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  1. Article ; Online: Blood-based biomarkers in patients with non-small cell lung cancer treated with immune checkpoint blockade.

    Tsai, Yo-Ting / Schlom, Jeffrey / Donahue, Renee N

    Journal of experimental & clinical cancer research : CR

    2024  Volume 43, Issue 1, Page(s) 82

    Abstract: The paradigm of non-small cell lung cancer (NSCLC) treatment has been profoundly influenced by the development of immune checkpoint inhibitors (ICI), but the range of clinical responses observed among patients poses significant challenges. To date, ... ...

    Abstract The paradigm of non-small cell lung cancer (NSCLC) treatment has been profoundly influenced by the development of immune checkpoint inhibitors (ICI), but the range of clinical responses observed among patients poses significant challenges. To date, analyses of tumor biopsies are the only parameter used to guide prognosis to ICI therapy. Tumor biopsies, however, are often difficult to obtain and tissue-based biomarkers are limited by intratumoral heterogeneity and temporal variability. In response, there has been a growing emphasis on the development of "liquid biopsy"‒ derived biomarkers, which offer a minimally invasive means to dynamically monitor the immune status of NSCLC patients either before and/or during the course of treatment. Here we review studies in which multiple blood-based biomarkers encompassing circulating soluble analytes, immune cell subsets, circulating tumor DNA, blood-based tumor mutational burden, and circulating tumor cells have shown promising associations with the clinical response of NSCLC patients to ICI therapy. These investigations have unveiled compelling correlations between the peripheral immune status of patients both before and during ICI therapy and patient outcomes, which include response rates, progression-free survival, and overall survival. There is need for rigorous validation and standardization of these blood-based assays for broader clinical application. Integration of multiple blood-based biomarkers into comprehensive panels or algorithms also has the potential to enhance predictive accuracy. Further research aimed at longitudinal monitoring of circulating biomarkers is also crucial to comprehend immune dynamics and resistance mechanisms and should be used alongside tissue-based methods that interrogate the tumor microenvironment to guide treatment decisions and may inform on the development of novel therapeutic strategies. The data reviewed here reinforce the opportunity to refine patient stratification, optimize treatments, and improve outcomes not only in NSCLC but also in the wider spectrum of solid tumors undergoing immunotherapy.
    MeSH term(s) Humans ; Carcinoma, Non-Small-Cell Lung/pathology ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Lung Neoplasms/genetics ; Biomarkers, Tumor/genetics ; Prognosis ; Tumor Microenvironment
    Chemical Substances Immune Checkpoint Inhibitors ; Biomarkers, Tumor
    Language English
    Publishing date 2024-03-16
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 803138-1
    ISSN 1756-9966 ; 0392-9078
    ISSN (online) 1756-9966
    ISSN 0392-9078
    DOI 10.1186/s13046-024-02969-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Phosphoflow cytometry to assess cytokine signaling pathways in peripheral immune cells: potential for inferring immune cell function and treatment response in patients with solid tumors.

    Toney, Nicole J / Schlom, Jeffrey / Donahue, Renee N

    Journal of experimental & clinical cancer research : CR

    2023  Volume 42, Issue 1, Page(s) 247

    Abstract: Tumor biopsy is often not available or difficult to obtain in patients with solid tumors. Investigation of the peripheral immune system allows for in-depth and dynamic profiling of patient immune response prior to and over the course of treatment and ... ...

    Abstract Tumor biopsy is often not available or difficult to obtain in patients with solid tumors. Investigation of the peripheral immune system allows for in-depth and dynamic profiling of patient immune response prior to and over the course of treatment and disease. Phosphoflow cytometry is a flow cytometry‒based method to detect levels of phosphorylated proteins in single cells. This method can be applied to peripheral immune cells to determine responsiveness of signaling pathways in specific immune subsets to cytokine stimulation, improving on simply defining numbers of populations of cells based on cell surface markers. Here, we review studies using phosphoflow cytometry to (a) investigate signaling pathways in cancer patients' peripheral immune cells compared with healthy donors, (b) compare immune cell function in peripheral immune cells with the tumor microenvironment, (c) determine the effects of agents on the immune system, and (d) predict cancer patient response to treatment and outcome. In addition, we explore the use and potential of phosphoflow cytometry in preclinical cancer models. We believe this review is the first to provide a comprehensive summary of how phosphoflow cytometry can be applied in the field of cancer immunology, and demonstrates that this approach holds promise in exploring the mechanisms of response or resistance to immunotherapy both prior to and during the course of treatment. Additionally, it can help identify potential therapeutic avenues that can restore normal immune cell function and improve cancer patient outcome.
    MeSH term(s) Humans ; Immunotherapy ; Neoplasms/therapy ; Biopsy ; Cytokines ; Signal Transduction ; Tumor Microenvironment
    Chemical Substances Cytokines
    Language English
    Publishing date 2023-09-23
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 803138-1
    ISSN 1756-9966 ; 0392-9078
    ISSN (online) 1756-9966
    ISSN 0392-9078
    DOI 10.1186/s13046-023-02802-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The Importance of Cellular Immunity in the Development of Vaccines and Therapeutics for COVID-19.

    Schlom, Jeffrey / Donahue, Renee N

    The Journal of infectious diseases

    2020  Volume 222, Issue 9, Page(s) 1435–1438

    Abstract: It is important to develop vaccines that can also mediate T-cell responses to SARS-CoV-2 to limit severity of infections, and to analyze the cellular immunome in the use of anti-SARS-CoV-2 therapeutics. ...

    Abstract It is important to develop vaccines that can also mediate T-cell responses to SARS-CoV-2 to limit severity of infections, and to analyze the cellular immunome in the use of anti-SARS-CoV-2 therapeutics.
    MeSH term(s) Aging/immunology ; Antigens, CD/blood ; Betacoronavirus/immunology ; COVID-19 ; COVID-19 Vaccines ; Coronavirus Infections/drug therapy ; Coronavirus Infections/immunology ; Coronavirus Infections/prevention & control ; Drug Development ; Flow Cytometry ; Humans ; Immunity, Cellular ; Leukocytes, Mononuclear/immunology ; Pandemics/prevention & control ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/immunology ; Pneumonia, Viral/prevention & control ; SARS-CoV-2 ; Viral Vaccines
    Chemical Substances Antigens, CD ; COVID-19 Vaccines ; Viral Vaccines
    Keywords covid19
    Language English
    Publishing date 2020-07-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 3019-3
    ISSN 1537-6613 ; 0022-1899
    ISSN (online) 1537-6613
    ISSN 0022-1899
    DOI 10.1093/infdis/jiaa415
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: The Importance of Cellular Immunity in the Development of Vaccines and Therapeutics for COVID-19

    Schlom, Jeffrey / Donahue, Renee N

    J Infect Dis

    Abstract: It is important to develop vaccines that can also mediate T-cell responses to SARS-CoV-2 to limit severity of infections, and to analyze the cellular immunome in the use of anti-SARS-CoV-2 therapeutics. ...

    Abstract It is important to develop vaccines that can also mediate T-cell responses to SARS-CoV-2 to limit severity of infections, and to analyze the cellular immunome in the use of anti-SARS-CoV-2 therapeutics.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #639019
    Database COVID19

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  5. Article ; Online: The Importance of Cellular Immunity in the Development of Vaccines and Therapeutics for COVID-19

    Schlom, Jeffrey / Donahue, Renee N

    The Journal of Infectious Diseases

    2020  Volume 222, Issue 9, Page(s) 1435–1438

    Abstract: Abstract It is important to develop vaccines that can also mediate T-cell responses to SARS-CoV-2 to limit severity of infections, and to analyze the cellular immunome in the use of anti-SARS-CoV-2 therapeutics. ...

    Abstract Abstract It is important to develop vaccines that can also mediate T-cell responses to SARS-CoV-2 to limit severity of infections, and to analyze the cellular immunome in the use of anti-SARS-CoV-2 therapeutics.
    Keywords Immunology and Allergy ; Infectious Diseases ; covid19
    Language English
    Publisher Oxford University Press (OUP)
    Publishing country uk
    Document type Article ; Online
    ZDB-ID 3019-3
    ISSN 1537-6613 ; 0022-1899
    ISSN (online) 1537-6613
    ISSN 0022-1899
    DOI 10.1093/infdis/jiaa415
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Immune correlates with response in patients with metastatic solid tumors treated with a tumor targeting immunocytokine NHS-IL12.

    Toney, Nicole J / Gatti-Mays, Margaret E / Tschernia, Nicholas P / Strauss, Julius / Gulley, James L / Schlom, Jeffrey / Donahue, Renee N

    International immunopharmacology

    2023  Volume 116

    Abstract: The immunocytokine NHS-IL12 delivers IL-12 to the tumor microenvironment by targeting DNA/histones in necrotic areas. The first-in-human clinical trial administered NHS-IL12 subcutaneously in 59 patients treated every four weeks (Q4W), with a maximum ... ...

    Abstract The immunocytokine NHS-IL12 delivers IL-12 to the tumor microenvironment by targeting DNA/histones in necrotic areas. The first-in-human clinical trial administered NHS-IL12 subcutaneously in 59 patients treated every four weeks (Q4W), with a maximum tolerated dose of 16.8 mcg/kg. The phase I study was expanded to include a high-exposure cohort that received bi-weekly treatment (Q2W) with two dose levels of NHS-IL12: 12.0 mcg/kg and 16.8 mcg/kg. Here, patients given NHS-IL12 were analyzed both prior to and early after treatment for effects on 10 serum soluble analytes, complete blood counts, and 158 peripheral immune subsets. Higher levels of immune activation were seen with a dose of 16.8 mcg/kg versus 12.0 mcg/kg in patients in the high-exposure cohort, as evidenced by greater increases in serum IFNγ, TNFα, and soluble PD-1, and greater increases in frequencies of peripheral ki67
    MeSH term(s) Humans ; Ki-67 Antigen ; State Medicine ; Interleukin-12 ; Neoplasms/drug therapy ; Killer Cells, Natural ; Tumor Microenvironment
    Chemical Substances Ki-67 Antigen ; Interleukin-12 (187348-17-0)
    Language English
    Publishing date 2023-02-16
    Publishing country Netherlands
    Document type Clinical Trial, Phase I ; Journal Article
    ZDB-ID 2043785-7
    ISSN 1878-1705 ; 1567-5769
    ISSN (online) 1878-1705
    ISSN 1567-5769
    DOI 10.1016/j.intimp.2023.109736
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Efficacy, safety, and biomarker analyses of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with advanced non-small cell lung cancer.

    Rajan, Arun / Abdul Sater, Houssein / Rahma, Osama / Agajanian, Richy / Lassoued, Wiem / Marté, Jennifer L / Tsai, Yo-Ting / Donahue, Renee N / Lamping, Elizabeth / Bailey, Shania / Weisman, Andrew / Walter-Rodriguez, Beatriz / Ito, Rena / Vugmeyster, Yulia / Sato, Masashi / Machl, Andreas / Schlom, Jeffrey / Gulley, James L

    Journal for immunotherapy of cancer

    2024  Volume 12, Issue 3

    Abstract: ... with stage IIIb/IV NSCLC who were either immune checkpoint inhibitor (ICI)-naïve (n=18) or ICI-experienced (n ... 23) were enrolled. The primary endpoint was the best overall response. Paired biopsies (n=9/41) and ... peripheral blood (n=14/41) pretreatment and on-treatment were studied to determine the immunological effects ...

    Abstract Background: Bintrafusp alfa, a first-in-class bifunctional fusion protein targeting transforming growth factor-β (TGF-β) and programmed cell death ligand 1, has demonstrated encouraging efficacy as second-line treatment in patients with non-small cell lung cancer (NSCLC) in a dose expansion cohort of the phase 1, open-label clinical trial (NCT02517398). Here, we report the safety, efficacy, and biomarker analysis of bintrafusp alfa in a second expansion cohort of the same trial (biomarker cohort).
    Methods: Patients with stage IIIb/IV NSCLC who were either immune checkpoint inhibitor (ICI)-naïve (n=18) or ICI-experienced (n=23) were enrolled. The primary endpoint was the best overall response. Paired biopsies (n=9/41) and peripheral blood (n=14/41) pretreatment and on-treatment were studied to determine the immunological effects of treatment and for associations with clinical activity.
    Results: Per independent review committee assessment, objective responses were observed in the ICI-naïve group (overall response rate, 27.8%). No new or unexpected safety signals were identified. Circulating TGF-β levels were reduced (>97%; p<0.001) 2 weeks after initiation of treatment with bintrafusp alfa and remained reduced up to 12 weeks. Increases in lymphocytes and tumor-associated macrophages (TAMs) were observed in on-treatment biospies, with an increase in the M2 (tumor trophic TAMs)/M1 (inflammatory TAMs) ratio associated with poor outcomes. Specific peripheral immune analytes at baseline and early changes after treatment were associated with clinical response.
    Conclusions: Bintrafusp alfa was observed to have modest clinical activity and manageable safety, and was associated with notable immunologic changes involving modulation of the tumor immune microenvironment in patients with advanced NSCLC.
    MeSH term(s) Humans ; Carcinoma, Non-Small-Cell Lung/pathology ; Lung Neoplasms/pathology ; B7-H1 Antigen ; Immunologic Factors/therapeutic use ; Immunotherapy ; Tumor Microenvironment
    Chemical Substances B7-H1 Antigen ; Immunologic Factors
    Language English
    Publishing date 2024-03-13
    Publishing country England
    Document type Clinical Trial, Phase I ; Journal Article
    ZDB-ID 2719863-7
    ISSN 2051-1426 ; 2051-1426
    ISSN (online) 2051-1426
    ISSN 2051-1426
    DOI 10.1136/jitc-2023-008480
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Immune correlates of clinical parameters in patients with HPV-associated malignancies treated with bintrafusp alfa.

    Tsai, Yo-Ting / Strauss, Julius / Toney, Nicole J / Jochems, Caroline / Venzon, David J / Gulley, James L / Schlom, Jeffrey / Donahue, Renee N

    Journal for immunotherapy of cancer

    2022  Volume 10, Issue 4

    Abstract: ... Patients and methods: The peripheral immunome of patients (n=65) with HPV: Results: Interrogation ...

    Abstract Purpose: Bintrafusp alfa is a bifunctional agent consisting of an anti-human PD-L1 antibody linked to two TGFβRII. It is designed to act both as a checkpoint inhibitor and to 'trap' TGFβ in the tumor microenvironment. Phase I and II clinical studies demonstrated clinical activity in patients with a range of human papillomavirus (HPV)-associated cancers. The purpose of the studies reported here was the interrogation of various aspects of the peripheral immunome in patients with HPV-associated cancers, both prior to and early in the treatment regimen of bintrafusp alfa to better understand the mode of action of the agent and to help define which patients are more likely to benefit from bintrafusp alfa treatment.
    Patients and methods: The peripheral immunome of patients (n=65) with HPV
    Results: Interrogation of the peripheral immunome prior to bintrafusp alfa treatment revealed several factors that associated with clinical response, including (1) higher levels of sCD27:sCD40L ratios, (2) lower levels of TGFβ1 and 12 additional factors associated with tumor mesenchymalization, and (3) higher CD8
    Conclusions: These studies add insight into the mechanism of action of bintrafusp alfa and provide evidence that the interrogation of both cellular and soluble components of the peripheral immunome of patients with HPV-associated malignancies, either prior to or early in the therapeutic regimen, can provide information as to which patients are more likely to benefit with bintrafusp alfa therapy.
    MeSH term(s) Alphapapillomavirus ; CD8-Positive T-Lymphocytes/pathology ; Humans ; Immunologic Factors/therapeutic use ; Neoplasms/drug therapy ; Papillomaviridae ; Papillomavirus Infections/complications ; Papillomavirus Infections/drug therapy ; Papillomavirus Infections/pathology ; Tumor Microenvironment
    Chemical Substances Immunologic Factors
    Language English
    Publishing date 2022-04-13
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2719863-7
    ISSN 2051-1426 ; 2051-1426
    ISSN (online) 2051-1426
    ISSN 2051-1426
    DOI 10.1136/jitc-2022-004601
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Phase 1 trial of CV301 in combination with anti-PD-1 therapy in nonsquamous non-small cell lung cancer.

    Rajan, Arun / Gray, Jhanelle E / Devarakonda, Siddhartha / Birhiray, Ruemu / Korchin, Borys / Menius, Erika / Donahue, Renee N / Schlom, Jeffrey / Gulley, James L

    International journal of cancer

    2022  Volume 152, Issue 3, Page(s) 447–457

    Abstract: CV301, a poxviral-based vaccine, has been evaluated in a phase 1 clinical trial (NCT02840994) and shown to be safe and immunologically active (phase 1a). Preclinical data support a combination of CV301 with programmed death-1 inhibitors, which has been ... ...

    Abstract CV301, a poxviral-based vaccine, has been evaluated in a phase 1 clinical trial (NCT02840994) and shown to be safe and immunologically active (phase 1a). Preclinical data support a combination of CV301 with programmed death-1 inhibitors, which has been evaluated in the phase 1b part of this trial and is reported here. Patients with advanced nonsquamous non-small cell lung cancer (NSCLC) without actionable genomic alterations received two priming doses of modified vaccinia Ankara-BN-CV301 (MVA) 4 weeks apart, followed by boosting doses of fowlpox-CV301 (FPV) at increasing time intervals for a maximum of 17 doses in combination with nivolumab for cohort 1 (C1) and 15 doses in combination with pembrolizumab for cohort 2 (C2). The primary objective was evaluation of safety and tolerability. Between October 2017 and September 14, 2018, patients were enrolled (C1: 4; median age: 64 years). Mean treatment duration was 332 days in C1 and 289 days in C2. CTCAE ≥grade 3 adverse events (AEs) were observed in four (100%) patients in C1 and three (37.5%) patients in C2. There was one death on trial. Immune-related AEs (irAEs) fulfilling criteria for a dose-limiting toxicity included 1 case of pneumonitis. Among 11 evaluable patients, 1 (9%) had a complete response, 1 (9%) had a partial response and 9 (82%) had stable disease. We conclude that CV301 administered with PD-1 inhibitors is safe and clinically active in patients with advanced NSCLC. The frequency or severity of AEs is not increased, including irAEs for each component of the combination.
    MeSH term(s) Humans ; Middle Aged ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/metabolism ; Drug Therapy, Combination/adverse effects ; Lung Neoplasms/drug therapy ; Lung Neoplasms/metabolism ; Nivolumab/therapeutic use
    Chemical Substances Nivolumab (31YO63LBSN)
    Language English
    Publishing date 2022-09-09
    Publishing country United States
    Document type Clinical Trial, Phase I ; Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218257-9
    ISSN 1097-0215 ; 0020-7136
    ISSN (online) 1097-0215
    ISSN 0020-7136
    DOI 10.1002/ijc.34267
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Early changes in immune cell subsets with corticosteroids in patients with solid tumors: implications for COVID-19 management.

    Marté, Jennifer L / Toney, Nicole J / Cordes, Lisa / Schlom, Jeffrey / Donahue, Renee N / Gulley, James L

    Journal for immunotherapy of cancer

    2020  Volume 8, Issue 2

    Abstract: ... Patients (n=48) with a variety of solid tumors received prednisone, methylprednisolone, or dexamethasone ...

    Abstract Background: The risk-benefit calculation for corticosteroid administration in the management of COVID-19 is complex and urgently requires data to inform the decision. The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation associated with poor prognosis in both COVID-19 and cancer. Investigating NLR as an inflammatory marker and lymphocyte levels as a critical component of antiviral immunity may inform the dilemma of reducing toxic hyperinflammation while still maintaining effective antiviral responses.
    Methods: We performed a retrospective analysis of NLR, absolute neutrophil counts (ANCs) and absolute lymphocyte counts (ALCs) in patients with cancer enrolled in immunotherapy trials who received moderate-dose to high-dose corticosteroids. We compared paired presteroid and available poststeroid initiation values daily during week 1 and again on day 14 using the Wilcoxon signed-rank test. Associated immune subsets by flow cytometry were included where available.
    Results: Patients (n=48) with a variety of solid tumors received prednisone, methylprednisolone, or dexamethasone alone or in combination in doses ranging from 20 to 190 mg/24 hours (prednisone equivalent). The median NLR prior to steroid administration was elevated at 5.0 (range: 0.9-61.2). The corresponding median ANC was 5.1 K/µL (range: 2.03-22.31 K/µL) and ALC was 1.03 K/µL (0.15-2.57 K/µL). One day after steroid administration, there was a significant transient drop in median ALC to 0.54 K/µL (p=0.0243), driving an increase in NLR (median 10.8, p=0.0306). Relative lymphopenia persisted through day 14 but was no longer statistically significant. ANC increased steadily over time, becoming significant at day 4 (median: 7.31 K/µL, p=0.0171) and remaining significantly elevated through day 14. NLR was consistently elevated after steroid initiation, significantly at days 1, 7 (median: 8.2, p=0.0272), and 14 (median: 15.0, p=0.0018). Flow cytometry data from 11 patients showed significant decreases in activated CD4 cells and effector memory CD8 cells.
    Conclusions: The early drop in ALC with persistent lymphopenia as well as the prolonged ANC elevation seen in response to corticosteroid administration are similar to trends associated with increased mortality in several coronavirus studies to include the current SARS-CoV-2 pandemic. The affected subsets are essential for effective antiviral immunity. This may have implications for glucocorticoid therapy for COVID-19.
    MeSH term(s) Adrenal Cortex Hormones/administration & dosage ; Adult ; Aged ; CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/virology ; COVID-19/complications ; COVID-19/drug therapy ; COVID-19/pathology ; COVID-19/virology ; Female ; Humans ; Immunotherapy/adverse effects ; Inflammation/drug therapy ; Inflammation/immunology ; Inflammation/pathology ; Inflammation/virology ; Lymphocyte Count ; Lymphocytes/immunology ; Lymphocytes/virology ; Male ; Middle Aged ; Neoplasms/blood ; Neoplasms/complications ; Neoplasms/pathology ; Neoplasms/therapy ; Neutrophils/immunology ; Neutrophils/virology ; Pandemics ; Risk Assessment ; SARS-CoV-2/pathogenicity
    Chemical Substances Adrenal Cortex Hormones
    Language English
    Publishing date 2020-11-20
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 2719863-7
    ISSN 2051-1426 ; 2051-1426
    ISSN (online) 2051-1426
    ISSN 2051-1426
    DOI 10.1136/jitc-2020-001019
    Database MEDical Literature Analysis and Retrieval System OnLINE

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