Cell-cell communication in kidney fibrosis.

Kidney fibrosis is a common outcome of a wide variety of chronic kidney diseases, in which virtually all kinds of renal resident and infiltrating cells are involved. As such, well-orchestrated intercellular communication is of vital importance in coordinating complex actions during renal fibrogenesis. Cell-cell communication in multicellular organisms is traditionally assumed to be mediated by direct cell contact or soluble factors, including growth factors, cytokines and chemokines, through autocrine, paracrine, endocrine and juxtacrine signaling mechanisms. Growing evidence also demonstrates that extracellular vesicles, naturally released lipid bilayer-encircled particles from almost all types of cells, can act as a vehicle to transfer a diverse array of biomolecules including proteins, mRNA, miRNA and lipids to mediate cell-cell communication. We recently described a new mode of intercellular communication via building a special extracellular niche by insoluble matricellular proteins. Kidney cells, upon injury, produce and secrete different matricellular proteins, which incorporate into local extracellular matrix network, and regulate the behavior, trajectory and fate of neighboring cells in a spatially confined fashion. This extracellular niche-mediated cell-cell communication is unique in that it restrains the crosstalk between cells within a particular locality. Detailed delineation of this unique manner of intercellular communication will help to elucidate the mechanism of kidney fibrosis and could offer novel insights in developing therapeutic intervention.

Oxidatively stressed extracellular microenvironment drives fibroblast activation and kidney fibrosis.

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.

Proteomic landscape of the extracellular matrix in the fibrotic kidney.

The extracellular matrix (ECM) is a complex three-dimensional network of proteins surrounding cells, forming a niche that controls cell adhesion, proliferation, migration and differentiation. The ECM network provides an architectural scaffold for surrounding cells and undergoes dynamic changes in composition and contents during the evolution of chronic kidney disease (CKD). Here, we unveiled the proteomic landscape of the ECM by delineating proteome-wide and ECM-specific alterations in normal and fibrotic kidneys. Decellularized kidney tissue scaffolds were made and subjected to proteomic profiling by liquid chromatography with tandem mass spectrometry. A total of 172 differentially expressed proteins were identified in these scaffolds from mice with CKD. Through bioinformatics analysis and experimental validation, we identified a core set of nine signature proteins, which could play a role in establishing an oxidatively stressed, profibrotic, proinflammatory and antiangiogenetic microenvironment. Among these nine proteins, glutathione peroxidase 3 (GPX3) was the only protein with downregulated expression during CKD. Knockdown of GPX3 in vivo augmented ECM expression and aggravated kidney fibrotic lesions after obstructive injury. Transcriptomic profiling revealed that GPX3 depletion resulted in an altered expression of the genes enriched in hypoxia pathway. Knockdown of GPX3 induced NADPH oxidase 2 expression, promoted kidney generation of reactive oxygen species and activated p38 mitogen-activated protein kinase. Conversely, overexpression of exogenous GPX3 alleviated kidney fibrosis, inhibited NADPH oxidase 2 and p38 mitogen-activated protein kinase. These findings suggest that oxidative stress is a pivotal element of the fibrogenic microenvironment. Thus, our studies represent a comprehensive proteomic characterization of the ECM in the fibrotic kidney and provide novel insights into molecular composition of the fibrogenic microenvironment.

Fibrillin-1-enriched microenvironment drives endothelial injury and vascular rarefaction in chronic kidney disease.

Endothelial cell injury leading to microvascular rarefaction is a characteristic feature of chronic kidney disease (CKD). However, the mechanism underlying endothelial cell dropout is poorly defined. Here, we show a central role of the extracellular microenvironment in controlling endothelial cell survival and proliferation in CKD. When cultured on a decellularized kidney tissue scaffold (KTS) from fibrotic kidney, endothelial cells increased the expression of proapoptotic proteins. Proteomics profiling identified fibrillin-1 (FBN1) as a key component of the fibrotic KTS, which was up-regulated in animal models and patients with CKD. FBN1 induced apoptosis of endothelial cells and inhibited their proliferation in vitro. RNA sequencing uncovered activated integrin αvß6/transforming growth factor-ß signaling, and blocking this pathway abolished FBN1-triggered endothelial injury. In a mouse model of CKD, depletion of FBN1 ameliorated renal fibrotic lesions and mitigated vascular rarefaction. These studies illustrate that FBN1 plays a role in mediating vascular rarefaction by orchestrating a hostile microenvironment for endothelial cells.

The relationship between pancreatic cancer and type 2 diabetes: cause and consequence.

Pancreatic cancer (PC) is a devastating and lethal malignant disease and it is well known that there is a complex bidirectional relationship between PC and type 2 diabetes mellitus (T2DM). In order to more deeply summarize the relationship between them, this article summarizes the epidemiological data on the relationship between PC and T2DM in the past 5 years, and further explains the mechanism of interaction between them. Meanwhile, it also summed up the effects of drug therapy for T2DM on PC and the impact of T2DM on surgical resection of PC. Epidemiological studies clearly indicate that the risk of PC is increased in patients with T2DM. But increasing epidemiological data points out that PC also acts as a cause of T2DM and new-onset T2DM is sign and consequence of PC. Insulin resistance, hyperinsulinemia, hyperglycemia, and chronic inflammation are the mechanisms of T2DM-Associated PC. Metformin decreases the risk of PC, while insulin therapy increases the risk of PC. Besides, studies have shown that T2DM decreases the survival in patients with PC resection.

The Efficacy of Different Chemotherapy Regimens for Advanced Biliary Tract Cancer: A Systematic Review and Network Meta-Analysis.

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.

The Prognostic and Clinicopathological Roles of PD-L1 Expression in Colorectal Cancer: A Systematic Review and Meta-Analysis.

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).

Artificial liver research output and citations from 2004 to 2017: a bibliometric analysis.

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 (r 2 = 0.133, p < 0.001), and countries (r 2 = 0.275, p < 0.001), while no correlations of the number of citations with the years since publication (r 2 = 0.016, p = 0.216), and funding (r 2 < 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.

Nomograms to predict overall survival and cancer-specific survival in patients with adrenocortical carcinoma.

PURPOSE: To develop nomogram models to predict individualized estimates of overall survival (OS) and cancer-specific survival (CSS) in patients with adrenocortical carcinoma (ACC). PATIENTS AND METHODS: A total of 751 patients with ACC were identified within the Surveillance Epidemiology, and End Results (SEER) database between 1973 and 2015. The predictors comprised marital status, sex, age at diagnosis, year of diagnosis, laterality, histologic grade, ethnicity, historic stage, radiation therapy, chemotherapy, and surgery of primary site. Based on the results of the multivariate logistic regression analyses, the nomogram models were used for predicting OS and CSS in patients with ACC. The nomograms were tested using concordance index (C-index) and calibration curves. RESULTS: In univariate and multivariate analyses of OS, OS was significantly associated with age at diagnosis, year of diagnosis, histologic grade, historic stage, and chemotherapy. In univariate and multivariate analyses of CSS, age at diagnosis, year of diagnosis, historic stage, and chemotherapy were the independent risk factors with CSS. These characteristics were included in the nomograms predicting OS and CSS. The nomograms demonstrated good accuracy in predicting OS and CSS, with the C-index of 0.677 and 0.672. CONCLUSION: These clinically useful tools predicted OS and CSS in patients with ACC using readily available clinicopathologic factors and could aid individualized clinical decision making.

The Clinicopathologic and Prognostic Significance of Programmed Cell Death Ligand 1 (PD-L1) Expression in Patients With Prostate Cancer: A Systematic Review and Meta-Analysis.

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 I 2 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.

The preparation of magnetic molecularly imprinted nanoparticles for the recognition of bovine hemoglobin.

The protein imprinted technique combining surface imprinting and nano-sized supports materials is an attractive strategy for protein recognition and rapid separation. In this work, we imprinted bovine hemoglobin (BHb) on magnetic nanoparticles. With itaconic acid (IA) and acrylamide (AAm) as the monomers, the experiment was carried out in aqueous media via surface-imprinting technique. The effects of initial concentration and adsorption time over the adsorption capacity of both imprinted and non-imprinted nanoparticles were analyzed. The maximum adsorption capability of imprinted nanoparticles was found to be 77.6 mg g(-1), which was 3.1-4.3 times higher than that of the non-imprinted nanoparticles prepared at the same conditions. This resulted in the successful formation of imprinting cavities. Moreover, in selective adsorption experiment and competitive batch rebinding test, imprinted nanoparticles exhibited a high specific recognition of the template protein over the non-imprinted protein.