Risk of cervical intraepithelial neoplasia grade 3 or more diagnoses for human papillomavirus16/18-positive women by cytology and co-infection status.

BACKGROUND: Human papillomavirus (HPV) 16 and 18 cause approximately 70% of cervical cancer cases. The aim of this study was to evaluate whether co-infected with other HPV genotypes will affect the risk of cervical carcinogenesis in HPV16/18 positive-women. METHODS: In this cross-sectional study, cervical cytology and histological classifications from women who tested positive for HPV 16/18 and underwent colposcopy within 6 months, between January 2010 and May 2021 were obtained from West China Second University Hospital of Sichuan University. MAIN OUTCOMES AND MEASURES: Immediate risk of cervical intraepithelial neoplasia grade 3 or more diagnoses (CIN 3+). RESULTS: A total of 7940 HPV 16/18-positive women were included, with a median age of 40 years (range 25-84 years). Among them, 2710 (34.1%) were infected with multiple genotypes, 6533 (82.28%) had cytology results and 2116 (26.65%) women were diagnosed with CIN 3+. The effects of HPV 16/18 coinfecting with other HPV on CIN3 + risk varied with specific HPV genotypes. After adjusting for cofactors, compared to single HPV 16 infection, the CIN 3 + risk was significantly reduced in women infected with HPV 16 + other high-risk HPV (hrHPV) [odds ratio (OR) = 0.621, 95% confidence interval (CI) 0.511-0.755], HPV 16 + low-risk HPV (lrHPV) (OR = 0.620, 95% CI 0.436-0.883), and HPV 16 + lrHPVs + other hrHPVs (OR = 0.248, 95% CI 0.157-0.391). The prevalence of CIN 3 + was associated with increased severity of cytologic abnormalities in HPV 16/18-positive women and peaked at cytology HSIL + (89.9% and 82.3%), which held a substantially greater risk than that of NILM (OR = 65.466, 95% CI 50.234-85.316). CONCLUSIONS: In this cross-sectional study of HPV 16/18-positive women, the effects of multiple infection were likely complicated and varied with specific HPV genotypes. The coinfection of HPV 16 and other genotypes of HPV except HPV 18 was associated with decreased CIN 3 + risk. Cytologic results were informative when HPV 16/18 was positive. It might be reasonable to recommend expedited treatment for patients with HPV 16/18 positive and HSIL + cytology in the Chinese population.

m6A-modified circNFIX promotes ovarian cancer progression and immune escape via activating IL-6R/JAK1/STAT3 signaling by sponging miR-647.

BACKGROUND: Ovarian cancer (OC) is one of the most common gynecological malignant cancers. Our previous work confirmed that circNFIX acted as an oncogene in OC, which could promote malignant proliferation, metastasis and angiogenesis. However, the role and mechanism of circNFIX in OC immune escape remain unclear. METHODS: The RNA and protein levels were determined by qRT-PCR and western blot assays. The malignant phenotypes were tested by cell count kit-8, EdU staining, flow cytometry and transwell assays. The immune cytokines levels were measured by ELISA analysis. Molecular interactions were verified employing RNA immunoprecipitation, meRIP and dual luciferase methods. In vivo validation was performed by xenograft tumor and lung metastasis model. Hematoxylin & eosin and immunohistochemistry staining were used to observe the pathological changes. RESULTS: The levels of circNFIX, PD-L1, and IL-6R were upregulated in OC tissues and cell lines, while miR-647 was downregulated. Functional assays showed that loss of circNFIX suppressed the growth, metastasis and immune escape of OC cells both in vitro and in vivo. On the molecular level, the m6A modification of circNFIX was elevated in OC cells, and its expression was positively correlated to m6A modification and depended on IGF2BP1 âˆ¼ 3 recognition. Moreover, circNFIX acted as a competing endogenous RNA for miR-647 to upregulate IL-6R expression, thereby activating JAK/STAT3 signaling and elevating PD-L1 expression. Rescue assays revealed that co-silencing of miR-647 reversed the antitumor effects of circNFIX knockdown on cell proliferation, metastasis and immune escape of OC cells. CONCLUSION: This study provided a comprehensive understanding of the molecular mechanism about circNFIX in OC, demonstrating m6A activated-circNFIX accelerated OC development and immune escape via regulating miR-647/IL-6R/PD-L1 pathway.

Exosomal circNFIX promotes angiogenesis in ovarian cancer via miR-518a-3p/TRIM44 axis.

Ovarian cancer (OC) is a gynecological cancer with high mortality. OC-derived exosomal circRNAs can regulate angiogenesis. This study aims to explore the role and mechanism of exosomal circRNA nuclear factor I X (CircNFIX) derived from OC cells in angiogenesis. Quantitative real-time polymerase chain reaction was employed to evaluate the levels of circNFIX, miR-518a-3p, and tripartite motif protein 44 (TRIM44) in OC and adjacent tissues. Exosomes from the ovarian surface epithelial cell (HOSEpiC) and OC cells (SKOV3 or OVCAR3) were isolated by differential centrifugation. Exosomes were cocultured with the human umbilical vein endothelial cells (HUVECs). The angiogenesis capacity was analyzed by Tube formation assay. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and Transwell assays were used to determine the cell viability and migration ability. The dual-luciferase report, RNA immunoprecipitation (RIP), and RNA pull-down assays were applied to validate the gene's interaction. CircNFIX and TRIM44 expression were higher and miR-518a-3p was lower in OC tissues than in the adjacent tissues. Upregulated circNFIX and TRIM44 were significantly correlated with the tumor size and International Federation of Gynecology and Obstetrics (FIGO) stage of OC patients. HUVECs treated OC-derived exosomes had higher proliferation, migration, and angiogenesis capacities than the control group. While OC-derived exosomal circNFIX silencing restrained HUVECs' proliferation, migration, and angiogenesis, compared with the OC-derived exosomes group. OC-derived exosomal circNFIX positively regulated TRIM44 expression by targeting miR-518a-3p in HUVECs. OC-derived exosomal circNFIX promoted angiogenesis by regulating the Janus-activated kinase/signal transducer and activator of transcription 1 (JAK/STAT1) pathway via miR-518a-3p/TRIM44 axis in HUVECs.

CircNFIX stimulates the proliferation, invasion, and stemness properties of ovarian cancer cells by enhancing SH3RF3 mRNA stability via binding LIN28B.

We aimed to study the regulatory roles and mechanism of circular nuclear factor IX (circNFIX) in cancer growth and stemness properties of ovarian cancer (OC). CircNFIX and SH3RF3 levels in OC tissues and cells were tested by quantitative real-time PCR. RNase R treatment quantified circNFIX RNA stability. Molecular interaction among circNFIX, LIN28B, and SH3RF3 was predicted by bioinformatics software and validated through RNA immunoprecipitation (RIP) assay. The gain- or loss-experiments of circNFIX on capabilities of metastasis and stemness in vitro were assessed using Cell Counting Kit-8, Transwell, western blot, and sphere-formation assays. CircNFIX and SH3RF3 were markedly elevated in OC tissues and OC cells. Knocking down circNFIX repressed the proliferation, migration, invasion, and stemness properties of A2780 and SKOV3 cells. The RIP assay verified the direct binding relationship between LIN28B, circNFIX, and SH3RF3. Additionally, overexpression of circNFIX elevated the SH3RF3 expression, while this effect was reversed by LIN28B silence. Rescue experiments demonstrated that the overexpression of SH3RF3 reversed the knockdown of circNFIX on OC cells' proliferation, metastasis, and stemness properties. CircNFIX improved the mRNA stability and translation of SH3RF3 via recruiting LIN28B, thus promoting the proliferation, invasion, and stemness properties of OC cells in vitro.

Errate: Efficacy and Toxicity of Adjuvant Therapies for High-Risk Endometrial Cancer in Stage I-III: A Systematic Review and Network Meta-Analysis.

Source of support: This study was supported by grants from the Key Research and Development projects of Sichuan Province (No.2020YFS0129) and the Natural Science Foundation of China (No.61875249). Reference: Mengyin Ao, Ting Ding, Dan Tang, Mingrong Xi: Efficacy and Toxicity of Adjuvant Therapies for High-Risk Endometrial Cancer in Stage I-III: A Systematic Review and Network Meta-Analysis. Med Sci Monit, 2020; 26: e925595. DOI: 10.12659/MSM.925595.

A retrospective study of cytology and HPV genotypes results of 3229 vaginal intraepithelial neoplasia patients.

To analyze the distribution of human papillomavirus (HPV) genotype, cytology, and the clinical characteristics of vaginal intraepithelial neoplasia (VaIN). All patients with histological-proven VaIN at West China Second University Hospital, between January 1, 2014, and October 1, 2020, were retrospectively identified. The demographics, medical history, HPV genotype, viral load, and cytology results were retrieved. Standard statistical analyses were conducted. Of 3229 patients included, 42.3% were diagnosed with VaIN 1, 30.3% with VaIN 2% and 27.4% with VaIN 3. Patients with VaIN 3 were the oldest (p < 0.001). The leading HPV genotypes were HPV 16, 52, 58, 53, 56 and 81. The positive rate of HPV 16 was positively correlated with the grade of VaIN and infected most VaIN 3 patients (76.0%). The sensitivities of cytology for VaIN only, concomitant VaIN, and VaIN after hysterectomy were 75.6%, 78.8%, and 82.9%, respectively (p = 0.013), and the sensitivities of HPV were 91.1%, 93.5%, and 91.7%, respectively (p = 0.205). Cotesting improved the sensitivities, up to 96.9%, 97.1%, and 98.1%, respectively. VaIN can occur alone or be concomitant with cervical or vulvar intraepithelial neoplasia. Most of those with VaIN 2/3 are infected with HPV 16. The sensitivity of cytology and HPV testing is non-inferior to that of cervical intraepithelial neoplasia 2+. Therefore, these testings might be helpful in the early detection of VaIN.

Risk factors analysis of persistence, progression and recurrence in vaginal intraepithelial neoplasia.

OBJECTIVE: to profile patients with vaginal intraepithelial neoplasia (VAIN), to evaluate natural history and to identify risk factors for persistence, progression and recurrence. METHODS: At West China Second University Hospital, all patients with histologically confirmed VAIN over a five-year period with minimum follow-up of 6 months were retrospectively identified. Demographics, medical history and clinical information related to the diagnosis and treatment were extracted. Clinical outcomes included normalization, persistence, progression and recurrence. We evaluated risk factors by univariate and multivariate analyses. RESULTS: A total of 1478 patients fulfilled the inclusion criteria with a median follow-up of 14 months (range, 6-60 months). In 86.6% of patients, VAIN went into normalization, 6.4% persisted, 3.5% progressed and 3.5% recurred. Besides, 24 (7.1%) VAIN 3 patients and 4 (0.8%) progressed to cancer, accounting for 85.7% and 14.3% of cancer cases, respectively. VAIN 3 patients treated with excision yielded superior outcomes. Risk factors for persistence were HPV 16, 56, 59 and 43 infections, for progression were prior hysterectomy for cervical lesions and HPV 56 infection, for recurrence were HPV 61 infection. CONCLUSION: Although VAIN will regress in most patients, there are still risks of persistence, recurrence and progression, even malignancy. Therefore, a long-term follow-up is recommended. Patients with VAIN 3 are at higher risk of progressing to cancer and excision is preferred. HPV 16, 56, 59 and 43 infections might associate with an increased risk of persistence and patients with prior hysterectomy for cervical lesions tend to progress.

Efficacy and Toxicity of Adjuvant Therapies for High-Risk Endometrial Cancer in Stage I-III: A Systematic Review and Network Meta-Analysis.

BACKGROUND The use of adjuvant therapy for high-risk endometrial cancer patients (HREC) in International Federation of Gynecology and Obstetrics (FIGO) stage I-III remains debatable. This network meta-analysis was conducted to compare and rank adjuvant therapies based on efficacies and toxicities to facilitate clinical decision-making and further research. MATERIAL AND METHODS We searched 3 databases - PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials - from inception to December 9, 2019. Only randomized controlled trials that compared any of these adjuvant therapies (pelvic radiotherapy, vaginal brachytherapy, chemotherapy, and chemoradiotherapy) with each other or surgery alone were included. The network meta-analysis was performed in a frequentist framework using Stata software 15.0. RESULTS Fourteen RCTs with 5872 participants were eligible. No significant difference between treatments was observed in 5-year overall survival (OS) or distant metastasis. Compared with surgery alone, adjuvant pelvic radiotherapy plus chemotherapy (pelvic RT-CT) prolonged 5-year progression-free survival (PFS) and pelvic radiotherapy (pelvic RT) (RR=0.61, 95% CI 0.39-0.96; RR=0.779, 95% CI 0.63-0.95). Compared with surgery alone, pelvic RT, the combination of pelvic RT and vaginal brachytherapy (pelvic RT-VBT), chemotherapy (CT), and pelvic RT-CT led to fewer local recurrences (RR=0.33, 95% CI 0.21-0.50; RR=0.15, 95% CI 0.03-0.74; RR=0.39, 95% CI 0.21-0.73; RR=0.17, 95% CI 0.06-0.46). Adjuvant CT was found to result in more grade III/IV late toxicities than surgery alone (RR=11.8, 95% CI 1.02-137.14). Pelvic RT-CT ranked first for OS, PFS, distant metastasis, and local recurrence. CONCLUSIONS Pelvic RT-CT is superior to other treatments for PFS and local recurrence rate, and associated related toxicities are tolerable, suggesting it may be an ideal adjuvant therapy for HREC patients.