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关键词： Rheumatoid Arthritis   Schizophrenia   HLA genes   Non-HLA genes  

摘要： Background: : The link between rheumatoid arthritis (RA) and schizophrenia (SZ) has long been a hot topic of deliberation among scientists from various fields. Especially when it comes to genetics, the connection between RA and SZ is still up for discussion, as can be observed in this study. The HLA genes are the most disputed in identifying a connection between the two diseases, but a more thorough investigation of other genes that may be ignored could yield something even more interesting. Thus, finding the genes responsible for this long-sought relationship will necessitate looking for them. Materials and Methods: : Shared and overlapped associated genes involved between SZ and RA were extracted from four databases. The overlapping genes were examined using Database for Annotation, Visualization and Integrated Discovery (DAVID) and InnateDB to search the pertinent genes that concatenate between these two disorders. Results: : A total of 91 overlapped genes were discovered, and that 13 genes, divided into two clusters, showed a similarity in function, suggesting that they may serve as an important meeting point. FCGR2A, , IL18R, , BTNL2, , AGER, , and CTLA4 are five non-HLA genes related to the immune system, which could lead to new discoveries about the connection between these two disorders. Conclusion: : An in-depth investigation of these functionally comparable non-HLA genes that overlap could reveal new interesting information in both diseases. Understanding the molecular and immune-related aspects of RA and SZ may shed light on their etiology and inform future research on targeted treatment strategies.

关键词： HLA   HLA-B*51:411   novel allele   sequencing-based typing  

摘要： HLA-B*51:411 differs from HLA-B*51:01:01:01 by one nucleotide substitution in codon 235 in exon 4.

关键词： biomarkers   IL-8   pulpal diagnosis   pulpitis   TNF-alpha  

摘要： Aim: The success of vital pulp treatment (VPT) procedures is dependent on an accurate diagnosis of the pulpal inflammatory condition. Compared with current subjective pulpal diagnostic tests, inflammatory molecular biomarkers involved in the pathogenesis of pulpitis represent potential objective indicators of the degree of pulpal inflammation. Therefore, the aim of this study was to quantify level of inflammatory biomarkers - Interleukin 8 (IL-8) and TNF-alpha in patients diagnosed with reversible pulpitis (RP), irreversible pulpitis (IR) and normal pulp (NP) and investigate their diagnostic accuracy in differentiating between healthy and inflamed conditions. Methodology: This prospective, cross-sectional study enrolled 72 patients aged 14-53 years with extremely deep carious lesions after establishing a clinical diagnosis of RP (n = 42), symptomatic IR (n = 22) and NP (n = 8). 50 mu L of pulpal blood sample was collected from all the patients using a micropipette after pulpal exposure. The level of IL-8 and TNF-alpha was assessed in pg/mL using enzyme-linked immunosorbent assays. Mann-Whitney U test was applied to establish the association between IL-8/TNF-alpha level and degree of pulp inflammation. Receiver operating curve (ROC) analysis was carried out to calculate area under the curve (AUC) for RP versus IR. Cut-off values were established using Youden's index. ResultsIL-8 and TNF-alpha levels differed significantly between RP and IR groups (p <= .001). The median value of IL-8 in RP and IP groups was 259.8 pg/mL [187.5-310.0] and 1357.8 pg/mL [1036.7-2177.6] respectively. The AUC-ROC curve for RP versus IR was 0.997 with 95.5% sensitivity and 99.76% specificity. The median value of TNF-alpha in RP and IR groups was 75.4 pg/mL [62.7-95.8] and 157.6 pg/mL [94.1-347.3]. The AUC-ROC curve for TNF-alpha was 0.812 with a sensitivity and specificity of 59.1% and 92.1%, respectively. IL-8 and TNF-alpha levels were below detection levels for all NP samples. Conclusion:

关键词： cystathionine gamma-lyase   hydrogen sulfide   TNF-alpha   inflammation   colonic epithelial cells   colonoids  

摘要： Cystathionine gamma-lyase (CSE) and TNF-alpha are now recognized as key regulators of intestinal homeostasis, inflammation, and wound healing. In colonic epithelial cells, both molecules have been shown to influence a variety of biological processes, but the specific interactions between intracellular signaling pathways regulated by CSE and TNF-alpha are poorly understood. In the present study, we investigated these interactions in normal colonocytes and an organoid model of the healthy human colon using CSE-specific pharmacological inhibitors and siRNA-mediated transient gene silencing in analytical and functional assays in vitro. We demonstrated that CSE and TNF-alpha mutually regulated each other's functions in colonic epithelial cells. TNF-alpha treatment stimulated CSE activity within minutes and upregulated CSE expression after 24 h, increasing endogenous CSE-derived H2S production. In turn, CSE activity promoted TNF-alpha-induced NF-& kgreen;B and ERK1/2 activation but did not affect the p38 MAPK signaling pathway. Inhibition of CSE activity completely abolished the TNF-alpha-induced increase in transepithelial permeability and wound healing. Our data suggest that CSE activity may be essential for effective TNF-alpha-mediated intestinal injury response. Furthermore, CSE regulation of TNF-alpha-controlled intracellular signaling pathways could provide new therapeutic targets in diseases of the colon associated with impaired epithelial wound healing.

关键词： IL-6 receptor   tocilizumab   atopic dermatitis   eczema   mendelian randomization   transethnic  

摘要： Background: Dermatitis has been reported after initiation of association studies of atopic dermatitis (AD) have implicated IL6R pathway signaling. However, causality remains unclear. As the indications for IL-6Ri expand, so do the clinical importance of determining whether there is mechanistic evidence linking it Objective: Our aim was to examine the association between IL6Ri and risk of AD. Methods: To genetically mimic IL-6Ri, we selected singlenucleotide polymorphisms within or near the IL6R gene associated with C-reactive protein at genome-wide significance among 343,524 individuals. Genetic data were obtained from 10,788 individuals with AD and 30,047 controls of European ancestry. We used inverse variance-weighted and pleiotropyrobust methods and examined genetic confounding using colocalization. Analyses were replicated by using 13,473 Finnish and 2,385 East Asian individuals with AD. The results from 3 independent analyses were pooled by meta-analysis. Results: Genetically proxied IL-6Ri was associated with increased risk of AD (odds ratio [OR] = 1.78 per 4.4-mg/L reduction in C-reactive protein level [95% CI = 1.28-2.48] [P = 6.5 x 10-4]). The results were replicated using Finnish outcome data (OR = 2.07 [95% CI = 1.58-2.72] [P = 1.57 x 10-7]) and Eastern Asian data (OR = 1.68 [95% CI = 1.12-2.54] [P = .013]). Meta-analysis of 3 independent populations (OR = 1.89 [95% CI = 1.57-2.28] [P = 2.68 x 10-11]) showed no evidence of heterogeneity (P = .65). We found no statistical evidence for pleiotropy or genetic confounding. Conclusion: This genetic investigation provides consistent evidence (across independent multiancestry populations) that IL-6R signaling is causally implicated in AD susceptibility. Clinicians should remain vigilant for adverse effects resembling AD when using IL-6R inhibitors for immune-mediated inflammatory diseases. (J Allergy Clin Immunol 2024;154:6669.)

关键词： Anti-HLA antibodies   HLA-mismatched   Hematopoietic stem cell transplantation   Survival  

摘要： Background: While the detrimental role of donor-specific anti-HLA antibodies (DSAs) is well-described in the setting of hematopoietic stem cell transplantation (HSCT), few studies focus on non donor-specific ones and with controversial results. Methods: We here report our monocenter experience on 64 adult patients receiving allogeneic HSCT from a HLAmismatched donor between 2014 and 2022 who were tested for the presence of anti-HLA antibodies before transplant, focusing on fifteen patients with non donor-specific anti-HLA antibodies. Results: The survival of patients with non donor-specific anti-HLA antibodies was inferior with respect to patients without anti-HLA antibodies and similar to patients with DSAs. Median survival of patients with non donorspecific anti-HLA antibodies was 21 months (95 % CI: 9-42) vs. 61 months (95 % CI: 17-77) among the antiHLA antibody-negative patients, with a significantly higher mortality incidence rate ratio (3.3 times-fold greater, p = 0.01). No pattern of death causes was found Conclusions: In this monocenter series of HLA-mismatched HSCTs, impaired survival was observed in adult patients having non donor-specific anti-HLA antibodies before transplant, similar to those with DSAs. Our findings support those antibodies as a negative predictive factor even if they are not directed against the donor, thus warranting further investigation on larger cohorts.

摘要： Chimeric antigen receptor (CAR) T cells can effectively treat leukemias, but sustained antitumor responses can be hindered by a lack of CAR T-cell persistence. Cytotoxic effector T cells are short-lived, and establishment of CAR-T cells with memory to ensure immune surveillance is important. Memory T cells depend on cytokine support, with IL7 activation of the IL7 receptor (IL7R) being critical. However, IL7R surface expression is negatively regulated by exposure to IL7. We aimed to support CAR T-cell persistence by equipping CAR-T cells with a sustained IL7R alpha signal. We engineered T cells to constitutively secrete IL7 or to express an anti-acute myeloid leukemia-targeted IL7R alpha-chimeric cytokine receptor (CCR) and characterized the phenotype of these cell types. Canonical downstream signaling was activated in CCR-T cells with IL7R activation. When coexpressed with a cytotoxic CAR, functionality of both the CCR and CAR was maintained. We designed hybrid CAR-CCR and noted membrane proximity of the intracellular domains as vital for signaling. These data show cell-intrinsic cytokine support with canonical signaling, and functionality can be provided via expression of an IL7R alpha domain whether independently expressed or incorporated into a cytotoxic CAR for use in anticancer ***: To improve the phenotype of tumor-directed T-cell therapy, we show that provision of cell-intrinsic IL7R-mediated signaling is preferable to activation of cells with exogenous IL7. We engineer this signaling via independent receptor engineering and incorporation into a CAR and validate maintained antigen-specific cytotoxic activity.

关键词： Antioxidant   Blood Glucose   Hibiscus Sabdariffa   Malondialdehyde   Tumor Necrosis Factor-alpha  

摘要： Introduction: Traditionally and empirically, Hibiscus sabdariffa L. have been used in treating diabetes mellitus due to their antioxidant activity. This study aims to investigate the effect of administering the ethyl acetate fraction of hibiscus calyxes on malondialdehyde (MDA) levels, Tumor Necrosis Factor-alpha (TNF-alpha) levels, bleeding time, and platelet count in male white rats induced with streptozotocin-induced diabetes. Method: Thirty-six Wistar Kyoto rats were induced with intra-peritoneal streptozotocin at 55 mg/kg BW and stabilized for five days to obtain diabetic conditions. Diabetic animals were divided into four groups;the diabetic group was given vehicle, the glibenclamide group was given 0.45 mg/kg BW of Glibenclamide, and two groups were administered the ethyl acetate fraction of hibiscus calyxes (EAFHC) at doses of 100 mg/kg BW and 200 mg/kg BW for five days. Subsequently, the MDA, TNF-alpha, bleeding time and platelet count levels were examined on days 1, 3, and 5, respectively. All data were analyzed using two-way ANOVA followed by the Duncan Multiple Rank Test (DMRT). Results: EAFHC significantly reduced MDA and TNF-alpha levels (p<0.05). Additionally, this fraction appeared to shorten bleeding time and decrease platelet count in diabetic rats. Administration of the EAFHC for five days effectively lowered MDA and TNF-alpha levels significantly, decreased platelet counts and prolonged coagulation (p<0.05) in diabetic rats. Conclusion: This study demonstrates that EAFHC effectively reduces MDA and TNF-alpha levels and reduces the risk of hypercoagulability in diabetic model

关键词： autism spectrum disorder (ASD)   interleukin 6 (IL-6)   interleukin 8 (CXCL8)   tumor necrosis factor alpha (TNF-alpha)   immunological biomarkers   neuroinflammation  

摘要： Background: Autism spectrum disorder (ASD) has seen a rise in prevalence, and the immune system's role in brain development is increasingly recognized. This study investigates the relationship between immune dysregulation and ASD by examining serum concentrations of interleukin 6 (IL-6), interleukin 8 (CXCL8), and tumor necrosis factor alpha (TNF-alpha) in children. Methods: Serum samples from 45 children with ASD and 30 controls, aged 2 to 12 years, were analyzed using electrochemiluminescence, chemiluminescent microparticle immunoassay, and chemiluminescent immunoassay. ASD symptoms were assessed using the Autism Spectrum Rating Scale (ASRS) and Social Communication Questionnaire (SCQ). Results: No significant correlation was observed between CXCL8 levels and ASD. IL-6 levels showed a trend toward elevation in boys with ASD. TNF-alpha levels were significantly higher in children with ASD under 5 years compared to older children and controls, though no correlation with symptom severity was found. Conclusions: TNF-alpha may be a potential biomarker for early ASD detection, especially in younger children. Further research on larger cohorts is needed to understand the role of immune dysregulation in ASD.