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摘要： Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by a high metastatic potential with an overall survival rate of similar to 5%. The transcription factor signal transducer and activator of transcription 3 (STAT3) is overexpressed by >50% of tumors, including SCLC, but its role in SCLC development and metastasis is unclear. Here, we show that, while STAT3 deletion restricts primary tumor growth, it paradoxically enhances metastatic spread by promoting immune evasion. This occurs because STAT3 is crucial for maintaining the immune sensor stimulator of interferon (IFN) genes (STING). Without STAT3, the cyclic adenosine monophosphate-guanosine monophosphate synthase-STING pathway is inactive, resulting in decreased type I IFN secretion and an IFN gene signature. Importantly, restoration of IFN signaling through re-expression of endogenous STING, enforced expression of IFN response factor 7 or administration of recombinant type I IFN re-established antitumor immunity, inhibiting metastatic SCLC in vivo. These data show the potential of augmenting the innate immune response to block metastatic SCLC.

关键词： Tyrosine kinase 2 (TYK2)   TYK2-deficient mice   Aged B cells   Marginal zone B cells   Follicular B cells   Toll-like receptor 7 (TLR7)   Type I IFN   IFN alpha   beta receptor  

摘要： Tyrosine kinase 2 (TYK2) is involved in type I interferon (IFN-I) signaling through IFN receptor 1 (IFNAR1). This signaling pathway is crucial in the early antiviral response and remains incompletely understood on B cells. Therefore, to understand the role of TYK2 in B cells, we studied these cells under homeostatic conditions and following in vitro activation using Tyk2-deficient (Tyk2 -/- ) mice. Splenic B cell subpopulations were altered in Tyk2 -/- compared to wild type (WT) mice. Marginal zone (MZ) cells were decreased and aged B cells (ABC) were increased, whereas follicular (FO) cells remained unchanged. Likewise, there was an imbalance in transitional B cells in juvenile Tyk2 -/- mice. RNA sequencing analysis of adult MZ and FO cells isolated from Tyk2 -/- and WT mice in homeostasis revealed altered expression of IFN-I and Toll-like receptor 7 (TLR7) signaling pathway genes. Flow cytometry assays corroborated a lower expression of TLR7 in MZ B cells from Tyk2 -/- mice. Splenic B cell cultures showed reduced proliferation and differentiation responses after activation with TLR7 ligands in Tyk2 -/- compared to WT mice, with a similar response to lipopolysaccharide (LPS) or anti-CD40 + IL-4. IgM, IgG, IL-10 and IL-6 secretion was also decreased in Tyk2 -/- B cell cultures. This reduced response of the TLR7 pathway in Tyk2 -/- mice was partially restored by IFN alpha addition. In conclusion, there is a crosstalk between TYK2 and TLR7 mediated by an IFN-I feedback loop, which contributes to the establishment of MZ B cells and to B cell proliferation and differentiation.

关键词： Rheumatoid arthritis   Janus Kinase inhibitors   Tocilizumab   bDMARD   Cardiovascular disease   Mortality  

摘要： Background: We aimed to compare the risk of major adverse cardiovascular events (MACE) and all-cause of death (ACD) in patients with rheumatoid arthritis (RA) treated with JAK inhibitors (JAKi) or tocilizumab (TCZ) versus tumor necrosis factor (TNF) inhibitors (TNFi). Methods: We performed a systematic review of six medical databases until May, 2024 for phase 2-4 randomized controlled trials (RCTs) evaluating patients with RA treated with TCZ or JAKi (intervention arm) compared with controls (TNFi or placebo). The study data were independently assessed by 3 investigators. The risk of bias was assessed using the Cochrane Collaboration tool. We performed a network meta-analysis with random effects to evaluate the risk of MACE (primary outcome) and ACD (secondary outcome) compared to TNFi. We also calculated the posterior probability of increasing the primary and secondary outcomes by 15% or more (PP15%) 15% ) following Bayes' theorem. Results: This meta-analysis included 18 RCTs with 21,432 patients and 57,040 patient-years. JAKi were linked to a non-statistically significant increase in the risk of MACE and ACD as compared to TNFi (ORs of 1.232 [95%CI 0.86-1.76];p = 0.56 and ORs = 1.3903[95%CI 0.94-2.07];p = 0.10, respectively). By Bayesian analysis, a high clinical probability of more frequent MACE (PP15% 15% of 61%) and ACD (PP15% 15% of 84%) was found in the JAKi group than in the TNFi group. No statistical difference was found between TCZ and TNFi in relation to MACE (1.029 [95%CI 0.75-1.40];p = 0.86) and ACD (1.072 [95%CI 0.78-1.48];p = 0.67]) in the traditional meta-analysis. In the Bayesian approach, the probability of a difference in clinical relevance was low (PP15% 15% for MACE of 11% and PP 15% for ACD of 25%). Discussion: The main limitation of this study is the small number of events with JAKi other than tofacitinib, reflecting the importance of ORAL SURVEILLANCE. Despite this, these data reinforce the recommendations of regulatory agencies and rheumatol

关键词： Snake venom   Dendritic cells   Mediators  

摘要： The effect of Bothrops atrox venom (BaV) on the maturation of bone marrow-derived dendritic cells (BMDCs) from mice was investigated, with a focus on selected cell markers, TAP1 expression, and the release of proinflammatory cytokines during this process. The objective was to evaluate BaV's impact on dendritic cell (DC) function, as DCs are pivotal in antigen presentation and responsible for initiating the immune response mediated by na & iuml;ve T cells, as well as regulating the immune system. Bone marrow cells were obtained from Swiss mice, and hematopoietic precursors were differentiated into BMDCs using GM-CSF and IL-4. On the 7th day, BaV and LPS were introduced into the culture, and the cells were analyzed 24 h later. BaV's ability to stimulate BMDC maturation was assessed through the analysis of surface marker expression. The findings demonstrated that BMDCs are highly influenced by culture environment factors, such as GM-CSF and IL-4, and are sensitive to additional stimuli like LPS and BaV. Mature DCs exhibited elevated levels of critical markers for T cell activation, such as MHC-II, CD80, and CD86, displaying specific phenotypic characteristics. However, the observed reduction in MHC-II and CD86 expression following BaV exposure suggests a substantial impact on the immunological activation capacity of these cells, potentially interfering with the adaptive immune response. Furthermore, the selective release of cytokines, such as IL-6, but not TNF-alpha or IL-1 beta, indicates differentiated modulation of inflammatory responses by DCs under various stimulation conditions.

关键词： cloning   HLA-B*40:298:02   long-range PCR   novel allele   Sanger sequencing  

摘要： HLA-B*40:298:02 differs from HLA-B*40:01:01 by eight nucleotide positions residing in exon 1 to intron 6.

关键词： cinnamaldehyde   articular inflammation   synovial inflammation   osteoarthritis  

摘要： Inflammatory disorders encompass a range of conditions, including osteoarthritis (OA), characterized by the body's heightened immune response to diverse stimuli. OA is a prevalent degenerative joint disease characterized by the progressive deterioration of joint cartilage and subchondral bone, leading to pain, limited mobility, and physical disability. Synovitis, the inflammation of the synovial membrane, is increasingly recognized as a critical factor in OA pathogenesis and progression. This study evaluates the therapeutic potential of cinnamaldehyde (CA), a bioactive compound derived from cinnamon, on synovial and articular inflammation in OA. Given CA's established anti-inflammatory, antioxidant, and antibacterial properties, this research explores its specific impact on OA and synovitis. The cytotoxicity of CA was assessed using a CCK-8 assay in human IL-1 beta pretreated chondrocytes and synoviocytes, which serve as in vitro models of OA and synovitis. The study further examined the effects of CA on the expression of proinflammatory cytokines, including IL-6, COX-2, and TNF-alpha, utilizing multiple analytical techniques. Additionally, the production of matrix metalloproteinases (MMP-3 and MMP-13) and the activation of the NF-kappa B signaling pathway, particularly the phosphorylation of p65 (pp65), were investigated. The role of the NF-kappa B inhibitor 5HPP-33 and its downstream effects on gene expression, including COX-2 and IL-6, as well as the MAPK pathway components (p38, ERK, and JNK), were also explored. An MEK inhibitor (U0126) was employed to assess its downstream impact on COX-2 and IL-6 expressions. The results demonstrated that CA significantly inhibited the expression of proinflammatory cytokines and suppressed NF-kappa B activation in IL-1 beta pretreated chondrocytes and synoviocytes. These findings suggest that CA, in a dose-dependent manner, may serve as an effective therapeutic agent for preventing OA and synovitis, offering valuable insights

关键词： IL-8   Aged patient   Sepsis   Mortalities  

摘要： Background: Sepsis significantly impacts morbidity and mortality, particularly among older adults. Despite extensive research, early recognition and prognosis prediction of sepsis remain challenging. IL-8, a chemokine produced by inflammatory cells like monocytes and endothelial cells, has shown potential in predicting mortality in sepsis patients, though its role in elderly sepsis remains unexplored. Objectives: The present study aimed to explore the predictive ability of interleukin-8 (IL-8) for mortality risk in elderly septic patients. Methods: 220 elderly sepsis patients were included in the present study. Serum samples were obtained within 1 h of admission to assess serum IL-8, white blood cell (WBC), procalcitonin (PCT), C-reactive protein (CRP), and lactic acid (LAC) levels. The Sequential Organ Failure Score (SOFA) and Acute Physiological and Chronic Health Assessment II (APACHE II) were recorded. Logistic regression analysis was employed to identify independent predictors of mortality within 28 days for elderly patients diagnosed with sepsis. Further, the capacity of these factors to predict 28-day mortality within this patient cohort was evaluated. Results: SOFA score, APACHE II score, LAC, and IL-8 were all significant independent predictors for 28-day mortality in elderly sepsis patients (P < 0.05). The AUC of the ROC curve for IL-8 was calculated to be 0.701, indicating a moderately predictive performance. In comparison, the AUC for LAC was marginally higher at 0.708. Nevertheless, the results of the statistical analysis revealed no significant difference in the predictive value between IL-8 and LAC. Moreover, the present findings indicate that the combined assessment of IL-8 and SOFA score demonstrated superior predictive value for mortality compared to using IL-8 alone. Conclusions: IL-8 LAC, APACHE II, and SOFA can be considered independent predictors factors for mortality of elderly sepsis patients. Utilizing the combination of IL-8 and SOFA demons

关键词： Low-dose interleukin 2 therapy   Primary Sj & ouml   gren's syndrome   Profile hydrophilic metabolites   T helper cell   Treg  

摘要： Objectives Low-dose interleukin 2 (Ld-IL2) is increasingly being explored as an immune-modulating treatment for autoimmune diseases which mainly affect T cell subsets. This study investigates the metabolic effects of Ld-IL2 therapy in patients with primary Sj & ouml;gren's syndrome (pSS). Method A total of 60 patients were recruited to conduct a double-blind, randomized clinical trial. Of these patients, 50% (30/60) received Ld-IL2 therapy along with standard treatment for 12 weeks, followed by 12 weeks of follow-up. The effectiveness was evaluated by Sj & ouml;gren's Tool for Assessing Response (STAR). An untargeted analysis was performed to profile hydrophilic metabolites. Results Metabolic profiling revealed significant alterations post-treatment, notably in metabolites like acetyl-CoA, ascorbic acid, and glutathione, which are beneficial in managing autoimmune diseases. In addition, the levels of metabolite accumulation were correlated with variations in immune cell subsets (p < 0.05), particularly Tregs. Moreover, patients exhibiting a specific metabolic profile, including lower serum levels of isoleucine, ADP, Thymidine 5'-triphosphate, and other metabolites, had a high response rate (91.7%-98.6%), as indicated by the receiver operating characteristic (ROC) curve. Conclusions These findings suggest that Ld-IL2 therapy influences metabolic pathways in pSS, offering insights into the systemic effects of Ld-IL2 therapy beyond immune modulation.

关键词： GEO database   IL-18   NLRP3   sepsis-associated AKI  

摘要： BackgroundSepsis-associated acute kidney injury (SA-AKI) is a common complication that can lead to renal failure in patients, significantly affecting the prognosis and survival of *** this study, we aimed to evaluate the predictive value of NOD-like receptor protein 3 (NLRP3) and interleukin 18 (IL-18) in peripheral blood mononuclear cells (PBMCs) of SA patients for the occurrence of *** and MethodsWe screened AKI-related data sets using the Gene Expression Omnibus (GEO) database and identified differentially expressed genes (DEGs) associated with AKI. KEGG and GO analysis were used to identify enriched molecular functions and pathways. The study included 62 SA patients admitted to the Department of Intensive Care Medicine of our hospital from February 2021 to June 2022, including 34 non-AKI cases and 28 AKI cases, and 25 healthy volunteers were used as the control group. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the levels of NLRP3 and IL-18 in PBMCs of the *** analysis and experimental validation showed that the expression levels of NLRP3 and IL-18 were significantly upregulated in SA-AKI patients. In addition, the expressions of NLRP3 and IL-18 were positively correlated with APACHE II scores. ROC curve analysis revealed that NLRP3 and IL-18 have the potential to diagnose *** study provides preliminary evidence for NLRP3 and IL-18 as potential diagnostic biomarkers for SA-AKI.

关键词： DQA1*05:05:23   DQB1*03:562   HLA-DQ   novel allele  

摘要： Description of the novel HLA-DQA1*05:05:23 and -DQB1*03:562 alleles.