Development Of Cervical Intraepithelial Neoplasia Research Articles

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.

Identification of potential miRNAs and candidate genes of cervical intraepithelial neoplasia by bioinformatic analysis.

The objective of this study was to predict potential target genes and key miRNAs for cervical intraepithelial neoplasia (CIN) by bioinformatics analysis. The microarray data of GSE51993 were downloaded from Gene Expression Omnibus (GEO) database. Total 30 chips data from two platforms (each platform including eight CIN III samples data and seven normal cervix samples data) were used to identify the feature miRNAs and genes between CIN III and normal samples, respectively. Then the miRNA- mRNA regulatory network was constructed using Cytoscape software. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed for all target genes with the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tool. Transcription factors (TFs) and cancer-related genes were analyzed. Total 21 putative target miRNAs and 361 putative target mRNAs were gained. The miRNA-mRNA regulatory network results showed that miR-338-5p, miR-193a-5p, and miR-216b were top three hub nodes. GO terms significantly enriched were extracellular region (p = 0.004191) and embryonic skeletal system (p = 0.004742). No significantly enriched KEGG pathway term was found in this study. PBXl (pre-B-cell leukemia transcription factor 1) and LAMC2 (laminin subunit gamma-2) were cancer-promoting genes and also, PBX was TF. PBXl and LAMC2 may be target genes for CIN. MiR-338, and miR-216 may be key miRNAs in CIN development.

The association between methylated CDKN2A and cervical carcinogenesis, and its diagnostic value in cervical cancer: a meta-analysis.

BackgroundCervical cancer is the second deadliest gynecologic malignancy, characterized by apparently precancerous lesions and cervical intraepithelial neoplasia (CIN), and having a long course from the development of CIN to cervical cancer. Cyclin-dependent kinase inhibitor 2A (CDKN2A) is a well-documented tumor suppressor gene and is commonly methylated in cervical cancer. However, the relationship between methylated CDKN2A and carcinogenesis in cervical cancer is inconsistent, and the diagnostic accuracy of methylated CDKN2A is underinvestigated. In this study, we attempted to quantify the association between CDKN2A methylation and the carcinogenesis of cervical cancer, and its diagnostic power.MethodsWe systematically reviewed four electronic databases and identified 26 studies involving 1,490 cervical cancers, 1,291 CINs, and 964 controls. A pooled odds ratio (OR) with corresponding 95% confidence intervals (95% CI) was calculated to evaluate the association between methylated CDKN2A and the carcinogenesis of cervical cancer. Specificity, sensitivity, the area under the receiver operating characteristic curve, and the diagnostic odds ratio were computed to assess the effect of methylated CDKN2A in the diagnosis of cervical cancer.ResultsOur results indicated an upward trend in the methylation frequency of CDKN2A in the carcinogenesis of cervical cancer (cancer vs control: OR =23.67, 95% CI =15.54–36.06; cancer vs CIN: OR =2.53, 95% CI =1.79–3.5; CIN vs control: OR =9.68, 95% CI =5.82–16.02). The specificity, sensitivity, area under the receiver operating characteristic curve, and diagnostic odds ratio were 0.99 (95% CI: 0.97–0.99), 0.36 (95% CI: 0.28–0.45), 0.93 (95% CI: 0.91–0.95), and 43 (95% CI: 19–98), respectively.ConclusionOur findings indicate that abnormal CDKN2A methylation may be strongly correlated with the pathogenesis of cervical cancer. Our results also demonstrate that CDKN2A methylation might serve as an early detector of cervical cancer. These findings require further confirmation.

Association between folate status and cervical intraepithelial neoplasia.

Background/Objectives:To investigate the effect of folate status on cervical intraepithelial neoplasia (CIN) progression and its relationship with high-risk human papillomavirus (hrHPV).Subjects/Methods:We evaluated 20 000 sexually active women aged <65 years in Yangqu County by using a questionnaire; the subjects were also screened using the ThinPrep cytologic test (TCT). Patients with abnormal TCT results (other than glandular cell abnormalities) who were willing to provide informed consent were further diagnosed using colposcopy and histopathological examination. We investigated 247 cases of low-grade cervical squamous intraepithelial lesions (LSIL), 125 cases of high-grade cervical squamous intraepithelial lesions (HSIL) and 877 controls. A 24-item food frequency questionnaire was filled out by the investigator to estimate the consumption of dietary folate. Positivity for hrHPV from residual exfoliated cervical cells was tested; serum folate was also measured.Results:The hrHPV infection rate in HSIL patients (77.6%) was higher than that in LSIL (33.2%) and control (32.0%) patients. Dietary folate intakes in controls, LSIL and HSIL were 306.9±176.6, 321.8±168.0 and 314.7±193.8 μg/kcal, respectively. The levels of serum folate in controls, LSIL and HSIL were 18.2±7.9, 15.9±7.1 and 14.3±7.5 nmol/l, respectively. Increased CIN correlated with higher rates of hrHPV infection and lower levels of serum folate.Conclusions:Low levels of serum folate may increase the risk of CIN progression. Furthermore, potential synergy may exist between low serum folate levels and hrHPV infection to promote CIN development.

Causative relations between human papilloma virus infection and cervical intraepithelial neoplasia

ABSTRACTThe aim of this study was to assess the correlation between human papilloma virus (HPV) infections and cervical intraepithelial neoplasia (CIN). The study included 421 women (aged 18–45 years) who were examined gynecologicaly; their medical history and Pap smear results were collected and colposcopy and HPV tests were performed. In those cases where colposcopy and cytological evidence of atypism was found, biopsy or abrasion from the uterine cervix was performed. The GenoFlow HPV Array Test Kit was used to analyse the HPV status in cervical samples collected during the study. The obtained results showed that, one/more HPV genotypes were identified in 42% (177/421) and HPV(−) in 58% (244/421) of the examined women. In the HPV(+) group, CIN was diagnosed in 57 (13.5%) women, whereas, in the HPV(−) group, in 44 (10.5%) women. There was a significant dependence between HPV(+) status and development of CIN (p = 0.001), but the statistical analysis did not reveal sufficient positive predictive value or precision (p > 0.05), i.e. probability that (randomly selected) HPV(+) patients have CIN; neither sensitivity (p > 0.05), i.e. probability that (randomly selected) CIN patients are HPV(+); nor specificity (p > 0.05), i.e. probability that (randomly selected) women without CIN are HPV(−). These results indicate that infection with HPV is probably not the only cause for development of CIN.

Роль генотипических вариантов полиморфизма RS1800629 гена фактора некроза опухоли-α в формировании интраэпителиальных неоплазий шейки матки

Роль генотипических вариантов полиморфизма RS1800629 гена фактора некроза опухоли-α в формировании интраэпителиальных неоплазий шейки матки

Lamin A/C deficiency is an independent risk factor for cervical cancer.

In the past, cervical cancer has been linked to Human Papilloma Virus (HPV) infection. Previously, we found that pre-neoplastic breast and ovarian lesions may be associated with lamin A/C deficiency, resulting in abnormal nuclear morphologies and chromosomal instability. Ultimately, these phenomena are thought to lead to cancer. Here, we assessed lamin A/C deficiency as an indicator for the risk to develop cervical cancer. The expression of lamin A/C was assessed by Western blotting in cervical uterine smears (CUS) of 76 adult women from Benin concomitant with nuclear morphology assessment and HPV genotyping using microscopy and PCR-based assays, respectively. In vitro analyses were performed to uncover the mechanism underlying lamin A/C expression alterations observed in vivo. The presence of cervical intra-epithelial neoplasia (CIN) was assessed by colposcopy. Normal lamin A/C expression (group A) was observed in 39% of the CUS, weak lamin A/C expression (group B) was observed in 28% of the CUS and no lamin A/C expression (group C) was observed in 33% of the CUS tested. Infection with oncogenic HPV was found to be significantly higher in group C (36%) than in groups A (17%) and B (14%). Two years after our first assessment, CIN was observed in 20% of the women in group C. The in vitro application of either a histone deacetylase inhibitor (trichostatin) or a protein kinase inhibitor (staurosporine) was found to restore lamin A/C expression in cervical cancer-derived cells. Lamin A/C deficiency may serve as an independent risk factor for CIN development and as an indicator for preventive therapy in cervical cancer.

Langerhans cells from women with cervical precancerous lesions become functionally responsive against human papillomavirus after activation with stabilized Poly-I:C

Human papillomavirus (HPV)-mediated suppression of Langerhans cell (LC) function can lead to persistent infection and development of cervical intraepithelial neoplasia (CIN). Women with HPV-induced high-grade CIN2/3 have not mounted an effective immune response against HPV, yet it is unknown if LC-mediated T cell activation from such women is functionally impaired against HPV. We investigated the functional activation of in vitro generated LC and their ability to induce HPV16-specific T cells from CIN2/3 patients after exposure to HPV16 followed by treatment with stabilized Poly-I:C (s-Poly-I:C). LC from patients exposed to HPV16 demonstrated a lack of costimulatory molecule expression, inflammatory cytokine secretion, and chemokine-directed migration. Conversely, s-Poly-I:C caused significant phenotypic and functional activation of HPV16-exposed LC, which resulted in de novo generation of HPV16-specific CD8+ T cells. Our results highlight that LC of women with a history of persistent HPV infection can present HPV antigens and are capable of inducing an adaptive T cell immune response when given the proper stimulus, suggesting that s-Poly-I:C compounds may be attractive immunomodulators for LC-mediated clearance of persistent HPV infection.

Association of -463G/A MPO gene polymorphism and risk of cervical intraepithelial neoplasia.

The MPO system plays an important role in the control of infections and the deletion of malignant cells. Nevertheless, alternations in the MPO system can lead to DNA damage and carcinogenesis. Polymorphisms in the MPO Gene have been associated with an increased expression of MPO and a higher risk for development of cancer. This study evaluates the association between -463G/A MPO gene polymorphism and the risk for CIN. The MPO gene polymorphism (-463G/A) was investigated in 616 women with cervical intraepithelial neoplasia and in 206 healthy women. Association between MPO gene polymorphism and risk of cervical intraepithelial neoplasia were analyzed by univariate and multivariable models. No significant difference in genotype distribution of the MPO gene polymorphism was observed in women with CIN and controls (p = 0.4; OR 1.2, 95 % CI 0.8-1.6). A subgroup analysis only including women with CIN did not show an association between -463G/A MPO gene polymorphism and risk for high-grade CIN (CIN 2/3) (p = 0.09; OR 1.5, 95 % CI 0.9-2.3). The investigated MPO gene polymorphism is not associated with risk for the development of cervical intraepithelial neoplasia.

Quantitative survey of multiple CpGs from 5 genes identifies CpG methylation panel discriminating between high- and low-grade cervical intraepithelial neoplasia.

BackgroundStudies of methylation biomarkers for cervical cancer often involved only few randomly selected CpGs per candidate gene analyzed by methylation-specific PCR-based methods, with often inconsistent results from different laboratories. We evaluated the role of different CpGs from multiple genes as methylation biomarkers for high-grade cervical intraepithelial neoplasia (CIN).ResultsWe applied a mass spectrometry-based platform to survey the quantitative methylation levels of 34 CpG units from SOX1, PAX1, NKX6-1, LMX1A, and ONECUT1 genes in 100 cervical formalin-fixed paraffin-embedded (FFPE) tissues. We then used nonparametric statistics and Random Forest algorithm to rank significant CpG methylations and support vector machine with 10-fold cross validation and 200 times bootstrap resampling to build a predictive model separating CIN II/III from CIN I/normal subjects. We found only select CpG units showed significant differences in methylation between CIN II/III and CIN I/normal groups, while mean methylation levels per gene were similar between the two groups for each gene except PAX1. An optimal classification model involving five CpG units from SOX1, PAX1, NKX6-1, and LMX1A achieved 81.2% specificity, 80.4% sensitivity, and 80.8% accuracy.ConclusionsOur study suggested that during CIN development, the methylation of CpGs within CpG islands is not uniform, with varying degrees of significance as biomarkers. Our study emphasizes the importance of not only methylated marker genes but also specific CpGs for identifying high-grade CINs. The 5-CpG classification model provides a promising biomarker panel for the early detection of cervical cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-014-0037-1) contains supplementary material, which is available to authorized users.

369 Diagnosis and molecular targeting for individualized treatment of patients with pre-neoplastic lesions and locally advanced cervical cancer

Background: The natural history of HPV infection and development of cervical intraepithelial neoplasia indicate that most lesions disappear without treatment in contrast to a significant proportion of high-grade lesions that progress to invasive cancer if not treated. Persistent infection with high-risk HPV may be necessary for the development of cervical cancer. The purpose of the study was make a retrospective molecular diagnosis that include detection of HPV16 variants, polymorphism Arg72Pro of P53, expression of anti-apoptotic markers such as IGF-1R and Survivin, and hypoxic markers and glycolytic as GLUT1 and CAIX and markers of progression as hTERT in samples invasive cancer and preneoplastic lesions taken in 2002 and 1986; the results may be useful to propose an appropriate therapeutic management.

Genotyping of human papillomavirus in women under 25 years old treated in the screening program for cervical cancer

In Chile, cervical cancer (CC) is the second leading cause of death from malignancy in women. The main causal agent of cervical cancer is the human papillomavirus (HPV). This virus is the most common sexually transmitted infection among sexually active youth. An early onset of sexual life increases the chances of HPV infection; this may involve a possible early development of cervical intraepithelial neoplasia and CC, creating a major public health problem. To present HPV frequency in women under the age of 25, treated in the CC screening program and their follow-up after histopathological diagnosis. 173 cervical samples were genotyped by polymerase chain reaction and non-radioactive reverse hybridization (line blot). The overall frequency of HPV was 84.8%. HPV16 was the most prevalent. In 12.1% of women the cervical lesion persisted or progressed. 28.9% of women had irregular follow-up; in this group, 88% were HPV(+) and 52% had no record of Pap smear in the past 3 years. The results reaffirm the usefulness of complementing the Pap and HPV detection as a primary screening tool in sexually active women. They also suggest the possibility of extending the age coverage of the national screening program.

Examining IL-33 expression in the cervix of HPV-infected patients: a preliminary study comparing IL-33 levels in different stages of disease and analyzing its potential association with IFN-γ.

Research has shown the essential role of interleukin-33 (IL-33) in driving protective anti-viral immunity. IFN-γ has been reported to improve IL-33 expression in cultured epithelial cells. The development of cervical intraepithelial neoplasia (CIN) and carcinogenesis was closely related to human papilloma virus (HPV) infection and defective anti-viral immunity. The aim of this study was to investigate IL-33 expression alternation during the disease progress and its association with IFN-γ in HPV-positive patients. IL-33 was detected in endothelial cells and populations of epithelial cells in cervix. Though there was no statistically significant difference of IL-33 levels in cervical lavage and serum among different stages of disease (P > 0.05), the IL-33 protein and mRNA levels in cervical tissues were significantly lower in severe CIN patients than that of mild CIN or no CIN patients (P < 0.05). In addition, IL-33 protein levels were positively correlated with IFN-γ mRNA levels in all groups except cervical cancer (CA) group (r = 0.546, P < 0.01). In vitro, IFN-γ was also found to upregulate IL-33 expression in human epidermal keratinocytes (NHEKs) in a dose-dependent manner. However, CA tissues did not show further reduced IL-33 protein and mRNA levels compared with severe CIN tissues (P > 0.05). IFN-γ mRNA levels were even higher in CA tissues than in severe CIN tissues (P < 0.05). Therefore, in cervical precancerous tissues, IL-33 levels were lower in more severe lesions and that may be related to diminished local IFN-γ.

The distribution of high-risk human papillomavirus genotype in high-grade cervical intraepithelial neoplasia of Korean women

The aim of this study was to assess the distribution of HPV genotypes in high-grade cervical intraepithelial neoplasia (CIN) in Korea. This prospective study included consecutive 1009 patients who referred for cervical biopsy due to abnormal cytology. HPV genotyping was performed on the cervical smear using PCR-based DNA chip test for 21 high-risk HPV types. Histologic diagnosis was chronic cervicitis (CC), CIN 1, CIN 2, CIN3, and invasive carcinoma (IC) in 332 (32.9 %), 143 (14.1 %), 104 (10.3 %), 351 (34.7 %), and 79 (7.8 %) patients, respectively. High-risk HPV DNA was detected in 591 (58.7 %) patients and multiple HPV types were identified in 181 (17.9 %) patients. High-risk HPV DNA was detected in 41.5 %, 50.3 %, 63.4 %, 72.3 %, and 77.2% of patients with CC, CIN 1, CIN 2, CIN 3, and IC, respectively. The leading HPV types were HPV 16 (31.0 %), HPV 58 (12.9 %), HPV 18 (8.9 %), HPV 52 (7.4 %), HPV 31 (5.6 %), and HPV 33 (5.2%) for patients with high-grade lesions (CIN 2/3 and IC). The overall positivity rate of HPV 16 (odds ratio [OR], 6.83; 95 % confidence interval [CI], 4.54-10.29; p<0.001), HPV 18 (OR, 2.04; 95% CI, 1.20-3.45; p=0.008), HPV 31 (OR, 5.09; 95 % CI, 2.22-11.71; p=0.001), HPV 33 (OR, 3.19; 95% CI, 1.53-6.64; p=0.002), HPV 52 (OR, 2.56; 95% CI, 1.46-4.50; p=0.001), and HPV 58 (OR, 2.16; 95% CI, 1.65-4.13; p<0.001) was significantly higher in high-grade lesions than in low-grade lesions. HPV 30, 35, and 45 were overrepresented in high-grade lesions than in low-grade lesions, but the differences were not statistically significant. HPV 16, 58, 18, 52, 31, and 33 were the most common genotypes which are represented in high-grade CIN and these were significantly associated with development of high-grade CIN. The development of vaccines against these HPV types is required in Korea.

Chromosomal damage as prognosis marker in cervical carcinogenesis

Cancer of the uterine cervix is the third most common cancer in women worldwide and the most common cancer among Mexican and Latin American women. Risk factors that have been associated with the development of cervical intraepithelial neoplasia suggest that Human Papillomavirus (HPV) types 16, 18, 31, and 33 entail a high risk of developing a malignancy of this type. The accumulation of genetic alterations allows the growth of neoplastic cells; chromosomal instability is an event that occurs in the precancerous stages. The candidate cancer risk biomarkers include cytogenetic endpoints, such as chromosomal aberrations, sister chromatid exchange, micronuclei, and the outcomes of comet assay and DNA breakage detection-fluorescence in situ hybridization. The patterns identified in these cytogenetic studies indicate that chromosomal instability is a transient and chromosomally unstable intermediate in the development of cervical lesions. In this context, the mechanisms that may underlie the progressive increase in genetic instability in these patients seem to be related directly to HPV infection. The studies discussed in this paper show that chromosomal instability may serve as a biomarker by predicting the progression of cervical intraepithelial neoplasia. Nevertheless, these results should be validated in larger, prospective studies.

Association of TP53 codon 72 and intron 3 16-bp Ins/Del polymorphisms with cervical cancer risk.

Cervical cancer incidence has grown worldwide, with it being a more significant problem in developing countries. Invasive squamous cell cervical cancers are preceded by a long phase of preinvasive disease, known as cervical intraepithelial neoplasia. Cervical cancer can develop when the virus takes advantage of any TP53 gene dysfunction of the host organism. TP53 is responsible for encoding the tumor suppressor p53 phosphoprotein, which helps preserve genome integrity. Currently, many studies have focused on genetic polymorphisms as an important contribution to cancer susceptibility, but few related to cervical intraepithelial neoplasia (CIN). Thus, the present study aimed to see whether patients with suspected CIN had TP53 gene polymorphisms that might have contributed to the development of neoplasia. This study included 133 women who were referred to the Cervical Pathology Clinic of the Maternity School Assis Chateaubriand MEAC for suspected cervical lesions. Polymorphism genotyping was carried out by the PCR-RFLP technique using DNA extracted from patients' blood. The most frequent genotype in both CIN(+) and CIN(-) patients was Arg/Pro TP53 codon 72 and A1A1 for 16-bp Del in intron 3. No risk of cervical cancer was found for the polymorphisms studied. However, a significant association was found when the two polymorphisms were combined: patients with the A1A1/ArgPro genotype were statistically more frequent in the CIN(-) group (p = 0.042), while A2A2-A1A2/ProArg was significantly more frequent in the CIN(+) group. The results of our study suggest that combined analysis of TP53 polymorphisms Arg72Pro and 16-bp Ins/Del may help to monitor the development of CIN in Brazilian women.

Risk for Cervical Intraepithelial Neoplasia in Systemic Lupus Erythematosus is not Related to Disease Severity.

Cervical intraepithelial neoplasia (CIN) is increased in women with systemic lupus erythematosus (SLE). Cervical neoplasia is caused by human papilloma virus (HPV) infection which persists and causes malignant transformation of infected cervical cells. Women with lupus have impaired immune systems which can facilitate HPV persistence. We hypothesized that women with SLE who developed CIN would be younger, have more severe disease and received more immunosuppressive treatment. To test this hypothesis, a case-control study was conducted focusing on two key variables, SLE disease severity and immunosuppressive treatment, which we believed would be the major determinants of CIN development in SLE. A case control analysis was performed to compare the clinical characteristics of SLE women with cervical neoplasia (cases) to SLE women without cervical neoplasia (controls). Formalin fixed blocks of neoplastic cervical tissue were obtained from 113 women with SLE and tissue histology confirmed by 2 pathologists. Clinical data was obtained by retrospective chart reviews. Logistic regression was used to evaluate for any significant differences in clinical variables between the cases and the controls. Two sets of controls were used for comparison with a 2:1 match for each control group to cases group. Using matched controls adjusting for age and race, logistic regression analysis showed no significant difference between cases and controls for any of the clinical variables. In particular, there were no significant differences between cases vs. matched and vs. unmatched controls for factors related to SLE (disease severity, use of immunosuppressive drugs), chronic metabolic diseases (hypertension, diabetes) and HPV risk factors (marital status, smoking, gravidity parity). The key finding of this study is that SLE patients who develop CIN are not clinically different from SLE patients who do not develop CIN. Thus, lupus disease severity and immunosuppressive treatment were not susceptibility factors for CIN in our female lupus cohort.

High-Risk and Low-Risk Human Papillomavirus and the Absolute Risk of Cervical Intraepithelial Neoplasia or Cancer

To determine the absolute risk of cervical intraepithelial neoplasia (CIN) grade 3 or cervical cancer (CIN 3 or worse) after detection of low-risk human papillomavirus (HPV) and after a negative high-risk HPV test. In this prospective cohort study, consecutive liquid-based cervical cytology samples were collected from women screened for cervical cancer in Copenhagen, Denmark, during 2002-2005. Samples were tested with a clinical test for 13 high-risk and five low-risk HPV types. The cohort (N=35,539; aged 14-90 years) was monitored in a nationwide pathology register for up to 10.5 years for development of CIN 3 or worse. The 8-year absolute risk of CIN 3 or worse was 1.1% (95% confidence interval [CI] 1.0-1.3%) for HPV-negative women; 1.7% (0.8-2.6%) for low-risk HPV-positive women without concurrent high-risk HPV; 17.4% (16.4-18.5%) for high-risk HPV-positive women without concurrent low-risk HPV; and 15.9% (13.5-18.3%) for women with concurrent high-risk and low-risk HPV. The 8-year absolute risk of CIN 3 or worse after a negative high-risk HPV test (irrespective of low-risk HPV status) was lower than after a normal cytology result among women aged younger than 30 years (3.5% [95% CI, 2.9-4.0%] compared with 6.9% [6.2-7.5%], P<.001) and women aged 30 years or older (0.7% [95% CI, 0.6-0.9%] compared with 1.8% [95% CI, 1.6-2.0%], P<.001). A negative high-risk HPV test provides greater long-term reassurance against CIN 3 or worse than normal cytology. Detection of low-risk HPV does not predict CIN 3 or worse. Cervical cancer screening should not include testing for low-risk HPV types. II.

Efficacy and Safety of Nonbiologic Immunosuppressants in the Treatment of Nonrenal Systemic Lupus Erythematosus: A Systematic Review

To analyze the efficacy and safety of nonbiologic immunosuppressants in the treatment of nonrenal systemic lupus erythematosus (SLE). We conducted a sensitive literature search in Medline, Embase, and the Cochrane Central Register of Controlled Trials up to October 2011. The selection criteria were studies including adult patients with SLE, a treatment intervention with nonbiologic immunosuppressants, a placebo or active comparator group, and outcome measures assessing efficacy and/or safety. Meta-analyses, systematic reviews, clinical trials, and cohort studies were included. The quality of each study was evaluated using Jadad’s scale and the Oxford Levels of Evidence. In total, 158 of the 2,827 initially found articles were selected for detailed review; 65 studies fulfilled the predetermined criteria. Overall, the studies were low quality, with only 11 randomized controlled trials (RCTs). Cyclophosphamide demonstrated efficacy for neuropsychiatric SLE, preventing relapses with an additional steroid sparing effect, although its use was associated with cumulative damage, development of cervical intraepithelial neoplasia,and ovarian failure. Other immunosuppressants (azathioprine, methotrexate, leflunomide, mycophenolate mofetil,and cyclosporin A) demonstrated efficacy in reducing nonrenal activity and flares with a steroid-sparing effect, although only on occasion in non–placebo-controlled RCTs of small numbers of patients. Several immunosuppressants demonstrated their safety and efficacy in nonrenal SLE. A specific drug for each particular manifestation cannot be recommended, although cyclophosphamide may be used in more severe cases, and methotrexate may be the first option in most cases of moderately active SLE. High-quality RCTs of larger numbers of patients are needed.

Expression of Toll-like receptor 4 in cervical cell lines and cervical lesions and its relation to HPV16 infection

To explore the relation between human papillomavirus (HPV16) infection and expression of Toll-like receptor 4 (TLR4) in cervical cell lines and cervical lesion tissues and to investigate the effect of TLR4 on cervical cancer progression. Expression of HPV16 E6 mRNA was detected by RT-PCR. Western blot and immunohistochemistry were used to detect the expression of TLR4 in H8, SiHa, Caski cell lines and formalin-fixed and paraffin-embedded cervical tissue specimens with cervicitis, cervical intraepithelial neoplasia (CIN) and cervical squamous cell carcinama (CSCC). DNA was extracted from paraffin-embedded cervical cancer tissues and HPV16 genes were detected. The differentiation expression of HPV16 E6 mRNA and TLR4 in SiHa and Caski was significantly higher than that of normal cervical cell H8 (P<0.05). The positive expression rates of TLR4 and HPV16 in chronic cervicitis, CIN, and cervical cancer were 32.0%, 59.4%, and 77.8% (P<0.01) and 8.0%, 48.4%, and 81.0% (P<0.01), respectively. Up-regulation of TLR4 was correlated with tumor differentiation (P<0.01), but not with FIGO stages or lymph node metastasis (P>0.05). The expression of TLR4 was significantly correlated with HPV16 infection in CIN and CSCC (r=0.303, P<0.05, r=0.633, P<0.05). High expression of TLR4 may play important roles in the development and progression of CIN and CSCC, and the expression of TLR4 can be up-regulated by HPV16 infection.