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.

Vaginal micro-environment disorder promotes malignant prognosis of low-grade cervical intraepithelial neoplasia: a prospective community cohort study in Shanxi Province, China.

PURPOSE: Emerging evidence suggests that vaginal micro-environment disorder is closely related to the development of cervical lesions. Low-grade cervical intraepithelial neoplasia (CIN1), as an early stage of cervical lesions, exhibits a high risk of progressing to high-grade lesions or even cervical cancer. However, the effect of vaginal micro-environment on the malignant prognosis of CIN1 remains uncertain. METHODS: A total of 504 patients diagnosed with CIN1 by pathology, who were from the population-based cohorts established in Shanxi Province, China, were enrolled and followed up for 2 years. Micro-environmental factors such as vaginal pH, cleanliness, hydrogen peroxide (H2O2), ß-glucuronidase (GUSB), leucocyte esterase (LE), and sialidase (SNA) were detected to evaluate their effect on the malignant prognosis of CIN1. RESULTS: Abnormal vaginal pH (HR = 1.472, 95%CI 1.071-2.022), cleanliness (HR = 1.446, 95%CI 1.067-1.960), H2O2 (HR = 1.525, 95%CI 1.155-2.013), GUSB (HR = 1.739, 95%CI 1.235-2.448), LE (HR = 1.434, 95%CI 1.038-1.981), and SNA (HR = 1.411, 95%CI 1.065-1.870) could promote a higher incidence of CIN1 malignant prognosis, and the combined effects of these micro-environmental factors resulted in a nearly twofold increased risk (HR = 2.492, 95%CI 1.773-3.504) compared to any single factor alone, especially under the high-risk human papillomavirus (HR-HPV) infection. Notably, the cumulative incidence of malignant prognosis for CIN1 gradually increased during the early follow-up period, reaching its peak at approximately 8 months, and then stabilizing. CONCLUSION: Vaginal micro-environment disorder could promote CIN1 malignant prognosis, particularly in HR-HPV-infected women. Taking micro-environmental factors as the breakthrough, our study provides a feasible vision for preventing early stage cervical lesions.

Cervicovaginal microbiota disorder combined with the change of cytosine phosphate guanine motif- toll like receptor 9 axis was associated with cervical cancerization.

BACKGROUND: Convincing studies demonstrated that cervicovaginal microbiota disorder and toll-like receptor 9 (TLR9) high expression were related to cervical carcinogenesis. However, the effects of cervicovaginal microbiota integration TLR9 in cervical cancerization are unclear. Based on the biological basis that unmethylated cytosine-phosphate-guanine (CpG) motifs of bacteria could activate TLR9, we explored the effects of cervicovaginal microbiota disorder and CpG motif-TLR9 axis change in cervical carcinogenesis. METHODS: A total of 341 participants, including 124 normal cervical (NC), 90 low-grade cervical intraepithelial neoplasia (CIN1), 78 high-grade cervical intraepithelial neoplasia (CIN2/3) and 49 squamous cervical cancer (SCC), diagnosed by pathology were enrolled in the study. Here, metagenomic shotgun sequencing was used to reveal cervicovaginal microbiota characteristics, and TLR9 protein was detected by western blotting. RESULTS: Our results showed that the diversity of cervicovaginal microbiota gradually increased along with the poor development of cervical lesions, showing the abundance of Lactobacillus crispatus and Lactobacillus iners decreased, while the abundance of pathogenic bacteria gradually increased. The level of TLR9 expression was gradually increased with cervicovaginal microbiota diversity increasing, the abundance of Lactobacillus decreasing, and we found a positive correlation dependency relationship (r = 0.384, P = 0.002) between TLR9 and GTCGTT motif content. Stratified analysis based on HPV16 infection, we found that the characteristics of cervicovaginal microbiota and increased TLR9 expression were also closely related to HPV16 infection. CONCLUSIONS: Cervicovaginal microbiota dysbiosis might lead to the CpG motif increased, which was closely associated with TLR9 high expression, and ultimately might promote the progression of cervical lesions.

hnRNP K induces HPV16 oncogene expression and promotes cervical cancerization.

PURPOSE: This study aims to explore the expression of hnRNP K in cervical carcinogenesis and to investigate the regulatory role of hnRNP K on HPV16 oncogene expression as well as biological changes in cervical cancer cells. METHODS: In total 1042 subjects, including 573 with the normal cervix and 469 with different grades of cervical lesions were enrolled in this study to explore the association between hnRNP K and HPV16 oncogene expression in cervical carcinogenesis. Additionally, the Gene Omnibus (GEO) database was used to analyze hnRNP K mRNA expression in cervical cancerization. Meanwhile, the effects of hnRNP K on cell biological functions and HPV16 oncogene expression were investigated in Siha cells. Moreover, Function analyses were conducted using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases after ChIP-seq. RESULTS: hnRNP K was highly expressed in cervical cancer and precancerous lesions, and positively correlated with HPV16 E6, but negatively correlated with HPV16 E2 and HPV16 E2/E6 ratio. hnRNP K induced cell proliferation, inhibited apoptosis and caused cell cycle arrest in the S phase, and particularly increased HPV16 E6 protein expression. CONCLUSION: This study revealed that hnRNP K overexpression has important warning significance for the malignant transformation of cervical lesions, and could be used as a potential therapeutic target for inhibiting the carcinogenicity of HPV16 and prevention of cervical carcinogenesis.

The effects of social comparison and self-construal on creative idea generation: An EEG study.

Social comparisons usually occur in teams when members are tasked with generating creative ideas. However, it is unclear how these comparisons influence creative idea generation, which may be due to a lack of research on the interpretations of social comparison feedback. Self-construal is a psychological characteristic wherein individuals attempt to explain their cooperation and personal behaviours. Therefore, this study explored the influence of social comparison and self-construal on creative idea generation and the underlying neural mechanisms by recording electroencephalogram (EEG) activity. Individuals with independent and interdependent self-construal were randomly assigned to upward or downward comparison conditions and completed an alternative uses task. Results indicated that interdependent self-construal individuals had better originality and flexibility performance in the upward comparison condition compared to those in the downward comparison condition. The EEG results further revealed that, among interdependent self-construal individuals, the upward comparison condition elicited greater alpha synchronization in the bilateral frontal, right parietal, and right temporal regions compared to the downward comparison condition. Moreover, in the upward comparison condition, left frontal alpha synchronization mediated the effect of interdependent self-construal on creative idea generation. These findings support the notion of the joint effect of self-construal and social comparison on creative idea generation and suggest that interdependent self-construal individuals are better able to control irrelevant interfering information and form novel associations during an upward comparison situation compared to a downward comparison situation.

hnRNP E1 Regulates HPV16 Oncogene Expression and Inhibits Cervical Cancerization.

hnRNP E1 (heterogeneous nuclear ribonucleoprotein E1) is an important RNA-binding protein (RBPs) that plays a vital role in tumor development. Human papillomavirus 16 (HPV16) contains numerous sites that can bind to RNA/DNA and may be modified by multiple RBPs, which contribute to HPV gene expression and HPV-associated cancer development. However, the effects of hnRNP E1 on HPV16 oncogenes in the development of cervical lesions remain unclear. A total of 816 participants with different grades of cervical lesions were enrolled in a community-based cohort established in Shanxi Province, China. The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to analyze the association between hnRNP E1 mRNA expression and cervical lesions. Cells with up_ and down_regulated hnRNP E1 were established. hnRNP E1 functions were evaluated using cell counting kit-8, flow cytometry analyses, and chromatin immunoprecipitation sequencing. Our results showed that hnRNP E1 expression was linearly dependent on the severity of the cervical lesions. Low expression of HPV16 E2, high expression of E6, and a low ratio of E2 to E6 could increase the risk of cervical lesions. hnRNP E1 expression was correlated with HPV16 oncogene expression. hnRNP E1-relevant genes were involved in the dopaminergic synapses, Wnt signaling pathway, gnRH secretion, and mTOR signaling pathway. hnRNP E1 significantly inhibited cell proliferation, induced apoptosis, arrested the cell cycle at the G0/G1 stage, and decreased HPV16 E6 expression. Our results indicate that hnRNP E1 could downregulate HPV16 E6 oncogene expression and inhibit cervical cancerization, which sheds new light on preventing the carcinogenicity of HPV across a range of diseases by regulating RNA-binding proteins.

Genotype-specific Distribution and Change of High-risk Human Papillomavirus Infection and the Association with Cervical Progression Risk in Women with Normal Pathology and Abnormal Cytology in a Population-based Cohort Study in China.

Objectives: Women with normal pathology screened from abnormal cervical cytology are a special population with higher progression risk than women with normal cytology. However, the associations between genotype distribution and changes of high-risk human papillomavirus (HR-HPV) infection and cervical progression risk in this special population remain unclear. Methods: A total of 1232 women with normal pathology screened from abnormal cervical cytology were enrolled into this cohort with 2-year follow-up. HPV genotyping detection was performed through flow-through hybridization. Hazard ratios (HRs) and Odds ratios (ORs) were calculated using Cox proportional hazard regression and logistic regression models, respectively. Results: Overall HR-HPV prevalence at baseline was 29.0%, with HPV16, 52, 58, 53 and 51 the top five genotypes. The 2-year persistence rate of HR-HPV infection was 31.9%. Compared with HR-HPV negative, the adjusted HRs of overall HR-HPV, HPV16, 31/33, 58, 51, and 53 infections for the progression risk of normal cervix were 5.31, 7.10, 6.95, 5.74, 5.04, and 4.88, respectively. Multiple HR-HPV infection cannot lead to an additional risk of progression relative to single HR-HPV infection. In comparison with HR-HPV persistently negative, same-type HR-HPV persistence was positively associated with progression risk of normal cervix (adjusted OR: 22.26), but different-type HR-HPV persistence was not linked to cervical progression. Conclusion: Genotypes and persistence of HR-HPV infection could stratify the cervical progression risk in women with normal cervical pathology and abnormal cytology and provide evidence for development of next generation of vaccines. HPV51 and 53 deserved attention apart from HPV16, 31, 33, and 58.

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.

Association between Vaginal Micro-environment Disorder and Cervical Intraepithelial Neoplasia in a Community Based Population in China.

There are other factors that contribute to cervical carcinogenesis except HPV infection. This study aimed to investigate the association between vaginal micro-environment factors, including H2O2, vaginal PH value, vagina cleanness, ß-glucuronidase, coagulase, neuraminidase and leukocyte esterase and cervical intraeipithelial neoplasia (CIN). In total 1019 participants, including 623 normal cervical (NC) women, 303 patients with low-grade cervical intraepithelial neoplasia (CIN1) and 93 patients with high-grade cervical intraepithelial neoplasia (CIN2/3), were enrolled into the study. HPV genotyping was detected by flow-through hybridization and gene chip. Vaginal H2O2, ß-glucuronidase, coagulase, neuraminidase and leukocyte esterase were detected by Aerobic Vaginitis (AV) / Bacterial Vaginal Disease (BV) Five Joint Test Kit. Vaginal PH was measured on the glass slide after microscopy, using color strips with a PH range of 3.8-5.4. Vagina cleanness was determined according to the National Clinical Laboratory Practice Guideline. χ2 test and Logistic regression were operated using SPSS 22.0 software. Our results showed that HPV16 infection rate and the abnormal rates of H2O2, PH, vagina cleanness, ß-glucuronidase or neuraminidase increased gradually along with the severity of CIN (P<0.05). Abnormities of H2O2, cleanness, ß-glucuronidase and neuraminidase were risk factors for CIN regardless of HPV16 infection, furthermore, abnormities of PH value, leukocyte esterase could also increase the risk of CIN in HPV16 positive group. In addition, women with abnormal vaginal micro-environment factors in HPV16 positive group had a significantly higher risk of developing CIN than HPV16 negative group. The results from generalized multifactor dimensionality reduction (GMDR) model showed that there was interaction effect with abnormities of vagina cleanness, H2O2, ß-glucuronidase and neuraminidase on CIN2/3 in HPV16 negative group, while, there was interaction effect with abnormities of vagina cleanness, ß-glucuronidase and neuraminidase on CIN1 and with abnormities of vagina cleanness, PH, H2O2, ß-glucuronidase, neuraminidase and leukocyte esterase on CIN2/3 in HPV16 positive group. Our results suggested that vaginal micro-environment disorder could increase the risk of CIN, especially, the abnormality of H2O2, cleanness, ß-glucuronidase and neuraminidase. There were interaction effects with abnormities of H2O2, vagina cleanness, ß-glucuronidase and neuraminidase on CIN whether HPV16 was infected or not.

Influencing Factors of High-Risk Human Papillomavirus Infection and DNA Load According to the Severity of Cervical Lesions in Female Coal Mine Workers of China.

High-risk human papillomavirus (HR-HPV) plays an aetiological role in the progression of cervical cancer and precancerous lesions. Determining the risk factors of HR-HPV infection is useful for HR-HPV infection surveillance and control. We aimed to explore the influencing factors of HR-HPV infection in female coal mine workers, and to evaluate the associations between HR-HPV DNA load and cytological and histological changes of cervix. In total 6,325 participants completed standard questionnaire on potential influencing factors of HR-HPV infection and underwent gynecological examinations, HPV test as well as Thinprep cytology test (TCT). 1,512 women with positive results of HPV and/or TCT were referred to colposcopy with biopsy and histological examination. HR-HPV DNA load was evaluated by Digene second generation hybrid capture (HC2) assay. Multiple unconditional logistic regression analysis was used to determine the influencing factors for HR-HPV infection. Of 6,325 study participants, 1,405 (22.2%) were HR-HPV positive. HR-HPV infection rate was higher in women aged 30-50 years, with lower education level, working inside the mines and engaging in shift work. Risk factors for HR-HPV infection in female coal mine workers included contraception (OR=1.395, 95%CI=1.102-1.458), previous artificial abortion (OR=1.603, 95%CI=1.202-1.856), working inside the mines (OR=1.230, 95%CI=1.056-1.528) and history of gynecological diseases (OR=1.198, 95%CI=1.001-1.462), while menopause was a protective factor (OR=0.402, 95%CI=0.306-0.507). The HR-HPV DNA load significantly increased with the severity of cervical cytological (χ 2 trend=177.372, p<0.001) and histological (χ 2 trend=194.501, p<0.001) changes. The results indicated that HR-HPV infection is highly prevalent in female coal mine workers in China. Contraception, artificial abortion, working inside the mines and gynecological diseases could increase the risk of HR-HPV infection in these women. HR-HPV DNA load might predict risks of cervical precancerous lesions and cancer. Our findings could provide scientific basis for reducing the risk of HR-HPV infection and cervical cancer in this vulnerable population.

Roles of integrin ß3 cytoplasmic tail in bidirectional signal transduction in a trans-dominant inhibition model.

We evaluated the roles of calpain cleavage-related mutations of the integrin ß3 cytoplasmic tail in integrin αIIbß3 bidirectional signaling using a trans-dominant inhibition model. Chimeric Tac-ß3 proteins (i.e., Tac-ß3, Tac-ß3Δ741, Tac-ß3Δ747, Tac-ß3Δ754, Tac-ß3Δ759, and Tac-ß3ΔNITY) consisting of the extracellular and transmembrane domains of human IL-2 receptor (Tac) and the human integrin ß3 cytoplasmic domain were stably expressed in the 123 CHO cells harboring human glycoprotein Ib-IX and wild-type integrin αIIbß3. The different cells were assayed for stable adhesion and spreading on immobilized fibrinogen, and for binding soluble fibrinogen representing outside-in and inside-out signaling events, respectively. The chimeric protein Tac-ß3 inhibited, and Tac-ß3ΔNITY partially attenuated stable adhesion and spreading. Tac-ß3, Tac-ß3Δ759, Tac-ß3ΔNITY, and Tac-ß3Δ754, but not Tac-ß3Δ747 or Tac-ß3Δ741, impaired the soluble fibrinogen binding. Results indicated that the bidirectional signaling was significantly inhibited by Tac-ß3 and Tac-ß3ΔNITY, albeit to a much lesser extent. Moreover, only inside-out signaling was impaired in the 123/Tac-ß3Δ759 and 123/Tac-ß3Δ754 cells in contrast to an intact bidirectional signaling in the 123/Tac-ß3Δ747 and 123/Tac-ß3Δ741 cells. In conclusion, the calpain cleavage of integrin ß3 resulted in the regulatory effects on signaling by interrupting its interaction with cytoplasmic proteins rather than altering its conformation, and may thus regulate platelet function.