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Kidney fibrosis is associated with tubular injury, oxidative stress and activation of interstitial fibroblasts. However, whether these events are somehow connected is poorly understood. In this study, we show that glutathione peroxidase-3 (GPX3) depletion in renal tubular epithelium after kidney injury plays a central role in orchestrating an oxidatively stressed extracellular microenvironment, which drives interstitial fibroblast activation and proliferation. Through transcriptional profiling by RNA-sequencing, we found that the expression of GPX3 was down-regulated in various models of chronic kidney disease (CKD), which was correlated with induction of nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase-4 (NOX4). By using decellularized extracellular matrix (ECM) scaffold, we demonstrated that GPX3-depleted extracellular microenvironment spontaneously induced NOX4 expression and reactive oxygen species (ROS) production in renal fibroblasts and triggered their activation and proliferation. Activation of NOX4 by advanced oxidation protein products (AOPPs) mimicked the loss of GPX3, increased the production of ROS, stimulated fibroblast activation and proliferation, and activated protein kinase C-α (PKCα)/mitogen-activated protein kinase (MAPK)/signal transducer and activator of transcription 3 (STAT3) signaling. Silencing NOX4 or inhibition of MAPK with small molecule inhibitors hampered fibroblast activation and proliferation. In mouse model of CKD, knockdown of NOX4 repressed renal fibroblast activation and proliferation and alleviated kidney fibrosis. These results indicate that loss of GPX3 orchestrates an oxidatively stressed extracellular microenvironment, which promotes fibroblast activation and proliferation through a cascade of signal transduction. Our studies underscore the crucial role of extracellular microenvironment in driving fibroblast activation and kidney fibrosis.

Background: Although gemcitabine plus cisplatin (GP) is considered as standard chemotherapy for patients with advanced biliary tract cancer (BTC), the optimal regimen remains unknown.Methods: Using Network meta-analysis (NMA), a systematic review was conducted to find the most effective chemotherapy regimen for advanced BTC. We searched PubMed, Web of Science, Embase, Scopus and the Cochrane Library for articles published before October 6, 2018. Articles about chemotherapeutic comparisons were included. Hazard ratios (HRs) for overall survival (OS) and progression free survival (PFS) were estimated while odd ratios (ORs) was assessed for objective response rate (ORR).Results: The NMA included 25 studies and 3,312 individuals. Among all the regimens, Folfox-4 regimen obtained a superior difference in OS (BSC vs. Folfox-4, HR 3.4, 95% CI 1.7-6.7). XP was slightly better than GP in OS and GS approximately obtained the same efficacy to GP (HR for XP vs. GP 0.74, 95% CI 0.51-1.1; HR for GS vs. GP 1.1, 95% CI 0.71-1.5). Most of the targeted therapies included in this study tend to achieve better results in PFS and ORR but failed to improve OS, in which E-GEMOX achieved the best ORR when compared to BSC (OR 0.03, 95% CI 0.00-0.94).Conclusions: Folfox-4 regimen is likely to be the optimal chemotherapy for patients with advanced BTC and the predominant targeted therapy hasn't achieved significant success currently. XP and GS can be considered as alternatives for advanced BTC.

Background: Studies evaluating the prognostic significance of programmed death-ligand 1 (PD-L1) expression in colorectal cancer (CRC) are limited and remain controversial. This meta-analysis was conducted in order to evaluate the clinicopathological and prognostic significance of PD-L1 expression in CRC patients.Methods: A comprehensive search was performed against the Medline/PubMed, Embase, Cochrane Library, Web of Science (WoS) and Scopus databases. Data were extracted with name of the first author, year of publication, country of origin, tumor type, number of cases, staining method, cut-off values, PD-L1 positive expression, clinicopathological parameters, outcome, and quality assessment score, and statistical analysis was conducted using Review Manager Version 5.3 (Revman the Cochrane Collaboration; Oxford, England) and STATA version 14 (Stata Corporation; College Station, TX, USA).Results: Ten studies were included in this meta-analysis, in which the pooled hazard ratio (HR) showed that PD-L1 expression in tumor cells was significantly associated with a poor overall survival (HR = 1.50, 95% CI 1.05–2.13, P = 0.03). The pooled HR for disease-free survival (DFS) indicated that PD-L1 expression was significantly associated with shorter DFS (HR = 2.57, 95% CI 1.40–4.75, P = 0.002). The pooled odds ratios (ORs) showed that PD-L1 expression was associated with poor differentiation (OR = 3.47, 95% CI 1.37–8.77, P = 0.008) and right colon cancer (OR = 2.38, 95% CI 1.57–3.60, P < 0.0001). However, the expression of PD-L1 was independent of gender, age, tumor size, tumor stage, lymph node metastasis, and tumor-node metastasis stage.Conclusion: This meta-analysis indicated that a high level of PD-L1 expression might be a biomarker for a poor prognosis in CRC patients. This information may be helpful for clinicians to stratify CRC patients for anti-PD-1/PD-L1 therapy, particularly patients with microsatellite instability high (MSI-H).

Background: Programmed cell death ligand 1 (PD-L1) expression has been shown to correlate with poor prognosis in diverse human cancers. However, limited data exist on the prognostic and clinicopathologic significance of PD-L1 expression in prostate cancers (PCa), and the curative effect of anti-PD-1/PD-L1 therapy remains controversial. In this systematic review and meta-analysis, we aimed to evaluate the prognostic and clinicopathologic value of PD-L1 in PCa.Methods: We performed a systematic literature search in the PubMed, Cochrane Library, EMBASE, Web of Science, and SCOPUS databases up to July 21st, 2018. Pooled prevalence of PD-L1 in PCa was calculated using Freeman-Tukey double arcsine transformation by R software version 3.5.0. The data from the studies were examined by a meta-analysis using Review Manager software 5.3 to calculate pooled hazard ratios (HRs) and pooled odds ratios (ORs) with 95% confidence intervals (CIs) to estimate the prognostic and clinicopathologic value of PD-L1 in PCa. Heterogeneity was tested by the Chi-squared test and I2 statistic.Results: Five studies with 2,272 patients were included in this meta-analysis. The pooled prevalence of PD-L1 in PCa was 35% (95% CI 0.32 to 0.37). Both PD-L1 expression (HR = 1.78; 95% CI 1.39 to 2.27; p < 0.00001) and PD-L1 DNA methylation (HR = 2.23; 95% CI 1.51 to 3.29; p < 0.0001) were significantly associated with poor biochemical recurrence-free survival (BCR-FS). PD-L1 tended to have high expression levels in high Gleason score cases (OR = 1.54; 95% CI, 1.17 to 2.03; P = 0.002) and androgen receptor-positive cases (OR = 2.42, 95% CI 1.31 to 4.50; P = 0.005). However, PD-L1 had relatively weak correlation with age, pathologic stage, lymph node metastasis and preoperative PSA level.Conclusions: This meta-analysis confirms the negative prognostic significance of PD-L1 expression and mPD-L1 in PCa patients. Additionally, PD-L1 has a statistically significant correlation with Gleason score and androgen receptor status, while the correlations with age, pathologic stage, lymph node metastasis, and preoperative PSA level were not statistically significant. However, the number of included studies is too small to make the conclusions more convincing, so more retrospective large-cohort studies are expected for the further confirmation of these findings.

Background Researches on artificial livers greatly contribute to the clinical treatments for liver failure. This study aimed to evaluate the research output of artificial livers and citations from 2004 to 2017 through a bibliometric analysis. Methods A list of included articles on artificial livers were generated after a comprehensive search of the Web of Science Core Collection (from 2004 to 2017) with the following basic information: number of publications, citations, publication year, country of origin, authors and authorship, funding source, journals, institutions, keywords, and research area. Results A total of 968 included articles ranged from 47 citations to 394 citations with a fluctuation. The publications were distributed in 12 countries, led by China (n = 212) and the US (n = 207). There were strong correlations of the number of citations with authors (r2 = 0.133, p < 0.001), and countries (r2 = 0.275, p < 0.001), while no correlations of the number of citations with the years since publication (r2 = 0.016, p = 0.216), and funding (r2 < 0.001, p = 0.770) were identified. Keyword analysis demonstrated that with the specific change of “acute liver failure,” decrease in “bioartificial livers” and “hepatocyte,” and increase in “tissue engineering” were identified. The top 53 cited keyword and keyword plus (including some duplicates counts) were identified, led by bioartificial liver (405 citations) and hepatocyte (248 citations). The top 50 cited keywords bursts were mainly “Blood” (2004–2008), “hepatocyte like cell” (2008–2015), and “tissue engineering” (2014–2017). All keywords could be classified into four categories: bioartificial livers (57.40%), blood purification (25.00%), clinical (14.81%), and other artificial organs (2.78%). Discussion This study shows the process and tendency of artificial liver research with a comprehensive analysis on artificial livers. However, although it seems that the future of artificial livers seems brighter for hepatocyte transplantation, the systems of artificial livers now are inclined on focusing on blood purification, plasma exchange, etc.

The article discusses chronic kidney disease (CKD) has become a major public health problem worldwide. Topics include endothelial cell injury leading to microvascular rarefaction has a characteristic feature of chronic kidney disease; and the prevalence of CKD has high, ranging from 10 to 13% in the adult population.