Molecular markers of human papillomavirus (HPV) infection and epidemiologic risk factors for squamous intraepithelial lesions (SIL) of the cervix

Infection with certain types of HPV is a necessary event in the development of cervical carcinoma; however, not all women who become infected will progress. While much is known about the molecular influence of HPV E6 and E7 proteins on the malignant transformation, little is known about the additional factors needed to drive the process. Currently, conventional cervical screening is insufficient at identifying women who are likely to progress from premalignant lesions to carcinoma. Aneuploidy and chromatin texture from image cytometry have been suggested as quantitative measures of nuclear damage in premalignant lesions and cancer, and traditional epidemiologic studies have identified potential factors to aid in the discrimination of those lesions likely to progress. ^ In the current study, real-time PCR was used to quantitate mRNA expression of the E7 gene in women exhibiting normal epithelium, LSIL, and HSIL. Quantitative cytometry was used to gather information about the DNA index and chromatin features of cells from the same women. Logistic regression modeling was used to establish predictor variables for histologic grade based on the traditional epidemiologic risk factors and molecular markers. ^ Prevalence of mRNA transcripts was lower among women with normal histology (27%) than for women with LSIL (40%) and HSIL (37%) with mean levels ranging from 2.0 to 4.2. The transcriptional activity of HPV 18 was higher than that of HPV 16 and increased with increasing level of dysplasia, reinforcing the more aggressive nature of HPV 18. DNA index and mRNA level increased with increasing histological grade. Chromatin score was not correlated with histology but was higher for HPV 18 samples and those with both HPV 18 and HPV 16. However, chromatin score and DNA index were not correlated with mRNA levels. The most predictive variables in the regression modeling were mRNA level, DNA index, parity, and age, and the ROC curves for LSIL and HSIL indicated excellent discrimination. ^ Real-time PCR of viral transcripts could provide a more efficient method to analyze the oncogenic potential within cells from cervical swabs. Epidemiological modeling of malignant progression in the cervix should include molecular markers, as well as the traditional epidemiological risk factors. ^

Micronutrient intakes and their associations with markers of inflammation, subclinical atherosclerosis, cardiovascular disease, type II diabetes and metabolic syndrome

We investigated cross-sectional associations between intakes of zinc, magnesium, heme- and non heme iron, beta-carotene, vitamin C and vitamin E and inflammation and subclinical atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA). We also investigated prospective associations between those micronutrients and incident MetS, T2D and CVD. Participants between 45-84 years of age at baseline were followed between 2000 and 2007. Dietary intake was assessed at baseline using a 120-item food frequency questionnaire. Multivariable linear regression and Cox proportional hazard regression models were used to evaluate associations of interest. Dietary intakes of non-heme iron and Mg were inversely associated with tHcy concentrations (geometric means across quintiles: 9.11, 8.86, 8.74, 8.71, and 8.50 µmol/L for non-heme iron, and 9.20, 9.00, 8.65, 8.76, and 8.33 µmol/L for Mg; ptrends <0.001). Mg intake was inversely associated with high CC-IMT; odds ratio (95% CI) for extreme quintiles 0.76 (0.58, 1.01), ptrend: 0.002. Dietary Zn and heme-iron were positively associated with CRP (geometric means: 1.73, 1.75, 1.78, 1.88, and 1.96 mg/L for Zn and 1.72, 1.76, 1.83, 1.86, and 1.94 mg/L for heme-iron). In the prospective analysis, dietary vitamin E intake was inversely associated with incident MetS and with incident CVD (HR [CI] for extreme quintiles - MetS: 0.78 [0.62-0.97] ptrend=0.01; CVD: 0.69 [0.46-1.03]; ptrend =0.04). Intake of heme-iron from red meat and Zn from red meat, but not from other sources, were each positively associated with risk of CVD (HR [CI] - heme-iron from red meat: 1.65 [1.10-2.47] ptrend = 0.01; Zn from red meat: 1.51 [1.02 - 2.24] ptrend =0.01) and MetS (HR [CI] - heme-iron from red meat: 1.25 [0.99-1.56] ptrend =0.03; Zn from red meat: 1.29 [1.03-1.61]; ptrend = 0.04). All associations evaluated were similar across different strata of gender, race-ethnicity and alcohol intake. Most of the micronutrients investigated were not associated with the outcomes of interest in this multi-ethnic cohort. These observations do not provide consistent support for the hypothesized association of individual nutrients with inflammatory markers, MetS, T2D, or CVD. However, nutrients consumed in red meat, or consumption of red meat as a whole, may increase risk of MetS and CVD.^