BGB-A445, a novel non-ligand-blocking agonistic anti-OX40 antibody, exhibits superior immune activation and antitumor effects in preclinical models / 医学前沿

OX40 is a costimulatory receptor that is expressed primarily on activated CD4+, CD8+, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.

Phospholipase A2 of Peroxiredoxin 6 Plays a Critical Role in Cerebral Ischemia/Reperfusion Inflammatory Injury.

Microglia-mediated inflammation is an important step in the progression of cerebral ischemia/reperfusion injury and the associated production of receptors of immunomoudulation, including Toll-like receptors (TLRs). Peroxiredoxin 6 (Prdx6) has been demonstrated as the endogenous antioxidant protein for its peroxidase properties. However, the role of the independent phospholipase A2 (iPLA2) activity of Prdx6 in stroke has not been well studied. In this study, we evaluated whether blocking the calcium-iPLA2 activity of Prdx6 using siRNA and inhibitors (1-hexadecyl-3-(trifluoroethgl)-sn-glycerol-2 phosphomethanol, MJ33) would have a critical effect on inflammatory brain damage. We conducted oxygen-glucose deprivation (OGD)/recovery (R) in vitro and middle cerebral artery occlusion (MCAO) in vivo in a microglia/neuron co-culture system and in rats. In vitro, we found that Prdx6-iPLA2 activity was associated with the secretion of neurotoxic inflammatory mediators interleukin1ß (IL-1ß), interleukin-17 (IL-17) and interleukin-23 (IL-23) and elevated expression of Toll-like receptor 2/4 (TLR2/4), leading to the formation of nuclear factor-kappa B (NF-κB), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in microglial cells. In vivo, combined treatment with Prdx6-iPLA2 activity inhibitor MJ33 showed a greater diminution in neurologic deficits, cerebral infarction, brain water content and inflammatory molecules than Prdx6-siRNA treatment alone. Our findings provide new insight into Prdx6-iPLA2 function in the brain. Inhibition of Prdx6-iPLA2 activity by gene therapy and/or pharmacology may constitute a promising new therapeutic approach to the treatment of stroke.

Effect of laparoscopic myomectomy on the changes of T cell subsets in patients with uterine fibroids / 中国生化药物杂志

Objective To study the effect of laparoscopic myomectomy on the curative effect and postoperative rehabilitation of patients with uterine fibroids (UM).Methods From March 2014 to March 2016, selected 84 patients with UM in the people's hospital of Baoding Xushui district were divided into observation group (n=43) and control group(n=41) according to the different operation procedures, the observation group were treated with laparoscopic myomectomy and the control group were treated with open uterine fibroids.Serum T cell subsets (CD4+, CD8+, CD4+/ CD8+) between the two groups before and 1 day after operation were compared, and CA125, Cor, IL-1β levels, and surgery condition, postoperative recovery, complicationsand postoperative 12 months of recurrence were statistically compared.Results The serum CD4+, CD8+, CD4+/CD8+ levels in the observation group were significantly higher than those in the control group at 1 day after operation, the difference was statistically significant (P<0.05);the first exhaust time and hospitalization of the observation group were significantly shorter than those of the control group, and the intraoperative blood loss and postoperative pain score (VAS) were significantly lower than those in the control group (P<0.05);The incidence of postoperative complications in the observation group (6.98%, 3/43) was significantly lower than that in the control group (26.83%, 11/41), by follow-up, the recurrence rate (2.33%, 1/43) was lower than that of the control group (19.51%, 8/41), the difference was statistically significant (P<0.05).Conclusion Treatment of uterinemyoma using laparoscopic myomectomy gets a significant effect, and the body inflammation, stress response lighter and the effect of immune function is small, which can reduce the postoperative complications and recurrence rate and promote the rehabilitation of patients, and less impact on immune function.

Constructing linkage map based on a four-way cross population.

Currently, developing genetic linkage map mostly use the derived-populations from crossing of two homogenous parents, which only covers limited genetic diversity and is inappropriate for some species, such as tobacco with lower diversity in genome. It is very general that there are no sufficient polymorphic markers to construct linkage map and ineffective to conduct marker-assisted selection (MAS) and quantitative trait locus (QTL) mapping based on lower density linkage map. This study proposed a method for developing genetic linkage map based on a four-way cross population. Computer simulation was conducted to investigate the feasibility and effectiveness of the method and a supporting program was designed. The main procedures and features of the proposed method were summarized as follows: 1) estimating genetic distance of any paired markers based on maximum likelihood method; 2) splitting all markers into different groups (linkage group) by cluster analysis based on genetic distance of markers; 3) for each linkage group, two end markers were first determined, then the marker order could be determined by inserting other markers in appropriate position by distance analysis of any three neighboring markers. Monte Carlo simulation showed that the proposed method is feasible, effective, and applicable in other derived populations from crossing of two homogenous parents.

A clinical study on treatment of stageⅢdiabetic nephropathy by Qizhi Jiangtang capsule / 中国中西医结合急救杂志

Objective To observe the effect of stageⅢdiabetic nephropathy(DN)treated by Qizhi Jiangtang capsule and explore its potential mechanism. Methods According to digital table method,the patients who conformed to the diagnostic criteria of stageⅢDN were randomly divided into two groups:an experiment group and a control group. All the patients in the two groups took elution treatment for 2 weeks,and then were treated with western basic therapy. The patients in the experiment group were administered orally with Qizhi Jiangtang capsule(2.5 g once, 3 times a day),while those in the control group treated with valsartan 80 mg,once a day. Urine microalbumin(mALB), mALB/urine creatinine(UCr),β2-microglobulin(β2-MG),α1-microglobulin(α1-MG)were observed in the two groups,endothelin-1(ET-1),nitric oxide(NO),thromboxane B2(TXB2),6-keto prostaglandin F1α(6-keto-PGF1α) were also determined. Serum creatinine(SCr),blood urea nitrogen(BUN),serum cystatin-C(Cys-C),retinol-binding protein(RBP),β2-MG were detected in the blood biochemistry automatic analyzer. These laboratory markers were inspected before treatment and at the 4th,8th and 12th week after treatment. Results Ninety-six patients in the experiment group and 95 patients in the control group were effectively included in the end. Before treatment,there were no statistic significant differences in urine mALB,mALB/UCr,β2-MG,α1-MG and blood ET-1,NO,TXB2, 6-keto-PGF1α between two groups(all P>0.05). Along with the prolongation of treatment,urine mALB,mALB/UCr,β2-MG,α1-MG and ET-1,TXB2 were significantly reduced,while NO,6-keto-PGF1α were significantly raised in the two groups after treatment,and the above changes in the experimental group were more obvious. There were statistic significant differences of mALB,mALB/UCr,β2-MG,α1-MG and TXB2,6-keto-PGF1αbetween two groups at the 12th week after treatment〔mALB(mg/L):36.6±9.2 vs. 78.6±16.5,mALB/UCr(mg/mmol):3.90±1.97 vs. 9.70±2.90,β2-MG(mg/L):0.25±0.10 vs. 0.40±0.12,α1-MG(mg/L):8.40±2.26 vs. 12.50±3.21,TXB2 (ng/L):75.8±18.7 vs. 94.7±21.7,6-keto-PGF1α(ng/L):73.4±15.2 vs. 65.2±11.5,P0.05〕. In each of the two groups,the comparisons of the levels of SCr,BUN before and after treatment,there was no statistical significant difference at any time point;the same comparisons between the two groups,there was also no statistic significant difference before treatment and at each of the same time-point after treatment(all P>0.05). The levels of Cys-C,RBP andβ2-MG of the control group after treatment had the tendency of decreasing,but no statistic significant differences were found(all P>0.05). The levels of Cys-C,RBP,β2-MG of the experimental group at the 12th week after treatment were significantly lower than those before treatment〔Cys-C(mg/L):0.72±0.07 vs. 0.89±0.12,RBP (mg/L):53.0±14.2 vs. 66.1±16.5,β2-MG(mg/L):1.86±0.71 vs. 2.79±0.82,all P<0.05〕. Conclusions Qizhi Jiangtang capsule can significantly reduce the levels of urine mALB and mALB/UCr of patients with stageⅢDN and stabilize their renal functions;its therapeutic effect is better then that of valsartan. Its mechanisms are related to the reduction of ET-1,elevation of NO,maintenance of dynamic equilibrium of thromboxane A2/prostacycline(TXA2/PGI2) and protection of vascular endothelial cells.