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1.  Lower Risk of Cervical Intraepithelial Neoplasia in Women with High Plasma Folate and Sufficient Vitamin B12 in the Post-Folic Acid Fortification Era 
The purpose of this study was to determine the influence of plasma folate and vitamin B12 concentrations on cervical cancer risk in the U.S. after the folic acid fortification era. The study included 376 premenopausal women of childbearing age who tested positive for infections with high-risk (HR) human papillomaviruses (HPVs) and were diagnosed with cervical intraepithelial neoplasia (CIN) grade 2 or higher (CIN 2+, cases) or ≤CIN 1 (noncases). CIN 2+ (yes/no) was the dependent variable in logistic regression models that specified plasma folate concentrations combined with plasma B12 concentrations as the independent predictors of primary interest, adjusting for age, race, education, smoking, parity, number of lifetime male sexual partners, use of contraceptives, waist circumference, physical activity, healthy eating index, and circulating concentrations of vitamins A, C, tocopherol, and total carotene. Women with supraphysiologic concentrations of plasma folate (>19.8 ng/mL) who also had sufficient plasma vitamin B12 (≥200.6 pg/mL) had 70% lower odds of being diagnosed with CIN 2+ (P = 0.04) when compared with women with plasma folate of ≤19.8 ng/mL and plasma vitamin B12 of <200.6 pg/mL. Our results do not corroborate the concern that supraphysiologic plasma folate concentrations seen in the post-U.S. folic acid fortification era increase the risk of CIN in premenopausal women of childbearing age. In fact, higher folate is associated with significantly lower risk of CIN, especially when vitamin B12 is sufficient, demonstrating the importance of vitamin B12 in the high-folate environment created by the folic acid fortification program.
doi:10.1158/1940-6207.CAPR-08-0175
PMCID: PMC4737591  PMID: 19542191
2.  Folate and vitamin B12 may play a critical role in lowering the HPV 16 methylation associated risk of developing higher grades of CIN 
We previously reported that a higher degree of methylation of CpG sites in the promoter (positions 31, 37, 43, 52 and 58) and enhancer site 7862 of HPV 16 was associated with a lower likelihood of being diagnosed with HPV 16-associated CIN 2+. The purpose of the current study was to replicate our previous findings and in addition to evaluate the influence of plasma concentrations of folate and vitamin B12 on the degree of HPV 16 methylation (HPV 16m). The study included 315 HPV 16 positive women diagnosed with either CIN 2+ or ≤ CIN 1. Pyrosequencing technology was used to quantify the degree of HPV 16m. We reproduced the previously reported inverse association between HPV 16m and risk of being diagnosed with CIN 2+. In addition, we observed that women with higher plasma folate and higher HPV 16m or those with higher plasma vitamin B12 and higher HPV 16m were 75% (P<0.01) and 60% (P=0.02) less likely to be diagnosed with CIN 2+, respectively. With a tertile increase in the plasma folate or vitamin B12, there was a 50% (P=0.03) and 40% (P=0.07) increase in the odds of having a higher degree of HPV 16m, respectively. The present study provides initial evidence that methyl donor micronutrients, folate and vitamin B12, may play an important role in maintaining a desirably high degree of methylation at specific CpG sites in the HPV E6 promoter and enhancer that are associated with the likelihood of being diagnosed with CIN 2+.
doi:10.1158/1940-6207.CAPR-14-0143
PMCID: PMC4711818  PMID: 25145486
HPV; methylation; folate; vitamin B12; CIN
3.  Functional variants in CYP1A1 and GSTM1 are associated with clearance of cervical HPV infection 
Gynecologic oncology  2014;135(3):560-564.
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 a 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.
doi:10.1016/j.ygyno.2014.09.015
PMCID: PMC4268049  PMID: 25281494
CYP1A1; GSTT1; GSTM1; Host genetics; ALTS
4.  Assessing the Risk of Ovarian Malignancy in Asymptomatic Women With Abnormal CA 125 and Transvaginal Ultrasound in the Prostate, Lung, Colorectal, and Ovarian Screening Trial 
Obstetrics and gynecology  2013;121(1):25-31.
Objective
To estimate the risk of ovarian malignancy among asymptomatic women with abnormal transvaginal ultrasound or CA 125 and to provide guidance to physicians managing these women.
Methods
A cohort of women from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial with abnormal ovarian results at the initial (T0) and subsequent (T1+) screens were analyzed to estimate which findings were associated with high risk of ovarian cancer. Risks of cancer of greater than 10% were designated as high and risks of 3% or less as low.
Results
For the T0 screen, two high-risk categories were identified: CA 125 of 70 or more with negative transvaginal ultrasound (positive predictive value [PPV] 15.9%, CI 14.7%–17.7%); and positive for both CA 125 and transvaginal ultrasound (PPV 25.0%, CI 23.3%–27.3%). For T1+ screens, three high-risk categories were identified: negative transvaginal ultrasound with change in CA 125 greater than 45 or more (PPV 29.0%, CI 28.3%–30.3%); increase in size of cyst 6 cm or greater with negative CA 125 (PPV 13.3%, CI 10.5%–18.0%); and positive for both tests (PPV 42.9%, CI 40.0%–46.0%). High-risk criteria for T0 provide a sensitivity of 60%, specificity 96.2%, PPV 19.7%, and a negative predictive value (NPV) of 99.3%. T1+ criteria yielded a sensitivity of 85.3%, specificity 95.6%, PPV 29.6% and NPV 99.7%.
Conclusions
High risk categories for predicting risk of cancer in women with abnormal CA 125, TVU or both at initial and subsequent screens have been identified. The large number of women in this study, the four year complete follow-up, and very small number of invasive cancers in the low risk categories provides guidance for clinical decisions regarding need for surgery in these women.
PMCID: PMC3711412  PMID: 23262924
5.  A Study of the Relationship between Food Group Recommendations and Perceived Stress: Findings from Black Women in the Deep South 
Journal of Obesity  2015;2015:203164.
Black women in the Deep South experience excess morbidity/mortality from obesity-related diseases, which may be partially attributable to poor diet. One reason for poor dietary intake may be high stress, which has been associated with unhealthy diets in other groups. Limited data are available regarding dietary patterns of black women in the Deep South and to our knowledge no studies have been published exploring relationships between stress and dietary patterns among this group. This cross-sectional study explored the relationship between stress and adherence to food group recommendations among black women in the Deep South. Participants (n = 355) provided demographic, anthropometric, stress (PSS-10), and dietary (NCI ASA-24 hour recall) data. Participants were obese (BMI = 36.5 kg/m2) and reported moderate stress (PSS-10 score = 16) and minimal adherence to Dietary Guidelines for Americans food group recommendations (1/3 did not meet recommendations for any food group). Participants reporting higher stress had higher BMIs than those reporting lower stress. There was no observed relationship between stress and dietary intake in this sample. Based on these study findings, which are limited by potential misreporting of dietary intake and limited variability in stress measure outcomes, there is insufficient evidence to support a relationship between stress and dietary intake.
doi:10.1155/2015/203164
PMCID: PMC4364113  PMID: 25821595
6.  Epithelial ovarian cancer: An overview 
Ovarian cancer is the second most common gynecological cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which accounts for over 95 percent of the ovarian malignancies. We will present various theories about the potential origin of ovarian malignancies. We will discuss the genetic anomalies and syndromes that may cause ovarian cancers with emphasis on Breast cancer type 1/2 mutations. The pathology and pathogenesis of ovarian carcinoma will also be presented. Lastly, we provide a comprehensive overview of treatment strategies and staging of ovarian cancer, conclusions and future directions.
doi:10.5528/wjtm.v3.i1.1
PMCID: PMC4267287  PMID: 25525571
Epithelial ovarian cancer; Breast cancer type 1; Chemotherapy
7.  Disparities in Cervical Cancer Mortality Rates as Determined by the Longitudinal Hyperbolastic Mixed-Effects Type II Model 
PLoS ONE  2014;9(9):e107242.
Background
The main purpose of this study was to model and analyze the dynamics of cervical cancer mortality rates for African American (Black) and White women residing in 13 states located in the eastern half of the United States of America from 1975 through 2010.
Methods
The cervical cancer mortality rates of the Surveillance, Epidemiology, and End Results (SEER) were used to model and analyze the dynamics of cervical cancer mortality. A longitudinal hyperbolastic mixed-effects type II model was used to model the cervical cancer mortality data and SAS PROC NLMIXED and Mathematica were utilized to perform the computations.
Results
Despite decreasing trends in cervical cancer mortality rates for both races, racial disparities in mortality rates still exist. In all 13 states, Black women had higher mortality rates at all times. The degree of disparities and pace of decline in mortality rates over time differed among these states. Determining the paces of decline over 36 years showed that Tennessee had the most rapid decline in cervical cancer mortality for Black women, and Mississippi had the most rapid decline for White Women. In contrast, slow declines in cervical cancer mortality were noted for Black women in Florida and for White women in Maryland.
Conclusions
In all 13 states, cervical cancer mortality rates for both racial groups have fallen. Disparities in the pace of decline in mortality rates in these states may be due to differences in the rates of screening for cervical cancers. Of note, the gap in cervical cancer mortality rates between Black women and White women is narrowing.
doi:10.1371/journal.pone.0107242
PMCID: PMC4167327  PMID: 25226583
9.  Disparities in Use of Gynecologic Oncologists for Women with Ovarian Cancer in the United States 
Health Services Research  2012;48(3):1135-1153.
Objective
To examine disparities in utilization of gynecologic oncologists (GOs) across race and other sociodemographic factors for women with ovarian cancer.
Data Sources
Obtained SEER-Medicare linked dataset for 4,233 non-Hispanic White, non-Hispanic African American, Hispanic of any race, and Non-Hispanic Asian women aged ≥66 years old diagnosed with ovarian cancer during 2000–2002 from 17 SEER registries. Physician specialty was identified by linking data to the AMA master file using Unique Physician Identification Numbers.
Study Design
Retrospective claims data analysis for 1999–2006. Logistic regression models were used to analyze the association between GO utilization and race/ethnicity in the initial, continuing, and final phases of care.
Principal Findings
GO use decreased from the initial to final phase of care (51.4–28.8 percent). No racial/ethnic differences were found overall and by phase of cancer care. Women >70 years old and those with unstaged disease were less likely to receive GO care compared to their counterparts. GO use was lower in some SEER registries compared to the Atlanta registry.
Conclusions
GO use for the initial ovarian cancer treatment or for longer term care was low but not different across racial/ethnic groups. Future research should identify factors that affect GO utilization and understand why use of these specialists remains low.
doi:10.1111/1475-6773.12012
PMCID: PMC3681247  PMID: 23206237
Disparities; ovarian cancer; gynecologic oncologists; utilization
10.  Oxidatively Modified Proteins in the Serous Subtype of Ovarian Carcinoma 
BioMed Research International  2014;2014:585083.
Serous subtype of ovarian cancer is considered to originate from fallopian epithelium mucosa that has been exposed to physiological changes resulting from ovulation. Ovulation influences an increased in inflammation of epithelial ovarian cells as results of constant exposure of cells to ROS. The imbalance between ROS and antioxidant capacities, as well as a disruption of redox signaling, causes a wide range of damage to DNA, proteins, and lipids. This study applied spectrophotometric, dinitrophenylhydrazone (DNPH) assay, two-dimensional gel electrophoresis, and Western blot analyses to assess the levels of oxidatively modified proteins in 100 primary serous epithelial ovarian carcinoma and normal/surrounding tissues. These samples were obtained from 56 Caucasian and 44 African-American patients within the age range of 61 ± 10 years. Analyses showed that the levels of reactive protein carbonyl groups increased as stages progressed to malignancy. Additionally, the levels of protein carbonyls in serous ovarian carcinoma among African Americans are 40% (P < 0.05) higher relative to Caucasian at similar advanced stages. Results suggest that oxidative stress is involved in the modification of carbonyl protein groups, leading to increased aggressiveness of epithelial ovarian tumors and may contribute to the disease's invasiveness among African Americans.
doi:10.1155/2014/585083
PMCID: PMC3985143  PMID: 24795885
11.  Acceptability and usability of self-collected sampling for HPV testing among African American women living in the Mississippi Delta 
Background
HPV DNA testing has been shown to be an effective approach to cervical cancer screening, and self-collection sampling for HPV testing could be a potential alternative to Pap test, provided that women who tested positive by any method get timely follow-up and care. This feasibility study examined acceptability and usability of self-collected sampling for HPV testing among African American (AA) women in the Mississippi Delta in order to inform the development of interventions to promote cervical cancer screening in this population.
Methods
The study consisted of two phases. Phase I consisted of eight focus groups (N=87) with AA women to explore knowledge, attitudes, and beliefs about cervical cancer and HPV infection as well as acceptability of self-collected sampling for HPV testing. In Phase II, we examined the usability of this technology through one discussion group (N=9). The Health Belief Model guided data collection and analysis.
Results
Although participants perceived themselves as susceptible to cervical cancer and acknowledged its severity, there was a lack of knowledge of the link between HPV and cervical cancer, and they expressed a number of misconceptions. The most frequent barriers to screening included embarrassment, discomfort, and fear of the results. Women in both phases were receptive to self-collection sampling for HPV testing. All participants in the usability phase expressed that self-collection was easy and they did not experience any difficulties.
Conclusion
Self-collection for HPV testing is an acceptable and feasible method among AA women in the Mississippi Delta to complement current cytology cervical cancer screening programs.
doi:10.1016/j.whi.2012.12.003
PMCID: PMC3596478  PMID: 23410619
gynecological cancer; sexually transmitted infections; health disparities
12.  The 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 current study, we tested whether this protective association is modified by the circulating riboflavin status in the same study population.
Methods
Riboflavin status was assessed by the erythrocyte glutathione reductase (EGR) assay and expressed in terms of an EGR activity coefficient (EGRAC). The status of MTHFR polymorphism, riboflavin, and circulating concentrations of folate, vitamins B-12, A, E, 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 (HR-HPV). 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 to 355 women without cervical lesions. Based on the median EGRAC of 1.4, women were grouped into low (> 1.4) and high (≤1.4) riboflavin status.
Results
Women with MTHFR polymorphism and low riboflavin status were significantly less likely to have CIN 2 or 3 than 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.
Conclusions
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.
doi:10.1016/j.nut.2006.12.006
PMCID: PMC2025704  PMID: 17303386
MTHFR; riboflavin; cervical; neoplasia
13.  A Lower Degree of PBMC L1 Methylation Is Associated with Excess Body Weight and Higher HOMA-IR in the Presence of Lower Concentrations of Plasma Folate 
PLoS ONE  2013;8(1):e54544.
Background
Identification of associations between global DNA methylation and excess body weight (EBW) and related diseases and their modifying factors are an unmet research need that may lead to decreasing DNA methylation-associated disease risks in humans. The purpose of the current study was to evaluate the following; 1) Association between the degree of peripheral blood mononuclear cell (PBMC) L1 methylation and folate, and indicators of EBW, 2) Association between the degree of PBMC L1 methylation and folate, and insulin resistance (IR) as indicated by a higher homeostasis model assessment (HOMA-IR).
Methods
The study population consisted of 470 child-bearing age women diagnosed with abnormal pap. The degree of PBMC L1 methylation was assessed by pyrosequencing. Logistic regression models specified indicators of EBW (body mass index–BMI, body fat–BF and waist circumference–WC) or HOMA-IR as dependent variables and the degree of PBMC L1 methylation and circulating concentrations of folate as the independent predictor of primary interest.
Results
Women with a lower degree of PBMC L1 methylation and lower plasma folate concentrations were significantly more likely to have higher BMI, % BF or WC (OR = 2.49, 95% CI:1.41–4.47, P = 0.002; OR = 2.49, 95% CI:1.40–4.51, P = 0.002 and OR = 1.98, 95%  = 1.14–3.48 P = 0.0145, respectively) and higher HOMA-IR (OR = 1.78, 95% CI:1.02–3.13, P = 0.041).
Conclusion
Our results demonstrated that a lower degree of PBMC L1 methylation is associated with excess body weight and higher HOMA-IR, especially in the presence of lower concentrations of plasma folate.
doi:10.1371/journal.pone.0054544
PMCID: PMC3554730  PMID: 23358786
14.  Human papillomavirus genotypes detected in clinician-collected and self-collected specimens from women living in the Mississippi Delta 
Background
There are no data available on human papillomavirus (HPV) infections in women living in the Mississippi Delta, where cervical cancer incidence and mortality among African American women is among the highest in the United States. The aim of this analysis was to report the age-specific prevalence of HPV in this population.
Methods
We recruited 443 women, 26–65 years of age, from the general population of women living in the Mississippi Delta to participate; 252 women had been screened for cervical cancer within the last 3 years while 191 had not. Women underwent a pelvic exam and had clinician-collected Pap sample taken for the routine cervical cancer screening by cytology. Women were asked to collect a self-collected specimen at home and return it to the clinic. Both specimens were tested for HPV genotypes.
Results
Four hundred and six women (91.6%) had HPV genotyping results for the clinician-collected and self-collected specimens. The prevalence of carcinogenic HPV was 18.0% (95% CI: 14.4%-22.1%) for clinician-collected specimens and 26.8% (95% CI: 22.6%-31.4%) for self-collected specimens. The concordance for the detection of carcinogenic HPV between clinician-collected and self-collected specimens was only fair (kappa = 0.54). While the prevalence of carcinogenic HPV in either sample decreased sharply with increasing age (ptrend< 0.01), the prevalence of non-carcinogenic HPV did not, especially the prevalence of HPV genotypes in the alpha 3/4/15 phylogenetic group.
Conclusions
The prevalence of carcinogenic HPV in our sample of women living in the Mississippi Delta was greater than the prevalence reported in several other U.S. studies. The high carriage of HPV infection, along with lack of participation in cervical cancer screening by some women, may contribute to the high cervical cancer burden in the region.
doi:10.1186/1471-2334-13-5
PMCID: PMC3570306  PMID: 23289357
Human papillomavirus (HPV); Self-collection; Pap; Cervical intraepithelial neoplasia; Cervix
15.  BRCA1 proteins regulate growth of ovarian cancer cells by tethering Ubc9 
Mutation in the BRCA1 gene is associated with increased risk for hereditary breast and ovarian cancers. In sporadic ovarian tumors, BRCA1 dysfunction is thought to be common. BRCA1 is a nuclear-cytoplasm shuttling protein. Our group has previously reported that BRCA1 proteins, unlike K109R and cancer-predisposing mutant C61G BRCA1 proteins, bind the sole SUMO E2-conjugating enzyme Ubc9. In this study, we examined the result of altered Ubc9 binding and knockdown on the sub-cellular localization and growth inhibitory function of BRCA1 proteins in ovarian cancer cells. Using live imaging of YFP, RFP-tagged BRCA1 and BRCA1a proteins, our results show enhanced cytoplasmic localization of K109R and C61G mutant BRCA1 proteins in ES-2, NIHOVCAR3 and UWB 1.289 ovarian cancer cells. Down-regulation of Ubc9 in ovarian cancer cells using Ubc9 siRNA resulted in cytoplasmic localization of BRCA1 and BRCA1a proteins. These mutant BRCA1a proteins were impaired in their capacity to inhibit growth of ES-2 ovarian cancer cells. Several ovarian cancer cells, including a BRCA1-null ovarian cancer cell line, showed higher levels of expression of Ubc9. This is the first study demonstrating the physiological link between loss of Ubc9 binding and loss of growth suppression of disease-associated mutant BRCA1a proteins in ovarian cancer cells. BRCA1, by turning off or on Ubc9 binding, regulates growth of ovarian cancers.
PMCID: PMC3433105  PMID: 22957306
BRCA1; BRCA1a; Ubc9; Ovarian cancer; RING domain mutants; nuclear import; Growth suppression
16.  Creating a 21st Century Global Health Agenda 
Diabetes Care  2011;34(6):1440-1441.
doi:10.2337/dc11-9999
PMCID: PMC3114344  PMID: 21593305
17.  Comparative Community Outreach to Increase Cervical Cancer Screening in the Mississippi Delta † 
Preventive medicine  2011;52(6):452-455.
Objective
To increase participation in cervical cancer screening of under-served women living in the Mississippi Delta, a U.S. population at high risk for cervical cancer
Methods
We conducted a door-to-door feasibility study of women living in the Mississippi Delta to increase participation in cervical cancer screening in 2009-10. Women (n=119) aged 26-65 years who had not been screened in last 3 years or more, were not pregnant, and had a cervix were offered a choice: clinic-based Pap testing or home self-collection with HPV DNA testing.
Results
Seventy-seven women (64.7%) chose self-collection with HPV testing, of which 62 (80.5%) returned their self-collected specimen. By comparison, 42 women (35.3%) chose Pap testing, of which 17 (40.5%) attended their clinic appointment. Thus there was an almost 4-fold greater participation of under-screened women in self-collection with HPV testing than in free Pap testing (78.4% vs. 21.5%).
Conclusions
We found that offering self-collection will increase participation in cervical cancer screening among under-screened populations living in the Mississippi Delta. Based on these preliminary results, we suggest that self-collection with HPV DNA testing might complement current Pap testing programs to reach under-screened populations of women, such as those living in the Mississippi Delta.
doi:10.1016/j.ypmed.2011.03.018
PMCID: PMC3114876  PMID: 21497619
Pap; cervical intraepithelial neoplasia (CIN); cervical cancer; human papillomavirus (HPV); atypical squamous cells of undetermined significance (ASC-US); Hybrid Capture 2 (HC2); health disparities; cervical cancer screening
18.  Comparative Performance of Human Papillomavirus DNA Testing Using Novel Sample Collection Methods ▿  
Journal of Clinical Microbiology  2011;49(12):4185-4189.
To explore alternative cervical cancer screening approaches in an underserved population, we compared the performance of human papillomavirus (HPV) DNA assays in combination with different sample collection methods for primary cervical screening in the Mississippi Delta region. Three specimens were collected from women aged 26 to 65 years who were either routinely undergoing screening (n = 252) or not (n = 191): clinician-collected cervical specimens, clinician-collected cervicovaginal specimens, and self-collected cervicovaginal specimens taken at home. A novel collection device and medium were used for cervicovaginal sampling. Specimens were tested by three HPV DNA assays: hybrid capture 2 (HC2; Qiagen Corp., Gaithersburg, MD), Linear Array (LA; Roche Molecular Systems, Pleasanton, CA), and Amplicor (Roche Molecular Systems, Pleasanton, CA). Liquid-based cytology was performed on cervical specimens. We compared the overall positivity (a proxy for clinical specificity) for any carcinogenic HPV genotype and calculated the agreement across assay and specimen type using McNemar's test for differences in test positivity. Across all three assays there were no significant differences between clinician-collected and self-collected cervicovaginal specimens (P > 0.01 for all comparisons). For both cervicovaginal specimens (clinician collected and self-collected), fewer women tested positive by HC2 than by LA or Amplicor (P < 0.01 for all comparisons). HC2 had the best agreement between specimens for all assays. HC2 is likely more clinically specific, although possibly less sensitive, than either PCR test. Thus, use of HC2 on cervicovaginal specimens for screening could result in fewer referrals compared to LA and Amplicor.
doi:10.1128/JCM.01254-11
PMCID: PMC3232937  PMID: 21998422
19.  A higher degree of LINE-1 methylation in peripheral blood mononuclear cells, a one-carbon nutrient related epigenetic alteration, is associated with a lower risk of developing cervical intraepithelial neoplasia 
Objective
The objective of the study was to evaluate LINE-1 methylation as an intermediate biomarker for the effect of folate and vitamin B12 on the occurrence of higher grades of cervical intraepithelial neoplasia (CIN 2+).
Methods
Study included 376 women who tested positive for HR-HPVs and were diagnosed with CIN 2+ (cases) or ≤ CIN 1 (non-cases). CIN 2+ (yes/no) was the dependent variable in logistic regression models that specified the degree of LINE-1 methylation of peripheral blood mononuclear cells (PBMCs) and of exfoliated cervical cells (CCs) as the independent predictors of primary interest. In analyses restricted to non-cases, PBMC LINE-1 methylation (≥70% vs. <70%) and CC LINE-1 methylation (≥54% vs. <54%) were the dependent variables in logistic regression models that specified the circulating concentrations of folate and vitamin B12 as the primary independent predictors.
Results
Women in the highest tertile of PBMC LINE-1 methylation had 56% lower odds of being diagnosed with CIN 2+ (OR = 0.44; 95% CI, 0.24-0.83; P = 0.011) while there was no significant association between degree of CC LINE-1 methylation and CIN 2+ (OR = 0.86; 95% CI, 0.51-1.46; P = 0.578). Among non-cases, women with supra-physiologic concentrations of folate (>19.8 ng/mL) and sufficient concentrations of plasma vitamin B12 (≥ 200.6 ng/mL) were significantly more likely to have highly methylated PBMCs compared to women with lower folate and lower vitamin B12 (OR = 3.92; 95% CI, 1.06-14.52; P = 0.041). None of the variables including folate and vitamin B12 were significantly associated with CC LINE-1 methylation.
Conclusions
These results suggest that a higher degree of LINE-1 methylation in peripheral blood mononuclear cells, a one-carbon nutrient related epigenetic alteration, is associated with a lower risk of developing cervical intraepithelial neoplasia.
doi:10.1016/j.nut.2010.08.018
PMCID: PMC3070926  PMID: 21463750
methylation; cervical; neoplasia
20.  Ubc9 Mediates Nuclear Localization and Growth Suppression of BRCA1 and BRCA1a Proteins 
Journal of Cellular Physiology  2011;226(12):3355-3367.
BRCA1 gene mutations are responsible for hereditary breast and ovarian cancers. In sporadic breast tumors, BRCA1 dysfunction or aberrant subcellular localization is thought to be common. BRCA1 is a nuclear–cytoplasm shuttling protein and the reason for cytoplasmic localization of BRCA1 in young breast cancer patients is not yet known. We have previously reported BRCA1 proteins unlike K109R and cancer-predisposing mutant C61G to bind Ubc9 and modulate ER-α turnover. In the present study, we have examined the consequences of altered Ubc9 binding and knockdown on the subcellular localization and growth inhibitory function of BRCA1 proteins. Our results using live imaging of YFP, GFP, RFP-tagged BRCA1, BRCA1a and BRCA1b proteins show enhanced cytoplasmic localization of K109 R and C61G mutant BRCA1 proteins in normal and cancer cells. Furthermore, down-regulation of Ubc9 in MCF-7 cells using Ubc9 siRNA resulted in enhanced cytoplasmic localization of BRCA1 protein and exclusive cytoplasmic retention of BRCA1a and BRCA1b proteins. These mutant BRCA1 proteins were transforming and impaired in their capacity to inhibit growth of MCF-7 and CAL51 breast cancer cells. Interestingly, cytoplasmic BRCA1a mutants showed more clonogenicity in soft agar and higher levels of expression of Ubc9 than parental MCF7 cells. This is the first report demonstrating the physiological link between cytoplasmic mislocalization of mutant BRCA1 proteins, loss of ER-α repression, loss of ubiquitin ligase activity and loss of growth suppression of BRCA1 proteins. Thus, binding of BRCA1 proteins to nuclear chaperone Ubc9 provides a novel mechanism for nuclear import and control of tumor growth.
doi:10.1002/jcp.22695
PMCID: PMC3329759  PMID: 21344391
21.  A higher degree of methylation of the HPV 16 E6 gene is associated with a lower likelihood of being diagnosed with cervical intraepithelial neoplasia 
Cancer  2010;117(5):957-963.
Background
Even though HPV 16 is the most common HPV genotype associated with cancerous lesions of the cervix, only a fraction of HPV 16 infected women are diagnosed with pre-cancerous lesions of the cervix. Therefore, molecular changes in HPV 16 rather than infections per se may serve as better screening or diagnostic biomarkers. The purpose of the study was to evaluate whether methylation status of specific regions of the HPV E6 gene promoter and enhancer is independently associated with the likelihood of being diagnosed with higher grades of cervical intraepithelial neoplasia (CIN 2+).
Methods
The study included 75 HPV 16 positive women diagnosed with CIN 2+ or ≤ CIN 1. Pyrosequencing technology was applied to quantify methylation at 6 cytosine guanine dinucleotide (CpG) sites of the HPV 16 E6 promoter and enhancer. CIN 2+ (yes/no) was the dependent variable in logistic regression models that specified the degree of methylation of the CpG sites of the HPV 16 E6 gene as the primary independent predictors. All models were adjusted for demographic, lifestyle, known risk factors for cervical cancer and circulating concentrations of “cancer-protective” micronutrients.
Results
The odds of being diagnosed with CIN 2+ was 79% lower when the degree of methylation of the HPV 16 enhancer and promoter sites were ≥9.5% (OR= 0.21; 95% CI, 0.06–0.79; P=0.02).
Conclusions
Results suggested that CpG methylation is independently involved in the biology of HPV-16 as well as in the development of higher grades of CIN.
doi:10.1002/cncr.25511
PMCID: PMC3023831  PMID: 20945322
HPV 16; methylation; cervical; neoplasia
22.  Predictors of Retention of African American Women in a Walking Program 
Objective
To predict retention of African American women 6 months after initiating a community walking program.
Methods
Demographics, health status, cancer-related health behaviors, and network membership data from baseline wellness questionnaires of 1322 African American women participating in the walking program were analyzed using multivariate logistic regression models.
Results
Seventy-eight percent (n=1032) of African American women were retained at 6 months. DSN membership was the primary predictor of retention.
Conclusions
Women affiliated with our comprehensive network, which provides ongoing cancer awareness, screening, and prevention programs to reduce cancer health disparities, were more likely to accomplish the first major milestone of the program.
PMCID: PMC3086025  PMID: 20950157
African American; women; retention; physical activity; cancer prevention and control
23.  Cancer Health Disparities: What We Have Done 
PMCID: PMC3230119  PMID: 18461726
Health disparities; Cancer prevention; African American; Breast cancer; Cervical cancer; Rural medicine
24.  Usefulness of serum mass spectrometry to identify women diagnosed with higher grades of cervical intraepithelial neoplasia may differ by race 
Background
An early detection of precursor lesions of cervical cancer will help to eliminate the worldwide burden of cervical cancer.
Methods
This exploratory study aimed to identify, by matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS), serum protein profiles that distinguish cervical intraepithelial neoplasia grades CIN 1 or lower (≤CIN 1) from CIN 2+ among 127 women infected with human papillomavirus (HPV) 16. Of these 127 women, 25 and 23 were diagnosed with CIN 2 or CIN 3, respectively (cases), and 79 were diagnosed with ≤CIN 1 (non-cases). Serum protein profiles were generated by MALDI-TOF-MS. A total of 95 m/z peaks were tested for association with case status by two racial groups, African American (AAs) and Caucasian American (CAs).
Results
Overall, 2 protein peaks identified by our study demonstrated higher specificity for identifying CIN 2+ than previously published studies. An increasing intensity of [m/z 4459] was associated with a higher risk of being a case, regardless of race with a specificity of 58% for CIN 2 and a specificity of 75% for CIN 3. An increasing intensity of [m/z 4154] was not only associated with a higher risk of being a case only among CAs, but also had an opposite effect among AAs.
Conclusion
Identification of specific proteins associated with the peaks detected in serum and development of antibody-based tests such as ELISA should lead to the development of race-specific, non-invasive and cost effective screening tests with higher specificity for identifying HPV 16 associated CIN 2+.
doi:10.2147/IJWH.S20685
PMCID: PMC3140814  PMID: 21792340
serum mass spectrometry; cervical intraepithelial neoplasia; race
25.  Cervical Cancer Prevention: New Tools and Old Barriers 
Cancer  2010;116(11):2531-2542.
Cervical cancer is the second most common female tumor worldwide and its incidence is disproportionately high (>80%) in the developing world. In the U.S., where Pap tests have reduced the annual incidence to approximately 11,000 cervical cancers, more than 60% of cases occur in medically-underserved populations as part of a complex of diseases linked to poverty, race/ethnicity, and/or health disparities. Because carcinogenic human papillomavirus (HPV) infections cause virtually all cervical cancer, two new approaches for cervical cancer prevention have emerged: 1) HPV vaccination to prevent infections in younger women (≤18 years old) and 2) carcinogenic HPV detection in older women (≥30 years old). Together, HPV vaccination and testing, if used in an age-appropriate manner, have the potential to transform cervical cancer prevention particularly among underserved populations. Yet significant barriers of access, acceptability, and adoption to any cervical cancer prevention strategy remain. Without understanding and addressing these obstacles, these promising new tools for cervical cancer prevention may be futile. We share our experiences in the delivery of cervical cancer prevention strategies to U.S. populations experiencing high cervical cancer burden: African-American women in South Carolina, Alabama, Mississippi; Haitian immigrant women in Miami; Hispanic women in the U.S.-Mexico Border; Sioux/Native American women in the Northern Plains; white women in the Appalachia; and Vietnamese-American women in Pennsylvania and New Jersey. Our goal is to inform future research and outreach efforts to reduce the burden of cervical cancer in underserved populations.
doi:10.1002/cncr.25065
PMCID: PMC2876205  PMID: 20310056

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