{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T15:26:41Z","timestamp":1769095601337,"version":"3.49.0"},"reference-count":68,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2020,11,6]],"date-time":"2020-11-06T00:00:00Z","timestamp":1604620800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Melanoma releases numerous tumor cells into the circulation; however, only a very small fraction of these cells is able to establish distant metastasis. Intravascular survival of circulating tumor cells is limited through hemodynamic forces and by the lack of matrix interactions. The extravasation step is, thus, of unique importance to establish metastasis. Similar to leukocyte extravasation, this process is under the control of adhesion molecule pairs expressed on melanoma and endothelial cells, and as for leukocytes, ligands need to be adequately presented on cell surfaces. Based on melanoma plasticity, there is considerable heterogeneity even within one tumor and one patient resulting in a mixture of invasive or proliferative cells. The molecular control for this switch is still ill-defined. Recently, the balance between two kinase pathways, p38 and JNK, has been shown to determine growth characteristics of melanoma. While an active JNK pathway induces a proliferative phenotype with reduced invasive features, an active p38\/MK2 pathway results in an invasive phenotype and supports the extravasation step via the expression of molecules capable of binding to endothelial integrins. Therapeutic targeting of MK2 to prevent extravasation might reduce metastatic spread.<\/jats:p>","DOI":"10.3390\/ijms21218344","type":"journal-article","created":{"date-parts":[[2020,11,8]],"date-time":"2020-11-08T19:03:37Z","timestamp":1604862217000},"page":"8344","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Prevention of Melanoma Extravasation as a New Treatment Option Exemplified by p38\/MK2 Inhibition"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7080-5259","authenticated-orcid":false,"given":"Peter","family":"Petzelbauer","sequence":"first","affiliation":[{"name":"Skin &amp; Endothelial Research Division, Department of Dermatology, Medical University Vienna, A-1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1002\/jcp.21494","article-title":"Tumor lymphangiogenesis and melanoma metastasis","volume":"216","author":"Rinderknecht","year":"2008","journal-title":"J. Cell Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/nrd3455","article-title":"Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases","volume":"10","author":"Carmeliet","year":"2011","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/bjd.12688","article-title":"Blood microvessel density, lymphatic microvessel density and lymphatic invasion in predicting melanoma metastases: Systematic review and meta-analysis","volume":"170","author":"Pastushenko","year":"2014","journal-title":"Br. J. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.1172\/JCI44751","article-title":"Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse","volume":"121","author":"Kerjaschki","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2925","DOI":"10.1084\/jem.20091739","article-title":"Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels","volume":"206","author":"Pflicke","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4499","DOI":"10.1038\/onc.2011.602","article-title":"Interaction of tumor cells and lymphatic vessels in cancer progression","volume":"31","author":"Alitalo","year":"2012","journal-title":"Oncogene"},{"key":"ref_7","first-page":"773","article-title":"Metastasis: Quantitative analysis of distribution and fate of tumor emboli labeled with 125 I-5-iodo-2\u2019-deoxyuridine","volume":"45","author":"Fidler","year":"1970","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3864","DOI":"10.1016\/j.celrep.2020.02.080","article-title":"Cancer Cells Resist Mechanical Destruction in Circulation via RhoA\/Actomyosin-Dependent Mechano-Adaptation","volume":"30","author":"Moose","year":"2020","journal-title":"Cell Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s10585-019-10009-y","article-title":"The contribution of platelets to intravascular arrest, extravasation, and outgrowth of disseminated tumor cells","volume":"37","author":"Foss","year":"2020","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7051","DOI":"10.18632\/oncotarget.2251","article-title":"Critical role of STAT3 in melanoma metastasis through anoikis resistance","volume":"5","author":"Fofaria","year":"2014","journal-title":"Oncotarget"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.ccell.2017.07.001","article-title":"Intravascular Survival and Extravasation of Tumor Cells","volume":"32","author":"Strilic","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Jahanban-Esfahlan, R., Seidi, K., Manjili, M.H., Jahanban-Esfahlan, A., Javaheri, T., and Zare, P. (2019). Tumor Cell Dormancy: Threat or Opportunity in the Fight against Cancer. Cancers, 11.","DOI":"10.3390\/cancers11081207"},{"key":"ref_13","first-page":"550","article-title":"Pathogenesis of metastasis formation observed in vivo in the rabbit ear chamber","volume":"66","author":"Wood","year":"1958","journal-title":"AMA Arch. Pathol."},{"key":"ref_14","first-page":"38","article-title":"The fate of circulating tumors cells. I. Passage of cells through capillaries","volume":"21","author":"Zeidman","year":"1961","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/1074-7613(94)90107-4","article-title":"Neutrophil tethering to and rolling on E-selectin are separable by requirement for L-selectin","volume":"1","author":"Lawrence","year":"1994","journal-title":"Immunity"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1615\/CritRevImmunol.v31.i2.40","article-title":"Novel regulators of lymphocyte trafficking across high endothelial venules","volume":"31","author":"Umemoto","year":"2011","journal-title":"Crit. Rev. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3633","DOI":"10.1364\/BOE.395289","article-title":"Heterogeneity of circulating tumor cell dissemination and lung metastases in a subcutaneous Lewis lung carcinoma model","volume":"11","author":"Fitzgerald","year":"2020","journal-title":"Biomed. Opt. Express"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s10719-020-09912-4","article-title":"The physiological and pathological roles and applications of sialyl Lewis x, a common carbohydrate ligand of the three selectins","volume":"37","author":"Jin","year":"2020","journal-title":"Glycoconj. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"C701","DOI":"10.1152\/ajpcell.00245.2008","article-title":"Integrin VLA-4 enhances sialyl-Lewisx\/a-negative melanoma adhesion to and extravasation through the endothelium under low flow conditions","volume":"295","author":"Liang","year":"2008","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_20","first-page":"3233","article-title":"Involvement of very late activation antigen 4 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) in tumor necrosis factor alpha enhancement of experimental metastasis","volume":"54","author":"Okahara","year":"1994","journal-title":"Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1126\/science.2588007","article-title":"An inducible endothelial cell surface glycoprotein mediates melanoma adhesion","volume":"246","author":"Rice","year":"1989","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6993","DOI":"10.1038\/ncomms7993","article-title":"Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis","volume":"6","author":"Tichet","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1038\/nri3908","article-title":"How leukocytes cross the vascular endothelium","volume":"15","author":"Vestweber","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4096","DOI":"10.1158\/0008-5472.CAN-10-2794","article-title":"A novel function of junctional adhesion molecule-C in mediating melanoma cell metastasis","volume":"71","author":"Langer","year":"2011","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1002\/ijc.29370","article-title":"CD146 mediates VEGF-induced melanoma cell extravasation through FAK activation","volume":"137","author":"Jouve","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"28845","DOI":"10.1074\/jbc.M109.042150","article-title":"Crosstalk between protease-activated receptor 1 and platelet-activating factor receptor regulates melanoma cell adhesion molecule (MCAM\/MUC18) expression and melanoma metastasis","volume":"284","author":"Melnikova","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1101\/gad.329771.119","article-title":"Melanoma plasticity and phenotypic diversity: Therapeutic barriers and opportunities","volume":"33","author":"Rambow","year":"2019","journal-title":"Genes Dev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.cell.2010.04.020","article-title":"A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth","volume":"141","author":"Roesch","year":"2010","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1126\/science.aad0501","article-title":"Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq","volume":"352","author":"Tirosh","year":"2016","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/bjc.2016.428","article-title":"Giving AXL the axe: Targeting AXL in human malignancy","volume":"116","author":"Gay","year":"2017","journal-title":"Br. J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1111\/j.1755-148X.2012.00986.x","article-title":"Systematic classification of melanoma cells by phenotype-specific gene expression mapping","volume":"25","author":"Widmer","year":"2012","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1158\/0008-5472.CAN-07-2491","article-title":"In vivo switching of human melanoma cells between proliferative and invasive states","volume":"68","author":"Hoek","year":"2008","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1038\/nature00766","article-title":"Mutations of the BRAF gene in human cancer","volume":"417","author":"Davies","year":"2002","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2448","DOI":"10.1038\/jid.2011.218","article-title":"Human cutaneous melanomas lacking MITF and melanocyte differentiation antigens express a functional Axl receptor kinase","volume":"131","author":"Sensi","year":"2011","journal-title":"J. Investig. Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/nrc2694","article-title":"Signal integration by JNK and p38 MAPK pathways in cancer development","volume":"9","author":"Wagner","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Hammouda, M.B., Ford, A.E., Liu, Y., and Zhang, J.Y. (2020). The JNK Signaling Pathway in Inflammatory Skin Disorders and Cancer. Cells, 9.","DOI":"10.3390\/cells9040857"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/j.jid.2016.01.020","article-title":"Opposing Roles of JNK and p38 in Lymphangiogenesis in Melanoma","volume":"136","author":"Puujalka","year":"2016","journal-title":"J. Investig. Dermatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1111\/j.1755-148X.2011.00908.x","article-title":"The role of mitogen- and stress-activated protein kinase pathways in melanoma","volume":"24","year":"2011","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1038\/nsmb.2668","article-title":"Mechanism and consequence of the autoactivation of p38alpha mitogen-activated protein kinase promoted by TAB1","volume":"20","author":"DeNicola","year":"2013","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/ni1177","article-title":"Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases","volume":"6","author":"Salvador","year":"2005","journal-title":"Nat. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/sj.cr.7290257","article-title":"Activation and signaling of the p38 MAP kinase pathway","volume":"15","author":"Zarubin","year":"2005","journal-title":"Cell Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Afasizheva, A., Devine, A., Tillman, H., Fung, K.L., Vieira, W.D., Blehm, B.H., Kotobuki, Y., Busby, B., Chen, E.I., and Tanner, K. (2016). Mitogen-activated protein kinase signaling causes malignant melanoma cells to differentially alter extracellular matrix biosynthesis to promote cell survival. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2211-7"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1016\/j.molonc.2014.05.008","article-title":"Interleukin-6 drives melanoma cell motility through p38alpha-MAPK-dependent up-regulation of WNT5A expression","volume":"8","author":"Linnskog","year":"2014","journal-title":"Mol. Oncol."},{"key":"ref_44","first-page":"2123","article-title":"Roles of p38alpha and p38beta mitogenactivated protein kinase isoforms in human malignant melanoma A375 cells","volume":"44","author":"Wen","year":"2019","journal-title":"Int. J. Mol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"8509","DOI":"10.1038\/sj.onc.1207831","article-title":"Loss of E-cadherin leads to upregulation of NFkappaB activity in malignant melanoma","volume":"23","author":"Kuphal","year":"2004","journal-title":"Oncogene"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.jid.2019.08.451","article-title":"Inhibition of p38\/MK2 Signaling Prevents Vascular Invasion of Melanoma","volume":"140","author":"Wenzina","year":"2020","journal-title":"J. Investig. Dermatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.molonc.2014.01.004","article-title":"Honokiol inhibits epithelial-mesenchymal transition in breast cancer cells by targeting signal transducer and activator of transcription 3\/Zeb1\/E-cadherin axis","volume":"8","author":"Avtanski","year":"2014","journal-title":"Mol. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1002\/jcp.25338","article-title":"Phosphorylation Regulates Functions of ZEB1 Transcription Factor","volume":"231","author":"Llorens","year":"2016","journal-title":"J. Cell Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1111\/j.1471-4159.2009.05900.x","article-title":"Sonic Hedgehog signaling in astrocytes is dependent on p38 mitogen-activated protein kinase and G-protein receptor kinase 2","volume":"108","author":"Atkinson","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5606","DOI":"10.1158\/0008-5472.CAN-11-1194","article-title":"TGF-beta\/SMAD\/GLI2 signaling axis in cancer progression and metastasis","volume":"71","author":"Javelaud","year":"2011","journal-title":"Cancer Res."},{"key":"ref_51","first-page":"271","article-title":"Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (review)","volume":"22","author":"Katoh","year":"2008","journal-title":"Int. J. Mol. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"76062","DOI":"10.18632\/oncotarget.12584","article-title":"Hedgehog and TGFbeta signaling converge on Gli2 to control bony invasion and bone destruction in oral squamous cell carcinoma","volume":"7","author":"Cannonier","year":"2016","journal-title":"Oncotarget"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1111\/pcmr.12149","article-title":"GLI2 cooperates with ZEB1 for transcriptional repression of CDH1 expression in human melanoma cells","volume":"26","author":"Perrot","year":"2013","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1111\/jcmm.12340","article-title":"From cell membrane to the nucleus: An emerging role of E-cadherin in gene transcriptional regulation","volume":"18","author":"Du","year":"2014","journal-title":"J. Cell Mol. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.jid.2019.11.025","article-title":"Cellular Phenotypic Plasticity of Cutaneous Melanoma: A Complex Puzzle","volume":"140","author":"Joshi","year":"2020","journal-title":"J. Investig. Dermatol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"8649","DOI":"10.1038\/s41598-017-08851-9","article-title":"Prognostic Significance of EDIL3 Expression and Correlation with Mesenchymal Phenotype and Microvessel Density in Lung Adenocarcinoma","volume":"7","author":"Jeong","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s40364-017-0090-y","article-title":"Podocalyxin-like and RNA-binding motif protein 3 are prognostic biomarkers in urothelial bladder cancer: A validatory study","volume":"5","author":"Boman","year":"2017","journal-title":"Biomark Res."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Kaprio, T., Fermer, C., Hagstrom, J., Mustonen, H., Bockelman, C., Nilsson, O., and Haglund, C. (2014). Podocalyxin is a marker of poor prognosis in colorectal cancer. BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-493"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1111\/cas.13018","article-title":"Podocalyxin-like protein, linked to poor prognosis of pancreatic cancers, promotes cell invasion by binding to gelsolin","volume":"107","author":"Taniuchi","year":"2016","journal-title":"Cancer Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1016\/j.yexcr.2008.03.009","article-title":"Expression of podocalyxin enhances the adherence, migration, and intercellular communication of cells","volume":"314","author":"Larrucea","year":"2008","journal-title":"Exp. Cell Res."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Sun, S., Dong, H., Yan, T., Li, J., Liu, B., Shao, P., Li, J., and Liang, C. (2020). Role of TSP-1 as prognostic marker in various cancers: A systematic review and meta-analysis. BMC Med. Genet., 21.","DOI":"10.1186\/s12881-020-01073-3"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/10061","article-title":"MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis","volume":"1","author":"Kotlyarov","year":"1999","journal-title":"Nat. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"9733","DOI":"10.1074\/jbc.M611165200","article-title":"Crystal structure of the p38 alpha-MAPKAP kinase 2 heterodimer","volume":"282","author":"Prabhakar","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"6353","DOI":"10.1073\/pnas.0701679104","article-title":"2nd: Molecular basis of MAPK-activated protein kinase 2:p38 assembly","volume":"104","author":"White","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3609","DOI":"10.1021\/acs.jmedchem.5b01457","article-title":"Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts to Lead Small Molecule Inhibitors to Clinical Trials","volume":"59","author":"Fiore","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.1093\/carcin\/bgp238","article-title":"MK2 regulates the early stages of skin tumor promotion","volume":"30","author":"Johansen","year":"2009","journal-title":"Carcinogenesis"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1186\/s13046-019-1115-1","article-title":"MAPKAPK2: The master regulator of RNA-binding proteins modulates transcript stability and tumor progression","volume":"38","author":"Soni","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.cell.2015.05.053","article-title":"A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer","volume":"162","author":"Dietlein","year":"2015","journal-title":"Cell"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/21\/8344\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:30:26Z","timestamp":1760178626000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/21\/8344"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,6]]},"references-count":68,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["ijms21218344"],"URL":"https:\/\/doi.org\/10.3390\/ijms21218344","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,6]]}}}