{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T01:07:46Z","timestamp":1788052066072,"version":"build-2784847793"},"reference-count":53,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T00:00:00Z","timestamp":1609372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National institute of Health","award":["HD094378"],"award-info":[{"award-number":["HD094378"]}]},{"name":"National Institute of Health","award":["ES028615"],"award-info":[{"award-number":["ES028615"]}]},{"name":"National Institute of Health","award":["MD007602"],"award-info":[{"award-number":["MD007602"]}]},{"name":"National Institute of Health","award":["HD094380"],"award-info":[{"award-number":["HD094380"]}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["FAPESP 2017\/24448-1"],"award-info":[{"award-number":["FAPESP 2017\/24448-1"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Uterine leiomyosarcoma (LMS) is an aggressive tumor that presents a poor prognosis, high rates of recurrence, and metastasis. Because of its rarity, there is no information available concerning LMS molecular mechanisms of origin and development. Here, we assessed the expression profile of Hedgehog (HH) signaling pathway markers and the effects of their pharmacological inhibition on uterine smooth muscle (UTSM), leiomyoma, and LMS cells. Additionally, we also evaluated the effects of DNMTs inhibition on LMS cell behavior. Cell proliferation, migration and apoptosis rates were evaluated by MTT, Scratch, and Annexin V assays, respectively. RNA expression and protein levels were assessed by qRT-PCR and Western blot. We found that SMO and GLIs (1, 2, and 3) expression was upregulated in LMS cells, with increased nuclear levels of GLI proteins. Treatment with LDE225 (SMOi) and Gant61 (GLIi) resulted in a significant reduction in Glis protein levels in LMS (p &lt; 0.05). Additionally, the expression of DNMT (1, 3a, and 3b), as well as GLI1 nuclear expression, was significantly decreased after treatment with HH inhibitor in LMS cells. Our results showed that blocking of SMO, GLI, and DNMTs is able to inhibit LMS proliferation, migration, and invasion. Importantly, the combination of those treatments exhibited a potentiated effect on LMS malignant features due to HH pathway deactivation.<\/jats:p>","DOI":"10.3390\/cells10010053","type":"journal-article","created":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T10:10:37Z","timestamp":1609409437000},"page":"53","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Targeting Hedgehog Pathway and DNA Methyltransferases in Uterine Leiomyosarcoma Cells"],"prefix":"10.3390","volume":"10","author":[{"given":"Natalia","family":"Garcia","sequence":"first","affiliation":[{"name":"Department of Surgery, University of Illinois at Chicago, Chicago, IL 60607, USA"},{"name":"Laborat\u00f3rio de Ginecologia Estrutural e Molecular (LIM 58), Disciplina de Ginecologia, Departamento deObstetricia e Ginecologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, HCFMUSP, SP, BR Av. Dr Arnaldo 455, sala 4121, Cerqueira Cesar, S\u00e3o Paulo 05403-010, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayman","family":"Al-Hendy","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Illinois at Chicago, Chicago, IL 60607, USA"},{"name":"Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edmund C.","family":"Baracat","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Ginecologia Estrutural e Molecular (LIM 58), Disciplina de Ginecologia, Departamento deObstetricia e Ginecologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, HCFMUSP, SP, BR Av. Dr Arnaldo 455, sala 4121, Cerqueira Cesar, S\u00e3o Paulo 05403-010, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7295-678X","authenticated-orcid":false,"given":"Katia Candido","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Ginecologia Estrutural e Molecular (LIM 58), Disciplina de Ginecologia, Departamento deObstetricia e Ginecologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, HCFMUSP, SP, BR Av. Dr Arnaldo 455, sala 4121, Cerqueira Cesar, S\u00e3o Paulo 05403-010, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7131-8946","authenticated-orcid":false,"given":"Qiwei","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Illinois at Chicago, Chicago, IL 60607, USA"},{"name":"Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.ygyno.2009.09.023","article-title":"Uterine sarcomas: A review","volume":"116","author":"Prat","year":"2010","journal-title":"Gynecol. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1111\/aogs.12930","article-title":"Uterine leiomyosarcoma-incidence, treatment, and the impact of morcellation. A nationwide cohort study","volume":"95","author":"Skorstad","year":"2016","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.ygyno.2017.02.012","article-title":"Prognosis and treatment of uterine leiomyosarcoma: A National Cancer Database study","volume":"145","author":"Seagle","year":"2017","journal-title":"Gynecol. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.ygyno.2008.03.010","article-title":"Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma: A Gynecologic Oncology Group phase II trial","volume":"109","author":"Hensley","year":"2008","journal-title":"Gynecol. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1006\/gyno.1996.0185","article-title":"Uterine leiomyosarcoma: Analysis of treatment failures and survival","volume":"62","author":"Gadducci","year":"1996","journal-title":"Gynecol. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.humpath.2015.08.026","article-title":"May Sonic Hedgehog proteins be markers for malignancy in uterine smooth muscle tumors?","volume":"50","author":"Garcia","year":"2016","journal-title":"Hum. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"33004","DOI":"10.18632\/oncotarget.8844","article-title":"Gli-1\/PI3K\/AKT\/NF-kB pathway mediates resistance to radiation and is a target for reversion of responses in refractory acute myeloid leukemia cells","volume":"7","author":"Li","year":"2016","journal-title":"Oncotarget"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"956","DOI":"10.3389\/fphar.2017.00956","article-title":"SMO Inhibition Modulates Cellular Plasticity and Invasiveness in Colorectal Cancer","volume":"8","author":"Magistri","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"655","DOI":"10.2174\/1381612822666161208100325","article-title":"Targeting the Hedgehog Pathway for Locally Advanced and Metastatic Basal Cell Carcinoma","volume":"23","author":"Yin","year":"2017","journal-title":"Curr. Pharm. Des."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8","DOI":"10.17305\/bjbms.2018.2756","article-title":"The role of the Hedgehog signaling pathway in cancer: A comprehensive review","volume":"18","author":"Skoda","year":"2018","journal-title":"Bosn. J. Basic Med Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12964-018-0220-7","article-title":"A highlight on Sonic hedgehog pathway","volume":"16","author":"Carballo","year":"2018","journal-title":"Cell Commun. Signal."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Zeng, X., and Ju, D. (2018). Hedgehog Signaling Pathway and Autophagy in Cancer. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082279"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.ejca.2005.08.039","article-title":"GLI transcription factors: Mediators of oncogenic Hedgehog signalling","volume":"42","author":"Kasper","year":"2006","journal-title":"Eur. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"487","DOI":"10.26502\/jcsct.5079089","article-title":"The Role of Hedgehog Pathway in Female Cancers","volume":"4","author":"Garcia","year":"2020","journal-title":"J. Cancer Sci. Clin. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1111\/cas.12697","article-title":"Cooperatively transcriptional and epigenetic regulation of sonic hedgehog overexpression drives malignant potential of breast cancer","volume":"106","author":"Duan","year":"2015","journal-title":"Cancer Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1111\/j.1349-7006.2010.01495.x","article-title":"Expression and regulation mechanisms of Sonic Hedgehog in breast cancer","volume":"101","author":"Cui","year":"2010","journal-title":"Cancer Sci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Loh, M., Liem, N., Vaithilingam, A., Lim, P.L., Sapari, N.S., Elahi, E., Mok, Z.Y., Cheng, C.L., Yan, B., and Pang, B. (2014). DNA methylation subgroups and the CpG island methylator phenotype in gastric cancer: A comprehensive profiling approach. BMC gastroenterol., 14.","DOI":"10.1186\/1471-230X-14-55"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"24179","DOI":"10.18632\/oncotarget.8253","article-title":"Hedgehog pathway maintains cell survival under stress conditions, and drives drug resistance in lung adenocarcinoma","volume":"7","author":"Lin","year":"2016","journal-title":"Oncotarget"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3768","DOI":"10.1158\/1078-0432.CCR-07-1181","article-title":"Down-regulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma","volume":"14","author":"Tada","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_20","first-page":"887","article-title":"Antitumor effects of a combined 5-aza-2\u2032deoxycytidine and valproic acid treatment on rhabdomyosarcoma and medulloblastoma in Ptch mutant mice","volume":"69","author":"Ecke","year":"2009","journal-title":"Cancer Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s10549-006-9440-4","article-title":"Unmasking of epigenetically silenced genes reveals DNA promoter methylation and reduced expression of PTCH in breast cancer","volume":"105","author":"Wolf","year":"2007","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/1476-4598-7-84","article-title":"Alterations in candidate genes PHF2, FANCC, PTCH1 and XPA at chromosomal 9q22.3 region: Pathological significance in early- and late-onset breast carcinoma","volume":"7","author":"Sinha","year":"2008","journal-title":"Mol. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1073\/pnas.0907606106","article-title":"DNA methylation of developmental genes in pediatric medulloblastomas identified by denaturation analysis of methylation differences","volume":"107","author":"Diede","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Brinkhuizen, T., Hurk, K.V.D., Winnepenninckx, V.J.L., De Hoon, J.P., Van Marion, A.M., Veeck, J., Van Engeland, M., and Van Steensel, M.A.M. (2012). Epigenetic changes in Basal Cell Carcinoma affect SHH and WNT signaling components. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0051710"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"679","DOI":"10.3892\/ol.2014.2178","article-title":"Role of PTCH1 gene methylation in gastric carcinogenesis","volume":"8","author":"Zuo","year":"2014","journal-title":"Oncol Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1007\/s13277-014-2707-1","article-title":"Inactivation of PTCH1 is associated with the development of cervical carcinoma: Clinical and prognostic implication","volume":"36","author":"Chakraborty","year":"2015","journal-title":"Tumour Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.3892\/etm.2013.1334","article-title":"Detection and analysis of the methylation status of PTCH1 gene involved in the hedgehog signaling pathway in a human gastric cancer cell line","volume":"6","author":"Zuo","year":"2013","journal-title":"Exp. Ther. Med."},{"key":"ref_28","first-page":"5","article-title":"Hedgehog signaling is a potent regulator of liver lipid metabolism and reveals a GLI-code associated with steatosis","volume":"5","author":"Rennert","year":"2016","journal-title":"eLife"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nprot.2007.30","article-title":"In Vitro scratch assay: A convenient and inexpensive method for analysis of cell migration in vitro","volume":"2","author":"Liang","year":"2007","journal-title":"Nat. Protoc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1242\/jcs.061093","article-title":"The perennial organelle: Assembly and disassembly of the primary cilium","volume":"123","author":"Seeley","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1007\/s00018-015-2127-4","article-title":"Hedgehog signaling pathway: A novel model and molecular mechanisms of signal transduction","volume":"73","author":"Gorojankina","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1038\/bjc.2014.421","article-title":"Inhibition of Hedgehog signalling by NVP-LDE225 (Erismodegib) interferes with growth and invasion of human renal cell carcinoma cells","volume":"111","author":"Amato","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Jalili, A., Mertz, K.D., Romanov, J., Wagner, C., Kalthoff, F., Stuetz, A., Pathria, G., Gschaider, M., Stingl, G., and Wagner, S.N. (2013). NVP-LDE225, a potent and selective SMOOTHENED antagonist reduces melanoma growth in vitro and in vivo. PLoS ONE, 8.","DOI":"10.1371\/annotation\/ddd22094-5d8d-43ef-ad81-b95afe392ec7"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1038\/labinvest.2017.34","article-title":"Hedgehog signaling pathway affects the sensitivity of hepatoma cells to drug therapy through the ABCC1 transporter","volume":"97","author":"Ding","year":"2017","journal-title":"Lab. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4686","DOI":"10.1158\/1078-0432.CCR-14-3319","article-title":"SMO Gene Amplification and Activation of the Hedgehog Pathway as Novel Mechanisms of Resistance to Anti-Epidermal Growth Factor Receptor Drugs in Human Lung Cancer","volume":"21","author":"Bellevicine","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"25476","DOI":"10.1038\/srep25476","article-title":"Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia","volume":"6","author":"Irvine","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"84697","DOI":"10.18632\/oncotarget.20949","article-title":"Overcoming resistance to single-agent therapy for oncogenic BRAF gene fusions via combinatorial targeting of MAPK and PI3K\/mTOR signaling pathways","volume":"8","author":"Jain","year":"2017","journal-title":"Oncotarget"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9250","DOI":"10.18632\/oncotarget.7062","article-title":"In Vitro and in vivo inhibition of breast cancer cell growth by targeting the Hedgehog\/GLI pathway with SMO (GDC-0449) or GLI (GANT-61) inhibitors","volume":"7","author":"Benvenuto","year":"2016","journal-title":"Oncotarget"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"12151","DOI":"10.18632\/oncotarget.2569","article-title":"GLI inhibitor GANT-61 diminishes embryonal and alveolar rhabdomyosarcoma growth by inhibiting Shh\/AKT-mTOR axis","volume":"5","author":"Srivastava","year":"2014","journal-title":"Oncotarget"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8455","DOI":"10.1073\/pnas.0609699104","article-title":"Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists","volume":"104","author":"Lauth","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1111\/1471-0528.14579","article-title":"Uterine leiomyosarcoma: A review of recent advances in molecular biology, clinical management and outcome","volume":"124","author":"Cui","year":"2017","journal-title":"BJOG"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Chen, Q., Xu, R., Zeng, C., Lu, Q., Huang, D., Shi, C., Zhang, W., Deng, L., Yan, R., and Rao, H. (2014). Down-regulation of Gli transcription factor leads to the inhibition of migration and invasion of ovarian cancer cells via integrin beta4-mediated FAK signaling. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0088386"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2989","DOI":"10.1002\/cam4.833","article-title":"The hedgehog pathway in triple-negative breast cancer","volume":"5","author":"Habib","year":"2016","journal-title":"Cancer Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.juro.2010.03.007","article-title":"Gli2 expression and human bladder transitional carcinoma cell invasiveness","volume":"184","author":"Mechlin","year":"2010","journal-title":"J. Urol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s11010-018-3448-z","article-title":"Inhibition of sonic hedgehog and PI3K\/Akt\/mTOR pathways cooperate in suppressing survival, self-renewal and tumorigenic potential of glioblastoma-initiating cells","volume":"454","author":"Nanta","year":"2019","journal-title":"Mol. Cell. Biochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e42","DOI":"10.1038\/oncsis.2013.5","article-title":"NVP-LDE-225 (Erismodegib) inhibits epithelial-mesenchymal transition and human prostate cancer stem cell growth in NOD\/SCID IL2Rgamma null mice by regulating Bmi-1 and microRNA-128","volume":"2","author":"Nanta","year":"2013","journal-title":"Oncogenesis"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5704","DOI":"10.1002\/cam4.1827","article-title":"Dihydroartemisinin induces apoptosis and inhibits proliferation, migration, and invasion in epithelial ovarian cancer via inhibition of the hedgehog signaling pathway","volume":"7","author":"Liu","year":"2018","journal-title":"Cancer Med."},{"key":"ref_48","first-page":"2689","article-title":"Combination of phospholipase Cepsilon knockdown with GANT61 sensitizes castrationresistant prostate cancer cells to enzalutamide by suppressing the androgen receptor signaling pathway","volume":"41","author":"Sun","year":"2019","journal-title":"Oncol. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1080\/1120009X.2019.1584422","article-title":"GLI inhibitors overcome Erlotinib resistance in human pancreatic cancer cells by modulating E-cadherin","volume":"31","author":"Ghanbari","year":"2019","journal-title":"J. Chemother."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3641","DOI":"10.1002\/jcb.26572","article-title":"GANT-61 and GDC-0449 induce apoptosis of prostate cancer stem cells through a GLI-dependent mechanism","volume":"119","author":"Tong","year":"2018","journal-title":"J. Cell. Biochem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.3390\/ph6111429","article-title":"Hedgehog pathway blockade inhibits melanoma cell growth in vitro and in vivo","volume":"6","author":"Lizcano","year":"2013","journal-title":"Pharmaceuticals"},{"key":"ref_52","first-page":"1991","article-title":"Combined inhibition of sonic Hedgehog signaling and histone deacetylase is an effective treatment for liver cancer","volume":"41","author":"Li","year":"2019","journal-title":"Oncol. Rep."},{"key":"ref_53","first-page":"1337","article-title":"Targeted inhibition of histone deacetylases and hedgehog signaling suppress tumor growth and homologous recombination in aerodigestive cancers","volume":"5","author":"Chun","year":"2015","journal-title":"Am. J. Cancer Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/1\/53\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:48:35Z","timestamp":1760179715000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/1\/53"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,31]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["cells10010053"],"URL":"https:\/\/doi.org\/10.3390\/cells10010053","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,31]]}}}