{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:30:04Z","timestamp":1760236204042,"version":"build-2065373602"},"reference-count":55,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,11,7]],"date-time":"2021-11-07T00:00:00Z","timestamp":1636243200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Malignant pleural mesothelioma (MESO) has a poor prognosis despite aggressive treatment with surgery, radiation and chemotherapy, and novel therapeutic approaches are needed. IRF3 is a downstream molecule of the cGAS\/STING signaling pathway, but its roles have not been investigated in MESO. Methods: Various murine mesothelioma cell lines were inoculated into wild type (WT) and IRF3 knockout (IRF3KO) mice to compare tumor growth. AE17-bearing mice were treated with local radiotherapy (LRT) to evaluate the effect on tumor growth, and immune cell infiltration was analyzed by flow cytometry 20 days after tumor inoculation. TCGA data were used to examine the relationship between mRNA expression of IRF3 and genes of the cGAS\/STING signaling cascade on prognosis in MESO. Correlations between gene expression of IRF3, cGAS\/STING signaling pathway, and immune checkpoints were analyzed in TCGA MESO and our scRNA-Seq data from MESO patients. Results: In mouse mesothelioma models, AK7, RN5 and ZiP3 were completely rejected in IRF3KO mice 20 days after the tumor challenge. AE17tumor volume was slightly larger than WT mice around day 10 before shrinking and becoming significantly smaller than WT mice on day 20. LRT accelerated tumor shrinkage of AE17 tumors in IRF3KO mice. Compared with WT mice, the number of macrophages infiltrating the tumor of IRF3KO mice was significantly reduced, and CD4+ T cells and CD8+IFN\u03b3+ T cells were significantly increased. TCGA data showed that IRF3 expression was an unfavorable prognostic factor in MESO patients. IRF3 expression, the cGAS\/STING signaling pathway, and immune checkpoints were positively correlated. Conclusion: IRF3 could play a critical role in the tumor immune microenvironment of MESO.<\/jats:p>","DOI":"10.3390\/jcm10215196","type":"journal-article","created":{"date-parts":[[2021,11,7]],"date-time":"2021-11-07T20:41:14Z","timestamp":1636317674000},"page":"5196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["IRF3 Knockout Results in Partial or Complete Rejection of Murine Mesothelioma"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1769-5382","authenticated-orcid":false,"given":"Masaya","family":"Aoki","sequence":"first","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Princess Margaret Cancer Research Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Licun","family":"Wu","sequence":"additional","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Princess Margaret Cancer Research Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7697-2725","authenticated-orcid":false,"given":"Junichi","family":"Murakami","sequence":"additional","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Princess Margaret Cancer Research Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yidan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Princess Margaret Cancer Research Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hana","family":"Yun","sequence":"additional","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Princess Margaret Cancer Research Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2000-9427","authenticated-orcid":false,"given":"Marc","family":"de Perrot","sequence":"additional","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Princess Margaret Cancer Research Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada"},{"name":"Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada"},{"name":"Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0022-5223(19)36577-8","article-title":"The role of extrapleural pneumonectomy in malignant pleural mesothelioma. A Lung Cancer Study Group trial","volume":"102","author":"Rusch","year":"1991","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/BF02306613","article-title":"Surgically debulked malignant pleural mesothelioma: Results and prognostic factors","volume":"4","author":"Pass","year":"1997","journal-title":"Ann. Surg. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e532","DOI":"10.1016\/S1470-2045(17)30459-X","article-title":"Radiotherapy for the treatment of malignant pleural mesothelioma","volume":"18","author":"Wu","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1097\/JTO.0000000000000078","article-title":"A Feasibility Study Evaluating Surgery for Mesothelioma After Radiation Therapy: The \u201cSMART\u201d Approach for Resectable Malignant Pleural Mesothelioma","volume":"9","author":"Cho","year":"2014","journal-title":"J. Thorac. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/S1470-2045(20)30606-9","article-title":"Surgery for malignant pleural mesothelioma after radiotherapy (SMART): Final results from a single-centre, phase 2 trial","volume":"22","author":"Cho","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1067\/mtc.2001.116560","article-title":"A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma","volume":"122","author":"Rusch","year":"2001","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1093\/annonc\/mdm093","article-title":"Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma","volume":"18","author":"Weder","year":"2007","journal-title":"Ann. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3007","DOI":"10.1200\/JCO.2008.20.3943","article-title":"Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma","volume":"27","author":"Krug","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1183\/09031936.00039510","article-title":"European Organisation for Research and Treatment of Cancer (EORTC) Lung Cancer Group. Trimodality therapy for malignant pleural mesothelioma: Results from an EORTC phase II multicentre trial","volume":"36","author":"Baas","year":"2010","journal-title":"Eur. Respir. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/s10147-015-0925-1","article-title":"Trimodality strategy for treating malignant pleural mesothelioma: Results of a feasibility study of induction pemetrexed plus cisplatin followed by extrapleural pneumonectomy and postoperative hemithoracic radiation (Japan Mesothelioma Interest Group 0601 Trial)","volume":"21","author":"Hasegawa","year":"2015","journal-title":"Int. J. Clin. Oncol."},{"key":"ref_11","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_12","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1016\/j.jtho.2018.05.038","article-title":"Programmed Death 1 Blockade With Nivolumab in Patients With Recurrent Malignant Pleural Mesothelioma","volume":"13","author":"Zimmerman","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S1470-2045(18)30765-4","article-title":"Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): A multicentre, open-label, randomised, non-comparative, phase 2 trial","volume":"20","author":"Scherpereel","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1016\/j.annonc.2020.09.009","article-title":"A multicentre randomised phase III trial comparing pembrolizumab versus single-agent chemotherapy for advanced pre-treated malignant pleural mesothelioma: The European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial","volume":"31","author":"Popat","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.4049\/jimmunol.2000487","article-title":"Foxp3+ Regulatory T Cell Depletion after Nonablative Oligofractionated Irradiation Boosts the Abscopal Effects in Murine Malignant Mesothelioma","volume":"205","author":"Kohno","year":"2020","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Murakami, J., Wu, L., Kohno, M., Chan, M.-L., Zhao, Y., Yun, Z., Cho, B.C.J., and de Perrot, M. (2021). Triple-modality therapy maximizes antitumor immune responses in a mouse model of mesothelioma. Sci. Transl. Med., 13.","DOI":"10.1126\/scitranslmed.abd9882"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2988","DOI":"10.21037\/tlcr-20-673","article-title":"Immunotherapy in malignant pleural mesothelioma: A review of literature data","volume":"10","author":"Menis","year":"2021","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1126\/science.1232458","article-title":"Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway","volume":"339","author":"Sun","year":"2012","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.cytogfr.2014.05.003","article-title":"MITA\/STING: A central and multifaceted mediator in innate immune response","volume":"25","author":"Ran","year":"2014","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.omtn.2018.11.003","article-title":"An Analysis of the Expression and Association with Immune Cell Infiltration of the cGAS\/STING Pathway in Pan-Cancer","volume":"14","author":"An","year":"2018","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5675","DOI":"10.2147\/IJGM.S328225","article-title":"Overexpression of IRF3 Predicts Poor Prognosis in Clear Cell Renal Cell Carcinoma","volume":"14","author":"Wu","year":"2021","journal-title":"Int. J. Gen. Med."},{"key":"ref_22","first-page":"1","article-title":"Potential for treatment benefit of STING agonists plus immune checkpoint inhibitors in oral squamous cell carcinoma","volume":"21","author":"Zhu","year":"2021","journal-title":"BMC Oral Heal."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Decout, A., Katz, J.D., Venkatraman, S., and Ablasser, A. (2021). The cGAS\u2013STING pathway as a therapeutic target in inflammatory diseases. Nat. Rev. Immunol., 1\u201322.","DOI":"10.1038\/s41577-021-00524-z"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1777624","DOI":"10.1080\/2162402X.2020.1777624","article-title":"Trial watch: STING agonists in cancer therapy","volume":"9","author":"Zitvogel","year":"2020","journal-title":"OncoImmunology"},{"key":"ref_25","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_26","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1038\/s41388-018-0153-z","article-title":"How asbestos drives the tissue towards tumors: YAP activation, macrophage and mesothelial precursor recruitment, RNA editing, and somatic mutations","volume":"37","author":"Rehrauer","year":"2018","journal-title":"Oncogene"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5502","DOI":"10.1158\/1078-0432.CCR-17-0438","article-title":"In Situ Vaccination after Accelerated Hypofractionated Radiation and Surgery in a Mesothelioma Mouse Model","volume":"23","author":"Wu","year":"2017","journal-title":"Clin Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13073-018-0590-x","article-title":"Landscape of genomic alterations in high-grade serous ovarian cancer from exceptional long- and short-term survivors","volume":"10","author":"Yang","year":"2018","journal-title":"Genome Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5137","DOI":"10.1038\/s41467-021-25432-7","article-title":"Pan-cancer analysis of longitudinal metastatic tumors reveals genomic alterations and immune landscape dynamics associated with pembrolizumab sensitivity","volume":"12","author":"Lien","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.cell.2019.05.035","article-title":"The Cytoplasmic DNA Sensor cGAS Promotes Mitotic Cell Death","volume":"178","author":"Zierhut","year":"2019","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4774","DOI":"10.1158\/1078-0432.CCR-15-1362","article-title":"Molecular Pathways: Targeting the Stimulator of Interferon Genes (STING) in the Immunotherapy of Cancer","volume":"21","author":"Corrales","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1038\/ni.3558","article-title":"Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing","volume":"17","author":"Chen","year":"2016","journal-title":"Nat. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1172\/JCI86892","article-title":"The host STING pathway at the interface of cancer and immunity","volume":"126","author":"Corrales","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_34","first-page":"5148","article-title":"In vivo interferon regulatory factor 3 tumor suppressor activity in B16 melanoma tumors","volume":"62","author":"Duguay","year":"2002","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"15272","DOI":"10.1074\/jbc.M205792200","article-title":"Oncogenic Potential of a Dominant Negative Mutant of Interferon Regulatory Factor 3","volume":"278","author":"Kim","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5253","DOI":"10.1073\/pnas.1803936115","article-title":"Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice","volume":"115","author":"Yanai","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2835","DOI":"10.4049\/jimmunol.1201788","article-title":"STING\/MPYS mediates host defense against Listeria monocytogenes infection by regulating Ly6C(hi) monocyte migration","volume":"190","author":"Jin","year":"2013","journal-title":"J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1161\/HYPERTENSIONAHA.116.08395","article-title":"Ablation of Interferon Regulatory Factor 3 Protects Against Atherosclerosis in Apolipoprotein E\u2013Deficient Mice","volume":"69","author":"Liu","year":"2017","journal-title":"Hypertension"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Zhang, Q., Liu, L., Gong, C.-Y., Shi, H.-S., Zeng, Y.-H., Wang, X.-Z., Zhao, Y.-W., and Wei, Y.-Q. (2012). Prognostic Significance of Tumor-Associated Macrophages in Solid Tumor: A Meta-Analysis of the Literature. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0050946"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1016\/j.ccr.2014.05.016","article-title":"Targeting Tumor-Associated Macrophages with Anti-CSF-1R Antibody Reveals a Strategy for Cancer Therapy","volume":"25","author":"Ries","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1158\/2159-8274.CD-10-0028","article-title":"Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy","volume":"1","author":"DeNardo","year":"2011","journal-title":"Cancer Discov."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.ccell.2014.09.006","article-title":"Macrophage IL-10 Blocks CD8+ T Cell-Dependent Responses to Chemotherapy by Suppressing IL-12 Expression in Intratumoral Dendritic Cells","volume":"26","author":"Ruffell","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4224","DOI":"10.1172\/JCI127458","article-title":"Type I IFN protects cancer cells from CD8+ T cell-mediated cytotoxicity after radiation","volume":"129","author":"Chen","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"12468","DOI":"10.18632\/oncotarget.3487","article-title":"Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model","volume":"6","author":"Wu","year":"2015","journal-title":"Oncotarget"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/s41416-020-0942-3","article-title":"Radiation-induced bystander and abscopal effects: Important lessons from preclinical models","volume":"123","author":"Daguenet","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"398","DOI":"10.4049\/jimmunol.1900217","article-title":"IRF3 Signaling within the Mouse Stroma Influences Sepsis Pathogenesis","volume":"206","author":"Heipertz","year":"2020","journal-title":"J. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5368","DOI":"10.1158\/1078-0432.CCR-18-1038","article-title":"Resistance to Radiotherapy and PD-L1 Blockade Is Mediated by TIM-3 Upregulation and Regulatory T-Cell Infiltration","volume":"24","author":"Oweida","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_48","first-page":"101","article-title":"TIM-3 restrains anti-tumour immunity by regulating inflammasome activation","volume":"595","author":"Dixon","year":"2021","journal-title":"Nat. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nri.2018.3","article-title":"The tumour glyco-code as a novel immune checkpoint for immunotherapy","volume":"18","author":"Schetters","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.ccell.2019.06.006","article-title":"Glycosylation in the Era of Cancer-Targeted Therapy: Where Are We Heading?","volume":"36","author":"Mereiter","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1084\/jem.20171116","article-title":"Targeting IRF3 as a YAP agonist therapy against gastric cancer","volume":"215","author":"Jiao","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"E3769","DOI":"10.1073\/pnas.1722434115","article-title":"Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor\u2013stroma crosstalk","volume":"115","author":"Orozco","year":"2018","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Cagnoni, A.J., Giribaldi, M.L., Blidner, A.G., Cutine, A.M., Gatto, S.G., Morales, R.M., Salatino, M., Abba, M.C., Croci, D.O., and Mari\u00f1o, K.V. (2021). Galectin-1 fosters an immunosuppressive microenvironment in colorectal cancer by reprogramming CD8+ regulatory T cells. Proc. Natl. Acad. Sci., 118.","DOI":"10.1073\/pnas.2102950118"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"5553","DOI":"10.1172\/JCI129025","article-title":"Galectin-1\u2013driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance","volume":"129","author":"Nambiar","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5762","DOI":"10.1038\/s41467-020-19627-7","article-title":"IRF3 prevents colorectal tumorigenesis via inhibiting the nuclear translocation of \u03b2-catenin","volume":"11","author":"Tian","year":"2020","journal-title":"Nat. Commun."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/21\/5196\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:27:01Z","timestamp":1760167621000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/21\/5196"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,7]]},"references-count":55,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["jcm10215196"],"URL":"https:\/\/doi.org\/10.3390\/jcm10215196","relation":{},"ISSN":["2077-0383"],"issn-type":[{"type":"electronic","value":"2077-0383"}],"subject":[],"published":{"date-parts":[[2021,11,7]]}}}