{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T01:23:31Z","timestamp":1766712211108,"version":"build-2065373602"},"reference-count":63,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T00:00:00Z","timestamp":1656633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"TecNM project 13747.22-P Modelizado computacional y experimentos in silico aplicados al an\u00e1lisis y control de sistemas biol\u00f3gicos","award":["14166.22-P"],"award-info":[{"award-number":["14166.22-P"]}]},{"name":"Yolocuauhtli Salazar by the TecNM","award":["14166.22-P"],"award-info":[{"award-number":["14166.22-P"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Cancer with all its more than 200 variants continues to be a major health problem around the world with nearly 10 million deaths recorded in 2020, and leukemia accounted for more than 300,000 cases according to the Global Cancer Observatory. Although new treatment strategies are currently being developed in several ongoing clinical trials, the high complexity of cancer evolution and its survival mechanisms remain as an open problem that needs to be addressed to further enhanced the application of therapies. In this work, we aim to explore cancer growth, particularly chronic lymphocytic leukemia, under the combined application of CAR-T cells and chlorambucil as a nonlinear dynamical system in the form of first-order Ordinary Differential Equations. Therefore, by means of nonlinear theories, sufficient conditions are established for the eradication of leukemia cells, as well as necessary conditions for the long-term persistence of both CAR-T and cancer cells. Persistence conditions are important in treatment protocol design as these provide a threshold below which the dose will not be enough to produce a cytotoxic effect in the tumour population. In silico experimentations allowed us to design therapy administration protocols to ensure the complete eradication of leukemia cells in the system under study when considering only the infusion of CAR-T cells and for the combined application of chemoimmunotherapy. All results are illustrated through numerical simulations. Further, equations to estimate cytotoxicity of chlorambucil and CAR-T cells to leukemia cancer cells were formulated and thoroughly discussed with a 95% confidence interval for the parameters involved in each formula.<\/jats:p>","DOI":"10.3390\/pharmaceutics14071396","type":"journal-article","created":{"date-parts":[[2022,7,4]],"date-time":"2022-07-04T20:59:18Z","timestamp":1656968358000},"page":"1396","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Chemoimmunotherapy Administration Protocol Design for the Treatment of Leukemia through Mathematical Modeling and In Silico Experimentation"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6567-1065","authenticated-orcid":false,"given":"Paul A.","family":"Valle","sequence":"first","affiliation":[{"name":"Postgraduate Program in Engineering Sciences, BioMath Research Group, Tecnol\u00f3gico Nacional de M\u00e9xico\/IT Tijuana, Blvd. Alberto Lim\u00f3n Padilla s\/n, Tijuana 22454, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9887-1514","authenticated-orcid":false,"given":"Raul","family":"Garrido","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Engineering Sciences, BioMath Research Group, Tecnol\u00f3gico Nacional de M\u00e9xico\/IT Tijuana, Blvd. Alberto Lim\u00f3n Padilla s\/n, Tijuana 22454, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5563-2692","authenticated-orcid":false,"given":"Yolocuauhtli","family":"Salazar","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Engineering, Tecnol\u00f3gico Nacional de M\u00e9xico\/IT Durango, Blvd. Felipe Pescador 1830 ote., Durango 34080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1219-0433","authenticated-orcid":false,"given":"Luis N.","family":"Coria","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Engineering Sciences, BioMath Research Group, Tecnol\u00f3gico Nacional de M\u00e9xico\/IT Tijuana, Blvd. Alberto Lim\u00f3n Padilla s\/n, Tijuana 22454, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6453-9529","authenticated-orcid":false,"given":"Corina","family":"Plata","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Engineering Sciences, BioMath Research Group, Tecnol\u00f3gico Nacional de M\u00e9xico\/IT Tijuana, Blvd. Alberto Lim\u00f3n Padilla s\/n, Tijuana 22454, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,1]]},"reference":[{"key":"ref_1","unstructured":"Chennamadhavuni, A., Lyengar, V., and Shimanovsky, A. (2022, May 23). Leukemia, StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK560490\/."},{"key":"ref_2","unstructured":"(2022, May 23). Global Cancer Observatory. Available online: https:\/\/gco.iarc.fr\/."},{"key":"ref_3","unstructured":"C Codes (2022, May 23). National Cancer Institute, Available online: https:\/\/training.seer.cancer.gov\/icd10cm\/neoplasm\/c-codes.htmll."},{"key":"ref_4","unstructured":"Chronic Lymphocytic Leukemia (CLL) (2022, May 23). American Cancer Society. Available online: https:\/\/www.cancer.org\/cancer\/chronic-lymphocytic-leukemia.html\/."},{"key":"ref_5","unstructured":"(2022, May 23). SEER Cancer Stat Facts: Chronic Lymphocytic Leukemia, Available online: https:\/\/seer.cancer.gov\/statfacts\/html\/clyl.html."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1002\/ajh.26367","article-title":"Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures","volume":"96","author":"Hallek","year":"2021","journal-title":"Am. J. Hematol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"303ra139","DOI":"10.1126\/scitranslmed.aac5415","article-title":"Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia","volume":"7","author":"Porter","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1111\/bjh.16625","article-title":"A five-year follow-up of untreated patients with chronic lymphocytic leukaemia treated with ofatumumab and chlorambucil: Final analysis of the Complement 1 phase 3 trial","volume":"190","author":"Offner","year":"2020","journal-title":"Br. J. Haematol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1182\/blood.V126.23.184.184","article-title":"Anti-CD19 chimeric antigen receptor-modified T Cell therapy for B cell non-Hodgkin lymphoma and chronic lymphocytic leukemia: Fludarabine and cyclophosphamide lymphodepletion improves in vivo expansion and persistence of CAR-T cells and clinical outcomes","volume":"126","author":"Turtle","year":"2015","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1093\/neuonc\/noy032","article-title":"CAR T-cell therapy for glioblastoma: Recent clinical advances and future challenges","volume":"20","author":"Bagley","year":"2018","journal-title":"Neuro-Oncology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.apsb.2018.03.001","article-title":"The application of CAR-T cell therapy in hematological malignancies: Advantages and challenges","volume":"8","author":"Zhao","year":"2018","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_12","unstructured":"National Cancer Institute (2022, May 23). CAR T Cells: Engineering Patients Immune Cells to Treat Their Cancers, Available online: https:\/\/www.cancer.gov\/about-cancer\/treatment\/research\/car-t-cells."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ivica, N.A., and Young, C.M. (2021). Tracking the CAR-T revolution: Analysis of Clinical Trials of CAR-T and TCR-T therapies for the treatment of cancer (1997\u20132020). Healthcare, 9.","DOI":"10.20944\/preprints202107.0198.v1"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Mancikova, V., and Smida, M. (2021). Current state of car T-cell therapy in chronic lymphocytic leukemia. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115536"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"660","DOI":"10.3390\/hemato2040043","article-title":"Current Status of CAR-T Cell Therapy in Multiple Myeloma","volume":"2","year":"2021","journal-title":"Hemato"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1038\/s41423-020-00555-x","article-title":"Clinical development of CAR T cell therapy in China: 2020 update","volume":"18","author":"Wei","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/s41434-021-00246-w","article-title":"Current status and perspective of CAR-T and CAR-NK cell therapy trials in Germany","volume":"28","author":"Albinger","year":"2021","journal-title":"Gene Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/mt.2011.272","article-title":"Mathematical modeling in immunotherapy of cancer: Personalizing clinical trials","volume":"20","author":"Agur","year":"2012","journal-title":"Mol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Cristini, V., Koay, E., and Wang, Z. (2017). An Introduction to Physical Oncology: How Mechanistic Mathematical Modeling Can Improve Cancer Therapy Outcomes, CRC Press.","DOI":"10.4324\/9781315374499"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Valle, P.A., Coria, L.N., and Plata, C. (2021). Personalized Immunotherapy Treatment Strategies for a Dynamical System of Chronic Myelogenous Leukemia. Cancers, 13.","DOI":"10.3390\/cancers13092030"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kronik, N., Kogan, Y., Elishmereni, M., Halevi-Tobias, K., Vuk-Pavlovi\u0107, S., and Agur, Z. (2010). Predicting outcomes of prostate cancer immunotherapy by personalized mathematical models. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0015482"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.apm.2020.09.021","article-title":"Chemoimmunotherapy for the treatment of prostate cancer: Insights from mathematical modelling","volume":"90","author":"Valle","year":"2021","journal-title":"Appl. Math. Model."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Oke, S.I., Matadi, M.B., and Xulu, S.S. (2018). Optimal control analysis of a mathematical model for breast cancer. Math. Comput. Appl., 23.","DOI":"10.20944\/preprints201802.0004.v1"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Mehdizadeh, R., Shariatpanahi, S.P., Goliaei, B., Peyvandi, S., and R\u00fcegg, C. (2021). Dormant tumor cell vaccination: A mathematical model of immunological dormancy in triple-negative breast cancer. Cancers, 13.","DOI":"10.3390\/cancers13020245"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Guzev, E., Luboshits, G., Bunimovich-Mendrazitsky, S., and Firer, M.A. (2021). Experimental Validation of a Mathematical Model to Describe the Drug Cytotoxicity of Leukemic Cells. Symmetry, 13.","DOI":"10.3390\/sym13101760"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.jtbi.2003.11.024","article-title":"A mathematical model for chronic myelogenous leukemia (CML) and T cell interaction","volume":"227","author":"Moore","year":"2004","journal-title":"J. Theory Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"105684","DOI":"10.1016\/j.cnsns.2020.105684","article-title":"CAR T cells for T-cell leukemias: Insights from mathematical models","volume":"96","author":"Rosa","year":"2021","journal-title":"Commun. Nonlinear Sci. Numer. Simul."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"105570","DOI":"10.1016\/j.cnsns.2020.105570","article-title":"CAR T cell therapy in B-cell acute lymphoblastic leukaemia: Insights from mathematical models","volume":"94","author":"Sabir","year":"2021","journal-title":"Commun. Nonlinear Sci. Numer. Simul."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"441","DOI":"10.3390\/hemato2030028","article-title":"CAR-T Cell Therapy for the Treatment of ALL: Eradication Conditions and In Silico Experimentation","volume":"2","author":"Valle","year":"2021","journal-title":"Hemato"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6640051","DOI":"10.1155\/2021\/6640051","article-title":"Lung Cancer Radiotherapy: Simulation and Analysis Based on a Multicomponent Mathematical Model","volume":"2021","author":"Hong","year":"2021","journal-title":"Comput. Math. Methods Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1007\/s00262-007-0387-z","article-title":"Improving alloreactive CTL immunotherapy for malignant gliomas using a simulation model of their interactive dynamics","volume":"57","author":"Kronik","year":"2008","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.mbs.2017.04.006","article-title":"Quantifying the role of immunotherapeutic drug T11 target structure in progression of malignant gliomas: Mathematical modeling and dynamical perspective","volume":"289","author":"Khajanchi","year":"2017","journal-title":"Math. Biosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.chaos.2018.06.028","article-title":"Modeling the dynamics of glioma-immune surveillance","volume":"114","author":"Khajanchi","year":"2018","journal-title":"Chaos Solitons Fractals"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s002850050127","article-title":"Modeling immunotherapy of the tumor\u2013immune interaction","volume":"37","author":"Kirschner","year":"1998","journal-title":"J. Math. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7950","DOI":"10.1158\/0008-5472.CAN-05-0564","article-title":"A validated mathematical model of cell-mediated immune response to tumor growth","volume":"65","author":"Radunskaya","year":"2005","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.jtbi.2005.06.037","article-title":"Mixed immunotherapy and chemotherapy of tumors: Modeling, applications and biological interpretations","volume":"238","author":"Gu","year":"2006","journal-title":"J. Theor. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1080\/17486700802216301","article-title":"Mathematical model creation for cancer chemo-immunotherapy","volume":"10","author":"Gu","year":"2009","journal-title":"Comput. Math. Methods Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1142\/S0218127410025417","article-title":"Chaos in a three-dimensional cancer model","volume":"20","author":"Itik","year":"2010","journal-title":"Int. J. Bifurc. Chaos"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Le\u00f3n-Triana, O., P\u00e9rez-Mart\u00ednez, A., Ram\u00edrez-Orellana, M., and P\u00e9rez-Garc\u00eda, V.M. (2021). Dual-target CAR-Ts with on-and off-tumour activity may override immune suppression in solid cancers: A mathematical proof of concept. Cancers, 13.","DOI":"10.3390\/cancers13040703"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.1109\/9.975508","article-title":"Stability properties of equilibria of classes of cooperative systems","volume":"46","author":"Aeyels","year":"2001","journal-title":"IEEE Trans. Autom. Control"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4012","DOI":"10.1200\/JCO.2007.14.3065","article-title":"New technologies for human cancer imaging","volume":"26","author":"Frangioni","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Milo, R., and Phillips, R. (2016). Cell Biology by the Numbers, Garland Science, Taylor & Francis Group, LLC.","DOI":"10.1201\/9780429258770"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"012004","DOI":"10.1088\/1742-6596\/811\/1\/012004","article-title":"Modeling cancer evolution: Evolutionary escape under immune system control","volume":"811","author":"Korobeinikov","year":"2017","journal-title":"J. Phys. Conf. Ser."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/S0140-6736(14)61403-3","article-title":"T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial","volume":"385","author":"Lee","year":"2015","journal-title":"Lancet"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Chen, Y., Sun, J., Liu, H., Yin, G., and Xie, Q. (2019). Immunotherapy deriving from CAR-T cell treatment in autoimmune diseases. J. Immunol. Res., 2019.","DOI":"10.1155\/2019\/5727516"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/s41388-020-01501-x","article-title":"Counteracting CAR T cell dysfunction","volume":"40","author":"Poorebrahim","year":"2021","journal-title":"Oncogene"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Thomas, P., Galopin, N., Bon\u00e9randi, E., Cl\u00e9menceau, B., Fougeray, S., and Birkl\u00e9, S. (2021). CAR T Cell Therapy\u2019s Potential for Pediatric Brain Tumors. Cancers, 13.","DOI":"10.3390\/cancers13215445"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3","DOI":"10.14694\/EdBook_AM.2014.34.3","article-title":"Cancer log-kill revisited","volume":"34","author":"Norton","year":"2014","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"ref_49","unstructured":"Britannica, The Editors of Encyclopaedia (2022, April 02). Avogadros Number. Encyclopedia Britannica., Available online: https:\/\/www.britannica.com\/science\/Avogadros-number."},{"key":"ref_50","unstructured":"National Center for Biotechnology Information (2022, April 02). PubChem Compound Summary for CID 2708, Chlorambucil, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Chlorambucil."},{"key":"ref_51","unstructured":"Drugbank Online (2022, April 02). Chlorambucil. Available online: https:\/\/go.drugbank.com\/drugs\/DB00291."},{"key":"ref_52","unstructured":"Access Pharmacy (2022, April 02). Drug Monogrpahs: Chlorambucil. Available online: https:\/\/accesspharmacy.mhmedical.com\/."},{"key":"ref_53","unstructured":"(2022, April 02). MSD Manuals: Body Mass Index. Available online: https:\/\/www.msdmanuals.com\/."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"vii154","DOI":"10.1093\/annonc\/mdq373","article-title":"Chronic lymphocytic leukemia","volume":"21","author":"Hallek","year":"2010","journal-title":"Ann. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Byers, J.P., and Sarver, J.G. (2009). Pharmacokinetic modeling. Pharmacology, Elsevier.","DOI":"10.1016\/B978-0-12-369521-5.00010-5"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1038\/s41596-020-00467-0","article-title":"Comparative analysis of assays to measure CAR T-cell-mediated cytotoxicity","volume":"16","author":"Kiesgen","year":"2021","journal-title":"Nat. Protoc."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/ni.2035","article-title":"T cell exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_58","unstructured":"(2022, April 02). SciPy Documentation. Curve Fit. Available online: https:\/\/docs.scipy.org\/doc\/scipy\/reference\/generated\/scipy.optimize.curve_fit.html."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1155\/2018\/9787015","article-title":"Bounding the Dynamics of a Chaotic-Cancer Mathematical Model","volume":"2018","author":"Valle","year":"2018","journal-title":"Math. Probl. Eng."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.physleta.2005.12.104","article-title":"Localization of compact invariant sets of the Lorenz system","volume":"353","author":"Krishchenko","year":"2006","journal-title":"Phys. Lett. A"},{"key":"ref_61","unstructured":"Khalil, H.K. (2002). Nonlinear Systems, Prentice-Hall. [3rd ed.]."},{"key":"ref_62","unstructured":"Hahn, W., Hosenthien, H.H., and Lehnigk, S.H. (2019). Theory and Application of Liapunov\u2019s Direct Method, Dover Publications, Inc."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1016\/j.mcm.2004.09.008","article-title":"A mathematical model of vascular tumor treatment by chemotherapy","volume":"42","author":"Liu","year":"2005","journal-title":"Math. Comput. Model."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/7\/1396\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:41:52Z","timestamp":1760139712000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/7\/1396"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,1]]},"references-count":63,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["pharmaceutics14071396"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14071396","relation":{},"ISSN":["1999-4923"],"issn-type":[{"type":"electronic","value":"1999-4923"}],"subject":[],"published":{"date-parts":[[2022,7,1]]}}}