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关键词： Predictive marker   IrAE   Risk factor   Immunotherapy   Genetic factors  

摘要： BackgroundImmune checkpoint inhibitors (ICI) are highly effective but may induce severe or even fatal and unpredictable immune-related adverse events (irAEs). It is unclear whether human leukocyte antigen (HLA) genes contribute to the susceptibility of developing irAEs during ICI *** multicentre retrospective study investigated the association of irAE and outcome with HLA-A*02:01 status in a cohort of 97 patients with metastatic melanoma undergoing ICI therapy. Organ-specific irAEs and therapy outcome as assessed by response rate, progression-free survival (PFS) and overall survival (OS) were analysed depending on HLA type HLA-A*02:01. For the outcome only patients with cutaneous melanoma were analysed. Chi square test, exact fisher test, Kruskal Wallis test and log rank test were employed for statistical analysis (p <= 0.05).ResultsThe cohort included 38 HLA-A*02:01 positive (39.2%) and 59 HLA-A*02:01 negative (60.8%) patients. Data showed no evidence of an association of HLA-A*02:01 with organ-specific irAEs except for a numerical difference in immune-related colitis. Furthermore, response rates of the subgroup of patients with metastatic cutaneous melanoma did not differ between the two cohorts. The median PFS was 5 months and 8 months in HLA-A*02:01 positive and negative patients with cutaneous melanoma, ***-A*02:01 was not associated with specific checkpoint inhibitor-induced organ toxicity in this cohort of HLA-A-typed melanoma patients. Interestingly, in the relatively small subgroup of patients with cutaneous melanoma an earlier progression in HLA-A*02:01 positive patients was observed, however not in the long term. These findings are exploratory due to the limited sample size and require validation in larger, prospective cohorts.

关键词： Chinese herbal formula   Premature ovarian insufficiency   Autophagy   Mechanistic target of rapamycin complex 1   Granulosa cell  

摘要： Background: Autophagy defect has been detected in premature ovarian insufficiency (POI) patients. Aim: The aim of this study was to evaluate the efficacy and explore the mechanism of Zigui-Changqi decoction (ZCD) in the treatment of POI. Materials and Methods: Rat model of POI was established to evaluate the efficacy of ZCD on serum hormone levels, ovarian index, and ovarian cell apoptosis. The effect of ZCD on the autophagy of granulosa cell was assessed. Network pharmacology was used to predict potential targets of ZCD against POI. Results: ZCD attenuated tripterygium glycoside-induced damage to ovarian tissues in rats by improving ovarian index, moderating serum hormone levels, inhibiting ovarian cell apoptosis, and increasing the number of ovarian stromal cells. ZCD moderated the expression of autophagy-related markers, including BECN1, p62, and LC3. Through network pharmacological analysis, the predicted hub genes were EGFR, ERBB2, AKT1, IL6, PTEN, and TP53. After molecular docking and detection of cell expression levels, EGFR, ERBB2, AKT1, and IL6 were inhibited by ZCD, as well as mechanistic target of rapamycin complex 1. Conclusion: ZCD can ameliorate POI, maybe by moderating autophagy via EGFR/ERBB2/IL6/AKT1 signals.

关键词： Pentylenetetrazol (PTZ)   Ketamine-Xylazine   NMRI mice   Neuroinflammation   Anticonvulsant  

摘要： Introduction and Objective: Epilepsy is one of the most common chronic brain disorders worldwide. This study aimed to determine the effect of Galbanic acid on seizures. Materials and Methods: In this study, 40 NMRI mice were used and divided into 4 groups. The control group received 10 mg/kg normal saline. Three groups received Galbanic acid at doses of 10, 20, and 40 mg/kg. The positive control group received diazepam with a dose of 10 mg/kg. All injections were made intraperitoneally for one week. Seizures were induced in all mice by injection of 90 mg/kg Pentylenetetrazole (PTZ). Then the latency of seizure onset in each of the experimental groups was recorded. After anesthesia with Ketamine 100 mg/kg and Xylazine 10 mg/kg, blood samples were taken and after decapitation, the hippocampus was isolated and the expression of alpha TNF-, IL1 beta, and TLR4 genes in this region was measured. Results: Galbanic acid increased the delay in seizure onset, decreased brain and serum nitrite levels, and decreased the expression of alpha TNF-, IL1 beta, and TLR4 genes in brain tissue compared to the control group (P < 0.01, p < 0.001). Conclusion: Galbanic acid reduced nitrite and the expression of alpha TNF-, IL1 beta, and TLR4, leading to a decrease in neuroinflammation and, as a result, a delay in seizure onset in mice.

关键词： 盖塔病毒   原核表达   单克隆抗体   胶体金试纸条   双抗体夹心法  

摘要： 通过原核表达系统进行盖塔病毒(Getahvirus,GETV)E1蛋白的表达,制备了1株GETV E1单克隆抗体SD17/09GE1Gm Ab,建立了包被2株GETVE1单克隆抗体的胶体金双抗体夹心检测方法.结果显示,制备的胶体金试纸条灵敏度良好,并与其他常见的猪病毒阳性组织样本不发生交叉反应;试纸条与IFA检测GETV符合率较高,可在37℃下保存1个月,室温下至少保存3个月.结果表明.成功制备了一种快速检测盖塔病毒的胶体金抗体检测试纸条,为盖塔病毒检测提供了有力的工具.

关键词： 肺动脉高压   白细胞介素-9   β-神经营养因子   全基因组关联研究   孟德尔随机化  

摘要： 目的通过双向孟德尔随机化（MR）方法评估系统性炎症调节因子对肺动脉高压的影响。方法使用了两个不同的数据集进行研究。细胞因子的数据，包括41种循环细胞因子，来源于一项基因组关联研究（GWAS）数据集，该数据集包含8，293名欧洲人群参与者。另一方面，肺动脉高压的数据集来自包含11，744名欧洲裔个体的GWAS数据集。通过采用多种孟德尔随机化方法，并进行多变量孟德尔随机化分析，深入探讨了细胞因子对肺动脉高压的潜在影响。结果 IVW分析结果发现IL-9与肺动脉高压之间可能存在因果关系(OR：0.63，95%CI：0.50-0.78，P=3.88×10-5)。此外，还发现β-NGF与肺动脉高压之间可能存在因果关联（OR：1.34，95%CI：1.00-1.79，P=0.049）。如果进行多重检验校正，只有IL-9保持统计学显著性。此外，还进行了多变量孟德尔随机化（MVMR）分析（MVMR-IVW），并且在分析中发现IL-9与肺动脉高压之间仍然存在关联(OR：0.57，95%CI=0.44-0.72，P=6.11×10-6)，β-NGF与肺动脉高压之间也仍然存在关联（OR：1.47，95%CI=1.10-1.97，P=0.009）。另一种多变量分析方法MVMR-Lasso分析的结果与MVMR-IVW分析的结果一致。这些结果表明IL-9和β-NGF对肺动脉高压的发展有独立的作用。结论IL-9水平升高与肺动脉高压风险降低之间可能存在因果关系，而β-NGF水平升高可能会增加肺动脉高压的风险。

关键词： IL-15   NK cells   AML   immunocytokines   Fc-optimized antibodies   Clec12A   CLL-1  

摘要： Despite recent advancements, acute myeloid leukemia (AML) remains a therapeutic challenge. While monoclonal antibodies (mAbs) leveraging natural killer (NK) cells through antibody-dependent cellular cytotoxicity show great potential, none have gained clinical approval for AML. Immunocytokines have emerged as a promising strategy to overcome the limited efficacy of therapeutic antibodies. IL-15 stimulates activation, proliferation cytotoxic activity of NK cells, but its clinical use is prevented by short half-life, poor accumulation in the tumor, and toxicity due to systemic off-target immune activation. Here we report on the generation and preclinical characterization of modified immunocytokines consisting of an Fc-optimized CLEC12A (CLL-1) antibody fused to an IL-15 moiety with E46K mutation. The mutation abrogates binding to IL-15R alpha, thereby enabling substitution of physiological trans-presentation by target binding and thus conditional IL-15R beta/gamma stimulation to reduce systemic toxicity. An optimal CLEC12A binder was selected from a range of murine mAbs, based on analysis of AML cell lines and leukemic cells from patients. This antibody was then used to construct an immunocytokine (MIC12) that subsequently was characterized functionally. Analysis of NK cell activation, cytokine release, proliferation and anti-leukemia reactivity demonstrated that MIC12 induced superior target cell killing and NK cell expansion compared to Fc-optimized CLEC12A antibody, with efficacy being dependent on target antigen binding. Our results show that novel immunocytokines with conditional IL-15 activity are capable of inducing potent NK cell responses against AML cells and identify MIC12 as promising therapeutic candidate for leukemia treatment.