2353978

    Abstract: Importance: Physicians are exposed to high stress and strain that results in burnout, which affects them, their families, their patients, and the entire health care system; thus, there is an urgent need to develop methods to increase the resiliency of ... ...

    Abstract Importance: Physicians are exposed to high stress and strain that results in burnout, which affects them, their families, their patients, and the entire health care system; thus, there is an urgent need to develop methods to increase the resiliency of physicians. Sudarshan Kriya Yoga (SKY) is a comprehensive yoga breathing and meditation-based program that is a potential approach to mitigate physician burnout.
    Objective: To determine whether SKY can reduce psychological distress and improve wellness in physicians.
    Design, setting, and participants: This randomized clinical trial assessed the potential efficacy of SKY compared with a stress management education (SME) training as control. This study was conducted online from November 11, 2021, to March 14, 2022, and included physicians from Turkey, Germany, and Dubai. Both the SKY and the SME control groups received 1.5 hours of training for 3 consecutive days via a group video conference call. Participants were physicians willing to do some form of relaxation exercise everyday for 2 months. Exclusion criteria included presence of major illness and maintaining a regular mind-body program practice. Statistical analysis took place from March to November 2023.
    Interventions: Participants were randomly assigned 1:1 into 2 groups-the SKY group or the SME (control) group-using a computer algorithm. After the 3-day instruction period, the participants in the SKY group practiced for approximately 30 minutes per day on their own and participated in a weekly 1-hour, group-based online follow-up practice. After the 3-day instruction period, participants in the SME group reviewed and applied the notes from stress management education training at their initiative and had a weekly 1-hour group-based online follow-up session.
    Main outcomes and measures: The primary outcomes were stress and depression (measured by the 42-item Depression, Anxiety, and Stress Scale [DASS-42]) and insomnia measured by the Regensburg Insomnia Scale (RIS) with primary end point at 8 weeks. Secondary outcomes included anxiety (DASS-42); optimism (Life Orientation Test-Revised [LOT-R]); professional fulfillment, work exhaustion, interpersonal disengagement, and overall burnout (Professional Fulfillment Index [PFI]); and self-reported professional errors (Self-Reported Professional Error Questionnaire).
    Results: This study included 129 participants (SME, 63 participants [48.9%]; SKY, 66 participants [51.1%]; 115 females [89.2%]; 14 males [10.8%]; mean [SD] age, 46.2 [9.0] years). Compared with the SME control group, participants in the SKY group had significantly decreased stress on the DASS-42 at posttraining (difference, -6.8 points; 95% CI, -9.6 to -4.1 points; P = .006) and at postintervention (difference, -6.0 points; 95% CI, -8.8 to -3.3 points; P = .03), significantly decreased depression at posttraining (difference, -5.7 points; 95% CI, -8.6 to -2.8 points; P < .001) and postintervention (difference, -5.4 points; 95% CI, -8.3 to -2.5 points; P < .001), and significantly decreased anxiety at postintervention. In addition, there was a significant decrease in insomnia from baseline to postintervention in the SKY group (difference, -0.3 points; 95% CI, -2.3 to 1.7 points; P = .01). The SKY group also showed significantly increased professional fulfillment as well as significant decreases in work exhaustion, interpersonal disengagement, and burnout. There was no effect on self-reported medical errors.
    Conclusions and relevance: In this randomized clinical trial, physicians who regularly practiced SKY throughout a 2-month period experienced improvements in wellness and decreased burnout. These data suggest that SKY may be an effective, practical, and safe strategy to increase wellness and mitigate burnout in physicians.
    Trial registration: ClinicalTrials.gov Identifier: NCT05956470.
    MeSH term(s) Female ; Male ; Humans ; Middle Aged ; Meditation ; Yoga ; Sleep Initiation and Maintenance Disorders ; Burnout, Psychological ; Respiration
    Language English
    Publishing date 2024-01-02
    Publishing country United States
    Document type Randomized Controlled Trial ; Journal Article
    ISSN 2574-3805
    ISSN (online) 2574-3805
    DOI 10.1001/jamanetworkopen.2023.53978
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  5. Article ; Online: Effect of stimulation time on the expression of human macrophage polarization markers.

    Unuvar Purcu, Duygu / Korkmaz, Asli / Gunalp, Sinem / Helvaci, Derya Goksu / Erdal, Yonca / Dogan, Yavuz / Suner, Asli / Wingender, Gerhard / Sag, Duygu

    PloS one

    2022  Volume 17, Issue 3, Page(s) e0265196

    Abstract: Macrophages are highly plastic cells that can polarize into functionally distinct subsets in vivo and in vitro in response to environmental signals. The development of protocols to model macrophage polarization in vitro greatly contributes to our ... ...

    Abstract Macrophages are highly plastic cells that can polarize into functionally distinct subsets in vivo and in vitro in response to environmental signals. The development of protocols to model macrophage polarization in vitro greatly contributes to our understanding of macrophage biology. Macrophages are divided into two main groups: Pro-inflammatory M1 macrophages (classically activated) and anti-inflammatory M2 macrophages (alternatively activated), based on several key surface markers and the production of inflammatory mediators. However, the expression of these common macrophage polarization markers is greatly affected by the stimulation time used. Unfortunately, there is no consensus yet regarding the optimal stimulation times for particular macrophage polarization markers in in vitro experiments. This situation is problematic, (i) as analysing a particular marker at a suboptimal time point can lead to false-negative results, and (ii) as it clearly impedes the comparison of different studies. Using human monocyte-derived macrophages (MDMs) in vitro, we analysed how the expression of the main polarization markers for M1 (CD64, CD86, CXCL9, CXCL10, HLA-DR, IDO1, IL1β, IL12, TNF), M2a (CD200R, CD206, CCL17, CCL22, IL-10, TGM2), and M2c (CD163, IL-10, TGFβ) macrophages changes over time at mRNA and protein levels. Our data establish the most appropriate stimulation time for the analysis of the expression of human macrophage polarization markers in vitro. Providing such a reference guide will likely facilitate the investigation of macrophage polarization and its reproducibility.
    MeSH term(s) Biomarkers/metabolism ; Humans ; Interleukin-10/metabolism ; Macrophage Activation ; Macrophages/metabolism ; Reproducibility of Results
    Chemical Substances Biomarkers ; Interleukin-10 (130068-27-8)
    Language English
    Publishing date 2022-03-14
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0265196
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  6. Article: The Role of TRAIL/DRs in the Modulation of Immune Cells and Responses.

    Sag, Duygu / Ayyildiz, Zeynep Ozge / Gunalp, Sinem / Wingender, Gerhard

    Cancers

    2019  Volume 11, Issue 10

    Abstract: Expression of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) by immune cells can lead to the induction of apoptosis in tumor cells. However, it becomes increasingly clear that the interaction of TRAIL and its death receptors (DRs) can ... ...

    Abstract Expression of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) by immune cells can lead to the induction of apoptosis in tumor cells. However, it becomes increasingly clear that the interaction of TRAIL and its death receptors (DRs) can also directly impact immune cells and influence immune responses. Here, we review what is known about the role of TRAIL/DRs in immune cells and immune responses in general and in the tumor microenvironment in particular.
    Language English
    Publishing date 2019-09-30
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers11101469
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  7. Article ; Online: Improved Detection of Cytokines Produced by Invariant NKT Cells.

    Sag, Duygu / Özkan, Müge / Kronenberg, Mitchell / Wingender, Gerhard

    Scientific reports

    2017  Volume 7, Issue 1, Page(s) 16607

    Abstract: Invariant Natural killer T (iNKT) cells rapidly produce copious amounts of multiple cytokines after in vivo activation, allowing for the direct detection of a number of cytokines directly ex vivo. However, for some cytokines this approach is suboptimal. ... ...

    Abstract Invariant Natural killer T (iNKT) cells rapidly produce copious amounts of multiple cytokines after in vivo activation, allowing for the direct detection of a number of cytokines directly ex vivo. However, for some cytokines this approach is suboptimal. Here, we report technical variations that allow the improved detection of IL-4, IL-10, IL-13 and IL-17A ex vivo. Furthermore, we describe an alternative approach for stimulation of iNKT cells in vitro that allows a significantly improved detection of cytokines produced by iNKT cells. Together, these protocols allow the detection of iNKT cell cytokines ex vivo and in vitro with increased sensitivity.
    MeSH term(s) Animals ; Biomarkers ; Cell Death ; Cell Proliferation ; Cytokines/biosynthesis ; Humans ; Immunophenotyping ; Mice ; Natural Killer T-Cells/immunology ; Natural Killer T-Cells/metabolism ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism
    Chemical Substances Biomarkers ; Cytokines
    Language English
    Publishing date 2017-11-30
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-017-16832-1
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  8. Article ; Online: NKT10 cells: a novel iNKT cell subset.

    Wingender, Gerhard / Sag, Duygu / Kronenberg, Mitchell

    Oncotarget

    2015  Volume 6, Issue 29, Page(s) 26552–26553

    MeSH term(s) Animals ; Antigens/metabolism ; Antigens, CD1d/metabolism ; Cell Line ; Cytokines/metabolism ; Galactosylceramides/metabolism ; Humans ; Immunity, Innate/immunology ; Inflammation ; Interferon-gamma/immunology ; Mice ; Natural Killer T-Cells/cytology ; T-Lymphocyte Subsets/cytology
    Chemical Substances Antigens ; Antigens, CD1d ; Cytokines ; Galactosylceramides ; alpha-galactosylceramide ; Interferon-gamma (82115-62-6)
    Language English
    Publishing date 2015-09-29
    Publishing country United States
    Document type Editorial
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.5270
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  9. Article ; Online: Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment.

    Cekic, Caglar / Day, Yuan-Ji / Sag, Duygu / Linden, Joel

    Cancer research

    2014  Volume 74, Issue 24, Page(s) 7250–7259

    Abstract: High concentrations of adenosine in tumor microenvironments inhibit antitumor cytotoxic lymphocyte responses. Although T cells express inhibitory adenosine A2A receptors (A2AR) that suppress their activation and inhibit immune killing of tumors, a role ... ...

    Abstract High concentrations of adenosine in tumor microenvironments inhibit antitumor cytotoxic lymphocyte responses. Although T cells express inhibitory adenosine A2A receptors (A2AR) that suppress their activation and inhibit immune killing of tumors, a role for myeloid cell A2ARs in suppressing the immune response to tumors has yet to be investigated. In this study, we show that the growth of transplanted syngeneic B16F10 melanoma or Lewis lung carcinoma cells is slowed in Adora2a(f/f)-LysMCre(+/-) mice, which selectively lack myeloid A2ARs. Reduced melanoma growth is associated with significant increases in MHCII and IL12 expression in tumor-associated macrophages and with >90% reductions in IL10 expression in tumor-associated macrophages, dendritic cells (DC), and Ly6C(+) or Ly6G(+) myeloid-derived suppressor cells (MDSC). Myeloid deletion of A2ARs significantly increases CD44 expression on tumor-associated T cells and natural killer (NK) cells. Depletion of CD8(+) T cells or NK cells in tumor-bearing mice indicates that both cell types initially contribute to slowing melanoma growth in mice lacking myeloid A2A receptors, but tumor suppression mediated by CD8(+) T cells is more persistent. Myeloid-selective A2AR deletion significantly reduces lung metastasis of melanomas that express luciferase (for in vivo tracking) and ovalbumin (as a model antigen). Reduced metastasis is associated with increased numbers and activation of NK cells and antigen-specific CD8(+) T cells in lung infiltrates. Overall, the findings indicate that myeloid cell A2ARs have direct myelosuppressive effects that indirectly contribute to the suppression of T cells and NK cells in primary and metastatic tumor microenvironments. The results indicate that tumor-associated myeloid cells, including macrophages, DCs, and MDSCs all express immunosuppressive A2ARs that are potential targets of adenosine receptor blockers to enhance immune killing of tumors.
    MeSH term(s) Adenosine A2 Receptor Antagonists/administration & dosage ; Animals ; CD8-Positive T-Lymphocytes/immunology ; Carcinoma, Lewis Lung/immunology ; Carcinoma, Lewis Lung/metabolism ; Cell Proliferation/genetics ; Gene Expression Regulation, Neoplastic ; Humans ; Immunotherapy ; Killer Cells, Natural/immunology ; Killer Cells, Natural/metabolism ; Lymphocyte Activation/immunology ; Melanoma, Experimental/immunology ; Melanoma, Experimental/pathology ; Melanoma, Experimental/therapy ; Mice ; Myeloid Cells/immunology ; Receptor, Adenosine A2A/biosynthesis ; Receptor, Adenosine A2A/immunology ; Receptor, Adenosine A2A/metabolism ; T-Lymphocytes, Cytotoxic/immunology ; Tumor Microenvironment/immunology
    Chemical Substances Adenosine A2 Receptor Antagonists ; Receptor, Adenosine A2A
    Language English
    Publishing date 2014-12-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-13-3583
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  10. Article ; Online: Extracellular adenosine regulates naive T cell development and peripheral maintenance.

    Cekic, Caglar / Sag, Duygu / Day, Yuan-Ji / Linden, Joel

    The Journal of experimental medicine

    2013  Volume 210, Issue 12, Page(s) 2693–2706

    Abstract: Adenosine produced as a byproduct of metabolic activity is present in all tissues and produces dose-dependent suppression of TCR signaling. Naive T cell maintenance depends on inhibition of TCR signals by environmental sensors, which are yet to be fully ... ...

    Abstract Adenosine produced as a byproduct of metabolic activity is present in all tissues and produces dose-dependent suppression of TCR signaling. Naive T cell maintenance depends on inhibition of TCR signals by environmental sensors, which are yet to be fully defined. We produced mice with a floxed adenosine A2A receptor (A2AR) gene, Adora2a, and show that either global A2AR deletion or cre-mediated T cell deletion elicits a decline in the number of naive but not memory T cells. A2AR signaling maintains naive T cells in a quiescent state by inhibiting TCR-induced activation of the phosphatidylinositide 3-kinase (PI3K)-AKT pathway, thereby reducing IL-7Rα down-regulation and naive T cell apoptosis. Patterns of IL-7Rα expression on T cells in chimeric mice reconstituted with Adora2a(+/+) and Adora2a(-/-) bone marrow cells suggest that decreased IL-7Rα in naive T cells is a cell-intrinsic consequence of Adora2a deletion. In addition, A2AR expression increases in early thymic T cell development and contributes to progression of double-negative thymic precursors to single-positive thymocytes with increased IL-7Rα expression. Therefore, A2AR signaling regulates T cell development and maintenance to sustain normal numbers of naive T cells in the periphery.
    MeSH term(s) Adenosine/metabolism ; Animals ; Apoptosis ; Cell Differentiation ; Cell Proliferation ; Cell Survival ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Extracellular Space/metabolism ; Female ; Gene Expression Regulation ; Immunologic Memory ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Receptor, Adenosine A2A/deficiency ; Receptor, Adenosine A2A/genetics ; Receptor, Adenosine A2A/metabolism ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Interleukin-7/genetics ; Receptors, Interleukin-7/metabolism ; Signal Transduction ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
    Chemical Substances Receptor, Adenosine A2A ; Receptors, Antigen, T-Cell ; Receptors, Interleukin-7 ; interleukin-7 receptor, alpha chain ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; Adenosine (K72T3FS567)
    Language English
    Publishing date 2013-10-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20130249
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