Uncovering new therapeutic targets for renal fibrosis holds promise for the treatment of chronic kidney diseases. Bromodomain and extra-terminal (BET) protein inhibitors have been shown to effectively ameliorate pathological fibrotic responses. However, the pharmacological effects and underlying mechanisms of these inhibitors in renal fibrosis remain elusive. In this study, we determined that the inhibition of Brd4, a BET family member, with a selective potent chemical inhibitor, JQ1, could prevent the development of renal fibrosis and block the progression of fibrosis in rats that have undergone unilateral ureteral obstruction (UUO). Inhibiting Brd4 with either JQ1 or genetic knockdown resulted in decreased expression of fibrotic genes such as α-smooth muscle actin, collagen IV and fibronectin both in UUO-induced fibrosis and upon TGF-β1 stimulation in HK-2 cells. Brd4 inhibition also suppressed the oxidative stress induced by UUO in vivo or by TGF-β1 in HK-2 cells. Moreover, Nox4, which is constitutively active in renal cells and is involved in the generation of hydrogen peroxide, was up-regulated during UUO-mediated fibrosis and induced by TGF-β1 in HK-2 cells, and this up-regulation could be blunted by Brd4 inhibition. Consistently, Nox4-mediated ROS generation and fibrotic gene expression were attenuated upon Brd4 inhibition. Further, the transcriptional activity of Nox4 was suppressed by JQ1 or siRNA against Brd4. Additionally, Smad3 and ERK1/2 phosphorylation, which are upstream signals of Nox4 expression, were inhibited both in JQ1-administered UUO rats and Brd4-inhibited HK-2 cells. In conclusion, these results indicated that the inhibition of Brd4 might protect against renal fibrosis by blocking the TGF-β-Nox4-ROS-fibrosis axis, suggesting that Brd4 could be a promising therapeutic target.

Lymph node status is one of the key parameters used for determining the stage of breast cancer progression. The relationship of lymphatic vessel density (LVD), lymphovascular invasion (LVI), and lymph node metastasis (LNM) has not been clearly demonstrated yet. Databases of PubMed, Embase, and Web of Science were searched from inception up to 25 May 2016. Spearman correlation coefficient (r) and 95% confidence interval (CI) were used to determine the relationship within each group. Based on pre-established inclusion criteria, 28 studies involving 2920 breast cancer patients were included in this study. The r values of LVD-LVI, LVD-LNM, and LVI-LNM were 0.45 (95% CI: 0.31 to 0.57), 0.32 (95% CI: 0.23 to 0.40), and 0.24 (95% CI: 0.19 to 0.28), respectively. Compared with intratumoral LVD, peritumoral LVD showed more robust correlation with LVI (r = 0.53, 95% CI: 0.27 to 0.72) and LNM (r = 0.33, 95% CI: 0.18 to 0.46). The patients in LNM positive group presented with higher LVI detection rate of 45.85%, while in LNM negative group with detection rate of 23.85%. The results describe a triangle relationship between LVD, LVI, and LNM in breast cancer. Both LVD and LVI are indicated to be valuable predictors of LNM occurrence. Compared with intratumoral lymphatic vessels, peritumoral lymphatics might be the main disseminate route for breast tumor cells.

<b><i>Background:</i></b> The relationship between magnesium and mortality in hemodialysis patients has been evaluated in several prospective studies, but few have assessed the risk of all-cause mortality in elderly hemodialysis patients. The aim of this study was to evaluate the association between magnesium levels and the risk of cardiovascular and overall mortality in elderly maintenance hemodialysis patients. <b><i>Methods:</i></b> This was a retrospective study, and patients undergoing maintenance hemodialysis were screened for eligibility at a single dialysis center between July and December 2016. Patients were divided into two groups based on their magnesium levels: a low magnesium level group and a high magnesium level group. Associations between magnesium level and risk of cardiovascular and all-cause mortality were analyzed with a Cox proportional hazards regression model. <b><i>Results:</i></b> In total, 413 patients were included with a median follow-up period of 12 months. We found that compared to patients with high magnesium levels, those with low magnesium levels had significantly lower levels of hemoglobin, urea, creatinine, uric acid, phosphate, potassium, chloride, albumin, and spKt/V (<i>p</i> &#x3c; 0.05 for each parameter). There was a strong correlation between the baseline mean serum magnesium concentration 1 year prior and the concentration 1 year later (<i>r</i>² = 0.519, <i>p</i> &#x3c; 0.001). After adjustment for confounding factors, multivariate Cox proportional hazards analysis showed hypomagnesemia to be an independent predictor of all-cause and cardiovascular mortality in chronic hemodialysis patients. Furthermore, subgroup analysis was performed, revealing that serum magnesium levels were still strongly associated with all-cause mortality and cardiovascular mortality in patients older than 60 years, with HR values of 0.020 (95% CI 0.001–0.415) and 0.010 (95% CI 0.000–0.491), respectively. In addition, there were still significant associations between the serum magnesium level and all-cause mortality and cardiovascular mortality in elderly dialysis patients at the 6-month follow-up visit. <b><i>Conclusion:</i></b> Our study indicates that lower serum magnesium levels are strongly associated with cardiovascular and all-cause mortality in maintenance hemodialysis patients, especially in the short term and in those who are elderly. Factors affecting serum magnesium concentrations in hemodialysis patients should be investigated, and correcting hypomagnesemia may benefit elderly hemodialysis patients.

Background: The transcriptome public database and advances in biological discoveries contributed to significant progresses in identifying the drivers of cancer progression. Cellular senescence (CS) is considered as a leading factor resulting in cancer development. The purpose of this study was to explore the significance of CS-related genes in the molecular classification and survival outcome of clear cell renal cell carcinoma (ccRCC).Methods: CS-related genes were obtained from the CellAge database, and patients from TCGA-KIRC dataset and ICGC dataset were clustered by ConsesusClusterPlus. The characteristics of overall survival (OS), genomic variation, and tumor microenvironment (TME) of each cluster were analyzed. Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analysis was conducted to develop a CS-related risk model to score ccRCC patients and assess the risk scores in predicting patients' response to immunotherapy and chemotherapy. A nomogram based on the risk model was established to improve the risk stratification of patients.Results: CcRCC was divided into three molecular subtypes based on CSrelated genes. The three molecular phenotypes showed different OS and clinical manifestations, mutation patterns, and TME states. Five genes were obtained from nine differentially expressed CS-related genes in the three molecular subtypes to develop a risk model. Patients with ccRCC were Frontiers in Immunology frontiersin.org 01