Gut Microbiome Dysbiosis in Patients with Endometrial Cancer vs. Healthy Controls Based on 16S rRNA Gene Sequencing.

Metabolic diseases like obesity, diabetes, and hypertension are considered major risk factors associated with endometrial cancer. Considering that an imbalance in the gut microbiome may lead to metabolic alterations, we hypothesized that alteration in the gut microbioma might be an indirect factor in the development of endometrial cancer. Our aim was to profile the gut microbiota of patients with endometrial cancer compared with healthy controls in this study. Thus, we used 16S rRNA high-throughput gene sequencing on the Illumina NovaSeq platform to profile microbial communities. Fecal samples were collected from 33 endometrial cancer patients (EC group) and 32 healthy controls (N group) between February 2021 and July 2021. The total numbers of operational taxonomic units (OTUs) in the N and EC groups were 28,537 and 18,465, respectively, while the number of OTUs shared by the two groups was 4771. This study was the first to report that the alpha diversity of the gut microbiota was significantly reduced in endometrial cancer patients vs. healthy controls. Also, there was a significant difference in the distribution of microbiome between the two groups: the abundance of Firmicutes, Clostridia, Clostridiales, Ruminococcaceae, Faecalibacterium, and Gemmiger_formicis decreased, while that of Proteobacteria, Gammaproteobacteria, Enterobacteriales, Enterobacteriaceae and Shigella increased significantly in the EC group vs. healthy controls (all p < 0.05). The predominant intestinal microbiota of the endometrial cancer patients was Proteobacteria, Gammaproteobacteria, Enterobacteriales, Enterobacteriaceae, and Shigella. These results imply that adjusting the composition of the gut microbiota and maintaining microbiota homeostasis may be an effective strategy for preventing and treating endometrial cancer.

Efficacy and pregnancy outcomes of hysteroscopic surgery combined with progestin as fertility-sparing therapy in patients with early stage endometrial cancer and atypical hyperplasia.

PURPOSE: This study aims to evaluate the efficacy of hysteroscopic curettage combined with progestin therapy in young patients with early-stage endometrial cancer (EC) and endometrial atypical hyperplasia (EAH) who wished to preserve their fertility. METHODS: This prospective cohort study included 16 patients with early-stage EC and 25 patients with EAH in Dalian Maternal and Child Health Hospital from August 2014 to October 2018. All patients received fertility-sparing therapy with hysteroscopic evaluation every 3 months until achieving complete response (CR). Demographic, clinical, and pathological data follow-up information as well as fertility outcomes was analyzed. RESULTS: There were 92.6% (37/41) patients who achieved CR. The mean treatment duration to CR was 7.47 ± 2.91 months. BMI ≤ 30 kg/m2 was associated with shorter treatment duration to achieve CR (P = 0.003). Among the patients who attempted to conceive, 30.3% (10/33) had successful pregnancy, and 18.2% (6/33) delivered live births. The implementation of assisted reproductive technology (ART) is closely associated with pregnancy (P = 0.001). CONCLUSION: The fertility-sparing therapy, hysteroscopic curettage combined with progestin therapy, of early young EC and EAH patients is safe and effective. BMI is the main factor affecting the duration of CR. After achieving CR, ART can significantly improve the pregnancy rate of these patients.

ATF3 regulates oxidative stress and extracellular matrix degradation via p38/Nrf2 signaling pathway in pelvic organ prolapse.

Pelvic organ prolapse (POP) is a common disorder in women, and it is characterized by weakening of pelvic supportive structure with extracellular matrix (ECM) degradation. Activating transcription factor 3 (ATF3) was upregulated in anterior vaginal wall tissues of POP patients. We hypothesized that upregulation of ATF3 might contribute to POP development. This study aims to unveil the role of ATF3 in the pathogenesis of POP using a H2O2-induced in vitro model. Vaginal fibroblasts were isolated from woman with POP-Q stage greater than II and asymptomatic women with normal pelvic floor support. Knockdown of ATF3 enhanced cell viability and decreased cell apoptosis. Flow cytometry and immunnofluorescence showed that ATF3 deficiency inhibited H2O2-induced ROS production and the expression of 8 OHdG and 4-HNE. Western blot and Real-time PCR analysis revealed that ATF3 deficiency attenuated ECM component degradation (increasing collagen I, collagen III and elastin) and MMPs/TIMPs imbalance (decreasing MMP2 and MMP9 and increasing TIMP2). Moreover, knockdown of ATF3 induced the activation of p38/Nrf2/HO-1 signaling pathway. Further treatment with p38 inhibitor SB203580 abolished the protection of ATF3 deficiency against H2O2-induced cell damage, which was reverted by Nrf2 activator TBHQ. Thus, ATF3 likely contributes to POP progression by inducing cell apoptosis, oxidative stress and ECM degradation via regulating p38/Nrf2 pathway, which provides a potential therapeutic target for POP.

Effects of the decrease of ß-catenin expression on human vaginal fibroblasts of women with pelvic organ prolapse.

BACKGROUND: Pelvic organ prolapse (POP) lowers the quality of life in elderly women, and there have been no studies on its role in the pathogenesis of POP. The purpose of this study is to investigate the effect of ß-catenin on proliferation and collagen anabolism in human vaginal fibroblasts (HVFs). MATERIALS AND METHODS: The adherence and differential adherence methods were used to culture and purify HVFs. RNA interference was applied to knockdown ß-catenin and lithium chloride was used to activate Wnt/ß-catenin signaling pathway. ß-catenin nuclear translocation was tested by immunofluorescence, and HVF proliferation was detected by performing MTT assays. RESULTS: The expression of ß-catenin, phosphorylated-ß-catenin, phosphorylated-glycogen synthase kinase 3ß (p-GSK3ß), collagen I, matrix metalloproteinase 2 (MMP2), and tissue-derived inhibitors of metalloproteinases 2 (TIMP2) was assessed by western blot analysis. The expression of ß-catenin and collagen I was lower in HVFs of POP group than that of control group. The proliferation rate of HVFs in POP group was lower than that in control group. Knockdown of ß-catenin decreased the cell proliferation rate and the expression of collagen I. Lithium chloride can activate the Wnt/ß-catenin signaling pathway. CONCLUSION: ß-catenin participates in the proliferation and collagen I synthesis of HVFs. The decrease of ß-catenin expression may be closely related to the occurrence, and development of POP. LiCl can activate the Wnt/ß-catenin signaling pathway in HVFs and thus increase HVFs proliferation and collagen synthesis.

Clinical analysis of pain after transvaginal mesh surgery in patients with pelvic organ prolapse.

BACKGROUND: The purpose of this study was to investigate the relevant factors of pain after transvaginal mesh (TVM) surgery for the treatment of pelvic organ prolapse and to analyse the management and relief of the pain. METHODS: A multicentre retrospective study of a clinical database of patients who underwent TVM surgery was conducted, and pain related aspects were analysed. RESULTS: A total of 1855 patients were included in the study. We divided the patients into two groups: pain-free (1805 patients) and pain (50 patients) group. The incidence of pain after TVM surgery was 2.70%, with a median occurrence time of 7.5 months. Pain mainly involved the vagina, perineum, buttocks, groin, inner thighs, and lower abdomen. Excessive intraoperative blood loss (OR = 1.284, 95% CI 0.868-2.401) and postoperative anatomic failure (OR = 1.577, 95% CI 0.952-3.104) were analysed as risk factors with statistical significance. Mesh exposure rate in the pain group was 38%, showing a significant difference between the groups (P < 0.01). Forty patients underwent non-surgical treatment, with a relief rate of 40.0%, 33 patients received surgical treatment, 15 underwent partial mesh removal, and 18 underwent complete mesh removal, with a relief rate of 84.8%. The total relief rate was 88% within all 50 patients suffering from pain. CONCLUSIONS: Excessive intraoperative bleeding and unsatisfactory postoperative anatomic outcomes can increase the risk of postoperative pain; mesh exposure is also associated with the pain. Most patients can get pain relief with proper management, more than half of whom may need mesh removal with differing approach.

Changes in ß-Catenin Expression in the Anterior Vaginal Wall Tissues of Women With Pelvic Organ Prolapse: A Potential Pathophysiological Mechanism.

OBJECTIVES: The purpose of this study was to investigate the expression of ß-catenin in the lamina propria of the anterior vaginal wall of women with pelvic organ prolapse (POP) compared with the expression in the controls. METHODS: Anterior vaginal wall tissues were obtained from women undergoing POP surgery for stage 3 or greater POP (POP group, n = 30; age, 58 ± 7.839 years), with a menopause rate of 70%, and from women without POP undergoing hysterectomy for benign indications (control group, n = 30; age, 54.7 ± 7.173 years), with a menopause rate of 50%. Hematoxylin and eosin staining and Masson trichrome staining were performed on anterior vaginal wall sections. ß-Catenin, p-ß-catenin, glycogen synthase kinase 3ß (GSK3ß), p-GSK3ß, collagen I, collagen III, MMP2, MMP9, TIMP2, caspase 3, proliferating cell nuclear antigen, and cyclin D1 were evaluated using immunohistochemical analysis. Lamina propria tissues were obtained for Western blot analyses. RESULTS: Hematoxylin and eosin staining and Masson trichrome staining showed that the collagen fibers were more disorganized and fragmented in the POP group than in the control group. In the POP samples, ß-catenin (mean density, POP vs control, 0.43 ± 0.13 vs 0.58 ± 0.16), p-GSK3ß, collagen I, collagen III, proliferating cell nuclear antigen, and cyclin D1 were downregulated in the lamina propria, whereas in the control group, p-ß-catenin, TIMP2, and caspase 3 were downregulated (P < 0.05 for all). GSK3ß was not different between the 2 groups (P > 0.05). CONCLUSION: We demonstrated that decreased ß-catenin may play an important role in the onset of POP by affecting collagen anabolism.

Enhanced recovery after surgery versus traditional care in total pelvic floor reconstruction surgery with transvaginal mesh.

OBJECTIVE: To investigate the impact of enhanced recovery after surgery (ERAS) on perioperative outcomes after total pelvic floor reconstruction surgery with transvaginal mesh. METHODS: A single-center, retrospective observational cohort study involved 177 patients who underwent total pelvic floor reconstruction surgery with transvaginal mesh between August 2015 and November 2017. Eighty-five patients treated according to a traditional protocol formed the control group and 92 patients treated using the ERAS pathway were assigned to the ERAS group. Registered outcomes included demographic characteristics, intraoperative and postoperative data (first assisted walking time, first intestinal exhaust time, length of stay, hospital costs), and complications. RESULTS: The first assisted walking time (40.6 ± 1.48 vs 23.56 ± 3.26 hours, P<0.001) and the first intestinal exhaust time (27.65 ± 11.63 vs 18.65 ± 10.68 hours, P<0.001) were earlier in the ERAS group. The implementation of the ERAS pathway was associated with shorter length of stay (121.35 vs 70.25 hours, P<0.001) and lower hospital costs (46 838.65 ± 2584.08 vs 42 793.57 ± 2560.3 RMB, P<0.001). There was no difference in surgical outcomes or postoperative complications between the two groups. CONCLUSION: ERAS is safe, economical, and reliable after total pelvic floor reconstruction surgery and promotes perioperative recovery without increasing complication rates.

Collagen changes in pelvic support tissues in women with pelvic organ prolapse.

Pelvic organ prolapse is a group of diseases caused by weakened pelvic supportive tissue, but the pathophysiology is not completely understood. Collagen is one of the most important components of the extracellular matrix in connective tissue, as it maintains the supportive functions of the pelvic floor. Collagen I and III are two major subtypes in pelvic tissues. With conflicting results of different studies, changes of their content and ratio are still disputed. The structure of collagen fibrils of pelvic organ prolapse patients become loose, disorderly and discontinuous and become stiffer than control group. Strong mechanical stress and imbalance matrix metalloproteinases /tissue-derived inhibitors of metalloproteinases can lead to collagen anabolism abnormalities causing changes of collagen content and structure. These changes are inter-influenced and are involved by multiple signaling pathways, including TGF-ß/Smad, AGE/RAGE, MAPK, PI3K/AKT, and NF-κB. Collagen changes, including content, morphologic and biomechanical changes and catabolism abnormalities, can destroy the supportive function of the pelvic floor and are closely related to the development of pelvic organ prolapse. Epidemiological data also show a genetic predisposition to collagen changes. Research about collagen changes in the pelvic floor supportive tissues is limited and controversial. Small sample sizes and different recruitment criteria, biopsy sites, and research methods make comparisons between various studies difficult. More research concerning collagen changes is needed to better understand the pathogenesis of pelvic organ prolapse.