Rick J. Jansen

Determinants and Consequences of Arsenic Metabolism Efficiency among 4,794 Individuals: Demographics, Lifestyle, Genetics, and Toxicity

Background: Exposure to inorganic arsenic (iAs), a class I carcinogen, affects several hundred million people worldwide. Once absorbed, iAs is converted to monomethylated (MMA) and then dimethylated forms (DMA), with methylation facilitating urinary excretion. The abundance of each species in urine relative to their sum (iAs%, MMA%, and DMA%) varies across individuals, reflecting differences in arsenic metabolism capacity. Methods: The association of arsenic metabolism phenotypes with participant characteristics and arsenical skin lesions was characterized among 4,794 participants in the Health Effects of Arsenic Longitudinal Study (Araihazar, Bangladesh). Metabolism phenotypes include those obtained from principal component (PC) analysis of arsenic species. Results: Two independent PCs were identified: PC1 appears to represent capacity to produce DMA (second methylation step), and PC2 appears to represent capacity to convert iAs to MMA (first methylation step). PC1 was positively associated (P <0.05) with age, female sex, and BMI, while negatively associated with smoking, arsenic exposure, education, and land ownership. PC2 was positively associated with age and education but negatively associated with female sex and BMI. PC2 was positively associated with skin lesion status, while PC1 was not. 10q24.32/AS3MT region polymorphisms were strongly associated with PC1, but not PC2. Patterns of association for most variables were similar for PC1 and DMA%, and for PC2 and MMA% with the exception of arsenic exposure and SNP associations. Conclusions: Two distinct arsenic metabolism phenotypes show unique associations with age, sex, BMI, 10q24.32 polymorphisms, and skin lesions. Impact: This work enhances our understanding of arsenic metabolism kinetics and toxicity risk profiles. Cancer Epidemiol Biomarkers Prev; 25(2); 381–90. ©2015 AACR.

Fatty acids found in dairy, protein and unsaturated fatty acids are associated with risk of pancreatic cancer in a case–control study

Although many studies have investigated meat and total fat in relation to pancreatic cancer risk, few have investigated dairy, fish and specific fatty acids (FAs). We evaluated the association between intake of meat, fish, dairy, specific FAs and related nutrients and pancreatic cancer. In our American‐based Mayo Clinic case–control study 384 cases and 983 controls frequency matched on recruitment age, race, sex and residence area (Minnesota, Wisconsin or Iowa, USA) between 2004 and 2009. All subjects provided demographic information and completed 144‐item food frequency questionnaire. Logistic regression‐calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) were adjusted for age, sex, cigarette smoking, body mass index and diabetes mellitus. Significant inverse association (trend p‐value < 0.05) between pancreatic cancer and the groupings (highest vs. lowest consumption quintile OR [95% CI]) was as follows: meat replacement (0.67 [0.43–1.02]), total protein (0.58 [0.39–0.86]), vitamin B12 (0.67 [0.44, 1.01]), zinc (0.48 [0.32, 0.71]), phosphorus (0.62 [0.41, 0.93]), vitamin E (0.51 [0.33, 0.78]), polyunsaturated FAs (0.64 [0.42, 0.98]) and linoleic acid (FA 18:2) (0.62 [0.40–0.95]). Increased risk associations were observed for saturated FAs (1.48 [0.97–2.23]), butyric acid (FA 4:0) (1.77 [1.19–2.64]), caproic acid (FA 6:0) (2.15 [1.42–3.27]), caprylic acid (FA 8:0) (1.87 [1.27–2.76]) and capric acid (FA 10:0) (1.83 [1.23–2.74]). Our study suggests that eating a diet high in total protein and certain unsaturated FAs is associated with decreased risk of developing pancreatic cancer in a dose‐dependent manner, whereas fats found in dairy increase risk.

Meat-Related Mutagens and Pancreatic Cancer: Null Results from a Clinic-Based Case–Control Study

Background: Pancreatic cancer is a devastating disease for which the role of dietary factors remains inconclusive. The study objective was to evaluate risk of pancreatic cancer associated with meat preparation methods and meat-related mutagen consumption using a clinic-based case–control design. Methods: There were 384 cases and 983 controls; subjects provided demographic information and completed a 144-item food frequency questionnaire, which was used to estimate meat mutagen intake using the National Cancer Institutes CHARRED database (Bethesda, MD). Logistic regression was used to calculate ORs and 95% confidence intervals (CI), adjusted for factors including age, sex, cigarette smoking, body mass index, and diabetes mellitus. Results: Overall, the findings were null with respect to meat mutagen intake and pancreatic cancer. Conclusions: The results do not support an association between well-done meat or meat-related mutagen intake and pancreatic cancer and contrast with generally increased risks reported in previous studies. Impact: These data contribute to evidence about pancreatic cancer and potentially carcinogenic compounds in meat. Cancer Epidemiol Biomarkers Prev; 22(7); 1336–9. ©2013 AACR.

Polymorphisms in metabolism/antioxidant genes may mediate the effect of dietary intake on pancreatic cancer risk.

Objectives A source of variation for inconsistent dietary-pancreatic cancer associations may be individuals carrying constitutional metabolism/antioxidant gene variants that differentially benefit compared to homozygous individuals. Seventy-six tag single-nucleotide polymorphisms were genotyped in 13 candidate genes to test differential associations with pancreatic adenocarcinoma. Methods A clinic-based case-control design was used to rapidly ascertain 251 cases and 970 frequency matched controls who provided blood samples and completed a 144-item food frequency questionnaire. Single-nucleotide polymorphisms were evaluated using a dominant genetic model and dietary categories split on controls’ median intake. Logistic regression was used to calculate odds ratios and 95% confidence intervals, adjusted for potential confounders. Results Significant increased associations (Bonferroni corrected P ⩽ 0.0007) were observed for carriers of greater than or equal to 1 minor allele for rs3816257 (glucosidase, &agr;; acid [GAA]) and lower intake of deep-yellow vegetables (1.90 [1.28-2.83]); and carriers of no minor allele for rs12807961 (catalase [CAT]) and high total grains intake (2.48 [1.50–4.09]), whereas those with greater than or equal to 1 minor allele had a decreasing slope (across grains). The reference group was no minor alleles with low dietary intake. Conclusions Interindividual variation in metabolism/antioxidant genes could interact with dietary intake to influence pancreatic cancer risk.

Enforcement Associated With Higher School-Reported Immunization Rates

INTRODUCTION North Dakotas school-reported kindergarten immunization rates were among the lowest in the U.S. during the 2015-2016 school year. Ninety percent of kindergartners were fully immunized in accordance with state requirements, 3% had an exemption, and as many as 7% were noncompliant. School enforcement of immunization requirements has been noted as variable. This study sought to better understand the relationship between school-reported immunization rates and the enforcement of immunization requirements. METHODS Kindergarten immunization rates were compared between schools annually enforcing immunization requirements to the point of excluding noncompliant children and schools not enforcing. In addition, immunization rates were assessed after an educational intervention that led some school districts to change their enforcement policies during the 2015-2016 school year. Analyses were completed in 2016 and 2017. RESULTS Kindergarten immunization rates were significantly higher in schools that annually enforced compared with schools that did not enforce (p≤0.001, all vaccines; difference between means: diphtheria-tetanus-attenuated pertussis=7.5% [95% CI=3.9%, 11.1%]; polio=6.2% [95% CI=3.3%, 9.1%]; measles, mumps, and rubella=7% [95% CI=3.5%, 10.5%]; hepatitis B=3.7% [95% CI=1.5%, 5.9%]; and varicella=6.9% [95% CI=3.4%, 10.4%]). School districts that began enforcing saw a significant increase in vaccination rates (diphtheria-tetanus-attenuated pertussis=6% [95% CI=2%, 11%] and measles, mumps, and rubella=7% [95% CI=3%, 11%]). Enforcement in newly enforcing districts led to a large decrease in the number of noncompliant students and did not lead to significant increases in exemption rates. CONCLUSIONS In North Dakota, lack of school enforcement is strongly associated with lower immunization rates and a large noncompliant population. Addressing noncompliance through school enforcement could significantly increase school-reported immunization rates.

SIAH and EGFR, Two RAS Pathway Biomarkers, are Highly Prognostic in Locally Advanced and Metastatic Breast Cancer

Background Metastatic breast cancer exhibits diverse and rapidly evolving intra- and inter-tumor heterogeneity. Patients with similar clinical presentations often display distinct tumor responses to standard of care (SOC) therapies. Genome landscape studies indicate that EGFR/HER2/RAS “pathway” activation is highly prevalent in malignant breast cancers. The identification of therapy-responsive and prognostic biomarkers is paramount important to stratify patients and guide therapies in clinical oncology and personalized medicine. Methods In this study, we analyzed matched pairs of tumor specimens collected from 182 patients who received neoadjuvant systemic therapies (NST). Statistical analyses were conducted to determine whether EGFR/HER2/RAS pathway biomarkers and clinicopathological predictors, alone and in combination, are prognostic in breast cancer. Findings SIAH and EGFR outperform ER, PR, HER2 and Ki67 as two logical, sensitive and prognostic biomarkers in metastatic breast cancer. We found that increased SIAH and EGFR expression correlated with advanced pathological stage and aggressive molecular subtypes. Both SIAH expression post-NST and NST-induced changes in EGFR expression in invasive mammary tumors are associated with tumor regression and increased survival, whereas ER, PR, and HER2 were not. These results suggest that SIAH and EGFR are two prognostic biomarkers in breast cancer with lymph node metastases. Interpretation The discovery of incorporating tumor heterogeneity-independent and growth-sensitive RAS pathway biomarkers, SIAH and EGFR, whose altered expression can be used to estimate therapeutic efficacy, detect emergence of resistant clones, forecast tumor regression, differentiate among partial responders, and predict patient survival in the neoadjuvant setting, has a clear clinical implication in personalizing breast cancer therapy. Funding This work was supported by the Dorothy G. Hoefer Foundation for Breast Cancer Research (A.H. Tang); Center for Innovative Technology (CIT)-Commonwealth Research Commercialization Fund (CRCF) (MF14S-009-LS to A.H. Tang), and National Cancer Institute (CA140550 to A.H. Tang).

Detection of DNA damage in peripheral blood mononuclear cells from pancreatic cancer patients.

DNA repair is a key mechanism in maintaining genomic stability: repair deficiencies increase DNA damage and mutations that lead to several diseases, including cancer. We extracted DNA from peripheral blood mononuclear cells (PBMCs) of 48 pancreatic adenocarcinoma cases and 48 healthy controls to determine relative levels of nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) damage by QPCR. All participants were never smokers and between the ages of 60 and 69. Average levels among cases were compared to controls using a rank sum test, and logistic regression adjusted for potential confounding factors (age, sex, and diabetes mellitus). Cases had less DNA damage, with a significant decrease in mtDNA damage (P‐value = 0.03) and a borderline significant decrease in nDNA damage (P = 0.08). Across samples, we found mtDNA abundance was higher among non‐diabetics compared to diabetics (P = 0.04). Our results suggest that patients with pancreatic adenocarcinoma have less DNA damage in their PBMCs, and that having diabetes, a known pancreatic cancer risk factor, is associated with lower levels of mtDNA abundance.

Association between Alcohol Consumption, Folate Intake, and Risk of Pancreatic Cancer: A Case-Control Study

Pancreatic cancer is one of the most fatal common cancers affecting both men and women, representing about 3% of all new cancer cases in the United States. In this study, we aimed to investigate the association of pancreatic cancer risk with alcohol consumption as well as folate intake. We performed a case-control study of 384 patients diagnosed with pancreatic cancer from May 2004 to December 2009 and 983 primary care healthy controls in a largely white population (>96%). Our findings showed no significant association between risk of pancreatic cancer and either overall alcohol consumption or type of alcohol consumed (drinks/day). Our study showed dietary folate intake had a modest effect size, but was significantly inversely associated with pancreatic cancer (odds ratio (OR) = 0.99, p < 0.0001). The current study supports the hypothesis that pancreatic cancer risk is reduced with higher food-based folate intake.

A mathematical model of case-ascertainment bias: Applied to case-control studies nested within a randomized screening trial

When some individuals are screen-detected before the beginning of the study, but otherwise would have been diagnosed symptomatically during the study, this results in different case-ascertainment probabilities among screened and unscreened participants, referred to here as lead-time-biased case-ascertainment (LTBCA). In fact, this issue can arise even in risk-factor studies nested within a randomized screening trial; even though the screening intervention is randomly allocated to trial arms, there is no randomization to potential risk-factors and uptake of screening can differ by risk-factor strata. Under the assumptions that neither screening nor the risk factor affects underlying incidence and no other forms of bias operate, we simulate and compare the underlying cumulative incidence and that observed in the study due to LTBCA. The example used will be constructed from the randomized Prostate, Lung, Colorectal, and Ovarian cancer screening trial. The derived mathematical model is applied to simulating two nested studies to evaluate the potential for screening bias in observational lung cancer studies. Because of differential screening under plausible assumptions about preclinical incidence and duration, the simulations presented here show that LTBCA due to chest x-ray screening can significantly increase the estimated risk of lung cancer due to smoking by 1% and 50%. Traditional adjustment methods cannot account for this bias, as the influence screening has on observational study estimates involves events outside of the study observation window (enrollment and follow-up) that change eligibility for potential participants, thus biasing case ascertainment.

Ripple Effects of the Communities Preventing Childhood Obesity Project

This research examines the practice of community coaching within coalitions in the Communities Preventing Childhood Obesity project. A quasi-experimental design was used in seven Midwestern states. Each state selected two rural, low-income communities with functioning health coalitions. Coalitions were randomly assigned to be intervention or comparison communities. After 4 years of the coaching intervention, ripple effect mapping served as one method for examining the coalitions’ work that may affect children’s weight status. A research team from each state conducted ripple effect mapping with their two coalitions, resulting in 14 ripple maps. Community capitals framework and the social–ecological model were used for coding the items identified within the ripple maps. A quantitative scoring analysis determined if differences existed between the intervention and comparison coalitions in terms of the activities, programs, funding, and partnerships for social–ecological model score (e.g., individual, community, policy levels), community capitals score, and ripples score (e.g., number of branches formed within the maps). All scores were higher in intervention communities; however, the differences were not statistically significant (p > .05). Assessing community assets, such as availability of a community coach, is necessary in order to decide whether to deploy certain resources when designing health promotion strategies.