{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T09:25:28Z","timestamp":1774085128696,"version":"3.50.1"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T00:00:00Z","timestamp":1615852800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T00:00:00Z","timestamp":1615852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["POCI-01-0145-FEDER-007274"],"award-info":[{"award-number":["POCI-01-0145-FEDER-007274"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["POCI-01-0145-FEDER-007274"],"award-info":[{"award-number":["POCI-01-0145-FEDER-007274"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PDTC\/MED_ONC\/31438\/2017"],"award-info":[{"award-number":["PDTC\/MED_ONC\/31438\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Dismal prognosis of glioblastoma (GBM) prompts for the identification of response predictors and therapeutic resistance mechanisms of current therapies. The authors investigated the impact of c-Met, HGF, VEGFR2 expression and microvessel density (MVD) in GBM patients submitted to second-line chemotherapy with bevacizumab. Immunohistochemical expression of c-Met, HGF, VEGFR2, and MVD was assessed in tumor specimens of GBM patients treated with bevacizumab, after progression under temozolomide. Survival analysis was evaluated according to the expression of the aforementioned biomarkers. c-Met overexpression was associated with a time-to-progression (TTP) after bevacizumab of 3\u00a0months (95% CI, 1.5\u20134.5) compared with a TTP of 7\u00a0months (95% CI, 4.6\u20139.4) in patients with low or no expression of c-Met (<jats:italic>p<\/jats:italic>\u2009=\u20090.05). VEGFR2 expression was associated with a TTP after bevacizumab of 3\u00a0months (95% CI, 1.8\u20134.2) compared with a TTP of 7\u00a0months (95% CI, 5.7\u20138.3) in patients with no tumoral expression of VEGFR2 (<jats:italic>p<\/jats:italic>\u2009=\u20090.009). Concomitant c-Met\/VEGFR2 overexpression was associated with worse overall survival (13\u00a0months) compared with concomitant c-Met\/VEGFR2 negative expression (19\u00a0months; <jats:italic>p<\/jats:italic>\u2009=\u20090.025). Our data support the hypothesis that c-Met and VEGFR2 overexpression have a role in the development of glioblastoma early resistance and might predict poorer responses to anti-angiogenic therapies.<\/jats:p>","DOI":"10.1038\/s41598-021-85385-1","type":"journal-article","created":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T11:14:42Z","timestamp":1615893282000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["The role of c-Met and VEGFR2 in glioblastoma resistance to bevacizumab"],"prefix":"10.1038","volume":"11","author":[{"given":"Bruno","family":"Carvalho","sequence":"first","affiliation":[]},{"given":"Jos\u00e9 Manuel","family":"Lopes","sequence":"additional","affiliation":[]},{"given":"Roberto","family":"Silva","sequence":"additional","affiliation":[]},{"given":"Joana","family":"Peixoto","sequence":"additional","affiliation":[]},{"given":"Dina","family":"Leit\u00e3o","sequence":"additional","affiliation":[]},{"given":"Paula","family":"Soares","sequence":"additional","affiliation":[]},{"given":"Ana Catarina","family":"Fernandes","sequence":"additional","affiliation":[]},{"given":"Paulo","family":"Linhares","sequence":"additional","affiliation":[]},{"given":"Rui","family":"Vaz","sequence":"additional","affiliation":[]},{"given":"Jorge","family":"Lima","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2021,3,16]]},"reference":[{"key":"85385_CR1","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/S1470-2045(09)70025-7","volume":"10","author":"R Stupp","year":"2009","unstructured":"Stupp, R. et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10, 459\u2013466. https:\/\/doi.org\/10.1016\/S1470-2045(09)70025-7 (2009).","journal-title":"Lancet Oncol."},{"key":"85385_CR2","doi-asserted-by":"publisher","first-page":"2306","DOI":"10.1001\/jama.2017.18718","volume":"318","author":"R Stupp","year":"2017","unstructured":"Stupp, R. et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: A randomized clinical trial. JAMA 318, 2306\u20132316. https:\/\/doi.org\/10.1001\/jama.2017.18718 (2017).","journal-title":"JAMA"},{"key":"85385_CR3","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1016\/S1470-2045(14)70314-6","volume":"15","author":"W Taal","year":"2014","unstructured":"Taal, W. et al. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): A randomised controlled phase 2 trial. Lancet Oncol. 15, 943\u2013953. https:\/\/doi.org\/10.1016\/S1470-2045(14)70314-6 (2014).","journal-title":"Lancet Oncol."},{"key":"85385_CR4","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1634\/theoncologist.2009-0121","volume":"14","author":"MH Cohen","year":"2009","unstructured":"Cohen, M. H., Shen, Y. L., Keegan, P. & Pazdur, R. FDA drug approval summary: Bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist 14, 1131\u20131138. https:\/\/doi.org\/10.1634\/theoncologist.2009-0121 (2009).","journal-title":"Oncologist"},{"key":"85385_CR5","doi-asserted-by":"publisher","first-page":"4733","DOI":"10.1200\/JCO.2008.19.8721","volume":"27","author":"HS Friedman","year":"2009","unstructured":"Friedman, H. S. et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J. Clin. Oncol. 27, 4733\u20134740. https:\/\/doi.org\/10.1200\/JCO.2008.19.8721 (2009).","journal-title":"J. Clin. Oncol."},{"key":"85385_CR6","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1056\/NEJMoa1308345","volume":"370","author":"OL Chinot","year":"2014","unstructured":"Chinot, O. L. et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 709\u2013722. https:\/\/doi.org\/10.1056\/NEJMoa1308345 (2014).","journal-title":"N. Engl. J. Med."},{"key":"85385_CR7","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1056\/NEJMoa1308573","volume":"370","author":"MR Gilbert","year":"2014","unstructured":"Gilbert, M. R. et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 699\u2013708. https:\/\/doi.org\/10.1056\/NEJMoa1308573 (2014).","journal-title":"N. Engl. J. Med."},{"key":"85385_CR8","doi-asserted-by":"publisher","first-page":"1954","DOI":"10.1056\/NEJMoa1707358","volume":"377","author":"W Wick","year":"2017","unstructured":"Wick, W. et al. Lomustine and bevacizumab in progressive glioblastoma. N. Engl. J. Med. 377, 1954\u20131963. https:\/\/doi.org\/10.1056\/NEJMoa1707358 (2017).","journal-title":"N. Engl. J. Med."},{"key":"85385_CR9","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1002\/cncr.28935","volume":"121","author":"KM Field","year":"2015","unstructured":"Field, K. M., Jordan, J. T., Wen, P. Y., Rosenthal, M. A. & Reardon, D. A. Bevacizumab and glioblastoma: Scientific review, newly reported updates, and ongoing controversies. Cancer 121, 997\u20131007. https:\/\/doi.org\/10.1002\/cncr.28935 (2015).","journal-title":"Cancer"},{"key":"85385_CR10","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1016\/S1470-2045(10)70232-1","volume":"11","author":"AM Jubb","year":"2010","unstructured":"Jubb, A. M. & Harris, A. L. Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol. 11, 1172\u20131183. https:\/\/doi.org\/10.1016\/S1470-2045(10)70232-1 (2010).","journal-title":"Lancet Oncol."},{"key":"85385_CR11","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1093\/neuonc\/nou092","volume":"16","author":"R Stupp","year":"2014","unstructured":"Stupp, R. & Weller, M. Questions regarding the optimal use of bevacizumab in glioblastoma: A moving target. Neuro Oncol. 16, 765\u2013767. https:\/\/doi.org\/10.1093\/neuonc\/nou092 (2014).","journal-title":"Neuro Oncol."},{"key":"85385_CR12","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1159\/000431236","volume":"38","author":"BF Carvalho","year":"2015","unstructured":"Carvalho, B. F. et al. Second-line chemotherapy in recurrent glioblastoma: A 2-cohort study. Oncol. Res. Treat. 38, 348\u2013354. https:\/\/doi.org\/10.1159\/000431236 (2015).","journal-title":"Oncol. Res. Treat."},{"key":"85385_CR13","doi-asserted-by":"publisher","first-page":"2721","DOI":"10.1200\/JCO.2015.62.3637","volume":"33","author":"TM Mayer","year":"2015","unstructured":"Mayer, T. M. Can we predict bevacizumab responders in patients with glioblastoma?. J. Clin. Oncol. 33, 2721\u20132722. https:\/\/doi.org\/10.1200\/JCO.2015.62.3637 (2015).","journal-title":"J. Clin. Oncol."},{"key":"85385_CR14","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/nrclinonc.2009.63","volume":"6","author":"RK Jain","year":"2009","unstructured":"Jain, R. K. et al. Biomarkers of response and resistance to antiangiogenic therapy. Nat. Rev. Clin. Oncol. 6, 327\u2013338. https:\/\/doi.org\/10.1038\/nrclinonc.2009.63 (2009).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"85385_CR15","doi-asserted-by":"publisher","first-page":"221","DOI":"10.3389\/fonc.2020.00221","volume":"10","author":"Y Haibe","year":"2020","unstructured":"Haibe, Y. et al. Resistance mechanisms to anti-angiogenic therapies in cancer. Front. Oncol. 10, 221. https:\/\/doi.org\/10.3389\/fonc.2020.00221 (2020).","journal-title":"Front. Oncol."},{"key":"85385_CR16","doi-asserted-by":"publisher","first-page":"1773","DOI":"10.1158\/1078-0432.CCR-12-1281","volume":"19","author":"A Jahangiri","year":"2013","unstructured":"Jahangiri, A. et al. Gene expression profile identifies tyrosine kinase c-Met as a targetable mediator of antiangiogenic therapy resistance. Clin. Cancer Res. 19, 1773\u20131783. https:\/\/doi.org\/10.1158\/1078-0432.CCR-12-1281 (2013).","journal-title":"Clin. Cancer Res."},{"key":"85385_CR17","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1002\/cncr.23972","volume":"115","author":"DS Kong","year":"2009","unstructured":"Kong, D. S. et al. Prognostic significance of c-Met expression in glioblastomas. Cancer 115, 140\u2013148. https:\/\/doi.org\/10.1002\/cncr.23972 (2009).","journal-title":"Cancer"},{"key":"85385_CR18","doi-asserted-by":"publisher","first-page":"52423","DOI":"10.18632\/oncotarget.9387","volume":"7","author":"R Tamura","year":"2016","unstructured":"Tamura, R. et al. Histopathological investigation of glioblastomas resected under bevacizumab treatment. Oncotarget 7, 52423\u201352435. https:\/\/doi.org\/10.18632\/oncotarget.9387 (2016).","journal-title":"Oncotarget"},{"key":"85385_CR19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1056\/NEJM199101033240101","volume":"324","author":"N Weidner","year":"1991","unstructured":"Weidner, N., Semple, J. P., Welch, W. R. & Folkman, J. Tumor angiogenesis and metastasis\u2013Correlation in invasive breast carcinoma. N. Engl. J. Med. 324, 1\u20138. https:\/\/doi.org\/10.1056\/NEJM199101033240101 (1991).","journal-title":"N. Engl. J. Med."},{"key":"85385_CR20","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1007\/s11060-020-03404-z","volume":"147","author":"B Carvalho","year":"2020","unstructured":"Carvalho, B. et al. Hypertension and proteinuria as clinical biomarkers of response to bevacizumab in glioblastoma patients. J. Neurooncol. 147, 109\u2013116. https:\/\/doi.org\/10.1007\/s11060-020-03404-z (2020).","journal-title":"J. Neurooncol."},{"key":"85385_CR21","doi-asserted-by":"publisher","first-page":"31050","DOI":"10.18632\/oncotarget.2910","volume":"6","author":"T Kessler","year":"2015","unstructured":"Kessler, T. et al. Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma. Oncotarget 6, 31050\u201331068. https:\/\/doi.org\/10.18632\/oncotarget.2910 (2015).","journal-title":"Oncotarget"},{"key":"85385_CR22","doi-asserted-by":"publisher","unstructured":"Nishikawa, R. et al. Biomarker (BM) evaluations in the phase III AVAglio study of bevacizumab (Bv) plus standard radiotherapy (RT) and temozolomide (T) for newly diagnosed gliobastoma (GBM). J. Clin. Oncol. 31, https:\/\/doi.org\/10.1200\/jco.2013.31.15_suppl.2023 (2013).","DOI":"10.1200\/jco.2013.31.15_suppl.2023"},{"key":"85385_CR23","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1093\/neuonc\/not226","volume":"16","author":"E Tabouret","year":"2014","unstructured":"Tabouret, E. et al. Association of matrix metalloproteinase 2 plasma level with response and survival in patients treated with bevacizumab for recurrent high-grade glioma. Neuro Oncol. 16, 392\u2013399. https:\/\/doi.org\/10.1093\/neuonc\/not226 (2014).","journal-title":"Neuro Oncol."},{"key":"85385_CR24","doi-asserted-by":"publisher","first-page":"116433","DOI":"10.1016\/j.jns.2019.116433","volume":"405","author":"L Petrova","year":"2019","unstructured":"Petrova, L. et al. Cerebral blood volume and apparent diffusion coefficient\u2014Valuable predictors of non-response to bevacizumab treatment in patients with recurrent glioblastoma. J. Neurol. Sci. 405, 116433. https:\/\/doi.org\/10.1016\/j.jns.2019.116433 (2019).","journal-title":"J. Neurol. Sci."},{"key":"85385_CR25","doi-asserted-by":"publisher","first-page":"1774","DOI":"10.1002\/cam4.1439","volume":"7","author":"SW Choi","year":"2018","unstructured":"Choi, S. W. et al. Identification of transcriptome signature for predicting clinical response to bevacizumab in recurrent glioblastoma. Cancer Med. 7, 1774\u20131783. https:\/\/doi.org\/10.1002\/cam4.1439 (2018).","journal-title":"Cancer Med."},{"key":"85385_CR26","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1007\/s11060-019-03102-5","volume":"142","author":"KE Hovinga","year":"2019","unstructured":"Hovinga, K. E. et al. EGFR amplification and classical subtype are associated with a poor response to bevacizumab in recurrent glioblastoma. J. Neurooncol. 142, 337\u2013345. https:\/\/doi.org\/10.1007\/s11060-019-03102-5 (2019).","journal-title":"J. Neurooncol."},{"key":"85385_CR27","doi-asserted-by":"publisher","first-page":"2735","DOI":"10.1200\/JCO.2015.61.5005","volume":"33","author":"T Sandmann","year":"2015","unstructured":"Sandmann, T. et al. Patients with proneural glioblastoma may derive overall survival benefit from the addition of bevacizumab to first-line radiotherapy and temozolomide: Retrospective analysis of the AVAglio Trial. J. Clin. Oncol. 33, 2735\u20132744. https:\/\/doi.org\/10.1200\/JCO.2015.61.5005 (2015).","journal-title":"J. Clin. Oncol."},{"key":"85385_CR28","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.1158\/1078-0432.CCR-13-0051","volume":"19","author":"JH McCarty","year":"2013","unstructured":"McCarty, J. H. Glioblastoma resistance to anti-VEGF therapy: Has the challenge been MET?. Clin. Cancer Res. 19, 1631\u20131633. https:\/\/doi.org\/10.1158\/1078-0432.CCR-13-0051 (2013).","journal-title":"Clin. Cancer Res."},{"key":"85385_CR29","doi-asserted-by":"publisher","first-page":"49","DOI":"10.2217\/cns.12.36","volume":"2","author":"KV Lu","year":"2013","unstructured":"Lu, K. V. & Bergers, G. Mechanisms of evasive resistance to anti-VEGF therapy in glioblastoma. CNS Oncol. 2, 49\u201365. https:\/\/doi.org\/10.2217\/cns.12.36 (2013).","journal-title":"CNS Oncol."},{"key":"85385_CR30","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1158\/1078-0432.CCR-12-2832","volume":"19","author":"Y Zhang","year":"2013","unstructured":"Zhang, Y. et al. Hepatocyte growth factor sensitizes brain tumors to c-MET kinase inhibition. Clin. Cancer Res. 19, 1433\u20131444. https:\/\/doi.org\/10.1158\/1078-0432.CCR-12-2832 (2013).","journal-title":"Clin. Cancer Res."},{"key":"85385_CR31","doi-asserted-by":"publisher","unstructured":"Bais, C. et al. Tumor microvessel density as a potential predictive marker for bevacizumab benefit: GOG-0218 biomarker analyses. J. Natl. Cancer Inst. 109, https:\/\/doi.org\/10.1093\/jnci\/djx066 (2017).","DOI":"10.1093\/jnci\/djx066"},{"key":"85385_CR32","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1007\/s11060-017-2648-9","volume":"136","author":"R Tamura","year":"2018","unstructured":"Tamura, R. et al. Histopathological vascular investigation of the peritumoral brain zone of glioblastomas. J. Neurooncol. 136, 233\u2013241. https:\/\/doi.org\/10.1007\/s11060-017-2648-9 (2018).","journal-title":"J. Neurooncol."},{"key":"85385_CR33","first-page":"2283","volume":"31","author":"F Nassiri","year":"2011","unstructured":"Nassiri, F. et al. Endoglin (CD105): A review of its role in angiogenesis and tumor diagnosis, progression and therapy. Anticancer Res. 31, 2283\u20132290 (2011).","journal-title":"Anticancer Res."},{"key":"85385_CR34","doi-asserted-by":"publisher","unstructured":"Manneh Kopp, R. A. et al. Correlation of radiological and immunochemical parameters with clinical outcome in patients with recurrent glioblastoma treated with bevacizumab. Clin. Transl. Oncol. 21, 1413\u20131423, https:\/\/doi.org\/10.1007\/s12094-019-02070-6 (2019).","DOI":"10.1007\/s12094-019-02070-6"},{"key":"85385_CR35","doi-asserted-by":"publisher","first-page":"3871","DOI":"10.21873\/anticanres.11767","volume":"37","author":"T Okuda","year":"2017","unstructured":"Okuda, T. et al. Efficacy of combination therapy with MET and VEGF inhibitors for MET-overexpressing glioblastoma. Anticancer Res. 37, 3871\u20133876. https:\/\/doi.org\/10.21873\/anticanres.11767 (2017).","journal-title":"Anticancer Res."},{"key":"85385_CR36","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/s12943-018-0796-y","volume":"17","author":"Y Zhang","year":"2018","unstructured":"Zhang, Y. et al. Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol. Cancer 17, 45. https:\/\/doi.org\/10.1186\/s12943-018-0796-y (2018).","journal-title":"Mol. Cancer"},{"key":"85385_CR37","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1200\/JCO.2015.64.7685","volume":"35","author":"T Cloughesy","year":"2017","unstructured":"Cloughesy, T. et al. Randomized, double-blind, placebo-controlled, multicenter phase II study of onartuzumab plus bevacizumab versus placebo plus bevacizumab in patients with recurrent glioblastoma: Efficacy, safety, and hepatocyte growth factor and O(6)-methylguanine-DNA methyltransferase biomarker analyses. J. Clin. Oncol. 35, 343\u2013351. https:\/\/doi.org\/10.1200\/JCO.2015.64.7685 (2017).","journal-title":"J. Clin. Oncol."},{"key":"85385_CR38","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1007\/s11060-019-03337-2","volume":"146","author":"M van den Bent","year":"2020","unstructured":"van den Bent, M. et al. A phase Ib\/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma. J. Neurooncol. 146, 79\u201389. https:\/\/doi.org\/10.1007\/s11060-019-03337-2 (2020).","journal-title":"J. Neurooncol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85385-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85385-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85385-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T05:19:01Z","timestamp":1670044741000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85385-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,16]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["85385"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-85385-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,16]]},"assertion":[{"value":"28 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 February 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"6067"}}