bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A88: Genome-wide association study identifies variants in several loci associated with circulating vitamin E levels
Authors: Major Jacqueline M. , Yu Kai , Zhang Hong , Wheeler William , Cornelis Marilyn , Yeager Meredith , Snyder Kirk , Hunter David , Chanock Stephen , Kraft Peter , Albanes Demetrius
Published: January 2011

Background: Observed associations between vitamin E status and certain cancers (e.g., lung, prostate, colorectal, cervical and ovarian) suggest a protective relation may exist, with many studies focusing on the antioxidant and antiproliferative properties of alpha-tocopherol. Recent findings suggest that gamma-tocopherol may play a similar role that is independent of alpha-tocopherol. The purpose of this study was to identify genetic variants associated with circulating levels of alpha- and gamma-tocopherol. This is the first genome-wide association study (GWAS) to examine these two nutritional phenotypes.

Methods: Prior to analysis, tocopherol levels were log-transformed to normalize the distributions. General linear models were used to relate the log-transformed outcomes to a SNP by assuming an additive mode of inheritance. Analyses were adjusted for the effects of age, cancer status, body mass index, and cholesterol (because it is well established that vitamin E levels are affected by circulating lipids).

Results: Based on the combined data from the two adult cohorts (the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial (PLCO) cohorts) comprising 5,006 men of European descent, we found evidence of novel loci associated with circulating vitamin E, including BUD13 (rs964184, P=3.5 x 10-10), CYP4F2 (rs2108622, P=7.8 x 10-9), and SCARB1 (rs11057830, P=3.0 x 10-7), all of which meet genome-wide level of significance for their association with alpha-tocopherol. Our three identified single nucleotide polymorphisms (SNPs) have previously been reported to be associated with HDL cholesterol and triglycerides, which are involved in vitamin E transport. We further replicated the most significant findings in an independent data set of 2,769 women, with combined meta-analysis significance of P=1.1 x 10-12 (BUD13, rs964184), P=1.1 x 10-9 (CYP4F2, rs2108622), and P=3.5 x 10-8 (SCARB1, rs11057830). The genome-wide significant associations for gamma-tocopherol levels and SNPs in four gene regions did not replicate, however.

Conclusion: Our findings reveal specific, previously unknown proteins related to vitamin E biochemical status that add to our understanding of this membrane-integrated micronutrient and that can be investigated with respect to cancer and other disease phenotypes.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A88.
Abstract A9: UDP-glucuronosyltransferase 2B7 (UGT2B7) inhibits melanoma invasiveness
Authors: Dellinger Ryan W. , Matundan Harry H. , West Alisa L. , Meyskens Frank L.
Published: January 2011

The UDP-glucuronosyltransferase (UGT) family of enzymes catalyzes the glucuronidation of a variety of endogenous compounds such as bilirubin and steroid hormones, as well as xenobiotics including chemotherapeutic agents and environmental carcinogens. Glucuronidation of these substrates inactivates them by making them more hydrophilic and easily excreted. UGTs are expressed primarily in the liver, but are also expressed in several extrahepatic tissues including prostate, breast, colon, lung, brain, kidney, bladder, and ovary. However, there have been no reports measuring UGTs in melanocytes or melanoma.

We screened several primary melanocyte cultures from neonatal foreskin as well as several primary and metastatic melanoma cell lines for UGT expression by RT-PCR. Three UGT family members, UGT2B7, UGT2B10, and UGT2B15, were found to be expressed in melanocytes. Interestingly, of all the melanoma cell lines screened only WM115, a primary melanoma, had UGT expression. Again, only UGT2B7, UGT2B10, and UGT2B15 were detected. UGT expression was not detected in another primary melanoma cell line, WM3211, or in any metastatic melanoma cell line assayed suggesting that loss of UGT expression occurs during melanoma progression.

Knockdown of UGT2B7 in WM115 cells using shRNA resulted in a 2.6-fold increase in invasiveness as measured by migration through Matrigel. Conversely, stable expression of UGT2B7 in the metastatic melanoma cell line SKmel28 (which lacks UGT expression) resulted in dramatic reduction of invasiveness. Furthermore, treatment of SKmel28 cells stably expressing UGT2B7 with β-estradiol (a competitive inhibitor of UGT2B7) restored invasiveness of this cell line to parental levels. Thus, glucuronidation prevents invasiveness in melanoma.

Taken together, we hypothesize that the observed loss of UGT expression is required for melanoma progression and that preventing the loss of UGT expression may be a viable strategy for melanoma chemoprevention.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A9.
Abstract A93: Lapatinib suppresses RTK-mediated signaling through multiple signaling pathways in the chemically induced ER+ model of mammary cancer
Authors: Grubbs Clinton J. , Li Jixia , Cho Yeon-Yong , Ericson Marna , Lubet Ronald , Bode Ann
Published: January 2011

Activation of receptor tyrosine kinases (RTKs) plays a key role in the prognosis of mammary cancer. EGFR and HER2 are validated therapeutic targets. Lapatinib is a small molecule dual RTK inhibitor that targets EGFR and HER2. Identifying the protein targets involved in the effects of lapatinib and other RTK inhibitors might help determine why preventive efficacy varies. In this study, female Sprague-Dawley rats (50 days old) were given methylnitrosourea (MNU) by IV injection through the jugular vein (75 mg/kg BW). The rats developed multiple ER+ tumors. Two different approaches were taken to evaluate the efficacy of lapatinib as either a chemopreventive or chemotherapeutic drug. First, we demonstrated that treatment with lapatinib beginning 5 days after MNU was highly effective in preventing tumor development. In addition, we treated rats with palpable mammary tumors with lapatinib (75mg/KgBW/day). In some of the tumor bearing animals, treatment proceeded for 42 days, and therapeutic results were obtained. In a separate group, rats bearing tumors were treated for 5 days, and the resulting lesions examined for biomarkers modulation. Lapatinib caused a marked inhibition of mammary cancers, and effectively suppressed the abundance of both HER2, phosphorylated HER2 (Tyr1221, Tyr1222) and phosphorylated EGFR (Tyr1173, Tyr1110) compared to tumors from untreated control rats. Protein array analyses allowed parallel determination of the effect of lapatinib on the relative levels of protein phosphorylation and apoptosis. Interestingly, unlike Gefitinib (Iressa), which appears to target EGFR signaling mediated primarily through the ERK MAP kinases, lapatinib seems to suppress EGFR/HER2 signaling primarily through Src-related proteins, Lyn and Lck, Akt and GSK3. The complete signaling cascade involves a number of signaling molecules potentially leading to impaired proliferation, apoptosis or cell cycle arrest.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A93.
Abstract A98: Prevention of gastrointestinal adenomas in the ApcMin mouse by high-fiber rice bran
Authors: Jones Donald JL , Horner-Glister Emma , Norris Leonie , Gescher Andreas , Sale Stewart
Published: January 2011

Consumption of dietary bran has been considered to be beneficial to health. It has also been linked to a lower risk of developing malignancies, most notably, colorectal cancer. Rice bran (containing 23-35% dietary fiber) at 30% in the diet interfered with adenoma development in the ApcMin mouse, a preclinical model of colorectal cancer (Verschoyle et al., Br J Cancer 2007). Here we used a high fiber rice bran extract (Nutracea, USA), with a fiber content of 40-50% to explore whether an increase in fiber imparts higher efficacy in the ApcMin mouse. The bran was mixed in with the diet at three concentrations: 5, 15 and 30% (n=19-22 per group) and administered to ApcMin mice from 4 weeks of age until termination of study at 16 weeks. Adenoma numbers were reduced by 12, 26, 74 % and adenoma burden by 30, 26 and 84 %, respectively, in the treatment groups in comparison to control mice, with reduction being significant only at the highest dose (p<0.05). The high fiber rice bran seems to be more efficacious than the rice bran used in the previous study in which 30% rice bran reduced adenoma numbers by 51% (Verschoyle et al., Br J Cancer 2007). Plasma samples from each experimental group were collected and undergo proteomic analysis using liquid chromatography-mass spectrometry to identify potential biomarkers of efficacy. This study highlights the potential health benefit of high-fiber rice bran, but further investigations are warranted to better understand the role of fiber in colorectal cancer prevention.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A98.
Abstract A99: Evaluation of the effects of naproxen in human colon polyp cells using gene expression and pathway analysis
Authors: Elmore Eugene , Steele Vernon E. , Redpath John L.
Published: January 2011

Cultures of human colon polyp cells were treated with naproxen to determine its potential efficacy as a chemopreventive agent for colon cancer. The exposures and naproxen concentration used were selected to be similar to the anticipated exposures that would be used in a clinical trial. We treated the human precancerous colon polyp cell line, VACO-235, with naproxen at a clinically achievable concentration of 1 µg/mL. The exposure was continuous over 96 hr with treatment media replenishment every 24 hr. This treatment allowed the naproxen induced changes in the cultures to reach a steady state prior to the assessing gene expression levels. For the gene expression analysis, five separate cultures were used to generate five arrays for the control and treated cultures. Gene expression was assessed using Human gene 1.0 ST arrays from Affymetrix (Santa Clara, CA). The quality of the data from each array was assessed using the manufacturer's software and no outliers were found. Gene expression was assessed using JMP Genomics 4.1 (Cary, NC). The relative gene expression in naproxen treated cultures was compared to the matched controls. Pathway analysis was done using Ariadne Genomics, Pathway Studio 7.1 (Rockville, MD). The data were evaluated using pathway analysis to identify pathway specific changes that were relevant to regulation of growth, metabolism, cell cycle regulation, and cancer. Of the forty-one functional classes and cellular processes associated with the notch pathway, thirty-two showed reduced gene expression or function. In the growth factor receptor pathway associated with AP-1, CREB/CREBBP/ELK-SRF/Myc signaling, thirty-eight of forty-five genes, transcription factors, or functional classes were reduced in expression. Naproxen showed inhibition of genes related to transcription of oncogenes including Ras, Fos, Myc, Jun, Vav1, ELK1, ELK4, multiple map kinases, and TGFBR1 signaling. The data suggest that 96 hr continuous exposure to naproxen at a relevant human serum level was sufficient to reduce the expression of genes in pathways that relate to cancer and growth in the Human colon polyp cells. Supported by NCI contract #N01-CN-43300.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A99.
Abstract B11: Risk of fracture and androgen deprivation therapy
Authors: Shao Joni Y. , Moore Dirk F. , Shih Weichung , Lin Yong , Lu-Yao Grace L.
Published: January 2011

Background: Extended use of androgen deprivation therapy (ADT) is common among elderly men; however, the associated long-term toxic effects have not been well documented.

Methods: We conducted a population based cohort study by analyzing a total of 46,587 men diagnosed with localized prostate cancer and survived at least 5 years after diagnosis in the Surveillance, Epidemiology, and End Results (SEER) -Medicare program to estimate the risk of fracture among men who received long-term ADT.

Results: More than 46% of ADT users received more than 25 months of treatment. The hazard ratio (HR) of hospitalized fracture was 1.47 (95 percent confidence interval, 1.29 to 1.67) among men receiving 36 or more doses of Gonadotropin-releasing hormone (Gn-RH) agonist. Men treated with ADT were associated with a 57.8% increase in the risk of multiple fractures after the first 24 months of treatment. Older age, higher comorbidity, history of fracture and stoke were independently associated with increased fracture risk. Men who were 75 years of age or older and received GnRH agonist for more than 24 months were associated with a 3.63 times risk of having fracture, compared with those aged 66 to 74 and have ADT shorter than 24 months.

Conclusion: Men who are older and with comorbidity are more likely to received long-term ADT than attempted curative treatment. However, those men are also at substantial risk of fracture. The increased risk of fracture along with ADT should be carefully evaluated before initiating a treatment.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B11.
Abstract B14: Psychosocial correlates to intention to participate in CRC screening among an urban sample of nonscreened African Americans
Authors: Lawsin Catalina , DuHamel Katherine , Jandorf Lina
Published: January 2011

African Americans have the highest mortality rates for colorectal cancer (CRC) in the United States. Unfortunately, this disparity may be related to underscreening. While a variety of psychosocial factors have been shown to contribute to their low CRC screening rates as compared to African Americans’ screening rates for other cancers, the construct of tolerance for ambiguity (TFA) has yet to be examined in the context of CRC screening. TFA describes the level of uncertainty an individual can manage and has been shown to influence decision making, such that individuals with a higher tolerance are more likely to enter ambiguous situations. This study sought to examine the role of TFA as a possible barrier to screening amongst a group of African American individuals (N= 93) who have yet to participate in CRC screening in an urban outpatient clinic. Participants ranged in ages between 50 and 87 (mean age = 56, SD = 6.693) and were from lower socioeconomic backgrounds (63% earned less than $15,000 per year and 27% completed less than 11 years of schooling). Correlational analysis between TFA, screening intention in the next year, and psychosocial factors previously shown to influence decision to screen including: knowledge of screening, perceived risk, collectivism, and worry was conducted. Contrary to hypothesis, TFA was not shown to be significantly associated with intent to screen. Instead, among the psychosocial factors, knowledge of screening demonstrated the strongest relationship with intention to have a colonoscopy in the next year (P< 0.01). However, TFA was shown to be significantly related to higher collectivism (P< 0.01) and education levels (P< 0.04). TFA does not appear to be a primary barrier to screening, however warrants further examination as to how it contributes or possibly overlaps with other psychosocial factors. Results suggest that amid this sample of African American non-screeners, providing adequate information regarding the need for screening remains an important factor that may improve screening rates, particularly among those from lower socio-economic backgrounds. Acknowledgement of funding: NCI: CA104130-01

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B14.
Abstract B17: A novel cancer prevention management strategy at the Comprehensive Cancer Center Freiburg (CCCF), Germany
Authors: Leifert Jens A. , Schulz Cornelia , Jaehne Andreas , Elze Mirjam , Balmford James , Opitz Oliver
Published: January 2011

Background: Smoking is a significant risk factor for cancer. Over 90% of smokers consider quitting, but the majority does not use professional support, thus foregoing substantially higher chances of success (tenfold higher 1-year abstinence-rate). Hospitalized patients are especially receptive to cessation advice, but structured counseling of smoking in-patients is rarely available.

The aim of the project at the Comprehensive Cancer Center Freiburg (CCCF)/University Medical Center Freiburg (UMCF) is to establish a Cancer Prevention Management Team (CPMT) dedicated to identify smoking patients, motivate them to quit and link them to appropriate smoking cessation programs offered by external providers.

Methods: The CPMT was implemented as a structure to identify smoking patients to provide them with intensive counseling based on Motivational Interviewing, to enhance their motivation to quit and to refer them to suitable cessation programs. Enrolled patients (treatment arm) were referred to at least one form of cessation treatment (structured multicomponent program: individual/group setting, use of self-help materials, nicotine replacement therapy (NRT)) and received continued weekly telephone support by the CPMT. Enrolled patients who were unwilling to use any cessation therapy were followed up only (observation arm).

Results: CPMT structures and a screening system for smoking patients have been successfully implemented in 24 departments of the UMCF (1.113 hospital beds) organized in 60 wards and 10 outpatient departments. A network of 52 regional providers of evidence based cessation programs has been established. Within the first 15 months 703 smoking patients were counselled; 371 (52%) patients agreed to participate in the study. Out of these, 337 patients were included in the treatment arm, 34 patients were included in the observation arm of the program. The majority of the patients were suffering from patients (36%) or cardiovascular disease (19%).

Abstinence rates after 3 months (n=122) were 34.4% overall, counting patients with lost contact (n=24) as smokers. Among patients in the treatment arm, abstinence rates were higher in patients using behavioural therapy (BT) (44.0%) compared to patients not using BT (41.1%).

Conclusion: A Cancer Prevention Management Team is a highly efficient structure in large hospitals to screen patients for smoking status and motivate them to enter into a cessation program. Quit rates after 3 months were high, considering that all of these patients were treated in-hospital for severe illnesses and none of the patients had an initial intention to quit when entering the hospital.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B17.
Abstract B2: Conceptual barriers in cancer prevention research
Authors: Aktipis C. Athena , Johnson Kathryn , Dong Elizabeth , Kwan Virgina S. Y. , Neuberg Steven L. , Maley Carlo C.
Published: January 2011

Neoplastic progression is an evolutionary process and cancer prevention is successful to the extent that it can impact that process, reducing the likelihood that premalignant cells will evolve invasive or metastatic phenotypes. Despite the centrality of somatic evolution in cancer progression, evolutionary tools and analyses have rarely been applied to the development and implementation of interventions to reduce cancer incidence. Conceptual barriers such as cognitive biases, misperceptions about the nature of cancer, or the use of misleading metaphors may interfere with the effective incorporation of evolutionary principles into cancer prevention and treatment. We analyzed cancer articles for evidence of several biases that are likely to interfere with evolutionary thinking and conducted surveys to measure these cognitive biases. We found evidence for several biases, including a failure to recognize the mutability of neoplasms. Further, our surveys indicated that respondents favor metaphors for cancer (as an invading enemy or parasite) that may bias towards overly aggressive interventions. By identifying cognitive barriers to the penetration of evolutionary principles in cancer research and prevention, we will be able to more effectively offset these biases and expand the conceptual framing of cancer so as to facilitate cancer prevention research, improve patient management and prevent over-treatment.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B2.
Abstract B20: Identification of age-dependent biomarkers for early detection of breast cancer using metabolite profiling: A multisite study
Authors: Asiago Vincent M. , Shanaiah Narasimhamurthy , Gowda Nagana G. , Owusu-Sarfo Kwadwo , Alvarado leiddy , Liu Lingyang , Heiligstedt Heather , Raftery Daniel
Published: January 2011

This abstact is being presented as a short talk in Concurrent Session 9. A full abstract is printed in the Proffered Abstracts section (PR-06) of the Conference Proceedings.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B20.
Abstract B33: Serum hormone concentrations in women who yield breast nipple aspirate fluid (NAF) and those who do not
Authors: Khan Seema A. , Chatterton Robert T. , Heinz Richard , Fought Angela , Kmiecik Thomas , McGathey Claire , Scholtens Denise
Published: January 2011

Objective: Determine whether differences in serum hormone concentrations explain the lack of NAF yield among women participating in a study of NAF hormone concentrations in breast cancer cases and screening controls.

Methods: 80 NAF yielders (Y) and 80 non-yielders (NY) were randomly selected from women who had completed participation in an ongoing case-control study, equally divided by menopausal status and case-control status (only the contralateral breast was aspirated in cases). Average age of premenopausal women was 45.95 years and of postmenopausal women was 57.54 years. The percentage of African American and Caucasian subjects was similar among those who yielded NAF and those who did not. Serum was collected on the same day that nipple aspiration was attempted and the serum was assayed for estradiol, progesterone, and FSH by standard immunoassays. Hormonal concentrations were compared among 80 subjects who produced >2 microliters of NAF and 80 who did not. Wilcoxon tests were used to compare rank distributions of the values for yielders and non-yielders within each menopausal and case/control category.

Results: Hormonal data were analyzed in quintiles with the following comparisons: premenopausal cases Y vs NY; postmenopausal cases Y vs NY; premenopausal controls N vs NY; postmenopausal controls N vs NY. Among premenopausal cases estradiol was significantly greater at the P = 0.0067 level among those who did not produce NAF. This remained significant after correction for multiple comparisons. The difference remained significant after combining cases and controls at the P = 0.021 level. The other comparisons were not significant. Analyses of progesterone and FSH yielded no significant differences.

Discussion: The inhibition of breast fluid accumulation by estradiol is consistent with the effect of ovarian steroids on milk secretion observed after parturition. The observation that this effect was greater in cases is interesting and will be investigated further to ascertain whether other factors associated with breast cancer may play a role in the observed inhibition.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B33.
Abstract B39: Estrogen and cytochrome P450 1B1 contribute to early-stage head and neck carcinogenesis
Authors: Shatalova Ekaterina G. , Cukierman Edna , Clapper Margie L.
Published: January 2011

Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most common type of cancer in the U.S. Major risk factors for HNSCC include tobacco and alcohol use. Data from this group and others suggest that estrogens may also contribute to the development of HNSCCs. We demonstrated previously that various cell lines derived from both premalignant (MSK-Leuk1) and HNSCCs express estrogen metabolism genes, including cytochrome P450 1B1 (CYP1B1) and estrogen receptor β (ERβ). CYP1B1 is the major enzyme that catalyzes the formation of carcinogenic metabolites of both 17β-estradiol (E2) and constituents of tobacco smoke. The goal of the present study was to assess the impact of E2 exposure on CYP1B1 expression and evaluate the role of E2 and CYP1B1 in regulating motility, apoptosis and proliferation of epithelial cells of the head and neck. Cell lines established from a dysplastic leukoplakia of the oral cavity (MSK-Leuk1) and five human tongue SCCs were exposed to either vehicle (0.01% ethanol) or E2 (1 nM) for 24 hours and the level of CYP1B1 transcripts was analyzed by quantitative real-time PCR. Exposure to E2 induced CYP1B1 expression in MSK-Leuk1 cells (2.3-fold relative to vehicle-treated controls, P=0.0004) but not in HNSCC cells.

To further evaluate the contribution of CYP1B1 to early head and neck carcinogenesis, CYP1B1 was knocked down in MSK-Leuk1 cells by lentivirus encoded shRNA, and the effect of CYP1B1 depletion on cell motility, proliferation and apoptosis was analyzed. Cell motility was evaluated by monitoring the ability of vector and shRNA-expressing cells to close an evenly distributed gap in the cell monolayer over a 16-hour period. CYP1B1 knockdown inhibited the migration of MSK-Leuk1 cells by 57%. Proliferation and apoptosis were assessed in MSK-Leuk1 cells (expressing either vector or CYP1B1 shRNA) exposed to either vehicle or E2 (1 nM) for 3 days. CYP1B1 knockdown inhibited the proliferation of MSK-Leuk1 cells by 45%, relative to vector expressing cells, as measured by total DNA content. E2 inhibited apoptosis by 26%, as compared to vehicle-treated cells, as measured using a Nexin kit.

These data provide novel insight into the mechanisms underlying head and neck carcinogenesis and may facilitate the identification new targets for chemopreventive intervention.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B39.
Abstract B57: Modulation of prostaglandin E2 by statins in human bronchial epithelial cells harboring K-ras mutation: The potential advantage of combination therapy
Authors: Hazra Saswati , Lee Gina , Grant Jeanette , Walser Tonya , Prasad Sri , Larsen Jill E. , Minna John , Dubinett Steven M.
Published: January 2011

Statin drugs, such as lovastatin and simvastatin, block cholesterol synthesis by inhibiting the function of HMG-CoA reductase in the cellular cholesterol biosynthesis pathway. In a recent large case-control study, statins reduced the risk of lung cancer suggesting the utility of statins for lung cancer chemoprevention. In our studies, while both lovastatin and simvastatin dose-dependently decreased proliferation in both histologically normal and K-ras mutated human bronchial epithelial cells (HBECs), it also unexpectedly increased expression of PGE2 in mutated HBECs. The statin-mediated upregulation of PGE2 is most pronounced in K-ras mutated HBECs compared to P53 deleted or EGFR mutated HBECs. Treatment with the cholesterol precursor, mevalonic acid, inhibited statin mediated up-regulation of PGE2 indicating that the effect of the statins on PGE2 is sterol-dependent. We found that the suppression of proliferation by statins is also sterol dependent. Statins up-regulate the production of PGE2 by up-regulating mRNA and protein expression of COX-2. The addition of the MEK inhibitor (U0126) revealed the potential involvement of the ERK pathway for statin-mediated upregulation of PGE2 in HBECs. The combination of statins and a low dose of celecoxib (0.1 micro molar), a COX-2 inhibitor, suppressed the increased production of PGE2 by K-ras mutated HBECs. Studies are underway to determine the effect of statin-mediated upregulation of PGE2 on apoptosis resistance and invasion in K-ras mutated HBECs. Our studies suggest that the combination of statins with a low dose of celecoxib overcomes the upregulation of PGE2 induced by statins alone. Thus the combination represents a potentially effective lung cancer chemopreventative regimen worthy of further investigation.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B57.
Abstract B77: High-risk human papillomavirus genotypes among HIV-negative black women with or without cervical disease in South Africa
Authors: McDonald Alicia C. , Kuhn Louise , Denny Lynette , Wright Thomas C.
Published: January 2011

Objective: Persistent high-risk human papillomavirus (HPV) infections are associated with cervical pre-malignant lesions and cervical cancer. Women in sub-Saharan Africa are at high risk of advanced cervical disease as well as cervical cancer. We examined the prevalence and distribution of high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 66) among HIV-negative Black women enrolled in three cervical cancer screening studies in Cape Town, South Africa. Knowledge of the epidemiology of high-risk HPV types in this population will help target prevention interventions.

Methods: Black women, aged 17-65 years, were tested for high risk HPV DNA using the Hybrid Capture 2 (HC2) assay and positive samples were typed by PCR to determine the specific genotype. Cervical disease status was determined by colposcopy and cervical biopsy. The prevalence and distribution of high-risk HPV types as well as the frequency of multiple high-risk HPV types were examined by age and cervical disease.

Results: Among 8,073 HIV-negative women included in the study, 20.9% (n=1689) were HC2 HPV DNA positive; and, in 73.62% (n=1223/1661) of these positives, a specific high-risk HPV type was detected. Overall, the prevalence of high-risk types was 19.94%. The most common high-risk types across cervical disease status were HPV 16 and 35. Among women without cervical disease, younger women, aged 17-29 years, had the highest prevalence of high-risk types in comparison to older women. Among women with CIN 2 or CIN 3, a higher prevalence of HPV 16 and 45 was observed among older women, aged 40-65 years, than among younger women, aged 17-29 years; as for HPV 35, the prevalence was stable across age groups. The distribution of HPV 16, 35, and 33 were statistically significantly higher among HC2 DNA positive, high-risk HPV positive women with advanced cervical disease than women with no cervical disease or CIN 1 (p-values < 0.02). Younger women, aged 17-29 years, had more multiple types overall and across all cervical disease status than older women, aged 40-65 years.

Conclusion: HPV 16 and 35 are the leading contributors of cervical disease among HIV-negative Black South African women. Therefore, the HPV vaccine has the capacity to result in significant reduction in HPV-related cervical disease in this population.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B77.
Abstract B80: Melanoma incidence rates among whites in the U.S. military
Authors: Zhou Jing , Enewold Lindsey , Zahm Shelia H. , Devesa Susan S. , Anderson William F. , Potter John F. , McGlynn Katherine A. , Zhu Kangmin
Published: January 2011

Melanoma incidence rates may differ between the U.S. active-duty military population and the U.S. general population due to potentially higher exposure to sunlight among military personnel and other risk factors for melanoma. However, few studies have compared melanoma incidence rates and trends over time between the military and the general population. The purpose of this study was to examine melanoma incidence rates from 1990 to 2004 among white active-duty military personnel and the general U.S. population, using data from the military's Automated Central Tumor Registry (ACTUR) and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. Age-adjusted melanoma rates overall were significantly lower in the military than in the general population; the incidence rate ratio (IRR) was 0.75 for men and 0.56 for women. Age-specific rates, however, were significantly lower among younger individuals aged <45 years but significantly higher among those aged 45 years or older (p-values<0.05). Melanoma incidence rose from 1990-1994 to 2000-2004 in both populations, with the most rapid increase (40%) among younger men in the military. Melanoma incidence rates also varied by branch of military service with rates highest in the Air Force. These results suggest that melanoma incidence rate patterns differ between the two populations, and further studies of risk factors for melanoma in the military are needed to explain these findings.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B80.
Abstract B85: Childhood obesity and risk of adult squamous-cell carcinoma of the esophagus in a high risk area
Authors: Etemadi Arash , Golozar Asieh , Freedman Neal , Kamangar Farin , Shakeri Ramin , Islami Farhad , Boffetta Paolo , Brennan Paul , Abnet Christian , Dawsey Sanford , Malekzadeh Reza
Published: January 2011

Background: Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer worldwide and the first cause of cancer morbidity and mortality in parts of the world, including northeastern Iran. While obesity has been shown to be a risk factor for esophageal adenocarcinoma, little is known about the association between childhood obesity and ESCC.

Methods: As part of the Gastroesophageal Malignancies in Northern Iran (GEMINI) project, a case-control study was conducted between December 2003 and March 2007 in Golestan Province, in northeastern Iran. Newly-diagnosed histologically-proven cases of esophageal squamous cell carcinoma were recruited from the only GI specialty clinic in the region. Two neighborhood controls, matched by age and sex, were recruited for each case. We collected demographic and health-related information from participants using structured questionnaires. In addition, each individual was shown a standard pictogram validated for this population to report the body size at present and at age 15, starting with picture 1 (very slim) to 7 in men and 9 in women (very obese). We used conditional logistic regression (matched on age, sex and current place of residence) to analyze the association between cancer and body size at 15. The model was further adjusted for ethnicity, education, number of siblings, smoking, as well as childhood place of residence, use of piped water, physical activity, therapeutic opium use, early smoking age, and oral health.

Results: There were 300 cases and 571 age and sex-matched controls. Twenty-seven percent of cases and 26% of controls were urban residents, and 57% versus 55% were from Turkmen ethnicity, respectively. 10.4% of cases and 4.4% of controls had been very obese at the age of 15 (p<0.001). In the adjusted model, women reporting the highest level of obesity at age 15 had an OR of 2.9 (95%CI: 1.3-6.6) for developing ESCC. In men, this was not significant (OR=1.3, 95% CI: 0.3-5.2) For all participants, body size at 15 showed a positive association with the risk of ESCC (OR=1.1 for each level of increase, 95% CI: 1.05-1.2). In addition, physical activity level during childhood was inversely associated with ESCC risk (OR=0.8, 95%CI: 0.7-0.9).

Conclusion: Children, especially girls, with higher weight and low physical activity may be at increased risk of developing squamous cell carcinoma of the esophagus as adults. This underlines the importance of lifestyle modifications much earlier than what is generally considered for ESCC prevention.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B85.
Abstract B94: An integrated database in colorectal cancer outcomes, prognosis, and epidemiology (The COPE database)
Authors: Liu Richard Z. , Fulton Ariel , Ge William , Shibata David , Eschrich Steven A. , Siegel Erin M.
Published: January 2011

Introduction: With the move towards a completely electronic medical record system in the United States, there is an opportunity to leverage these electronic data for longitudinal epidemiological studies. Capturing data electronically that would otherwise have been manually abstracted reduces errors and increases the possible number of data elements collected; however these integrated data systems are not readily available. Therefore, for the purposes of a longitudinal study of colorectal cancer patient prognosis, we constructed an Oracle database to integrate multiple data sources.

Experimental Procedures: A molecular epidemiology study was initiated to measure outcomes, epidemiology risk factors, obesity and inflammation-related molecular markers. An integrated Oracle database was constructed that combines several disparate data sources, including realtime messaging for clinic schedules (HL7), outcomes from a cancer registry and paper-based questionnaires into a single Oracle database. A web-based frontend was created to manage study activities.

Results: The IRB-approved cohort study involves the identification of colorectal cancer patients, study-specific consenting and tracking of follow-up questionnaires and blood draws. A web-based interface was created to assist study coordinators and physicians in identifying eligible patients based on a real-time feed of scheduling and admissions. Once a patient has consented to the study, basic demographic information from clinical systems is populated into the study database. A web-based calendar view allows for scheduling study participants’ follow-up visits at 3, 6 and 12 months for blood draws and questionnaires during normal clinic visits. Patient questionnaire data is currently filled out on paper, scanned into electronic form and loaded into the database. Additional data, including anthropometric measurements and blood draw information are manually entered in the system. Although currently entered manually, research tissue collection details will be automatically populated within the study database. The integration of tissue gene expression data and biomarker results is currently under development.

Conclusion: An integrated database system for patient accrual, consent status, patient information, questionnaires, anthropometric measurements and blood draws enables the successful collection of data for colorectal cancer prognosis cohort studies. This database serves as a prototype that can be customized for larger cohort studies that focus on cancer prognosis and survivorship.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B94.
Abstract B96: Stimulation of lung adenocarcinoma by social stress
Authors: Unger Hussein A. Al-Wadei, Benjamin , Brody Joel , Schuller Hildegard M.
Published: January 2011

Lung cancer is one of the most common cancers and the leading cause of cancer deaths.

Adenocarcinoma (AC) is the leading histological type of lung cancer in all investigated populations and shows a significantly lower association with smoking than other lung cancers. We have previously reported that the proliferation and migration of human AC cells in vitro is stimulated by beta-adrenergic receptors (β-ARs). Agonists for these receptors promoted the progression of AC in hamsters while a beta-blocker had strong cancer preventive effects. The stress neurotransmitters noradrenaline and adrenaline are the physiological agonists for β-ARs. They are released from nerve endings and the adrenal medulla in response to nicotinic acetylcholine receptor (nAChR) stimulation by acetylcholine. Our current study has therefore tested the hypothesis that social stress stimulates the growth of xenografts from human ACs and that nAChRs are involved in this response. Social stress was induced in accordance with published procedures in nude mice carrying xenografts from AC cell lines NCI-H322 and NCI-H441. The diameters of xenografts in mice expose to social stress versus unstressed mice were measured. Levels of noradrenaline and adrenaline, the stress hormone cortisol, the neurotransmitter γ-aminobutyric acid (GABA) in serum and xenograft tissues and levels of cAMP in the cellular fraction of blood and in xenograft tissue were assessed by immunoassays. The levels of GAD65, GAD67, nAChRs and signaling proteins downstream of β-ARs in the tumor tissue were determined by Western blotting. Our data show a significant stimulation of xenograft growth by social stress accompanied by elevated levels of stress neurotransmitters, cortisol and cAMP. In addition, protein expression of nAChR subunits α 3, α4, α5 and α7 as well as β-adrenergic signaling proteins were upregulated while GABA and both GAD enzymes were downregulated. Our data provide first experimental evidence for a significant role of social stress in the development and progression of AC.

Supported by Challenge grant 1RC1CA144640-01 with National Institutes of Health.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B96.
Abstract CN02-04: Phase II study of genistein in men with prostate cancer
Authors: Bergan Raymond C.
Published: January 2011

Progression of cells to a metastatic phenotype begins in the primary organ and represents an important chemoprevention target. In preclinical studies, genistein induces reversion of human prostate cancer (PCa) cells to a less metastatic phenotype. In a phase II study, men with localized PCa were randomized between genistein treatment versus not prior to radical prostatectomy. Analysis of prostate epithelial cells within harvested organs revealed that genistein had the following effects: 1) it decreased matrix metalloproteinase 2 (MMP-2) expression; 2) it induced nuclear spreading; a surrogate marker of inhibition of cell detachment; and 3) gene expression profiling demonstrated selective modulation of genes associated with regulation of cell motility in other cell types. By engineering the expression of these genes in cell lines, we demonstrated that they were important regulators of human PCa cell invasion. Genistein increased the expression of genes that suppress invasion and decreased the expression of genes that enhance invasion. Together, this study demonstrates that genistein induces reversion of human prostate cells in man to a less metastatic phenotype. Importantly, this study demonstrates the proof-of-principal concept that the conduct of molecular screens in human chemoprevention trials has the ability to identify the mechanism of action of investigational agents.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN02-04.
Abstract CN07-03: Natural history of bronchial preneoplasia
Authors: Lam Stephen , Daniels Johannes M.A. , Sutedja Thomas , Thunnissen Eric , Shibuya Kiyoshi , Hoshino Hidehisa , Thiberville Luc , McWilliams Annette , leRiche Jean C. , Lockwood William , Lam Wan , Gazdar Adi
Published: January 2011

Preinvasive bronchial lesions defined as dysplasia and carcinoma in-situ (CIS) have been considered as precursors of squamous cell carcinoma of the lung. The risk and rate of progression of preinvasive lesions to invasive squamous cell carcinoma as well as the mechanism of progression or regression are incompletely understood. The evidence for the multistage, stepwise progression model is weak with relatively few documented lesions that progress through normal to hyperplasia, metaplasia and various grades of dysplasia to CIS and then to invasive carcinoma. Collective data from longitudinal studies using autofluorescence bronchoscopy directed sequential bronchial biopsies from the Netherlands, Canada, France, and Japan as well as published data suggest that the time to development of CIS or invasive squamous cell carcinoma from precursor lesions does not follow an anticipated trend from a stepwise progression model. Aside from severe dysplasia that has the shortest progression time, there is no pattern between the baseline pathology and the time of development of CIS or invasive cancer. The presence of dyspalsia or CIS is a field cancerization risk marker for lung cancer both in the central airways and peripheral lung. Specific genetic alterations and host factors such as the inflammatory load and levels of anti-inflammatory proteins in the lung likely influence the progression or regression of pre-invasive lesions. Recently, using integrative genomic approach, combining high-resolution comparative genomic hybridization and gene expression microarray profiles, the focal amplification of an oncogene -BRF2 in chromosome region 8p12 was found to be specific for development of lung squamous cell carcinoma through the increase of Pol III mediated transcription. BRF2 was frequently activated in carcinoma in situ and dysplasia (PLoS Med 7(7): e1000315. doi:10.1371/journal.pmed.1000315). Molecular analysis of rare lesions that progress from normal, hyperplasia, metaplasia or dysplasia to CIS or invasive cancer will shed further light on the key molecular determinants driving development to an invasive phenotype versus those associated with tobacco smoke damage.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN07-03.
Abstract CN07-05: Efficient designs for lung cancer prevention trials: Lessons learned and moving forward
Authors: Lee J. Jack
Published: January 2011

Despite intense efforts, there are few lung cancer prevention trials showing positive results in the past few decades. Smoking cessation remains an important yet challenging public health issue. Multiple chemopeventive agents have been tested but, to date, there is none ready for clinical use and some even showed harmful effects in subgroups of subjects. To make progress, we need to learn from our past experiences and incorporate efficient designs in future trials. A few key areas will be reviewed and discussed in the presentation including the followings: (1) The success rate for large, randomized, phase III trials based solely on epidemiology data or retrospective analysis is low. (2) It is important to identify high-risk populations to increase the study efficiency. (3) Although several lung cancer risk models for predicting individual's cancer risk have been proposed, validation studies are needed to confirm their clinical applicability. (4) Similarly, markers for predicting lung cancer risks have been proposed but required independent validation. (5) Surrogate endpoints such as biomarker modulation are often used in prevention trials because it is often not feasible to use cancer development as the primary endpoint. However, surrogate endpoints are valuable only if they are associated with clinically meaningful endpoints. (6) Identification of prognostic and predictive markers for prevention can increase the study efficiency by stratifying subjects and focusing on the subgroups who are more likely to benefit. (7) Construct efficient designs for evaluating multiple preventive agents by applying adaptive designs to allow early stopping due to futility, efficacy, or equivalence, adding/dropping arms based on interim data, adaptive randomization to assign more patients to the more effective arms, seamless phase II/III studies, etc. In addition, evaluate the use of multistage designs to efficiently evaluate the treatment effect, identify important markers, and study the interaction between treatments and markers. (8) Screen preventive agents by using windows of opportunity trials with short term intervention and endpoints. (9) Encourage more randomized phase II trials and discourage lunching definitive phase III trial prematurely. (10) Develop a platform and modular clinical trial design approach for the development of preventive agents.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN07-05.
Abstract PL02-03: Cancer risk stratification through biophotonic detection of field carcinogenesis
Authors: Roy Hemant K.
Published: January 2011

One of the major hurdles for population screening for cancer is the low prevalence of disease (generally significantly less than 10%) in the target population. Devising an accurate, minimally-intrusive risk-stratification technique is therefore of paramount importance for efficacious population screening. Our group has developed a suite of light-scattering technologies that allow quantification of subtle micro/nanoscale architecture consequences of the well-established genetic/epigenetic alterations of field carcinogenesis. These occur in the microscopically normal mucosa as the particle sizes (e.g., ribosomes, mitochondria, macromolecular complexes) are below the diffraction limit of light (∼0.5 microns). We have used these techniques to interrogate easily accessible surrogate sites for cancer risk assessment. For instance, using a fiberoptic probe inserted into the rectum can sense the risk of advanced adenomas with ∼90% accuracy. Furthermore, buccal swabs have been shown to discriminate between smokers with and without lung cancer with excellent performance. This paradigm may exist for a number of cancer types (esophageal, ovarian, pancreas, etc.) thereby providing a broad platform for population prescreening.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):PL02-03.