Progression Of Cervical Lesions Research Articles

Changes in the incidence of cervical lesions owing to the development of rheumatoid arthritis treatment and the impact of cervical lesions on patients’ quality of life

Objectives: To clarify changes in the incidence of cervical lesions in rheumatoid arthritis (RA) patients with advanced treatment and the impact of cervical lesions on the patients’ quality of life (QOL).Methods: Incidence of radiographic cervical lesions in 1333 RA patients in 2015 was compared with that in our 1999 survey. The association between cervical lesions and QOL evaluated using three different patient-based questionnaires was also analyzed.Results: The incidence of atlantoaxial subluxation (AAS), vertical subluxation (VS), and subaxial subluxation (SAS) in 2015 decreased by 50%, 75%, and 5%, respectively, compared to the 1999 survey. Although QOL, evaluated using the Japanese Orthopedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ; specific to myelopathy), deteriorated as the cervical lesion progressed, there was no association between cervical lesion progression and QOL evaluated using the Short Form-8™ (SF-8™; comprehensive health-related QOL). Cervical lesion progression was also associated with QOL deterioration evaluated using the Health Assessment Questionnaire Disability Index (HAQ-DI; specific to RA), but age and disease duration had stronger influences.Conclusion: The incidence of cervical lesions decreased in 2015 compared to 1999. Cervical lesion progression may be associated with QOL deterioration due to myelopathy. Age and disease duration have more impact on disease-specific QOL.

Prevalence of and Risk Factors for the Progression of Upper Cervical Lesions in Patients with Rheumatoid Arthritis.

We investigated the prevalence of and risk factors for the progression of upper cervical lesions (UCLs) in patients with rheumatoid arthritis (RA). A retrospective analysis of 49 patients with RA (4 males, 45 females) was conducted. The UCLs included atlanto-axial subluxation and vertical subluxation. We investigated the clinical factors including the Disease Activity Score 28 based on C-reactive protein (DAS28-CRP) and the modified Health Assessment Questionnaire-Disability Index as well as radiographic changes between the baseline (at May 2010 to April 2013) and final follow-up. Forty patients (81.6%) were classified as the non-progressive group, and the other 9 patients (18.4%) comprised the progressive group. The progressive group's final CRP values, baseline or final MMP-3 levels, DAS28-CRP, and rate of pre-existing lesions at baseline were all significantly higher than those of the non-progressive group (p=0.017, p=0.043, p=0.002, p=0.008, p<0.001, and p=0.008 respectively). A multivariate logistic regression analysis demonstrated that DAS28-CRP at baseline was a risk factor for radiographic progression (p=0.018, odds ratio: 2.54, 95% confidence interval: 1.17-5.51). Our findings indicate that higher disease activity might influence the progression of UCLs in patients with RA.

Progression of Precancerous Cervical Lesion Predicted by p16 Protein Immunohistochemistry in Rajavithi Hospital.

Objective:To assess the association of p16 immunohistochemical (IHC) staining in cervical squamous intraepithelial lesions (SIL) and progression of cervical intraepithelial neoplasia (CIN) 1 to CIN2+ or recurrence of CIN2+. Material and Methods:A retrospective cohort study of women with newly diagnosed SIL from colposcopy-directed biopsy at Rajavithi Hospital, 2013-2017. Pathologic specimens were reviewed and submitted to p16-IHC staining. Adjusted hazard ratios (HR) of disease-free interval (DFI) and 95% confidence intervals (CI) were carried out using the Cox proportional hazard regression model. Results:A total of 187 women was recruited, 91 cases of positive p16-IHC staining and 96 cases of negative staining. With the median follow-up time of 22 months, women with positive p16-IHC had significantly lower 1-year DFI than those with negative p16-IHC (86.8% vs. 96.6%, p = 0.006). Women with CIN 1 had 22.6% of positive p16-IHC, while those with CIN2-3 had 86.7%. From multivariate analysis, the positive p16-IHC and age > 35 years were the significant prognostic factors of progression/recurrent CIN2+ (adjusted HR 5.33, 95%CI 1.77-16.01, p = 0.003; and adjusted HR 5.80, 95%CI 1.34-25.08, p = 0.019, respectively). From subgroup analysis, the positive p16-IHC was the significant prognostic factor in women with initial CIN1 (HR 5.29, 95%CI 1.18-23.76, p = 0.030), but was not associated with prognosis in women with initial CIN 2-3 (HR 2.13, 95%CI 0.28-16.38, p = 0.468). Conclusion:Overexpression of p16 protein has the prognostic significance of SIL. Using p16-IHC may help stratify patients as low-risk and high-risk groups to progression/recurrence CIN2+.

Role of B7-H4 in the Progression and Prognosis of Cervical Inflammation to Cancer After Human Papilloma Virus Infection.

The immune checkpoint molecule B7-H4 is highly expressed in various types of cancer, but little is known about its role in the development of cervical lesions associated with human papilloma virus (HPV). This study aimed to investigate the role of B7-H4 in cervical lesion progression and the relationship between B7-H4 and HPV infection. This was a retrospective study of tissue samples from 30 patients with cervical cancer, 28 with cervical intraepithelial neoplasia (CIN), and 75 with cervical inflammatory lesions. Serum-soluble B7-H4 (sB7-H4) was assessed by ELISA. Tissue B7-H4 expression was measured by RT-PCR and immunochemistry. Expression of B7-H4 in dendritic cells was assessed by flow cytometry. sB7H4 increased gradually from the patients with cervical inflammation to patients with cervical cancer and decreased after treatment. sB7-H4 had a diagnostic value in cervical intraepithelial neoplasia (CIN (area under the curve (AUC) = 0.8929) and cervical cancer (AUC = 0.9545). B7-H4 expression in inflammatory cervical tissue and peripheral blood dendritic cells (DCs) increased gradually from inflammation to cancer (P < 0.001). sB7-H4 was positively associated with B7-H4 expression in cervical tissue and DCs and with the frequency of CD4+CD25+Foxp3+ regulatory T cells (P < 0.001). The level of sB7-H4, and tissue and DC B7-H4 expression were associated with HPV infection (P < 0.001). These data strongly support the use of sB7-H4 for monitoring the progression of cervical cancer associated with HPV, and for evaluating the immune status of the patients.

J-108 Role of DNA methylation in prediction of human papillomavirus persistence and carcinogenesis

J-108 Role of DNA methylation in prediction of human papillomavirus persistence and carcinogenesis

Evaluation of Ki-67 marker in differentiating cervical intraepithelial neoplasia and benign lesions: A study of 50 cases

Introduction: Cervical cancer is the worldwide third most common cancer and fourth most common cause of cancer related deaths in female population, accounting to approximately 453,300 cases per year and 275, 100 deaths in the year 2008.According to the latest WHO global cancer statistics, the cumulative risk (%) (Age 0-74) of cervical carcinoma is 0.9 with age adjusted ratio of 9.0 (Jemal et al., 2011). Supplementary methods using objective biomarkers are needed to achieve more accurate diagnosis.Ki-67 is a well known proliferative marker, useful for confirmation of the diagnosis in ambiguous cases and CIN grading. Aims: The aim of this study is to evaluate Ki-67 marker by immunohistochemical methods in differentiating CIN from benign cervical lesions. Materials and Methods: The study was done at Department of Pathology, MGMCH, Jaipur it was a Hospital-based observational study consisting of 50 cases. Statistical methods: sensitivity, positive predictive value, negative predictive value, and specificity was calculated. Results: Proliferative index was 50%in neoplastic cases. Accordingly scoring for Ki-67 stained nuclei was done with score 0 means no staining, 1 means weak positive (50%). In our study Statistical analysis of Ki-67 marker shows that sensitivity of this marker is 94.7%, specificity is 96.7%, positive predictive value 94.7%, negative predictive value 96.7% and accuracy is 96%.P value is Conclusion: In summary many studies have shown that there is statistically significant relation between proliferative activity, distribution of Ki-67 positive cells and CINgrade. Ki-67 antigen could be a tool to identify women who are at higher risk for progression and/or recurrence of cervical squamous precancerous lesion and in differenciating between benign and malignant cervical lesions. Keywords: Cervix, Ki-67, Benign, Malignant, Cervical intraepithelial neoplasia

LC-MS/MS-based screening of new protein biomarkers for cervical precancerous lesions and cervical cancer

To screen potential plasma protein biomarkers for the progression of cervical precancerous lesions into cervical carcinoma and analyze their functions. Plasma samples obtained from healthy control subjects, patients with low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), cervical cancer (CC), and patients with CC after treatment were enriched for low-abundance proteins for liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The MS data of the samples were analyzed using Discoverer 2.2 software, and the differential proteins (peptide coverage ≥20%, unique peptides≥2) were screened by comparison of LSIL, HSIL and CC groups against the control group followed by verification using target proteomics technology. Protein function enrichment and coexpression analyses were carried out to explore the role of the differentially expressed proteins as potential biomarkers and their pathological mechanisms. Compared with the control group, both LSIL group and HSIL group showed 9 differential proteins; 5 differentially expressed proteins were identified in CC group. The proteins ORM2 and HPR showed obvious differential expressions in LSIL and HSIL groups compared with the control group, and could serve as potential biomarkers for the progression of cervical carcinoma. The expression of F9 increased consistently with the lesion progression from LSIL to HSIL and CC, suggesting its value as a potential biomarker for the progression of cervical cancer. CFI and AFM protein levels were obviously decreased in treated patients with CC compared with the patients before treatment, indicating their predictive value for the therapeutic efficacy. Protein function enrichment analysis showed that all these differentially expressed proteins were associated with the complement system and the coagulation cascades pathway. We identified 5 new protein biomarkers (F9, CFI, AFM, HPR, and ORM2) for cervical precancerous lesions and for prognostic evaluation of CC, and combined detection of these biomarkers may help in the evaluation of the development and progression of CC and also in improving the diagnostic sensitivity and specificity of cervical lesions.

TNFR1 single nucleotide polymorphisms are not associated with cervical HPV-induced pre-malignant lesion but regulate in situ cervical TNFR1 expression.

TNF-α is involved in HPV infection control by triggering cell signaling through binding in specific receptors TNFR1 and TNFR2. Genetic polymorphisms in these receptors may influence TNF-α signaling. Herein, we investigated TNFR1 rs767455 and rs2234649 single nucleotide polymorphisms, and TNFR1 protein expression in cervical squamous intraepithelial lesions (SIL) to identify their role in cervical pre-malignant development. SIL patients (n = 179) and healthy volunteers (n = 227) were enrolled for TNFR1 genotyping analysis by PCR-RFLP in blood samples and TNFR1 protein expression in cervical tissue by immunohistochemistry. No statistical differences regard genotypes and allelic frequencies for both polymorphisms were observed. Cervical TNFR1-expressing cells were rare in epithelium and basal layer regardless the groups. However, a progressive increase in infiltrating cells was observed in the stromal area, mainly in high SIL (HSIL) group compared to low SIL (LSIL, p < 0.001) and control (p < 0.001) groups. TNFR1-expressing cells frequency was higher in TNFR1 rs767455AG/GG (p < 0.001), and in rs2234649AA (p < 0.001) genotypes carries in HSIL subgroup. These data indicated that TNFR1-expression is abrogated in cervical epithelium, where HPV-induced pre-malignant lesion occurs, increasing its frequency in inflammatory cells in stroma, and is genetically controlled by TNFR1 rs767455AG/GG and rs234649AA genotypes. These biomarkers may be useful to identify cervical precancerous lesions progression.

Interplay between toothbrush stiffness and dentifrice abrasivity on the development of non-carious cervical lesions.

This study investigated the effect of toothbrush stiffness and dentifrice slurry abrasivity on the development and progression of simulated non-carious cervical lesions (NCCLs). Human maxillary premolars were allocated to 12 groups generated by the association between toothbrushes, soft, medium, and hard stiffness, and simulated dentifrice slurries, lower, medium, and higher; deionized water (DI) served as negative control. Teeth were mounted on acrylic blocks, and their root surfaces partially covered with acrylic resin to simulate gingiva, leaving a 2-mm area apical to the cemento-enamel junction exposed to toothbrushing. Specimens were brushed with the test slurries for 35,000 and 65,000 double strokes. Impressions taken at baseline and after both brushing periods were scanned by a 3D optical profilometer. Dentin volume loss (mm3) was calculated by image subtraction. Data were analyzed using three-way ANOVA and Fisher's PLSD tests. All toothbrushes caused higher volume loss when associated to higher abrasive slurry, compared to medium- and lower-abrasive slurries. Medium caused more volume loss than lower-abrasive slurry, which led to more volume loss than DI. Hard and medium toothbrushes were not different when used with medium- or higher-abrasive slurries. There were no differences among toothbrushes when used with DI and lower-abrasive slurry. Overall, 35,000 brushing strokes resulted in significantly less volume loss than 65,000. Toothbrush stiffness was an important factor on NCCL development, especially when brushing with medium- and higher-abrasive slurries. Medium and hard toothbrushes associated with medium- and high-abrasive toothpastes can yield more severe NCCLs.

Competitive adsorption on gold nanoparticles for human papillomavirus 16 L1 protein detection by LDI-MS.

The detection of the HPV L1 protein provides information about the infection status of the virus, reflects the replication status of the HPV virus in cervical cells, and helps understand the regression and progress of cervical lesions. Herein, we report a novel laser desorption ionization mass spectrometry (LDI MS) method for the sensitive detection of the HPV 16 L1 protein, based on non-covalent competitive adsorption between the HPV 16 L1 aptamer and melamine on gold nanoparticles (AuNPs). The intensity of the MS signal corresponding to the mass tag shows a linear relationship with the HPV 16 L1 concentration in the range 2-80 ng mL-1, with a limit of detection (LOD) of 58.8 pg mL-1. Using this method, the HPV 16 L1 protein is quantitatively analyzed in both clinical and vaccine samples. The described method is simple and has high sensitivity and good reliability.

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 (χ2trend=177.372, p<0.001) and histological (χ2trend=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.

Cyclin-dependent kinase 9 promotes cervical cancer development via AKT2/p53 pathway.

Aberrant activation of cyclin-dependent kinase 9 (CDK9) is widespread in human cancers. However, the underlying mechanisms of CDK9 activation and the therapeutic potential of CDK9 inhibition in cervical cancer remain largely unknown. Here, we report that CDK9 is gradually upregulated during cervical lesion progression and regulated by HPV16 E6. CDK9 levels are highly correlated with FIGO stage, pathological grade, deep-stromal invasion, tumor size, and lymph nodes metastasis. Knockdown of CDK9 by specific siRNA inhibits cervical cancer cell proliferation in vitro, as well as tumorigenesis in vivo. CDK9 inhibition causes a significant decreased AKT2 and increased p53 protein expression revealing novel CDK9-regulatory mechanisms. Overexpression of AKT2 rescued the suppressive effects caused by CDK9 knockdown, suggesting that AKT2 induction is essential for CDK9-induced transformation. Moreover, CDK9 expression was positively correlated with AKT2 and negatively correlated with p53 in cervical cancer tissues with HPV16 infection. Our findings demonstrate for the first time that CDK9 acts as a proto-oncogene in cervical cancer, modulating cell proliferation and apoptosis through AKT2/p53 pathway. Therefore, our data provide novel mechanistic insights into the role of CDK9 in cervical cancer development. © 2018 IUBMB Life, 71(3):347-356, 2019.

Association of HLA-G 3\u2032 UTR polymorphism and expression with the progression of cervical lesions in human papillomavirus 18 infections

BackgroundHuman leukocyte antigen (HLA)-G is an immune checkpoint molecule, which expression in cervical cancer cells enables them to escape immunosurveillance. To date, limited information has been published on the association of HLA-G genetic background in malignant cells with levels of HLA-G expression and the clinical outcome of patients.MethodsWe investigated the influence of the HLA-G 14 bp In/Del (rs66554220) and + 3142C/G (rs1063320) polymorphisms in 130 cases of HPV16 infection, 130 cases of HPV18 infection and 185 age-matched, unrelated, HPV-negative, and cytologically normal Chinese Han women. Case-matched cervical biopsy tissues were evaluated by immunohistochemistry.ResultsOur findings show that the frequency of alleles, 14 bp In (38.5% vs 29.2%, OR = 1.52, P < 0.05) and + 3142G (72.7% vs 57.0%, OR = 2.01, P < 0.05), were significantly increased in the HPV18-infected group compared with the control group. The HLA-G polymorphisms (alleles 14 bp In and + 3142G) are also associated with the progression of HPV18-related cervical lesions. Moreover, HLA-G expression increased from CIN1 to CIN2/3 lesions and was highest in patients with adenocarcinoma; however, a significant association between these characteristics and the HLA-G polymorphisms was not observed.ConclusionOur results support that the HLA-G 14 bp In and + 3142G alleles are risk factors for HPV18 infections and influence the progression of HPV18-related cervical lesions. This suggests that HLA-G-driven immune mechanisms play an important role in cervical carcinogenesis.

The clinical significance of FAM19A4 methylation in high-risk HPV-positive cervical samples for the detection of cervical (pre)cancer in Chinese women

BackgroundTo explore the diagnostic value of FAM19A4 methylation in high-risk human papilloma virus (hrHPV)-positive cervical samples from Chinese women for estimating cervical cancer or its precancerous lesions.MethodsCervical samples from 215 women infected with high-risk HPV were collected by smear testing. We purposely chose 61 patients with cervical cancer, 57 with high-grade squamous intraepithelial lesions (HSIL), 31 with low-grade squamous intraepithelial lesions (LSIL), and 66 without cervical intraepithelial neoplasia (CIN) after histological confirmation. Taqman probe-based quantitative PCR (qPCR) was utilized to detect the methylation status of FAM19A4 in the cervical samples and further evaluate the use of this gene in the diagnosis of cervical cancer.Results(1) An increasing level of FAM19A4 methylation was detected with increasing progression of cervical lesions, with methylation rates of 10.61%(7/66), 35.48%(11/31), 56.14%(32/57) and 93.44%(57/61) in no CIN, LSIL, HSIL and cervical carcinoma samples respectively. (2) In all hrHPV-positive samples, the levels of FAM19A4 methylation in HPV16/18 groups were higher than that in 12 other hrHPV groups (P < 0.05), but there was no significant difference between two groups after grouping cervical lesions into cervical cancer, HSIL, LSIL and no CIN groups (P>0.05). (3)There were no significant differences of FAM19A4 methylation in different clinicopathological parameters of cervical cancer. (4) Though the sensitivity of FAM19A4 methylation test was inferior to that of cytology and FAM19A4 combining with HPV16/18 genotyping, but showed the best specificity with 81.44% both for detection HSIL alone and ≥ HSIL, with favorable youden index (YI) and area under curve (AUC).ConclusionFAM19A4 is a specific biomarker of cancerous lesions of the cervix. FAM19A4 methylation analysis may serve as an auxiliary screening method for diagnosis of cervical (pre)cancer. However, in consideration of the limitations of this retrospective study, prospective population-based studies are necessary for further confirmation of the diagnostic value of FAM19A4 methylation for detection of cervical (pre)cancer in Chinese women.

Human papillomavirus DNA, HPV L1 capsid protein and p16INK4a protein as markers to predict cervical lesion progression.

Cervical cancer is the most common malignant tumors in women leading to serious morbidity and mortality worldwide, especially among developing countries. A main cause of the disease is the high-risk human papillomavirus (HR-HPV) infection. HSIL usually progress to cervical cancer, and low-grade lesions, including LSIL and ASCUS, mostly turn to normal or benign lesions, but there are still a small number of patients who will progress to HSIL. Up to now there is no efficient biomarker clinically available to predict people with high risk to progress into HSIL. This study was conducted to evaluate the value of human papillomavirus (HPV) DNA, p16INK4a protein, and HPV L1 capsid protein in predicting HSIL and minimizing unnecessary colposcopy treatments. 1222 patients with HR-HPV infection or with abnormal Thinprep cytologic test (TCT) were chosen to conduct colposcopy in the cervical out-patient clinic of Shanghai First Maternity and Infant Hospital affiliated to Shanghai Tongji University from June 2014 to January 2017. TCT, cervical biopsy, HPV DNA and HPVL1 were performed on all patients. 110 patients were selected to detect p16INK4a protein. Hybrid capture 2 (HC-2) was used to detect HPV DNA, and their subgroups using gene typing system. Immunohistochemical technology was used to detect HPV L1 and p16. HPV DNA was positive in 1097 cases, with the positive rate of 89.7% (1097/1222). In particular, the positive expression rates of HPV DNA were 82.3, 95.7, 96.6 and 100% in Normal/CC, LSIL, HSIL and cervical cancer groups, respectively (p < 0.001). HPV L1 was negative in 781 cases with HR-HPV infection, and the overall negative rate is 71.1%. In patients with Normal/CC, LSIL and HSIL, the negative expression rates of HPV L1 were 91.3, 40 and 81.2%, respectively (p value < 0.001). In the 110 patients, HPV L1 was negative in 98.1% (53/54) of Normal/CC, 42.9% (12/28) of LSIL and 85.1% (23/27) of HSIL (p value = 0.0043). P16-positive rates in patients with Normal/CC, LSIL and HSIL were 33.3% (18/54), 75% (21/28) and 96.2% (26/27), respectively (p value < 0.001). 18 out of 28 cases express low positive (+) in LSIL, 25 out of 27 cases express strong positive (3+) in HSIL. Patients with L1(-)p16(+) including 18.5% (10/54) of normal/cervicitis, 60.7% (17/28) of LSIL and 85.1% (23/27) of HSIL (p value < 0.005). Furthermore, patients with L1(-)p16(1+) included 37% (10/27) of normal/cervicitis 59.3% (16/27) of LSIL and 3.7% (1/27) of HSIL; patients with L1(-)p16(2+) consisted of 0% of normal/cervicitis/LSIL and 100% (1/1) of HSIL; patients with L1(-)p16(3+) were composed of 0% of normal/cervicitis, 4.5% (1/22) of LSIL and 95.5% (21/22) of HSIL (p value < 0.005) (Table6). With the increase in the degree of the cervical lesions, the expression of HPV DNA and p16 is up-regulated while HPV L1 protein is down-regulated. HPV DNA, HPV L1 and p16 are useful markers for the prediction of HSIL. Combined detection of these three markers has important potential to predicting HSIL and minimizing unnecessary colposcope examination.

Association of TNF-308 G>A polymorphism located in tumor necrosis factor a with the risk of developing cervical cancer and results of pap smear.

Tumor necrosis factor a (TNFa) is an inflammatory cytokine that plays a crucial role in the immune response and the progression of cervical lesions. There is a growing body of data evaluating the value of a genetic variant in the TNFa gene with the risk of developing cervical cancer. The aim of this study was to explore the association of a variant, TNF-308 G>A, residing in the TNFa gene with cervical cancer. A total of 91 women with cervical cancer and 161 women as the control group were recruited. DNA was extracted, and Taqman®-probes-based assay was used for genotyping. Our results showed that the minor allele frequency was 0.3 in total population, and the frequency of minor allele A was more in the case group compared with the control.The regression models in different genetic models also revealed that the allele A is a potential risk factor for the development of cervical cancer. In particular, in the dominant model, patients with AG and AA genotypes had a higher risk of developing cervical cancer with odds ratio (OR) of 2.75 (95% confidence interval [CI]: 1.57-4.83, <0.001) and OR of 7.27 (95%CI: 2.5-20.8, <0.001), compared with the GG genotype. Moreover, a similar outcome was obtained for smear test results. Our study demonstrated that TNF-308 G>A located on TNF-a was associated with the risk of cervical cancer, supporting further studies in a larger population and multicenter setting to show the value of emerging markers as risk stratification biomarkers in cervical cancer.

Predictors for progression of two different types of cervical lesions in rheumatoid arthritis treated with biologic agents

BackgroundBiologic agents (BAs) enabled not only a reduction of disease activity but also a slowing down of structural damage to the joints in patients with rheumatoid arthritis (RA). However, the incidence of cervical lesions in patients with RA is still high. PurposeTo elucidate the predictors for the progression of two different cervical lesions in patients with RA under BA treatment. MethodsOf 151 subjects who received more than two years of continuous BA treatment, 101 subjects who had cervical X-ray images taken at baseline and final visit were enrolled. The mean disease duration and mean radiography interval were 10.6 years and 4.4 years, respectively. The existence and progression of cervical lesions (atlanto-axial subluxation [AAS], vertical subluxation [VS], and subaxial subluxation [SS]) were investigated. And predictors for the AAS or VS progression were analyzed by multivariate logistic regression analysis. ResultsThe incidence of cervical lesions at baseline were no pre-existing cervical lesion (none) in 50 cases (50%), AAS only in 32 (32%), both AAS and VS in 12 (12%), and VS only in 7 cases (7%). In the none group, only 4 cases of AAS progression (8%) was observed during the follow-up. In contrast, in the groups with pre-existing cervical lesions, a high incidence of VS progression was observed (63% in the AAS only group, 58% in the AAS + VS group, and 71% in the VS only group). Multivariate regression analysis demonstrated that the DAS-CRP value at baseline (odds ratio [OR] = 9.23) and matrix metaloprotease-3 level at baseline (OR = 1.01) were significant predictors for the progression of AAS, and pre-existing AAS (OR = 18.38) was a sole significant predictor for the progression of VS. ConclusionsCervical lesions progressed irrespective of disease activity after AAS development. Strict disease control before the development of AAS is crucial for preventing further progression and development of cervical lesions.

Th17 response in patients with cervical cancer.

Persistent infection by high-risk human papillomavirus (HR-HPV) is the main risk factor for uterine cervical cancer (UCC). However, viral infection alone is not sufficient for the development and progression of premalignant cervical lesions for cancer. In previous years it has been suggested that the adaptive immune response triggered by the differentiation of naïve helper T cells in Th17 cells may serve an important role in disease development. It has been hypothesized that Th17 cells may be involved in the promotion of UCC, as high levels of interleukin 17 (IL17) expression have been detected in the mucosa of the uterine cervix of patients affected by the disease. However, the role of Th17 cells in the tumor development and progression remains unclear. It is believed that the immune response of the Th17 type during persistent infection of the genital tract with HR-HPV triggers chronic inflammation with a long duration with the production of IL17 and other pro-inflammatory cytokines, creating a favorable environment for tumor development. These cytokines are produced by immune system cells in addition to tumor cells and appear to function by modulating the host immune system, resulting in an immunosuppressive response as opposed to inducing an effective protective immune response, thus contributing to the growth and progression of the tumor. In the present review, the latest advances are presented about the function of Th17 cells and the cytokines produced by them in the development and progression of UCC.

The Burden of Human Papillomavirus andChlamydia trachomatisCoinfection in Women: A Large Cohort Study in Inner Mongolia, China

Chlamydia trachomatis may coinfect with human papillomavirus (HPV) and complicate the cervical pathogenesis. This study aimed to evaluate the prevalence, risk factors, and clinical outcomes of HPV/C. trachomatis coinfection in women from Inner Mongolia, China. We performed a polymerase chain reaction (PCR)-based HPV/C. trachomatis screening and cervical samples were analyzed by thinprep cytologic test. Statistical analysis was used to assess the association between demographic factors and coinfection. Among the 2345 women recruited, the prevalences of HPV, C. trachomatis, and HPV/C. trachomatis coinfection were 36.0%, 14.3%, and 4.8%, respectively. The rate of multiple HPV genotypes was higher in coinfected women. HPV66 was the most frequently identified genotype in coinfected participants. The HPV DNA load was significantly higher in HPV monoinfected cases. In contrast, the DNA load of C. trachomatis was significantly higher in the coinfection group. Risk factors, including single women (odds ratio [OR] = 6.0, 95% confidence interval [CI], 4.044-8.782) and women with multiple sex partners (OR = 1.9, 95% CI, 1.324-2.824), were associated with coinfection. Importantly, coinfection was associated with increased risk for high-grade squamous intraepithelial lesions. HPV and C. trachomatis coinfection is an important risk factor for the progression of cervical lesions.

HPV16 E2 variants correlated with radiotherapy treatment and biological significance in cervical cell carcinoma

Specific genetic mutations in human papillomavirus type 16 (HPV16) DNA are considered important in cervical lesion progression. This study analyzes to what extent radiotherapy treatment contributes to viral DNA mutation in cervical cell carcinomas, and the biological significance of these mutations. Serial tumor tissue, including 44 cervical cancer samples, collected before and after radiotherapy, and 52 biopsies with benign cervices, were tested and analyzed for the presence of HPV16, and for the integrity of the E2 gene. Analysis was performed with polymerase chain reaction (PCR), and a bidirectional sequencing assay was performed to find HPV16 E2 gene variants. HPV16 E2 accounted for 81.8% and 37.5% among tumor and benign cervices respectively (p = 0.02). The incremental number of DNA mutations was associated with radiotherapy treatment. Most E2 gene mutations involved regions encoding the amino-terminal and carboxy-terminal regions of E2 in the tumor irradiated samples. Amino acid changes T135 K, A143T, N203D and P208A in the amino-terminal region were the most common mutations across the irradiated samples. Rather, the mutations in the carboxy-terminal region (T3694A and T3805G) were synonymous changes. Specific nucleotide deletions were detected in the hinge domain, at positions 3455A > −, 3466 T > −, and 3501A > −. The mutation degree is influenced by the irradiation modalities, interestingly E2 sequence mutation being found widely after radiotherapy treatment with a total fractioned dose of 50 Gy (p = 0.004).E2 mutation has predictive and biological significance in cervical cancer patients receiving curative radiation therapy. Possibly, E2 mutation could influence viral genome intactness and could serve as an intrinsic marker for cervical cancer.