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关键词： Chimeric cytokine receptor   CAR-NK   TGF-beta   IL-21   Gastric cancer   Immunosuppressive tumor microenvironment  

摘要： Gastric cancer remains a significant global health burden, characterized by regional variations in incidence and poor survival prospects in advanced stages. Natural killer (NK) cells play a crucial role in the body's anti-cancer defense, and chimeric antigen receptor (CAR)-NK cell therapy is gaining attention as a cutting-edge and promising treatment method. This study aims to tackle the challenge of TGF-R-mediated tumor immune evasion within the immunosuppressive tumor microenvironment by designing a novel chimeric cytokine receptor TRII/ 21 R, which consists of extracellular domains of TGF-R receptor II (TRII) and transmembrane and intracellular domains of IL-21 receptor (21 R) and can convert the immunosuppressive signal from TGF-R in the tumor microenvironment (TME) into an NK cell activation signal through the IL-21R-STAT3 pathway. We successfully constructed NKG2D-CAR-NK cells expressing TRII/21 R and demonstrated strong anti-tumor activity against cancer cells both in vitro and in vivo. The co-expression of TRII/21 R in CAR-NK cells enhanced the cytotoxicity, promoted proliferation and survival capabilities, and reduced the expression of exhaustion markers. In the xenograft mouse model, TRII/21R-CAR-NK cells significantly inhibited tumor growth and improved the survival rate of tumor-bearing mice compared to the mice receiving control CAR-NK cells. Additionally, TRII/21 R coexpression enhanced NK cells' infiltration, activation, and persistence within the tumor, indicating a robust anti-tumor response mediated by the JAK-STAT3 signaling pathway. This study underscores the therapeutic potential of TRII/21R-modified CAR-NK cells as a breakthrough strategy for combating cancer.

关键词： Africa   HLA   human molecular diversity   malaria   pathogen-driven selection   plasmodium falciparum  

摘要： African populations remain underrepresented in studies of human genetic diversity, despite a growing interest in understanding how they have adapted to the diverse environments they live in. In particular, understanding the genetic basis of immune adaptation to pathogens is of paramount importance in a continent such as Africa, where the burden of infectious diseases is a major public health challenge. In this study, we investigated the molecular variation of four Human Leukocyte Antigens (HLA) class II genes (DRB1, DQA1, DQB1 and DPB1), directly involved in the immune response to parasitic infections, in more than 1000 individuals from 23 populations across North, East, Central and West Africa. By analyzing the HLA molecular diversity of these populations in relation to various geographical, cultural and environmental factors, we identified divergent genetic profiles for several (semi-)nomadic populations of the Sahel belt as a signature of their unique demography. In addition, we observed significant genetic structuring supporting both substantial geographic and linguistic differentiations within West Africa. Furthermore, neutrality tests suggest balancing selection has been shaping the diversity of these four HLA class II genes, which is consistent with molecular comparisons between HLA genes and their orthologs in chimpanzees (Patr). However, the most striking observation comes from linear modeling, demonstrating that the prevalence of Plasmodium falciparum, the primary pathogen of malaria in Africa, significantly explains a large proportion of the nucleotide diversity observed at the DPB1 gene. DPB1*01:01, a highly frequent allele in Burkinab & eacute;populations, is identified as a potential protective allele against malaria, suggesting that strong pathogen-driven positive selection at this gene has shaped HLA variation in Africa. Additionally, two low-frequency DRB1 alleles, DRB1*08:06 and DRB1*11:02, also show significant associations with P. falciparum prev

关键词： binding specificity   cytokine receptors   cytokines   gp130   interleukin-6 family   pleiotropy  

摘要： Historically, cytokines belonging to the gp130 family bind to specific ligand-binding receptors that stimulate cell signaling through a receptor complex comprising gp130 or gp130 together with another structurally related signaling receptor. However, recent findings increasingly dispel these stereotypes and suggest that the receptor specificity of gp130-activating cytokines is less strict than originally assumed. Weitz et al. now provide the latest example of this pleiotropy and report that human interleukin-6 can bind and stimulate signaling via the interleukin-11 receptor. Possible biological and therapeutic consequences of these findings are discussed.

关键词： SFTS   interleukin 6   interleukin 10   prognosis.  

摘要： Introduction: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with a high mortality rate and is a public health concern. This study aimed to investigate the associations of serum interleukin 6 (IL-6) and interleukin 10 (IL-10) levels with the prognosis of SFTS patients. Methodology: A total of 95 patients with confirmed SFTS were included. Clinical and laboratory data were compared between the survival and non-survival groups. Multivariate logistic regression analysis was used to assess independent risk factors for mortality. The predictive efficacies of laboratory markers were evaluated using receiver operating characteristic (ROC) curves. Survival analysis was performed using Kaplan-Meier curves based on the log-rank test. Results: The levels of IL-6 and IL-10 at admission were significantly greater in the non-survival group than in the survival group (p < 0.05). Multivariate logistic regression analysis indicated that the IL-6 and IL-10 levels, estimated glomerular filtration rate, and activated partial thromboplastin time (APTT) were independent risk factors for a poor prognosis in patients with SFTS. ROC curve analysis revealed that the IL-6 and IL-10 levels and the APTT had a greater predictive value than other measured laboratory markers. Kaplan-Meier survival analysis demonstrated that SFTS patients with IL-6 > 39.5 pg/mL or IL-10 > 45.2 pg/mL had significantly lower survival within a 30-day follow-up period. Conclusions: The levels of IL-6 and IL-10 at admission are the best markers for predicting in-hospital mortality of SFTS patients and have potential prognostic value in patients with SFTS.

关键词： nuclear factor kappa B (NF-kappa B)   tumour necrosis factor alpha (TNF-alpha)   signalling pathways   MG-63 cells   zirconia   titanium  

摘要： Dental implant therapy is a widely used clinical procedure for restoring missing teeth in patients. Zirconia implants were introduced as an alternative to titanium implants due to their excellent biocompatibility and esthetic properties. The nuclear factor kappa B (NF-kappa B) signalling pathway is responsible for multiple aspects of innate and adaptive immune functions and serves as a significant and crucial mediator of inflammatory processes. The dysregulation of NF-kappa B activation induces pathological processes in multiple diseases. The purpose of this study was to investigate the activation of the NF-kappa B pathway upon stimulation with tumour necrosis factor (TNF)-alpha in osteoblast-like cells (MG-63) cultured on zirconia surfaces in comparison to titanium surfaces. Several methods such as immunoblot, immunofluorescence, MTT assay, and flow cytometry were used in this study. We observed that human recombinant TNF-alpha caused a strong activation of the NF-kappa B pathway on both zirconia and titanium discs and in wells without any discs. This activation was marked by the upregulation of MHC class I proteins in MG-63 cells grown on both titanium and zirconia discs;however, there was no effect on MHC class II protein expression. In summary, the present study has shown that TNF-alpha stimulation equally activates the NF-kappa B pathway in MG-63 cells cultured on both titanium and zirconia surfaces.

关键词： HLA   HLA-B*38:121   novel allele   sequencing-based typing  

摘要： HLA-B*38:121 differs from HLA-B*38:01:01:01 by one nucleotide substitution in codon 106 in exon 3.

关键词： HLA-DQB1*03:572   NGS-based typing   novel allele  

摘要： HLA-DQB1*03:572 differs from DQB1*03:01:01:01 by one nucleotide substitution at position 208G>T in exon 2.

关键词： autoimmunity   HLA   homozygosity   genetic diversity   immunogenetics  

摘要： Background: HLA homozygosity of specific alleles at a single locus is associated with increased risk for autoimmunity and/or more severe clinical phenotypes. However, the contribution of the overall limitation of HLA diversity across multiple loci to autoimmunity risk remains to be determined. Methods: We conducted a proof-of-concept case-control study of 413 individuals (279 cases with pediatric-onset autoimmune rheumatic diseases, 134 matched controls) examining the "Limitation of HLA Diversity" (LoHLAD) across multiple loci as an allele-independent risk factor for autoimmunity. We examined the association of LoHLAD with pediatric-onset autoimmune rheumatic diseases at five HLA loci (A, B, DQB1, DRB1, DRB3/4/5). LoHLAD was defined as (1) homozygosity at any of the examined loci, and/or (2) the presence of a single allele or the complete lack of an allele at the HLA-DRB3/4/5 locus. Results: The frequency of LoHLAD at any locus was significantly higher in cases compared to controls (65.95% vs. 30.60%, OR 4.39 [2.82-6.84], p < 0.0001). Higher frequencies of LoHLAD in cases compared to controls were observed at both class I (19.35% vs. 10.45%, OR 2.06 [1.10-3.86], p = 0.031) and class II (54.48% vs. 20.15%, OR 4.74 [2.92-7.69], p < 0.0001) loci. Specifically, significant differences between cases and controls were observed at the B (OR 8.63 [1.14-65.55], p = 0.016), DQB1 (OR 3.34 [1.27-8.78], p = 0.016), and DRB3/4/5 (OR 4.64 [2.77-7.75], p < 0.0001) loci. Multiple logistic regression models confirmed the ability of LoHLAD to positively predict autoimmunity. Conclusions: LoHLAD is a significant allele-independent risk factor for pediatric-onset autoimmune rheumatic disease.

关键词： NOX2   Rheumatoid arthritis   Pathomechanism   Anti-TNF alpha agents   Pharmacogenomics  

摘要： The aim of this research was to prospectively evaluate the impact of NOX2 gene expression profile (including NCF1, NCF2 and NCF4 genes) in peripheral blood mononuclear cells (PBMCs) on immune signatures, clinical characteristics and responsiveness to anti-TNF treatment in RA patients. Blood specimens were collected from 31 rheumatoid arthritis (RA) patients and 25 healthy controls, and 16 RA patients were followed at two timepoints during anti-TNF treatment. mRNA expression levels of selected genes and immunoregulatory cytokines concentrations were determined. We observed the significant upregulation of NCF4 and CD14 expression in RA group. The mRNA levels of NCF1 and CD14 positively correlated both in groups of RA patients and healthy controls. NOX2 gene expression profile was not associated with anti-TNF responsiveness, nor with RA clinical features. TNF alpha inhibition has not influenced NOX2 expression either. Notably, this study indicate the novel links between expression levels of NCF1 and monocyte differentiation antigen CD14.