{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:10:52Z","timestamp":1759191052903,"version":"3.44.0"},"reference-count":50,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CytoMed Therapeutics Limited"},{"name":"National Institutes of Health\/National Cancer Institute","award":["P30CA016672"],"award-info":[{"award-number":["P30CA016672"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Venetoclax-based combination therapies have provided treatment options for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. However, venetoclax resistance is common, and for such patients, the prognosis is dismal, and treatment approaches with different mechanisms of action are urgently needed. \u03b3\u03b4 T cells are a promising candidate owing to their good safety profile and cytotoxic effects in various types of cancers but are mostly unstudied in AML. Methods: Here we used flow cytometry to profile the subtype and memory phenotype of peripheral blood \u03b3\u03b4 T cells in AML patients and investigate the feasibility of using donor-derived V\u03b39V\u03b42 T cells to treat AML as both a single agent and in combination with venetoclax. Additionally, we used bioluminescence imaging to examine the effect of donor-derived V\u03b39V\u03b42 T cells on AML xenograft models alone and in combination with venetoclax. Results: We observed that V\u03b42 T cells were less abundant and the TEMRA (terminally differentiated effector memory) phenotype was more prevalent as compared with that of healthy donors, suggesting that replenishing patients with V\u03b42 T cells may be an effective treatment option. We found that donor-derived V\u03b39V\u03b42 T cells that V\u03b39V\u03b42 T cells efficiently induced apoptosis in AML cells from eight cell lines and three primary cultures in an effector-to-target cell ratio-dependent manner. Moreover, V\u03b39V\u03b42 T cells showed potent cytotoxicity against the venetoclax-resistant OCI-AML3 cell line and remained potent in the presence of venetoclax. Treatment with V\u03b39V\u03b42 T cells significantly extended survival in two AML xenograft models established with the aggressive Molm-13 and the venetoclax-resistant OCI-AML3 cell lines. An additive effect of venetoclax and V\u03b39V\u03b42 T cells was observed in the latter model. Conclusions: Overall, these findings suggest V\u03b39V\u03b42 T cells as a promising \u201coff-the-shelf\u201d immunotherapy approach for AML patients, especially for patients with venetoclax-resistant disease.<\/jats:p>","DOI":"10.3390\/cancers17193166","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T12:59:46Z","timestamp":1759150786000},"page":"3166","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Donor-Derived V\u03b39V\u03b42 T Cells for Acute Myeloid Leukemia: A Promising \u201cOff-the-Shelf\u201d Immunotherapy Approach"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9511-3408","authenticated-orcid":false,"given":"Amanda","family":"Eckstrom","sequence":"first","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anudishi","family":"Tyagi","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"},{"name":"Department of Internal Medicine, Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maryam","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenny","family":"Borgman","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jieming","family":"Zeng","sequence":"additional","affiliation":[{"name":"CytoMed Therapeutics Limited, Singapore 149544, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adishwar","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abhishek","family":"Maiti","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Venkata Lokesh","family":"Battula","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"},{"name":"Department of Internal Medicine, Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"ref_1","unstructured":"Vakiti, A., Reynolds, S.B., and Mewawalla, P. (2024). Acute Myeloid Leukemia, StatPearls Publishing."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/S0140-6736(18)31041-9","article-title":"Acute myeloid leukaemia","volume":"392","author":"Short","year":"2018","journal-title":"Lancet"},{"key":"ref_3","unstructured":"Larson, R.A., and Rosmarin, A.G. (2022). Acute Myeloid Leukemia in Adults: Overveiw, UpToDate [Internet]."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1080\/17474086.2023.2256472","article-title":"Clinical status of induction therapy incorporating a hypomethylating agent for newly diagnosed adult acute myeloid leukemia compared to the standard 7 + 3 regimen","volume":"16","author":"Ohmoto","year":"2023","journal-title":"Expert Rev. Hematol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"789","DOI":"10.2217\/fon-2022-1286","article-title":"Therapies for acute myeloid leukemia in patients ineligible for standard induction chemotherapy: A systematic review","volume":"19","author":"Heuser","year":"2023","journal-title":"Future Oncology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1007\/s00277-015-2351-x","article-title":"Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States","volume":"94","author":"Medeiros","year":"2015","journal-title":"Ann. Hematol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1182\/blood.2022016867","article-title":"Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN","volume":"140","author":"Wei","year":"2022","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1056\/NEJMoa2012971","article-title":"Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia","volume":"383","author":"DiNardo","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"894","DOI":"10.3324\/haematol.2020.252569","article-title":"Outcomes of relapsed or refractory acute myeloid leukemia after frontline hypomethylating agent and venetoclax regimens","volume":"106","author":"Maiti","year":"2021","journal-title":"Haematologica"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"966","DOI":"10.20892\/j.issn.2095-3941.2020.0801","article-title":"Cellular immunotherapy for hematological malignancy: Recent progress and future perspectives","volume":"18","author":"Xu","year":"2021","journal-title":"Cancer Biol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/s41408-021-00459-7","article-title":"CAR-T cell therapy: Current limitations and potential strategies","volume":"11","author":"Sterner","year":"2021","journal-title":"Blood Cancer J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1016\/j.stem.2021.11.004","article-title":"Into the multiverse of gene edited NK cell-based therapeutic strategies","volume":"28","author":"Goldenson","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1002\/ijc.30109","article-title":"Regulatory and effector functions of gamma-delta (gammadelta) T cells and their therapeutic potential in adoptive cellular therapy for cancer","volume":"139","author":"Paul","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e002274","DOI":"10.1136\/jitc-2020-002274","article-title":"Dichotomous and stable gamma delta T-cell number and function in healthy individuals","volume":"9","author":"Ou","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1038\/s41423-020-0503-y","article-title":"Ligand recognition by the \u03b3\u03b4 TCR and discrimination between homeostasis and stress conditions","volume":"17","author":"Deseke","year":"2020","journal-title":"Cell. Mol. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1038\/nm.3909","article-title":"The prognostic landscape of genes and infiltrating immune cells across human cancers","volume":"21","author":"Gentles","year":"2015","journal-title":"Nat. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.jtct.2021.06.003","article-title":"Enhanced Immune Reconstitution of \u03b3\u03b4 T Cells after Allogeneic Stem Cell Transplantation Overcomes the Negative Impact of Pretransplantation Minimal Residual Disease-Positive Status in Patients with Acute Myelogenous Leukemia","volume":"27","author":"Klyuchnikov","year":"2021","journal-title":"Transplant. Cell. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/sj.bmt.1705650","article-title":"Long term disease-free survival in acute leukemia patients recovering with increased \u03b3\u03b4 T cells after partially mismatched related donor bone marrow transplantation","volume":"39","author":"Godder","year":"2007","journal-title":"Bone Marrow Transplant."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Minculescu, L., Marquart, H.V., Ryder, L.P., Andersen, N.S., Schjoedt, I., Friis, L.S., Kornblit, B.T., Petersen, S.L., Haastrup, E., and Fischer-Nielsen, A. (2019). Improved Overall Survival, Relapse-Free-Survival, and Less Graft-vs.-Host-Disease in Patients with High Immune Reconstitution of TCR Gamma Delta Cells 2 Months After Allogeneic Stem Cell Transplantation. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01997"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.bbmt.2014.09.027","article-title":"Gamma Delta T Cell Reconstitution is Associated with Fewer Infections and Improved Event-Free Survival after Hematopoietic Stem Cell Transplantation for Pediatric Leukemia","volume":"21","author":"Perko","year":"2015","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12967-017-1378-2","article-title":"Gamma-delta (gammadelta) T cells: Friend or foe in cancer development?","volume":"16","author":"Zhao","year":"2018","journal-title":"J. Transl. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5795","DOI":"10.1158\/1078-0432.CCR-16-0597","article-title":"Delta One T Cells for Immunotherapy of Chronic Lymphocytic Leukemia: Clinical-Grade Expansion\/Differentiation and Preclinical Proof of Concept","volume":"22","author":"Almeida","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"753","DOI":"10.3109\/14653249.2011.553595","article-title":"Human V\u03b41 \u03b3\u03b4 T cells expanded from peripheral blood exhibit specific cytotoxicity against B-cell chronic lymphocytic leukemia-derived cells","volume":"13","author":"Siegers","year":"2011","journal-title":"Cytotherapy"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1111\/cas.13005","article-title":"IL-17A-producing CD30+ V\u03b41 T cells drive inflammation-induced cancer progression","volume":"107","author":"Kimura","year":"2016","journal-title":"Cancer Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.ejca.2016.06.001","article-title":"Proportions of blood-borne V\u03b41+ and V\u03b42+ T-cells are associated with overall survival of melanoma patients treated with ipilimumab","volume":"64","author":"Martens","year":"2016","journal-title":"Eur. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1002\/ijc.29818","article-title":"Phenotypic characterization and prognostic impact of circulating \u03b3\u03b4 and \u03b1\u03b2 T-cells in metastatic malignant melanoma","volume":"138","author":"Schilling","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.3748\/wjg.v22.i13.3573","article-title":"Analysis of tumor-infiltrating gamma delta T cells in rectal cancer","volume":"22","author":"Rong","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6942","DOI":"10.1038\/s41467-023-42619-2","article-title":"Unlocking the potential of allogeneic V\u03b42 T cells for ovarian cancer therapy through CD16 biomarker selection and CAR\/IL-15 engineering","volume":"14","author":"Lee","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.immuni.2020.02.014","article-title":"Butyrophilin-2A1 Directly Binds Germline-Encoded Regions of the V\u03b39V\u03b42 TCR and Is Essential for Phosphoantigen Sensing","volume":"52","author":"Karunakaran","year":"2020","journal-title":"Immunity"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Herrmann, T., Fichtner, A.S., and Karunakaran, M.M. (2020). An Update on the Molecular Basis of Phosphoantigen Recognition by V\u03b39V\u03b42 T Cells. Cells, 9.","DOI":"10.3390\/cells9061433"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e007981","DOI":"10.1136\/jitc-2023-007981","article-title":"Gamma delta T cells in acute myeloid leukemia: Biology and emerging therapeutic strategies","volume":"12","author":"Rao","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e232","DOI":"10.1016\/j.clml.2023.02.003","article-title":"A Phase I Trial of Allogeneic \u03b3\u03b4 T Lymphocytes From Haploidentical Donors in Patients with Refractory or Relapsed Acute Myeloid Leukemia","volume":"23","author":"Vydra","year":"2023","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.bbi.2010.01.002","article-title":"Phenotypic characterization of \u03b3\u03b4 T cells mobilized in response to acute psychological stress","volume":"24","author":"Anane","year":"2010","journal-title":"Brain Behav. Immun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1002\/eji.200525983","article-title":"Differential requirements for antigen or homeostatic cytokines for proliferation and differentiation of human V\u03b39V\u03b42 naive, memory and effector T cell subsets","volume":"35","author":"Caccamo","year":"2005","journal-title":"Eur. J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1182\/blood-2004-01-0331","article-title":"Fc\u03b3RIII discriminates between 2 subsets of V\u03b39V\u03b42 effector cells with different responses and activation pathways","volume":"104","author":"Angelini","year":"2004","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3271","DOI":"10.1182\/blood-2012-03-417519","article-title":"Dysfunctional V\u03b39V\u03b42 T cells are negative prognosticators and markers of dysregulated mevalonate pathway activity in chronic lymphocytic leukemia cells","volume":"120","author":"Coscia","year":"2012","journal-title":"Blood"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"CT024","DOI":"10.1158\/1538-7445.AM2025-CT024","article-title":"Abstract CT024: \u03b39\u03b42 T-cell (\u03b3\u03b4TC) activation and azacitidine-venetoclax (AV) for older\/unfit adults with newly diagnosed (ND) acute myeloid leukemia (AML) induces high rates of complete remission (CR): Preliminary efficacy, safety, pharmacodynamics (PD) and dose selection of ICT01 in the phase 1 study EVICTION","volume":"85","author":"Maiti","year":"2025","journal-title":"Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Du, S.H., Li, Z., Chen, C., Tan, W.K., Chi, Z., Kwang, T.W., Xu, X.H., and Wang, S. (2016). Co-Expansion of Cytokine-Induced Killer Cells and V\u03b39V\u03b42 T Cells for CAR T-Cell Therapy. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0161820"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3890","DOI":"10.1182\/blood-2006-04-017061","article-title":"T lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells","volume":"108","author":"Vera","year":"2006","journal-title":"Blood"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"380","DOI":"10.20517\/cdr.2021.125","article-title":"Venetoclax resistance: Mechanistic insights and future strategies","volume":"5","author":"Ong","year":"2022","journal-title":"Cancer Drug Resist."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"105207","DOI":"10.1016\/j.tiv.2021.105207","article-title":"Embelin potentiates venetoclax-induced apoptosis in acute myeloid leukemia cells","volume":"76","author":"Branco","year":"2021","journal-title":"Toxicol. Vitro"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e120974","DOI":"10.1172\/jci.insight.120974","article-title":"Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy","volume":"3","author":"Knaus","year":"2018","journal-title":"JCI Insight"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Zhou, H., Jia, B., Annageldiyev, C., Minagawa, K., Zhao, C., Mineishi, S., Ehmann, W.C., Naik, S.G., Cioccio, J., and Wirk, B. (2023). CD26lowPD-1+ CD8 T cells are terminally exhausted and associated with leukemia progression in acute myeloid leukemia. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1169144"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Barros, M.S., de Ara\u00fajo, N.D., Magalh\u00e3es-Gama, F., Pereira Ribeiro, T.L., Alves Hanna, F.S., Tarrag\u00f4, A.M., Malheiro, A., and Costa, A.G. (2021). \u03b3\u03b4 T Cells for Leukemia Immunotherapy: New and Expanding Trends. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.729085"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3233","DOI":"10.1111\/cas.15014","article-title":"The CD226-ERK1\/2-LAMP1 pathway is an important mechanism for V\u03b39V\u03b42 T cell cytotoxicity against chemotherapy-resistant acute myeloid leukemia blasts and leukemia stem cells","volume":"112","author":"Wu","year":"2021","journal-title":"Cancer Sci."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Jiang, S., Zheng, S., Yao, C., Ning, D., Zou, S., Zhan, J., Lan, T., Yi, T., Jin, Z., and Wu, X. (2025). Heterogeneity of \u03b3\u03b4 T-cell subsets and their clinical correlation in patients with AML. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1552235"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Wu, Z., Zhang, H., Wu, M., Peng, G., He, Y., Wan, N., and Zeng, Y. (2021). Targeting the NKG2D\/NKG2D-L axis in acute myeloid leukemia. Biomed. Pharmacother., 137.","DOI":"10.1016\/j.biopha.2021.111299"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1182\/blood-2024-202223","article-title":"Venetoclax Enhances Human \u0393\u03b4t Cells Anti-Leukemia Immunity through Metabolic Reprogramming","volume":"144","author":"Xingchi","year":"2024","journal-title":"Blood"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"22020","DOI":"10.1074\/jbc.M313234200","article-title":"Degradation of Mcl-1 by Granzyme B: Implications for bim-mediated mitochondrial apoptotic events","volume":"279","author":"Han","year":"2004","journal-title":"J. Biol. Chemistry"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"6868","DOI":"10.1074\/jbc.M114.631564","article-title":"Mouse cytotoxic T cell-derived granzyme B activates the mitochondrial cell death pathway in a Bim-dependent fashion","volume":"290","author":"Simon","year":"2015","journal-title":"J. Biol. Chem."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/19\/3166\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T13:14:26Z","timestamp":1759151666000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/19\/3166"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,29]]},"references-count":50,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["cancers17193166"],"URL":"https:\/\/doi.org\/10.3390\/cancers17193166","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,29]]}}}