{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T05:45:19Z","timestamp":1791870319786,"version":"4.3.4"},"reference-count":62,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,12,13]],"date-time":"2019-12-13T00:00:00Z","timestamp":1576195200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>In the last decades CD38 has emerged as an attractive target for multiple myeloma (MM). CD38 is a novel multifunctional glycoprotein that acts as a receptor, adhesion molecule interacting with CD31 and as an ectoenzyme. As an ectoenzyme, CD38 functions as a metabolic sensor catalyzing the extracellular conversion of NAD+ to the immunosuppressive factor adenosine (ADO). Other ectoenzymes, CD73 and CD203a, together with CD38, are also involved in the alternative axis of extracellular production of ADO, bypassing the canonical pathway mediated by CD39. CD38 is ubiquitously expressed in the bone marrow microenvironment; however, only MM cells display a very high surface density, which lead to the development of several anti-CD38 monoclonal antibodies (mAbs). The efficacy of anti-CD38 mAbs depends from the presence of CD38 on the surface of MM and immune-microenvironment cells. Interestingly, it has been reported that several drugs like lenalidomide, panobinostat, the all-trans retinoic acid and the DNA methyltransferase inhibitors may increase the expression of CD38. Hence, the possibility to modulate CD38 by increasing its expression on MM cells is the pre-requisite to potentiate the clinical efficacy of the anti-CD38 mAbs and to design clinical trials with the combination of anti-CD38 mAbs and these drugs.<\/jats:p>","DOI":"10.3390\/cells8121632","type":"journal-article","created":{"date-parts":[[2019,12,13]],"date-time":"2019-12-13T11:27:22Z","timestamp":1576236442000},"page":"1632","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["CD38 Expression by Myeloma Cells and Its Role in the Context of Bone Marrow Microenvironment: Modulation by Therapeutic Agents"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1742-9212","authenticated-orcid":false,"given":"Federica","family":"Costa","sequence":"first","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedetta","family":"Dalla Palma","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"},{"name":"Hematology, \u201cAzienda Ospedaliero-Universitaria di Parma\u201d, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3457-3774","authenticated-orcid":false,"given":"Nicola","family":"Giuliani","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"},{"name":"Hematology, \u201cAzienda Ospedaliero-Universitaria di Parma\u201d, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"xi","DOI":"10.1016\/j.hoc.2014.08.001","article-title":"Multiple myeloma","volume":"28","author":"Anderson","year":"2014","journal-title":"Hematol. Oncol. Clin. North. Am."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"99","DOI":"10.2119\/molmed.2013.00009","article-title":"Anti-CD38 antibody therapy: Windows of opportunity yielded by the functional characteristics of the target molecule","volume":"19","author":"Chillemi","year":"2013","journal-title":"Mol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1016\/S0140-6736(15)01120-4","article-title":"Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): An open-label, randomised, phase 2 trial","volume":"387","author":"Lonial","year":"2016","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1080\/1744666X.2018.1443809","article-title":"CD38-targeting antibodies in multiple myeloma: Mechanisms of action and clinical experience","volume":"14","author":"Frerichs","year":"2018","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1111\/bjh.15504","article-title":"Efficacy of retreatment with immunomodulatory drugs and proteasome inhibitors following daratumumab monotherapy in relapsed and refractory multiple myeloma patients","volume":"183","author":"Oostvogels","year":"2018","journal-title":"Br. J. Haematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1182\/blood-2016-03-705210","article-title":"Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma","volume":"128","author":"Usmani","year":"2016","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1056\/NEJMoa1607751","article-title":"Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma","volume":"375","author":"Dimopoulos","year":"2016","journal-title":"New Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1182\/blood-2016-03-703439","article-title":"CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma","volume":"128","author":"Nijhof","year":"2016","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1056\/NEJMra041875","article-title":"Multiple myeloma","volume":"351","author":"Kyle","year":"2004","journal-title":"New Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1056\/NEJMra1011442","article-title":"Multiple myeloma","volume":"364","author":"Palumbo","year":"2011","journal-title":"New Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.leukres.2003.09.015","article-title":"Flow cytometric detection of aneuploid CD38(++) plasmacells and CD19(+) B-lymphocytes in bone marrow, peripheral blood and PBSC harvest in multiple myeloma patients","volume":"28","author":"Santonocito","year":"2004","journal-title":"Leuk. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e1217374","DOI":"10.1080\/2162402X.2016.1217374","article-title":"Immunotherapies targeting CD38 in Multiple Myeloma","volume":"5","author":"Atanackovic","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1056\/NEJMoa1506348","article-title":"Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma","volume":"373","author":"Lokhorst","year":"2015","journal-title":"New Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2658","DOI":"10.1182\/blood.V81.10.2658.2658","article-title":"Phenotypic difference of normal plasma cells from mature myeloma cells","volume":"81","author":"Harada","year":"1993","journal-title":"Blood"},{"key":"ref_15","first-page":"1234","article-title":"The phenotype of normal, reactive and malignant plasma cells. Identification of \u201cmany and multiple myelomas\u201d and of new targets for myeloma therapy","volume":"91","author":"Bataille","year":"2006","journal-title":"Haematologica"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1182\/blood-2015-12-687749","article-title":"Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma","volume":"128","author":"Krejcik","year":"2016","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1152\/physrev.00035.2007","article-title":"Evolution and function of the ADP ribosyl cyclase\/CD38 gene family in physiology and pathology","volume":"88","author":"Malavasi","year":"2008","journal-title":"Physiol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.molmed.2008.02.005","article-title":"CD38 at the junction between prognostic marker and therapeutic target","volume":"14","author":"Deaglio","year":"2008","journal-title":"Trends Mol. Med."},{"key":"ref_19","first-page":"99","article-title":"CD38\/CD31, a receptor\/ligand system ruling adhesion and signaling in human leukocytes","volume":"75","author":"Deaglio","year":"2000","journal-title":"Chem. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"395","DOI":"10.4049\/jimmunol.160.1.395","article-title":"Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, an Ig superfamily member","volume":"160","author":"Deaglio","year":"1998","journal-title":"J. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3109\/10428199509056827","article-title":"PECAM-1: Its expression and function as a cell adhesion molecule on hemopoietic and endothelial cells","volume":"17","author":"Watt","year":"1995","journal-title":"Leuk. Lymphoma"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1111\/j.1365-2141.1999.01321.x","article-title":"Human myeloma cells express the CD38 ligand CD31","volume":"105","author":"Vallario","year":"1999","journal-title":"Br. J. Haematol."},{"key":"ref_23","first-page":"S54","article-title":"The Loss of Cd38 Expression by Myeloma Plasma Cells May Occur in the Extramedullary Disease","volume":"103","author":"Accardi","year":"2018","journal-title":"Haematologica"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"30327","DOI":"10.1074\/jbc.270.51.30327","article-title":"ADP-ribosyl cyclase and CD38 catalyze the synthesis of a calcium-mobilizing metabolite from NADP","volume":"270","author":"Aarhus","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e26246","DOI":"10.4161\/onci.26246","article-title":"A CD38\/CD203a\/CD73 ectoenzymatic pathway independent of CD39 drives a novel adenosinergic loop in human T lymphocytes","volume":"2","author":"Horenstein","year":"2013","journal-title":"Oncoimmunology"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Horenstein, A.L., Quarona, V., Toscani, D., Costa, F., Chillemi, A., Pistoia, V., Giuliani, N., and Malavasi, F. (2016). Adenosine Generated in the Bone Marrow Niche Through a CD38-Mediated Pathway Correlates with Progression of Human Myeloma. Mol. Med., 22.","DOI":"10.2119\/molmed.2016.00198"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e1458809","DOI":"10.1080\/2162402X.2018.1458809","article-title":"Microvesicles released from multiple myeloma cells are equipped with ectoenzymes belonging to canonical and non-canonical adenosinergic pathways and produce adenosine from ATP and NAD+","volume":"7","author":"Morandi","year":"2018","journal-title":"Oncoimmunology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"520","DOI":"10.3390\/cells4030520","article-title":"NAD+-Metabolizing Ectoenzymes in Remodeling Tumor-Host Interactions: The Human Myeloma Model","volume":"4","author":"Horenstein","year":"2015","journal-title":"Cells"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2484","DOI":"10.1182\/blood-2003-11-3839","article-title":"Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: A vicious cycle between bone destruction and myeloma expansion","volume":"104","author":"Abe","year":"2004","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/nyas.12485","article-title":"Unraveling the contribution of ectoenzymes to myeloma life and survival in the bone marrow niche","volume":"1335","author":"Quarona","year":"2015","journal-title":"Ann. New York Acad. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"56598","DOI":"10.18632\/oncotarget.17896","article-title":"Expression of CD38 in myeloma bone niche: A rational basis for the use of anti-CD38 immunotherapy to inhibit osteoclast formation","volume":"8","author":"Costa","year":"2017","journal-title":"Oncotarget"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1038\/leu.2015.123","article-title":"Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab","volume":"29","author":"Nijhof","year":"2015","journal-title":"Leukemia"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1083\/jcb.146.5.1161","article-title":"CD38\/ADP-ribosyl cyclase: A new role in the regulation of osteoclastic bone resorption","volume":"146","author":"Sun","year":"1999","journal-title":"J. Cell Biol."},{"key":"ref_34","first-page":"369","article-title":"Disordered osteoclast formation and function in a CD38 (ADP-ribosyl cyclase)-deficient mouse establishes an essential role for CD38 in bone resorption","volume":"17","author":"Sun","year":"2003","journal-title":"Faseb J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_35","first-page":"302","article-title":"A novel mechanism for coupling cellular intermediary metabolism to cytosolic Ca2+ signaling via CD38\/ADP-ribosyl cyclase, a putative intracellular NAD+ sensor","volume":"16","author":"Sun","year":"2002","journal-title":"Faseb J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1002\/jcp.22411","article-title":"T cell suppression by osteoclasts in vitro","volume":"226","author":"Grassi","year":"2011","journal-title":"J. Cell. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1038\/35046102","article-title":"T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma","volume":"408","author":"Takayanagi","year":"2000","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1182\/blood-2016-03-707547","article-title":"Osteoclasts promote immune suppressive microenvironment in multiple myeloma: Therapeutic implication","volume":"128","author":"An","year":"2016","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4290","DOI":"10.1158\/1078-0432.CCR-16-3192","article-title":"Targeting CD38 Suppresses Induction and Function of T Regulatory Cells to Mitigate Immunosuppression in Multiple Myeloma","volume":"23","author":"Feng","year":"2017","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1111\/imr.12389","article-title":"Monoclonal antibodies targeting CD38 in hematological malignancies and beyond","volume":"270","author":"Janmaat","year":"2016","journal-title":"Immunol. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/leu.2015.240","article-title":"SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide","volume":"30","author":"Jiang","year":"2016","journal-title":"Leukemia"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.imlet.2018.04.005","article-title":"Immunomodulatory effects of CD38-targeting antibodies","volume":"199","year":"2018","journal-title":"Immunol. Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1111\/bjh.13776","article-title":"Re-challenging with anti-CD38 monotherapy in triple-refractory multiple myeloma patients is a feasible and safe approach","volume":"174","author":"Alici","year":"2016","journal-title":"Br. J. Haematol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7498","DOI":"10.1158\/1078-0432.CCR-17-2027","article-title":"Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab","volume":"23","author":"Krejcik","year":"2017","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3386","DOI":"10.1182\/blood-2017-03-770776","article-title":"Panobinostat induces CD38 upregulation and augments the antimyeloma efficacy of daratumumab","volume":"129","author":"Gogishvili","year":"2017","journal-title":"Blood"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3176","DOI":"10.1158\/1078-0432.CCR-18-1597","article-title":"The Mechanism of Action of the Anti-CD38 Monoclonal Antibody Isatuximab in Multiple Myeloma","volume":"25","author":"Moreno","year":"2019","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"15429","DOI":"10.1074\/jbc.273.25.15429","article-title":"Molecular mechanism of human CD38 gene expression by retinoic acid. Identification of retinoic acid response element in the first intron","volume":"273","author":"Kishimoto","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1189\/jlb.0109025","article-title":"All-trans retinoic acid and a novel synthetic retinoid tamibarotene (Am80) differentially regulate CD38 expression in human leukemia HL-60 cells: Possible involvement of protein kinase C-delta","volume":"90","author":"Uruno","year":"2011","journal-title":"J. Leukoc. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1046\/j.1365-2141.2002.03601.x","article-title":"Phosphatidylinositol 3-kinases are involved in the all-trans retinoic acid-induced upregulation of CD38 antigen on human haematopoietic cells","volume":"118","author":"Lewandowski","year":"2002","journal-title":"Br. J. Haematol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/leu.2009.236","article-title":"Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma","volume":"24","author":"Quach","year":"2010","journal-title":"Leukemia"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.exphem.2012.11.005","article-title":"Immunomodulatory drugs lenalidomide and pomalidomide inhibit multiple myeloma-induced osteoclast formation and the RANKL\/OPG ratio in the myeloma microenvironment targeting the expression of adhesion molecules","volume":"41","author":"Bolzoni","year":"2013","journal-title":"Exp. Hematol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1182\/blood-2018-05-850727","article-title":"IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos","volume":"132","author":"Fedele","year":"2018","journal-title":"Blood"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e498","DOI":"10.1016\/S2352-3026(16)30133-8","article-title":"Panobinostat plus bortezomib and dexamethasone for relapsed myeloma","volume":"3","author":"Pratt","year":"2016","journal-title":"Lancet Haematol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1038\/nrc3091","article-title":"Cancer biology and NuRD: A multifaceted chromatin remodelling complex","volume":"11","author":"Lai","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1111\/bjh.15673","article-title":"Class 1 HDAC and HDAC6 inhibition inversely regulates CD38 induction in myeloma cells via interferon-alpha and ATRA","volume":"185","author":"Nakamura","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3858","DOI":"10.4049\/jimmunol.159.8.3858","article-title":"Human CD38, a leukocyte receptor and ectoenzyme, is a member of a novel eukaryotic gene family of nicotinamide adenine dinucleotide+-converting enzymes: Extensive structural homology with the genes for murine bone marrow stromal cell antigen 1 and aplysian ADP-ribosyl cyclase","volume":"159","author":"Ferrero","year":"1997","journal-title":"J. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1089\/107999099313299","article-title":"Upregulation of CD38 gene expression in leukemic B cells by interferon types I and II","volume":"19","author":"Bauvois","year":"1999","journal-title":"J. Interferon Cytokine Res. Off. J. Int. Soc. Interferon Cytokine Res."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Choudhry, P., Mariano, M.C., Geng, H., Martin, T.G., Wolf, J.L., Wong, S.W., Shah, N., and Wiita, A.P. (2019). DNA methyltransferase inhibitors upregulate CD38 protein expression and enhance daratumumab efficacy in multiple myeloma. Leukemia.","DOI":"10.1038\/s41375-019-0587-5"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1056\/NEJMoa1817249","article-title":"Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma","volume":"380","author":"Facon","year":"2019","journal-title":"New Engl. J. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1182\/blood-2017-05-785246","article-title":"Daratumumab plus pomalidomide and dexamethasone in relapsed and\/or refractory multiple myeloma","volume":"130","author":"Chari","year":"2017","journal-title":"Blood"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3294","DOI":"10.1182\/blood-2016-09-740787","article-title":"A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed\/refractory multiple myeloma","volume":"129","author":"Martin","year":"2017","journal-title":"Blood"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1182\/blood-2019-02-895193","article-title":"A phase 1b study of isatuximab plus pomalidomide\/dexamethasone in relapsed\/refractory multiple myeloma","volume":"134","author":"Mikhael","year":"2019","journal-title":"Blood"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/12\/1632\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:42:11Z","timestamp":1760190131000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/12\/1632"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,13]]},"references-count":62,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["cells8121632"],"URL":"https:\/\/doi.org\/10.3390\/cells8121632","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,13]]}}}