Prehabilitation program composed of blood flow restriction training and sports nutrition improves physical functions in abdominal cancer patients awaiting surgery.

INTRODUCTION: The impact of prehabilitation remains controversial due to a short presurgical waiting period and the diminished capacity of the patient population. A strategy to augment and optimize the effectiveness of prehabilitations for abdominal cancer patients may be found in the unlikely field of sport science. We investigated the use of blood flow restriction training and sport nutrition supplementation to augment functional capacity and increase muscle strength in twenty-four abdominal cancer patients awaiting surgery. MATERIALS AND METHODS: The sport science-based program was comprised of blood flow restriction exercise 5 to 6 times per week and a daily sports nutrition supplement containing l-citrulline, creatine monohydrate, and whey protein. RESULTS: After 4 weeks of prehabilitation, 6-min walk test, timed up and go, short physical performance battery, 5-chair stand test and physical component score of quality of life were significantly improved (all p < 0.05). Total body and appendicular lean mass as assessed by dual energy X-ray absorptiometry increased by 0.73 ± 1.04 kg (p = 0.004) and 0.42 ± 0.64 kg (p = 0.006), respectively. Total body fat mass and trunk fat mass decreased (p = 0.004 and p = 0.021). There were no significant changes in hand grip strength, fear of falling, the mental component summary of quality of life, or fasting serum concentrations of myostatin, follistatin, and growth hormone. CONCLUSION: A multimodal prehabilitation program, which encompasses blood flow restriction training and sports nutrition supplements, is both feasible and effective in improving lean mass and physical function in abdominal cancer patients prior to surgery.

Weight estimation among multi-racial/ethnic infants and children aged 0-5·9 years in the USA: simple tools for a critical measure.

OBJECTIVE: In resource-constrained facilities or during resuscitation, immediate paediatric weight estimation remains a fundamental challenge. We aimed to develop and validate weight estimation models based on ulna length and forearm width and circumference measured by simple and portable tools; and to compare them against previous methods (advanced paediatric life support (APLS), Theron and Traub-Johnson formulas). DESIGN: Cross-sectional analysis of anthropometric measurements. Four ulna- and forearm-based weight estimation models were developed in the training set (n 1016). Assessment of bias, precision and accuracy was examined in the validation set (n 457). SETTING: National Children's Study-Formative Research in Anthropometry (2011-2012). SUBJECTS: Multi-racial/ethnic infants and children aged <6 years (n 1473). RESULTS: Developed Models 1-4 had high predictive precision (R 2=0·91-0·97). Mean percentage errors between predicted and measured weight were significantly smaller across the developed models (0·1-0·7 %) v. the APLS, Theron and Traub-Johnson formulas (-1·7, 9·2 and -4·9 %, respectively). Root-mean-squared percentage error was overall smaller among Models 1-4 v. the three existing methods (range=7·5-8·7 v. 9·8-13·3 %). Further, Models 1-4 were within 10 and 20 % of actual weight in 72-87 and 95-99 % of the weight estimations, respectively, which outperformed any of the three existing methods. CONCLUSIONS: Ulna length, forearm width and forearm circumference by simple and portable tools could serve as valid and reliable surrogate measures of weight among infants and children aged <6 years with improved precision over the existing age- or length-based methods. Further validation of these models in physically impaired or non-ambulatory children is warranted.

Food Insecurity and Hunger: Quiet Public Health Problems on Campus.

Food insecurity and hunger are gaining traction as recognized public health problems on college campuses in the United States. Data from recent publications and reports suggest the prevalence of food insecurity among U.S. undergraduate students ranges from 14.1 to 58.8%, compared to 12.3% of U.S. households. Undergraduate students (N=1,069) were surveyed at the University of Texas at Austin in 2014-2015. The survey questionnaire included the validated 6-item short-form of the USDA food security module, was distributed and completed in class and answered anonymously. The demographic characteristics of the sample are representative of all undergraduates on campus. Food insecurity was reported by 23.5% of students surveyed; ever being hungry by 31% and 12.5% of the ever-hungry also report being food-insecure. Importantly, most of the food insecure (96%) did not report experiencing food insecurity prior to matriculation. In multiple logistic regression models, the factors associated with a higher odds ratio of food insecurity include: being a first-generation college student; Hispanic ethnicity; third-born child or later in the family; and less confident about financial management skills. The factors associated with a higher adjusted odds ratio of hunger include: being of Asian or other ethnicity (vs. non-Hispanic white) and having limited confidence about financial management skills. The results, from one of the largest surveys of food insecurity and hunger among undergraduate students on a single campus in the U.S., suggest that transition to college is a vulnerable window for the emergence of food insecurity and hunger. More research is needed on the long-term effects of food insecurity in this population and the effectiveness of campus policy and interventions addressing food insecurity and hunger.

Predictive Models for Characterizing Disparities in Exclusive Breastfeeding Performance in a Multi-ethnic Population in the US.

OBJECTIVES: Maternal lactation performance varies across populations, yet the relative impact of maternal sociodemographics, perinatal factors, and birth outcomes on disparities in exclusive breastfeeding (XBR) outcomes is not well known. We aimed to develop predictive models and compare the relative contribution of predictors for XBR initiation and XBR ≥ 6 months. METHODS: Infant feeding data were obtained from women with children aged 0-6 years (n = 1471) in a multi-ethnic cross-sectional study in the US (2011-2012). We compared discriminant ability of predictors for ever XBR and XBR ≥ 6 months using discriminant function analysis, respectively. We also calculated adjusted ORs for factors associated with XBR outcomes and breast-bottle feeding (BrBot) subgroups. RESULTS: Maternal sociodemographics (education level, marital status, nativity, and age at childbirth) had greater discriminating abilities in predicting ever XBR and XBR ≥ 6 months than birth outcomes and perinatal factors. Foreign-born women were two-fold more likely to initiate XBR but not necessarily continue to 6 months compared to their US-born counterparts. Factors associated with BrBot subgroups differed from those associated with XBR outcomes, whereas maternal age was the only predictor consistently associated with ever XBR, XBR ≥ 6 months, and BrBot subgroups. The areas under the receiver operating characteristic curves for models predicting ever XBR and XBR ≥ 6 months were 0.88 (95 % CI 0.85, 0.91) and 0.90 (95 % CI 0.88, 0.93), respectively. CONCLUSIONS: Findings underscore the importance of educational, clinical, and social support to promote XBR in mothers with sociodemographic factors predictive of none or poor XBR outcomes.

Longer breastfeeding duration reduces the positive relationships among gestational weight gain, birth weight and childhood anthropometrics.

BACKGROUND: The relationship between gestational weight gain (GWG) and childhood growth remains controversial. An examination on whether infant feeding practices mediate this relationship may improve our understanding of it. METHODS: We investigated whether the relationships among GWG, birth weight and childhood anthropometrics were mediated through infant feeding practices (breastfeeding duration and age at introduction of solid foods) in a cross-sectional multiethnic study of 1387 mothers and their children aged 0-5.9 years in the USA (2011-2012). Child anthropometrics included age-specific and sex-specific z-scores for weight-for-age (WAZ), height/length-for-age (HAZ), weight-for-height/length (WHZ) and body mass index-for-age (BMIZ); and ulnar length, a marker for limb growth. We used structural equation modelling to calculate standardised path coefficients and total, direct and indirect associations of GWG, birth weight and infant feeding practices with child anthropometrics. RESULTS: Maternal GWG had a positive indirect association with all anthropometrics mediated via birth weight, whereas longer breastfeeding duration reduced the positive associations of GWG and birth weight with WAZ, WHZ and BMIZ in non-Hispanics (ß=-0.077, -0.064 and -0.106, respectively). Longer breastfeeding duration and introducing solid foods at a later age were positively associated with ulnar length (ß=0.023 and 0.030, respectively) but not HAZ, suggesting a distinct association, for the first time, with limb growth. CONCLUSIONS: Findings suggest that promoting longer breastfeeding duration among women with excessive GWG who had high birthweight newborns may mitigate the potential for their offspring to develop obesity. In addition, findings reinforce the importance of promoting appropriate GWG and preventing high birth weight, which are positively associated with childhood anthropometrics.

Arm span and ulnar length are reliable and accurate estimates of recumbent length and height in a multiethnic population of infants and children under 6 years of age.

Surrogate measures are needed when recumbent length or height is unobtainable or unreliable. Arm span has been used as a surrogate but is not feasible in children with shoulder or arm contractures. Ulnar length is not usually impaired by joint deformities, yet its utility as a surrogate has not been adequately studied. In this cross-sectional study, we aimed to examine the accuracy and reliability of ulnar length measured by different tools as a surrogate measure of recumbent length and height. Anthropometrics [recumbent length, height, arm span, and ulnar length by caliper (ULC), ruler (ULR), and grid (ULG)] were measured in 1479 healthy infants and children aged <6 y across 8 study centers in the United States. Multivariate mixed-effects linear regression models for recumbent length and height were developed by using ulnar length and arm span as surrogate measures. The agreement between the measured length or height and the predicted values by ULC, ULR, ULG, and arm span were examined by Bland-Altman plots. All 3 measures of ulnar length and arm span were highly correlated with length and height. The degree of precision of prediction equations for length by ULC, ULR, and ULG (R(2) = 0.95, 0.95, and 0.92, respectively) was comparable with that by arm span (R(2) = 0.97) using age, sex, and ethnicity as covariates; however, height prediction by ULC (R(2) = 0.87), ULR (R(2) = 0.85), and ULG (R(2) = 0.88) was less comparable with arm span (R(2) = 0.94). Our study demonstrates that arm span and ULC, ULR, or ULG can serve as accurate and reliable surrogate measures of recumbent length and height in healthy children; however, ULC, ULR, and ULG tend to slightly overestimate length and height in young infants and children. Further testing of ulnar length as a surrogate is warranted in physically impaired or nonambulatory children.

Investigating multiple candidate genes and nutrients in the folate metabolism pathway to detect genetic and nutritional risk factors for lung cancer.

PURPOSE: Folate metabolism, with its importance to DNA repair, provides a promising region for genetic investigation of lung cancer risk. This project investigates genes (MTHFR, MTR, MTRR, CBS, SHMT1, TYMS), folate metabolism related nutrients (B vitamins, methionine, choline, and betaine) and their gene-nutrient interactions. METHODS: We analyzed 115 tag single nucleotide polymorphisms (SNPs) and 15 nutrients from 1239 and 1692 non-Hispanic white, histologically-confirmed lung cancer cases and controls, respectively, using stochastic search variable selection (a Bayesian model averaging approach). Analyses were stratified by current, former, and never smoking status. RESULTS: Rs6893114 in MTRR (odds ratio [OR] = 2.10; 95% credible interval [CI]: 1.20-3.48) and alcohol (drinkers vs. non-drinkers, OR = 0.48; 95% CI: 0.26-0.84) were associated with lung cancer risk in current smokers. Rs13170530 in MTRR (OR = 1.70; 95% CI: 1.10-2.87) and two SNP*nutrient interactions [betaine*rs2658161 (OR = 0.42; 95% CI: 0.19-0.88) and betaine*rs16948305 (OR = 0.54; 95% CI: 0.30-0.91)] were associated with lung cancer risk in former smokers. SNPs in MTRR (rs13162612; OR = 0.25; 95% CI: 0.11-0.58; rs10512948; OR = 0.61; 95% CI: 0.41-0.90; rs2924471; OR = 3.31; 95% CI: 1.66-6.59), and MTHFR (rs9651118; OR = 0.63; 95% CI: 0.43-0.95) and three SNP*nutrient interactions (choline*rs10475407; OR = 1.62; 95% CI: 1.11-2.42; choline*rs11134290; OR = 0.51; 95% CI: 0.27-0.92; and riboflavin*rs8767412; OR = 0.40; 95% CI: 0.15-0.95) were associated with lung cancer risk in never smokers. CONCLUSIONS: This study identified possible nutrient and genetic factors related to folate metabolism associated with lung cancer risk, which could potentially lead to nutritional interventions tailored by smoking status to reduce lung cancer risk.

Associations between dietary intake of choline and betaine and lung cancer risk.

Evidence from human and animal research indicates that choline metabolic pathways may be activated during a variety of diseases, including cancer. We report results of a case-control study of 2821 lung cancer cases and 2923 controls that assessed associations of choline and betaine dietary intakes with lung cancer. Using multivariable logistic regression analyses, we report a significant association between higher betaine intake and lower lung cancer risk that varied by smoking status. Specifically, no significant association was observed between betaine intake and lung cancer among never-smokers. However, higher betaine intake was significantly associated with reduced lung cancer risk among smokers, and the protective effect was more evident among current than former smokers: for former and current smokers, the ORs (95% CI) of lung cancer for individuals with highest as compared to lowest quartiles of intake were 0.70(0.55-0.88) and 0.51(0.39-0.66) respectively. Significant linear trend of higher betaine intake and lower lung cancer risk was observed among both former (p(trend) = 0.002) and current (p(trend)<0.0001) smokers. A similar protective effect was also observed with choline intake both in overall analysis as well as among current smokers, with p-values for chi-square tests being 0.001 and 0.004 respectively, but the effect was less evident, as no linear trend was observed. Our results suggest that choline and betaine intake, especially higher betaine intake, may be protective against lung cancer through mitigating the adverse effect of smoking.

Data Acquisition and Preprocessing in Studies on Humans: What Is Not Taught in Statistics Classes?

The aim of this paper is to address issues in research that may be missing from statistics classes and important for (bio-)statistics students. In the context of a case study, we discuss data acquisition and preprocessing steps that fill the gap between research questions posed by subject matter scientists and statistical methodology for formal inference. Issues include participant recruitment, data collection training and standardization, variable coding, data review and verification, data cleaning and editing, and documentation. Despite the critical importance of these details in research, most of these issues are rarely discussed in an applied statistics program. One reason for the lack of more formal training is the difficulty in addressing the many challenges that can possibly arise in the course of a study in a systematic way. This article can help to bridge this gap between research questions and formal statistical inference by using an illustrative case study for a discussion. We hope that reading and discussing this paper and practicing data preprocessing exercises will sensitize statistics students to these important issues and achieve optimal conduct, quality control, analysis, and interpretation of a study.

Dietary isothiocyanates, GSTM1, GSTT1, NAT2 polymorphisms and bladder cancer risk.

Isothiocyanates (ITCs) are nonnutrient compounds in cruciferous vegetables with anticarcinogenic properties. ITCs down-regulate cytochrome P-450 biotransformation enzyme levels, activate Phase II detoxifying enzymes and induce apoptosis. On the other hand, ITCs also serve as a substrate for GSTs. Experimental evidences suggest that ITCs have anticarcinogenic effect on bladder cancer. Therefore, we evaluated dietary intake of ITCs, GSTM1, GSTT1 and NAT2 polymorphisms, and bladder cancer risk in a case-control study. There were 697 newly diagnosed bladder cancer cases identified from The University of Texas M. D. Anderson Cancer Center and 708 healthy controls matched to cases by age (+/-5), gender and ethnicity. Participants underwent an in-person interview, in which epidemiologic and food frequency questionnaires were administered to collect demographic and dietary intake data. Median ITC intake per day was statistically significantly lower in cases than in controls (0.23 vs. 0.33, p < 0.001). High ITC intake was associated with 29% decreased risk of bladder cancer [Odds ratio (OR) = 0.71, 95% confidence interval (CI) = 0.57, 0.89]. The protective effect was more evident in older individuals (> or =64-years-old), men, ever smokers and heavy smokers in stratified analysis. Compared with NAT2 rapid acetylator, NAT2 slow acetylator had an increased risk of bladder cancer in Caucasians (OR = 1.31, 95% CI = 1.02, 1.69). There was no main effect associated with the GSTM1 or GSTT1 genotypes. The protective effect of ITCs against bladder cancer was not modified by GSTM1, GSTT1 or NAT2 genotypes. This is the first epidemiological report that ITCs from cruciferous vegetable consumption protect against bladder cancer.

Dietary phytoestrogens and lung cancer risk.

CONTEXT: Despite lung-specific in vitro and in vivo studies that support a chemopreventive role for phytoestrogens, there has been little epidemiologic research focused on dietary intake of phytoestrogens and risk of lung cancer. OBJECTIVE: To examine the relationship between dietary intake of phytoestrogens and risk of lung cancer. DESIGN, SETTING, AND PARTICIPANTS: Ongoing US case-control study of 1674 patients with lung cancer (cases) and 1735 matched healthy controls. From July 1995 through October 2003, participants were personally interviewed with epidemiologic and food frequency questionnaires to collect demographic information and to quantify dietary intake of 12 individual phytoestrogens. MAIN OUTCOME MEASURE: Risk of lung cancer, estimated using unconditional multivariable logistic regression analyses stratified by sex and smoking status and adjusted for established and putative lung cancer risk factors. RESULTS: Reductions in risk of lung cancer tended to increase with each increasing quartile of phytoestrogen intake. The highest quartiles of total phytosterols, isoflavones, lignans, and phytoestrogens were each associated with reductions in risk of lung cancer ranging from 21% for phytosterols (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.64-0.97; P = .03 for trend) to 46% for total phytoestrogens from food sources only (OR, 0.54; 95% CI, 0.42-0.70; P<.001 for trend). Sex-specific effects were also apparent. For men, statistically significant trends for decreasing risk with increasing intake were noted for each phytoestrogen group, with protective effects for the highest quartile of intake ranging from 24% for phytosterols (OR, 0.76; 95% CI, 0.56-1.02; P = .04 for trend) to 44% for isoflavones (OR, 0.56; 95% CI, 0.41-0.76; P<.001 for trend), while in women, significant trends were only present for intake of total phytoestrogens from food sources only, with a 34% (OR, 0.66; 95% CI, 0.46-0.96; P = .01 for trend) protective effect for the highest quartile of intake. The apparent benefits of high phytoestrogen intake were evident in both never and current smokers but less apparent in former smokers. In women, statistically significant joint effects were evident between hormone therapy use and phytoestrogen intake. Specifically, high intake of the lignans enterolactone and enterodiol and use of hormone therapy were associated with a 50% (OR, 0.50; 95% CI, 0.31-0.68; P = .04 for interaction) reduction in risk of lung cancer. CONCLUSIONS: While there are limitations and concerns regarding case-control studies of diet and cancer, these data provide further support for the limited but growing epidemiologic evidence that phytoestrogens are associated with a decrease in risk of lung cancer. Confirmation of these findings is still required in large-scale, hypothesis-driven, prospective studies.

Polymorphisms of methionine synthase and methionine synthase reductase and risk of lung cancer: a case-control analysis.

Although tobacco is the major lung cancer risk factor, folate deficiency has also been implicated as a risk. Methionine synthase (MS; gene symbol, MTR) and methionine synthase reductase (MSR; gene symbol, MTRR) play important roles in the folate metabolism pathway. It was hypothesized that polymorphisms of MTR and MTRR are associated with lung cancer risk and interact with dietary intake of folate-related nutrients in lung cancer etiology. In a hospital-based, case-control study of 1,035 lung cancer cases and 1,148 controls of non-Hispanic whites, frequency matched by age, sex, ethnicity and smoking status, the MTR 2756A>G and MTRR 66A>G polymorphisms were genotyped. It was found that the MTRRG allele was associated with a significantly increased lung cancer risk [adjusted odd ratio (OR)=1.34, 95% confidence interval (CI)=1.06-1.70 for the AG genotype and OR=1.39, 95% CI=1.08-1.78 for the GG genotype compared to the AA genotype]. Further analysis suggested some evidence of gene-diet interactions between the MTRR 66A>G polymorphism and dietary intake of total folate and vitamin B12. When the two polymorphisms were evaluated together by the number of the variant alleles (i.e. the MTR2756G and MTRR66A), lung cancer risk was significantly increased in a dose-dependent manner (Ptrend=0.045). The risk of lung cancer was 1.29 (0.98-1.69) for one variant allele, and 1.36 (1.04-1.77) for two or more variant alleles compared to the wild-type (0 variant allele) genotype. In conclusion, our data provide evidence supporting the association between the MTR 2756A>G and MTRR 66A>G polymorphisms and lung cancer risk, which may be modulated by dietary nutrient intake.

Sex differences in risk of lung cancer associated with methylene-tetrahydrofolate reductase polymorphisms.

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the metabolism of folate and nucleotides needed for DNA synthesis and repair. Variations in MTHFR functions likely play roles in the etiology of lung cancer. The MTHFR gene has three nonsynonymous single nucleotide polymorphisms (i.e., C677T, A1298C, and G1793A) that have a minor allele frequency of >5%. We investigated the associations between the frequencies of MTHFR variant genotypes and risk of lung cancer in a hospital-based case-control study of 1,051 lung cancer patients and 1,141 cancer-free controls in a non-Hispanic White population. We found that compared with the MTHFR 1298AA genotype, the 1298CC genotype was associated with a significantly increased risk of lung cancer in women [(odds ratio (OR), 2.09; 95% confidence interval (95% CI), 1.32-3.29)] but not in men (OR, 0.95; 95% CI, 0.62-1.45). The MTHFR 677TT genotype was associated with a significantly decreased risk of lung cancer in women (OR, 0.60; 95% CI, 0.40-0.92) but not in men. No association was found between the MTHFR G1793A polymorphism and risk of lung cancer. Further analysis suggested evidence of gene-dietary interactions between the MTHFR C677T polymorphism and dietary intake of vitamin B6, vitamin B12, and methionine in women and evidence of gene-environment interactions between the MTHFR C677T and A1298C polymorphisms and tobacco smoking in men. In conclusion, the polymorphisms of MTHFR may contribute to the risk of lung cancer in non-Hispanic Whites and modify the risk associated with the dietary and environmental exposure in a sex-specific manner.

Case-control analysis of dietary folate and risk of bladder cancer.

Dietary folate, a water-soluble B vitamin found in a variety of fruits and vegetables, is of particular interest as a chemopreventive agent due to its role in DNA methylation and DNA synthesis and repair. We hypothesized that individuals with low folate intake would be at an increased risk for bladder cancer. Using an ongoing case-control study we assessed dietary folate in 409 incident bladder cancer patients and 451 healthy control subjects. A food-frequency questionnaire was used to estimate naturally occurring food folate (microg/kcal/day), dietary folate equivalents (DFE) from food sources (microg DFE/kcal/day), and DFE from all sources (microg DFE/kcal/day). Unconditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Bladder cancer patients reported a statistically significant lower intake of folate than control subjects for food folate and DFE from food sources (P < 0.001) but not for DFE from all sources (P = 0.061). In the highest quartile of food folate intake there was a 54% reduced risk for bladder cancer (OR = 0.46; 95% CI = 0.29-0.73) after adjusting for age, gender, ethnicity, smoking, and total energy intake. Similarly, the highest quartile of intake was associated with a 59% reduced risk for DFE from food sources (OR = 0.41; 95% CI = 0.26-0.65) and a 35% reduced risk for DFE from all sources (OR = 0.65; 95% CI = 0.42-1.00). In the joint-effects analyses using never smokers with high folate intake as the reference group (OR = 1.0), heavy smokers with low food folate intake had a 2.31-fold (95% CI = 1.11-4.82) increased risk, whereas heavy smokers with high folate intake had a reduced OR of 1.31 (95% CI = 0.53-3.26). Although the ORs were not statistically significant, light smokers and high folate intake exhibited a protective effect (OR = 0.62; 95% CI = 0.20-1.94), whereas an increased risk was observed for light smoking and low folate intake (OR = 1.41; 95% CI = 0.57-3.45). These patterns were consistent for the joint effects of smoking and DFE from food sources and DFE from all sources. In summary, high intake of dietary folate was associated with an overall decrease in bladder cancer risk. These data may have important implications for cancer prevention; however, large, hypothesis-driven, population-based clinical trials will be required to confirm these findings.

Dietary carotenoids and genetic instability modify bladder cancer risk.

In vitro and in vivo studies have shown that carotenoid supplementation is associated with decreased DNA damage, but the role of dietary carotenoids in cancer risk remains controversial because epidemiologic studies have yielded conflicting results. Limited data exist regarding the role of dietary carotenoids in the context of constitutional genetic instability in cancer risk. This case-control study estimated dietary carotenoid intake [microg/(kJ . d)] from a FFQ for 423 patients with bladder cancer and 467 healthy controls, and quantified baseline and benzo[a]pyrene diol epoxide (BPDE)- and gamma-radiation-induced DNA damage in the peripheral blood lymphocytes using the comet assay. Overall, intake of total carotenoids was lower (P < 0.01) for bladder cancer cases (mean +/- SD: 1273.4 +/- 688.9) compared with healthy controls (1501.3 +/- 791.5). When categorized into quartiles, there was an inverse association between increasing levels of carotenoid intake and bladder cancer risk with greatest protective effect [odds ratio (OR) = 0.56, 95% CI, 0.37-0.85] in the quartile with the highest level of intake. Baseline and mutagen-induced DNA damage was significantly higher in cases than in controls; when analyzed jointly with carotenoid intake, high DNA damage and low carotenoid intake were associated with the highest risk. For example, with high baseline DNA damage and low total carotenoid intake, the OR was 3.08 (95% CI, 1.64-5.77); with high baseline DNA damage and high total carotenoid intake, the risk was somewhat attenuated (OR = 2.49, 95% CI, 1.28-4.84). The risk was decreased further for low baseline DNA damage and low total carotenoid intake (OR = 2.18; 95% CI, 1.13-4.22). This study provides evidence of a preventive role for carotenoids in bladder cancer, and these data may have important implications for cancer prevention, especially for individuals susceptible to DNA damage.

Polymorphisms of folate metabolic genes and susceptibility to bladder cancer: a case-control study.

Epidemiological studies have shown an association between low folate intake and an increased cancer risk. Major genes involved in folate metabolism include methylene-tetrahydrofolate reductase (MTHFR) and methionine synthase (MS). We investigated joint effects of polymorphisms of the MTHFR (677 C-->T, 1298A-->C) and MS genes (2756 A-->G), dietary folate intake and cigarette smoking on the risk of bladder cancer in a case-control study. The study population consisted of 457 bladder cancer patients and 457 healthy controls, matched to the cases in terms of age, gender and ethnicity. Genotype data were analyzed in a subset of 410 Caucasian cases and 410 controls. Compared with individuals carrying the MTHFR 677 wild-type (CC) and reporting a high folate intake, those carrying the variant genotype (CT or TT) and reporting a low folate intake were at a significantly 3.51-fold increased risk of bladder cancer (95% CI: 1.59-6.52). In contrast, individuals carrying a variant genotype and reporting a high folate intake were at only a 1.39-fold increased risk (95% CI: 0.71-2.70), and those carrying the wild-type and reporting a low folate intake were at only 1.56-fold increased risk (95% CI: 0.82-2.97). The interaction between genetic polymorphisms and folate intake was significant on the multiplicative scale (P = 0.01). When analyzed in the context of smoking status, compared with never smokers with the MTHFR 677 wild-type, the risk increased to 6.56-fold (95% CI: 3.28-13.12) in current smokers carrying the variant genotype. Analyses of the MTHFR 1298, MS 2756 genes revealed similar results. In addition, age at cancer onset in former smokers increased as the proportion of the heteromorphic haplotype in the individual increased (P = 0.005). Our results strongly suggest that polymorphisms of the MTHFR and MS genes act together with low folate intake and smoking to increase bladder cancer risk. These results have important implications for cancer prevention in susceptible populations.