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关键词： Anti-TNF-α therapy   Cell trajectory   Conventional dendritic cells   Single-cell RNA sequencing   Ulcerative colitis  

摘要： Background: Ulcerative colitis (UC) is a chronic nonspecific inflammatory disease that belongs to the inflammatory bowel disease (IBD). The complex etiology of UC contributes to heterogeneous clinical outcomes in treatment. In clinical practice, approximately 30% of UC patients do not respond to first-line treatment with anti-TNF-α therapy. Methods: In this study, we performed single-cell sequencing of intestinal mucosal tissue before (pre) and after (post) anti-TNF-α therapy in UC patients and analyzed it in relation to therapy response (-R) and non-response (-NR). Results: We found that immune cell profiles differed between the pre-R and post-R groups. Specifically, the proportion of type 3 conventional dendritic cells (cDC3s) with distinct transcriptomes was lower in the post-R group than in the pre-R group and was not different between the pre-NR and post-NR groups. Cell trajectory analysis revealed that the number of cells differentiated into cDC3s significantly decreased in the post-R group, and the genes related to the MAPK signaling pathway obviously increased in these cells. Additionally, the interaction analysis of ligands and receptors revealed that the interactions between HLA-DPA1/DPB1 in fibroblasts and TNFSF9 in cDC3s and between CD44 in fibroblasts and TYROBP in cDC3s were significantly weakened in the post-R group compared to the pre-R group. Conclusion: We provide a comprehensive resource detailing the dynamic changes in immune cells during TNF-α therapy in UC patients and identify the reduction in the number of functionally distinct cDC3s as a potential biomarker for predicting anti-TNF-α therapy outcomes. © The Author(s) 2025.

关键词： CAR-T cell therapy   HLA molecules   HLA regulation   Hematological malignancies   Immune evasion  

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关键词： Autoimmunity   Celiac disease   HLA   Mammalian target of rapamycin   MHC   MTORC1   Oxidative stress   RNA sequencing   Small bowel  

摘要： Background: Celiac disease is associated with HLA-risk haplotypes, but non-HLA genes and environmental factors are also linked to disease susceptibility. In this study, we explore the molecular pathways involved in celiac disease by analyzing the differential expression of genes in both the gut and peripheral blood across various celiac disease phenotypes. Methods: Whole genome RNA sequencing was performed on 283 samples from intestinal mucosa and peripheral blood from 72 cases with either active, potential, or treated celiac disease and 73 disease controls. Enrichr pathway analysis of top differentially expressed genes was performed. Results: Overall, 7565 genes in intestinal biopsies and 542 genes in blood samples were differentially expressed between cases and controls. Compared with controls, immunoglobulin heavy variable 5–51 (IGHV5-51) (p = 1.05 × 10⁻¹⁴) and tissue transglutaminase (TGM2) (p = 5.29 × 10⁻¹⁰), encoding for TG2, the main autoantigen in celiac disease, were two of the top up-regulated genes in intestinal biopsies from celiac cases. TGM2 was also slightly upregulated in blood cells from cases with active disease compared with controls (p = 0.05). The topmost differentially expressed genes in peripheral blood were HLA-DQB1, HLA-DQB2, and GSTM1. Among pathways identified containing transcriptionally differentiated genes were antioxidant defense systems (e.g., nuclear factor (erythroid-derived 2)-like 2 (Nrf2), glutathione, ergothioneine, and peroxisome metabolism), as well as MHC class 1 antigen presentation, amino acid transport, mTORC1, bilirubin and lipid metabolism, liver homeostasis, the complement system, and interferon signaling. Conclusions: Differentially expressed genes in cases and controls indicate crosstalk between molecular pathways involved in antioxidant defense, immune regulation, and nutrient signaling in the pathogenesis of celiac disease. © The Author(s) 2025.

关键词： ABO   HLA   HSCT   Overall survival   Tunisians  

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关键词： Flexography printing   Graphite   Carbon dots   Interleukin 8   Non-faradaic biosensor   Disability  

摘要： Interleukin-8 (IL-8) is a key biomarker linked to inflammation and disability in neonates. However, current IL-8 detection methods are often costly, labor-intensive, and require highly trained personnel. While electrochemical techniques have been employed for sensitive IL-8 quantification, they typically rely on redox probes and threeelectrode electrochemical cells, leading to issues such as toxicity, prolonged fabrication time, and increased waste generation. Additionally, conventional electrochemical biosensors fabrication techniques are expensive and time-consuming, limiting their scalability for mass disease screening. In this study, we introduce a low-cost, non-faradaic electrochemical nanobiosensor for the direct detection of IL-8. The sensor consists of interdigitated graphite/carbon dot conjugates flexographically printed onto a flexible polyimide substrate. The printed layer's physical properties were systematically characterized using SEM, AFM and surface profilometer, and biofunctionalization was achieved using aminopropyltriethoxysilane (APTES) and glutaraldehyde. Successful surface modification was confirmed through ATR-FTIR and EDS elemental mapping. Electrochemical impedance spectroscopy (EIS) analysis demonstrated the nanobiosensor's response to varying IL-8 concentrations, with capacitance, Zmod, Zreal, and Zimag measurements. Among these, Zimag exhibited the highest sensitivity, with a response of 2.7 k Omega/log(ng/mL) and a detection limit of 50 pg/mL-well below the clinically established threshold of 600 pg/mL. This study demonstrates that, in addition to capacitance, there are multiple parameters that warrant exploration in non-faradaic biosensors to improve their sensing performance. The nanobiosensor fabrication via flexographic printing enables scalable, cost-effective production while maintaining high sensitivity and selectivity through a non-faradaic detection mechanism. This work paves the way for the development of affordable, mass-produ

摘要： Mast cells (MC) serve as pivotal sentinels in the regulation of immune responses and inflammation, yet their function in lung adenocarcinoma (LUAD) remains largely neglected. To decode their heterogeneity, we perform single-cell transcriptomic analysis of LUAD-infiltrating MCs. Our study uncovers the complexity in MC composition and identifies 9 distinct states, including proinflammation, chemotaxis, and antigen presentation. The proinflammatory MC subset, characterized by high IL-18 expression, is associated with improved outcomes for LUAD patients. This pro-inflammatory property is regulated by the activation of NLRP3 inflammasome within MCs, resulting in the formation of GSDMD pores and successive pyroptosis. Moreover, these MCs enhance the innate-like anti-tumor activity of MAIT cells by upregulating NKG2D and IFN-γ through the cytokine-activation mechanism. Our results uncover an unappreciated state of MCs and describe an inflammasome-dependent, MC-mediated regulation of MAIT cells in LUAD. These findings diversify our understanding of the functional repertoire and mechanistic equipment of MCs and MAIT cells, and suggest a potential therapeutic target for cancer treatment. © The Author(s) 2025.

关键词： HLA-B44 supertype   Human leukocyte antigen class Ⅰ genotype   Prognosis   Small-cell lung cancer   Therapeutic marker  

摘要： The human leukocyte antigen class I (HLA-I) genotypes have been proven to have an impact on the oncogenic mutational landscape and immunotherapy outcomes in several cancers. However, the HLA-I genotype landscape and its implications for lung cancer remain largely unknown. In this study, whole blood samples from 400 Chinese lung cancer patients were subjected to DNA sequencing for the detection of HLA-I genotypes. RNA sequencing data from 32 SCLC primary tumors were analyzed for immune cell infiltration and activity. Additionally, we collected HLA-I genotype and transcriptome data from 445 LUAD and 430 LUSC patients from The Cancer Genome Atlas (TCGA) database for comparisons. The proportion of HLA supertypes was similar among lung cancer patients with different pathological types but different among patients of different races. Chinese SCLC patients with the B44 supertype had more potent cytolytic activity and increased expression of MHC-II genes, interferon-gamma (IFN-γ), and chemokine signature genes than Chinese patients with other supertypes. Moreover, increased expression levels of immune checkpoint molecules were observed in tumors from B44(+) patients. Most importantly, we analyzed the correlation between the HLA supertype and prognosis and found that the positive effect of the HLA-B44 supertype on PFS verifies the prognostic value of HLA-B44 in SCLC. In conclusion, this study is among the first to depict the landscape of HLA-I genotypes in lung cancer patients. Comprehensive analysis revealed the effect of the B44 supertype on the tumor immune microenvironment and survival outcome of Chinese SCLC patients, providing fresh insight for the treatment of SCLC. © The Author(s) 2025.

关键词： Chronic hepatitis virus C infection   Hepatocellular carcinoma risk   IL-1β C/T gene polymorphism   Interleukin IL-1β   Interleukin IL-1β genotype   Polymerase chain reaction  

摘要： Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, frequently linked to chronic Hepatitis C virus (HCV) infection. Interleukin-1β (IL-1β), a pro-inflammatory cytokine, mediates hepatic inflammation, stimulates neovascularization, and enhances tumor aggressiveness. Genetic variation in the IL-1β promoter region, particularly the -511 C/T polymorphism, has been proposed to influence susceptibility to HCC, though published data are conflicting. Objective: This study aimed to evaluate the relationship between IL-1β (-511 C/T) polymorphism, circulating IL-1β concentrations, and the development of HCC among patients with chronic HCV infection. Methods: Ninety volunteers were enrolled and categorized into three groups: 30 controls (Group I), 30 HCV + patients without HCC (Group II), and 30 HCV + with HCC patients (Group III). The IL-1β (-511 C/T) polymorphism was identified through PCR-based analysis, and circulating IL-1β levels were measured using enzyme-linked immunoassays. Results: A significant increase in IL-1B (-511) T allele frequency in group II and III HCV patients than controls (n = 26 (43.5%), n = 39(65.5%), and n = 8(13.5%), respectively, P < 0.001), odds ratio (OR) = 4.97 (1.87- 13.61) and 12.07 (4.47- 33.7) (p < 0.05), respectively). C allele frequency was significantly lower in group II and group III than in controls (n = 34(56.5%), n = 21(34.5%), and n = 52 (86.5%), respectively, p < 0.001). IL-1β serum levels were significantly increased in patients compared to controls, with more increase in group III than group II (t = 13.69, P < 0.0001). TT and CT genotypes have increased IL-1β levels than CC carriers. Conclusion: The IL-1β (-511 C/T) polymorphism is associated with elevated IL-1β levels, contributing to an increased risk of HCC in HCV-infected Egyptian patients. © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2025.

关键词： 嵌合抗原受体T细胞   质量控制   放行检测  

摘要： 嵌合抗原受体T细胞免疫疗法(CAR-T)作为肿瘤免疫治疗的突破性技术,通过基因修饰患者T细胞靶向杀伤肿瘤,展现出特殊疗效,为癌症患者带来了新希望。CAR-T治疗产品的质量与其临床疗效紧密相关,如何持续生产高质量的CAR-T治疗产品,已成为CAR-T细胞疗法实现广泛应用的关键。本文对自体CAR-T细胞产品生产过程的质量控制要点和产品的质量放行进行了综述,以期为更多CAR-T细胞产品的研究和应用提供参考。

关键词： Diffuse large B-cell lymphoma, ITK   Immune microenvironment   Rituximab   TCR signaling pathway  

摘要： Diffuse Large B-Cell Lymphoma (DLBCL) is the most prevalent pathological subtype of non-Hodgkin lymphoma (NHL). Patients with DLBCL often experience extremely poor prognoses due to drug resistance or relapse, and the limitations of existing treatment regimens are evident. This study focuses on the mechanistic role and clinical significance of interleukin-2-inducible T-cell kinase (ITK) in DLBCL. Through bioinformatics analysis, it was found that ITK, as a key molecule in the T Cell Receptor (TCR) signaling pathway, is significantly underexpressed in DLBCL. This underexpression is associated with a poorer overall survival (OS) of patients and exhibits a negative correlation with the expression of the immune checkpoint molecule Programmed Death Ligand 1 (PD-L1), suggesting its potential involvement in the regulation of T cell exhaustion. In vitro experiments demonstrated that overexpression of Itk significantly enhanced the immunological activity of mouse T lymphocytes (CTLL-2), activating the TCR-Ca²⁺-Calcineurin-NFAT-IFN-γ signaling pathway. This led to improved calcium ion responsiveness in T cells, increased calcineurin activity, and nuclear translocation of Nuclear Factor of Activated T Cells (NFAT). It also enhanced cytokine secretion levels and proliferative capacity of cytotoxic T lymphocytes (CD8⁺ T cells), thereby driving an anti-tumor immune response. In a co-culture model, overexpression of Itk significantly augmented the killing effect of CTLL-2 cells on DLBCL, inducing apoptosis in DLBCL cells. Furthermore, T cells overexpressing Itk exhibited a synergistic effect when combined with Rituximab, significantly enhancing the inhibition of DLBCL cell proliferation. This provides a clinically feasible approach to address the challenge of drug resistance in DLBCL treatment. This study unveils the molecular mechanism by which ITK enhances anti-tumor immunity through remodeling the T cell receptor signaling pathway, offering new theoretical