Dietary Energy Intake and Presence of Aberrant Crypt Foci Are Associated with Phospholipid, Purine, and Taurine Metabolite Abundances in C57BL/6N Mouse Colon.

SCOPE: Colon metabolomes associated with high-fat (H) versus energy-restricted (E) diets in early colorectal cancer (CRC) models have never been directly compared. The objectives of this study are to elucidate metabolites associated with diet, aberrant crypt foci (ACF), and diet:ACF interaction, using a lifetime murine model. METHODS AND RESULTS: Three-week-old mice consumed control (C), E, or H initiation diets for 18 weeks. ACF formation is initiated weeks 16-21 with azoxymethane injections, followed by progression diet crossover (to C, E, or H) through week 60. Colon extracts are analyzed using ultra-high-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). Metabolites associated with diet, ACF, or diet:ACF are determined using regression models (FDR-adjusted p-value <0.05). No metabolites are significantly associated with initiation diets, but concentrations of acylcarnitines and phospholipids are associated with C, E, and H progression diets. Purines, taurine, and phospholipids are associated with ACF presence. No significant associations between metabolites and diet:ACF interaction are observed. CONCLUSIONS: These results suggest that recent, rather than early-life, diet is more closely associated with the colon metabolome, particularly lipid metabolism. Results from this study also provide candidate biomarkers of early CRC development and provide support for the importance of early diet on influencing pre-CRC risk.

Clinical encounter with three cancer patients affected by groundwater contamination at Camp Lejeune: a case series and review of the literature.

BACKGROUND: Advanced understanding of tumor biology has recently revealed the complexity of cancer genetics, intra/inter-tumor heterogeneity, and diverse mechanisms of resistance to cancer treatment. In turn, there has been a growing interest in cancer prevention and minimizing exposure to potential environmental carcinogens that surround us. In the 1980s, several chemical carcinogens, including perchloroethylene (PCE), trichloroethylene (TCE), and benzene, were detected in water systems supplying Camp Lejeune, a US Marine Corps Base Camp located in North Carolina. CASE PRESENTATION: This article presents three cases of cancer patients who have lived at Camp Lejeune, and, decades later, came to our clinic located 1000 miles from the original exposure site. The first patient is a young Caucasian man who was diagnosed with T cell acute lymphoblastic leukemia at the age of 37, and the second patient is a Caucasian man who had multiple types of cancer in the prostate, lung, and colon as well as chronic lymphocytic leukemia in his 60s and 70s. The third patient is another Caucasian man who had recurrent skin cancers of different histology, namely basal cell carcinomas, squamous cell carcinomas, and melanoma, from his 50s to 70s. CONCLUSIONS: The US Congress passed the Honoring America's Veterans and Caring for Camp Lejeune Families Act in 2012, which covers appropriate medical care for the people affected by the contamination. We hope that this article raises awareness about the history of Camp Lejeune's water contamination among cancer care providers, so the affected patients can receive appropriate medical coverage and cancer screening across the country.

Borage oil intake by overweight young adults: no effect on metabolic rate; beneficial effects on plasma triglyceride and HDL cholesterol readings.

Some research has raised the possibility that gamma linolenic acid (GLA) can increase resting metabolic rate (RMR), which can help with weight control. However, in overweight young adults with a family history of obesity, no effect on RMR was seen after a 6 weeks treatment with borage oil (880 mg GLA per day) or evening primrose oil (540 mg GLA per day). On the other hand, borage oil did lower plasma triglyceride readings and raise HDL cholesterol readings (mean starting values in normal range for triglycerides, borderline low for HDL). No effect was seen for body mass index, plasma total cholesterol, LDL cholesterol, or glucose. Thus, in the type of subjects studied here, borage oil, a source of GLA, did not show promise as a weight control aid, but could help prevent undesirable readings for two blood lipid measures.

Associations of Dairy Intake with Circulating Biomarkers of Inflammation, Insulin Response, and Dyslipidemia among Postmenopausal Women.

BACKGROUND: Cardiometabolic diseases are prevalent in aging Americans. Although some studies have implicated greater intake of dairy products, it is not clear how dairy intake is related to biomarkers of cardiometabolic health. OBJECTIVE: Our aim was to test the hypothesis that associations of dairy foods with biomarkers of lipid metabolism, insulin-like growth factor signaling, and chronic inflammation may provide clues to understanding how dairy can influence cardiometabolic health. DESIGN: This was a cross-sectional study in the Women's Health Initiative using baseline food frequency questionnaire data to calculate dairy intake. PARTICIPANTS/SETTING: Participants were 35,352 postmenopausal women aged 50 to 79 years at 40 clinical centers in the United States. MAIN OUTCOME MEASURES: Baseline (1993-1998) concentrations of 20 circulating biomarkers were measured. STATISTICAL ANALYSES: Multivariable-adjusted linear regression was used to estimate percent difference in biomarker concentrations per serving of total dairy and individual foods (milk, cheese, yogurt, butter, and low-fat varieties). RESULTS: Lower triglyceride concentrations were associated with greater intake of total dairy (-0.8% [95% CI -1.2% to -0.3%]), mainly driven by full-fat varieties. Individual dairy foods had specific associations with circulating lipid components. For example, greater total milk intake was associated with lower concentrations of total cholesterol (-0.4% [95% CI -0.7% to -0.2%]) and high-density lipoprotein cholesterol (-0.5% [95% CI -0.9% to -0.1%]), whereas greater butter intake was associated with higher total cholesterol (0.6% [95% CI 0.2% to 1.0%]) and high-density lipoprotein cholesterol (1.6% [95% CI 1.1% to 2.0%]) concentrations. In contrast, higher total yogurt intake was associated with lower total cholesterol (-1.1% [95% CI -2.0% to -0.2%]) and higher high-density lipoprotein cholesterol (1.8% [95% CI 0.5% to 3.1%]). Greater total dairy intake (regardless of fat content), total cheese, full-fat cheese, and yogurt were consistently associated with lower concentrations of glucose, insulin, and C-reactive protein. However, milk and butter were not associated with these biomarkers. CONCLUSIONS: Higher dairy intake, except butter, was associated with a favorable profile of lipids, insulin response, and inflammatory biomarkers, regardless of fat content. Yet, specific dairy foods might influence these markers uniquely. Findings do not support a putative role of dairy in cardiometabolic diseases observed in some previous studies.

Ten-year cardiovascular risk among cancer survivors: The National Health and Nutrition Examination Survey.

BACKGROUND: Cancer survivors have a higher risk of developing and dying from cardiovascular disease (CVD) compared to the general population. We sought to determine whether 10-year risk of atherosclerotic CVD (ASCVD) is elevated among those with vs. without a cancer history in a nationally representative U.S. sample. METHODS: Participants aged 40-79 years with no CVD history were included from the 2007-2016 National Health and Nutrition Examination Survey. Cancer history was self-reported and 10-year risk of ASCVD was estimated using Pooled Cohort Equations. We used logistic regression to estimate associations between cancer history and odds of elevated (≥7.5%) vs. low (<7.5%) 10-year ASCVD risk. An interaction between age and cancer history was examined. RESULTS: A total of 15,095 participants were included (mean age = 55.2 years) with 12.3% (n = 1,604) reporting a cancer history. Individuals with vs. without a cancer history had increased odds of elevated 10-year ASCVD risk (OR = 3.42, 95% CI: 2.51-4.66). Specifically, those with bladder/kidney, prostate, colorectal, lung, melanoma, or testicular cancer had a 2.72-10.47 higher odds of elevated 10-year ASCVD risk. Additionally, age was an effect modifier: a cancer history was associated with 1.24 (95% CI: 1.19-4.21) times higher odds of elevated 10-year ASCVD risk among those aged 60-69, but not with other age groups. CONCLUSIONS: Adults with a history of self-reported cancer had higher 10-year ASCVD risk. ASCVD risk assessment and clinical surveillance of cardiovascular health following a cancer diagnosis could potentially reduce disease burden and prolong survival, especially for patients with specific cancers and high ASCVD risk.

Statin users have an elevated risk of dysglycemia and new-onset-diabetes.

OBJECTIVE: Statins are one of the most widely prescribed medications in the United States; however, there is a concern that they are associated with new-onset-diabetes (NOD) development. We sought to understand the risk of dysglycemia and NOD for a cohort of individuals that reflect real-world physician prescribing patterns. METHODS: A retrospective cohort study was conducted among individuals with indications for statin use (n = 7064). To examine elevated glycosylated hemoglobin (>6.0%), logistic regression with inverse probability weighting was used to create balance between incident statin users and nonusers. To evaluate the risk of NOD development, Cox PH models with time varying statin use compared NOD diagnoses among statin users and nonusers. RESULTS: A higher prevalence of elevated HbA1c (PD = 0.065; 95% CI: 0.002, 0.129, P = 0.045) occurred among nondiabetic incident users of statins. Additionally, statin users had a higher risk of developing NOD (AHR = 2.20; 95% CI: 1.35, 3.58, P = 0.002). Those taking statins for 2 years or longer (AHR = 3.33; 95% CI: 1.84, 6.01, P < 0.001) were at the greatest risk of developing NOD; no differences were observed by statin class or intensity of dose. CONCLUSION: As lifestyle programs like the Diabetes Prevention Program are promoted in primary care settings, we hope physicians will integrate and insurers support healthy lifestyle strategies as part of the optimal management of individuals at risk for both NOD and cardiovascular disease. The relationships between statin use and glycemic control should be evaluated in large cohort studies, medical record databases, and mechanistic investigations to inform clinical judgment and treatment.

Characteristics of Children 2 to 5 Years of Age With Severe Obesity.

BACKGROUND AND OBJECTIVES: As a distinct group, 2- to 5-year-olds with severe obesity (SO) have not been extensively described. As a part of the Expert Exchange Workgroup on Childhood Obesity, nationally-representative data were examined to better characterize children with SO. METHODS: Children ages 2 to 5 (N = 7028) from NHANES (1999-2014) were classified as having normal weight, overweight, obesity, or SO (BMI ≥120% of 95th percentile). Sociodemographics, birth characteristics, screen time, total energy, and Healthy Eating Index 2010 scores were evaluated. Multinomial logistic and linear regressions were conducted, with normal weight as the referent. RESULTS: The prevalence of SO was 2.1%. Children with SO had higher (unadjusted) odds of being a racial and/or ethnic minority (African American: odds ratio [OR]: 1.7; Hispanic: OR: 2.3). They were from households with lower educational attainment (OR: 2.4), that were single-parent headed (OR: 2.0), and that were in poverty (OR: 2.1). Having never been breastfed was associated with increased odds of obesity (OR: 1.5) and higher odds of SO (OR: 1.9). Odds of >4 hours of screen time were 1.5 and 2.0 for children with obesity and SO. Energy intake and Healthy Eating Index 2010 scores were not significantly different in children with SO. CONCLUSIONS: Children ages 2 to 5 with SO appear to be more likely to be of a racial and/or ethnic minority and have greater disparities in social determinants of health than their peers and are more than twice as likely to engage in double the recommended screen time limit.

Association of Burnout with Workforce-Reducing Factors among EMS Professionals.

OBJECTIVES: Emergency medical services (EMS) professionals often work long hours at multiple jobs and endure frequent exposure to traumatic events. The stressors inherent to the prehospital setting may increase the likelihood of experiencing burnout and lead providers to exit the profession, representing a serious workforce and public health concern. Our objectives were to estimate the prevalence of burnout, identify characteristics associated with experiencing burnout, and quantify its relationship with factors that negatively impact EMS workforce stability, namely sickness absence and turnover intentions. METHODS: A random sample of 10,620 emergency medical technicians (EMTs) and 10,540 paramedics was selected from the National EMS Certification database to receive an electronic questionnaire between October, 2015 and November, 2015. Using the validated Copenhagen Burnout Inventory (CBI), we assessed burnout across three dimensions: personal, work-related, and patient-related. We used multivariable logistic regression modeling to identify burnout predictors and quantify the association between burnout and our workforce-related outcomes: reporting ten or more days of work absence due to personal illness in the past 12 months, and intending to leave an EMS job or the profession within the next 12 months. RESULTS: Burnout was more prevalent among paramedics than EMTs (personal: 38.3% vs. 24.9%, work-related: 30.1% vs. 19.1%, and patient-related: 14.4% vs. 5.5%). Variables associated with increased burnout in all dimensions included certification at the paramedic level, having between five and 15 years of EMS experience, and increased weekly call volume. After adjustment, burnout was associated with over a two-fold increase in odds of reporting ten or more days of sickness absence in the past year. Burnout was associated with greater odds of intending to leave an EMS job (personal OR:2.45, 95% CI:1.95-3.06, work-related OR:3.37, 95% CI:2.67-4.26, patient-related OR: 2.38, 95% CI:1.74-3.26) or the EMS profession (personal OR:2.70, 95% CI:1.94-3.74, work-related OR:3.43, 95% CI:2.47-4.75, patient-related OR:3.69, 95% CI:2.42-5.63). CONCLUSIONS: The high estimated prevalence of burnout among EMS professionals represents a significant concern for the physical and mental well-being of this critical healthcare workforce. Further, the strong association between burnout and variables that negatively impact the number of available EMS professionals signals an important workforce concern that warrants further prospective investigation.

An Evaluation of Reach for a Work Site Implementation of the National Diabetes Prevention Program Focusing on Diet and Exercise.

PURPOSE: Our objective is to evaluate the "reach" component of the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) framework by comparing prediabetics who were and were not interested in enrolling in a free work site diabetes prevention program (DPP) during the first year of the program. Reach is defined as the proportion of eligible participants who enroll in a health program. DESIGN: A cross-sectional study design was used. SETTING: The setting was a large health system in the Midwest. PARTICIPANTS: Prediabetic health plan enrollees and spouses (N = 2158). MEASURES: An online health survey, annual voluntary biometric screenings delivered by a trained health-care professional using standardized protocols via point-of-care testing, and records from the DPP office were the sources of data for this study. ANALYSIS: Health behaviors and biometric screening results were simultaneously compared using multivariable logistic regression. RESULTS: The study population was 63% female, 79% white, and 16% black, and the mean age was 50.2 years (SD = 10.2). The reach of this program was 10%. Prediabetics were more likely to express interest in the DPP, if they were female (adjusted odds ratio [AOR]: 2.4; 95% confidence interval [95% CI]: 1.55-3.72; P < .001), black (AOR = 2.23; 95% CI: 1.43-3.47; P < .001), older in age (AOR: 1.08; 95% CI: 0.99-1.17; P = .05), or had a high-risk waist circumference (AOR = 1.44; 95% CI: 0.98-2.13; P = .07), lower self-efficacy to make healthy changes (AOR = 0.48; 95% CI: 0.26-0.91; P = .03), and 5 or more doctor visits in the last year (AOR = 2.13; 95% CI: 0.99-4.57; P = .05), after controlling for other covariates. CONCLUSION: Current recruitment and implementation strategies are reaching only a small group of individuals who are not representative of the larger prediabetic population. These findings inform future engagement strategies, and we recommend that public health practitioners evaluate reach to ensure that health promotion programs are of high value.

Menstrual and reproductive factors and lung cancer risk: A pooled analysis from the international lung cancer consortium.

Many clinical features of lung cancer are different in women and men. Sex steroid hormones exert effects in nonreproductive organs, such as the lungs. The association between menstrual and childbearing factors and the risk of lung cancer among women is still debated. We performed a pooled analysis of eight studies contributing to the International Lung Cancer Consortium (4,386 cases and 4,177 controls). Pooled associations between menstrual or reproductive factors and lung cancer were estimated using multivariable unconditional logistic regression. Subgroup analyses were done for menopause status, smoking habits and histology. We found no strong support for an association of age at menarche and at menopause with lung cancer, but peri/postmenopausal women were at higher risk compared to premenopausal (OR 1.47, 95% CI 1.11-1.93). Premenopausal women showed increased risks associated with parity (OR 1.74, 95% CI 1.03-2.93) and number of children (OR 2.88, 95% CI 1.21-6.93 for more than 3 children; p for trend 0.01) and decreased with breastfeeding (OR 0.54, 95% CI 0.30-0.98). In contrast, peri/postmenopausal subjects had ORs around unity for the same exposures. No major effect modification was exerted by smoking status or cancer histology. Menstrual and reproductive factors may play a role in the genesis of lung cancer, yet the mechanisms are unclear, and smoking remains the most important modifiable risk factor. More investigations in large well-designed studies are needed to confirm these findings and to clarify the underlying mechanisms of gender differences in lung cancer risk.

Alcohol and lung cancer risk among never smokers: A pooled analysis from the international lung cancer consortium and the SYNERGY study.

It is not clear whether alcohol consumption is associated with lung cancer risk. The relationship is likely confounded by smoking, complicating the interpretation of previous studies. We examined the association of alcohol consumption and lung cancer risk in a large pooled international sample, minimizing potential confounding of tobacco consumption by restricting analyses to never smokers. Our study included 22 case-control and cohort studies with a total of 2548 never-smoking lung cancer patients and 9362 never-smoking controls from North America, Europe and Asia within the International Lung Cancer Consortium (ILCCO) and SYNERGY Consortium. Alcohol consumption was categorized into amounts consumed (grams per day) and also modelled as a continuous variable using restricted cubic splines for potential non-linearity. Analyses by histologic sub-type were included. Associations by type of alcohol consumed (wine, beer and liquor) were also investigated. Alcohol consumption was inversely associated with lung cancer risk with evidence most strongly supporting lower risk for light and moderate drinkers relative to non-drinkers (>0-4.9 g per day: OR = 0.80, 95% CI = 0.70-0.90; 5-9.9 g per day: OR = 0.82, 95% CI = 0.69-0.99; 10-19.9 g per day: OR = 0.79, 95% CI = 0.65-0.96). Inverse associations were found for consumption of wine and liquor, but not beer. The results indicate that alcohol consumption is inversely associated with lung cancer risk, particularly among subjects with low to moderate consumption levels, and among wine and liquor drinkers, but not beer drinkers. Although our results should have no relevant bias from the confounding effect of smoking we cannot preclude that confounding by other factors contributed to the observed associations. Confounding in relation to the non-drinker reference category may be of particular importance.

The Impact of Dietary Energy Intake Early in Life on the Colonic Microbiota of Adult Mice.

The complex and dynamic interactions between diet, gut microbiota (GM) structure and function, and colon carcinogenesis are only beginning to be elucidated. We examined the colonic microbiota and aberrant crypt foci (ACF) in C57BL/6N female mice fed various dietary interventions (control, energy restricted and high-fat) provided during two phases (initiation and progression) of azoxymethane (AOM)-induced early colon carcinogenesis. During progression (wks. 22-60), a high-fat diet enhanced ACF formation compared to a control or energy restricted diet. In contrast, energy restriction during initiation phase (wks. 3-21) enhanced ACF burden at 60 weeks, regardless of the diet in progression phase. Alterations in GM structure during the initiation phase diet were partially maintained after changing diets during the progression phase. However, diet during the progression phase had major effects on the mucosal GM. Energy restriction in the progression phase increased Firmicutes and reduced Bacteroidetes compared to a high-fat diet, regardless of initiation phase diet, suggesting that diet may have both transient effects as well as a lasting impact on GM composition. Integration of early life and adult dietary impacts on the colonic microbial structure and function with host molecular processes involved in colon carcinogenesis will be key to defining preventive strategies.

Differential Serum Cytokine Levels and Risk of Lung Cancer Between African and European Americans.

BACKGROUND: African Americans have a higher risk of developing lung cancer than European Americans. Previous studies suggested that certain circulating cytokines were associated with lung cancer. We hypothesized that variations in serum cytokine levels exist between African Americans and European Americans, and increased circulating cytokine levels contribute to lung cancer differently in the two races. METHODS: Differences in 10 serum cytokine levels, IL1ß, IL4, IL5, IL6, IL8, IL10, IL12, granulocyte macrophage colony-stimulating factor, IFNγ, and TNFα, between 170 African-American and 296 European-American controls from the National Cancer Institute-Maryland (NCI-MD) case-control study were assessed. Associations of the serum cytokine levels with lung cancer were analyzed. Statistically significant results were replicated in the prospective Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the Wayne State University Karmanos Cancer Institute case-control study. RESULTS: Six cytokines, IL4, IL5, IL8, IL10, IFNγ, and TNFα, were significantly higher among European-American as compared with African-American controls. Elevated IL6 and IL8 levels were associated with lung cancer among both races in all three studies. Elevated IL1ß, IL10, and TNFα levels were associated with lung cancer only among African Americans. The association between elevated TNFα levels and lung cancer among European Americans was significant after adjustment for additional factors. CONCLUSIONS: Serum cytokine levels vary by race and might contribute to lung cancer differently between African Americans and European Americans. IMPACT: Future work examining risk prediction models of lung cancer can measure circulating cytokines to accurately characterize risk within racial groups.

A DRD1 polymorphism predisposes to lung cancer among those exposed to secondhand smoke during childhood.

Lung cancer has a familial component which suggests a genetic contribution to its etiology. Given the strong evidence linking smoking with lung cancer, we studied miRNA-related loci in genes associated with smoking behavior. CHRNA, CHRNB gene families, CYP2A6, and DRD1 (dopamine receptor D1) were mined for SNPs that fell within the seed region of miRNA binding sites and then tested for associations with risk in a three-stage validation approach. A 3'UTR (untranslated region) SNP in DRD1 was associated with a lower risk of lung cancer among individuals exposed to secondhand smoke during childhood [OR, 0.69; 95% confidence interval (CI), 0.60-0.79; P < 0.0001]. This relationship was evident in both ever (OR, 0.74; 95% CI, 0.62-0.88; P = 0.001) and never smokers (OR, 0.61; 95% CI, 0.47-0.79; P < 0.0001), European American (OR, 0.65; 95% CI, 0.53-0.80; P < 0.0001), and African American (OR, 0.73; 95% CI, 0.62-0.88; P = 0.001) populations. Although much remains undefined about the long-term risks associated with exposure to secondhand smoke and heterogeneity between individuals in regard to their susceptibility to the effects of secondhand smoke, our data show an interaction between an SNP in the 3'UTR of DRD1 and exposure to secondhand smoke during childhood. Further work is needed to explore the mechanistic underpinnings of this SNP and the nature of the interaction between DRD1 and exposure to secondhand smoke during childhood.

Favorable effects of low-fat and low-carbohydrate dietary patterns on serum leptin, but not adiponectin, among overweight and obese premenopausal women: a randomized trial.

PURPOSE: The most effective dietary pattern for breast cancer prevention has been greatly debated in recent years. Studies have examined hypocaloric diets, with particular emphasis on macronutrient composition, yielding inconclusive data. The objective of this study was to examine the effects of calorie-restricted low-fat and low-carbohydrate diets (LFD and LCD, respectively) on circulating adipokines among overweight and obese premenopausal women. METHODS: Seventy-nine overweight and obese premenopausal women were randomized to either LFD or LCD, with increased physical activity, for 52 weeks. Serum adiponectin, leptin and the adiponectin-to-leptin ratio (A/L) were measured at baseline, and at weeks 34 and 52 to assess intervention effects. RESULTS: While there were no significant changes in serum adiponectin concentrations following the LCD and LFD interventions, leptin concentrations significantly decreased by week 34 of the intervention period (LCD: 35.3%, P = 0.004; LFD: 30.0%, P = 0.01), with no difference by intervention arm. At week 52, these reductions were statistically non-significant, indicating a return to baseline levels by the end of the intervention. While there were non-significant increases in the A/L ratio following the LCD and LFD intervention arms, the overall trend, across groups, was marginally significant (P = 0.05) with increases of 16.2% and 35.1% at weeks 34 and 52, respectively. CONCLUSIONS: These findings suggest that caloric-restricted LCD and LFD dietary patterns favorably modify leptin and possibly the A/L ratio, and lend support to the hypothesis that these interventions may be effective for obesity-related breast cancer prevention through their effects on biomarkers involved in metabolic pathways. CLINICAL TRIAL REGISTRATION NUMBER: NCT01559194.

Effects of calorie restriction and diet-induced obesity on murine colon carcinogenesis, growth and inflammatory factors, and microRNA expression.

Obesity is an established colon cancer risk factor, while preventing or reversing obesity via a calorie restriction (CR) diet regimen decreases colon cancer risk. Unfortunately, the biological mechanisms underlying these associations are poorly understood, hampering development of mechanism-based approaches for preventing obesity-related colon cancer. We tested the hypotheses that diet-induced obesity (DIO) would increase (and CR would decrease) colon tumorigenesis in the mouse azoxymethane (AOM) model. In addition, we established that changes in inflammatory cytokines, growth factors, and microRNAs are associated with these energy balance-colon cancer links, and thus represent mechanism-based targets for colon cancer prevention. Mice were injected with AOM once a week for 5 weeks and randomized to: 1) control diet; 2) 30% CR diet; or 3) DIO diet. Mice were euthanized at week 5 (n = 12/group), 10 (n = 12/group), and 20 (n = 20/group) after the last AOM injection. Colon tumors were counted, and cytokines, insulin-like growth factor 1 (IGF-1), IGF binding protein 3 (IGFBP-3), adipokines, proliferation, apoptosis, and expression of microRNAs (miRs) were measured. The DIO diet regimen induced an obese phenotype (∼36% body fat), while CR induced a lean phenotype (∼14% body fat); controls were intermediate (∼26% body fat). Relative to controls, DIO increased (and CR decreased) the number of colon tumors (p = 0.01), cytokines (p<0.001), IGF-1 (p = 0.01), and proliferation (p<0.001). DIO decreased (and CR increased) IGFBP-3 and apoptosis (p<0.001). miRs including mir-425, mir-196, mir-155, mir-150, mir-351, mir-16, let-7, mir34, and mir-138 were differentially expressed between the dietary groups. We conclude that the enhancing effects of DIO and suppressive effects of CR on colon carcinogenesis are associated with alterations in several biological pathways, including inflammation, IGF-1, and microRNAs.

Evidence that the lung Adenocarcinoma EML4-ALK fusion gene is not caused by exposure to secondhand tobacco smoke during childhood.

BACKGROUND: The EML4-ALK fusion gene is more frequently found in younger, never smoking patients with lung cancer. Meanwhile, never smokers exposed to secondhand tobacco smoke (SHS) during childhood are diagnosed at a younger age compared with never smoking patients with lung cancer who are not exposed. We, therefore, hypothesized that SHS, which can induce DNA damage, is associated with the EML4-ALK fusion gene. METHODS: We compared the frequency of the EML4-ALK fusion gene among 197 never smoker patients with lung cancer with and without a history of exposure to SHS during childhood at Mayo Clinic. RESULTS: The EML4-ALK fusion gene was detected in 33% of cases from never smokers with a history of SHS exposure during childhood, whereas 47% of never smoking lung cancer cases without a history of childhood SHS exposure tested positive for the fusion gene. CONCLUSIONS: The EML4-ALK fusion gene is not enriched in tumors from individuals exposed to SHS during childhood. IMPACT: These data suggest that childhood exposure to SHS is not a significant etiologic cause of the EML4-ALK fusion gene in lung cancer.

Continuous retinoic acid induces the differentiation of mature regulatory monocytes but fails to induce regulatory dendritic cells.

BACKGROUND: Myeloid cells (MC) have potent immunoregulatory abilities that can be therapeutically useful to treat inflammatory disease. However, the factors which promote regulatory myeloid cell differentiation remain poorly understood. We have previously shown that estriol (E3) induces mature regulatory dendritic cells in vivo. To determine whether additional steroid hormones could induce mature regulatory myeloid cells, we investigated the effects of retinoic acid (RA) on MCs. Retinoic acid is a steroid hormone important in regulating mucosal immunity in the gut and promoting myeloid differentiation. We hypothesized that the presence of RA during differentiation would promote the formation of mature regulatory myeloid cells (MCregs). METHODS: To determine RA's ability to induce regulatory myeloid cells, we differentiated bone marrow progenitor cells with granulocytic-macrophage colony-stimulating factor (GM-CSF) under the influence of RA. We found that day 7 MCs differentiated in the presence of RA had an increase in the percent positive and relative expression levels of both maturation (CD80, CD86, and MHCII) and inhibitory (PD-L1 and PD-L2) markers compared to control cells. Functionally, these day 7 RA MCs expressed increased intracellular IL-10, induced regulatory T cells in vitro compared to controls and suppressed the proliferation of responder immune cells even after inflammatory challenge with LPS. CONCLUSION: RA induced mature regulatory myeloid cells that were suppressive and had a CD11b+ CD11c-Ly6C low/intermediate monocyte phenotype. Surprisingly, RA CD11c+ dendritic cells were not suppressive and could contribute to enhanced proliferation. These results suggest that continuous RA has unique effects on different myeloid populations during monopoeisis and dendropoiesis and promotes a population of regulatory monocytes.

Identification of myeloid derived suppressor cells in the peripheral blood of tumor bearing dogs.

BACKGROUND: Myeloid derived suppressor cells (MDSCs) are a recently described population of immune cells that significantly contribute to the immunosuppression seen in cancer patients. MDSCs are one of the most important factors that limit the efficacy of cancer immunotherapy (e.g. cancer vaccines) and MDSC levels are increased in cancer in multiple species. Identifying and targeting MDSCs is actively being investigated in the field of human oncology and is increasingly being investigated in veterinary oncology. The treatment of canine cancer not only benefits dogs, but is being used for translational studies evaluating and modifying candidate therapies for use in humans. Thus, it is necessary to understand the immune alterations seen in canine cancer patients which, to date, have been relatively limited. This study investigates the use of commercially available canine antibodies to detect an immunosuppressive (CD11b low/CADO48 low) cell population that is increased in the peripheral blood of tumor-bearing dogs. RESULTS: Commercially available canine antibodies CD11b and CADO48A were used to evaluate white blood cells from the peripheral blood cells of forty healthy control dogs and forty untreated, tumor-bearing dogs. Tumor-bearing dogs had a statistically significant increase in CD11b low/CADO48A low cells (7.9%) as compared to the control dogs (3.6%). Additionally, sorted CD11b low/CADO48A low generated in vitro suppressed the proliferation of canine lymphocytes. CONCLUSIONS: The purpose of this study was aimed at identifying potential canine specific markers for identifying MDSCs in the peripheral blood circulation of dogs. This study demonstrates an increase in a unique CD11b low/CADO48A low cell population in tumor-bearing dogs. This immunophenotype is consistent with described phenotypes of MDSCs in other species (i.e. mice) and utilizes commercially available canine-specific antibodies. Importantly, CD11b low/CADO48A low from a tumor environment suppress the proliferation of lymphocytes. These results provide a useful phenotype of cells increased in canine cancer patients that may serve as a useful prognostic marker for assessing immune status and functional response to cancer immunotherapies in dogs. Understanding MDSCs in dogs will allow for increased effectiveness of cancer immunotherapy in both dogs and humans.

Effects of tomato- and soy-rich diets on the IGF-I hormonal network: a crossover study of postmenopausal women at high risk for breast cancer.

To determine whether dietary modifications with tomato products and/or a soy supplement affected circulating levels of insulin-like growth factor (IGF)-1 and other markers of cell signaling in postmenopausal women at risk for developing breast cancer. Eligible and consented postmenopausal women at high risk for developing breast cancer were enrolled in a 26-week, two-arm (tomato and soy, 10 weeks each) longitudinal dietary intervention study in which each woman served as her own control. Changes in biochemical endpoints including IGF-I, IGF-binding protein (IGFBP)-3, estradiol, sex hormone-binding globulin (SHBG), C-peptide, and insulin were measured for each intervention arm. Carotenoid and isoflavone levels were measured to assess adherence. Significant increases in carotenoid and isoflavone levels during the tomato and soy study arms, respectively, suggested that women were adherent to both arms of the intervention. The tomato-rich diet had little effect on cell-signaling biomarkers previously associated with breast cancer risk. However, results of the soy intervention showed that concentrations of IGF-I and IGFBP-3 increased by 21.6 and 154.7 µmol/L, respectively (P = 0.001 for both) and SHBG decreased by 5.4 µmol/L (P < 0.001) after consumption of the soy protein supplement. Increased soy protein intake may lead to small, but significant, increases in IGF-I and IGFBP-3. Soy consumption also led to a significant decrease in SHBG, which has been hypothesized to promote, rather than prevent, cancer growth. Previous epidemiologic studies, however, have confirmed protective effect of soy on breast cancer. Additional investigation about the effect of soy on breast cancer risk and its mechanism of action is warranted.