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Objective: To explore the characteristics and correlations of vaginal flora in women with cervical lesions. Methods: A total of 132 women, including 41 women diagnosed with normal cervical (NC), 39 patients with low-grade cervical intraepithelial neoplasia (CIN 1), 37 patients with high-grade cervical intraepithelial neoplasia (CIN 2/3) and 15 patients with cervical squamous cell carcinoma (SCC), who came from the gynecological clinic of Second Hospital of Shanxi Medical University during January 2018 to June 2018, were enrolled in this study according to the inclusive and exclusive criteria strictly. The vaginal flora was detected by 16S rDNA sequencing technology. Co-occurrence network analysis was used to investigate the Spearman correlations between different genera of bacteria. Results: The dominant bacteria in NC, CIN 1 and CIN 2/3 groups were Lactobacillus [constituent ratios 79.4% (1 869 598/2 354 098), 63.6% (1 536 466/2 415 100) and 58.3% (1 342 896/2 301 536), respectively], while Peptophilus [20.4% (246 072/1 205 154) ] was the dominant bacteria in SCC group. With the aggravation of cervical lesions, the diversity of vaginal flora gradually increased (Shannon index: F =6.39, P =0.001; Simpson index: F =3.95, P =0.012). During the cervical lesion progress, the ratio of Lactobacillus gradually decreased, the ratio of other anaerobes such as Peptophilus, Sneathia, Prevotella and etc. gradually increased, and the differential bacteria (LDA score >3.5) gradually evolved from Lactobacillus to other anaerobes. The top 10 relative abundance bacteria, spearman correlation coefficient>0.4 and P <0.05 were selected. Co-occurrence network analysis showed that Prevotella, Peptophilus, Porphyrinomonas, Anaerococcus, Sneathia, Atopobium, Gardnerella and Streptococcus were positively correlated in different stages of cervical lesions, while Lactobacillus was negatively correlated with the above anaerobes. It was found that the relationship between vaginal floras in CIN 1 group was the most complex and only Peptophilus was significantly negatively correlated with Lactobacillus in SCC group. Conclusions: The increased diversity and changed correlations between vaginal floras are closely related to cervical lesions. Peptophilus is of great significance in the diagnosis, prediction and early warning of cervical carcinogenesis.

Objective: To evaluate the relationship between red blood cell folate (RBC folate) and the prognosis of low-grade cervical intraepithelial neoplasia (CIN 1). Methods: In the married women cohort established in 2014, 564 women with CIN 1 diagnosed by pathology were recruited. The demographic characteristics and factors of cervical intraepithelial neoplasia were collected. Meanwhile, the infection status of human papillomavirus (HPV) was detected by molecular diversion hybridization, and the level of RBC folate was measured by chemical photoimmunoassay. After 24 months of follow-up, pathological examination was performed again to observe the prognosis of participants. The women with reversal were taken as the control group,and those with continuous and progressive CIN 1 were taken as the case group respectively. The relationship between RBC folate and CIN 1 outcome was evaluated by logistic regression model. Results: 453 women completed the follow-up, aged (49.72±6.84) years old. CIN 1 was reversed in 342 women, continued in 58 cases and progressed in 53 cases. The RBC folate level M ( Q 1, Q 3 ) were 399.01 (307.10, 538.97) ng/ml, 316.98 (184.74, 428.49) ng/ml and 247.14 (170.54, 348.97) ng/ml, respectively. With the decrease of RBC folate, the risk of continuous and progressive CIN 1 increased (all P <0.001), while the risk of reversal CIN 1 decreased gradually ( P <0.001). Combined with high-risk human papillomavirus (HR-HPV) infection status, low level of RBC folate could increase the risk of CIN 1 progression regardless of HR-HPV infection (HR-HPV infection: OR =21.34, 95% CI : 3.98-114.54; HR-HPV uninfection: OR =11.15, 95% CI : 2.34-53.13). Conclusion: Low level of RBC folate could increase the risk of CIN 1 persistence and progression regardless of HR-HPV infection.

Objective: To investigate the effect of red blood cell folate on the prognosis of high-risk human papillomavirus (HR-HPV) infection . Methods: A total of 564 participants with low-grade cervical intraepithelial neoplasias (CINⅠ) were selected from the community-based married women cohort established in 2014. The general baseline information and factors related to HPV infection were collected. Meanwhile, HPV genotyping and levels of folate were measured. The subjects were divided into different levels of exposure group according to the folate levels and followed up for 24 months to observe the changes of HR-HPV infection status. There were four changes, including persistent infection, infection turned negative, from negative to positive and constant negative by comparing HR-HPV infection status at baseline and follow-up to 24 months. Results: 483 participators completed 24 months of follow-up observation, with a follow-up rate of 85.64% (483/564). The rates of persistent infection, infection turned negative, from negative to positive, and the constant negative were 52.45% (75/143), 47.55% (68/143), 19.71% (67/340), 80.29% (273/340), respectively. Our results demonstrated that the risk of persistent infection (a RR =2.50, 95% CI : 1.55-4.02) and from negative to positive (a RR =4.55, 95% CI : 2.52-8.23) in the low level of folate were significantly higher than that in the high level of folate, especially the risk of homotype persistent infection (a RR =2.72, 95% CI : 1.51-4.90). The risk of persistent infection (trend χ 2 =20.62, P <0.001), from negative to positive (trend χ 2 =31.76, P <0.001), persistent homotypic infection (trend χ 2 =20.09, P <0.001) increased with the decrease of red blood cell folate level. On the contrary, no similar results were found in persistent heterotypic infection. Conclusions: A low level of red blood cell folate could increase the risk of HR-HPV persistent infection and from negative to positive. In women with HR-HPV infection, the risk of persistent homotypic infection is higher.

Objective: To investigate the effects of polycyclic aromatic hydrocarbons (PAHs) exposure on the prognosis of high risk human papillomavirus (HR-HPV) infection. Methods: In this prospective study, 564 patients with low-grade cervical intraepithelial neoplasia confirmed by pathology were selected from the natural cohort population established by our research group in Shanxi province in 2014. Based on the baseline data of demographic characteristics and factors related to HPV infection, the concentrations of 1-hydroxypyrene in urine samples of the patients were determined by high performance liquid chromatography to define the exposure level of PAHs. At baseline survey and follow-up after 24 months, flow-through hybridization was used to detect HPV infection types, and to evaluate the prognosis of HR-HPV (persistent infection, negative conversion, positive conversion and persistent negative status). Results: Of the 564 subjects, 483 completed the follow-up, with a follow-up rate of 85.6% (483/564). Among them, the persistent infection rate was 52.4% (75/143), the persistent homotype infection rate was 35.7% (51/143), the negative conversion rate was 47.6% (68/143), the positive conversion rate was 19.7% (67/340), and the persistent negative rate was 80.3% (273/340). The follow-up results showed that the persistent infection rate (a RR= 3.22, 95% CI : 1.85-5.62) and positive conversion rate (a RR =2.84, 95% CI : 1.64-4.94) of HR-HPV in high PAHs exposure group were higher than those in low PAHs exposure group, while the persistent negative rate (a RR= 0.55, 95% CI : 0.43-0.70) of HR-HPV in high PAHs exposure group were lower than those in low PAHs exposure group. Based on restrictive cubic spline analysis, the results showed that the effects of PAHs exposure on persistent HR-HPV infection and persistent homotype infection showed an ascending linear dose-response relationship, while on HR-HPV positive conversion and persistent negative status showed an ascending and declining nonlinear dose-response relationship respectively ( P <0.01). Conclusions: High PAHs exposure could promote persistent HR-HPV infection and persistent homotypic infection. Reducing PAHs exposure might conducive to HR-HPV continuous negative maintenance. Active prevention and control of PAHs exposure is of great significance to prevent HR-HPV infection and persistent infection.

Objective: To evaluate the relationship between serum folate and the prognosis of cervical intraepithelial neoplasia grade I (CIN1) and the interaction between folate and high risk human papillomavirus (HR-HPV) infection. Methods: From a community-based married women cohort established in Jiexiu and Yangqu County of Shanxi Province from June to December 2014, a total of 564 eligible women with CIN1 by pathologically diagnosed were recruited. The pathological examination was performed again 12 months later. According to the prognosis of CIN1, participants were divided into CIN1 regression group, persistence and progression group, respectively. Nested case-control study was used to explore the relationship between serum folate and CIN1 prognosis, and additive model was used to analyze the interaction between serum folate and HR-HPV infection. Results: Among 564 CIN1 patients, 479 cases underwent pathological examination again, 331 were divided in CIN1 regression group and other 148 in persistence and progression group. The levels of serum folate in CIN1 regression group and persistence and progression group were (18.890±8.360) and (15.640±5.550) nmol/L, respectively, and the difference was statistically significant ( Z =-6.937, P <0.001). HPV infection was detected in 154 patients, including 148 cases of HR-HPV infection and 6 cases of low risk human papillomavirus (LR-HPV) infection. Univariate analysis showed that there were significant differences in the age, passive smoking, frequency of pudendal cleaning, frequency of cleaning after sex, frequency of changing underwear, serum folate and HR-HPV infection between regression group and persistence and progression group ( P <0.05). Multivariate logistic regression analysis showed that the frequency of pudendal cleaning ( OR =0.422, 95% CI : 0.238-0.750), frequency of changing underwear ( OR =0.574, 95% CI : 0.355-0.928), serum folate (13.06-16.78nmol/L: OR =4.806, 95% CI: 2.355-9.810; ≤13.05nmol/L: OR =8.378, 95% CI: 4.024-17.445), HR-HPV infection ( OR =1.852, 95% CI: 1.170-2.933) were the independent influencing factors of CIN1 prognosis. Interaction analysis showed that the relative excess risk of low serum folate level and HR-HPV infection for the CIN1 persistence and progression was 4.992 (95% CI: 0.189-9.796), attributable proportion due to interaction was 0.552 (95% CI: 0.279-0.824), synergy index was 2.632 (95% CI: 1.239-5.588), a OR of serum folate≤16.78 nmol/L and HR-HPV infection positive was 9.055 (95% CI: 4.878-16.807). Conclusion: Low serum folate level could increase the risk of CIN1 persistence and progression, and might enhance the risk when combined with HR-HPV infection.

Objective: To describe the characteristics of high-risk human papillomavirus (HR-HPV) infection and its influences by vaginal micro-environmental factors. Methods: A total of 421 women with HR-HPV infection and normal cervix diagnosed by pathology were selected from a community cohort established earlier by our research group for a 24-month follow-up. The baseline data were collected at enrollment. The vaginal micro-environmental factors were detected by using the combined detection kit of aerobic vaginitis and bacterial vaginosis. And the HPV was detected by using the flow-through hybridization technology. According to the HR-HPV infection status in baseline and 24 months of follow-up, with the prognosis characteristics of HR-HPV infection described, the impact of vaginal micro-environmental factors on the prognosis of HR-HPV infection was explored as well. Results: Among 390 HR-HPV infected women who completed 24 months of follow-up, the top five types of persistent HR-HPV infection rate appeared as HPV16 (24.1%), HPV58 (22.2%), HPV53 (21.7%), HPV52 (20.0%), and HPV39 (11.8%), respectively. The results showed that women with abnormal vaginal pH (a OR =1.74, 95% CI : 1.08-2.80), abnormal neuraminidase (a OR =2.70, 95% CI : 1.52-4.83), or abnormal leucocyte esterase (a OR =3.41, 95% CI : 2.13-5.44), the risk of HR-HPV persistent infection increased. The abnormalities of neuraminidase and leukocyte esterase could increase the risk of persistent infection of homotype and heterotypic HR-HPV. Conclusions: HPV16 was prone to persistent infection. Abnormalities of vaginal pH, neuraminidase, and leukocyte esterase might increase the risk of HR-HPV persistent infection. Both the abnormalities of neuraminidase and leukocyte esterase play an essential role in the HR-HPV persistent infection.

Objective: To investigate the diagnostic value of different vaginal micro-environmental factors in low-grade cervical intraepithelial neoplasia (CIN Ⅰ) and determine the optimal model in high-risk human papillomavirus (HR-HPV) infection. Methods: A total of 926 women, including 623 with normal cervical (NC) condition and 303 CINⅠ patients, had undergone pathological examinations, and were enrolled in the study. All the women were from a community previously established cohort. Vaginal cleanliness, pH, H 2 O 2 , β-glucuronidase, coagulase, sialidase, and leukocyte esterase (LE) were detected by the combined detection method aerobic vaginitis/bacterial vaginosis in vaginal secretions. HPV genotyping was performed by using the flow-through hybridization technology. The data were analyzed by SAS 9.2 and SPSS 23.0. Results: The vaginal cleanliness, pH, sialidase, and LE were determined as the representative vaginal micro-environment factors by principal component analysis. Based on logistic regression theory to analyze the ROC curve, the results showed that the highest sensitivity was with pH value (76.2%), and the highest specificity was with sialidase (90.9%). The area under ROC curve were higher in combination detection modes of sialidase+LE (0.714), pH+sialidase+LE (0.719), vaginal cleanness+sialidase+LE (0.713) and pH+vaginal cleanness+sialidase+LE (0.709). According to HR-HPV infection status, the TOPSIS method was used to analyze the combined detection optimal model. Specifically, we found that the best diagnostic model was pH+sialidase +LE ( C i =0.585) in the HR-HPV positive group and vaginal cleanness+sialidase+LE ( C i =0.641) in the negative group. Conclusions: The combined detection of vaginal microenvironment factors could be used for auxiliary diagnosis for CINⅠ. It would be more effective when detecting pH, sialidase, and LE in HR-HPV positive women while vaginal cleanness, sialidase, and LE in HR-HPV negative women at the same time.

Objective: To explore the effect of dietary water-soluble vitamins on the poor prognosis of low-grade cervical intraepithelial neoplasia (CINⅠ). Methods: A total of 564 participants with CINⅠ were selected from a community-based married women cohort established in 2014. The general baseline information was collected, and HPV genotyping was detected. A food frequency questionnaire was used to investigate dietary water-soluble vitamins' consumption and determine their exposure levels. The follow-up program was carried out for 12 months, and the regression, persistence, and progression of CINⅠ was determined according to histopathological results at 12-month. Results: The low-levels of dietary water-soluble vitamins could promote CINⅠ's persistence and progression, showing the increasing tendency of CINⅠ poor prognosis with the decrease of water-soluble vitamin levels. Especially folate, VB1, VB2, VB6, niacin, biotin, and VC ( RR values were 15.22, 1.86, 1.92, 2.11, 2.98, 2.14, 2.19, respectively) played an important role. Considering the status of high-risk human papillomavirus (HR-HPV) infection, our results showed that the low levels of folate, niacin, biotin could promote the poor prognosis of CINⅠ. Conclusions: The low-level of dietary water-soluble vitamins could facilitate the poor prognosis of CINⅠ. In addition, folate, niacin, biotin were more effective on HR-HPV positive women.

Objective: To explore the effects of hnRNP E1 on the expression of early genes E2, E6 of HPV16 and the biological function in cervical cancer SiHa cell lines. Methods: The cell experiments in vitro were carried out in cervical cancer cell lines SiHa. The expression levels of E2, E6 mRNA and protein of HPV16 were detected by Real-time PCR and Western blot, respectively, before and after up-regulating hnRNP E1. Meanwhile, the cell proliferation, cycle and apoptosis were evaluated by CCK-8 and flow cytometry. Data analyses were performed using SPSS 22.0 and Graphpad Prism 7.0 software. Results: Compared with the blank and the blank plasmid group, the cells activity and proliferation decreased at 24, 48 and 72 h after up-regulating hnRNP E1 ( P <0.05), while the percentage of cells in G0/G1 phase increased and the percentage in S and G2/M phase and proliferation index decreased ( P <0.05). Moreover, the late apoptotic rate and the total apoptotic rate increased ( P <0.05). The expression levels of E6 mRNA and protein of HPV16 in hnRNP E1 up-regulated group were significantly lower than that in both blank group and blank plasmid group, the differences were significant ( P <0.05), showing the tendency of cells proliferation index decrease and total apoptotic rate increase with decreased HPV16 E6 expression. There were no significant differences in the expression of E2 mRNA of HPV16 among the three groups ( P =0.427), and no E2 protein of HPV16 was detected. Conclusions: hnRNP E1 could inhibit the transcription and translation of E6 oncogene of HPV16 and further inhibit the proliferation and promote apoptosis of cervical cancer cells, suggesting that hnRNP E1 might be a potential target marker to prevent cervical lesions. But no association between hnRNP E1 and HPV16 E2 was found in SiHa cells.

Objective: To investigate the role of human papillomavirus (HPV) 16 early genes E2 and E6 and heterogeneous nuclear ribonucleoprotein (hnRNP) E2 and their interaction effects in the progression of the cervical cancer. Methods: Women with normal cervix (NC), low cervical intraepithelial neoplasia (CIN Ⅰ) and high cervical intraepithelial neoplasia (CIN Ⅱ/Ⅲ) from the cervical lesions cohort in Jiexiu County of Shanxi Province from June 2014 to September 2014, and patients with cervical squamous cell carcinoma (SCC) treated at the Second Hospital of Shanxi Medical University in the same period were enrolled in this study. There were 257 participants, about 67 NC cases (26.07%), 69 CIN Ⅰ cases (26.85%), 68 CIN Ⅱ/Ⅲ cases (26.46%), and 53 SCC cases (20.62%), respectively. The information of demographic characteristics, life health habits and cervical lesions were collected by using the structured questionnaire. Cervical exfoliated cells and cervical biopsy tissues were collected to detect the infection of HPV16 and the protein expression levels of hnRNP E2, HPV16 E2 and E6. According to the median-value of the protein expression levels of hnRNP E2, HPV16 E2 and E6 and E2/E6 ratio in the NC group, the study participants were divided into the high and low expression groups/ratio groups. The multivariate logistic regression model was used to analyze the correlation between HPV16 early gene E2 and E6, hnRNP E2 and cervical cancer. The interaction effect was analyzed by using the generalized multifactor dimensionality reduction (GMDR) model. Results: The ages of NC, CIN Ⅰ, CIN Ⅱ/Ⅲ and SCC groups were (47.00±9.07), (47.64±7.35), (46.37±8.67) and (51.26±8.03) years old, respectively. The multivariate logistic regression model analysis showed that the HPV16 E2 low expression, E6 high expression and E2/E6 low ratio could increase the risk of CIN Ⅱ/Ⅲ, about OR (95 %CI ) values 11.11 (1.63-75.56), 8.00 (1.28-50.04), and 9.75 (1.22-77.72), respectively and SCC, about OR (95 %CI ) values 14.22 (2.11-95.88), 10.33 (1.67-64.00), and 12.38 (1.56-97.91), respectively. The hnRNP E2 low expression could increase the risk of CIN Ⅱ/Ⅲ and SCC, about OR (95 %CI ) values 3.35 (1.39-8.10) and 5.53 (1.54-19.88). The result of GMDR showed that there were interaction effects of the hnRNP E2 low expression, HPV16 E2 low expression and HPV16 E6 high expression in both CIN Ⅱ/Ⅲ and SCC groups. Conclusion: The HPV16 E2 low expression, HPV16 E6 high expression and hnRNP E2 low expression could increase the risk of high-grade cervical intraepithelial neoplasia and cervical cancer, and they might have an important interaction effect in the progression of the cervical cancer.

Objective: To investigate the effect of heterogeneous nuclear ribonucleoprotein K (hnRNP K) and its interaction with human papillomavirus 16 (HPV16) on cervical intraepithelial neoplasia (CIN). Methods: The participants included 67 women with normal cervix (NC), 69 women with CINⅠ and 68 women with CINⅡ/Ⅲ in a community cohort of pathologically diagnosed women established in Jiexiu of Shanxi province, from June 2014 to June 2015. A structured questionnaire was used to collect the demographic data of the subjects and the related factors of cervical lesions. Cervical exfoliated cells and cervical tissues from biopsy or surgery were selected. The infection status of HPV16 was detected by flow-through hybridization. The protein expression levels of hnRNP K were evaluated by Western blot. SPSS 23.0 software was used to collate and analyze the data. To study the differences in demographic characteristics, related factors, hnRNP K protein and HPV16 infection among NC, CINⅠand CINⅡ/Ⅲgroups, χ (2) test, trend χ (2) test, and Kruskal-Wallis H test were conducted. Multiple comparisons of hnRNP K protein in three groups were completed by using the Bonferroni method. The OR and its 95 %CI of hnRNP K, HPV16 and CIN were calculated by using the unconditional logistic regression models. Two-way interactions between hnRNP K protein and HPV16 infection on CIN were analyzed by using additive model and related indicators. Results: HPV16 infection rates were 10.4% in women with normal cervix, 14.5% in women with CINⅠ and 41.2% in women with CINⅡ/Ⅲ, respectively. The differences among three groups were significant ( P <0.001). Moreover, the infection rates of HPV16 gradually increased with the increasing severity of CIN (trend χ (2)=18.512, P <0.001). The differences in protein expression of hnRNP K among three groups were significant ( H =48.138, P <0.001) and the expressionincreased with the development of cervical lesionss (trend χ (2)=21.765, P <0.001). Results from the interaction analysis indicated that there were additive effects between high expression of hnRNP K protein and HPV16 in CINⅡ/Ⅲ group compared with normal group ( API =0.639, 95 %CI : 0.083-1.196). In contrast, no such additive effect was found in CINⅠ group. Conclusions: HPV16 infection and over-expression of hnRNP K protein were associated with the increased risk of cervical intraepithelial neoplasia. There might be interaction between hnRNP K protein overexpression and HPV16 infection existed on the progress of CINⅡ/Ⅲ.

Objective: To analyze the reported data of national rural cervical cancer screening project from 2012 to 2013 and to evaluate the project implementation condition., Methods: Data of the national breast carcinoma and cervical cancer (two-cancer) screening project for rural women were collected from the online report system of key women and children's public health service programs.The screening items included: preliminary screening of cervical lesions (cervical cytology, using Traian Bethesda System(TBS) or Pap grading for classification and reporting), acetate/iodide staining (VIA/VILI), colposcopy, histopathological examination, and pathological diagnosis. The study collected the quarterly reported data from 1 183 counties of 30 provinces in 2014 and 1 130 counties of 30 provinces in 2013. Chi-square test was used to test the difference of positive detection rate, as well as precancerous cervical lesions, and cervical cancer detection rates among difference preliminary screening methods in 2012 and 2013., Results: In 2012 and 2013, the number of cervical cancer screening was 10 621 482 and 10 321 835. The percentage of using ThinPrep cytological test as the screening method was 77.17% (n=8 196 627) and 77.07% (n=7 954 949) in 2012 and 2013, respectively. Among these ThinPrep cytological tests in these two years, 65.49% (n=5 368 194) and 71.67% (n=5 701 033) used TBS report system. The abnormality rate of colposcopy increased from 27.29% (170 063/623 161) to 31.15% (203 397/652 935) (χ(2)=2 295.94,P<0.001). The abnormality rate of histopathology test increased from 19.54% (37 992/194 394) to 35.43% (59 004/166 518) (χ(2)=11 523.58, P<0.001). All together, 27 341 cervical cancer or precancerous lesions have been detected in these two years. The detection rate of invasive cervical cancer increased from 18.02/100 000 in 2012 to 19.71/100 000 (χ(2)=7.90,P=0.005) in 2013 and that of precancerous lesions rose from 106.85/100 000 to 119.26/100 000 (χ(2)=70.82,P<0.001). The early detection rate was 89.60% (11 883/13 263), and 89.57% (12 609/14 078), respectively in 2012 and 2013. In these two years, the rank of the detection rate of each cervical lesion were CIN1, CIN2, CIN3, invasive carcinoma, adenocarcinoma in situ, and microinvasive carcinoma, from the highest rate to the lowest rate., Conclusion: The program has achieved certain screening effect and the screening method has been improved. However, the quality of colposcope and histopathology should be enhanced.