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关键词： IL-17信号通路   炎症相关疾病   细胞因子   肿瘤   靶向治疗   综述  

摘要： 白细胞介素17（IL-17）信号通路在多种炎症相关疾病及肿瘤的发病机制中扮演着重要角色。IL-17家族细胞因子，尤其是IL-17A，已被广泛研究，显示出其促炎作用及在免疫反应中的双重性。近年来的研究表明，IL-17不仅促进自身免疫性疾病如银屑病和强直性脊柱炎的进展，还在肿瘤微环境中通过调节免疫逃逸机制促进肿瘤的发展。尽管靶向IL-17的治疗策略展现出良好的临床潜力，但其在不同患者及疾病状态下的效果差异仍需进一步研究。本综述将探讨IL-17信号通路的生物学功能、在不同疾病中的双重作用、以及当前靶向治疗的挑战与未来研究方向。

关键词： glioblastoma   IL-1 beta   IL-1RA   Tolcapone   MyD88   NF-kappa B   autophagy   apoptosis  

摘要： Interleukin-1 beta(IL-1 beta) is the major driving force in neuroinflammation. Here, we report on (i) the role of (IL-1 beta) in activating a signaling cascade that leads to proliferation and metastasis in glioblastoma cancer pathogenesis as well as (ii) the therapeutic role for IL-1 Receptor Antagonist (IL-1RA) and Tolcapone against untoward aspects of tumor pathogenesis. Here, we report that IL-1 beta treatment at 50 ng/mL for 48 h increased proliferation and metastasis by 30-fold (p <= 0.05), leading to the formation of clones of rapidly dividing cancer cells, leading to the formation of organized glial fibrillary acid protein (GFAP)-immunoreactive, clone-like structures with protruding spikes. Further, IL-1 beta treatment significantly increased the expression of mRNA levels of the IL-1 beta-driven pathway TLR-MyD88-NF-kappa B-TNF alpha and IL-6 (p <= 0.05). IL-1 beta also increased autophagy via elevation of mRNA and protein levels of cathepsin B, LAMP-2, and LC3B. In contrast, IL-1RA and Tolcapone inhibited this proliferation and the expression of these mRNAs and proteins, inhibiting autophagy by downregulating these autophagy proteins and inducing apoptosis by upregulating the expression of pro-apoptotic proteins like caspase-8 and caspase-3. IL-1 beta and its receptor can be targeted for successful anticancer therapy, as shown here with the use of IL-1RA and/or Tolcapone.

摘要： Dysregulated levels of pro-inflammatory cytokines such as interleukin (IL)-23 have been linked to multiple inflammatory diseases, including psoriatic arthritis (PsA) and ankylosing spondylitis. This systematic review explored the effect of IL-12 and/or IL-23 inhibitors on the aetiology of axial PsA (axPsA) and axial spondyloarthritis (axSpA). We conducted a literature review of published articles up to June 2023. The outcomes assessed included Ankylosing Spondylitis Disease Activity Score, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASDAI-50, and modified BASDAI. Given the heterogeneity of study populations, designs, and outcome measures of the included studies, we performed a narrative synthesis. The data from the limited literature did not find any efficacy of IL-12 and/or IL-23 inhibitors for the management of axSpA, except for one observational study. However, reported data showed improvements in BASDAI, modified BASDAI, and Ankylosing Spondylitis Disease Activity Score for patients with axPsA. Limited and heterogeneous data currently leaves the effectiveness of IL-12 and/or IL-23 inhibitors for axSpA inconclusive. Yet, improvements in disease activity scores for patients with axPsA hint at the potential of IL-12 and/or IL-23 inhibitors in managing this condition. More extensive studies with larger samples are needed to definitively confirm the role of IL-12 and/or IL-23 inhibitors in axSpA and PsA.

关键词： Systemic lupus erythematosus   renal lupus   nephritis  

摘要： Objectives Aim of this study was to investigate the expression of interleukin (IL)-40, a cytokine associated with B cells homoeostasis and immune response, in Systemic lupus erythematosus (SLE) and SLE associated *** 32 patients with SLE and 21 controls were enrolled. Serum concentration of IL-40 was assessed by ELISA and cellular sources of IL-40 were determined by flow-cytometry. An in vitro assay with recombinant IL-40 (rIL-40) was performed to detect the effect on cytokine production from peripheral blood mononuclear cells (PBMC). In kidney biopsies obtained from patients with lupus nephritis (LN) immunofluorescence was performed to assess IL-40 expression and detect its cellular sources at tissue *** Serum IL-40 levels show a decreasing trend in SLE with LN, compared with SLE without LN and controls. No differences between SLE and controls were evidenced in urinary IL-40 levels;in the percentage of CD3+IL40+, CD19+IL40+ and CD14+IL40+;and in the production of pro-inflammatory cytokines by PBMC stimulated with rIL-40. IL-40 expression was markedly increased in kidney tissue from LN patients, with a significant increase of IL40+ cells in LN samples compared to controls, as confirmed by the quantification *** To the best of our knowledge this is the first demonstration of IL-40 expression at kidney level in SLE. These preliminary data suggest a possible role of IL-40 in LN. In particular, IL-40 could be a marker of kidney tissue damage, although its specific mechanism of action needs to be further elucidated.

关键词： Saliva   Inflammatory factors   HPV-associated OPSCC   Radiotherapy sensitivity   Predictive value  

摘要： ObjectiveThis investigation focused on analyzing saliva inflammatory factors (IL-6, IL-8, and TNF-alpha) to predict radiotherapy response and determine prognostic value in individuals with HPV-linked oropharyngeal squamous cell carcinoma (OPSCC).MethodsSixty patients diagnosed with HPV-associated OPSCC and treated with 3D conformal intensity-modulated radiotherapy at our hospital from June 2016 to June 2020 were selected, as well as 60 healthy individuals who underwent outpatient physical exams as the control group. The relationship between saliva IL-6, IL-8, and TNF-alpha and clinicopathological features was analyzed. The relationship between HPV status and radiotherapy response in OPSCC patients was analyzed, and the predictive value of saliva inflammatory factors on radiotherapy response was analyzed by ROC curves, and the factors influencing the prognosis of OPSCC were analyzed by Cox *** IL-6, IL-8, and TNF-alpha in OPSCC patients did not show any statistically significant differences when analyzed across different genders, ages, tumor sites, histological grades, tumor sizes, clinical stages, cervical lymph node metastasis, and HPV status. IL-6, IL-8, and TNF-alpha in OPSCC patients were higher than those in healthy individuals. Patients with HPV-positive OPSCC were more sensitive to radiotherapy compared to those with HPV-negative. Saliva TNF-alpha levels were elevated in the radiotherapy-sensitive OPSCC patients, with IL-6 and IL-8 levels being lower than those in radiotherapy-insensitive patients. For predicting radiotherapy response, the AUC for IL-6, IL-8, and TNF-alpha was 0.744, 0.750, and 0.742, respectively, with the combination yielding an AUC of 0.821. Among OPSCC patients, those who survived showed higher TNF-alpha levels in saliva and lower IL-6 and IL-8 levels compared with those died. Elevated TNF-alpha level in saliva and sensitivity to radiotherapy were protective factors affecting prognosis, and elevated IL-6 and IL-8 were

摘要： Developing a highly effective malaria vaccine remains challenging due to 's antigenic diversity and human leukocyte antigen (HLA) polymorphisms, which complicate vaccine antigen selection and limit immune protection. The first recommended malaria vaccine, RTS,S, provides only partial, allele-specific protection with waning immunity over time, and the more recently developed R21 vaccine will likely encounter the same hurdles. To address these challenges, we developed a computational tool that integrates sequence diversity, predicted T cell epitope-HLA binding affinities, and HLA allele frequencies from sub-Saharan Africa to identify conserved, immunogenic epitopes with broad population coverage. We analyzed 42 proteins, previously identified as vaccine candidate antigens, and generated consensus sequences using data from 18 African countries, and then incorporated HLA allele frequencies from 24 sub-Saharan populations. CD8+ and CD4+ T cell epitopes were predicted using NetMHCpan-4.1 and NetMHCIIpan-4.1. Our novel tool, T cell Epitope Nomination (TEpiNom), used greedy optimization to filter and select epitopes based on epitope sequence conservation (>95%), binding affinity (median rank <10%), and broad HLA coverage, minimizing redundancy to reduce immune escape risk. Our tool identified 2,265 MHC I and 1,992 MHC II conserved epitopes spanning pre-erythrocytic, erythrocytic, and sexual stage proteins. Key MHC I epitopes from pre-erythrocytic antigens HSP70-2, SLARP/SAP1, p36, FabZ, LISP1, LSA1, UIS3, p24_2, PL, and FabG achieved near 100% HLA-A, HLA-B, and HLA-C coverage, and MHC II epitopes from pre-erythrocytic, erythrocytic, or sexual antigens provided 98.5%-100% coverage for a given parasite life stage. This strategy advances malaria vaccine design by integrating epitope promiscuity and multistage antigen selection to support broad, durable protection and identify promising multi-epitope malaria vaccine candidates for subsequent experimental validation. Our comp

关键词： 细胞培养   单克隆抗体   曲妥珠单抗   机理模型   智能算法  

摘要： 机理模型通过数学方程描述细胞代谢行为， 是优化和预测生物过程的重要理论工具， 本研究基于Monod生长代谢模型， 构建了曲妥珠单抗生物类似药的细胞培养机理模型。针对微分方程参数拟合复杂度高且容易陷入局部最优的问题， 通过引入粒子群优化算法 (particle swarm optimization， PSO)、灰狼优化算法 (grey wolf optimizer， GWO) 和差分进化算法 (differential evolution， DE) 对模型参数拟合。结果表明， GWO在全局搜索能力和拟合精度方面表现最佳， 在处理多参数拟合问题时具有更高的稳定性和适应性。进一步对GWO算法的位置更新与速度更新方法进行改进， 改进的灰狼算法 (improved grey wolf optimizer， IGWO) 显著提升了模型的预测能力， 能够精准预测细胞密度、代谢物浓度及抗体滴度。本研究为提高生物药物生产效率、降低开发成本及优化细胞培养工艺提供了重要理论支持。

关键词： Ptpmt1   heart development   left ventricular non-compaction   mitochondria   mitochondrial phosphatase  

摘要： Left ventricular non-compaction cardiomyopathy (LVNC) is a congenital heart disease characterized by abnormal prenatal development of the left ventricle that has an aberrantly thick trabecular layer and a thinner compacted myocardial layer. However, the underlying molecular mechanisms of LVNC regulated by mitochondrial phosphatase genes remain largely unresolved. We generated a mouse model with cardiac-specific deletion (CKO) of , a type of mitochondrial phosphatase gene, using the , and investigated the effects of cardiac-specific deficiency on cardiac development. Morphological, histological, and immunofluorescent analyses were conducted in CKO and littermate controls. A transcriptional atlas was identified by RNA sequencing (RNA-seq) analysis. We found that CKO mice were born at the Mendelian ratio with normal body weights. However, most of the CKO mice died within 24 h after birth, developing spontaneous ventricular tachycardia. Morphological and histological analysis further revealed that newborn CKO mice developed an LVNC phenotype, evidenced by a thicker trabecular layer and a thinner myocardium layer, when compared with the littermate control. We then examined the embryonic hearts and found that such an LVNC phenotype could also be observed in CKO hearts at E15.5 but not at E13.5. We also performed the EdU incorporation assay and demonstrated that cardiac cell proliferation in both myocardium and trabecular layers was significantly reduced in CKO hearts at E15.5, which is also consistent with the dysregulation of genes associated with heart development and cardiomyocyte proliferation in CKO hearts at the same stage, as revealed by both the transcriptome analysis and the quantitative real-time PCR. Deletion of in mouse cardiomyocytes also induced an increase in phosphorylated eIF2α and ATF4 levels, indicating a mitochondrial stress response in CKO hearts. Our results demonstrated that may play an essential role in regulating left ventricular compaction

关键词： 迈之灵   急性膝关节创伤性滑膜炎   疗效   骨保护素   转化生长因子-β1   白细胞介素6  

摘要： 目的 探讨迈之灵治疗急性膝关节创伤性滑膜炎的疗效及对血清骨保护素（osteoprotegerin ，OPG）、转化生长因子-β1（transforming growth factor-β1，TGF-β1）、白细胞介素 6（interleukin 6，IL- 6）水平的影响。方法 选取100例急性膝关节创伤性滑膜炎患者，随机分为对照组与观察组，每组50例，对照组常规治疗，观察组在对照组治疗基础上加用迈之灵口服治疗，疗程14d，采用视觉模拟评分法（Visual analogue scale ，VAS）、麦克马斯特大学骨关节炎指数（Western Ontario and McMaster Universities osteoarthritis index ，WOMAC）及膝关节Lysholm评分、滑膜厚度、积液深度、膝关节周径差值及血清OPG、TGF-β1、IL- 6水平变化。结果 两组治疗前的VAS评分、WOMAC评分、Lysholm评分、滑膜厚度、积液深度、膝关节周径差值比较差异均无统计学意义（P>0.05），治疗后VAS评分、WOMAC评分、滑膜厚度、积液深度、膝关节周径差值与治疗前比较下降（P<0.05），且观察组低于对照组（P<0.05），Lysholm评分与治疗前比较升高（P<0.05），且观察组高于对照组（P<0.05）；两组治疗前的血清OPG、TGF-β1、IL- 6水平比较差异均无统计学意义（P>0.05），治疗后血清OPG、TGF-β1与治疗前比较升高（P<0.05），且观察组高于对照组（P<0.05），IL- 6与治疗前比较下降（P<0.05），且观察组低于对照组（P<0.05）；观察组治疗疗效优于对照组（P<0.05）；对照组及观察组不良反应发生率分别为14.00%、18.00%，比较差异无统计学意义（P>0.05）。结论 迈之灵治疗急性膝关节创伤性滑膜炎可提高治疗疗效，改善OPG、TGF-β1、IL-6水平，其作用可能与改善患者膝关节骨代谢、促进创伤修复及减轻炎性反应等途径有关。

关键词： HLA   T cell Receptor - TCR   Immunotherapy   T cell  

摘要： Background Public neoantigens, including KRAS, TP53, and PIK3CA mutations, which are shared across various tumor types, have demonstrated significant immunogenicity and offer great promise for cancer immunotherapy. Clinical trials targeting these public neoantigens have yielded encouraging results, including tumor regression and prolonged relapse-free survival. This study evaluates the human leukocyte antigen (HLA) binding properties of T-cell epitopes derived from these public neoantigens to identify optimal T-cell target and further develops T-cell receptor (TCR)-based *** The binding properties of public neoantigens to HLA-I molecules were evaluated using peptide-HLA binding affinity and stability assays. Naive T-cell repertoires were used to expand and detect neoantigen-specific TCRs. TCR clones were characterized for functionality using TCR-Jurkat cells and TCR-T cells. Peptide specificity was assessed using an HLA transgenic cell panel and the X-scan assay. In vivo antitumor efficacy of TCR-T cells was tested in xenograft mouse models of solid *** The analysis of HLA binding properties for public neoantigens revealed that HLA-A*11:01-presented KRASG12V epitopes exhibited the strongest HLA binding stability. Four TCR clones specific to the 9-mer KRASG12V peptide (KRASG12V[9]) were identified. All KRASG12V[9]-specific TCRs, both newly identified by us and previously reported, exhibited varying degrees of cross-recognition of the exogenous self-antigen RAB7B. Among the four TCR clones, one TCR (KT18) exhibited superior functional avidity, effectively recognizing and eliminating KRASG12V mutant tumor cells without off-target activity against endogenous RAB7B or similar peptides. Significantly, KT18 TCR-T cells efficiently mediated tumor regression in multiple xenograft models of solid *** These findings highlight significant differences in peptide-HLA binding affinity and stability across public neoantigen-HLA pairings. T