Endometriosis (EMs) is characterized by dysregulated persistence and enhanced invasiveness of ectopic endometrial cells. Current treatment strategies remain limited by high recurrence rates and considerable adverse effects. Although iron overload is a recognized feature of EMs, ectopic lesions paradoxically demonstrate resistance to ferroptosis, an iron-dependent cell death mechanism. The mechanistic involvement of microsomal glutathione S-transferase 3 (MGST3) in this process remains to be clarified. This study examined MGST3 expression and its functional role in EMs using in vitro assays and an in vivo murine model. MGST3 expression was markedly increased in ectopic endometrial cells compared with controls. Functional analyses indicated that MGST3 enhances the invasive phenotype of immortalized human ectopic endometrial stromal cells while concurrently inhibiting apoptosis. Furthermore, treatment with GSTO-IN-2 in the mouse model attenuated ectopic lesion growth and significantly altered ferroptosis-associated markers. However, due to the lack of specificity of GSTO-IN-2 for MGST3, these in vivo findings cannot be directly attributed to an MGST3-specific effect. Collectively, these results indicate that MGST3 may play a role in the regulation of ferroptosis in EMs, with its overexpression contributing to ferroptosis-associated survival phenotypes in endometrial stromal cells. MGST3 may therefore serve as a potential biomarker and requires further investigation as a therapeutic target in EMs.

OBJECTIVE:To evaluate the safety and efficacy of sequential combination therapy comprising gonadotropin-releasing hormone agonist (GnRH-a), hysteroscopic surgery (residual lesion resection plus endometrial ablation), and levonorgestrel-releasing intrauterine system (LNG-IUS) insertion in patients with adenomyosis who exhibited suboptimal response to high-intensity focused ultrasound (HIFU) ablation (non-perfused volume (NPV) ratio < 50%). METHODS:This retrospective study enrolled 71 patients with adenomyosis who underwent HIFU ablation with an NPV ratio < 50% and subsequently received three doses of GnRH-a, followed by hysteroscopic surgery (residual lesion resection plus endometrial ablation) with concurrent LNG-IUS insertion (HIFU-GHL regimen). All patients completed a minimum follow-up of 24 months. Clinical efficacy was assessed using the visual analogue scale (VAS) for dysmenorrhea and the sensation quantity scale (SQS) for menstrual blood volume at baseline and at 6, 12, 18, and 24 months post-treatment. RESULTS:The median follow-up duration was 39 months (IQR: 29-53 months). The median NPV ratio following HIFU ablation was 22.2% (IQR: 12.0%-36.2%). Compared with baseline, significant reductions in both VAS and SQS scores were observed at all post-treatment time points (all p < 0.05), with no significant differences among the four follow-up intervals (p > 0.05). Only two patients (2.8%) required re-intervention for recurrent dysmenorrhea. CONCLUSIONS:The sequential regimen of GnRH-a, hysteroscopic surgery (lesion resection plus endometrial ablation), and LNG-IUS insertion is a safe and effective uterine-preserving salvage strategy for adenomyosis patients with suboptimal HIFU ablation (NPV ratio < 50%). Prospective randomized trials with extended follow-up are warranted to validate these findings.

Background Gestational diabetes mellitus (GDM) poses a significant health burden on women worldwide, necessitating the search for predictive, diagnostic and therapeutic approaches. Increasing evidence suggests that the receptor activator of NF-κB ligand (RANKL) is closely associated with GDM, and this study explored whether RANKL can be used as a biomarker for GDM. Methods We conducted a cross-sectional study on pregnant women attending prenatal examinations in China. 399 pregnancies were finally enrolled, of which 101 were diagnosed with GDM, and the other 298 were non-GDM. Moreover, GDM mouse model was generated with HFD-fed mice. The HFD-fed mice contained two groups, in which one was injected with recombinant protein mouse-derived RANKL and the other was injected equal volume of saline. Tropboblasts were used to investigate the mechanism of RANKL in maternal metabolism homeostasis. Results There was a negative correlation between serum RANKL level and the risk of GDM in both crude and adjusted models [OR = 0.993 (95%CI: 0.99–0.996), OR = 0.994 (95%CI: 0.99–0.997)]. Using restricted cubic spline plateau points to determine the optimal effect of serum RANKL. Threshold range is about 800–900 pg/mL. ROC analysis showed that serum RANKL had a high diagnostic value for GDM [AUC = 0.7024 (95% CI: 0.6520–0.7529), p < 0.0001, sensitivity = 0.842, specificity = 0.574]. Conclusions RANKL-treated HFD-fed mice exhibited improvements in glucose and insulin tolerance and serum insulin concentrations in animal model. Meanwhile, RANKL could promote glucose transported proteins ( Gluts ) mRNA expression. RANKL might be a diagnostic biomarker of GDM and as a potential drug target for GDM therapy via improving insulin sensitivity.

OBJECTIVE:This study aimed to retrospectively evaluate the efficacy and safety of high-intensity focused ultrasound (HIFU) versus uterine artery embolization (UAE) as pretreatment prior to ultrasound-guided suction curettage in the management of cervical pregnancy. METHODS:A retrospective review was conducted on 41 patients diagnosed with cervical pregnancy. Among them, 20 patients underwent UAE and 21 received HIFU treatment, both followed by ultrasound-guided suction curettage. RESULTS:None of the 41 patients required additional interventions due to active uterine bleeding following curettage. No significant differences were observed between the two groups in terms of age, number of previous abortions, days of amenorrhea, pretreatment serum β-hCG levels, average diameter of the gestational sac/mass, or blood loss during curettage (p > .05). Compared to the UAE group, the HIFU group exhibited significantly lower hospitalization costs, shorter hospital stays, and less pain intensity (p < .05). In the UAE group, 7 out of 20 patients experienced reduced menstrual flow; among them, 5 patients with fertility intentions underwent hysteroscopic adhesiolysis, resulting in 2 successful pregnancies. Of the remaining 13 patients in the UAE group without menstrual changes, 2 patients with fertility intentions achieved pregnancy. In the HIFU group, no patients reported alterations in menstrual volume. Among 10 patients with fertility intentions, 9 patients had pregnancies. CONCLUSIONS:In this pilot retrospective study, both UAE and HIFU demonstrated efficacy as pretreatment modalities prior to ultrasound-guided suction curettage for cervical pregnancy. HIFU showed potential advantages in pain reduction, hospitalization days, hospitalization expenses, and fertility preservation. These preliminary findings warrant validation in larger, prospective, multi-center trials.

Endometriosis (EMs) is a chronic enigmatic gynecological disorder which pathogenesis have not been fully elucidated. Exosomes have been proven to participate in endometriosis. However, the role of exosomes in the pathogenesis of EMs remains poorly defined. Exosomes were isolated from cyst fluid of EMs patients and pelvic fluid of non-EMs patients, and characterized by transmission electron microscopy, nanoparticle tracking analysis and western blot. Exosomal miRNAs were performed by small RNA sequencing. Q-PCR and cell function were performed to identify the relationship between exosomal miRNAs and endometriosis. Dual luciferase reporter assay, cell transfection, Q-PCR, Western blotting and CCK8 assays, Transwell assays and Boyden assays were conducted to explore the regulatory effects of exosomal miRNA on EMs pathogenesis in vitro using primary human endometrial stromal cells (HESCs) derived from endometriotic lesions. Compare with non-EMs group, there are 118 miRNAs were up-regulated and 40 miRNAs were down-regulated in CF group, meanwhile 22 miRNAs were up-regulated and 32 miRNAs were down-regulated in PF group. Q-PCR verified that miR-125b-5p, miR-328-3p, miR-125a-5p, miR-30e-3p were significant down-regulated, whereas miR-3141, miR-223-3p, miR-142-5p, miR-1246 were significant up-regulated in EMs patients. ROC analysis indicated that miR-125b-5p (AUC = 0.925, p < 0.001) was highly correlated with EMs pathogenesis. Dual luciferase reporter assay results demonstrated miR-125b-5p directly targeted VEGF gene. MiR-125b-5p suppressed endometrial stromal cells proliferation, migration and invasion by regulating the Phosphatidylinositol 3-Kinase (PI3K) /Protein Kinase B (AKT) signaling pathway. Exosomal miR-125b-5p was highly correlated with EMs, and it regulates the PI3K/Akt signaling pathways through VEGF to inhibit endometrial stromal cells proliferation, migration and invasion, acting as an important suppressing miRNA in endometriosis pathogenesis.

Endometrial cancer, accounting for over 90% of uterine malignancies, has experienced a significant global rise in incidence and mortality. Conventional therapies face limitations including fertility compromise, systemic toxicity, drug resistance, and poor outcomes in advanced/recurrent cases. Considering the unique physical and chemical properties of nanomaterials, the emerging drug delivery approaches based on nanomaterials are regarded as a promising pathway for enhanced therapeutic efficiency to combat endometrial cancer. Herein, this mini-review discusses emerging drug delivery approaches to overcome current treatment challenges. We classify common therapeutic nanomaterials into polymer-based nanocarriers, quantum dots, liposomes, and exosomes, analyzing their synthesis, mechanisms, and preclinical efficacy. Finally, scientific challenges and future perspectives for ongoing research in this field are presented.

BACKGROUND:Various studies have shown an association between metals exposure and gestational diabetes mellitus (GDM). However, the mediating mechanisms underlying this relationship remain unclear. This study mainly investigate the mediation effect of blood cell count in the relationship between metals exposure with blood glucose homeostasis during pregnancy. METHODS:Blood cell counts and six blood metals were measured in pregnant women at 10-12 weeks of gestation. An oral glucose tolerance test (OGTT) was performed to diagnose GDM in the second trimester. Bayesian kernel machine regression (BKMR) was used to analyze mixed- and single-metal exposure models. Linear and logistic regression models were used to assess associations of metal levels with blood cell counts, blood glucose levels, and GDM risk. The role of blood cell counts on the association between metal concentrations and levels of blood glucose was assessed using mediation analysis. RESULTS:The single-exposure analysis indicated that blood zinc (Zn) exposure levels were significantly and positively correlated with OGTT glucose values and GDM risk. Mediation analysis revealed that the association of Zn with 1 h glucose, 2 h glucose, and AUC (area under the curve) was mediated by WBC counts and neutrophil counts. CONCLUSIONS:This study demonstrated that WBC and neutrophil counts mediated the relationship between blood Zn exposure in early pregnancy and blood glucose homeostasis in the second trimester. These findings provide inspiration for further mechanism research.

High-intensity focused ultrasound ablation combined with systemic methotrexate treatment of intramural ectopic pregnancy following adenomyomectomy: A case reportY Peng, Y Dai, G Yu, P Jin*Department of Gynecology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China.*Correspondence: P Jin, MD, Department of Gynecology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, 518000, China. Email pingjin66@126.comObjective To explore high-intensity focused ultrasound (HIFU) ablation combined with systemic methotrexate treatment for intramural ectopic pregnancy (IMP).Design A case report.Setting Gynaecological department in a single hospital.Population A patient diagnosed as IMP with adenomyosis 5 years post open adenomyomectomy.Methods The diagnosis of IMP was made through MRI and a 1.0-cm sinus tract was found to connect the gestational sac (GS) and endometrial cavity, and the GS was located in the adenomyosis leison. HIFU treatment combined with systemic MTX was performed.Main outcome measures Effects of HIFU combined with systemic MTX in treating IMP.Results The serum β-hCG level declined to normal 4 weeks after HIFU treatment. The GS were not foundon MRI after 4 months.Conclusions HIFU ablation combined with systemic MTX is effective in the treatment of IMP with adenomyosis and favorable for maintaining fertility.Keywords Intramural ectopic pregnancy; high-intensity focused ultrasound ablation; adenomyosis; methotrexate; adenomyomectomyTweetable abstract HIFU combined with systemic MTX is effective in treating IMP.

Objective This study aims to assess the clinical efficacy and safety of combining high-intensity focused ultrasound (HIFU) with ultrasound-guided suction curettage for the treatment of cesarean scar pregnancy (CSP) at different time intervals.Methods A total of 115 CSP patients were enrolled and divided into two groups based on the time between HIFU ablation and suction curettage. Group A (n = 50) underwent suction curettage 24-48 h after HIFU ablation, while Group B (n = 65) had suction curettage within 6 h of HIFU ablation. The study compared and analyzed the clinical characteristics, treatment success rates, and intraoperative hemorrhage during ultrasound-guided suction curettage.Results The demographic characteristics of the two groups were similar, with no statistically significant differences observed in HIFU parameters, treatment success rates, blood loss, the use of Foley catheter balloons, or hospital expenses (p > 0.05). Importantly, suction curettage performed within 6 h after HIFU ablation resulted in shorter hospitalization times compared to suction curettage performed 24-48 h after the ablation (p < 0.05).Conclusions Suction curettage within 6 h after HIFU ablation is an effective, safe, and cost-efficient treatment for patients diagnosed with CSP.

Objectives To observe the therapeutic efficacy of high-intensity focused ultrasound (HIFU) combined with different pharmacological treatments for adenomyosis.Materials and methods A total of 126 patients with adenomyosis who underwent HIFU combined with pharmacological treatment were retrospectively reviewed. Patients were treated with either dienogest (DNG) (Group A, N = 38) or GnRH-a (Group B, N = 88) for three months after HIFU, and received levonorgestrel-releasing intrauterine systems (LNG-IUS) at the end of the third month. Visual Analog Scale (VAS) and Pictorial Blood Loss Assessment Chart (PBAC) scores were used for evaluating symptom improvement.Results After propensity score matching (1:2), 38 patients were included in Group A and 76 in Group B. All patients showed significant improvement in VAS and PBAC scores after HIFU, but the PBAC score of Group A was significantly higher than that of patients in Group B at 18 months [11.50 (1.00, 29.50) vs. 0.00 (0.00, 16.50), p < 0.01] and 24 months [4.00 (0.25, 27.75) vs. 0.00 (0.00, 12.75), p = 0.04] after HIFU. Furthermore, patients in Group B had a greater uterine volume reduction at 24 months after HIFU than that of patients in Group A [51.00 (27.00, 62.00) vs. 30.00 (17.00, 42.75, p = 0.02)]. However, the adverse effects in Group A were lower than those in Group B [7 (15.79) vs. 35 (46.05), p < 0.01]. No significant difference was observed in the recurrence rate between the two groups.Conclusions HIFU combined with DNG and LNG-IUS is a safe and effective treatment for patients with adenomyosis.

宫腔粘连是最常见的子宫内膜损伤疾病,导致闭经、月经少、不孕或流产,严重影响妇女的健康和生育能力.水凝胶制剂不仅可作为物理屏障,还具有可控生物活性,促进损伤子宫内膜的修复,在宫腔粘连治疗的探索性研究中取得了一定的进展,成为近年研究的热点.本文根据水凝胶制剂的不同作用,作为物理屏障和药物传递系统在宫腔粘连治疗中的应用及机制作一综述,旨在为宫腔粘连治疗提供新的思路与方法.

Objective To assess the safety and clinical efficacy of high-intensity focused ultrasound (HIFU) combined with gonadotropin-releasing hormone agonists (GnRH-a), hysteroscopic surgery (hysteroscopic resection of adenomyosis and endometrial ablation) and levonorgestrel intrauterine system (LNG-IUS) for the treatment of adenomyosis patients with an unsatisfactory HIFU ablation. Design A retrospective analysis. Setting A specialized hospital in China. Population In all, 25 adenomyosis patients with HIFU ablation, the the non-perfused volume (NPV) ratio＜50%, without fertility requirement. Methods All patients underwent HIFU ablation combined with GnRH-a, hysteroscopic surgery and LNG-IUS treatment (HGHL), with a follow-up period of at least 12 months. Main outcome measures The changes in dysmenorrhea and menstrual volume before, and at 3, 6 and 12 months following HGHL treatment. Results All 25 patients enrolled in the study were successfully treated with the HGHL combination with a median follow-up length of 15 months (range, 12–30 months). Mean value of the NPV ratio calculated immediately after the HIFU treatment was (32.8±10.4)%. Mean operation time, median intraoperative blood loss and median length of hospital stay of hysteroscopic surgery were 42.9±12.8 min, 10 (5,15) ml, and 3 (3,3) days, respectively. No significant complications were observed during HGHL treatment. Compared with the symptom scores before the HIFU treatment, the score of dysmenorrhea and menstrual volume decreased significantly at 3, 6 and 12 months after HGHL treatment ( p< 0.05), and no significant difference was observed between 3, 6 and 12 months after HGHL treatment ( p> 0.05). No recurrence was observed during the follow-up. Conclusions HGHL is a novel and effective combination therapy for adenomyosis with unsatisfactory HIFU ablation with the goal of preserving as much of the uterus as possible.

Triple-negative breast cancer (TNBC) is an aggressive cancer that poses a significant threat to women's health. Unfortunately, the lack of clinical targets leads the poor clinical outcomes in TNBC. Many cancers demonstrate overexpression of receptor for advanced glycation end products (RAGE), which can contribute to cancer progression. Despite the potential therapeutic value of blocking RAGE for TNBC treatment, effective peptide drugs have yet to be developed. In our study, we observed that RAGE was highly expressed in TNBC and was associated with poor disease progression. We subsequently investigated the antitumor effects and underlying mechanisms of the RAGE antagonist peptide RP7 in both in vitro and in vivo models of TNBC. Our study revealed that RP7 selectively binds to RAGE-overexpressing TNBC cell lines, including MDA-MB-231 and BT549, and significantly inhibits cell viability, migration, and invasion in both cell lines. Furthermore, RP7-treatment suppressed tumor growth in TNBC xenograft mouse models without inducing detectable toxicity in normal tissues. Mechanistically, RP7 was found to inhibit the phosphorylation of ERK1/2, IKKα/β, IKBα, and p65 to block the NF-κB pathway, prevent the entry of p65 into the nucleus, decrease the protein expression of Bcl-2 and HMGB1, and promote the release of cytochrome C from the mitochondria into the cytoplasm. These effects were observed to activate apoptosis and inhibit epithelial-mesenchymal transition (EMT) in TNBC cells. This study highlights RAGE as a candidate therapeutic target for TNBC treatment and suggests that the RAGE antagonist peptide RP7 is a promising anticancer drug for TNBC.

OBJECTIVE:To investigate the clinical efficacy and safety of high intensity focused ultrasound (HIFU) combined with ultrasound-guided suction curettage in patients with type I/II/III cesarean scar pregnancy (CSP).METHODS:A total of 153 patients with CSP were enrolled and classified according to the type of CSP. All of them were treated by HIFU combined with ultrasound-guided suction curettage. When active uterine bleeding was observed after curettage, a Foley balloon was used for hemostasis by compression. Baseline characteristics, technical parameters of HIFU, intraoperative blood loss in suction curettage, the time for serum β-HCG to return to normal levels, reproductive outcomes, and adverse effects were recorded and analyzed.RESULTS:152 patients completed one session of HIFU combined with suction curettage except one patient transferred to surgery. Total energy used for ablation and the time for serum β-HCG return to normal level in type II and III were significantly higher than type I (p < .05). The treatment time and sonication time of HIFU in type III were significantly longer than type I (p < .05). Vaginal bleeding after curettage and the rate of using Foley catheter balloon in type III was larger than type I and II.CONCLUSIONS:HIFU combined with ultrasound-guided suction curettage is a safe and effective treatment option for patients with type I/II/III CSP and desire for fertility. Patients with type III CSP were more dependent on Foley catheter balloon compression therapy than the other two types after HIFU combined with curettage.

目的 比较高强度聚焦超声(HIFU)与子宫动脉栓塞(UAE)联合负压吸宫术治疗剖宫产瘢痕妊娠(CSP)的临床疗效及对再次妊娠的影响.方法 回顾性分析2017年1月至2019年3月在深圳市妇幼保健院接受HIFU联合吸宫或UAE联合吸宫治疗的134例CSP患者的临床资料,其中HIFU组73例,UAE组61例,随访时间>6个月,有生育要求者随访时间>18个月.比较两组患者的吸宫出血量、住院时间、住院费用、疼痛评分、术后月经情况和再次妊娠率等指标.结果 HIFU组患者的住院时间、住院费用、疼痛评分、术后月经量减少发生率分别为3(3,5)d、(11880.19±1376.51)元、2(1,2)分、2.7％,明显低于UAE组的5(4,6)d、(14787.28±2750.36)元、6(6,7)分、29.5％,差异均有统计学意义(P<0.05);HIFU组患者的再次妊娠率为93.3％,明显高于UAE组的48.1％,差异有统计学意义(P<0.05);两组患者的吸宫出血量、吸宫总体有效率、β-HCG下降至正常的时间、月经复潮时间、HCG下降不满意发生率、不全流产发生率和再次CSP发生率比较差异均无统计学意义(P>0.05).结论 HIFU与UAE联合吸宫术均可有效治疗CSP,相对于UAE联合吸宫术,HIFU联合吸宫术治疗CSP在减轻疼痛、减少住院时间和住院费用方面有优势,对术后月经量及再次妊娠影响小,并发症少,适合有再生育需求的CSP患者.

OBJECTIVE:To investigate the clinical effect of high intensity focused ultrasound (HIFU) ablation combined with gonadotropin-releasing hormone agonist (GnRH-a) and levonorgestrel-releasing intrauterine system (LNG-IUS) in the treatment of adenomyosis patients who failed to respond to drug therapies. STUDY DESIGN:A total of 47 patients with adenomyosis who had failed to respond to drug therapies and had no fertility desires were treated with HIFU combined with GnRH-a and LNG-IUS. The score of dysmenorrhea and menstrual volume were measured at pre and 6-, 12-, 18-, 24-month post-HIFU. RESULTS:All patients completed HIFU ablation without major postoperative complications. Compared with the symptom scores before the HIFU treatment, the score of dysmenorrhea and menstrual volume decreased significantly at 6, 12, 18 and 24 months after HIFU treatment (p < 0.05), but no significant difference was observed between 6, 12, 18 and 24 months after HIFU (p > 0.05). The clinical success rate was 100%, 100%, 95.7% and 93.6% respectively at 6, 12, 18 and 24 months after the combined treatment. CONCLUSION:The combined therapeutic regimen of HIFU, GnRH-a and LNS-IUS is safe and effective, which can be an alternative treatment option for patients with adenomyosis who failed to respond to drug therapies to avoid adenomyomectomy or hysterectomy.

Abstract Background: Endometriosis (EMS) is a chronic gynaecological disease. Exosomal miRNAs appear to be associated with the progression of EMS, which suggest potential circulating biomarkers in EMS.Methods: Differential centrifugation, illumina small RNA sequencing, bioinformatics analysis and qRT-PCR are used to compare the pelvic fluid of patients with a clinical diagnosis of EMS and matched controls.Results: Six miRNAs (miR-135a-5p, miR-196a-5p, miR-449b-5p, miR-4454, miR-4286, and miR-5100) showed significant differences in the EMS group in initial screening (log2FC > 2). Receiver-operator curve (ROC) analysis further indicated miR-4454 (area under the curve (AUC) = 0.956, P < 0.05) and miR-5100(area under the curve (AUC) = 0.900, P < 0.05) were highly correlated with the pathogenesis of EMS. Validation on the samples from 10 patients and 10 healthy people.Conclusion: Our miRNA expression data provide altered expression and potential prospects for biomarkers in EMS.

Choriocarcinoma is characterized by malignant proliferation and transformation of trophoblasts and is currently treated with systemic chemotherapeutic agents. The lack of specific targets for chemotherapeutic agents results in indiscriminate drug distribution. In our study, we aimed to delineate the mechanism by which G protein-coupled receptor 1 (GPR1) regulates the development of choriocarcinoma and thus investigated GPR1 as a prospective chemotherapeutic target. In this study, GPR1 expression levels were examined in several trophoblast cell lines. We found significantly higher GPR1 expression in choriocarcinoma cells (JEG3 and BeWo) than in normal trophoblast cells (HTR-8/SVneo). Additionally, we studied the role of GPR1 in choriocarcinoma in vitro and in vivo. GPR1 knockdown suppressed proliferation, invasion, and Akt and ERK phosphorylation in vitro and slowed tumor growth in vivo. Interestingly, GPR1 overexpression promoted increased proliferation, invasion, and Akt and ERK phosphorylation in vitro. Furthermore, we identified a specific GPR1-binding seven-amino acid peptide, LRH7-G3, that might also suppress choriocarcinoma in vitro and in vivo through phage display. Our study is the first to report that GPR1 may play a role in regulating choriocarcinoma progression through the Akt and ERK pathways. GPR1 could be a promising potential pharmaceutical target for choriocarcinoma.