{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:41:05Z","timestamp":1791405665126,"version":"4.3.3"},"reference-count":51,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T00:00:00Z","timestamp":1691107200000},"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>The exact mechanism of desmoplastic stromal reaction (DSR) formation is still unclear. The interaction between cancer cells and cancer-associated fibroblasts (CAFs) has an important role in tumor progression, while stromal changes are a poor prognostic factor in pleural mesothelioma (PM). We aimed to assess the impact of CAFs paracrine signaling within the tumor microenvironment and the DSR presence on survival, in a cohort of 77 PM patients. DSR formation was evaluated morphologically and by immunohistochemistry for Fibroblast activation protein alpha (FAP). Digital gene expression was analyzed using a custom-designed CodeSet (NanoString). Decision-tree-based analysis using the \u201cconditional inference tree\u201d (CIT) machine learning algorithm was performed on the obtained results. A significant association between FAP gene expression levels and the appearance of DSR was found (p = 0.025). DSR-high samples demonstrated a statistically significant prolonged median survival time. The elevated expression of MYT1, KDR, PIK3R1, PIK3R4, and SOS1 was associated with shortened OS, whereas the upregulation of VEGFC, FAP, and CDK4 was associated with prolonged OS. CIT revealed a three-tier system based on FAP, NF1, and RPTOR expressions. We could outline the prognostic value of CAFs-induced PI3K signaling pathway activation together with FAP-dependent CDK4 mediated cell cycle progression in PM, where prognostic and predictive biomarkers are urgently needed to introduce new therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms241512426","type":"journal-article","created":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T09:27:48Z","timestamp":1691141268000},"page":"12426","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Cancer-Associated Fibroblasts Influence Survival in Pleural Mesothelioma: Digital Gene Expression Analysis and Supervised Machine Learning Model"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0447-3206","authenticated-orcid":false,"given":"Sabrina","family":"Borchert","sequence":"first","affiliation":[{"name":"Institute of Pathology, University Hospital Essen, University of Duisburg Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Mathilakathu","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Essen, University of Duisburg Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Nath","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Essen, University of Duisburg Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4399-8646","authenticated-orcid":false,"given":"Michael","family":"Wessolly","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Essen, University of Duisburg Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Mairinger","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Essen, University of Duisburg Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Kreidt","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Essen, University of Duisburg Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Steinborn","sequence":"additional","affiliation":[{"name":"Center for Pathology in Essen-Mitte, 45131 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert F. H.","family":"Walter","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Essen, University of Duisburg Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3151-6427","authenticated-orcid":false,"given":"Daniel C.","family":"Christoph","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Evangelische Kliniken Essen-Mitte, 45131 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8048-3895","authenticated-orcid":false,"given":"Jens","family":"Kollmeier","sequence":"additional","affiliation":[{"name":"Department of Pneumology, Helios Klinikum Emil von Behring, 14165 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2682-2489","authenticated-orcid":false,"given":"Jeremias","family":"Wohlschlaeger","sequence":"additional","affiliation":[{"name":"Department of Pathology, Diakonissenkrankenhaus Flensburg, 24939 Flensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0037-0066","authenticated-orcid":false,"given":"Thomas","family":"Mairinger","sequence":"additional","affiliation":[{"name":"Department of Tissue Diagnostics, Helios Klinikum Emil von Behring, 14165 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9098-8416","authenticated-orcid":false,"given":"Luka","family":"Brcic","sequence":"additional","affiliation":[{"name":"Diagnostic and Research Institute of Pathology, Medical University of Graz, 8036 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1067-0051","authenticated-orcid":false,"given":"Fabian D.","family":"Mairinger","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Essen, University of Duisburg Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/S0046-8177(88)80265-X","article-title":"Desmoplastic reaction of gastric carcinoma: A light- and electron-microscopic immunohistochemical analysis using collagen type-specific antibodies","volume":"19","author":"Minamoto","year":"1988","journal-title":"Hum. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1007\/s00268-005-0391-4","article-title":"Desmoplastic stromal reaction in medullary thyroid cancer-an intraoperative \u201cmarker\u201d for lymph node metastases","volume":"30","author":"Scheuba","year":"2006","journal-title":"World J. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1111\/j.1365-2559.2008.03002.x","article-title":"Desmoplasia in medullary thyroid carcinoma: A reliable indicator of metastatic potential","volume":"52","author":"Koperek","year":"2008","journal-title":"Histopathology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/s41416-019-0705-1","article-title":"The life cycle of cancer-associated fibroblasts within the tumour stroma and its importance in disease outcome","volume":"122","author":"Wu","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/nrm809","article-title":"Myofibroblasts and mechano-regulation of connective tissue remodelling","volume":"3","author":"Tomasek","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.1016\/j.yexcr.2010.04.032","article-title":"Activation of fibroblasts in cancer stroma","volume":"316","author":"Rasanen","year":"2010","journal-title":"Exp. Cell Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/nrc1877","article-title":"Fibroblasts in cancer","volume":"6","author":"Kalluri","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.gde.2009.01.003","article-title":"Cancer-associated fibroblasts and tumor growth\u2014Bystanders turning into key players","volume":"19","author":"Ostman","year":"2009","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"137","DOI":"10.2147\/CMAR.S231356","article-title":"Desmoplastic Reaction and Tumor Budding in Cervical Squamous Cell Carcinoma are Prognostic Factors for Distant Metastasis: A Retrospective Study","volume":"12","author":"Cao","year":"2020","journal-title":"Cancer Manag. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1097\/PAS.0000000000000946","article-title":"Desmoplastic Pattern at the Tumor Front Defines Poor-prognosis Subtypes of Colorectal Cancer","volume":"41","author":"Ueno","year":"2017","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S39","DOI":"10.21037\/tlcr.2020.02.01","article-title":"How asbestos and other fibers cause mesothelioma","volume":"9","author":"Gaudino","year":"2020","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1158\/1078-0432.CCR-11-2259","article-title":"Molecular pathways: Targeting mechanisms of asbestos and erionite carcinogenesis in mesothelioma","volume":"18","author":"Carbone","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1093\/carcin\/bgt166","article-title":"Molecular pathogenesis of malignant mesothelioma","volume":"34","author":"Sekido","year":"2013","journal-title":"Carcinogenesis"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.ceb.2016.05.002","article-title":"Stromal dynamic reciprocity in cancer: Intricacies of fibroblastic-ECM interactions","volume":"42","author":"Alexander","year":"2016","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.critrevonc.2015.09.008","article-title":"Paracrine tumor signaling induces transdifferentiation of surrounding fibroblasts","volume":"97","author":"Heneberg","year":"2016","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Spaeth, E.L., Dembinski, J.L., Sasser, A.K., Watson, K., Klopp, A., Hall, B., Andreeff, M., and Marini, F. (2009). Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0004992"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"544789","DOI":"10.3389\/fonc.2020.544789","article-title":"Tumor Microenvironment-Associated Immune-Related Genes for the Prognosis of Malignant Pleural Mesothelioma","volume":"10","author":"Xu","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Schober, M., Jesenofsky, R., Faissner, R., Weidenauer, C., Hagmann, W., Michl, P., Heuchel, R.L., Haas, S.L., and Lohr, J.M. (2014). Desmoplasia and chemoresistance in pancreatic cancer. Cancers, 6.","DOI":"10.3390\/cancers6042137"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3932","DOI":"10.7150\/thno.25541","article-title":"Carcinoma-associated fibroblasts promote the stemness and chemoresistance of colorectal cancer by transferring exosomal lncRNA H19","volume":"8","author":"Ren","year":"2018","journal-title":"Theranostics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e352","DOI":"10.1038\/oncsis.2017.54","article-title":"Matrix stiffness induces epithelial-mesenchymal transition and promotes chemoresistance in pancreatic cancer cells","volume":"6","author":"Rice","year":"2017","journal-title":"Oncogenesis"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.cell.2018.01.009","article-title":"CD10(+)GPR77(+) Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness","volume":"172","author":"Su","year":"2018","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ejca.2020.09.015","article-title":"Machine learning reveals a PD-L1-independent prediction of response to immunotherapy of non-small cell lung cancer by gene expression context","volume":"140","author":"Wiesweg","year":"2020","journal-title":"Eur. J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1093\/annonc\/mdz049","article-title":"Machine learning-based predictors for immune checkpoint inhibitor therapy of non-small-cell lung cancer","volume":"30","author":"Wiesweg","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2930","DOI":"10.1172\/JCI91190","article-title":"IFN-\u03b3-related mRNA profile predicts clinical response to PD-1 blockade","volume":"127","author":"Ayers","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s40425-018-0367-1","article-title":"Pan-cancer adaptive immune resistance as defined by the Tumor Inflammation Signature (TIS): Results from The Cancer Genome Atlas (TCGA)","volume":"6","author":"Danaher","year":"2018","journal-title":"J. Immunother. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"H2211","DOI":"10.1152\/ajpheart.00966.2011","article-title":"TGF-\u03b2 and Smad3 modulate PI3K\/Akt signaling pathway in vascular smooth muscle cells","volume":"302","author":"Suwanabol","year":"2012","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"372","DOI":"10.3109\/07853890.2014.912836","article-title":"PI3K\/AKT signaling pathway and cancer: An updated review","volume":"46","author":"Martini","year":"2014","journal-title":"Ann. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nrm2882","article-title":"The emerging mechanisms of isoform-specific PI3K signalling","volume":"11","author":"Vanhaesebroeck","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_29","first-page":"1034","article-title":"Cytokine activation of phosphoinositide 3-kinase sensitizes hematopoietic cells to cisplatin-induced death","volume":"63","author":"Nimbalkar","year":"2003","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"27850","DOI":"10.1074\/jbc.M506005200","article-title":"Mechanism of constitutive phosphoinositide 3-kinase activation by oncogenic mutants of the p85 regulatory subunit","volume":"280","author":"Shekar","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.ccr.2009.10.016","article-title":"Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation","volume":"16","author":"Jaiswal","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1126\/science.1164382","article-title":"An integrated genomic analysis of human glioblastoma multiforme","volume":"321","author":"Parsons","year":"2008","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4061","DOI":"10.1158\/0008-5472.CAN-11-0549","article-title":"PIK3R1 (p85\u03b1) is somatically mutated at high frequency in primary endometrial cancer","volume":"71","author":"Urick","year":"2011","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1158\/2159-8290.CD-11-0039","article-title":"High Frequency of PIK3R1 and PIK3R2 Mutations in Endometrial Cancer Elucidates a Novel Mechanism for Regulation of PTEN Protein Stability","volume":"1","author":"Cheung","year":"2011","journal-title":"Cancer Discov."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Jan\u00e9, P., G\u00f3gl, G., Kostmann, C., Bich, G., Girault, V., Caillet-Saguy, C., Eberling, P., Vincentelli, R., Wolff, N., and Trav\u00e9, G. (2020). Interactomic affinity profiling by holdup assay: Acetylation and distal residues impact the PDZome-binding specificity of PTEN phosphatase. PLoS ONE, 15.","DOI":"10.1101\/2020.07.01.181487"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Jiang, Z., Zhang, T., Chen, C., Sun, L., Li, S., and Ding, X. (2020). New PTEN mutation identified in a patient with rare bilateral choroidal ganglioneuroma. BMC Ophthalmol., 20.","DOI":"10.1186\/s12886-020-01760-y"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Tian, T., Li, X., and Zhang, J. (2019). mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030755"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1038\/bjc.2014.220","article-title":"Multipoint targeting of the PI3K\/mTOR pathway in mesothelioma","volume":"110","author":"Zhou","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1007\/BF01221191","article-title":"Cytokinetic effects of cisplatin on diverse human head and neck carcinomas in vitro: Dependence on the tumor sensitivity to cisplatin","volume":"122","author":"Jackel","year":"1996","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s002800050641","article-title":"Cell cycle perturbations in cisplatin-sensitive and resistant human ovarian carcinoma cells following treatment with cisplatin and low dose rate irradiation","volume":"40","author":"Wilkins","year":"1997","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S0968-0004(00)89005-2","article-title":"D-type cyclins","volume":"20","author":"Sherr","year":"1995","journal-title":"Trends Biochem. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Vogl, M., Rosenmayr, A., Bohanes, T., Scheed, A., Brndiar, M., Stubenberger, E., and Ghanim, B. (2021). Biomarkers for Malignant Pleural Mesothelioma-A Novel View on Inflammation. Cancers, 13.","DOI":"10.3390\/cancers13040658"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.humpath.2015.02.006","article-title":"Prognostic factors in malignant pleural mesothelioma","volume":"46","author":"Davidson","year":"2015","journal-title":"Hum. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.lungcan.2012.05.111","article-title":"A multicenter phase II study of cisplatin, pemetrexed, and bevacizumab in patients with advanced malignant mesothelioma","volume":"77","author":"Dowell","year":"2012","journal-title":"Lung Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.jtho.2021.12.014","article-title":"The 2021 WHO Classification of Tumors of the Pleura: Advances Since the 2015 Classification","volume":"17","author":"Sauter","year":"2022","journal-title":"J. Thorac. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Brierley, J.D., Gospodarowicz, M.K., and Wittekind, C. (2017). TNM Classification of Malignant Tumours, Wiley. [8th ed.].","DOI":"10.1002\/9780471420194.tnmc26.pub3"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1093\/annonc\/mdh059","article-title":"Modified RECIST criteria for assessment of response in malignant pleural mesothelioma","volume":"15","author":"Byrne","year":"2004","journal-title":"Ann. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.ctrv.2007.07.012","article-title":"Assessment of tumor response in malignant pleural mesothelioma","volume":"33","author":"Ceresoli","year":"2007","journal-title":"Cancer Treat. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1158\/1078-0432.CCR-06-1746","article-title":"Clinical implications of fibroblast activation protein in patients with colon cancer","volume":"13","author":"Henry","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Brcic, L., Mathilakathu, A., Walter, R.F.H., Wessolly, M., Mairinger, E., Beckert, H., Kreidt, D., Steinborn, J., Hager, T., and Christoph, D.C. (2021). Digital Gene Expression Analysis of Epithelioid and Sarcomatoid Mesothelioma Reveals Differences in Immunogenicity. Cancers, 13.","DOI":"10.3390\/cancers13081761"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1198\/106186006X133933","article-title":"Unbiased Recursive Partitioning: A Conditional Inference Framework","volume":"15","author":"Hothorn","year":"2006","journal-title":"J. Comput. Graph. Stat."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/15\/12426\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:25:58Z","timestamp":1760127958000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/15\/12426"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,4]]},"references-count":51,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["ijms241512426"],"URL":"https:\/\/doi.org\/10.3390\/ijms241512426","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,4]]}}}