{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T07:16:11Z","timestamp":1792826171369,"version":"4.5.0"},"reference-count":69,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T00:00:00Z","timestamp":1692921600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Oncolytic adenoviruses (OAds) present a promising path for cancer treatment due to their selectivity in infecting and lysing tumor cells and their ability to stimulate the immune response. In this study, we use an ordinary differential equation (ODE) model of tumor growth inhibited by oncolytic virus activity to parameterize previous research on the effect of genetically re-engineered OAds in A549 lung cancer tumors in murine models. We find that the data are best fit by a model that accounts for an immune response, and that the immune response provides a mechanism for elimination of the tumor. We also find that parameter estimates for the most effective OAds share characteristics, most notably a high infection rate and low viral clearance rate, that might be potential reasons for these viruses\u2019 efficacy in delaying tumor growth. Further studies observing E1A and P19 recombined viruses in different tumor environments may further illuminate the extent of the effects of these genetic modifications.<\/jats:p>","DOI":"10.3390\/v15091812","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T08:33:09Z","timestamp":1692952389000},"page":"1812","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Mathematical Modeling of Oncolytic Virus Therapy Reveals Role of the Immune Response"],"prefix":"10.3390","volume":"15","author":[{"given":"Ela","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Physics & Astronomy, Texas Christian University, Fort Worth, TX 76109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3592-6770","authenticated-orcid":false,"given":"Hana M.","family":"Dobrovolny","sequence":"additional","affiliation":[{"name":"Department of Physics & Astronomy, Texas Christian University, Fort Worth, TX 76109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1001\/jama.2021.5469","article-title":"The leading causes of death in the US for 2020","volume":"325","author":"Ahmad","year":"2021","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3674","DOI":"10.1002\/cncr.34407","article-title":"Risk of prostate cancer and death after benign transurethral resection of the prostate\u2014A 20-year population-based analysis","volume":"128","author":"Hilscher","year":"2022","journal-title":"Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1007\/s00520-007-0380-2","article-title":"Symptoms and treatment burden associated with cancer treatment: Results from a cross-sectional national survey in the US","volume":"16","author":"Henry","year":"2008","journal-title":"Support. Care Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/j.mcna.2017.06.003","article-title":"Long-Term and Latent Side Effects of Specific Cancer Types","volume":"101","author":"Gegechkori","year":"2017","journal-title":"Med. Clin. N. Am."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1001\/jamaoncol.2016.2064","article-title":"Oncolytic viruses in cancer treatment: A review","volume":"3","author":"Lawler","year":"2017","journal-title":"JAMA Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3390\/biomedicines8030061","article-title":"Cancer vaccines and oncolytic viruses exert profoundly lower side effects in cancer patients than other systemic therapies: A comparative analysis","volume":"8","author":"Schirrmacher","year":"2020","journal-title":"Biomedicines"},{"key":"ref_7","first-page":"4192","article-title":"Advances in the clinical development of oncolytic viruses","volume":"14","author":"Li","year":"2022","journal-title":"Am. J. Transl. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"141","DOI":"10.2174\/156800907780058817","article-title":"Clinical trials with oncolytic adenovirus in China","volume":"7","author":"Yu","year":"2007","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"103","DOI":"10.2217\/imt.15.116","article-title":"Interview with Robert Coffin, inventor of T-VEC: The first oncolytic immunotherapy approved for the treatment of cancer","volume":"8","author":"Coffin","year":"2016","journal-title":"Immunotherapy"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.bulm.2003.08.016","article-title":"Analysis of a three-way race between tumor growth, a replication-competent virus and an immune response","volume":"66","author":"Wu","year":"2004","journal-title":"Bull. Math. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"971674","DOI":"10.3389\/fimmu.2022.971674","article-title":"The gamble between oncolytic virus therapy and IFN","volume":"13","author":"Li","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"163","DOI":"10.3390\/biomedicines2020163","article-title":"Tumor Restrictions to Oncolytic Virus","volume":"2","author":"Hinkkanen","year":"2014","journal-title":"Biomedicines"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"229","DOI":"10.5501\/wjv.v10.i5.229","article-title":"Oncolytic virus therapy in cancer: A current review","volume":"10","author":"Apolonio","year":"2021","journal-title":"World J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8636","DOI":"10.1002\/jcp.27850","article-title":"Oncolytic adenovirus: A tool for cancer therapy in combination with other therapeutic approaches","volume":"234","author":"Goradel","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10522","DOI":"10.3390\/ijms221910522","article-title":"Concepts in oncolytic adenovirus therapy","volume":"22","author":"Mantwill","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1158\/1535-7163.MCT-21-0240","article-title":"Novel group C oncolytic adenoviruses carrying a microRNA inhibitor demonstrate enhanced oncolytic activity in vitro and in vivoEnhanced oncolytic activity using a miRNA inhibitor","volume":"21","author":"Doerner","year":"2022","journal-title":"Mol. Cancer Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/nrmicro1927","article-title":"Reprogrammed viruses as cancer therapeutics: Targeted, armed and shielded","volume":"6","author":"Cattaneo","year":"2008","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10664","DOI":"10.1158\/0008-5472.CAN-07-3107","article-title":"Matrix metalloproteinases-1 and -8 improve the distribution and efficacy of an oncolytic virus","volume":"67","author":"Mok","year":"2007","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1038\/mt.2010.98","article-title":"Potentiating Cancer Immunotherapy Using an Oncolytic Virus","volume":"18","author":"Bridle","year":"2010","journal-title":"Mol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1038\/mt.2010.173","article-title":"Minimal RB-responsive E1A promoter modification to attain potency, selectivity, and transgene-arming capacity in oncolytic adenoviruses","volume":"18","author":"Rojas","year":"2010","journal-title":"Mol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"10712","DOI":"10.18632\/oncotarget.3544","article-title":"Therapy of prostate cancer using a novel cancer terminator virus and a small molecule BH-3 mimetic","volume":"6","author":"Sarkar","year":"2015","journal-title":"Oncotarget"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1038\/srep01363","article-title":"RNAi suppressor P19 can be broadly exploited for enhanced adenovirus replication and microRNA knockdown experiments","volume":"3","author":"Rauschhuber","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1002\/wsbm.1332","article-title":"Computational modeling approaches to the dynamics of oncolytic viruses","volume":"8","author":"Wodarz","year":"2016","journal-title":"Wiley Interdiscip. Rev. Syst. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8760371","DOI":"10.1155\/2018\/8760371","article-title":"Developing a minimally structured mathematical model of cancer treatment with oncolytic viruses and dendritic cell injections","volume":"2018","author":"Gevertz","year":"2018","journal-title":"Comput. Math. Methods Med."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Mahasa, K.J., Eladdadi, A., de Pillis, L., and Ouifki, R. (2017). Oncolytic potency and reduced virus tumor-specificity in oncolytic virotherapy. A mathematical modelling approach. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0184347"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"151","DOI":"10.3389\/fphys.2020.00151","article-title":"Modeling Oncolytic Viral Therapy, Immune Checkpoint Inhibition, and the Complex Dynamics of Innate and Adaptive Immunity in Glioblastoma Treatment","volume":"11","author":"Storey","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s10441-019-09357-9","article-title":"Investigating Macrophages Plasticity Following Tumour-Immune Interactions During Oncolytic Therapies","volume":"67","author":"Eftimie","year":"2020","journal-title":"Acta Biotheoret."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"705443","DOI":"10.3389\/fphar.2021.705443","article-title":"Mechanistic Modeling of a Novel Oncolytic Virus, V937, to Describe Viral Kinetic and Dynamic Processes Following Intratumoral and Intravenous Administration","volume":"12","author":"Freshwater","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.jtbi.2014.04.030","article-title":"Modeling oncolytic virotherapy: Is complete tumor-tropism too much of a good thing?","volume":"358","author":"Okamoto","year":"2014","journal-title":"J. Theor. Biol."},{"key":"ref_30","first-page":"28","article-title":"Modeling the spatiotemporal dynamics of virotherapy and immune response as a treatment for cancer","volume":"2019","author":"Simbawa","year":"2019","journal-title":"Comm. Math. Biol. Neurosci."},{"key":"ref_31","first-page":"1317","article-title":"Validation and analysis of a mathematical model of a replication-competent oncolytic virus for cancer treatment: Implications for virus design and delivery","volume":"63","author":"Wein","year":"2003","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"103116","DOI":"10.1016\/j.nonrwa.2020.103116","article-title":"Analysis of a delayed and diffusive oncolytic M1 virotherapy model with immune response","volume":"55","author":"Elaiw","year":"2020","journal-title":"Nonlin. Anal. Real World Appl."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1158\/0008-5472.CAN-08-2173","article-title":"A Multiscale Mathematical Model for Oncolytic Virotherapy","volume":"60","author":"Paiva","year":"2009","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2932","DOI":"10.1007\/s11538-011-9653-5","article-title":"Multi-Stability and Multi-Instability Phenomena in a Mathematical Model of Tumor-Immune-Virus Interactions","volume":"73","author":"Eftimie","year":"2011","journal-title":"Bull. Math. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.mbs.2015.01.015","article-title":"Analysis of virotherapy in solid tumor invasion","volume":"263","author":"Malinzi","year":"2015","journal-title":"Math. Biosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"877155","DOI":"10.3389\/fonc.2022.877155","article-title":"Efficacy and Safety of Recombinant Human Adenovirus Type 5 (H101) in Persistent, Recurrent, or Metastatic Gynecologic Malignancies: A Retrospective Study","volume":"12","author":"Zhang","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7590","DOI":"10.1128\/JVI.01623-05","article-title":"Kinetics of influenza A virus infection in humans","volume":"80","author":"Baccam","year":"2006","journal-title":"J. Virol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Pawelek, K.A., Huynh, G.T., Quinlivan, M., Cullinane, A., Rong, L., and Perelson, A.S. (2012). Modeling Within-Host Dynamics of Influenza Virus Infection Including Immune Responses. PLoS Comp. Biol., 8.","DOI":"10.1371\/journal.pcbi.1002588"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1098\/rsif.2009.0067","article-title":"Towards a quantitative understanding of the within-host dynamics of influenza A infections","volume":"7","author":"Handel","year":"2010","journal-title":"J. R. Soc. Interface"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Yu, J.L., Jang, S.R., and Liu, K.Y. (2023). Exploring the Interactions of Oncolytic Viral Therapy and Immunotherapy of Anti-CTLA-4 for Malignant Melanoma Mice Model. Cells, 12.","DOI":"10.3390\/cells12030507"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Rodriguez-Brenes, I.A., Hofacre, A., Fan, H., and Wodarz, D. (2017). Complex Dynamics of Virus Spread from Low Infection Multiplicities: Implications for the Spread of Oncolytic Viruses. PLoS Comp. Biol., 13.","DOI":"10.1371\/journal.pcbi.1005241"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s10589-010-9329-3","article-title":"Implementing the Nelder-Mead simplex algorithm with adaptive parameters","volume":"51","author":"Gao","year":"2012","journal-title":"Comput. Optim. Appl."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1109\/MCSE.2007.55","article-title":"Matplotlib: A 2D graphics environment","volume":"9","author":"Hunter","year":"2007","journal-title":"Comput. Sci. Eng."},{"key":"ref_44","first-page":"54","article-title":"Bootstrap methods for standard errors, confidence intervals, and other measures of statistical accuracy","volume":"1","author":"Efron","year":"1986","journal-title":"Stat. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Bagheri, N., Shiina, M., Lauffenburger, D.A., and Korn, W.M. (2011). A Dynamical Systems Model for Combinatorial Cancer Therapy Enhances Oncolytic Adenovirus Efficacy by MEK-Inhibition. PLoS Comp. Biol., 7.","DOI":"10.1371\/journal.pcbi.1001085"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1109\/TAC.1974.1100705","article-title":"A new look at the statistical model identification","volume":"19","author":"Akaike","year":"1974","journal-title":"IEEE Trans. Autom. Control"},{"key":"ref_47","unstructured":"Sakamoto, Y., Ishiguro, M., and Kitagawa, G. (1986). Akaike Information Criterion Statistics, D. Reidel."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1002\/cpt.2937","article-title":"Assessment of clinical response to V937 oncolytic virus after intravenous or intratumoral administration using physiologically-based modelling","volume":"114","author":"Mayawala","year":"2023","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1089\/hum.2009.135","article-title":"The case of oncolytic viruses versus the immune system: Waiting on the judgment of Solomon","volume":"20","author":"Prestwich","year":"2009","journal-title":"Hum. Gene Ther."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Godlewski, J., Farhath, M., Ricklefs, F.L., Passaro, C., Kiel, K., Nakashima, H., Chiocca, E.A., and Bronisz, A. (2021). Oncolytic Virus Therapy Alters the Secretome of Targeted Glioblastoma Cells. Cancers, 13.","DOI":"10.3390\/cancers13061287"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"24694","DOI":"10.18632\/oncotarget.15788","article-title":"Interferon alpha antagonizes the anti-hepatoma activity of the oncolytic virus M1 by stimulating anti-viral immunity","volume":"8","author":"Ying","year":"2017","journal-title":"Oncotarget"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1093\/jnci\/djm229","article-title":"Effect of tumor microenvironment modulation on the efficacy of oncolytic virus therapy","volume":"99","author":"Kurozumi","year":"2007","journal-title":"J. Nat. Cancer Inst."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"44892","DOI":"10.18632\/oncotarget.6285","article-title":"Sensitivity of human pleural mesothelioma to oncolytic measles virus depends on defects of the type I interferon response","volume":"6","author":"Achard","year":"2015","journal-title":"Oncotarget"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"105749","DOI":"10.1016\/j.isci.2022.105749","article-title":"Cellular resistance to an oncolytic virus is driven by chronic activation of innate immunity","volume":"26","author":"Larrieux","year":"2022","journal-title":"iScience"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/cgt.2011.49","article-title":"Vesicular stomatitis virus as a treatment for colorectal cancer","volume":"18","author":"Stewart","year":"2011","journal-title":"Cancer Gene Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1038\/77558","article-title":"Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus","volume":"6","author":"Stojdl","year":"2000","journal-title":"Nat. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.virol.2014.10.026","article-title":"Induction of apoptosis in pancreatic cancer cells by vesicular stomatitis virus","volume":"474","author":"Felt","year":"2015","journal-title":"Virology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1007\/s11538-018-0424-4","article-title":"Mathematical modelling of the interaction between cancer cells and an oncolytic virus: Insights into the effects of treatment protocols","volume":"80","author":"Jenner","year":"2018","journal-title":"Bull. Math. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.3934\/mbe.2020126","article-title":"Application of control theory in a delayed-infection and immune-evading oncolytic virotherapy","volume":"17","author":"Lee","year":"2020","journal-title":"Math. Biosci. Eng."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1051\/mmnp\/201611505","article-title":"Bifurcations and Chaotic Dynamics in a Tumour-Immune-Virus System","volume":"11","author":"Eftimie","year":"2016","journal-title":"Math. Model. Nat. Phenom."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Kim, D., Shin, D.H., and Sung, C.K. (2022). The Optimal Balance between Oncolytic Viruses and Natural Killer Cells: A Mathematical Approach. Mathematics, 10.","DOI":"10.3390\/math10183370"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s11538-021-00903-6","article-title":"Natural Killer Cells Recruitment in Oncolytic Virotherapy: A Mathematical Model","volume":"83","author":"Senekal","year":"2021","journal-title":"Bull. Math. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Friedman, A., and Lai, X. (2018). Combination therapy for cancer with oncolytic virus and checkpoint inhibitor: A mathematical model. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0192449"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.bbrc.2014.09.107","article-title":"Establishment of a mouse melanoma model system for the efficient infection and replication of human adenovirus type 5-based oncolytic virus","volume":"453","author":"Kang","year":"2014","journal-title":"Biochem. Biophys. Res. Comm."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/s12276-019-0321-4","article-title":"High levels of Daxx due to low cellular levels of HSP25 in murine cancer cells result in inefficient adenovirus replication","volume":"51","author":"Han","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_66","first-page":"433","article-title":"Differences in Innate Immune Response between Man and Mouse","volume":"34","author":"Zschaler","year":"2014","journal-title":"Crit. Rev. Immunol."},{"key":"ref_67","first-page":"134","article-title":"Translating Mouse Models: Immune Variation and Efficacy Testing","volume":"45","author":"Sellers","year":"2017","journal-title":"Crit. Rev. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1098\/rsif.2009.0386","article-title":"The construction of next-generation matrices for compartmental epidemic models","volume":"7","author":"Diekmann","year":"2010","journal-title":"J. R. Soc. Interface"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"24","DOI":"10.21105\/joss.00024","article-title":"Corner.py: Scatterplot matrices in python","volume":"1","year":"2016","journal-title":"J. Open Source Softw."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/9\/1812\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:39:08Z","timestamp":1760128748000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/9\/1812"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,25]]},"references-count":69,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["v15091812"],"URL":"https:\/\/doi.org\/10.3390\/v15091812","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,25]]}}}