Background::Radiation (IR)-induced DNA damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvironment (TME). Wee1, a cell cycle regulator, can eliminate G2/M arrest by phosphorylating cyclin-dependent kinase 1 (CDK1). Meanwhile, programed death-1/programed death ligand-1 (PD-1/PDL-1) blockade is closely related to TME. This study aims to investigate the effects and mechanisms of Wee1 inhibitor AZD1775 and anti-PD-1 antibody (anti-PD-1 Ab) on radiosensitization of hepatoma.Methods::The anti-tumor activity of AZD1775 and IR was determined by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) assay on human and mouse hepatoma cells HepG2, Hepa1-6, and H22. The anti-hepatoma mechanism of AZD1775 and IR revealed by flow cytometry and Western blot in vitro. A hepatoma subcutaneous xenograft mice model was constructed on Balb/c mice, which were divided into control group, IR group, AZD1775 group, IR + AZD1775 group, IR + anti-PD-1 Ab group, and the IR + AZD1775 + anti-PD-1 Ab group. Cytotoxic CD8 + T cells in TME were analyzed by flow cytometry. Results::Combining IR with AZD1775 synergistically reduced the viability of hepatoma cells in vitro. AZD1775 exhibited antitumor effects by decreasing CDK1 phosphorylation to reverse the IR-induced G2/M arrest and increasing IR-induced DNA damage. AZD1775 treatment also reduced the proportion of PD-1 +/CD8 + T cells in the spleen of hepatoma subcutaneous xenograft mice. Further studies revealed that AZD1775 and anti-PD-1 Ab could enhance the radiosensitivity of hepatoma by enhancing the levels of interferon γ (IFNγ) + or Ki67 + CD8 T cells and decreasing the levels of CD8 + Tregs cells in the tumor and spleen of the hepatoma mice model, indicating that the improvement of TME was manifested by increasing the cytotoxic factor IFNγ expression, enhancing CD8 + T cells proliferation, and weakening CD8 + T cells depletion. Conclusions::This work suggests that AZD1775 and anti-PD-1 Ab synergistically sensitize hepatoma to radiotherapy by enhancing IR-induced DNA damage and improving cytotoxic CD8 + T cells in TME.

Objective::This study aimed to evaluate the major adverse cardiovascular and cerebrovascular events (MACCEs) and overall safety profile associated with iodixanol in Chinese patients undergoing percutaneous coronary intervention (PCI).Methods::Patients at 30 centers in China registered in the OpenClinic v3.6 database from October 30, 2013, to October 7, 2015, were included in the study. The primary endpoint was in-hospital MACCEs including target lesion revascularization (TLR), stroke, stent thrombosis, cardiac death, and PCI-related myocardial infarction (MI) within 72 h post-PCI. Secondary endpoints were MACCEs from 72 h to 30 d post-PCI and other safety events within 30 d post-PCI.Results::A total of 3,042 patients were enrolled. The incidence of MACCEs within 72 h post-PCI was 2.33% ( n = 71), including cardiac death (0.03%, n = 1) and PCI-related MI (2.30%, n = 70). The incidence of MACCEs from 72 h to 30 d post-PCI was 0.16% ( n = 5), including cardiac death (0.10%, n = 3), PCI-related MI (0.03%, n = 1), and TLR for stent thrombosis (0.03%, n = 1). The incidence of composite angiographic or procedural complications was 2.86% ( n = 87); 233 (7.86%) patients had results suggesting contrast-induced acute kidney injury. Conclusions::These findings indicate that the use of iodixanol in Chinese patients undergoing PCI is associated with a low incidence of MACCEs, confirming its safety in this population.

Objective::This study aimed to evaluate the major adverse cardiovascular and cerebrovascular events (MACCEs) and overall safety profile associated with iodixanol in Chinese patients undergoing percutaneous coronary intervention (PCI).Methods::Patients at 30 centers in China registered in the OpenClinic v3.6 database from October 30, 2013, to October 7, 2015, were included in the study. The primary endpoint was in-hospital MACCEs including target lesion revascularization (TLR), stroke, stent thrombosis, cardiac death, and PCI-related myocardial infarction (MI) within 72 h post-PCI. Secondary endpoints were MACCEs from 72 h to 30 d post-PCI and other safety events within 30 d post-PCI.Results::A total of 3,042 patients were enrolled. The incidence of MACCEs within 72 h post-PCI was 2.33% ( n = 71), including cardiac death (0.03%, n = 1) and PCI-related MI (2.30%, n = 70). The incidence of MACCEs from 72 h to 30 d post-PCI was 0.16% ( n = 5), including cardiac death (0.10%, n = 3), PCI-related MI (0.03%, n = 1), and TLR for stent thrombosis (0.03%, n = 1). The incidence of composite angiographic or procedural complications was 2.86% ( n = 87); 233 (7.86%) patients had results suggesting contrast-induced acute kidney injury. Conclusions::These findings indicate that the use of iodixanol in Chinese patients undergoing PCI is associated with a low incidence of MACCEs, confirming its safety in this population.

Background::Ubiquitination plays an essential role in many biological processes, including viral infection, and can be reversed by deubiquitinating enzymes (DUBs). Although some studies discovered that DUBs inhibit or enhance viral infection by various mechanisms, there is lack of information on the role of DUBs in virus regulation, which needs to be further investigated.Methods::Immunoblotting, real-time polymerase chain reaction, in vivo/ in vitro deubiquitination, protein immunoprecipitation, immunofluorescence, and co-localization biological techniques were employed to examine the effect of ubiquitin-specific protease 3 (USP3) on APOBEC3G (A3G) stability and human immunodeficiency virus (HIV) replication. To analyse the relationship between USP3 and HIV disease progression, we recruited 20 HIV-infected patients to detect the levels of USP3 and A3G in peripheral blood and analysed their correlation with CD4 + T-cell counts. Correlation was estimated by Pearson correlation coefficients (for parametric data). Results::The results demonstrated that USP3 specifically inhibits HIV-1 replication in an A3G-dependent manner. Further investigation found that USP3 stabilized 90% to 95% of A3G expression by deubiquitinating Vif-mediated polyubiquitination and blocking its degradation in an enzyme-dependent manner. It also enhances the A3G messenger RNA (mRNA) level by binding to A3G mRNA and stabilizing it in an enzyme-independent manner. Moreover, USP3 expression was positively correlated with A3G expression ( r= 0.5110) and CD4 + T-cell counts ( r= 0.5083) in HIV-1-infected patients. Conclusions::USP3 restricts HIV-1 viral infections by increasing the expression of the antiviral factor A3G. Therefore, USP3 may be an important target for drug development and serve as a novel therapeutic strategy against viral infections.

Objective To evaluate the effects of hyperbaric oxygen post-conditioning on the expression of P2X4 receptors in the spinal dorsal horn and hippocampus of rats with neuropathic pain (NP).Methods Seventytwo male Sprague-Dawley rats,aged 8-10 weeks,weighing 300-350 g,were randomly divided into 3 groups (n =24 each) using a random number table:sham operation group (group S),NP group and hyperbaric oxygen postconditioning group (group H).NP was induced by chronic constrictive injury.The rats in group H underwent hyperbaric oxygen treatment once a day for 7 consecutive days starting from 1 day after NP was successfully induced.After the rats were placed in the hyperbaric oxygen chamber,the pressure was increased at a rate of 10 kPa/min until the hyperbaric oxygen was at 2.0 atmosphere absolute,and maintained at this level for 60 min,and then the pressure was decreased at a rate of 10 kPa/min until the normal pressure was reached.The mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) were measured at 1 day before NP was induced and 1,3,7 and 14 days after NP was induced.After the end of measurement,6 rats were randomly chosen from each group and then sacrificed and the L4-6 segments of the spinal cord and hippocampal tissues were removed for determination of the expression of P2X4 receptors (by immunohistochemistry).Results Compared with group S,the MWT was significantly decreased,TWL was shortened,and P2X4 receptor expression in the spinal dorsal horn and hippocampus was up-regulated in NP and H groups.Compared with group NP,the MWT was significantly increased and TWL was prolonged,and P2X4 receptor expression in the spinal dorsal horn and hippocampus was down-regulated in group H.Conclusion Hyperbaric oxygen post-conditioning mitigates NP by down-regulating the expression of P2X4 receptors in the spinal dorsal horn and hippocampus of rats.