Ubiquitin-specific peptidase 14 maintains estrogen receptor α stability via its deubiquitination activity in endometrial cancer.

USP14 deubiquitinates ERα to maintain its stability in ECEndometrial cancer (EC) is one of the common gynecological malignancies of which the incidence has been rising for decades. It is considered that continuously unopposed estrogen exposure is the main risk factor for EC initiation. Thus, exploring the modulation of estrogen/estrogen receptor α (ERα) signaling pathway in EC would be helpful to well understand the mechanism of EC development and find the potential target for EC therapy. Ubiquitin-specific peptidase 14 (USP14), a member of the proteasome-associated deubiquitinating enzyme family, plays a crucial role in a series of tumors. However, the function of USP14 in EC is still elusive. Here, our results have demonstrated that USP14 is highly expressed in EC tissues compared with that in normal endometrial tissues, and higher expression of USP14 is positively correlated with poor prognosis. Moreover, USP14 maintains ERα stability through its deubiquitination activity. Our results further demonstrate that USP14 depletion decreases the expression of ERα-regulated genes in EC-derived cell lines. Moreover, knockdown of USP14 or USP14-specific inhibitor treatment significantly suppresses cell growth and migration in EC cell lines or in mice. We further provide the evidence to show that the effect of USP14 on EC cell growth, if not all, at least is partially related to ERα pathway. Our study provides new sights for USP14 to be a potential therapeutic target for the treatment of EC, especially for EC patients with fertility preservation needs.

In-bag extraction of tissue through an incision in the posterior vaginal wall in laparoscopic myomectomy: a large retrospective study.

BACKGROUND: Our purpose was to describe the outcomes of transvaginal in-bag tissue extraction tissue through an incision in the posterior vaginal wall the middle part incision of posterior vagina in laparoscopic myomectomy. METHODS: This was a retrospective study of patients who received laparoscopic myomectomy and in-bag tissue extraction through an incision in the posterior vaginal wall between January 2016 and December 2022. Patient characteristics, intra- and post-operative complications, and outcomes were collected and analyzed. RESULTS: A total of 511women were included in the analysis. The mean largest myoma diameter was 8.44 ± 3.56 cm; mean specimen weight was 789.23 ± 276.97 g; mean operative time was 129.01 ± 53.13minutes; and mean blood loss was 175.99 ± 210.96 mL. Within 30-days of surgery, no fever, infection, or vaginal bleeding was noted in any patient, and the vaginal incisions of all patients had healed well. There were no incisional hernias, pelvic infections, and vaginal adhesions noted at follow-up 3 months after the operation. There were 37 cases of vaginal delivery of the patients after surgery, and there were no lacerations of the posterior wall vaginal incision. CONCLUSIONS: Transvaginal in-bag extraction though an incision in the posterior vaginal wall is feasible and safe for removing tissue after laparoscopic myomectomy.

Noncoding RNAs related to the hedgehog pathway in cancer: clinical implications and future perspectives.

Cancer is a type of malignant affliction threatening human health worldwide; however, the molecular mechanism of cancer pathogenesis remains to be elusive. The oncogenic hedgehog (Hh) pathway is a highly evolutionarily conserved signaling pathway in which the hedgehog-Patched complex is internalized to cellular lysosomes for degradation, resulting in the release of Smoothened inhibition and producing downstream intracellular signals. Noncoding RNAs (ncRNAs) with diversified regulatory functions have the potency of controlling cellular processes. Compelling evidence reveals that Hh pathway, ncRNAs, or their crosstalk play complicated roles in the initiation, metastasis, apoptosis and drug resistance of cancer, allowing ncRNAs related to the Hh pathway to serve as clinical biomarkers for targeted cancer therapy. In this review, we attempt to depict the multiple patterns of ncRNAs in the progression of malignant tumors via interactions with the Hh crucial elements in order to better understand the complex regulatory mechanism, and focus on Hh associated ncRNA therapeutics aimed at boosting their application in the clinical setting.

Levonorgestrel-releasing intrauterine device plus metformin, or megestrol acetate plus metformin for fertility-sparing treatment of atypical endometrial hyperplasia and early endometrial carcinoma: a prospective, randomized, blind-endpoint design trial protocol.

BACKGROUND: Endometrial adenocarcinoma (EC) is the fifth most common cancer in women worldwide, standard treatment for EC includes hysterectomy, but it results in the loss of reproductive function. Thus, conservative treatment for these patients is strongly demanded, progestin therapy is widely accepted as the main fertility-sparing treatment for young women with endometrial hyperplasia with atypia (EHA) and well-differentiated endometrioid endometrial cancer. This trial will investigate the effectiveness of conservative treatment for obese women with early-stage EC. METHOD AND DESIGN: This will be an open-label, 2-armed, randomized, phase-II single-center trial of LNG-IUD plus metformin or megestrol acetate (MA) plus metformin. A total of 88 participants will be randomly assigned into 2 treatment arms in a 1:1 ratio. Clinical, laboratory, ultrasound and radiology data, will be collected at baseline, and then at 3, 6, 9, 12, 18, and 24 months. EC biomarkers will be collected at baseline. The primary aim is to determine the efficacy of a levonorgestrel-releasing intrauterine device (LNG-IUD) plus metformin, or megestrol acetate (MA) plus metformin in achieving pathological complete response (pCR) at 12 months, as well as post-treatment pregnancy outcomes and recurrence rate. The secondary aims are to predict the response to an LNG-IUD plus metformin and MA plus metformin via clinical, blood, and tissue predictive biomarkers. CONCLUSIONS: Prospective evidence for conservative treatment of EC is limited. New methods to achieve better CR rates with fewer side effects are needed. This trial will investigate the effectiveness of LNG-IUD plus metformin, and MA plus metformin, in obese women with early-stage EC, providing a non-surgical treatment option for these patients. Trial registration ChiCTR2200055624. The trial was registered at http://www.chictr.org.cn/listbycreater.aspx on January 15, 2022.

Endometrial adenocarcinoma (EC) is the fifth most common cancer in women worldwide, and up to 90% of EC patients are obese. Standard treatment for EC includes hysterectomy, but it leads to loss of reproductive function. This trial will investigate the effectiveness of non-surgical treatment for obese women with early-stage EC. There is limited prospective evidence for the conservative treatment of EC. New methods to achieve better CR rates with fewer side effects are needed. In this trial, patients with early-stage EC will be randomly assigned in a 1:1 ratio to receive treatment with a levonorgestrel-releasing intrauterine device (LNG-IUD) plus metformin, or megestrol acetate (MA) plus metformin. The primary aims are to determine the effectiveness of the 2 treatments to achieve a pathological complete response (pCR) at 12 months, pregnancy outcomes, and recurrence rate. The secondary aims are to predict the response to the 2 treatments using clinical data and blood and tissue predictive biomarkers. If the trial results indicate the treatments are effective, they may significantly reduce the incidence of adverse events in obese EC patients receiving current treatments, and preserve fertility; thereby improving patients' quality of life and reducing healthcare costs.

Histone acetyltransferase MOF is involved in suppression of endometrial cancer and maintenance of ERα stability.

Histone acetyltransferase MOF is involved in active transcription regulation through histone H4K16 acetylation. MOF is downexpressed in a number of human tumors, but biological function of MOF in endometrial cancer has not been fully defined. The estrogen receptor α (ERα) is a transcription factor that regulates estrogen-stimulated cell proliferation in hormone-responsive tumors. However, ERα expression is decreased in grade III ECa samples and high expression of ERα is associated with long disease-free survival in ECa. The molecular mechanism for these observations is still unclear. Here we demonstrate knockdown of MOF promotes ECa cell growth and proliferation in vitro and in vivo. Clinical evidence indicates that expression MOF is decreased and positively correlated with that of ERα in ECa tissues. Furthermore, MOF physically interacts with ERα and modulates ERα stability in ECa cells. In addition, MOF modulates expression of a subset of endogenous genes regulated by ERα. Taken together, our results define MOF as a potential tumor suppressor in ECa participates in maintenance of ERα protein stability and regulation of ERα action.

SNORD89 promotes stemness phenotype of ovarian cancer cells by regulating Notch1-c-Myc pathway.

BACKGROUND: Ovarian cancer is the leading cause of death in gynecological cancer. Cancer stem cells (CSCs) contribute to the occurrence, progression and resistance. Small nucleolar RNAs (SnoRNAs), a class of small molecule non-coding RNA, involve in the cancer cell stemness and tumorigenesis. METHODS: In this study, we screened out SNORNAs related to ovarian patient's prognosis by analyzing the data of 379 cases of ovarian cancer patients in the TCGA database, and analyzed the difference of SNORNAs expression between OVCAR-3 (OV) sphere-forming (OS) cells and OV cells. After overexpression or knockdown SNORD89, the expression of Nanog, CD44, and CD133 was measured by qRT-PCR or flow cytometry analysis in OV, CAOV-3 (CA) and OS cells, respectively. CCK-8 assays, plate clone formation assay and soft agar colony formation assay were carried out to evaluate the changes of cell proliferation and self-renewal ability. Scratch migration assay and trans-well invasion analysis were used for assessing the changes of migration and invasion ability. RESULTS: High expression of SNORD89 indicates the poor prognosis of ovarian cancer patients and was associated with patients' age, therapy outcome. SNORD89 highly expressed in ovarian cancer stem cells. The overexpression of SNORD89 resulted in the increased stemness markers, S phase cell cycle, cell proliferation, invasion and migration ability in OV and CA cells. Conversely, these phenomena were reversed after SNORD89 silencing in OS cells. Further, we found that SNORD89 could upregulate c-Myc and Notch1 expression in mRNA and protein levels. SNORD89 deteriorates the prognosis of ovarian cancer patients by regulating Notch1-c-Myc pathway to promote cell stemness and acts as an oncogene in ovarian tumorigenesis. Consequently, SNORD89 can be a novel prognostic biomarker and therapeutic target for ovarian cancer.

Analysis of factors affecting the prognosis of patients with intrauterine adhesions after transcervical resection of adhesions.

OBJECTIVES: To study the factors affecting the prognosis of patients with intrauterine adhesions (IUAs) after transcervical resection of adhesions (TCRA), analyze the reproductive outcome, and guide prognostic improvements. DESIGN: Prospective study. PATIENTS: Our study included 292 patients diagnosed with IUAs who underwent follow-up office hysteroscopy at Shenyang Women's and Children's Hospital between June 2018 and June 2022. INTERVENTIONS: Patients were divided into case (52 patients whose hysteroscopy results indicated the presence of IUAs) and nocase (240 patients whose uterine cavity had returned to normal shape without obvious adhesion) groups on the basis of the results of a 2-month follow-up hysteroscopy following TCRA. Clinical data were collected and compared with various influencing factors, and the combined effect of these factors was assessed using multifactorial logistic regression analysis. A nomogram prediction model was constructed and internally validated on the basis of multifactorial analysis. MAIN OUTCOME MEASURES: Intrauterine re-adhesion was observed at a 2-month follow-up after TCRA. RESULTS: Postoperative re-adhesion occurred in 52 of 292 patients with IUAs. Multifactorial binary logistic regression analysis showed that IUA barrier gel reapplication 5 days after TCRA was a protective factor. In contrast, the preoperative American Fertility Society scores demonstrated that severe IUAs and chronic endometritis were risk factors. The results of the multifactorial analysis were used to build a nomogram model, and the area under the curve value of the nomogram model for predicting postoperative recurrence was 0.914 (95% confidence interval: 0.864-0.956). The bootstrap method was subsequently used to resample 1,000 times for internal validation. The results showed that the internal validation C-index was 0.9135, and the calibration and ideal curves were well-matched. CONCLUSION: The prognosis of patients with IUAs after TCRA is related to the severity of preoperative IUAs, presence of chronic endometritis, and IUA barrier gel reapplication 5 days after TCRA. Therefore, clinicians should monitor patients using targeted data to reduce recurrence risk after TCRA and improve the prognosis of patients with IUAs.

Manganese and IL-12 treatment alters the ovarian tumor microenvironment.

Metal immunotherapy is a novel adjuvant immunotherapy. Mn2+ can activate STING-a type I IFN response protein-that promotes innate immunity and increases anti-tumor activity by promoting macrophage phagocytosis. IL-12, a cytokine that increases the antigen-presenting ability to promote effector T-cell activation, has potent antitumor activity, albeit with severe adverse effects. In this study, we observed that the combination of Mn2+ and IL-12 has a better antitumor effect and possibly reflects a better safety profile, providing a novel approach and theoretical basis for safe and rapid cancer treatment.

Risk factors for pathological upgrading in perimenopausal women with cervical intraepithelial neoplasia grade 2/3 following conization.

Postmenopausal women have a high risk for pathological upgrading in conization specimens due to pathological changes of the cervix. This study aimed to investigate the risk factors for pathological upgrading in conization specimens in Chinese women with cervical intraepithelial neoplasia grade 2/3 (Cervical intraepithelial neoplasia 2/3) ≥ 50 years of age. From January 2015 to December 2019, 443 CIN2/3 patients ≥ 50 years of age were retrospectively included and divided into the upgrade group (n = 47) and the non-upgrade group (n = 396) according to the presence or absence of pathological upgrading in the conization specimens. Multivariate logistic regression model was performed to analyze risk factors associated with pathological upgrading. The upgrade group was more likely to have gravidity < 2 times, postmenopausal period ≥ 5 years, higher incidences of endocervical glandular involvement (EGI) and human papillomavirus (HPV) 16/18 infection, as well as a lower incidence of cervical contactive bleeding and fewer cases undergoing endocervical curettage (all P < .05) than the non-upgrade group. Multivariate model showed that factors associated with pathological upgrading were postmenopausal period ≥ 5 years (OR = 2.55), EGI (OR = 17.71), endocervical curettage (OR = 0.33), and HPV type 16/18 (OR = 3.41) (all P < .05). The receiver operating characteristic analysis showed an area under curve of 0.782 (P < .001). Pathological upgrading in conization specimens is not uncommon in Chinese CIN2/3 patients ≥ 50 years of age. For those with high-risk factors of pathological upgrading (postmenopausal period ≥ 5 years, EGI, and HPV 16/18 infection), the follow-up interval can be appropriately shortened, and active intervention could be considered.

Strengthen the sacral ligament and paravagina by equilibrium control severe pelvic organ prolapse.

Objective: To evaluate and analyze the clinical effect of the combination of laparoscopic sacrocolpopexy (LSC), sacral ligament fusion and vaginal suspension in the treatment of severe pelvic organ prolapse. Methods: A total of 76 cases of patients with pelvic organ prolapse in our hospital between January 2010 to December 2020 were enrolled for research. They had been evaluated pre- and post-operative through pelvic organ prolapse quantification (POP-Q) system, Pelvic Floor Dysfunction Questionnaire Short Form (PFDI-20), Pelvic Floor Function Impact Questionnaire Short form (PFIQ-7), and the Sexual Function Questionnaire Score (PIQS-31). Results: All 76 patients went through the procedure successfully without any complications. None of the 76 cases had relapsed. Post-operational results of PFDI-20 and PFIQ-7 were evidently lower than pre-operational results, post-operational results of PIQS-31 were higher than before operation. Conclusions: For patients with severe pelvic organ prolapse,a balanced control of the pelvic floor centred on the preservation of the stereoscopic ring around the cervix through revascularization is significantly effective, and has no recurrence after surgery, high patient satisfaction, fewer postoperative complications. It is safe and reliable and worthy of clinical application and promotion.

Laparoendoscopic single-site compared with conventional laparoscopic surgery for gynaecological acute abdomen in pregnant women.

OBJECTIVE: To estimate the safety and feasibility of laparoendoscopic single-site surgery (LESS) in pregnant patients with acute abdomen. METHODS: Baseline characteristics, surgical results, and obstetric and neonatal outcomes were retrospectively compared between single and multiport procedures in patients who underwent laparoscopic surgery during pregnancy between 2017 and 2021. RESULTS: Fifty-four pregnant patients were included: 26 who underwent LESS (salpingectomy, 11 cases/cystectomy, 15 cases) and 28 who underwent conventional laparoscopic surgeries (salpingectomy, 12 cases/cystectomy, 16 cases) during pregnancy. One patient in the single-port group required additional ports. No patients converted to laparotomy. In patients undergoing salpingectomy, the single-port group showed lower 8- and 24-h postoperative pain scores, shorter hospital stays, and lower Self-rating Anxiety Scale scores prior to discharge versus conventional laparoscopy. One patient experienced postoperative vaginal bleeding and a missed abortion during follow-up. In patients receiving cystectomy, 8- and 24-h pain scores, postoperative hospital stay, and anxiety scores were lower in the single-port versus multiport group. Other outcomes were comparable between the groups. CONCLUSION: The feasibility and efficacy of laparoscopic surgery during pregnancy is similar between single- or multiport routes, however, the single-port route may be associated with less postoperative pain, shorter hospital stay, and lower anxiety.

Combined Serum DKK3 and Circulating CD133 Cells as Prognostic Biomarkers for Ovarian Cancer Patients.

INTRODUCTION: Ovarian cancer (OV) can seriously endanger women's physical and mental health. Serum DKK3 has been used for the diagnosis and prognosis of patients with ovarian cancer. However, the specificity of antibodies may lead to errors in the detection of plasma protein. METHODS: Circulating CD133+ cells from blood samples were separated by magnetic microbeads. Serum DKK3 levels were determined by ELISA. The roles of DKK3 in OV cells were analyzed in vitro. RESULTS: In this study, we found that the CD133+ subpopulation in circulating tumor cells can indicate the overall survival rate of OV patients. Serum DKK3 levels were negatively correlated with the number of circulating CD133+ cells in OV patients. In addition, we confirmed the inhibitory effect of recombinant human DKK3 (rhDKK3) on OV cells via reversal of the epithelial-mesenchymal transition (EMT) process. CONCLUSION: Both serum DKK3 levels and circulating CD133+ tumor cells can be used as prognostic markers for patients with ovarian cancer.

hsa-microRNA-411-5p regulates proliferation, migration and invasion by targeting the hyaluronan mediated motility receptor in ovarian cancer.

The mortality rate of ovarian cancer is the highest out of all gynecological malignancies worldwide. Therefore, it is important to understand the mechanisms of ovarian cancer, identify new biomarkers and develop targeted drugs. The role and molecular mechanisms of hsa-microRNA (miR)-411-5p in ovarian cancer have not been fully elucidated. The present study investigated the ovarian cancer cell lines OVCAR-8 and SKOV3. After transfection with miRNA mimics, cell proliferation was monitored by a proliferation assay. Furthermore, cell migration was measured by a cell wound healing assay and cell invasion was measured by Matrigel invasion assays. A miRNA luciferase reporter assay was used to analyze the relationship between miRNAs and the target gene HMMR, which was then further evaluated by gene differential analysis. In the current study, hsa-mir-411-5p was identified as a miRNA regulator of the hyaluronan mediated motility receptor, which negatively regulated the activity of ERK1/2 and ultimately inhibited ovarian cancer cell proliferation and motility. Although hsa-mir-411-5p may have different roles in other types of cancer, the present study suggested that miR-411-5p functions as a negative tumor regulator in ovarian cancer cells, displaying the potential of miR-411-5p as a biomarker for ovarian cancer.

Effects of early second-look hysteroscopy combined with intrauterine balloon dilatation on reproductive outcomes for women with intrauterine adhesions.

OBJECTIVE: To investigate the effect of early second-look office hysteroscopy combined with intrauterine balloon dilatation on prognosis and pregnancy rate for women with intrauterine adhesions. METHODS: A retrospective analysis of 156 women diagnosed with intrauterine adhesions by hysteroscopy at Shenyang Women's and Children's Hospital, China, from April 2017 to January 2019. The study women underwent intrauterine balloon dilatation 10 days after transcervical resection of adhesion (TCRA) and hysteroscopy 20 days after TCRA (n=81). The control women underwent hysteroscopy 3 months after TCRA (n=75). Estrogen and aspirin were routinely administered postoperatively to all women. Data, including American Fertility Society (AFS) scores assessed by hysteroscopy, endometrial thickness measured by ultrasound, and menstruation and pregnancy outcomes assessed by interview, were compared between the two groups. RESULTS: The degree of intrauterine adhesions, menstrual status, and endometrial thickness were improved in both groups after TCRA. Greater improvement in AFS score, menstruation, and endometrial thickness was observed in the study group than in the control group. After follow-up, more women in the study group achieved pregnancy (48.1% vs 30.7%, P<0.05). CONCLUSION: Early second-look of hysteroscopy combined with intrauterine balloon dilatation after hysteroscopic TRCA might improve the prognosis and postoperative pregnancy rate for women with intrauterine adhesions.

The anti-nephritic activity of a polysaccharide from okra (Abelmoschus esculentus (L.) Moench) via modulation of AMPK-Sirt1-PGC-1α signaling axis mediated anti-oxidative in type 2 diabetes model mice.

Diabetic nephropathy (DN) with high morbidity and mortality is one of the most severe diabetes complications and affects nearly one-third of people with diabetes. Our present experiment was designed to assess the potential therapeutic of a polysaccharide purified from okra (OP) on DN in high-fat diet-fed and streptozotocin (STZ)-induced diabetic mice. We found that an 8-week treatment with OP could significantly decrease the 24-h urine protein (24-h UP), serum creatinine (Scr), serum urea nitrogen (SUN) and glycosylated hemoglobin (HbA1c) levels, which are regard as the biomarkers of renal injury. The results of immunohistochemical analysis and histopathological examination showed that the diabetic-induced microstructural changes and fibrosis in kidney can be alleviated by the administration of OP (400 mg/kg). Our immunofluorescences results demonstrated that OP (400 mg/kg) could greatly reduce the level of reactive oxygen species (ROS) in kidney. In addition, we also studied the level of SOD, GSH, CAT, HO-1, Nrf2, p-AMPK, PGC-1α, Sirt1, Bcl-2, cleaved caspase-3 and Bax in renal tissue by assay kit and western blot. Our results suggested that OP ameliorated DN in diabetic mice, which is possibly related to suppressing apoptosis and oxidative stress through activating AMPK-Sirt1-PGC-1α signaling axis.

Association of C8orf4 expression with its methylation status, aberrant ß-catenin expression, and the development of cervical squamous cell carcinoma.

Chromosome 8 open reading frame 4 (C8orf4) is an activator of Wnt signaling pathway, and participates in the tumorigenesis and progression of many tumors. The expression levels of C8orf4 and ß-catenin were assessed via immunohistochemical staining in 100 cervical squamous cell carcinoma (CSCC) tissues, 50 high-grade squamous intraepithelial lesions (HSILs), 50 low-grade squamous intraepithelial lesions (LSILs), and 50 normal cervical tissues. Bisulfite sequencing polymerase chain reaction analysis was used to examine the methylation status of the C8orf4 locus in CSCC and normal cervical tissues. The expression rates of C8orf4 and ß-catenin were significantly higher in CSCCs or HSILs than in LSILs or normal cervical tissues (P < .05). C8orf4 expression was positively correlated with the poor differentiation of CSCCs (P = .009), and with aberrant expression of ß-catenin in CSCCs (P = .002) and squamous intraepithelial lesions (P < .001). The methylation rate of C8orf4 in CSCCs was significantly lower than that in normal cervical tissues (P = .001). The Cancer Genome Atlas genomics data also confirmed that the mRNA expression of C8orf4 was positively associated with the copy number alteration of C8orf4 (correlation coefficient = 0.213, P < .001), and negatively correlated with the methylation level of C8orf4 (correlation coefficient = -0.408, P < .001). In conclusion, the expressions of C8orf4 and ß-catenin were synergistically increased in CSCCs and HSILs and higher than those in LSILs and normal cervical tissues. The methylation level of C8orf4 is decreased in CSCCs and is responsible for the increased expression of C8orf4.