Effect Modification of Selenium Supplementation by Intake and Serum Concentrations of Antioxidants on the Development of Metachronous Colorectal Adenoma.

BACKGROUND: Selenium (Se) is a trace element that has been investigated as a potential chemopreventive agent for colorectal cancer. Dietary intake of other antioxidant nutrients may modify the effect of Se. OBJECTIVE: We examined the association between intake and serum concentrations of retinol, ß-carotene, ß-cryptoxanthin, lycopene, lutein/zeaxanthin, and α- and γ-tocopherol and the development of metachronous colorectal adenoma, and if these nutrients modified the effect of Se. METHODS: We conducted a prospective study of 1874 participants from the Se Trial with data for antioxidant intake, as well as a subcohort of 508 participants with serum biomarker concentrations. RESULTS: Statistically significantly lower odds for the development of metachronous adenoma were observed for those participants in the highest tertile of intake for lutein/zeaxanthin compared to the lowest, with an OR (95% CI) of 0.72 (0.56-0.94). No effect modification for intake of any nutrient was observed. However, circulating concentrations of lycopene exhibited statistically significant effect modification of selenium supplementation (p < 0.06). CONCLUSION: These findings show that intake and circulating concentrations of antioxidant nutrients were not consistently associated with reduced odds for the development of metachronous lesions, although blood concentrations of lycopene may modify the effect of selenium supplementation.

Genome-Wide Association Study of Metachronous Colorectal Adenoma Risk among Participants in the Selenium Trial.

Genetic variants related to colorectal adenoma may help identify those who are at highest risk of colorectal cancer development or illuminate potential chemopreventive strategies. The purpose of this genome-wide association study was to identify genetic variants that are associated with risk of developing a metachronous colorectal adenoma among 1,215 study participants of European descent from the Selenium Trial. Associations of variants were assessed with logistic regression analyses and validated in an independent case-control study population of 1,491 participants from the Colorectal Cancer Study of Austria (CORSA). No statistically significant genome-wide associations between any variant and metachronous adenoma were identified after correction for multiple comparisons. However, an intron variant of FAT3 gene, rs61901554, showed a suggestive association (P = 1.10 × 10-6) and was associated with advanced adenomas in CORSA (P = 0.04). Two intronic variants, rs12728998 and rs6699944 in NLRP3 were also observed to have suggestive associations with metachronous lesions (P = 2.00 × 10-6) in the Selenium Trial and were associated with advanced adenoma in CORSA (P = 0.03). Our results provide new areas of investigation for the genetic basis of the development of metachronous colorectal adenoma and support a role for FAT3 involvement in the Wnt/ß-catenin pathway leading to colorectal neoplasia.Trial Registration number: NCT00078897 (ClinicalTrials.gov).

Mail-Based Self-Sampling to Complete Colorectal Cancer Screening: Accelerating Colorectal Cancer Screening and Follow-up Through Implementation Science.

Introduction: Leveraging cancer screening tests, such as the fecal immunochemical test (FIT), that allow for self-sampling and postal mail for screening invitations, test delivery, and return can increase participation in colorectal cancer (CRC) screening. The range of approaches that use self-sampling and mail for promoting CRC screening, including use of recommended best practices, has not been widely investigated. Methods: We characterized self-sampling and mail strategies used for implementing CRC screening across a consortium of 8 National Cancer Institute Cancer Moonshot Initiative Accelerating Colorectal Cancer Screening and Follow-up through Implementation Science (ACCSIS) research projects. These projects serve diverse rural, urban, and tribal populations in the US. Results: All 8 ACCSIS projects leveraged self-sampling and mail to promote screening. Strategies included organized mailed FIT outreach with mailed invitations, including FIT kits, reminders, and mailed return (n = 7); organized FIT-DNA outreach with mailed kit return (n = 1); organized on-demand FIT outreach with mailed offers to request a kit for mailed return (n = 1); and opportunistic FIT-DNA with in-clinic offers to be mailed a test for mailed return (n = 2). We found differences in patient identification strategies, outreach delivery approaches, and test return options. We also observed consistent use of Centers for Disease Control and Prevention Summit consensus best practice recommendations by the 7 projects that used mailed FIT outreach. Conclusion: In research projects reaching diverse populations in the US, we observed multiple strategies that leverage self-sampling and mail to promote CRC screening. Mail and self-sampling, including mailed FIT outreach, could be more broadly leveraged to optimize cancer screening.

Genome-Wide Association Study of Response to Selenium Supplementation and Circulating Selenium Concentrations in Adults of European Descent.

BACKGROUND: Selenium (Se) is a trace element that has been linked to many health conditions. Genome-wide association studies (GWAS) have identified variants for blood and toenail Se levels, but no GWAS has been conducted to date on responses to Se supplementation. OBJECTIVES: A GWAS was performed to identify the single nucleotide polymorphisms (SNPs) associated with changes in Se concentrations after 1 year of supplementation. A GWAS of basal plasma Se concentrations at study entry was conducted to evaluate whether SNPs for Se responses overlap with SNPs for basal Se levels. METHODS: A total of 428 participants aged 40-80 years of European descent from the Selenium and Celecoxib Trial (Sel/Cel Trial) who received daily supplementation with 200 µg of selenized yeast were included for the GWAS of responses to supplementation. Plasma Se concentrations were measured from blood samples collected at the time of recruitment and after 1 year of supplementation. Linear regression analyses were performed to assess the relationship between each SNP and changes in Se concentrations. We further examined whether the identified SNPs overlapped with those related to basal Se concentrations. RESULTS: No SNP was significantly associated with changes in Se concentration at a genome-wide significance level. However, rs56856693, located upstream of the NEK6, was nominally associated with changes in Se concentrations after supplementation (P = 4.41 × 10-7), as were 2 additional SNPs, rs11960388 and rs6887869, located in the dimethylglycine dehydrogenase (DMGDH)/betaine-homocysteine S-methyltransferase (BHMT) region (P = 0.01). Alleles of 2 SNPs in the DMGDH/BHMT region associated with greater increases in Se concentrations after supplementation were also strongly associated with higher basal Se concentrations (P = 8.67 × 10-8). CONCLUSIONS: This first GWAS of responses to Se supplementation in participants of European descent from the Sel/Cel Trial suggests that SNPs in the NEK6 and DMGDH/BHMT regions influence responses to supplementation.

Effects of a Community-to-Clinic Navigation Intervention on Colorectal Cancer Screening Among Underserved People.

BACKGROUND: Colorectal cancer screening remains suboptimal among poor and underserved people. PURPOSE: We tested the effectiveness of a community-to-clinic navigator intervention to guide multicultural, underinsured individuals into primary care clinics to complete colorectal cancer screening. METHODS: This two-phase behavioral intervention study was conducted in Phoenix, Arizona (2012-2018). Community sites were randomized to group education or group education plus tailored navigation to increase attendance at primary care clinics (Phase I). Individuals who completed a clinic appointment received the tailored navigation in person or via phone (Phase II). RESULTS: In Phase I (N = 345), 37.9% of the intervention group scheduled a clinic appointment versus 19.4% of the comparison group. In Phase II, 26.5% of the original intervention group were screened versus only 10.4% of the original comparison group. Those in the intervention group were 3.84 times more likely to be screened than were those in the comparison group (odds ratio = 3.84; 95% confidence interval = 1.81-6.92). CONCLUSIONS: Translation of an efficacious tailored navigation intervention for colorectal cancer screening to a community-to-clinic context is associated with significantly increased rates of colorectal cancer screening. Navigation assistance to address barriers to screening may serve as the most important component of any educational program to increase individual adherence to colorectal cancer screening.

Longitudinal examination of changing fertility intentions and behaviors over a four-year period in urban Senegal.

BACKGROUND: Fertility intentions and contraceptive use are often used to demonstrate gaps in programs and policies to meet the contraceptive needs of women and couples. Prior work demonstrated that fertility intentions are fluid and change over a woman's (or couple's) life course with changing marital status, childbearing, and education/employment opportunities. This study uses longitudinal data to better examine the fluidity of women's fertility intentions and disentangle the complex interrelationships between fertility and contraceptive use. METHODS: Using survey data from three time points and three urban sites in Senegal, this study examines how women's fertility intentions and contraceptive use in an earlier period affect pregnancy experience and the intentionality of experienced pregnancies among a sample of 1050 women who were in union at all three time points. We apply correlated random effect longitudinal regression methods to predict a subsequent birth by fertility intentions and modern contraceptive use at an earlier period addressing endogeneity concerns of earlier analyses that only include two time periods. RESULTS: Descriptive results demonstrate some change in fertility desires over time such that 6-8% of women who reported their pregnancy as intended (i.e., wanted to get pregnant at time of pregnancy) reported earlier that they did not want any(more) children. Multivariate analyses demonstrate that women who want to delay or avoid a pregnancy and are using modern contraception are the least likely to get pregnant. Among women who became pregnant, the only factor differentiating whether the pregnancy is reported as intended or unintended (mistimed or unwanted) was prior fertility intention. Women who wanted to delay a pregnancy previously were more likely to report the pregnancy as unintended compared to women who wanted to get pregnant soon. CONCLUSIONS: These results suggest some post-hoc rationalization among women who are getting pregnant. Women who say they do not want to get pregnant may be choosing not to use a contraceptive method in this urban Senegal context of high fertility. Programs seeking to reach these women need to consider their complex situations including their fertility intentions, family planning use, and the community norms within which they are reporting these intentions and behaviors.

Assessing the sustainability of the Nigerian urban reproductive health initiative facility-level programming: longitudinal analysis of service quality.

BACKGROUND: To date, there is little information on the sustainability of family planning (FP) service quality after completion of a donor-funded program. This paper examines the sustainability of the Nigerian Urban Reproductive Health Initiative (NURHI) program on quality of FP services in two cities: Ilorin, where the program ended in March 2015 and Kaduna where the program continued. METHODS: Data come from three time periods: 2011, before program implementation; 2014, near Phase 1 completion; and 2017, two-years post Phase 1. In 2011, we undertook a facility audit and provider surveys in all public sector facilities in each city as well as all private facilities mentioned as the source for FP or maternal, newborn, and child health services in a 2010 women's household survey. In 2014 and 2017, we returned to the same facilities to undertake the facility audit and provider surveys. Quality is measured from principal component analyses of 30 items from the facility audit and provider surveys. Service use outcomes are measured as the ratio of FP clients (total and new) to the number of reproductive health staff members. Multivariate random effect models are estimated to examine changes in the outcomes over time, between NURHI and non-NURHI facilities and by city. RESULTS: We demonstrate that NURHI facilities had better quality and higher service use than non-NURHI facilities. Further, while quality of services was higher in Ilorin in 2011, by 2014 and three years later (2017), the quality was better in Kaduna where the program continued. In addition, while no difference was found in service utilization between Ilorin and Kaduna in 2014, by 2017, Kaduna had significantly more new FP users than Ilorin. CONCLUSIONS: In Ilorin, quality of services did not continue its strong upward trend after the program ended. Programs need to consider long-term strategies that support continuation of program components post program implementation. This may include ensuring continued training of providers and addressing equipment and commodity stock-outs through system changes rather than specific facility-level changes. The findings from this study can be used to inform future programs seeking to improve quality of FP services in a sustainable manner.

Higher Plasma Selenium Concentrations Are Associated with Increased Odds of Prevalent Type 2 Diabetes.

Background: Selenium, an essential trace element, has been investigated as a potential cancer prevention agent. However, several studies have indicated that selenium supplementation may be associated with an increased risk of type 2 diabetes (T2D), although an equivocal relation of this nature requires confirmation. Objective: We examined the association between baseline plasma concentrations of selenium and the prevalence of T2D, as well as whether participant characteristics or intake of other antioxidant nutrients modified this relation. Methods: We conducted cross-sectional analyses of 1727 participants from the Selenium Trial, a randomized clinical trial of selenium supplementation for colorectal adenoma chemoprevention that had data for baseline selenium plasma concentrations, T2D status, and dietary intake. Logistic regression modeling was used to evaluate the associations between plasma selenium concentrations and prevalent T2D, adjusting for confounding factors. Heterogeneity of effect by participant characteristics was evaluated utilizing likelihood-ratio tests. Results: Mean ± SD plasma selenium concentrations for those with T2D compared with those without T2D were 143.6 ± 28.9 and 138.7 ± 27.2 ng/mL, respectively. After adjustment for confounding, higher plasma selenium concentrations were associated with a higher prevalence of T2D, with ORs (95% CIs) of 1.25 (0.80, 1.95) and 1.77 (1.16, 2.71) for the second and third tertiles of plasma selenium, respectively, compared with the lowest tertile (P-trend = 0.007). No significant effect modification was observed for age, sex, body mass index, smoking, or ethnicity. Increased odds of T2D were seen among those who were in the highest tertile of plasma selenium and the highest category of intake of ß-cryptoxanthin (P-trend = 0.03) and lycopene (P-trend = 0.008); however, interaction terms were not significant. Conclusions: These findings show that higher plasma concentrations of selenium were significantly associated with prevalent T2D among participants in a selenium supplementation trial. Future work is needed to elucidate whether there are individual characteristics, such as blood concentrations of other antioxidants, which may influence this relation.

Inactivation of Adenomatous Polyposis Coli Reduces Bile Acid/Farnesoid X Receptor Expression through Fxr gene CpG Methylation in Mouse Colon Tumors and Human Colon Cancer Cells.

BACKGROUND: The farnesoid X receptor (FXR) regulates bile acid (BA) metabolism and possesses tumor suppressor functions. FXR expression is reduced in colorectal tumors of subjects carrying inactivated adenomatous polyposis coli (APC). Identifying the mechanisms responsible for this reduction may offer new molecular targets for colon cancer prevention. OBJECTIVE: We investigated how APC inactivation influences the regulation of FXR expression in colonic mucosal cells. We hypothesized that APC inactivation would epigenetically repress nuclear receptor subfamily 1, group H, member 4 (FXR gene name) expression through increased CpG methylation. METHODS: Normal proximal colonic mucosa and normal-appearing adjacent colonic mucosa and colon tumors were collected from wild-type C57BL/6J and Apc-deficient (Apc(Min) (/+)) male mice, respectively. The expression of Fxr, ileal bile acid-binding protein (Ibabp), small heterodimer partner (Shp), and cyclooxygenase-2 (Cox-2) were determined by real-time polymerase chain reaction. In both normal and adjacent colonic mucosa and colon tumors, we measured CpG methylation of Fxr in bisulfonated genomic DNA. In vitro, we measured the impact of APC inactivation and deoxycholic acid (DCA) treatment on FXR expression in human colon cancer HCT-116 cells transfected with silencing RNA for APC and HT-29 cells carrying inactivated APC. RESULTS: In Apc(Min) (/+) mice, constitutive CpG methylation of the Fxrα3/4 promoter was linked to reduced (60-90%) baseline Fxr, Ibabp, and Shp and increased Cox-2 expression in apparently normal adjacent mucosa and colon tumors. Apc knockdown in HCT-116 cells increased cellular myelocytomatosis (c-MYC) and lowered (∼50%) FXR expression, which was further reduced (∼80%) by DCA. In human HCT-116 but not HT-29 colon cancer cells, DCA induced FXR expression and lowered CpG methylation of FXR. CONCLUSIONS: We conclude that the loss of APC function favors the silencing of FXR expression through CpG hypermethylation in mouse colonic mucosa and human colon cells, leading to reduced expression of downstream targets (SHP, IBABP) involved in BA homeostasis while increasing the expression of factors (COX-2, c-MYC) that contribute to inflammation and colon cancer.

CYP24A1 and CYP27B1 Polymorphisms, Concentrations of Vitamin D Metabolites, and Odds of Colorectal Adenoma Recurrence.

Development of colorectal adenoma and cancer are associated with low circulating 25-hydroxyvitamin D [25(OH)D] levels. However, less is known regarding colorectal neoplasia risk and variation in CYP27B1 or CYP24A1, genes encoding the enzymes responsible for the synthesis and catabolism of 1α,25-hydroxyvitamin D [1,25(OH)2D]. This study examined associations between CYP27B1 and CYP24A1 polymorphisms, circulating 25(OH)D and 1,25(OH)2D concentrations, and colorectal adenoma recurrence in a pooled sample from 2 clinical trials (n = 1,188). Nominal associations were observed between increasing copies of the T allele in CYP24A1 rs927650 and 25(OH)D concentrations (P = 0.02); as well as colorectal adenoma recurrence, with odds ratios (95% confidence intervals) of 1.30 (0.99-1.70) and 1.38 (1.01-1.89) for heterozygotes and minor allele homozygotes, respectively (P = 0.04). In addition, a statistically significant relationship between CYP24A1 rs35051736, a functional polymorphism, and odds for advanced colorectal adenoma recurrence was observed (P < 0.001). Further, nominally statistically significant interactions were observed between rs2296241 and 25(OH)D as well as rs2762939 and 1,25(OH)2D (P(interaction) = 0.10, respectively). Overall, CYP24A1 polymorphisms may influence the development of advanced lesions, and modify the effect of vitamin D metabolites on adenoma recurrence. Further study is necessary to characterize the differences between circulating vitamin D metabolite measurements compared to cellular level activity in relation to cancer risk.

Fertility desires, family planning use and pregnancy experience: longitudinal examination of urban areas in three African countries.

BACKGROUND: Many women have inconsistent fertility desires and contraceptive use behaviors. This increases their risk of unintended pregnancies. Inconsistencies may reflect barriers to family planning (FP) use but may also reflect ambivalence toward future childbearing. Using urban data from Kenya, Nigeria, and Senegal, this study examines the role of fertility desires and FP use behaviors on pregnancy experience over a 2-year follow-up period. METHODS: Data come from baseline and 2-year follow-up among urban women interviewed in Kenya, Nigeria, and Senegal. At baseline (2010/2011), women were asked about their future fertility desires (want child soon, want to delay >2 years, does not want) and current FP use. At midterm (2012/2013), women were asked if they were currently pregnant or had a birth in the 2-year period. We examine the association between baseline fertility desires and FP use with pregnancy experience and desirability of an experienced pregnancy. RESULTS: In the 2-year follow-up period, 27-39% of women in union experienced a pregnancy or birth. In Kenya and Nigeria, 30-35% of women using a modern FP method experienced a pregnancy/birth; the percentage with a pregnancy/birth was slightly higher among women not using at baseline (41% in both countries). In Senegal, the distinction between pregnancy experience between users and non-users was greater (16% vs. 31%, respectively). In all countries, pregnancy was less common among users of long-acting and permanent methods; only a small percentage of women use these methods. Women not wanting any(more) children were the least likely to experience a pregnancy in the 2-year follow-up period. No differences were observed between those who wanted to delay and those who wanted soon. Multivariate findings demonstrate distinctions in pregnancy experience by fertility desires among modern FP users. Non-users have similar pregnancy experience by fertility desires. CONCLUSIONS: Fertility desires are not stable; providers need to consider the fluidity of fertility desires in counseling clients. Programs focusing on new FP users may miss women who are the most motivated to avoid a pregnancy and need to switch to a more effective method; this will result in less unintended pregnancies overall.

Descriptive study of the role of household type and household composition on women's reproductive health outcomes in urban Uttar Pradesh, India.

BACKGROUND: More needs to be known about the role intra-familial power dynamics play in women's reproductive health outcomes, particularly in societies like Northern India characterized by patriarchy and extended families. The key research question we explore is: how important are living arrangements (e.g., presence of the mother-in-law, presence of an elder sister-in-law, and living in the husband's natal home) on contraceptive use behaviors and decision to deliver at an institution? METHODS: Representative data collected in 2010 from six cities in Uttar Pradesh are used to examine the above research question. This study uses multivariable logistic regression methods to examine the association between women's household type (husband's natal home vs. not husband's natal home) and household composition (lives with mother-in-law; and lives with elder sister-in-law) and modern family planning use and institutional delivery. RESULTS: More than sixty percent of women in the sample live in their husband's natal home, one-third live with their mother-in-law, and only three percent live with an elder sister-in-law. Findings demonstrate that women who live either with the mother-in-law or in the husband's natal home are more likely to use modern family planning than those women living neither with the mother-in-law nor in the husband's natal home. In addition, living with an elder sister-in-law is associated with less family planning use. For institutional delivery, women who live with the mother-in-law have higher institutional delivery than those not living with the mother-in-law. Multivariable analyses demonstrate that, controlling for other factors associated with modern family planning use, women living with neither the mother-in-law nor in the husband's natal home are the least likely to use modern family planning. Similar findings are found for institutional delivery such that those women living with neither the mother-in-law nor in the husband's natal home are the least likely to have an institutional delivery, controlling for demographic factors associated with institutional delivery. CONCLUSIONS: Where women live and who they live with matters. Future reproductive health programs for urban India should consider these context specific factors in programs seeking to improve women's reproductive health outcomes.

Colorectal cancers soon after colonoscopy: a pooled multicohort analysis.

OBJECTIVE: Some individuals are diagnosed with colorectal cancer (CRC) despite recent colonoscopy. We examined individuals under colonoscopic surveillance for colonic adenomas to assess possible reasons for diagnosing cancer after a recent colonoscopy with complete removal of any identified polyps. DESIGN: Primary data were pooled from eight large (>800 patients) North American studies in which participants with adenoma(s) had a baseline colonoscopy (with intent to remove all visualised lesions) and were followed with subsequent colonoscopy. We used an algorithm based on the time from previous colonoscopy and the presence, size and histology of adenomas detected at prior exam to assign interval cancers as likely being new, missed, incompletely resected (while previously an adenoma) or due to failed biopsy detection. RESULTS: 9167 participants (mean age 62) were included in the analyses, with a median follow-up of 47.2 months. Invasive cancer was diagnosed in 58 patients (0.6%) during follow-up (1.71 per 1000 person-years follow-up). Most cancers (78%) were early stage (I or II); however, 9 (16%) resulted in death from CRC. We classified 30 cancers (52%) as probable missed lesions, 11 (19%) as possibly related to incomplete resection of an earlier, non-invasive lesion and 14 (24%) as probable new lesions. The cancer diagnosis may have been delayed in three cases (5%) because of failed biopsy detection. CONCLUSIONS: Despite recent colonoscopy with intent to remove all neoplasia, CRC will occasionally be diagnosed. These cancers primarily seem to represent lesions that were missed or incompletely removed at the prior colonoscopy and might be avoided by increased emphasis on identifying and completely removing all neoplastic lesions at colonoscopy.

Associations between circulating 1,25(OH)2D concentration and odds of metachronous colorectal adenoma.

Cellular-level studies demonstrate that the availability of the secosteroid hormone 1α,25-dihydroxyvitamin D [1,25(OH)2D] to colon cells promotes anti-carcinogenic activities. Although epidemiological data are relatively sparse, suggestive inverse trends have been reported between circulating 1,25(OH)2D concentration and colorectal neoplasia. We therefore sought to evaluate the relationship between circulating 1,25(OH)2D concentrations and odds for metachronous colorectal adenomas among 1,151 participants from a randomized trial of ursodeoxycholic acid for colorectal adenoma prevention. No relationship between 1,25(OH)2D and overall odds for metachronous lesions was observed, with ORs (95% CIs) of 0.80 (0.60-1.07) and 0.81 (0.60-1.10) for participants in the second and third tertiles, respectively, compared with those in the lowest (p-trend = 0.17). However, a statistically significant inverse association was observed between circulating 1,25(OH)2D concentration and odds of proximal metachronous adenoma, with an OR (95% CI) of 0.71 (0.52-0.98) for individuals in the highest tertile of 1,25(OH)2D compared with those in the lowest (p-trend = 0.04). While there was no relationship overall between 1,25(OH)2D and metachronous distal lesions, there was a significantly reduced odds for women, but not men, in the highest 1,25(OH)2D tertile compared with the lowest (OR 0.53; 95% CI 0.27-1.03; p-trend = 0.05; p-interaction = 0.08). The observed differences in associations with proximal and distal adenomas could indicate that delivery and activity of vitamin D metabolites in different anatomic sites in the colorectum varies, particularly by gender. These results identify novel associations between 1,25(OH)2D and metachronous proximal and distal colorectal adenoma, and suggest that future studies are needed to ascertain potential mechanistic differences in 1,25(OH)2D action in the colorectum.

Sedentary behavior is associated with colorectal adenoma recurrence in men.

PURPOSE: The association between physical activity and colorectal adenoma is equivocal. This study was designed to assess the relationship between physical activity and colorectal adenoma recurrence. METHODS: Pooled analyses from two randomized, controlled trials included 1,730 participants who completed the Arizona Activity Frequency Questionnaire at baseline, had a colorectal adenoma removed within 6 months of study registration, and had a follow-up colonoscopy during the trial. Logistic regression modeling was employed to estimate the effect of sedentary behavior, light-intensity physical activity, and moderate-vigorous physical activity on colorectal adenoma recurrence. RESULTS: No statistically significant trends were found for any activity type and odds of colorectal adenoma recurrence in the pooled population. However, males with the highest levels of sedentary time experienced 47% higher odds of adenoma recurrence. Compared to the lowest quartile of sedentary time, the ORs (95% CIs) for the second, third, and fourth quartiles among men were 1.23 (0.88, 1.74), 1.41 (0.99, 2.01), and 1.47 (1.03, 2.11), respectively (p(trend) = 0.03). No similar association was observed for women. CONCLUSIONS: This study suggests that sedentary behavior is associated with a higher risk of colorectal adenoma recurrence among men, providing evidence of detrimental effects of a sedentary lifestyle early in the carcinogenesis pathway.

Association between circulating concentrations of 25(OH)D and colorectal adenoma: a pooled analysis.

The relationship between the biomarker of vitamin D status, 25(OH)D, and the risk for colorectal neoplasia is suggestive but equivocal. Questions remain regarding whether there are differential associations between 25(OH)D and colorectal adenoma by gender, colorectal subsite or features of baseline and recurrent adenomas. We sought to investigate the relationship between 25(OH)D and both baseline and recurrent adenoma characteristics. Our study was conducted among 2,074 participants in a pooled population of two clinical intervention trials of colorectal adenoma recurrence. A cross-sectional analysis of 25(OH)D and baseline adenoma characteristics and a prospective study of recurrent adenomas and their characteristics were conducted. There was a statistically significant inverse association between the concentrations of 25(OH)D and the presence of three or more adenomas at baseline. Compared to participants with 25(OH)D levels of <20 ng/mL, the adjusted odds ratios (ORs) (95% condifdence intervals [CIs]) were 0.99 (0.70-1.41) for those with concentrations of ≥20 and <30 ng/mL, and 0.73 (0.50-1.06) among participants with levels of ≥30 ng/mL (p-trend = 0.05). Baseline villous histology was also significantly inversely related to 25(OH)D levels (p-trend = 0.04). Conversely, 25(OH)D concentrations were not associated with overall colorectal adenoma recurrence, with ORs (95% CIs) of 0.91 (0.71-1.17) and 0.95 (0.73-1.24; p-trend = 0.85). These findings support the concept that the relationship between vitamin D and colorectal neoplasia may vary by stage of adenoma development.

IL1ß-mediated Stromal COX-2 signaling mediates proliferation and invasiveness of colonic epithelial cancer cells.

COX-2 is a major inflammatory mediator implicated in colorectal inflammation and cancer. However, the exact origin and role of COX-2 on colorectal inflammation and carcinogenesis are still not well defined. Recently, we reported that COX-2 and iNOS signalings interact in colonic CCD18Co fibroblasts. In this article, we investigated whether activation of COX-2 signaling by IL1ß in primary colonic fibroblasts obtained from normal and cancer patients play a critical role in regulation of proliferation and invasiveness of human colonic epithelial cancer cells. Our results demonstrated that COX-2 level was significantly higher in cancer associated fibroblasts than that in normal fibroblasts with or without stimulation of IL-1ß, a powerful stimulator of COX-2. Using in vitro assays for estimating proliferative and invasive potential, we discovered that the proliferation and invasiveness of the epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts than with normal fibroblasts, with or without stimulation of IL1ß. Further analysis indicated that the major COX-2 product, prostaglandin E(2), directly enhanced proliferation and invasiveness of the epithelial cancer cells in the absence of fibroblasts. Moreover, a selective COX-2 inhibitor, NS-398, blocked the proliferative and invasive effect of both normal and cancer associate fibroblasts on the epithelial cancer cells, with or without stimulation of IL-1ß. Those results indicate that activation of COX-2 signaling in the fibroblasts plays a major role in promoting proliferation and invasiveness of the epithelial cancer cells. In this process, PKC is involved in the activation of COX-2 signaling induced by IL-1ß in the fibroblasts.

iNOS signaling interacts with COX-2 pathway in colonic fibroblasts.

COX-2 and iNOS are two major inflammatory mediators implicated in colorectal inflammation and cancer. Previously, the role of colorectal fibroblasts involved in regulation of COX-2 and iNOS expression was largely ignored. In addition, the combined interaction of COX-2 and iNOS signalings and their significance in the progression of colorectal inflammation and cancer within the fibroblasts have received little investigation. To address those issues, we investigated the role of colonic fibroblasts in the regulation of COX-2 and iNOS gene expression, and explored possible mechanisms of interaction between COX-2 and iNOS signalings using a colonic CCD-18Co fibroblast line and LPS, a potential stimulator of COX-2 and iNOS. Our results clearly demonstrated that LPS activated COX-2 gene expression and enhanced PGE(2) production, stimulated iNOS gene expression and promoted NO production in the fibroblasts. Interestingly, activation of COX-2 signaling by LPS was not involved in activation of iNOS signaling, while activation of iNOS signaling by LPS contributed in part to activation of COX-2 signaling. Further analysis indicated that PKC plays a major role in the activation and interaction of COX-2 and iNOS signalings induced by LPS in the fibroblasts.

Carcinogen metabolism genes, red meat and poultry intake, and colorectal cancer risk.

Diets high in red meat are established risk factors for colorectal cancer (CRC). Carcinogenic compounds generated during meat cooking have been implicated as causal agents. We conducted a family-based case-control study to investigate the association between polymorphisms in carcinogen metabolism genes (CYP1A2 -154A>C, CYP1B1 Leu432Val, CYP2E1 -1054C>T, GSTP1 Ile105Val, PTGS2 5UTR -765, EPHX1 Tyr113His, NAT2 Ile114Thr, NAT2 Arg197Gln and NAT2 Gly286Glu) and CRC risk. We tested for gene-environment interactions using case-only analyses (N = 577) and compared statistically significant results to those obtained using case-unaffected sibling comparisons (N = 307 sibships). Our results suggested that CYP1A2 -154A>C might modify the association between intake of red meat cooked using high temperature methods and well done on the inside and CRC risk (case-only interaction OR = 1.53; 95% CI = 1.19-1.97; p = 0.0008) and the association between intake of red meat heavily browned on the outside and rectal cancer risk (case-only interaction OR = 0.65; 95% CI = 0.48-0.86; p = 0.003). We also found that GSTP1 Ile105Val might modify the association between intake of poultry cooked with high temperature methods and CRC risk (p = 0.0035), a finding that was stronger among rectal cancer cases. Our results support a role for heterocyclic amines that form in red meat as a potential explanation for the observed association between diets high in red meat and CRC. Our findings also suggest a possible role for diets high in poultry cooked at high temperatures in CRC risk.

Stromal COX-2 signaling activated by deoxycholic acid mediates proliferation and invasiveness of colorectal epithelial cancer cells.

COX-2 is a major regulator implicated in colonic cancer. However, how COX-2 signaling affects colonic carcinogenesis at cellular level is not clear. In this article, we investigated whether activation of COX-2 signaling by deoxycholic acid (DCA) in primary human normal and cancer associated fibroblasts play a significant role in regulation of proliferation and invasiveness of colonic epithelial cancer cells. Our results demonstrated while COX-2 signaling can be activated by DCA in both normal and cancer associated fibroblasts, the level of activation of COX-2 signaling is significantly greater in cancer associated fibroblasts than that in normal fibroblasts. In addition, we discovered that the proliferative and invasive potential of colonic epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts pre-treated with DCA than with normal fibroblasts pre-treated with DCA. Moreover, COX-2 siRNA attenuated the proliferative and invasive effect of both normal and cancer associate fibroblasts pre-treated with DCA on the colonic cancer cells. Further studies indicated that the activation of COX-2 signaling by DCA is through protein kinase C signaling. We speculate that activation of COX-2 signaling especially in cancer associated fibroblasts promotes progression of colonic cancer.