课程文献中心 更多>>

关键词： Rheumatoid arthritis   Comorbidities   Disease-modifying antirheumatic drugs   Biomarkers  

摘要： The role of Interleukin-40 (IL-40) in rheumatoid arthritis (RA) is not well understood, and this study was designed to explore serum IL-40 levels in RA patients to assess its potential as a disease biomarker. In this research, serum IL-40 levels were determined using enzyme-linked immunosorbent assay in 116 patients with RA, 40 with osteoarthritis (OA), 29 with systemic lupus erythematosus (SLE), and 66 healthy controls (HCs). Paired serum samples were collected from 86 of the 116 patients treated during follow-up visits at week 12. Group comparison analysis showed that serum IL-40 levels were significantly higher in patients with RA than in HCs, and the areas under the curve for IL-40 were 0.688, 0.865, and 0.870 for distinguishing patients with RA from HCs and those with OA and SLE, respectively. Furthermore, in RA, serum IL-40 levels were lower in patients with comorbidities of cardiovascular diseases or OA. Correlation analyses revealed that serum IL-40 levels were positively associated with RA-related autoantibodies and coagulation-related indicators, whereas no correlation was observed with disease activity-associated factors. When comparing paired samples, treatment with TNF inhibitors (TNFi) significantly reduced serum IL-40 levels, emphasizing its potential as a treatment guide.

摘要： ObjectiveAutoantibodies serve as essential clinical biomarkers and may indicate etiological mechanisms in rheumatic diseases. In light of the increasing knowledge concerning the diversity and biologic implications of anti-citrullinated peptide/protein antibodies (ACPAs), we have re-evaluated the association between the ACPA response and the HLA-DRB1 allelic groups, known to represent a major genetic risk factor for rheumatoid arthritis (RA).MethodsWe explored a collection of 4,392 well-characterized incident patients with RA of White European descent from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) new-onset RA study, as well as 1,199 cases of patients with RA of Southeast Asian origin from the Malaysian EIRA study. We focused on a quantitative analysis of the levels of anti-cyclic citrullinated peptide IgG antibodies, including those falling below the diagnostic *** data show that non-shared epitope alleles HLA-DRB1*09 and *15 exhibit significant associations with ACPA levels. Notably, these novel associations were independent of ethnicity. To validate our findings, we conducted an additional replication study in an independent pool of 4,109 patients with RA of White European *** results indicate a new, previously overlooked, role for the HLA locus in the regulation of the levels of ACPA RA-specific autoantibodies that goes beyond the shared epitope-defined gene variants.

关键词： 肝细胞癌   补体系统   免疫调节   治疗  

摘要： 目的 了解补体系统在肝细胞癌（hepatocellularcarcinoma,HCC）免疫机制中的作用及其潜在的治疗价值。方法 查阅国内外关于HCC与补体系统相关研究的文献并进行综述。结果 基于HCC作为一种免疫原性癌症，补体系统作为先天免疫系统的一部分，它在免疫治疗中具有潜在的应用价值。已总结了8种补体成分（补体固有成分C1q、C3和甘露糖结合凝集素，补体调节蛋白中的可溶性蛋白补体因子H、C4b和膜型调节蛋白CD46和CD59，以及补体受体C5aR1）与HCC密切相关。补体系统激活可通过多种机制参与HCC的发生及发展，作为补体抑制剂可调控补体相关激活途径的活性，增强抗肿瘤能力，为HCC的免疫治疗提供了潜在的新策略。结论 目前研究仅发现了少部分补体成分在HCC中的研究，虽然已有研究成果发现了多种补体成分在调控HCC免疫机制中发挥作用，但是仍无确切或公认的理论基础，未来仍需要进一步探索补体成分在HCC免疫中起保护性或致病性作用的机制，客观评价补体相关抑制剂疗法以及与其他抗肿瘤免疫治疗联合应用存在的风险和益处。

摘要： PURPOSE:Advanced urothelial cancer generally has high mortality despite modern anti-PD-1/L1 antibody-based combinations. Augmenting checkpoint inhibitor-mediated immune responses with lymphocyte growth factors may improve outcomes. We conducted a randomized phase II study (CITN-14) in 47 patients to explore whether human recombinant IL-7 (CYT107) could be safely combined with PD-L1 inhibition to enhance responses. PATIENTS AND METHODS:Patients with urothelial cancer following platinum chemotherapy were randomized to atezolizumab alone or with CYT107 weekly for four doses. The primary objective was clinical efficacy by objective response rate (ORR). Secondary objectives included safety, toxicity, and other clinical outcomes. Correlative endpoints included peripheral immunophenotyping and quantification of cytokines. RESULTS:CYT107 plus atezolizumab was well-tolerated, without dose-limiting toxicities (DLTs), and lower grade 3-4 treatment-related adverse events (TRAEs) compared to atezolizumab. The ORR was 26.3% for the combination versus 23.8% for atezolizumab alone (p = 0.428). The complete response (CR) rate was 10.5% for the combination versus 4.8% for monotherapy. Three patients on the combination had responses >21 months versus one with monotherapy. CD4+ and CD8+ T lymphocyte expansion occurred in patients with response to combination therapy, with the greatest effect in T memory stem cell (Tscm) cells. Responding patients had elevated baseline CCL4 and decreased VEGF-A and TNF. CONCLUSIONS:Combining CYT107 with atezolizumab was safe and resulted in lymphocyte expansion, a doubling of the CR rate, and durable responses exceeding 2 years, however, the ORR was similar to atezolizumab alone. Increased and sustained doses of CYT107 coupled with patient selection strategies should be further investigated.

关键词： remote ischemic conditioning (RIC)   hypoxia   immunomodulation   tumor perfusion   melanoma (B16)  

摘要： Introduction Hypoxia can drive tumor progression, suppress anti-tumor immunity, and reduce the effectiveness of radiotherapy and chemotherapy. This study aimed to assess the impact of remote ischemic conditioning (RIC) on tumor oxygenation (sO2) and the anti-tumor immune *** and methods Fourteen B16-Ova tumor-bearing C57BL/6N mice received six 5-minute RIC cycles, while another fourteen underwent anesthesia only. Pimonidazole was administered 1.5 hours before sacrifice. Blood flow, sO2, and hemoglobin levels were measured in the non-ischemic hind limb and tumor. Tumor hypoxia was assessed using pimonidazole and CA IX immunohistochemistry, and T cell infiltration by CD3 and FoxP3 staining. Serum levels of 23 cytokines were analyzed using a multiplex *** Isoflurane anesthesia caused a slight intraindividual increase in blood flow (p = 0.07) and sO2 (p = 0.06) of the hind limb and a sole increase in tumor sO2 (p = 0.035), whereas RIC improved sO2 of the tumor in relation to the hind limb (p=0.03). The median of the tumor oxygen saturation reached 51.4% in the control group and 62.7% in the RIC group (p = 0.09), exhibiting a slight tendency towards better oxygenation in the RIC group. Pimonidazole (p=0.24) and CA IX hypoxia score (p=0.48) did not reveal statistically significant differences between the two groups. In RIC-treated tumors, the number of CD3 (p=0.006), but not FoxP3- positive cells (p = 0.84), in the tumor core was significantly higher compared to the control group. In the RIC group, the mean fluorescence intensity (MFI) of IL-17 was significantly higher (p=0.035), and TNF-alpha was trend-wise higher (p=0.063) compared to the control *** Both isoflurane anesthesia and RIC have an impact on microcirculation. The application of RIC counteracted some of the effects of isoflurane, primarily in healthy tissue, and led to a significant improvement in relative tumor tissue oxygenation compared to the non-ischemic hind lim

摘要： The non-polymorphic HLA-E molecule offers opportunities for new universal immunotherapeutic approaches to chronic infectious diseases. Chronic Hepatitis B virus (HBV) infection is driven in part by T cell dysfunction due to elevated levels of the HBV envelope (Env) protein hepatitis B surface antigen (HBsAg). Here we report the characterization of three genotypic variants of an HLA-E-binding HBsAg peptide, Env371-379, identified through bioinformatic predictions and verified by biochemical and cellular assays. Using a soluble affinity-enhanced T cell receptor (TCR) (a09b08)-anti-CD3 bispecific molecule to probe HLA-E presentation of the Env371-379 peptides, we demonstrate that only the most stable Env371-379 variant, L6I, elicits functional responses to a09b08-anti-CD3-redirected polyclonal T cells co-cultured with targets expressing endogenous HBsAg. Furthermore, HLA-E-Env371-379 L6I-specific CD8+ T cells are detectable in HBV-na & iuml;ve donors and people with chronic HBV after in vitro priming. In conclusion, we provide evidence for HLA-E-mediated HBV Env peptide presentation, and highlight the effect of viral mutations on the stability and targetability of pHLA-E molecules. Chronic Hepatitis B virus (HBV) is associated with elevated levels of hepatitis B surface antigen (HBsAg). Here the authors characterize the T cell responses to three variants of an HBsAg, Evn371-379, to find only the most stable L6I variant eliciting HBsAg responses, while T cells specific for L6I are detectable in both control and people with chronic HBV.

关键词： IL-41/Metrnl   Acute lung injury   AMPK/SIRT1 pathway   Apoptosis   Inflammation  

摘要： Introduction: Interleukin-41 (IL-41), also known as Metrnl, is a multifunctional adipokine recognized for its neurotrophic and anti-inflammatory properties that play a significant role in diseases such as sepsis and chronic obstructive pulmonary disease. Despite its crucial biological functions, the mechanisms by which IL-41 mitigates lipopolysaccharide (LPS)-induced acute lung injury (ALI) are not well understood. This study aimed to elucidate the protective effects of IL-41 against LPS-induced inflammation and apoptosis in a murine model and in vitro using bronchial epithelial cells (Beas-2b). Methods: We administered recombinant IL-41 to mice subjected to LPS-induced ALI and observed changes in lung histopathology, inflammation, and apoptosis. Concurrently, Beas-2b cells were transfected with IL-41 constructs, and the role of the AMPK/SIRT1 pathway was investigated using specific inhibitors and agonists. Results: Our results demonstrated that LPS-induced ALI is characterized by increased inflammatory cell chemotaxis in lung lavage fluid, enhanced phosphorylation of NF kappa B p65, and elevated Bax protein expression, coupled with a decrease in IL-41 protein levels. Treatment with recombinant IL-41 effectively mitigated these pathological changes by upregulating AMPK phosphorylation and SIRT1 expression and inhibiting I kappa B/NF kappa B p65 phosphorylation. In cellular assays, overexpression of IL-41 reversed LPS-induced oxidative stress, apoptosis, and the secretion of inflammatory cytokines, whereas suppression of IL-41 or inhibition of AMPK reversed these protective effects. Conclusions: In conclusion, IL-41 exerts significant protective effects against ALI by activating the AMPK/SIRT1 signaling pathway and reducing excessive inflammation and apoptosis. These findings suggest that IL-41 holds promise as a therapeutic target for ALI, potentially allowing for personalized treatments based on serum IL-41 levels.

关键词： 乳腺癌   气血两虚证   益气养荣汤   针灸   T淋巴细胞亚群   嗜铬粒蛋白A   可溶性细胞间黏附因子-1   人生长分化因子3  

摘要： 目的 研究益气养荣汤联合针灸对乳腺癌术后气血两虚证患者T淋巴细胞亚群及血清嗜铬粒蛋白A（granin A，CGA）、可溶性细胞间黏附因子-1（soluble intercellular adhesion factor-1slCAM-1）、人生长分化因子3（human growth differentiation factor 3，GDF3）水平的影响。方法 乳腺癌术后气血两虚证患者92例均于2020-05至2023-05于我院接受治疗，分为对照组与试验组，各46例，方法为随机数字表法。对照组予以CEF方案化疗治疗，试验组在CEF方案化疗的基础上予以益气养荣汤联合针灸治疗，21d为1个周期，共治疗4个周期。比较两组治疗前、治疗4个周期后生命质量、血清CGA、slCAM-1、GDF3水平、T淋巴细胞亚群，治疗4个周期后疗效，治疗期间不良反应发生情况。结果 较治疗前，治疗4个周期后两组功能维度、总体生命质量评分升高，且试验组更高（P<0.05）。与治疗前比较，治疗4个周期后症状维度评分/血清CGA、slCAM-1、GDF3水平降低，且试验组更低（P<0.05）。与治疗前比较，治疗4个周期后两组均降低，且试验组更低（P<0.05）。与治疗前比较，治疗4个周期后试验组全血CD4+、CD4+/CD8+水平升高，对照组全血CD4+、CD4+/CD8+水平降低，试验组更高（P<0.05）；试验组全血CD8+水平降低，对照组全血CD8+水平升高，试验组更低（P<0.05）。与对照组治疗4个周期后的总有效率61.36%（27/44）比较，试验组总有效率83.33%（35/42）更高（P<0.05）。治疗期间，两组均未因治疗出现明显不良反应而终止治疗，试验组不良反应发生率更低（P<0.05）。结论 益气养荣汤联合针灸可调节乳腺癌术后气血两虚证患者T淋巴细胞亚群水平，抑制血清CGA、slCAM-1、GDF3表达，控制癌细胞异常增殖，提高生命质量，疗效确切，降低术后化疗并发症发生风险。

关键词： IL-13Rα2   T2 asthma   airway fibroblast   eosinophils   eotaxin   leptin   obesity  

摘要： BACKGROUND:Airway tissue eosinophilia can be an observed feature of obesity associated T2 asthma, but the processes mediating this inflammation are unknown. OBJECTIVE:We investigated a process whereby leptin, an adipokine elevated in obesity, potentiates pulmonary eosinophilia and eotaxin production by airway fibroblasts in T2 asthma. METHODS:We assessed associations between body mass index and airway eosinophilia, leptin and eotaxin production in 78 asthma participants, 36 of which exhibited obesity. Cultured human airway fibroblasts and mouse models of chronic allergic airway disease were used to evaluate leptin's effect on eotaxin production and lung eosinophilia. The role of interleukin-13 receptor alpha 2 (IL-13Rα2) in mediating these processes was examined using specific neutralizing antibodies in vitro. RESULTS:In T2 asthma participants with obesity, we observed that airway tissue eosinophilia did not associate with traditional T2 inflammation metrics such as peripheral and/or bronchoalveolar lavage fluid (BALF) eosinophil counts or with fractional concentration of exhaled nitric oxide (FeNO). Alternatively, we observed elevated BALF leptin and eotaxin-1 levels. In airway fibroblasts from asthma participants, leptin augmented IL-13-induced eotaxin-1 and -3 production and IL13RA2 expression. In mice, elevated leptin promoted airway IL-13Rα2 and eotaxin production by lung fibroblasts and lung tissue eosinophilia following chronic house dust mite allergen exposure. Inhibition of IL-13Rα2 reduced combined leptin and IL-13-stimulated eotaxin secretion by human airway fibroblasts. CONCLUSION:We identified a potential association explaining airway tissue eosinophil retention in obesity-associated T2 asthma through leptin-mediated enhancement of IL-13-induced eosinophil chemokine production by airway fibroblasts, a process requiring IL-13Rα2.