LASS2 enhances chemosensitivity to cisplatin by inhibiting PP2A-mediated ß-catenin dephosphorylation in a subset of stem-like bladder cancer cells.

BACKGROUND: The benefits of first-line, cisplatin-based chemotherapy for muscle-invasive bladder cancer are limited due to intrinsic or acquired resistance to cisplatin. Increasing evidence has revealed the implication of cancer stem cells in the development of chemoresistance. However, the underlying molecular mechanisms remain to be elucidated. This study investigates the role of LASS2, a ceramide synthase, in regulating Wnt/ß-catenin signaling in a subset of stem-like bladder cancer cells and explores strategies to sensitize bladder cancer to cisplatin treatment. METHODS: Data from cohorts of our center and published datasets were used to evaluate the clinical characteristics of LASS2. Flow cytometry was used to sort and analyze bladder cancer stem cells (BCSCs). Tumor sphere formation, soft agar colony formation assay, EdU assay, apoptosis analysis, cell viability, and cisplatin sensitivity assay were used to investigate the functional roles of LASS2. Immunofluorescence, immunoblotting, coimmunoprecipitation, LC-MS, PCR array, luciferase reporter assays, pathway reporter array, chromatin immunoprecipitation, gain-of-function, and loss-of-function approaches were used to investigate the underlying mechanisms. Cell- and patient-derived xenograft models were used to investigate the effect of LASS2 overexpression and a combination of XAV939 on cisplatin sensitization and tumor growth. RESULTS: Patients with low expression of LASS2 have a poorer response to cisplatin-based chemotherapy. Loss of LASS2 confers a stem-like phenotype and contributes to cisplatin resistance. Overexpression of LASS2 results in inhibition of self-renewal ability of BCSCs and increased their sensitivity to cisplatin. Mechanistically, LASS2 inhibits PP2A activity and dissociates PP2A from ß-catenin, preventing the dephosphorylation of ß-catenin and leading to the accumulation of cytosolic phospho-ß-catenin, which decreases the transcription of the downstream genes ABCC2 and CD44 in BCSCs. Overexpression of LASS2 combined with a tankyrase inhibitor (XAV939) synergistically inhibits tumor growth and restores cisplatin sensitivity. CONCLUSIONS: Targeting the LASS2 and ß-catenin pathways may be an effective strategy to overcome cisplatin resistance and inhibit tumor growth in bladder cancer patients.

Association between the systemic immune-inflammation index and GnRH antagonist protocol IVF outcomes: a cohort study.

RESEARCH QUESTION: What is the relationship between the systemic immune-inflammation index (SII) and IVF outcomes in women undergoing a gonadotrophin-releasing hormone (GnRH) antagonist protocol? DESIGN: This retrospective cohort study analysed clinical data and blood samples collected before oocyte retrieval from participants undergoing IVF with the GnRH antagonist protocol. Logistic regression and generalized additive models were used to examine the association between SII quartiles and continuous SII values and IVF outcomes. RESULTS: Higher SII values correlated negatively with biochemical pregnancy, clinical pregnancy, live birth and implantation rates, and positively with early pregnancy loss, independent of age, body mass index, anti-Müllerian hormone and stimulation parameters. The most significant adverse outcomes were observed in the highest SII quartile. A non-linear relationship was identified between log-transformed SII and IVF outcomes, with an inflection point at an SII of approximately 6.72, indicating a threshold effect. CONCLUSIONS: Elevated SII is associated with poorer IVF outcomes in women after the GnRH antagonist protocol, suggesting its potential as a predictive marker in IVF treatments. Further research is needed to confirm these findings and explore the underlying mechanisms.

The role and controversy of pelvic lymph node dissection in prostate cancer treatment: a focused review.

Pelvic lymph node dissection (PLND) is commonly performed alongside radical prostatectomy. Its primary objective is to determine the lymphatic staging of prostate tumors by removing lymph nodes involved in lymphatic drainage. This aids in guiding subsequent treatment and removing metastatic foci, potentially offering significant therapeutic benefits. Despite varying recommendations from clinical practice guidelines across countries, the actual implementation of PLND is inconsistent, partly due to debates over its therapeutic value. While high-quality evidence supporting the superiority of PLND in oncological outcomes is lacking, its role in increasing surgical time and risk of complications is well-recognized. Despite these concerns, PLND remains the gold standard for lymph node staging in prostate cancer, providing invaluable staging information unattainable by other techniques. This article reviews PLND's scope, guideline perspectives, implementation status, oncologic and non-oncologic outcomes, alternatives, and future research needs.

The influence of preoperative urodynamic parameters on clinical results in patients with benign prostatic hyperplasia after transurethral resection of the prostate.

PURPOSE: To identify the urodynamic parameters affecting the clinical outcomes of transurethral resection of the prostate(TURP) surgery for patients with benign prostatic hyperplasia(BPH) by multifactor analysis and establish a regression model with diagnostic values. METHODS: The medical records of patients who underwent TURP surgery for BPH between December 2018 and September 2021 were collected from the urology department of the Second Affiliated Hospital of Kunming Medical University, Kunming, China. The patients' clinical data and urodynamic parameters were collected before surgery. The urodynamic parameters affecting surgical efficacy were identified by multifactor analysis, and a regression model with diagnostic values was established and evaluated. RESULTS: A total of 201 patients underwent TURP, of whom 144 had complete preoperative urodynamic data. Each urodynamic factor was subjected to multifactor analysis, and the bladder contractility index (BCI), bladder outflow obstruction index (BOOI), bladder residual urine, and bladder compliance (BC) were found to be independent influence factors on the efficacy of TURP in patients with BPH. The diagnostic value of the regression model was analyzed by receiver operating characteristics (ROC) analysis, and it was found that the AUC = 0.939 (95% CI 0.886-0.972), for which the sensitivity and specificity were 95.19% and 80%, respectively. CONCLUSIONS: The regression model had high diagnostic sensitivity and specificity in predicting the efficacy of surgery, and the diagnostic value was higher than that of individual urodynamic factors. Therefore, BCI, BOOI, bladder residual urine, and BC should be considered as independent influence factors on the efficacy of TURP surgery for BPH.

Effect of preoperative prophylactic antibiotic use on postoperative infection after percutaneous nephrolithotomy in patients with negative urine culture: a single-center randomized controlled trial.

PURPOSE: To compare the effects of different preoperative antibiotic prophylaxis (ABP) regimens on the incidence of sepsis after percutaneous nephrolithotomy (PCNL) in patients with negative urine culture. METHODS: A single-center, randomized controlled trial (June 2022-December 2023) included 120 patients with negative preoperative urine cultures for upper urinary tract stones who underwent PCNL (chictr.org.cn; ChiCTR2200059047). The experimental group and the control group were respectively given different levofloxacin-based preoperative ABP regimes, including 3 days before surgery and no ABP before surgery. Both groups were given a dose of antibiotics before the operation. The primary outcome was differences in the incidence of postoperative sepsis. RESULTS: A total of 120 subjects were included, including 60 patients in the experimental group and 60 patients in the control group. The baseline characteristics of the two groups were comparable and intraoperative characteristics also did not differ. The sepsis rate was not statistically different between the experimental and control groups (13.3% vs.13.3%, P = 1.0). A multivariate logistic regression analysis revealed that body mass index (BMI) (OR = 1.3; 95% CI = 1.1-1.6; P = 0.003) and operating time (OR = 1.1; 95% CI = 1.0-1.1; P = 0.012) were independent risk factors of sepsis. CONCLUSION: Our study showed that prophylactic antibiotic administration for 3 days before surgery did not reduce the incidence of postoperative sepsis in patients with negative urine cultures undergoing PCNL. For this subset of patients, we recommend that a single dose of antibiotics be given prior to the commencement of surgery seems adequate.

17ß-Estradiol Mediates Staphylococcus aureus Adhesion in Vaginal Epithelial Cells via Estrogen Receptor α-Associated Signaling Pathway.

Staphylococcus aureus, a major opportunistic pathogen in aerobic vaginitis (AV), can potentially invade the host and occasionally cause infections. Estrogen is associated with an altered immune response of vaginal epithelial cells and prevention of certain vaginal infectious diseases. However, the molecular mechanisms involving estrogen and S. aureus adhesion to vaginal epithelial cells remain unclear. Thus, here, VK2/E6E7 vaginal epithelial cells were infected with S. aureus, and the role of the estrogen receptor α-associated signaling pathway (ERα/FAK/Src/iNOS axis) in S. aureus adhesion was evaluated. The estrogen-associated phosphorylation status of ERα, FAK, and Src and the protein level of iNOS were assessed by western blotting. We used a specific ERα inhibitor to validate the involvement of the ERα-associated signaling pathway. The results showed that with exposure to 1 nM estrogen for 24 h, transient ERα-associated pathway activation was observed, and the protein expression upregulation was accompanied by a dose-dependent increase in 17-ß-estradiol (E2) content and increased S. aureus adherence to vaginal epithelial cells. Estrogen-induced activation of the ERα/FAK/Src/iNOS axis was notably inhibited by the specific ERα inhibitor (ICI 182780). Simultaneously, a significant decrease in the number of adherent S. aureus was observed. However, this inhibitory effect diminished after inhibitor treatment for 24 h. Our findings suggested that the ERα-associated signaling pathway might be involved in S. aureus adherence to vaginal epithelial cells, which appeared to be linked to enhanced cell adhesion leading to AV.

The Influence of Preoperative Hydronephrosis on the Prognosis after Radical Cystectomy among Patients with Different Pathological Stages of Bladder Cancer.

INTRODUCTION: Preoperative hydronephrosis is closely associated with the prognosis of patients with bladder cancer. This study assesses the effect of preoperative hydronephrosis on the prognosis after radical cystectomy (RC) among patients with different pathological stages of bladder urothelial carcinoma. METHODS: We retrospectively analyzed the clinical data of 231 patients who underwent RC because of bladder urothelial carcinoma at our institution from January 2013 to December 2017. The overall survival (OS) in patients with or without preoperative hydronephrosis was followed up and compared, and the prognostic role that preoperative hydronephrosis played in patients with different pathological stages of bladder cancer was analyzed. Multivariate analysis was performed with the help of Cox proportional hazards regression models, the postoperative survival was analyzed with the help of Kaplan-Meier plots and log-rank test, and the p values of multiple testing were corrected using the Bonferroni correction. RESULTS: Of 231 patients, 96 were patients with preoperative hydronephrosis and 115 patients had died by the end of the follow-up. Survival analysis found the 3- and 5-year survival rates after radical surgery of patients with preoperative hydronephrosis were significantly lower than those of patients without preoperative hydronephrosis (p < 0.001). Multivariate analysis found preoperative hydronephrosis, T stage of tumor, and lymphatic metastasis were independent influencing factors of postoperative OS (p < 0.05). Survival analysis of subgroups according to pathological stages found in pT3-4N0M0 patients had a significant difference in postoperative survival between the group with preoperative hydronephrosis and the group without preoperative hydronephrosis (p < 0.0001). CONCLUSION: The results indicate that preoperative hydronephrosis mainly affects postoperative OS in the patients whose pathological stage of bladder cancer is pT3-4N0M0.

The role of IL-15 on vulvovaginal candidiasis in mice and related adverse pregnancy outcomes.

Vulvovaginal candidiasis (VVC), a major gynecological disease with high recurrence rate, increases the risk of abortion, intrauterine infection, premature rupture of membranes, and premature birth in pregnancy. However, the exact pathogenesis of this disease has yet to be elucidated. To facilitate understanding of the pathogenesis of VVC in pregnancy, this study sought to establish an animal model of vaginal infection with Candida albicans in pregnant mice. Female mice were mated with male mice, and female mice were infected with C. albicans at E4.5 (embryonic day 4.5). The weight and abortion rate of pregnant mice at E0.5, E4.5, E8.5, E11.5, and E18.5 were recorded, respectively, as well as the weights of fetus and placenta on E18.5. Fetal weight at E18.5 and the weight growth rate in the experimental mice was lower than those in the control mice, but the placenta weight at E18.5 and the abortion rate in the experimental mice were increased with those of the control mice. Hematoxylin-eosin (H&E) staining, Gomori-Grocott staining and vaginal lavage culturing were conducted to verify that the experimental mice were infected with C. albicans. Differentially expressed gene IL-15 was screened out by polymerase chain reaction (PCR) array between the two groups. Enzyme-linked immunosorbent assay (ELISA) showed that IL-15 expression in plasma of the mice was decreased in the experimental group compared with the control group. RT-qPCR confirmed that IL-15 mRNA expression was increased in placental tissues, while mRNA expression of IL-15R/JAK1-JAK3/PI3K/PDK1/AKT/P70S6K-mTOR was decreased in placental tissues. In conclusion, this study demonstrated that VVC in BALB/c pregnant mice led to a series of adverse pregnancy outcomes that were related to changes in IL-15 and its downstream signaling pathways, which may indicate a potential therapy for VVC during pregnancy in humans.

Value of Quantitative SPECT/CT Lymphoscintigraphy in Improving Sentinel Lymph Node Biopsy in Breast Cancer.

Methods: We retrospectively enrolled breast cancer patients who underwent SPECT/CT prior to sentinel lymph node biopsy. Quantification of radiotracer uptake from SPECT/CT data was performed. A radioactivity count threshold (R SPECT) using SPECT/CT was calculated for detecting metastatic sentinel lymph nodes. To localize sentinel lymph nodes exactly, we compared the positions of sentinel lymph nodes localized using SPECT/CT with positions localized surgically using an intraoperative γ-probe. Results: 491 patients were included, with a median of 3 sentinel lymph nodes/patient detected by the γ-probe and 2 sentinel lymph nodes/patient detected by SPECT/CT. As the number of sentinel lymph nodes visualized on SPECT/CT images, the metastasis incidence of lymph nodes in the ≤2 SLNs group was significantly higher than that in the >2 SLNs group (35% vs. 15%, P < 0.001). No metastasis was found in lymph nodes with R SPECT ≤ 30% in the >2 SLNs group, and thus, 30% (157/526) of SPECT/CT-identified nodes would avoid unnecessary removal. The positions of sentinel lymph nodes localized by SPECT/CT and γ-probe were identical in 42% (39/93) of patients. Conclusions: Quantitative Tc-99 m SC SPECT/CT imaging has the potential to preoperatively locate sentinel lymph nodes and intraoperatively avoid unnecessary sentinel lymph node biopsy.

Study on perinatal-related factors of maternity and newborn in parturients with intrapartum fever in part of Eastern China: A cross-sectional study.

BACKGROUND: Maternal intrapartum fever has a serious impact on mother and child. However, the corresponding study seems to be in short. METHODS: The role of inflammatory cells in patients who were diagnosed with intrapartum fever lived in part of Eastern China was evaluated. The obstetrics outcomes, complete blood cell count (CBC) and thereby converted neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio, monocyte to lymphocyte ratio (MLR), and vaginal secretion were compared in different groups. RESULTS: Prepartum values of white blood cell (WBC), red blood cell (RBC), and hemoglobin (Hb) were all a little higher in the febrile group than in the afebrile group, and postpartum WBC in the afebrile group was still higher while postpartum RBC and Hb were inferior to non-fever maternity. Postpartum NLR and MLR were all higher in the fever group but not preferred overtly difference before delivery. Additionally, the comparison of WBC, RBC, Hb, platelets, neutrophils, and monocytes in prepartum and postpartum all showed significant differences. CONCLUSION: The parturition could bring about the value change of CBC and intrapartum fever might aggravate or alleviate this change. Besides, the intrapartum fever might not be caused mainly by infection and the difference between bacteria and fungus could reflect in the CBC.

Pain management of nalbuphine and sufentanil in patients admitted intensive care unit of different ages.

BACKGROUND: Pain relief for patients in the intensive care unit (ICU) can improve treatment outcomes and reduce the burden on doctors and nurses. This study aims to report the clinical analgesic and sedative effects of nalbuphine and sufentanil on ICU patients. METHODS: This study retrospectively analyzed the medical records of 87 critically ill patients who received nalbuphine or sufentanil infusion in the ICU, including demographic data, diagnosis, Acute Physiology and Chronic Health Evaluation (APACHE) II, Critical Care Pain Observation Tool (CPOT), Richmond Agitation-Sedation Scale (RASS), systolic and diastolic blood pressure, heart rate and blood oxygen saturation (SpO2). The primary outcomes of this study were CPOT and RASS scores. The secondary outcomes were hemodynamic changes, including systolic blood pressure, diastolic blood pressure, heart rate, and SpO2. The adverse events recorded during pain management, such as hypoxemia, respiration depression and bradycardia, were also collected and analyzed. RESULTS: None of the patients in both groups experienced episode of hypoxemia, respiration depression and bradycardia. However, age-stratified analyses showed that nalbuphine has a better analgesic effect than sufentanil for patients aged ≤ 60 (P < 0.05). In contrast, sufentanil showed a better analgesic effect than nalbuphine for patients aged > 60 ( P < 0.05). Furthermore, nalbuphine has a significantly better sedative effect than sufentanil for patients aged ≤ 60 (P < 0.05). CONCLUSION: ICU patients of different age groups may be suitable for different analgesics. For patients under the age of 60, nalbuphine has better analgesia and sedation than sufentanil, and does not cause respiratory depression and drastic hemodynamic changes.

The Role of 17ß-Estrogen in Escherichia coli Adhesion on Human Vaginal Epithelial Cells via FAK Phosphorylation.

Estrogen, the predominant sex hormone, has been found to be related to the occurrence of vaginal infectious diseases. However, its role in the occurrence and development of bacterial vaginitis caused by Escherichia coli is still unclear. The objective of this study was to investigate the role of 17ß-estrogen in E. coli adhesion on human vaginal epithelial cells. The vaginal epithelial cell line VK2/E6E7 was used to study the molecular events induced by estrogen between E. coli and cells. An adhesion study was performed to evaluate the involvement of the estrogen-dependent focal adhesion kinase (FAK) activation with cell adhesion. The phosphorylation status of FAK and estrogen receptor α (ERα) upon estrogen challenge was assessed by Western blotting. Specific inhibitors for ERα were used to validate the involvement of ERα-FAK signaling cascade. The results showed that, following stimulation with 1,000 nM estrogen for 48 h, transient activation of ERα and FAK was observed, as was an increased average number of E. coli cells adhering to vaginal epithelial cells. In addition, estrogen-induced activation of ERα and FAK was inhibited by the specific inhibitor of ERα, especially when the inhibitor reached a 10 µM concentration and acted for 1 h, and a decrease in the number of adherent E. coli cells was observed simultaneously. However, this inhibitory effect diminished as the concentration of estrogen increased. In conclusion, FAK and ERα signaling cascades were associated with the increasing E. coli adherence to vaginal epithelial cells, which was promoted by a certain concentration of estrogen.

Identification of a novel metabolism-related gene signature associated with the survival of bladder cancer.

BACKGROUND: Bladder cancer (BC) is one of the most common malignancies and has a relatively poor outcome worldwide. In this study, we attempted to construct a novel metabolism-related gene (MRG) signature for predicting the survival probability of BC patients. METHODS: First, differentially expressed MRGs between BC and normal samples were identified and used to construct a protein-protein interaction (PPI) network and perform mutation analysis. Next, univariate Cox regression analysis was utilized to select prognostic genes, and multivariate Cox regression analysis was applied to establish an MRG signature for predicting the survival probability of BC patients. Moreover, Kaplan-Meier (KM) survival analysis and receiver operating characteristic (ROC) analysis were performed to evaluate the predictive capability of the MRG signature. Finally, a nomogram based on the MRG signature was established to better predict the survival of BC. RESULTS: In the present study, 27 differentially expressed MRGs were identified, most of which presented mutations in BC patients, and LRP1 showed the highest mutation rate. Next, an MRG signature, including MAOB, FASN and LRP1, was established by using univariate and multivariate Cox regression analysis. Furthermore, survival analysis indicated that BC patients in the high-risk group had a dramatically lower survival probability than those in the low-risk group. Finally, Cox regression analysis showed that the risk score was an independent prognostic factor, and a nomogram integrating age, pathological tumor stage and risk score was established and presented good predictive ability. CONCLUSION: We successfully constructed a novel MRG signature to predict the prognosis of BC patients, which might contribute to the clinical treatment of BC.

MicroRNA-20a Targeting LASS2 Promotes the Proliferation, Invasiveness and Migration of Bladder Cancer.

BACKGROUND: Abnormal expression of miR 20a is reported in various types of malignancy neoplasms. However, its function is not consistent in different tumors. This study aims to explore the potential functions of miR 20a and its underlying mechanisms in bladder cancer. METHODS: Ninety-six patients diagnosed with bladder cancer were recruited into the study. The expression levels of miR-20a in bladder cancer samples and adjacent non-tumor samples were investigated by qRT-PCR. Wound healing, CCK8, and transwell migration assays were carried out for determining the functions of miR20a. Bioinformatics analysis was used for predicting the downstream gene of miR-20a. Western blot, qRT-PCR, and fluorescent reporter assays were used to verify the target gene. RESULTS: MiR-20a was significantly increased in bladder cancer tissues, and its rising level was closely correlated with histological grade, clinical stage, recurrence and metastasis in bladder cancer. Exogenous upregulation of miR-20a expression obviously enhanced the aggressive biological functions of bladder cancer in vitro. LASS2 was verified to be a target gene of miR-20a. Moreover, miR-20a can negatively regulate LASS2 at protein and mRNA levels. CONCLUSIONS: Increasing miR-20a is closely related to aggressive clinicopathological features. MiR 20a plays an oncogenic role in bladder cancer, which contributes to target LASS2 directly.

The Effect of Sildenafil Citrate on Poor Endometrium in Patients Undergoing Frozen-Thawed Embryo Transfer following Resection of Intrauterine Adhesions: A Retrospective Study.

BACKGROUND: The recent studies have shown that sildenafil citrate can enhance estrogen-induced proliferation of the endometrium in infertile women. OBJECTIVE: This study was aimed to investigate whether sildenafil citrate could affect pregnancy outcomes in infertile women receiving frozen-thawed embryo transfer (FET) after resection of intrauterine adhesions (IUAs). MATERIALS AND METHODS: A total of 310 subjects who met the inclusion criteria were recruited and divided into the control group (group A) and the sildenafil citrate group (or the SC group, group B). The 2 groups were, respectively, divided into 2 subgroups based on the severity of reformed adhesions: (1) group A1 (with mild IUAs) and group A2 (with moderate to severe IUAs) and (2) group B1 (with mild IUAs) and group B2 (with moderate to severe IUAs). Therapeutic effects of sildenafil citrate on the cases were evaluated after resection of IUAs during FET cycles. Endometrial thickness, endometrial pattern, and pregnancy outcomes were evaluated and compared between the 2 groups. RESULTS: There was no significant difference in the number of embryos transferred between the 2 groups. The endometrial thickness in group B (0.80 [0.68-0.90] cm) was significantly higher than that in group A (0.73 [0.35-0.80] cm). Besides, the biochemical pregnancy rate, clinical pregnancy rate, and live birth rate (LBR) were 71.60, 50.83, and 39.17% in group B, which were significantly higher than those in group A, namely, 57.36, 34.73, and 23.68%, respectively (p < 0.05). The univariate analysis and multivariate logistic regression showed that the LBR in either subgroups of group B after vaginal sildenafil treatment was significantly higher than that in the corresponding control group (p < 0.05). CONCLUSIONS: It was observed that the administration of sildenafil citrate during FET could effectively improve the poor endometrial conditions after FET following the resection of IUAs.

Antifungal Effect of Long Noncoding RNA 9708-1 in the Vulvovaginal Candidiasis Murine Model.

Vulvovaginal candidiasis (VVC) caused by Candida spp. affects 70-75% of women at least once during their lives. We aim to elucidate the potential mechanism of VVC and investigate the therapeutic effects of long noncoding RNA 9708-1. Female BALB/c mice were randomized to four treatment groups, including the blank control group, VVC control group, vehicle control group and lncRNA 9708-1-overexpressed group. Mice were euthanized on Day 4, Day 7 and Day 14 after treatment. Colony-forming unit (CFU) was measured, and the inflammation was detected by hematoxylin and eosin (H&E). Gene and protein expression levels of lncRNA 9708-1 and FAK were determined by real-time PCR, Western blot and immunohistochemistry. The overexpression of lncRNA 9708-1 significantly decreased the fungal load from Day 4 to 7. H&E staining indicated that the impaired histological profiles were improved in lncRNA 9708-1-overexpressed group. LncRNA 9708-1 led to a significant increase in FAK level of vagina tissue which is expressed mainly in epithelial basal layer. This study suggests that lncRNA 9708-1 played a protective role on murine experimental VVC by upregulating the expression levels of FAK.

The Role of 17ß-Estrogen in Candida albicans Adhesion on Human Vaginal Epithelial Cells via FAK Phosphorylation.

PURPOSES: To investigate the role of 17ß-estrogen in Candida albicans (C. albicans) adhesion on human vaginal epithelial cells in vulvovaginal candidiasis (VVC). METHODS: The vaginal epithelial cell line, VK2/E6E7, was used to study the estrogen-induced molecular events between C. albicans and cells. An adhesion study was performed to evaluate the involvement of the estrogen-dependent focal adhesion kinase (FAK) activation in cell adhesion. The phosphorylation status of FAK and estrogen receptor α (ERα) upon estrogen challenge was assessed by western blotting. Specific inhibitors for ERα were used to validate the involvement of ERα-FAK signaling cascade. RESULTS: A transient activation of ERα and FAK was observed following the stimulation with 1000 nM estrogen for 48 h, as well as the increased average number of C. albicans adhering to each vaginal epithelial cell. Estrogen-induced activation of ERa and FAK was inhibited by the specific inhibitor of ERα, especially when the inhibitor reached a 10 µM concentration and allowed to act for 12 h. Simultaneously, a decrease in the number of adherent C. albicans was observed. However, this inhibitory effect diminished as the concentration of estrogen increased. CONCLUSION: FAK and ERα signaling cascades were involved in the early interaction between the vaginal epithelial cells and C. albicans, which appeared to be linked with the enhanced cell adhesion leading to VVC and promoted by a certain concentration of estrogen.

MicroRNA-98 promotes drug resistance and regulates mitochondrial dynamics by targeting LASS2 in bladder cancer cells.

MicroRNA-98(miR-98) has been shown to be critical for tumorigenesis, however its involvement in bladder cancer are unclear. The present study aims to investigate the expression, biological roles and potential mechanisms of miR-98 in human bladder cancer. We found that miR-98 was upregulated in bladder urothelial carcinoma tissues compared with adjacent normal tissues. In addition, miR-98 expression was higher in bladder cancer cell lines than in uroepithelial cell line SV-HUC-1. Functional studies revealed that miR-98 mimic promoted proliferation of T24 cells while miR-98 inhibitor inhibited proliferation of BIU-87 cells. Moreover, miR-98 mimic increased cisplatin/doxorubicin resistance and inhibited apoptosis in T24 cells, while miR-98 inhibitor decreased chemoresistance and facilitated apoptosis in BIU-87 cells. Further experiments using MitoTracker and JC-1 staining showed that miR-98 could regulate mitochondrial fission/fusion balance and mitochondrial membrane potential. Western blot showed that miR-98 upregulated cyclin D1, p-Drp1 and Drp1. Using luciferase reporter assay, we demonstrated that LASS2 acted as a direct target of miR-98. LASS2 overexpression induced mitochondrial fusion and downregulated mitochondrial potential, with decreased p-Drp1 status. Additionally, LASS2 siRNA abrogated the effects of miR-98 mimic on Drp1phosphorylation and chemoresistance. We also found a negative correlation between LASS2 and miR-98 in bladder cancer tissues. In conclusion, our study demonstrates that miR-98 targets LASS2 and regulates bladder cancer chemoresistance through modulation of mitochondrial function.

A Novel Long Non-Coding RNA KMU15 Promotes Growth and Chemoresistance of Bladder Cancer.

BACKGROUND: Chemotherapy constitutes one of the most important adjuvant treatments for bladder cancer. However, many patients usually develop chemoresistance during chemotherapy. At present, lncRNA has been confirmed not only to be involved in tumorigenesis and progression, but also in tumor chemoresistance. However, the relationship between lncRNAs and chemoresistance of bladder cancer have been rarely reported. METHODS: The novel lncRNA-KMU15 was screened by lncRNAs microarray and determination of IC50 in bladder cancer. The expression of KMU15 was evaluated by qRT-PCR. The correlation between KMU15 and clinicopathological parameters was analyzed from clinical cases. The effects of KMU15 on the biological behavior and chemoresistance were investigated by [3H]-TdR incorporation assay and other experiments. The effects of KMU15 on the growth of xenograft tumors and the survival of nude mice under cisplatin were examined in a xenograft mouse model. RESULTS: We confirmed that KMU15 was expressed higher in bladder cancer tissues than paired control tissues. Moreover, the expression of KMU15 was significantly positively correlated with the grade, stage, metastasis, and recurrence of bladder cancer and was significantly negatively correlated with the prognosis. In addition, KMU15 knockdown could significantly inhibit bladder cell proliferation, adhesion, migration, and chemoresistance and promoted apoptosis. Knockdown of KMU15 inhibited the growth of xenografts in nude mice and significantly prolonged the survival of tumor-bearing mice under cisplatin. CONCLUSIONS: The novel lncRNA KMU15, which is highly expressed in bladder cancer tissues, could promote the proliferation and progression and was closely related to the malignant degree of bladder cancer. It could also significantly enhance the chemoresistance of bladder cancer cells. Therefore, it was expected to be a new therapy target for bladder cancer and a potential prognosis biomarker for chemotherapy.

Hsa-miR-3658 Promotes Cell Proliferation, Migration and Invasion by Effecting LASS2 in Bladder Cancer.

BACKGROUND: Hsa-miR-3658 is upregulated in various tumors, but its expression in bladder cancer has been rarely studied. METHODS: In this study, hsa-miR-3658 expressions in several bladder cancer cell lines were examined, and its effect on the malignant degree of bladder cancer and whether hsa-miR-3658 regulates tumor biological behaviors through LASS2 and its downstream molecular pathway were studied and validated. RESULTS: It was found miR-3658 expressions differed among different cell lines, which may be an influence factor on the malignancy. MiR-3658 can enhance the proliferation, migration and invasion of bladder cancer cells, inhibit cell adhesion and reduce cell chemosensitivity. MiR-3658 can promote the epithelial-mesenchymal transition of bladder cancer cells through the molecular mechanism of affecting the expressions of epithelial-mesenchymal transition marker protein and related transcription factors. CONCLUSIONS: MiRNA-3658 is upregulated in bladder cancer cells, and this change is associated with the proliferation, invasion and resistance of bladder cancer cells. The effect of miR-3658 on bladder cancer cell biology may be associated with the effect on LASS2.