Sustained expression of programmed cell death receptor-1 (PD-1) is correlated with the exhaustion of T cells, and blockade of the PD-1 pathway is an effective immunotherapeutic strategy for treating various cancers. However, response rates are limited, and many patients do not achieve durable responses. Thus, it is important to seek additional strategies that can improve anticancer immunity. Here, we report that the bromodomain and extraterminal domain (BET) inhibitor JQ1 inhibits PD-1 expression in Jurkat T cells, primary T cells, and T-cell exhaustion models. Furthermore, JQ1 dramatically impaired the expression of PD-1 and T-cell immunoglobulin mucin-domain-containing-3 (Tim-3) and promoted the secretion of cytokines in T cells from patients with acute myeloid leukemia (AML). In line with that, BET inhibitor-treated CD19-CAR T and CD123-CAR T cells have enhanced anti-leukemia potency and resistant to exhaustion. Mechanistically, BRD4 binds to the NFAT2 and PDCD1 (encoding PD-1) promoters, and NFAT2 binds to the PDCD1 and HAVCR2 (encoding Tim-3) promoters. JQ1-treated T cells showed downregulated NFAT2, PD-1, and Tim-3 expression. In addition, BET inhibitor suppressed programmed death-ligand 1 (PD-L1) expression and cell growth in AML cell lines and in primary AML cells. We also demonstrated that JQ1 treatment led to inhibition of leukemia progression, reduced T-cell PD-1/Tim-3 expression, and prolonged survival in MLL-AF9 AML mouse model and Nalm6 (B-cell acute lymphoblastic leukemia cell)-bearing mouse leukemia model. Taken together, BET inhibition improved anti-leukemia immunity by regulating PD-1/PD-L1 expression, and also directly suppressed AML cells, which provides novel insights on the multiple effects of BET inhibition for cancer therapy.

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Huoxue Huayu therapy (HXHY) has been widely used to treat cardiovascular diseases in traditional Chinese medicine (TCM), such as hypertension, and coronary heart disease (CHD). This study describes a meta-analysis of a series of prospective randomized, double-blind, placebo-controlled trials conducted to evaluate the effect of HXHY on patients with CHD after percutaneous coronary intervention (PCI).The Cochrane Library, PubMed, EMBASE, the China National Knowledge Infrastructure (CNKI), the Chinese Biomedical Literature database and the Wanfang database were searched up until June 2018. A series of randomized controlled clinical trials were included and the subjects were patients with CHD who had undergone PCI. The experimental group was treated with HXHY therapy, and the control group was treated with placebo; meanwhile, all the patients accepted conventional Western medicine. Review Manager 5.3 software was used for the statistical analysis. Ten trials were included in the final study. The overall risk of bias assessment was low. HXHY had a greater beneficial effect on reducing the in-stent restenosis (ISR) rate (RR=0.57, 95% CI [0.40, 0.80], P=0.001) and the degree of restenosis (MD=-8.89, 95% CI [-10.62, -7.17], P<0.00001) compared with Placebo. Moreover, HXHY was determined to be more effective in improving Seattle Angina Questionnaires (SAQ) and the revascularization rate (RR=0.54, 95% CI [0.32, 0.90], P=0.02) compared with Placebo, whereas the rate of death and MI of patients treated with HXHY were no different from those treated with the placebo (P>0.05). Therefore, HXHY is an effective and safe therapy for CHD 1# These authors contributed equally to this work.

Aims The present study assessed the effect of Sigma-1 receptor (S1R) stimulation on autonomic nerve dysfunction and atrial fibrillation susceptibility in rat depression models. Methods and Results Male rats were randomly divided into four treatment groups for four weeks: saline (CTL), saline+ intragastric administration of SA4503 (agonist of the S1R, CTS), chronic unpredictable mild stress (CUMS) to produce depression(MDD), and CUMS+ intragastric administration of SA4503 (MDS). After 4 weeks, depression-like behaviors, such as sucrose preference, body weight, and immobility during forced swimming improved in the MDS group. Compared with CTL, MDD showed augmented sympathetic activity, reduced parasympathetic activity, decreased heart rate variability, and significantly lowered S1R expression in the atrium and in hippocampal tissues (all P<0.01). However, the MDS group showed mitigation of most of the above alterations and improved electrical remodeling (all P<0.01). Furthermore, the MDS group showed shortened activation latencies, increases in the effective refractory period, and lower frequency of AF incidence duration and fibrosis compared to MDD (all P<0.01). Conclusions The results indicate that S1R stimulation reduces sympathetic activity and atrial fibrillation susceptibility by improving depressive behaviours, modulating cardiac autonomic nerve balance, lightening nerve remodeling, and up-regulating S1R expression.