The consumption of micronutrients in relation to calorie intake and risk of insulin resistance.

BACKGROUND AND AIMS: Adequate dietary intakes of essential micronutrients are critical to prevent insulin resistance (IR)-related diseases. Even though the excess calorie intake linked with obesity is also associated with such diseases, no previous studies evaluated the importance of meeting the Dietary Reference Intake (DRI) of micronutrients in relation to calorie intake in those at risk for developing IR. METHODS AND RESULTS: We evaluated the relationship between the ability or failure to meet the DRI of micronutrients in relation to daily calorie intake in 463 childbearing-age women with a higher prevalence of IR. 56-65% women met the DRIs for vitamin B12, vitamin C, thiamine, and riboflavin while only 0%-49% met the DRIs for folate, pyridoxine, niacin, pantothenic acid, total carotene, vitamins A, D and E by consuming an acceptable number of calories. Women who met the DRIs of folate and vitamin C within acceptable daily calorie intakes were 59% and 66% less likely to have higher Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) compared to women who did not. CONCLUSIONS: Understanding the mechanisms that explain our findings will be of value to address IR-associated with exposure to high calorie/low-micronutrient dense diets consumed by childbearing-age women. Since there is a global recognition that IR has been increasing in adults and children, similar studies of this nature in pregnant women at risk for IR will provide much needed data to assess the burden of such adverse dietary habits in the offspring. Our study approach may form the foundation for such studies.

Human papillomavirus sequencing reveals its usefulness for the management of HIV-infected women at risk for developing cervical cancer.

AIM: Next-generation sequencing (NGS) is able to describe the composition of human papillomaviruses (HPVs) as percent (%) reads rather than positive/negative results. Therefore, we used this unique approach to assess the prevalence of cervical HPVs of HIV infected (HIV+) in order to understand the determinants of being infected with higher % reads of high risk (HR)-HPVs and cervical abnormalities of atypical squamous cells of unknown significance or higher (ASCUS+). METHODS: Study included 66 women characterized for relevant risk factors/cytology. Receiver-operating curve curve was used to derive the optimal % read cut point to identify ASCUS+ in relation to any HR-HPV genotype or other specific HPV genotypes. The determinants of ASCUS+ and HR-HPVs were tested using logistic regression. RESULTS: Women with >20% reads of any HR-HPV or >12% any HR-HPV other than HPV 16/18 were 5.7 and 12.6 times more likely to be diagnosed with ASCUS+, respectively. Lower CD4 count was a significant determinant of >20% reads of HR-HPV (odds ratio [OR] = 4.1) or >12% any HR-HPV other than HPV 16/18 (OR = 4.5). CONCLUSION: We envision that the NGS-based HPV detection will be more accurate for screening and management of HIV+ at risk for developing cervical cancer (CC). We raise concerns regarding the limitations of 16/18-based HPV testing for triage and the efficacy of current HPV vaccines for preventing CC in HIV+.

Expression of p16INK4A in cervical precancerous lesions that is unlikely to be preventable by human papillomavirus vaccines.

BACKGROUND: Whether higher grade cervical intraepithelial neoplasia (CIN grade 2 or greater [CIN ≥ 2]) that develops because of human papillomavirus (HPV) genotypes not included in vaccines may progress to cervical cancer is largely unknown. The objectives of this study were to document expression of the cyclin-dependent kinase inhibitor 2A (p16) tumor-suppressor protein p16INK4A as a biomarker of cervical carcinogenesis or of malignant potential and to evaluate whether its expression differs between lesions associated with vaccine and nonvaccine high-risk (HR) human papillomavirus (HPV) genotypes. METHODS: The study population consisted of 371 women who had not received HPV vaccines. Women were categorized into vaccine and nonvaccine HR-HPV genotypes and lesions associated with those types. Logistic regression analyses were used to determine the association between positive expression p16INK4A and the risk of being diagnosed with CIN 2 or CIN 3. Differences in the proportion of CIN ≥2 lesions that were positive for p16INK4A expression by vaccine-related or nonvaccine-related HR-HPV genotype were determined using the Pearson chi-square test. RESULTS: Specimens that were positive for p16INK4A expression were 5.3 and 16.6 times more likely to be diagnosed as CIN 2 and CIN 3 lesions, respectively, compared to CIN 1 lesions. CIN ≥ 2 lesions that were negative for the bivalent and 9-valent HR-HPV genotypes had similar rates of positive p16INK4A expression compared with lesions that were positive for those HR-HPV genotypes. CONCLUSIONS: Lesions that may develop because of HR-HPV genotypes not included in HPV vaccines are likely to have similar malignant potential, suggesting that well developed screening programs combined with nonvaccine-based approaches may be needed to manage the residual risk of developing cervical cancer in the post-HPV vaccination era. Cancer 2016;122:3615-23. © 2016 American Cancer Society.

Accuracy of urinary human papillomavirus testing for the presence of cervical human papillomaviruses and higher grades of cervical intraepithelial neoplasia.

BACKGROUND: Although urine-based testing for human papillomavirus (HPV) is being explored as a practical approach for cervical cancer screening, whether the results differ by age, race, or indicators of excess body weight or in populations exposed to HPV vaccines has not been documented by previous studies. The purpose of this study was to determine the accuracy of urinary HPV testing for the presence of cervical HPVs and high-grade cervical intraepithelial lesions (grade 2 and 3 cervical intraepithelial neoplasia [CIN]) by the aforementioned population characteristics. METHODS: The study population consisted of 502 women diagnosed with different grades of CIN. HPV testing was performed with paired urine and cervical cell DNA with the Roche Diagnostics Linear Array test. Agreement coefficient 1 and probabilities were calculated to determine the accuracy of urinary HPV testing for the presence of cervical HPVs and CIN lesions. RESULTS: Substantial to almost perfect agreement (0.66-0.83) was observed in the detection of any HPV genotype in urine specimens versus cervical specimens, regardless of the population characteristics. Although the positive predictive value for the detection of CIN lesions was relatively low, the negative predictive value for CIN-3 was high (≥90%) among women positive for any of the urinary or cervical high-risk human papillomavirus (HR-HPV) genotypes or HPV genotypes not included in currently available HPV vaccines. CONCLUSIONS: The results demonstrate that urinary HPV testing provides highly satisfactory results for excluding the possibility of any cervical HPV infections, including HPV types not included in vaccines and CIN lesions associated with any HR-HPV, regardless of a woman's age, race, or excess body weight. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2836-2844. © 2016 American Cancer Society.

Homocysteinemia is Associated with a Lower Degree of PBMC LINE-1 Methylation and a Higher Risk of CIN 2C in the U.S. Post-Folic Acid Fortification Era.

The primary aim of the study was to determine whether plasma concentrations of homocysteine (Hcy), a functional indicator of methyl donor nutrients, are associated with altered risk of higher grades of cervical intraepithelial neoplasia (CIN 2+) and the degree of methylation in long interspersed nucleotide elements (LINE-1s) of peripheral blood mononuclear cells, a potential biomarker of CIN 2+ in a population of women exposed to the United States folic acid fortification program. The secondary aim was to assess the determinants of plasma Hcy in the same population. The study included 457 women diagnosed with either CIN 2+ (cases, n = 132) or ≤ CIN 1 (non-cases, n = 325). Unconditional logistic regression models were used to test the associations after adjusting for relevant risk factors of cervical cancer. Women with higher Hcy concentrations were at a greater risk of being diagnosed with CIN 2+ [odds ratio (OR) = 1.86, P = 0.005]. Higher plasma folate concentrations were a significant determinant of lower Hcy (OR = 0.40, P = 0.0002). Women with higher Hcy concentrations were more likely to have a lower degree of LINE-1 methylation (OR = 2.30, P = 0.0007). These results suggested that further improvement in folate status in this population may be beneficial for lowering Hcy and improving the degree of LINE-1 methylation.

Functional variants in CYP1A1 and GSTM1 are associated with clearance of cervical HPV infection.

OBJECTIVE: We evaluated time to clearance of high risk (HR) HPV infection in relation to functional variants in three genes (CYP1A1, GSTT1, and GSTM1). METHODS: The study group consisted of 450 HR-HPV infected women from the Atypical squamous cells of undetermined significance-low-grade squamous intraepithelial Lesion Triage Study (ALTS) cohort followed up at the clinical center at Birmingham, Alabama. The Cox proportional hazard model with the Wei-Lin-Weisfeld (WLW) approach was used, controlling for relevant covariates. RESULTS: Women who were polymorphic for CYP1A1 experienced an HR-HPV clearance rate that was 20% (HR=0.80, p=0.04) lower than women without the polymorphism for CYP1A1, adjusting for all other cofactors. The GSTM1 null genotype was associated with higher HR-HPV clearance rate (HR=1.39, p=0.006). The polymorphism in GSTT1 was not significantly associated with time to clearance of HR-HPV. CONCLUSIONS: Xenobiotic metabolism genes may influence the natural history of HR-HPV infection and its progression to cervical cancer.

Potential Effects of Age-Based Changes in Screening Guidelines on the Identification of Women at Risk for Developing Cervical Cancer.

Current American Cancer Society guidelines estimated that screening starting at the age of 25 years with Pap and/or human papillomavirus (HPV) testing is sufficient to prevent cervical cancer. The effect of having HPV infections without Pap-based care until age 25 on the prevalence of higher grades of cervical intraepithelial neoplasia (≥CIN 2) and their determinants are largely unknown. The objectives of the study were to document the potential effects of age-based changes in screening guidelines on the identification of ≥CIN 2 and their determinants. The study included 1,584 women diagnosed with abnormal Pap and tested for HPVs and histologic diagnoses of cervical lesions. The association between demographic/lifestyle factors and HPV status and risk of being diagnosed with ≥CIN 2 among younger (21-<25 years) or older (≥25 year) women was tested using unconditional multiple logistic regression models. We observed that younger women who are not screened have a similar or higher risk of developing specific high-risk HPV genotype-associated ≥CIN 2 lesions compared with older women who are screened according to the current guidelines. In addition, younger women who reported live births, smoking, contraceptive use, and a higher number of sexual partners were significantly at higher risk of being diagnosed with ≥CIN 2. Targeted screening of younger women at risk for developing ≥CIN 2 will address the concern of overtreatment while providing the recommended care to those who require such care to prevent the development of cervical cancer. PREVENTION RELEVANCE: This study documents the concerns of the age-based changes in screening guidelines on the identification of higher grades of cervical intraepithelial neoplasia and their determinants in women diagnosed with abnormal Pap smear and emphasize the need for targeted screening of younger women to prevent cervical cancer.

Micronutrients and prevention of cervical pre-cancer in HPV vaccinated women: a cross-sectional study.

Objectives: Prophylactic vaccines against high-risk human papillomaviruses (HR-HPVs) hold promise to prevent the development of higher grade cervical intraepithelial neoplasia (CIN 2+) and cervical cancer (CC) that develop due to HR-HPV genotypes that are included, in HPV vaccines, but women will continue to develop CIN 2+ and CC due to HR-HPV genotypes that are not included in the quadrivalent HPV vaccine (qHPV) and 9-valent HPV vaccine (9VHPV). Thus, the current vaccines are likely to decrease but not entirely prevent the development of CIN 2+ or CC. The purpose of the study was to determine the prevalence and determinants of CIN 2+ that develop due to HR-HPVs not included in vaccines. Methods: Study population consisted of 1476 women tested for 37 HPVs and known to be negative for qHPVs (6/11/16/18, group A, n = 811) or 9VHPVs (6/11/16/18/31/33/45/52/58, group B, n = 331), but positive for other HR-HPVs. Regression models were used to determine the association between plasma concentrations of micronutrients, socio-demographic, lifestyle factors and risk of CIN 2+ due to HR-HPVs that are not included in vaccines. Results: The prevalence of infections with HPV 31, 33, 35 and 58 that contributed to CIN 2+ differed by race. In group A, African American (AA) women and current smokers were more likely to have CIN 2 (OR = 1.76, P = 0.032 and 1.79, P = 0.016, respectively) while in both groups of A and B, those with higher vitamin B12 were less likely to have similar lesions (OR = 0.62, P = 0.036 and 0.45, P = 0.035, respectively). Conclusions: We identified vitamin B12 status and smoking as independent modifiable factors and ethnicity as a factor that needs attention to reduce the risk of developing CIN 2+ in the post vaccination era. Continuation of tailored screening programs combined with non-vaccine-based approaches are needed to manage the residual risk of developing HPV-related CIN 2+ and CC in vaccinated women.

Potential effects of age-based changes in screening guidelines on the identification of women at risk for developing cervical cancer.

Current American Cancer Society (ACS) guidelines estimated that screening starting at the age of 25 years with Pap and/or human papillomavirus (HPV) testing is sufficient to prevent cervical cancer (CC). The effect of having HPV infections without Pap-based care until age 25 on the prevalence of higher grades of cervical intraepithelial neoplasia (≥ CIN 2) and their determinants are largely unknown. The objectives of the study were to document the potential effects of age-based changes in screening guidelines on the identification of ≥ CIN 2 and their determinants. The study included 1584 women diagnosed with abnormal Pap and tested for HPVs and histological diagnoses of cervical lesions. The association between demographic/lifestyle factors and HPV status and risk of being diagnosed with ≥ CIN 2 among younger (21-<25 years) or older (≥ 25 year) women was tested using unconditional multiple logistic regression models. We observed that younger women who are not screened have a similar or higher risk of developing specific high risk (HR)-HPV genotype-associated ≥ CIN 2 lesions compared to older women who are screened according to the current guidelines. In addition, younger women who reported live births, smoking, contraceptive use and a higher number of sexual partners were significantly at higher risk of being diagnosed with ≥ CIN 2. Targeted screening of younger women at risk for developing ≥ CIN 2 will address the concern of overtreatment while providing the recommended care to those who require such care to prevent the development of CC.

HPV E1 qPCR, a Low-Cost Alternative Assay to Roche Diagnostic Linear Array is Effective in Identifying Women at Risk for Developing Cervical Cancer.

OBJECTIVE: Since a quantitative polymerase chain reaction (qPCR) assay targeting the E1 region of HPV genome is cost-effective/simple to perform, we evaluated the agreement between the Roche Diagnostics Linear Array (RDLA) genotyping test and qPCR-based E1 assay to detect HR-HPV genotypes that are included or not included in HPV vaccines and compared their accuracy to detect CIN 2+. METHODS: Study population included 257 African American (AA) and 266 Caucasian American (CA) diagnosed with intraepithelial neoplasia (CIN) grades ≤CIN 1 or ≥CIN 2 (CIN 2+) and tested for HPV by the RDLA and E1 assay. The concordance was determined using Gwet's AC1. The calculated positive predictive value (PPV) and negative predictive value (NPV) of the two assays were used to determine their suitability to detect CIN lesions. RESULTS: Overall, the E1 assay showed substantial agreement with the RDLA assay to detect any HR-HPV genotype and the agreement was higher in women diagnosed with CIN 2+ than ≤CIN 1. The concordance was largely higher in Cas than in Aas. The NPV and PPV values to detect CIN lesions were similar between the two assays. CONCLUSION: Utilization of the HPV E1 assay as a tool for CC screening could be a cost-effective approach that applies to both vaccinated and unvaccinated populations.

The dataset for the assessment of the inflammatory potential of the overall diet consumed by women of childbearing age.

The data presented in this article is related to the research article titled "Racial differences in dietary choices and their relationship to inflammatory potential in childbearing age women at risk for exposure to COVID-19". This data article provides details of dietary intake data from 509 women (African American, n = 327 and Caucasian American, n = 182) who are residents of Birmingham, AL. All women were characterized for demographic and lifestyle factors and indicators of excess body weight (EBW) that are likely to influence overall dietary habits. Dietary intake data was collected by administering the modified version of the NCI validated Block food frequency questionnaire (98.2-isoflav version) that includes 110 food items of the original version (98.2 version) and an additional 24 phytochemical rich food items. The data article describes our approach to derive the dietary inflammatory score using a validated empirical dietary inflammatory index based on the frequency and the amount of consumption of each food item with minor modifications. This data will allow researchers to understand the composition of a Southern-style diet consumed by women of childbearing age and its relationship to inflammatory potential, EBW, dietary guidelines, dietary reference intakes or diet quality indices.

Racial differences in dietary choices and their relationship to inflammatory potential in childbearing age women at risk for exposure to COVID-19.

Since the ongoing coronavirus disease 2019 (COVID-19) pandemic is linked to chronic inflammation, people with initial lower inflammatory status could have better outcomes from exposure to this disease. Because dietary habits are one of the most important modifiable risk factors for inflammation, identification of dietary components associated with inflammation could play a significant role in controlling or reducing the risk of COVID-19. We investigated the inflammatory potential of diets consumed by African American (AA) and Caucasian American (CA) women of childbearing age (n = 509) who are at high risk for exposure to COVID-19 by being residents of Birmingham, Alabama, a city severely affected by this pandemic. The overall pro- and anti- inflammatory scores were calculated using dietary intake data gathered using Block food frequency questionnaire. The proinflammatory potential of diets consumed by AAs was significantly higher compared to CAs. Several anti- and proinflammatory nutrients and food groups consumed differed by race. With consumption of a greater number of antioxidants and B-vitamins, CAs switched toward an anti-inflammatory score more effectively than AAs while AAs performed better than CAs in improving the anti-inflammatory score with the consumption of a greater number of minerals and vitamin D. Effective race-specific dietary modifications or supplementation with nutrients identified will be useful to improve proinflammatory diets toward anti-inflammatory. This approach could aid in controlling the current COVID-19 pandemic and future pandemics of a similar nature in women at risk for exposure.

The accuracy of HPV genotyping in isolation and in combination with CD4 and HIV viral load for the identification of HIV-infected women at risk for developing cervical cancer.

BACKGROUND: Human papillomavirus (HPV) genotype testing has limited utility to identify human immunodeficiency virus-infected (HIV+) women's risk for developing cervical cancer (CC) due to high positivity rate of high-risk (HR) HPVs. We investigated the accuracy of HPV testing in isolation/in combination with CD4 and HIV viral load (VL) to identify HIV+ women at risk for developing CC. METHODS: Study consisted of 344 HIV+ women on combination antiretroviral therapy (cART), tested for cervical cytology/HPV using the Cobas test and had data on absolute CD4 count and VL measurements. We calculated the positive predictive value (PPV) and negative predictive value (NPV) of HPV testing, pre-, post-cART, and current CD4 and VL in isolation and in combinations to identify those with or free of higher than atypical squamous cells of unknown significance (ASCUS+) or low-grade intraepithelial lesions (LSIL+). RESULTS: HPV test in combination with pre-/post-cART or current CD4 counts and VL had higher PPVs compared to HPV test alone for identifying ASCUS+ or LSIL+. PPV of HPV-CD4 combinations yielded higher PPVs compared to HPV-VL combinations. The NPVs with pre-, post-cART, or current CD4 count and VL in isolation or in combinations were comparable to that of HPV test alone. CONCLUSIONS: Our results provide a more accurate tool for managing HIV+ women by combining Cobas HPV with CD4 and VL, especially those who had an undesirable pre-cART CD4 and VL status. Our results also indicate the usefulness of CD4 and VL measurements to identify those at lower risk in the absence of HPV testing.

Aflatoxin B1 albumin adducts in plasma and aflatoxin M1 in urine are associated with plasma concentrations of vitamins A and E.

BACKGROUND: Although aflatoxin exposure has been associated with micronutrient deficiency in animals, there are few investigations on the effects of aflatoxin exposure on micronutrient metabolism in humans. OBJECTIVE: To examine the relationship between aflatoxin B1 (AFB1) albumin adducts (AF-ALB) in plasma and the aflatoxin M1 (AFM1) metabolite in urine and plasma concentrations of retinol (vitamin A) and alpha-tocopherol (vitamin E) in Ghanaians. METHODS: A cross-sectional study of 147 adult participants was conducted. Blood and urine samples were tested for aflatoxin and vitamins A and E levels. RESULTS: Multivariable analysis showed that participants with high AF-ALB (>or=0.80 pmol/mg albumin) had increased odds of having vitamin A deficiency compared to those with lower AF-ALB [Odds Ratio (OR)=2.61; CI=1.03-6.58; p=0.04]. Participants with high AF-ALB also showed increased odds of having vitamin E deficiency but this was not statistically significant (OR=2.4; CI=0.96-6.05; p=0.06). Conversely, those with higher AFM1 values had a statistically nonsignificant reduced odds of having vitamin A deficiency (OR=0.31; CI=0.09-1.02; p=0.05) and a statistically significant reduced odds of having vitamin E deficiency (OR=0.31; CI=0.10-0.97; p=0.04). Participants with high AF-ALB or high AFM1 (>or=437.95 pg/dL creatinine) were almost 6 times more likely to be hepatitis B virus surface antigen (HBsAg)-positive (OR=5.88; CI=1.71-20.14; p=0.005) and (OR=5.84; CI=1.15-29.54; p=0.03) respectively. CONCLUSIONS: These data indicate that aflatoxin may modify plasma micronutrient status. Thus, preventing aflatoxin exposure may reduce vitamin A and E deficiencies.

A rigorous exploration of anal HPV genotypes using a next-generation sequencing (NGS) approach in HIV-infected men who have sex with men at risk for developing anal cancer.

BACKGROUND: There are no HPV-based measures for managing anal cancer (AC) in HIV-infected (HIV+) men who have sex with men (MSM) because of the high positivity of high-risk (HR)-HPVs. As next-generation sequencing (NGS) is able to describe the composition of HPVs as percent (%) reads rather than positive vs negative results, we used NGS approach to detect HPVs in anal samples of HIV+ MSM to test its ability to differentiate those who are diagnosed with atypical squamous cells of unknown significance or greater (ASCUS+) from those who are free of such lesions and to understand the burden of HPV infections in relation to HPV vaccines. METHODS: Study included 81 HIV+ MSM characterized for demographics, patient-reported outcome measures, HIV related laboratory measures and anal cytology. We summarized NGS HPV data using % read cut points (>0%->30%) and tested the relationship between % reads of HR-HPVs and risk of ASCUS+ using logistic regression. RESULTS: Forty-six HPVs were detected at the >0% read cut point. The prevalence of any HR-HPVs varied from 100% to 40% with >0% to >30% reads while ≥99% were infected with HR-HPVs included or not included in the 9 valent HPV vaccine at the >0% read cut point. MSM with >30% HR-HPV reads were 4.5 times more likely to be diagnosed with ASCUS+ compared to ≤30% reads (P = .033). CONCLUSION: NGS-based approach is more accurate than PCR-based HPV testing for identifying HIV+ MSM at risk for developing AC. We raise the concern regarding the efficacy of current HPV vaccines for preventing AC in this high-risk population.

Mandatory fortification with folic acid in the United States is associated with increased expression of DNA methyltransferase-1 in the cervix.

OBJECTIVE: The objective of this study was to evaluate whether mandatory fortification of grain products with folic acid in the United States is associated with changes in DNA methyltransferase-1 (Dnmt-1) expression in cells involved in cervical carcinogenesis. METHODS: Archived specimens of cervical intraepithelial neoplasia (CIN) diagnosed before (1990-1992) and after (2000-2002) mandatory folic acid fortification were used to examine the expression of Dnmt-1 in specific lesions involved in cervical carcinogenesis by immunohistochemistry. The total number of lesions examined was 101 in the prefortification period and 96 in the postfortification period. Immunohistochemical staining for Dnmt-1, its assessment, and data entry were blinded with regard to the fortification status. RESULTS: Age- and race-adjusted mean percentage of cells positive for Dnmt-1 or the Dnmt-1 score was significantly higher in all lesion types (i.e., normal cervical epithelium, reactive cervical epithelium, metaplastic cervical epithelium, CIN, or carcinoma in situ) detected in the postfortification period compared with the prefortification period (P < 0.05, all comparisons). The degree of Dnmt-1 was significantly higher (P < 0.0001) in CIN > or = 2 lesions compared with CIN < or = 1 lesions, regardless of the fortification group. CONCLUSION: These results suggest that mandatory fortification with folic acid in the United States seems to have resulted in a change in the degree of expression of Dnmt-1 in cells involved in cervical carcinogenesis. Because the approach we have taken to demonstrate these differences have limitations inherent to a study of this nature and this is the first study to report a folate fortification associated change in Dnmt-1, validating these results in other study populations and/or with other techniques of assessing Dnmt-1 will increase the scientific credibility of these findings.

Lower red blood cell folate enhances the HPV-16-associated risk of cervical intraepithelial neoplasia.

OBJECTIVE: We previously reported that higher circulating concentrations of folate are independently associated with a lower likelihood of becoming positive for high-risk human papillomaviruses (HR-HPVs) and of having a persistent HR-HPV infection and a greater likelihood of becoming HR-HPV negative (Cancer Res 2004;64:8788-93). In the present study conducted in the same study population, we tested whether circulating folate concentrations modify the risk of cervical intraepithelial neoplasia (CIN) > or =2 associated with specific types of HR-HPV. METHODS: Multiple logistic regression models were used to assess associations (odds ratio with 95% confidence intervals) across HR-HPV, folate, and rigorously reviewed cervical histology of each subject. RESULTS: HPV-16-positive women with low red blood cell folate were significantly more likely to be diagnosed with CIN > or =2 than were HPV-16-negative women with higher red blood cell folate (odds ratio 9, 95% confidence interval 3.3-24.8). CONCLUSION: To our knowledge, this is the first study reporting an independent association of folate with risk of having CIN > or =2 in a population tested extensively for HR-HPV and CIN that also adequately controlled for several other micronutrients and known risk factors for CIN. Our findings suggest that improving the folate status in HR-HPV-infected women may reduce the risk of CIN and thus the risk of cervical cancer. Folate supplementation should be tested as a means of reducing the risk of developing CIN > or =2 in women exposed to HR-HPV, especially HPV-16.

Protective association of MTHFR polymorphism on cervical intraepithelial neoplasia is modified by riboflavin status.

OBJECTIVES: We previously reported that women polymorphic for the methylenetetrahydrofolate reductase (MTHFR) gene were less likely to have cervical intraepithelial neoplasia (CIN) 2 or 3 (odds ratio [OR] 0.40, 95% confidence interval [CI] 0.21-0.78, P = 0.007). In the present study, we tested whether this protective association is modified by circulating riboflavin status in the same study population. METHODS: Riboflavin status was assessed by the erythrocyte glutathione reductase assay and expressed in terms of an erythrocyte glutathione reductase activity coefficient. The status of MTHFR polymorphism, riboflavin, and circulating concentrations of folate, vitamins B12, A, E, and C, and total carotene were ascertained in 170 White and 265 African-American women positive for the cervical presence of high-risk human papilloma virus. Presence/absence of CIN 2 or 3 was determined histologically, and associations with risk factors were examined using multiple logistic regression. Eighty women with CIN 2 or 3 lesions were compared with 355 women without cervical lesions. Based on the median erythrocyte glutathione reductase activity coefficient of 1.4, women were grouped into low (>1.4) and high (< or =1.4) riboflavin status. RESULTS: Women with MTHFR polymorphism and low riboflavin status were significantly less likely to have CIN 2 or 3 than was the referent group of women without the polymorphism and high riboflavin status (OR 0.35, 95% CI 0.13-0.92, P = 0.034). MTHFR polymorphism was not associated with CIN 2 or 3 in women with high riboflavin status (OR 0.51, 95% CI 0.22-1.19, P = 0.119), nor were any of the associations influenced by folate levels. CONCLUSION: A further inactivation of polymorphic MTHFR by low riboflavin status and a resulting shift in the folate metabolic pathway toward DNA synthesis may explain these observations. The practical implications of this complex gene-nutrient-disease interaction will require further investigation.

Update on micronutrients and cervical dysplasia.

This manuscript reviews the current state of knowledge of cervical carcinogenesis and present recent results and introduces ongoing studies on the relationships among micronutrients and natural history of high-risk human papillomaviruses (HR-HPVs) and cervical intraepithelial neoplasia (CIN). Numerous studies have attempted to determine associations between micronutrients and risk of CIN and cervical cancer. Studies that were conducted before a reliable test for assessing HPV infections was available may have resulted in misclassification because of differences in assay sensitivity, which could have led to residual confounding. Another limitation in previous studies may be related to methodologic limitations such as the proper choice of controls for case-control studies. Since cervical cancer does not develop in the absence of HR-HPV infections, only controls exposed to HR-HPV should be included in studies that investigate cofactors for CIN or cervical cancer. Also, the recruitment of subjects for these studies had been based on screening programs that used different approaches such as cytology, colposcopic impression, or biopsy to identify pre-neoplastic cervical lesions. Recent studies have demonstrated that some of these approaches could lead to substantial underdetection and misclassification of preneoplastic lesions of the cervix. Recent studies that addressed these issues have demonstrated that folate is an important micronutrient in cervical cancer prevention via its influence on HR-HPV and the development of CIN. Carefully designed ongoing studies are expected to generate data on whether folate-related biomarkers could be used to identify subjects who are at risk of developing cervical cancer and whether folate supplementation will be beneficial in preventing cervical cancer in women exposed to HR-HPV.

A higher degree of expression of DNA methyl transferase 1 in cervical cancer is associated with poor survival outcome.

BACKGROUND: Even though novel therapies based on aberrant DNA methylation could be of particular importance for the treatment of cervical cancer (CC) because the oncoproteins E6/E7 of high-risk human papillomaviruses, the causative agents for developing CC, have the capacity to bind and upregulate DNA methyltransferases (DNMTs), to our knowledge, no previous studies have evaluated the expression of this enzyme in CC in relation to survival outcomes. The purpose of the study was to evaluate the expression of DNMT1 in CC and its association with survival outcomes. METHODS: The study population consisted of 76 women treated for primary CC and followed up by the University of Alabama at Birmingham (UAB) cancer registry. The expression of DNMT1 was examined using immunohistochemistry, and the degree of expression of DNMT1 was expressed as a percentage of cells positive for DNMT1 and its intensity. Cox proportional hazards model was used to assess the relationship between the degree of expression of DNMT1 and overall survival after adjusting for relevant covariates. RESULTS: The expression of DNMT1 was significantly higher in CC cells compared to that in the normal cervical epithelium. A higher percentage of cells positive for DNMT1 and a higher intensity score for DNMT1 were significantly associated with poor survival outcome (hazard ratio [HR] =4.3, P=0.03 and HR =4.9, P=0.02, respectively). CONCLUSION: Our findings suggested that the degree of expression of DNMT1 could be considered as a target in the epigenetic treatment of CC. Replication of our results in other study populations with CC could create the opportunity of using DNMT inhibitors to treat CC.