Circ_0007445 inhibits trophoblast cell proliferation, migration and invasion by mediating the miR-4432/HTRA1 axis in preeclampsia.

BACKGROUND: : Circular RNAs (circRNAs) have been shown to be extensively involved in preeclampsia progression. At present, the role of circ_0007445 in preeclampsia progression is not clear. METHODS: A total of 30 preeclampsia patients and 30 normal pregnant women were recruited in our study. The function of trophoblast cells was explored to clarify the role and mechanism of circ_0007445 on the preeclampsia progression. The expression of circ_0007445, microRNA (miR)-4432 and high temperature requirement A1 (HTRA1) was analyzed by quantitative real-time PCR. The proliferation, migration and invasion of trophoblast cells were determined by cell counting kit 8 assay, EdU assay, colony formation assay, flow cytometry, and transwell assay. Protein expression was examined by western blot analysis. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pull-down assay were used to assess RNA interaction relationships. RESULTS: Our data suggested that circ_0007445 had increased expression in preeclampsia patients. Knockdown of circ_0007445 enhanced trophoblast cell proliferation, migration and invasion. MiR-4432 was lowly expressed in preeclampsia patients, and it could be sponged by circ_0007445. MiR-4432 inhibitor overturned the promotion effects of circ_0007445 knockdown on trophoblast cell functions. HTRA1 was highly expressed in preeclampsia patients, and it could be targeted by miR-4432. HTRA1 overexpression could also reverse the proliferation, migration and invasion of trophoblast cells promoted by miR-4432 mimic. In addition, circ_0007445 positively regulated HTRA1 through targeting miR-4432. CONCLUSION: :Our results suggested that circ_0007445 facilitated the development of preeclampsia by suppressing trophoblast cell function through miR-4432/HTRA1 axis.

The efficacy and safety of 5-fluorouracil/cisplatin/vincristine as a multi-agent chemotherapy regimen in gestational trophoblastic neoplasia.

Objective: To determine the efficacy and safety of the 5-fluorouracil (5-FU), cisplatin, and vincristine (FPV) chemotherapy regimen in patients with gestational trophoblastic neoplasia (GTN). Methods: We performed a retrospective study of 96 GTN patients with International Federation of Gynecology and Obstetrics (FIGO) scores of 5 or greater in the Second Affiliated Hospital of Zhengzhou University from October 2013 to October 2019, including 54 patients who received FPV chemotherapy and 42 who received 5-FU/actinomycin D/vincristine (FAV) chemotherapy. A pulsed intravenous device was used to administer 5-FU. The clinical characteristics, adverse events, and response rates were compared between the groups. Results: The patients in the FPV and FAV groups received a total of 228 and 190 courses of chemotherapy, respectively. Complete response (CR) was found in 88.89% (48/54) and 90.48% (38/42) of patients in the FPV group and FAV group, respectively (p = 0.801). Both chemotherapy regimens yielded CR in all low-risk patients (100% vs. 100%), whereas 86.67% and 88.24% of high-risk patients achieved CR (FPV vs. FAV, p = 0.836), respectively. The most common adverse events (AEs) were myelosuppression and gastrointestinal reactions including neutropenia (83.97%), anemia (60.05%), and nausea (46.41%). In comparison to those in the FAV group, patients in the FPV group reported higher rates of grade 1/2 nausea (53.51% vs. 37.89%, p = 0.001), hepatotoxicity (28.95% vs. 17.89%, p = 0.008), oral mucositis (23.25% vs. 10.53%, p = 0.001), and grade 3/4 neutropenia (47.37% vs. 27.37%, p < 0.001), while grade 1/2 diarrhea (7.46% vs. 13.68%, p = 0.037) and grade 3/4 oral mucositis (0 vs. 6.32%, p < 0.001) were much more common in the FAV group. The rate of overall survival at 5 years was 96.8% in the FPV group and 97.3% in the FAV group (p = 0.760), whereas the 5-year disease-free survival rates were 95.9% and 93.9% (p = 0.754), respectively. Conclusion: The FPV and FAV regimens with pulsed intravenous 5-FU yielded comparable CR rates and tolerability in patients with GTN with FIGO scores of >5. Further randomized controlled trials are warranted to validate their efficacy.

Exosome-delivered circRNA circSYT15 contributes to cisplatin resistance in cervical cancer cells through the miR-503-5p/RSF1 axis.

The development of chemotherapy resistance is a major obstacle for cervical cancer (CC) patients. Exosome-mediated transfer of circular RNAs (circRNAs) was found to have relevance to the CC. This study is designed to explore the role and mechanism of exosomal circRNA synaptotagmin 15 (circSYT15) on cisplatin (DDP) resistance in CC. Cell proliferation ability and apoptosis rate were detected by Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), colony formation, and flow cytometry assays. CircSYT15, microRNA-503-5p (miR-503-5p), Remodeling spacing factor 1 (RSF1) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Exosomes were analyzed by a transmission electron microscope and nanoparticle tracking analysis. CD63, CD81, TSC101, Bcl-2, Bax, C-caspase 3, and RSF1 protein levels were examined by western blot assay. The binding between miR-503-5p and circSYT15 or RSF1 was predicted by circBank or Starbase and then verified by a dual-luciferase reporter and RNA Immunoprecipitation (RIP). The biological role of exosomal circSYT15 in DDP resistance of CC in vivo. CircSYT15 was upregulated in the DDP-resistant CC cells and exosomes isolated from DDP-resistant CC cells. CircSYT15 knockdown repressed the proliferation and drug resistance of CC and induced apoptosis in CC cells. Exosomes shuttled circSYT15 act as a sponge to affect RSF1 expression, thereby promoting proliferation and drug resistance and repressing apoptosis of sensitive CC cells. Exosomal circSYT15 boost DDP resistance of cervical cancer in vivo. Exosome-mediated transfer of circSYT15 enhanced DDP resistance in CC partly by targeting the miR-503-5p/RSF1 axis, providing a foundation for future clinical applications of CC drug resistance.

[In vitro study on cytotoxicity, osteogenic potential and antibacterial activity of silicate root canal sealers].

PURPOSE: To evaluate the in vitro biocompatibility and antibacterial activity of a new type of strontium silicate-based C-Root SP root canal sealer, and to provide a reference for clinical selection of sealers. METHODS: C-Root SP, iRoot SP and AH Plus extracts were prepared, L929 cells and MC3T3-E1 cells were cultured in vitro, and the cytotoxicity and osteogenic potential of the three sealers were compared. Fresh sealers were mixed with Enterococcus faecalis solution and the antibacterial activity of the sealer was determined by direct contact text (DCT). SPSS 25.0 software package was used for statistical analysis. RESULTS: At 24, 48, and 72 h, the cytotoxicity of the sealers in each group were significantly different (P＜0.01). Compared with AH Plus, the cytotoxicity of C-Root SP was lower (P＜0.01). C-Root SP was superior to AH Plus in promoting the activity of alkaline phosphatase(ALP) (P＜0.01). iRoot SP was the strongest in promoting the formation of mineralized nodules, followed by C-Root SP, and the weakest was AH Plus(P＜0.01). C-Root SP inhibited the growth of Enterococcus faecalis, and its antibacterial rate was significantly higher than AH Plus(P＜0.01). CONCLUSIONS: The strontium silicate root canal sealer C-Root SP has low cytotoxicity, certain osteogenic potential and antibacterial activity against Enterococcus faecalis, so it can be used for root canal filling.

Impact of HR-HPV infection on oncological outcomes in early cervical cancer.

Background: This study aimed to investigate the differences in long-term oncological outcomes between high-risk human papillomavirus (HR-HPV) negative and HR-HPV positive early-stage cervical cancers. Methods: We retrospectively analysed 2061 cases of early-stage cervical cancer from the Chinese cervical cancer clinical diagnosis and treatment database. Kaplan-Meier curves were used to describe the survival outcomes of different HR-HPV infections. Cox proportional hazard regression model was used to analyze and determine independent risk factors. Results: K-M analysis revealed no significant difference in 5-year OS between HR-HPV negative and HR-HPV positive groups (OS: 95.0% vs.95.6%, P=0.900). A significant difference was observed in 5-year DFS between the HR-HPV negative and HR-HPV positive groups (DFS: 87.2% vs.91.9%, P=0.025). Cox proportional hazard regression model indicated that HR-HPV infection (negative vs. positive) was an independent factor influencing 5-year DFS after early cervical cancer surgery (DFS: hazard ratio [HR]=1.862, P=0.022). HR-HPV infection (negative vs positive) was not an independent factor influencing 5-year OS after early cervical cancer surgery (OS: P=0.813). After 1:1 PSM pairing, there was no significant difference in 5-year OS and DFS between HR-HPV negative group and HR-HPV positive group (OS: 91.6% vs.95.0%, P=0.297; DFS: 87.2% vs.85.1%, P=0.758). Cox multivariate analysis indicated that HR-HPV infection was not an independent factor influencing 5-year OS and DFS after early cervical cancer surgery (OS: P=0.806, DFS: P=0.251). Conclusions: The tumour results of HR-HPV negative group and HR-HPV positive group were similar, after eliminating the differences in known variables that affect the oncological outcomes of cervical cancer. The treatment plan of HR-HPV positive cervical cancer is suitable for HR-HPV negative cervical cancer.

Lymph node metastasis-related gene signature shows good performance in predicting prognosis and immune infiltration in cervical cancer.

Aims: This study aimed to construct a lymph node metastasis-related gene signature to predict prognosis and immune infiltration in patients with cervical cancer. Methods: Clinical and RNA sequencing data of 193 patients with cervical cancer, which were divided into lymph node metastasis (N1) and non-lymph node metastasis (N0) groups, were acquired from TCGA. Differentially expressed genes (DEGs) between the N1 and N0 groups were detected, and protein-protein interaction combined with LASSO analysis was conducted to further screen lymph node metastasis-related genes. Univariate and multivariate Cox regression analyses were performed to establish a predictive signature. The genetic features, potential biological behavior, and immune infiltration characteristics of the predictive signature were explored. Furthermore, the sensitivity of patients to chemotherapy drugs was estimated based on the predictive signature and the expression of TEKT2 and RPGR was investigated in the cervical cancer tissue samples. Results: A total of 271 lymph node metastasis-related DEGs, including 100 upregulated and 171 downregulated genes, were identified. Two genes, TEKT2 and RPGR, were associated with lymph node metastasis and prognosis in cervical cancer, and were used to construct a lymph node metastasis-related predictive signature. Based on the predictive signature, patients with cervical cancer were divided into high- and low-risk groups. The high-risk group, characterized by a higher tumor mutation burden and somatic mutation rate, indicated a poor overall survival. The activation of immune infiltration and increased expression of checkpoint genes were observed in the high-risk group, indicating that they might benefit from immunotherapy. Cytarabine, FH535, and procaspase-activating compound-1 were estimated as reasonable chemotherapy options for patients in the high-risk group, whereas two taxanes and five tyrosine kinase inhibitors, including etoposide and vinorelbine, had therapeutic significance for patients in the low-risk group. The expression of TEKT2 and RPGR was significantly downregulated in cervical cancer tissues, especially in metastatic lymph node tissues. Discussion: The lymph node metastasis-related predictive signature based on TEKT2 and RPGR showed good performance in predicting the survival outcomes of patients with cervical cancer. The risk score of the predictive signature was related to genetic variation and immune infiltration, which could guide immunotherapy and chemotherapy strategies.

Identification of stemness subtypes and features to improve endometrial cancer treatment using machine learning.

Endometrial cancer is one of the most common malignant tumours in women, and cancer stem cells are known to play an important role in its growth, invasion, metastasis, and drug resistance. Immunotherapy for endometrial cancer is still under research. In this study, a total of 547 endometrial cancer cases were randomly divided into training set (351 cases) set and test set (196 cases). The stemness index of patients was calculated using the One-Class Logistic Regression (OCLR) machine learning algorithm to explore the clinicopathological differences between index levels. Stemness subtypes were determined according to the characteristics of cancer stemness and their clinicopathological characteristics, immune features, and therapeutic effects were described. Our study suggests that endometrial cancer is classified into two stemness subtypes. Stemness subtypes, which are associated with its clinical features, may be independent prognostic factors for endometrial cancer. The stemness subtypes differed significantly in immune activity, immune cell infiltration, and the immune microenvironment, including sensitivity to chemotherapeutic drugs and potential therapeutic compounds. Algorithms were utilised to construct a stemness subtype prediction model and predictor. These findings will provide guidance for the clinical diagnosis, treatment, and prognosis of endometrial cancer.

Prognosis, immune microenvironment, and personalized treatment prediction in Rho GTPase-activating protein 4-mutant cervical cancer: Computer strategies for precision oncology.

AIMS: Cervical cancer with different mutations is associated with specific genomic differences. We developed a new mutation prediction model of the ARHGAP4 gene for cervical cancer. MAIN METHODS: We conducted a panoramic analysis of CESC mutations based on The Cancer Genome Atlas-Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA-CESC) database. We made copy number variation analysis and correlation analysis of somatic mutations and tumor mutation load fraction. Then we established a prediction model of ARHGAP4 mutation, screened related genes based on the risk scores, calculated the correlation between the risk score and immune microenvironment, and analyzed drug sensitivity. KEY FINDINGS: The prediction model of ARHGAP4 mutation based on mRNA expression is closely related to the survival rate of cervical cancer patients and to the effect of immunotherapy. The prediction model is also related to the infiltration of immune cells and human leukocyte antigen family expression in the immune microenvironment. After computational analysis, three drugs (cytarabine, docetaxel, imatinib) were identified as potential agents for the ARHGAP4 mutation high-risk group, and two drugs (erlotinib, methotrexate) were shown to have therapeutic significance for patients in the low-risk group. The expression of ARHGAP4 was higher in cervical cancer tissues. The proliferation ability of HeLa and SiHa cells decreased after ARHGAP4 knockdown. SIGNIFICANCE: This study provides not only a new approach for the prediction of the response of the cervical cancer patients to targeted drug therapy but also a new strategy for combining risk stratification with precision treatment.

LncRNA CARMN inhibits cervical cancer cell growth via the miR-92a-3p/BTG2/Wnt/ß-catenin axis.

Long noncoding RNA (lncRNA) cardiac mesoderm enhancer-associated noncoding RNA (CARMN) is a newly discovered tumor-suppressor lncRNA in cancers. However, its role in cervical cancer (CC) remains elusive. This study was conducted to analyze the molecular mechanism of CARMN in CC cell growth and provide a novel theoretical basis for CC treatment. RT-qPCR and clinical analysis revealed that CARMN and B-cell translocation gene 2 (BTG2) were downregulated, whereas miR-92a-3p was upregulated in CC tissues and cells and their expressions were correlated with clinicopathological characteristics and prognosis. MTT assay, flow cytometry, and Transwell assays revealed that CARMN overexpression reduced proliferation, migration, and invasion and increased apoptosis rate in CC cells. Mechanically, CARMN repressed miR-92a-3p to promote BTG2 transcription. Functional rescue assays revealed that miR-92a-3p overexpression or BTG2 downregulation reversed the inhibitory role of CARMN overexpression in CC cell growth. Western blot analysis elicited that Wnt3a and ß-catenin were elevated in CC cells and CARMN blocked the Wnt/ß-catenin signaling pathway via the miR-92a-3p/BTG2 axis. Overall, our findings demonstrated that CARMN repressed miR-92a-3p to upregulate BTG2 transcription and then blocked the Wnt/ß-catenin signaling pathway, thereby suppressing CC cell growth.

A Review of the research methods and progress of biocompatibility evaluation of root canal sealers.

The function of root canal sealer was to achieve an appropriate three-dimensional filling effect by filling the root canal and some irregular lumen, thereby inhibiting the residual bacteria. There were many types of sealers, but research to find the most suitable ones was still ongoing. In recent years, researchers had continuously improved the performance of sealers by developing new sealers or adding active ingredients to the sealers. However, most sealers exhibit varying degrees of cytotoxicity and tissue responses, which affect clinical therapy efficacy. This review describes different technical approaches, and recent research progress in the biocompatibility evaluation of root canal sealers and provides brief insights into this field by summarising the performance studies of different root canal sealers.

The pathological risk score: A new deep learning-based signature for predicting survival in cervical cancer.

PURPOSE: To develop and validate a deep learning-based pathological risk score (RS) with an aim of predicting patients' prognosis to investigate the potential association between the information within the whole slide image (WSI) and cervical cancer prognosis. METHODS: A total of 251 patients with the International Federation of Gynecology and Obstetrics (FIGO) Stage IA1-IIA2 cervical cancer who underwent surgery without any preoperative treatment were enrolled in this study. Both the clinical characteristics and WSI of each patient were collected. To construct a prognosis-associate RS, high-dimensional pathological features were extracted using a convolutional neural network with an autoencoder. With the score threshold selected by X-tile, Kaplan-Meier survival analysis was applied to verify the prediction performance of RS in overall survival (OS) and disease-free survival (DFS) in both the training and testing datasets, as well as different clinical subgroups. RESULTS: For the OS and DFS prediction in the testing cohort, RS showed a Harrell's concordance index of higher than 0.700, while the areas under the curve (AUC) achieved up to 0.800 in the same cohort. Furthermore, Kaplan-Meier survival analysis demonstrated that RS was a potential prognostic factor, even in different datasets or subgroups. It could further distinguish the survival differences after clinicopathological risk stratification. CONCLUSION: In the present study, we developed an effective signature in cervical cancer for prognosis prediction and patients' stratification in OS and DFS.

Gene signatures, immune infiltration, and drug sensitivity based on a comprehensive analysis of m6a RNA methylation regulators in cervical cancer.

BACKGROUND: Cervical cancer is the fourth most common cancer in women. N6-dimethyladenosine (m6A) mRNA methylation is closely associated with cervical cancer. METHODS: Using TCGA database, we studied the expression and mutation of m6A-related genes in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and obtained genetic characteristics based on an m6A risk model and prognostic value of m6A. We studied the effects of the m6A risk score on immune features and genomic changes of patients with CESC, evaluated the sensitivity of patients with CESC to different small-molecule drugs based on the m6A risk score, and established a clinical prediction model. RESULTS: Ten m6A-related genes were differentially expressed between CESC and normal tissues. High-risk patients had a low overall survival (OS) and significantly low immune scores but showed no significantly altered stromal scores. The tumor mutation burden (TMB) and tumor neoantigen levels significantly differed between the high- and low-risk groups. In the high-risk group, copy number variation (CNV) changes mainly led to gene amplification, while in the low-risk group, CNV changes primarily manifested as gene copy number deletions. ZC3H13 expression was low in CESC tissues. ZC3H13 knockdown promoted CESC cell proliferation, migration, and invasion, reducing the RNA methylation levels. Rapamycin suppressed the CESC cell proliferation, migration, and invasion abilities, increasing the m6A levels. CONCLUSION: m6A mRNA methylation is closely related to the occurrence, development, immune invasion, drug sensitivity, and prognosis of cervical cancer. The prognostic m6A feature model of m6A signature genes can accurately predict the OS of patients with CESC. Drugs targeting factors regulating m6A mRNA methylation might offer a good prospect for treating cervical cancer.

Comparison of the Oncological Outcomes Between Robot-Assisted and Abdominal Radical Hysterectomy for Cervical Cancer Based on the New FIGO 2018 Staging System: A Multicentre Retrospective Study.

Objective: To compare the 3-year oncological outcomes of robot-assisted radical hysterectomy (RRH) and abdominal radical hysterectomy (ARH) for cervical cancer. Methods: Based on the clinical diagnosis and treatment for cervical cancer in the China database, patients with FIGO 2018 stage IA with lymphovascular space invasion (LVSI)-IB2 cervical cancer disease who underwent RRH and ARH from 2004 to 2018 were included. Kaplan-Meier survival analysis was used to compare the 3-year overall survival (OS) and disease-free survival (DFS) rate between patients receiving RRH and those receiving ARH. The Cox proportional hazards model and propensity score matching were used to estimate the surgical approach-specific survival. Results: A total of 1,137 patients with cervical cancer were enrolled in this study, including the RRH group (n = 468) and the ARH group (n = 669). The median follow-up time was 45 months (RRH group vs. ARH group: 24 vs. 60 months). Among the overall study population, there was no significant difference in 3-year OS and DFS between the RRH group and the ARH group (OS: 95.8% vs. 97.6% p = 0.244). The Cox proportional hazards analysis showed that RRH was not an independent risk factor for 3-year OS (HR: 1.394, 95% CI: 0.552-3.523, p = 0.482). However, RRH was an independent risk factor for 3-year DFS (HR: 1.985, 95% CI: 1.078-3.655 p = 0.028). After 1:1 propensity score matching, there was no significant difference in 3-year OS between the RRH group and the ARH group (96.6% vs. 98.0%, p = 0.470); however, the 3-year DFS of the RRH group was lower than that of the ARH group (91.0% vs. 96.1%, p = 0.025). The Cox proportional hazards analysis revealed that RRH was not an independent risk factor for 3-year OS (HR: 1.622, 95% CI: 0.449-5.860 p = 0.461), but RRH was an independent risk factor for 3-year DFS (HR: 2.498, 95% CI: 1.123-5.557 p = 0.025). Conclusion: Among patients with stage I A1 (LVSI +)-I B2 cervical cancer based on the FIGO 2018 staging system, RRH has a lower 3-year DFS than ARH, suggesting that RRH may not be suitable for early cervical cancer patients.

The significance of m6A RNA methylation modification in prognosis and tumor microenvironment immune infiltration of cervical cancer.

Recent studies have highlighted that N6-methyladenosine (m6A) plays a significant role in tumorigenicity and progression. However, the mechanism of m6A modifications in the tumor microenvironment (TME) immune cell infiltration in cervical cancer (CC) remains unclear. Clinical and RNA sequencing data of 25 m6A RNA methylation regulators were acquired from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. LASSO Cox regression analysis was used to generate a prognostic risk signature. m6A modification patterns were identified based on the expression of 25 m6A regulators, and their correlation with TME immune cell-infiltrating characterization was analyzed. Principal component analysis was used to construct an m6A-scoring signature (m6A score) to evaluate the m6A modification patterns of individual CC samples and guide the selection of more effective immunotherapeutic strategies. Genetic and expression alterations of 25 m6A regulators were highly heterogeneous between CC and normal tissues. METTL14 and IGF2BP1 were selected to conduct the prognostic risk signature. Three m6A modification patterns were identified in 659 CC samples, which were associated with distinct clinical outcomes and biological pathways. The TME immune cell-infiltrating characterization of the three m6A modification patterns was highly consistent with 3 tumor immune phenotypes, including immune-excluded, immune-inflamed, and immune-desert phenotypes. Due to the heterogeneity of m6A modification patterns, an m6A scoring signature was established to evaluate the m6A modification patterns of individual CC samples. Univariate and multivariate Cox regression analyses revealed that the m6A score is a robust and independent prognostic biomarker for assessing the prognosis of CC patients. A low m6A score, characterized by higher somatic mutation and higher expression of proliferation-related and DNA repair-related genes, indicated poor overall survival. Activation of immune infiltration was exhibited by the high m6A score, which was likely to have a good response and clinical benefits to antiPD-1/L1 immunotherapy. This study highlights the prognostic value of 25 m6A regulators in CC. The m6A modification is related to immune regulation and the formation of TME heterogeneity and complexity. An m6A scoring signature to clarify the individual m6A modification pattern could enhance our understanding of TME immune cell-infiltrating characterization and guide immunotherapy strategies.

[Analysis of phenotype and FH gene variation in a pedigree affected with hereditary leiomyomatosis and renal cell carcinoma syndrome].

OBJECTIVE: To analyze clinical phenotype and genetic variants in a Chinese pedigree of hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. METHODS: Whole exome sequencing was carried out for the proband from the pedigree. Suspected FH gene variants were validated by Sanger sequencing. Clinical manifestation and histopathological examination were used to analyze the pedigree comprehensively. RESULTS: The pedigree met the clinical diagnostic criteria for HLRCC syndrome. The whole exome sequencing showed that the FH gene of the proband had a heterozygous missense variant of c.1490T>C (p.F497S), which was consistent with the Sanger sequencing. The mother, daughter and son of the proband all had the heterozygous missense variant of c.1490T>C (p.F497S). According to the American Society of Medical Genetics and Genomics Classification Standards and Guidelines for Genetic Variations, c.1490T>C (p.F497S) (PM2+PP1-M+PP3+PP4) was a possible pathogenic variant. Based on our literature search, this variant was a new variant that had not been reported. CONCLUSION: The FH gene missense variant of c.1490T>C (p.F497S) may be the cause of the HLRCC syndrome pedigree, which provides a basis for the genetic diagnosis and genetic counseling of the HLRCC syndrome.

Discussion on the rationality of FIGO 2018 stage IIIC for cervical cancer with oncological outcomes: a cohort study.

Background: This study explored the rationality of the 2018 International Federation of Gynecology and Obstetrics (FIGO) stage IIIC for cervical cancer to determine outcomes. Methods: We conducted a retrospective study of cervical cancer patients who had received radical surgery or Radiotherapy. Multivariate analysis was used to compare 5-year overall survival (OS) and disease-free survival (DFS) for FIGO 2018 stages IIIA, IIIB, and IIIC cervical cancer patients. Based on tumor-node-metastasis (TNM) staging, IIIC cases were divided into 5 subgroups: T1a, T1b, T2a, T2b, and T3. The 5-year OS and DFS of the different IIIC subgroups were further compared using multivariate analysis. Results: (I) The 5-year OS for FIGO 2018 IIIA (n=251), IIIB (n=1,824), and IIIC (n=3,137) were 73.7%, 69.0%, and 74.3%, respectively (P<0.001), and DFS rates were 64.3%, 60.6%, and 68.0%, respectively (P<0.001). Multivariate analysis indicated that IIIA was associated with 5-year OS [hazard ratio (HR) =0.998, 95% confidence interval (CI): 0.739-1.349, P=0.990], but there was no significant correlation with DFS (HR =1.081, 95% CI: 0.843-1.387, P=0.539). Compared with IIIC, IIIB had a lower 5-year OS (HR =1.291, 95% CI: 1.135-1.468, P<0.001) and DFS (HR =1.354, 95% CI: 1.215-1.508, P<0.001). (II) The 5-year OS of the T1a group (n=4), T1b group (n=861), T2a group (n=587), T2b (n=641) group, and T3 group (n=1,044) were 100.0%, 81.9%, 76.1%, 74.0%, and 65.0%, respectively (P<0.001), and the 5-year DFS were 100.0%, 74.5%, 65.9%, 72.6%, and 61.3%, respectively (P<0.001). Multivariate analysis indicated that compared with the T1b group, T2a (HR =1.405, 95% CI: 1.076-1.834, P=0.012), T2b (HR =1.592, 95% CI: 1.203-2.108, P=0.001), and T3 (HR =2.495, 95% CI: 1.971-3.157, P<0.001) were associated with a lower 5-year OS. T2a (HR =1.372, 95% CI: 1.108-1.699, P=0.004), T2b (HR =1.337, 95% CI: 1.061-1.684, P=0.014), and T3 (HR =2.015, 95% CI: 1.659-2.446, P<0.001) were associated with lower 5-year DFS. Conclusions: The outcome for FIGO 2018 stage IIIC cervical cancer is not worse than that for stage IIIB or IIIA. The outcome for stage IIIC is related to local tumor factors. As the local tumor progresses, the oncological outcome worsens.

Role of lncRNA TUG1 in Adenomyosis and its Regulatory Mechanism in Endometrial Epithelial Cell Functions.

OBJECTIVE: Adenomyosis (AM) is a common gynecological disorder that can cause pelvic pain. The regulatory role of long noncoding RNAs (lncRNAs) in AM progression has been widely reported. This study investigated the effect and mechanism of lncRNA taurine-upregulated gene 1 (TUG1) on endometrial epithelial cells (EECs) in AM. METHODS: Endometrial tissues of AM patients and controls were collected. A murine model of AM was established by tamoxifen induction. TUG1 expression in endometrial tissues of AM patients and mice was determined. In vivo, the effect of TUG1 on AM mice was measured through H&E staining, Masson's staining, uterine weight, and estradiol concentration. EECs isolated from AM patients were transfected with sh-TUG1. In vitro, the effect of TUG1 on the proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and angiogenesis of EECs was evaluated by CCK8, colony formation, immunofluorescence, wound healing, and Transwell assays. The binding relationship among TUG1, E2F4, and KLF5 was confirmed using RNA immunoprecipitation and RNA pull-down assays. A function rescue experiment was designed to verify the effect of KLF5 on EECs. RESULTS: TUG1 expression was elevated in AM mice and patients. Downregulation of TUG1 promoted the recovery of AM mice. Downregulation of TUG1 suppressed proliferation, migration, invasion, EMT, and angiogenesis of EECs. Mechanically, TUG1 suppressed KLF5 transcription by binding to E2F4. Downregulation of KLF5 reversed the inhibitory effect of TUG1 silencing on the functions of EECs. CONCLUSION: TUG1 expression was elevated in AM, and TUG1 facilitated proliferation, migration, invasion, EMT, and angiogenesis of EECs via E2F4/KLF5, thereby aggravating AM.

Gonadotropin-releasing hormone agonist versus expectant management for treating multiple leiomyomas after myomectomy: the study protocol for a multicentre, prospective, randomised controlled clinical trial.

INTRODUCTION: Leiomyoma recurrence is a major concern for long-term myomectomy management, especially for multiple leiomyomas. Gonadotropin-releasing hormone agonist (GnRHa) is one of the most effective medications to reduce the volume of fibroids and the uterus. However, its role in preventing recurrence after conservative surgery remains unclear. At present, there is no randomised clinical trial determining the efficacy of GnRHa treatment for preventing multiple leiomyomas recurrence after myomectomy. METHODS AND ANALYSIS: We are conducting a phase IV randomised controlled trial in women aged 18-45 undergoing myomectomy for multiple leiomyomas. After surgery, women whose pathological result confirms multiple leiomyomas are randomised in a 1:1 ratio into an observation or GnRHa group. The primary outcome is the recurrence of either clinical symptoms or fibroids on imaging. Patients will be assessed for adverse events during the follow-up. ETHICS AND DISSEMINATION: The study was approved by the Medical Ethics Committee of the Tongji Hospital Affiliated with the Tongji Medical College of Huazhong University of Science and Technology (TJ-IRB20180311) according to the submitted study protocol (V.1.0, 10 November 2017) and informed consent (V.1.0, 10 November 2017). The results will be presented at domestic and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR-IPR-17012992.

Neoadjuvant Chemotherapy Followed by Surgery Versus Abdominal Radical Hysterectomy Alone for Oncological Outcomes of Stage IB3 Cervical Cancer-A Propensity Score Matching Analysis.

OBJECTIVE: To compare the 5-year overall survival (OS) and disease-free survival (DFS) of patients with cervical cancer who received neoadjuvant chemotherapy followed by surgery (NACT) with those who received abdominal radical hysterectomy alone (ARH). METHODS: We retrospectively compared the oncological outcomes of 1410 patients with stage IB3 cervical cancer who received NACT (n=583) or ARH (n=827). The patients in the NACT group were divided into an NACT-sensitive group and an NACT-insensitive group according to their response to chemotherapy. RESULTS: The 5-year oncological outcomes were significantly better in the NACT group than in the ARH group (OS: 96.2% vs. 91.2%, respectively, p=0.002; DFS: 92.2% vs. 87.5%, respectively, p=0.016). Cox multivariate analysis suggested that NACT was independently associated with a better 5-year OS (HR=0.496; 95% CI, 0.281-0.875; p=0.015), but it was not an independent factor for 5-year DFS (HR=0.760; 95% CI, 0.505-1.145; p=0.189). After matching, the 5-year oncological outcomes of the NACT group were better than those of the ARH group. Cox multivariate analysis suggested that NACT was still an independent protective factor for 5-year OS (HR=0.503; 95% CI, 0.275-0.918; p=0.025). The proportion of patients in the NACT group who received postoperative radiotherapy was significantly lower than that in the ARH group (p<0.001). Compared to the ARH group, the NACT-sensitive group had similar results as the NACT group. The NACT-insensitive group and the ARH group had similar 5-year oncological outcomes and proportions of patients receiving postoperative radiotherapy. CONCLUSION: Among patients with stage IB3 cervical cancer, NACT improved 5-year OS and was associated with a reduction in the proportion of patients receiving postoperative radiotherapy. These findings suggest that patients with stage IB3 cervical cancer, especially those who are sensitive to chemotherapy, might consider NACT followed by surgery.