Progression Of Cervical Lesions Research Articles

The expression analysis of human endogenous retrovirus-K Env, Np9, and Rec transcripts in cervical cancer.

While infection with high-risk human papillomavirus (HPV) types is necessary for cervical cancer (CC) development, it is not enough, and other risk factors are required. Several studies have reported the activation of HERV-K in different cancers; however, the investigation of HERV-K expression levels in CC is scarce. In this study, it was hypothesized that activation of HERV-K could play an essential role in CC development. In this order, the expression levels of HERV-K Env, Np9, and Rec transcripts were investigated on 147 normal to CC uterine cervical tissues using quantitative real-time PCR. The significantly higher levels of HERV-K Env and Np9 transcripts were found in patients with cervical intraepithelial neoplasia (CIN) II-III and CC groups compared to those in the normal/CIN I group. Expression of Rec transcript was also higher only in the CC group than normal/CIN I group. Among CC patients, meaningfully higher levels of HERV-K Env and Np9 transcripts were found in patients with squamous cell carcinoma rather than in adenocarcinoma. When only the HPV 16 positive samples were investigated, it was found that the mean difference in Env and Np9 mRNA levels was meaningfully higher among precancer lesions and the cancer group in comparison with the normal group. However, the Rec mRNA level showed no significant differences. The association between the expression of HERV-K genes was investigated, and a significant positive correlation of Env expression with Np9 transcript was found only in the group with precancer lesions (R = 0.6, p = 0.0037). Moreover, a significant positive correlation was found between Rec and Np9 transcripts in patients with normal cervix tissues (R = 0.26, p = 0.033). However, no correlations were observed between the expression of Env and Rec in the three groups. In conclusion, our results showed that HERV-K transcripts, especially Env and Np9, upregulated during cervical lesion progression. These findings highlight the potential use of HERV-K Env and Np9 as biomarkers for CC diagnosis and prognosis. Further investigation is needed to determine the clinical utility of these markers and whether targeting HERV-K oncogenes could be a viable therapeutic strategy for CC.

Root coverage with the restoration of non-carious cervical lesions: A systematic review and meta-analysis.

The progression of non-carious cervical lesions (NCCLs) leads to gingival recession (GR), which is restored with restorative materials, using different periodontal plastic surgery procedures. There is no consensus on which technique is superior to others. Therefore, the present systematic review aimed to assess the effectiveness of root coverage (RC) procedures in the restored and unrestored NCCLs in terms of clinical and patient-centered outcomes.We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) while searching 5 databases in addition to the gray literature. The Medical Subject Headings (MeSH) terms and keywords in the title and abstract fields, as well as in headings, were used to search the existing literature for the relevant publications on the effectiveness of RC procedures with the restoration of NCCLs over the past 3 decades (January 1990-July 2021). After applying the inclusion and exclusion criteria, 13 articles were read in full and critically analyzed. The quality analysis was performed using the Cochrane RevMan software.A total of 222 potentially relevant titles and abstracts were found after the initial electronic and manual search, and after removing duplicates. Applying the inclusion and exclusion criteria yielded 23 publications that were further analyzed for relevance and applicability. Following critical analysis, 13 publications were used for validity assessment and data extraction.In the teeth with NCCLs and GR, the restoration of NCCLs does not affect the percentage RC. However, it significantly decreases dentin hypersensitivity, and the patients' perception of esthetics and satisfaction.

A Prospective Study on the Progression, Recurrence, and Regression of Cervical Lesions: Assessing Various Screening Approaches.

(1) Background: The prediction of cervical lesion evolution is a challenge for clinicians. This prospective study aimed to determine and compare the predictive accuracy of cytology, HPV genotyping, and p16/Ki67 dual staining alone or in combination with personal risk factors in the prediction of progression, regression, or persistence of cervical lesions in human papillomavirus (HPV)-infected patients; (2) Methods: This prospective study included HPV-positive patients with or without cervical lesions who underwent follow-up in a private clinic. We calculated the predictive performance of individual tests (cervical cytology, HPV genotyping, CINtecPlus results, and clinical risk factors) or their combination in the prediction of cervical lesion progression, regression, and persistence; (3) Results: The highest predictive performance for the progression of cervical lesions was achieved by a model comprising a Pap smear suggestive of high-grade squamous intraepithelial lesion (HSIL), the presence of 16/18 HPV strains, a positive p16/Ki67 dual staining result along with the presence of at least three clinical risk factors, which had a sensitivity (Se) of 74.42%, a specificity of 97.92%, an area under the receiver operating curve (AUC) of 0.961, and an accuracy of 90.65%. The prediction of cervical lesion regression or persistence was modest when using individual or combined tests; (4) Conclusions: Multiple testing or new biomarkers should be used to improve HPV-positive patient surveillance, especially for cervical lesion regression or persistence prediction.

Single-cell RNA sequencing of cervical exfoliated cells reveals potential biomarkers and cellular pathogenesis in cervical carcinogenesis

Cervical cancer (CC) is a common gynecological malignancy. Despite the current screening methods have been proved effectively and significantly decreased CC morbidity and mortality, deficiencies still exist. Single-cell RNA sequencing (scRNA-seq) approach can identify the complex and rare cell populations at single-cell resolution. By scRNA-seq, the heterogeneity of tumor microenvironment across cervical carcinogenesis has been mapped and described. Whether these alterations could be detected and applied to CC screening is unclear. Herein, we performed scRNA-seq of 56,173 cervical exfoliated cells from 15 samples, including normal cervix, low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), and malignancy. The present study delineated the alteration of immune and epithelial cells derived during the cervical lesion progression. A subset of lipid-associated macrophage was identified as a tumor-promoting element and could serve as a biomarker for predicting the progression of LSIL into HSIL, which was then verified by immunofluorescence. Furthermore, cell–cell communication analysis indicated the SPP1-CD44 axis might exhibit a protumor interaction between epithelial cell and macrophage. In this study, we investigated the cervical multicellular ecosystem in cervical carcinogenesis and identified potential biomarkers for early detection.

Evaluation of HPV 16 and HPV 18 Oncoprotein Expression as Alternative Diagnostic Tools in Cervical Lesion.

The study aimed to evaluate E6 and E7 oncoproteins of HPV16 and HPV18 expression in formalin - fixed paraffin embedded (FFPE) tissue in different grades of the cervical lesion and evaluate the potential use of E6 and E7 oncoproteins derived from HPV 16 and 18 as diagnostic protein biomarkers for triaging cervical lesions. A total of 102 FFPE cervical tissues were collected from 2 tertiary hospitals and immunohistochemical reactivity staining of E6 and E7 oncoproteins of HPV16 and HPV18 were evaluated using immunoreactive scoring (IRS) system and analysed statistically. The result showed an increased oncoprotein expression with the progression of cervical lesions. There is a statistically significant association between histology grade and HPV16/18-E6 expression (p = 0.028). However, there are no significant association of histological grade to HPV16-E7 immunoreactivity score (p = 0.264) and HPV18-E7 (p=0.080). The immunohistochemical expression of HPV oncoproteins is a potential alternative diagnostic tool applicable in a low-resource laboratory setting. The advantage of the histochemical evaluation is that this method is simpler to apply and less expensive in comparison to in situ mRNA hybridization. Nevertheless, our study also found that antibodies against HPV that are commercially available suffer quite substantial specificity issues such as background staining and inconsistency between different batches. Hence, the utilization of antibody-based staining warrants stringent quality control.

Objective assessment of simulated non-carious cervical lesion by tridimensional digital scanning – An in vitro study

ObjectiveClinical assessment of progression of non-carious cervical lesions (NCCLs) is currently based on subjective methods. We hypothesize that 3D digital intraoral scanners (IOS) can provide quantitative outcomes for objective measuring and monitoring of NCCLs. This in vitro study verified the reliability of IOS to monitor dental structure loss of simulated NCCLs, in comparison to a reference bench-top 3D optical profilometer (BTS). MethodsNCCLs of different severity levels (early, moderate, or severe, n = 150) were simulated in a preceding study. Impressions of the lesions were taken and scanned with both BTS (ProScan; Scantron) and IOS (TRIOS4; 3Shape). Generated 3D images were analyzed for volumetric tooth loss (mm3) by superimposition followed by subtraction analysis. ProForm (Scantron) and WearCompare (Leeds Digital Dentistry) software were used in association to BTS and IOS, respectively. Agreement was assessed using intraclass correlation coefficient (ICC, alpha=0.05) and Bland-Altman plots. ResultsICC (confidence interval at 95 %) between IOS and BTS for all data combined was 0.962 (0.942–0.973), showing excellent reliability. Subset analyses showed that NCCLs with lower volume loss (early- and moderate-stage lesions) resulted in moderate ICCs, whereas severe lesions showed excellent ICC. Bland-Altman plots demonstrated general good agreement, with narrower limits for early stage-lesions. ConclusionIOS data demonstrated good agreement to BTS, when measuring tooth structure loss in simulated NCCLs, with particularly higher ICC in more severe lesions. Considering the accessibility and ease-of-use, IOS showed to be a good alternative for the objective assessment of NCCLs in vitro. Clinical significance3D intraoral scanners’ accessibility and objectivity make them potentially valuable tools for assessing and monitoring NCCLs.

Predicting cervical intraepithelial neoplasia and determining the follow-up period in high-risk human papillomavirus patients.

Despite strong efforts to promote human papillomavirus (HPV) vaccine and cervical cancer screening, cervical cancer remains a threat to women's reproductive health. Some high-risk HPV types play a crucial role in the progression of cervical cancer and precancerous lesions. Therefore, HPV screening has become an important means to prevent, diagnose, and triage cervical cancer. This study aims to leverage artificial intelligence to predict individual risks of cervical intraepithelial neoplasia (CIN) in women with high-risk HPV infection and to recommend the appropriate triage strategy and follow-up period according to the risk level. A total of 475 cases were collected in this study. The sources were from the Department of Gynecology and Obstetrics in a tertiary hospital, a case report on HPV from the PubMed website, and clinical data of cervical cancer patients from The Cancer Genome Atlas (TCGA) database. Through in-depth study of the interaction between high-risk HPV and its risk factors, the risk factor relationship diagram structure was constructed. A Classification of Lesion Stages (CLS) algorithm was designed to predict cervical lesion stages. The risk levels of patients were analyzed based on all risk factors, and follow-up periods were formulated for each risk level. Our proposed CLS algorithm predicted the probability of occurrence of CIN3-the precancerous lesion stage of cervical cancer. This prediction was based on patients' HPV-16 and -18 infection status, age, presence of persistent infection, and HPV type. Follow-up periods of 3-6 months, 6-12 months, and 3- to 5-year intervals were suggested for high-risk, medium-risk, and low-risk patients, respectively. A lesion prediction model was constructed to determine the probabilities of occurrence of CIN by analyzing individual data, such as patient lifestyle, physical assessments, and patient complaints, in order to identify high-risk patients. Furthermore, the potential implications of the calculated features were mined to devise prevention strategies.

Epidemiology and genotypes analysis of human papillomavirus infection in Beijing, China

BackgroundThis study aimed to investigate the epidemiology of high-risk human papillomavirus (HPV) in the female population in Beijing, China, and identify the relationship between HPV genotypes and host factors.MethodsHPV testing was performed on women aged 15–89 (mean age 38.0 ± 10.9 years) from Beijing in 2020. High-risk HPV genotyping real-time polymerase chain reaction was used to determine HPV genotypes. The overall prevalence, age-specific prevalence, genotype distribution, and the correlation between HPV genotypes and cervical cytology were analyzed.ResultsAmong the 25,344 study participants, the single and double infection rates were 18.8% (4,777/25,344) and 4.2% (1,072/25,344), respectively. A total of 6,119 HPV-positive individuals were found to have 91.6% negative results for intraepithelial lesion or malignancy (NILM), 5.8% atypical squamous cells of undetermined significance (ASC-US), 0.9% low-grade squamous intraepithelial lesion (LSIL), and 1.7% high-grade squamous intraepithelial lesion (HSIL). In single HPV infections, the HPV16 genotype was highly associated with cervical cytology severity (χ2 trend = 172.487, P < 0.001). Additionally, HPV infection rates increased gradually with age, and statistical differences were observed across age groups (χ2 = 180.575; P < 0.001). High-risk HPV genotypes were highly prevalent in women below 25 years of age and those aged 55–59 years. Cluster analysis revealed that the 13 HPV genotypes could be roughly divided into two groups in a single infection; however, patterns of infection consistent with biological characteristics were not observed.ConclusionHigh-risk HPV was found in 24.1% of outpatients, with HPV52, HPV58, HPV16, HPV39, and HPV51 being the most common high-risk genotypes. Single high-risk HPV infection was predominant. HPV16, HPV39, HPV51, and HPV52 were associated with cervical lesion progression. HPV16 infection was especially worrying since it aggravates cervical lesions. Because the infection rates of the 13 HPV genotypes differed by age, the peak HPV infection rate should not guide vaccination, screening, and prevention programs. Instead, these initiatives should be tailored based on the regional HPV distribution characteristics. Moreover, it was determined that Beijing’s populace needed to receive treatment for HPV39 infection.

Associations of Single Versus Multiple Human Papillomavirus Infections With the Prevalence of Cervical Intraepithelial Neoplasia 2/3 and Squamous Cell Carcinoma Lesions: Human Papillomavirus Type–Specific Attribution

The risk of developing cervical squamous lesions in women with multiple high-risk human papillomavirus (hrHPV) infections is uncertain. The aim of this retrospective study was to investigate the type-specific attribution and phylogenetic effects of single and multiple hrHPV subtypes in cervical squamous lesions. All cases with cervical histopathologic diagnosis and human papillomavirus (HPV) genotyping results in the 6 months preceding biopsy from October 2018 to December 2022 were studied and analyzed. Over the study period, 70,361 cases with histopathologic follow-up and prior HPV genotyping were identified. The hrHPV-positive rate was 55.6% (39,104/70,361), including single hrHPV detected in 27,182 (38.6%), 2 types of hrHPV detected in 8158 (11.6%), and 3 types of hrHPV detected in 2486 (3.5%). Among 16,457 cases with a histologically diagnosed squamous lesion (cervical intraepithelial neoplasia 1: 11411; cervical intraepithelial neoplasia 2/3: 4192; squamous cell carcinoma: 854 cases), the prevalence of single hrHPV infection increased, but the rate of multiple concomitant hrHPV infections showed negative association as the degree of squamous lesions increased. Among women with a single HPV16 infection, cervical intraepithelial neoplasia 2/3 and squamous cell carcinoma (CIN2+) diagnostic rate was 30.6%, and it increased to 47.6% when coinfected with HPV33 (P < .001) but significantly decreased when coinfected with all other hrHPV types (P < .05). By comparing CIN2+ diagnostic rates in 40 most common 2 types of hrHPV infections with related single hrHPV infection, CIN2+ rates were decreased in 12 combinations (30.0%), equivalent in 26 combinations (65.0%), and increased in 2 combinations (5.0%). The cases with 3 types of HPV infections reduced the risk for CIN2+ compared with related single HPV infections. HPV16+52+53, HPV16+52+68, HPV16+52+51, HPV16+39+52, and HPV16+58+53 significantly decreased the risk of CIN2+ compared with HPV16 single infection (P < .05). This study demonstrates that multiple hrHPV infections are not associated with cumulatively higher risk for CIN2+ development, suggesting that oncogenic progression of multiple hrHPV-associated cervical squamous lesions is neither synergistic nor a cumulative effect at the phylogenetic level, possibly a way of competitive interference.

Relationship between vaginal microecology and human papillomavirus infection as well as cervical intraepithelial neoplasia in 2,147 women from Wenzhou, the southeast of China.

The female reproductive tract is a significant microecological region, and its micro-environment can directly affect women's cervical health. This research aimed to investigate the effect of vaginal microecology on human papillomavirus (HPV) infection and cervical intraepithelial neoplasia(CIN). A retrospective cohort study enrolling 2,147 women who underwent a colposcopic examination between August 2021 and August 2022 was conducted. The relationship between vaginal microecology and HPV infection as well as cervical lesions were assessed using the chi-square test, univariate and multivariate logistic regression analyses, and Cochran-Armitage trend test. HPV infection was linked to the imbalance of vaginal microecology [odds ratio (OR)=3.00, 95% confidence interval (CI)=1.66-5.43; P<0.001]. Clue cell (OR=1.59, 95% CI=0.99-2.54; P=0.054) and sialidase (OR=1.54, 95% CI=1.01-2.35; P<0.046) were considered as significant risk factors for HPV infection. Further analysis showed that vaginal microecological disorder was more likely to be detected in patients infected with HPV 16/18 subtypes (OR=9.86, 95% CI=2.37-41.80; P=0.002). Although there was no significant correlation between the incidence of vaginal microecological disorder and the severity of cervical lesions (P > 0.05), the proportions of abnormal PH value (OR=2.6, 95% CI=1.63-10.42; P=0.001) and abnormal vaginal cleanliness (OR=2.6, 95% CI=1.36-4.0; P= 0.004) increased as the histological stage progressed. Vaginal microecology associates with HPV infection and the progression of cervical lesions. Detection of vaginal secretion may contribute to the development of targets for micro-environmental modulation with probiotics and the reduction of the incidence of cervical cancer.

Impact of cervical intraepithelial neoplasia and treatment on IVF/ICSI outcomes.

Does treatment selection for cervical lesions affect the outcome of IVF/ICSI? There was no difference in pregnancy outcome between treated and untreated groups, or between different types of IVF/ICSI treatment. Human papillomavirus (HPV) infection and HPV-induced cervical lesions are associated with decreased fertility, and cervical intraepithelial neoplasia (CIN) treatment may increase the risk of adverse pregnancy outcomes. Between 2018 and 2020, 190 women with infertility who had abnormal HPV screening or cytology results prior to IVF/ICSI, and were diagnosed with CIN2/CIN3 by colposcopy biopsy at a tertiary hospital, were enrolled in a retrospective cohort study with follow-up until 31 December 2021. Patients with infertility who were diagnosed with CIN2/CIN3 by colposcopy biopsy were divided into the treatment and expectant management groups. The treatment group was divided into two intervention subgroups: the ablative therapy group and the surgical treatment group. The baseline data, number of oocytes retrieved, and rates of fertilization, high-quality embryos, positive serum HCG, clinical pregnancy, abortion, live birth, and cumulative pregnancy were compared among groups. Among the 190 patients included in the study, 152 were diagnosed with CIN2, and 38 patients had CIN3. There was no significant difference in the baseline data between the treatment and expectant groups. The time from confirmed lesions to the onset of gonadotrophin administration in the surgical treatment group was significantly longer than in the ablative therapy group and the expectant group (P = 0.007 and P = 0.024, respectively). For the treatment and expectant groups, respectively, the average number of oocytes retrieved (12.95 ± 8.77; 13.32 ± 9.16), fertilization rate (71.01 ± 23.86; 64.84 ± 26.24), and high-quality embryo rate (48.93 ± 30.72; 55.17 ± 34.13) did not differ, and no differences were detected between the different treatment subgroups. There were no differences among groups in rates of HCG positivity, clinical pregnancy, miscarriage, live birth, or cumulative pregnancy. The live birth rate in the surgical treatment group was slightly higher than that in the expectant groups (77.78% versus 66.67%), but the difference was not statistically significant. The 3-year cumulative pregnancy rates in the surgical treatment and expectant groups were 58.19% and 64.00%, respectively. This is a retrospective study, which by nature can include selection bias, and the number of cases in the expectant group was <30, which may result in a false-negative result owing to the small sample size. For patients with CIN2/CIN3, the treatment of cervical lesions does not affect the outcome of IVF/ICSI. Patients with CIN2 can enroll for IVF/ICSI cycles, with close follow-up to prevent the progression of cervical lesions, in order to avoid further delay in starting ART. For patients with CIN3, ovulation induction and embryo cryopreservation can be initiated as soon as possible after cervical lesions are treated, and frozen-thawed embryo transfer can be carried out 9-12 months later. This work was funded by the Key Clinical Projects of the Peking University Third Hospital (to Y.W., BYSYZD2021014). The authors declare no conflicts of interest. N/A.

HIV gp120/Tat protein-induced epithelial–mesenchymal transition promotes the progression of cervical lesions

BackgroundHuman immunodeficiency virus (HIV) infection is associated with an elevated incidence of cervical cancer, and accelerated disease progression, but the underlying mechanisms are not well understood. This study aimed to investigate the relationship between HIV infection and epithelial–mesenchymal transition (EMT) in cervical cancer.MethodsTissue samples from HIV-positive and negative patients with cervical intraepithelial neoplasia (CIN) and cervical cancer were analyzed for EMT-related proteins. Human cervical cancer SiHa cells were treated with HIV Tat and gp120 proteins to test their effects on EMT, migration, and invasion.ResultsHIV-positive patients had lower E-cadherin and cytokeratin, and higher N-cadherin and vimentin levels than HIV-negative patients. HIV Tat and gp120 proteins induced EMT, migration, and invasion in SiHa cells. Transcriptome sequencing analysis revealed that, compared to the control group, the protein-treated group showed upregulation of 22 genes and downregulation of 77 genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed the involvement of the Wnt signaling pathway in EMT. Further analysis of gene expression related to this pathway revealed upregulation of DVL1, TCF7, KRT17, and VMAC, while GSK3β, SFRP2, and CDH1 were downregulated. Immunofluorescence assay demonstrated that HIVgp120 and Tat proteins treatment induced elevated β-catenin expression with nuclear accumulation in SiHa cells.ConclusionsThe treatment of SiHa cells with HIV Tat and gp120 proteins induces EMT and activates the Wnt/β-catenin pathway, suggesting that the Wnt/β-catenin pathway may play a crucial role in promoting EMT progression in cervical lesion tissues of HIV-infected patients.

Vaginal microecology and its role in human papillomavirus infection and human papillomavirus associated cervical lesions.

The vaginal microecology comprises the vaginal microbiome, immune microenvironment, vaginal anatomy, and the cervicovaginal fluid, which is rich in metabolites, enzymes, and cytokines. Investigating its role in the female reproductive system holds paramount significance. The advent of next-generation sequencing enabled a more profound investigation into the structure of the vaginal microbial community in relation to the female reproductive system. Human papillomavirus infection is prevalent among women of reproductive age, and persistent oncogenic HPV infection is widely recognized as a factor associated with cervical cancer. Extensive previous research has demonstrated that dysbiosis of vaginal microbiota characterized by a reduction in Lactobacillus species, heightens susceptivity to HPV infection, consequently contributing to persistent HPV infection and the progression of cervical lesion. Likewise, HPV infection can exacerbate dysbiosis. This review aims to provide a comprehensive summary of current literatures and to elucidate potential mechanisms underlying the interaction between vaginal microecology and HPV infection, with the intention of offering valuable insights for future clinical interventions.

Epigenome-wide methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2+): a prospective cohort study in the United States

BackgroundMethylation levels may be associated with and serve as markers to predict risk of progression of precancerous cervical lesions. We conducted an epigenome-wide association study (EWAS) of CpG methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2 +) following an abnormal screening test.MethodsA prospective US cohort of 289 colposcopy patients with normal or CIN1 enrollment histology was assessed. Baseline cervical sample DNA was analyzed using Illumina HumanMethylation 450K (n = 76) or EPIC 850K (n = 213) arrays. Participants returned at provider-recommended intervals and were followed up to 5 years via medical records. We assessed continuous CpG M values for 9 cervical cancer-associated genes and time-to-progression to CIN2+. We estimated CpG-specific time-to-event ratios (TTER) and hazard ratios using adjusted, interval-censored Weibull accelerated failure time models. We also conducted an exploratory EWAS to identify novel CpGs with false discovery rate (FDR) < 0.05.ResultsAt enrollment, median age was 29.2 years; 64.0% were high-risk HPV-positive, and 54.3% were non-white. During follow-up (median 24.4 months), 15 participants progressed to CIN2+. Greater methylation levels were associated with a shorter time-to-CIN2+ for CADM1 cg03505501 (TTER = 0.28; 95%CI 0.12, 0.63; FDR = 0.03) and RARB Cluster 1 (TTER = 0.46; 95% CI 0.29, 0.71; FDR = 0.01). There was evidence of similar trends for DAPK1 cg14286732, PAX1 cg07213060, and PAX1 Cluster 1. The EWAS detected 336 novel progression-associated CpGs, including those located in CpG islands associated with genes FGF22, TOX, COL18A1, GPM6A, XAB2, TIMP2, GSPT1, NR4A2, and APBB1IP.ConclusionsUsing prospective time-to-event data, we detected associations between CADM1-, DAPK1-, PAX1-, and RARB-related CpGs and cervical disease progression, and we identified novel progression-associated CpGs.ImpactMethylation levels at novel CpG sites may help identify individuals with ≤CIN1 histology at higher risk of progression to CIN2+ and inform risk-based cervical cancer screening guidelines.

Associations of multi-human papillomavirus infections with expression of p16 in a cohort of women who underwent colposcopy: a retrospective study of 5165 patients.

Investigate HPV types in cervical specimens, their correlation with p16 expression in lesions, and diagnostic value for cervical lesions. Enhance clinical diagnosis reliability. Retrospective cross-sectional study at Fujian Maternity and Child Health Hospital's Cervical Disease Center (Jun 2019-Dec 2021). Patients with abnormal cervical screening underwent colposcopy and conization. Pathological diagnosis based on colposcopy, cervical biopsy, ECC, and conization. Analyzed HPV genotyping (18 HR-HPV, 5 LR-HPV) and p16 expression correlation. Statistical analysis used R software. he expression of p16 is significantly associated with the infection of high-risk HPV types, such as 16, 33, 52, and 58, with an increased risk of 1.4 times or higher (OR=1.91, 3.14, 1.40, and 1.78, respectively). The risk of p16 expression increased 4-fold for multiple high-risk HPV types [adjusted OR (95% CI) = 4 (2.92~5.5), P-value <0.001]. Compared to the p16(-) group, the p16(+) group had a higher association with cervical lesions worse than HSIL (High-grade Squamous Intraepithelial Lesions).In the group with multiple Human Papillomavirus Infections with types 16, 33, 52, and 58, the risk of cervical lesions worse than HSIL increased by up to 660-fold compared to the negative group (adjusted OR=660.62, 95% CI: 91.39~4775.53, P<0.001), indicating that this combination of HPV types posed the greatest risk for cervical lesions above HSIL. p16 plays a crucial role in cervical lesion progression, linked to high-risk HPV. Combining p16 with HPV screening improves cervical cancer detection. Studying multiple HPV infections will enhance prevention and management.

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

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. 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. 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. 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.

HPV16 E7 oncoprotein test as a triage strategy for HPV16-positive women in cervical cancer screening: long-term follow-up outcome.

Colposcopy is recommended once human papillomavirus (HPV)16/18 infection is detected. However, not all HPV16/18-positive women will necessarily develop cervical lesions. Therefore, this study aimed to investigate the application of quantitative HPV16 E7 oncoprotein detection as a cervical cancer screening method for more efficient screening while minimizing unnecessary colposcopy. E7 oncoprotein (HPV16) was quantitatively detected in cervical exfoliated cells of HPV16-positive women. The levels of HPV16 E7 oncoprotein in different degrees of cervical lesions were compared, and the optimal cut-off value for identifying HSIL+ was determined by receiver operating characteristic (ROC) curve analysis. With a pathological diagnosis as the gold standard, the sensitivity (SEN), specificity (SPE), positive predictive value (PPV), negative predictive value (NPV), and Kappa value were calculated to verify the diagnostic value of the method. Women diagnosed with low-grade squamous intraepithelial lesions (LSIL) and normal women were followed up for 5 years to evaluate the predictive value of HPV16 E7 protein for disease progression/persistent infection. The expression level of HPV16 E7 oncoprotein was positively correlated with the degree of the cervical lesion (r = 0.589, P < 0.01). The area under the ROC curve (AUC) was 0.817 (confidence interval: 0.729-0.904). The cut-off value of E7 oncoprotein for identifying HSIL+ was 8.68 ng/ml. The SEN, SPE, PPV, NPV, and Kappa values of HPV16 E7 oncoprotein for the identification of HSIL+ were 87.1%,70.0%, 87.1%, 70.0%, and 0.571, respectively, which were higher than those of ThinPrep cytology test (TCT). The SEN, SPE, PPV, and NPV of HPV16 E7 oncoprotein in predicting disease progression/persistent infection were 93.75%, 91.30%, 88.24%, and 95.45%, respectively. The quantitative detection of HPV 16 E7 oncoprotein can not only accurately screen cervical lesions but also achieve efficient colposcopy referral. Additionally, HPV16 E7 oncoprotein can accurately predict the progression of cervical lesions and persistent HPV infection.

Four conserved amino acids on human papillomavirus E6 predict clinical high-risk types.

Human papillomavirus (HPV) types included in the genus alpha papillomavirus (alpha-HPVs) are subdivided into high- and low-risk HPVs associated with tumorigenicity. According to conventional risk classification, over 30 alpha-HPVs remain unclassified and HPV groups phylogenetically classified using the L1 gene do not exactly correspond to the conventional risk classification groups. Here, we propose a novel cervical lesion progression risk classification strategy. Using four E6 risk distinguishable amino acids (E6-RDAAs), we successfully expanded the conventional classification to encompass alpha-HPVs and resolve discrepancies. We validated our classification system using alpha-HPV-targeted sequence data of 325 cervical swab specimens from participants in Japan. Clinical outcomes significantly correlated with the E6-RDAA classification. Four of five HPV types in the data set that were not conventionally classified (HPV30, 34, 67, and 69) were high-risk according to our classification criteria. This report sheds light on the carcinogenicity of rare genital HPV types using a novel risk classification strategy.

Exploring Microbiota Diversity in Cervical Lesion Progression and HPV Infection through 16S rRNA Gene Metagenomic Sequencing.

(1) Background: Cervical cancer is a significant health concern, with the main cause being persistent infection with high-risk Human Papillomavirus (hrHPV). There is still no evidence for why viral persistence occurs in some women, but recent studies have revealed the interplay between cervical microbiota and hrHPV. This research aimed to characterize the cervicovaginal microbiota in cervical lesion progression and HPV infection status. (2) Methods: This study included 85 cervical specimens from women from the north-eastern region of Romania. DNA was isolated from cervical secretion for HPV genotyping and 16S ribosomal RNA gene NGS sequencing. (3) Results: Our study revealed a distinct pattern within the studied group when considering Lactobacillus species, which differs from findings reported in other populations. Specifically, the presence of Lactobacillus iners coupled with the absence of Lactobacillus crispatus alongside Atopobium spp., Prevotella spp., and Gardnerella spp. could serve as defining factors for severe cervical lesions. The results also showed a significant association between microbiota diversity, HPV infection, and cervical lesion progression. (4) Conclusions: As the microbiota profile seems to vary among different populations and individuals, a deeper comprehension of its composition has the potential to develop personalized detection and treatment approaches for cervical dysplasia and cancer.

Molecular markers predicting the progression and prognosis of human papillomavirus-induced cervical lesions to cervical cancer.

Persistent Human Papillomavirus (HPV) infection is linked to 99% of cervical cancer (CC) cases. HPV types 16 and 18 aloneresult in 75% of CC cases and thus are considered to be high-risk types (HR-HPV). CC is thethird most common cancer among women globally. Approximately, 7000 patients die from it yearly. It is worthy to note that not every patient with HPV precancerous lesions will progress to CC. The objectives of this review is to explore the utilization ofmolecular and viral biomarkers asa tool for early detection and prediction of HPV-induced cervical lesions that might progress to CC. The data basesPubMed, Google Scholar, EBSCO were searched using keywords CC screening, HPV, and recent molecular biomarkers. The search time frame was within the last 7years. Studies on HPV-induced cancers other than CC were excluded; a total of 200 eligible articles were retrieved. In this review we explored the current literature about HPV virology, virulence genes and early diagnostic/prognostic molecular biomarkers in CC. The oncogenic property of HPV is attributed to viral expression of various early proteins (E5, E6, E7). The interaction between viral oncoproteins and the cellular genetic apparatus alters the expression of many genes at different phases of the disease. There was an association between cervical lesions induced by HR-HPV andtheoverexpression of markers of oxidative DNA damage and other proteins. The markersp16INK4a, programmed cell death-1 (PD-1)/programmed cell death ligand 1, mismatch repair enzymes (MMR), miRNA-377, claudin family (CLDN)are dysregulated and are associated with high risk lesions. Furthermore, advanced older cervical lesions were associated with high methylation levels and higherrisk to progress to CC. Adding differentthe abovemarkers to the CC screening program scheme might offera triage for prioritizing patient management.