{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T16:41:28Z","timestamp":1777912888949,"version":"3.51.4"},"reference-count":40,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[1998,5,1]],"date-time":"1998-05-01T00:00:00Z","timestamp":893980800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxicol Pathol"],"published-print":{"date-parts":[[1998,5]]},"abstract":"<jats:p>Spontaneous proliferative lesions in the nasopharyngeal meatus were identified as the cause of death in 12 of 1,600 male and 5 of 1,600 female Fischer 344 (F344) rats used in 2-yr carcinogenicity studies; none of the lesions were considered treatment related. All the rats showed dyspnea, abdominal distension, and clinical deterioration. Gross features were characterized by simultaneous occurrence of conspicuous gaseous distension of the intestinal tract, especially in the ileum and cecum, and focal nodular lesions in the nasopharyngeal meatus. Histopathologically, the nasopharyngeal meatus was partially obstructed by the following proliferative lesions: 3 areas of hyperplasia of the ectopic sebaceous glands in the soft and hard palate, 4 areas of squamous metaplasia (SM) with massive hyperkeratosis, 5 squamous cell papillomas (SCPs), and 5 squamous cell carcinomas (SCCs). No pathological changes were found in the distended portion of the intestinal tract. Formalin-fixed, paraffin-embedded samples of the proliferative lesions from the nasopharyngeal meatus were examined for the presence of mutations in the c-H-ras and c-K-ras genes. In vitro amplification of DNA using a polymerase chain reaction was combined with a nonisotopic method for selective oligonucleotide hybridization. Two of the 4 SM lesions, 3 of the 5 SCPs, and 5 of the 5 SCCs contained 1-3 point mutations in the c-H-ras and\/or c-K-ras gene. Immunohistochem-ically, overexpression of p53 protein was found in 1 area of SM with a dysplastic lesion and 2 SCCs. These findings indicate that detailed examination of the upper respiratory system, including the nasopharyngeal meatus, may be particularly helpful for identifying primary occult lesions in F344 rats that show only gut distension at necropsy in long-term toxicity studies. In addition, mutations of the ras genes may be an important step in the early stages of carcinogenesis in the rat nasopharyngeal meatus, whereas p53 mutations could occur relatively late.<\/jats:p>","DOI":"10.1177\/019262339802600317","type":"journal-article","created":{"date-parts":[[2009,9,14]],"date-time":"2009-09-14T21:30:11Z","timestamp":1252963811000},"page":"419-427","source":"Crossref","is-referenced-by-count":7,"title":["Spontaneous Proliferative Lesions in the Nasopharyngeal Meatus of F344 Rats"],"prefix":"10.1177","volume":"26","author":[{"given":"Shim-Mo","family":"Hayashi","sequence":"first","affiliation":[{"name":"Pharmacology Laboratories, Takeda Chemical Industries, 2-17-85 Juso Honmachi, Yodogawa-ku, Osaka 532\u20138686, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ikuo","family":"Mori","sequence":"additional","affiliation":[{"name":"Drug Safety Research Laboratories Hikari Branch, Takeda Chemical Industries, 4720 Mitsui, Hikari, Yamaguchi 743\u20138502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Nonoyama","sequence":"additional","affiliation":[{"name":"Drug Safety Research Laboratories Hikari Branch, Takeda Chemical Industries, 4720 Mitsui, Hikari, Yamaguchi 743\u20138502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[1998,5,1]]},"reference":[{"key":"atypb1","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-230X(08)60222-5"},{"key":"atypb2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1994.tb19910.x"},{"key":"atypb3","doi-asserted-by":"publisher","DOI":"10.2307\/3430690"},{"key":"atypb4","doi-asserted-by":"publisher","DOI":"10.1177\/0192623391019004-105"},{"key":"atypb5","first-page":"111","volume-title":"Patlwbiology of the Aging Rat","author":"Clair MBG St","year":"1992"},{"key":"atypb6","doi-asserted-by":"publisher","DOI":"10.3109\/10408449109019571"},{"key":"atypb7","first-page":"531","volume":"8","author":"Finlay CA","year":"1988","journal-title":"Uol. Cell Biol."},{"key":"atypb8","first-page":"1209","volume":"6","author":"Furihata M","year":"1995","journal-title":"Int. J. Oncol."},{"key":"atypb9","first-page":"555","volume-title":"Pathology of the Fischer Rat-Reference and Atlas","author":"Haseman JK","year":"1990"},{"key":"atypb10","first-page":"629","volume-title":"Pathobiology of the Aging Rat","author":"Haseman JK","year":"1994"},{"key":"atypb11","volume-title":"IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Overall Evaluations of Carcinogenicity","author":"IARC","year":"1987"},{"key":"atypb12","volume-title":"International Classification of Rodent Tumours, Part I-The Rat. 1. Respiratory System.","author":"IARC (WHO)","year":"1992"},{"key":"atypb13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.11.4850"},{"key":"atypb14","doi-asserted-by":"publisher","DOI":"10.1016\/1040-8428(94)00169-3"},{"key":"atypb15","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.62.10.3903-3906.1988"},{"key":"atypb16","first-page":"6578","volume":"49","author":"Konno A","year":"1989","journal-title":"Cancer Res."},{"key":"atypb17","first-page":"4090","volume":"51","author":"Lehman TA","year":"1991","journal-title":"Cancer Res."},{"key":"atypb18","doi-asserted-by":"publisher","DOI":"10.1258\/002367789780810572"},{"key":"atypb19","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.1997.tb00357.x"},{"key":"atypb20","doi-asserted-by":"publisher","DOI":"10.1177\/019262339402200402"},{"key":"atypb21","doi-asserted-by":"publisher","DOI":"10.2307\/3430688"},{"key":"atypb22","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1080\/10917691.1994.12288916","volume":"6","author":"Morgan KT","year":"1994","journal-title":"Inhal. Toxicol."},{"key":"atypb23","doi-asserted-by":"publisher","DOI":"10.2307\/3430684"},{"key":"atypb24","volume-title":"Carcinogenesis Bioassay of 1,2-Dibromo-3-chloropropane in F344 Rats and B6C3F1 Mice (Inhalation Study). Technical Report Series","author":"National Toxicology Program","year":"1982"},{"key":"atypb25","first-page":"5514","volume":"48","author":"Newcomb EW","year":"1988","journal-title":"Cancer Res."},{"key":"atypb26","doi-asserted-by":"publisher","DOI":"10.1038\/320182a0"},{"key":"atypb27","first-page":"6113","volume":"52","author":"Recio L","year":"1992","journal-title":"Cancer Res."},{"key":"atypb28","doi-asserted-by":"publisher","DOI":"10.1126\/science.2448875"},{"key":"atypb29","first-page":"697","volume":"3","author":"Shin DM","year":"1994","journal-title":"Cancer Epidemiol. Biol. Prev."},{"key":"atypb30","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/14.3.503"},{"key":"atypb31","doi-asserted-by":"publisher","DOI":"10.1016\/0300-483X(94)02991-3"},{"key":"atypb32","doi-asserted-by":"publisher","DOI":"10.2307\/3430683"},{"key":"atypb33","first-page":"3864","volume":"54","author":"Vancutsem PM","year":"1994","journal-title":"Cancer Res."},{"key":"atypb34","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(86)90335-5"},{"key":"atypb35","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/16.4.697"},{"key":"atypb36","doi-asserted-by":"publisher","DOI":"10.1006\/taap.1995.1083"},{"key":"atypb37","doi-asserted-by":"publisher","DOI":"10.1177\/019262339502300501"},{"key":"atypb38","doi-asserted-by":"publisher","DOI":"10.1177\/030098589902700608"},{"key":"atypb39","doi-asserted-by":"publisher","DOI":"10.1016\/S0272-0590(81)80037-1"},{"key":"atypb40","doi-asserted-by":"publisher","DOI":"10.3109\/00016489409126024"}],"container-title":["Toxicologic Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/019262339802600317","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/019262339802600317","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T16:07:01Z","timestamp":1777651621000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/019262339802600317"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1998,5]]},"references-count":40,"journal-issue":{"issue":"3","published-print":{"date-parts":[[1998,5]]}},"alternative-id":["10.1177\/019262339802600317"],"URL":"https:\/\/doi.org\/10.1177\/019262339802600317","relation":{},"ISSN":["0192-6233","1533-1601"],"issn-type":[{"value":"0192-6233","type":"print"},{"value":"1533-1601","type":"electronic"}],"subject":[],"published":{"date-parts":[[1998,5]]}}}