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关键词： alendronate   cancer   CD137L   cell therapy   cytotoxicity   expansion   gamma delta T cells   MT: Regular Issue   oncology   Vd2 cells  

摘要： The increasing success of allogenic Vδ2 T cell immunotherapy for the treatment of cancer has been demonstrated in recent studies. Vδ2 T cells recognize phosphoantigens, intermediates of the mevalonate pathway, through butyrophilin molecules, and they are not major histocompatibility complex (MHC) restricted. Allogeneic transfer of in vitro expanded Vδ2 T cells has shown more promising results than autologous strategies, although the clinical benefit remains limited. One of the issues leading to less-than-optimal responses relates to the polyclonal expansion of Vδ2 T cell subsets with variable cytotoxic capacity. Previous work developed protocols to expand Vδ2 T cells, although to our knowledge, ours is the first comprehensive study that has produced a simple, antigen-presenting feeder-free culture that produced an average expansion of 3,000-fold and more than 95% pure Vδ2 T cells avoiding additional isolation steps. Here, we show the in vitro expansion of cytotoxic Vδ2 T cells expressing CD16 and NKG2A enriched in granzyme B that displayed enhanced antitumor activity of up to 40% against leukemia and ovarian, breast, and lung cancer cells. Our work warrants clinical testing to evaluate the therapeutic potential of these highly cytotoxic cells, paving the way for improved efficacy of personalized cell-based immunotherapies. © 2025 The Authors

关键词： NAT10   T细胞   肿瘤相关巨噬细胞   肾透明细胞癌   糖酵解   免疫逃逸  

摘要： 目的 探讨NAT10对肾透明细胞癌糖酵解代谢的影响并进一步研究其对肿瘤细胞免疫逃逸的作用。方法 通过TCGA数据库分析临床样本中NAT10表达水平与肾透明细胞癌患者预后的关联；慢病毒稳转方法构建过表达NAT10细胞株；CCK-8评估肾透明细胞癌细胞（ACHN和Caki-1）增殖能力变化；划痕实验评估ACHN和Caki-1细胞迁移能力变化；免疫荧光检测NAT10过表达后ACHN和Caki-1细胞糖酵解关键基因GLUT1、HK2、LDHA、MCT4以及肿瘤细胞表面PD-L1水平的表达；乳酸检测试剂盒评估肾透明细胞癌细胞乳酸LDHA水平变化；NAT10过表达后ACHN和Caki-1细胞与CD8+ T细胞共培养，CCK-8评估T细胞增殖以及ELISA检测IFN-γ和TNF-α分泌变化；NAT10过表达后ACHN和Caki-1细胞与肿瘤相关巨噬细胞TAMs共培养，评估检测M2型巨噬细胞极化比例以及ELISA检测IL-10和TGF-β1分泌变化。结果 NAT10高表达与患者生存期显著缩短相关。过表达NAT10后，ACHN和Caki-1细胞的增殖能力和侵袭能力均显著增强。此外，过表达NAT10导致ACHN和Caki-1细胞中糖酵解关键基因GLUT1、HK2和LDHA以及PD-L1的表达水平显著增加。在共培养体系中，过表达NAT10的ACHN和Caki-1细胞显著抑制CD8+ T细胞增殖，并降低IFN-γ的分泌水平。在肿瘤相关巨噬细胞（TAMs）共培养实验中，过表达NAT10的ACHN和Caki-1细胞显著提高了M2型极化比例同时促进IL-10和TGF-β1分泌。结论 NAT10通过调控GLUT1、HK2和LDHA的表达，影响肾透明细胞癌的糖酵解代谢重编程，并促进免疫逃逸。

关键词： 前列腺癌   前列腺特异性膜抗原   前列腺活检   靶向穿刺   系统穿刺  

摘要： 目的 探究是否可以在进行前列腺活检时,通过检测穿刺组织的123I标记的前列腺特异性膜抗原(123I-PSMA)放射值达到术中实时、快速、准确分辨良恶性前列腺组织,用以改善当前临床活检策略,以更少的穿刺针数实现前列腺癌的术中准确诊断。方法 前瞻性、诊断性试验中纳入疑似前列腺癌病人29例,所有病人均在注射123I-PSMA 24小时内,进行超声引导下经会阴联合活检,共穿刺435针,用伽马计数器术中实时测量穿刺组织的放射值。Pearson检验放射值与组织病理性相关联。结果 前列腺癌组织放射值中位值（1 906.50 cpm）高于良性前列腺组织（415.00 cpm）,区分良恶性前列腺组织的放射值的最佳截止值为828.50 cpm;临床显著性前列腺癌组织的放射值中位值（2 652.50 cpm）显著高于无临床意义前列腺癌（1 386.00 cpm）,区分临床显著性前列腺癌组织与无临床意义前列腺癌组织的放射值的最佳截止值为1 767.00 cpm。穿刺组织放射值与组织病理分级之间具有显著正相关性（r=0.834）。结论 通过检测前列腺穿刺组织的123I-PSMA放射值可实现术中实时、快速、准确地分辨良恶性前列腺组织。

关键词： 白细胞介素-35   富含丝氨酸-精氨酸剪接因子6   结核性胸膜炎   胸膜厚度   胸膜结核瘤  

摘要： 目的 分析白细胞介素-35(IL-35)、富含丝氨酸-精氨酸剪接因子6(SRSF6)水平与结核性胸膜炎胸膜厚度的关系及联合评估患者胸膜结核瘤发生风险的价值。方法 选取2022年1月—2024年7月于浙江大学医学院附属第二医院临平院区收治的100例结核性胸膜炎。检测患者的胸腔积液IL-35、SRSF6水平及胸膜厚度。分析IL-35、SRSF6水平与结核性胸膜炎患者胸膜厚度的关系。随访1年,结核组患者根据是否发生胸膜结核瘤分为发生组与未发生组,分析结核性胸膜炎患者发生胸膜结核瘤的危险因素,分析IL-35和SRSF6评估结核性胸膜炎患者胸膜结核瘤发生风险的价值。结果 结核性胸膜炎患者的胸腔积液IL-35水平为(529.78±146.85) ng/L、胸腔积液SRSF6水平(1.44±0.43) ng/ml,胸膜厚度为(4.07±0.53) mm。结核性胸膜炎患者胸腔积液IL-35、SRSF6水平与胸膜厚度呈正相关(P<0.05)。logistic分析显示,结核性胸膜炎患者出现胸水分隔包裹、胸膜厚度异常及胸腔积液IL-35、SRSF6水平上升时,其发生胸膜结核瘤的风险显著增加(P<0.05)。绘制受试者工作特征(ROC)曲线分析显示,胸腔积液IL-35和SRSF6水平联合预测结核性胸膜炎患者发生胸膜结核瘤的曲线下面积(AUC)、特异度、灵敏度均高于两者单独检测值(P<0.05)。结论 IL-35和SRSF6水平与结核性胸膜炎胸膜厚度呈正相关,两者联合检测可有效评估结核性胸膜炎患者胸膜结核瘤发生风险。

关键词： Epithelial–mesenchymal transition   Inflammation   NLRP3   Peritoneal fibrosis   Resveratrol glycoside  

摘要： OBJECTIVE:Resveratrol glycoside (also known as polydatin, PLD), known for its anti-inflammatory and anti-fibrotic properties, has shown potential in mitigating fibrosis in various organs. This study aimed to investigate the effects of PLD on high glucose-induced peritoneal fibrosis and its underlying mechanisms, focusing on the NOD-like receptor protein 3 (NLRP3)/interleukin-1 beta (IL-1β)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. METHODS:Eighteen Sprague-Dawley rats were divided into three groups: control, peritoneal fibrosis, and resveratrol glycoside treatment. Histological and immunohistochemical analyses were performed to assess peritoneal fibrosis. Human peritoneal mesothelial cells (HMrSV5) were treated with high glucose and PLD to evaluate cell morphology, viability, and the expression of fibrosis and inflammatory markers via Western Blot and immunofluorescence. RESULTS:PLD significantly reduced peritoneal fibrosis in rats, as evidenced by histological analyses showing decreased tissue thickness and collagen deposition. It also downregulated the expression of transforming growth factor beta 1 (TGF-β1), collagen type I (Col I), alpha-smooth muscle actin (α-SMA), vascular endothelial growth factor (VEGF), NLRP3, phosphorylated p65 subunit of NF-κB (p-p65), IL-1β, interleukin-18 (IL-18), cleaved caspase-1 p20 subunit (caspase-1p20) and ROS level, while upregulating E-cadherin. In HMrSV5 cells, PLD mitigated high glucose-induced epithelial-mesenchymal transition, angiogenesis, reactive oxygen species (ROS) production and inflammation, which was reversed by overexpression of NLRP3, suggesting the involvement of the NLRP3/IL-1β/NF-κB pathway. CONCLUSION:PLD alleviates high glucose-induced peritoneal fibrosis, angiogenesis, ROS production and inflammation by inhibiting the NLRP3/IL-1β/NF-κB signaling pathway, highlighting its potential as a therapeutic agent for peritoneal fibrosis.

关键词： 腹膜透析相关性腹膜炎   扶肾颗粒   驻留巨噬细胞   细胞因子   中药复方   随机对照试验  

摘要： 目的观察扶肾颗粒干预Vsig4驻留巨噬细胞治疗腹膜透析相关性腹膜炎（PDAP）的临床疗效和作用机制。方法本研究通过随机对照试验评估扶肾颗粒联合抗生素治疗PDAP的有效性。纳入天津中医药大学第一附属医院2023年7月—2024年2月就诊的40例PDAP患者，随机分为扶肾颗粒组20例，对照组20例。对照组控制患者血压、血糖，予患者腹腔注射敏感抗生素治疗14天。扶肾颗粒组在对照组的基础上，加用口服扶肾颗粒治疗，每次2袋，每天2次，共治疗14天。记录患者PDAP转阴时间及腹膜透析总超滤量变化；收集PDAP治疗前后的腹膜透析液样本，检测腹腔Vsig4驻留巨噬细胞、T细胞和细胞因子IL-6、IL-10、TNF-α的变化。结果扶肾颗粒组患者平均转阴时间[（2.50±0.26）天]短于对照组[（3.30±0.25）天，t=-2.223,P=0.032]。与对照组比较，第3天时扶肾颗粒组超滤量更多（P<0.05）。与本组治疗前比较，两组IL-6、IL-10、TNF-α浓度降低（P<0.01）；扶肾颗粒组CD3+T细胞、CD14+巨噬细胞、Vsig4+巨噬细胞、Vsig4+巨噬细胞/CD14+巨噬细胞水平升高（P<0.05,P<0.01），对照组CD3+T细胞、Vsig4+巨噬细胞、Vsig4+巨噬细胞/CD14+巨噬细胞水平亦升高（P<0.05,P<0.01）。与对照组比较，扶肾颗粒组Vsig4+巨噬细胞的比例及IL-10浓度更高（P<0.05）,IL-6浓度更低（P<0.01）。结论PDAP患者早期应用扶肾颗粒能够缩短腹透液常规转阴时间，其作用机制可能与其调节Vsig4驻留巨噬细胞比例和细胞因子浓度减轻腹腔炎症反应有关。

关键词： X射线   辐照   淋巴细胞   血常规   剂量  

摘要： 考察了X射线辐照抑制血液中淋巴细胞增殖的效果,以确定预防输血相关性移植物抗宿主病(TA-GVHD)的最佳辐照剂量。实验在150 kV管电压、8 mA束流下进行,通过调整辐照距离和时间控制剂量。结果显示,40 Gy剂量下,淋巴细胞增殖抑制率达92.62%±1.32%,且对血常规参数无显著不良影响。当剂量提高到70 Gy时,尽管淋巴细胞增殖抑制率没有显著提升,却导致红细胞内钾离子浓度急剧升高,引发溶血。这表明高剂量辐照会损害红细胞完整性。因此,40Gy被认为是全血X射线辐照的最佳剂量,能在有效抑制淋巴细胞增殖的同时保持血液成分稳定性。此剂量下,能够有效降低TA-GVHD风险,且不会对血液质量造成显著影响。该研究为临床输血安全提供了重要的实验数据和指导,有助于优化辐照参数,提高输血安全性及有效性,减少不良反应的发生。

关键词： HLA   T cell receptor   computational protein design   human leukocyte antigen   peptide antigen  

摘要： Recognition of epitopic peptide antigens presented on class I major histocompatibility complex (MHC-I) proteins by T cell receptors (TCRs) forms the cornerstone of immune surveillance, leading to a plethora of adaptive immune responses. Characterization of TCR:peptide/MHC-I interactions is critical for understanding immune recognition, and developing immunotherapies, but the large variation in docking orientations of TCRs on their peptide/MHC-I targets challenges structural modeling. NMR spectroscopy could potentially resolve this ambiguity, but the large size of the TCR:peptide/MHC-I complex limits data quality. Here, we demonstrate that a designed MHC-I protein, SMART A*02:01, enables facile solution mapping of MHC-I:TCR interactions at scale. Our approach can be combined with computational modeling and structure-guided engineering to aid the development of TCR-based therapeutics.

关键词： Asthma   Immunology   Inflammation   Pulmonology  

摘要： The mechanism of neutrophilic and mixed neutrophilic-eosinophilic asthma is poorly understood. We found that extracellular DNA and nucleosomes (Nuc) were elevated in the airways from neutrophilic-eosinophilic asthma patients and correlated with bronchoalveolar lavage neutrophils. Bronchial tissue from neutrophilic-eosinophilic asthma expressed increased DNA sensor-positive cells. Intranasally administered DNA did not induce airway hyperreactivity (AHR) or any pathology but induced AHR and neutrophilic-eosinophilic inflammation when co- administered with the allergen Alternaria (Alt). Nuc alone induced anti-inflammatory/defensive genes whereas the Nuc-Alt combo increased TNF and innate cytokines. The Alt-Nuc phenotype was abolished in Cgas-/-, ALR-/-, Sting-/-, LysMCre:Stingf/f, IL7RCre:Rorαf/f and Tnfr2-/- mice. Alt, unexpectedly, played an essential role in the Nuc-induced phenotype. It abrogated Nuc-induction of anti-inflammatory genes, facilitated Nuc uptake, induced ILC2s, which, in presence of Nuc, produced high levels of TNFα and promoted neutrophilic infiltration. We established a paradigm where allergens inhibit the anti-inflammatory effects of DNA/Nuc and facilitate STING-TNFα-driven neutrophilic-eosinophilic inflammation in asthma.

关键词： Cytokines   Genetics   Immunology   Innate immunity   Molecular genetics  

摘要： Loss-of-function (LOF) variants in IL6ST, encoding GP130, can cause hyper-IgE syndrome (HIES). Monoallelic LOF variants in IL6ST lead to HIES when located in the intracellular domain downstream of box 1/2 and upstream of the STAT3 phosphorylation sites and the recycling motif, due to their dominant negative (DN) activity. In this region, two previously unreported IL6ST variants, p.K702Sfs7* and p.Y759Wfs26*, were identified in two families with autosomal dominant (AD) HIES. Both variants were LOF, exhibited DN effects, leading to the accumulation of mutant GP130 on the cell surface. The p.K702Sfs7* mutation was the most upstream N-terminal mutation linked to HIES caused by heterozygous IL6ST variants. Comprehensive screening of IL6ST mutants revealed that most premature terminations downstream of amino acid F641, at the end of the transmembrane domain, resulted in LOF and DN effects via GP130 accumulation on the cell surface. The absence of the recycling motif (positions 782-787) in surface-expressed LOF GP130 led to its accumulation, contributing to the DN effect. The importance of intracellular truncating IL6ST variants can possibly be predicted based on the location of the premature stop codon. GP130 accumulation on the cell surface is a characteristic and potentially diagnostic finding in HIES patients with heterozygous IL6ST variants.