Effect of coexisting adenomyosis on tumour characteristics and prognosis of endometrial cancer: A systematic review and meta-analysis.

To compare clinicopathological features and survival outcomes in patients with endometrial cancer, with and without associated adenomyosis. PubMed, Embase and Scopus databases were systematically searched for relevant observational studies. The pooled effect sizes were reported as either hazards ratio (HR) for survival-related outcomes or as odds ratio (OR) for other categorical outcomes. Weighted mean difference (WMD) was reported for continuous outcomes. All the analyses used the random effects model. A total of 21 studies (N = 46,420) were included. Compared to endometrial cancer patients without adenomyosis, patients with associated adenomyosis had improved overall 5-year survival (OS) (HR 0.62, 95% CI: 0.50, 0.79) and disease-free survival (DFS) (HR 0.60, 95% CI: 0.44, 0.82). Disease-specific survival was statistically similar in patients with and without adenomyosis (HR 0.60, 95% CI: 0.35, 1.05). Among patients with adenomyosis, the risk of having an advanced tumour grade (Grade 2 or 3) was lower (OR 0.51, 95% CI: 0.42, 0.62) and a risk of having International Federation of Gynaecology and Obstetrics (FIGO) stage I or II was higher (OR 2.23, 95% CI: 1.65, 3.01). Patients with adenomyosis had lower risk of tumour invasion of adnexa, cervical stromal invasion, deep myometrial involvement (DMI), lympho-vascular space invasion (LVSI) and peritoneal invasion. Presence of adenomyosis in patients with endometrial cancer is associated with favourable tumour characteristics and may improve the survival.

Levonorgestrel-releasing intrauterine system effects on metabolic variables in PCOS.

BACKGROUND: We aimed to determine and compare the reproductive hormone level and metabolic of patients with polycystic ovary syndrome (PCOS) when treated with a levonorgestrel-releasing intrauterine system (LNG-IUS). OBJECTIVES: Sixty-four women with PCOS (Group A) and sixty-six healthy women inserted with a LNG-IUS for conception (Group B) were recruited from the Department of Obstetrics and Gynecology in Jinhua Hospital Zhejiang University School of Medicine. METHOD: We compared the general characteristics of the cases between the two groups, including age, body mass index (BMI), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), abdominal circumference (AC) and waist circumference (WC). Each patient was evaluated by transvaginal ultrasonography (TVS) to determine the number of oocytes and ovarian volume, and the intima-media thickness (IMT) of the common carotid artery was measured on an ECG image from the left common carotid artery before and six months, 12 months and 24 months after patients were inserted with the LNG-IUS. Hormone levels (follicle stimulating hormone, luteinizing hormone, serum estradiol and total testosterone), serum insulin, sex hormone binding globulin (SHBG), total cholesterol (TC), high density lipoprotein (HDL), and triglyceride (TG), were evaluated before and six months, 12 months and 24 months after patients were inserted with an LNG-IUS. The levels of testosterone (T) in the non-HA (hyperandrogenemia) group and HA group in PCOS group were compared with the baseline. We also compared cases without insulin resistance in the PCOS group with their baseline. RESULTS: Prior to LNG-IUS insertion, the PCOS group had significantly higher total testosterone levels (p < 0.05), lower HDL levels (p < 0.05), and a greater ovarian volume (p < 0.05) than the control group. Compared to baseline values, there was a significant increase in fasting glycemia at six months after LNG-IUS insertion (p < 0.05). Mean ovarian volume was significantly smaller than the volume prior to LNG-IUS insertion (p < 0.05); LDL and TC were significantly reduced when compared to baseline evaluation in the PCOS group. The remaining variables did not differ significantly during the 24 months follow-up period. The control group did not show any significant changes when compared to the period before LNG-IUS insertion. When the groups were compared after the 24-month follow-up, WC, AC, FSH, LH, T, SHBG, HDL, FINs, FAI and ovarian volume were significantly different when compared between the two groups (p < 0.05) . CONCLUSION: The LNG-IUS is an effective and safe non-surgical device and the use of this system for 24 months did not result in significant changes in the clinical and metabolic variables in women with PCOS and healthy control females.

Surgical Efficacy among Laparoscopic Ultrasonic Dissectors in Adenomyosis.

OBJECTIVES: The present study aimed to investigate the efficacy of ultrasonic dissectors for adenomyomectomy using the double/multiple-flap method combined with temporary occlusion of the temporary bilateral uterine artery and the utero-ovarian vessels for the treatment of symptomatic adenomyosis. DESIGN: This was a retrospective study. PARTICIPANTS: In total, 162 patients with symptomatic adenomyosis were included, and all of them had originally been scheduled to group A (n = 82) and group B (n = 80) with each group representing a different surgical application. All eligible women were informed of the potential complications, benefits, and alternatives of each approach before they were assigned to one of the two groups, and patients chose group A or group B by themselves. In group A, we performed laparoscopic ultrasonic dissectors in adenomyosis with the double/multiple-flap method combined with temporary occlusion of the bilateral uterine artery and utero-ovarian vessels, while in group B, we performed adenomyomectomy with scissors. During the period of treatment, we evaluated operative time, intraoperative blood loss, and the degree of fatigue of surgeons' fingers. RESULTS: The estimated blood loss, operative time, and the degree of fatigue of surgeons' fingers in group A were significantly lower than that in group B (p < 0.001). No serious perioperative complications were observed in either group. LIMITATIONS: This was a retrospective study. CONCLUSION: The use of ultrasonic dissectors in laparoscopic adenomyomectomy with temporary occlusion of the bilateral uterine artery and the utero-ovarian vessels leads to improvements and releases the fatigue of surgeons' fingers in laparoscopic adenomyomectomy.

The management of caesarian scar pregnancy with or without a combination of methods prior to hysteroscopy: Ovarian reserve trends and patient outcomes.

STUDY OBJECTIVE: This study compared the efficacy and safety of a combination of uterine artery embolization or methotrexate before hysteroscopy in the treatment of cesarean scar pregnancy. METHODS: We divided 276 cesarean scar pregnancy patients into three groups. Group A underwent direct hysteroscopy; Group B received uterine artery embolization plus hysteroscopy; Group C received the systemic administration of methotrexate prior to hysteroscopy. RESULTS: The patients in Group A lost significantly more blood than those in Groups B (P < 0.05). There were no significant differences between the three groups with regards to massive hemorrhage and transfusion (P > 0.05). None of the patients required hysterectomy. Group A was also associated with a significantly shorter period of hospitalization, reduced medical costs, and fewer adverse events than either Group B or C (P < 0.05). Moreover, among women of advanced age (≥35y), the levels of serum anti-Mullerian hormone in Group B were significantly lower than those of the baseline group (P<0.05), which were significantly lower than those in Group A after surgery (4.22 ± 2.35 vs 2.78± 1.89 ng/ml, P < 0.05). CONCLUSION: Direct hysteroscopy is a reliable treatment option for most early type I cesarean scar pregnancy patients with a gestational sac. A combination of methotrexate and uterine artery embolization before hysteroscopy in these patients has limited remedial effects. uterine artery embolization may reduce ovarian reserve in patients aged ≥35y.

Harmine-based dual inhibitors targeting histone deacetylase (HDAC) and DNA as a promising strategy for cancer therapy.

Overexpression of histone deacetylases (HDACs) are observed in different types of cancers, but histone deacetylase inhibitors (HDACIs) have not shown significant efficacy as monotherapy against solid tumors. Recently, studies demonstrated that it is promising to combine HDACIs with DNA damage agents to improve DNA damage level to gain better effect on treating solid tumor. Harmine has been demonstrated to cause DNA damage by intercalating DNA. Therefore, we designed a series of harmine-based inhibitors targeting HDAC and DNA with multi-target strategy, the most potential compound 27 could bind to DNA and cause DNA damage. Furthermore 27 caused cells apoptosis through p53 signaling pathway, and exhibited significant anti-proliferation effects against HCT-116 cells (IC50 = 1.41 µM). As a DNA damage agent, 27 displayed low toxicity in normal cells. Compound 27 was demonstrated as a dual inhibitor targeting HDAC (HDAC1 IC50 = 0.022 µM and HDAC6 IC50 = 0.45 µM) and DNA, and had the potential in the treatment of solid tumor.

Discovery of PT-65 as a highly potent and selective Proteolysis-targeting chimera degrader of GSK3 for treating Alzheimer's disease.

GSK3 is a promising target for the treatment of Alzheimer's disease. Here, we describe the design and synthesize of a series of GSK3 degraders based on a click chemistry platform. A series of highly potent GSK3 degraders were obtained. Among them, PT-65 exhibited most potent degradation potency against GSK3α (DC50 = 28.3 nM) and GSK3ß (DC50 = 34.2 nM) in SH-SY5Y cells. SPR assay confirmed that PT-65 binds to GSK3ß with high affinity (KD = 12.41 nM). The proteomic study indicated that PT-65 could selectively induced GSK3 degradation. Moreover, PT-65 could effectively suppress GSK3ß and Aß mediated tau hyperphosphorylation in a dose-dependent manner and protect SH-SY5Y cells from Aß caused cell damage. We also confirmed that PT-65 could suppress OA induced tau hyperphosphorylation and ameliorate learning and memory impairments in vivo model of AD. In summary, PT-65 might be a promising candidate for the treatment of AD.

Discovery of First-in-Class Dual PARP and EZH2 Inhibitors for Triple-Negative Breast Cancer with Wild-Type BRCA.

PARP inhibitors have highly significant effects on BRCA mutant cells, allowing targeted therapy of triple-negative breast cancer (TNBC). However, some TBNC patients lack BRCA mutations. Recent studies have shown that EZH2 inhibitors can increase the sensitivity of wild-type BRCA cells to PARP inhibitors. We designed a series of dual PARP and EZH2 inhibitors, and the most promising compound, 5a, showed good inhibitory activity against PARP-1 and EZH2 and good inhibitory effects on MDA-MB-231 (IC50 = 2.63 µM) and MDA-MB-468 (IC50 = 0.41 µM) cells with wild-type BRCA. Compared with that of olaparib, the growth inhibitory activities against these two cell types increased by approximately 15- and 80-fold, respectively, which was even more effective than the combination of olaparib and tazemetostat/GSK126. 5a can induce autophagy death of tumor cells and cause less damage to normal cells. Therefore, 5a, as a first-in-class dual PARP and EZH2 inhibitor, is a potential anticancer drug candidate for the treatment of TNBC.

Synthesis and evaluation of multi-target-directed ligands with BACE-1 inhibitory and Nrf2 agonist activities as potential agents against Alzheimer's disease.

Cumulative evidence suggests that ß-amyloid and oxidative stress are closely related with each other and play key roles in the process of Alzheimer's disease (AD). Multitarget regulation of both pathways might represent a promising therapeutic strategy. Here, a series of selenium-containing compounds based on ebselen and verubecestat were designed and synthesized. Biological evaluation showed that 13f exhibited good BACE-1 inhibitory activity (IC50 = 1.06 µΜ) and potent GPx-like activity (ν0 = 183.0 µM min-1). Aß production experiment indicated that 13f could reduce the secretion of Aß1-40 in HEK APPswe 293T cells. Moreover, 13f exerted a cytoprotective effect against the H2O2 or 6-OHDA caused cell damage via alleviation of intracellular ROS, mitochondrial dysfunction, Ca2+ overload and cell apoptosis. The mechanism studies indicated that 13f exhibited cytoprotective effect by activating the Keap1-Nrf2-ARE pathway and stimulating downstream anti-oxidant protein including HO-1, NQO1, TrxR1, GCLC, and GCLM. In addition, 13f significantly reduced the production of NO and IL-6 induced by LPS in BV2 cells, which confirmed its anti-inflammatory activity as a Nrf2 activator. The BBB permeation assay predicted that 13f was able to cross the BBB. In summary, 13f might be a promising multi-target-directed ligand for the treatment of AD.

Laparoscopically assisted Adenomyomectomy Using the Double/Multiple-Flap Method with Temporary Occlusion of the Bilateral Uterine Artery and Utero-Ovarian Vessels in Comparison with the Double/Multiple-Flap Only Method.

Introduction Adenomyomectomy is the most conservative surgical treatment for adenomyosis. However, the surgical efficacy of this treatment and the best approach to use are still debated. We aimed to evaluate the efficacy of laparoscopic adenomyomectomy using the double/multiple-flap method combined with temporary occlusion of the bilateral uterine artery and the utero-ovarian vessels to treat symptomatic adenomyosis. Patients We recruited 155 patients with symptomatic adenomyosis and divided them into group A (n = 76) and group B (n = 79), with each group treated using a different surgical approach. All eligible women were informed of the potential complications, benefits, and alternatives of each approach before they were assigned into one of the two groups. In group A, we performed laparoscopic adenomyomectomy with the double/multiple-flap method while in group B, we performed a double/multiple-flap adenomyomectomy combined with temporary occlusion of the bilateral uterine artery and utero-ovarian vessels. Over a 24-month follow-up period, we evaluated operating time, intraoperative blood loss, visual analog scale (VAS) scores, anti-Mullerian hormone levels, uterine volume, and relief of menorrhagia. Results There were no significant differences between groups A and B with respect to VAS scores, relief of menorrhagia and uterine volume at 3 months, 6 months, 12 months and 24 months after surgery (p > 0.05). Both groups showed significant improvement of these parameters after surgery compared with preoperative values (p < 0.05). Blood loss in group B was significantly lower than in group A (p < 0.001) while there was no significant difference in operating times (p > 0.05). Levels of AMH did not differ significantly between the groups throughout the follow-up period (p > 0.05). Conclusion Laparoscopic adenomyomectomy with temporary occlusion of the bilateral uterine artery and the utero-ovarian vessels offers a feasible surgical option to treat symptomatic adenomyoma.

Rhodium(iii) catalyzed olefination and deuteration of tetrahydrocarbazole.

The rhodium-catalyzed olefination and deuteration of tetrahydrocarbazoles in water with the aid of an N,N-dimethylcarbamoyl-protected group is presented. This olefination method features a broad substrate scope, good functional-group tolerance, and high efficiency in water. Practical applications of the protocol are illustrated by the synthesis of various evodiamine derivatives. As such, this environmentally friendly approach to directly modify natural products will attract much attention in academic and industrial research.

Optimization of WZ4003 as NUAK inhibitors against human colorectal cancer.

NUAK, the member of AMPK (AMP-activated protein kinase) family of protein kinases, is phosphorylated and activated by the LKB1 (liver kinase B1) tumor suppressor protein kinase. Recent work has indicated that NUAK1 is a key component of the antioxidant stress response pathway, and the inhibition of NUAK1 will suppress the growth and survival of colorectal tumors. As a promising target for anticancer drugs, few inhibitors of NUAK were developed. With this goal in mind, based on NUAK inhibitor WZ4003, a series of derivatives has been synthesized and evaluated for anticancer activity. Compound 9q, a derivative of WZ4003 by removing a methoxy group, was found to be the most potential one with stronger inhibitory against NUAK1/2 enzyme activity, tumor cell proliferation and inducing apoptosis of tumor cells. By in vivo efficacy evaluations of colorectal SW480 xenografts, 9q suppresses tumor growth more effectively with an excellent safety profile in vivo and is therefore seen as a suitable candidate for further investigation.

Identification and optimization of piperlongumine analogues as potential antioxidant and anti-inflammatory agents via activation of Nrf2.

Oxidative stress and inflammation are significant risk factors for neurodegenerative disease. The Keap1-Nrf2-ARE pathway is one of the most promising defensive systems against oxidative stress. Here, dozens of piperlongumine analogues were designed, synthesized, and tested on PC12 cells to examine neuroprotective effects against H2O2 and 6-OHDA induced damage. Among them, 6d was found to be able to alleviate the accumulation of ROS, inhibit the production of NO and downregulate the level of IL-6, which indicated its potential antioxidant and anti-inflammatory activity. Further studies proved that 6d could activate Nrf2 signaling pathway, induce the translocation of Nrf2 from cell cytosol to nucleus and upregulate the related phase II antioxidant enzymes including NQO1, HO-1, GCLC, GCLM and TrxR1. These results confirmed that 6d exerted antioxidant and anti-inflammatory activities by activating Nrf2 signaling pathway. Moreover, the parallel artificial membrane permeability assay indicated that 6d can cross the blood-brain barrier. In general, 6d is promising for further development as a therapeutic drug against oxidative stress and inflammation related neurodegenerative disorders.

Development of a Tau-Targeted Drug Delivery System Using a Multifunctional Nanoscale Metal-Organic Framework for Alzheimer's Disease Therapy.

Alzheimer's disease (AD) is a widespread and burdensome neurodegenerative disease; effective diagnostic methods are lacking, and it remains incurable. The clinical applications of nanoscale metal-organic frameworks (NMOFs) have mainly focused on disease diagnosis and treatment of cancer. A multifunctional NMOF-based nanoplatform was successfully developed for the application in AD diagnosis and therapy. The magnetic nanomaterial Fe-MIL-88B-NH2 was selected to encapsulate methylene blue (MB, a tau aggregation inhibitor) and used as a magnetic resonance contrast material. Subsequently, the targeting reagent 5-amino-3-(pyrrolo[2,3-c]pyridin-1-yl)isoquinoline (defluorinated MK6240, DMK6240) was connected to the surface of Fe-MIL-88B-NH2 via 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) to enhance hyperphosphorylated tau targeting, resulting in the formation of an advanced drug delivery system, Fe-MIL-88B-NH2-NOTA-DMK6240/MB. The surface properties of Fe-MIL-88B-NH2-NOTA-DMK6240/MB enable outstanding magnetic resonance imaging capability, as well as amelioration of AD symptoms in vitro and in vivo via the inhibition of hyperphosphorylated tau aggregation and impediment of neuronal death. In conclusion, a tau-targeted drug delivery platform with both disease diagnostics and treatment functions was developed in order to promote new applications of MOFs in the fields of AD and has potential applications in other neurodegenerative diseases.

A modified technique to perform para-aortic lymphadenectomy up to the renal vein.

OBJECTIVE: To investigate the safety and feasibility of our modified technique to perform lymph node excision up to the renal vein in cases of gynecological cancer. MATERIALS AND METHODS: 87 patients with endometrial or ovarian neoplasms underwent laparoscopic para-aortic lymphadenectomy (LPAL) up to the left renal vein were enrolled prospectively. During surgery, the surgeon was positioned to the right side of the patient and an additional trocar was introduced into the upper right abdomen. The laparoscopic video screen was placed to the side of the patient's head. Three-fan retractor forceps were used to hold up the duodenum and small bowel. The rest of the procedure was the same as conventional LPAL. RESULTS: The median operating time for LPAL was 72 min (range: 40-115 min) and the median estimated blood loss was 45 ml (range: 15-1000 mL). There were two cases of intra-operative vascular injury. The median number of retrieved para-aortic lymph nodes (PALNs) was 18 (range: 10-37). Of the 87 patients, 11 patients had positive PALNs. None of the cases required laparotomy. CONCLUSION: Our findings demonstrate that our modified LPAL technique is feasible, reproducible, can achieve good exposure and reduces surgical difficulty.

Laparoscopic Myomectomy with Temporary Bilateral Uterine Artery and Utero-Ovarian Vessels Occlusion Compared with Traditional Surgery for Uterine Fibroids: Blood Loss and Recurrence.

AIM: To determine the optimal hemostatic technique for laparoscopic myomectomy (LM) by comparing temporary uterine artery blockage alone or combined with blockage of the utero-ovarian vessels. PATIENTS: Women with symptomatic uterine myoma attending the Department of Obstetrics and Gynecology in Jinhua Municipal Central Hospital. METHOD: A total of 200 patients with symptomatic uterine fibroids were randomly divided into Group A (n = 65), Group B (n = 67) and Group C (n = 68). At the beginning of the procedure, 6 U of vasopressin was injected into the myometrium of all women. LM was performed in Group A; temporary bilateral uterine artery occlusion and myomectomy were performed in Group B and temporary bilateral uterine artery and utero-ovarian vessel occlusion was performed in Group C. We then evaluated operative time, perioperative bleeding, follow-up relief of menorrhagia, and the recurrence of fibroids. RESULTS: General characteristics of the patients were similar across all 3 groups. All patients underwent successful laparoscopic operation and none of the cases needed to be converted to laparotomy; there were no intraoperative complications. There was no significant difference in the operative time between groups (p = 0.332 and p = 0.346 for single-myoma and multiple-myoma respectively), and for both single and multiple-myoma groups, the blood loss was significantly lower in Group C than Groups A and B (p < 0.001). There were no differences in the recurrence rate and menorrhagia symptom relief outcomes when -compared across the 3 groups at the 30-month follow-up (p = 0.953 and p = 0.841, respectively). At final follow-up, the pregnancy rate of the sexually active patients without contraception was not statistically significant (p = 0.958). The fertility index of anti-Mullerian hormone showed no statistical difference between groups preoperatively or at 2 days, 3 months, 6 months, and 1 year postoperatively (p = 0.998, p = 0.965, p = 0.999, p = 0.994 and p = 0.993, respectively). CONCLUSION: LM with temporary bilateral uterine artery and utero-ovarian vessels occlusion has the advantages of less intraoperative bleeding compared with LM and laparoscopic transient uterine artery ligation and does not increase the mean operative time.

Laparoscopic Myomectomy with Temporary Bilateral Uterine Artery Occlusion Compared with Traditional Surgery for Uterine Myomas: Blood Loss and Recurrence.

STUDY OBJECTIVE: To compare the surgical technique of temporary bilateral uterine artery blockage with titanium clips in laparoscopic myomectomy with traditional surgery for uterine myomas to determine efficacy, ability to control bleeding, and recurrence. DESIGN: Randomized, controlled, prospective study (Canadian Task Force classification I). SETTING: Obstetrics and gynecology department in Jinhua Municipal Central Hospital. PATIENTS: Women with symptomatic uterine myoma. INTERVENTIONS: Sixty-four patients with symptomatic uterine myomas were randomly divided into trial (group A, n = 33) and control groups (group B, n = 31). Temporary bilateral uterine artery occlusion and myomectomy were used in group A and laparoscopic myomectomy only in group B. Operative time, perioperative bleeding, follow-up relief of menorrhagia, and recurrence of myomas were evaluated. MEASUREMENTS AND MAIN RESULTS: All patients in this study underwent successful laparoscopic operation without intraoperative complications. Operative time between groups was not significantly different (p = .255 in single-myoma group and p = .811 in multiple-myoma group), blood loss in group A was notably lower than the conventional surgery group (p < .001). At final follow-up (2 years), recurrence rate and menorrhagia symptom relief were not statistically significant (p = .828 and p > .999, respectively). The fertility index of antimüllerian hormone showed no statistical difference between groups preoperatively or at 2 days, 3 months, 6 months, and 1 year postoperatively (p = .086, p = .247, p = .670, p = .753, and p = .857, respectively). CONCLUSION: Temporary bilateral uterine artery occlusion during laparoscopic myomectomy does not increase mean operative time, offers a possible option to reduce blood loss effectively, improves menorrhagia, and does not impact recurrence rate compared with conventional surgery.