Platelet-derived extracellular vesicles are associated with kidney injury in patients with urosepsis.

BACKGROUND: There is increasing evidence that platelet-derived extracellular vesicles (PEVs) may be involved in the mechanisms of inflammatory storm and organ damage in sepsis. However, there are no available studies on PEVs and renal injury in patients with urosepsis. METHODS: We analyzed the concentration and ratio of PEVs in plasma by flow cytometry and measured plasma IL-1ß/IL-6/TNF-α/NGAL levels by ELISA. Correlation analysis was also used to examine the concentration of PEVs in relation to levels of inflammatory factors and indicators of kidney damage, as well as the severity of the disease. Finally, the receiver operating characteristic curves were produced for PEVs concentrations as a diagnosis of S-AKI/AKI. RESULTS: We found significantly higher levels of IL-1ß/IL-6/TNF-α/NGAL in patients with urogenital sepsis. Furthermore, the concentrations of PEVs in plasma were significantly elevated in patients with urosepsis, especially in patients with Gram-negative bacterial infections, which were significantly and positively correlated with IL-1ß/IL-6/TNF-α/NGAL levels. The area under the curve for PEVs diagnosing S-AKI and AKI was 0.746 [0.484, 1.000] and 0.943 [0.874, 1.000] respectively. CONCLUSION: Overall, the present study suggested that PEVs may mediate the release of inflammatory mediators in patients with urosepsis and participate in the mechanism of acute kidney injury, as well as having potential as diagnostic indicators of S-AKI and AKI and as early warning indicators of the severity of patients with urosepsis.

Developing a diagnostic model for predicting prostate cancer: a retrospective study based on Chinese multicenter clinical data.

ABSTRACT: The overdiagnosis of prostate cancer (PCa) caused by nonspecific elevation serum prostate-specific antigen (PSA) and the overtreatment of indolent PCa have become a global problem that needs to be solved urgently. We aimed to construct a prediction model and provide a risk stratification system to reduce unnecessary biopsies. In this retrospective study, clinical data of 1807 patients from three Chinese hospitals were used. The final model was built using stepwise logistic regression analysis. The apparent performance of the model was assessed by receiver operating characteristic curves, calibration plots, and decision curve analysis. Finally, a risk stratification system of clinically significant prostate cancer (csPCa) was created, and diagnosis-free survival analyses were performed. Following multivariable screening and evaluation of the diagnostic performances, a final diagnostic model comprised of the PSA density and Prostate Imaging-Reporting and Data System (PI-RADS) score was established. Model validation in the development cohort and two external cohorts showed excellent discrimination and calibration. Finally, we created a risk stratification system using risk thresholds of 0.05 and 0.60 as the cut-off values. The follow-up results indicated that the diagnosis-free survival rate for csPCa at 12 months and 24 months postoperatively was 99.7% and 99.4%, respectively, for patients with a risk threshold below 0.05 after the initial negative prostate biopsy, which was significantly better than patients with higher risk. Our diagnostic model and risk stratification system can achieve a personalized risk calculation of csPCa. It provides a standardized tool for Chinese patients and physicians when considering the necessity of prostate biopsy.

YY1 complex in M2 macrophage promotes prostate cancer progression by upregulating IL-6.

BACKGROUND: Tumor-associated macrophages are mainly polarized into the M2 phenotype, remodeling the tumor microenvironment and promoting tumor progression by secreting various cytokines. METHODS: Tissue microarray consisting of prostate cancer (PCa), normal prostate, and lymph node metastatic samples from patients with PCa were stained with Yin Yang 1 (YY1) and CD163. Transgenic mice overexpressing YY1 were constructed to observe PCa tumorigenesis. Furthermore, in vivo and in vitro experiments, including CRISPR-Cas9 knock-out, RNA sequencing, chromatin immunoprecipitation (ChIP) sequencing, and liquid-liquid phase separation (LLPS) assays, were performed to investigate the role and mechanism of YY1 in M2 macrophages and PCa tumor microenvironment. RESULTS: YY1 was highly expressed in M2 macrophages in PCa and was associated with poorer clinical outcomes. The proportion of tumor-infiltrated M2 macrophages increased in transgenic mice overexpressing YY1. In contrast, the proliferation and activity of anti-tumoral T lymphocytes were suppressed. Treatment targeting YY1 on M2 macrophages using an M2-targeting peptide-modified liposome carrier suppressed PCa cell lung metastasis and generated synergistic anti-tumoral effects with PD-1 blockade. IL-4/STAT6 pathway regulated YY1, and YY1 increased the macrophage-induced PCa progression by upregulating IL-6. Furthermore, by conducting H3K27ac-ChIP-seq in M2 macrophages and THP-1, we found that thousands of enhancers were gained during M2 macrophage polarization, and these M2-specific enhancers were enriched in YY1 ChIP-seq signals. In addition, an M2-specific IL-6 enhancer upregulated IL-6 expression through long-range chromatin interaction with IL-6 promoter in M2 macrophages. During M2 macrophage polarization, YY1 formed an LLPS, in which p300, p65, and CEBPB acted as transcriptional cofactors. CONCLUSIONS: Phase separation of the YY1 complex in M2 macrophages upregulated IL-6 by promoting IL-6 enhancer-promoter interactions, thereby increasing PCa progression.

Expression of FOXA1 Is Associated with the Tumor-Infiltrating M2 Macrophage, Cytotoxic T Lymphocyte, and Effect of Chemotherapy in Bladder Cancer.

PURPOSE: Cisplatin-containing combination chemotherapy has been the standard of care since the late 1980s, but the response rate is <50%. Studies have shown that the efficiency of chemotherapy differs among molecular subtypes of bladder cancer. In this study, we aimed to correlate FOXA1, a marker for differentiation of the basal and luminal subtypes, with tumor immune cell infiltration and the effect of chemotherapy in bladder cancer. MATERIALS AND METHODS: Eighty-three patients with bladder cancer treated with chemotherapy were reviewed. Clinicopathological variables for each case were recorded. FOXA1, M2 tumor-associated macrophage (TAM), dendritic cell (DC), and cytotoxic T lymphocyte (CTL) were examined by immunohistochemistry. The relationship between FOXA1, immune cell infiltration, and clinical response to chemotherapy was assessed. RESULTS: The overall objective response rate was 34%. The objective response rate for tumors with lower FOXA1 expression was 58% and for tumors with higher FOXA1 expression was 12%. Tumors with infiltrated M2 TAM proportion <3% had a higher objective response rate compared with infiltrated M2 TAM proportion >3% tumors (46% vs. 21%, p = 0.02). Tumors with infiltrated CTL proportion >5% had a higher objective response rate compared with infiltrated CTL proportion <5% tumors (50% vs. 17%, p = 0.002). DCs showed no significant differences. We found that the objective response rate for tumors with lower FOXA1 expression, proportion <3% M2 TAM infiltration, and proportion >5% CTL infiltration is 82%. Lower FOXA1 expression was associated with low M2 TAM infiltration and high CTL infiltration. CONCLUSIONS: Thus, we showed that in patients with bladder cancer who received chemotherapy, the higher clinical response rate is associated with low FOXA1 expression, low M2 TAM infiltration, and high CTL infiltration.

The predictive value of prognostic nutritional index on early complications after robot-assisted radical cystectomy.

Objective: The purpose of the study was to evaluate the predictive value of prognostic nutritional index (PNI) on early complications (within 30-day) after robot-assisted radical cystectomy (RARC) and urinary diversion. Patients and methods: Patients underwent RARC and urinary diversion between November 2018 and December 2021 in our centre were screened in this retrospective study. Baseline characteristics and perioperative data were recorded. Early complications after surgery were classified according to Clavien-Dindo system. Univariate and multivariate logistic analysis were performed to decide the potential factors associated with post-RARC complications. The receiver operating characteristic (ROC) curve was conducted to determine the predictive value of PNI on early overall and major complications after RARC. Results: Overall 139 men and 13 women with a median age of 69 years and mean BMI of 24.4 kg/m2 were included in this study. As for urinary diversion, most patients (n = 111, 73%) received cutaneous ureterostomy, 36 patients (23.7%) underwent orthotopic neobladder and 5 patients (3.3%) received ileal conduit. The incidence of postoperative complication rate was 44.7%, which included 82.2% minor complications and 17.8% major complications. Further univariate and multivariate logistic analyses demonstrated that hypertension (OR = 2.96, 95% CI: 1.24-7.07, P = 0.015), PNI (OR = 0.73, 95% CI: 0.62-0.86, P < 0.001), and CCI (OR = 1.44, 95% CI: 1.01-2.06, P = 0.047) were independent risk factors of early complications after RARC. Moreover, PNI (OR = 0.72, 95% CI: 0.60-0.86, P < 0.001) was also the predictor of major complications after RARC. The ROC curve demonstrated that PNI (AUC = 0.829; AUC = 0.840) has a great predictive value in early overall and major complications after RARC. Conclusion: PNI can be an early alert for RARC patients thus aiding in closer monitoring and postoperative management.

A novel 17 apoptosis-related genes signature could predict overall survival for bladder cancer and its associations with immune infiltration.

Background: Apoptosis-related genes (ARGs) were used to develop a novel signature for forecasting overall survival (OS) and examining their relationships with immune infiltrates in bladder cancer (BC). Methods: Gene expression matrices as well as related clinical data were acquired for BC samples from online datasets. According to differentially expressed ARGs acquired from normal bladder tissues and cancer samples, functional enrichment analyses were conducted. With the assistance of LASSO and Cox regression analysis, a novel model was successfully established and evaluated by external and internal validations. Results: Eventually, 17 ARGs (SLC5A6, GULP1, TAP1, MMP9, P4HB, FOXL2, CIDEC, EN2, NES, EPHA7, SUSD2, TMPRSS3, HOXB7, SATB1, MEST, PCDHGC3, ASPM) were utilized to construct the signature. Our constructed signature significantly distinguished high-risk from low-risk BC patients of OS by internal and external validations and was also proven to be able to serve as an independent prognostic biomarker (all P < 0.05). Furthermore, a prognostic nomogram was also constructed based on TCGA dataset to predict OS prognosis in BC suffers. Besides, this ARG based model was markedly associated with clinical characteristics like tumor stage (P = 3.98e-06), race (P = 8.255e-06), N stage (P = 0.002), T stage (P = 3.679e-05) and M stage (P = 0.002). As for immune infiltration, our established model was significantly associated with seven tumor-infiltrating immune cells. Conclusions: A prognostic signature was successfully developed by us according to 17 ARGs in BC using external and internal verifications, enabling clinicians to predict BC suffers' OS and promote specific individualization of patient care.

Transgenic construction and functional miRNA analysis identify the role of miR-7 in prostate cancer suppression.

Although miR-7 suppresses the initiation and progression in cancers, little is known about its role in prostate cancer, especially in transgenic mouse models. In present study, we found that expression of miR-7, regulated by p53, was lower in prostate cancer tissues, and miR-7 overexpression significantly mitigated prostate cancer cells growth both in vitro, in organoids and in vivo regardless of p53 status. After we generated miR-7 overexpression transgenic mice and miR-7+/TRAMP mice, we found that transgenic overexpression of miR-7 in mice is safe and miR-7+/TRAMP mice have a preferred overall survival. Moreover, in vivo treatment of miR-7 inhibited subcutaneous tumour growth in mice and prolonged the survival of mice harboring prostate cancer lung metastasis when co-injection with PD-1 antibody. In addition, miR-7 downregulated glycolysis of prostate cancer cells by inhibiting several key pathways including HIF-1α, and subsequently remodeled acidic tumour microenvironment, PanKLa level and T cell infiltration. In summary, our findings highlighted a promising target for development of miRNA-based therapeutics for prostate cancer patients regardless of p53 status.

Transfection with Plasmid-Encoding lncRNA-SLERCC nanoparticle-mediated delivery suppressed tumor progression in renal cell carcinoma.

BACKGROUND: The accumulating evidence confirms that long non-coding RNAs (lncRNAs) play a critical regulatory role in the progression of renal cell carcinoma (RCC). But, the application of lncRNAs in gene therapy remains scarce. Here, we investigated the efficacy of a delivery system by introducing the plasmid-encoding tumor suppressor lncRNA-SLERCC (SLERCC) in RCC cells. METHODS: We performed lncRNAs expression profiling in paired cancer and normal tissues through microarray and validated in our clinical data and TCGA dataset. The Plasmid-SLERCC@PDA@MUC12 nanoparticles (PSPM-NPs) were tested in vivo and in vitro, including cellular uptake, entry, CCK-8 assay, tumor growth inhibition, histological assessment, and safety evaluations. Furthermore, experiments with nude mice xenografts model were performed to evaluate the therapeutic effect of PSPM-NPs nanotherapeutic system specific to the SLERCC. RESULTS: We found that the expression of SLERCC was downregulated in RCC tissues, and exogenous upregulation of SLERCC could suppress metastasis of RCC cells. Furthermore, high expression DNMT3A was recruited at the SLERCC promoter, which induced aberrant hypermethylation, eventually leading to downregulation of SLERCC expression in RCC. Mechanistically, SLERCC could directly bind to UPF1 and exert tumor-suppressive effects through the Wnt/ß-catenin signaling pathway, thereby inhibiting progression and metastasis in RCC. Subsequently, the PSPM-NPs nanotherapeutic system can effectively inhibit the growth of RCC metastases in vivo. CONCLUSIONS: Our findings suggested that SLERCC is a promising therapeutic target and that plasmid-encapsulated nanomaterials targeting transmembrane metastasis markers may open a new avenue for the treatment in RCC.

Urine Exosomal AMACR Is a Novel Biomarker for Prostate Cancer Detection at Initial Biopsy.

Objectives: The aim of this study is to identify and validate urine exosomal AMACR (UE-A) as a novel biomarker to improve the detection of prostate cancer (PCa) and clinically significant PCa (Gleason score ≥ 7) at initial prostate biopsy. Methods: A total of 289 first-catch urine samples after the digital rectal exam (DRE) were collected from patients who underwent prostatic biopsy, and 17 patients were excluded due to incomplete clinical information. Urine exosomes were purified, and urinary exosomal AMACR (UE-A) was measured by enzyme-linked immunosorbent assay (ELISA). The diagnostic performance of UE-A was evaluated by receiver operating characteristic (ROC) analysis, decision curve analysis (DCA), and waterfall plots. Results: The expression of AMACR in PCa and csPCa was significantly higher than that in BPH and non-aggressive (p < 0.001). The UE-A presented good performance in distinguishing PCa from BPH or BPH plus non-significant PCa (nsPCa) from csPCa with an area under the ROC curve (AUC) of 0.832 and 0.78, respectively. The performance of UE-A was further validated in a multi-center cohort of patients with an AUC of 0.800 for detecting PCa and 0.749 for detecting csPCa. The clinical utility assessed by DCA showed that the benefit of patients using UE-A was superior to PSA, f/t PSA, and PSAD in both the training cohort and the validation cohort in terms of all threshold probabilities. Setting 95% sensitivity as the cutoff value, UE-A could avoid 27.57% of unnecessary biopsies, with only 4 (1.47%) csPCa patients missed. Conclusions: We demonstrated the great performance of UE-A for the early diagnosis of PCa and csPCa. UE-A could be a novel non-invasive diagnostic biomarker to improve the detection of PCa and csPCa.

Circular RNA circPOLR2A promotes clear cell renal cell carcinoma progression by facilitating the UBE3C-induced ubiquitination of PEBP1 and, thereby, activating the ERK signaling pathway.

BACKGROUND: Increasing evidence has demonstrated that circular RNAs (circRNAs) are implicated in cancer progression. However, the aberrant expression and biological functions of circRNAs in clear cell renal cell carcinoma (cRCC) remain largely elusive. METHOD: Differentially expressed circRNAs in cRCC were filtered via bioinformatics analysis. Aberrant circPOLR2A expression was validated in cRCC tissues and cell lines via qRT-PCR. Sanger sequencing was used to identify the backsplicing site of circPOLR2A. In vitro and in vivo functional experiments were performed to evaluate the role of circPOLR2A in cRCC malignancy. RNA pull-down, mass spectrometry, RIP, FISH and immunofluorescence assays were used to identify and validate the circPOLR2A-interacting proteins. Ubiquitination modification and interaction between proteins were detected via Co-IP and western blotting. The m6A modification in circPOLR2A was validated by the meRIP assay. RESULTS: Bioinformatics analysis revealed that circPOLR2A was highly expressed in cRCC tissues and metastatic cRCC tissues. CircPOLR2A expression was associated with tumor size and TNM stage in cRCC patients. In vitro and in vivo functional assays revealed that circPOLR2A accelerated cRCC cell proliferation, migration, invasion and angiogenesis, while inhibiting apoptosis. Further mechanistic research suggested that circPOLR2A could interact with UBE3C and PEBP1 proteins, and that UBE3C could act as a specific ubiquitin E3 ligase for the PEBP1 protein. The UBE3C/circPOLR2A/PEBP1 protein-RNA ternary complex enhanced the UBE3C-mediated ubiquitination and degradation of the PEBP1 protein which could inactivate the ERK signaling pathway. Rescue experiments revealed that the PEBP1 protein was the functional downstream target of circPOLR2A. Furthermore, m6A modification in circPOLR2A was confirmed, and the m6A reader YTHDF2 could regulate circPOLR2A expression. CONCLUSION: Our study demonstrated that circPOLR2A modulated the UBE3C-mediated ubiquitination and degradation of the PEBP1 protein, and further activated the ERK pathway during cRCC progression and metastasis. The m6A reader, YTHDF2, regulated circPOLR2A expression in cRCC. Hence, circPOLR2A could be a potential target for the diagnosis and treatment of cRCC.

Robot-Assisted Laparoscopic Radical Cystectomy and Modified Y-Shaped Ileal Orthotopic Neobladder Reconstruction.

Background: Orthotopic neobladder reconstruction has become the preferred method of urinary diversion after radical cystectomy in major medical centers. We performed modified Y-shaped ileal orthotopic neobladder reconstruction and presented the functional results and postoperative complications of the modified surgery. Methods: We included 21 patients with bladder cancer who underwent radical cystectomy at our center between February 2019 and December 2019. All patients underwent robotic-assisted laparoscopic radical cystectomy and lymph node dissection plus modified Y-shaped ileal orthotopic neobladder reconstruction. We collected the demographic and pathological history of the patients, and perioperative and postoperative functional outcomes and postoperative complications were recorded. Results: All surgeries were successful and no serious postoperative complications occurred. The mean operative time was 321.43 ± 54.75 min, including 101.67 ± 10.88 min required for neobladder reconstruction. Liquid intake was encouraged about 5 days after surgery, stent and catheter were removed after 13.52 ± 3.28 days, and the patients were discharged 1-2 days after removing the catheter. No ureteral anastomotic and neobladder urethral anastomotic strictures occurred. The volume of the neobladder at 1-year post-surgery was 195.24 ± 16.07 mL and the maximum urinary flow rate was 20.64 ± 2.22 mL/s. Conclusion: We describe the robotic-assisted modified Y-shaped ileal orthotopic neobladder reconstruction performed at our center, which requires a simple suture and short neobladder construction time, minimizes the occurrence of anastomotic stenosis, facilitates smooth patient emptying, and is clinically scalable and applicable.

Roles of m5C RNA Modification Patterns in Biochemical Recurrence and Tumor Microenvironment Characterization of Prostate Adenocarcinoma.

Background: Prostate cancer is the second most common cancer with a high risk of biochemical recurrence (BCR) among men. Recently, 5-methylcytosine (m5C) modification has attracted more attention as a new layer of RNA post-transcriptional regulation. Hence, we aimed at investigating the potential roles of m5C modification regulators in the BCR of prostate adenocarcinoma (PRAD). Methods: CNV data, mutation annotation data, mRNA expression profiles, and clinical data were downloaded from TCGA and GEO databases. Kaplan-Meier curves analysis, log-rank test, univariate and multivariate Cox regression, and time-dependent ROC curves analysis were performed to evaluate the prognostic factors. Principal components analysis (PCA) was applied to validate the distinction between subgroups. Gene set variation analysis (GSVA) was used to investigate the underlying pathways associated with m5C modification patterns. Single sample gene set enrichment analysis (ssGSEA) was utilized to assess the infiltration of distinct immune cells. Tumor Immune Dysfunction and Exclusion (TIDE) prediction was carried out to assess the potential response to immune checkpoint blockade (ICB) therapy. The m5C modification signature was constructed via LASSO Cox's proportional hazards regression method. Results: After comprehensively analyzing various types of data from TCGA dataset, and exploring the differential expression and prognostic value of each m5C regulator, we identified m5C modification patterns based on 17 m5C regulators. Two patterns presented a significant difference in the risk of BCR, the tumor microenvironment (TME), and immunotherapy response in PRAD. We found that TET2, which was highly expressed in adjacent normal tissues compared to tumor tissues, was closely associated with many infiltrating immune cells. The m5C modification signature was constructed for the clinical application. Risk score calculated by m5C signature was associated with T stage, N stage, Gleason score, and the possibility of BCR (HR, 4.197; 95% CI, 3.016-5.842; p < 0.001). A higher risk score also represented the possibility of immunotherapy response. Finally, the potential roles of m5C modification signature were validated in the testing dataset. Conclusions: Our study revealed the potential roles of m5C modification in the PRAD BCR and TME diversity, which may provide new insight into the field of prostate cancer in future research.

Prognostic Significance of Pre- to Postoperative Dynamics of Sarcopenia for Patients with Renal Cell Carcinoma Undergoing Laparoscopic Nephrectomy.

Background: The aim of this study was to investigate the prognostic role of the dynamics of sarcopenia in the pre- to postoperative for patients with renal cell carcinoma (RCC) undergoing laparoscopic nephrectomy. Methods: This study included 261 patients who underwent laparoscopic nephrectomy between 2014 and 2019. The skeletal muscle index (SMI) of the L3 lumbar region was used to assess sarcopenia. The overall population was divided into four groups according to the dynamics of sarcopenia from pre- to postoperative: group 1 (both pre- and postoperative sarcopenia), group 2 (preoperative non-sarcopenia to postoperative sarcopenia), group 3 (preoperative sarcopenia to postoperative non-sarcopenia), and group 4 (both pre- and postoperative non-sarcopenia). The endpoints of the study were overall survival (OS) and cancer-specific survival (CSS). Results: Of the 261 patients who underwent laparoscopic nephrectomy, 103 (39.5%) had preoperative sarcopenia and 183 (70.1%) had postoperative sarcopenia. Patients with pre- or postoperative sarcopenia had poor survival outcomes. Sarcopenia dynamic was a better predictor of OS (AUC = 0.737) and CSS (AUC = 0.696) in patients with RCC than pre- and postoperative sarcopenia, and patients in group 4 of sarcopenia dynamic had the best OS and CSS. In addition, sarcopenia dynamics was an independent risk factor for OS and CSS, with a 94.5% reduction in OS risk (HR = 0.055, 95% CI 0.007-0.407, p = 0.003) and a 91.9% reduction in CSS risk (HR = 0.081, 95% CI 0.011-0.616, p = 0.015) in the group 4 compared with the group 1. Conclusion: Our study is the first to assess the prognostic value of pre- and postoperative sarcopenia dynamics in patients with RCC.

Role of tumor-derived exosomes in metastasis, drug resistance and diagnosis of clear cell renal cell carcinoma.

Renal cancer is one of the most extensively studied human tumors today, with clear cell renal cell carcinoma accounting for approximately 80% of all cases. Despite recent advances in research on clear cell renal cell carcinoma, advanced distant metastasis of the disease, delay in diagnosis, as well as drug resistance remain major problems. In recent years, as an important mediator of material and information exchange between cells in the tumor microenvironment, exosomes have attracted widespread attention for their role in tumor development. It has been reported that tumor-derived exosomes may act as regulators and have an important effect on the metastasis, drug resistance formation, and providing targets for early diagnosis of clear cell renal cell carcinoma. Therefore, the extensive study of tumour-derived exosomes will provide a meaningful reference for the development of the diagnostic and therapeutic field of clear cell renal cell carcinoma. This article reviews the biological role and research progress of tumor-derived exosomes in different aspects of premetastatic niche formation, tumor angiogenesis, and epithelial-mesenchymal transition during the progression of clear cell renal cell carcinoma. In addition, the role of tumor-derived exosomes in the development of drug resistance in clear cell renal cell carcinoma is also addressed in this review. Furthermore, recent studies have found that cargoes of exosomes in serum and urine, for example, a series of miRNAs, have the potential to be biological markers of clear cell renal cell carcinoma and provide meaningful targets for early diagnosis and monitoring of tumors, which is also covered in this article.

Curative Effect and Survival Assessment Comparing Gemcitabine and Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin and Cisplatin as Neoadjuvant Therapy for Bladder Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Neoadjuvant chemotherapy has been accepted as an effective curative treatment for muscle-invasive bladder cancer patients and has resulted in better survival outcomes than radical cystectomy or a cisplatin-based regimen. In the present study, we aimed to compare the two most commonly used cisplatin-based neoadjuvant chemotherapies, gemcitabine plus cisplatin and methotrexate plus vinblastine plus doxorubicin plus cisplatin, by summarizing and analyzing clinical data and outcomes of published research. METHODS: We searched for qualified studies that compared these two types of neoadjuvant chemotherapy, including 4 randomized controlled trials and 14 retrospective studies. Data and information on pathological responses and long-term survival studies were extracted and analyzed separately. RESULTS: A total of 18 studies with 3116 patients were selected from 1188 studies, which contained data on pathological complete response, pathological partial response, and overall survival. In contrast to the results of previous studies, there was no significant difference in pathological complete response (odds ratio, 0.97; 95% confidence interval, 0.81-1.15), pathological partial response (odds ratio, 0.85; 95% confidence interval, 0.72-1.14), and overall survival (hazard ratio, 0.99; 95% confidence interval, 0.83-1.17) between GC and MVAC in this meta-analysis. CONCLUSION: No significant differences were observed between GC and MVAC in the muscle-invasive bladder cancer treatment due to the similar curative effect and parallel long survival outcomes due to the similar curative effect and parallel long survival outcomes. The priority selection of GC or MVAC in the clinic should be guided by further investigation, and the clinical standard strategy still counts on the results of more randomized controlled trials in the future.

[Nur77 inhibits the proliferation of prostate cancer cells].

OBJECTIVE: To study the effects of Nur77 on prostate cancer (PCa) cell growth and its potential value in the treatment of PCa. METHODS: We detected the expression of the NUR77 protein in human PCa tissues and cells by Western blot and determined the effects of Nur77 on the proliferation and apoptosis of the PCa cells by flow cytometry. RESULTS: Nur77 and AR were expressed in the human PCa tissue and cells, and overexpressed NUR77 inhibited the proliferation and cell cycle progression of the PCa LNCaP cells. The small-molecule receptor agonists cytosporone B and DIMC of Nur7 significantly suppressed the growth and induced the apoptosis of the PCa LNCaP cells. CONCLUSIONS: Nur77 inhibits the proliferation and induces the apoptosis of PCa cells, and is expected to be a potential molecular target for the treatment of PCa.

Bortezomib alleviates antibody-mediated rejection in kidney transplantation by facilitating Atg5 expression.

Antibody-mediated rejection (AMR) is one of the most dominant mechanisms responsible for the loss of kidney grafts. Previous researches have shown that donor-specific antibodies (DSAs) are the major mediators of AMR. In order to prolong the survival time of grafts, it is vital to reduce the incidence of AMR and inhibit the generation of DSAs. We established an animal model of AMR by performing kidney transplantation in pre-sensitized rats. Then, we investigated the effect of bortezomib (BTZ) on AMR. We found that BTZ could reduce the serum level of DSAs and alleviate post-transplantation inflammation in peritubular capillaries (PTCs) and glomeruli, which was demonstrated by the reduction of C4d and IgG deposition in PTCs, and the reduced number of B cell and plasma cell in peripheral blood and the transplanted kidney (p < 0.05). Our results also suggested that BTZ increased the number of regulatory T cell (Treg) and significantly reduced the proportion of T helper (Th17) cell (p < 0.05). Besides, BTZ induced the significant upregulation of anti-inflammatory cytokines but downregulated pro-inflammatory cytokines (p < 0.05). After dealing with Atg5 siRNA-lentivirus, the effect of BTZ alleviating AMR was reversed and Th17/Treg proportions were also significantly modulated. Collectively, these findings show that BTZ slows down the process of AMR and Atg5 may be the key mechanism. Furthermore, Atg5 silencing results may be demonstrated that Atg5 alleviated AMR by modulating the ratio of Th17/Treg.

ciRS-7 is a prognostic biomarker and potential gene therapy target for renal cell carcinoma.

Circular RNAs are a new class of non-coding RNAs that have been shown to play critical roles in the development and progression of renal cell carcinoma (RCC). However, little is known about the functional mechanisms and therapeutic role of ciRS-7 in RCC. A series of in vitro and in vivo experiments were performed to investigate the functional mechanism and therapeutic role of ciRS-7, such as real-time quantitative PCR, CCK-8, wound healing, transwell, colony formation, Edu, tumor xenograft and lung metastasis in NSG mice. RNA pull-down, dual luciferase reporter, fluorescence in situ hybridization (FISH) and rescue assays were used to determine the relationship between ciRS-7, miR-139-3p and TAGLN. In addition, we constructed PBAE/si-ciRS-7 nanocomplexes with PBAE material to evaluate the therapeutic effect of the nanocomplexes on tumor in vivo. ciRS-7 was highly expressed in RCC tumor tissues and cell lines, and high ciRS-7 expression correlated with tumor size, high Fuhrman grade and poor survival. Depletion of ciRS-7 significantly inhibited RCC cell proliferation, invasion, tumor growth and metastasis in vivo, while overexpression of ciRS-7 had the opposite effect. Mechanistically, ciRS-7 acts as a "ceRNA" for miR-139-3p to prevent TAGLN degradation and promoting RCC progression and metastasis via the PI3K/AKT signaling pathway. In addition, miR-139-3p mimics or inhibitor could reverse the altered malignant tumor behavior caused by ciRS-7 overexpression or silencing. Furthermore, the PBAE/siciRS-7 nanocomplexes could significantly inhibit RCC tumor progression and metastasis in vivo. ciRS-7 acts as a tumor promoter by regulating the miR-139-3p/TAGLN axis and activating the PI3K/AKT signaling pathway to promote RCC progression and metastasis. Drug development of PBAE/si-ciRS-7 nanocomplexes targeting ciRS-7 may represent a promising gene therapeutic strategy for RCC.

Multi-Omics analysis identifies a lncRNA-related prognostic signature to predict bladder cancer recurrence.

Bladder cancer (BLCA) is one of the most common cancers worldwide with high recurrence rate. Hence, we intended to establish a recurrence-related long non-coding RNA (lncRNA) model of BLCA as a potential biomarker based on multi-omics analysis. Multi-omics data including copy number variation (CNV) data, mutation annotation files, RNA expression profiles and clinical data of The Cancer Genome Atlas (TCGA) BLCA cohort (303 cases) and GSE31684 (93 cases) were downloaded from public database. With multi-omics analysis, twenty lncRNAs were identified as the candidates related with BLCA recurrence, CNVs and mutations in training set. Ten-lncRNA signature were established using least absolute shrinkage and selection operation (LASSO) and Cox regression. Then, various survival analysis was used to assess the power of lncRNA model in predicting BLCA recurrence. The results showed that the recurrence-free survival time of high-risk group was significantly shorter than that of low-risk group in training and testing sets, and the predictive value of ten-lncRNA signature was robust and independent of other clinical variables. Gene Set Enrichment Analysis (GSEA) showed this signature were associated with immune disorders, indicating this signature may be involved in tumor immunology. After compared with the other reported lncRNA signatures, ten-lncRNA signature was validated as a superior prognostic model in predicting the recurrence of BLCA. The effectiveness of the model was also evaluated in bladder cancer samples via qRT-PCR. Thus, the novel ten-lncRNA signature, constructed based on multi-omics data, had robust prognostic power in predicting the recurrence of BLCA and potential clinical implications as biomarkers.