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Background:Germline mutations in DNA mismatch repair (MMR) genes cause Lynch syndrome colon cancers. Less understood is the risk of colon cancer associated with common polymorphisms in MMR genes and the potential interacting role of lifestyle factors known to damage DNA.Methods:A study was conducted to examine whether MLH1 (-93G>A and Ile219Val) and MSH6 (Gly39Glu) polymorphisms were associated with risk of colon cancer in data from 1609 colon cancer cases and 1972 controls. Genotype data were further stratified by microsatellite instability status, smoking, alcohol, Western diet, alcohol and obesity, to investigate potential heterogeneity.Results:The MSH6 39Glu allele was associated with increased risk of colon cancer among men (Gly/Glu or Glu/Glu vs Gly/Gly, OR 1.27; 95% CI 1.04 to 1.54). Neither MLH1 polymorphism was associated with colon cancer risk overall. When stratified by microsatellite stability status, however, the MLH1 -93A allele was associated with a more than doubling in microsatellite instability (MSI)-positive colon cancer risk (AA vs GG, OR 2.47; 95% CI 1.48 to 4.11); no associations were observed between the MMR polymorphisms examined and MSI-negative colon cancer. Statistically significant interactions were observed between: MLH1 -93G>A and smoking (MSI-negative colon cancer only, p value interaction: 0.005); and MLH1 Ile219Val and Western diet (p value interaction: 0.03).Conclusions:The MSH6 Gly39Glu and MLH1 -93G>A polymorphisms were associated with risk of overall colon and MSI-positive colon cancers, respectively. Risk for colon cancer, stratified by MMR genotype, was further modified by smoking and Western diet.

The periods of circadian clocks are relatively temperature-insensitive. Indeed, the perL mutation in the Drosophila melanogaster period gene, a central component of the clock, affects temperature compensation as well as period length. The per protein (PER) contains a dimerization domain (PAS) within which the perL mutation is located. Amino acid substitutions at the perL position rendered PER dimerization temperature-sensitive. In addition, another region of PER interacted with PAS, and the perL mutation enhanced this putative intramolecular interaction, which may compete with PAS-PAS intermolecular interactions. Therefore, temperature compensation of circadian period in Drosophila may be due in part to temperature-independent PER activity, which is based on competition between inter- and intramolecular interactions with similar temperature coefficients.

IntroductionPancreas adenocarcinoma (PC) has an undefined hereditary component. We quantified the familial risk of PC among relatives of patients diagnosed with PC and stratified it based on anatomic location of PC and age and sex of the proband.MethodsThis is a retrospective, population-based, case–control study of PC diagnosed in Utah between 1980 and 2011. The Utah population database and cancer registry were used to identify index patients with PC. The risk of PC in first-degree relatives (FDRs), second-degree relatives (SDRs), and first cousins (FCs) of probands was compared with randomly selected sex- and age-matched population controls.ResultsA total of 4,095 patients and 40,933 controls were identified. The relative risk (RR) of PC was 1.76 (95% CI 1.35–2.29) in FDRs, 1.42 (95% CI 1.18–1.7) in SDRs and 1.08 (95% CI 0.95–1.23) in FCs of probands compared to relatives of PC-free controls. The RR were elevated in FDRs (1.96, 95% CI 1.45–2.65), SDRs (1.54, 95% CI 1.19–1.98) and FCs (1.18, 95% CI 1.0–1.64) of female probands. Among probands diagnosed as < 65 years, RR was 2.12 (95% CI 1.37–3.28) in FDRs, 1.94 (95% CI 1.44–2.62) in SDRs, and 1.28 (95% CI 1.0–1.64) in FCs. Overall, the RR for PC was elevated in FDRs regardless of the anatomic location of PC.DiscussionThere is an increased risk of PC in FDR and more distant relatives of patients with PC. Relatives of female patients with PC and patients diagnosed at age < 65 years are at a significantly increased risk of PC.

Some studies have shown an inverse relationship between microsatellite instability in colon cancer and mutations in p53 and K- ras, whereas others have not. We therefore evaluated these features in a population-based sample of 496 individuals with colon cancer. Microsatellite instability was determined by a panel of 10 tetranucleotide repeats, the Bethesda consensus panel of mono- and dinucleotide repeats, and coding mononucleotide repeats in transforming growth factor-beta receptor type II, hMSH3, BAX, hMSH6, and insulin-like growth factor receptor type II. Mutations in codons 12 and 13 in K- ras were evaluated by sequencing. p53 overexpression (as detected by immunohistochemistry) was used as an indicator of p53 mutation; this was evaluated in 275 of the tumors. K- ras mutations were present in 33.2% of tumors, p53 overexpression in 51.5%, and microsatellite instability (as determined by the Bethesda consensus panel) in 12.5%. K- ras mutations were significantly less common in unstable tumors than stable tumors (11.8% versus 36.9%, P < 0.001). p53 overexpression was significantly less common in unstable tumors than stable tumors (20.0% versus 55.7%, P < 0.001). These inverse relationships between microsatellite instability and ras gene mutations and p53 overexpression were shown to be independent of tumor site in logistic regression analyses. All other measures of instability also showed statistically significant inverse relationships independent of tumor site with alterations in ras and p53, and instability results determined by the panel of 10 tetranucleotide repeats were highly significantly related to those determined by the Bethesda consensus panel. Coding mononucleotide repeat mutations were significantly more common in unstable tumors than stable tumors (85.7% versus 1.0%, P < 0.001). We conclude that there is an inverse relationship between microsatellite instability and mutations in p53 and K- ras, and that the molecular profile of colon cancers with microsatellite instability is characterized by relatively infrequent mutations in K- ras and p53 and relatively frequent mutations in coding mononucleotide repeats.

In this paper, the results of a pilot study of willingness to pay (WTP) to avoid poultry-borne illness are reported. Through this, the problems of devising an economic measure of the ‘intangible’ benefits of prevention of food-borne risk are explored. The study is the first to allow those against a prevention policy (irradiation of poultry-meat) to register their WTP not to have the policy implemented. The study demonstrates that it is feasible to obtain answers to WTP questions from a self-selected sample. Future studies should ensure greater representativeness of respondents, that better information about benefits is provided to respondents and that an appropriate method of aggregation of benefits is used.

We hypothesize that the peroxisome proliferator-activated receptor-γ (PPARγ) is associated with colorectal cancer given its association with insulin, diabetes, obesity, and inflammation. In this study, we evaluated the association between colorectal cancer and specific tumor mutations and the Pro12A1a (P12A) PPARγ polymorphism. We also evaluated interactions between the PPARγ gene and other insulin-related genes and use of aspirin and nonsteroidal anti-inflammatory drug use. Data were available from 1,577 cases of colon cancer that were matched to 1,971 population-based controls and 794 cases of rectal cancer that were matched to 1,001 population-based controls. Colon tumors from the case subjects were evaluated for p53 and Ki-ras mutations and microsatellite instability (MSI). Insulin-related genes evaluated were the Bsm1, polyA, and Fok1 polymorphisms of the VDR gene; the G972R IRS1 polymorphism; the G1057D IRS2 polymorphism; the 19CA repeat polymorphism of the IGF1 gene; and the −200A>C IGFBP3 polymorphism. The odds ratio (OR) between the PA/AA genotypes and proximal tumors was 0.83 (95% CI: 0.69-1.01); for distal tumors was 1.00 (95% CI: 0.83-1.21); and for rectal tumors was 1.04 (95% CI: 0.86-1.25). Evaluation of specific types of tumor mutations showed that colon cancer cases with the PA or AA genotypes were less likely to have p53 tumor mutations (OR 0.78; 95% CI: 0.62-0.99), specifically transition mutations (OR 0.74; 95% CI: 0.56-0.97). Colon cancer cases also were less likely to have a tumor with MSI if they had the PA or AA PPARγ genotype (OR 0.68; 95% CI: 0.47-0.98); differences in Ki-ras mutations were not seen in colon tumors by PPARγ genotype. Those who did not take ibuprofen-type drugs and had the PA or AA genotypes were at a significantly greater risk of rectal cancer (OR 2.11; 95% CI: 1.52-2.92; p interaction 0.03) than people with the PP genotype regardless of ibuprofen-type drug use. There was a significant interaction between the −200A>C IGFBP3 polymorphism and the Pro12Ala PPARγ polymorphism and risk of colon cancer (p for interaction = 0.02) with individuals being at significantly lower risk if they had both the CC IGFBP3 genotype and the PA/AA PPARγ genotype. For rectal cancer there was a significant interaction between the Bsm1/polyA polymorphisms (p = 0.001) of the VDR gene and the PA/AA Pro12Ala PPARγ polymorphism with the highest risk group being those with both the PA/AA Pro12Ala PPARγ and the BB/SS VDR genotypes. These data suggest that PPARγ may be associated with many aspects of colorectal cancer including insulin- and inflammation-related mechanisms.

Circulating concentrations of IGF-I and IGFBP-3 are associated with risk of pre-menopausal breast cancer. Racial differences in levels of these factors have been reported, and determinants of IGF-I and IGFBP-3 levels within racial and ethnic groups are unclear. In this study we examine genetic, anthropometric, diet, and lifestyle factors that may predict serum levels of IGF-I and IGFBP-3 among Hispanic and non-Hispanic white women. A sample of healthy controls participating in the SHINE (Southwest Hormone, Insulin, Nutrition, and Exercise Study) case-control breast cancer in Arizona, Colorado, New Mexico, and Utah were included in these analyses. Subjects included 210 Hispanic and 284 non-Hispanic white women. Hispanic women had significantly lower levels of IGFBP-3 (mean=3764.3 mcg/ml) after adjusting for age, body size, physical activity, menopausal status, and dietary factors than non-Hispanic white women (mean=4058.0 mcg/ml; p<0.01). The CC genotype of the -202 A>C polymorphism of the IGFBP3 gene was associated with lower IGFBP-3 levels in both ethnic groups. The frequency of the IGFBP3 C allele differed between Hispanic (0.65) and non-Hispanic white women (0.53), but serum levels of IGFBP-3 were lower for Hispanic women than non-Hispanic after accounting for IGFBP3 genotype. Body size indicators, vigorous physical activity, and dietary factors appeared to influence serum levels of IGF-1 and the ratio of IGF-1 to IGFBP-3 in pre-menopausal women more than in post-menopausal women. On the other hand, using aspirin/NSAIDs appeared to increase IGFBP-3 levels significantly among pre-menopausal Hispanic women. Results from this study suggest that differences in IGFBP-3 levels exist in Hispanic and non-Hispanic white women. These differences could be due to the combined effects of genetic and behavioral factors which could account for ethnic differences in the risk of breast cancer and other chronic diseases.

Objectives: Hormone replacement therapy (HRT) has been inversely associated with colon cancer incidence in several epidemiologic studies. In this study we used data from a population-based incident case-control study of colon cancer to evaluate the role of HRT use in survival after diagnosis with colon cancer. Methods: Data from 815 postmenopausal women living in Utah, California, and Minnesota diagnosed between 1 September 1991 and 30 September 1994 were used to examine associations between HRT and survival. Results: After adjusting for age at time of diagnosis, stage of disease at time of diagnosis, study center, and body mass index (BMI), we observed that women who had ever used HRT had a 30% lesser probability of dying of any cause and a 40% lower probability of dying from colon cancer specifically during the follow-up period. Further evaluation by years of HRT use showed that those who had used HRT for 4 or more years had the lowest risk of dying of colon cancer (hazard rate ratio 0.5, 95% confidence interval 0.3-0.9). Evaluation of other lifestyle variables with HRT use did not show significant confounding or effect modification. Conclusions: These findings suggest that HRT use may improve short-term survival after diagnosis with colon cancer; there is no suggestion that HRT use is detrimental to survival.

Objective: Phase II metabolizing enzymes such as glutathione S-transferases and N-acetyltransferase are involved in the detoxification of carcinogens. Genetic variants of genes coding for these enzymes have been evaluated as to their association with colon cancer, both as independent risk factors and as effect modifiers for associations with diet and cigarette smoking. In this study, we evaluate associations between the GSTM-1 genotype and the NAT2-imputed phenotype and acquired mutations in tumors Methods: Data is taken from a set of 1836 cases and 1958 controls with colon cancer who were part of a large case-control study of colon cancer and whose tumors were previously analyzed for Ki-ras, p53, and microsatellite instability (MSI). We also evaluate the modifying effects of these genetic variants with diet and cigarette smoking, factors previously identified as being associated with specific tumor alterations. Results: Neither GSTM-1 nor the NAT2-imputed phenotype was independently associated with Ki-ras, p53, or MSI. Cigarette smoking significantly increased the risk of tumors involving the MSI pathway. Additionally, cigarette smoking doubled the risk of p53 transversion mutations among those who were GSTM-1 present. Cases were slightly more likely to have a p53 mutation if they frequently consumed red meat and had the imputed NAT2 intermediate/rapid phenotype relative to slow phenotype/infrequent consumers of red meat (OR 2.0, 95% CI 1.3-3.0 for intermediate/rapid). Conclusions: These data provide support that diet and cigarette smoking may be associated with specific disease pathways, although GSTM-1 and NAT2 do not independently appear to alter susceptibility to these diet and lifestyle factors.

This study compared two work-based learning interventions, service learning and paid internships, across group and time on work performance and social competence among high school students with emotional and behavioral disorders (N=57). Results found a significant interaction effect for group and time, favoring service learning, on several dimensions of work performance and social competence, including work motivation, personal presentation, overall social competence, peer relations, and school adjustment.