{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:34:39Z","timestamp":1791387279928,"version":"4.3.3"},"reference-count":51,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T00:00:00Z","timestamp":1724284800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K08812"],"award-info":[{"award-number":["23K08812"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Approximately 660,000 women are diagnosed with cervical cancer annually. Current screening options such as cytology or human papillomavirus testing have limitations, creating a need to identify more effective ancillary biomarkers for triage. Here, we evaluated whether metabolomic analysis of cervical mucus metabolism could be used to identify biomarkers of cervical intraepithelial neoplasia (CIN) and cervical cancer. The case\u2013control group consisted of 181 CIN, 69 squamous cell carcinoma (SCC) patients, and 48 healthy controls in the primary cohort. We undertook metabolomic analyses using ultra\u2010HPLC\u2013tandem mass spectrometry. Univariate and multivariate analyses were carried out to profile metabolite characteristics, and receiver operating characteristic (ROC) analysis identified biomarker candidates. Five metabolites conferred the highest discriminatory power for SCC: oxidized glutathione (GSSG) (area under the ROC curve, 0.924; 95% confidence interval, 0.877\u20130.971), malic acid (0.914, 0.859\u20130.968), kynurenine (0.884, 0.823\u20130.945), GSSG\/glutathione (GSH) (0.936, 0.892\u20130.979), and kynurenine\/tryptophan (0.909, 0.856\u20130.961). Malic acid was the best marker for detection of CIN2 or worse (0.858, 0.793\u20130.922) and was a clinically useful metabolite. We confirmed the reproducibility of the results by validation cohort. Additionally, metabolomic analyses revealed eight pathways strongly associated with cervical neoplasia. Of these, only the tricarboxylic acid cycle was strongly associated with all CINs and cancer, indicating active energy production. Aberrant arginine metabolism by decreasing arginine and increasing citrulline might reduce tumor immunity. Changes in cysteine\u2010methionine and GSH pathways might drive the initiation and progression of cervical cancer. These results suggest that metabolic analysis can identify ancillary biomarkers and could improve our understanding of the pathophysiological mechanisms underlying cervical neoplasia.<\/jats:p>","DOI":"10.1111\/cas.16323","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T19:55:12Z","timestamp":1724356512000},"page":"3672-3681","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cervical mucus can be used for metabolite screening in cervical cancer"],"prefix":"10.1111","volume":"115","author":[{"given":"Rie","family":"Kawasaki","sequence":"first","affiliation":[{"name":"Department of Gynecology, School of Medicine Fujita Health University  Toyoake Japan"},{"name":"Department of Obstetrics and Gynecology, School of Medicine Fujita Health University  Toyoake Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iwao","family":"Kukimoto","sequence":"additional","affiliation":[{"name":"Pathogen Genomics Center National Institute of Infectious Diseases  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7502-8724","authenticated-orcid":false,"given":"Tetsuya","family":"Tsukamoto","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine Fujita Health University  Toyoake Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiji","family":"Nishio","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, School of Medicine Fujita Health University  Toyoake Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Iwata","sequence":"additional","affiliation":[{"name":"Department of Gynecology, School of Medicine Fujita Health University  Toyoake Japan"},{"name":"Department of Obstetrics and Gynecology, School of Medicine Fujita Health University  Toyoake Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7233-8663","authenticated-orcid":false,"given":"Takuma","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Gynecology, School of Medicine Fujita Health University  Toyoake Japan"},{"name":"Department of Obstetrics and Gynecology, School of Medicine Fujita Health University  Toyoake Japan"},{"name":"Fujita Health University Okazaki Medical Center  Okazaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,8,22]]},"reference":[{"key":"e_1_2_10_2_1","volume-title":"GLOBOCON 2022: Fact Sheets","author":"World Health Organization International Agency for Cancer Research","year":"2024"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(07)70283-8"},{"key":"e_1_2_10_4_1","volume-title":"The Role of Colposcopy in Cervical Precancer. 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