{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T17:27:33Z","timestamp":1784654853221,"version":"3.55.0"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T00:00:00Z","timestamp":1620864000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T00:00:00Z","timestamp":1620864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Supported in part by the National Institute of General Medical Sciences of the National Institutes of Health, which funds the Louisiana Clinical and Translational Science Center.","award":["U54 GM104940"],"award-info":[{"award-number":["U54 GM104940"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Renal Cell Carcinoma (RCC) is the most common form of kidney cancer, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. There are limited curable treatments available for metastatic ccRCC because this disease is unresponsive to conventional targeted systemic pharmacotherapy. Exosomes (Exo) are small extracellular vesicles (EVs) secreted from cancer cells with marked roles in tumoral signaling and pharmacological resistance. Ketoconazole (KTZ) is an FDA approved anti-fungal medication which has been shown to suppress exosome biogenesis and secretion, yet its role in ccRCC has not been identified. A time-course, dose-dependent analysis revealed that KTZ selectively decreased secreted Exo in tumoral cell lines. Augmented Exo secretion was further evident by decreased expression of Exo biogenesis (Alix and nSMase) and secretion (Rab27a) markers. Interestingly, KTZ-mediated inhibition of Exo biogenesis was coupled with inhibition of ERK1\/2 activation. Next, selective inhibitors were employed and showed ERK signaling had a direct role in mediating KTZ\u2019s inhibition of exosomes. In sunitinib resistant 786-O cells lines, the addition of KTZ potentiates the efficacy of sunitinib by causing Exo inhibition, decreased tumor proliferation, and diminished clonogenic ability of RCC cells. Our findings suggest that KTZ should be explored as an adjunct to current RCC therapies.<\/jats:p>","DOI":"10.1038\/s41598-021-89655-w","type":"journal-article","created":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T10:03:16Z","timestamp":1620900196000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma"],"prefix":"10.1038","volume":"11","author":[{"given":"Jacob W.","family":"Greenberg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hogyoung","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed A.","family":"Moustafa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amrita","family":"Datta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro C.","family":"Barata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Hamid","family":"Boulares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asim B.","family":"Abdel-Mageed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis S.","family":"Krane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,13]]},"reference":[{"key":"89655_CR1","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.urolonc.2016.12.002","volume":"35","author":"PJ Siska","year":"2017","unstructured":"Siska, P. J., Beckermann, K. E., Rathmell, W. K. & Haake, S. M. Strategies to overcome therapeutic resistance in renal cell carcinoma. Urol. Oncol. 35, 102\u2013110 (2017).","journal-title":"Urol. Oncol."},{"key":"89655_CR2","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/j.ccell.2016.03.004","volume":"29","author":"L Qu","year":"2016","unstructured":"Qu, L. et al. Exosome-transmitted lncARSR promotes sunitinib resistance in renal cancer by acting as a competing endogenous RNA. Cancer Cell 29, 653\u2013668 (2016).","journal-title":"Cancer Cell"},{"key":"89655_CR3","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1038\/s41585-019-0233-z","volume":"16","author":"A Brodziak","year":"2019","unstructured":"Brodziak, A. et al. Drug resistance in papillary RCC: From putative mechanisms to clinical practicalities. Nat. Rev. Urol. 16, 655\u2013673 (2019).","journal-title":"Nat. Rev. Urol."},{"key":"89655_CR4","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1111\/j.1349-7006.2011.02054.x","volume":"102","author":"T Yuasa","year":"2011","unstructured":"Yuasa, T., Takahashi, S., Hatake, K., Yonese, J. & Fukui, I. Biomarkers to predict response to sunitinib therapy and prognosis in metastatic renal cell cancer. Cancer Sci. 102, 1949\u20131957 (2011).","journal-title":"Cancer Sci."},{"key":"89655_CR5","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/s13045-015-0181-x","volume":"10","author":"X Zhang","year":"2015","unstructured":"Zhang, X. et al. Exosomes in cancer: Small particle, big player. J. Hematol. Oncol. 10, 83. https:\/\/doi.org\/10.1186\/s13045-015-0181-x (2015).","journal-title":"J. Hematol. Oncol."},{"key":"89655_CR6","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1007\/s00467-017-3816-z","volume":"34","author":"AL St\u00e5hl","year":"2019","unstructured":"St\u00e5hl, A. L., Johansson, K., Mossberg, M., Kahn, R. & Karpman, D. Exosomes and microvesicles in normal physiology, pathophysiology, and renal diseases. Pediatr. Nephrol. 34, 11\u201330 (2019).","journal-title":"Pediatr. Nephrol."},{"key":"89655_CR7","doi-asserted-by":"publisher","first-page":"84","DOI":"10.15586\/jkcvhl.2014.19","volume":"1","author":"AL Teixeira","year":"2014","unstructured":"Teixeira, A. L., Dias, F., Gomes, M., Fernandes, M. & Medeiros, R. Circulating biomarkers in renal cell carcinoma: The link between microRNAs and extracellular vesicles, where are we now?. J. Kidney Cancer VHL 1, 84\u201398 (2014).","journal-title":"J. Kidney Cancer VHL"},{"key":"89655_CR8","doi-asserted-by":"publisher","first-page":"143","DOI":"10.3390\/cancers12010143","volume":"12","author":"R Garje","year":"2020","unstructured":"Garje, R., An, J., Greco, A., Vaddepally, R. K. & Zakharia, Y. The future of immunotherapy-based combination therapy in metastatic renal cell carcinoma. Cancers (Basel) 12, 143 (2020).","journal-title":"Cancers (Basel)"},{"key":"89655_CR9","doi-asserted-by":"publisher","first-page":"011503","DOI":"10.1063\/1.5087122","volume":"3","author":"X Li","year":"2019","unstructured":"Li, X. et al. Challenges and opportunities in exosome research: Perspectives from biology, engineering, and cancer therapy. APL Bioeng. 3, 011503. https:\/\/doi.org\/10.1063\/1.5087122 (2019).","journal-title":"APL Bioeng."},{"key":"89655_CR10","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1146\/annurev-physiol-021014-071641","volume":"77","author":"S Kourembanas","year":"2015","unstructured":"Kourembanas, S. Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu. Rev. Physiol. 77, 13\u201327 (2015).","journal-title":"Annu. Rev. Physiol."},{"key":"89655_CR11","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.canlet.2017.08.020","volume":"408","author":"A Datta","year":"2017","unstructured":"Datta, A. et al. Manumycin A suppresses exosome biogenesis and secretion via targeted inhibition of as\/Raf\/ERK1\/2 signaling and hnRNP H1 in castration-resistant prostate cancer cells. Cancer Lett. 408, 73\u201381 (2017).","journal-title":"Cancer Lett."},{"key":"89655_CR12","doi-asserted-by":"publisher","first-page":"8161","DOI":"10.1038\/s41598-018-26411-7","volume":"8","author":"A Datta","year":"2018","unstructured":"Datta, A. et al. High-throughput screening identified selective inhibitors of exosome biogenesis and secretion: A drug repurposing strategy for advanced cancer. Sci. Rep. 8, 8161. https:\/\/doi.org\/10.1038\/s41598-018-26411-7 (2018).","journal-title":"Sci. Rep."},{"key":"89655_CR13","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1016\/j.hoc.2011.05.003","volume":"25","author":"S Chowdhury","year":"2011","unstructured":"Chowdhury, S. et al. Systemic therapy for metastatic non-clear-cell renal cell carcinoma: Recent progress and future directions. Hematol. Oncol. Clin. North Am. 25, 853\u2013869 (2011).","journal-title":"Hematol. Oncol. Clin. North Am."},{"key":"89655_CR14","doi-asserted-by":"publisher","first-page":"113","DOI":"10.4196\/kjpp.2018.22.2.113","volume":"22","author":"YS Kim","year":"2018","unstructured":"Kim, Y. S. et al. The potential theragnostic (diagnostic+therapeutic) application of exosomes in diverse biomedical fields. Korean J. Physiol. Pharmacol. 22, 113\u2013125 (2018).","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"89655_CR15","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1016\/j.bbrc.2017.08.107","volume":"492","author":"K Horie","year":"2017","unstructured":"Horie, K. et al. Exosomes expressing carbonic anhydrase 9 promote angiogenesis. Biochem. Biophys. Res. Commun. 492, 356\u2013361 (2017).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"89655_CR16","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1146\/annurev-cellbio-101512-122326","volume":"30","author":"M Colombo","year":"2014","unstructured":"Colombo, M., Raposo, G. & Th\u00e9ry, C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 30, 255\u2013289. https:\/\/doi.org\/10.1146\/annurev-cellbio-101512-122326 (2014).","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"89655_CR17","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.semcancer.2012.06.004","volume":"23","author":"R Fisher","year":"2013","unstructured":"Fisher, R., Gore, M. & Larkin, J. Current and future systemic treatments for renal cell carcinoma. Semin. Cancer Biol. 23, 38\u201345 (2013).","journal-title":"Semin. Cancer Biol."},{"key":"89655_CR18","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/j.ejca.2013.08.021","volume":"50","author":"AM Molina","year":"2014","unstructured":"Molina, A. M. et al. Sunitinib objective response in metastatic renal cell carcinoma: analysis of 1059 patients treated on clinical trials. Eur. J. Cancer 50, 351\u2013358 (2014).","journal-title":"Eur. J. Cancer"},{"key":"89655_CR19","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1021\/jm00194a023","volume":"22","author":"J Heeres","year":"1979","unstructured":"Heeres, J., Backx, L. J., Mostmans, J. H. & Van Cutsem, J. Antimycotic, imidazoles. Part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent. J. Med. Chem. 22, 1003\u20131005 (1979).","journal-title":"J. Med. Chem."},{"key":"89655_CR20","doi-asserted-by":"publisher","first-page":"7099","DOI":"10.1158\/1078-0432.CCR-09-1722","volume":"15","author":"ME Taplin","year":"2009","unstructured":"Taplin, M. E. et al. Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer. Clin. Cancer Res. 15, 7099\u20137105 (2009).","journal-title":"Clin. Cancer Res."},{"key":"89655_CR21","doi-asserted-by":"publisher","first-page":"2175","DOI":"10.1093\/annonc\/mdq230","volume":"21","author":"YW Lim","year":"2010","unstructured":"Lim, Y. W. et al. Pharmacokinetics and pharmacodynamics of docetaxel with or without ketoconazole modulation in chemonaive breast cancer patients. Ann. Oncol. 21, 2175\u20132182 (2010).","journal-title":"Ann. Oncol."},{"key":"89655_CR22","first-page":"891","volume":"18","author":"CT Lu","year":"2019","unstructured":"Lu, C. T. et al. Inhibition of proliferation and migration of melanoma cells by ketoconazole and Ganoderma immunomodulatory proteins. Oncol. Lett. 18, 891\u2013897 (2019).","journal-title":"Oncol. Lett."},{"key":"89655_CR23","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.jhep.2018.09.022","volume":"70","author":"Y Chen","year":"2019","unstructured":"Chen, Y. et al. Ketoconazole exacerbates mitophagy to induce apoptosis by downregulating cyclooxygenase-2 in hepatocellular carcinoma. J. Hepatol. 70, 66\u201377 (2019).","journal-title":"J. Hepatol."},{"key":"89655_CR24","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1200\/JCO.2004.06.037","volume":"22","author":"EJ Small","year":"2004","unstructured":"Small, E. J. et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: A phase III trial (CALGB 9583). J. Clin. Oncol. 22, 1025\u20131033 (2004).","journal-title":"J. Clin. Oncol."},{"key":"89655_CR25","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.1200\/JCO.2009.24.1281","volume":"28","author":"CJ Ryan","year":"2010","unstructured":"Ryan, C. J. et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J. Clin. Oncol. 28, 1481\u20131488 (2010).","journal-title":"J. Clin. Oncol."},{"key":"89655_CR26","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1016\/S0140-6736(15)00046-X","volume":"387","author":"U Capitanio","year":"2016","unstructured":"Capitanio, U. & Montorsi, F. Renal cancer. Lancet 387, 894\u2013906 (2016).","journal-title":"Lancet"},{"key":"89655_CR27","doi-asserted-by":"publisher","first-page":"4712","DOI":"10.3390\/ijms20194712","volume":"20","author":"N B\u00e6k M\u00f8ller","year":"2019","unstructured":"B\u00e6k M\u00f8ller, N. et al. Drug-induced hypertension caused by multikinase inhibitors (Sorafenib, Sunitinib, Lenvatinib and Axitinib) in renal cell carcinoma treatment. Int. J. Mol. Sci. 20, 4712. https:\/\/doi.org\/10.3390\/ijms20194712 (2019).","journal-title":"Int. J. Mol. Sci."},{"key":"89655_CR28","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.1002\/ijc.32543","volume":"146","author":"J He","year":"2020","unstructured":"He, J. et al. Extracellular vesicles transmitted miR-31-5p promotes sorafenib resistance by targeting MLH1 in renal cell carcinoma. Int. J. Cancer 146, 1052\u20131063 (2020).","journal-title":"Int. J. Cancer"},{"key":"89655_CR29","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.canlet.2019.12.005","volume":"471","author":"PM Chow","year":"2020","unstructured":"Chow, P. M. et al. The covalent CDK7 inhibitor THZ1 enhances temsirolimus-induced cytotoxicity via autophagy suppression in human renal cell carcinoma. Cancer Lett. 471, 27\u201337 (2020).","journal-title":"Cancer Lett."},{"key":"89655_CR30","doi-asserted-by":"publisher","first-page":"911","DOI":"10.2147\/DDDT.S160557","volume":"12","author":"Y Zeng","year":"2018","unstructured":"Zeng, Y. et al. Attenuation of everolimus-induced cytotoxicity by a protective autophagic pathway involving ERK activation in renal cell carcinoma cells. Drug Des. Dev. Ther. 12, 911\u2013920 (2018).","journal-title":"Drug Des. Dev. Ther."},{"key":"89655_CR31","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1186\/s12885-019-5704-3","volume":"19","author":"H Deng","year":"2019","unstructured":"Deng, H. et al. Pazopanib has equivalent anti-tumor effectiveness and lower Total costs than Sunitinib for treating metastatic or advanced renal cell carcinoma: A meta-analysis. BMC Cancer 19, 489. https:\/\/doi.org\/10.1186\/s12885-019-5704-3 (2019).","journal-title":"BMC Cancer"},{"key":"89655_CR32","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1002\/stem.1619","volume":"32","author":"ZY Abd Elmageed","year":"2014","unstructured":"Abd Elmageed, Z. Y. et al. Neoplastic reprogramming of patient-derived adipose stem cells by prostate cancer cell-associated exosomes. Stem Cells 32, 983\u2013997 (2014).","journal-title":"Stem Cells"},{"key":"89655_CR33","doi-asserted-by":"publisher","first-page":"153303381876345","DOI":"10.1177\/1533033818763450","volume":"17","author":"C Zhang","year":"2018","unstructured":"Zhang, C., Ji, Q., Yang, Y., Li, Q. & Wang, Z. Exosome: Function and role in cancer metastasis and drug resistance. Technol. Cancer Res. Treat. 17, 1533033818763450. https:\/\/doi.org\/10.1177\/1533033818763450 (2018).","journal-title":"Technol. Cancer Res. Treat."},{"key":"89655_CR34","doi-asserted-by":"publisher","first-page":"620","DOI":"10.21037\/tcr.2017.05.19","volume":"6","author":"NJ Farber","year":"2017","unstructured":"Farber, N. J. et al. Renal cell carcinoma: The search for a reliable biomarker. Transl. Cancer Res. 6, 620\u2013632 (2017).","journal-title":"Transl. Cancer Res."},{"key":"89655_CR35","first-page":"371","volume":"55","author":"PM Wierzbicki","year":"2019","unstructured":"Wierzbicki, P. M. et al. Prognostic significance of VHL, HIF1A, HIF2A, VEGFA and p53 expression in patients with clear-cell renal cell carcinoma treated with sunitinib as first-line treatment. Int. J. Oncol. 55, 371\u2013390 (2019).","journal-title":"Int. J. Oncol."},{"key":"89655_CR36","doi-asserted-by":"publisher","first-page":"33","DOI":"10.32607\/20758251-2019-11-4-33-41","volume":"11","author":"VM Ukrainskaya","year":"2019","unstructured":"Ukrainskaya, V. M. et al. The role of tumor-derived vesicles in the regulation of antitumor immunity. Acta Nat. 11, 33\u201341 (2019).","journal-title":"Acta Nat."},{"key":"89655_CR37","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1159\/000348747","volume":"91","author":"L Yang","year":"2013","unstructured":"Yang, L., Wu, X., Wang, D., Luo, C. & Chen, L. Renal carcinoma cell-derived exosomes induce human immortalized line of Jurkat T lymphocyte apoptosis in vitro. Urol. Int. 91, 363\u2013369 (2013).","journal-title":"Urol. Int."},{"key":"89655_CR38","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1007\/s13318-015-0264-7","volume":"41","author":"EL Chee","year":"2016","unstructured":"Chee, E. L., Lim, A. Y., Modamio, P., Fernandez-Lastra, C. & Segarra, I. Sunitinib tissue distribution changes after coadministration with ketoconazole in mice. Eur. J. Drug Metab. Pharmacokinet. 41, 309\u2013319 (2016).","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"89655_CR39","first-page":"1442","volume":"18","author":"L Luo","year":"2019","unstructured":"Luo, L. et al. Significance of cyclooxygenase-2, prostaglandin E2 and CD133 levels in sunitinib-resistant renal cell carcinoma. Oncol. Lett. 18, 1442\u20131450 (2019).","journal-title":"Oncol. Lett."},{"key":"89655_CR40","doi-asserted-by":"publisher","first-page":"e51623","DOI":"10.3791\/51623","volume":"92","author":"SL Maas","year":"2014","unstructured":"Maas, S. L., Vrii, J. D. & Broekman, M. L. D. Quantification and size-profiling of extracellular vesicles using tunable resistive pulse sensing. J. Vis. Exp. 92, e51623. https:\/\/doi.org\/10.3791\/51623 (2014).","journal-title":"J. Vis. Exp."},{"key":"89655_CR41","doi-asserted-by":"publisher","first-page":"253","DOI":"10.2119\/molmed.2011.00001","volume":"19","author":"H Kim","year":"2013","unstructured":"Kim, H. et al. PDZK1 is a novel factor in breast cancer that is indirectly regulated by estrogen through IGF-1R and promotes estrogen-mediated growth. Mol. Med. 19, 253\u2013262 (2013).","journal-title":"Mol. Med."},{"key":"89655_CR42","doi-asserted-by":"publisher","first-page":"2774","DOI":"10.3892\/or.2017.5932","volume":"38","author":"N Khurana","year":"2017","unstructured":"Khurana, N. et al. Multimodal actions of the phytochemical sulforaphane suppress both AR and AR-V7 in 22Rv1 cells: Advocating a potent pharmaceutical combination against castration-resistant prostate cancer. Oncol. Rep. 38, 2774\u20132786 (2017).","journal-title":"Oncol. Rep."},{"key":"89655_CR43","doi-asserted-by":"publisher","first-page":"1609","DOI":"10.3892\/ijo.2016.3641","volume":"49","author":"N Khurana","year":"2016","unstructured":"Khurana, N. et al. Sulforaphane increases the efficacy of anti-androgens by rapidly decreasing androgen receptor levels in prostate cancer cells. Int. J. Oncol. 49, 1609\u20131619 (2016).","journal-title":"Int. J. Oncol."},{"key":"89655_CR44","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.cellsig.2007.10.007","volume":"20","author":"M Zerfaoui","year":"2008","unstructured":"Zerfaoui, M. et al. Nuclear translocation of P65 Nf-\u039ab is sufficient for Vcam-1, but not Icam-1, expression In Tnf-stimulated smooth muscle cells: differential requirement for parp-1 expression and interaction. Cell Signal. 20, 186\u2013194 (2008).","journal-title":"Cell Signal."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89655-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89655-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89655-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T08:18:17Z","timestamp":1670055497000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89655-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,13]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["89655"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-89655-w","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,13]]},"assertion":[{"value":"21 April 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 April 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 May 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":"10200"}}