Association of Central and General Obesity Measures With Pelvic Organ Prolapse.

OBJECTIVE: To examine the association between the combination of central and general obesity measures and the risk of pelvic organ prolapse (POP). METHODS: Waist/height ratio and body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) for 251,143 participants (aged 39-71 years) without pre-existing POP from the UK Biobank were collected at enrollment between 2006 and 2010. Participants were followed through December 19, 2022. Incident POP was identified using International Classification of Diseases, Tenth Revision codes and operating procedure codes in the medical records. Cox proportional hazards model was used to estimate the association between obesity measures and incident POP. Population-attributable fractions were calculated to indicate the proportion of cases that were attributable to obesity measures. RESULTS: During a median follow-up of 13.8 years, 9,781 POP cases were recorded. Central obesity (waist/height ratio 0.5 or greater) was associated with a 48% increased risk of POP regardless of BMI (hazard ratio [HR] 1.48; 95% CI, 1.41-1.56). Approximately 21.7% (95% CI, 19.1-24.4%) of all POP cases were attributable to central obesity. In addition, overweight without central obesity (BMI 25-29.9 and waist/height ratio less than 0.5) was associated with a 23% higher risk of POP (HR 1.23; 95% CI, 1.14-1.34), and this accounted for 2.0% (95% CI, 1.1-2.9%) of all POP cases. The magnitude of increased POP risk associated with central obesity varied by age (younger than 60 years vs 60 years or older: 57% vs 39%) and by history of hysterectomy (no vs yes: 54% vs 27%). CONCLUSION: Central obesity and overweight without central obesity are risk factors for POP.

Accelerometer-measured physical activity, sedentary behavior, and risk of incident pelvic organ prolapse: a prospective cohort study in the UK Biobank.

BACKGROUND: Previous studies on physical activity (PA) and pelvic organ prolapse (POP) were largely limited to self-reported PA in athletes, soldiers, and women in postpartum. We aimed to investigate the association of accelerometer-measured PA and sedentary behavior with the risk of POP in middle-aged and elderly women. METHODS: In this prospective cohort derived from the UK Biobank, the intensity and duration of PA and sedentary behavior were measured with wrist-worn accelerometers over a 7-day period in 2013-2015 for 47,674 participants (aged 42.8-77.9 years) without pre-existing POP. Participants were followed up until the end of 2022, during which incident POP was ascertained mainly by the electronic health records. Multivariable-adjusted Cox proportional hazards models and restricted cubic splines were used to assess the associations of interest. Isotemporal substitution models were applied to test the effects of substituting a type of activity with equivalent duration of others. RESULTS: During a median follow-up of 8.0 years, 779 cases of POP were recorded. The duration of light-intensity PA (LPA) was positively whereas sedentary time was negatively associated with the risk of POP. Every additional 1 h/day of LPA elevated the risk of POP by 18% (95% confidence interval [CI], 10%-26%). In contrast, the risk decreased by 5% (95% CI, 0-8%) per 1 h/day increment in sedentary behavior. No associations were found between moderate-intensity PA (MPA) or vigorous-intensity PA (VPA) and POP, except that women who had a history of hysterectomy were more likely to develop POP when performing more VPA (53% higher risk for every additional 15 min/day). Substituting 1 h/day of LPA with equivalent sedentary time was associated with a 18% (95% CI, 11%-24%) lower risk of POP. The risk can also be reduced by 17% (95% CI, 7%-25%) through substituting 30 min/day of LPA with MPA. CONCLUSIONS: More time spent in LPA or less sedentary time was linked to an elevated risk of POP in middle-aged and elderly women, while MPA or VPA was not. Substituting LPA with equivalent duration of sedentary behavior or MPA may lower the risk of POP.

Effectiveness of Laparoscopic Pectopexy for Pelvic Organ Prolapse Compared with Laparoscopic Sacrocolpopexy.

STUDY OBJECTIVE: To evaluate the clinical benefits of laparoscopic pectopexy vs laparoscopic sacrocolpopexy in women with pelvic organ prolapse (POP). DESIGN: Prospective cohort study. SETTING: A tertiary hospital. PATIENTS: We included 203 patients with POP. INTERVENTIONS: Laparoscopic pectopexy or laparoscopic sacrocolpopexy. MEASUREMENTS AND MAIN RESULTS: Anatomic effectiveness was measured using the POP Quantification system, both before and after operation. Functional recovery effectiveness was evaluated using complications and recurrence rates within 1 year. Quality of life was assessed by the Pelvic Floor Distress Inventory-20 and Incontinence Quality of Life questionnaires at enrollment and postoperative months 3, 6, and 12. Comparisons between groups were performed using t test, chi-square test, and mixed-effects model with repeated measures. The analysis included 203 eligible patients (sacrocolpopexy, 101; pectopexy, 102). The proportion of robotic-assisted surgeries was lower in the pectopexy group than in the sacrocolpopexy group (15.7% vs 41.6%, p <.001). The average operation time of pectopexy was shorter than that of sacrocolpopexy (174.2 vs 187.7 minutes) with a mean difference of 13.5 minutes (95% confidence interval, 3.9-23.0; p = .006). Differences of intraoperative blood loss, length of hospital stay, and postoperative 7-day complications between groups were not significant. Anatomic successes were obtained in both groups with similar improvement in POP Quantification scores. The rate of urinary symptoms recurrence was higher in the pectopexy group (13.7%) than in the sacrocolpopexy group (5.0%) at the 1-year follow-up (odds ratio, 3.1; 95% confidence interval, 1.1-8.8, p = .032). The Pelvic Floor Distress Inventory-20 and Incontinence Quality of Life scores were better improved at postoperative months 3, 6, and 12 for laparoscopic pectopexy than for sacrocolpopexy. CONCLUSION: Laparoscopic pectopexy revealed comparable anatomic success, shorter operation time, and better improvement in quality of life scores of prolapse, colorectal-anal, and urinary symptoms at 1-year follow-up, possibly being an alternative when sacrocolpopexy is not practicable. However, clinicians should pay more attention to the recurrence of urinary symptoms after pectopexy.

LncRNA UCA1 promotes cisplatin resistance in gastric cancer via recruiting EZH2 and activating PI3K/AKT pathway.

Background: Drug resistance of cancer cells is one of the major causes of chemotherapy failure. Recently research demonstrated that long non-coding RNA Urothelial cancer associated 1 (UCA1) could promote tumor cisplatin resistance. In this study, we aim to investigate the role of UCA1 in the cisplatin treatment of gastric cancer and its underlying mechanism. Methods: Cell counting kit-8 (CCK-8) assay and apoptosis assay were used to detect the effects of different doses of cisplatin on the proliferation and apoptosis of gastric cancer. We examined the expression relationship between the Enhancer of Zeste Homologue 2 (EZH2) and UCA1 by quantitative Real-time polymerase chain reaction (qRT-PCR) and western blot analysis. Western blot analysis was also performed to detect the expression levels of apoptosis-related proteins, EZH2 and key genes in PI3K/AKT signaling pathway, RIP and RNA pull down assays were performed to explore the interaction between UCA1 and EZH2. Results: We demonstrated that higher the UCA1 expression levels in GC tissues correlated with the poorer the prognosis of patients according to the TCGA database, the GEO database. Moreover, overexpression of UCA1 promotes GC cell proliferation and inhibits cisplatin-induced apoptosis. Knockdown of UCA1 showed the opposite results. Besides, UCA1 exerted its function through interacting with EZH2 and regulates EZH2 expression, knockdown of EZH2 decreased cisplatin resistance of GC cells. Hence, UCA1 promotes cisplatin resistance of GC via recruiting EZH2 and activating PI3K/AKT pathway. Conclusion: Our research revealed the lncRNA UCA1 promoted the cisplatin resistance of GC by recruiting EZH2 and activating PI3K/AKT pathway to modulate cell apoptosis, indicating treatments targeting UCA1 or EZH2 might provide meaningful therapeutic strategies for cisplatin-resistance GC patients.

LncRNA MALAT1 Regulates the Cell Proliferation and Cisplatin Resistance in Gastric Cancer via PI3K/AKT Pathway.

BACKGROUND: Many studies showed that long non-coding RNA MALAT1 is served as an oncogene. However, the specific role of MALAT1 in gastric cancer is not fully elucidated. The aim of this study is to elucidate the regulatory effects of MALAT1 on tumor development and cisplatin resistance in gastric cancer. METHODS: TCGA database was applied to investigate the expression levels of MALAT1 in GC tissues and normal gastric tissues and its correlation with GC patients' survival. Univariate and multivariate analysis were performed to investigate whether MALAT1 expression is an independent risk for overall survival of gastric cancer patients. The expression of MALAT1 was detected by Quantitative real-time PCR. After knockdown or overexpression of MALAT1, the cellular functions of GC cells were detected by cell-proliferation, flow cytometry, transwell assay and colony formation assays, respectively. Western blot analysis was performed to detect the protein levels of Bcl-2 and key genes in the PI3K/AKT pathway in GC cells. Finally, CCK-8 assay was performed to explore the effect of MALAT1 on cisplatin resistance of GC cells. RESULTS: Higher expression of MALAT1 was detected in GC tissues than that of adjacent normal tissues, high MALAT1 expression is an independent risk for overall survival of gastric cancer patients. Knockdown of MALAT1 inhibited proliferation, migration and invasion of GC cells, while overexpression of MALAT1 Overexpression of MALAT1 yielded opposite results. Western blot results showed that protein expressions of p-PI3K, p-AKT and p-STAT3 were downregulated after MALAT1 knockdown in GC cells, while these proteins were upregulated after MALAT1 overexpression. Additionally, the IC50 in MGC803/CDDP cells transfected with si-MALAT1 was lower than in those transfected with si-NC. The apoptotic rate in MGC803 cells transfected with pcDNA-MALAT1 was remarkably lower than those transfected with NC. CONCLUSION: We demonstrated that MALAT1 is highly expressed in GC, high MALAT1 expression is an independent risk factor for OS among GC patients. Moreover, MALAT1 promotes malignant progression of GC and contributes to cisplatin resistance of GC cells, indicating MALAT1 may serve as a biological hallmark for predicting the prognosis of GC.

Three Biomarkers Predict Gastric Cancer Patients' Susceptibility To Fluorouracil-based Chemotherapy.

Background: Fluorouracil-based chemotherapy is recommended by the main clinical guidelines for post-operative gastric cancer (GC) patient's chemotherapy treatment, this study aim to establish relate model to predict patients' susceptibility to fluorouracil-based chemotherapy to prevent patients' unnecessary exposure to chemotherapy treatments and improve patients' treatment. Methods: Data from Gene Expression Omnibus (GEO) database, Cancer Cell Line Encyclopedia (CCLE) database, Cancer Therapeutics Response Portal (CTRP) and The Cancer Genome Atlas (TCGA) were used. A predictive model was built based on univariate and multivariate Cox analysis and visualized by nomogram. Survival analysis was performed using Kaplan-Meier and log-rank test. Results: A total of 514 differentially expressed genes (DEGs) were identified between fluorouracil-resistant cell lines and fluorouracil-sensitive cell lines based on CCLE database. A total of 300 patients who had radical gastrectomy were recruited, of which 144 received fluorouracil-based chemotherapy and 156 were untreated. Three biomarkers (CTF1, BTN3A3, ADAD2) were finally selected by univariate and multivariate Cox regression analysis to establish the predictive models visualized by nomogram. This model could precisely predict both the Disease free survival (DFS) and Overall survival (OS) of patients treated with fluorouracil-based chemotherapy after surgery compared to untreated GC patients validated by both GEO database and TCGA database. Conclusion: Our data established three genes-based predictive model which might predict GC patients' susceptibility to fluorouracil and help clinicians develop personalized treatment.

Palmitate acid promotes gastric cancer metastasis via FABP5/SP1/UCA1 pathway.

BACKGROUND: Gastric cancer (GC) has a clear predilection for metastasis toward omentum which is primarily composed of adipose tissue, combine with our previous research that long non-coding RNA Urothelial cancer associated 1 (UCA1) could promote the peritoneal metastasis of GC, we put forward the hypothesis that fatty acids (FAs) might contribute to these phenomena and a connection between FAs and UCA1 might exist. METHODS: TCGA database was applied to investigate the expression levels of UCA1 in GC tissues and normal gastric tissues and its correlation with GC patients' survival. Transfection of siRNA was utilized to knockdown cellular levels of FA-binding protein 5 (FABP5), SP1, UCA1. Migration assay and invasion assay were performed to assess the biological effects of palmitate acid (PA), FABP5, SP1 and UCA1 on GC metastasis. The underlying mechanism was investigated via western blot, immunofluorescence (IF), semi-quantitative RT-PCR (sqRT-PCR) and quantitative RT-PCR (qRT-PCR) analysis. RESULTS: Here we demonstrated that PA could promote the nuclear transport of FABP5, which then increased the nuclear protein levels of SP1. Consequently, GC cellular expression levels of UCA1 were increased which promoted the metastatic properties of GC. Besides, the cellular levels of UCA1 in GC tumor tissues were significantly higher than that in normal tissues. Its levels in GC tumor tissues also negatively correlated with the prognosis of GC patients using TCGA database. CONCLUSIONS: Our research revealed the potential tumor-promoting effect of FA transport protein FABP5. We also established a connection between non-coding RNA and FA metabolism, treatment targeted either to patients' diets or FABP5 might improve the prognosis of GC patients.

Prediction of platinum-resistance patients of gastric cancer using bioinformatics.

Lack of guidelines for personalized chemotherapy treatment after surgery has caused gastric cancer (GC) patients' unnecessary exposure to toxicity and the financial burden of chemotherapy treatments. In our study, we aimed to identify potential biomarkers to predict GC patients' susceptibility to platinum-based on Gene Expression Omnibus (GEO) data sets. A total of 603 differentially expressed genes (DEGs) were identified between platinum-resistant cell lines and platinum-sensitive cell lines based on the Cancer Cell Line Encyclopedia (CCLE) data sets. A total of 253 patients who had accepted radical gastrectomy were recruited, of which 97 received platinum-based chemotherapy and 156 were untreated. Three biomarkers (BRMS1, ND6, SRXN1) were then selected by univariate and multivariate Cox regression analysis to establish the predictive models using nomogram. Then this model was further validated through the GEO data set (GSE62254) which showed that this model could precisely predict the disease-free survival and overall survival of patients treated with platinum-based chemotherapy after surgery compared with untreated GC patients (P < 0.0001). This predictive model might provide helpful messages about the patients' susceptibility to platinum to guide personalized chemotherapy.

CD36 mediates palmitate acid-induced metastasis of gastric cancer via AKT/GSK-3ß/ß-catenin pathway.

BACKGROUND: Gastric cancer (GC) has a clear predilection for metastasis toward the omentum which is primarily composed of adipose tissue, indicating that fatty acids may contribute to this phenomenon. However their function remains poorly understood in GC. In this study, we investigated the role of palmitate acid (PA) and its cellular receptor CD36 in the progression of GC. METHODS: Immunohistochemical (IHC) staining was performed to detect CD36 expression in GC tissues and its clinical significance was determined statistically. CD36 over-expression and knock-down expression cell models were developed and tested in vitro. Wound-healing assays, migration assays, and invasion assays were performed and peritoneal implants into nude mice were done to assess the biological effects of PA and CD36. The underlying mechanisms were investigated using western blot, immunofluorescence (IF), quantitative real-time PCR (qRT-PCR) and antibody blocking assays. RESULTS: PA promoted the metastasis of GC by phosphorylation of AKT, which facilitated the nuclear localization of ß-catenin through inactivation of GSK-3ß via phosphorylation. This tumor-promoting effect of PA was mediated by CD36, a cell surface receptor of fatty acids (FAs). The higher the CD36 expression levels in GC tissues correlated with the poorer the prognosis of patients according to the TCGA database, the GEO database and our own clinical data. CONCLUSIONS: Our experiments established CD36 as a key mediator of FA-induced metastasis of GC via the AKT/GSK-3ß/ß-catenin signaling pathway. CD36 might, therefore, constitute a potential therapeutic target for clinical intervention in GC.