{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T09:08:35Z","timestamp":1765357715975,"version":"build-2065373602"},"reference-count":51,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T00:00:00Z","timestamp":1729728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Carsten Bender-Leuk\u00e4mie-Stiftung"},{"name":"Werner-Otto-Foundation"},{"name":"Mildred Scheel Nachwuchszentrum"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Comprehensive characterization of AML-associated T cells during disease progression is essential to identify relevant immune escape mechanisms and new immunotherapeutic approaches. Investigating the processes that lead to an immunosuppressive environment under progression of AML is difficult in humans, because by the time of diagnosis the disease is often progressed far beyond the initial stages. Therefore, to investigate T-cell phenotypes during progression a C57BL\/6 mouse model was used. The CD3+ T cells were characterized by performing multiparametric flow analyses at different time points (day 0 = healthy mice, day 7, day 14, and day 21). The study revealed that the spleen is highly infiltrated by reg CD4+ T cells at day 21 of AML progression. These spleen-infiltrating reg CD4+ T cells mainly showed an effector memory differentiation with high expression and co-expression of the checkpoint molecules TIGIT, PD-1, OX40, and the two ectoenzymes CD39 and CD73. Substantial expression of the checkpoint molecules was restricted to the central memory and effector memory compartments. Furthermore, functional evaluation of TIGIT was performed. Blocking TIGIT resulted in a significantly increased lysis of C1498 AML cells in cocultures with AML-primed CD3+ T cells. Together these data confirm that the expression of the checkpoint receptor TIGIT is relevant for dysfunction of AML-associated T cells and, thus, represents a suitable target for future immunotherapeutic approaches.<\/jats:p>","DOI":"10.3390\/ijms252111412","type":"journal-article","created":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T04:11:38Z","timestamp":1729743098000},"page":"11412","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Murine Regulatory CD4+ T Cells Are Increased in Leukemic Spleens and Show High Co-Expression of Co-Regulatory Molecules CD39, CD73, PD1, and TIGIT"],"prefix":"10.3390","volume":"25","author":[{"given":"Julius","family":"Kr\u00fcger","sequence":"first","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8067-2314","authenticated-orcid":false,"given":"Jasmin","family":"Wellbrock","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marius","family":"Witt","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niklas","family":"Kruppa","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jana","family":"Muschhammer","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6071-7810","authenticated-orcid":false,"given":"Carsten","family":"Bokemeyer","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5897-3310","authenticated-orcid":false,"given":"Franziska","family":"Modemann","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0275-8803","authenticated-orcid":false,"given":"Walter","family":"Fiedler","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3255-7504","authenticated-orcid":false,"given":"Lena","family":"Behrmann","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franziska","family":"Brauneck","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s13045-023-01417-5","article-title":"Treatment Outcomes for Newly Diagnosed, Treatment-Na\u00efve TP53-Mutated Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis","volume":"16","author":"Daver","year":"2023","journal-title":"J. Hematol. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1172\/JCI129204","article-title":"Immune Escape and Immunotherapy of Acute Myeloid Leukemia","volume":"130","author":"Vago","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"n2026","DOI":"10.1136\/bmj.n2026","article-title":"Advances in Acute Myeloid Leukemia","volume":"375","author":"Newell","year":"2021","journal-title":"BMJ"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s13045-021-01062-w","article-title":"Emerging Agents and Regimens for AML","volume":"14","author":"Liu","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1038\/s41571-022-00689-z","article-title":"Clinical Implications of T Cell Exhaustion for Cancer Immunotherapy","volume":"19","author":"Chow","year":"2022","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.immuni.2018.03.014","article-title":"Regulation and Function of the PD-L1 Checkpoint","volume":"48","author":"Sun","year":"2018","journal-title":"Immunity"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.1158\/1078-0432.CCR-15-2626","article-title":"T-Cell Immunoglobulin and ITIM Domain (TIGIT) Associates with CD8+ T-Cell Exhaustion and Poor Clinical Outcome in AML Patients","volume":"22","author":"Kong","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1930391","DOI":"10.1080\/2162402X.2021.1930391","article-title":"Increased Frequency of TIGIT+ CD73-CD8+ T Cells with a TOX+ TCF-1low Profile in Patients with Newly Diagnosed and Relapsed AML","volume":"10","author":"Brauneck","year":"2021","journal-title":"Oncoimmunology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.apsb.2019.08.010","article-title":"Therapeutic Strategies for the Costimulatory Molecule OX40 in T-Cell-Mediated Immunity","volume":"10","author":"Fu","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"37588","DOI":"10.18632\/oncotarget.5940","article-title":"OX40 Expression Enhances the Prognostic Significance of CD8 Positive Lymphocyte Infiltration in Colorectal Cancer","volume":"6","author":"Weixler","year":"2015","journal-title":"Oncotarget"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Shi, H., Dai, H., Sun, Q., Wang, S., and Chen, Y. (2023). CD73, a Significant Protein in Liver Diseases. Front. Med., 10.","DOI":"10.3389\/fmed.2023.1147782"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.coph.2020.07.001","article-title":"Targeting CD73 to Augment Cancer Immunotherapy","volume":"53","author":"Roh","year":"2020","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6780","DOI":"10.4049\/jimmunol.177.10.6780","article-title":"T Regulatory and Primed Uncommitted CD4 T Cells Express CD73, Which Suppresses Effector CD4 T Cells by Converting 5\u2032-Adenosine Monophosphate to Adenosine","volume":"177","author":"Kobie","year":"2006","journal-title":"J. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1038\/s41590-023-01578-y","article-title":"Hallmarks of CD8+ T Cell Dysfunction Are Established within Hours of Tumor Antigen Encounter before Cell Division","volume":"24","author":"Rudloff","year":"2023","journal-title":"Nat. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Mopin, A., Driss, V., and Brinster, C. (2016). A Detailed Protocol for Characterizing the Murine C1498 Cell Line and Its Associated Leukemia Mouse Model. J. Vis. Exp., e54270.","DOI":"10.3791\/54270"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/s41374-018-0137-1","article-title":"Characterization of Immune Cell Subtypes in Three Commonly Used Mouse Strains Reveals Gender and Strain-Specific Variations","volume":"99","author":"Hensel","year":"2019","journal-title":"Lab. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.4049\/jimmunol.2300111","article-title":"Acute Myeloid Leukemia Causes T Cell Exhaustion and Depletion in a Humanized Graft-versus-Leukemia Model","volume":"211","author":"Jia","year":"2023","journal-title":"J. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Brauneck, F., Weimer, P., Schulze zur Wiesch, J., Weisel, K., Leypoldt, L., Vohwinkel, G., Fritzsche, B., Bokemeyer, C., Wellbrock, J., and Fiedler, W. (2021). Bone Marrow-Resident V\u03b41 T Cells Co-Express TIGIT With PD-1, TIM-3 or CD39 in AML and Myeloma. Front. Med., 8.","DOI":"10.3389\/fmed.2021.763773"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/cyto.a.21015","article-title":"SPICE: Exploration and Analysis of Post-cytometric Complex Multivariate Datasets","volume":"79A","author":"Roederer","year":"2011","journal-title":"Cytom. Part A"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e2103730118","DOI":"10.1073\/pnas.2103730118","article-title":"Critical Role of the CD44lowCD62Llow CD8+ T Cell Subset in Restoring Antitumor Immunity in Aged Mice","volume":"118","author":"Nakajima","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kim, D.Y., Lee, S., Kim, D.Y., and Lee, J.Y. (2020). Effective Murine Model Induction for Niche Study in Immune Cells Against Leukemia. Oxygen Transport to Tissue XLI, Springer.","DOI":"10.1007\/978-3-030-34461-0_53"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"100351","DOI":"10.1016\/j.xpro.2021.100351","article-title":"Analysis of T Cells in Mouse Lymphoid Tissue and Blood with Flow Cytometry","volume":"2","author":"Skordos","year":"2021","journal-title":"STAR Protoc."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Dong, Y., Han, Y., Huang, Y., Jiang, S., Huang, Z., Chen, R., Yu, Z., Yu, K., and Zhang, S. (2020). PD-L1 Is Expressed and Promotes the Expansion of Regulatory T Cells in Acute Myeloid Leukemia. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01710"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Han, Y., Dong, Y., Yang, Q., Xu, W., Jiang, S., Yu, Z., Yu, K., and Zhang, S. (2018). Acute Myeloid Leukemia Cells Express ICOS Ligand to Promote the Expansion of Regulatory T Cells. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02227"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3793","DOI":"10.1182\/blood-2009-03-208181","article-title":"Depletion of Endogenous Tumor-Associated Regulatory T Cells Improves the Efficacy of Adoptive Cytotoxic T-Cell Immunotherapy in Murine Acute Myeloid Leukemia","volume":"114","author":"Zhou","year":"2009","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e151797","DOI":"10.1172\/jci.insight.151797","article-title":"Tnfrsf4-Expressing Regulatory T Cells Promote Immune Escape of Chronic Myeloid Leukemia Stem Cells","volume":"6","author":"Hinterbrandner","year":"2021","journal-title":"JCI Insight"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1016\/j.ccell.2014.10.018","article-title":"The Immunoreceptor TIGIT Regulates Antitumor and Antiviral CD8+ T Cell Effector Function","volume":"26","author":"Johnston","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ackermann, C., Smits, M., Woost, R., Eberhard, J.M., Peine, S., Kummer, S., Marget, M., Kuntzen, T., Kwok, W.W., and Lohse, A.W. (2019). HCV-Specific CD4+ T Cells of Patients with Acute and Chronic HCV Infection Display High Expression of TIGIT and Other Co-Inhibitory Molecules. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-47024-8"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e004794","DOI":"10.1136\/jitc-2022-004794","article-title":"TIGIT Blockade Repolarizes AML-Associated TIGIT + M2 Macrophages to an M1 Phenotype and Increases CD47-Mediated Phagocytosis","volume":"10","author":"Brauneck","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Brauneck, F., Seubert, E., Wellbrock, J., Schulze zur Wiesch, J., Duan, Y., Magnus, T., Bokemeyer, C., Koch-Nolte, F., Menzel, S., and Fiedler, W. (2021). Combined Blockade of TIGIT and CD39 or A2AR Enhances NK-92 Cell-Mediated Cytotoxicity in AML. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222312919"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5269","DOI":"10.1038\/s41388-018-0288-y","article-title":"Immune Checkpoints PVR and PVRL2 Are Prognostic Markers in AML and Their Blockade Represents a New Therapeutic Option","volume":"37","author":"Stamm","year":"2018","journal-title":"Oncogene"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/s41590-018-0132-0","article-title":"Blockade of the Checkpoint Receptor TIGIT Prevents NK Cell Exhaustion and Elicits Potent Anti-Tumor Immunity","volume":"19","author":"Zhang","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"145","DOI":"10.4049\/jimmunol.1402381","article-title":"Divergent Phenotypes of Human Regulatory T Cells Expressing the Receptors TIGIT and CD226","volume":"195","author":"Fuhrman","year":"2015","journal-title":"J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.immuni.2014.02.012","article-title":"Treg Cells Expressing the Coinhibitory Molecule TIGIT Selectively Inhibit Proinflammatory Th1 and Th17 Cell Responses","volume":"40","author":"Joller","year":"2014","journal-title":"Immunity"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1182\/blood-2009-03-206672","article-title":"PD-1\/PD-L1 Interactions Inhibit Antitumor Immune Responses in a Murine Acute Myeloid Leukemia Model","volume":"114","author":"Zhang","year":"2009","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Pan, S., Cai, Q., Wei, Y., Tang, H., Zhang, Y., Zhou, W., Deng, T., Mo, W., Wang, S., and Wang, C. (2024). Increased Co-Expression of ICOS and PD-1 Predicts Poor Overall Survival in Patients with Acute Myeloid Leukemia. Immunobiology, 229.","DOI":"10.1016\/j.imbio.2024.152804"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e20182232","DOI":"10.1084\/jem.20182232","article-title":"PD-1 Restraint of Regulatory T Cell Suppressive Activity Is Critical for Immune Tolerance","volume":"218","author":"Tan","year":"2021","journal-title":"J. Exp. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e85935","DOI":"10.1172\/jci.insight.85935","article-title":"PD-1 Marks Dysfunctional Regulatory T Cells in Malignant Gliomas","volume":"1","author":"Lowther","year":"2016","journal-title":"JCI Insight"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"9999","DOI":"10.1073\/pnas.1822001116","article-title":"PD-1 + Regulatory T Cells Amplified by PD-1 Blockade Promote Hyperprogression of Cancer","volume":"116","author":"Kamada","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Marconato, M., Kauer, J., Salih, H.R., M\u00e4rklin, M., and Heitmann, J.S. (2022). Expression of the Immune Checkpoint Modulator OX40 Indicates Poor Survival in Acute Myeloid Leukemia. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-19972-1"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1007\/s12016-015-8498-3","article-title":"OX40, OX40L and Autoimmunity: A Comprehensive Review","volume":"50","author":"Webb","year":"2016","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_42","first-page":"4213","article-title":"Crucial Role of OX40\/OX40L Signaling in a Murine Model of Asthma","volume":"17","author":"Lei","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_43","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_44","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/cmi.2016.30","article-title":"Human CD39hi Regulatory T Cells Present Stronger Stability and Function under Inflammatory Conditions","volume":"14","author":"Gu","year":"2017","journal-title":"Cell Mol. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Wang, H., Wei, Y., and Wang, N. (2024). Purinergic Pathways and Their Clinical Use in the Treatment of Acute Myeloid Leukemia. Purinergic Signal.","DOI":"10.1007\/s11302-024-09997-8"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1186\/s12967-018-1563-y","article-title":"Long Term Impact of CTLA4 Blockade Immunotherapy on Regulatory and Effector Immune Responses in Patients with Melanoma","volume":"16","author":"Retseck","year":"2018","journal-title":"J. Transl. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4175","DOI":"10.1158\/1078-0432.CCR-17-1846","article-title":"T-Cell Exhaustion Signatures Vary with Tumor Type and Are Severe in Glioblastoma","volume":"24","author":"Woroniecka","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/nri3862","article-title":"Molecular and Cellular Insights into T Cell Exhaustion","volume":"15","author":"Wherry","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Mohme, M., and Neidert, M.C. (2020). Tumor-Specific T Cell Activation in Malignant Brain Tumors. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00205"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.immuni.2024.01.010","article-title":"LAG-3, TIM-3, and TIGIT: Distinct Functions in Immune Regulation","volume":"57","author":"Joller","year":"2024","journal-title":"Immunity"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Wegrzyn, A.S., Kedzierska, A.E., and Obojski, A. (2023). Identification and Classification of Distinct Surface Markers of T Regulatory Cells. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1055805"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/21\/11412\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:19:11Z","timestamp":1760113151000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/21\/11412"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,24]]},"references-count":51,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["ijms252111412"],"URL":"https:\/\/doi.org\/10.3390\/ijms252111412","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,10,24]]}}}