bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 892: Recurrence prediction model for early gastric cancer
Authors: Hoon Kim Joo , Kim Hyo Song , Chung Hyun Cheol , Noh Sung Hoon , Rha Sun Young
Published: February 2011

Recurrence Prediction Model for Early Gastric Cancer

Joo Hoon Kim, Hyo Song Kim, Kiyeol Kim, MD, 5 Ji Fu Lai, MD, Hyun Cheol Chung, MD, 2,3,4 Sung Hoon Noh, MD 1,2,3 Sun Young Rha, MD, 2,3,4

1Cancer Metastasis Research Center, 2National Biochip Research Center, 3Brain Korea 21 Project for Medical Science, 4Yonsei Cancer Center, Yonsei Cancer Research Institute, 5Department of Internal Medicine, 1 Department of Surgery, Yonsei University College of Medicine

5 Oral cancer research institute,

Purpose: Recurrence in early gastric cancer (EGC) after curative resection is rare, and in which type of EGC would recur is not well studied. We tried to make a predicting system for recurrence in EGC after curative resection.

Methods: From January 1987 to April 2005, 2923 patients with EGC underwent R0 curative resection in at Severance Hospital, Yonsei University were enrolled. Logistic regression was performed to identify independent risk factors for recurrence in EGC. Nomogram was developed on the basis of the Cox regression. The concordance index (c-index) was used for accuracy measure, with bootstrapping to correct for optimistic bias. Calibration plots were constructed.

Results: Out of enrolled 2923 patients, 79 patients were recurred (2.7%). The median time to recurrence was 20.5 months, and among them early recurrence developed within 2 years after surgery were 60.7%. In logistic results, lymph node metastasis and elevated gross type were independent risk factors for overall recurrence; whereas overall recurrence rate was higher in patients with both identified risk factors (17.5%). Meanwhile, male gender, elevated gross type and lymph node metastasis were significantly associated with early recurrence, and in patients with all identified risk factors above, the early recurrence rate was 12.2%. Nomogram for predicting the disease-free survival after curative surgery was constructed. Its c-index was 0.79 and the calibration appeared to be accurate as internal validation.

Conclusion: Recurrence in EGC after R0 resection is predictable by using common clinical characteristics. Analyzing the combination of independent risk factors, patients in high risk of early and overall recurrence could be identified. An internally validated nomogram is established to predict disease-free survival accurately and individually.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 892.
Abstract 90: Mining for cancer causing mutations in whole genome sequence data
Authors: Menzies Andrew , Stephens Philip J. , Beare David , Butler Adam , Forbes Simon , Jia Mingming , Jones David , Leroy Catherine , Marshall John , Raine Keiran , Stebbings Lucy A. , Teague Jon W. , Futreal P Andrew , Stratton Michael R. , Campbell Peter J.
Published: February 2011

The Cancer Genome Project at the Wellcome Trust Sanger Institute, UK is using massively parallel sequencing technologies to systematically screen exome and genome sequence for diverse categories of mutations. The rapid developments in new sequencing technologies have allowed many new approaches for the detection and characterisation of a wide range of mutation types. We employ a variety of automated and semi-automated techniques to identify and classify copy number variation, chromosomal rearrangements, small insertion/deletion and substitution mutations in both cell lines and primary tumours.

Large scale, genome wide changes are detected by mapping read-pairs to a reference genome. Copy number is assessed by taking correctly mapping read-pairs, applying a circular binary segmentation algorithm and correcting for regional mapping bias throughout the genome. Using the high quality read mappings where the paired reads are an unexpected distance apart, putative rearrangements can be identified and confirmed either by local de novo sequence assembly where high sequencing coverage is available or by capillary sequencing for low coverage data.

Smaller scale mutations are detected using local read coverage to provide detailed information on the genotype and allelic content of samples. The detection techniques can be used on both whole genome and exome pull-down sequence data. Substitutions are detected using a novel algorithm based on expectation maximisation (Calculate Variants with Expectation Maximisation using New sequencing technology, or CaVEMaN) written in-house and confirmed using capillary sequencing.

Putative mutations of all types are compared to external resources (eg Ensembl, dbSNP) to infer genomic context and possible deleterious consequences. In-house tools have been developed to help automate the curation and annotation of mutations and once confirmed they are submitted to COSMIC as gene associated mutations, small scale intragenic mutations, chromosomal rearrangements or fusion gene products.

Reference URL's

Wellcome Trust Sanger Institute - http://www.sanger.ac.uk

COSMIC - http://www.sanger.ac.uk/genetics/CGP/cosmic

CGP - http://www.sanger.ac.uk/genetics/CGP/

Ensembl - http://www.ensembl.org

dbSNP - http://www.ncbi.nlm.nih.gov/projects/SNP

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 90.
Abstract 900: Associations between orotate phosphoribosyl transferase polymorphism and survival in patients with colorectal cancer treated with 5-FU-based adjuvant chemotherapy: A thirteen year follow-up study
Authors: Lai Ching-Yu , Chang Shih-Ni , Sung Fung-Chang , Hsieh Ling-Ling , Tang Reiping , Yeh Chih-Ching
Published: February 2011

Introduction: 5-Fluorouracil (5-FU) is one of the first line anti-cancer drugs used in the chemotherapy for colorectal cancer (CRC) in older to raise survival rate. Orotate phosphoribosyl transferase (OPRT) plays an important role to regulate the 5-FU activity. This study examined the association between OPRT polymorphism and overall survival of CRC patients treated with 5-FU-based chemotherapy.

Method: A total of 532 patients diagnosed with CRC and received 5-FU-based chemotherapy after surgery between 1995 January and 2001 December was included in the present study. We genotyped the OPRT G638C (Gly213Ala) polymorphism using the polymerase chain reaction combined with the restriction fragment length polymorphism analysis (PCR-RFLP). Survival analyses on OPRT polymorphism were displayed with Kaplan-Meier curves and performed with log-rank test. The association between OPRT genotypes and survival was analyzed using Cox proportional hazard models.

Results: There were no significantly genetic effects on overall survival, even the adjustment for age, gender, or tumor stage in the Cox proportional hazard models. However, the Kaplan-Meier curves showed that stage II and III CRC patients with OPRT G/G genotype had a significantly poor survival (log-rank p = 0.02). Compared to the OPRT G/G genotype, the OPRT G/C + C/C genotype was significantly associated with better overall survival (Hazard ratio (HR) = 0.64, 95% CI = 0.43 − 0.96).

Conclusion: Our findings suggest that the OPRT polymorphism may modify drugs activity to serve a prognostic predictor for CRC patients who receive 5-FU-based chemotherapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 900.
Abstract 907: Subtypes, race and long-term survival in the Carolina Breast Cancer Study
Authors: O'Brien Katie M. , Millikan Robert C. , Cole Stephen R.
Published: February 2011

Previous analyses from the Carolina Breast Cancer Study identified significant differences in breast cancer (BC) specific mortality across the four ‘intrinsic’ BC subtypes: luminal A, luminal B, basal-like, and human epidermal growth factor receptor 2 positive / estrogen receptor negative (HER2+/ER-). Here, we expand the assessment by including additional cases and longer follow-up time, and present analyses stratified by race and menopausal status. We used immunohistochemical markers to subtype 1149 invasive BC cases (518 Black, 631 Non-black) in this population-based epidemiologic study of women diagnosed with BC in North Carolina between 1993 and 2001. Vital status was determined through 2006 using the National Death Index, with median follow-up of 9.1 years. Hazard ratios (HRs) were estimated using Cox proportional hazards models for BC-specific mortality. Compared to Luminal A, women with HER2+/ER- BC had the highest mortality (HR=2.3, 95% CI: 1.5, 3.6, adjusting for age at diagnosis, race, and year of diagnosis), followed by basal-like BC (HR=1.7, 95% CI: 1.2, 2.4). Differences in mortality by subtype remained, albeit attenuated, after further adjustment for stage at diagnosis. Race-stratified HRs were similar for HER2+/ER- BC (HR=2.4, 95% CI: 1.2, 4.7 and HR=2.3, 95% CI: 1.3, 4.0 for non-Blacks and Blacks, respectively), but appeared to differ for basal-like BC (HR=2.0, 95% CI: 1.2, 3.4 for non-Blacks and HR=1.5, 95% CI: 1.0, 2.4 for Blacks). For basal-like BC, mortality was slightly higher among premenopausal, non-Black women (HR=1.8, 95% CI: 1.0, 3.4) compared to premenopausal Black women (HR=1.3, 95% CI: 0.8, 2.3). HRs for basal-like versus Luminal A BC were highest among postmenopausal women (HR=3.9, 95% CI: 1.5, 10.0 for non-Blacks; HR=1.9, 95% CI: 0.9, 3.8 for Blacks). Stage, tumor size and lymph node status were associated with mortality in all subtypes. We also used flexible models to permit departures from the proportional hazards assumption and therefore allow HRs for BC to vary over time since diagnosis. In summary, these results confirmed previous analyses that during a time interval prior to the introduction of Herceptin®, HER2+/ER- cases exhibited the highest mortality of the four subtypes. Possible racial differences in mortality were observed according to BC subtype. Additional analyses are needed in populations with known treatment profiles to more fully understand the role of intrinsic subtypes and race in BC survival.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 907.
Abstract 910: Isothiocyanate-gene interactions and endometrial cancer risk: the California Teachers Study
Authors: Horn-Ross Pamela L. , Canchola Alison J. , Bernstein Leslie , Van Den Berg David , Ursin Giske
Published: February 2011

Background: Cruciferous vegetables may reduce the risk of endometrial cancer, although the evidence is mixed. However, as observed for other cancers, this association may be modified by polymorphic variation in phase I genes (e.g., CYP1A1 which also controls estrogen metabolism) and phase II genes (e.g., GSTs). Such interactions have not been previously examined for endometrial cancer.

Methods: A nested case-control study of type 1 invasive endometrial cancer was conducted within the California Teachers Study (CTS) cohort. 320 women (age≥50) with incident cancer, identified through the California Cancer Registry and diagnosed after joining the cohort and before January 2005, and 629 controls, frequency-matched on age, race/ethnicity, and broad geographic region of residence within California, provided a DNA sample and had complete epidemiologic data. Consumption of cruciferous vegetables was assessed using a validated food-frequency questionnaire at the time women joined the cohort in 1995-96. Isothiocyanate (ITC) consumption was estimated using values obtained from prior analysis of California foods and was based on frequency and portion size of usual consumption of cruciferous vegetables. Selected single nucleotide polymorphisms (SNP) in several phase I and II genes were genotyped. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression, adjusting for matching variables.

Results: Neither cruciferous vegetable or ITC intake, nor variants in CYP1A1 MspI (rs4646903), GSTM1, or GSTT1 were directly associated with endometrial cancer risk. The Val/Val genotype of GSTP1 Ile105Val was associated with increased endometrial cancer risk (OR=1.64, 95% CI: 1.07-2.53) and the Val/Val genotype of CYP1A1 Ile462Val was associated with reduced risk (OR=0.63, 95% CI: 0.37-1.08). There was no interaction, however, between cruciferous vegetable or ITC intake and any of these genes.

Conclusion: Consistent with some, but not all, previous studies we observed a significant reduction in risk associated with the Val/Val genotype of CYP1A1 Ile462Val. This study also confirms a single previous, but smaller report of an association between type I endometrial cancer and the Ile105Val SNP in GSTP1. However, while the prospective assessment of dietary intake minimizes recall bias, we found no evidence of an interaction between these genetic variants and ITC consumption.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 910.
Abstract 913: 5,10-Methylenetetrahydrofolate reductase C677T allele frequency and childhood leukemia incidence in predominantly European ancestry countries
Authors: Johnson Kimberly J. , Spector Logan G.
Published: February 2011

5,10-Methylentetrahydrofolate reductase (MTHFR) single nucleotide polymorphisms (SNPs) have been intensely studied as cancer susceptibility alleles. For childhood leukemia, data have indicated that the most commonly studied MTHFR SNP, C677T, is associated with a slightly reduced risk of acute lymphoblastic leukemia (ALL). Both childhood leukemia incidence and MTHFR allele frequencies show variation worldwide. Our objective was to conduct an ecologic study to determine whether the MTHFR C677T allele frequency and childhood leukemia incidence are associated. We used cancer incidence data collected by the International Agency for Cancer Research from 22 registries that captured 19,025 leukemia cases diagnosed between the ages of 0 and 14 years from the United States, Canada, Australia, and 18 European countries; data were restricted to registries with majority European ancestry populations in order to minimize confounding by ancestry. MTHFR allele frequencies were gathered from the literature to match as closely as possible the registry populations. We modeled the association between childhood leukemia incidence and MTHFR C677T allele frequency using Poisson regression to calculate rate ratios (RRs) and 95% confidence intervals (CIs). Estimates of the minor C677T allele frequency ranged from 24% in Finland to 44% in Italy. There was a weak inverse correlation between leukemia incidence and MTHFR C677T allele frequency (r=0.19), that was stronger for ALL (r=0.30). Acute nonlymphoblastic leukemia (ANLL) incidence was positively correlated with MTHFR C677T allele frequency (r=0.36). Poisson regression results from linear models showed that the incidence of childhood leukemia decreased by 5% (95% CI 3%-6%) for every 5% increase in the C677T allele frequency. A similar pattern was observed for ALL with a RR of 0.93 (95% CI=0.92-0.95) but not acute non-lymphoblastic leukemia (ANLL) (RR=1.04, 95% CI=1.00-1.07). The significant inverse associations between the C677T allele frequency and leukemia and ALL incidence were specific to incidence rates for children diagnosed <10 years. These results are consistent with the results of case-control studies of the association between childhood leukemia and MTHFR allele frequency suggesting a modest risk reduction in association with the C677T allele. The strengths and limitations of ecological vs. case control study designs will be discussed in the context of these results to provide insight into the causal relationship between the MTHFR minor allele frequency and childhood leukemia risk.

This research was supported by NIH grant T32 CA099936.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 913.
Abstract 918: Glucuronidation genotypes and nicotine metabolic phenotypes: Importance of UGT2B10 and UGT2B17 knock-out polymorphisms
Authors: Chen Gang , Giambrone Nino E. , Dluzen Doug , Blevins-Primeau Andrea S. , Gallagher Carla , McCloskey Diane , Lazarus Philip
Published: February 2011

Glucuronidation is an important pathway in the metabolism of nicotine, with ∼28% of urinary nicotine metabolites in the form of glucuronidated compounds. Recent in vitro studies have suggested that the UGTs 2B10 and 2B17 play major roles in nicotine glucuronidation with polymorphisms in both enzymes shown to significantly alter the levels of nicotine-, cotinine-, and trans-3-hydroxy-cotinine (3HC)-glucuronides in human liver microsomes in vitro. In the present study, the relationship between the levels of urinary nicotine metabolites and functional polymorphisms in UGTs 2B10 and 2B17 were analyzed in urine specimens from 104 Caucasian smokers. The levels of nicotine-glucuronide and cotinine-glucuronide were 47 (p<0.0005) and 47% (p<0.0001) lower, respectively, in urine from smokers exhibiting the UGT2B10 (*1/*2) genotype, and 98 (p<0.0001) and 99 (p<0.0001), respectively, in urine from smokers with the UGT2B10 (*2/*2) genotype, as compared to the urinary levels in wild-type UGT2B10 smokers. The levels of 3HC-glucuronide was 64% (p<0.0001) lower in the urine from smokers exhibiting the homozygous UGT2B17 (*2/*2) deletion genotype as compared to the levels in urine from wild-type UGT2B17 subjects. These data are consistent with previous in vitro studies and demonstrate that UGTs 2B10 and 2B17 play important roles in the glucuronidation of nicotine, cotinine and 3HC in vivo, and suggest the UGT2B10 codon 67 SNP and the UGT2B17 deletion significantly reduce overall glucuronidation rates of nicotine and its major metabolites in smokers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 918.
Abstract 925: Common variants in genes related to immune response and childhood leukemia risk
Authors: Han Sohee , Lan Qing , Park Ae Kyung , Lee Kyoung-Mu , Park Sue K. , Ahn Hyo Seop , Shin Hee Young , Kang Hyoung Jin , Koo Hong Hoe , Seo Jong Jin , Choi Ji Eun , Ahn Yoon-Ok , Chanock Stephen J. , Kim Ho , Rothman Nathaniel , Kang Daehee
Published: February 2011

Objective: In order to investigate possible genetic contribution to childhood leukemia in the immune system, we evaluated the associations between 786 SNPs in 68 genes/gene regions related to immune response and childhood leukemia risk.

Methods: Incident childhood leukemia cases (n=136) and non-cancer controls (n=254) were recruited from three teaching hospitals in Seoul between 2003 and 2006. Candidate genes/gene regions were selected based on SNP databases (CGAP and SNP500 database), and genotype assay was performed using GoldenGate (Illumina) oligonucleotide pool assay (OPA). First, we selected SNPs with dose response effect (Ptrend<0.001). The 16 SNPs deemed unusable due to failure of genotyping or monomorphism (9 SNPs), low yield (2 SNPs), HWE p <0.001 (5 SNPs) in each case and control were excluded from the analysis. A gene-level minP was computed using a permutation-based re-sampling procedure (10,000 permutations) taking all SNPs in each gene/gene region into account. We considered minP <0.05 as noteworthy. Childhood leukemia risk was estimated as odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age, gender and birth weight.

Results: Among the 786 SNPs, 134 SNPs in 7 genes/gene regions were significantly associated with childhood leukemia risk (Ptrend <0.001). Five out of 7 genes/gene regions of immune response (MDM2 (murine double minute 2), CD81 (CD81 molecule), IL-2 (interleukin 2), TNF/LTA (tumor necrosis factor-a (TNF) and lymphotoxin-a), RELB (v-rel reticuloendotheliosis viral oncogene homolog B)) were significantly associated with childhood leukemia risk (minP <0.01).

Discussion: Our results suggest that genetic polymorphisms in immune regulatory may play a role in childhood leukemia development. Further large study is warranted confirm our findings.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 925.
Abstract 937: Nicotinic acetylcholine receptor polymorphisms, secondhand smoke and lung cancer risk
Authors: Asomaning Kofi , Zhai Rihong , Sheu Chau-Chyun , Heist Rebecca , Chen Feng , Liu Geoffrey , Su Li , Lin Xihong , Christiani David
Published: February 2011

Introduction: Passive or secondhand smoke (SHS) exposure is an independent risk factor for adult non-small cell lung cancer (NSCLC). In 2008, three genome wide association studies (GWAS) identified a locus on chromosome region 15q24-25.1 that was strongly associated with lung cancer. In this study, we assessed the interaction of the two most significant single nucleotide polymorphisms (SNPs) reported (rs8034191, rs1051730) with SHS on lung cancer risk. We hypothesize that after adjusting for active cigarette smoking, individuals with the risk alleles and the highest cumulative exposure to SHS are at the greatest risk of lung cancer.

Methods: This study population is derived from a large ongoing case control study evaluating the molecular epidemiology of lung cancer, which began in 1992 at the Massachusetts General Hospital. The polymorphisms were genotyped by the 5V nuclease assay (Taqman) using the ABI Prism 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA). Interviewer-administered questionnaires collected information on demographics, and detailed smoking histories from each subject. Second hand smoke exposure duration and frequency was self-reported for three different activities (leisure, work and at home). The cumulative SHS exposure was the sum of all durations multiplied by their frequency weight. We used the co-dominant genetic model for individual SNPs, controlling for age, gender, pack years, years since smoking cessation and smoking status. We tested for interaction using the Likelihood Ratio Test by incorporating cross product interaction terms of indicator variables for each SNP and quartiles of cumulative exposure.

Results: A total of 2071 cases and 1506 controls were analyzed. Among cases, exposure to SHS at home 1924(93%), work 1727 (83%), leisure 1791 (86%); among controls 1328 (88%), 1044 (69%) and 1233 (82%) respectively. In stratified analysis, for study participants in the highest quartile of cumulative SHS exposure and comparing the homozygous variant to the wildtype, the adjusted odds ratio (AOR) for lung cancer was 1.55 (0.99-2.44) (rs8034191) and 1.66 (1.05-2.62) (rs1051730). In the lowest quartile of SHS exposure the corresponding results were 0.94 (0.47-1.89) (rs8034191) and 0.91(0.45-1.84) (rs1051730). There was no evidence for gene-SHS interaction.

Conclusion: Our results indicate that secondhand smoke does not modify the association of rs1051730 and rs8034191 with non-small cell lung cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 937.
Abstract 939: Chemoprevention of familial adenomatous polyposis by EM011 in the ApcMin/+ mouse model
Authors: Li Shiwang , Ghaleb Amy M. , He Jing , Bughani Usha , Bialkowska Agnieszka B. , Yang Vincent W. , Joshi Harish C.
Published: February 2011

Abstract

Germline mutation of the tumor suppressor gene, adenomatous polyposis coli (APC), is responsible for familial adenomatous polyposis (FAP) with nearly 100% risk for colon cancer at an early age. Although FAP is involved in only 1% of all colon cancer cases, over 80% of sporadic cancers harbor somatic mutations of APC. We show here that 9-bro-noscapine (EM011), a rationally-designed synthetic derivative of a natural non-toxic tubulin-binding alkaloid−noscapine, that reduces the dynamics of microtubules, causes a reversible G2/M arrest in wild type mouse embryonic fibroblasts (MEFs), but an aberrant exit from a brief mitotic block, followed by apoptosis in MEFs isolated from ApcMin/+ mice. Furthermore, both β-catenin levels and activity fell to half the original levels with a concomitant reduction of cell proliferation-inducing cyclin D1, c-Myc, and induction of cytostatic protein p21 prior to caspase-3 activation. Additionally, we show a statistically significant reduction in the number of newly emerging intestinal polyps (to 35% compared with untreated mice) as well as the mean size of polyps (to 42% compared with untreated mice) in EM011-treated ApcMin/+ mice as compared to their sham-treated control littermates. The remaining polyps in the EM011 treated group of ApcMin/+ mice showed evidence of elevated apoptosis as revealed by immunohistochemistry. We failed to detect any evidence of histopathological and hematological toxicities following EM011 treatment. Taken together, our data are persuasive that a clinical trial of EM011 is possible for the prevention/amelioration of polyposis in FAP patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 939.
Abstract 944: Preventive effects of UV radiation and dietary vitamin D on autochthonous murine mammary tumors
Authors: Davari Parastoo , Gorouhi Farzam , Green Jeffrey E. , Epstein Ervin H.
Published: February 2011

Epidemiologic studies support an inverse correlation between solar UV radiation and breast cancer incidence and mortality, a matter of some concern in a society being urged to avoid sun exposure. We assessed directly whether UV radiation of skin has any preventive effect on mammary tumor carcinogenesis in the C3(1)SV40 Tag transgenic mouse. Mice fed diets depleted of vitamin D (+ rescue minerals) were treated with 0 [group A] or 350mJ/cm2 UV 3 times a week without [Group B] or with [Group C] topical 7-dehydrocholesterol, the precursor of cutaneous vitamin D3. Control mice were fed an otherwise identical diet but containing normal levels of vitamin D (1,000IU/kg + rescue minerals) [Group D]. We also fed mice a separate diet containing high (20,000IU/kg) [Group E] or normal (1,000IU/kg) [Group F] vitamin D. We examined mice and excised all palpable tumors (“lumpectomies”) every two weeks at ages 16-28 weeks. Blood was collected at the end of the study. Analyses were performed using Krusskal Wallis test, Mann Whitney test, Spearman's test, life table survival analysis, and log rank test. Circulating 25-hydroxyvitamin D3 (25D3) levels in 59 mice, measured in ng/mL [median (interquartile range)] in groups A-F were 3.0(1.0) 34.0(26.3), 26.0(18.0), 28.0(13.0), 121.0(82.5), and 42.0(15.5), respectively (p<0.001). We found no significant correlation among groups between 25D3 levels and tumor number, mean size, or total tumor volume/mouse. Mice fed the vitamin D depleted diet had a tumor burden that was reduced by UV radiation or by addition of dietary vitamin D, and UV-treated mice had a longer tumor free survival than did the D-depleted mice not so treated. By contrast, the high vitamin D diet, despite tripling the circulating 25D3 level, by comparison to the control diet did not influence mammary tumor number or size or tumor free survival. We interpret these data to suggest that although UV can inhibit development of autochthonous murine mammary tumors, the failure of tumor development to correlate strictly with circulating 25OH D3 levels suggests that its effects may be mediated in part by non-obvious pathways and/or that the anti-mammary cancer effects of vitamin D may plateau.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 944.
Abstract 947: Effect of estrogen on gene expression profiling in endometrium of obese, insulin resistant animals
Authors: Zhang Qian , Celestino Joseph , Zhang Jiexin , Loose David , Lu Karen H.
Published: February 2011

Introduction: Epidemiologic studies have demonstrated that obese women have a 2-3.5-fold increased risk for endometrial cancer. In an animal model of obesity and insulin resistance, we previously showed that estrogen enhances obese rat endometrial cell proliferation through induction of pro-proliferative gene expression and suppression of anti-proliferative genes. The purpose of the current study is to find new markers that are associated with the pronounced estrogen effect in obese, insulin resistant rat endometrium.

Methods: Using ovariectomized Zucker Fa/Fa obese rats and lean control, we compared estrogen induced signaling with cDNA micro-array analysis between obese and lean rat endometrium. RT-qPCR analysis was used to validate micro-array data. For one novel gene, cgrrf1, expression was examined in normal human endometrium and hyperplasia tissue.

Results: Micro-array analysis demonstrated that 3040 gene responded to estrogen treatment in lean rat endometrium, while 3291 gene showed response in obese rats. Among them 1927 gene expression were changed in both lean and obese rat. 470 genes expression had pronounced alteration in obese rats than the lean one. These genes included a wide variety of signal pathway like metabolism signaling, acute response signaling, cell cycle, G1/S check point regulation signaling, PI3K/AKT signaling, G-protein coupled receptor signaling and Wnt β-catenin signaling. RT-qPCR analysis of gene c-fos and EIG121 expression validated micro-array data, and expression of c-Myc and cyclin A from our previous study also confirmed the micro-array data. Tumor suppressor gene cgrrf1 is one of the genes demonstrating pronounced estrogen effect in obese, insulin resistant rat endometrium: micro-array data showed estrogen treatment significantly decreased cgrrf1 expression in obese rats endometrium (p<0.001), while in lean rats no change was noticed; qPCR data also showed that estrogen had a differential effect on cgrrf1 expression. The inhibiting effect was stronger in obese rats compared with lean rats (decreased 83.3% in obese vs. 68% in lean rats, p<0.05). cgrrf1 expression was significantly lower in hyperplasia compared to normal human endometrium (p<0.001). Insulin sensitizer metformin treatment significantly increased cgrrf1 expression in obese rats (p<0.05), while in lean rats no metformin effect was observed.

Conclusion: Micro-array data identified differential gene expression between lean and obese, insulin resistant endometrium. cgrrf1 is a new marker whose expression was down regulated by estrogen treatment in obese, insulin resistant rat endometrium. In human hyperplasia tissue, cgrrf1 expression is significantly down regulated.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 947.
Abstract 955: n-3 polyunsaturated fatty acids promote apoptosis in oxidatively stressed transgenic mouse models
Authors: Fan Yang-Yi , Toyokuni Shinya , Callaway Evelyn S. , Ran Qitao , Lupton Joanne R. , Chapkin Robert S.
Published: February 2011

Colorectal cancer is the second most common cause of cancer death in the United States. An increase in reactive oxygen species (ROS) generated from oxidative stress is generally associated with abnormal cancer cell growth and reflects a disruption of redox homeostasis. Manganese superoxide dismutase (SOD2) and glutathione peroxidase 4 (Gpx4) are two of the most important antioxidant defense enzymes that protect cells against oxidative stress. Interestingly, we have recently demonstrated that n-3 polyunsaturated fatty acids (PUFA) enhance apoptosis, a useful marker of colorectal cancer risk, in colonocytes by enhancing phospholipid oxidation. In order to elucidate the mechanisms regulating oxidative stress-induced apoptosis in vivo, we fed SOD2het, Gpx4het and Gpx4 over-expressing (Gpx4TG) transgenic mouse models diets containing either n-3 or n-6 PUFA (control). Animals were fed diets containing either 15% corn oil by weight (CO, enriched in n-6 PUFA) or 3.5% CO + 11.5% fish oil (FO, enriched in n-3 PUFA) for 4 wk. Apoptotic cells in the distal colon were enumerated in situ. Relative to their respective wild type siblings, Gpx4het and SOD2het mice had significantly (P<0.05) enhanced levels of colonocyte apoptosis, 63% and 20%, respectively. In contrast, apoptosis in Gpx4TG mice was significantly (P<0.05) reduced by 16% compared to wild type siblings. FO vs CO feeding further increased (P<0.05) apoptosis in Gpx4het and SOD2het mice by 42% and 18%, respectively. In addition, n-3 PUFA elevated apoptosis in Gpx4TG mice back to a level comparable with wild type (control) siblings. These data indicate that dietary and/or genetic pre-deposition to oxidative stress facilitates apoptosis in the colon, thereby reducing colon cancer risk. Supported in part by NIH grants CA59034, CA129444, P30ES09106, and USDA 2008-34402-19195, “Designing Foods for Health” through the Vegetable & Fruit Improvement Center.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 955.
Abstract 959: Sulindac resistant colon tumors possess an altered molecular phenotype
Authors: Greenspan Emily J. , Nichols Frank C. , Rosenberg Daniel W.
Published: February 2011

Although non-steroidal anti-inflammatory drugs (NSAIDs), including sulindac, have been used extensively as chemopreventive agents for colorectal cancer (CRC), results are not consistent. NSAIDs, most reportedly sulindac, often do not cause a complete regression of adenomas and some patients develop resistance to NSAID treatment. In this study we evaluated the effect of sulindac on colon tumorigenesis in the ApcMin/+ mouse model. Sulindac (180 ppm) given in drinking water for 9 weeks to ApcMin/+ mice significantly reduced the size of colon tumors, but actually caused an increase in colon tumor multiplicity relative to untreated controls (average of 5.5 vs. 1.6 tumors/mouse, respectively; P<0.0001). This indicated that the drug could inhibit colon tumor progression but not initiation. In the small intestine, sulindac significantly reduced tumor size and multiplicity relative to untreated controls (average of 2.3 vs. 42.0 tumors/mouse, respectively; P<0.0001). Generation of a panel of prostanoids was comparably suppressed in the small intestine and colon by sulindac treatment. Sulindac is also known to have many non-COX targets, including p21, β-catenin, E-cadherin, mitochondrial apoptotic proteins and PPARγ. Our goal was to determine whether alterations in these cellular mediators might be responsible for the observed increase in tumor multiplicity in the colon. We found that sulindac treatment protected against E-cadherin loss in colon tumors, with associated inhibition of nuclear β-catenin accumulation. Importantly, p21WAF1/cip1 and PPARγ expression were absent in colon tumors from sulindac-treated mice, suggesting that loss of these proteins is necessary for lack of response to sulindac. Together, these observations may be translatable to designing novel clinical therapies utilizing combinations of agents that target multiple molecular pathways to overcome sulindac resistance.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 959.
Abstract 96: Conformational and thermodynamics analyses of the regulation of trifluoperazine on camodulin binding to Fas: Implications for cancer chemotherapy
Authors: Pan Di , Yan Qi , Chen Yabing , McDonald Jay M. , Song Yuhua
Published: February 2011

Fas-mediated signaling pathway is an important mechanism for apoptosis in a variety of cells, including cholangiocarcinoma and other cancer cells. The formation of death inducing signaling complex (DISC) is a critical step for Fas-mediated signaling. Recent experimental studies showed that calmodulin (CaM) binds to Fas and regulates Fas-mediated DISC formation and the binding of CaM to Fas is inhibited by the CaM antagonist, trifluoperazine (TFP) (J Cell Biochem, 103:788, 2008). The present study sought to determine the structural basis and molecular mechanisms of TFP regulation of Fas-mediated DISC formation. We used a combination of molecular dynamics simulations and binding free energy analyses to investigate the effect of TFP on CaM-Fas binding. We studied the interactions of different number(s) of TFP(s) with CaM and the effect of the resulting conformational changes of CaM on CaM/Fas binding. We found that the binding affinity of one TFP with CaM was affected by the sequential binding of other TFP(s) to CaM, which was consistent with near-UC circular dichroism data (Biochemistry 37:15300, 1998). The number of TFP(s) bound to CaM was shown to affect the conformational and motion changes of CaM, and thus directly affect CaM binding to Fas. Consistent with previous experimental observations that CaM-Fas binding was affected by TFP concentrations (J Biol Chem, 280:29964, 2005), we demonstrated that one TFP bound to CaM inhibited CaM-Fas binding while the subsequent two TFPs or four TFPs bound to CaM resulted in the recovery of CaM-Fas binding (Table 1). Results also showed that conformational and motional changes of Fas by binding to CaM were directly related to the number of TFPs bound to CaM, which could further affect Fas recruitment of FADD to the DISC. This study provides structural and thermodynamics evidence elucidating the role of the CaM antagonist, TFP, in regulating CaM-Fas binding and Fas-mediated DISC formation and apoptosis.Table 1.The change of CaM-Fas binding affinity by the CaM antagonist, TFP. CaM_Fas_WTCaM_1TFP_FasCaM_2TFPs_FasCaM_4TFPs_FasΔG−7.11±4.67−1.32±0.99−6.96±3.47−6.42±1.06ΔΔG 5.79*0.150.69All values in this table were expressed in terms of kcal/mol. ΔG is the binding free energy for the complex, and ΔΔG is the relative binding free energies with respect to the CaM-Fas complex without CaM antagonist TFP(s). * Differences are statistically significant (Student's t-test, p<0.05)

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 96.
Abstract 961: Higher activity of δ-tocopherol (δ-T) than γ-tocopherol and α-tocopherol in the inhibition of lung cancer H1299 xenograft tumors in mice
Authors: Li Guangxun , Picinich Sonia C. , Lee Mao-Jung , Liu Anna Ba , Lu Gary , Yang Chung S.
Published: February 2011

Our previous study showed that γ-TmT (a tocopherol mixture containing 57% γ-T, 24% δ-T, 13% α-T and 1.5% β-T) effectively inhibited colon and lung carcinogenesis as well as the growth of transplanted human lung cancer in mice. This study aims to determine the more active constituents in this mixture in a xenograft model. After injection of human lung cancer H1299 cells into NCr nu/nu nude mice, the mice were maintained on a standard AIN93M diet or diet enriched with α-T, γ-T, δ-T or γ-TmT (each at 0.3% and 0.17%) for 50 days. Dietary δ-T showed the strongest inhibition based on final tumor weight (35.6% and 57.6% reduction from the control by 0.17% and 0.3% δ-T, respectively). Dietary 0.3% γ-T and γ-TmT also showed significant inhibition (37.4% and 46% reduction from control, respectively). However, an inhibitory effect was not observed with dietary α-T group. Consistent with the animal study, the growth of H1299 cells was inhibited by tocopherols with their effectiveness following the order of δ-T > γ-TmT > γ-T, but α-T was not effective. We also found that dietary α-T, γ-T and δ-T treatment respectively increased serum α-T, γ-T and δ-T levels (up to 45, 9.7 and 1.2μM, respectively). However, the serum α-T level was decreased by dietary γ-T and δ-T; for example, at 0.3% they decreased α-T levels by 50% and 42% from the control group, respectively. The results suggest a competition among different forms of tocopherols. Dietary treatment with each form of tocopherol also increased the corresponding side-chain degradation metabolites: carboxyethyl hydroxychromans (CEHC) and carboxymethylbutyl hydroxychromans (CMBHC). With 0.3% α-, γ- and δ-T in the diet, the mean serum levels of α-, γ- and δ-CEHC were 0.08, 0.7 and 3.0μM, respectively; and α-, γ- and δ-CMBHC were 0.14, 0.83 and 4.0μM, respectively. These metabolites retain the intact chromanol ring and, similar to their parent tocopherols, could trap reactive oxygen and nitrogen species. δ-CEHC and δ-CMBHC, which are present at rather high concentrations, may play an important role in inhibiting xenograph and tumor growth. The present results show that δ-T and γ-T effectively inhibited human lung cancer xenograft tumors and the inhibition may be due to the apoptosis-inducing, antioxidative, and reactive nitrogen species-trapping activities of these tocopherols and their metabolites (Supported by NIH grants CA120915, CA122474, and CA133021).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 961.
Abstract 968: Effects of different types of high fat diets rich in omega-3 or omega-6 fatty acids on uvb-induced complete skin carcinogenesis in skh-1 mice
Authors: Lou You-Rong , Peng Qing-Yun , Li Tao , Medvecky Christopher M. , Wagner George C. , Lu Yao-ping
Published: February 2011

Our previous studies reported that oral administration of caffeine or voluntary exercise may have decreased skin tumor multiplicity, in part, by decreasing fat levels in the dermis and the size of parametrial fat pads. Our studies also showed that surgical removal of the parametrial fat pads (partial lipectomy) enhanced UVB-induced apoptosis in the epidermis. These data suggest that tissue fat may play an important role in regulating UVB-induced apoptosis and skin carcinogenesis. Accordingly, in the present study, we explored the effects of two different types of high fat diets (as described by Rao et al., Cancer Research 61:1927-33, 2001) on UVB-induced complete skin carcinogenesis in SKH-1 hairless mice. Eighty female SKH-1 mice (7-8 weeks old) were equally divided into two groups (40 mice per group). They were irradiated with 30 mJ/cm2 of ultraviolet light B (UVB) once each day, two times per week for 39 weeks. From the beginning of UVB treatment, one group of the mice was given high fat diet containing 32% of polyunsaturated omega-3 fatty acids (HFFO) and the other group of the mice was given high fat diet containing 28% of polyunsaturated omega-6 fatty acids (HFML). Our results showed that although both groups of animals gained weight dramatically, there were no statistical differences on body weight, weight of parametrial fat pad, or thickness of the dermal fat layer. Gross examination showed that HFFO treatment delayed the appearance of UVB-induced skin lesions, decreased the number of mice with tumors and decreased the number and size of tumors per mouse. Histopathological characterization of the skin lesions revealed that HFFO administration decreased the number of squamous cell papillomas per mouse by 64%, decreased the number of keratoacanthomas per mouse by 52% and decreased the number of squamous cell carcinomas per mouse by 46%. In addition to reducing the number of skin tumors, HFFO diet substantially decreased the size of the tumors. That is, the HFFO diet decreased the total volume of squamous cell papillomas per mouse by 98%, decreased the total volume of keratoacanthomas per mouse by 80% and deceased the total volume of squamous cell carcinomas per mouse by 83%. Finally, animals fed the HFFO diet had 22% lower blood levels of tryglycerides (79.3±5.1 mg/dL) than the mice fed the HFML diet (102.0±6.3 mg/dL) (p<0.01), but there was no difference in levels of blood glucose. The effects described here indicate that omega-3 fatty acids in HFFO diet may have beneficial effects against UVB-induced skin carcinogenesis. (Supported by NIH Grant RO1 CA128997)

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 968.
Abstract 973: The NCI Biospecimen Research Network
Authors: Sawyer Sherilyn , Moore Helen M. , Lim Mark David , Vaught Jimmie , Compton Carolyn C.
Published: February 2011

The National Cancer Institute's (NCI) Office of Biorepositories and Biospecimen Research (OBBR) initiated the Biospecimen Research Network (BRN) in early 2006 to coordinate and support systematic investigation into how collection, processing, and storage of human biospecimens affect subsequent analysis. To support this goal, the BRN sponsors, conducts and collaborates on studies to evaluate the effects of biospecimen pre-analytical variables on the outcomes of molecular assays for cancer diagnosis and research. BRN supported findings will contribute to the development of evidence-based best practices for the collection, processing, storage and transport of biospecimens; building on the “NCI Best Practices for Biospecimen Resources.” Currently the BRN sponsors a variety of initiatives aimed to develop and support the research efforts of the biospecimen science community. Through its newly launched extramural research program the BRN supports a portfolio of projects addressing biospecimen pre-analytical variables and biospecimen integrity. Furthermore, the BRN aims to significantly improve biospecimen-based diagnostic and research capabilities by communicating the results of such research to the scientific and clinical communities. The Biospecimen Research Database and the annual BRN symposium, Advancing Cancer Research Through Biospecimen Science are forums established for effective exchange of biospecimen research results. The BRN also supports new research and innovation through its collaborations with other NCI programs such as NCI Innovative Molecular Analysis Technologies (IMAT), the NCI Small Business Innovation Research Development Center (SBIR), the Clinical Proteomics Technologies for Cancer (CPTC) and the Cancer Genome Atlas (TCGA). Through these partnerships, the BRN serves as a resource for program awardees and presents new opportunities for research.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 973.