circ-ZNF609: A potent circRNA in human cancers.

Circular RNAs (circRNAs) are a novel group of endogenous RNAs with a circular structure. Growing evidence indicates that circRNAs are involved in a variety of human diseases including malignancies. CircRNA ZNF609 (circ-ZNF609), derived from the ZNF609 gene sequence, has been demonstrated to be involved in the development and progression of many diseases. circ-ZNF609 is thought to be a viable diagnostic and prognostic biomarker for several diseases and might be a new therapeutic target, but further research is needed to accelerate clinical application. Here, we review the biogenesis and function of circRNAs and the functional roles and molecular mechanism related to circ-ZNF609 in neoplasms and other diseases.

MicroRNA-133b suppresses bladder cancer malignancy by targeting TAGLN2-mediated cell cycle.

MicroRNAs (miRNAs), a group of small noncoding RNAs, are widely involved in the regulation of gene expression via binding to complementary sequences at 3'-untranslated regions (3'-UTRs) of target messenger RNAs. Recently, downregulation of miR-133b has been detected in various human malignancies. Here, the potential biological role of miR-133b in bladder cancer (BC) was investigated. In this study, we found the expression of miR-133b was markedly downregulated in BC tissues and cell lines (5637 and T24), and was correlated with poor overall survival. Notably, transgelin 2 (TAGLN2) was found to be widely upregulated in BC, and overexpression of TAGLN2 also significantly increased risks of advanced TMN stage. We further identified that upregulation of miR-133b inhibited glucose uptake, invasion, angiogenesis, colony formation and enhances gemcitabine chemosensitivity in BC cell lines by targeting TAGLN2. Additionally, we showed that miR-133b promoted the proliferation of BC cells, at least partially through a TAGLN2-mediated cell cycle pathway. Our results suggest a novel miR-133b/TAGLN2/cell cycle pathway axis controlling BC progression; a molecular mechanism which may offer a potential therapeutic target.

A Molecular Signature of Two Long Non-Coding RNAs in Peripheral Blood Predicts Acute Renal Allograft Rejection.

BACKGROUND/AIMS: Acute rejection (AR) is a major complication post renal transplantation, with no widely-accepted non-invasive biomarker. This study aimed to explore the expression profiles of long non-coding RNAs (lncRNAs) in the peripheral blood (PB) of renal transplant recipients and their potential diagnostic values. METHODS: The genome-wide lncRNA expression profiles were analyzed in 150 PB samples from pediatric and adult renal transplant (PRTx and ARTx) cohorts. The diagnostic performance of differentially expressed lncRNA was determined using receiver operator characteristic curve, with area under the curve (AUC) and 95% confidential interval (CI). Finally, a risk score was constructed with logistical regression model. RESULTS: A total of 162 lncRNAs were found differentially expressed in PRTx cohort, while 163 in ARTx cohort. Among these identified lncRNAs, 23 deregulated accordingly in both cohorts, and could distinguish AR recipients from those without AR. Finally, a risk score with two most significant lncRNAs (AF264622 and AB209021) was generated and exhibited excellent diagnostic performance in both PRTx (AUC:0.829, 95% CI:0.735-0.922) and ARTx cohorts (AUC: 0.889, 95% CI: 0.817-0.960). CONCLUSION: A molecular signature of two lncRNAs in PB could serve as a novel non-invasive biomarker for the diagnosis of AR in both pediatric and adult renal transplant recipients.

MicroRNA expression profiles in muscle-invasive bladder cancer: identification of a four-microRNA signature associated with patient survival.

Bladder cancer ranks the second most common genitourinary tract cancer, and muscle-invasive bladder cancer (MIBC) accounts for approximately 25 % of all bladder cancer cases with high mortality. In the current study, with a total of 202 treatment-naïve primary MIBC patients identified from The Cancer Genome Atlas dataset, we comprehensively analyzed the genome-wide microRNA (miRNA) expression profiles in MIBC, with the aim to investigate the relationship of miRNA expression with the progression and prognosis of MIBC, and generate a miRNA signature of prognostic capabilities. In the progression-related miRNA profiles, a total of 47, 16, 3, and 84 miRNAs were selected for pathologic T, N, M, and histologic grade, respectively. Of the eight most important progression-related miRNAs, four (let-7c, mir-125b-1, mir-193a, and mir-99a) were significantly associated with survival of patients with MIBC. Finally, a four-miRNA signature was generated and proven as a promising prognostic parameter. In summary, this study identified the specific miRNAs associated with the progression and aggressiveness of MIBC and a four-miRNA signature as a promising prognostic parameter of MIBC.

Identification and significance of mobilized endothelial progenitor cells in tumor neovascularization of renal cell carcinoma.

Neovascularization is a key role of renal cell carcinoma (RCC) and the status of neovascularization in RCC is closely correlated with the tumor development and patient prognosis. Endothelial progenitor cells (EPCs) are considered as important building blocks for neovascularization. However, the role of mobilized EPCs in RCC remains unknown. In this study, the orthotopic RCC model was established to investigate the distribution, frequency, and significance of mobilized EPCs. We found that circulating endothelial progenitor cell (CEPC) levels and plasma angiogenic factors (vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) were higher in peripheral blood (PB) of the RCC than those in the normal group and positively correlated with each other. EPC levels in adjacent nonmalignant kidney tissue (AT) were significantly higher than those in tumor tissue (TT) and normal kidney tissue (NT), which were positively correlated with CEPC levels. VEGF, VEGF receptor-2 (Flk), and SDF-1 and its SDF-1 receptor (CXCR4) expression in AT was significantly higher than that in TT and NT. Levels of these angiogenic factors in AT were positively correlated with those in PB. Mean microvessel density (MVD) was higher in AT than in TT, and that in TT was slightly lower than that in NT. Our findings propose that mobilized EPCs play an important role in RCC neovascularization. EPCs in PB and AT can be used as a biomarker for predicting RCC progression.

The association between RASSF1A promoter methylation and prostate cancer: evidence from 19 published studies.

Ras-associated domain family 1A (RASSF1A) is a putative tumor suppressor gene located at 3p21.3, and the epigenetic inactivation of RASSF1A by hypermethylation of CpG islands within the promoter region has been observed in various cancer types, including prostate cancer (PCa). However, results from published studies on the association between RASSF1A promoter methylation and PCa risk are conflicting and inconclusive. Hence, we conducted a meta-analysis of 19 eligible studies with odds ratio (OR) and its corresponding 95% confidence intervals (95% CI) in order to investigate the strength of relationship of RASSF1A promoter methylation with PCa risk and its clinicopathological variables. Overall, the RASSF1A promoter methylation was significantly associated with PCa risk (OR = 9.58, 95% CI 5.64-16.88, P heterogeneity <0.001) and Gleason score (GS) (OR = 2.58, 95% CI 1.64-4.04, P(heterogeneity) = 0.019). In addition, subgroup analysis by testing material demonstrated the significant association between RASSF1A methylation and GS (OR = 3.09, 95% CI 1.92-4.97, P heterogeneity =0.042), PSA level (OR = 2.75, 95% CI 1.67-4.52, P(heterogeneity) = 0.639), and tumor stage (OR = 1.74, 95% CI 1.05-2.87, P(heterogeneity) = 0.026) in tissue rather than urine samples. In conclusion, this meta-analysis suggested that RASSF1A promoter methylation was significantly associated with an increased risk for PCa; furthermore, the RASSF1A methylation status in tissue rather than urine was positively correlated with GS, serum PSA level, and tumor stage, which can be utilized for the early detection and prognosis prediction of PCa.

Lack of association between interferon gamma +874 T/A polymorphism and cancer risk: an updated meta-analysis.

Interferon gamma (IFN-γ) is a potent proinflammatory cytokine which plays a pivotal role in the antiviral, antiproliferative, and antitumor activities. A T-to-A transition at the position +874 of human IFN-γ gene (IFNG) has been reported to influence the secretion of IFN-γ and affect cancer susceptibility. However, results from published studies on the association between IFNG +874 T/A polymorphism and cancer risk are inconclusive or even controversial. In order to derive a more precise estimation of the association, a meta-analysis of 38 eligible studies including 5,630 cases and 6,096 controls was conducted with odds ratio (OR) and its corresponding 95 % confidence interval (95 % CI). Overall, no significant association was detected in allelic model (A allele vs. T allele-OR = 0.96, 95 % CI, 0.86-1.08), homozygote comparison (AA vs. TT-OR = 0.97, 95 % CI, 0.79-1.21), heterozygote comparison (AT vs. TT-OR = 1.03, 95 % CI, 0.87-1.23), dominant model (AA + AT vs. TT-OR = 1.00, 95 % CI, 0.87-1.15), nor recessive model (AA vs. AT + TT-OR = 0.93, 95 % CI, 0.78-1.12). Further subgroup analyses based on ethnicity, cancer types, and Hardy-Weinberg equilibrium status failed to demonstrate any significant relationship except in African population under recessive model (AA vs. AT + TT-OR = 0.68, 95 % CI, 0.47-0.97). In conclusion, the current meta-analysis suggested that IFNG +874 T/A polymorphism may not contribute to cancer susceptibility, and further well-designed studies with large sample size are warranted to validate our conclusion.

Association of polymorphisms in estrogen receptors (ESR1 and ESR2) with male infertility: a meta-analysis and systematic review.

PURPOSE: Estrogens play an important role in male reproduction via interacting with estrogen receptors (ERs), whose expression can be regulated by the polymorphisms in different regions of ESR1 and ESR2 genes. However, results from published studies on the association between four well-characterized polymorphisms (PvuII, XbaI, RsaI, and AluI) in the gene of ERs (ESR1 and ESR2) and male infertility risk are inconclusive. METHODS: To investigate the strength of relationship of PvuII and XbaI in ESR1 and RsaI and AluI in ESR2 with male infertility, we conducted a meta-analysis of 12 eligible studies with odds ratio (OR) and its corresponding 95 % confidence intervals (95 % CI). RESULTS: Overall, ESR1 PvuII and ESR2 RsaI polymorphisms were significantly associated with male infertility risk. The subgroup analyses by ethnicities demonstrated that in Asians, ESR1 PvuII, XbaI and ESR2 RsaI polymorphisms were significantly associated with a decreased infertility risk, while in Caucasians both ESR1 PvuII and ESR2 RsaI polymorphisms increased the susceptibility to male infertility. As for ESR2 AluI polymorphism, no significant association was detected in either overall analysis or subgroup analyses by ethnicities/genotyping methods. CONCLUSIONS: This meta-analysis suggested that polymorphisms in the genes of ERs (ESR1 and ESR2) may have differential roles in the predisposition to male infertility according to the different ethnic backgrounds. Further well-designed and unbiased studies with larger sample size and diverse ethnic backgrounds should be conducted to verify our findings.

Association between interferon gamma +874 T>A polymorphism and acute renal allograft rejection: evidence from published studies.

Interferon gamma is involved in the acute rejection (AR) episodes of transplant recipients. However, results from published studies on the association of interferon gamma (IFNG) +874 T>A (rs2430561) polymorphism with AR of renal allograft are conflicting. To investigate the association between IFNG +874 T>A polymorphism with AR after renal transplantation, relevant studies were selected from PUBMED, EMBASE, Wanfang database and China National Knowledge Infrastructure until March 1st 2013. According the predesigned selection criteria, a total of 525 AR cases and 1,126 non-AR cases from 13 case-control studies were included to identify the strength of association with odds ratio (OR) and 95 % confidence intervals (95 % CI). Overall, a significant correlation between IFNG +874 T>A polymorphism and susceptibility to AR was detected (T allele vs. A allele: OR = 1.19, 95 % CI 1.02-1.38; TT/AT vs. AA: OR = 1.36, 95 % CI 1.07-1.73; TT vs. AA: OR = 1.42, 95 % CI 1.05-1.93; AT vs. AA: OR = 1.30, 95 % CI 1.01-1.68). In addition, ethnicity subgroup analysis revealed that high produce genotype (TT/AT) was associated with an increased risk of AR for Caucasians (TT/AT vs. AA: OR = 1.56, 95 % CI 1.14-2.12; TT vs. AA: OR = 1.64, 95 % CI 1.18-2.26). Furthermore, donor source subgroup analysis observed an increased risk for patients undergoing cadaveric kidney transplantation (TT/AT vs. AA: OR = 1.90, 95 % CI 1.12-3.24; TA vs. AA: OR = 2.16, 95 % CI 1.24-3.74). In conclusion, this meta-analysis suggested that IFNG +874 T>A polymorphism was associated with AR of renal transplant recipients, especially among Caucasians and those receiving cadaveric renal allograft. Additional well-designed studies with large sample size are warranted to validate our conclusion.

Pre-transjugular-intrahepatic-portosystemic-shunt measurement of hepatic venous pressure gradient and its clinical application: A comparison study.

BACKGROUND: It is controversial whether transjugular intrahepatic portosystemic shunt (TIPS) placement can improve long-term survival. AIM: To assess whether TIPS placement improves survival in patients with hepatic-venous-pressure-gradient (HVPG) ≥ 16 mmHg, based on HVPG-related risk stratification. METHODS: Consecutive variceal bleeding patients treated with endoscopic therapy + nonselective ß-blockers (NSBBs) or covered TIPS placement were retrospectively enrolled between January 2013 and December 2019. HVPG measurements were performed before therapy. The primary outcome was transplant-free survival; secondary endpoints were rebleeding and overt hepatic encephalopathy (OHE). RESULTS: A total of 184 patients were analyzed (mean age, 55.27 years ± 13.86, 107 males; 102 in the EVL+NSBB group, 82 in the covered TIPS group). Based on the HVPG-guided risk stratification, 70 patients had HVPG < 16 mmHg, and 114 patients had HVPG ≥ 16 mmHg. The median follow-up time of the cohort was 49.5 mo. There was no significant difference in transplant-free survival between the two treatment groups overall (hazard ratio [HR], 0.61; 95% confidence interval [CI]: 0.35-1.05; P = 0.07). In the high-HVPG tier, transplant-free survival was higher in the TIPS group (HR, 0.44; 95%CI: 0.23-0.85; P = 0.004). In the low-HVPG tier, transplant-free survival after the two treatments was similar (HR, 0.86; 95%CI: 0.33-0.23; P = 0.74). Covered TIPS placement decreased the rate of rebleeding independent of the HVPG tier (P < 0.001). The difference in OHE between the two groups was not statistically significant (P = 0.09; P = 0.48). CONCLUSION: TIPS placement can effectively improve transplant-free survival when the HVPG is greater than 16 mmHg.

The post-transcriptional inhibition of CXCR4 expression by miR-139 regulates the proliferation of human kidney cancer cells.

The C-X-C chemokine receptor 4 (CXCR4) has been reported to be involved in several cancer related processes. The current study was designed to investigate the role of CXCR4 in human kidney cancer and to unveil the underlying molecular mechanisms. The results showed the expression of CXCR4 to be significantly (P<0.05) upregulated in human renal cancer tissues and cell lines. Silencing of CXCR4 lead to a significant (P<0.05) decline of cell proliferation and colony formation of the Caki-1 and A498 kidney cancer cells. Moreover, the migration and invasion of the Caki-1 and A498 cells was also significantly (P<0.05) inhibited upon CXCR4 silencing. TargetScan analysis and dual luciferase assay revealed that CXCR4 interacts with microRNA-139 (miR-139). The expression of miR-139 was found to be significantly (P<0.05) downregulated in human kidney cancer cells lines. Overexpression of miR-139 caused post-transcriptional suppression of CXCR4 expression and significant (P<0.05) inhibition of the Caki-1 and A498 cell proliferation. Nonetheless, CXCR4 overexpression could nullify the inhibitory effects of miR-139 on the proliferation of Caki-1 and A498 cells. Taken together, the results revealed that CXCR/miR-139 axis regulates the proliferation, migration, and invasion of human kidney cancer cells and may act as a therapeutic target.

Comprehensive insight into endothelial progenitor cell-derived extracellular vesicles as a promising candidate for disease treatment.

Endothelial progenitor cells (EPCs), which are a type of stem cell, have been found to have strong angiogenic and tissue repair capabilities. Extracellular vesicles (EVs) contain many effective components, such as cellular proteins, microRNAs, messenger RNAs, and long noncoding RNAs, and can be secreted by different cell types. The functions of EVs depend mainly on their parent cells. Many researchers have conducted functional studies of EPC-derived EVs (EPC-EVs) and showed that they exhibit therapeutic effects on many diseases, such as cardiovascular disease, acute kidney injury, acute lung injury, and sepsis. In this review article, we comprehensively summarized the biogenesis and functions of EPCs and EVs and the potent role of EPC-EVs in the treatment of various diseases. Furthermore, the current problems and future prospects have been discussed, and further studies are needed to compare the therapeutic effects of EVs derived from various stem cells, which will contribute to the accelerated translation of these applications in a clinical setting.

The Role of P4HA1 in Multiple Cancer Types and its Potential as a Target in Renal Cell Carcinoma.

Background: Prolyl 4-hydroxylase subunit alpha 1 (P4HA1) provides the majority of the catalytic site of the active P4H enzyme. Emerging evidence has revealed that P4HA1 participates in the initiation and development of several malignant tumors. However, a pan-cancer analysis of P4HA1 has not been performed. Methods: In this study, we carried out an in-depth analysis of the expression patterns and prognostic value of P4HA1 using the datasets of The Cancer Genome Atlas (TCGA) and Kaplan-Meier Plotter. Genomic and epigenetic alterations of P4HA1 and the correlation of P4HA1 with DNA methylation in different cancers were also analyzed across multiple databases. In addition, the purity-adjusted partial Spearman's correlation test was utilized to evaluate the correlation between P4HA1 expression and immune cell infiltration. We also further explored the biological function and mechanism of P4HA1 in renal cell carcinoma (RCC). Results: We characterized the expression profiles and prognostic values of P4HA1 in multiple cancer types. P4HA1 expression was increased in clear cell renal cell carcinoma (RCC) compared to adjacent normal tissues, and P4HA1 positively correlated with the overall survival (OS) and disease-free survival (DFS) in papillary RCC. In addition, a positive correlation between P4HA1 expression and immune cell infiltration was observed in clear cell RCC. We also identified a strong correlation between P4HA1 expression and immune checkpoint gene expression, microsatellite instability, and tumor mutation burden in chromophobe RCC. Finally, the results of in vitro experiments verified that overexpression of P4HA1 promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition of RCC cells. Conclusion: Overall, our study has suggested that P4HA1 might play a significant role in tumorigenesis in RCC and may be a prognostic biomarker and therapeutic target for several malignant tumors, including RCC.

Pan-Cancer Transcriptomic Analysis Identifies PLK1 Crucial for the Tumorigenesis of Clear Cell Renal Cell Carcinoma.

BACKGROUND: Polo-like kinase 1 (PLK1) belongs to polo-like kinases family and affects cell cycles. However, the role of PLK1 in some malignant tumors remains unclear. METHODS: To obtain a comprehensive view of PLK1 expression patterns, public databases including The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, the Genotype-Tissue Expression, and human cell landscape databases were employed. The correlation of PLK1 expression with prognosis, immune infiltrations, immune checkpoint genes, tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and DNA methylation was examined. Besides, we validated the results of clear cell renal cell carcinoma (ccRCC) in two cohorts, with quantitative real-time PCR, Western blot, and loss-of-function experiments. RESULTS: By mining public datasets, we discovered that PLK1 expression in tumor tissues and cancer cell lines displayed heterogeneity compared to normal controls across different cancers. Besides, high expression of PLK1 results in shorter survival time in 15 cancer types, especially in ccRCC. PLK1 expression showed strong association with immune cell infiltration and immune checkpoint genes across cancer types. Moreover, we identified a strong association between PLK1 expression and TMB, MSI MMR, and DNA methylation. PLK1 was validated to be highly expressed in ccRCC tissues and promote ccRCC cell proliferation, migration, invasion, and cell cycle. Mechanistically, PLK1 could regulate forkhead box protein M1 and target cell cycle-associated genes to participate in cell cycle control. CONCLUSION: PLK1 has important prognostic value and is associated with tumor immunity across cancer types including ccRCC.

Tumor Cell-Derived Exosomal circ-PRKCI Promotes Proliferation of Renal Cell Carcinoma via Regulating miR-545-3p/CCND1 Axis.

Renal cell carcinoma (RCC) originates from the epithelial cells of the renal tubules and has a high degree of malignancy and heterogeneity. Recent studies have found that exosomes regulate intercellular communication via transferring various bioactive molecules, such as circular RNAs (circRNAs), which are critical for cancer progression. However, the role of tumor cell-derived exosomal circRNAs in RCC remains unclear. In this study, we reported the high expression of circ-PRKCI in RCC tissues and serum exosomes. We also found that circ-PRKCI could be transferred exosomally from highly malignant RCC cells to relatively less malignant RCC cells. Tumor cell-derived exosomal circ-PRKCI promoted the proliferation, migration, and invasion of RCC cells, while inhibiting their apoptosis. Mechanistically, we found that circ-PRKCI promoted the proliferation of RCC via the miR-545-3p/CCND1 signaling pathway. Our study is the first to report the potential mechanisms of tumor cell-derived exosomal circ-PRKCI in RCC. In conclusion, this study will provide a new understanding about the molecular mechanisms of RCC progression.

Circular RNA ITCH: A novel tumor suppressor in multiple cancers.

Circular RNAs (circRNAs) are a new type of endogenous noncoding RNAs with closed circular structure. Emerging evidence indicates that circRNAs play crucial roles in many biological processes by regulating linear RNA transcription, downstream gene expression and protein production. Meanwhile, recent studies have suggested that circRNAs have the potential to be oncogenic or anti-oncogenic and play vital regulatory roles in the initiation and progression of tumors. Circular RNA itchy E3 ubiquitin protein ligase (circ-ITCH), a novel circular RNA originated from several exons of ITCH and located on chromosome 20q11.22, was proved to be declined in many malignant tumors, such as melanoma and ovarian cancer, resulting in tumor occurrence and progression. This review summarizes the biogenesis, characteristics, and functions of circRNAs, as well as recent progression regarding the biological functions and potential molecular mechanisms of circ-ITCH, and future challenges in cancer research.

The Potential Roles of RNA N6-Methyladenosine in Urological Tumors.

N6-methyladenosine (m6A) is regarded as the most abundant, prevalent and conserved internal mRNA modification in mammalian cells. M6A can be catalyzed by m6A methyltransferases METTL3, METTL14 and WTAP (writers), reverted by demethylases ALKBH5 and FTO (erasers), and recognized by m6A -binding proteins such as YTHDF1/2/3, IGF2BP1/2/3 and HNRNPA2B1 (readers). Emerging evidence suggests that m6A modification is significant for regulating many biological and cellular processes and participates in the pathological development of various diseases, including tumors. This article reviews recent studies on the biological function of m6A modification and the methylation modification of m6A in urological tumors.

Transjugular intrahepatic portosystemic shunt and splenectomy are more effective than endoscopic therapy for recurrent variceal bleeding in patients with idiopathic noncirrhotic portal hypertension.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS), splenectomy plus esophagogastric devascularization (SED) and endoscopic therapy + non-selective ß-blockers (ET + NSBB) are widely applied in secondary prevention of recurrent gastroesophageal variceal bleeding in patients with liver cirrhosis. These different treatments, however, have not been compared in patients with idiopathic non-cirrhotic portal hypertension (INCPH). AIM: To compare the outcomes of TIPS, SED and ET + NSBB in the control of variceal rebleeding in patients with INCPH. METHODS: This retrospective study recruited patients from six centers across China. Demographic characteristics, baseline profiles and follow-up clinical outcomes were collected. Post-procedural clinical outcomes, including incidence of rebleeding, hepatic encephalopathy (HE), portal vein thrombosis (PVT) and mortality rates, were compared in the different groups. RESULTS: In total, 81 patients were recruited, with 28 receiving TIPS, 26 SED, and 27 ET + NSBB. No significant differences in demographic and baseline characteristics were found among these three groups before the procedures. After treatment, blood ammonia was significantly higher in the TIPS group; hemoglobin level and platelet count were significantly higher in the SED group (P < 0.01). Rebleeding rate was significantly higher in the ET + NSBB group (P < 0.01). Mortality was 3.6%, 3.8% and 14.8% in the TIPS, SED and ET + NSBB groups, respectively, with no significant differences (P = 0.082). Logistic regression analysis showed that mortality was significantly correlated with rebleeding, HE, portal thrombosis and superior mesenteric vein thrombosis (P < 0.05). CONCLUSION: In patients with INCPH, TIPS and SED were more effective in controlling rebleeding than ET + NSBB, but survival rates were not significantly different among the three groups. Mortality was significantly correlated with rebleeding, HE and PVT.

Correction: Limited Clinical Utility of Remote Ischemic Conditioning in Renal Transplantation: A Meta-Analysis of Randomized Controlled Trials.

[This corrects the article DOI: 10.1371/journal.pone.0170729.].

Identification of hub miRNA biomarkers for bladder cancer by weighted gene coexpression network analysis.

Bladder cancer (BC) is a common urinary system tumor with high aggressiveness, and it results in relatively high mortality due to a lack of precise and suitable biomarkers. In this study, we applied the weighted gene coexpression network analysis method to miRNA expression data from BC patients, and screened for network modules associated with BC progression. Hub miRNAs were selected, followed by functional enrichment analyses of their target genes for the most closely related module. These hub miRNAs were found to be involved in several functional pathways including pathway in cancer, regulation of actin cytoskeleton, PI3K-Akt signaling pathway, mitogen-activated protein kinase (MAPK) signaling pathway, Wnt signaling pathway, proteoglycans in cancer, focal adhesion and p53 signaling pathway via regulating target genes. Finally, their prognostic significance was tested using analyses of overall survival. A few novel prognostic miRNAs were identified based on expression profiles and related survival data. In conclusion, several miRNAs that were critical in BC initiation and progression have been identified in this study. These miRNAs, which may contribute to a comprehensive understanding of the pathogenesis of BC, could serve as potential biomarkers for BC prognosis or as new therapeutic targets.