{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T23:27:03Z","timestamp":1792106823894,"version":"4.4.0"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) are clonal hematological diseases classified as Philadelphia chromosome-negative myeloproliferative neoplasms (MPN). MPN pathogenesis is associated with the presence of somatic driver mutations, bone marrow (BM) niche alterations, and tumor inflammatory status. The relevance of soluble mediators in the pathogenesis of MPN led us to analyze the levels of cytokines, chemokines, and growth factors related to inflammation, angiogenesis and hematopoiesis regulation in the BM niche of MPN patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Soluble mediator levels in BM plasma samples from 17 healthy subjects, 28 ET, 19 PV, and 16 PMF patients were determined using a multiplex assay. Soluble mediator signatures were created from categorical analyses of high mediator producers. Soluble mediator connections and the correlation between plasma levels and clinic-laboratory parameters were also analyzed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The soluble mediator signatures of the BM niche of PV patients revealed a highly inflammatory and pro-angiogenic milieu, with increased levels of chemokines (CCL2, CCL5, CXCL8, CXCL12, CXCL10), and growth factors (GM-CSF M-CSF, HGF, IFN-\u03b3, IL-1\u03b2, IL-6Ra, IL-12, IL-17, IL-18, TNF-\u03b1, VEGF, and VEGF-R2). ET and PMF patients presented intermediate inflammatory and pro-angiogenic profiles. Deregulation of soluble mediators was associated with some clinic-laboratory parameters of MPN patients, including vascular events, treatment <jats:italic>status<\/jats:italic>, risk stratification of disease, hemoglobin concentration, hematocrit, and red blood cell count.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Each MPN subtype exhibits a distinct soluble mediator signature. Deregulated production of BM soluble mediators may contribute to MPN pathogenesis and BM niche modification, provides pro-tumor stimuli, and is a potential target for future therapies.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2021.665037","type":"journal-article","created":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T04:49:02Z","timestamp":1621313342000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":25,"title":["Bone Marrow Soluble Mediator Signatures of Patients With Philadelphia Chromosome-Negative Myeloproliferative Neoplasms"],"prefix":"10.3389","volume":"11","author":[{"given":"Ju\u00e7ara Gastaldi","family":"Cominal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maira da Costa","family":"Cacemiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Gabriela","family":"Berzoti-Coelho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Illy Enne Gomes","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiani Gai","family":"Frantz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth Xisto","family":"Souto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimas Tadeu","family":"Covas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena Lobo de","family":"Figueiredo-Pontes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Carolina","family":"Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelen Cristina Ribeiro","family":"Malmegrim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fab\u00edola Atti\u00e9 de","family":"Castro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-03-643544","article-title":"The 2016 Revision to the World Health Organization Classification of Myeloid Neoplasms and Acute Leukemia","volume":"127","author":"Arber","year":"2016","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-10-695940","article-title":"Genetic Basis and Molecular Pathophysiology of Classical Myeloproliferative Neoplasms","volume":"129","author":"Vainchenker","year":"2017","journal-title":"Blood"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-06-782037","article-title":"Myeloproliferative Neoplasms: From Origins to Outcomes","volume":"130","author":"Nangalia","year":"2017","journal-title":"Blood"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2507","DOI":"10.1182\/blood-2014-05-579136","article-title":"Long-Term Survival and Blast Transformation in Molecularly Annotated Essential Thrombocythemia, Polycythemia Vera, and Myelofibrosis","volume":"124","author":"Tefferi","year":"2014","journal-title":"Blood"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.htct.2019.07.008","article-title":"Clinical and Molecular Profile of a Brazilian Cohort of Patients With Classical BCR-ABL1-negative Myeloproliferative Neoplasms","volume":"42","author":"Porto-Soares","year":"2019","journal-title":"Hematol Transfus Cell Ther"},{"key":"B6","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.jaut.2017.06.010","article-title":"Inflammation and Myeloproliferative Neoplasms","volume":"85","author":"Lussana","year":"2017","journal-title":"J Autoimmun"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2012.10.020","article-title":"Chronic Inflammation as a Promotor of Mutagenesis in Essential Thrombocythemia, Polycythemia Vera and Myelofibrosis. A Human Inflammation Model for Cancer Development","volume":"37","author":"Hasselbalch","year":"2013","journal-title":"Leuk Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2015.02.014","article-title":"Normal and Leukemic Stem Cell Niches: Insights and Therapeutic Opportunities","volume":"16","author":"Schepers","year":"2015","journal-title":"Cell Stem Cell"},{"key":"B9","first-page":"17","article-title":"Biology and Biochemistry of the Chemokines: A Family of Chemotactic and Inflammatory Cytokines","volume":"12","author":"Miller","year":"1992","journal-title":"Crit Rev Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01338","article-title":"A Modular Cytokine Analysis Method Reveals Novel Associations With Clinical Phenotypes and Identifies Sets of Co-Signaling Cytokines Across Influenza Natural Infection Cohorts and Healthy Controls","volume":"10","author":"Cohen","year":"2019","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210758","article-title":"Aberrant Cytokine Signaling in Leukemia","volume":"26","author":"Van Etten","year":"2007","journal-title":"Oncogene"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nature07205","article-title":"Cancer-Related Inflammation","volume":"454","author":"Mantovani","year":"2008","journal-title":"Nature"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.htct.2017.12.003","article-title":"Philadelphia-Negative Myeloproliferative Neoplasms as Disorders Marked by Cytokine Modulation","volume":"40","author":"Cacemiro M da","year":"2018","journal-title":"Hematol Transfus Cell Ther"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2013.09.001","article-title":"Increased Prevalence of Autoimmune Phenomena in Myelofibrosis: Relationship With Clinical and Morphological Characteristics, and With Immunoregulatory Cytokine Patterns","volume":"37","author":"Barcellini","year":"2013","journal-title":"Leuk Res"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.26008","article-title":"Polycythemia Vera and Essential Thrombocythemia: 2021 Update on Diagnosis, Risk-Stratification and Management","volume":"95","author":"Tefferi","year":"2020","journal-title":"Am J Hematol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.24293","article-title":"Validation of the Revised International Prognostic Score of Thrombosis for Essential Thrombocythemia (IPSET-Thrombosis) in 585 Mayo Clinic Patients: Validation of the Revised Ipset-Thrombosis","volume":"91","author":"Haider","year":"2016","journal-title":"Am J Hematol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.32.2446","article-title":"Dipss Plus: A Refined Dynamic International Prognostic Scoring System for Primary Myelofibrosis That Incorporates Prognostic Information From Karyotype, Platelet Count, and Transfusion Status","volume":"29","author":"Gangat","year":"2011","journal-title":"J Clin Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.2008.02167.x","article-title":"Strategy to Assess the Overall Cytokine Profile of Circulating Leukocytes and its Association With Distinct Clinical Forms of Human Chagas Disease","volume":"68","author":"Vitelli-Avelar","year":"2008","journal-title":"Scand J Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jir439","article-title":"Cytokine Signatures of Innate and Adaptive Immunity in 17DD Yellow Fever Vaccinated Children and its Association With the Level of Neutralizing Antibody","volume":"204","author":"Luiza-Silva","year":"2011","journal-title":"J Infect Dis"},{"key":"B21","doi-asserted-by":"publisher","first-page":"2136","DOI":"10.3390\/cells9092136","article-title":"Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants","volume":"9","author":"Masselli","year":"2020","journal-title":"Cells"},{"key":"B22","doi-asserted-by":"publisher","first-page":"869242","DOI":"10.1155\/2015\/869242","article-title":"Cytokine Regulation of Microenvironmental Cells in Myeloproliferative Neoplasms","volume":"2015","author":"Hoermann","year":"2015","journal-title":"Mediators Inflamm"},{"key":"B23","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/S0145-2126(02)00268-0","article-title":"Bone Marrow Immunohistochemical Studies of Angiogenic Cytokines and Their Receptors in Myelofibrosis With Myeloid Metaplasia","volume":"27","author":"Chou","year":"2003","journal-title":"Leuk Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64511-7","article-title":"Bone Marrow in Polycythemia Vera, Chronic Myelocytic Leukemia, and Myelofibrosis has an Increased Vascularity","volume":"157","author":"Lundberg","year":"2000","journal-title":"Am J Pathol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S253255","article-title":"Cytokineexplore: An Online Tool for Statistical Analysis of Cytokine Concentration Datasets","volume":"13","author":"Kassem","year":"2020","journal-title":"J Inflamm Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0557-0","article-title":"Cytokines in the Balance","volume":"20","year":"2019","journal-title":"Nat Immunol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2015\/145293","article-title":"Pathogenesis of Myeloproliferative Neoplasms: Role and Mechanisms of Chronic Inflammation","volume":"2015","author":"Hermouet","year":"2015","journal-title":"Mediators Inflamm"},{"key":"B28","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1038\/onc.2010.479","article-title":"Anti-Inflammatory Cytokines Hepatocyte Growth Factor and interleukin-11 are Over-Expressed in Polycythemia Vera and Contribute to the Growth of Clonal Erythroblasts Independently of JAK2V617F","volume":"30","author":"Boissinot","year":"2011","journal-title":"Oncogene"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2014.01.006","article-title":"Cytokine Profiles in Polycythemia Vera and Essential Thrombocythemia Patients: Clinical Implications","volume":"42","author":"Pourcelot","year":"2014","journal-title":"Exp Hematol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"e0216810","DOI":"10.1371\/journal.pone.0216810","article-title":"Gene Expression Profiling Distinguishes Prefibrotic From Overtly Fibrotic Myeloproliferative Neoplasms and Identifies Disease Subsets With Distinct Inflammatory Signatures","volume":"14","author":"Wong","year":"2019","journal-title":"PloS One"},{"key":"B31","doi-asserted-by":"publisher","first-page":"e371","DOI":"10.1097\/HS9.0000000000000371","article-title":"Longitudinal Cytokine Profiling Identifies Gro-\u03b1 and EGF as Potential Biomarkers of Disease Progression in Essential Thrombocythemia","volume":"4","author":"\u00d8bro","year":"2020","journal-title":"HemaSphere"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1785021","DOI":"10.1155\/2016\/1785021","article-title":"Generation of Soluble Interleukin-11 and Interleukin-6 Receptors: A Crucial Function for Proteases During Inflammation","volume":"2016","author":"Lokau","year":"2016","journal-title":"Mediators Inflamm"},{"key":"B33","doi-asserted-by":"publisher","first-page":"100280","DOI":"10.1016\/j.eclinm.2020.100280","article-title":"Loss-of-Function Polymorphism in IL6R Reduces Risk of JAK2V617F Somatic Mutation and Myeloproliferative Neoplasm: A Mendelian Randomization Study","volume":"21","author":"Pedersen","year":"2020","journal-title":"EClinicalMedicine"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020002683","article-title":"The Transition of M-CSF\u2013derived Human Macrophages to a Growth-Promoting Phenotype","volume":"4","author":"Hamidzadeh","year":"2020","journal-title":"Blood Adv"},{"key":"B35","doi-asserted-by":"publisher","first-page":"e333","DOI":"10.1097\/HS9.0000000000000333","article-title":"Mutant Calreticulin in the Myeloproliferative Neoplasms","volume":"4","author":"Prins","year":"2020","journal-title":"Hemasphere"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.23295","article-title":"Plasma Cytokines in Polycythemia Vera: Phenotypic Correlates, Prognostic Relevance, and Comparison With Myelofibrosis","volume":"87","author":"Vaidya","year":"2012","journal-title":"Am J Hematol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.32.9490","article-title":"Circulating Interleukin (IL)-8, IL-2R, Il-12, and IL-15 Levels are Independently Prognostic in Primary Myelofibrosis: A Comprehensive Cytokine Profiling Study","volume":"29","author":"Tefferi","year":"2011","journal-title":"J Clin Oncol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2015\/670580","article-title":"Circulating Cytokine Levels as Markers of Inflammation in Philadelphia Negative Myeloproliferative Neoplasms: Diagnostic and Prognostic Interest","volume":"2015","author":"Mondet","year":"2015","journal-title":"Mediators Inflamm"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.11.010","article-title":"The Interleukin-1 Family: Back to the Future","volume":"39","author":"Garlanda","year":"2013","journal-title":"Immunity"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201303286","article-title":"Interleukin-18 Produced by Bone Marrow-Derived Stromal Cells Supports T -Cell Acute Leukaemia Progression","volume":"6","author":"Uzan","year":"2014","journal-title":"EMBO Mol Med"},{"key":"B41","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1016\/j.ccell.2018.02.007","article-title":"Dysregulated IL-18 is a Key Driver of Immunosuppression and a Possible Therapeutic Target in the Multiple Myeloma Microenvironment","volume":"33","author":"Nakamura","year":"2018","journal-title":"Cancer Cell"},{"key":"B42","doi-asserted-by":"publisher","first-page":"108756","DOI":"10.1016\/j.biopha.2019.108756","article-title":"Interleukin-18 Promotes Fibroblast Senescence in Pulmonary Fibrosis Through Down-Regulating Klotho Expression","volume":"113","author":"Zhang","year":"2019","journal-title":"Biomed Pharmacother"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehx261","article-title":"Il-18 Cleavage Triggers Cardiac Inflammation and Fibrosis Upon \u03b2-Adrenergic Insult","volume":"39","author":"Xiao","year":"2018","journal-title":"Eur Heart J"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-08-661785","article-title":"CXCR2 and CXCL4 Regulate Survival and Self-Renewal of Hematopoietic Stem\/Progenitor Cells","volume":"128","author":"Sinclair","year":"2016","journal-title":"Blood"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1634\/stemcells.2007-0250","article-title":"Transcriptional Analysis of Quiescent and Proliferating CD34+ Human Hemopoietic Cells From Normal and Chronic Myeloid Leukemia Sources","volume":"25","author":"Graham","year":"2007","journal-title":"Stem Cells"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvn029","article-title":"Understanding the Immunoangiostatic CXC Chemokine Network","volume":"78","author":"Balestrieri","year":"2008","journal-title":"Cardiovasc Res"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201801931R","article-title":"CXCL8 Derived From Mesenchymal Stromal Cells Supports Survival and Proliferation of Acute Myeloid Leukemia Cells Through the PI3K\/AKT Pathway","volume":"33","author":"Cheng","year":"2019","journal-title":"FASEB J"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-12-4415","article-title":"IL-8 and its CXCR1 and CXCR2 Receptors Participate in the Control of Megakaryocytic Proliferation, Differentiation, and Ploidy in Myeloid Metaplasia With Myelofibrosis","volume":"105","author":"Emadi","year":"2005","journal-title":"Blood"},{"key":"B49","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1182\/blood-2020-138843","article-title":"Increased Interleukin-8 (Il8)-Cxcr2 Signaling Promotes Progression of Bone Marrow Fibrosis in Myeloproliferative Neoplasms","volume":"136","author":"Dunbar","year":"2020","journal-title":"Blood"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1824","DOI":"10.3390\/ijms18081824","article-title":"Chemokines as a Conductor of Bone Marrow Microenvironment in Chronic Myeloid Leukemia","volume":"18","author":"Mukaida","year":"2017","journal-title":"Int J Mol Sci"},{"key":"B51","doi-asserted-by":"publisher","first-page":"100005","DOI":"10.1016\/j.cytox.2019.100005","article-title":"Cytokines Frequently Implicated in Myeloproliferative Neoplasms","volume":"1","author":"Wang","year":"2019","journal-title":"Cytokine X"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/12.2.151","article-title":"Il-12 Synergizes With IL-18 or IL-1beta for IFN-gamma Production From Human T Cells","volume":"12","author":"Tominaga","year":"2000","journal-title":"Int Immunol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1002\/art.11143","article-title":"Anti-Interleukin-6 Receptor Antibody Therapy Reduces Vascular Endothelial Growth Factor Production in Rheumatoid Arthritis","volume":"48","author":"Nakahara","year":"2003","journal-title":"Arthritis Rheumatol"},{"key":"B54","article-title":"Synergistic Effects Between GM-CSF and G-CSF or M-CSF on Highly Enriched Human Marrow Progenitor Cells","volume":"4","author":"Bot","year":"1990","journal-title":"Leukemia"},{"key":"B55","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2014\/590654","article-title":"Regulation of Chemokine Ccl5 Synthesis in Human Peritoneal Fibroblasts: A Key Role of IFN- \u03b3","volume":"2014","author":"Kawka","year":"2014","journal-title":"Mediators Inflamm"},{"key":"B56","doi-asserted-by":"publisher","first-page":"107602961989511","DOI":"10.1177\/1076029619895111","article-title":"Effect of Hydroxyurea Treatment on the Inflammatory Markers Among Children With Sickle Cell Disease","volume":"26","author":"Zahran","year":"2020","journal-title":"Clin Appl Thromb Hemost"},{"key":"B57","doi-asserted-by":"publisher","first-page":"14829","DOI":"10.1038\/s41598-019-51339-x","article-title":"Hydroxyurea Alters Circulating Monocyte Subsets and Dampens its Inflammatory Potential in Sickle Cell Anemia Patients","volume":"9","author":"Guarda","year":"2019","journal-title":"Sci Rep"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-03-460154","article-title":"Myeloproliferative Neoplasms and Thrombosis","volume":"122","author":"Barbui","year":"2013","journal-title":"Blood"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-010-0596-7","article-title":"Circulating Endothelial Cells in Essential Thrombocythemia and Polycythemia Vera: Correlation With JAK2-V617F Mutational Status, Angiogenic Factors and Coagulation Activation Markers","volume":"91","author":"Treli\u0144ski","year":"2010","journal-title":"Int J Hematol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00373","article-title":"MIF and CXCL12 in Cardiovascular Diseases: Functional Differences and Similarities","volume":"6","author":"van der Vorst","year":"2015","journal-title":"Front Immunol"},{"key":"B61","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1186\/1742-2094-9-235","article-title":"Polymorphism of Tumor Necrosis Factor Alpha (TNF-Alpha) Gene Promoter, Circulating TNF-alpha Level, and Cardiovascular Risk Factor for Ischemic Stroke","volume":"9","author":"Cui","year":"2012","journal-title":"J Neuroinflammation"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.665037\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T04:49:06Z","timestamp":1621313346000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.665037\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,18]]},"references-count":61,"alternative-id":["10.3389\/fonc.2021.665037"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2021.665037","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,18]]},"article-number":"665037"}}