Inhibition of STAT3 by S3I-201 suppress peritoneal fibroblast phenotype conversion and alleviate peritoneal fibrosis.

Peritoneal fibrosis is a common pathological response to long-term peritoneal dialysis (PD) and a major cause for PD discontinuation. Understanding the cellular and molecular mechanisms underlying the induction and progression of peritoneal fibrosis is of great interest. In our study, in vitro study revealed that signal transducer and activator of transcription 3 (STAT3) is a key factor in fibroblast activation and extracellular matrix (ECM) synthesis. Furthermore, STAT3 induced by IL-6 trans-signalling pathway mediate the fibroblasts of the peritoneal stroma contributed to peritoneal fibrosis. Inhibition of STAT3 exerts an antifibrotic effect by attenuating fibroblast activation and ECM production with an in vitro co-culture model. Moreover, STAT3 plays an important role in the peritoneal fibrosis in an animal model of peritoneal fibrosis developed in mice. Blocking STAT3 can reduce the peritoneal morphological changes induced by chlorhexidine gluconate. In conclusion, our findings suggested STAT3 signalling played an important role in peritoneal fibrosis. Therefore, blocking STAT3 might become a potential treatment strategy in peritoneal fibrosis.

Serum angiopoietin-2/angiopoietin-1 ratio is associated with cardiovascular and all-cause mortality in peritoneal dialysis patients: a prospective cohort study.

INTRODUCTION: Our objective was to examine the factors associated with the serum angiopoietin-2/angiopoietin-1 (Angpt-2/Angpt-1) ratio in peritoneal dialysis (PD) patients and to investigate the association between Angpt-2/Angpt-1 ratio and cardiovascular and all-cause mortality. METHODS: Patients on PD who were prevalent between January 2014 and April 2015 in the center of Renji Hospital were enrolled. At the time of enrollment, serum and dialysate samples were collected to detect biochemical parameters, serum angiopoietin-2 and angiopoietin-1 levels. Patients were dichotomized into two groups according to a median of Angpt-2/Angpt-1 ratio and followed up prospectively until the end of the study. RESULTS: A total of 325 patients were enrolled, including 168 males (51.7%) with a mean age of 56.9 ± 14.2 years and a median PD duration of 32.4 (9.8-55.9) months. Multiple linear regression showed pulse pressure (ß = 0.206, p < .001) and high-sensitivity C-reactive protein (hs-CRP) (ß = 0.149, p = .011) were positively correlated with serum Angpt-2/Angpt-1 ratio, while residual renal function (RRF) (ß= -0.219, p < .001) was negatively correlated with serum Angpt-2/Angpt-1 ratio. Multivariate Cox regression analysis showed the high serum Angpt-2/Angpt-1 ratio was an independent predictor of cardiovascular mortality (hazard ratio (HR)=2.467, 95% confidence interval (CI) 1.243-4.895, p = .010) and all-cause mortality (HR = 1.486, 95%CI 1.038-2.127, p = .031). In further subgroup analysis by gender, a significant association was shown in high Angpt-2/Angpt-1 ratio with all-cause mortality in male (p < .05), but not in female patients (p>.05). CONCLUSIONS: High Angpt-2/Angpt-1 ratio is an independent risk factor for cardiovascular and all-cause mortality in PD patients.

Expression of microRNA-99a-3p in Prostate Cancer Based on Bioinformatics Data and Meta-Analysis of a Literature Review of 965 Cases.

BACKGROUND microRNAs (miRNAs) have a role as biomarkers in human cancer. The aim of this study was to use bioinformatics data, and review of cases identified from the literature, to investigate the role of microRNA-99a-3p (miR-99a-3p) in prostate cancer, including the identification of its target genes and signaling pathways. MATERIAL AND METHODS Meta-analysis from a literature review included 965 cases of prostate cancer. Bioinformatics databases interrogated for miR-99a-3p in prostate cancer included The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and ArrayExpress. Twelve computational predictive algorithms were developed to integrate miR-99a-3p target gene prediction data. Bioinformatics analysis data from Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) network analysis were used investigate the possible pathways and target genes for miR-99a-3p in prostate cancer. RESULTS TCGA data showed that miR-99a was down-regulated in prostate cancer when compared with normal prostate tissue. Receiver-operating characteristic (ROC) curve area under the curve (AUC) for miR-99a-3p was 0.660 (95% CI, 0.587-0.732) or a moderate level of discriminations. Pathway analysis showed that miR-99a-3p was associated with the Wnt and vascular endothelial growth factor (VEGF) signaling pathways. The PPP3CA and HYOU1 genes, selected from the PPI network, were highly expressed in prostate cancer tissue compared with normal prostate tissue, and negatively correlated with the expression of miR-99a-3p. CONCLUSIONS In prostate cancer, miR-99a-3p expression was associated with the Wnt and VEGF signaling pathways, which might inhibit the expression of PPP3CA or HYOU1.

Lymphotoxin-ß promotes breast cancer bone metastasis colonization and osteolytic outgrowth.

Bone metastasis is a lethal consequence of breast cancer. Here we used single-cell transcriptomics to investigate the molecular mechanisms underlying bone metastasis colonization-the rate-limiting step in the metastatic cascade. We identified that lymphotoxin-ß (LTß) is highly expressed in tumour cells within the bone microenvironment and this expression is associated with poor bone metastasis-free survival. LTß promotes tumour cell colonization and outgrowth in multiple breast cancer models. Mechanistically, tumour-derived LTß activates osteoblasts through nuclear factor-κB2 signalling to secrete CCL2/5, which facilitates tumour cell adhesion to osteoblasts and accelerates osteoclastogenesis, leading to bone metastasis progression. Blocking LTß signalling with a decoy receptor significantly suppressed bone metastasis in vivo, whereas clinical sample analysis revealed significantly higher LTß expression in bone metastases than in primary tumours. Our findings highlight LTß as a bone niche-induced factor that promotes tumour cell colonization and osteolytic outgrowth and underscore its potential as a therapeutic target for patients with bone metastatic disease.

High intraperitoneal interleukin-6 levels predict ultrafiltration (UF) insufficiency in peritoneal dialysis patients: A prospective cohort study.

Introduction: UF insufficiency is a major limitation in PD efficiency and sustainability. Our study object to investigate the efficacy of intraperitoneal inflammation marker, IL-6 level as a predictor of UF insufficiency in continuous ambulatory peritoneal dialysis (CAPD) patients. Methods: Stable prevalent CAPD patients were enrolled in this prospective study. IL-6 concentration in the overnight effluent was determined and expressed as the IL-6 appearance rate (IL-6 AR). Patients were divided into two groups according to the median of IL-6 AR and prospectively followed up until death, transfer to permanent HD, recovery of renal function, kidney transplantation, transfer to other centers, lost to follow-up or to the end of study (January 31, 2021). Factors associated with UF capacity as well as dialysate IL-6 AR were assessed by multivariable linear regression. Cox proportional hazards model was used to examine the association between dialysate IL-6 AR and UF insufficiency. Results: A total of 291 PD patients were enrolled, including 148 males (51%) with a mean age of 56.6 ± 14.1 years and a median PD duration of 33.4 (12.7-57.5) months. No correlation was found between dialysate IL-6 AR and UF capacity at baseline. PD duration was found positively correlated with baseline dialysate IL-6 AR, while 24h urine volume was negatively correlated with baseline dialysate IL-6 AR (P < 0.05). By the end of study, UF insufficiency was observed in 56 (19.2%) patients. Patients in the high IL-6 AR group showed a significantly inferior UF insufficiency-free survival when compared with their counterparts in the low IL-6 AR group (P = 0.001). In the multivariate Cox regression analysis, after adjusting for DM, previous peritonitis episode and 24h urine volume, higher baseline dialysate IL-6 AR (HR 3.639, 95% CI 1.776-7.456, P = 0.002) were associated with an increased risk of UF insufficiency. The area under the ROC curve (AUC) for baseline IL-6 AR to predict UF insufficiency was 0.663 (95% CI, 0.580-0.746; P < 0.001). Conclusion: Our study suggested that the dialysate IL-6 AR could be a potential predictor of UF insufficiency in patients undergoing PD.

Assisted peritoneal dialysis: a feasible KRT modality for frail older patients with end-stage kidney disease (ESKD).

Assisted PD is used as an alternative option for the growing group of frail, older ESKD patients unable to perform their own PD. This study was undertaken to investigate the outcomes of assisted PD in older patients by comparing assisted PD patients with self-care PD patients. This study included all patients aged 70 and above who started on PD in our hospital from 2009 to 2018. Patients were followed up until death, PD cessation or to the end of the study (December 31, 2019). Risk factors associated with mortality, peritonitis and technique failure were evaluated using both cause-specific hazards and subdistribution hazards models. 180 patients were enrolled, including 106 (58.9%) males with a median age of 77.5 (77.2-81.2) years. Among the 180 patients, 62 patients (34.4%) were assisted. Patients on assisted PD group were older, more likely to be female, more prevalent in DM and CVD, with a higher Charlson score than patients undergoing self-care PD (P all < 0.05). In the multivariable analysis, assisted patients had a comparable patient survival and peritonitis-free survival compared to self-care PD patients either in the Cox or in the FG models. According to a Cox model, the use of assisted PD was associated with a lower risk of technique failure (cs-HR 0.20, 95% CI 0.04-0.76), but the association lost its statistical significance in the Fine and Gray model. Our results suggest that assisted PD could be a safe and effective KRT modality for older ESKD patients who need assistance.

Dual-channel Microchip Electrophoresis with Amperometric Detection System for Rapid Analysis of Cefoperazone and Sulbactam.

A dual-channel microchip electrophoresis (ME) with in-channel amperometric detection was developed for cefoperazone and sulbactam determination simultaneously. In this study, a microelectrode detector was made of gold nanoparticles (GNPs) modified indium tin oxide (ITO)-coated poly-ethylene terephthalate (PET) film. The parameters including detection potential applied on working electrode, buffer concentration and pH value were optimized to improve the detection sensitivity and separation efficiency of cefoperazone and sulbactam. Under the optimal conditions, sensitive detection of cefoperazone and sulbactam was obtained with limits of detection (LODs) (S/N = 3) of 0.52 and 0.75 µg/mL, respectively. The plasma sample, which was from a patient with a brain injury taking Sulperazone, was successfully detected with a simple sample pretreatment process by dual-channel ME amperometric detection. This rapid and sensitive method possesses practical potential in clinical applications, and could provide a guidance for clinical rational drug use.