Effect of exercise on metabolic syndrome in black women by family history and predicted risk of breast cancer: The FIERCE Study.

BACKGROUND: This study examined the effects of supervised and home-based exercise interventions on changes in metabolic syndrome (MetS) according to breast cancer risk (high vs low) in black women enrolled in the Focused Intervention on Exercise to Reduce Cancer (FIERCE) trial. METHODS: Postmenopausal, obese, metabolically unhealthy black women, 45 to 65 years old, were randomized to supervised aerobic exercise (73 women), home-based walking-based exercise (69 women), or a control arm (71 women). Participants in the exercise arms underwent a 6-month intervention with study assessments conducted at the baseline and 6 months. The primary outcome measure was MetS (fasting glucose, waist circumference, blood pressure, serum triglycerides, and high-density lipoprotein [HDL]). The intervention effects on MetS, stratified by breast cancer risk as measured by the family history of breast cancer and model-based projected breast cancer risk, were examined with intent-to-treat analyses using generalized estimating equation models. RESULTS: Among women with a family history of breast cancer, the exercise arms had lower mean MetS z scores, which suggested an improvement in the metabolic profile, than controls at 6 months (controls, + 0.55; home-based arm, -0.97, P < .01; supervised arm, -0.89, P < .01). Stratified analyses by projected breast cancer risk suggested similar but statistically nonsignificant findings, with those at high risk having more favorable changes in the MetS z score in the exercise arms versus the control arm. These changes were primarily attributable to changes in blood pressure, triglycerides, and HDL. CONCLUSIONS: Short-term aerobic activity regimens may improve the metabolic profile and thereby reduce breast cancer risk in obese, metabolically unhealthy black women at high risk for cancer. © 2018 American Cancer Society.

Changes in the diagnosis of congenital cardiovascular malformations during the 1st year of life: impacts on epidemiological risk factor associations.

Many epidemiological studies base their classification of congenital cardiovascular malformations in newborns upon a single, initial diagnosis. This study aimed to evaluate the effect of subsequent diagnostic investigations on the results of epidemiological studies. We used diagnostic codes from the Baltimore-Washington Infant Study from the time of birth and at ~1 year of age. Odds ratios and 95% confidence intervals were used to identify associations between changes in diagnoses and infant characteristics, time period, that is, before and after introduction of color flow Doppler imaging, and diagnostic variables. Of the 3054 patients with data at both time points, 400 (13.1%) had diagnostic changes. For congenital cardiovascular malformations of early cardiogenesis, such as laterality and looping defects, conotruncal malformations, and atrioventricular septal defects, significant associations were observed between diagnostic change and case infants large for gestational age (odds ratio=0.22, p=0.01), diagnosed initially by echocardiography only (odds ratio=2.05, p=0.001), or with non-cardiac malformations (odds ratio=0.60, p=0.03). For all other congenital cardiovascular malformations, significant associations were observed with echocardiography-only diagnosis (odds ratio=1.43, p=0.04) and non-cardiac malformations (odds ratio=0.57, p<0.001). We found no statistically significant differences between risk factor odds ratios calculated using initial diagnoses versus those calculated using 1-year update diagnoses. Changes in congenital cardiovascular malformation diagnoses from birth to year 1 interval were significantly associated with infant characteristics and diagnostic modality but did not materially affect the outcome of risk factor associations.

Macronutrient Composition or Social Determinants? Impact on Infant Outcomes With Gestational Diabetes Mellitus.

The purpose of this study was to examine, through a randomized, controlled trial, the effects of a maternal carbohydrate-restricted diet on maternal and infant outcomes in gestational diabetes mellitus (GDM). Women diagnosed with GDM were randomly allocated into one of two groups: an intervention group that was placed on a lower-carbohydrate diet (35-40% of total calories) or a control group that was placed on the usual pregnancy diet (50-55% carbohydrate). A convenience sample of participants diagnosed with GDM (ages 18-45 years) was recruited from two different sites: one urban and low-income and the other suburban and more affluent. Individual face-to-face diet instruction occurred with certified diabetes educators at both sites. Participants tested their blood glucose four times daily. Specific socioeconomic status indicators included enrollment in the Supplemental Nutrition Program for Women, Infants and Children or Medicaid-funded health insurance, as well as cross-sectional census data. All analyses were based on an intention to treat. Although there were no differences found between the lower-carbohydrate and usual-care diets in terms of blood glucose or maternal-infant outcomes, there were significant differences noted between the two sites. There was a lower mean postprandial blood glucose (100.59 ± 7.3 mg/dL) at the suburban site compared to the urban site (116.3 ± 15 mg/dL) (P <0.01), even though there was no difference in carbohydrate intake. There were increased amounts of protein and fat consumed at the suburban site (P <0.01), as well as lower infant complications (P <0.01). Further research is needed to determine whether these disparities in outcomes were the result of macronutrient proportions or environmental conditions.

Relationships among folate, alcohol consumption, gene variants in one-carbon metabolism and p16INK4a methylation and expression in healthy breast tissues.

p16(INK4a) is a tumor suppressor gene, frequently hypermethylated in breast cancer; this epigenetic silencing of p16(INK4a) occurs early in carcinogenesis. The risk factors and functional consequences of p16(INK4a) methylation are unknown. Alcohol consumption, a breast cancer risk factor, impedes folate metabolism and may thereby alter gene methylation since folate plays a pivotal role in DNA methylation. In a cross-sectional study of 138 women with no history of breast cancer who underwent reduction mammoplasty, we studied breast cancer risk factors, plasma and breast folate concentrations, variation in one-carbon metabolism genes, p16(INK4a) promoter methylation and P16 protein expression. Logistic regression was used to estimate multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI). p16(INK4a) methylation was negatively correlated with P16 expression (r = -0.28; P = 0.002). Alcohol consumption was associated with lower breast folate (P = 0.03), higher p16(INK4a) promoter methylation (P = 0.007) and less P16 expression (P = 0.002). Higher breast folate concentrations were associated with lower p16(INK4a) promoter methylation (P = 0.06). Genetic variation in MTRR (rs1801394) and MTHFD1 (rs1950902) was associated with higher p16 (INK4a) promoter methylation (OR = 2.66, 95% CI: 1.11-6.42 and OR = 2.72, 95% CI: 1.12-6.66, respectively), whereas variation in TYMS (rs502396) was associated with less P16 protein expression (OR = 0.22, 95% CI: 0.05-0.99). Given that this is the first study to indicate that alcohol consumption, breast folate and variation in one-carbon metabolism genes are associated with p16(INK4a) promoter methylation and P16 protein expression in healthy tissues; these findings require replication.

A non-iterative extension of the multivariate random effects meta-analysis.

Multivariate methods in meta-analysis are becoming popular and more accepted in biomedical research despite computational issues in some of the techniques. A number of approaches, both iterative and non-iterative, have been proposed including the multivariate DerSimonian and Laird method by Jackson et al. (2010), which is non-iterative. In this study, we propose an extension of the method by Hartung and Makambi (2002) and Makambi (2001) to multivariate situations. A comparison of the bias and mean square error from a simulation study indicates that, in some circumstances, the proposed approach perform better than the multivariate DerSimonian-Laird approach. An example is presented to demonstrate the application of the proposed approach.

Social networks and physical activity behaviors among cancer survivors: data from the 2005 Health Information National Trends Survey.

The study examined the relation between social networks and physical activity behaviors among cancer survivors. The authors examined 873 cancer survivors (596 women, 277 men) 50 years of age or older who participated in the 2005 Health Information National Trends Survey. Multivariate logistic regression analysis showed that survivors who talked about health with friends/family were more likely to pay attention to new physical activity recommendations (OR = 2.89, CI [1.01, 8.33]). Female survivors were more likely to pay attention to new physical activity recommendations (OR = 2.65, CI [1.55, 4.53]) and more likely to have seen, heard, or read physical activity/exercise and cancer information within the past 12 months (OR = 2.09, CI [1.13, 3.85]) compared with their male counterparts. For male survivors, those who were a member of at least one community organization were more likely to pay attention to new physical activity/exercise recommendations (OR = 5.31, CI [1.32, 21.22]) than the men who were not members. Overall, cancer survivors with a social network (i.e., talking to family/friends about health) were more likely to pay attention to new exercise recommendations compared with those who did not have a social network. Significant differences were also observed by gender with physical activity levels, knowledge, and attitudes. Social networking is an important component in cancer survivorship and further research is needed to encourage social networking strategies that might facilitate in increasing physical activity behaviors among cancer survivors.

Plasma IGF-1 and IGFBP-3 may be imprecise surrogates for breast concentrations: an analysis of healthy women.

We investigated insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-3 concentrations in histologically normal breast tissues and assessed their association with plasma concentrations, and breast cancer risk factors. IGF-1 and IGFBP-3 were assessed in plasma and breast tissues of 90 women with no history of any cancer and undergoing reduction mammoplasty. Pearson correlations and ANOVAs were used to describe plasma-breast associations and biomarker differences by breast cancer risk factors, respectively. Multivariable regression models were used to determine associations between risk factors, and breast IGF-1 and IGFBP-3. The mean age of the study sample was 37.3 years, 58 % were white, and generally these women were obese (mean BMI = 30.8 kg/m(2)). We observed no plasma-breast correlation for IGF-1, IGFBP-3, or IGF-1/IGFBP-3 (r = -0.08, r = 0.14, and r = 0.03, respectively; p-values >0.05). Through age- and BMI-adjusted analysis, BMI and years of oral contraceptive (OC) use were inversely associated with breast IGF-1 (p-values = 0.02 and 0.003, respectively) and age was associated with breast IGFBP-3 (p = 0.01), while breast IGF-1/IGFBP-3 was higher in blacks than whites (1.08 vs. 0.68, p = 0.04) and associated with age and BMI (p-values = 0.03 and 0.002, respectively). In multivariable-adjusted models, some breast cancer risk factors studied herein explained 24, 10, and 15 % of the variation in breast IGF-1, IGFBP-3, and IGF-1/IGFBP-3, respectively. While reasons for the lack of plasma-breast hormone correlations in these cancer-free women are unknown, several factors were shown to be associated with breast concentrations. The lack of correlation between blood and tissue IGF-1 and IGFBP-3 suggests that studies of breast cancer risk assessing blood IGF-1 and IGFBP-3 may have important limitations in understanding their role in breast carcinogenesis.

Consumption of dairy and meat in relation to breast cancer risk in the Black Women's Health Study.

PURPOSE: Dairy and meat consumption may impact breast cancer risk through modification of hormones (e.g., estrogen), through specific nutrients (e.g., vitamin D), or through products formed in processing/cooking (e.g., heterocyclic amines). Results relating meat and dairy intake to breast cancer risk have been conflicting. Thus, we examined the risk of breast cancer in relation to intake of dairy and meat in a large prospective cohort study. METHODS: In the Black Women's Health Study, 1,268 incident breast cancer cases were identified among 52,062 women during 12 years of follow-up. Multivariable (MV) relative risks (RRs) and 95 % confidence intervals (CIs) were calculated using Cox proportional hazards models. RESULTS: Null associations were observed for total milk (MV RR = 1.05, 95 % CI 0.74-1.46 comparing ≥1,000-0 g/week) and total meat (MV RR = 1.04, 95 % CI 0.85-1.28 comparing ≥1,000 < 400 g/week) intake and risk of breast cancer. Associations with intakes of specific types of dairy, specific types of meat, and dietary calcium and vitamin D were also null. The associations were not modified by reproductive (e.g., parity) or lifestyle factors (e.g., smoking). Associations with estrogen receptor (ER) positive (+), ER negative (-), progesterone receptor (PR) +, PR-, ER+/PR+, and ER-/PR- breast cancer were generally null. CONCLUSIONS: This analysis of African-American women provides little support for associations of dairy and meat intake with breast cancer risk.

Restaurant foods, sugar-sweetened soft drinks, and obesity risk among young African American women.

BACKGROUND: The prevalence of obesity is disproportionately high in African American women, and consumption of fast foods and sugar-sweetened soft drinks is also especially high among African Americans. OBJECTIVE: We investigated the relation of intakes of sugar-sweetened soft drinks and specific types of restaurant foods to obesity in the Black Women's Health Study. DESIGN: In this prospective cohort study, 19,479 non-obese women aged 21-39 years at baseline were followed for 14 years (1995-2009). Dietary intake was assessed by validated food frequency questionnaire in 1995 and 2001. MAIN OUTCOME MEASURES: Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of intakes of restaurant foods and sugar-sweetened soft drinks with incident obesity. RESULTS: Higher intakes of burgers from restaurants and sugar-sweetened soft drinks were associated with greater risk of becoming obese. The associations were present in models that included both factors and adjusted for overall dietary pattern. The HR of obesity in relation to restaurant burger consumption of > or = 2 times/week compared with < 5 times/year was 1.26 (95% CI: 1.14-1.40; P-trend<.001). For sugar-sweetened soft drink intake, the HR was 1.10 (95% CI: .99-1.23; P-trend = .14) for > or = 2 drinks/day compared with < 1 drink/month. The associations were stronger among women younger than age 30 with normal weight at baseline. CONCLUSIONS: Frequent consumption of burgers from restaurants and sugar-sweetened soft drinks contribute to obesity among young African American women.

Toxicity and efficacy of CAR T-cell therapy in primary and secondary CNS lymphoma: a meta-analysis of 128 patients.

Relapsed/refractory primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) are associated with short survival and represent an unmet need, requiring novel effective strategies. Anti-CD19 chimeric antigen receptor (CAR) T cells, effective in systemic large B-cell lymphoma (LBCL), have shown responses in PCNSL and SCNSL in early reports, but with limited sample size. We, therefore, performed a comprehensive systematic review and meta-analysis of all published data describing CAR T-cell use in PCNSL and SCNSL. This identified 128 patients with PCNSL (30) and SCNSL (98). Our primary objectives were to evaluate CAR T-cell specific toxicity (immune effector cell-associated neurotoxicity syndrome [ICANS] and cytokine release syndrome [CRS]) as well as response rates in these 2 populations. Seventy percent of patients with PCNSL had CRS of any grade (13% grade 3-4) and 53% had ICANS of any grade (18% grade 3-4). Comparatively, 72% of the SCNSL cohort experienced CRS of any grade (11% grade 3-4) and 48% had ICANS of any grade (26% grade 3-4). Of the patients with PCNSL, 56% achieved a complete remission (CR) with 37% remaining in remission at 6 months. Similarly, 47% of patients with SCNSL had a CR, with 37% in remission at 6 months. In a large meta-analysis of central nervous system (CNS) lymphomas, toxicity of anti-CD19-CAR T-cell therapy was similar to that of registrational studies in systemic LBCL with no increased signal of neurotoxicity observed. Encouraging efficacy was demonstrated in patients with CNS lymphoma with no discernible differences between PCNSL and SCNSL.

Telomere length variation in normal epithelial cells adjacent to tumor: potential biomarker for breast cancer local recurrence.

A better understanding of the risk of local recurrence (LR) will facilitate therapeutic decision making in the management of early breast cancers. In the present study, we investigated whether telomere length in the normal breast epithelial cells surrounding the tumor is predictive of breast cancer LR; 152 women who were diagnosed with breast cancer at the Lombardi Comprehensive Cancer Center were included in this nested case-control study. Cases (patients had LR) and controls (patients had no LR) were matched on year of surgery, age at diagnosis and type of surgery. Telomere fluorescent in situ hybridization was used to determine the telomere length using formalin fixed paraffin-embedded breast tissues. Small telomere length variation (TLV), defined as the coefficient variation of telomere lengths among examined cells, in normal epithelial cells adjacent to the tumor was significantly associated with a 5-fold (95% confidence interval = 1.2-22.2) increased risk of breast cancer LR. When the subjects were categorized into quartiles, a significant inverse dose-response relationship was observed with lowest versus highest quartile odds ratio of 15.3 (P(trend) = 0.012). Patients who had large TLV had significantly better 10 year recurrence free survival rate compared with patients who had small TLV (80 versus 33%). The present study revealed that TLV in normal epithelial cells adjacent to tumor is a strong predictor of breast cancer LR. If confirmed by future studies, TLV in normal epithelial cells adjacent to tumor has the potential to become a promising biomarker for predicting breast cancer LR after breast conserving surgery.

Cholesterol, lipoproteins, and breast cancer risk in African American women.

BACKGROUND: Lipid levels, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides, have been reported to be associated with breast cancer risk. METHODS: We studied African American women (97 breast cancer cases and 102 controls) accrued through a population-based, case-control study in the Washington, DC metropolitan area during 1997 and 1998. Plasma lipid levels were measured using enzymatic methods. Logistic regressions (adjusted for age, age at menarche, parity, previous alcohol consumption, and education) were used to explore the associations between lipid levels and breast cancer. RESULTS: Through multivariable-adjusted regression, we observed a significant inverse association between breast cancer risk and increasing levels of total cholesterol (OR=.46, 95% Cl = .25-.85) and LDL (OR = .41, 95% CI = .21-.81), whereas lower levels of HDL were associated with a significant increase in risk (OR = 1.99, 95% CI = 1.06-3.74). CONCLUSIONS: Our data demonstrate significant reductions in breast cancer risk with high levels of total cholesterol and significant increase in risk when HDL levels are low. These data are in support of a protective effect of cholesterol which has been reported in other populations; further, these findings add to the literature in an understudied population, African American women.

Use of multivitamins, folic acid and herbal supplements among breast cancer survivors: the black women's health study.

BACKGROUND: Complementary and alternative medicine (CAM) use, including herbals and multivitamin supplements, is quite common in the U.S., and has been shown to be highest in breast cancer survivors. However, limited data are currently available for CAM usage among African Americans. Thus, we sought to determine the prevalence of multivitamins, folic acid and herbal supplement usage in African American breast cancer survivors, and to compare the characteristics of users and nonusers. METHODS: A cohort study of breast cancer survivors, who completed the 1999 Black Women's Health Study questionnaire and self-reported having been diagnosed with breast cancer between 1995 and 1999, comprised the study population. In this study, the intake of natural herbs, multivitamins and folic acid at least three days per week within the past two years was used as a proxy for typical usage of this complimentary alternative medicine (CAM) modality. RESULTS: A total of 998 breast cancer survivors were identified. Overall, 68.2% had used either herbals or multivitamin supplements or both. The three most frequently used herbals were garlic (21.2%), gingko (12.0%), and echinacea (9.4%). The multivariate analysis determined that single marital status (OR=1.58; 95%CI: 1.04-2.41), and alcohol consumption of 1-3 drinks per week (OR=1.86, 95%CI: 1.28-2.68) were significantly associated with increased herbal use. Multivitamin use was significantly lower among obese women (OR=0.66, 95%CI: 0.46-0.94) and current smokers (OR=0.53, 95%CI: 0.34-0.82). CONCLUSIONS: A significant number of African American breast cancer survivors are using herbals and multivitamins as CAM modality. Additional research is needed to understand the impact of herbals and multivitamins in African American breast cancer survivors.

An assessment of the CES-D scale factor structure in black women: The Black Women's Health Study.

This study investigates the dimensional structure of the Center for Epidemiologic Studies Depression (CES-D) scale in US Black women with and without history of cancer via single-group and multi-group analyses. The CES-D questionnaire was administered in 1999 to 50,774 black women who are participants in the Black Women's Health Study (BWHS). For our analysis, we utilized a group of 690 women with a history of at least one of the three types of cancer (breast cancer, colon cancer or lung cancer) and an age-matched group of 1,380 healthy women with no history of any cancer or other chronic conditions including myocardial infarctions, stroke, angina, diabetes, lupus, and sarcoidosis. Three a priori hypothesized models were tested via confirmatory factor analysis: single-, three- and four-factor structures. The four-factor model provided the best fit and remained largely invariant across the groups when tested via multi-group comparisons. Two internal consistency measures of the scale (Cronbach's alpha coefficient and split-half coefficient) were also shown to be satisfactory. We concluded that the CES-D scale is appropriate for use in black women regardless of their cancer status.

Breast cancer risk assessments comparing Gail and CARE models in African-American women.

The Gail model has been used to predict invasive breast cancer risk in women using risk factors of age, age at menarche, age at first live birth, number of first-degree relatives with breast cancer, and number of previous benign breast biopsies. However, this model underestimates breast cancer risk in African-American women. The Contraceptive and Reproductive Experience (CARE) model has been developed to replace the Gail model in predicting breast cancer risk in African-American women. In a sample of 883 women who participated in the breast cancer screening program at Howard University Cancer Center, we compared the breast cancer risk estimates from the Gail model and the CARE model. The mean 5-year breast cancer risk was 0.88% (Range: 0.18-6.60%) for the Gail model and 1.29% (Range: 0.20-4.50%) for the CARE model. Using the usual cutoff-point of 1.67% or above for elevated risk, there is a significant difference in the proportion of women with elevated breast cancer risk between the Gail and the CARE models (McNemar's test, p < 0.0001). For both models, there was a significant mean risk difference between those with and without a family history of breast cancer (Wilcoxon rank-sum test, p < 0.0001). Our results confirm the need for validation of the Gail model in African-Americans and diversity in research. Although these findings are not perfect and perhaps not definitive, they are additive in the discussions during counseling and risk assessment in African-Americans. Furthermore, these findings will be complemented by new technologies such as genomics in refining our ability to assess risk.

Homeoprotein DLX4 expression is increased in inflammatory breast cancer cases from an urban African-American population.

Protein expression of Distal-less homeobox 4 (DLX4) was analyzed in inflammatory breast cancer (IBC) cases from an African-American (AA) population to determine if a) DLX4 gene over expression exists in this cohort and b) if the overexpression is associated with breast cancer clinicopathological characteristics (ER, PR, HER2, triple-negative). Twenty-nine blocks of formalin-fixed paraffin-embedded (FFPE) tissue from well-characterized human IBC cases were used for immunohistochemical staining (IHC). IHC results were assigned an intensity and percentage score. Percentage scores were assigned as 0, 1, 2, 3, or 4 and intensity scores were assigned 0, 1+, 2+ or 3+. For the analysis of the IHC, a percentage score of 3 or 4 and an intensity score of 2+ or 3+ were categorized as high. Chi-square or Fisher's exact tests were used to compare the high and low groups. In this cohort, 89.7% (26 out of 29) of IBC cases showed high percentages of positive cells staining for the DLX4 protein, while 40.0% (12 out of 30) of normal breast tissue from reduction mammoplasty cases demonstrated DLX4 expression (p < 0.01). In IBC patients, 65.5% of cases showed a high level of staining intensity, compared to 20.0% of normal breast tissues (test, p = 0.001). Intensity to DLX4 was higher in the HER2 negative status (78.3%) than the HER2 positive status (16.7%) (test, p = 0.011). DLX4 expression is higher in the IBC cases in this study of an urban AA population than in normal breast tissue cases. HER2 negative status is positively associated with high intensity of DLX4.

Physician Intervention and Chinese Americans' Colorectal Cancer Screening.

OBJECTIVE: We conducted a cluster-randomized trial evaluating an intervention that trained Chinese-American primary care physicians to increase their Chinese patients' colorectal cancer (CRC) screening. METHODS: Twenty-five physicians (13 randomized to the intervention arm and 12 to the control arm) and 479 of their patients (aged 50-75 and nonadherent to CRC screening guidelines) were enrolled. The intervention, guided by Social Cognitive Theory, included a communication guide and 2 in-office training sessions to enhance physicians' efficacy in com- municating CRC screening with patients. Patients' CRC screening rates (trial outcome) and rating of physician communication before intervention and at 12-month follow-up were assessed. Intention-to-treat analysis for outcome evaluation was conducted. RESULTS: Screening rates were slightly higher in the intervention vs. the control arm (24.4% vs. 17.7%, p = .24). In post hoc analyses, intervention arm patients who perceived better communication were more likely to be screened than those who did not (OR = 1.09, 95% CI: 1.03, 1.15). This relationship was not seen in the control arm. CONCLUSIONS: This physician-focused intervention had small, non-significant effects in increasing Chinese patients' CRC screening rates. Physician communication appeared to explain intervention efficacy. More intensive interventions are needed to enhance Chinese patients' CRC screening.

PCB exposure and potential future cancer incidence in Slovak children: an assessment from molecular finger printing by Ingenuity Pathway Analysis (IPA®) derived from experimental and epidemiological investigations.

The risk of cancer due to PCB exposure in humans is highly debated. In eastern Slovakia, high exposure of the population to organochlorines (especially PCBs) was associated with various disease and disorder pathways, viz., endocrine disruption, metabolic disorder & diabetes, and cancer, thereby disturbing several cellular processes, including protein synthesis, stress response, and apoptosis. We have evaluated a Slovak cohort (45-month children, at lower and higher levels of PCB exposure from the environment) for disease and disorder development to develop early disease cancer biomarkers that could shed new light on possible mechanisms for the genesis of cancers under such chemical exposures, and identify potential avenues for prevention.Microarray studies of global gene expression were conducted from the 45-month-old children on the Affymetrix platform followed by Ingenuity Pathway Analysis (IPA®) to associate the affected genes with their mechanistic pathways. High-throughput qRT-PCR TaqMan low-density array (TLDA) was performed to further validate the selected genes on the whole blood cells of the most highly exposed children from the study cohort (n = 71). TP53, MYC, BCL2, and LRP12 differential gene expressions suggested strong relationships between potential future tumor promotion and PCB exposure in Slovak children. The IPA analysis further detected the most important signaling pathways, including molecular mechanism of cancers, prostate cancer signaling, ovarian cancer signaling, P53 signaling, oncostatin M signaling, and their respective functions (viz., prostate cancer, breast cancer, progression of tumor, growth of tumor, and non-Hodgkin's disease). The results suggest that PCB exposures, even at the early age of these children, may have lifelong consequences for the future development of chronic diseases.

Detection of a lipid peroxidation-induced DNA adduct across liver disease stages.

BACKGROUND: Oxidative stress and chronic inflammation can increase cellular levels of reactive oxygen species and lipid peroxidation (LPO) when associated with the pathogenesis of hepatocellular carcinoma (HCC), which can develop following the progression of steatosis, fibrosis and cirrhosis. Using a monoclonal antibody for cyclic γ-hydroxy-1, N2 -propanodeoxyguanosine (γ-OHPdG), a promutagenic DNA adduct formed endogenously by LPO, we examined its formation across liver disease stages to understand it's potential role in HCC development. METHODS: Formalin-fixed paraffin embedded (FFPE) liver tissue samples from 49 patients representing normal, steatosis, fibrosis, cirrhosis and HCC were stained for γ-OHPdG and 8-hydroxydeoxyguanosine (8-oxo-dG), an oxidative damage biomarker. Quantification of immunohistochemical (IHC) staining was performed using histological scoring of intensity and distribution. Using primary human hepatocytes (HH) and a stellate cell (SC) co-culture, immunocytochemical staining of γ-OHPdG and Nile Red was performed to determine if the formation of γ-OHPdG was consistent between the clinical sample disease stages and the in vitro steatotic and fibrotic conditions. RESULTS: γ-OHPdG levels varied significantly between the stages of normal and steatosis, steatosis and fibrosis, and steatosis and cirrhosis (P≤0.005). There was a trend, although not significant, of increased levels of γ-OHPdG in HCC compared to the other groups. A strong correlation was observed (Pearson's, R2 =0.85) between levels of γ-OHPdG and 8-oxo-dG across the disease spectrum. The increase of γ-OHPdG in steatosis and decrease in fibrosis was a pattern confirmed in an in vitro model using primary HH co-cultured with human SCs. CONCLUSIONS: γ-OHPdG was detected in FFPE liver tissues of patients with different stages of liver disease and in vitro studies, demonstrating that its formation is consistent with LPO in early stages of liver disease and suggesting that it may be a source of mutagenic DNA damage in liver disease progression.