{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T11:02:22Z","timestamp":1789988542247,"version":"4.0.1"},"reference-count":25,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,12]],"date-time":"2025-01-12T00:00:00Z","timestamp":1736640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,1,12]],"date-time":"2025-01-12T00:00:00Z","timestamp":1736640000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DE031270"],"award-info":[{"award-number":["R01DE031270"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Periodontal Research"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>To investigate additional factors contributing to the pathophysiology of chemotherapy\u2010induced oral mucositis and periodontitis beyond the systemic immune suppression caused by the chemotherapeutic agent 5\u2010Fluorouracil (5\u2010FU).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>5\u2010Fluorouracil was topically delivered to the non\u2010keratinized, rapidly proliferating junctional epithelium (JE) surrounding the dentition, and acts as an immunologic and functional barrier to bacterial ingression. Various techniques, including EdU incorporation, quantitative immunohistochemistry (qIHC), histology, enzymatic activity assays, and micro\u2010computed tomographic (\u03bcCT) imaging, were employed to analyze the JE at multiple time points following topical 5\u2010FU treatment. Systemic 5\u2010FU delivery was used for comparison, and all 5\u2010FU treated tissues were compared to vehicle\u2010treated controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We first showed that systemic 5\u2010FU blocked mitotic activity that rapidly led to JE atrophy. This atrophy was accompanied by suppression of the immune system. We then demonstrated that topical 5\u2010FU delivery effectively inhibited cell proliferation in the JE. Quantitative immunohistochemical (qIHC) analyses further demonstrated a progressive breakdown in JE barrier functions following topical 5\u2010FU. CBC analyses confirmed that topical 5\u2010FU did not alter the innate immune system but did suppress the local immune response of the JE. The longer\u2010term consequences of this disruption in JE barrier functions were significant alveolar bone loss and an increase in porosity. Together, these results document the essential requirement for rapid JE cell proliferation to maintain homeostasis of the periodontium.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The reduction of cell division in the JE due to 5\u2010FU treatment directly compromises both its structural integrity and immune surveillance capabilities, contributing to the destruction of periodontal hard tissues.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/jre.13375","type":"journal-article","created":{"date-parts":[[2025,1,12]],"date-time":"2025-01-12T08:14:49Z","timestamp":1736669689000},"page":"66-75","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["5\u2010FU Weakens Defensive Functions of the Junctional Epithelium"],"prefix":"10.1111","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8854-4253","authenticated-orcid":false,"given":"Fabiana","family":"Aellos","sequence":"first","affiliation":[{"name":"Department of Surgery Stanford University School of Medicine  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amarissa","family":"Ramos","sequence":"additional","affiliation":[{"name":"Department of Surgery Stanford University School of Medicine  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alba","family":"Civit\u2010Balta","sequence":"additional","affiliation":[{"name":"Department of Surgery Stanford University School of Medicine  Stanford California USA"},{"name":"Facultat de Biologia Universitat de Barcelona (UB)  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph A.","family":"Grauer","sequence":"additional","affiliation":[{"name":"Department of Surgery Stanford University School of Medicine  Stanford California USA"},{"name":"Dr. Gerald Niznick College of Dentistry University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro L.","family":"Cuevas","sequence":"additional","affiliation":[{"name":"Department of Surgery Stanford University School of Medicine  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samyak","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Surgery Stanford University School of Medicine  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head &amp; Neck Surgery, School of Medicine Indiana University  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Surgery Stanford University School of Medicine  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0463-396X","authenticated-orcid":false,"given":"Jill A.","family":"Helms","sequence":"additional","affiliation":[{"name":"Department of Surgery Stanford University School of Medicine  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,12]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-020-01715-7"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/14656566.2016.1217993"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00784-022-04588-6"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00520-014-2186-3"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00520-014-2563-y"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05934-6"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07205"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/idj.12133"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-010-1409-7"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.01204"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2017.08.024"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tripleo.2005.12.016"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40168-019-0679-5"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1177\/1535370217753842"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1074"},{"key":"e_1_2_10_17_1","article-title":"The Junctional Epithelium Is Maintained by a Stem Cell Population","volume":"100","author":"Yuan X.","year":"2020","journal-title":"Journal of Dental Research"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0765.1998.tb02203.x"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.658636"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24054989"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-051X.1991.tb02312.x"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2022.13298"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mucimm.2024.07.004"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2017.08.005"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2021.153712"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.676669"}],"container-title":["Journal of Periodontal Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jre.13375","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jre.13375","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jre.13375","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:38:03Z","timestamp":1789987083000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jre.13375"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,12]]},"references-count":25,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1111\/jre.13375"],"URL":"https:\/\/doi.org\/10.1111\/jre.13375","archive":["Portico"],"relation":{},"ISSN":["0022-3484","1600-0765"],"issn-type":[{"value":"0022-3484","type":"print"},{"value":"1600-0765","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,12]]},"assertion":[{"value":"2024-08-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}