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关键词： Immunotherapy   Lung Cancer   Tumor infiltrating lymphocyte - TIL  

摘要： Background A subset of CD4+ T cells with cytotoxic activity has been identified, and these cells exert their effects by expressing perforin and granzymes. Despite the progress made in characterizing cytotoxic CD4+ T cells in various diseases, the status of cytotoxic CD4+ T cells in non-small cell lung cancer (NSCLC) and the underlying mechanisms involved in promoting intratumoral cytotoxic CD4+ T-cell activation remain *** We used flow cytometry to examine the phenotypic and functional properties of CD4+GzmB+ T cells in the peripheral blood and tumor tissues of patients with NSCLC. Loss-of-function analyses and RNA sequencing were used to identify the underlying mechanisms involved in the effects of interleukin (IL)-15 on the restoration of CD4+GzmB+ T-cell function in vitro. A patient-derived lung cancer explant model and an animal model were used to verify the effects of immune checkpoint inhibitors on CD4+GzmB+ T-cell *** In patients with NSCLC, impaired cytolytic function of tumor-infiltrated granzyme B (GzmB)-expressing CD4+ T cells was restored by IL-15 through activation of the AKT-FOXO1-T-bet axis. Moreover, IL-15 stimulation increased solute carrier family 7 member 5 (SLC7A5) expression in CD4+GzmB+ T cells in an Protein Kinase B (AKT)-dependent manner, and inhibition of SLC7A5 abrogated the effect of IL-15 on CD4+GzmB+ T cells. Additionally, we showed that the immune checkpoint molecules programmed cell death-1 (PD-1) and CD85j were mutually exclusively expressed in CD4+GzmB+ T cells and that dual targeting of PD-1 and CD85j enhanced the effector function of CD4+GzmB+ T cells by activating the AKT pathway. Notably, tumor cells expressing major histocompatibility complex (MHC)-II and IL-15 determine the effectiveness of CD4+GzmB+ T-cell-mediated antitumor immunity in response to *** Our study demonstrated that tumor-infiltrating CD4+GzmB+ T cells fail to eliminate tumors. Dual blockade of PD-1 and CD85j along

摘要： Purpose:Mesenchymal stem cells (MSCs) represent a promising therapeutic strategy in clinical research for dry eye, and their immunomodulatory effects can be enhanced through genetic modification. In this study, we constructed interleukin-10 (IL-10) gene-modified adipose-derived MSCs (IL-10-ADSCs) and investigated their protective effects and underlying mechanisms on rabbit autoimmune dacryoadenitis, an animal model of autoimmune dry eye. Methods:ADSCs were isolated from rabbit adipose tissue and transduced with IL-10 overexpressing lentivirus. Then the preventive and therapeutic effects of IL-10-ADSCs on rabbit autoimmune dacryoadenitis were evaluated. Flow cytometry and Western blot were performed to assess the immunomodulatory effects of IL-10-ADSCs on T follicular helper (Tfh) cells. Bioinformatic analyses and functional gain and loss assays were used to determine the molecular mechanism underlying the effects of IL-10-ADSCs on Tfh responses. Results:We demonstrated that IL-10-ADSCs maintain the cell surface phenotype and multi-differentiation potentials of MSCs. Intravenous injection of IL-10-ADSCs markedly attenuated autoimmune dacryoadenitis, yielding significantly superior clinical and pathological improvements compared to ADSCs. Further investigation revealed that IL-10-ADSCs administration significantly suppressed Tfh cell responses in vivo and in vitro, contributing to reduced inflammation and improved tissue damage. Mechanistically, IL-10-ADSCs exert their suppressive function on Tfh cells partially through the miR-142-5p/RC3H1 axis. Notably, IL-10-ADSCs subconjunctivally administered after disease onset efficiently ameliorated the severity of autoimmune dacryoadenitis. Conclusions:IL-10-ADSCs ameliorate autoimmune dacryoadenitis by suppressing Tfh cell responses via suppressing the miR-142-5p/RC3H1 axis. The enhanced therapeutic effects of IL-10-ADSCs could be of significant value in improving the effectiveness of stem cell therapy in autoimmune dry eye.

关键词： biased agonist   generative artificial intelligence   IFN-γ   IFN-γ receptor   viral IFN-binding protein  

摘要： IFN-γ is a pleiotropic antiviral cytokine that coordinates innate and adaptive immune responses and induces both immunostimulatory and immunosuppressive activities, limiting its use in the clinic. Due to its antiviral role, several viruses express proteins that bind IFN-γ, blocking its interaction with the IFN-γ receptor (IFNGR). However, varicella zoster virus glycoprotein C binds IFN-γ and induces the expression of a subset of specific ISGs, similar to biased IFN-γ agonists generated based on the crystal structure of the IFN-γ – IFNGR complex. Here, we propose using structural and mechanistic information from viral proteins and biased agonists to design novel IFN-γ agonists that fine-tune IFN-γ – IFNGR activity, reducing the immunosuppressive and toxic effects of this cytokine. © 2025 The Authors

关键词： 温经通络汤   多发性骨髓瘤   周围神经毒性   炎症因子  

摘要： 目的探究温经通络汤对硼替佐米所致周围神经毒性患者神经疼痛程度、生活质量及IL-6、超敏C反应蛋白水平的影响。方法选择该院收治的60例多发性骨髓瘤经硼替佐米治疗后相关的周围神经毒性患者为研究对象,应用随机数字表法将其分为两组,对照组30例患者给予甲钴胺片口服治疗,研究组30例患者在对照组基础上给予温经通络汤进行治疗,对比两组患者在治疗前后神经疼痛、生活质量、IL-6和CRP水平的差异。结果总有效率方面,治疗后研究组(80.00%)较对照组(53.33%)高,差异明显(P<0.05);两组患者治疗后神经病变程度和VAS评分随时间的增长而逐步下降,且治疗后研究组神经病变程度和VAS评分较对照组低,差异明显(P<0.05);两组患者治疗后QOL-C30功能量表评分、QOL-C30总体生活质量评分随时间的增长而逐步升高,QOL-C30症状量表评分、QOL-C30单项指标评分随时间的增长而逐步下降,且治疗后研究组QOL-C30功能量表评分、QOL-C30总体生活质量评分显著高于对照组,QOL-C30症状量表评分、QOL-C30单项指标评分较对照组低,差异明显(P<0.05);两组患者治疗后CRP、IL-6随时间的增长而逐步下调,且治疗后研究组CRP、IL-6显著低于对照组,差异明显(P<0.05)。结论应用硼替佐米而导致周围神经病变的多发性骨髓瘤患者在常规甲钴胺片治疗的基础上加用温经通络汤可有效降低患者神经病变程度和神经疼痛程度,提高患者生活质量并降低炎症因子水平的升高,且具备较高的安全性,在临床上值得推广。

关键词： 儿童   复发急性淋巴细胞白血病   预后   嵌合抗原受体T细胞疗法   异基因造血干细胞移植  

摘要： 目的探讨急性淋巴细胞白血病(ALL)复发患儿的临床特征及分析影响预后的因素。方法选取2006年2月至2019年12月接受国内儿童急性淋巴细胞白血病协作组方案治疗的458例初诊ALL儿童,回顾性分析76例复发ALL儿童的临床特征及影响预后因素。结果本中心儿童ALL总体复发率为16.6%(76/458);复发ALL患儿死亡率57.9%(44/76),复发ALL患儿5年总体生存率为(38.6±5.9)%。按复发时间分组,极早期复发26例、早期复发30例、晚期复发20例,三组5年总体总生存率(OS)差异有统计学意义(P<0.001)。按复发部位分组,单纯骨髓复发57例,髓外复发12例及髓内外联合复发7例,三组5年OS率差异有统计学意义(P<0.05)。76例复发儿童11例放弃治疗,65例接受再次治疗,未获得2次完全缓解(CR2)14例,获CR251例,两组5年OS率差异有统计学意义(P<0.001)。按照复发后治疗方式分组分为异基因造血干细胞移植组(Allo-HSCT)22例(33.8%),嵌合抗原受体T细胞疗法(CART)治疗组8例(12.3%),CART联合Allo-HSCT组14例(21.5%),单纯化疗和(或)靶向药物组21例(32.2%),组间比较5年OS率差异有统计学意义(P<0.001)。单因素预后分析显示初诊白细胞>100×10^(9)/L、初诊危险度、复发时间、复发部位、复发后危险度、复发后治疗方案、是否获得CR2是影响复发ALL儿童预后的独立危险因素(P<0.05)。Cox回归模型进行多因素预后分析,极早期复发和复发后未获得CR2是影响复发ALL患儿预后的独立危险因素(P<0.05),复发后接受CART细胞衔接移植治疗是复发ALL患儿预后保护因素。结论本中心儿童ALL复发时间以早期复发为主,复发部位以骨髓复发为主。多因素预后分析极早期复发和复发后未获得CR2是复发ALL患儿预后的独立危险因素(P<0.05)。CART联合Allo-HSCT可改善复发急淋患儿预后。

关键词： 氧化石墨烯   羟基磷灰石   复合涂层   巨噬细胞   钛合金   电沉积化  

摘要： 背景:纯钛种植体植入机体后存在骨融合失败或者种植体周围感染等问题,因此对钛种植体表面进行改良已成研究的热门话题。巨噬细胞是机体应对外界刺激的一道免疫防线,任何生物材料植入体内后的相关免疫反应均与巨噬细胞相关。目的:采用电化学沉积法在纯钛片表面制备氧化石墨烯/羟基磷灰石复合涂层,分析涂层的表面特征及对RAW264.7巨噬细胞生长、极化的影响。方法:采用电化学沉积法在纯钛片表面分别制备单纯氧化石墨烯涂层、氧化石墨烯/羟基磷灰石复合涂层,表征涂层的物理性能。将纯钛片(空白组)、沉积单纯氧化石墨烯涂层的钛片(对照组)、沉积氧化石墨烯/羟基磷灰石复合涂层的钛片(实验组)分别与RAW264.7巨噬细胞共培养,采用CCK-8法、DAPI染色检测细胞增殖,扫描电镜观察细胞在钛片表面的黏附,流式细胞仪检测细胞极化表型。结果与结论:(1)扫描电镜下可见纯钛片有定向划痕与少量点状凹陷;沉积单纯氧化石墨烯涂层后,钛片表面可见较多裂纹沟壑和大小不均匀的颗粒状物,以及氧化石墨烯特征的褶皱样结构;沉积复合涂层后,钛片表面较光滑,可见团状颗粒,颗粒大小较为均匀。沉积复合涂层钛片的水接触接角小于纯钛片、沉积单纯氧化石墨烯涂层的钛片(P <0.05)。(2)CCK-8检测与DAPI染色显示,相较于空白组、对照组,实验组细胞增殖更快。扫描电镜下可见RAW264.7细胞均黏附于3组钛片表面,随着培养时间的延长细胞形态发生改变,由圆形向梭形转变,至培养7 d时,空白组细胞伸出的伪足短而少,对照组细胞伸出长而多的伪足,实验组细胞伸出短而多的伪足,并且实验组细胞整体饱满度最优。流式细胞仪检测显示,实验组细胞更高比例向抗炎方向M2型极化。(3)结果表明,氧化石墨烯/羟基磷灰石复合涂层具有良好的理化性能及生物学性能。

关键词： 手足口病   柯萨奇病毒A6型   CD80   CD86   Th1/Th2细胞因子  

摘要： 目的分析CD80、CD86及Th1/Th2细胞因子变化与柯萨奇病毒A6型(coxsackievirus A6,CVA6)手足口病(hand-foot-mouth disease,HFMD)重症化的关系。方法选取2021年1月至2024年1月中国人民解放军海军第九七一医院和联勤保障部队第九〇四医院收治的380例CVA6型HFMD患儿,根据其病情严重程度分为普通组与重症组,比较两组患儿CD80、CD86及Th1/Th2细胞因子[干扰素-γ(IFN-γ)、白介素-4(IL-4)]水平,采用ROC曲线分析CD80、CD86及IFN-γ、IL-4水平对CVA6型HFMD重症化的评估效能,多因素logistic回归分析CVA6型HFMD重症化的影响因素。结果重症组CD80、CD86、IFN-γ、IL-4水平均高于普通组(P<0.05)。CD80、CD86、IFN-γ、IL-4水平及其联合检测评估重症CVA6型HFMD的AUC值分别为0.769、0.717、0.756、0.864、0.917,联合检测的AUC值和特异度均高于各指标单一检测(P<0.05)。多因素logistic回归分析显示,年龄≤3岁是危险因素(P<0.05),发病至诊断时间≤3d、发热持续时间≤3d、WBC≤12×10^(9)/L、CD80低表达、IFN-γ低表达、IL-4低表达是保护因素(P<0.05)。结论CD80、CD86及Th1/Th2细胞因子(IFN-γ、IL-4)与CVA6型HFMD重症化有关,及早监测患儿CD80、CD86、IFN-γ、IL-4水平有利于了解其病情进展,指导医师治疗。

关键词： 胸腺瘤   重症肌无力   T淋巴细胞   细胞因子   自身抗体  

摘要： 胸腺瘤是一种起源于胸腺上皮的恶性肿瘤,是最常伴发自身免疫病的人类肿瘤之一[1]。通过评估胸腺的输出情况发现,胸腺瘤相关的重症肌无力(thymoma-associated myasthenia gravis,TAMG)患者胸腺瘤自身反应性T淋巴细胞输出增加,以CD4+的T淋巴细胞为主,在胸腺切除后明显下降,复发后又升高[2]。

摘要： Purpose:This study aimed to explore the relationship between corneal nerve degeneration and elevated dendritic cells (DCs) in diabetic keratopathy. Methods:Corneas from diabetic and healthy mice were analyzed using single-cell RNA sequencing. Corneal nerve density and DC and T-cell infiltration were quantified through whole-mount corneal staining. Freshly isolated mouse trigeminal ganglion (TG) neurons were co-cultured with immature DCs, mature DCs, activated CD8+ T cells, and CD4+CD25- T cells. TG neurite outgrowth was assessed to identify potential effector cells driving corneal nerve degeneration. In addition, interferon-gamma (IFN-γ) and blocking antibodies were used to evaluate their effects on TG neurite outgrowth and corneal nerve degeneration in mice. Results:Compared with age-matched healthy mice, diabetic mice exhibited a significant reduction in corneal nerve density and sensitivity, along with increased infiltration of DCs, CD4+ T cells, and CD8+ T cells. In vitro co-culture experiments revealed that CD4+CD25- T cells, rather than DCs and CD8+ T cells, significantly inhibited TG neurite outgrowth. Among cytokines, elevated IFN-γ in diabetic corneas impaired TG neurite outgrowth and induced corneal nerve degeneration, whereas IL-4 and IL-17 had no such effect. Blocking IFN-γ alleviated CD4+CD25- T-cell-induced inhibition of TG neurite outgrowth and corneal nerve degeneration in diabetic mice. Conclusions:CD4+CD25- T cells, but not DCs or CD8+ T cells, contribute to corneal nerve degeneration in diabetic mice, a process partially mediated by IFN-γ.