{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:48:29Z","timestamp":1790225309237,"version":"4.1.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T00:00:00Z","timestamp":1716249600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T00:00:00Z","timestamp":1716249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Hunan Provincial Joint Fund and Hunan Provincial Natural Science Foundation of China","award":["No. 2020JJ6105"],"award-info":[{"award-number":["No. 2020JJ6105"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Metab Brain Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Meningioma is a prevalent intracranial malignancy known for its aggressive growth.\u00a0Circular RNAs (circRNAs) play a crucial role in the development of various cancers. However, their\u00a0involvement in meningioma remains understudied. This study aimed to investigate the function and\u00a0underlying mechanism of hsa_circ_0004872 in meningioma.\u00a0The molecular expression of hsa_circ_0004872, PD-L1 and EIF4A3 was identified by RT-qPCR\u00a0and\/or western blot assays. Cell viability, migration, and invasion were assessed through\u00a0CCK-8 and Transwell assays, respectively. Cytotoxicity was determined using an LDH assay, and cell\u00a0apoptosis was monitored by flow cytometry. The RNA and protein interactions were assessed through\u00a0RNA-protein immunoprecipitation (RIP) and RNA pull down analyses.\u00a0Our findings revealed that hsa_circ_0004872 expression was significantly downregulated in\u00a0both meningioma tissue samples and cells. Overexpression of hsa_circ_0004872 inhibited the\u00a0proliferation, metastasis, and immune escape of meningioma cells, as well as enhanced the cytotoxicity\u00a0of CD8+ T cells by suppressing PD-L1. Furthermore, hsa_circ_0004872 directly interacted with\u00a0EIF4A3, leading to the degradation of PD-L1 mRNA. Finally, inhibiting EIF4A3 improved the\u00a0proliferation, metastasis, and immune escape of meningioma cells, as well as the cytotoxicity of CD8+\u00a0T cells.\u00a0Our study demonstrated that hsa_circ_0004872 mitigated the proliferation, metastasis,and immune escape of meningioma cells by targeting the EIF4A3\/PD-L1 axis. These findings\u00a0suggested that hsa_circ_0004872 and EIF4A3 might serve as promising biological markers and\u00a0therapeutic targets for meningioma treatment.<\/jats:p>","DOI":"10.1007\/s11011-024-01345-4","type":"journal-article","created":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T10:01:42Z","timestamp":1716285702000},"page":"895-907","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Hsa_circ_0004872 mitigates proliferation, metastasis and immune escape of meningioma cells by suppressing PD-L1"],"prefix":"10.1007","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0793-3192","authenticated-orcid":false,"given":"Kuo","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0006-5151","authenticated-orcid":false,"given":"Zhengming","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8880-8891","authenticated-orcid":false,"given":"Changsheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0657-0623","authenticated-orcid":false,"given":"Qian","family":"Ouyang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7135-8911","authenticated-orcid":false,"given":"Qing","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9246-3153","authenticated-orcid":false,"given":"Wei","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8188-7944","authenticated-orcid":false,"given":"Yongkai","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,21]]},"reference":[{"key":"1345_CR1","doi-asserted-by":"publisher","unstructured":"Arneth B (2019) Tumor Microenvironment. Med (Kaunas) 56(1). https:\/\/doi.org\/10.3390\/medicina56010015","DOI":"10.3390\/medicina56010015"},{"key":"1345_CR2","doi-asserted-by":"publisher","unstructured":"Cao Y, Liang W, Fang L, Liu MK, Zuo J, Peng YL,... Wang J (2022) PD-L1\/PD-L1 signalling promotes colorectal cancer cell migration ability through RAS\/MEK\/ERK. Clin Exp Pharmacol Physiol 49(12):1281\u20131293. https:\/\/doi.org\/10.1111\/1440-1681.13717","DOI":"10.1111\/1440-1681.13717"},{"key":"1345_CR3","doi-asserted-by":"publisher","unstructured":"Capel B, Swain A, Nicolis S, Hacker A, Walter M, Koopman P,... Lovell-Badge R (1993) Circular transcripts of the testis-determining gene sry in adult mouse testis. Cell 73(5):1019\u20131030. https:\/\/doi.org\/10.1016\/0092-8674(93)90279-y","DOI":"10.1016\/0092-8674(93)90279-y"},{"key":"1345_CR4","doi-asserted-by":"publisher","unstructured":"Chen RX, Liu HL, Yang LL, Kang FH, Xin LP, Huang LR,... Wang YL (2019) Circular RNA circRNA_0000285 promotes cervical cancer development by regulating FUS. Eur Rev Med Pharmacol Sci 23(20):8771\u20138778. https:\/\/doi.org\/10.26355\/eurrev_201910_19271","DOI":"10.26355\/eurrev_201910_19271"},{"key":"1345_CR5","doi-asserted-by":"publisher","unstructured":"Chen J, Wu Y, Luo X, Jin D, Zhou W, Ju Z,... Song Z (2021) Circular RNA circRHOBTB3 represses metastasis by regulating the HuR-mediated mRNA stability of PTBP1 in colorectal cancer. Theranostics 11(15):7507\u20137526. https:\/\/doi.org\/10.7150\/thno.59546","DOI":"10.7150\/thno.59546"},{"key":"1345_CR6","doi-asserted-by":"publisher","unstructured":"Chen J, Gu J, Tang M, Liao Z, Tang R, Zhou L,... Nie S (2022) Regulation of cancer progression by circRNA and functional proteins. J Cell Physiol 237(1):373\u2013388. https:\/\/doi.org\/10.1002\/jcp.30608","DOI":"10.1002\/jcp.30608"},{"key":"1345_CR7","doi-asserted-by":"publisher","unstructured":"Du Z, Abedalthagafi M, Aizer AA, McHenry AR, Sun HH, Bray MA,... Santagata S (2015) Increased expression of the immune modulatory molecule PD-L1 (CD274) in anaplastic meningioma. Oncotarget 6(7):4704\u20134716. https:\/\/doi.org\/10.18632\/oncotarget.3082","DOI":"10.18632\/oncotarget.3082"},{"issue":"5","key":"1345_CR8","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1002\/eji.201646875","volume":"47","author":"L Dyck","year":"2017","unstructured":"Dyck L, Mills KHG (2017) Immune checkpoints and their inhibition in cancer and infectious diseases. Eur J Immunol 47(5):765\u2013779. https:\/\/doi.org\/10.1002\/eji.201646875","journal-title":"Eur J Immunol"},{"issue":"7","key":"1345_CR9","doi-asserted-by":"publisher","first-page":"2189","DOI":"10.1016\/j.numecd.2021.04.005","volume":"31","author":"X Fu","year":"2021","unstructured":"Fu X, Niu T, Yang T, Li X (2021) CircMAPK1 promotes the proliferation and migration of vascular smooth muscle cells through miR-22-3p\/ methyl-CpG binding protein 2 axis. Nutr Metab Cardiovasc Dis 31(7):2189\u20132198. https:\/\/doi.org\/10.1016\/j.numecd.2021.04.005","journal-title":"Nutr Metab Cardiovasc Dis"},{"key":"1345_CR10","doi-asserted-by":"publisher","unstructured":"Ghafouri-Fard S, Abak A, Hussen BM, Taheri M, Sharifi G (2021) The emerging role of non-coding RNAs in pituitary gland tumors and meningioma. Cancers (Basel) 13(23). https:\/\/doi.org\/10.3390\/cancers13235987","DOI":"10.3390\/cancers13235987"},{"key":"1345_CR11","doi-asserted-by":"publisher","unstructured":"Han SJ, Reis G, Kohanbash G, Shrivastav S, Magill ST, Molinaro AM,... Okada H (2016) Expression and prognostic impact of immune modulatory molecule PD-L1 in meningioma. J Neurooncol 130(3):543\u2013552. https:\/\/doi.org\/10.1007\/s11060-016-2256-0","DOI":"10.1007\/s11060-016-2256-0"},{"key":"1345_CR12","doi-asserted-by":"publisher","unstructured":"Huang G, Liang M, Liu H, Huang J, Li P, Wang C,... Jiang X (2020) CircRNA hsa_circRNA_104348 promotes hepatocellular carcinoma progression through modulating miR-187-3p\/RTKN2 axis and activating Wnt\/\u03b2-catenin pathway. Cell Death Dis 11(12):1065. https:\/\/doi.org\/10.1038\/s41419-020-03276-1","DOI":"10.1038\/s41419-020-03276-1"},{"key":"1345_CR13","doi-asserted-by":"publisher","unstructured":"Jiang X, Wang J, Deng X, Xiong F, Ge J, Xiang B,... Zeng Z (2019) Role of the tumor microenvironment in PD-L1\/PD-1-mediated tumor immune escape. Mol Cancer 18(1):10. https:\/\/doi.org\/10.1186\/s12943-018-0928-4","DOI":"10.1186\/s12943-018-0928-4"},{"key":"1345_CR14","doi-asserted-by":"publisher","unstructured":"Jiang T, Xia Y, Lv J, Li B, Li Y, Wang S,... Xu Z (2021a) A novel protein encoded by circMAPK1 inhibits progression of gastric cancer by suppressing activation of MAPK signaling. Mol Cancer 20(1):66. https:\/\/doi.org\/10.1186\/s12943-021-01358-y","DOI":"10.1186\/s12943-021-01358-y"},{"key":"1345_CR15","doi-asserted-by":"publisher","unstructured":"Jiang Z, Tai Q, Xie X, Hou Z, Liu W, Yu Z,... Chen S (2021b) EIF4A3-induced circ_0084615 contributes to the progression of colorectal cancer via miR-599\/ONECUT2 pathway. J Exp Clin Cancer Res 40(1):227. https:\/\/doi.org\/10.1186\/s13046-021-02029-y","DOI":"10.1186\/s13046-021-02029-y"},{"issue":"1","key":"1345_CR16","first-page":"1","volume":"10","author":"X Ju","year":"2020","unstructured":"Ju X, Zhang H, Zhou Z, Wang Q (2020) Regulation of PD-L1 expression in cancer and clinical implications in immunotherapy. Am J Cancer Res 10(1):1\u201311","journal-title":"Am J Cancer Res"},{"key":"1345_CR17","doi-asserted-by":"publisher","unstructured":"Karimi S, Mansouri S, Mamatjan Y, Liu J, Nassiri F, Suppiah S,... Zadeh G (2020) Programmed death ligand-1 (PD-L1) expression in meningioma; prognostic significance and its association with hypoxia and NFKB2 expression. Sci Rep 10(1):14115. https:\/\/doi.org\/10.1038\/s41598-020-70514-z","DOI":"10.1038\/s41598-020-70514-z"},{"key":"1345_CR18","doi-asserted-by":"publisher","unstructured":"Karimi S, Mansouri S, Nassiri F, Bunda S, Singh O, Brastianos PK,... Zadeh G (2021) Clinical significance of checkpoint regulator programmed death ligand-1 (PD-L1) expression in meningioma: review of the current status. J Neurooncol 151(3):443\u2013449. https:\/\/doi.org\/10.1007\/s11060-020-03584-8","DOI":"10.1007\/s11060-020-03584-8"},{"key":"1345_CR19","doi-asserted-by":"publisher","unstructured":"Liang Y, Wang H, Chen B, Mao Q, Xia W, Zhang T,... Jiang F (2021) circDCUN1D4 suppresses tumor metastasis and glycolysis in lung adenocarcinoma by stabilizing TXNIP expression. Mol Ther Nucleic Acids 23:355\u2013368. https:\/\/doi.org\/10.1016\/j.omtn.2020.11.012","DOI":"10.1016\/j.omtn.2020.11.012"},{"key":"1345_CR20","doi-asserted-by":"publisher","unstructured":"Liu Y, Song J, Zhang H, Liao Z, Liu F, Su C,... Chen X (2022) EIF4A3-induced circTOLLIP promotes the progression of hepatocellular carcinoma via the miR-516a-5p\/PBX3\/EMT pathway. J Exp Clin Cancer Res 41(1):164. https:\/\/doi.org\/10.1186\/s13046-022-02378-2","DOI":"10.1186\/s13046-022-02378-2"},{"issue":"7","key":"1345_CR21","doi-asserted-by":"publisher","first-page":"e23866","DOI":"10.1002\/jcla.23866","volume":"35","author":"Y Lu","year":"2021","unstructured":"Lu Y, Li Z, Lin C, Zhang J, Shen Z (2021) Translation role of circRNAs in cancers. J Clin Lab Anal 35(7):e23866. https:\/\/doi.org\/10.1002\/jcla.23866","journal-title":"J Clin Lab Anal"},{"key":"1345_CR22","doi-asserted-by":"publisher","unstructured":"Ma C, Wang X, Yang F, Zang Y, Liu J, Wang X,... Liu Z (2020) Circular RNA hsa_circ_0004872 inhibits gastric cancer progression via the miR-224\/Smad4\/ADAR1 successive regulatory circuit. Mol Cancer 19(1):157. https:\/\/doi.org\/10.1186\/s12943-020-01268-5","DOI":"10.1186\/s12943-020-01268-5"},{"key":"1345_CR23","doi-asserted-by":"crossref","unstructured":"Maggio I, Franceschi E, Tosoni A, Nunno VD, Gatto L, Lodi R, Brandes AA (2021) Meningioma: not always a benign tumor. A review of advances in the treatment of meningiomas. CNS Oncol 10(2). Cns72","DOI":"10.2217\/cns-2021-0003"},{"key":"1345_CR24","doi-asserted-by":"publisher","unstructured":"Nowosielski M, Galldiks N, Iglseder S, Kickingereder P, von Deimling A, Bendszus M,...\u00a0 Sahm F (2017) Diagnostic challenges in meningioma. Neuro Oncol 19(12):1588\u20131598. https:\/\/doi.org\/10.1093\/neuonc\/nox101","DOI":"10.1093\/neuonc\/nox101"},{"key":"1345_CR25","doi-asserted-by":"publisher","unstructured":"Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C, Barnholtz-Sloan JS (2017) CBTRUS Statistical Report: primary brain and other central nervous system tumors diagnosed in the United States in 2010\u20132014. Neuro Oncol 19(suppl5):v1\u2013v88. https:\/\/doi.org\/10.1093\/neuonc\/nox158","DOI":"10.1093\/neuonc\/nox158"},{"key":"1345_CR26","doi-asserted-by":"publisher","unstructured":"Patop IL, W\u00fcst S, Kadener S (2019) Past, present, and future of circRNAs. Embo J 38(16):e100836. https:\/\/doi.org\/10.15252\/embj.2018100836","DOI":"10.15252\/embj.2018100836"},{"key":"1345_CR27","doi-asserted-by":"publisher","unstructured":"Pawloski JA, Fadel HA, Huang YW, Lee IY (2021) Genomic biomarkers of Meningioma: a focused review. Int J Mol Sci 22(19). https:\/\/doi.org\/10.3390\/ijms221910222","DOI":"10.3390\/ijms221910222"},{"key":"1345_CR28","doi-asserted-by":"publisher","unstructured":"Rogers L, Zhang P, Vogelbaum MA, Perry A, Ashby LS, Modi JM,... Mehta MP (2018) Intermediate-risk meningioma: initial outcomes from NRG Oncology RTOG 0539. J Neurosurg 129(1):35\u201347. https:\/\/doi.org\/10.3171\/2016.11.Jns161170","DOI":"10.3171\/2016.11.Jns161170"},{"issue":"12","key":"1345_CR29","doi-asserted-by":"publisher","first-page":"4504","DOI":"10.1080\/15548627.2021.1985881","volume":"17","author":"D Sakellariou","year":"2021","unstructured":"Sakellariou D, Frankel LB (2021) EIF4A3: a gatekeeper of autophagy. Autophagy 17(12):4504\u20134505. https:\/\/doi.org\/10.1080\/15548627.2021.1985881","journal-title":"Autophagy"},{"key":"1345_CR30","doi-asserted-by":"publisher","unstructured":"Song H, Liu Y, Li X, Chen S, Xie R, Chen D,... Yang X (2020) Long noncoding RNA CASC11 promotes hepatocarcinogenesis and HCC progression through EIF4A3-mediated E2F1 activation. Clin Transl Med 10(7):e220. https:\/\/doi.org\/10.1002\/ctm2.220","DOI":"10.1002\/ctm2.220"},{"key":"1345_CR31","doi-asserted-by":"publisher","unstructured":"Spill F, Reynolds DS, Kamm RD, Zaman MH (2016) Impact of the physical microenvironment on tumor progression and metastasis. Curr Opin Biotechnol 40:41\u201348. https:\/\/doi.org\/10.1016\/j.copbio.2016.02.007","DOI":"10.1016\/j.copbio.2016.02.007"},{"key":"1345_CR32","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.omtn.2021.07.003","volume":"26","author":"X Wang","year":"2021","unstructured":"Wang X, Chen M, Fang L (2021a) hsa_circ_0068631 promotes breast cancer progression through c-Myc by binding to EIF4A3. Mol Ther Nucleic Acids 26:122\u2013134. https:\/\/doi.org\/10.1016\/j.omtn.2021.07.003","journal-title":"Mol Ther Nucleic Acids"},{"key":"1345_CR33","doi-asserted-by":"publisher","unstructured":"Wang X, Li J, Bian X, Wu C, Hua J, Chang S,... Lin W (2021b) CircURI1 interacts with hnRNPM to inhibit metastasis by modulating alternative splicing in gastric cancer. Proc Natl Acad Sci U S A 118(33). https:\/\/doi.org\/10.1073\/pnas.2012881118","DOI":"10.1073\/pnas.2012881118"},{"key":"1345_CR34","doi-asserted-by":"publisher","unstructured":"Wei Y, Lu C, Zhou P, Zhao L, Lyu X, Yin J,...\u00a0 You Y (2021) EIF4A3-induced circular RNA ASAP1 promotes tumorigenesis and temozolomide resistance of glioblastoma via NRAS\/MEK1\/ERK1-2 signaling. Neuro Oncol 23(4):611\u2013624. https:\/\/doi.org\/10.1093\/neuonc\/noaa214","DOI":"10.1093\/neuonc\/noaa214"},{"key":"1345_CR35","doi-asserted-by":"publisher","unstructured":"Yang M, Hu H, Wu S, Ding J, Yin B, Huang B,... Han L (2022) EIF4A3-regulated circ_0087429 can reverse EMT and inhibit the progression of cervical cancer via mir-5003-3p-dependent upregulation of OGN expression. J Exp Clin Cancer Res 41(1):165. https:\/\/doi.org\/10.1186\/s13046-022-02368-4","DOI":"10.1186\/s13046-022-02368-4"},{"key":"1345_CR36","doi-asserted-by":"publisher","unstructured":"Zhang X, Schwartz JC, Guo X, Bhatia S, Cao E, Lorenz M,... Almo SC (2004) Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity 20(3):337\u2013347. https:\/\/doi.org\/10.1016\/s1074-7613(04)00051-2","DOI":"10.1016\/s1074-7613(04)00051-2"},{"issue":"1","key":"1345_CR37","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1186\/s13046-020-01687-8","volume":"39","author":"H Zhang","year":"2020","unstructured":"Zhang H, Zhu C, He Z, Chen S, Li L, Sun C (2020) LncRNA PSMB8-AS1 contributes to pancreatic cancer progression via modulating miR-382-3p\/STAT1\/PD-L1 axis. J Exp Clin Cancer Res 39(1):179. https:\/\/doi.org\/10.1186\/s13046-020-01687-8","journal-title":"J Exp Clin Cancer Res"},{"key":"1345_CR38","doi-asserted-by":"publisher","unstructured":"Zheng X, Huang M, Xing L, Yang R, Wang X, Jiang R,... Chen J (2020) The circRNA circSEPT9 mediated by E2F1 and EIF4A3 facilitates the carcinogenesis and development of triple-negative breast cancer. Mol Cancer 19(1):73. https:\/\/doi.org\/10.1186\/s12943-020-01183-9","DOI":"10.1186\/s12943-020-01183-9"}],"container-title":["Metabolic Brain Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11011-024-01345-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11011-024-01345-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11011-024-01345-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T04:07:21Z","timestamp":1720498041000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11011-024-01345-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,21]]},"references-count":38,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["1345"],"URL":"https:\/\/doi.org\/10.1007\/s11011-024-01345-4","relation":{},"ISSN":["1573-7365"],"issn-type":[{"value":"1573-7365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,21]]},"assertion":[{"value":"10 April 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 May 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 May 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The data used in this study has never been published before.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"All procedures performed in studies were approved by the Ethics Committee of Zhuzhou Hospital affiliated to Xiangya Medical College of Central South University.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"All participants were informed and provided written consent.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"The authors declare that they have no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}