{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T01:10:44Z","timestamp":1780449044995,"version":"3.54.1"},"reference-count":49,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T00:00:00Z","timestamp":1656374400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology, Taiwan","award":["MOST 110-2314-B-038-058"],"award-info":[{"award-number":["MOST 110-2314-B-038-058"]}]},{"name":"Ministry of Science and Technology, Taiwan","award":["MOST 109-2314-B-038-052-MY3"],"award-info":[{"award-number":["MOST 109-2314-B-038-052-MY3"]}]},{"name":"Ministry of Science and Technology, Taiwan","award":["MOST 110-2635-B-038-001"],"award-info":[{"award-number":["MOST 110-2635-B-038-001"]}]},{"name":"Ministry of Science and Technology, Taiwan","award":["MOST 110-2314-B-038-060"],"award-info":[{"award-number":["MOST 110-2314-B-038-060"]}]},{"name":"Ministry of Science and Technology, Taiwan","award":["MOST 109-2314-B-038-107-MY3"],"award-info":[{"award-number":["MOST 109-2314-B-038-107-MY3"]}]},{"name":"Ministry of Science and Technology, Taiwan","award":["TMU 108-AE1-B35 to R.-L.H."],"award-info":[{"award-number":["TMU 108-AE1-B35 to R.-L.H."]}]},{"name":"Taipei Medical University, Taiwan","award":["MOST 110-2314-B-038-058"],"award-info":[{"award-number":["MOST 110-2314-B-038-058"]}]},{"name":"Taipei Medical University, Taiwan","award":["MOST 109-2314-B-038-052-MY3"],"award-info":[{"award-number":["MOST 109-2314-B-038-052-MY3"]}]},{"name":"Taipei Medical University, Taiwan","award":["MOST 110-2635-B-038-001"],"award-info":[{"award-number":["MOST 110-2635-B-038-001"]}]},{"name":"Taipei Medical University, Taiwan","award":["MOST 110-2314-B-038-060"],"award-info":[{"award-number":["MOST 110-2314-B-038-060"]}]},{"name":"Taipei Medical University, Taiwan","award":["MOST 109-2314-B-038-107-MY3"],"award-info":[{"award-number":["MOST 109-2314-B-038-107-MY3"]}]},{"name":"Taipei Medical University, Taiwan","award":["TMU 108-AE1-B35 to R.-L.H."],"award-info":[{"award-number":["TMU 108-AE1-B35 to R.-L.H."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Endometrial cancer (EC) rates are rising annually. Additional prediction markers need to be evaluated because only 10\u201320% of EC cases show an objective response to immune-checkpoint inhibitors (ICIs). Our previous methylomic study found that BHLHE22 is hypermethylated in EC tissues and can be detected using a Pap-smear sample. BHLHE22, a basic helix loop helix transcription factor family member, is known as a transcriptional repressor and is involved in cell differentiation. However, the role of BHLHE22 in EC remains poorly understood. Herein, we analyzed BHLHE22 expression in 54 paired cancer and normal endometrial tissue samples, and confirmed with databases (TCGA, GTEx, and human protein atlas). We found that BHLHE22 protein expression was significantly downregulated in EC compared with normal endometrium. High BHLHE22 expression was associated with microsatellite-instable subtype, endometrioid type, grade, and age. It showed a significant favorable survival. BHLHE22 overexpression inhibited the proliferation and migration of EC cells. Functional enrichment analysis showed that BHLHE22 was significantly associated with immune-related pathways. Furthermore, BHLHE22 was positively correlated with proinflammatory leukocyte infiltration and expression of chemokine genes in EC. In conclusion, BHLHE22 regulates immune-related pathways and modulates the immune microenvironment of EC.<\/jats:p>","DOI":"10.3390\/ijms23137158","type":"journal-article","created":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T23:59:22Z","timestamp":1656460762000},"page":"7158","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["BHLHE22 Expression Is Associated with a Proinflammatory Immune Microenvironment and Confers a Favorable Prognosis in Endometrial Cancer"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5018-2381","authenticated-orcid":false,"family":"Darmawi","sequence":"first","affiliation":[{"name":"International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Translational Epigenetics Center, Shuang Ho Hospital, Taipei Medical University, New Taipei 235, Taiwan"},{"name":"Department of Histology, Faculty of Medicine, Universitas Riau, Pekanbaru 28293, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4870-3664","authenticated-orcid":false,"given":"Lin-Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Translational Epigenetics Center, Shuang Ho Hospital, Taipei Medical University, New Taipei 235, Taiwan"},{"name":"Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei 235, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1114-6382","authenticated-orcid":false,"given":"Po-Hsuan","family":"Su","sequence":"additional","affiliation":[{"name":"Translational Epigenetics Center, Shuang Ho Hospital, Taipei Medical University, New Taipei 235, Taiwan"},{"name":"Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei 235, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2156-5628","authenticated-orcid":false,"given":"Phui-Ly","family":"Liew","sequence":"additional","affiliation":[{"name":"Department of Pathology, Shuang Ho Hospital, Taipei Medical University, New Taipei 235, Taiwan"},{"name":"Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Chen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, National Defense Medical Center, Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Chun","family":"Weng","sequence":"additional","affiliation":[{"name":"Translational Epigenetics Center, Shuang Ho Hospital, Taipei Medical University, New Taipei 235, Taiwan"},{"name":"Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei 235, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui-Lan","family":"Huang","sequence":"additional","affiliation":[{"name":"Translational Epigenetics Center, Shuang Ho Hospital, Taipei Medical University, New Taipei 235, Taiwan"},{"name":"Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei 235, Taiwan"},{"name":"Department of Obstetrics and Gynecology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung-Cheng","family":"Lai","sequence":"additional","affiliation":[{"name":"Translational Epigenetics Center, Shuang Ho Hospital, Taipei Medical University, New Taipei 235, Taiwan"},{"name":"Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei 235, Taiwan"},{"name":"Department of Obstetrics and Gynecology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, National Defense Medical Center, Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.3389\/fonc.2019.01440","article-title":"Global, Regional, and National Burden of Endometrial Cancer, 1990\u20132017: Results From the Global Burden of Disease Study, 2017","volume":"9","author":"Zhang","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5","DOI":"10.3322\/caac.21254","article-title":"Cancer statistics, 2015","volume":"65","author":"Siegel","year":"2015","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer Statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2787","DOI":"10.1002\/cncr.30094","article-title":"Endometrial cancer: Not your grandmother\u2019s cancer","volume":"122","author":"McAlpine","year":"2016","journal-title":"Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/s10552-018-1018-z","article-title":"Hysterectomy-corrected rates of endometrial cancer among women younger than age 50 in the United States","volume":"29","author":"Temkin","year":"2018","journal-title":"Cancer Causes Control"},{"key":"ref_6","unstructured":"(2021, April 07). Surveillance, Epidemiology, and End Results (SEER) Program. Cancer Stat Facts: Uterine Cancer, Available online: https:\/\/seer.cancer.gov\/statfacts\/html\/corp.html."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1080\/14737140.2018.1491311","article-title":"Management Strategies for Recurrent Endometrial Cancer","volume":"18","author":"Connor","year":"2018","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1016\/S0140-6736(15)00130-0","article-title":"Endometrial cancer","volume":"387","author":"Morice","year":"2016","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1056\/NEJMra1514010","article-title":"Endometrial Cancer","volume":"383","author":"Lu","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/nature12113","article-title":"The Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma","volume":"497","author":"Levine","year":"2013","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1001\/jamaoncol.2015.2151","article-title":"Association of Polymerase e-Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1","volume":"1","author":"Howitt","year":"2015","journal-title":"JAMA Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1056\/NEJMoa1500596","article-title":"PD-1 Blockade in Tumors with Mismatch-Repair Deficiency","volume":"372","author":"Le","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1200\/JCO.2017.72.5952","article-title":"Safety and Antitumor Activity of Pembrolizumab in Advanced Programmed Death Ligand 1-Positive Endometrial Cancer: Results From the KEYNOTE-028 Study","volume":"35","author":"Ott","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e003777","DOI":"10.1136\/jitc-2021-003777","article-title":"Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient\/microsatellite instability-high (dMMR\/MSI-H) or proficient\/stable (MMRp\/MSS) endometrial cancer: Interim results from GARNET-a phase I, single-arm study","volume":"10","author":"Oaknin","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1158\/1078-0432.CCR-16-0863","article-title":"Integrated Epigenomics Analysis Reveals a DNA Methylation Panel for Endometrial Cancer Detection Using Cervical Scrapings","volume":"23","author":"Huang","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1186\/s13148-019-0765-3","article-title":"Combined genetic mutations and DNA-methylated genes as biomarkers for endometrial cancer detection from cervical scrapings","volume":"11","author":"Liew","year":"2019","journal-title":"Clin. Epigenetics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1006\/geno.2002.6833","article-title":"Functional and structural characterization of the human gene BHLHB5, encoding a basic helix-loop-helix transcription factor","volume":"80","author":"Xu","year":"2002","journal-title":"Genomics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.neuron.2011.09.035","article-title":"Bhlhb5 and Prdm8 form a repressor complex involved in neuronal circuit assembly","volume":"73","author":"Ross","year":"2012","journal-title":"Neuron"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1126\/science.1197454","article-title":"The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2","volume":"331","author":"Li","year":"2011","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5538","DOI":"10.3892\/mmr.2015.4070","article-title":"HAND2-mediated proteolysis negatively regulates the function of estrogen receptor \u03b1","volume":"12","author":"Fukuda","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9596","DOI":"10.1074\/jbc.RA120.012753","article-title":"The transcription factor HAND2 up-regulates transcription of the IL15 gene in human endometrial stromal cells","volume":"295","author":"Murata","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1097\/PGP.0000000000000106","article-title":"Heart and Neural Crest Derivatives Expressed Transcript 2 (HAND2): A novel biomarker for the identification of atypical hyperplasia and Type I endometrial carcinoma","volume":"34","author":"Cavallo","year":"2015","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/j.it.2020.09.002","article-title":"Transcription Factor Bhlhe40 in Immunity and Autoimmunity","volume":"41","author":"Cook","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.immuni.2019.08.013","article-title":"The Transcription Factor Bhlhe40 Programs Mitochondrial Regulation of Resident CD8(+) T Cell Fitness and Functionality","volume":"51","author":"Li","year":"2019","journal-title":"Immunity"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1093\/bioinformatics\/btz931","article-title":"ShinyGO: A graphical gene-set enrichment tool for animals and plants","volume":"36","author":"Ge","year":"2020","journal-title":"Bioinformatics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2612","DOI":"10.1038\/ncomms3612","article-title":"Inferring tumour purity and stromal and immune cell admixture from expression data","volume":"4","author":"Yoshihara","year":"2013","journal-title":"Nat Commun"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e108","DOI":"10.1158\/0008-5472.CAN-17-0307","article-title":"TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells","volume":"77","author":"Li","year":"2017","journal-title":"Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e26476","DOI":"10.7554\/eLife.26476","article-title":"Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data","volume":"6","author":"Racle","year":"2017","journal-title":"Elife"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1126\/science.aan6733","article-title":"Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade","volume":"357","author":"Le","year":"2017","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4485","DOI":"10.2147\/OTT.S324641","article-title":"Endometrial Tumors with MSI-H and dMMR Share a Similar Tumor Immune Microenvironment","volume":"14","author":"Song","year":"2021","journal-title":"OncoTargets Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"654256","DOI":"10.3389\/fgene.2021.654256","article-title":"Evolutionary Perspective and Expression Analysis of Intronless Genes Highlight the Conservation of Their Regulatory Role","volume":"12","author":"Muley","year":"2021","journal-title":"Front. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"143","DOI":"10.21037\/atm-21-6748","article-title":"A novel 12-gene prognostic signature in breast cancer based on the tumor microenvironment","volume":"10","author":"Zhu","year":"2022","journal-title":"Ann. Transl. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.brainres.2018.03.013","article-title":"bHLH transcription factors in neural development, disease, and reprogramming","volume":"1705","author":"Dennis","year":"2019","journal-title":"Brain Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7767","DOI":"10.1111\/jcmm.15408","article-title":"Prognostic significance of immune landscape in tumour microenvironment of endometrial cancer","volume":"24","author":"Li","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1067\/mai.2003.1594","article-title":"Chemokines: Roles in leukocyte development, trafficking, and effector function","volume":"111","author":"Ono","year":"2003","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1126\/science.1129139","article-title":"Type, density, and location of immune cells within human colorectal tumors predict clinical outcome","volume":"313","author":"Galon","year":"2006","journal-title":"Science"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1016\/j.cell.2016.04.009","article-title":"Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer","volume":"165","author":"Wang","year":"2016","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"379","DOI":"10.3389\/fimmu.2019.00379","article-title":"Chemokines and Chemokine Receptors: New Targets for Cancer Immunotherapy","volume":"10","author":"Massara","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Mughees, M., Kaushal, J.B., Sharma, G., Wajid, S., Batra, S.K., and Siddiqui, J.A. (2022). Chemokines and cytokines: Axis and allies in prostate cancer pathogenesis. Semin. Cancer Biol., in press.","DOI":"10.1016\/j.semcancer.2022.02.017"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/nri.2017.49","article-title":"Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy","volume":"17","author":"Nagarsheth","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.cell.2015.03.030","article-title":"Immune checkpoint targeting in cancer therapy: Toward combination strategies with curative potential","volume":"161","author":"Sharma","year":"2015","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Grywalska, E., Sobstyl, M., Putowski, L., and Roli\u0144ski, J. (2019). Current Possibilities of Gynecologic Cancer Treatment with the Use of Immune Checkpoint Inhibitors. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20194705"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1158\/2326-6066.CIR-18-0442","article-title":"PVRIG and PVRL2 Are Induced in Cancer and Inhibit CD8(+) T-cell Function","volume":"7","author":"Whelan","year":"2019","journal-title":"Cancer Immunol. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"pl1","DOI":"10.1126\/scisignal.2004088","article-title":"Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal","volume":"6","author":"Gao","year":"2013","journal-title":"Sci. Signal."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/s41587-020-0546-8","article-title":"Visualizing and interpreting cancer genomics data via the Xena platform","volume":"38","author":"Goldman","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6047","DOI":"10.1038\/s41598-021-84787-5","article-title":"Pancancer survival analysis of cancer hallmark genes","volume":"11","author":"Nagy","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"eaay5947","DOI":"10.1126\/science.aay5947","article-title":"An atlas of the protein-coding genes in the human, pig, and mouse brain","volume":"367","author":"Zhong","year":"2020","journal-title":"Science"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"D956","DOI":"10.1093\/nar\/gkx1090","article-title":"LinkedOmics: Analyzing multi-omics data within and across 32 cancer types","volume":"46","author":"Vasaikar","year":"2018","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/13\/7158\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:39:29Z","timestamp":1760139569000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/13\/7158"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,28]]},"references-count":49,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ijms23137158"],"URL":"https:\/\/doi.org\/10.3390\/ijms23137158","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,28]]}}}