{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T22:43:36Z","timestamp":1778885016653,"version":"3.51.4"},"reference-count":59,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T00:00:00Z","timestamp":1603929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010805","name":"Forskningsr\u00e5det i Syd\u00f6stra Sverige","doi-asserted-by":"publisher","award":["FORSS-481781"],"award-info":[{"award-number":["FORSS-481781"]}],"id":[{"id":"10.13039\/100010805","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ALF Grants, Region \u00d6sterg\u00f6tland, Sweden","award":["LIO-532021"],"award-info":[{"award-number":["LIO-532021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Phaeochromocytomas and paragangliomas (PPGLs) are neuroendocrine catecholamine-producing tumours that may progress into inoperable metastatic disease. Treatment options for metastatic disease are limited, indicating a need for functional studies to identify pharmacologically targetable pathophysiological mechanisms, which require biologically relevant experimental models. Recently, a human progenitor phaeochromocytoma cell line named \u201chPheo1\u201d was established, but its genotype has not been characterised. Performing exome sequencing analysis, we identified a KIF1B T827I mutation, and the oncogenic NRAS Q61K mutation. While KIF1B mutations are recurring somatic events in PPGLs, NRAS mutations have hitherto not been detected in PPGLs. Therefore, we aimed to assess its implications for the hPheo1 cell line, and possible relevance for the pathophysiology of PPGLs. We found that transient downregulation of NRAS in hPheo1 led to elevated expression of genes associated with cell adhesion, and enhanced adhesion to hPheo1 cells\u2019 extracellular matrix. Analyses of previously published mRNA data from two independent PPGL patient cohorts (212 tissue samples) revealed a subcluster of PPGLs featuring hyperactivated RAS pathway-signalling and under-expression of cell adhesion-related gene expression programs. Thus, we conclude that NRAS activity in hPheo1 decreases adhesion to their own extracellular matrix and mirrors a transcriptomic RAS-signalling-related phenomenon in PPGLs.<\/jats:p>","DOI":"10.3390\/ijms21218072","type":"journal-article","created":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T09:44:53Z","timestamp":1603964693000},"page":"8072","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Activation of RAS Signalling is Associated with Altered Cell Adhesion in Phaeochromocytoma"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3766-6258","authenticated-orcid":false,"given":"Hugo M.","family":"Rossitti","sequence":"first","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, Link\u00f6ping University, SE-58183 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ravi Kumar","family":"Dutta","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, Link\u00f6ping University, SE-58183 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catharina","family":"Larsson","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Cancer Center Karolinska, SE-17176 Stockholm, Sweden"},{"name":"Department of Clinical Pathology and Cytology, Karolinska University Hospital-Solna, SE-17176 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans K.","family":"Ghayee","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, University of Florida and the Malcolm Randall VAMC, Gainesville, FL 32608, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"S\u00f6derkvist","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, Link\u00f6ping University, SE-58183 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0054-664X","authenticated-orcid":false,"given":"Oliver","family":"Gimm","sequence":"additional","affiliation":[{"name":"Department of Surgery and Department of Biomedical and Clinical Sciences, Link\u00f6ping University, SE-58183 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"R9","DOI":"10.1530\/EJE-15-0549","article-title":"Management of Endocrine Disease: Outcome of adrenal sparing surgery in heritable pheochromocytoma","volume":"174","author":"Castinetti","year":"2016","journal-title":"Eur. J. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e84","DOI":"10.1002\/bjs.10744","article-title":"Extent of surgery for phaeochromocytomas in the genomic era","volume":"105","author":"Rossitti","year":"2018","journal-title":"Br. J. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Crona, J., Lamarca, A., Ghosal, S., Welin, S., Skogseid, B., and Pacak, K. (2019). Genotype-phenotype correlations in pheochromocytoma and paraganglioma. Endocr. Relat. Cancer.","DOI":"10.1530\/ERC-19-0024"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/S0090-4295(98)00612-8","article-title":"Pheochromocytomas: Can malignant potential be predicted?","volume":"53","author":"John","year":"1999","journal-title":"Urology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1002\/jso.23297","article-title":"Malignant pheochromocytoma and paraganglioma: A population level analysis of long-term survival over two decades","volume":"107","author":"Goffredo","year":"2013","journal-title":"J. Surg. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3296","DOI":"10.1210\/jc.2017-00992","article-title":"Malignant Pheochromocytoma and Paraganglioma: 272 Patients Over 55 Years","volume":"102","author":"Hamidi","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1210\/jc.2018-01968","article-title":"Prognosis of Malignant Pheochromocytoma and Paraganglioma (MAPP-Prono Study): A European Network for the Study of Adrenal Tumors Retrospective Study","volume":"104","author":"Hescot","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3974","DOI":"10.1093\/hmg\/ddr324","article-title":"Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma","volume":"20","author":"Burnichon","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1371\/journal.pgen.0010008","article-title":"A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas","volume":"1","author":"Dahia","year":"2005","journal-title":"PLoS Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1210\/me.2010-0256","article-title":"Research resource: Transcriptional profiling reveals different pseudohypoxic signatures in SDHB and VHL-related pheochromocytomas","volume":"24","author":"Munoz","year":"2010","journal-title":"Mol. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1002\/ijc.28868","article-title":"Opposing effects of HIF1alpha and HIF2alpha on chromaffin cell phenotypic features and tumor cell proliferation: Insights from MYC-associated factor X","volume":"135","author":"Qin","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"R253","DOI":"10.1530\/ERC-11-0170","article-title":"Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas","volume":"18","author":"Welander","year":"2011","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1210\/er.2017-00062","article-title":"New Perspectives on Pheochromocytoma and Paraganglioma: Toward a Molecular Classification","volume":"38","author":"Crona","year":"2017","journal-title":"Endocr. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ccell.2017.01.001","article-title":"Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma","volume":"31","author":"Fishbein","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1373\/clinchem.2010.153320","article-title":"Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma","volume":"57","author":"Eisenhofer","year":"2011","journal-title":"Clin. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Berends, A.M.A., Eisenhofer, G., Fishbein, L., Horst-Schrivers, A., Kema, I.P., Links, T.P., Lenders, J.W.M., and Kerstens, M.N. (2019). Intricacies of the Molecular Machinery of Catecholamine Biosynthesis and Secretion by Chromaffin Cells of the Normal Adrenal Medulla and in Pheochromocytoma and Paraganglioma. Cancers (Basel), 11.","DOI":"10.3390\/cancers11081121"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1002\/gcc.22347","article-title":"HRAS mutation prevalence and associated expression patterns in pheochromocytoma","volume":"55","author":"Stenman","year":"2016","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ghayee, H.K., Bhagwandin, V.J., Stastny, V., Click, A., Ding, L.H., Mizrachi, D., Zou, Y.S., Chari, R., Lam, W.L., and Bachoo, R.M. (2013). Progenitor cell line (hPheo1) derived from a human pheochromocytoma tumor. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0065624"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1055\/s-2004-830522","article-title":"Frequent promoter methylation of tumor-related genes in sporadic and men2-associated pheochromocytomas","volume":"113","author":"Dammann","year":"2005","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.cell.2018.03.035","article-title":"Oncogenic Signaling Pathways in The Cancer Genome Atlas","volume":"173","author":"Mina","year":"2018","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1101\/gad.1648608","article-title":"The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor","volume":"22","author":"Schlisio","year":"2008","journal-title":"Genes Dev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"E1352","DOI":"10.1210\/jc.2013-4375","article-title":"Rare germline mutations identified by targeted next-generation sequencing of susceptibility genes in pheochromocytoma and paraganglioma","volume":"99","author":"Welander","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1158\/0008-5472.CAN-11-2612","article-title":"A comprehensive survey of Ras mutations in cancer","volume":"72","author":"Prior","year":"2012","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1002\/ijc.29957","article-title":"Malignant pheochromocytomas\/paragangliomas harbor mutations in transport and cell adhesion genes","volume":"138","author":"Wilzen","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1158\/0008-5472.CAN-17-2463","article-title":"Germline Mutations in the Mitochondrial 2-Oxoglutarate\/Malate Carrier SLC25A11 Gene Confer a Predisposition to Metastatic Paragangliomas","volume":"78","author":"Buffet","year":"2018","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"L57","DOI":"10.1530\/ERC-17-0061","article-title":"KIF1B and NF1 are the most frequently mutated genes in paraganglioma and pheochromocytoma tumors","volume":"24","author":"Evenepoel","year":"2017","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1093\/bioinformatics\/btr260","article-title":"Molecular signatures database (MSigDB) 3.0","volume":"27","author":"Liberzon","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.matbio.2015.06.003","article-title":"The extracellular matrix: Tools and insights for the \u201comics\u201d era","volume":"49","author":"Naba","year":"2016","journal-title":"Matrix Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.ccr.2013.08.005","article-title":"Protein kinase C alpha is a central signaling node and therapeutic target for breast cancer stem cells","volume":"24","author":"Tam","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1089\/scd.2009.0430","article-title":"Enrichment for breast cancer cells with stem\/progenitor properties by differential adhesion","volume":"19","author":"Walia","year":"2010","journal-title":"Stem Cells Dev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"18772","DOI":"10.1038\/srep18772","article-title":"Low adherent cancer cell subpopulations are enriched in tumorigenic and metastatic epithelial-to-mesenchymal transition-induced cancer stem-like cells","volume":"6","author":"Jimenez","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1111\/exd.12683","article-title":"A new live-cell biobank workflow efficiently recovers heterogeneous melanoma cells from native biopsies","volume":"24","author":"Raaijmakers","year":"2015","journal-title":"Exp. Dermatol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Humphries, M.J. (2001). Cell-substrate adhesion assays. Curr. Protoc. Cell Biol., Chapter 9, Unit 9.1.","DOI":"10.1385\/MB:18:1:57"},{"key":"ref_35","first-page":"e55051","article-title":"A Rapid, Scalable Method for the Isolation, Functional Study, and Analysis of Cell-derived Extracellular Matrix","volume":"19","author":"Hellewell","year":"2017","journal-title":"J. Vis. Exp."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1530\/ERC-13-0384","article-title":"Frequent EPAS1\/HIF2alpha exons 9 and 12 mutations in non-familial pheochromocytoma","volume":"21","author":"Welander","year":"2014","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1210\/jc.2015-3889","article-title":"Pheo-Type: A Diagnostic Gene-expression Assay for the Classification of Pheochromocytoma and Paraganglioma","volume":"101","author":"Flynn","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"E1376","DOI":"10.1210\/jc.2013-3879","article-title":"H-RAS mutations are restricted to sporadic pheochromocytomas lacking specific clinical or pathological features: Data from a multi-institutional series","volume":"99","author":"Oudijk","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nrm2438","article-title":"Ras oncogenes: Split personalities","volume":"9","author":"Karnoub","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1042\/BST20180173","article-title":"RAS variant signalling","volume":"46","author":"Mo","year":"2018","journal-title":"Biochem. Soc. Trans."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1056\/NEJMoa1502583","article-title":"The Genetic Evolution of Melanoma from Precursor Lesions","volume":"373","author":"Shain","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4714","DOI":"10.1038\/sj.onc.1210250","article-title":"Conditional N-rasG12V expression promotes manifestations of neurofibromatosis in a mouse model","volume":"26","author":"Saito","year":"2007","journal-title":"Oncogene"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/B978-0-444-64076-5.00051-X","article-title":"Neurofibromatosis type 1","volume":"148","author":"Cimino","year":"2018","journal-title":"Handb. Clin. Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5406","DOI":"10.1093\/hmg\/dds402","article-title":"Integrative genomics reveals frequent somatic NF1 mutations in sporadic pheochromocytomas","volume":"21","author":"Welander","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/wdev.104","article-title":"Differential adhesion in model systems","volume":"2","author":"Foty","year":"2013","journal-title":"Wiley Interdiscip. Rev. Dev. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.tcb.2015.07.012","article-title":"Epithelial-Mesenchymal Plasticity: A Central Regulator of Cancer Progression","volume":"25","author":"Ye","year":"2015","journal-title":"Trends Cell Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1002\/ijc.23876","article-title":"Oncogenic NRAS has multiple effects on the malignant phenotype of human melanoma cells cultured in vitro","volume":"124","author":"Eskandarpour","year":"2009","journal-title":"Int. J. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4058","DOI":"10.1158\/0008-5472.CAN-07-5580","article-title":"Cells silenced for SDHB expression display characteristic features of the tumor phenotype","volume":"68","author":"Cervera","year":"2008","journal-title":"Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1530\/ERC-17-0212","article-title":"The microenvironment induces collective migration in SDHB-silenced mouse pheochromocytoma spheroids","volume":"24","author":"Martinelli","year":"2017","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"32955","DOI":"10.18632\/oncotarget.5106","article-title":"Deciphering the molecular basis of invasiveness in Sdhb-deficient cells","volume":"6","author":"Loriot","year":"2015","journal-title":"Oncotarget"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1002\/ijc.27524","article-title":"NF-kappaB inhibition significantly upregulates the norepinephrine transporter system, causes apoptosis in pheochromocytoma cell lines and prevents metastasis in an animal model","volume":"131","author":"Pacak","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1039\/c3ib40062j","article-title":"Network analysis of differential Ras isoform mutation effects on intestinal epithelial responses to TNF-alpha","volume":"5","author":"Lau","year":"2013","journal-title":"Integr. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Leibovich-Rivkin, T., Liubomirski, Y., Meshel, T., Abashidze, A., Brisker, D., Solomon, H., Rotter, V., Weil, M., and Ben-Baruch, A. (2014). The inflammatory cytokine TNFalpha cooperates with Ras in elevating metastasis and turns WT-Ras to a tumor-promoting entity in MCF-7 cells. BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-158"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"M111.014647","DOI":"10.1074\/mcp.M111.014647","article-title":"The matrisome: In silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices","volume":"11","author":"Naba","year":"2012","journal-title":"Mol. Cell Proteom."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.devcel.2010.06.012","article-title":"Collective chemotaxis requires contact-dependent cell polarity","volume":"19","author":"Theveneau","year":"2010","journal-title":"Dev. Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.cell.2018.03.022","article-title":"Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer","volume":"173","author":"Hoadley","year":"2018","journal-title":"Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"50691","DOI":"10.1074\/jbc.M304985200","article-title":"Molecular basis of constitutive production of basement membrane components. Gene expression profiles of Engelbreth-Holm-Swarm tumor and F9 embryonal carcinoma cells","volume":"278","author":"Futaki","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Geiger, B., and Yamada, K.M. (2011). Molecular architecture and function of matrix adhesions. Cold Spring Harb. Perspect. Biol., 3.","DOI":"10.1101\/cshperspect.a005033"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/21\/8072\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:26:21Z","timestamp":1760178381000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/21\/8072"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,29]]},"references-count":59,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["ijms21218072"],"URL":"https:\/\/doi.org\/10.3390\/ijms21218072","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,29]]}}}