{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T23:44:05Z","timestamp":1793058245572,"version":"4.5.0"},"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T00:00:00Z","timestamp":1658361600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>p16 (CDKN2A) is a member of the INK4 class of cell cycle inhibitors, which is often dysregulated in cancer. However, the prevalence of p16 expression in different cancer types is controversial. 15,783 samples from 124 different tumor types and 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format. p16 was detectable in 5,292 (45.0%) of 11,759 interpretable tumors. Except from adenohypophysis in islets of Langerhans, p16 staining was largely absent in normal tissues. In cancer, highest positivity rates were observed in uterine cervix squamous cell carcinomas (94.4%), non-invasive papillary urothelial carcinoma, pTaG2 (100%), Merkel cell carcinoma (97.7%), and small cell carcinomas of various sites of origin (54.5%-100%). All 124 tumor categories showed at least occasional p16 immunostaining. Comparison with clinico-pathological data in 128 vulvar, 149 endometrial, 295 serous ovarian, 396 pancreatic, 1365 colorectal, 284 gastric, and 1245 urinary bladder cancers, 910 breast carcinomas, 620 clear cell renal cell carcinomas, and 414 testicular germ cell tumors revealed only few statistically significant associations. Comparison of human papilloma virus (HPV) status and p16 in 497 squamous cell carcinomas of different organs revealed HPV in 80.4% of p16 positive and in 20.6% of p16 negative cancers (p&lt;0.0001). It is concluded, that a positive and especially strong p16 immunostaining is a feature for malignancy which may be diagnostically useful in lipomatous, urothelial and possibly other tumors. The imperfect association between p16 immunostaining and HPV infection with high variability between different sites of origin challenges the use of p16 immunohistochemistry as a surrogate for HPV positivity, except in tumors of cervix uteri and the penis.<\/jats:p>","DOI":"10.1371\/journal.pone.0262877","type":"journal-article","created":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T13:41:22Z","timestamp":1658410882000},"page":"e0262877","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":28,"title":["High prevalence of p16 staining in malignant tumors"],"prefix":"10.1371","volume":"17","author":[{"given":"No\u00e9mi","family":"De Wispelaere","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian Dwertmann","family":"Rico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas M.","family":"Luebke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Kluth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"B\u00fcscheck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Hube-Magg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doris","family":"H\u00f6flmayer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Gorbokon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f6ren","family":"Weidemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"M\u00f6ller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Fraune","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Bernreuther","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0158-4258","authenticated-orcid":true,"given":"Ronald","family":"Simon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"K\u00e4hler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Menz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Hinsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Jacobsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Lebok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Till","family":"Clauditz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Sauter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ria","family":"Uhlig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waldemar","family":"Wilczak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Steurer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eike","family":"Burandt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer","family":"Krech","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Dum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Till","family":"Krech","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Marx","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Minner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,7,21]]},"reference":[{"issue":"6473","key":"pone.0262877.ref001","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1038\/368753a0","article-title":"Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers","volume":"368","author":"T Nobori","year":"1994","journal-title":"Nature"},{"issue":"25","key":"pone.0262877.ref002","doi-asserted-by":"crossref","first-page":"5566","DOI":"10.1021\/bi200642e","article-title":"Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to cancer.","volume":"50","author":"J Li","year":"2011","journal-title":"Biochemistry"},{"issue":"6456","key":"pone.0262877.ref003","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/366704a0","article-title":"A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D\/CDK4","volume":"366","author":"M Serrano","year":"1993","journal-title":"Nature"},{"issue":"6","key":"pone.0262877.ref004","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1016\/0092-8674(90)90409-8","article-title":"The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53","volume":"63","author":"M Scheffner","year":"1990","journal-title":"Cell"},{"issue":"4893","key":"pone.0262877.ref005","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1126\/science.2537532","article-title":"The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product","volume":"243","author":"N Dyson","year":"1989","journal-title":"Science"},{"issue":"1","key":"pone.0262877.ref006","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/S0090-8258(03)00010-6","article-title":"Expression of p27, p21, and p16 protein in early squamous cervical cancer and its relation to prognosis","volume":"89","author":"G van de Putte","year":"2003","journal-title":"Gynecol Oncol"},{"issue":"22","key":"pone.0262877.ref007","first-page":"3007","article-title":"Different Expression of p16INK4a and p14ARF in cervical and lung cancers","volume":"17","author":"JG Li","year":"2013","journal-title":"Eur Rev Med Pharmacol Sci"},{"issue":"4","key":"pone.0262877.ref008","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1158\/1078-0432.CCR-05-1864","article-title":"Profiling markers of prognosis in colorectal cancer","volume":"12","author":"MS Lyall","year":"2006","journal-title":"Clin Cancer Res"},{"issue":"54","key":"pone.0262877.ref009","first-page":"1756","article-title":"Reduced p16 expression correlates with lymphatic invasion in colorectal cancers.","volume":"50","author":"T Tada","year":"2003","journal-title":"Hepatogastroenterology"},{"issue":"8","key":"pone.0262877.ref010","doi-asserted-by":"crossref","first-page":"2207","DOI":"10.1038\/bjc.2013.556","article-title":"The in situ local immune response, tumour senescence and proliferation in colorectal cancer","volume":"109","author":"CS Roxburgh","year":"2013","journal-title":"Br J Cancer"},{"issue":"6","key":"pone.0262877.ref011","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1111\/j.1365-2559.2010.03554.x","article-title":"Genomic and immunophenotypical differences between hepatocellular carcinoma with and without cirrhosis.","volume":"56","author":"MS Tretiakova","year":"2010","journal-title":"Histopathology"},{"issue":"1","key":"pone.0262877.ref012","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/S0304-3835(00)00385-2","article-title":"Loss of p16(INK4) protein, alone and together with loss of retinoblastoma protein, correlate with hepatocellular carcinoma progression.","volume":"154","author":"AM Hui","year":"2000","journal-title":"Cancer Lett"},{"issue":"3","key":"pone.0262877.ref013","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1097\/CMR.0b013e32831993f3","article-title":"Proteins involved in pRb and p53 pathways are differentially expressed in thin and thick superficial spreading melanomas","volume":"19","author":"BC de Sa","year":"2009","journal-title":"Melanoma Res"},{"issue":"4","key":"pone.0262877.ref014","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s00403-018-1818-8","article-title":"Reevaluation of established and new criteria in differential diagnosis of Spitz nevus and melanoma","volume":"310","author":"A Ritter","year":"2018","journal-title":"Arch Dermatol Res"},{"issue":"5","key":"pone.0262877.ref015","first-page":"1845","article-title":"Loss of nuclear p16 protein expression correlates with increased tumor cell proliferation (Ki-67) and poor prognosis in patients with vertical growth phase melanoma.","volume":"6","author":"O Straume","year":"2000","journal-title":"Clin Cancer Res"},{"issue":"1","key":"pone.0262877.ref016","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.lungcan.2008.02.013","article-title":"Frequent p16 inactivation by homozygous deletion or methylation is associated with a poor prognosis in Japanese patients with pleural mesothelioma","volume":"62","author":"N Kobayashi","year":"2008","journal-title":"Lung Cancer"},{"issue":"6","key":"pone.0262877.ref017","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1038\/modpathol.2008.45","article-title":"Diagnostic importance of 9p21 homozygous deletion in malignant mesotheliomas.","volume":"21","author":"S Chiosea","year":"2008","journal-title":"Mod Pathol"},{"issue":"3","key":"pone.0262877.ref018","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1111\/his.13392","article-title":"The epithelioid BAP1-negative and p16-positive phenotype predicts prolonged survival in pleural mesothelioma.","volume":"72","author":"A Chou","year":"2018","journal-title":"Histopathology"},{"issue":"5","key":"pone.0262877.ref019","doi-asserted-by":"crossref","first-page":"567","DOI":"10.5858\/2002-126-0567-AEOGRP","article-title":"Altered expression of G1 regulatory proteins in human soft tissue sarcomas","volume":"126","author":"J Yoo","year":"2002","journal-title":"Arch Pathol Lab Med"},{"issue":"10","key":"pone.0262877.ref020","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1097\/PAI.0000000000000677","article-title":"Diagnostic Utility and Limitations of Immunohistochemistry of p16, CDK4, and MDM2 and Automated Dual-color In Situ Hybridization of MDM2 for the Diagnosis of Challenging Cases of Dedifferentiated Liposarcoma.","volume":"27","author":"A Kobayashi","year":"2019","journal-title":"Appl Immunohistochem Mol Morphol"},{"issue":"3","key":"pone.0262877.ref021","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1097\/PAS.0b013e3182417330","article-title":"Diagnostic utility of p16, CDK4, and MDM2 as an immunohistochemical panel in distinguishing well-differentiated and dedifferentiated liposarcomas from other adipocytic tumors.","volume":"36","author":"K Thway","year":"2012","journal-title":"Am J Surg Pathol"},{"issue":"1","key":"pone.0262877.ref022","doi-asserted-by":"crossref","first-page":"R5","DOI":"10.1186\/bcr3376","article-title":"The prognostic significance and value of cyclin D1, CDK4 and p16 in human breast cancer","volume":"15","author":"E Peurala","year":"2013","journal-title":"Breast Cancer Res"},{"issue":"17","key":"pone.0262877.ref023","doi-asserted-by":"crossref","first-page":"3328","DOI":"10.1200\/JCO.2003.12.151","article-title":"Loss of p16 expression is of prognostic significance in locally advanced prostate cancer: an analysis from the Radiation Therapy Oncology Group protocol 86\u201310.","volume":"21","author":"A Chakravarti","year":"2003","journal-title":"J Clin Oncol"},{"issue":"2","key":"pone.0262877.ref024","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/sj.bjc.6603531","article-title":"Independent prognostic significance of cell cycle regulator proteins p16(INK4a) and pRb in advanced-stage ovarian carcinoma including optimally debulked patients: a translational research subprotocol of a randomised study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group.","volume":"96","author":"S Kommoss","year":"2007","journal-title":"Br J Cancer"},{"issue":"10","key":"pone.0262877.ref025","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.3748\/wjg.v9.i10.2202","article-title":"Expressing patterns of p16 and CDK4 correlated to prognosis in colorectal carcinoma","volume":"9","author":"P Zhao","year":"2003","journal-title":"World J Gastroenterol"},{"issue":"1","key":"pone.0262877.ref026","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1023\/A:1010623308275","article-title":"Overexpression of the p16 cell cycle inhibitor in breast cancer is associated with a more malignant phenotype","volume":"67","author":"K Milde-Langosch","year":"2001","journal-title":"Breast Cancer Res Treat"},{"issue":"9","key":"pone.0262877.ref027","doi-asserted-by":"crossref","first-page":"12655","DOI":"10.1007\/s13277-016-5167-y","article-title":"p16 upregulation is linked to poor prognosis in ERG negative prostate cancer","volume":"37","author":"C Burdelski","year":"2016","journal-title":"Tumour Biol"},{"issue":"1","key":"pone.0262877.ref028","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1002\/(SICI)1097-0215(19970220)74:1<57::AID-IJC10>3.0.CO;2-F","article-title":"Increased expression of cyclin-dependent kinase inhibitor 2 (CDKN2A) gene product P16INK4A in ovarian cancer is associated with progression and unfavourable prognosis.","volume":"74","author":"Y Dong","year":"1997","journal-title":"Int J Cancer"},{"issue":"9","key":"pone.0262877.ref029","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1007\/s10350-006-0650-y","article-title":"Colorectal mucinous adenocarcinoma: the clinicopathologic features and significance of p16 and p53 expression","volume":"49","author":"A King-Yin Lam","year":"2006","journal-title":"Dis Colon Rectum"},{"issue":"3","key":"pone.0262877.ref030","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0022-2836(05)80360-2","article-title":"Basic local alignment search tool","volume":"215","author":"SF Altschul","year":"1990","journal-title":"J Mol Biol"},{"issue":"23","key":"pone.0262877.ref031","first-page":"6078","article-title":"Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb","volume":"54","author":"Y Li","year":"1994","journal-title":"Cancer Res"},{"issue":"3","key":"pone.0262877.ref032","doi-asserted-by":"crossref","DOI":"10.3390\/biom10030420","article-title":"Role of p53 in the Regulation of Cellular Senescence.","volume":"10","author":"M Mijit","year":"2020","journal-title":"Biomolecules"},{"issue":"7471","key":"pone.0262877.ref033","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/nature12634","article-title":"Mutational landscape and significance across 12 major cancer types","volume":"502","author":"C Kandoth","year":"2013","journal-title":"Nature"},{"key":"pone.0262877.ref034","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1146\/annurev-biochem-060815-014710","article-title":"The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches","volume":"85","author":"AC Joerger","year":"2016","journal-title":"Annu Rev Biochem"},{"issue":"1","key":"pone.0262877.ref035","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1038\/s42003-020-0873-9","article-title":"Pan-cancer molecular analysis of the RB tumor suppressor pathway.","volume":"3","author":"ES Knudsen","year":"2020","journal-title":"Commun Biol"},{"issue":"6699","key":"pone.0262877.ref036","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/26155","article-title":"Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a","volume":"395","author":"AA Russo","year":"1998","journal-title":"Nature"},{"issue":"1","key":"pone.0262877.ref037","doi-asserted-by":"crossref","first-page":"e82185","DOI":"10.1371\/journal.pone.0082185","article-title":"An integrative CGH, MSI and candidate genes methylation analysis of colorectal tumors.","volume":"9","author":"H Brim","year":"2014","journal-title":"PLoS One"},{"key":"pone.0262877.ref038","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1186\/1471-2407-10-138","article-title":"p16INK4a hypermethylation and p53, p16 and MDM2 protein expression in esophageal squamous cell carcinoma","volume":"10","author":"N Taghavi","year":"2010","journal-title":"BMC Cancer"},{"issue":"3","key":"pone.0262877.ref039","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/sj.bjc.6601954","article-title":"Prediction of progression in pTa and pT1 bladder carcinomas with p53, p16 and pRb","volume":"91","author":"AW Hitchings","year":"2004","journal-title":"Br J Cancer"},{"issue":"1\u20132","key":"pone.0262877.ref040","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S0304-3835(00)00359-1","article-title":"Loss of p16 and p27 is associated with progression of human gastric cancer","volume":"153","author":"N Myung","year":"2000","journal-title":"Cancer Lett"},{"issue":"2","key":"pone.0262877.ref041","first-page":"261","article-title":"Simultaneous deregulation of p16 and cyclin D1 genes in pancreatic ductal adenocarcinoma: a combined immunohistochemistry and image analysis study based on tissue microarrays.","volume":"12","author":"E Tsiambas","year":"2007","journal-title":"J BUON"},{"issue":"1","key":"pone.0262877.ref042","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1097\/01.pap.0000201828.92719.f3","article-title":"p16 expression in the female genital tract and its value in diagnosis.","volume":"13","author":"CJ O\u2019Neill","year":"2006","journal-title":"Adv Anat Pathol"},{"issue":"4","key":"pone.0262877.ref043","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1136\/jcp.55.4.244","article-title":"The causal relation between human papillomavirus and cervical cancer","volume":"55","author":"FX Bosch","year":"2002","journal-title":"J Clin Pathol"},{"issue":"17","key":"pone.0262877.ref044","doi-asserted-by":"crossref","first-page":"4299","DOI":"10.1242\/dev.01232","article-title":"Rb family proteins differentially regulate distinct cell lineages during epithelial development","volume":"131","author":"KA Wikenheiser-Brokamp","year":"2004","journal-title":"Development"},{"issue":"3","key":"pone.0262877.ref045","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s00428-016-1982-1","article-title":"p16 overexpression in high-grade neuroendocrine carcinomas of the head and neck: potential diagnostic pitfall with HPV-related carcinomas.","volume":"469","author":"L Alos","year":"2016","journal-title":"Virchows Arch"},{"issue":"3","key":"pone.0262877.ref046","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1002\/(SICI)1096-9896(199911)189:3<358::AID-PATH452>3.0.CO;2-1","article-title":"Expression of p16 and lack of pRB in primary small cell lung cancer","volume":"189","author":"J Yuan","year":"1999","journal-title":"J Pathol"},{"issue":"2","key":"pone.0262877.ref047","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1097\/PAS.0b013e3182417d36","article-title":"Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors","volume":"36","author":"S Yachida","year":"2012","journal-title":"Am J Surg Pathol"}],"updated-by":[{"DOI":"10.1371\/journal.pone.0318271","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T00:00:00Z","timestamp":1737676800000}}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0262877","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T13:42:16Z","timestamp":1658410936000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0262877"}},"subtitle":[],"editor":[{"given":"Surinder K.","family":"Batra","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,7,21]]},"references-count":47,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7,21]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0262877","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,21]]}}}