{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T03:02:45Z","timestamp":1783738965308,"version":"3.55.0"},"reference-count":64,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2019,10,29]],"date-time":"2019-10-29T00:00:00Z","timestamp":1572307200000},"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>Malignant mesothelioma (MM) is an aggressive asbestos-linked neoplasm, characterized by dysregulation of signaling pathways. Due to intrinsic or acquired chemoresistance, MM treatment options remain limited. Calretinin is a Ca2+-binding protein expressed during MM tumorigenesis that activates the FAK signaling pathway, promoting invasion and epithelial-to-mesenchymal transition. Constitutive calretinin downregulation decreases MM cells\u2019 growth and survival, and impairs tumor formation in vivo. In order to evaluate early molecular events occurring during calretinin downregulation, we generated a tightly controlled IPTG-inducible expression system to modulate calretinin levels in vitro. Calretinin downregulation significantly reduced viability and proliferation of MM cells, attenuated FAK signaling and reduced the invasive phenotype of surviving cells. Importantly, surviving cells showed a higher resistance to cisplatin due to increased Wnt signaling. This resistance was abrogated by the Wnt signaling pathway inhibitor 3289-8625. In various MM cell lines and regardless of calretinin expression levels, blocking of FAK signaling activated the Wnt signaling pathway and vice versa. Thus, blocking both pathways had the strongest impact on MM cell proliferation and survival. Chemoresistance mechanisms in MM cells have resulted in a failure of single-agent therapies. Targeting of multiple components of key signaling pathways, including Wnt signaling, might be the future method-of-choice to treat MM.<\/jats:p>","DOI":"10.3390\/ijms20215391","type":"journal-article","created":{"date-parts":[[2019,10,31]],"date-time":"2019-10-31T05:18:26Z","timestamp":1572499106000},"page":"5391","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Modulation of Calretinin Expression in Human Mesothelioma Cells Reveals the Implication of the FAK and Wnt Signaling Pathways in Conferring Chemoresistance towards Cisplatin"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2487-7029","authenticated-orcid":false,"given":"Janine","family":"W\u00f6rthm\u00fcller","sequence":"first","affiliation":[{"name":"Anatomy, Section of Medicine, University of Fribourg, Route Albert-Gockel 1, 1700 Fribourg, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Salicio","sequence":"additional","affiliation":[{"name":"Anatomy, Section of Medicine, University of Fribourg, Route Albert-Gockel 1, 1700 Fribourg, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Oberson","sequence":"additional","affiliation":[{"name":"Anatomy, Section of Medicine, University of Fribourg, Route Albert-Gockel 1, 1700 Fribourg, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Blum","sequence":"additional","affiliation":[{"name":"Genetica AG, 8001 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8277-7555","authenticated-orcid":false,"given":"Beat","family":"Schwaller","sequence":"additional","affiliation":[{"name":"Anatomy, Section of Medicine, University of Fribourg, Route Albert-Gockel 1, 1700 Fribourg, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1002\/jcp.22724","article-title":"Malignant mesothelioma: Facts, myths, and hypotheses","volume":"227","author":"Carbone","year":"2012","journal-title":"J. Cell. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1080\/03008200802147761","article-title":"Malignant mesothelioma--a connective tissue tumor with proteoglycan-dependent differentiation","volume":"49","author":"Hjerpe","year":"2008","journal-title":"Connect. Tissue Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.bcp.2016.07.012","article-title":"New therapeutic strategies for malignant pleural mesothelioma","volume":"123","author":"Bonelli","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1177\/1753465816628800","article-title":"Malignant pleural mesothelioma: An update on diagnosis and treatment options","volume":"10","author":"Kondola","year":"2016","journal-title":"Ther. Adv. Respir. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2636","DOI":"10.1200\/JCO.2003.11.136","article-title":"Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma","volume":"21","author":"Vogelzang","year":"2003","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sneddon, S., Patch, A.M., Dick, I.M., Kazakoff, S., Pearson, J.V., Waddell, N., Allcock, R.J.N., Holt, R.A., Robinson, B.W.S., and Creaney, J. (2017). Whole exome sequencing of an asbestos-induced wild-type murine model of malignant mesothelioma. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3382-6"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1016\/j.jtho.2016.05.020","article-title":"The Genetic Landscape of Malignant Pleural Mesothelioma: Results from Massively Parallel Sequencing","volume":"11","author":"Hylebos","year":"2016","journal-title":"J. Thorac. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1177\/153537020322800903","article-title":"Apoptosis, chemoresistance, and breast cancer: Insights from the MCF-7 cell model system","volume":"228","author":"Simstein","year":"2003","journal-title":"Exp. Biol. Med. (Maywood)"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1177\/1534735413503544","article-title":"A novel herbal formula induces cell cycle arrest and apoptosis in association with suppressing the PI3K\/AKT pathway in human lung cancer A549 cells","volume":"13","author":"Xiong","year":"2014","journal-title":"Integr. Cancer Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1093\/molehr\/gas051","article-title":"Oncogenic Wnt\/beta-catenin signalling pathways in the cancer-resistant epididymis have implications for cancer research","volume":"19","author":"Wang","year":"2013","journal-title":"Mol. Hum. Reprod."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.ygyno.2005.11.017","article-title":"Acquisition of chemoresistance following discontinuous exposures to cisplatin is associated in ovarian carcinoma cells with progressive alteration of FAK, ERK and p38 activation in response to treatment","volume":"101","author":"Villedieu","year":"2006","journal-title":"Gynecol. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"230","DOI":"10.4103\/0973-029X.164537","article-title":"beta catenin in health: A review","volume":"19","author":"Prakash","year":"2015","journal-title":"J. Oral Maxillofac. Pathol."},{"key":"ref_13","first-page":"4547","article-title":"Wnt pathway activation in mesothelioma: Evidence of Dishevelled overexpression and transcriptional activity of beta-catenin","volume":"63","author":"Uematsu","year":"2003","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6672","DOI":"10.1038\/sj.onc.1207881","article-title":"Expression of the secreted frizzled-related protein gene family is downregulated in human mesothelioma","volume":"23","author":"Lee","year":"2004","journal-title":"Oncogene"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"952","DOI":"10.3892\/etm.2012.511","article-title":"Intratumoral Wnt2B expression affects tumor proliferation and survival in malignant pleural mesothelioma patients","volume":"3","author":"Kobayashi","year":"2012","journal-title":"Exp. Ther. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1690896","DOI":"10.1155\/2016\/1690896","article-title":"Wnt5a Increases Properties of Lung Cancer Stem Cells and Resistance to Cisplatin through Activation of Wnt5a\/PKC Signaling Pathway","volume":"2016","author":"Yang","year":"2016","journal-title":"Stem Cells Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1111\/jcmm.12908","article-title":"C-Jun N-terminal kinase signalling pathway in response to cisplatin","volume":"20","author":"Yan","year":"2016","journal-title":"J. Cell. Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1046\/j.1365-2443.2003.00662.x","article-title":"The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a\/JNK signalling pathway","volume":"8","author":"Oishi","year":"2003","journal-title":"Genes Cells"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/nrd4233","article-title":"Can we safely target the WNT pathway?","volume":"13","author":"Kahn","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1002\/(SICI)1097-0142(20000225)90:1<55::AID-CNCR8>3.0.CO;2-P","article-title":"Cytologic differential diagnosis among reactive mesothelial cells, malignant mesothelioma, and adenocarcinoma: Utility of combined E-cadherin and calretinin immunostaining","volume":"90","author":"Kitazume","year":"2000","journal-title":"Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S0344-0338(96)80208-1","article-title":"The calcium binding protein calretinin is a selective marker for malignant pleural mesotheliomas of the epithelial type","volume":"192","author":"Gotzos","year":"1996","journal-title":"Pathol. Res. Pract."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1097\/00000478-199609000-00001","article-title":"Calretinin: A novel immunocytochemical marker for mesothelioma","volume":"20","author":"Doglioni","year":"1996","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.5858\/133.8.1317","article-title":"Guidelines for pathologic diagnosis of malignant mesothelioma: A consensus statement from the International Mesothelioma Interest Group","volume":"133","author":"Husain","year":"2009","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"36256","DOI":"10.18632\/oncotarget.26332","article-title":"Calretinin promotes invasiveness and EMT in malignant mesothelioma cells involving the activation of the FAK signaling pathway","volume":"9","author":"Blum","year":"2018","journal-title":"Oncotarget"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.pharmthera.2014.10.001","article-title":"FAK signaling in human cancer as a target for therapeutics","volume":"146","author":"Lee","year":"2015","journal-title":"Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.2353\/ajpath.2009.080352","article-title":"SV40-induced expression of calretinin protects mesothelial cells from asbestos cytotoxicity and may be a key factor contributing to mesothelioma pathogenesis","volume":"174","author":"Henzi","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1002\/ijc.28218","article-title":"Calretinin is essential for mesothelioma cell growth\/survival in vitro: A potential new target for malignant mesothelioma therapy?","volume":"133","author":"Blum","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1023\/A:1023725029589","article-title":"FAK regulates biological processes important for the pathogenesis of cancer","volume":"22","author":"Schaller","year":"2003","journal-title":"Cancer Metastasis Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1038\/bjc.2016.331","article-title":"Co-targeting of FAK and MDM2 triggers additive anti-proliferative effects in mesothelioma via a coordinated reactivation of p53","volume":"115","author":"Ou","year":"2016","journal-title":"Br. J. Cancer"},{"key":"ref_30","first-page":"19","article-title":"Physiological regulation of Akt activity and stability","volume":"2","author":"Liao","year":"2010","journal-title":"Am. J. Transl. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"27105","DOI":"10.18632\/oncotarget.15637","article-title":"Noncanonical Wnt signaling plays an important role in modulating canonical Wnt-regulated stemness, proliferation and terminal differentiation of hepatic progenitors","volume":"8","author":"Fan","year":"2017","journal-title":"Oncotarget"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1097\/IGC.0b013e31820aaadb","article-title":"Wnt5a as a predictor in poor clinical outcome of patients and a mediator in chemoresistance of ovarian cancer","volume":"21","author":"Peng","year":"2011","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.bbrc.2013.09.025","article-title":"Expression profile and function of Wnt signaling mechanisms in malignant mesothelioma cells","volume":"440","author":"Fox","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1038\/onc.2009.80","article-title":"The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt\/beta-catenin pathway","volume":"28","author":"Flahaut","year":"2009","journal-title":"Oncogene"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"11725","DOI":"10.18632\/oncotarget.3955","article-title":"The emerging role of CaMKII in cancer","volume":"6","author":"Wang","year":"2015","journal-title":"Oncotarget"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1083\/jcb.200303158","article-title":"Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3-independent beta-catenin degradation","volume":"162","author":"Topol","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"16256","DOI":"10.1074\/jbc.M109.009647","article-title":"Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled","volume":"284","author":"Grandy","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.yexcr.2016.07.014","article-title":"Inhibition of disheveled-2 resensitizes cisplatin-resistant lung cancer cells through down-regulating Wnt\/beta-catenin signaling","volume":"347","author":"Luo","year":"2016","journal-title":"Exp. Cell Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.bcp.2015.08.103","article-title":"PKC-delta\/PKC-alpha activity balance regulates the lethal effects of cisplatin","volume":"98","author":"Muscella","year":"2015","journal-title":"Biochem. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"600","DOI":"10.2174\/187152011796817673","article-title":"FAK and WNT signaling: The meeting of two pathways in cancer and development","volume":"11","author":"Fonar","year":"2011","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Basu, A., and Krishnamurthy, S. (2010). Cellular responses to Cisplatin-induced DNA damage. J. Nucleic Acids, 2010.","DOI":"10.4061\/2010\/201367"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1002\/1097-0142(19940415)73:8<2013::AID-CNCR2820730802>3.0.CO;2-J","article-title":"Apoptosis. Its significance in cancer and cancer therapy","volume":"73","author":"Kerr","year":"1994","journal-title":"Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"362","DOI":"10.3892\/ijo.2017.4011","article-title":"The Wnt regulator SFRP4 inhibits mesothelioma cell proliferation, migration, and antagonizes Wnt3a via its netrin-like domain","volume":"51","author":"Perumal","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/path.1692","article-title":"Wnt signalling and the mechanistic basis of tumour development","volume":"205","author":"Ilyas","year":"2005","journal-title":"J. Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1016\/j.cellsig.2011.12.009","article-title":"Frizzled7 as an emerging target for cancer therapy","volume":"24","author":"King","year":"2012","journal-title":"Cell Signal."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1002\/ijc.27746","article-title":"Frizzled homolog proteins, microRNAs and Wnt signaling in cancer","volume":"132","author":"Ueno","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"65957","DOI":"10.18632\/oncotarget.19586","article-title":"FZD7 is a novel prognostic marker and promotes tumor metastasis via WNT and EMT signaling pathways in esophageal squamous cell carcinoma","volume":"8","author":"Cao","year":"2017","journal-title":"Oncotarget"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/nature12631","article-title":"A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing","volume":"503","author":"Florian","year":"2013","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Lim, X., and Nusse, R. (2013). Wnt signaling in skin development, homeostasis, and disease. Cold Spring Harb. Perspect. Biol., 5.","DOI":"10.1101\/cshperspect.a008029"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nri2360","article-title":"WNT signalling in the immune system: WNT is spreading its wings","volume":"8","author":"Staal","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.bbapap.2009.11.002","article-title":"c-Jun N-terminal kinase (JNK) signaling: Recent advances and challenges","volume":"1804","author":"Bogoyevitch","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/j.cellsig.2009.11.021","article-title":"Dishevelled: The hub of Wnt signaling","volume":"22","author":"Gao","year":"2010","journal-title":"Cell Signal."},{"key":"ref_53","first-page":"2041","article-title":"Inhibition of Wnt signaling pathway decreases chemotherapy-resistant side-population colon cancer cells","volume":"30","author":"Chikazawa","year":"2010","journal-title":"Anticancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.devcel.2010.07.015","article-title":"Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt\/c-Myc signaling","volume":"19","author":"Ashton","year":"2010","journal-title":"Dev. Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"237ra268","DOI":"10.1126\/scitranslmed.3008639","article-title":"Merlin deficiency predicts FAK inhibitor sensitivity: A synthetic lethal relationship","volume":"6","author":"Shapiro","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1002\/ijc.2910510220","article-title":"Hematopoietic growth factors secreted by seven human pleural mesothelioma cell lines: Interleukin-6 production as a common feature","volume":"51","author":"Schmitter","year":"1992","journal-title":"Int. J. Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1186\/s12931-015-0311-6","article-title":"Overexpression or absence of calretinin in mouse primary mesothelial cells inversely affects proliferation and cell migration","volume":"16","author":"Blum","year":"2015","journal-title":"Respir. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1007\/s11626-015-9885-z","article-title":"Establishment of immortalized murine mesothelial cells and a novel mesothelioma cell line","volume":"51","author":"Blum","year":"2015","journal-title":"Vitr. Cell. Dev. Biol. Anim."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C(T) method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"295","DOI":"10.21037\/tlcr.2017.06.01","article-title":"Novel systemic therapy against malignant pleural mesothelioma","volume":"6","author":"Mancuso","year":"2017","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"764","DOI":"10.4161\/cbt.9.10.11434","article-title":"PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments","volume":"9","author":"Tanjoni","year":"2010","journal-title":"Cancer Biol. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/nrc.2017.42","article-title":"Novel insights into mesothelioma biology and implications for therapy","volume":"17","author":"Yap","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1097\/PPO.0b013e318212dd3d","article-title":"Mechanism of cell adaptation: When and how do cancer cells develop chemoresistance?","volume":"17","author":"Fodale","year":"2011","journal-title":"Cancer J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.jare.2014.11.012","article-title":"Mesothelioma treatment: Are we on target? A review","volume":"6","author":"Hiddinga","year":"2015","journal-title":"J. Adv. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/21\/5391\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:30:19Z","timestamp":1760189419000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/21\/5391"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,29]]},"references-count":64,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["ijms20215391"],"URL":"https:\/\/doi.org\/10.3390\/ijms20215391","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,29]]}}}