bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Synthetic Triterpenoids Prolong Survival in a Transgenic Mouse Model of Pancreatic Cancer
Authors: Liby Karen T. , Royce Darlene B. , Risingsong Renee , Williams Charlotte R. , Maitra Anirban , Hruban Ralph H. , Sporn Michael B.
Published: March 2024

Abstract
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and is nearly always fatal. Whereas early detection offers the most promising approach for reducing the mortality of this disease, there is still a need to develop effective drugs for the prevention and treatment of pancreatic cancer. We tested two promising classes of noncytotoxic drugs, synthetic oleanane triterpenoids and rexinoids, for the prevention of carcinogenesis in the highly relevant LSL-KrasG12D/+;LSL-Trp53R127H/+;Pdx-1-Cre (KPC) mouse model of pancreatic cancer. KPC transgenic mice closely recapitulate the genetic mutations, clinical symptoms, and histopathology found in human pancreatic cancer. Beginning at 4 weeks of age, mice were fed powdered control diet or a diet containing the triterpenoids CDDO-methyl ester (CDDO-Me) or CDDO-ethyl amide, the rexinoid LG100268 (LG268), or the combination, until the mice displayed overt symptoms of pancreatic cancer. CDDO-Me, LG268, the combination of CDDO-Me and LG268, and the combination of CDDO-ethyl amide and LG268, all significantly (P < 0.05) increased survival in the KPC mice by 3 to 4 weeks. Recent studies have shown that gemcitabine, the current standard of care for human pancreatic cancer, does not extend survival in KPC mice. In cell lines developed from the KPC mice, the triterpenoids directly interact with both signal transducer and activator of transcription 3 and IκB kinase (IKK) to decrease constitutive interleukin-6 secretion, inhibit constitutive signal transducer and activator of transcription 3 phosphorylation, and block the degradation of IκBα when challenged with tumor necrosis factor α. These results suggest that oleanane triterpenoids and rexinoids have the potential to prevent pancreatic cancer. Cancer Prev Res; 3(11); 1427–34. ©2010 AACR.
Data from Is Prostate Cancer Prevention with Selenium All in the Genes?
Authors: Platz Elizabeth A.
Published: March 2024

Abstract
This perspective discusses how well-conducted research by Penney et al. (beginning on page 604 in this issue of the journal) contributes to the incremental uncovering of the complex association between selenium and prostate cancer. These investigators' earlier findings and current questions, approaches, and findings regarding selenium for prostate cancer prevention are discussed. This group's work raises the following important inferences: Selenium may prevent poorer-prognosis prostate cancer and its progression to bony metastases and death, but only in men with genetic backgrounds that influence the requirement for selenium. These inferences point toward how to reconcile inconsistent prostate cancer risk results from the two randomized trials of selenium conducted to date. Cancer Prev Res; 3(5); 576–8. ©2010 AACR.
Data from Genetic Driver Events in Premalignancy: LOH Validated for Marking the Risk of Oral Cancer
Authors: Cavenee Webster K.
Published: March 2024

Abstract
In this issue of the journal (beginning on page 1081), Zhang and colleagues extend the 30-year-old discovery of LOH profiles to provide validated markers of oral premalignant lesion risk for cancer. They prospectively show a dramatic difference in cancer progression between high-risk lesions (LOH) and low-risk (non-LOH) lesions (P = 0.002). This work has important implications for oral cancer prevention and risk modeling and for understanding genetic driver events in premalignancy. Cancer Prev Res; 5(9); 1073–4. ©2012 AACR.
Data from Sunitinib Prolongs Survival in Genetically Engineered Mouse Models of Multistep Lung Carcinogenesis
Authors: Gandhi Leena , McNamara Kate L. , Li Danan , Borgman Christa L. , McDermott Ultan , Brandstetter Kathleyn A. , Padera Robert F. , Chirieac Lucian R. , Settleman Jeffrey E. , Wong Kwok-Kin
Published: March 2024

Abstract
Non–small cell lung cancer (NSCLC) has a poor prognosis, with substantial mortality rates even among patients diagnosed with early-stage disease. There are few effective measures to block the development or progression of NSCLC. Antiangiogenic drugs represent a new class of agents targeting multiple aspects of tumor progression, including cell proliferation, invasion, migration, and outgrowth of metastatic deposits. We tested the multitargeted angiogenesis inhibitor sunitinib in a novel endogenous mouse model of NSCLC, which expresses a conditional activating mutation in Kras with or without conditional deletion of Lkb1; both alterations are frequent in human NSCLC. We showed that daily treatment with sunitinib reduced tumor size, caused tumor necrosis, blocked tumor progression, and prolonged median survival in both the metastatic (Lkb1/Kras) and nonmetastatic (Kras) mouse models; median survival was not reached in the nonmetastatic model after 1 year. However, the incidence of local and distant metastases was similar in sunitinib-treated and untreated Lkb1/Kras mice, suggesting that prolonged survival with sunitinib in these mice was due to direct effects on primary tumor growth rather than to inhibition of metastatic progression. These collective results suggest that the use of angiogenesis inhibitors in early-stage disease for prevention of tumor development and growth may have major survival benefits in the setting of NSCLC.
Data from Risk of Cardiovascular Events in a Randomized Placebo-Controlled, Double-Blind Trial of Difluoromethylornithine plus Sulindac for the Prevention of Sporadic Colorectal Adenomas
Authors: Zell Jason A. , Pelot Daniel , Chen Wen-Pin , McLaren Christine E. , Gerner Eugene W. , Meyskens Frank L.
Published: March 2024

Abstract
Nonsteroidal anti-inflammatory drugs (NSAID) have been associated with adverse cardiovascular (CV) outcomes in cancer prevention and other clinical trials. A recent meta-analysis suggested that baseline CV risk is associated with NSAID-associated adverse CV events. We evaluated the effect of baseline CV risk on adverse CV events in a phase III trial of difluoromethylornithine (DFMO) plus the NSAID sulindac versus placebo in preventing colorectal adenomas. Trial data were analyzed to determine baseline CV risk. CV toxicity outcomes were then assessed overall and excluding high CV-risk patients. Baseline CV risk scores were evenly distributed within our overall trial population of 184 placebo (low risk, 27%; moderate risk, 34%; high risk, 39%) and 191 DFMO/sulindac (low risk, 30%; moderate risk, 29%; high risk, 41%) patients. In patients with a high baseline CV risk, the number of adverse CV events was greater among DFMO/sulindac (n = 9) than among placebo (n = 3) patients. Excluding patients with a high baseline CV risk, the numbers of adverse CV events were similar in the DFMO/sulindac (n = 7) and placebo (n = 6) arms. A high CV risk score at baseline may confer an increased risk of CV events associated with treatment with DFMO/sulindac, and a low baseline score may not increase this risk. These results have implications for future NSAID-based cancer prevention clinical trials.
Data from Effect of Intermittent Dosing Regimens of Erlotinib on Methylnitrosourea-Induced Mammary Carcinogenesis
Authors: Lubet Ronald A. , Szabo Eva , Iwata Kenneth K. , Gill Stanley C. , Tucker Chris , Bode Ann , Steele Vernon E. , Juliana M. Margaret , Nicastro Holly L. , Grubbs Clinton J.
Published: March 2024

Abstract
EGF receptor (EGFR) inhibitors are used in the therapy of lung and pancreatic cancers and effectively prevent cancers in multiple animal models. Although daily dosing with erlotinib is effective, weekly dosing may reduce toxicity and have advantages, particularly for prevention. We tested alternative dosing regimens for preventive/therapeutic efficacy in a rat mammary cancer model. For prevention, erlotinib was administered by gavage beginning 5 days after methylnitrosourea (MNU). For therapy and biomarker studies, rats with palpable mammary cancers were treated for six weeks or for six days, respectively. Experiment A, erlotinib (6 mg/kg body weight/day, intragastric): daily (7 times/week); one day on/one day off; and two days on/two days off. All regimens decreased tumor incidence, increased tumor latency, and decreased cancer multiplicity versus controls (P < 0.01). However, intermittent dosing was less effective than daily dosing (P < 0.05). Experiment B, erlotinib (6 mg/kg body weight/day) daily or two days on/two days off or one time per week at 42 mg/kg body weight. All regimens reduced cancer incidence and multiplicity versus controls (P < 0.01). Interestingly, daily and weekly dosing were equally effective (P > 0.5). Experiment C, erlotinib administered at 42 or 21 mg/kg body weight 1 time per week, decreased tumor incidence and multiplicity (P < 0.01). Erlotinib had a serum half-life of ≤8 hours and weekly treatment yielded effective serum levels for ≤48 hours. Daily or weekly treatment of cancer bearing rats reduced mammary tumor size 25% to 35%, whereas control cancers increased >250%. Levels of phosphorylated extracellular signal-regulated kinase (ERK) were strongly decreased in rats treated daily/weekly with erlotinib. Thus, altering the dose of erlotinib retained most of its preventive and therapeutic efficacy, and based on prior clinical studies, is likely to reduce its toxicity. Cancer Prev Res; 6(5); 448–54. ©2013 AACR.
Data from Assessing Efficacy in Early-Phase Cancer Prevention Clinical Trials: The Case of Ki-67 in the Lung
Authors: Szabo Eva
Published: March 2024

Abstract
This perspective on Kim et al. (beginning on p. 148 in this issue of the journal) examines the value of the Ki-67 proliferation index as a surrogate end point in early-phase clinical lung cancer prevention trials. The clinical trial of Kim et al. shows an effect of the cyclooxygenase-2–selective inhibitor celecoxib at a high dose on Ki-67 expression in the normal bronchial epithelia of current and former smokers. The critical issue of how these data can be used to further drug development is discussed. Cancer Prev Res; 3(2); 128–31
Data from Profiles in Variation: Lung Carcinogenesis
Authors: Carbone David P.
Published: March 2024

Abstract
This perspective on Kadara et al. (beginning on p. 702 in this issue of the journal) examines the critical development of genomic and proteomic signatures of lung cancer risk, prognosis, and sensitivity to chemoprevention or chemotherapy. The novel work of Kadara et al. represents the first demonstration that a molecular signature developed in a premalignancy model (in this case, cultured normal human bronchial epithelial cells and increasingly transformed derivative cells) is clinically relevant to invasive lung cancer.
Data from Phase II Randomized, Placebo-Controlled Trial of Green Tea Extract in Patients with High-Risk Oral Premalignant Lesions
Authors: Tsao Anne S. , Liu Diane , Martin Jack , Tang Xi-ming , Lee J. Jack , El-Naggar Adel K. , Wistuba Ignacio , Culotta Kirk S. , Mao Li , Gillenwater Ann , Sagesaka Yuko M. , Hong Waun K. , Papadimitrakopoulou Vassiliki
Published: March 2024

Abstract
Epidemiologic and preclinical data support the oral cancer prevention potential of green tea extract (GTE). We randomly assigned patients with high-risk oral premalignant lesions (OPL) to receive GTE at 500, 750, or 1,000 mg/m2 or placebo thrice daily for 12 weeks, evaluating biomarkers in baseline and 12-week biopsies. The OPL clinical response rate was higher in all GTE arms (n = 28; 50%) versus placebo (n = 11; 18.2%; P = 0.09) but did not reach statistical significance. However, the two higher-dose GTE arms [58.8% (750 and 1,000 mg/m2), 36.4% (500 mg/m2), and 18.2% (placebo); P = 0.03] had higher responses, suggesting a dose-response effect. GTE treatment also improved histology (21.4% versus 9.1%; P = 0.65), although not statistically significant. GTE was well tolerated, although higher doses increased insomnia/nervousness but produced no grade 4 toxicity. Higher mean baseline stromal vascular endothelial growth factor (VEGF) correlated with a clinical (P = 0.04) but not histologic response. Baseline scores of other biomarkers (epithelial VEGF, p53, Ki-67, cyclin D1, and p16 promoter methylation) were not associated with a response or survival. Baseline p16 promoter methylation (n = 5) was associated with a shorter cancer-free survival. Stromal VEGF and cyclin D1 expression were downregulated in clinically responsive GTE patients and upregulated in nonresponsive patients at 12 weeks (versus at baseline). An extended (median, 27.5 months) follow-up showed a median time to oral cancer of 46.4 months. GTE may suppress OPLs, in part through reducing angiogenic stimulus (stromal VEGF). Higher doses of GTE may improve short-term (12-week) OPL outcome. The present results support longer-term clinical testing of GTE for oral cancer prevention.
Data from A Clinical Risk Prediction Model for Barrett Esophagus
Authors: Thrift Aaron P. , Kendall Bradley J. , Pandeya Nirmala , Vaughan Thomas L. , Whiteman David C.
Published: March 2024

Abstract
Barrett esophagus is the only known precursor to esophageal adenocarcinoma. As definitive diagnosis requires costly endoscopic investigation, we sought to develop a risk prediction model to aid in deciding which patients with gastroesophageal reflux symptoms to refer for endoscopic screening for Barrett esophagus.

The study included data from patients with incident nondysplastic Barrett esophagus (n = 285) and endoscopy control patients with esophageal inflammatory changes without Barrett esophagus (“inflammation controls”, n = 313). We used two phases of stepwise backwards logistic regression to identify the important predictors for Barrett esophagus in men and women separately: first, including all significant covariates from univariate analyses and then fitting non-significant covariates from univariate analyses to identify those effects detectable only after adjusting for other factors. The final model pooled these predictors and was externally validated for discrimination and calibration using data from a Barrett esophagus study conducted in western Washington State.

The final risk model included terms for age, sex, smoking status, body mass index, highest level of education, and frequency of use of acid suppressant medications (area under the ROC curve, 0.70; 95%CI, 0.66–0.74). The model had moderate discrimination in the external dataset (area under the ROC curve, 0.61; 95%CI, 0.56–0.66). The model was well calibrated (Hosmer–Lemeshow test, P = 0.75), with predicted probability and observed risk highly correlated.

The prediction model performed reasonably well and has the potential to be an effective and useful clinical tool in selecting patients with gastroesophageal reflux symptoms to refer for endoscopic screening for Barrett esophagus. Cancer Prev Res; 5(9); 1115–23. ©2012 AACR.
Data from Physical Activity and Survival in Postmenopausal Women with Breast Cancer: Results from the Women's Health Initiative
Authors: Irwin Melinda L. , McTiernan Anne , Manson JoAnn E. , Thomson Cynthia A. , Sternfeld Barbara , Stefanick Marcia L. , Wactawski-Wende Jean , Craft Lynette , Lane Dorothy , Martin Lisa W. , Chlebowski Rowan
Published: March 2024

Abstract
Although studies have shown that physically active breast cancer survivors have lower all-cause mortality, the association between change in physical activity from before to after diagnosis and mortality is not clear. We examined associations among pre- and postdiagnosis physical activity, change in pre- to postdiagnosis physical activity, and all-cause and breast cancer–specific mortality in postmenopausal women. A longitudinal study of 4,643 women diagnosed with invasive breast cancer after entry into the Women's Health Initiative study of postmenopausal women. Physical activity from recreation and walking was determined at baseline (prediagnosis) and after diagnosis (assessed at the 3 or 6 years post-baseline visit). Women participating in 9 MET-h/wk or more (∼3 h/wk of fast walking) of physical activity before diagnosis had a lower all-cause mortality (HR = 0.61; 95% CI, 0.44–0.87; P = 0.01) compared with inactive women in multivariable adjusted analyses. Women participating in ≥9 or more MET-h/wk of physical activity after diagnosis had lower breast cancer mortality (HR = 0.61; 95% CI, 0.35–0.99; P = 0.049) and lower all-cause mortality (HR = 0.54; 95% CI, 0.38–0.79; P < 0.01). Women who increased or maintained physical activity of 9 or more MET-h/wk after diagnosis had lower all-cause mortality (HR = 0.67; 95% CI, 0.46–0.96) even if they were inactive before diagnosis. High levels of physical activity may improve survival in postmenopausal women with breast cancer, even among those reporting low physical activity prior to diagnosis. Women diagnosed with breast cancer should be encouraged to initiate and maintain a program of physical activity. Cancer Prev Res; 4(4); 522–9. ©2011 AACR.
Data from Dietary Immunosuppressants Do Not Enhance UV-Induced Skin Carcinogenesis, and Reveal Discordance between p53-Mutant Early Clones and Carcinomas
Authors: Voskamp Pieter , Bodmann Carolien A , Koehl Gudrun E , Rebel Heggert G. , Van Olderen Marjolein G.E. , Gaumann Andreas , El Ghalbzouri Abdoel , Tensen Cornelis P. , Bavinck Jan N. Bouwes , Willemze Rein , Geissler Edward K. , De Gruijl Frank R.
Published: March 2024

Abstract
Immunosuppressive drugs are thought to cause the dramatically increased risk of carcinomas in sun-exposed skin of organ transplant recipients. These drugs differ in local effects on skin. We investigated whether this local impact is predictive of skin cancer risk and may thus provide guidance on minimizing the risk. Immunosuppressants (azathioprine, cyclosporine, tacrolimus, mycophenolate mofetil, and rapamycin) were assessed on altering the UV induction of apoptosis in human skin models and of p53 mutant cell clones (putative tumor precursors) and ensuing skin carcinomas (with mutant p53) in the skin of hairless mice. Rapamycin was found to increase apoptosis (three-fold), whereas cyclosporine decreased apoptosis (three-fold). Correspondingly, a 1.5- to five-fold reduction (P = 0.07) or a two- to three-fold increase (P < 0.001) was found in cell clusters overexpressing mutant p53 in chronically UV-exposed skin of mice that had been fed rapamycin or cyclosporine, respectively. Deep sequencing showed, however, that the allelic frequency (∼5%) of the hotspot mutations in p53 (codons 270 and 275) remained unaffected. The majority of cells with mutated p53 seemed not to overexpress the mutated protein. Unexpectedly, none of the immunosuppressants admixed in high dosages to the diet accelerated tumor development, and cyclosporine even delayed tumor onset by approximately 15% (P < 0.01). Thus, in contrast to earlier findings, the frequency of p53-mutant cells was not predictive of the incidence of skin carcinoma. Moreover, the lack of any accelerative effect on tumor development suggests that immunosuppressive medication is not the sole cause of the dramatic increase in skin cancer risk in organ transplant recipients. Cancer Prev Res; 6(2); 129–38. ©2012 AACR.
Data from Can Propranalol Prevent Hepatocellular Carcinoma?
Authors: London W. Thomas , McGlynn Katherine A.
Published: March 2024

Abstract
β-Adrenergic signaling is involved in many processes that may contribute to cancer progression. In this issue of the journal (beginning on page 1007), Nkontchou and colleagues report their retrospective observational finding that the β-blocker propranolol was associated with a highly statistically significant reduction in the incidence of hepatocellular carcinoma in patients with advanced cirrhosis and related esophageal varices. This surprising finding requires confirmation, but the result is biologically plausible. Epidemiologic studies have linked β-blockers with reduced rates of metastasis of other cancers and reduced cancer mortality. Laboratory studies suggest biologic mechanisms for anticancer effects of β-blockers. Cancer Prev Res; 5(8); 989–91. ©2012 AACR.
Data from Sulforaphane Bioavailability and Chemopreventive Activity in Women Scheduled for Breast Biopsy
Authors: Atwell Lauren L. , Zhang Zhenzhen , Mori Motomi , Farris Paige E. , Vetto John T. , Naik Arpana M. , Oh Karen Y. , Thuillier Philippe , Ho Emily , Shannon Jackilen
Published: March 2024

Abstract
Epidemiologic studies suggest a protective effect of cruciferous vegetables on breast cancer. Sulforaphane (SFN), an active food component derived from crucifers, has been shown to be effective in breast cancer chemoprevention. This study evaluated the chemopreventive effect of SFN on selective biomarkers from blood and breast tissues. In a 2- to 8-week double-blinded, randomized controlled trial, 54 women with abnormal mammograms and scheduled for breast biopsy were randomized to consume a placebo or a glucoraphanin (GFN) supplement providing SFN (n = 27). Plasma and urinary SFN metabolites, peripheral blood mononuclear cell (PBMC) histone deacetylase (HDAC) activity, and tissue biomarkers (H3K18ac, H3K9ac, HDAC3, HDAC6, Ki-67, p21) were measured before and after the intervention in benign, ductal carcinoma in situ, or invasive ductal carcinoma breast tissues. Within the supplement group, Ki-67 (P = 0.003) and HDAC3 (P = 0.044) levels significantly decreased in benign tissue. Pre-to-postintervention changes in these biomarkers were not significantly different between treatment groups after multiple comparison adjustment. GFN supplementation was associated with a significant decrease in PBMC HDAC activity (P = 0.04). No significant associations were observed between SFN and examined tissue biomarkers when comparing treatment groups. This study provides evidence that GFN supplementation for a few weeks is safe but may not be sufficient for producing changes in breast tissue tumor biomarkers. Future studies employing larger sample sizes should evaluate alternative dosing and duration regimens to inform dietary SFN strategies in breast cancer chemoprevention. Cancer Prev Res; 8(12); 1184–91. ©2015 AACR.
Data from Metabolic Syndrome and Mammographic Density in Mexican Women
Authors: Rice Megan S. , Biessy Carine , Lajous Martin , Bertrand Kimberly A. , Tamimi Rulla M. , Torres-Mejía Gabriela , López-Ridaura Ruy , Romieu Isabelle
Published: March 2024

Abstract
Metabolic syndrome has been associated with an increased risk of breast cancer; however, little is known about the association between metabolic syndrome and percent mammographic density, a strong predictor of breast cancer. We analyzed cross-sectional data from 789 premenopausal and 322 postmenopausal women in the Mexican Teacher's Cohort (ESMaestras). Metabolic syndrome was defined according to the harmonized definition. We measured percent density on mammograms using a computer-assisted thresholding method. Multivariable linear regression was used to estimate the association between density and metabolic syndrome, as well as its components by state (Jalisco, Veracruz) and menopausal status (premenopausal, postmenopausal). Among premenopausal women in Jalisco, women with metabolic syndrome had higher percent density than those without after adjusting for potential confounders including BMI [difference = 4.76; 95% confidence interval (CI), 1.72–7.81]. Among the metabolic syndrome components, only low high-density lipoprotein levels (<50 mg/dL) were associated with significantly higher percent density among premenopausal women in Jalisco (difference = 4.62; 95% CI, 1.73–7.52). Metabolic syndrome was not associated with percent density among premenopausal women in Veracruz (difference = −2.91; 95% CI, −7.19 to 1.38), nor among postmenopausal women in either state. Metabolic syndrome was associated with higher percent density among premenopausal women in Jalisco, Mexico, but was not associated with percent density among premenopausal women in Veracruz, Mexico, or among postmenopausal women in either Jalisco or Veracruz. These findings provide some support for a possible role of metabolic syndrome in mammographic density among premenopausal women; however, results were inconsistent across states and require further confirmation in larger studies. Cancer Prev Res; 6(7); 701–10. ©2013 AACR.
Data from Curcumin Suppresses Proliferation of Colon Cancer Cells by Targeting CDK2
Authors: Lim Tae-Gyu , Lee Sung-Young , Huang Zunnan , Lim Do Young , Chen Hanyong , Jung Sung Keun , Bode Ann M. , Lee Ki Won , Dong Zigang
Published: March 2024

Abstract
Curcumin, the yellow pigment of turmeric found in Southeast Indian food, is one of the most popular phytochemicals for cancer prevention. Numerous reports have demonstrated modulation of multiple cellular signaling pathways by curcumin and its molecular targets in various cancer cell lines. To identify a new molecular target of curcumin, we used shape screening and reverse docking to screen the Protein Data Bank against curcumin. Cyclin-dependent kinase 2 (CDK2), a major cell-cycle protein, was identified as a potential molecular target of curcumin. Indeed, in vitro and ex vivo kinase assay data revealed a dramatic suppressive effect of curcumin on CDK2 kinase activity. Furthermore, curcumin induced G1 cell-cycle arrest, which is regulated by CDK2 in HCT116 cells. Although the expression levels of CDK2 and its regulatory subunit, cyclin E, were not changed, the phosphorylation of retinoblastoma (Rb), a well-known CDK2 substrate, was reduced by curcumin. Because curcumin induced cell-cycle arrest, we investigated the antiproliferative effect of curcumin on HCT116 colon cancer cells. In this experiment, curcumin suppressed HCT116 cell proliferation effectively. To determine whether CDK2 is a direct target of curcumin, CDK2 expression was knocked down in HCT116 cells. As expected, HCT116 sh-CDK2 cells exhibited G1 arrest and reduced proliferation. Because of the low levels of CDK2 in HCT116 sh-CDK2 cells, the effects of curcumin on G1 arrest and cell proliferation were not substantially relative to HCT116 sh-control cells. From these results, we identified CDK2 as a direct target of curcumin in colon cancer cells. Cancer Prev Res; 7(4); 466–74. ©2014 AACR.
Data from Genome-Wide Catalogue of Chromosomal Aberrations in Barrett's Esophagus and Esophageal Adenocarcinoma: A High-Density Single Nucleotide Polymorphism Array Analysis
Authors: Gu Jian , Ajani Jaffer A. , Hawk Ernest T. , Ye Yuanqing , Lee Jeffrey H. , Bhutani Manoop S. , Hofstetter Wayne L. , Swisher Stephen G. , Wang Kenneth K. , Wu Xifeng
Published: March 2024

Abstract
To better understand the molecular mechanisms behind esophageal adenocarcinoma (EAC) tumorigenesis, we used high-density single nucleotide polymorphism arrays to profile chromosomal aberrations at each of the four sequential progression stages, Barrett's metaplasia (BM), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC, in 101 patients. We observed a significant trend toward increasing loss of chromosomes with higher progression stage. For BM, LGD, HGD, and EAC, respectively, the average numbers of chromosome arms with loss per sample were 0.30, 3.21, 7.70, and 11.90 (P for trend = 4.82 × 10−7), and the mean percentages of single nucleotide polymorphisms with allele loss were 0.1%, 1.8%, 6.6%, and 17.2% (P for trend = 2.64 × 10−6). In LGD, loss of 3p14.2 (68.4%) and 16q23.1 (47.4%) was limited to narrow regions within the FHIT (3p14.2) and WWOX (16q23.1) genes, whereas loss of 9p21 (68.4%) occurred in larger regions. A significant increase in the loss of other chromosomal regions was seen in HGD and EAC. Loss of 17p (47.6%) was one of the most frequent events in EAC. Many recurrent small regions of chromosomal loss disrupted single genes, including FHIT, WWOX, RUNX1, KIF26B, MGC48628, PDE4D, C20orf133, GMDS, DMD, and PARK2, most of which are common fragile site regions in the human genome. However, RUNX1 at 21q22 seemed to be a potential tumor suppressor gene in EAC. Amplifications were less frequent than losses and mostly occurred in EAC. 8q24 (containing Myc) and 8p23.1 (containing CTSB) were the two most frequently amplified regions. In addition, a significant trend toward increasing amplification was associated with higher progression stage. Cancer Prev Res; 3(9); 1176–86. ©2010 AACR.
Data from Cancer Vaccines: Moving toward Prevention?
Authors: Kwak Larry W.
Published: March 2024

Abstract
After several decades of research, recent successful phase III controlled clinical trials have renewed enthusiasm for vaccine treatment of cancer. This perspective on the report by Berta and colleagues in this issue of the journal (beginning on page 994) discusses the potential prevention of oral cancer through vaccine strategies and, in the broader context, ideal characteristics of tumor antigens as candidates for vaccines for both treating and preventing cancer, potential primary and secondary prevention settings for vaccines, desirable types of immune effectors induced by vaccines, and safety. Cancer Prev Res; 4(7); 954–6. ©2011 AACR.
Data from Physical Activity and Gastric Cancer: So What? An Epidemiologist's Confession
Authors: Byers Tim
Published: March 2024

Abstract
Epidemiologists, like many scientists, tend to become specialized and focused on a particular disease, even though behavioral risk factors such as physical activity have effects across many diseases. This commentary is a personal reflection by an epidemiologist on the shortcomings of this disease-oriented approach to prevention. Cancer Prev Res; 7(1); 9–11. ©2013 AACR.
Data from Curcumin Chemoprevention: The Long Road to Clinical Translation
Authors: Shureiqi Imad , Baron John A.
Published: March 2024

Abstract
Curcumin exhibits significant antitumorigenic activity in various preclinical models; data supporting its chemopreventive activity in humans, however, are lacking. To our knowledge, the first published results of a phase II chemoprevention study of curcumin are reported in this issue of the journal by Carroll and colleagues (beginning on page 354), who examined the effects of oral curcumin on various putative biomarkers of colonic tumorigenesis in smokers. This perspective discusses the potential significance and limitations of the current study findings in addressing the question of whether curcumin is clinically active as a chemopreventive agent. Cancer Prev Res; 4(3); 296–8. ©2011 AACR.
Data from A Phase 2a Study of Topical Perillyl Alcohol Cream for Chemoprevention of Skin Cancer
Authors: Stratton Steven P. , Alberts David S. , Einspahr Janine G. , Sagerman Paul M. , Warneke James A. , Curiel-Lewandrowski Clara , Myrdal Paul B. , Karlage Kelly L. , Nickoloff Brian J. , Brooks Chris , Saboda Kathylynn , Yozwiak Michael L. , Krutzsch Mary F. , Hu Chengcheng , Lluria-Prevatt Maria , Dong Zigang , Bowden G. Timothy , Bartels Peter H.
Published: March 2024

Abstract
The chemopreventive and antitumor properties of perillyl alcohol (POH) that were studied preclinically indicate that topical POH inhibits both UVB-induced murine skin carcinogenesis (squamous cell tumor models) and 7,12-dimethylbenz(a)anthracene–induced murine melanoma (transgenic models involving tyrosinase-driven Ras). A previous phase 1 clinical trial in participants with normal-appearing skin showed that topical POH cream was well tolerated at a dose of 0.76% (w/w). Here, we performed a 3-month, double-blind, randomized, placebo-controlled phase 2a trial of two different doses of topical POH in individuals with sun-damaged skin. Participants applied POH cream twice daily to each dorsal forearm. Baseline and end-of-study biopsies were taken from each participant to evaluate whether the topical application of POH was effective in reversing actinic damage as evidenced by normalization of quantitative skin histopathologic scores and change in nuclear chromatin pattern as measured by karyometric analysis. There was a borderline reduction in the histopathologic score of the lower-dose POH group compared with the placebo (P = 0.1), but this was not observed in the high-dose group. However, in the high-dose group, a statistically significant reduction in the proportion of nuclei deviating from normal was observed by the use of karyometric analysis (P < 0.01). There was no statistical significance shown in the lower-dose group. No changes were observed in p53 expression, cellular proliferation (by proliferating cell nuclear antigen expression), or apoptosis in either treatment group compared with the placebo group. These results suggest that whereas our karyometric analyses can detect a modest effect of POH in sun-damaged skin, improved delivery into the epidermis may be necessary. Cancer Prev Res; 3(2); 160–9
Data from Isoflavone Pharmacokinetics and Metabolism after Consumption of a Standardized Soy and Soy–Almond Bread in Men with Asymptomatic Prostate Cancer
Authors: Ahn-Jarvis Jennifer H. , Clinton Steven K. , Grainger Elizabeth M. , Riedl Kenneth M. , Schwartz Steven J. , Lee Mei-Ling T. , Cruz-Cano Raul , Young Gregory S. , Lesinski Gregory B. , Vodovotz Yael
Published: March 2024

Abstract
Epidemiologic associations suggest that populations consuming substantial amounts of dietary soy exhibit a lower risk of prostate cancer. A 20-week randomized, phase II, crossover trial was conducted in 32 men with asymptomatic prostate cancer. The crossover involved 8 weeks each of soy bread (SB) and soy–almond bread (SAB). The primary objective was to investigate isoflavone bioavailability and metabolite profile. Secondary objectives include safety, compliance, and assessment of biomarkers linked to prostate carcinogenesis. Two distinct SBs were formulated to deliver approximately 60 mg aglycone equivalents of isoflavones per day. The isoflavones were present as aglycones (∼78% as aglycones) in the SAB whereas in the standard SB predominantly as glucosides (18% total isoflavones as aglycones). Compliance to SB (97% ± 4%) and SAB (92% ± 18%) was excellent; toxicity was rare and limited to grade 1 gastrointestinal complaints. Pharmacokinetic studies between SB and SAB showed modest differences. Peak serum concentration time (Tmax) was significantly faster with SAB meal compared with SB in some isoflavonoids, and AUC0 to 24 h of dihydrodaidzein and O-desmethylangolensin was significantly greater after an SB meal. An exploratory cluster analysis was used to identify four isoflavone-metabolizing phenotypes. Insulin-like growth factor–binding protein increased significantly by 41% (P = 0.024) with soy intervention. Findings from this study provide the necessary framework to study isoflavone-metabolizing phenotypes as a strategy for identification of individuals that might benefit or show resistance to cancer preventive strategies using dietary soy. A standardized SB used for future large-scale randomized clinical trials to affect human prostate carcinogenesis is feasible. Cancer Prev Res; 8(11); 1045–54. ©2015 AACR.
Data from Association of Prostate Cancer Risk Loci with Disease Aggressiveness and Prostate Cancer–Specific Mortality
Authors: Pomerantz Mark M. , Werner Lillian , Xie Wanling , Regan Meredith M. , Lee Gwo-Shu Mary , Sun Tong , Evan Carolyn , Petrozziello Gillian , Nakabayashi Mari , Oh William K. , Kantoff Philip W. , Freedman Matthew L.
Published: March 2024

Abstract
Genome-wide association studies have detected more than 30 inherited prostate cancer risk variants. While clearly associated with risk, their relationship with clinical outcome, particularly prostate cancer–specific mortality, is less well known. We investigated whether the risk variants are associated with various measures of disease aggressiveness and prostate cancer–specific mortality. In a cohort of 3,945 men of European ancestry with prostate cancer, we genotyped 36 single nucleotide polymorphisms (SNP): 35 known prostate cancer risk variants and one SNP (rs4054823) that was recently reported to be associated with prostate cancer aggressiveness. The majority of subjects had a diagnosis of prostate cancer between 1995 and 2004, and the cohort included a total of 580 prostate cancer–specific deaths. We evaluated associations between the 36 polymorphisms and prostate cancer survival, as well as other clinical parameters including age at diagnosis, prostate-specific antigen (PSA) at diagnosis, and Gleason score. Two SNPs, rs2735839 at chromosome 19q13 and rs7679673 at 4q24, were associated with prostate cancer–specific survival (P = 7 × 10−4 and 0.014, respectively). A total of 12 SNPs were associated with other variables (P < 0.05): age at diagnosis, PSA at diagnosis, Gleason score, and/or disease aggressiveness based on D'Amico criteria. Genotype status at rs4054823 was not associated with aggressiveness or outcome. Our results identify two common polymorphisms associated with prostate cancer–specific mortality. Cancer Prev Res; 4(5); 719–28. ©2011 AACR.
Data from Aberrant Methylation of RASGRF1 Is Associated with an Epigenetic Field Defect and Increased Risk of Gastric Cancer
Authors: Takamaru Hiroyuki , Yamamoto Eiichiro , Suzuki Hiromu , Nojima Masanori , Maruyama Reo , Yamano Hiro-o , Yoshikawa Kenjiro , Kimura Tomoaki , Harada Taku , Ashida Masami , Suzuki Ryo , Yamamoto Hiroyuki , Kai Masahiro , Tokino Takashi , Sugai Tamotsu , Imai Kohzoh , Toyota Minoru , Shinomura Yasuhisa
Published: March 2024

Abstract
Aberrant DNA methylation is implicated in the epigenetic field defect seen in gastric cancer. Our aim in this study was to identify predictive biomarkers by screening for DNA methylation in noncancerous background gastric mucosa from patients with gastric cancer. Using methylated-CpG island amplification coupled with CpG island microarray (MCAM) analysis, we identified 224 genes that were methylated in the noncancerous gastric mucosa of patients with gastric cancer. Among them, RASGRF1 methylation was significantly elevated in gastric mucosa from patients with either intestinal or diffuse type gastric cancer, as compared with mucosa from healthy individuals (8.3% vs. 22.4%, P < 0.001; 8.3% vs. 19.4%, P < 0.001). RASGRF1 methylation was independent of mucosal atrophy and could be used to distinguish both serum pepsinogen test-positive [sensitivity, 70.0%; specificity, 86.7%; area under the receiver operator characteristic (ROC) curve, AUC, 0.763] and -negative patients with gastric cancer (sensitivity, 72.2%; specificity, 87.0%; AUC, 0.844) from healthy individuals. Ectopic expression of RASGRF1 suppressed colony formation and Matrigel invasion by gastric cancer cells, suggesting it may be involved in gastric tumorigenesis. Collectively, our data suggest that RASGRF1 methylation is significantly involved in an epigenetic field defect in the stomach, and that it could be a useful biomarker to identify individuals at high risk for gastric cancer. Cancer Prev Res; 5(10); 1203–12. ©2012 AACR.
Data from The Impact of Common Genetic Variations in Genes of the Sex Hormone Metabolic Pathways on Steroid Hormone Levels and Prostate Cancer Aggressiveness
Authors: Sun Tong , Oh William K. , Jacobus Susanna , Regan Meredith , Pomerantz Mark , Freedman Matthew L. , Lee Gwo-Shu Mary , Kantoff Philip W.
Published: March 2024

Abstract
Our previous work suggested that there was no significant association between plasma steroid hormone levels and prostate cancer tumor grade at diagnosis. In this study, we systematically tested the hypothesis that inherited variations in the androgen and estrogen metabolic pathways may be associated with plasma levels of steroid hormones, or prostate cancer aggressiveness at diagnosis. Plasma hormone levels including total testosterone, total estradiol, and sex hormone–binding globulin were measured in a cohort of 508 patients identified with localized prostate cancer. D'Amico risk classification at diagnosis was also determined. A total of 143 single-nucleotide polymorphisms (SNPs) from 30 genes that are involved in androgen and estrogen metabolism were selected for analysis. The global association of genotypes with plasma hormone levels and prostate cancer aggressiveness (D'Amico risk classification) was statistically analyzed. Q values were estimated to account for multiple testing. We observed significant associations between plasma testosterone level and SNPs in HSD17B2 (rs1424151), HSD17B3 (rs9409407), and HSD17B1 (rs12602084), with P values of 0.002, 0.006, and 0.006, respectively. We also observed borderline significant associations between prostate aggressiveness at diagnosis and SNPs in AKR1C1 (rs11252845; P = 0.005), UGT2B15 (rs2045100; P = 0.007), and HSD17B12 (rs7932905; P = 0.008). No individual SNP was associated with both clinical variables. Genetic variants of genes in hormone metabolic pathways may influence plasma androgen levels or prostate cancer aggressiveness. However, it seems that the inherited variations affecting plasma hormone levels differ from those affecting disease aggressiveness. Cancer Prev Res; 4(12); 2044–50. ©2011 AACR.
Data from Silencing hsp25/hsp27 Gene Expression Augments Proteasome Activity and Increases CD8+ T-Cell–Mediated Tumor Killing and Memory Responses
Authors: Nagaraja Ganachari M. , Kaur Punit , Neumann William , Asea Edwina E. , Bausero María A. , Multhoff Gabriele , Asea Alexzander
Published: March 2024

Abstract
Relatively high expression of Hsp27 in breast and prostate cancer is a predictor of poor clinical outcome. This study elucidates a hitherto unknown mechanism by which Hsp27 regulates proteasome function and modulates tumor-specific T-cell responses. Here, we showed that short-term silencing of Hsp25 or Hsp27 using siRNA or permanent silencing of Hsp25 using lentivirus RNA interference technology enhanced PA28α mRNA expression, PA28α protein expression, and proteasome activity; abrogated metastatic potential; induced the regression of established breast tumors by tumor-specific CD8+ T cells; and stimulated long-lasting memory responses. The adoptive transfer of reactive CD8+ T cells from mice bearing Hsp25-silenced tumors efficiently induced the regression of established tumors in nontreated mice which normally succumb to tumor burden. The overexpression of Hsp25 and Hsp27 resulted in the repression of normal proteasome function, induced poor antigen presentation, and resulted in increased tumor burden. Taken together, this study establishes a paradigm shift in our understanding of the role of Hsp27 in the regulation of proteasome function and tumor-specific T-cell responses and paves the way for the development of molecular targets to enhance proteasome function and concomitantly inhibit Hsp27 expression in tumors for therapeutic gain. Cancer Prev Res; 5(1); 122–37. ©2011 AACR.
Data from Dietary Folate Deficiency Blocks Prostate Cancer Progression in the TRAMP Model
Authors: Bistulfi Gaia , Foster Barbara A. , Karasik Ellen , Gillard Bryan , Miecznikowski Jeff , Dhiman Vineet K. , Smiraglia Dominic J.
Published: March 2024

Abstract
Dietary folate is essential in all tissues to maintain several metabolite pools and cellular proliferation. Prostate cells, due to specific metabolic characteristics, have increased folate demand to support proliferation and prevent genetic and epigenetic damage. Although several studies have found that dietary folate interventions can affect colon cancer biology in rodent models, its impact on prostate is unknown. The purpose of this study was to determine whether dietary folate manipulation, possibly being of primary importance for prostate epithelial cell metabolism, could significantly affect prostate cancer progression. Strikingly, mild dietary folate depletion arrested prostate cancer progression in 25 of 26 transgenic adenoma of the mouse prostate (TRAMP) mice, in which tumorigenesis is prostate-specific and characteristically aggressive. The significant effect on prostate cancer growth was characterized by size, grade, proliferation, and apoptosis analyses. Folate supplementation had a mild, nonsignificant, beneficial effect on grade. In addition, characterization of folate pools (correlated with serum), metabolite pools (polyamines and nucleotides), genetic and epigenetic damage, and expression of key biosynthetic enzymes in prostate tissue revealed interesting correlations with tumor progression. These findings indicate that prostate cancer is highly sensitive to folate manipulation and suggest that antifolates, paired with current therapeutic strategies, might significantly improve treatment of prostate cancer, the most commonly diagnosed cancer in American men. Cancer Prev Res; 4(11); 1825–34. ©2011 AACR.
Data from The Ultimate in Cancer Chemoprevention: Cancer Vaccines
Authors: Disis Mary L.
Published: March 2024

Abstract
This perspective on Beatty et al. (beginning on page 438 in this issue of the journal) discusses the role of the immune system as nature's ultimate chemoprevention agent. A successful immune response to vaccination results in immunologic memory. In the case of a successful cancer-related response, antigen-specific T cells will be poised to destroy an aberrantly expressed protein even if the host is not exposed until years after the end of immunizations. After the abnormal cell is eradicated, T cells will lie in wait for the next exposure. The ability to develop effective cancer vaccines for prevention is fast becoming a reality as immunogenic aberrant proteins that drive malignant transformation are identified. Cancer Prev Res; 3(4); 406–9. ©2010 AACR.
Data from Inflammatory Talk: Linking Obesity, NF-κB, and Aromatase
Authors: Hursting Stephen D.
Published: March 2024

Abstract
Obesity is associated with increased risk and worsened prognosis for postmenopausal breast cancer, but the underlying mechanisms remain unclear. Elegant work reported by Subbaramaiah and colleagues in this issue of the journal (beginning on page 329) adds important insights, particularly into the connections between obesity, inflammation, and aromatase via cross-talk among adipocytes, macrophages, and epithelial cells. This work provides several new molecular targets and strategies to test in model systems for preventing or controlling obesity-related breast cancer and provides a framework for studying the linkages among the complex mechanistic pathways underlying the obesity-cancer relationship. Cancer Prev Res; 4(3); 285–7. ©2011 AACR.
Data from Five-Year Cervical (Pre)Cancer Risk of Women Screened by HPV and Cytology Testing
Authors: Uijterwaal Margot H. , Polman Nicole J. , Van Kemenade Folkert J. , Van Den Haselkamp Sander , Witte Birgit I. , Rijkaart Dorien , Berkhof Johannes , Snijders Peter J.F. , Meijer Chris J.L.M.
Published: March 2024

Abstract
Primary human papillomavirus (HPV)–based cervical screening will be introduced in the Netherlands in 2016. We assessed the 5-year cervical (pre)cancer risk of women with different combinations of HPV and cytology test results. Special attention was paid to risks for cervical intraepithelial neoplasia grade 3 and 2 or more (CIN3+/2+) of HPV-positive women with a negative triage test, because this determines the safety of a 5-year screening interval for HPV-positive, triage test–negative women. In addition, age-related effects were studied. A total of 25,553 women were screened by HPV testing and cytology in a screening setting. Women were managed on the presence of HPV and/or abnormal cytology. Five-year cumulative incidences for CIN3+/2+ were calculated. Five-year CIN3+(2+) risk was 10.0% (17.7%) among HPV-positive women. When stratified by cytology, the CIN3+(CIN2+) risk was 7.9% (12.9%) for women with normal cytology and 22.2% (45.3%) for women with equivocal or mildly abnormal (i.e., BMD) cytology. For HPV-negative women, the 5-year CIN3+(2+) risk was 0.09% (0.21%). Additional triage of HPV-positive women with normal cytology by repeat cytology at 12 months showed a 5-year CIN3+(2+) risk of 4.1% (7.0%). HPV-non 16/18-positive women with normal cytology at baseline had comparable risks of 3.5% (7.9%). HPV-non 16/18-positive women with normal baseline cytology and normal repeat cytology had a 5-year CIN3+ risk of 0.42%. No age-related effects were detected. In conclusion, HPV-positive women with normal cytology and a negative triage test, either repeat cytology after 12 months or baseline HPV 16/18 genotyping, develop a non-negligible CIN3+ risk over 5 years. Therefore, extension of the screening interval over 5 years only seems possible for HPV screen–negative women. Cancer Prev Res; 8(6); 502–8. ©2015 AACR.