bluuebunny/crossref_metadata_2025 huggingface dataset:
Figure S1, Figure S2, Figure S3, Figure S4, Figure S5 from Proton Pump Inhibitor Omeprazole Suppresses Carcinogen-induced Colonic Adenoma Progression to Adenocarcinoma in F344 Rat
Authors: Madka Venkateshwar , Kumar Gaurav , Pathuri Gopal , Panneerselvam Janani , Zhang Yuting , Ganta Vishal , Lightfoot Stanley , Lubet Ronald , Suen Chen S. , Steele Vernon E. , Janakiram Naveena B. , Mohammed Altaf , Rao Chinthalapally V.
Published: April 2023

Supplementary Figure 1. Pathways coverage map of the significantly altered genes with OME 500ppm treatment in the rat colon tumors as identified using Reactome online tool. Supplementary Figure 2. Significantly down regulated Wnt signaling pathway candidates as visualized using Reactome online tool. (A). Wnt ligand biogenesis and trafficking (B). Degradation of beta-catenin by destruction complex. (C). TCF dependant signaling in response to WNT. (D) Beta-catenin independent WNT signaling. Supplementary Figure 3. Significantly down regulated chemokines related to inflammation pathway candidates as visualized using Reactome online tool. (A). Interleukin-6 family signaling. (B) Interleukin-1 family signaling. (C) Other interleukin signaling. Supplementary Figure 4. Significantly down regulated integrin signalling pathway candidates as visualized using Reactome online tool. Supplementary Figure 5. Significantly down regulated candidates of other key signaling pathways as visualized using Reactome online tool. (A) EGFR signaling. (B) MET signaling (C) Aryl-hydrocarbon signalling pathway
Supplemental Figure 1 from Isorhapontigenin (ISO) Inhibits Invasive Bladder Cancer Formation In Vivo and Human Bladder Cancer Invasion In Vitro by Targeting STAT1/FOXO1 Axis
Authors: Jiang Guosong , Wu Amy D. , Huang Chao , Gu Jiayan , Zhang Liping , Huang Haishan , Liao Xin , Li Jingxia , Zhang Dongyun , Zeng Xingruo , Jin Honglei , Huang Haojie , Huang Chuanshu
Published: April 2023

FOXO1 stably knockdown transfectants, including UMUC3 (shFOXO1-4), UMUC3 (shFOXO1-6) (A), T24T (shFOXO1-4) and T24T (shFOXO1-6) (B), as well as Nonsense transfectants were used for determination of their cell migration and invasion in presence of either vehicle or the indicated concentration of ISO treatment for 24 hours.
Supplementary Tables S1-S3 from Smoking, Helicobacter Pylori Serology, and Gastric Cancer Risk in Prospective Studies from China, Japan, and Korea
Authors: Butt Julia , Varga Matthew G. , Wang Tianyi , Tsugane Shoichiro , Shimazu Taichi , Zheng Wei , Abnet Christian C. , Yoo Keun-Young , Park Sue K. , Kim Jeongseon , Jee Sun Ha , Qiao You-lin , Shu Xiao-Ou , Waterboer Tim , Pawlita Michael , Epplein Meira
Published: April 2023

Supplementary Table S1: Smoking and gastric cancer risk by time between blood draw and diagnosis, the H. pylori Biomarker Cohort Consortium (HpBCC) Supplementary Table S2: Smoking and gastric cancer risk by sex, the H. pylori Biomarker Cohort Consortium (HpBCC) Supplementary Table S3: Smoking and gastric cancer risk by country, the H. pylori Biomarker Cohort Consortium (HpBCC)
Supplementary Table 1 from Cost Effectiveness of Whole Population BRCA Genetic Screening for Cancer Prevention in Israel
Authors: Michaan Nadav , Leshno Moshe , Safra Tamar , Sonnenblick Amir , Laskov Ido , Grisaru Dan
Published: April 2023

Supplementary Table 1 ovarian cancer treatment costs
Supplementary Figures from Inhibition of the Biosynthesis of Prostaglandin E2 By Low-Dose Aspirin: Implications for Adenocarcinoma Metastasis
Authors: Boutaud Olivier , Sosa I. Romina , Amin Taneem , Oram Denise , Adler David , Hwang Hyun S. , Crews Brenda C. , Milne Ginger , Harris Bradford K. , Hoeksema Megan , Knollmann Bjorn C. , Lammers Philip E. , Marnett Lawrence J. , Massion Pierre P. , Oates John A.
Published: April 2023

Supplementary figures
Supplementary Figure Legends from Methylseleninic Acid Superactivates p53-Senescence Cancer Progression Barrier in Prostate Lesions of Pten-Knockout Mouse
Authors: Wang Lei , Guo Xiaolan , Wang Ji , Jiang Cheng , Bosland Maarten C. , Lü Junxuan , Deng Yibin
Published: April 2023

Legend for Supplementary Figure 1.
Data from Phase II Prospective Randomized Trial of a Low-Fat Diet with Fish Oil Supplementation in Men Undergoing Radical Prostatectomy
Authors: Aronson William J. , Kobayashi Naoko , Barnard R. James , Henning Susanne , Huang Min , Jardack Patricia M. , Liu Bingrong , Gray Ashley , Wan Junxiang , Konijeti Ramdev , Freedland Stephen J. , Castor Brandon , Heber David , Elashoff David , Said Jonathan , Cohen Pinchas , Galet Colette
Published: April 2023

Abstract
Preclinical studies suggest lowering dietary fat and decreasing the ratio of omega-6 to omega-3 polyunsaturated fatty acids decreases the risk of prostate cancer development and progression. We conducted a phase II randomized trial to test the effect of decreasing dietary fat combined with decreasing the dietary omega-6:omega-3 ratio on biomarkers related to prostate cancer development and progression. Patients undergoing radical prostatectomy were randomly assigned to receive a low-fat diet with 5 grams of fish oil daily (dietary omega-6:omega-3 ratio of 2:1) or a control Western diet (omega-6:omega-3 ratio of 15:1) for four to six weeks prior to surgery. The primary endpoint was change in serum insulin-like growth factor I (IGF-1) between arms. Secondary endpoints were serum IGFBP-1, prostate prostaglandin E2 levels, omega-6:omega-3 fatty acid ratios, COX-2, and markers of proliferation and apoptosis. Fifty-five patients were randomized and 48 completed the trial. There was no treatment difference in the primary outcome. Positive secondary outcomes in the low-fat fish oil versus Western group were reduced benign and malignant prostate tissue omega-6:omega-3 ratios, reduced proliferation (Ki-67 index), and reduced proliferation in an ex vivo bioassay when patient sera was applied to prostate cancer cells in vitro. In summary, four to six weeks of a low-fat diet and fish oil capsules to achieve an omega-6:omega-3 fatty acid ratio of 2:1 had no effect on serum IGF-1 levels, though in secondary analyses, the intervention resulted in decreased prostate cancer proliferation and decreased prostate tissue omega-6:omega-3 ratios. These results support further studies evaluating reduction of dietary fat with fish oil supplementation on modulating prostate cancer biology. Cancer Prev Res; 4(12); 2062–71. ©2011 AACR.
Data from The Core Circadian Gene Cryptochrome 2 Influences Breast Cancer Risk, Possibly by Mediating Hormone Signaling
Authors: Hoffman Aaron E. , Zheng Tongzhang , Yi Chun-Hui , Stevens Richard G. , Ba Yue , Zhang Yawei , Leaderer Derek , Holford Theodore , Hansen Johnni , Zhu Yong
Published: April 2023

Abstract
As transcriptional regulators, circadian genes have the potential to influence a variety of biological pathways, including many cancer-related processes. Cryptochrome 2 (CRY2) is essential for proper circadian timing and is a key component of the circadian regulatory feedback loop. Here, we report findings from genetic, epigenetic, loss-of-function, and transcriptional profiling analyses of CRY2 in breast cancer. Six single-nucleotide polymorphisms in CRY2 were identified for genotyping in a case-control population (n = 441 cases and n = 479 controls), and three single-nucleotide polymorphisms (rs11038689, rs7123390, and rs1401417) were significantly associated with postmenopausal breast cancer risk, with significant effect modification by menopausal status [dominant model for rs11038689: odds ratio (OR), 0.71; 95% confidence interval (95% CI), 0.51-0.99; P for trend = 0.028; homozygous variants for rs7123390: OR, 0.44; 95% CI, 0.22-0.86; P for trend = 0.028; and rs1401417: OR, 0.44; 95% CI, 0.21-0.92; P for trend = 0.017]. Interestingly, this association was only evident in women with estrogen and progesterone receptor (ER/PR)–negative breast tumors but not with ER/PR-positive tumors. Breast cancer patients also had significantly higher levels of CRY2 promoter methylation relative to controls, which is consistent with tissue array data showing lower levels of CRY2 expression in tumor tissue relative to adjacent normal tissue. Furthermore, in vitro analyses identified several breast cancer–relevant genes that displayed altered expression following CRY2 knockdown. These findings suggest a role for CRY2 in breast tumorigenesis and provide further evidence that the circadian system may be an important modulator of hormone-related cancer susceptibility. Cancer Prev Res; 3(4); 539–48. ©2010 AACR.
Data from The Dawn of a Revolution in Personalized Lung Cancer Prevention
Authors: Khuri Fadlo R.
Published: April 2023

Abstract
Lung cancer prevention and early detection, which have fallen on hard times for more than the past 20 years, seem to have turned a corner toward better times ahead. Exciting new results of randomized controlled trials that targeted the arachidonic acid pathway, including a celecoxib trial reported by Mao and colleagues in this issue of the journal (beginning on page 984) and a trial of the prostacyclin analog iloprost, complement recently reported 20%–30% lung cancer mortality reductions, either with aspirin in targeting the arachidonic acid pathway or with computed tomography screening. The new results show encouraging activity personalized to former smokers and/or people expressing predictive biomarkers. These trials and technological advances in molecular profiling and imaging herald substantial clinical advances on the horizon of this field. Cancer Prev Res; 4(7); 949–53. ©2011 AACR.
Data from A Hexane Fraction of American Ginseng Suppresses Mouse Colitis and Associated Colon Cancer: Anti-inflammatory and Proapoptotic Mechanisms
Authors: Poudyal Deepak , Mai Le Phuong , Davis Tia , Hofseth Anne B. , Chumanevich Alena , Chumanevich Alexander A. , Wargovich Michael J. , Nagarkatti Mitzi , Nagarkatti Prakash S. , Windust Anthony , Hofseth Lorne J.
Published: April 2023

Abstract
Ulcerative colitis is a chronic inflammatory condition associated with a high colon cancer risk. We have previously reported that American ginseng extract significantly reduced the inflammatory parameters of chemically induced colitis. The aim of this study was to further delineate the components of American ginseng that suppress colitis and prevent colon cancer. Among five different fractions of American ginseng (butanol, hexane, ethylacetate, dichloromethane, and water), a hexane fraction has particularly potent antioxidant and proapoptotic properties. The effects of this fraction were shown in a mouse macrophage cell line (ANA-1 cells), in a human lymphoblastoid cell line (TK6), and in an ex vivo model (CD4+/CD25− primary effector T cells). A key in vivo finding was that compared with the whole American ginseng extract, the hexane fraction of American ginseng was more potent in treating colitis in a dextran sodium sulfate (DSS) mouse model, as well as suppressing azoxymethane/DSS-induced colon cancer. Furthermore, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL) labeling of inflammatory cells within the colonic mesenteric lymph nodes was elevated in mice consuming DSS + the hexane fraction of American ginseng. Results are consistent with our in vitro data and with the hypothesis that the hexane fraction of American ginseng has anti-inflammatory properties and drives inflammatory cell apoptosis in vivo, providing a mechanism by which this fraction protects from colitis in this DSS mouse model. This study moves us closer to understanding the molecular components of American ginseng that suppress colitis and prevent colon cancer associated with colitis. Cancer Prev Res; 5(4); 685–96. ©2012 AACR.
Data from Simple Clinical Risk Score Identifies Patients with Serrated Polyps in Routine Practice
Authors: Bouwens Mariëlle W.E. , Winkens Bjorn , Rondagh Eveline J.A. , Driessen Ann L. , Riedl Robert G. , Masclee Ad A.M. , Sanduleanu Silvia
Published: April 2023

Abstract
Large, proximal, or dysplastic (LPD) serrated polyps (SP) need accurate endoscopic recognition and removal as these might progress to colorectal cancer. Herewith, we examined the risk factors for having ≥1 LPD SP. We developed and validated a simple SP risk score as a potential tool for improving their detection. We reviewed clinical, endoscopic, and histologic features of serrated polyps in a study of patients undergoing elective colonoscopy (derivation cohort). A self-administered questionnaire was obtained. We conducted logistic regression analyses to identify independent risk factors for having ≥1 LPD SP and incorporated significant variables into a clinical score. We subsequently tested the performance of the SP score in a validation cohort. We examined 2,244 patients in the derivation and 2,402 patients in the validation cohort; 6.3% and 8.2% had ≥1 LPD SP, respectively. Independent risk factors for LPD SPs were age of more than 50 years [OR 2.2; 95% confidence interval (CI), 1.3–3.8; P = 0.004], personal history of serrated polyps (OR 2.6; 95% CI, 1.3–4.9; P = 0.005), current smoking (OR 2.2; 95% CI, 1.4–3.6; P = 0.001), and nondaily/no aspirin use (OR 1.8; 95% CI, 1.1–3.0; P = 0.016). In the validation cohort, a SP score ≥5 points was associated with a 3.0-fold increased odds for LPD SPs, compared with patients with a score <5 points. In the present study, age of more than 50 years, a personal history of serrated polyps, current smoking, and nondaily/no aspirin use were independent risk factors for having LPD SPs. The SP score might aid the endoscopist in the detection of such lesions. Cancer Prev Res; 6(8); 855–63. ©2013 AACR.
Data from Lactobacillus Salivarius REN Inhibits Rat Oral Cancer Induced by 4-Nitroquioline 1-Oxide
Authors: Zhang Ming , Wang Fang , Jiang Lu , Liu Ruihai , Zhang Lian , Lei Xingen , Li Jiyou , Jiang Jingli , Guo Huiyuan , Fang Bing , Zhao Liang , Ren Fazheng
Published: April 2023

Abstract
Despite significant advances in cancer therapy, cancer-related mobility and mortality are still rising. Alternative strategies such as cancer prevention thus become essential. Probiotics represent an emerging option for cancer prevention, but studies are limited to colon cancers. The efficiency of probiotics in the prevention of other cancers and the correlative mechanism remains to be explored. A novel probiotics Lactobacillus salivarius REN (L. salivarius REN) was isolated from centenarians at Bama of China, which showed highly potent antigenotoxicity in an initial assay. 4-nitroquioline 1-oxide (4NQO)-induced oral cancer model was introduced to study the anticancer activity of L. salivarius REN in vivo. The results indicated that oral administration of probiotic L. salivarius REN or its secretions could effectively suppress 4NQO-induced oral carcinogenesis in the initial and postinitial stage, and the inhibition was in a dose-dependent manner. A significant decrease of neoplasm incidence (65%–0%) was detected in rats fed with the high dose of L. salivarius REN [5 × 1010 CFU/kg body weight (bw)/d]. In vivo evidences indicated that the probiotics inhibited 4NQO-induced oral cancer by protecting DNA against oxidative damage and downregulating COX-2 expression. L. salivarius REN treatment significantly decreased the expression of proliferating cell nuclear antigen (PCNA) and induced apoptosis in a dose-dependent manner. Our findings suggest that probiotics may act as potential agents for oral cancer prevention. This is the first report showing the inhibitory effect of the probiotics on oral carcinogenesis. Cancer Prev Res; 6(7); 686–94. ©2013 AACR.
Data from Temporal and Spatial Evolution of Somatic Chromosomal Alterations: A Case-Cohort Study of Barrett's Esophagus
Authors: Li Xiaohong , Galipeau Patricia C. , Paulson Thomas G. , Sanchez Carissa A. , Arnaudo Jessica , Liu Karen , Sather Cassandra L. , Kostadinov Rumen L. , Odze Robert D. , Kuhner Mary K. , Maley Carlo C. , Self Steven G. , Vaughan Thomas L. , Blount Patricia L. , Reid Brian J.
Published: April 2023

Abstract
All cancers are believed to arise by dynamic, stochastic somatic genomic evolution with genome instability, generation of diversity, and selection of genomic alterations that underlie multistage progression to cancer. Advanced esophageal adenocarcinomas have high levels of somatic copy number alterations. Barrett's esophagus is a risk factor for developing esophageal adenocarcinoma, and somatic chromosomal alterations (SCA) are known to occur in Barrett's esophagus. The vast majority (∼95%) of individuals with Barrett's esophagus do not progress to esophageal adenocarcinoma during their lifetimes, but a small subset develop esophageal adenocarcinoma, many of which arise rapidly even in carefully monitored patients without visible endoscopic abnormalities at the index endoscopy. Using a well-designed, longitudinal case-cohort study, we characterized SCA as assessed by single-nucleotide polymorphism arrays over space and time in 79 “progressors” with Barrett's esophagus as they approach the diagnosis of cancer and 169 “nonprogressors” with Barrett's esophagus who did not progress to esophageal adenocarcinoma over more than 20,425 person-months of follow-up. The genomes of nonprogressors typically had small localized deletions involving fragile sites and 9p loss/copy neutral LOH that generate little genetic diversity and remained relatively stable over prolonged follow-up. As progressors approach the diagnosis of cancer, their genomes developed chromosome instability with initial gains and losses, genomic diversity, and selection of SCAs followed by catastrophic genome doublings. Our results support a model of differential disease dynamics in which nonprogressor genomes largely remain stable over prolonged periods, whereas progressor genomes evolve significantly increased SCA and diversity within four years of esophageal adenocarcinoma diagnosis, suggesting a window of opportunity for early detection. Cancer Prev Res; 7(1); 114–27. ©2013 AACR.
Data from Abdominal Obesity, Independent from Caloric Intake, Accounts for the Development of Intestinal Tumors in Apc1638N/+ Female Mice
Authors: Huffman Derek M. , Augenlicht Leonard H. , Zhang Xueying , Lofrese John J. , Atzmon Gil , Chamberland John P. , Mantzoros Christos S.
Published: April 2023

Abstract
To determine whether visceral fat (VF), independent of other confounders, is causally linked to intestinal tumorigenesis, we surgically removed visceral fat in Apc1638/N+ mice. At 15 weeks of age, male and female Apc1638/N+ mice were randomized to one of three groups: ad libitum, visceral fat removal (VF-) and ad libitum fed, or caloric restriction, and were studied for effects on tumorigenesis and survival. As compared with ad libitum, VF− and caloric restriction reduced macroadenomas to a similar extent (P < 0.05), but only caloric restriction significantly improved survival (P < 0.05). Given that a significant group × gender interaction was observed, we next examined males and females separately. In females, macroadenomas were markedly attenuated by VF− (1.33 ± 0.23 mean ± SE; P < 0.05), but not by caloric restriction (2.35 ± 0.25; P = 0.71), as compared with ad libitum (2.50 ± 0.34). In males, however, caloric restriction (1.71 ± 0.26; P < 0.01), but not VF− (2.94 ± 0.42; P = 0.29), reduced macroadenomas, as compared with ad libitum males (3.47 ± 0.30). In females, both VF− (P = 0.05) and caloric restriction (P < 0.01) improved survival, but not in male mice (P = 0.15). The benefits observed with caloric restriction were consistent with favorable metabolic adaptations, but protection conferred in VF− females was despite lower adiponectin levels (P < 0.05), and failure to reduce body mass, total adiposity, glucose, insulin, leptin, and chemokine (C–X–C motif) ligand 1 (CXCL-1) levels. In conclusion, these data provide the first causal evidence linking visceral fat to intestinal cancer risk, and suggest that factors, other than known metabolic mediators, may impact tumor development. Furthermore, these data emphasize that strategies designed to deplete visceral fat stores in humans should be considered in the prevention of intestinal cancer. Cancer Prev Res; 6(3); 177–87. ©2012 AACR.
Data from A Framework for Evaluating Biomarkers for Early Detection: Validation of Biomarker Panels for Ovarian Cancer
Authors: Zhu Claire S. , Pinsky Paul F. , Cramer Daniel W. , Ransohoff David F. , Hartge Patricia , Pfeiffer Ruth M. , Urban Nicole , Mor Gil , Bast Robert C. , Moore Lee E. , Lokshin Anna E. , McIntosh Martin W. , Skates Steven J. , Vitonis Allison , Zhang Zhen , Ward David C. , Symanowski James T. , Lomakin Aleksey , Fung Eric T. , Sluss Patrick M. , Scholler Nathalie , Lu Karen H. , Marrangoni Adele M. , Patriotis Christos , Srivastava Sudhir , Buys Saundra S. , Berg Christine D.
Published: April 2023

Abstract
A panel of biomarkers may improve predictive performance over individual markers. Although many biomarker panels have been described for ovarian cancer, few studies used prediagnostic samples to assess the potential of the panels for early detection. We conducted a multisite systematic evaluation of biomarker panels using prediagnostic serum samples from the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) screening trial.

Using a nested case–control design, levels of 28 biomarkers were measured laboratory-blinded in 118 serum samples obtained before cancer diagnosis and 951 serum samples from matched controls. Five predictive models, each containing 6 to 8 biomarkers, were evaluated according to a predetermined analysis plan. Three sequential analyses were conducted: blinded validation of previously established models (step 1); simultaneous split-sample discovery and validation of models (step 2); and exploratory discovery of new models (step 3). Sensitivity, specificity, sensitivity at 98% specificity, and AUC were computed for the models and CA125 alone among 67 cases diagnosed within one year of blood draw and 476 matched controls. In step 1, one model showed comparable performance to CA125, with sensitivity, specificity, and AUC at 69.2%, 96.6%, and 0.892, respectively. Remaining models had poorer performance than CA125 alone. In step 2, we observed a similar pattern. In step 3, a model derived from all 28 markers failed to show improvement over CA125.

Thus, biomarker panels discovered in diagnostic samples may not validate in prediagnostic samples; utilizing prediagnostic samples for discovery may be helpful in developing validated early detection panels. Cancer Prev Res; 4(3); 375–83. ©2011 AACR.
Data from Heme Iron from Meat and Risk of Colorectal Cancer: A Meta-analysis and a Review of the Mechanisms Involved
Authors: Bastide Nadia M. , Pierre Fabrice H.F. , Corpet Denis E.
Published: April 2023

Abstract
Red meat and processed meat intake is associated with a risk of colorectal cancer, a major cause of death in affluent countries. Epidemiological and experimental evidence supports the hypothesis that heme iron present in meat promotes colorectal cancer. This meta-analysis of prospective cohort studies of colon cancer reporting heme intake included 566,607 individuals and 4,734 cases of colon cancer. The relative risk of colon cancer was 1.18 (95% CI: 1.06–1.32) for subjects in the highest category of heme iron intake compared with those in the lowest category. Epidemiological data thus show a suggestive association between dietary heme and risk of colon cancer. The analysis of experimental studies in rats with chemically-induced colon cancer showed that dietary hemoglobin and red meat consistently promote aberrant crypt foci, a putative precancer lesion. The mechanism is not known, but heme iron has a catalytic effect on (i) the endogenous formation of carcinogenic N-nitroso compounds and (ii) the formation of cytotoxic and genotoxic aldehydes by lipoperoxidation. A review of evidence supporting these hypotheses suggests that both pathways are involved in heme iron toxicity. Cancer Prev Res; 4(2); 177–84. ©2011 AACR.
Data from Widefield Optical Imaging of Changes in Uptake of Glucose and Tissue Extracellular pH in Head and Neck Cancer
Authors: Luo Zhen , Loja Melissa N. , Farwell D. Greg , Luu Quang C. , Donald Paul J. , Amott Deborah , Truong Anh Q. , Gandour-Edwards Regina , Nitin Nitin
Published: April 2023

Abstract
The overall objective of this study was to develop an optical imaging approach to simultaneously measure altered cell metabolism and changes in tissue extracellular pH with the progression of cancer using clinically isolated biopsies. In this study, 19 pairs of clinically normal and abnormal biopsies were obtained from consenting patients with head and neck cancer at University of California, Davis Medical Center. Fluorescence intensity of tissue biopsies before and after topical delivery of 2-NBDG (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose) and Alexa 647-pHLIP [pH (low) insertion peptide] was measured noninvasively by widefield imaging, and correlated with pathologic diagnosis. The results of widefield imaging of clinical biopsies demonstrated that 2-NBDG and pHLIP peptide can accurately distinguish the pathologically normal and abnormal biopsies. The results also demonstrated the potential of this approach to detect subepithelial lesions. Topical application of the contrast agents generated a significant increase in fluorescence contrast (3- to 4-fold) in the cancer biopsies as compared with the normal biopsies, irrespective of the patient and location of the biopsy within a head and neck cavity. This unpaired comparison across all the patients with cancer in this study highlights the specificity of the imaging approach. Furthermore, the results of this study indicated that changes in intracellular glucose metabolism and cancer acidosis are initiated in the early stages of cancer, and these changes are correlated with the progression of the disease. In conclusion, this novel optical molecular imaging approach to measure multiple biomarkers in cancer has a significant potential to be a useful tool for improving early detection and prognostic evaluation of oral neoplasia. Cancer Prev Res; 7(10); 1035–44. ©2014 AACR.
Data from A Randomized Pilot Trial of Dietary Modification for the Chemoprevention of Noninvasive Bladder Cancer: The Dietary Intervention in Bladder Cancer Study
Authors: Parsons J. Kellogg , Pierce John P. , Natarajan Loki , Newman Vicky A. , Barbier Leslie , Mohler James , Rock Cheryl L. , Heath Dennis D. , Guru Khurshid , Jameson Michael B. , Li Hongying , Mirheydar Hossein , Holmes Michael A. , Marshall James
Published: April 2023

Abstract
Epidemiological data suggest robust associations of high vegetable intake with decreased risks of bladder cancer incidence and mortality, but translational prevention studies have yet to be conducted. We designed and tested a novel intervention to increase vegetable intake in patients with noninvasive bladder cancer. We randomized 48 patients aged 50 to 80 years with biopsy-proven noninvasive (Ta, T1, or carcinoma in situ) urothelial cell carcinoma to telephone- and Skype-based dietary counseling or a control condition that provided print materials only. The intervention behavioral goals promoted seven daily vegetable servings, with at least two of these as cruciferous vegetables. Outcome variables were self-reported diet and plasma carotenoid and 24-hour urinary isothiocyanate (ITC) concentrations. We used two-sample t tests to assess between-group differences at 6-month follow-up. After 6 months, intervention patients had higher daily intakes of vegetable juice (P = 0.02), total vegetables (P = 0.02), and cruciferous vegetables (P = 0.07); lower daily intakes of energy (P = 0.007), fat (P = 0.002) and energy from fat (P = 0.06); and higher plasma α-carotene concentrations (P = 0.03). Self-reported cruciferous vegetable intake correlated with urinary ITC concentrations at baseline (P < 0.001) and at 6 months (P = 0.03). Although urinary ITC concentrations increased in the intervention group and decreased in the control group, these changes did not attain between-group significance (P = 0.32). In patients with noninvasive bladder cancer, our novel intervention induced diet changes associated with protective effects against bladder cancer. These data show the feasibility of implementing therapeutic dietary modifications to prevent recurrent and progressive bladder cancer. Cancer Prev Res; 6(9); 971–8. ©2013 AACR.
Data from Epidermal Growth Factor Receptor Expression and Gene Copy Number in the Risk of Oral Cancer
Authors: Taoudi Benchekroun Mohammed , Saintigny Pierre , Thomas Sufi M. , El-Naggar Adel K. , Papadimitrakopoulou Vassiliki , Ren Hening , Lang Wenhua , Fan You-Hong , Huang Jianhua , Feng Lei , Lee J. Jack , Kim Edward S. , Hong Waun Ki , Johnson Faye M. , Grandis Jennifer R. , Mao Li
Published: April 2023

Abstract
Leukoplakia is the most common premalignant lesion of the oral cavity. Epidermal growth factor receptor (EGFR) abnormalities are associated with oral tumorigenesis and progression. We hypothesized that EGFR expression and gene copy number changes are predictors of the risk of an oral premalignant lesion (OPL) progressing to oral squamous cell carcinoma (OSCC). A formalin-fixed, paraffin-embedded OPL biopsy specimen was collected from each of 162 patients in a randomized controlled clinical trial. We assessed EGFR expression by immunohistochemistry with two methods: a semiquantitative analysis (145 evaluable specimens) and an automated quantitative analysis (127 evaluable specimens). EGFR gene copy number was assessed by fluorescence in situ hybridization (FISH) in a subset of 49 OPLs with high EGFR expression defined by the semiquantitative analysis. We analyzed EGFR abnormalities for associations with OSCC development. High EGFR expression occurred in 103 (71%) of the 145 OPLs and was associated with a nonsignificantly higher risk of OSCC (P = 0.10). Twenty (41%) of 49 OPLs assessed by FISH had an increased EGFR gene copy number (FISH-positive). Patients with FISH-positive lesions had a significantly higher incidence of OSCC than did patients with FISH-negative (a normal copy number) lesions (P = 0.0007). Of note, 10 of 11 OSCCs that developed at the site of the examined OPL were in the FISH-positive group, leaving only one FISH-negative OPL that did so (P < 0.0001). Our data indicate that an increased EGFR gene copy number is common in and associated with OSCC development in patients with OPLs expressing high EGFR, particularly OSCC developing at the site of a high-expression OPL; they also suggest that EGFR inhibitors may prevent oral cancer in patients with OPLs having an increased EGFR gene copy number. Cancer Prev Res; 3(7); 800–9. ©2010 AACR.
Data from Altered Gene Expression in Morphologically Normal Epithelial Cells from Heterozygous Carriers of BRCA1 or BRCA2 Mutations
Authors: Bellacosa Alfonso , Godwin Andrew K. , Peri Suraj , Devarajan Karthik , Caretti Elena , Vanderveer Lisa , Bove Betsy , Slater Carolyn , Zhou Yan , Daly Mary , Howard Sharon , Campbell Kerry S. , Nicolas Emmanuelle , Yeung Anthony T. , Clapper Margie L. , Crowell James A. , Lynch Henry T. , Ross Eric , Kopelovich Levy , Knudson Alfred G.
Published: April 2023

Abstract
We hypothesized that cells bearing a single inherited “hit” in a tumor suppressor gene express an altered mRNA repertoire that may identify targets for measures that could delay or even prevent progression to carcinoma. We report here on the transcriptomes of primary breast and ovarian epithelial cells cultured from BRCA1 and BRCA2 mutation carriers and controls. Our comparison analyses identified multiple changes in gene expression, in both tissues for both mutations, which were validated independently by real-time reverse transcription-PCR analysis. Several of the differentially expressed genes had been previously proposed as cancer markers, including mammaglobin in breast cancer and serum amyloid in ovarian cancer. These findings show that heterozygosity for a mutant tumor suppressor gene can alter the expression profiles of phenotypically normal epithelial cells in a gene-specific manner; these detectable effects of “one hit” represent early molecular changes in tumorigenesis that may serve as novel biomarkers of cancer risk and as targets for chemoprevention. Cancer Prev Res; 3(1); 48–61
Data from Basal Cell Carcinoma Chemoprevention with Nonsteroidal Anti-inflammatory Drugs in Genetically Predisposed PTCH1+/− Humans and Mice
Authors: Tang Jean Y. , Aszterbaum Michelle , Athar Mohammad , Barsanti Franco , Cappola Carol , Estevez Nini , Hebert Jennifer , Hwang Jimmy , Khaimskiy Yefim , Kim Arianna , Lu Ying , So Po-Lin , Tang Xiuwei , Kohn Michael A. , McCulloch Charles E. , Kopelovich Levy , Bickers David R. , Epstein Ervin H.
Published: April 2023

Abstract
In vitro and epidemiologic studies favor the efficacy of nonsteroidal anti-inflammatory drugs (NSAID) in preventing skin squamous photocarcinogenesis, but there has been relatively little study of their efficacy in preventing the more common skin basal cell carcinoma (BCC) carcinogenesis. We first compared the relative anti-BCC effects of genetic deletion and NSAID pharmacologic inhibition of cyclooxygenase (COX) enzymes in the skin of Ptch1+/− mice. We then assessed the effects of celecoxib on the development of BCCs in a 3-year, double-blinded, randomized clinical trial in 60 (PTCH1+/−) patients with the basal cell nevus syndrome. In Ptch1+/− mice, genetic deletion of COX1 or COX2 robustly decreased (75%; P < 0.05) microscopic BCC tumor burden, but pharmacologic inhibition with celecoxib reduced microscopic BCCs less efficaciously (35%; P < 0.05). In the human trial, we detected a trend for oral celecoxib reducing BCC burden in all subjects (P = 0.069). Considering only the 60% of patients with less severe disease (<15 BCCs at study entry), celecoxib significantly reduced BCC number and burden: subjects receiving placebo had a 50% increase in BCC burden per year, whereas subjects in the celecoxib group had a 20% increase (Pdifference = 0.024). Oral celecoxib treatment inhibited BCC carcinogenesis in PTCH1+/− mice and had a significant anti-BCC effect in humans with less severe disease. Cancer Prev Res; 3(1); OF1–11
Data from Bioavailability of Sulforaphane from Two Broccoli Sprout Beverages: Results of a Short-term, Cross-over Clinical Trial in Qidong, China
Authors: Egner Patricia A. , Chen Jian Guo , Wang Jin Bing , Wu Yan , Sun Yan , Lu Jian Hua , Zhu Jian , Zhang Yong Hui , Chen Yong Sheng , Friesen Marlin D. , Jacobson Lisa P. , Muñoz Alvaro , Ng Derek , Qian Geng Sun , Zhu Yuan Rong , Chen Tao Yang , Botting Nigel P. , Zhang Qingzhi , Fahey Jed W. , Talalay Paul , Groopman John D , Kensler Thomas W.
Published: April 2023

Abstract
One of several challenges in design of clinical chemoprevention trials is the selection of the dose, formulation, and dose schedule of the intervention agent. Therefore, a cross-over clinical trial was undertaken to compare the bioavailability and tolerability of sulforaphane from two of broccoli sprout–derived beverages: one glucoraphanin-rich (GRR) and the other sulforaphane-rich (SFR). Sulforaphane was generated from glucoraphanin contained in GRR by gut microflora or formed by treatment of GRR with myrosinase from daikon (Raphanus sativus) sprouts to provide SFR. Fifty healthy, eligible participants were requested to refrain from crucifer consumption and randomized into two treatment arms. The study design was as follows: 5-day run-in period, 7-day administration of beverages, 5-day washout period, and 7-day administration of the opposite intervention. Isotope dilution mass spectrometry was used to measure levels of glucoraphanin, sulforaphane, and sulforaphane thiol conjugates in urine samples collected daily throughout the study. Bioavailability, as measured by urinary excretion of sulforaphane and its metabolites (in approximately 12-hour collections after dosing), was substantially greater with the SFR (mean = 70%) than with GRR (mean = 5%) beverages. Interindividual variability in excretion was considerably lower with SFR than with GRR beverage. Elimination rates were considerably slower with GRR, allowing for achievement of steady-state dosing as opposed to bolus dosing with SFR. Optimal dosing formulations in future studies should consider blends of sulforaphane and glucoraphanin as SFR and GRR mixtures to achieve peak concentrations for activation of some targets and prolonged inhibition of others implicated in the protective actions of sulforaphane. Cancer Prev Res; 4(3); 384–95. ©2011 AACR.
Data from Aberrant DNA Methylation at Genes Associated with a Stem Cell-like Phenotype in Cholangiocarcinoma Tumors
Authors: Sriraksa Ruethairat , Zeller Constanze , Dai Wei , Siddiq Afshan , Walley Andrew J. , Limpaiboon Temduang , Brown Robert
Published: April 2023

Abstract
Genetic abnormalities of cholangiocarcinoma have been widely studied; however, epigenomic changes related to cholangiocarcinogenesis have been less well characterized. We have profiled the DNA methylomes of 28 primary cholangiocarcinoma and six matched adjacent normal tissues using Infinium's HumanMethylation27 BeadChips with the aim of identifying gene sets aberrantly and epigenetically regulated in this tumor type. Using a linear model for microarray data, we identified 1610 differentially methylated autosomal CpG sites, with 809 hypermethylated (representing 603 genes) and 801 hypomethylated (representing 712 genes) in cholangiocarcinoma versus adjacent normal tissues (false-discovery rate ≤ 0.05). Gene ontology and gene set enrichment analyses identified gene sets significantly associated with hypermethylation at linked CpG sites in cholangiocarcinoma including homeobox genes and target genes of PRC2, EED, SUZ12, and histone H3 trimethylation at lysine 27. We confirmed frequent hypermethylation at the homeobox genes HOXA9 and HOXD9 by bisulfite pyrosequencing in a larger cohort of cholangiocarcinoma (n = 102). Our findings indicate a key role for hypermethylation of multiple CpG sites at genes associated with a stem cell-like phenotype as a common molecular aberration in cholangiocarcinoma. These data have implications for cholangiocarcinogenesis, as well as possible novel treatment options using histone methyltransferase inhibitors. Cancer Prev Res; 6(12); 1348–55. ©2013 AACR.
Data from Lung Cancer Inhibitory Effect of Epigallocatechin-3-Gallate Is Dependent on Its Presence in a Complex Mixture (Polyphenon E)
Authors: Fu Huijing , He Jun , Mei Fan , Zhang Qi , Hara Yukihiko , Ryota Seto , Lubet Ronald A. , Chen Ruth , Chen Da-Ren , You Ming
Published: April 2023

Abstract
Green tea has been shown to exhibit cancer-preventive activities in preclinical studies. However, (−)-epigallocatechin-3-gallate (EGCG) alone was shown to be ineffective in preventing lung tumorigenesis in mice by aerosol administration. In this study, Polyphenon E and Polyphenon E without EGCG were administered by aerosol delivery to A/J mice 2 weeks after carcinogen treatment and continuing daily throughout the remainder of the study (20 weeks). An improved aerosol delivery system with a custom-built atomizer, an efficient solvent remove system, and a nose-only exposure chamber was used to provide aerosols with stable size distribution. There were no significant differences in the size distributions of Polyphenon E and Polyphenon E without EGCG. With a relatively low dose level (4.19 mg/kg), Polyphenon E decreased tumor multiplicity by 53%, whereas Polyphenon E without EGCG at the same dose failed to inhibit lung carcinogenesis. These results indicate that aerosol administration can be an effective approach in chemoprevention study, and aerosolized Polyphenon E can significantly inhibit pulmonary adenoma formation and growth in A/J mice. Furthermore, in aerosolized form, EGCG, which is thought to be the most active component of Polyphenon E, has to be present with other tea catechins to show chemopreventive activity on lung tumorigenesis.
Data from Bufalin, a Traditional Chinese Medicine Compound, Prevents Tumor Formation in Two Murine Models of Colorectal Cancer
Authors: Sun Xiao , Ng Tony T.H. , Sham Kathy W.Y. , Zhang Lin , Chan Matthew T.V. , Wu William K.K. , Cheng Christopher H.K.
Published: April 2023

Abstract
Chemoprevention is cost-effective for colorectal cancer when targeted at intermediate- or high-risk populations. Bufalin is a cardiac glycoside extracted from the traditional Chinese medicine (TCM) “Chan Su,” which has been used as an anticancer agent. On the basis of the relative safety of bufalin, we investigated whether bufalin could act as a chemoprophylactic agent to prevent colon tumorigenesis in two murine models, namely colitis-associated colorectal cancer and Apc germline mutation-developed colorectal cancer. Our results revealed that long-term (12–16 weeks) administration of low-dose bufalin (0.5 mg/kg) effectively suppressed tumorigenesis in both colorectal cancer models, accompanied by attenuated epithelial cell proliferation (reduced bromodeoxyuridine incorporation, lower levels of cyclin A, cyclin D1, cyclin E, and cyclin-dependent kinases-2/4, and higher levels of p21 and p27) and promoted apoptosis (increased TUNEL positivity and caspase-3/9 cleavages, reduced levels of Bcl-2, Bcl-xL and survivin, and increased levels of Bax and Bak). Bufalin also suppressed the expression of proinflammatory mediators [reduced levels of cyclooxygenase-2, tumor TNFα, IL1β, IL6, C-X-C motif chemokine ligand (CXCL)-1, CXCL-2, and CXCL-5] in the colitis-associated colorectal cancer model. These effects were associated with the inhibition of oncogenic NF-κB and PI3K/Akt pathways. Our findings unveil a novel chemoprophylactic action of bufalin in colorectal cancer in vivo and provided efficacy data and mechanistic evidence for further clinical evaluation of this TCM compound for colorectal cancer chemoprevention in individuals at risk of colorectal cancer.
Data from Suppression of Colon Tumorigenesis in Mutant Apc Mice by a Novel PDE10 Inhibitor that Reduces Oncogenic β-Catenin
Authors: Lee Kevin J. , Chang Wen-Chi L. , Chen Xi , Valiyaveettil Jacob , Ramirez-Alcantara Veronica , Gavin Elaine , Musiyenko Alla , Madeira da Silva Luciana , Annamdevula Naga S. , Leavesley Silas J. , Ward Antonio , Mattox Tyler , Lindsey Ashley S. , Andrews Joel , Zhu Bing , Wood Charles , Neese Ashleigh , Nguyen Ashley , Berry Kristy , Maxuitenko Yulia , Moyer Mary Pat , Nurmemmedov Elmar , Gorman Greg , Coward Lori , Zhou Gang , Keeton Adam B. , Cooper Harry S. , Clapper Margie L. , Piazza Gary A.
Published: April 2023

Abstract
Previous studies have reported that phosphodiesterase 10A (PDE10) is overexpressed in colon epithelium during early stages of colon tumorigenesis and essential for colon cancer cell growth. Here we describe a novel non-COX inhibitory derivative of the anti-inflammatory drug, sulindac, with selective PDE10 inhibitory activity, ADT 061. ADT 061 potently inhibited the growth of colon cancer cells expressing high levels of PDE10, but not normal colonocytes that do not express PDE10. The concentration range by which ADT 061 inhibited colon cancer cell growth was identical to concentrations that inhibit recombinant PDE10. ADT 061 inhibited PDE10 by a competitive mechanism and did not affect the activity of other PDE isozymes at concentrations that inhibit colon cancer cell growth. Treatment of colon cancer cells with ADT 061 activated cGMP/PKG signaling, induced phosphorylation of oncogenic β-catenin, inhibited Wnt-induced nuclear translocation of β-catenin, and suppressed TCF/LEF transcription at concentrations that inhibit cancer cell growth. Oral administration of ADT 061 resulted in high concentrations in the colon mucosa and significantly suppressed the formation of colon adenomas in the Apc+/min-FCCC mouse model of colorectal cancer without discernable toxicity. These results support the development of ADT 061 for the treatment or prevention of adenomas in individuals at risk of developing colorectal cancer.
Prevention Relevance:
PDE10 is overexpressed in colon tumors whereby inhibition activates cGMP/PKG signaling and suppresses Wnt/β-catenin transcription to selectively induce apoptosis of colon cancer cells. ADT 061 is a novel PDE10 inhibitor that shows promising cancer chemopreventive activity and tolerance in a mouse model of colon cancer.
Data from External Validation of Risk Prediction Models Incorporating Common Genetic Variants for Incident Colorectal Cancer Using UK Biobank
Authors: Saunders Catherine L. , Kilian Britt , Thompson Deborah J. , McGeoch Luke J. , Griffin Simon J. , Antoniou Antonis C. , Emery Jon D. , Walter Fiona M. , Dennis Joe , Yang Xin , Usher-Smith Juliet A.
Published: April 2023

Abstract
The aim of this study was to compare and externally validate risk scores developed to predict incident colorectal cancer that include common genetic variants (SNPs), with or without established lifestyle/environmental (questionnaire-based/classical/phenotypic) risk factors. We externally validated 23 risk models from a previous systematic review in 443,888 participants ages 37 to 73 from the UK Biobank cohort who had 6-year prospective follow-up, no prior history of colorectal cancer, and data for incidence of colorectal cancer through linkage to national cancer registries. There were 2,679 (0.6%) cases of incident colorectal cancer. We assessed model discrimination using the area under the operating characteristic curve (AUC) and relative risk calibration. The AUC of models including only SNPs increased with the number of included SNPs and was similar in men and women: the model by Huyghe with 120 SNPs had the highest AUC of 0.62 [95% confidence interval (CI), 0.59–0.64] in women and 0.64 (95% CI, 0.61–0.66) in men. Adding phenotypic risk factors without age improved discrimination in men but not in women. Adding phenotypic risk factors and age increased discrimination in all cases (P < 0.05), with the best performing models including SNPs, phenotypic risk factors, and age having AUCs between 0.64 and 0.67 in women and 0.67 and 0.71 in men. Relative risk calibration varied substantially across the models. Among middle-aged people in the UK, existing polygenic risk scores discriminate moderately well between those who do and do not develop colorectal cancer over 6 years. Consideration should be given to exploring the feasibility of incorporating genetic and lifestyle/environmental information in any future stratified colorectal cancer screening program.