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关键词： Glioblastoma   CircZEB1   Glioma stem cells   Limb-bud and heart   NF-kappa B signaling pathway  

摘要： Glioblastoma (GBM) is the most lethal and common primary tumor of central nervous system with a poor prognosis. Glioma stem cells (GSCs) are particularly significant in GBM proliferation, invasion, self-renewal and recurrence. Circular RNAs (circRNAs) play important roles in various physiological and pathological processes, including regulating the biological behavior of GBM. Therefore, discovering novel circRNAs related to GSCs may contribute to a promising approach for treatment of GBM. Herein, we find out a novel circRNA termed circZEB1 with a high expression in glioma. Limb-bud and heart (LBH) is a transcription cofactor and promotes glioma stem cell tumorigenicity in our study. Mechanistically, circZEB1 can upregulate the expression of transcription cofactor LBH via sponging miR-128-3p in GSCs. LBH can facilitate the expression of tumor necrosis factor-alpha (TNF-alpha), thus activating the NF-kappa B signaling pathway to promote the glioma progression. Meanwhile, LBH can also upregulate the RNA binding protein Fused in Sarcoma (FUS) expression, which can bind to and maintain the stability of circZEB1. A positive feedback loop is formed among FUS, circZEB1, miR-128-3p and LBH in GSCs. Our study uncovers a critical role of circZEB1 and provides a novel biomarker for treating GBM.

关键词： hepatitis B virus   single nucleotide polymorphism   zinc finger protein 350   Peg-IFN alpha   therapeutic effect  

摘要： Background: The varying individual responses to Pegylated interferon-alpha (Peg-IFN alpha) in patients with chronic hepatitis B (CHB) pose significant hurdles in treatment optimization, and the underlying mechanisms remain unclear. Objective: We aimed to identify genetic polymorphisms influencing the efficacy of Peg-IFN alpha in patients with HBeAg-positive CHB, with the goal to predict Peg-IFN alpha response before treatment. Methods: We employed an Asian Screening Array analysis involving 124 HBeAg-positive CHB patients treated with Peg-IFN alpha. We conducted assessment of immunological markers and mRNA expression of pivotal genes, establishing correlations with SNPs, functional genes of SNPs, and efficacy of Peg-IFN alpha therapy. In vitro experiments were performed to verify the functional involvement of the candidate SNPs. Results: The G allele presented in rs2278420 and rs6509607 were significantly more common in patients who achieved a complete response (CR) compared to those who had a suboptimal response (SR), and linked to an increased rates of HBeAg loss following Peg-IFN alpha treatment (all p < 0.05). Additionally, the mRNA level of ZNF350 varied notably across different genotypes of both SNPs as determined by eQTL analysis, and showed higher expression in patients achieved a SR (all p < 0.05). In vitro investigations with IFN alpha stimulation showed that the mRNA level of SOCS3 was elevated in patients with rs2278420 genotype AA, similarly, mRNA levels of PKR, STAT2, SOCS1, SOCS3, PIAS1, PTPN6 and TRIM8 were heightened in patients with rs6509607 genotype AA compared to those with genotypes (AG+GG) (all p < 0.05). Conclusion: The G allele of rs2278420 and rs6509607 were associated with mRNA level of ZNF350, with an increased probability of Peg-IFN alpha response in HBeAg-positive CHB patients, likely through the modulation of JAK-STAT signaling pathway.

关键词： 人类免疫缺陷病毒(HIV)   丝裂原活化蛋白激酶(MAPK)   T淋巴细胞   线粒体   抗逆转录病毒治疗(ART)   免疫  

摘要： 目的 阐明人类免疫缺陷病毒（HIV）感染通过丝裂原活化蛋白激酶（MAPK）通路介导CD4+T淋巴细胞(CD4+T细胞)线粒体损伤的机制。方法 在2022-10-01/2023-03-31之间招募47名接受4年抗逆转录病毒治疗（ART）的HIV感染者，包括22名免疫无应答者（INR）、25名应答者（IR）；以及26名性别和年龄匹配的未感染对照组参与者（HC）；并用流式细胞术分析免疫参数。最后，加入MAPK通路抑制剂SB203580处理来自HC或HIV感染者中外周血单个核细胞（PBMC），观察CD4+T细胞线粒体功能的变化。结果 与HC组相比，INR组和IR组的PBMC中CD4T细胞比例显著降低，并且INR组的PBMC中CD4+T细胞比例较IR组显著降低。此外，INR组的PBMC中幼稚(CD45RA+CD27+)T细胞的比例显著低于HC组和IR组。与HC组和IR组相比，INR组PBMC中CD4+程序性死亡受体1阳性(PD-1+)、CD4+膜联蛋白V阳性(Av+)和CD4+线粒体氧化阳性(MO+)比例，以及CD4+T细胞亚群中CD45RA++CD27++PD-1+、CD45RA++CD27++Av+、CD45RA++CD27++MO+比例均显著增加。与HC对照组相比，HIV对照组CD4+T细胞的基础呼吸、最大呼吸和中文腺苷三磷酸（ATP）产量均显著降低，和CD4+T细胞内线粒体膜电位（JC-1）(绿色/红色)显著增加。与HIV对照组相比，HIV-SB203580组CD4+T细胞的基础呼吸、最大呼吸、ATP产量、呼吸潜力均显著增加，和CD4+T细胞内JC-1（绿色/红色）显著降低。结论 在接受ART治疗的HIV感染者中，特别是在INR患者的CD4+T细胞中观察到MAPK信号通路异常激活，并可能导致线粒体功能受损和CD4+T细胞稳态异常。

关键词： manufacturability   viscosity   molecular descriptors   monoclonal antibodies  

摘要： Early-phase manufacturability assessment of high-concentration therapeutic monoclonal antibodies (mAbs) involves screening of process-related risks impacting their translation into the clinic. Manufacturing a mAb at scale relies on cost-effective and robust approaches to derisk manufacturability parameters, such as viscosity, conformational stability, aggregation, and process-related impurities. Using a panel of model anti-IL-8 IgG1 mutants, we investigate upstream and downstream processability, phase behavior, and process-related impurities. We correlate trends in the biophysical properties of mAbs with their cell growth, expression, filtration flux, solubility, and post-translational modifications. We find significant trends in increased relative free light chain expression with heavy chain mutants and detect a requirement for adjusted operation pH for cation exchange polishing steps with charge-altering variants. Moreover, trends between phase stability and high-concentration viscosity were observed. We also investigated unique correlations between increased glycosylation and biophysical behavior. Further in-depth analysis and modeling are required to elucidate the impact of the mAb sequence on the metabolism of the expression system, solubility limits, and alternative gelation models as future directions.

关键词： IFN gamma-secreting T cells   Mycobacterium tuberculosis   BCG   IL-2   intracellular mycobacteria   mRNA sequencing  

摘要： Cytokine of interferon-gamma (IFN gamma) plays a vital role in the immune response against Mycobacteria tuberculosis (Mtb) infection, yet the specific function of T cells producing IFN gamma in this process remains unclear. In this study, we first isolated IFN gamma+CD3+ T cells induced by Mtb antigens using surface staining assays. which showed a strong ability to inhibit the growth of intracellular mycobacteria in macrophages. Peripheral blood mononuclear cells (PBMCs) from healthy individuals were then challenged with Bacillus Calmette-Gu & eacute;rin (BCG) or Mtb, respectively, to sort IFN gamma-secreting T cells for mRNA sequencing to analyze the gene expression patterns. The results of the integrated data analysis revealed distinct patterns of gene expression between IFN gamma+CD3+ T cells induced by the BCG vaccine and those induced by Mtb pathogens. Further, unlike Mtb-induced cells, BCG-induced IFN gamma+CD3+ T cells expressed high levels of interleukin-2 (IL-2), which increased the frequencies of these cells and the production of effector cytokines IFN gamma and IL-2. Our findings suggested that IFN gamma+CD3+ T cells with high IL-2 expression presented potent effector functions to inhibit intracellular Mtb growth, while Mtb infection impaired IL-2 expression in IFN gamma+CD3+ T cells.

摘要： Red eye is a common condition characterized by eye redness, often accompanied by itching, burning, pain, or discharge. This condition can be caused by a multitude of factors, ranging from minor irritations to severe infections. Red eyes are a frequent complaint in outpatient practice. Only a small percentage of patients with red eyes require urgent ophthalmological referral and treatment, while the vast majority can be managed by a general practitioner.;L’œil rouge est une affection courante se manifestant par une rougeur de l’œil, souvent accompagnée d’un prurit, de brûlures, de douleurs ou de sécrétions. Cette condition peut être causée par une multitude de facteurs, allant des irritations mineures aux infections graves. Les yeux rouges sont une plainte fréquente en pratique ambulatoire. Seul un petit pourcentage de patients ayant les yeux rouges nécessite une orientation et un traitement ophtalmologique urgents, alors que la grande majorité peut être traitée par le médecin généraliste.

关键词： 荨麻疹   UAS7评分   白细胞介素9   人软骨糖蛋白39   白细胞介素31   诊断价值  

摘要： 目的 分析血清白细胞介素9（IL-9）、人软骨糖蛋白39（YKL-40）、白细胞介素31（IL-31）的检测对慢性自发性荨麻疹（CSU）诊断价值。方法 抽取2022年11月-2023年10月我院皮肤性病科诊治的90例活动期CSU患者为观察组，根据7日荨麻疹活动评分（UAS7）将活动期CSU患者细分为轻度、中度、重度3组；同时将治疗4周后进入疾病静止期的CSU患者纳入静止期组。另选同期90例健康体检者为对照组。采集各组受试者外周静脉血，比较血清IL-9、YKL-40、IL-31水平，采用受试者工作特征ROC曲线分析评价血清IL-9、YKL-40、IL-31水平在诊断CSU的价值。结果 观察组、静止期组、对照组血清IL-9水平[（139.57±19.68）、（104.38±16.35）、（102.41±15.64）pg/ml]、YKL-40水平[（994.74±87.67）、（652.53±62.44）、（634.27±59.36）pg/ml]、IL-31水平[（22.39±4.27）、（8.13±1.21）、（7.88±1.14）pg/ml]差异均有统计学意义（F=115.082、627.596、660.505，均P<0.001）。CSU活动期轻、中、重度患者血清IL-9水平[（113.54±15.64）、（132.62±16.32）、（155.35±23.66）pg/ml]、YKL-40水平[（757.21±77.67）、（884.52±81.64）、（1106.67±96.68）pg/ml]、IL-31水平[（14.84±2.86）、（19.67±3.33）、（25.58±4.24）pg/ml]组间比较差异均有统计学意义（F=27.691、99.880、51.110，P<0.001），其中轻度组均低于中度组与重度组，中度组低于重度组（均P<0.05）。CSU活动期患者血清IL-9、YKL-40、IL-31水平与UAS7评分之间均呈显著正相关（r=0.550、0.756、0.699，P<0.01）。ROC曲线显示，血清IL-9、YKL-40、IL-31的AUC分别为0.643、0.686和0.735，联合检测的AUC是0.842。结论 CSU活动期患者血清IL-9、YKL-40、IL-31水平均随着病情加重而明显提升，因此通过调控IL-9、YKL-40、IL-31表达有利于CSU病情康复。

关键词： T cell receptor   HLA   Alloselectivity   Structure-guided engineering   Affinity maturation   PRAME  

摘要： Specificity of a T cell receptor (TCR) is determined by the combination of its interactions to the peptide and human leukocyte antigen (HLA). TCR-based therapeutic molecules have to date targeted a single peptide in the context of a single HLA allele. Some peptides are presented on multiple HLA alleles, and by engineering TCRs for specific recognition of more than one allele, there is potential to expand the targetable patient population. Here, as a proof of concept, we studied two TCRs, S2 and S8, binding to the PRAME peptide antigen (ELFSYLIEK) presented by HLA alleles HLA-A*03:01 and HLA-A*11:01. By structure-guided affinity maturation targeting a specific residue on the HLA surface, we show that the affinity of the TCR can be modulated for different alleles. Using a combination of affinity maturation and functional T cell assay, we demonstrate that an engineered TCR can target the same peptide on two different HLA alleles with similar affinity and potency. This work highlights the importance of engineering alloselectivity for designing TCR based therapeutics suitable for differing global populations.