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Fink, Stephen P,Yang, Dong-Hoon,Barnholtz-Sloan, Jill S,Ryu, Yeon-Mi,Mikkola, Debra,Potter, John D,Lampe, Johanna W,Markowitz, Sanford D,Myung, Seung-Jae Plenum Pub. Corp.] 2013 Digestive diseases and sciences Vol.58 No.9
<P>15-Hydroxprostaglandin dehydrogenase (15-PGDH) mediates a colon neoplasia suppressor pathway, acting through metabolic antagonism of cyclooxygenase-mediated colon carcinogenesis. To determine whether the colon tumor prevention activity of 15-PGDH acts as a constant or variable effect among individuals, we determined whether 15-PGDH levels remain stable over subsite and time in the human colon, determined the extent of differences in 15-PGDH levels between different individuals, and determined whether 15-PGDH modulation mediates any part of the anti-colon tumor effect of aspirin.</P>
Sun, Xiangqing,Elston, Robert C.,Barnholtz-Sloan, Jill S.,Falk, Gary W.,Grady, William M.,Faulx, Ashley,Mittal, Sumeet K.,Canto, Marcia,Shaheen, Nicholas J.,Wang, Jean S.,Iyer, Prasad G.,Abrams, Julia American Association for Cancer Research 2016 Cancer Epidemiology, Biomarkers & Prevention Vol.25 No.5
<P><B>Background:</B> Barrett's esophagus is often asymptomatic and only a small portion of Barrett's esophagus patients are currently diagnosed and under surveillance. Therefore, it is important to develop risk prediction models to identify high-risk individuals with Barrett's esophagus. Familial aggregation of Barrett's esophagus and esophageal adenocarcinoma, and the increased risk of esophageal adenocarcinoma for individuals with a family history, raise the necessity of including genetic factors in the prediction model. Methods to determine risk prediction models using both risk covariates and ascertained family data are not well developed.</P><P><B>Methods:</B> We developed a Barrett's Esophagus Translational Research Network (BETRNet) risk prediction model from 787 singly ascertained Barrett's esophagus pedigrees and 92 multiplex Barrett's esophagus pedigrees, fitting a multivariate logistic model that incorporates family history and clinical risk factors. The eight risk factors, age, sex, education level, parental status, smoking, heartburn frequency, regurgitation frequency, and use of acid suppressant, were included in the model. The prediction accuracy was evaluated on the training dataset and an independent validation dataset of 643 multiplex Barrett's esophagus pedigrees.</P><P><B>Results:</B> Our results indicate family information helps to predict Barrett's esophagus risk, and predicting in families improves both prediction calibration and discrimination accuracy.</P><P><B>Conclusions:</B> Our model can predict Barrett's esophagus risk for anyone with family members known to have, or not have, had Barrett's esophagus. It can predict risk for unrelated individuals without knowing any relatives' information.</P><P><B>Impact:</B> Our prediction model will shed light on effectively identifying high-risk individuals for Barrett's esophagus screening and surveillance, consequently allowing intervention at an early stage, and reducing mortality from esophageal adenocarcinoma. <I>Cancer Epidemiol Biomarkers Prev; 25(5); 727–35. ©2016 AACR</I>.</P>
Yan, Min,Myung, Seung-Jae,Fink, Stephen P,Lawrence, Earl,Lutterbaugh, James,Yang, Peiying,Zhou, Xiaohua,Liu, Danielle,Rerko, Ronald M,Willis, Joseph,Dawson, Dawn,Tai, Hsin-Hsiung,Barnholtz-Sloan, Jill National Academy of Sciences 2009 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.106 No.23
<P>Pharmacologic inhibitors of the prostaglandin-synthesizing COX-2 oncogene prevent the development of premalignant human colon adenomas. However, resistance to treatment is common. In this study, we show that the adenoma prevention activity of the COX-2 inhibitor celecoxib requires the concomitant presence of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) tumor suppressor gene, and that loss of 15-PGDH expression imparts resistance to celecoxib's anti-tumor effects. We first demonstrate that the adenoma-preventive activity of celecoxib is abrogated in mice genetically lacking 15-PGDH. In FVB mice, celecoxib prevents 85% of azoxymethane-induced tumors >1 mm in size, but is essentially inactive in preventing tumor induction in 15-PGDH-null animals. Indeed, celecoxib treated 15-PGDH null animals develop more tumors than do celecoxib naive WT mice. In parallel with the loss of tumor prevention activity, celecoxib-mediated suppression of colonic PGE(2) levels is also markedly attenuated in 15-PGDH-null versus WT mice. Finally, as predicted by the murine models, humans with low colonic 15-PGDH levels also exhibit celecoxib resistance. Specifically, in a colon adenoma prevention trial, in all cases tested, individuals who developed new adenomas while receiving celecoxib treatment were also found as having low colonic 15-PGDH levels.</P>