Exposure to polycyclic aromatic hydrocarbons promotes the progression of low-grade cervical intraepithelial neoplasia: A population-based cohort study in China.

Low-grade cervical intraepithelial neoplasia (CIN1) is an early stage of cervical cancer development. Previously, we reported that exposure to polycyclic aromatic hydrocarbons (PAHs) increases the risk of cervical precancerous lesions, especially in females with a high-risk human papillomavirus (HR-HPV) infection. However, the effects of PAHs on CIN1 progression remain unclear. A community-based prospective cohort study was conducted to evaluate the role of exposure to PAHs in the progression of CIN1. A total of 564 patients diagnosed with CIN1 were followed-up at 6, 12, and 24 months, post-diagnosis, to determine CIN1 reversion, persistence, and progression. Exposure to PAHs was determined by the urine 1-hydroxipayrene (1-OHP) level. Our results showed that the 1-OHP level was significantly higher in patients with CIN1 persistence/progression than in those with reversion (P < .05). High exposure to PAHs increased the risk of CIN1 persistence/progression, with hazard ratios (HR), 95% confidence intervals (CI) of (1.62, 1.24-2.67), (1.98, 1.42-2.75), and (2.37, 1.61-3.49) at 6, 12, and 24 months, post-diagnosis, respectively. The effect was enhanced with HR-HPV positivity, as determined at 6 (1.82, 1.24-2.67), 12 (3.02, 1.74-5.23), and 24 (2.51, 1.48-4.26) months, post-diagnosis. Moreover, the predictive value of exposure to PAHs for CIN1 persistence/progression was higher in HR-HPV-positive patients than in HR-HPV-negative patients. The results revealed that exposure to PAHs facilitated the malignant progression of CIN1 and hindered its reversal, particularly in patients with HR-HPV infection. Our findings provide novel insights into early prevention and intervention targeting the initiation and progression of cervical neoplasia.

Exploring the potential prompting role of cervical human papilloma virus detection in vulvar lesions: a cross-sectional study in China.

Introduction: The etiology and clinical presentation of vulvar carcinomas, especially vulvar lesions, are not fully understood. Because the vulva and cervix are anatomically connected, human papillomavirus (HPV) is the main cause of cervical lesions. Thus, this study explored the potential characteristics and effects of specific HPV infection types across vulvar lesions and concurrent cervical lesions. Methods: This retrospective, cross-sectional study analyzed patients with cervical HPV or cytological results and concurrent vulvar biopsy who were seen in our hospital colposcopy clinic in Shanxi Province, China, between 2013 and 2023. Data on age, menopause status, vulvar manifestations, and cytology and HPV infection testing results were collected. Attributable fractions and multinominal logistic models were used to evaluate HPV genotyping and clinical characteristics across vulvar lesions. Results: Among the 1,027 participants, 83 (8.1%) had vulvar intraepithelial neoplasia (VIN) of high grade or worse (VIN2+), and 127 (12.4%) had non-neoplastic epithelial disorders of the vulva (NNEDV). A total of 175 patients had either VIN2+ or cervical intraepithelial neoplasia (CIN) lesions of grade 2 or worse (CIN2+). The most common HPV genotypes for VIN2+ or concurrent VIN2+/CIN2+ were HPV16, HPV52, and HPV58, although attributable fractions differed among lesions. Patients with normal cytological or histopathological result were more likely to have NNEDV detected, while abnormal cervical diagnosis was associated with higher detection of VIN2+. Multinominal logistic modeling showed that age and HPV16 infection were risk factors for VIN2+ or concurrent VIN2+/CIN2+; however, only vulvar presentation with depigmentation was a risk factor for NNEDV. Among patients with low-grade CIN1/VIN1, compared with those who were HPV16 negative, those who were HPV16 positive were at 6.63-fold higher risk of VIN2+/CIN2+ [95% confidence interval (CI): 3.32, 13.21]. Vulvar depigmentation was also associated with increased risk of NNEDV (odds ratio: 9.98; 95% CI: 3.02, 33.04). Conclusions: Chinese women may be at specific, high risk for HPV infection types associated with VIN or CIN. The use of cervical cell HPV detection along with vulvar presentation during cervical cancer screening may also contribute to vulvar lesion detection.

Interactions between vaginal local cytokine IL-2 and high-risk human papillomavirus infection with cervical intraepithelial neoplasia in a Chinese population-based study.

Background: Although interleukin-2 (IL-2) has long been associated with cancer development, its roles in the development of cervical cancer remains unclear. Few studies examined the associations between IL-2 and high-risk human papillomavirus (HPV) with risk of cervical intraepithelial neoplasia (CIN). Objective: We aimed to assess the association of IL-2 and high-risk HPV infection with risk of CIN as well as their interactions on the risk of CIN. Design: We performed a cross-sectional analysis of screening data in 2285 women aged 19-65 years who participated in an ongoing community-based cohort of 40,000 women in Shanxi, China in 2014-2015. Both categorical and spline analyses were used to evaluation the association between IL-2 in the local vaginal fluids and prevalence of CIN. In addition, 1503 controls were followed up until January 31, 2019), the nested case-control study design was adopted to evaluate the association of vaginal lavage IL-2 levels and the risk of CIN progression. Results: After adjusting for potential confounders, IL-2 levels were statistically inversely associated with prevalence of CIN (the 1st versus 4th quartile IL-2 levels: the respective odds ratio [OR] and 95% confidence intervals [CI] was: = 1.75 [1.37, 2.23] for CIN, 1.32 [1.01, 1.73] for CIN I, and 3.53 [2.26, 5.52] for CIN II/III). Increased IL-2 levels were inversely associated with prevalence of CIN (P-overall<0.01, P-nonlinearity<0.01 for CIN; P-overall<0.01, P-nonlinearity = 0.01 for CIN I; P-overall <0.01, P-nonlinearity = 0.62 for CIN II/III). The highest prevalence of CIN was observed in women with high-risk HPV, who also had the lowest IL-2 levels (P-interaction < 0.01). Nested case-control study observed an inverse association between IL-2 levels and risk of CIN progression (OR=3.43, [1.17, 10.03]). Conclusions: IL-2 levels in the local vaginal fluids were inversely associated with the risk of CIN in Chinese women either with or without high-risk HPV infection.

FAM201A Promotes Cervical Cancer Progression and Metastasis through miR-1271-5p/Flotillin-1 Axis Targeting-Induced Wnt/ß-Catenin Pathway.

This study investigated the role of the family with sequence similarity 201-member A (FAM201A), as previously reported oncogenic, in cervical cancer (CC). FAM201A expression in CC was analyzed through bioinformatics analyses, and its distribution in CC tissues/cells was determined by in situ hybridization. CC cells were transfected/cotransfected with FAM201A/flotillin-1 (FLOT1) overexpression plasmids and miR-1271-5p mimics, followed by functional analysis on viability, migration and invasion. Pearson's correlation tests were performed to analyze the correlation between FAM201A and miR-1271-5p in CC tissues. The targeting relationship between miR-1271-5p and FLOT1 was confirmed by dual-luciferase reporter assay. The expressions of FAM201A, miR-1271-5p, FLOT1, matrix metalloproteinases (MMP)-9, MMP-2, E-cadherin, N-cadherin, and the Wnt/ß-catenin pathway-related molecules (Wnt1, ß-catenin and p-ß-catenin) in CC cells or tissues were assessed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and/or western blot. The results showed that FAM201A was abundantly expressed and miR-1271-5p expression was downregulated in CC. FAM201A was enriched in CC cell cytoplasm and negatively correlated with miR-1271-5p in CC tissues. FAM201A overexpression enhanced the cell viability, migration, invasion, and tumorigenesis of CC in vivo and increased FLOT1 expression. These trends were all reversed by upregulating miR-1271-5p, which induced opposite effects to FAM201A overexpression. MiR-1271-5p upregulation depleted the levels of MMP-9, MMP-2, N-cadherin, and the Wnt/ß-catenin pathway-related molecules and upregulated E-cadherin expression. FLOT1 was a direct target of miR-1271-5p. FLOT1 overexpression induced effects contrary to the upregulation of miR-1271-5p and abolished miR-1271-5p upregulation-induced effects in CC cells. Overall, this study showed that FAM201A promoted cervical cancer progression and metastasis by targeting the miR-1271-5p/FLOT1 axis-induced Wnt/ß-catenin pathway.

Associations of RBC and Serum Folate Concentrations with Cervical Intraepithelial Neoplasia and High-Risk Human Papillomavirus Genotypes in Female Chinese Adults.

BACKGROUND: Although folate status is associated with cervical carcinogenesis, it is not clear whether folate deficiency is associated with risk of cervical intraepithelial neoplasia (CIN) progression and infection with high-risk human-papillomavirus (hrHPV). OBJECTIVES: To evaluate the associations of RBC and serum folate concentrations with prevalence of CIN grades and hrHPV infection, their interactions with prevalence of CIN grades, and RBC folate with the risk of CIN1 progressing to CIN2. METHODS: Using data from the Shanxi CIN cohort of 2304 female Chinese adults, we used logistic-regression model to estimate ORs and prevalence ratios (PRs) of RBC and serum folate concentrations with prevalence of CIN grades and hrHPV infection. Categoric and spline analyses were used to evaluate the dose-response relations. We estimated the association of RBC folate with risk of CIN1 progressing to CIN2 in the nested case-control cohort. RESULTS: An inverse association was observed between increased RBC folate concentration and the odds of all CIN grades [quartile 1 (Q1) compared with Q4: OR: 2.28; 95% CI: 1.77, 2.93; Ptrend < 0.001]. Significant interaction of RBC folate and hrHPV infection was observed for prevalence of CIN2 or above (Pinteraction < 0.01). No associations were found between RBC and serum folate with PRs of hrHPV in each CIN grade. Over a median follow-up of 21.0 mo, RBC folate was associated with increased risk of CIN1 progressing to CIN2 (Q1 compared with Q4: OR: 3.86; 95% CI: 1.01, 14.76). CONCLUSIONS: Our study indicates that RBC folate concentration is associated with prevalence of CIN grades and CIN1 progression in female Chinese adults. Maintenance of normal folate status is important for reducing the risk of CIN and its progression in women with or without hrHPV infection.

Efficient combination of Human Papillomavirus Genotyping for the triage of women with Atypical Squamous Cells of Undetermined Significance in Chinese rural population: A population-based study.

Objective: In this prospective, population-based study, we evaluated the utility of high-risk human papillomavirus (HR-HPV) genotyping for triaging women with atypical squamous cells of undetermined significance (ASC-US) in the Chinese rural area. Methods: A total of 40,000 women were recruited from rural areas of Shanxi Province, China, between June 2014 and December 2014. Women with Pap results of ASC-US underwent HPV genotyping, colposcopy and histopathological examination. For those with normal cervixes or cervical intraepithelial neoplasia (CIN) 1 on the initial evaluation, a 2-year follow-up study was performed. Results: The reporting rate of ASC-US was 5.76% (2,304/40,000) in the study population. The detection rates of CIN 2 or above (CIN2+) and CIN 3 or above (CIN3+) in women with ASC-US were 7.28% and 1.75%, respectively. HPV 16 (39.53%), HPV 58 (17.83%), and HPV 52 (15.50%) were the three most prevalent HR-HPV genotypes among all women with ASC-US cytology. The five most common HR-HPV genotypes in CIN3+ lesions were HPV16, HPV58, HPV33, HPV31 and HPV18. Compared with the 15 HR-HPV testing, genotyping for a combination of HPV16/18/31/33/58 increased specificity significantly with virtually no loss of sensitivity for detecting CIN2+ and CIN3+ lesions, as well as significantly reduced colposcopy referral rate (23.15% vs 33.70%, p<0.01). In addition, in the 2-year follow-up period, women with infection of HPV16, 18, 31, 33 or 58 genotypes were the most likely population (92%, 23/25) to develop CIN2 lesion. Conclusion: Our results demonstrate that genotyping for a combination of HPV16/18/31/33/58 provides a more efficient and cost-effective model to risk-stratify women with ASC-US in the Chinese rural population.

Lower dietary mineral intake is significantly associated with cervical cancer risk in a population-based cross-sectional study.

Population-based studies investigating the association between dietary mineral intake and risk of cervical intraepithelial neoplasia (CIN) or cervical cancer in Chinese women are few. We performed a cross-sectional analysis of screening data obtained from 2,304 women in 2014 within an ongoing cohort study comprising 40,000 women in China. Dietary intake was assessed using a semiquantitative food frequency questionnaire. Nutrition intake was calculated using a 26-item list of food sources drawn from a validated, comprehensive database. All participants were surveyed through in-person interviews, physical examinations, and laboratory tests. The Pearson chi-square test was used for categorical variables. Multivariable logistic regression models were used to evaluate the relationship between dietary mineral intake and CIN+ risk. The food frequency questionnaire exhibited acceptable reproducibility and reasonable validity in assessing nutrient intakes among these women. After adjusting for multiple potential confounders, low dietary calcium intake was associated with CIN2+ risk (first versus fourth quartile: odds ratio [OR]=1.52, 95% confidence interval [CI]: 1.01-2.32). Similar for magnesium (OR=1.80, 95% CI: 1.20-2.68), phosphorus (OR=1.69, 95% CI: 1.12-2.55), zinc (OR=1.55, 95% CI: 1.03-2.34), and potassium (OR=1.92, 95% CI: 1.28-2.88). Low dietary intakes of calcium and potassium were significantly associated with CIN1 risk. Increased CIN2+ risk correlated with rates of no oral contraceptives and lower levels of dietary Potassium. These results thus proposed that low dietary mineral intake was an independent risk factor, potential synergy may exist between low dietary mineral levels and oral contraceptives contribute to the development of higher-grade CIN and cervical cancer.

Dietary nutrient intake related to higher grade cervical intraepithelial neoplasia risk: a Chinese population-based study.

BACKGROUND: Dietary nutrient intake plays a significant role in carcinogenesis. Few studies have investigated the association between dietary nutrient intake and cervical intraepithelial neoplasia (CIN) risk in China. METHODS: Data on 2304 women from an ongoing cohort comprising 40,000 women from China in 2014 were included. Study randomly selected 218 out of 2304 people as subjects during 2019. All participants were surveyed through in-person interviews, physical examinations, and laboratory tests. Clinical data were obtained from physical examinations and laboratory tests. Dietary intakes were assessed using a semiquantitative food frequency questionnaire. Nutrition intakes from 26 food sources were calculated using a comprehensive validated database. Descriptive statistics were used to describe the frequency and proportion, and mean and standard deviation of the demographic characteristics. Characteristics were examined for significant differences, and Pearson chi-square tests were used for categoric variables. Logistic regression was used to obtain odds ratios (ORs) and confidence intervals (CIs) for CIN risk in each nutrient intake quartile relative to that in the highest quartile. RESULTS: The food frequency questionnaire exhibited acceptable reproducibility and reasonable validity in assessing nutrient intakes among these women. After adjusting for multiple confounders, several dietary nutrients showed significant associations with CIN2+ risk. Low dietary folate intake was associated with the risk of CIN2+ (first versus fourth quartile: OR = 1.55, 95% CI 1.03-2.33). Similar results were also observed for vitamin B6 (OR = 1.63, 95% CI 1.08-2.46), vitamin C (OR = 1.59, 95% CI 1.05-2.42), niacin (OR = 1.65, 95% CI 1.08-2.51), and vitamin K (second versus fourth quartile: OR = 1.60, 95% CI 1.05-2.44). CONCLUSIONS: Low folate; vitamin B6, C, and K; and niacin intakes were associated with CIN2+ risk. Nutrients may influence the development of higher grade CIN and cervical cancer. Trial registration The study was registered in the Chinese Clinical Trial Register (ChiCTR-ROC-15006479) ( https://www.chictr.org.cn ).

Prevalence and Genotype Distribution of High-Risk Human Papillomavirus Infection in Women with Abnormal Cervical Cytology: A Population-Based Study in Shanxi Province, China.

PURPOSE: High-risk human papillomavirus (HR-HPV) infection is widely known as the major cause of cervical cancer and there are notable differences in HR-HPV prevalence and genotype distribution in different populations. Women with abnormal cervical cytology are at increased risk of cervical cancer; however, the genotype distribution of HR-HPV in women with abnormal cervical cytology remains unclear. METHODS: A total of 2,300 women with abnormal cervical cytology (from 39,988 women completing a baseline survey in a cohort established during June 2014 to December 2014) were enrolled in this study. All participants gave informed consent and completed a questionnaire about characteristics related to HPV infection. HPV genotypes were identified using flow-through hybridization, and cytology was assessed by the ThinPrep cytological test. Data were analyzed using SPSS 22.0 for Windows. RESULTS: The overall prevalence of HR-HPV in the 2,300 women with abnormal cervical cytology was 32%, with single and multiple HR-HPV infections making up 70.2% and 29.8%, respectively. The top-five HR-HPV genotypes were HPV16 (13.5%), HPV58 (5.7%), HPV52 (4.9%), HPV53 (2.5%), and HPV51 (2.3%). The prevalence of HR-HPV in atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesions, and high-grade squamous intraepithelial lesions or higher was 30.8%, 36.5%, and 54.9%, respectively, showing an increasing trend with severity of cervical cytology (χ 2 trend=13.952, p<0.001). The prevalence of HPV16 and HPV33 increased significantly with the degree of cytological abnormality. HR-HPV infection risk was statistically higher in women aged 35-45 years, with low education, infrequent bathing, multiple gravidity, multiple parity, history of gynecological diseases, and premenopause. CONCLUSION: HR-HPV infection in women with abnormal cervical cytology was 32%, and the top-five HR-HPV genotypes were HPV16, HPV58, HPV52, HPV53, and HPV51 in Shanxi Province, China. These results shed light on demographic and behavioral characteristics related to HR-HPV infection in women with abnormal cervical cytology and provide an insight for the development of HPV vaccines.

Prevalence and distribution of human papillomavirus genotypes in cervical intraepithelial neoplasia in China: a meta-analysis.

BACKGROUND AND AIM: Data on type-specific human papillomavirus (HPV) are needed to investigate HPV-based screening tests and HPV vaccines. However, Chinese relevant data are insufficient. Therefore, this meta-analysis aimed to summarize and demonstrate the prevalence and distribution of HPV genotypes in cervical intraepithelial neoplasia (CIN) and compensate for the shortage of HPV vaccines in China. METHODS: The Medline, Embase, and the Cochrane Library databases, as well as references cited in the selected studies, were systematically searched for studies investigating the prevalence and distribution of HPV genotypes between January 2000 and April 2019 in China. RESULTS: A total of 8 studies were identified, which comprised 2950 patients with CIN1 and 5393 with CIN2/3. The overall HPV infection rate was 84.37%. The HPV infection rate was significantly higher in the CIN2/3 group (87.00%) than in the CIN1 group (79.56%) (χ2 = 80.095, P < 0.001). The most common HPV types in CIN1 in order of decreasing prevalence were as follows: HPV52 (20.31%), HPV16 (16.81%), HPV58 (14.44%), HPV18 (6.44%), and HPV53 (5.76%). However, in the CIN2/3 group, HPV16 (45.69%) was the predominant type, followed by HPV58 (15.50%), HPV52 (11.74%), HPV33 (9.35%), and HPV31 (4.34%). CONCLUSIONS: This study suggested that HPV16, HPV52, and HPV58 were the top three types of CIN in China. The findings might provide a reference for future HPV-based cervical cancer screening tests, treatment of HPV infection, and application of HPV vaccines in China.

Diagnostic Yield and Performance of a Large Population-Based Cervical Cancer Screening Program in High-Risk Rural China.

Primary cervical cancer screening by liquid-based cytology alone or with adjunctive HPV testing are available worldwide. However, little if any information is available about cervical cancer diagnostic yield of population-based cervical cancer screening in China. In response to it, we conducted a large prospective study on 40,000 women cervical cancer screening within six-month period in rural Shanxi Province, where has been reported as the highest cervical cancer rates in China. A standard cross-sectional survey by self-completed questionnaire was collected and followed by the liquid-based cytology screening. Follow-up biopsy with the diagnosis of cervical intraepithelial neoplasia 2 or higher lesion (CIN2+) were analyzed. Of initial 40,000 women participating in this study, 6.76% (2702/40,000) women had ASC-US or higher cytology screening results with ASC/SIL ratio at 6.14 (2381:388). Among them, 1.96% (782/40,000) women were found CIN lesions (95% CI, 1.68-2.23%) on confirmatory biopsies, including 0.55% (218/40,000) CIN2+ and 19 SCCa (47.5/100,000, 95% CI, 29-74/100,000). Women in Yangqu County had lower ASC/SIL ratio, but higher CIN2+ detection rate in comparison with that of Jiexiu County (6.69 vs. 8.84 and 56.7% vs. 43.9%), which reflects the cervical cancer distribution in different populations and regions. Analysis in age-stratified cytology results indicated women aged 60-65 years had the highest incidence of cytologic abnormality among all the age group; likewise, women aged >50 years were at higher risk in developing cervical high grade dysplasia or cancer than women aged <50 years (0.82% vs. 0.49%). This large-scale cervical cancer screening study provided important references as the instructive for establishing the nation-wide cervical cancer screening strategy.

Folate inhibits miR-27a-3p expression during cervical carcinoma progression and oncogenic activity in human cervical cancer cells.

BACKGROUND: Folate deficiency has been long implicated in cancer development. Although the role of folate in preventing cervical cancer is still unclear, emerging evidence shows that microRNAs (miRs) have great influence on tumor cell migration and invasion. OBJECTIVES: The purpose of this study was to conduct an integrated analysis of miR expression in squamous cell carcinoma tissues with adequate or deficient serum folate. Further, study conducted tissue validation and functional analysis of miRs to uncover novel pathogenic mechanisms on the role of folate in squamous cell carcinoma (SCC). MATERIALS AND METHODS: miR expression profiles were obtained from five paired primary SCC tumors with sufficient or deficient serum folate levels through Affymetrix GeneChip microRNA 4.0. This was followed by an integrated bioinformatics analysis and expanded sample size to verify core miRs by molecular biological validation. HeLa and SiHa cells with different concentrations of folate were used to clarify the roles of miR-27a on cell proliferation, migration, and invasion. MiR-27a expression was measured by the quantitative real-time polymerase chain reaction. Cell counting proliferation, wound healing, and transwell invasion assays were used to determine cell survival, proliferation, migration, and invasion abilities, respectively. RESULTS: Our study found increasing miR-27a expression in serum of normal, high-grade squamous intraepithelial lesion (HSIL), and SCC tissues (in order of magnitude), which trend was negatively correlated with serum folate content. Further, there were significant differences in cellular miR-27a expression between 200 nM and 500 nM folate concentrations, with higher folate concentrations showing lower proliferation, migration, and invasion in SCC. Finally, miR-27a promoted proliferation and invasion in HeLa cells, whereas a miR-27a inhibitor blocked cell proliferation and invasion. CONCLUSION: There is a significant association between miR-27a expression and folate during cervical carcinoma progression. Therefore, miR-27a could be used as a new biomarker for SCC diagnosis and prediction, suggesting a new therapeutic strategy for SCC treatment.

Prevalence, genotype distribution and risk factors of cervical HPV infection in Yangqu, China: a population-based survey of 10086 women.

Human papillomavirus(HPV) infection is a necessary factor for the development of cervical cancer. The HPV vaccine is currently available, but there is still a lack of large-scale research on the distribution and risk factors of HPV. The aim of this study is to investigate the genotype distribution and risk factors of HPV infection in Yangqu which is located in North China. This study enrolled 10086 women aged <65 years from Yangqu County. HPV genotypes were identified via standard HPV DNA testing. The overall prevalence of HPV infection was 8.92%. The prevalence of high-risk HPV types was 8.80%, and it was 0.38% for low-risk HPV types. Single genotype infection accounted for 67.91% in HPV-positive cases. The most common HPV genotypes were HPV-16, -52, and -58. HPV-18 was only the 11th most common type in HPV-positive cases. Women ≥50 years of age had the highest prevalence rate of HPV, and women <30 years had the lowest prevalence rate. The distribution of HPV genotypes also varied among the three age groups: <30, 30-49, and ≥50 years. The risk factors that contributed to the rate of HPV infection included low educational level, low income, smoking, age at first sexual encounter <23 years old, and number of births ≥3 times. This large routine clinical practice report of HPV prevalence and genotype distribution revealed the characteristics of HPV infection-type distributions in Shanxi Province, which should be considered in formulating comprehensive prevention strategies including vaccination for cervical cancer in China.

Interactions between serum folate and human papillomavirus with cervical intraepithelial neoplasia risk in a Chinese population-based study.

Background: Although folate deficiency has long been implicated in cancer development, uncertainties remain concerning its role in cervical cancer prevention. In particular, the interaction between human papillomavirus (HPV) and folate in the risk of cervical intraepithelial neoplasia (CIN) has been little studied. Objective: The goal of this study was to evaluate the dose-response association of serum folate with the risk of CIN, and the potential for HPV to modify the risk of CIN. Design: We performed a cross-sectional analysis of screening data in 2304 women aged 19-65 y who participated in an ongoing cohort of 40,000 women in China. Both categoric and spline analyses were used to evaluate the dose-response relation between serum folate and CIN risk. Results: After adjusting for potential confounders, a statistically significant inverse association between serum folate concentration and at least grade 2 CIN (CIN2+) risk was observed (1st quartile compared with 4th quartile: OR = 1.40; 95% CI: 1.09, 1.79; P-trend < 0.01); however, serum folate concentration was not associated with CIN1 risk. The risk patterns are similar when limited to only CIN2 and CIN3. An inverse linear relation between increased serum folate concentration and the risk of higher-grade CIN (CIN2, CIN3, and CIN2+) was also observed (for CIN2+: P-overall < 0.01, P-nonlinearity = 0.96). The highest risk of CIN2+ was observed in women with high-risk HPV types, who also had the lowest serum folate concentrations (P-interaction < 0.01). Conclusions: Our study indicates that serum folate is inversely associated with the risk of higher-grade CIN in Chinese women either with or without high-risk HPV infection. Thus, maintenance of normal serum folate levels may prove important for reducing the risk of CIN in women.

Prevalence and Distribution of HPV Genotypes in 1387 Women with Cervical Intraepithelial Neoplasia 2/3 in Shanxi Province, China.

Objective: The distribution of human papillomavirus (HPV) genotypes varies by countries and regions. Data regarding HPV genotype distribution for women with cervical intraepithelial neoplasia 2/3 (CIN2/3) are still limited. This study aimed to investigate the distribution of HPV genotypes for women with CIN2/3 in Shanxi province, China. Methods: Prior HPV testing/genotyping resulted from women with histologic diagnosis of CIN2/3 were retrospectively collected between August 2011 and August 2016. Results: A total of 1387 women with a diagnosis of CIN2/3 were included in this study. The average age of the women was 45.7 years and the average time period from HPV testing to histological diagnosis was 0.4 months. The overall high-risk HPV (hrHPV) positive rate was 91.6%. In all tested women, the most commonly detected hrHPV genotype was HPV16 (59.3%) followed by HPV58 (14.4%) and HPV33 (10.0%), while HPV18 was in the 6th position (6.0%). Conclusions: This is one of the largest studies of HPV genotyping for women with CIN2/3 in China. The prevalence and distribution of HPV genotypes in these Chinese women differed from those in women from Western countries. Our results provide important information for developing specific HPV vaccines for Chinese women.

Risk factors for cervical intraepithelial neoplasia and cervical cancer in Chinese women: large study in Jiexiu, Shanxi Province, China.

We aimed to investigate the risk factors for cervical intraepithelial neoplasia (CIN) in Jiexiu, Shanxi Province, China. Twenty thousand eligible married women (age: 18-65 years) were administered with a questionnaire on potential risk factors for CIN and underwent liquid based Pap test. All women with abnormal cytological results underwent colposcopy with biopsy. Based on the biopsy pathology results, women were then assigned to either study group (with CIN) or control group (negative for histological results and volunteered to participate in the follow up study). The women in both study group and control group underwent vaginal microflora detection and dietary survey. The potential risk factors were analyzed by using ordinal logistic regression. Among the 20,000 women ne 1,438 women (7.19%) had cytologic abnormalities and 410 (2.05%) women were diagnosed histologically with CIN lesions, including 317 (1.58%) with CIN1, 93 (0.50%) with CIN2/3and 11 (55/100,000) with squamous cell carcinoma (SCC). The average daily dietary folate intake was significantly lower in the study group (344.61±153.07µg) than in the control group (371.50±166.58µg; P<0.001). Multivariate analysis demonstrated that age of 56-65 years, farming as the husband's occupation, unwashing the vulva after sexual intercourse, and low self-reported folate intake were positively associated with CIN development and might have contribution to the increased CIN incidence in this population. These findings may provide help to develop the strategies to reduce the risk of cervical cancer in China.

Survivin Overexpression Is Associated with Aggressive Clinicopathological Features in Cervical Carcinoma: A Meta-Analysis.

OBJECTIVE: Overexpression of survivin has been reported in many human tumors. However, the clinicopathological features associated with survivin overexpression in cervical carcinoma remain controversial. Thus, the current meta-analysis was performed to assess the clinicopathological significance of survivin in cervical carcinoma. METHODS: PubMed, EMBASE, and Web of Science databases were searched for relevant studies published through November 1, 2015. A meta-analysis was performed to evaluate the association between survivin expression and clinicopathological outcome in cervical carcinoma. RESULTS: Eleven eligible studies with a total of 865 patients were included. Survivin overexpression was closely related to lymph node metastasis (odds ratio [OR] = 0.679, 95% confidence interval [CI]: 0.509-0.905, P = 0.008) but was not significantly associated with tumor FIGO stage (I+II vs. III+IV) (OR = 0.843, 95% CI: 0.626-1.137, P = 0.264), tumor grade (G1+G2 vs. G3) (OR = 0.913, 95% CI: 0.689-1.210, P = 0.527), tumor size (>4 vs. ≤4 cm) (OR = 0.825, 95% CI: 0.434-1.570, P = 0.559), or stromal involvement (OR = 0.820, 95% CI: 0.545-1.233, P = 0.340). The correlation between survivin expression and overall survival was evaluated among a total of 238 patients from three eligible studies. The pooled HR was 1.129 (95% CI: 0.597-1.661; P = 0.000), indicating that survivin expression was significantly associated with poor survival in cervical carcinoma. CONCLUSIONS: Based on the current meta-analysis, survivin is strongly associated with lymph node metastasis and poor prognosis. Additionally, survivin is a novel clinicopathological marker of cervical carcinoma and thus may be a therapeutic target for cervical carcinoma.

miR-375 Affects the Proliferation, Invasion, and Apoptosis of HPV16-Positive Human Cervical Cancer Cells by Targeting IGF-1R.

OBJECTIVE: The aim of this study was to examine the relationship between miR-375 expression and the proliferation, apoptosis, and migration of cervical cancer cells. To further explore the potential target gene of miR-375, insulin-like growth factor 1 receptor (IGF-1R) was detected in miR-375 overexpressed and inhibited cervical cancer cells, which clarified the potential mechanism of miR-375 in the growth and development of cervical cancer. METHODS: In a cervical cancer cell line (Caski), miR-375 overexpression and knockdown were achieved by transfection with a synthetic miR-375 mimic or miR-375-targeting inhibitor oligonucleotides, respectively, using siRNA-Mate transfection reagents. Real-time Polymerase Chain Reaction was performed to detect the expression level of miR-375. The functional effects of miR-375 on cell proliferation, migration, and apoptosis were evaluated using a Cell Counting Kit (CCK-8) and through scratch wound tests and apoptosis assays, respectively. Western blotting was performed to detect the expression level of the IGF-1R protein. RESULT: Transfection with the miR-375 mimic significantly upregulated the expression of miR-375 by approximately 7.76-fold (P < 0.05), reduced cell proliferation and migration (P < 0.05), increased apoptosis (P < 0.05), and decreased the expression of the IGF-1R protein by 24.73% (P < 0.05) compared with the negative control. In contrast, transfection of the miR-375 inhibitor decreased the expression of miR-375 by 14.39% (P < 0.05), significantly increased cell proliferation and migration (P < 0.05), significantly reduced the cell apoptosis (P < 0.05), and upregulated the expression of the IGF-1R protein by 2.29-fold (P < 0.05). The cells transfected with the negative control showed no significant changes compared with the blank control for each parameter (P > 0.05). CONCLUSIONS: miR-375 plays an important role in the tumorigenesis and development of cervical cancer. IGF-1R might represent a target gene of miR-375 in cervical cancer.

Cavitron Ultrasonic Surgical Aspirator in Laparoscopic Nerve-Sparing Radical Hysterectomy: A Pilot Study.

OBJECTIVE: Pelvic autonomic nerve preservation during radical hysterectomy for cervical cancer has become a priority in recent years. This pilot study was undertaken to evaluate laparoscopic nerve-sparing radical hysterectomy (L-NSRH) using the Cavitron Ultrasonic Surgical Aspirator (CUSA) in women with cervical cancer. METHODS: Patients with stage IB1 or IIA1 cervical cancer underwent L-NSRH with pelvic lymphadenectomy. The patients were randomly assigned to receive L-NSRH using a CUSA (CUSA group; n = 24) or using other techniques (non-CUSA group; n = 21). Recovery of bladder function (indwelling catheter time and time to spontaneous voiding) blood loss, duration of hospital stay, lymph node harvesting, and postoperative complications were compared between the 2 groups. Patients were followed for up to 3 years to determine the maintenance of effect. RESULTS: All patients underwent L-NSRH successfully. Intraoperative blood loss was significantly less in the CUSA than in the non-CUSA group (P = 0.005). Length of hospital stay (P = 0.006) and indwelling catheter time (P = 0.008) were both significantly reduced in the CUSA group compared with that in the non-CUSA group. The spontaneous voiding rate 10 days postoperatively was 95.8% with CUSA and 85.7% with non-CUSA techniques. Two patients developed postoperative complications in the CUSA group as did 3 patients in the non-CUSA group. These were cases of lymphocyst formation or urinary tract infection. CONCLUSIONS: Laparoscopic nerve-sparing radical hysterectomy using CUSA was safe and feasible in patients with cervical cancer. Our results provide initial evidence that L-NSRH using CUSA preserves pelvic autonomic nerve function.