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关键词： HLA   Immunogenetics   Islet autoimmunity   KIR   Killer-cell immunoglobulin-like receptors   Natural killer (NK) cells   Progression   Seroconversion   Type 1 diabetes  

摘要： AIMS/HYPOTHESIS:The aim of this work was to explore associations between type 1 diabetes progression from stages 1 or 2 to stage 3 and interacting ligand-receptor complexes of HLA class I (HLA-I) and KIR gene products. METHODS:Applying next-generation sequencing technology to genotype HLA-I genes (HLA-A, -B, -C) and KIR genes (KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DL1, KIR3DL3, KIR3DS1, KIR2DP1, KIR3DP1) from 1215 participants in the Diabetes Prevention Trial-Type 1 (DPT-1) and the Diabetes Prevention Trial (TN07), we systematically explored associations of HLA-I-KIR ligand-receptor interactions (LRIs) with disease progression via a Cox regression model. We investigated the structural properties of identified LRI complexes. RESULTS:KIR and HLA-I genes had no or sporadic associations with disease progression. Out of all possible LRIs, nine HLA-A ligands and 14 HLA-B ligands with corresponding receptors had modest associations with progression (p<0.05). As an example, carriers of A*03:01-KIR2DS4 had slower progression (HR 0.36, p=3.06 × 10), as did B*07:02-KIR2DL3 carriers (HR 0.26, p=7.76 × 10). Structural investigations of KIR-HLA-I complexes via homology modelling based on already-solved respective complex structures suggested that the respective electrostatic and van der Waals interactions encoded in the protein sequences result in strong biophysical LRIs, which could alter the progression of type 1 diabetes. CONCLUSIONS/INTERPRETATION:These results reveal that LRIs of KIR-HLA-I gene products, rather than individual genes, contribute to type 1 diabetes progression, and such interactions are likely to be stabilised by electrostatic and van der Waals forces. As the KIR-HLA-I interactions involve part of the C-terminus of the antigen-binding groove of HLA-I, but may be affected by the respective bound peptide, this suggests a new mechanism for type 1 diabetes pathogenesis. DATA AVAILABILITY:Clinical data on part

关键词： immunology   infectious disease   inflammation   microbiology  

关键词： 清宣导滞方   儿童   流感   随机对照研究   治疗  

摘要： 目的：观察清宣导滞方治疗儿童流行性感冒（肺胃积热证）的症状改善及抗原转阴率效果。设计：采用多中心随机对照的方法学设计，于2022年10月至2023年4月在北京中医药大学东方医院等8家医院儿科收集流感确诊病例。通过诊间招募180例符合标准的流感肺胃积热证患儿。将符合纳入标准的患儿采用区组随机的方法进行随机分组，试验组予清宣导滞方治疗5天，对照组予磷酸奥司他韦颗粒治疗5天。主要疗效指标：流感抗原检测转阴率；次要疗效指标：加拿大呼吸道疾病和流感量表（CARIFS）评分；并发症、重症及危重症发生率。入组当天、用药后48小时、用药后72小时、用药后6 ± 1天进行随访观察。结果：180例参与者随机分配到试验组（n=90）或对照组（n=90）。主要疗效指标：流感抗原检测结果比较：试验组流感抗原平均转阴时间为5.29 ± 1.245天，对照组流感抗原平均转阴时间为5.40 ± 1.681天，差异无统计学意义（P＞0.05）。干预5天后，试验组52例转阴，对照组51例转阴，差异无统计学意义（P＞0.05）。次要疗效指标：CARIFS评分：干预后72h，试验组与对照组在头痛、肌肉酸痛、需要额外照顾3项，差异有统计学意义（P＜0.05）。干预后6天±1天试验组与对照组在咽痛、睡眠不好、感觉不舒服、精神差易疲劳、比平时爱哭、要额外照顾、症状维度、功能维度、影响父母维度、总分计10项，差异有统计学意义（P＜0.05）。症状维度积分、功能维度积分、影响父母维度积分、CARIFS总分组内比较：随着随访时间后延，两组积分都出现明显下降，差异有统计学意义（P＜0.001）。组间比较，入组时试验组积分均值高于对照组，随着干预的进行，试验组积分下降较对照组明显，随访结束时，积分均值低于对照组，差异无统计学意义（P＞0.05）。并发症、重症及危重症发生率：两组均无并发症、重症及危重症，差异无统计学意义（P＞0.05）。结论：清宣导滞方治疗儿童流感（肺胃积热证）症状改善效果及抗原转阴率不劣于磷酸奥司他韦颗粒，患儿接受度较好，可以尝试更广泛的应用于临床治疗儿童流感（肺胃积热证）。

关键词： IL-6/JAK/STAT3   Rux   cancer cachexia   macrophages   muscle atrophy   systemic inflammatory response  

摘要： OBJECTIVES:Ruxolitinib (Rux), an oral Janus tyrosine Kinase (JAK) tyrosine kinase inhibitor, has demonstrated anti-inflammatory properties and the ability to mitigate denervation-induced skeletal muscle atrophy. Here, we checked the potential efficacy of Rux on cancer cachexia and tried to clarified its mechanisms. METHODS:The in vitro cell models of C26 or LLC CM-induced C2C12 myotubes were used to check the influence of Rux on myotube atrophy. C26 tumour-bearing mice (male BALB/c mice) were applied as the animal model to examine the effects of Rux in attenuating cachexia symptoms. Western blot analysis was utilized to investigate the potential mechanisms of Rux. KEY FINDINGS:Rux significantly attenuated C2C12 myotube atrophy in vitro. Rux suppressed the interleukin-6 secretion by inhibiting STAT3 activation in tumour cells and macrophages. The administration of Rux prevented body weight loss and muscle wasting in C26 tumour-bearing mice without affecting tumour growth. At the end of the experiment, mice in the Rux treatment group exhibited a 6.7% increase in body weight compared to the C26 model group. Furthermore, Rux enhanced in gastrocnemius myofibres cross-sectional area and grip strength. CONCLUSIONS:Rux ameliorates cancer cachexia muscle atrophy by inhibiting STAT3/Atrogin-1 signaling. Rux may represent a promising therapeutic candidate for the treatment of cancer cachexia.

关键词： aging   lung transplantation   organ donation criteria   telomeres   CT   computed tomography   DCD   donation after circulatory death   EBV   Epstein-Barr virus   HLA   heuman leukocyte antigen   LTx   lung transplantation   PET   positron-emission tomography   PTLD   post-transplant lymphoproliferative disease   teloFISH   telomere fluorescence in situ hybridization   TL   telomere length  

摘要： Lung transplantation (LTx) is challenged by a critical shortage of donors, prompting the extension of acceptance criteria, including donor age. Here, we report on a double-LTx from a 94-year-old donor. Despite the advanced age, the lungs were of good physiological quality, with unremarkable gas exchange, bronchoscopy, and radiography. The recipient, a 61-year-old COPD patient, had an uneventful recovery and favorable short-term outcomes but later developed infections and post-transplant lymphoproliferative disease. Lung telomere length analysis revealed a preserved biological reserve, reinforcing the potential to expand the donor pool by prioritizing biological over chronological age, while ensuring graft quality through rigorous evaluation.

关键词： 类风湿性关节炎   托法替布   传统DMARDs   白细胞介素-22   白细胞介素-23   Th22细胞亚群  

摘要： 目的：探讨托法替布联合传统疾病修饰抗风湿药（DMARDs）治疗对类风湿性关节炎（RA）患者外周血白细胞介素-22（IL-22）、白细胞介素-23（IL-23）及Th22细胞亚群的影响。方法：回顾性分析2022年12月至2024年12月本院收治的100例RA患者临床资料。使用随机数字表法分为常规组（n=33，给予传统DMARDs治疗）、单一组（n=34，给予托法替布）及联合组（n=33，给予托法替布联合传统DMARDs治疗）。比较三组血清IL-22、IL-23水平、Th22细胞亚群比例、关节功能恢复情况、疾病改善情况及不良反应等。结果：治疗3个月后三组的IL-22、IL-23及Th22细胞亚群比例均较治疗前降低，且联合组显著低于常规组与单一组（P<0.05）；治疗3个月后三组的抗-CCP、RF水平也均较治疗前下降，且联合组显著低于常规组与单一组（P<0.05）；治疗3个月后三组的关节肿胀频次、压痛关节数目、晨僵时间及VAS评分均较治疗前降低，且联合组显著低于常规组与单一组（P<0.05）；治疗3个月后三组的DAS28评分及HAQ评分均较治疗前降低，且联合组显著低于常规组与单一组（P<0.05）；在治疗期间，三组不良反应发生率比较，差异无统计学意义（Z =0.290，P=0.865）。结论：托法替布联合传统DMARDs治疗RA的临床效果显著，能有效降低血清IL-22、IL-23水平及自身抗体水平，调节Th22细胞亚群比例，减轻炎症反应，改善关节功能。

摘要： The standard of care in high-grade gliomas has remained unchanged in the past 20 years. Efforts to replicate effective immunotherapies in non-cranial tumors have led to only modest therapeutical improvements for patients with glioma. Here, we demonstrate that intratumoral (i.t.) administration of recombinant interleukin-12 (rIL-12) promotes local cytotoxic CD8 POS T cell accumulation and conversion into an effector-like state, resulting in a dose-dependent survival benefit in preclinical GB mouse models. This tumor-reactive CD8 T cell response is further supported by intratumoral rIL-12-sensing dendritic cells (DCs) and is accompanied by the co-stimulatory receptor 4-1BB expression in both cell types. Given that DCs and CD8 POS T cells are functionally suppressed in the tumor microenvironments (TME) of de novo and recurrent glioma patients, we tested whether anti-tumor response at the rIL-12-inflamed tumor site could be enhanced with 4-1BBL, the ligand of 4-1BB. 4-1BBL was delivered using an adeno-associated virus (AAV) vector targeting GFAP-expressing cells and resulted in prolonged survival of rIL-1 2-treated GB-bearing mice. This study establishes that tumor antigen (Ag)-specific CD8 T cell activity can be augmented by incorporating an AAV-vector-mediated gene therapy approach, effectively enhancing anti-GB immunity in the TME.

摘要： Neutrophils exert tumor-promoting roles in breast cancer and are particularly prominent in aggressive breast tumors. The pro-inflammatory signals TGF-β1 and TNF-α are upregulated in breast tumors and induce epithelial-to-mesenchymal transitions (EMT), a process linked to cancer cell aggressiveness. Here, we investigated the roles of TGF-β1 and TNF-α in the recruitment of neutrophils by breast cancer cells. Dual treatment with TGF-β1 and TNF-α induces EMT signatures in premalignant M2 cells, which are part of the MCF10A breast cancer progression model. Conditioned media (CM) harvested from M2 cells treated with TGF-β1/TNF-α gives rise to amplified neutrophil chemotaxis compared to CM from vehicle-treated M2 cells. This response correlates with higher levels of the neutrophil chemokines CXCL1 and CXCL8, in a p38MAPK-dependent manner, and is attenuated by CXCL8-neutralizing antibodies. We combined gene editing, immunological and biochemical assays to show that neutrophil recruitment and EMT are uncoupled in treated M2 cells. Finally, analysis of transcriptomic databases of cancer cell lines revealed a significant correlation between CXCL8 and TGF-β1/TNF-α-regulated or effector genes in breast cancer. These findings establish a novel role for the TGF-β1/TNF-α/p38 MAPK signaling axis in regulating neutrophil recruitment in breast cancer, independent of their profound impact on EMT.

摘要： This study aims to establish a two-dimensional PCR (2D-PCR) methodology capable of simultaneously identifying HLA-A*31:01 , HLA-B*15:02 , HLA-B*57:01 , and HLA-B*58:01 alleles to prevent adverse drug reactions (ADRs) and guide safe clinical medication use. To achieve this goal, key nucleotide sites were first selected through multiple sequence alignment for the purpose of identifying HLA alleles: c.243T and c.290T for HLA-A*31:01 ; c.206C, c.256G, and c.285G for HLA-B*58:01 ; c.362T and c.419C for HLA-B*57:01 ; and c.1012+104T (rs144012689) for HLA-B*15:02 . Using universal tag sequences linked to the 5' end of primers and base-quenched probes, high-throughput identification of multiple target genes was achieved through PCR amplification and melting curve analysis, followed by methodological optimization and evaluation. Results indicated that the 2D-PCR method has a detection limit of approximately 10 1 copies and achieves high specificity and accuracy. The entire detection process can be completed in approximately 100 minutes, with a cost of less than 1 USD. Furthermore, 2D-PCR overcomes the limitations of traditional fluorescent channels, providing technical support for the identification of multiple target genes. In conclusion, this study demonstrates that 2D-PCR offers a convenient and rapid approach for HLA allele identification to prevent ADRs and holds potential for clinical application.

关键词： IL-18   epithelial cell   inflammasome   innate immunity   intestine   stem cell  

摘要： IL-18 is a member of the IL-1 family of cytokines, which is highly expressed in intestinal epithelial cells (IECs). Upon barrier breach, IL-18 is matured to its bioactive form as a result of inflammasome activation, released from the cell via Gasdermin D pores, and sensed by IL-18 receptor 1-positive (IL18R1) immune cells to initiate an inflammatory response. In addition to this epithelial-out signaling network, we recently uncovered an epithelial-intrinsic IL-18 signaling pathway in the murine small intestine and identified enterochromaffin cells and revival stem cells (revSC) as IL18R1 bearing IEC populations in the recovering crypt. Here, we discuss the mechanism, and physiological relevance, as well as some of the open questions presented by this discovery in relation to intestinal health and disease.