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关键词： angiolymphoid hyperplasia   dupilumab   eosinophils  

关键词： dorsal root ganglion   interleukin-1β   interleukin-6   macrophage   neurogenic inflammation   psoriasis  

摘要：

关键词： italic>DPB1*1491:01HLA-DPB1   NGS   transplantation  

摘要： HLA-DPB1*1491:01 differs from HLA-DPB1*05:01:01:01 by a non-synonymous nucleotide substitution in Exon 2.

关键词： HLA-B*15:02   carbamazepine   CPOE reminders   pharmacogenomics  

摘要： Background: Carbamazepine (CBZ) is associated with severe cutaneous adverse reactions in individuals carrying the HLA-B*15:02 allele, which is prevalent in Asian populations. Genetic screening before the initiation of CBZ is recommended, yet screening is not always undertaken. Objectives: To determine the effect of implementing computerized physician order entry (CPOE) reminders on the screening rates of HLA-B*15:02 before CBZ prescription. Methods: We conducted a retrospective analysis of 1611 patients who were prescribed CBZ between 2012 and 2023 in a regional hospital in Taiwan. The intervention involved integrating automated HLA-B*15:02 screening reminders into the CPOE system in outpatient settings. Patients were divided into an outpatient (intervention) group and an inpatient (control) group, and their data were analyzed before and after the intervention. Screening rates were compared using Fisher's exact test, and subgroup analyses were conducted on the basis of age group and physician specialty. Results: After the intervention, the outpatient group exhibited an increase in screening rate from 23.7% to 55.6% (p < 0.001). However, no significant change was observed in the inpatient group. Subgroup analysis revealed major improvements among neurologists and patients aged 41-80 years in outpatient settings. Conclusions: Implementing CPOE reminders substantially improves rates of screening for HLA-B*15:02 in outpatient settings, indicating the effectiveness of informatic interventions in enhancing adherence to pharmacogenomic guidelines. Extending such interventions to inpatient settings may further mitigate the risk of CBZ-induced severe cutaneous adverse reactions.

摘要： Psoriasis is a chronic inflammatory skin disease, with the IL-17 pathway being a key contributor. Ym1, a positionally cloned inflammation regulatory gene linked to various disorders, has an unclear effect on skin inflammation. In this study, the role of Ym1 was investigated in both mannan and imiquimod-induced psoriasis-like dermatitis models, using Ym1-deficient congenic mice. Natural polymorphism of Ym1 influenced the development of skin inflammation, dependent on macrophages, since adoptive transferring of Ym1-deficient macrophages alleviated disease, whereas recombinant Ym1 worsened it. Particularly, Ym1 congenic mice exhibited decreased IL-17 production in innate immune cells, and depletion of gamma delta T cells mitigated disease and lowered skin IL-17 levels. Additionally, RNA-seq analysis revealed Ym1-regulated keratinization in lesional skin. Recombination Ym1 directly influenced the inflammatory response and proliferation of mouse primary keratinocytes. Collectively, we conclude that Ym1 regulates gamma delta T cell-derived IL-17 production and keratinocyte functionality, and thereby contributes to skin inflammation in mice.

关键词： AMPK   chondrocyte   osteoarthritis   PACAP   senescence   SIRT3  

摘要： Osteoarthritis (OA) is a degenerative joint disease closely associated with aging, in which chondrocyte senescence plays a critical role in cartilage degradation. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide known for its anti-inflammatory and cytoprotective effects;however, its role in chondrocyte senescence remains poorly understood. This study investigated the protective effects of PACAP38 on tumour necrosis factor-alpha (TNF-alpha)- induced chondrocyte senescence and the underlying mechanisms. Intracellular reactive oxygen species (ROS) levels were measured using 2 ',7 '-dichlorodihydrofluorescein diacetate (DCFH-DA) staining, oxidative DNA damage was assessed by 8-hydroxy-2 '-deoxyguanosine (8-OHdG) enzyme-linked immunosorbent assay (ELISA), and senescence markers were evaluated by senescence-associated beta-galactosidase (SA-beta-Gal) staining, telomerase activity assay, and telomere length analysis. Gene and protein expression were examined via real-time polymerase chain reaction (PCR) and Western blotting. We found that PACAP type I receptor (PAC1R), the receptor for PACAP, was expressed in both murine and human chondrocytes and was downregulated by TNF-alpha stimulation. PACAP38 treatment significantly reduced ROS and 8-OHdG levels, restored telomerase activity and telomere length, and decreased SA-beta-Gal activity. Mechanistically, PACAP38 upregulated sirtuin 3 (SIRT3), a mitochondrial deacetylase that regulates oxidative stress and metabolism, while suppressing acetylated p53 (ac-p53) and plasminogen activator inhibitor-1 (PAI-1) expression. Furthermore, PACAP38 reversed TNF-alpha-induced dephosphorylation of AMP-activated protein kinase alpha (AMPK-alpha) and its downstream target acetyl-CoA carboxylase (ACC). Importantly, inhibition of AMPK by compound C abolished these protective effects, confirming the essential role of the AMPK-SIRT3 signalling pathway. In conclusion, our findings demonstrate that PACAP38 mitigates TN

关键词： Hepatocellular carcinoma   CTLA-4   SPP-1   Combination therapy   Immunotherapy  

摘要： Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide, and secreted phosphoprotein 1 (SPP-1) is linked to tumor progression and immune evasion. This study investigates whether anti-SPP-1 therapy can enhance the anti-tumor effects of anti-CTLA-4 immunotherapy in HCC and elucidates the underlying molecular mechanisms. Data from The Cancer Genome Atlas (TCGA) comprising 374 HCC patients were analyzed to examine SPP-1 expression and its correlation with clinical prognosis using the Kaplan-Meier survival curve and multivariate Cox regression models. Multiple bioinformatics platforms including TIMER and TISIDB were employed to assess SPP-1's role in the tumor immune microenvironment. In vivo validation was performed in H22 hepatocellular carcinoma syngeneic mouse models treated with anti-SPP-1 and anti-CTLA-4 antibodies, where tumor growth and immune cell infiltration were evaluated using flow cytometry, immunohistochemistry, and molecular interaction studies. In the 374 HCC patient cohort, high SPP-1 expression was significantly associated with advanced TNM staging, pathological grading, and vascular invasion. Lower SPP-1 expression significantly correlated with improved overall survival, disease-specific survival, and progression-free intervals, confirming SPP-1 as an independent prognostic factor in multivariate analysis. Immune infiltration analysis revealed that SPP-1 was positively correlated with immune cells and checkpoint molecules including CTLA-4. In a syngeneic tumor model, combination therapy with anti-SPP-1 and anti-CTLA-4 significantly inhibited tumor growth, increased CD8+ T cell infiltration, and promoted M1 macrophage polarization. Mechanistically, combination therapy significantly reduced IL-6 expression and suppressed STAT3 signaling, while interferon-gamma levels were elevated in the combination therapy group. Co-immunoprecipitation experiments confirmed SPP-1/IL-6 protein interaction. SPP-1 serves as both a potential prognostic mar

关键词： non-HLA antibodies   antibody-mediated rejection   pediatric kidney transplantation   graft loss   pediatric kidney failure  

摘要： Antibody-mediated rejection (ABMR) is the leading cause of long-term graft loss in pediatric kidney transplantation (KTx). While donor-specific HLA antibodies are established contributors, emerging evidence suggests a role for non-HLA antibodies in ABMR pathogenesis. In this descriptive study, we analyzed 60 non-HLA antibodies in 77 pediatric KTx recipients using serum samples collected pre-transplant, post-transplant, and at ABMR diagnosis. During a median follow-up of 4.83 years, 29.8% developed ABMR, with a median onset of 3.67 years. Non-HLA antibody presence prior to KTx was not influenced by pre-transplant dialysis;over half of the patients already had >15 positive non-HLA antibodies. The cumulative antibody profile remained stable 1-2 years post-KTx, with no association between late ABMR and antibody strength or breadth. However, ACTIN (higher risk) and CGB5 (lower risk) at 1-2 years post-KTx, as well as SNRPB2 pre-transplant, were significantly associated with ABMR (p < 0.05). IL-21 levels increased in controls over time (p < 0.05), although driven by five patients with notably high levels. Our findings support a potential involvement of non-HLA antibodies in pediatric ABMR. Nevertheless, larger studies are needed to validate the predictive value of individual non-HLA antibodies for clinical application.

关键词： germinal center B cell   plasma cell differentiation   PTEN   signaling  

摘要： The germinal center (GC) reaction is essential for generating high-quality humoral memory. Positively selected GC B cells must decide whether to remain in the GC for further affinity maturation or differentiate into memory or plasma cells (PCs). Previously, we identified IL-21R and CD40 signaling as critical promoters of GC B cell effector differentiation. However, the mechanisms regulating the strength of these signals remain unclear. PTEN, a negative regulator of PI3K signaling, is markedly upregulated in GC B cells. To explore the role of PTEN in GC B cell fate decisions, we used a tamoxifen-driven Cre system to delete PTEN in B cells after GC reaction was fully established. We found that PTEN deletion in ongoing GC B cells led to significantly increased differentiation into PCs, while having limited effects on class switching or memory precursor differentiation. These results were further confirmed using a GC B cell transfer system, where wild-type and PTEN-deficient GC B cells were transferred into the same recipient mice. Mechanistically, PTEN deletion or inhibition in established GC B cells resulted in more sustained IL-21R signaling and enhanced CD40 signaling-both known to promote PC differentiation. Interestingly, Peyer's patch GC B cells exhibited higher PTEN levels than de novo GC B cells generated through immunization. Notably, PTEN deficiency selectively expanded GC B cells in Peyer's patches but had no impact on those induced by immunization. These findings reveal previously unrecognized roles for PTEN in regulating GC B cell signaling and limiting their differentiation into PCs.