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关键词： Interleukin 21 signaling   JAK/STAT3   AKT   IgM plus B cells   Cell proliferation   Antibody secretion  

摘要： IL-21 is a type I cytokine that is produced by activated CD4+ T cells and has a significant impact on the growth, survival, and functional activation of B lymphocytes. While IL-21 has been identified in several teleost fish species, its function and associated mechanisms focus on teleost fish B cells remain largely unknown. In this study, we aimed to investigate the effects of IL-21 (OnIL-21) on IgM+ B cells from Nile tilapia (Oreochromis niloticus), as well as the intracellular signaling transduction pathway involved. Through intraperitoneal injection of recombinant OnIL-21 (rOnIL-21), we observed that IL-21 exerted significant effects on Nile tilapia IgM+ B cells, including the promotion of IgM+ B cell proliferation, induction of IgM secretion, and up-regulation of inflammatory cytokines. These findings suggest that OnIL-21 enhances the ability of IgM+ B cells in humoral immunity. Furthermore, when IgM + B cells were stimulated with rOnIL-21 in vitro, we observed a significant upregulation in antibody secretion ability (sIgM), as well as increased expression of IFN-gamma and IL-10. To further understand the regulatory mechanism of OnIL-21, we demonstrated that OnIL-21 binds to its heterodimer receptor complex (OnIL-21R/On gamma c) to exert its function. This binding triggers the conserved JAK/STAT3 and AKT pathways, which in turn regulate the expression of genes involved in B cell proliferation, antibody secretion, and cytokine expression. Collectively, our findings establish that IL-21 plays a crucial role in the regulation of humoral immunity in lower vertebrates, and this regulation is mediated through conserved signaling pathways across vertebrates.

关键词： Gout   HLA-B5801   allopurinol   characteristics   flare  

摘要： Background/Aim: Allopurinol is a standard agent used for lowering uric acid levels. Human leukocyte antigen (HLA)- B5801 positivity increases the incidence of severe cutaneous adverse reactions (SCARs) in allopurinol users. HLA alleles HLA-B27 and HLA-B51 are frequently found in patients with ankylosing spondylitis and Beh & ccedil;et's disease, showing an association with distinct clinical features. In this study, we investigated the association between the HLA- B5801 genotype and patient characteristics and outcomes in gout. Patients and Methods: We retrospectively reviewed the medical records of 263 patients with gout who were not receiving uric acid-lowering therapy and were tested for HLA-B5801 positivity between March 2020 and February 2024. Patients were classified according to their HLA-B5801 status, and patient demographics and laboratory variables were compared. The incidence of gout flares or severe flares requiring hospital care within one year was investigated. Results: A total of 37 participants were HLA-B5801 positive (37/263, 14.1%). However, no significant differences were observed in demographic or laboratory variables between the HLA-B5801 positive and negative groups. Subgroup analyses of patients with new-onset gout, males, and those with an estimated glomerular filtration rate >= 60 ml/min/1.73 m2 also demonstrated no significant differences related to HLA-B5801 genotype positivity. The incidence of disease flares or severe flares between patients in the HLA-B5801 positive and negative groups was comparable during the one-year follow-up. Conclusion: Although HLA-B5801 was a significant predictor of allopurinol-associated SCARs, the impact of HLA- B5801 positivity on the clinical characteristics or flares was not evident in this population of patients with gout.

关键词： HLA novel allele   HLA-DPB1*1781:01   nanopore sequencing  

摘要： HLA-DPB1*1781:01 differs from HLA-DPB1*03:01:01:01 by one nonsynonymous nucleotide substitution in codon 5 in exon 1.

摘要： Macrophages stimulated by lipopolysaccharide (LPS) generate mitochondria-derived reactive oxygen species (mtROS) that act as antimicrobial agents and redox signals;however, the mechanism of LPS-induced mitochondrial superoxide generation is unknown. Here we show that LPS-stimulated bone-marrow-derived macrophages produce superoxide by reverse electron transport (RET) at complex I of the electron transport chain. Using chemical biology and genetic approaches, we demonstrate that superoxide production is driven by LPS-induced metabolic reprogramming, which increases the proton motive force (triangle p), primarily as elevated mitochondrial membrane potential (Delta psi m) and maintains a reduced CoQ pool. The key metabolic changes are repurposing of ATP production from oxidative phosphorylation to glycolysis, which reduces reliance on F1FO-ATP synthase activity resulting in a higher triangle p, while oxidation of succinate sustains a reduced CoQ pool. Furthermore, the production of mtROS by RET regulates IL-1 beta release during NLRP3 inflammasome activation. Thus, we demonstrate that ROS generated by RET is an important mitochondria-derived signal that regulates macrophage cytokine production.

关键词： HLA-B   Indian   next generation sequencing   novel allele  

摘要： HLA-B*27:05:02:44 differs from HLA-B*27:05:02:01 by a single nucleotide in intron 1.

关键词： APC   antigen-presenting cell   BCLC   Barcelona Clinic Liver Cancer   EBRT   external-beam radiation therapy   HCC   hepatocellular carcinoma   ICI   immune checkpoint inhibitor   IFN   interferon   OS   overall survival   PD   programmed death protein   PD-L   programmed death ligand   RE   radioembolization   RT   radiation therapy   STING   immunogenic stimulator of interferon genes   TAA   tumor-associated antigen   TME   tumor immune microenvironment   90Y   yttrium-90  

摘要： Hepatocellular carcinoma is a leading and increasing contributor to cancer-related death worldwide. Recent advancements in both liver-directed therapies in the form of yttrium-90 (90Y) radioembolization (RE) and systemic therapy in the form of immune checkpoint inhibitors (ICI) have expanded treatment options for patients with an otherwise poor prognosis. Despite these gains, ICIs and 90Y-RE each have key limitations with low objective response rates and persistent hazard of out-offield recurrence, respectively, and overall survival remains low. However, each therapy's strength may mitigate the other's weakness, making them potentially ideal partners for combination treatment strategies. This review discusses the scientific and clinical rationale for combining 90Y-RE with ICIs, highlights early clinical trial data on its safety and effectiveness, and proposes key issues to be addressed in this emerging field. With optimal strategies, combination therapies can potentially result in increasing likelihood of durable and curative outcomes in later stage patients.

关键词： Head and neck squamous cell carcinoma   AIM2   STAT1   IL17   MAPK pathway  

摘要： Chronic inflammation has been recognized as one of the hallmarks of head and neck squamous cell carcinoma (HNSCC), Absent In Melanoma 2(AIM2) has emerged as important regulators of chronic inflammatory, and participated in initiation, progression of kinds of human cancers. Nonetheless, the biological functions and underlying mechanisms of AIM2 in HNSCC remain inadequately understood. Based on the bioinformatics analysis of public databases, we identified elevated AIM2 expression in HNSCC, which positively correlates with disease stage and HPV infection, thereby possessing both diagnostic and prognostic significance. Immunohistochemistry on clinical samples revealed that AIM2 expression was frequently upregulated in cancerous tissues compared to paracancerous tissues, exhibiting a significant association with Ki-67 expression. Modulating AIM2 expression in HNSCC cell lines through transfection with inhibitors or mimics demonstrated that ectopic AIM2 expression enhances cell growth, migration, tumorigenesis, and metastasis both in vitro and in vivo. A dual luciferase reporter assay indicated that the transcription factor STAT1 can bind directly to the AIM2 promoter region and activate its transcription. The STAT1 inhibitor, fludarabine, reduces AIM2 expression and subsequently diminishes cell proliferation. Mechanistically, AIM2 exerts its tumor-promoting effects through the IL17-MAPK signaling pathway. Collectively, our data demonstrate that AIM2, transcriptionally activated by STAT1, exhibits oncogenic functions by promoting the IL-17-MAPK signaling pathway, suggesting that AIM2 may be a new intervention targets for the diagnostic and treatment of HNSCC.

摘要： Background: Chronic inflammation is a well-recognized contributor to hypertension pathogenesis. However, the role of targeting inflammation in hypertension treatment, particularly through modulation of inflammatory markers like interleukin-6 (IL-6), remains less understood. We investigated the effects of antihypertensive medications with and without IL-6-lowering properties on long-term blood pressure (BP) control in a multiethnic cohort in the Netherlands. Methods: Participants from HELIUS cohort receiving hypertension treatment were followed over six years. BP control at follow-up was determined using WHO criteria. Due to unavailability of IL-6 data, a literature review was conducted to classify antihypertensives based on their IL-6-lowering properties - a proxy approach. Logistic regression models were used to assess associations between the IL-6-lowering potential of antihypertensives and BP control, both within and between antihypertensive classes. Effect modification by ethnicity was explored. Results: A total of 1510 participants were included (mean age 57 years, 62 % women). Within the calcium channel blocker (CCB) class, medications with IL-6-lowering properties (amlodipine and barnidipine) were associated with superior BP control (aOR 1.41, 95 % confidence interval 1.05-1.90) compared to other CCBs (lercanidipine, nifedipine, verapamil, clevidipine, diltiazem). No significant associations were observed within angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs), between different antihypertensive drug classes, nor across ethnic groups. Conclusion: Amlodipine and barnidipine were associated with better BP control compared to other CCBs. Our findings provide an important starting point for understanding the role of IL-6 in hypertension management. Further studies are warranted to confirm these observations by directly measuring IL-6 levels and investigating underlying mechanisms.

关键词： HLA-A*31:01:58   novel allele   sequence-based typing  

摘要： The HLA-A*31:01:58 allele differs from HLA-A*31:01:02:01 by one nucleotide substitution in codon 130 in exon 3.

关键词： HLA-B*51:385   novel allele   sequencing-based typing  

摘要： The HLA-B*51:385 allele differs from HLA-B*51:285 by a single non-synonymous nucleotide change in exon 3.