Practice guideline on ovarian tissue cryopreservation and transplantation in the prevention and treatment of iatrogenic premature ovarian insufficiency.

Premature ovarian insufficiency (POI) refers to the decline of ovarian function before the age of 40. POI causes a reduction in or loss of female fertility, accompanied by different degrees of menopausal symptoms, which increases the risk of chronic diseases related to early menopause and seriously affects patients' quality of life and health. It is conservatively estimated that at least one million prepubertal girls and women of reproductive age in China are at risk of iatrogenic POI caused by radiotherapy and chemotherapy every year. With the development of medical technology and the breakthrough of scientific and technological advances, preventing and treating iatrogenic POI have become possible. International and national guidelines consider cryopreserved ovarian tissue transplantation to be the most promising method of preserving the ovarian function and fertility of prepubertal girls and women of reproductive age who cannot delay radiotherapy and chemotherapy. In order to guide the clinical application of ovarian tissue cryopreservation and transplantation technology in China, the Guideline Working Group finally included 14 scientific questions and 18 recommendations through a questionnaire survey, field investigation, and consultation of a large number of Chinese and English literature databases in order to provide a reference for colleagues in clinical practice.

Establishment and validation of a nomogram model for predicting adverse pregnancy outcomes of pregnant women with adenomyosis.

PURPOSE: To establish a reliable nomogram model to predict the risk of major adverse pregnancy outcomes in pregnant women with adenomyosis, and to provide a reference tool for the hierarchical management and the prenatal examination of pregnant women. METHODS: We collected the clinical data of pregnant women with adenomyosis who were treated in the First Affiliated Hospital of Chongqing Medical University, the Women and Children's Hospital of Chongqing Medical University, and Yubei District People's Hospital of Chongqing from January 2014 to June 2020. They were divided into the training cohort and the validation cohort, respectively. In the training cohort, we screened out risk factors associated with major adverse pregnancy outcomes and established a model, which was subsequently validated. RESULTS: In the training cohort, we found that previous parity, natural conception or not, type of adenomyosis, with or without endometriosis, history of infertility or adverse pregnancy outcomes, and history of uterine body surgery were associated with major adverse pregnancy outcomes of pregnant women with adenomyosis, and based on these factors, a nomogram model was constructed. The calibration curves of the model were well fitted in both the training and validation cohorts. The receiver-operating characteristic curve (ROC curve) showed that the area under the curve (AUC) was 0.873 and 0.851 in the training and validation cohorts, respectively. The optimal risk threshold of the model was 0.22, and this threshold can be applied to risk stratification of pregnant women. CONCLUSION: The nomogram model established in this study can reliably predict the risk of major APO in pregnant women with AD.

MitomiR-504 alleviates the copper-induced mitochondria-mediated apoptosis by suppressing Bak1 expression in porcine jejunal epithelial cells.

Copper (Cu), an environmental heavy metal pollutant, has been widely researched in its toxicology. Recently, an increasing number of mitochondrial microRNAs (mitomiRs) have been shown to involve in the metabolic regulation. However, the underlying mechanisms of mitomiRs on regulating apoptosis under Cu exposure are still unclear. Here, we proved that Cu induced mitochondria-mediated apoptosis in porcine jejunal epithelial cells, concomitant with distinct reduction of mitomiR-504 in vivo and in vitro. The miR-504 mimic notably enhanced the mRNA and protein expressions of Bak1, Bax, Cleaved-caspase3 and Caspase-9, and significantly decreased the apoptosis rate and Bcl-2 mRNA and protein levels, indicating that overexpression of mitomiR-504 attenuated the Cu-induced mitochondria-mediated apoptosis. Besides, Bak1 was confirmed as a direct target of mitomiR-504 by the bioinformatics analysis and dual-luciferase reporter assay. Subsequently, transfection of siRNA targeting Bak1 significantly enhanced the alleviating effect of miR-504 mimic on the Cu-induced mitochondria-mediated apoptosis. Overall, these suggested that overexpression of mitomiR-504 alleviated the Cu-induced mitochondria-mediated apoptosis in jejunal epithelial cells by suppressing Bak1 expression. These findings are conducive to elucidating the mechanism of Cu-induced jejunal epithelial pathologies, providing a new research idea for the Cu toxicology.

Predicting the Recurrence of Operable Cervical Cancer Patients Based on Hemoglobin, Albumin, Lymphocyte, and Platelet (HALP) Score and Classical Clinicopathological Parameters.

Objective: The purpose of this study was to evaluate the prognostic value of hemoglobin, albumin, lymphocyte, and platelet (HALP) score in patients with operable cervical cancer, and on this basis, combined with classical clinicopathological parameters to predict the recurrence of patients. Methods: A total of 1580 patients with stage IA-IIA cervical cancer were randomly divided into training cohort (n=1054) and validation cohort (n=526) according to the predefined ratio of 2:1. In the training cohort, the receiver operating characteristic (ROC) curve and Youden index were used to determine the optimal threshold of HALP score for predicting cervical cancer recurrence. On this basis, the independent related factors with cervical cancer recurrence were screened through univariate and multivariate Cox regression analysis, and then a nomogram model was further established. The internal and external validation of the model was carried out in the training cohort and the validation cohort respectively through the consistency index (C-index) and calibration curve. Results: ROC curve and Youden index showed that the optimal threshold of HALP score for predicting cervical cancer recurrence was 39.50. Multivariate analysis confirmed that HALP score and some other classic clinicopathological parameters were independently associated with cervical cancer recurrence. Based on the results of multivariate analysis, a nomogram model for predicting cervical cancer recurrence was successfully constructed. The internal and external calibration curves showed that the fitting degree of the model was good, and the C-index (the C-index of the training cohort and the validation cohort were 0.862 and 0.847, respectively) showed that the prediction accuracy of the model proposed in this study was better than other similar models. Conclusion: HALP score may be a novel predictor for predicting the cervical cancer recurrence. Nomogram model based on HALP score and classical clinicopathological parameters can better predict the recurrence of cervical cancer.

A retrospective study of estrogen in the pretreatment for medical management of early pregnancy loss and the inference from intrauterine adhesion.

BACKGROUND: Estrogen has been usually used in clinic for medical pretreatment of early pregnancy loss. There was little reported the effect of estrogen combined with prostaglandin analogs in the medical management of early pregnancy loss. This retrospective study aimed to evaluate the efficacy of estrogen pretreatment for medical management of early pregnancy loss and explore the confounding factor of intrauterine adhesion (IUA) on the outcome of medical management. METHODS: A total of 226 early pregnancy loss patients who received pretreatment with estradiol valerate and/or mifepristone, followed by carboprost methylate suppositories (study groups), or carboprost methylate suppositories alone (control group) in a regional central institution from March 2020 to February 2021 were retrospectively studied. All patients were evaluated by hysteroscopy 6 h after carboprost methylate suppositories use to assess whether the gestational sac was complete expulsion and assess the morphology of uterine cavity. RESULTS: The complete expulsion rate was 56.94% in the mifepristone and estradiol valerate-pretreatment group, 20.69% in the estradiol valerate-pretreatment group, 62.5% in the mifepristone-pretreatment group, and 12.5% in the control group. Compared with the control group, pretreatment with estradiol valerate did not increase the complete expulsion rate significantly (P = 0.297), pretreatment with mifepristone increased the complete expulsion rate significantly (P < 0.001). Pretreatment with mifepristone combined with estradiol valerate did not increase the complete expulsion rate significantly comparing with pretreatment with mifepristone (P = 0.222). The data of IUA showed that the complete expulsion rate in patients with IUA was lower than that in those patients without IUA (P < 0.001). CONCLUSIONS: Pretreatment with estrogen was not a sensible substitute for mifepristone in the medical management of early pregnancy loss. Mifepristone followed by carboprost methylate suppositories was likelihood of the ideal medical scheme in early pregnancy loss. IUA decreased the complete expulsion rate of medical management, it is cautious about medical management for early pregnancy loss with risk of IUA. TRIAL REGISTRATION NUMBER: ChiCTR2100046503. Date of registration (retrospectively registered): May 18, 2021. Trial registration website: http://www.chictr.org.cn/ .

A Nomogram Model for Predicting Recurrence of Stage I-III Endometrial Cancer Based on Inflammation-Immunity-Nutrition Score (IINS) and Traditional Classical Predictors.

Objective: The purpose of this study was to investigate the prognostic value of the inflammation-immunity-nutrition score (IINS) in patients with stage I-III endometrial cancer (EC) and establish a nomogram model to predict the recurrence of EC by combining IINS and traditional classical predictors. Methods: Seven hundred and seventy-five patients with stage I-III EC who underwent initial surgical treatment at the First Affiliated Hospital of Chongqing Medical University were included in this study as the training cohort. In the training cohort, IINS (0-3) was constructed based on preoperative C-reactive protein (CRP), lymphocytes (LYM), and albumin (ALB). Univariate and multivariate Cox regression analysis were used to screen independent predictors associated with recurrence of EC for developing the nomogram model. Internal validation of the model was performed in the training cohort by using the C-index and calibration curve, while external validation of the model was performed in another cohort (validation cohort) of 491 patients from the Second Affiliated Hospital of Chongqing Medical University. Results: IINS was successfully constructed, and survival analysis showed that patients with high IINS had a worse prognosis. Multivariate analysis showed that IINS, age, FIGO stage, pathological type, myometrial invasion, lymphatic vessel space invasion (LVSI), Ki67 expression, estrogen receptor (ER) expression, and P53 expression were significantly associated with shorter recurrence-free survival, and then a nomogram model for predicting the recurrence of EC was successfully established. The internal and external calibration curves of the model showed that the model fit well, and the C-index (0.887 in training cohort and 0.883 in validation cohort) showed that the model proposed in this study had better prediction accuracy than other prediction models. Conclusion: IINS may be a strong predictor of prognosis in patients with EC. The nomogram model incorporated into the IINS can better predict the recurrence of EC than the traditional models.

Toxicological mechanism of large amount of copper supplementation: Effects on endoplasmic reticulum stress and mitochondria-mediated apoptosis by Nrf2/HO-1 pathway-induced oxidative stress in the porcine myocardium.

Copper (Cu) is an essential micronutrient that is required by all living organisms. However, Cu can also be a potentially toxic metal if excessive dietary supplementation occurs. The current study aimed to investigate the mechanism of Cu toxicity in the cardiomyocytes of large mammal pigs. Here, we used pigs to explore Cu toxicity in the control group (10 mg/kg Cu) and treatment groups (125 mg/kg and 250 mg/kg Cu) for a period of 80 days. Consequently, we identified that large amount intake of Cu led to in oxidative damage, and activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)-mediated antioxidant pathway, indicating an imbalanced redox status in the myocardium. Furthermore, Cu exposure activated endoplasmic reticulum (ER) stress through upregulating levels of glucose-regulated protein 78 (GRP78), c-Jun N-terminal kinase (JNK), glucose-regulated protein 94 (GRP94), X-box binding protein 1 (XBP1), and C/EBP homologous protein (CHOP). Additionally, mitochondrial fission and fusion homeostasis was disrupted and the copy number of mitochondrial DNA (mtDNA) was reduced under Cu exposure. Furthermore, Cu exposure could induce apoptosis, evidenced by the increased terminal deoxynucleotidyl transferase biotin-d UTP nick end labeling (TUNEL)-positive staining, the upregulated expression levels of Cytoplasm-cytochrome C (Cytc), Bcl-2-associated X protein (Bax), and Cleaved-caspase3, and decreased expression level of B-cell lymphoma-2 (Bcl-2) and Mitochondrial-cytc. In summary, large amount of Cu could trigger Nrf2/HO-1 pathway-mediated oxidative stress, which promotes ER stress and mitochondrial damage pathways, causing apoptosis in cardiomyocytes.

Endoplasmic Reticulum Stress Contributes to Copper-Induced Pyroptosis via Regulating the IRE1α-XBP1 Pathway in Pig Jejunal Epithelial Cells.

Copper (Cu) is a common additive in food products, which poses a potential concern to animal and human health when it is in excess. Here, we investigated the relationship between endoplasmic reticulum (ER) stress and pyroptosis in Cu-induced toxicity of jejunum in vivo and in vitro. In in vivo experiments, excess intake of dietary Cu caused ER cavity expansion, elevated fluorescence signals of GRP78 and Caspase-1, and increased the mRNA and protein expression levels related to ER stress and pyroptosis in pig jejunal epithelium. Simultaneously, similar effects were observed in IPEC-J2 cells under excess Cu treatment. Importantly, 4-phenylbutyric acid (ER stress inhibitor) and MKC-3946 (IRE1α inhibitor) significantly inhibited the ER stress-triggered IRE1α-XBP1 pathway, which also alleviated the Cu-induced pyroptosis in IPEC-J2 cells. In general, these results suggested that ER stress participated in regulating Cu-induced pyroptosis in jejunal epithelial cells via the IRE1α-XBP1 pathway, which provided a novel view into the toxicology of Cu.

Mitochondrial miR-1285 regulates copper-induced mitochondrial dysfunction and mitophagy by impairing IDH2 in pig jejunal epithelial cells.

Copper (Cu), a hazardous heavy metal, can lead to toxic effects on host physiology. Recently, specific mitochondria-localized miRNAs (mitomiRs) were shown to modulate mitochondrial function, but the underlying mechanisms remain undefined. Here, we identified mitomiR-1285 as an important molecule regulating mitochondrial dysfunction and mitophagy in jejunal epithelial cells under Cu exposure. Mitochondrial dysfunction and mitophagy were the important mechanisms of Cu-induced pathological damage in jejunal epithelial cells, which were accompanied by significant increase of mitomiR-1285 in vivo and in vitro. Knockdown of mitomiR-1285 significantly attenuated Cu-induced mitochondrial respiratory dysfunction, ATP deficiency, mitochondrial membrane potential reduction, mitochondrial reactive oxygen species accumulation, and mitophagy. Subsequently, bioinformatics analysis and luciferase reporter assay demonstrated that IDH2 was a direct target of mitomiR-1285. RNA interference of IDH2 dramatically reversed the effect that mitomiR-1285 knockdown relieved mitochondrial dysfunction and mitophagy induced by Cu, and the opposite effect was shown by overexpression of IDH2. Therefore, our results suggested that mitomiR-1285 aggravated Cu-induced mitochondrial dysfunction and mitophagy via suppressing IDH2 expression. These findings identified the important mechanistic connection between mitomiRs and mitochondrial metabolism under Cu exposure, providing a new insight into Cu toxicology.

[Using Immunohistochemical Markers and Clinicopathological Factors to Predict the Prognostic Survival of Different Types of Endometrial Cancer Recurrence].

OBJECTIVE: To probe for factors that can be used effectively to predict the prognostic survival of patients with endometrial cancer recurrence. METHODS: The clinicopathological data of 473 patients with stage Ⅰ to Ⅲ endometrial cancer who underwent standard surgical treatment from October 2013 to May 2019 were retrospectively collected, and post-operative recurrence of the patients were followed up. Overall recurrence includes local recurrence and poor prognosis recurrence. The endpoint indicators of this study are the recurrence-free survival (RFS) and overall survival (OS) of patients with overall recurrence, local recurrence, and poor prognosis recurrence (PPR). The Kaplan-Meier survival curve was used to evaluate the OS and RFS of patients. Cox proportional-hazards model was used to identify factors affecting the prognostic survival of patients with endometrial cancer recurrence. RESULTS: Among the 473 patients, 406 did not experience recurrence. A total of 67 patients, accounting for 14.2%, had recurrence. Among them, 27 had local recurrence, accounting for 5.7%, while 40 had poor prognosis recurrence, accounting for 8.5%. The median follow-up time of patients with recurrence was 38 months. The survival curve showed that the RFS and OS of the patients in the recurrence-free group remained unchanged, while the patients in the recurrence group, regardless of whether they had overall recurrence, local recurrence or PPR, experienced a decrease in RFS and OS( P<0.001). The overall 3-year OS rate of patients with recurrence was 44.8%, the median survival time was 29 months, and the median recurrence time was 17 months. The 3-year OS rate of patients in the recurrence-free group was 98.8%, and the median survival time was 40 months; the 3-year OS rate of patients with local recurrence was 59.3%, the median survival time was 27 months, and the median recurrence time was 15 months. The 3-year OS rate of patients with PPR was only 35.0%, the median survival time was 22 months, and the median recurrence time was 10 months. The results of multivariate Cox regression analysis showed that, for overall recurrence patients, FIGO stage Ⅲ (hazard ratio ( HR)=3.432, P=0.005), increased expression of K-i67 ( HR=1.015, P=0.025), and decreased expression of estrogen receptor (ER) ( HR=0.985, P=0.005) are independent factors for the decline in RFS, FIGO stage Ⅲ ( HR=4.918, P=0.005) and the decreased expression of progesterone receptor (PR) ( HR=0.977, P=0.003) are independent factors for the decrease in OS. For patients with local recurrence, special pathological types ( HR=2.545, P=0.049) and increased expression of Ki-67 ( HR=1.024, P=0.033) are independent factors influencing the decrease in RFS, while decreased expression of PR ( HR=0.973, P=0.009) is an independent risk factor for decreased OS. For patients with PPR, FIGO stage Ⅲ ( HR=5.977, P=0.002) and decreased ER expression ( HR=0.984, P=0.023) are independent risk factors for the decline in RFS, while FIGO stage Ⅲ ( HR=10.098, P=0.001) is an independent factor influencing the decline of OS. CONCLUSION: FIGO stage Ⅲ, increased Ki-67 expression, and decreased ER expression can increase patients' risk of postoperative recurrence, and FIGO stage Ⅲ and decreased expression of PR can increase the risk of death in patients with recurrence.

The optimal cut-off value of immunohistochemical parameter P53 for predicting recurrence of endometrial cancer.

OBJECTIVE: To explore the optimal cut-off value of immunohistochemical parameter P53 for predicting the recurrence of Stage I-III endometrial cancer. METHODS: A total of 473 patients who were treated between October 2013 and May 2018 were retrospectively studied. Receiver operating characteristic (ROC) curves and the Youden index were used to calculate the optimal cut-off value of P53. Cox regression analysis was used to detect the association between the threshold of P53 and recurrence of endometrial cancer. Recurrence-free survival (RFS) and overall survival (OS) were exhibited by Kaplan-Meier curve. RESULTS: The study showed that 67% was the optimal cut-off value of P53 to predict the recurrence of endometrial cancer. P53 above 67% was an independent predictor for relapse of endometrial cancer (p < 0.001). The 3-year RFS was 89.7% in the low-value group and 66.6% in the high-value group (p < 0.001), while the 3-year OS was 93.9% and 76.4%, respectively (p < 0.001). Furthermore, the 3-year RFS of patients who did not receive adjuvant chemotherapy or radiotherapy was 95.7% and 78.2% between the two groups (p < 0.001). CONCLUSION: The optimal cut-off value of immunohistochemical parameter P53 for predicting recurrence was confirmed as 67% and a P53 index above 67% was an independent prognostic factor.

Prognostic Value of Ki67 in Patients with Stage 1-2 Endometrial Cancer: Validation of the Cut-off Value of Ki67 as a Predictive Factor.

OBJECTIVE: The purpose of this study was to find a cut-off value of the immunohistochemical parameter Ki67 for stage I-II endometrial cancer. MATERIALS AND METHODS: The clinicopathological data of 318 patients with stages I-II endometrial cancer who received primary surgical treatment were retrospectively analyzed. A cut-off value of Ki67 for predicting recurrence of endometrial cancer was determined by using the receiver operating characteristic curve and the Youden index. The Cox regression was performed to screen factors associated with recurrence of endometrial cancer. Based on the cut-off value of Ki67, the patients were divided into two groups, and the differences of clinicopathological parameters between the two groups were compared. RESULTS: The receiver operating characteristic curve showed that the optimal cut-off value of Ki67 for predicting recurrence of patients with stages I-II endometrial cancer was 38%. The multivariate Cox regression analysis demonstrated that the histotypes (P=0.012), myometrial invasion (P=0.014), cervical stromal invasion (P=0.001), Ki67 (P=0.002), estrogen receptor (ER) (P=0.045) and P53 (P=0.032) were significant prognostic predictors for recurrence of endometrial cancer. The recurrence-free survival and the disease-specific survival of patients in the high-Ki67 group (Ki67 ≥38%) were much lower than those in the low-Ki67 group (Ki67 <38%) (P=0.000, P=0.001, respectively). Among the 118 patients with early low-risk endometrial cancer who did not receive adjuvant treatment after surgery, the recurrence-free survival of patients in the high-Ki67 group was also lower than those in the low-Ki67 group (P=0.000). CONCLUSION: The Ki67 was demonstrated to be a useful prognostic factor in patients with stages I-II endometrial cancer, and the Ki67 labeling index 38.0% was optimal cut-off value for predicting recurrence.

Predicting Recurrence in Endometrial Cancer Based on a Combination of Classical Parameters and Immunohistochemical Markers.

OBJECTIVE: The aim of this study was to establish a nomogram to predict the recurrence of endometrial cancer (EC) by immunohistochemical markers and clinicopathological parameters and to evaluate the discriminative power of this model. METHODS: The data of 473 patients with stages I-III endometrial cancer who had received primary surgical treatment between October 2013 and May 2018 were randomly split into two sets: a training cohort and a validation cohort at a predefined ratio of 7:3. Univariate and multivariate Cox regression analysis of screening prognostic factors were performed in the training cohort (n=332) to develop a nomogram model for EC-recurrence prediction, which was further evaluated in the validation cohort (n=141). RESULTS: Univariate analysis found that FIGO stage, histological type, histological grade, myometrial invasion, cervical stromal invasion, postoperative adjuvant treatment, and four immunohistochemical markers (Ki67, ER, PR, and p53) were associated with recurrence in EC. Multivariate analysis showed that FIGO stage, histological type, ER, and p53 were superior parameters to generate the nomogram model for recurrence prediction in EC. Recurrence-free survival was better predicted by the proposed nomogram, with a C-index value of 0.79 (95% CI 0.66-0.92) in the validation cohort. CONCLUSION: This nomogram model involving immunohistochemical markers can better predict recurrence in FIGO stages I-III EC.

The combined ratio of estrogen, progesterone, Ki-67, and P53 to predict the recurrence of endometrial cancer.

BACKGROUND AND OBJECTIVES: We aimed to explore the capacity of the combined ratio of biomarkers to predict the recurrence of Stage I-III endometrial cancer (EC). METHODS: A total of 473 patients were enrolled after screening. The cut-off value of the ratio was calculated by the receiver operating characteristic curve (ROC). The univariate and multivariate Cox regression analysis was used to assess the correlation between the combined ratio and the recurrence of EC. The differences of clinicopathological parameters between the two groups divided based on the threshold were compared. RESULT: The ROC curve showed that 0.92 was the optimal cut-off value of the ratio ([ER + PR]/[P53 + Ki67]). The multivariate analysis demonstrated that only International Federation of Gynecology and Obstetrics stage (p = .031) and the combined ratio (p = .004) were independent risk factors of recurrence. The 3-year recurrence-free survival (RFS) and overall survival of patients in the low-ratio group were 54.1% and 66.8%, respectively; while in the high-ratio group were 94.9% and 97.9%, respectively (p < .001). The 3-year RFS of 194 patients, who did not receive the adjuvant therapy, was 54.7% and 97.2% between two groups (p < .001). CONCLUSIONS: The optimal cut-off value (0.92) of the combined ratio was demonstrated to be better to predict the recurrence of EC than a single immunohistochemical marker.

A Nomogram Model Involving Immunohistochemical Markers for Predicting the Recurrence of Stage I-II Endometrial Cancer.

BACKGROUND: The purpose of this study was to establish a nomogram combining classical parameters and immunohistochemical markers to predict the recurrence of patients with stage I-II endometrial cancer (EC). METHODS: 419 patients with stage I-II endometrial cancer who received primary surgical treatment at the First Affiliated Hospital of Chongqing Medical University were involved in this study as a training cohort. Univariate and multivariate Cox regression analysis of screening prognostic factors were performed in the training cohort to develop a nomogram model, which was further validated in 248 patients (validation cohort) from the Second Affiliated Hospital of Chongqing Medical University. The calibration curve was used for internal and external verification of the model, and the C-index was used for comparison among different models. RESULTS: There were 51 recurrent cases in the training cohort while 31 cases in the validation cohort. Univariate analysis showed that age, histological type, histological grade, myometrial invasion, cervical stromal invasion, postoperative adjuvant treatment, and four immunohistochemical makers (Ki67, estrogen receptor, progesterone receptor, P53) were the related factors for recurrence of EC. Multivariate analysis demonstrated that histological type (P = 0.029), myometrial invasion (P = 0.003), cervical stromal invasion (P = 0.001), Ki67 (P < 0.001), ER (P = 0.009) and P53 expression (P = 0.041) were statistically correlated with recurrence of EC. Recurrence-free survival was better predicted by the proposed nomogram with a C-index of 0.832 (95% CI, 0.752-0.912) in the training cohort, and the validation set confirmed the finding with a C-index of 0.861 (95% CI, 0.755-0.967). CONCLUSION: The nomogram model combining classical parameters and immunohistochemical markers can better predict the recurrence in patients with FIGO stage I-II EC.

Increased circulating miR-370-3p regulates steroidogenic factor 1 in endometriosis.

Endometriosis is a gynecologic disease common among reproductive-aged women caused by the growth of endometrial tissue outside the uterus. Altered expression of numerous genes and microRNAs has been reported in endometriosis. Steroidogenic factor 1 (SF-1), an essential transcriptional regulator of multiple genes involved in estrogen biosynthesis, is aberrantly increased and plays an important role in the pathogenesis of endometriosis. Here, we show the expression of SF-1 in endometriosis is regulated by miR-370-3p. Sera and tissue were collected from 20 women surgically diagnosed with endometriosis and 26 women without endometriosis. We found that miR-370-3p levels were decreased in the serum of patients with endometriosis while SF-1 mRNA levels were inversely upregulated in endometriotic lesions compared with respective controls. Transfection of primary endometriotic cells with miR-370-3p mimic or inhibitor resulted in the altered expression of SF-1 and SF-1 downstream target genes steroidogenic acute regulatory protein (StAR) and CYP19A1. Overexpression of miR-370-3p inhibited cell proliferation and induced apoptosis in endometriotic cells. This study reveals that miR-370-3p functions as a negative regulator of SF-1 and cell proliferation in endometriotic cells. We suggest a novel therapeutic strategy for controlling SF-1 in endometriosis.

Silencing nc886, a Non-Coding RNA, Induces Apoptosis of Human Endometrial Cancer Cells-1A In Vitro.

BACKGROUND The role that nc886, a non-coding microRNA, plays in human endometrial cancer is unknown. The present study aimed to describe the functional role of nc886 in human endometrial cancer-1A (HEC-1A) cell line, which may provide another target for human endometrial cancer treatment. MATERIAL AND METHODS The expression levels of nv886 in normal human endometrial tissue and the early phase and late phase of human endometrial cancer tissues were determined and compared by fluorescence in situ hybridization (FISH). Small interference RNA (siRNA) was used to inhibit nc886, and cell proliferation was evaluated with the MTT test. mRNA levels of PKR, NF-κB, vascular endothelial growth factor (VEGF), and caspase-3 were determined against glyceraldehyde 3-phosphate dehydrogenase (GAPDH between the HEC-1A control group and the silenced group (nc886 silenced with siRNA) by real-time reverse transcription polymerase chain reaction (RT-PCR). The protein levels of PKR (total and phosphorylated form), NF-κB, VEGF, and caspase-3 were determined against GAPDH by Western blotting, and cell apoptosis was determined by flow cytometry. RESULTS Our results indicated that a higher level of nc886 was expressed in the late phase of human endometrial cancer tissue, less than in the early phase but still higher than in normal human endometrial tissue. After nc886 was silenced, protein levels of p-PKR (phosphorylated PKR) and caspase-3 were increased, whereas NF-κB and VEGF were decreased. CONCLUSIONS The rate of apoptosis in the silenced group was increased and the rate of cell proliferation was slower in comparison to the control.

Stomatin-like protein 2 is involved in endometrial stromal cell proliferation and differentiation during decidualization in mice and humans.

The molecular mechanisms underlying endometrial stromal cell proliferation and differentiation (decidualization) are still not fully understood. This study revealed that increased Slp-2 expression is a significant factor modulating endometrial stromal cell proliferation and decidualization in both mice and humans. Our results showed a significant difference in the mRNA and protein levels between the implantation site and inter-implantation site on day 5 and day 6 of pregnancy in mice (all P < 0.05). Strong Slp-2 immunostaining was mainly localized within the decidual zone of mice through the post-implantation period. Mice with artificially induced deciduoma showed significantly higher expression of Slp-2 compared with uninduced controls (P < 0.005). Human stromal cells in the middle and late-secretory phases demonstrated significantly (all P < 0.05) upregulated SLP-2, compared with cells in the proliferative phase and early secretory phases. Further analyses of the SLP-2 gene knocked down revealed a significant (P < 0.005) repression of both the decidualization marker gene's expression (decidual/trophoblast prolactin-related protein in mice, insulin-like growth factor binding protein and prolactin in human) and the cell proliferation in in vitro-induced decidualized primary endometrial stromal cells in mice and humans.

nm23 regulates decidualization through the PI3K-Akt-mTOR signaling pathways in mice and humans.

STUDY QUESTION: Does nm23 have functional significance in decidualization in mice and humans? SUMMARY ANSWER: nm23 affects decidualization via the phosphoinositide 3 kinase/mammalian target of rapamycin (PI3K-Akt-mTOR) signaling pathways in mouse endometrial stromal cells (ESCs; mESCs) and human ESCs. WHAT IS KNOWN ALREADY: The function of nm23 in suppressing metastasis has been demonstrated in a variety of cancer types. nm23 also participates in the control of DNA replication and cell proliferation and differentiation. STUDY DESIGN, SIZE AND DURATION: We first analyzed the expression profile of nm23 in mice during early pregnancy (n = 6/group), pseudopregnancy (n = 6/group) and artificial decidualization (n = 6/group) and in humans during the menstrual cycle phases and the first trimester. We then used primary cultured mESCs and a human ESC line, T-HESC, to explore the hormonal regulation of nm23 and the roles of nm23 in in vitro decidualization, and as a possible mediator of downstream PI3K-Akt-mTOR signaling pathways. PARTICIPANTS/MATERIALS, SETTINGS AND METHODS: We evaluated the dynamic expression of nm23 in mice and humans using immunohistochemistry, western blot and real-time quantitative RT-PCR (RT-qPCR). Regulation of nm23 by steroid hormones was investigated in isolated primary mESCs and T-HESCs by western blot. The effect of nm23 knockdown (using siRNA) on ESC proliferation was analyzed by 5-ethynyl-2'-deoxyuridine staining (EdU) and proliferating cell nuclear antigen protein (PCNA) expression. The influence of nm23 expression on the differentiation of ESCs was determined by RT-qPCR using the mouse differentiation markers decidual/trophoblast PRL-related protein (dtprp, also named prl8a2) and prolactin family 3 subfamily c member 1 (prl3c1) and the human differentiation markers insulin-like growth factor binding protein 1 (IGFBP1) and prolactin (PRL). The effects of nm23 siRNA (si-nm23) and the PI3K inhibitor LY294002 on the downstream effects of nm23 on the PI3K-Akt-mTOR signaling pathway were estimated by western blot. MAIN RESULTS AND THE ROLE OF CHANCE: NM23-M1 was specifically expressed in the decidual zone during early pregnancy and in artificially induced deciduoma, and NM23-H1 was strongly expressed in human first trimester decidua. The expression of nm23 was upregulated by oestradiol and progesterone (P < 0.05 versus control) in vitro in mESCs and T-HESC, and this was inhibited by their respective receptor antagonists, ICI 182,780 and RU486. Mouse and human nm23 knockdown decreased ESC proliferation and differentiation (P < 0.05 versus control). The PI3K-Akt-mTOR signaling pathways were downstream mediators of nm23 in mESCs and T-HESCs decidualization. LIMITATIONS AND REASONS FOR CAUTION: Whether the nm23 regulates decidualization via the activation of AMPK, RAS, PKA, STAT3 or other signaling molecules remains to be determined. The role of nm23 in decidualization was tested in vitro only. WIDER IMPLICATIONS OF THE FINDINGS: Results demonstrate that nm23 plays a vital role in decidualization in mice and humans and that nm23 gene expression is hormonally regulated. The downregulation of nm23 in decidua during the first trimester may be associated with infertility in women. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the National Natural Science Foundation of China (grant nos. 81370731, 31571551 and 31571190), the Science and Technology Project of Chongqing Education Committee (KJ130309), open funding by the Chongqing Institute for Family Planning (1201) and the Excellent Young Scholars of Chongqing Medical University (CQYQ201302). The authors have no conflicts of interest to declare.

Clinicopathological significance of steroidogenic factor-1 expression in ovarian cancer versus ovarian sex cord stromal tumor.

The significance of steroidogenic factor-1 (SF-1) in human ovarian tumor has not been fully investigated. The purposes of this study are to provide a meta-analysis for SF-1 and to determine whether SF-1 is associated with ovarian tumor progression and clinicopathological characteristics. A detailed literature search was made for related research publications written in English. Methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analysis of pooled data was performed, and odds ratio (OR) and corresponding confidence intervals (CIs) were calculated and summarized respectively. Final analysis from seven eligible studies was performed. Aberrant SF-1 expression was significantly lower in ovarian cancer compared to that of normal ovarian tissue (OR = 0.02, 95% CI = 0.00-0.16, p = 0.0002). However, SF-1 protein expression was not significantly different between benign and malignant ovarian tumors (p = 0.35). Interestingly, aberrant SF-1 expression was significantly higher in ovarian sex cord stromal tumors than that of ovarian cancer (OR = 0.00, 95% CI = 0.00-0.01, p < 0.00001). The results of this meta-analysis suggest that SF-1 may play an important role in ovarian cancer initiation and progression. Moreover, SF-1 expression may serve as a marker in the differential diagnosis between ovarian sex cord stromal tumors and ovarian cancer.