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摘要： PURPOSE:Cytokine-engineering of chimeric antigen receptor-redirected T cells (CAR T cells) is a promising principle to overcome the limited activity of canonical CAR T cells against solid cancers. EXPERIMENTAL DESIGN:We developed an investigational medicinal product, GD2IL18CART, consisting of CAR T cells directed against ganglioside GD2 with CAR-inducible IL18 to enhance their activation response and cytolytic effector functions in the tumor microenvironment. To allow stratification of patients according to tumor GD2 expression, we established and validated immunofluorescence detection of GD2 on paraffin-embedded tumor tissues. RESULTS:Lentiviral all-in-one vector engineering of human T cells with the GD2-specific CAR with and without inducible IL18 resulted in cell products with comparable proportions of CAR-expressing central memory T cells. Production of IL18 strictly depends on GD2 antigen engagement. GD2IL18CART respond to interaction with GD2-positive tumor cells with higher IFNγ and TNFα cytokine release and more effective target cytolysis compared with CAR T cells without inducible IL18. GD2IL18CART further have superior in vivo antitumor activity, with eradication of GD2-positive tumor xenografts. Finally, we established GMP-compliant manufacturing of GD2IL18CART and found it to be feasible and efficient at clinical scale. CONCLUSIONS:These results pave the way for clinical investigation of GD2IL18CART in pediatric and adult patients with neuroblastoma and other GD2-positive cancers (EU CT 2022-501725-21-00).

关键词： 急性淋巴细胞白血病   MTHFR(1298A>C)   MTHFR(677C>T)   甲氨蝶呤  

摘要： 目的 研究MTHFR(1298A>C)和MTHFR(677C>T)位点多态性与甲氨蝶呤(methotrexate,MTX)血药浓度和不良反应的相关性。方法 选取2014年10月—2021年12月上海市儿童医院收治的185例急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)患儿，收集MTHFR(1298A>C)和MTHFR(677C>T)基因分型、不良反应和血药浓度等实验室检查指标结果。结果 185例患儿使用MTX后的总体不良反应发生率为95.1%。MTHFR(1298A>C)2种基因型不良反应发生率除粒细胞缺乏差异有统计学意义(P=0.006)外，其他均无统计学意义；MTHFR(677C>T)3种基因型的ALL患儿不良反应发生率除粒细胞缺乏(P=0.041/0.012)、消化道反应(P=0.037/0.011)和黏膜毒性(P=0.039/0.016)差异有统计学意义外，其他均无统计学意义；MTHFR(677C>T)3种基因型的ALL患儿在24 h的MTX血药浓度差异有统计学意义(P=0.021);MTHFR(677C>T)3种基因型的ALL患儿进行亚叶酸钙翻倍解救发生率差异有统计学意义(P=0.007/0.002)。结论 MTHFR(1298A>C)和MTHFR(677C>T)多态性可能不是预测儿童ALL进行MTX化疗的良好指标，结局提示了翻倍解救的重要性，即翻倍解救可以明显降低黏膜毒性和骨髓毒性高发患儿的此类不良反应发生率。

关键词： 慢性粒细胞白血病   稳定性   Hopf分支   周期解   细胞分化时滞  

摘要： 为了研究慢性粒细胞白血病干细胞分化时滞对白血病干细胞，白血病成熟细胞和效应T细胞之间的动力学行为影响，建立了带有干扰素-α和伊马替尼治疗项的慢性粒细胞白血病免疫时滞模型。通过对改进的时滞模型稳定性分析，依据规范型和中心流形理论，得到Hopf分支的临界条件与性质。并给出干扰素-α和伊马替尼联合效应T细胞控制慢性粒细胞白血病的条件，如在药物干预下，调节分化时滞会使慢性粒细胞白血病干细胞与白血病成熟细胞的数量呈现稳定不增状态，或由大振幅周期波动转向为小振幅波动状态。最后，数值模拟验证了所得理论。

关键词： 白细胞介素-6   D-二聚体   冠心病   Interleukin-6   D-Dimer   Coronary Heart Disease  

摘要： 冠心病是心血管疾病中最常见的疾病，冠状动脉粥样硬化的开始和发展是一个复杂的过程，由血栓形成和炎症共同驱动。白细胞介素作为重要的炎症因子，在动脉粥样硬化的发生和发展过程中起到了重要作用，其中白细胞介素-6 (Interleukin 6, IL-6)是家族中的重要一员。D-二聚体(D-dimer, DD)是由纤维蛋白溶解系统对血栓的有序分解产物，是临床凝血和纤溶激活的重要检测指标，在血栓性疾病中具有重要的临床价值。本文对就与冠心病关系较为密切的IL-6和D-二聚体的研究进展进行综述。

摘要： Wnt signaling plays an important role in adult brain function, and its dysregulation has been implicated in the loss of neuronal homeostasis. Despite the existence of many studies on the participation of the Wnt pathway in adult neurons, its regulation in astrocytes has been scarcely explored. Several reports point to the presence of Wnt ligands in astrocytes and their possible impact on neuronal plasticity or neuronal death. We aimed to analyze the effect of the neurotransmitter glutamate and the inflammatory cytokine TNFα on the mRNA and protein levels of the canonical Wnt agonist Wnt7a and the antagonist Dkk1 in cultured astrocytes. Primary astrocyte cultures from rat cerebral cortices were exposed to glutamate or TNFα. Wnt7a and Dkk1 expression was analyzed by RT-qPCR and its protein abundance and distribution was assessed by immunofluorescence. We found high basal expression and protein levels of Wnt7a and Dkk1 in unstimulated astrocytes and overproduction of Dkk1 mRNA induced by the two stimuli. These results reveal the astrocytic source of the canonical Wnt ligands Wnt7a and Dkk1, whose levels are differentially regulated by glutamate and TNFα. Astrocytes are a significant source of Wnt ligands, the production of which can be differentially regulated under excitatory or proinflammatory conditions, thereby impacting neuronal function.

关键词： IL-18   IL-18 receptor alpha   Th2 cell   allergic asthma  

摘要： Allergic asthma (AA) is closely associated with the polarization of T helper (Th)2 and Th17 cells. Interleukin (IL)-18 acts as an inducer of Th2 and Th17 cell responses. However, expressions of IL-18 and IL-18 receptor alpha (IL-18Rα) in blood Th2 and Th17 cells of patients with AA remain unclear. We therefore investigated their expressions in Th2 and Th17 cells using flow cytometric analysis, qPCR and murine AA model. We observed increased proportions of Th2, Th17, IL-18+, IL-18+ Th2 and IL-18+ Th17 cells in blood CD4+ T cells of patients with AA. Additionally, house dust mite seemed to upregulate further IL-18 expression in Th2 and Th17, and upregulate IL-18Rα expression in CD4+ T, Th2 and Th17 cells of AA patients. It was also found that the plasma levels of IL-4, IL-17A and IL-18 in AA patients were elevated, and they were correlated between each other. In OVA-induced asthma mouse (AM), we observed that the percentages of blood CD4+ T, Th2 and Th17 cells were increased. Moreover, OVA-induced AM expressed higher level of IL-18Rα in blood Th2 cells, which was downregulated by IL-18. Increased IL-18Rα expression was also observed in blood Th2 cells of OVA-induced FcεRIα-/-mice. Collectively, our findings suggest the involvement of Th2 cells in AA by expressing excessive IL-18 and IL-18Rα in response to allergen, and that IL-18 and IL-18Rα expressing Th2 cells are likely to be the potential targets for AA therapy.

关键词： ATDC5 cells   Akt/NF-κB.   MMPs   Syringic acid   osteoarthritis  

摘要： BACKGROUND:Osteoarthritis (OA) is a chronic progressive joint ailment that is largely predominant worldwide. However, it typically gets worse over time, occurs more frequently, and becomes more crippling. OBJECTIVES:Syringic acid (SA) is a well-known phenolic compound reported to suppress inflammation, cell proliferation, and apoptosis of various cancer cells. Since the role of SA in OA remains unknown, there is a need to hypothesize the anti-inflammatory activities of SA on IL- 1β-induced ATDC5 chondrocyte‑like cells and to elucidate its protective action against OA. METHODS:The cytotoxicity, inflammatory mediators, mRNA expression of MMPs, ADAMTS, COX-2, and Akt/NF-κB protein expression of SA activity on ATDC5 cells were examined through CCK-8 assay, ELISA, RT-qPCR, and western blot. It was found that SA (10, 20, and 30 μM) did not show any inhibitory effects on the viability of the ATDC5 cells in a concentrationdependent manner. RESULTS:SA markedly reduced the inflammatory mediators, cytokines, PGE2, MMPs, COX-2, and ADAMTS in a concentration-dependent manner. Likewise, SA expressively attenuated IL- 1β-stimulated Akt phosphorylation and NF-κB activation as well as IL-1β- induced ATDC5 chondrocytes. CONCLUSION:This study revealed that SA is a novel candidate applicable for the treatment of OA.

关键词： 免疫检查点抑制剂   一线治疗   非小细胞肺癌   疗效   安全性   系统评价/Meta分析  

摘要： 目的 系统评价免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）一线治疗晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）的疗效及安全性。方法 计算机检索PubMed、The Cochrane Library、EMbase数据库，收集ICIs一线治疗NSCLC患者的临床随机对照试验，检索时限为建库至2023年1月。采用Revman 5.4软件进行Meta分析。结果 纳入12项临床研究，质量评价皆为高质量文献，共7 121例患者。Meta分析结果显示：相较于化疗，ICIs一线治疗NSCLC患者能显著提高中位总生存期（overall survival,OS）[HR=0.72,95%CI(0.64,0.80),P<0.000 01]和中位无进展生存期（progression free survival,PFS）[HR=0.65,95%CI(0.53,0.78),P<0.000 01]，改善客观缓解率（objective response rate,ORR）[RR=1.52,95%CI(1.28,1.79),P<0.000 01]。亚组分析显示，相较于ICIs单一治疗组，ICIs联合治疗组能显著提高NSCLC患者的OS、PFS、ORR；在安全性方面，ICIs组发生任何级别治疗相关不良事件（Treatment-related adverse events,TRAEs）和3～5级TRAEs的风险均低于化疗组。在导致治疗停止TRAEs发生率方面，ICIs组高于化疗组。亚组分析显示，免疫联合治疗组发生任何级别、3～5级、导致治疗停止TRAEs发生率都高于免疫单一治疗组。结论 ICIs抑制剂一线治疗NSCLC患者对比化疗能显著改善患者的OS、PFS、ORR。相对于免疫单一治疗，免疫联合化疗能显著提高NSCLC患者的疗效，但患者发生TRAEs风险较高。

关键词： IFN-λ   IRF1   Nsp1   Swine acute diarrhea syndrome coronavirus   innate immune evasion  

摘要： Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel porcine enteric coronavirus that causes acute watery diarrhea, vomiting, and dehydration in newborn piglets. The type III interferon (IFN-λ) response serves as the primary defense against viruses that replicate in intestinal epithelial cells. However, there is currently no information available on how SADS-CoV modulates the production of IFN-λ. In this study, we utilized IPI-FX cells (a cell line of porcine ileum epithelium) as an in vitro model to investigate the potential immune evasion strategies employed by SADS-CoV against the IFN-λ response. Our results showed that SADS-CoV infection suppressed the production of IFN-λ1 induced by poly(I:C). Through screening SADS-CoV-encoded proteins, nsp1, nsp5, nsp10, nsp12, nsp16, E, S1, and S2 were identified as antagonists of IFN-λ1 production. Specifically, SADS-CoV nsp1 impeded the activation of the IFN-λ1 promoter mediated by MAVS, TBK1, IKKε, and IRF1. Both SADS-CoV and nsp1 obstructed poly(I:C)-induced nuclear translocation of IRF1. Moreover, SADS-CoV nsp1 degraded IRF1 via the ubiquitin-mediated proteasome pathway without interacting with it. Overall, our study provides the first evidence that SADS-CoV inhibits the type III IFN response, shedding light on the molecular mechanisms employed by SADS-CoV to evade the host immune response.