bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A52: Vitamin K1 enhances sorafenib effects on HCC and induces apoptosis: A nontoxic prevention strategy
Authors: Carr Brian , Wei Gang , Wang Meifung
Published: May 2012

A52

HCC is usually multifocal and non surgical at presentation in the US and arises on a cirrhotic liver which tolerates chemotherapy poorly. A defect in vitamin K metabolism in HCC results in secretion of the useful tumor marker DCP, or des gamma carboxy prothrombin. We previously showed that natural vitamin K, which has no known toxicities in adult humans, is a weak HCC growth inhibitor. The FDA recently approved the multikinase inhibitor sorafenib for HCC treatment. We now show that at doses of each agent (vitamin K1 12.5 μg/ml and sorafenib 2.5 μg/ml) that do not independently alter HCC growth, the combination inhibits growth of Hep3B, PLC/PRF/5 and JM1 HCC cell lines at 24-72 hr and induces apoptosis, as supported by FACS analysis (without G1 or S phase arrest), TUNEL stain, cleavage of caspase 3 and PARP and reduced expression of survivin, Bcl-2 and Mcl-1 at 6-24 hr. At later times, a profound decrease in phospho-ERK and cyclin D1 was found (36-48 hr). The results show that the non-toxic vitamin K1 can decrease the concentrations at which sorafenib works and provides a possible approach to cancer prevention in patients with cirrhosis, who are at risk for HCC development.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A52.
Abstract A54: Epigenetic changes in colon cancer cell lines treated with the tea polyphenolic, EGCG
Authors: Brown Vondina , Lane Hannah , Wargovich Michael
Published: May 2012

A54

Retinoids are known for their role in regulating cell growth and proliferation and for activating tumor suppressor genes. We have previously shown that Retinoid X Receptor alpha (RXR alpha) is silenced in tumors of the colon cancer AOM-APCmin+ mouse model. Upon treatment with green tea, RXR alpha expression was restored and intestinal tumorigenesis was inhibited. We hypothesize that tea polyphenols, especially epigallocatechin gallate (EGCG), induce modification of gene expression through effects of DNA methyltransferases (DNMTs). We first determined the optimal range of EGCG concentration with which to treat the cells by performing cytotoxcity assays. We treated HT-29 and HCT116 colon cancer cells with EGCG concentrations of 0, 50, 100 or 150µM for 24 and 48 hours. The cell lines were chosen based on their methylation status. HCT116 cells are sensitive to methylation while HT-29 cells are not. Using nuclear fractions of the cell lysates, we probed for presence of the most common DNMTs using western blotting. We found that expression of DNMT1, DNMT3a and DNMT3b was inhibited in a dose dependent manner following treatment with EGCG at both 24 and 48 hour time points. We also used the DNMT inhibitor 5-aza-2dC as a positive control to recover DNMT expression in the cells treated with EGCG. We can conclude that the silencing of RXR alpha may be due in part to by repressing effects of EGCG on DNMT activity.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A54.
Abstract A68: Molecular response of pediatric chronic myeloid leukemia (CML) with imatinib mesylate therapy
Authors: Basak Jayasri , Mukhopadhyay Soma , Konar Sukanta , Mukhopadhyay Ashis
Published: May 2012

A68

Background

Childhood cases (<18yrs of age) represent approximately 2% of all patients who develop chronic myeloid leukemia (CML). The disease in children is similar in behavior to that of adults, however the outcome of treatment with stem cell transplant is better in young individuals. The aim of our study was to see the molecular response of CML with imatinib mesylate therapy.

Materials and Methods

During the period from January 2003 to December 2007 we selected 56 cases of pediatric chronic myeloid leukemia who could not afford bone marrow transplant treatment in the pediatric Haemato-Oncolgy Department of Netaji Subhash Chandra Bose Cancer Research Institute, a tertiary cancer center from eastern India. All cases were Philadelphia chromosome and bcr/abl molecular transcript positive. The distribution of patients in the age group 1-5, 6-12 & 12-18 were 4 (7.14%), 15 (26.79%) and 37 (66.07%) respectively. The dose of imatinib mesylate (Veenat in Natco Pharma) given was 100 mg in 1-5 yrs, 200 mg in 6-12 yrs and 400 mg in older children. The maximum duration given was 5 years. bcr/abl molecular testing was done by RT-PCR method. In all patients it was done before diagnosis at 6 months, 1 year and then yearly up to 5years.

Result

With median follow up of 25 months (range 4 months - 48 months), Twenty-five children (44.64%) showed complete molecular response. Sixteen patients (28.57%) showed complete hematological, partial cytogenetic and partial molecular response. Eleven patients (19.64%) showed partial haematological response only. Four patients (7.14%) died during treatment because of blast crisis.

Conclusion

Imatinib is a good curative drug in chronic myeloid leukemia in pediatric patients.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A68.
Abstract A8: Deregulated microRNAs associated with cervical cancer metastasis
Authors: Wong Y.F. , Cheung T.H. , Yim S.F. , Man M.K.N. , Lau T.S. , Chan M.K.L. , Chung T.K.H.
Published: May 2012

A8

Cervical cancer is one of the most common gynecologic malignancy in Hong Kong. The identification of pretreatment markers with predictive significance for the presence of lymph node metastasis in low stage of cervical cancer is clinically important. MicroRNAs (miRNAs) are noncoding RNA molecules of 21 to 24 nt that regulate the expression of target genes in a post-transcriptional manner. Recent evidence indicates that miRNAs play essential roles in tumorigenesis and cancer metastasis. This study was to evaluate the deregulated miRNAs associated with cervical cancer metastasis. A total of 20 cervical squamous cell carcinomas, in which 10 had pathologically confirmed lymph node metastasis and 10 no metastasis, were included in the study. RNAs were extracted from microdissected tumor tissue specimens. Real-time reverse transcription PCR technology-based miRNA array enabling quantitation of 365 human mature miRNAs, was used to profile global miRNA expression in cervical cancer. dChip software was used for biostatistical analysis of data. Global miRNA expression data obtained from all 20 arrays were normalized, and then the corresponding model-based expression index was calculated. Unsupervised hierarchical clustering analysis of data showed a distinct separation between cancers in the presence and absence of lymph node metastasis. Supervised hierarchical clustering analysis revealed that of 13 significantly differentially expressed miRNAs, 10 miRNAs including miR-137 (4.76-fold), miR-203 (3.82-fold), miR-594 (3.58-fold), miR-149 (3.05-fold), mir-365 (2.61-fold), miR-556 (2.43-fold), miR-33 (2.32-fold), miR-627 (2.12-fold), miR-20a (2.05-fold) and mir-653 (2.04-fold) were up-regulated and 3 miRNAs including miR-187 (-4.31), miR-4095p (-2.65-fold) and miR-615 (-2.1-fold) were down-regulated in the cervical squamous cell carcinomas with lymph node metastasis compared to that without metastasis. The results obtained from this preliminary study indicate that the deregulation of miRNAs appears to be involved in the cervical cancer progression, and miRNA expression signature can be of potential importance as predictive biomarker in cervical cancer metastasis. Further validation of such microRNA pattern by the testing set and an independent cohort of patients with cervical cancer as well as the functional study of these deregulated miRNAs are ongoing.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A8.
Abstract B114: Soy isoflavones mediated inhibition of DLD-1 human colon adenocarcinoma cells is associated with up-regulation of estrogen receptor-β expression
Authors: Raju Jayadev , Bielecki Agnieszka , Roberts Jennifer , Mehta Rekha
Published: May 2012

B114

We have previously demonstrated that soy isoflavones elicit a colon cancer preventive effect when exposed throughout the lifetime of rats, inclusive of in utero and post-natal stages using an experimental model. We also showed that soy isoflavones increased the expression of colon tumor estrogen receptor (ER)-β, one of the main candidates in endocrine disruption during colon carcinogenesis. To further understand the relationship between the role of soy isoflavones and ER-β in colon carcinogenesis, we examined the effects of soy isoflavones in DLD-1 human colon adenocarcinoma cells in the presence of ER-β or when expression was decreased by RNA interference (siRNA) in vitro. DLD-1 cells were treated with increasing concentrations of soy isoflavones composed of genistein, daidzein and glycitein at a ratio of 1:1:0.2 representing human soy isoflavone-rich food intake. Markers of cell signaling were determined following treatment with or without soy isoflavones in the presence or absence of ER-β gene silencing. Soy isoflavones inhibited the growth of DLD-1 cells dose dependently, with an IC50 for cytotoxicity at 24.82 µg/mL and an IC50 for cell viability at 17.01 µg/mL. At sub-cytotoxic doses, soy isoflavones modulated the expression of markers associated with MAP kinase, AKT and NFκB signalling pathways, cell proliferation and cell cycle regulation, all conducive to a growth restrictive effect. A 75% knockdown of ER-β at the gene and protein level was achieved in DLD-1 cells using siRNA, and this caused a differential expression of the molecular markers studied above. Our results suggest that ER-β appears crucial in mediating the growth suppressive effects of soy isoflavones. ER-β may play an important role in the action of several endocrine disruptors including food chemical contaminants during colon carcinogenesis.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B114.
Abstract B117: Methylseleninic acid inhibits HIF-1α in hormone refractory prostate cancer cells in vitro
Authors: Sinha Raghu , Sinha Indu , Null Kevin , King Tonya , Wolter William , Suckow Mark
Published: May 2012

B117

There is a need to prevent the recurrence of the residual hormone refractory prostate cancer following a radical prostectomy. Till date, the approaches to effectively control the recurrence are not successful. To use an alternative strategy, we investigated the efficacy of methylseleninic acid (MSeA), a potent selenium compound, to inhibit growth of hormone refractory prostate adenocarcinoma (PAIII) cells. These PAIII cells were derived from a metastatic prostate tumor produced spontaneously in a Lobund-Wistar (LW) rat. Our results demonstrate that MSeA inhibits PAIII cell growth in vitro as measured by MTT assay and it induces apoptosis in these cells in a dose-dependent manner as evidenced by PARP-cleavage. Additionally, markers of survival and proliferation (p-AKT, PCNA) are reduced in PAIII cells in a dose-dependent treatment by MSeA. One of the key factors involved in progression of androgen independent prostate cancers, Aurora-B kinase is decreased in MSeA-treated PAIII cells. Hypoxia is a key regulatory factor in prostate cancer and compromised oxygenation of tumor tissue plays a role in the aggressive nature of PAIII tumors in LW rats. In MSeA-treated PAIII cells, the nuclear hypoxia inducible factor (HIF-1α) levels are decreased in a dose-dependent manner. We have further verified reduction in weights of subcutaneous tumors produced by PAIII cells pre-treated with MSeA in LW rats. The current study illustrates the efficacy of MSeA in controlling growth of hormone refractory prostate cancer in vitro.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B117.
Abstract B124: A prospective study of one-carbon metabolism biomarkers and risk of renal cell carcinoma.
Authors: Gibson Todd , Weinstein Stephanie , Mayne Susan , Selhub Jacob , Taylor Philip , Pfeiffer Ruth , Virtamo Jarmo , Albanes Demetrius , Stolzenberg-Solomon Rachael
Published: May 2012

B124

Background

Folate and other one-carbon nutrients have been hypothesized to play a role in carcinogenesis. No studies have examined biomarkers for nutrients involved in one-carbon metabolism and risk of renal cell carcinoma (RCC).

Methods

We conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a prospective study of Finnish male smokers aged 50-69 years. The Finnish population does not have mandatory folic acid fortification of the food supply. Prediagnostic folate, pyridoxal 5-phosphate (vitamin B6), vitamin B12, cysteine, riboflavin and homocysteine concentrations were measured in fasting serum from 224 incident RCC cases and 224 controls. Controls were alive and cancer-free at date of case diagnosis, and were matched to cases on age and date of baseline serum collection. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for smoking, body mass index, leisure physical activity, and dietary intake of fat, protein, methionine, and energy.

Results

Subjects with clinically deficient folate status (≤3ng/ml) had a significantly increased RCC risk compared to subjects with adequate status (>3 ng/ml) (OR=1.68, 95% CI 1.06-2.65). When analyzed in quartiles, serum folate also was inversely associated with RCC (highest vs. lowest quartile, OR=0.67, 95% CI 0.37-1.20, P-trend=0.19). The other one-carbon metabolism biomarkers were not associated with RCC risk. An analysis that included all biomarkers showed a non-significant reduced risk for the a priori expected lowest risk profile (above the median in all biomarkers and below the median for homocysteine) compared to all other subjects (OR=0.24, CI 0.05-1.13). Restricting the analysis to cases diagnosed after at least two years of follow-up did not appreciably change the risk estimates.

Conclusions

Our study in male smokers suggests that inadequate folate status may be associated with an increased risk of renal cell carcinoma. This suggestive association with RCC warrants further exploration in other epidemiologic studies that include women and non-smokers.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B124.
Abstract B145: Association between physical activity, sleep duration, and cancer risk among women in Washington County, MD: A prospective cohort study
Authors: James McClain , Clipp Sandra , Hoffman-Bolton Judith , Helzlsouer Kathy , Visvanathan Kala
Published: May 2012

B145

Background

Physical activity is known to be protective for multiple cancers including breast. Modulation of hormonal factors such as leptin, ghrelin, and hyperinsulinemia as well as energy balance and BMI are thought to play a protective role. Short duration of sleep appears to have an opposite effect on many of these factors.

Methods

In a population based prospective cohort (CLUE II), we assessed the association between physical activity energy expenditure (PAEE), sleep duration, and incidence of first cancer (all-site) in women. 5968 adult females who answered questions on sleep and physical activity on a 1998 follow up questionnaire were included in the study population. Incident cases were identified through linkage of cohort participants with the Washington County Cancer Registry and Maryland State Cancer Registry. Adjusted hazard ratios (HR) and 95% confidence intervals were estimated from Cox proportional hazards models. All statistical tests were two sided.

Results

During 9.6 years of follow up, 604 1st incident cancer cases including 186 breast cancers were diagnosed. Overall cancer risk (HR=0.80, 95% CI 0.68, 0.95) and breast cancer risk (HR=0.75, 95% CI 0.55, 1.01) were significantly reduced among women in the upper 50% of PAEE compared to the lower. Sleep duration was not significantly associated with overall or breast cancer risk in adjusted HR models, but with an increase in colon cancer risk (HR = 1.72, 95% CI 0.99, 2.78) though the sample size was small. Excluding elderly women (> 65 yrs in 1998) who may have different sleep patterns, sleep duration [≥ 7hrs/day vs. < 7hrs/day] significantly modified the association between PAEE [upper vs. lower 50%] and overall cancer risk (p interaction=0.014). A 1.5 fold increase in cancer risk (HR=1.47, 95% CI 1.05, 2.06) was observed among women ≤ 65 years in the upper 50% of PAEE who did not have sufficient sleep (< 7 hrs/day).

Conclusions

Increased PAEE was protective for cancer risk irrespective of age. In addition insufficient sleep may modify the observed protective effect of increased PAEE on cancer incidence among young and middle aged women.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B145.
Abstract B19: Aromatase inhibitor therapy, musculoskeletal symptoms and associations with vitamin D and C-reactive protein concentrations
Authors: Helzlsouer Kathy , Gallicchio Lisa , Wood Bethany , Kalesan Bindu , Appling Susan , Rushovich Errol , Fedarko Neal
Published: May 2012

B19

Background

Aromatase inhibitors are widely used for the treatment of post-menopausal breast cancer. Arthralgias and myalgias are major side effects. A case-control study was conducted to determine the prevalence and severity of musculoskeletal symptoms among women treated with aromatase inhibitors compared to women without a history of cancer and to examine the associations between symptoms and concentrations of C-reactive protein (CRP), a marker of systemic inflammation, and serum vitamin D for clues to their underlying etiology.

Methods

Cases were women undergoing adjuvant treatment for breast cancer with aromatase inhibitors (n = 102). Controls were women without a history of cancer (n = 146). Questionnaires assessed the presence, severity, and location of joint, muscle and bone pain. Participants with pain were asked to rate their pain on average, as well as the degree of pain at its worst, by marking a visual analogue scale. A blood sample was collected and processed within 4 hours of collection with serum stored at -70 degrees centigrade until assayed for vitamin D and CRP concentrations. Analyses were conducted using chi-square tests and unconditional logistic regression adjusting for age and season of blood draw.

Results

The mean ages of cases and controls were 61.2 and 60.8 years, respectively. After adjustment for age and season of blood draw, cases were more likely than controls to complain of muscle pain (OR 1.75 95% CI 1.00-3.05) and bone pain (OR 1.77 95% CI 0.98-3.20) but not joint pain (OR 0.86; 95% CI 0.46, 1.61). Average pain scores for joint and muscle symptoms were similar between cases and controls but cases rated their average bone pain higher than controls (5.1 versus 3.4; p=0.009). Serum vitamin D and CRP concentrations were not statistically significantly different between cases and controls and were not associated with location or severity of pain.

Conclusions

Arthralgias and myalgias are common complaints among women, regardless of aromatase inhibitor therapy. Compared to controls, cases described their pain as muscle or bone pain rather than joint pain. These symptoms were not associated with serum vitamin D or CRP concentrations.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B19.
Abstract B4: A home-based intervention among older long-term cancer survivors improves physical activity, diet quality, weight status, and physical functioning: Results of the RENEW (Reach-out to ENhancE Wellness) trial
Authors: Morey Miriam , Snyder Denise , Sloane Richard , Peterson Bercedis , Cohen Harvey , Miller Paige , Hartman Terryl , Demark-Wahnefried Wendy
Published: May 2012

B4

Cancer survival rates are ever increasing; currently two-thirds of cancer patients will be alive at least 5 years after diagnosis. Despite these gains, many cancer survivors are left with significant comorbidity and accelerated functional decline. Older survivors experience greater declines in function, threatening independence and resulting in increased health care costs. The aim of the RENEW trial was to determine if a year-long, diet-exercise intervention delivered to older long-term cancer survivors via telephone prompts, counseling, and mailed materials could effectively improve health behaviors, and result in improved weight status, and physical functioning. Cancer cases were ascertained from cancer registries and self-referral: 20,015 letters of invitation were posted, 1,208 survivors were screened [eligibility criteria: age 65+; breast, prostate or colorectal cancer diagnosed at least 5-years prior with no evidence of recurrence; body mass index (BMI-kg/m2) 25-40; <150 minutes of moderate-to-vigorous physical activity/week; community-dwelling; and no medical conditions precluding unsupervised exercise], and 641 participants were enrolled. Baseline and follow-up data were collected largely via computer-assisted telephone interviews using the following validated measures: physical functioning (SF-36 Physical Function Subscale and Late Life Function Basic and Advanced Lower Extremity Subscales); physical activity (Community Healthy Activities for Physical Activity in Older Adults Survey); diet quality [revised Healthy Eating Index (HEI) from 2-day dietary recalls]; and BMI. Participants were randomized to immediate- (n=319) or delayed- (n=322) intervention arms. At 1-year a 12.9% rate of attrition was observed. Baseline-to-follow-up change scores [means (SD); crude unadjusted p-values] in the intervention vs. delayed intervention arms were as follows: SF-36 physical functioning [-2.5 (1.1) vs. -5.3 (1.0) points; p=.04]; Basic Lower Extremity [+0.4 (0.7) vs. -2.1 (0.7) points; p=.005]; Advanced Lower Extremity [-0.4 (0.6) vs. -2.6 (0.6) points; p=.01]; Moderate-to-Vigorous Physical Activity [+44.9 (5.9) vs. +29.7 (6.2) minutes/week (111.7); p=.02]; HEI [+7.1 (0.9) vs. +1.4 (0.8) points; p<.0001]; and BMI [-0.8 (0.1) vs. -0.3 (0.1); p<.0001]. These preliminary findings suggest that older, long-term cancer survivors respond favorably to tailored home-based interventions and effectively improve not only their behaviors, but also experience significant and clinically meaningful improvements in body weight status and physical functioning.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B4.
Abstract B42: Polymorphism of CYP3A5 gene in Indian chronic myeloid leukemia patients
Authors: Bajpai Prachi , Tripathi A. , Agrawal Deepa
Published: May 2012

B42

Objective

Chronic myeloid leukemia (CML) is a clonal hematopoetic stem cell disorder characterized by the Philadelphia chromosome. Individuals vary in their ability to metabolize carcinogens and hence to detoxify chemicals, leading to different risk in getting cancer. The human CYP3A5 is a major P450 enzyme in the liver and represents 50% of the total hepatic CYP3A content in people expressing CYP3A5. Therefore, it is suggested that the CYP3A5 is an important genetic contributor to inter-individual differences in CYP3A-dependent drug metabolism. Owing to the importance of CYP3A5 genetic polymorphism as risk factor in various cancers, the study was aimed to detect the prevalence of genetic polymorphism of CYP3A5*3 gene in North Indian CML patients and racially matched controls. Further, it will help to determine the association of these allelic variants if any, as risk factor to develop CML.

Materials and Methods

Human blood was collected from 50 CML patients and 65 healthy individuals which were age and sex matched. DNA isolation was carried out by standard proteinase K and phenol chloroform method. The prevalence of CYP3A5*3 genotype was examined by PCR-RFLP method. PCR products were separated using 2% agarose gel.

In the analysis of the CYP3A5*3 polymorphism, a fragment of 155 base pairs (bp) was amplified by PCR, which was followed by restriction digestion by Dde I. The 155 bp product from the CYP3A5*1 allele was digested into 121 and 34 bp fragments, whereas the PCR product of the CYP3A5*3 was cleaved to 97, 34, and 24 bp fragments.

Results

The frequencies reported in controls were, 7/65 (10.76%) for homozygous CYP3A5*1/*1 , 28/65 (43.07%) for heterozygous CYP3A5*1/*3 and was 30/65 (46.15%) for homozygous CYP3A5*3/*3 respectively. The frequencies reported in cases were 5/50 (10%), 21/50 (42%) and 24/50 (48%) respectively. There was no significant difference between the frequencies of wild (*1/*1), heterozygous (*1/*3) & mutant allele (*3/*3), (control vs cases).

However, when these alleles where compared individually within a class, a higher frequency of

heterozygous & mutant allele, was reported as compared to the wild type, both in the cases and in controls. The combined frequency of heterozygous & mutant allele vs wild in controls was 89.22% and 10.76% respectively, and that in cases being 90% and 10% respectively.

Discussion

It is concluded that there is no association of this polymorphism with the risk of Chronic Myeloid Leukemia. However, due to the variable frequencies of xenobiotic metabolizing polymorphic alleles in different populations, further studies with different populations are required in order to investigate the association of polymorphic variability and its possible role in susceptibility to CML.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B42.
Abstract B44: Modulation of the effect of prenatal PAH exposure on PAH-DNA adducts in cord blood by plasma antioxidants
Authors: Kelvin Elizabeth , Jedrychowski Wieslaw , Tang Deliang , Schleicher Rosemary , Edwards Susan , Camann David , Perera Frederica
Published: May 2012

B44

The fetus is more susceptible than the adult to the effects of certain carcinogens, such as polycyclic aromatic hydrocarbons (PAHs). Nutritional factors, including antioxidants, have been shown to have a protective effect on carcinogen-DNA adducts and cancer risk in adults. We investigated whether the effect of prenatal airborne PAH exposure, measured by personal air monitoring during pregnancy, on the level of PAH-DNA adducts in a baby’s cord blood is modified by the concentration of micronutrients in maternal and cord blood. The micronutrients examined were: retinol (vitamin A), α- and γ-tocopherol (vitamin E), and carotenoids. Using multiple linear regression, we found a significant interaction between prenatal PAH exposure and cord blood concentration of α-tocopherol and carotenoids in predicting the concentration of PAH adducts in cord blood. The association between PAH exposure and PAH adducts was much stronger among those with low α-tocopherol (β=0.15, P-value=0.001) and among those with low carotenoids (β=0.16, P-value=0.000) compared to the babies with high levels of these micronutrients (among those with high α-tocopherol: β=0.05, P-value=0.165; among those with high carotenoids: β=0.06, P-value=0.111). These results suggest a protective effect of micronutrients on the DNA damage and potential cancer risk associated with prenatal PAH exposure.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B44.
Abstract B7: Breast cancer risks in women with a family history of breast or ovarian cancer who have tested negative for a BRCA1 or BRCA2 mutation
Authors: Metcalfe Kelly , Finch Amy , Poll Aletta , Horsman Doug , Kim-Sing Charmaine , Scott Jenna , Royer Robert , Sun Ping , Narod Steven
Published: May 2012

B7

Introduction

Genetic testing for mutations in BRCA1 and BRCA2 is available in Canada for women with a significant family history of breast cancer. For the majority of tested women, a BRCA1 or BRCA2 mutation is not found, and counselling regarding breast cancer risk is based on the review of the pedigree. In this prospective study, we estimate breast cancer risks in women with a family history of breast cancer and for whom the proband tested negative for a mutation in BRCA1 or BRCA2.

Methods

Families with two or more breast cancers under the age of 50, or with three cases of breast cancer at any age and who tested negative for a BRCA1 or BRCA2 mutation were identified. Follow-up information on cancer status was collected on all first-degree relatives of breast cancer cases. The standardized incidence ratios (SIRs) for breast cancer were calculated by dividing the observed numbers of breast cancer by the expected numbers of breast cancers, based on rates in the provincial cancer registries.

Results

1492 women from 365 families were included in the analyses. The 1492 first-degree relatives of breast cancer cases contributed 9109 person years of follow-up. 65 women developed breast cancer, compared to 15.2 expected number (SIR = 4.3). The SIR was highest for women under the age of 40 (SIR = 14.9) and decreased with increasing age. However, the absolute risk was higher for women between age 50 and 70 (1% per year) than for women between the ages of 30 and 50 (0.4% per year). There was no elevated risk for ovarian, colon or any other form of cancer.

Discussion

Women with a significant family history of breast cancer (ie. two or more breast cancers under the age of 50, or three or more breast cancers at any age) but who test negative for BRCA mutations have approximately a four-fold risk of breast cancer. Women in these families may be candidates for tamoxifen chemoprevention or intensified breast screening with MRI.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B7.
Abstract B83: Sulfiredoxin is an AP-1 target gene that is required for transformation and shows elevated expression in human skin tumors
Authors: Wei Qiou , Jiang Hong , Matthews Connie , Colburn Nancy
Published: May 2012

B83

Previous studies from others and our lab have shown that activator protein 1 (AP-1) plays a pivotal role in tumorigenesis in vitro and in vivo. Expression of a dominant negative form c-Jun, TAM67, dramatically inhibits tumor promoter induced skin carcinogenesis. In this study, our goals are to identify target genes that are specifically induced by tumor promoter and inhibited by TAM67, and to investigate their functional significances in tumor promotion and progression. First, we demonstrated that Sulfiredoxin (Srx) is a novel target of AP-1 activation and TAM67 inhibition. In mouse epidermis, expression of Srx was upregulated by tumor promoter and inhibited by TAM67 as revealed by DNA microarray. This was further confirmed in mouse epithelial-derived JB6 cells by RT-PCR, Western blotting, luciferase reporter and chromatin immunoprecipitation assays at transcript and protein levels. Next, we demonstrated that Srx is important for maintaining of cellular redox homeostasis through reduction of overoxidized Peroxiredoxins (Prxs). Knockdown of Srx led to a much slower reduction rate of overoxidized Prxs, whereas overexpression of Srx resulted in an increased reduction rate of overoxidized Prxs. Then we found that knockdown of Srx dramatically inhibited tumor promoter induced neoplastic transformation as indicated by anchorage-independent growth in soft agar. This effect was not due to the inhibition of cell proliferation as depletion of Srx stimulated cell proliferation under adherent conditions. Depletion of Srx also led to impaired AP-1 activation and increased cell death under oxidative conditions, which indicated that Srx might be involved in the regulation of AP-1 activity through a novel positive feedback loop. Finally, we examined the expression profiling of Srx in normal skin and tissues from patients with various skin diseases by tissue microarray. We found strong positive expression of Srx in skin malignant tumors. In summary, we identified Srx as a novel target of tumor promoter induced AP-1 activation and is inhibited by TAM67. We demonstrated that Srx is important for maintaining of cellular redox balance and is required for tumor promoter induced neoplastic transformation. We also found strong expression of Srx in human skin malignant tumors. Therefore, we propose that Srx can be used as a marker for skin malignancy, and manipulation of Srx expression may be of interest in cancer prevention and treatment.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B83.
Abstract B88: Plasma carotenoids, tocopherols, retinol and breast cancer risk: Results from the Shanghai Women's Health Study
Authors: Dorjgochoo Tsogzolmaa , Yu-Tang Gao , Chow Wong-Ho , Shu Xiao-ou , Li Honglan , Yang Gong , Cai Qiuyin , Rothman Nathaniel , Cai Hui , Franke Adrian , Zheng Wei , Dai Qi
Published: May 2012

B88

Objective

Studies conducted in Western countries have suggested that lipophilic antioxidants, particularly carotenoids, may have preventive effects on the risk of breast cancer. We prospectively investigated the associations of serum levels of tocopherols, total retinol, total and specific types of carotenoids with the risk of developing breast cancer among Chinese women; a population with low risk of breast cancer and low prevalence of vitamin supplement use.

Methods

A nested case-control study was conducted within the cohort of the Shanghai Women’s Health Study including 365 newly-diagnosed cases and 726 individually-matched controls 40-70 years of age who provided a blood sample at baseline. Multivariate conditional logistic regression analyses were used to assess associations between breast cancer risk and antioxidants.

Results

Overall, we did not observe significant associations between any of the tocopherols, retinol and most carotenoids, and breast cancer risk. Plasma levels of lycopene other than trans, 5-cis and 7-cis were associated with a reduced risk with an OR of 0.56 (95% CI: 0.32-0.97) for the highest quartile versus the lowest after adjusting for plasma levels of other antioxidants. This inverse association was seen predominantly among premenopausal women with a corresponding OR (95% CI) of 0.36 (0.16-0.80). We also found that trans α-cryptoxanthin was associated with a reduced risk of breast cancer in a dose-response manner, with a corresponding OR of 0.59 (95% CI: 0.34-1.01) (P trend, 0.02) and the inverse association for trans α-cryptoxanthin appeared in both pre- and post-menopausal women.

Conclusions

Our study did not show strong evidence for an overall protective effect of plasma lipophilic antioxidants on breast cancer risk. The few significant inverse associations for subtype carotenoids need to be confirmed in future studies.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B88.
Abstract B93: Concatenated multitype L2 fusion proteins as prophylactic human papillomavirus vaccines
Authors: Jagu Subhashini , Karanam Balasubramanyam , Gambhira Ratish , Chivukula Sudha , Chaganti Revathi , Lowy Douglas , Schiller John , Roden Richard
Published: May 2012

B93

Vaccination with minor capsid protein L2, is known to induce antibodies that cross-neutralize diverse papillomavirus types.However, neutralizing titers against the homologous type are generally much higher than the titers against heterologous types. We hypothesized that vaccination with concatenated multi-type L2 fusion proteins derived from known cross-protective epitopes of several divergent HPV types might increase immunity across medically significant HPV genotypes. Here, the antibody responses of mice and rabbits to vaccination with HPV16 L2 polypeptides comprising residues 1-88 or 11-200, was compared with multi-type L2 fusion proteins, namely 11-200x3 types (HPV6, 16, 18), 11-88x5 types (HPV1, 5, 6,16, 18), or 17-36x22 types (5 cutaneous, 2 mucosal low risk and 15 oncogenic types), and with a licensed quadrivalent HPV L1 virus-like particle (VLP) vaccine, Gardasil. The monotype L2 polypeptides generated robust neutralization titers against HPV16 but lower titers against other HPV types. In contrast, the antisera to the multi-type L2 fusion proteins, notably 11-200x3 and 11-88x5, induced high neutralizing titers against all heterologous HPVs tested. However, in mice, these neutralizing titers were consistently lower than those to L1 VLP. The in vitro neutralization titers elicited by vaccination with 11-200x3 in different adjuvant combinations tested were not significantly different at two weeks after immunization. However, the vaccines formulated in GPI-0100 adjuvant or alum and ISS 1018 protected mice against HPV16 challenge at four months after immunization in the same manner as HPV16 L1 VLP, whereas 11-200x3 alone or formulated with either alum or ISS 1018 alone was significantly less effective.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B93.
Abstract CN15-01: Aspirin, COX-2, and colorectal cancer
Authors: Chan Andrew
Published: May 2012

CN15-01

Considerable experimental, epidemiological, and clinical data has provided strong evidence for a causative link between chronic inflammation and colorectal cancer, including the well-described association between inflammatory bowel disease and colonic dysplasia. However, beyond inflammatory bowel disease, the precise role of inflammation in sporadic colorectal cancer remains undefined. Inflammation may predispose to cancer through enhanced cellular proliferation and mutagenesis, inability to adapt to oxidative stresses, promotion of angiogenesis, inhibition of apoptosis, and secretion of mediators that may promote tumorigenesis. A specific mechanism through which inflammation promotes carcinogenesis is the pro-inflammatory cyclooxygenase-2 pathway (COX-2). A role for COX-2 in neoplasia is supported by several lines of evidence: 1) “knock-out” of the COX-2 gene inhibits development of polyps in the APC mutant mice; 2) host expression of COX-2, but not COX-1, is required for survival of mouse tumor xenografts; 3) COX-2, but not COX-1, is progressively overexpressed in human colorectal adenomas and cancers; 4) COX-2 gene expression is highly upregulated even in morphologically normal mucosa of APC mutant mice and human colorectal cancer patients; 5) agents with COX-2 activity are effective in inhibiting neoplasia in both animals and humans. In fact, at least six randomized trials have demonstrate that anti-inflammatory drugs such as aspirin and COX-2 selective inhibitors reduce the risk of colorectal adenoma among patients with a prior history of colorectal neoplasia. Recently, in two large prospective cohorts, we observed that aspirin reduces risk of COX-2 positive colorectal cancer but not risk of COX-2 negative colorectal cancer. This data suggest that the anti-cancer benefit of aspirin is primarily mediated through COX-2 inhibition. However, the optimal use of aspirin in light of its associated toxicities remains uncertain. Nonetheless, these results support the importance of continued investigation into COX-2 and related inflammatory pathways to both define markers of susceptibility to colorectal cancer as well as spur development of new preventive interventions.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN15-01.
Abstract PR-5: A pooled analysis of 14 cohort studies of body mass index and pancreatic cancer risk
Authors: Genkinger Jeanine , Smith-Warner Stephanie , Prospective Studies of Diet & Cancer Investigators for the Pooling Project of
Published: May 2012

PR-5

Background

Overweight and obesity have been hypothesized to promote pancreatic carcinogenesis by increasing insulin and IGF-1 levels. These factors may stimulate cell division, promote tumor development and increase local blood flow. Studies have reported inconsistent results between overweight and obesity and pancreatic cancer risk.

Methods

A pooled analysis of the primary data from 14 prospective cohort studies was conducted. The study sample consisted of 786,042 men and women among whom 2,135 pancreatic cases were identified. All studies measured height and weight at baseline; weight in early adulthood was measured in 11 studies. Study-specific multivariate relative risks (MV RR) and 95% confidence intervals (CI) were calculated by Cox proportional hazards models, and then pooled by a random effects model.

Results

Compared to individuals with a BMI between 21-22.9 kg/m², a 16% (95% CI: 1-34%) and 47% (95% CI: 23-75%) higher pancreatic cancer risk was observed among overweight (BMI between 25-29.9 kg/m²) and obese (BMI≥30 kg/m²) individuals, respectively. Results were similar for men and women. A positive association was observed for BMI in early adulthood (pooled MV RR = 1.29, 95% CI= 1.07-1.55) comparing BMI≥25 kg/m² to a BMI between 21-22.9 kg/m². Pancreatic cancer risk was higher among individuals who were overweight in early adulthood (BMI≥25 kg/m²) and not obese at baseline (BMI<30 kg/m²) (pooled MV RR=1.30, 95% CI=1.08-1.57), among those who were not overweight in early adulthood (BMI<25 kg/m²) and obese at baseline (BMI≥30 kg/m²) (pooled MV RR=1.38, 95% CI=1.13-1.67) and among those who were overweight in early adulthood (BMI≥25 kg/m²) and obese at baseline (BMI≥30 kg/m²) (pooled MV RR=1.55, 95% CI=1.24-1.95) compared to individuals with a BMI in early adulthood<25 kg/m² and BMI at baseline<30kg/m². Although the association with BMI at baseline and BMI in early adulthood and pancreatic cancer risk was not significantly modified by smoking status, statistically significant positive associations were observed in never and past smokers, whereas a non-significant and weaker association was observed in current smokers.

Discussion and Conclusions

Overall, positive associations were observed for overweight and obese individuals and pancreatic cancer risk. As pancreatic tumors are highly fatal, determining preventive factors offers a feasible approach to reducing this disease’s morbidity and mortality. These results are in line with The World Cancer Research Fund recommendation to maintain body weight within the normal range, as overweight and obesity are also linked to other cancers, diabetes and cardiovascular disease.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):PR-5.
Abstract A1: An miR-502 binding site single-nucleotide polymorphism in the 3′-untranslated region of the SET8 gene is associated with early age of breast cancer onset
Authors: Song Fengju , Zheng Hong , Liu Ben , Wei Sheng , Dai Hongji , Zhang Lina , Calin George , Hao Xishan , Wei Qingyi , Zhang Wei , Chen Kexin
Published: May 2012

Purpose: MicroRNAs regulate gene expression by binding to the 3′-untranslated region (UTR) of target genes. Single-nucleotide polymorphisms of critical genes may affect their regulation by microRNAs. We have identified a single nucleotide polymorphism within the miR-502 seed binding region in the 3′-UTR of the SET8 gene. SET8 methylates TP53 and regulates genome stability. We investigated the role of this SET8 single nucleotide polymorphism and in concert with the TP53 codon72 single nucleotide polymorphism in the propensity for onset of breast cancer.

Experimental Design: We measured the SET8 single nucleotide polymorphisms in a case-control study on 1110 breast cancer cases and 1097 controls.

Results: The SET8 CC and TP53 GG genotypes were independently associated with an earlier age of breast cancer onset in an allele-dose-dependent manner (for SET8, 52.2 years for TT, 51.4 for TC, and 49.5 for CC; and for TP53, 53.1 years for CC, 51.5 for GC, 50.7 for GG). Individuals with combined SET8 CC and TP53 GG genotypes developed cancer at a median age of 47.7 years as compared with 54.6 years for individuals with combined SET8 TT and TP53 CC genotypes. In the 51 breast cancer tissue samples tested, the SET8 CC genotype was associated with reduced SET8, but not miR-502, transcript levels.

Conclusions: These data suggest that the miR-502 binding site single nucleotide polymorphism in the 3′-UTR of SET8 modulates SET8 expression and contributes to the early development of breast cancer, either independently or together with the TP53 codon 72 single nucleotide polymorphism. Larger studies with multiethnic groups are warranted to validate our findings.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A1.
Abstract A117: Physical activity and survival after prostate cancer diagnosis
Authors: Kenfield Stacey A. , Stampfer Meir J. , Giovannucci Edward , Chan June M.
Published: May 2012

Context: Higher levels of physical activity have been linked with a lower risk of advanced prostate cancer (PCa), but no studies have examined whether activity post-diagnosis is beneficial for PCa survivors.

Objective: To assess the relationship between physical activity, and duration and pace of walking, with total and PCa-specific mortality.

Design, Setting, and Participants: Prospective study of 2,686 men in the Health Professionals Follow-up Study diagnosed with PCa, and with follow-up from 1986 through 2008. Physical activity was assessed repeatedly both before and after diagnosis. To generate the total activity score, we summed activity-specific metabolic equivalent (MET)-hours per week. To reduce the potential influence of disease on activity level, we excluded from the analysis men with diagnosed metastases at diagnosis, and we only utilized activity information from four to six years before death. We used multivariable Cox proportional hazard models adjusted for risk factors for PCa mortality. We calculated hazard ratios for total mortality and PCa-specific mortality.

Results: Of the men who were alive for at least 4 years after their post-diagnosis physical activity assessments, we documented 554 deaths, with 22% due to prostate cancer. Men who were physically active, especially those engaging in 3 or more MET-hours of total activity, had a 35% lower risk of death from any cause (hazard ratio, 0.65 [95% CI, 0.52, 0.82]) and a modest non-significant reduction in risk of prostate cancer death (hazard ratio, 0.88 [95% CI, 0.52, 1.49]), after adjustment for other risk factors for PCa mortality and pre-diagnosis physical activity. While no benefit from walking was observed for PCa mortality, men who walked 4 or more hours per week versus those who walked less than 20 minutes per week had a 23% lower risk of all-cause mortality (95% CI, 0.61, 0.97; p-trend=0.01). In addition, compared to men who walked less than 90 minutes at an easy walking pace, those who walked 90 or more minutes at a normal to very brisk pace had a 51% lower risk of all-cause mortality (95% CI, 0.37, 0.64). More vigorous activity, and longer duration of activity, was associated with significant further reductions in risk for all-cause mortality. More vigorous activity was associated with a borderline-significant reduction in risk for PCa mortality.

Conclusions: In a cohort of men with PCa, physical activity was associated with a lower risk of overall mortality. Regular vigorous activity may reduce mortality from prostate cancer.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A117.
Abstract A12: Increased urinary 8-hydroxy-2′-deoxyguanosine excretion in long-distance bus drivers in Taiwan
Authors: Han Yueh-Ying , Donovan Maryann , Sung Fung-Chang
Published: May 2012

Objective: Professional bus drivers are exposed to environments containing air pollution and reactive oxygen species (ROS) that can induce cellular oxidative stress and DNA damage. This study investigated environmental factors associated with oxidative DNA damage in a cohort of long distance bus drivers.

Methods: In a comparison study, urinary 8-hydroxydeoxyguanosine (8-OHdG), a biomarker of DNA oxidative damage, was examined in 120 male long distance bus drivers and 58 male office workers in Taiwan. Multivariate logistic regression was used to analyze association between urinary 8-OHdG levels and environmental factors.

Results: Bus drivers had higher urinary 8-OHdG levels (adjusted odds ratio (aOR) = 9.4, 95% confidence interval (CI) = 3.5–28.2) compared with office workers. Increased urinary 8-OHdG level was significantly related to cigarette smoking (aOR = 18.0, 95% CI = 7.1–52.1), consumption of energy drinks (aOR = 5.0, 95% CI = 2.1–12.6), and regular exercise (aOR = 3.8, 95% CI = 1.5–10.2). A strong exposure-response relationship was found between urinary 8-OHdG and urinary cotinine (p < 0.0001). Among nonsmokers, bus drivers (aOR = 3.9, 95% CI = 1.0–17.7) had higher urinary 8-OHdG than office workers. Among both bus drivers and office workers, those who drank energy drinks (aOR = 3.7, 95% CI = 1.2–12.2) had higher 8-OHdG levels than those who did not drink energy drinks.

Conclusion: Adjusted for smoking, levels of 8-OHdG were increased in long-distance bus drivers exposed to traffic exhaust and ingested energy drinks. Future studies should explore what aspects of energy drinks may contribute to increased urinary 8-OHdG.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A12.