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关键词： esophageal squamous cell carcinoma   IL-6   PD-1 inhibitor   tumor microenvironment   prognosis  

摘要： Background Due to the low efficacy rates, effective biomarkers are desperately needed to determine populations of advanced esophageal squamous cell carcinoma (ESCC) that may benefit from immune checkpoint inhibitor (ICI) *** To explore the relationship between IL-6 and the esophageal cancer tumor immune microenvironment using online databases and esophageal cancer tissue microarrays and to investigate the predictive role of IL-6 for immunotherapy in esophageal squamous carcinoma patients through clinical study *** RNA-seq datasets of ESCC patients were obtained from TCGA, and the relationship between IL-6 and immune cells was discovered using TIMER 2.0 databases. CD8, IL-6, and PD-L1 expression in ESCC tissue microarrays were measured using immunohistochemistry, and then the tumor microenvironment was classified. Furthermore, blood specimens were collected from advanced ESCC patients before they received PD-1 inhibitors, and follow-up was conducted to gather clinical survival data. Based on IL-6 levels. We divided the population into the high and low IL-6 groups, comparing the efficacy and survival of the two *** IL-6 positively correlated with mRNA levels of PD-L1, negatively correlated with immune cells, and positively correlated with immunosuppressive cells. High IL-6 expression in tissues might make PD-1/L1 blockade therapy less effective. Individuals with higher baseline plasma IL-6 levels had significantly lower objective remission rates and inferior PFS and OS. Elevated baseline IL-6 was demonstrated to be an independent risk factor for the prognosis of advanced ESCC patients using PD-1 inhibitors, according to COX regression *** IL-6 overexpression correlates with the immunosuppressive tumor microenvironment in ESCC, and it can be a predictive biomarker in ESCC patients received with PD-1 inhibitors.

关键词： asymptomatic esophageal eosinophilia   brain-derived neurotrophic factor   EoE diagnostic panel   eosinophilic esophagitis   IL-13   iPSC-derived sensory neurons   neuropathic and inflammatory pain panel   neurotrophic receptor tyrosine kinase 2  

关键词： Cognitive impairment   Disturbed astrocyte   IL-33   Neuropathic pain   Oxidative stress   Synaptic plasticity  

摘要： Cognitive impairment is one of the most common comorbidities in individuals suffering from neuropathic pain. However, the mechanisms underlying pain-associated cognitive dysfunction remain unclear. Studies show that IL-33 is essential for synaptic plasticity, which is necessary for learning and memory formation. Here, we used a spared nerve injury (SNI) model in mice to induce cognitive dysfunction associated with neuropathic pain. Behavioral changes following surgery were assessed using Von Frey test, open field test and novel object recognition test. Immunofluorescence, chemical genetics, and stereotaxic injections were employed to investigate the potential mechanisms. Mitochondrial morphology and oxidative stress levels were evaluated using transmission electron microscopy and by measuring the superoxide dismutase (SOD) activity and reactive oxygen species (ROS) production. The data suggest that animals after SNI with comorbid memory dysfunction exhibited a decline in IL-33 levels in the dorsal hippocampal CA3 region, accompanied by deactivated astrocytes. The expression of IL-33-positive astrocytes was reduced, and the number of dendritic spines was decreased. Additionally, SOD activity was decreased, ROS production increased, accompanied with impaired mitochondrial morphology in synapses. Exogenous IL-33 administration or enhancing endogenous IL-33 release via chemogenetic activation of astrocytes alleviated cognitive impairment. These effects were mediated by improvement in mitochondrial morphology, reduction in oxidative stress levels, and increase in the number of dendritic spines. Findings indicated that IL-33 derived from astrocytes in the dorsal CA3 contributes to synaptic plasticity and oxidative stress in SNI mice. Accordingly, IL-33 may serve as a potential therapeutic target for pain-associated cognitive impairment.

关键词： IL-17A   COPD airway remodelling   Mouse bronchial fibroblasts   Autophagy  

摘要： The airway and lung tissue inflammation and structural changes caused by COPD lead to persistent and irreversible airflow limitation in patients. Several studies have associated IL-17A with COPD airway inflammation and collagen deposition, while autophagy is essential for maintaining normal cell function. Based on these findings, we propose a hypothesis that IL-17 affecting the autophagy of macrophages through the PI3K/AKT/mTOR pathway may contribute to the regulation of the airway remodeling process in COPD. The COPD airway remodelling model was confirmed by pulmonary function tests and HE and Masson staining. IL-17A, IL-6 and CCL20 were detected by ELISA, autophagosomes (APs) were observed by transmission electron microscopy, and western blotting was used to detect PI3K/AKT/mTOR-related proteins, autophagy-related proteins and collagen. Immunofluorescence revealed colocalization of LC3 in mouse bronchial fibroblasts (MBFs). MBFs were isolated and cultured via lentiviral transfection, IL-17RA overexpression or silencing, and quantitative analysis of PI3K/AKT/mTOR pathway-related proteins and autophagy-related proteins via western blotting. The results validated the establishment of the COPD model. Increased IL-17A in the COPD airway and increased IL-6 and CCL20 expression were observed in the COPD mice supplemented with the autophagy inhibitor 3MA. Using TEM, we observed a significant reduction in the number of APs in the airways in both the COPD and 3MA groups. Moreover, the PI3K/AKT/mTOR pathway phospho-p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR ratios were also increased in the COPD group. Moreover, as P62 increased, Beclin-1 and LC3II/I expression decreased correspondingly, while Collagen I and Collagen III also increased. In our study of cultured mouse MBFs, the results showed that overexpression (OE) virus-mediated transfection of MBFs overexpressing IL-17RA increased the p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR ratios, increased the P62 content and reduced the e

关键词： 猪繁殖与呼吸综合征病毒   非结构蛋白1α   原核表达   多克隆抗体   生物学特性  

摘要： 【目的】制备非结构蛋白1α (non-structural protein 1α， NSP1α)多克隆抗体，为深入研究NSP1α蛋白功能提供物质基础，并为猪繁殖与呼吸综合征（porcine reproductive and respiratory syndrome， PRRS）防控靶点的选择提供新思路。【方法】以pCAGGS–NSP1α–HA质粒为模板，聚合酶链式反应（polymerase chain reaction， PCR）扩增NSP1α基因，利用相关生物信息学在线软件分析PRRSV SD16毒株NSP1α基因和其他PRRSV毒株NSP1α基因序列同源性、蛋白的理化性质、氨基酸亲–疏水性、跨膜结构域、信号肽序列、磷酸化位点、二级和三级结构。通过EcoR I和Xho I酶切位点克隆至pET–28a–His原核表达载体。测序正确的pET–28a–NSP1α–His质粒转化至*** BL21（DE3）表达感受态细胞，将诱导表达、纯化复性后的NSP1α蛋白免疫小鼠制备多克隆抗体，Western blot和间接免疫荧光实验（indirect immunofluorescence assay， IFA）鉴定制备的多克隆抗体的反应原性，通过Western blot和激光共聚焦分析NSP1α蛋白亚细胞分布。【结果】信息学分析结果表明，SD16毒株NSP1α蛋白有501个氨基酸，为不稳定的疏水性蛋白，其序列与HLJ毒株序列同源性最高，与I型PRRSV序列同源性最低；NSP1α蛋白无信号肽序列，无跨膜结构域，存在13个磷酸化位点；二级结构主要包含α–螺旋、延伸链和无规则卷曲。将获得的高纯度并且有活性的NSP1α蛋白进行小鼠免疫，检测其血清抗体效价可达1:64 000。Western blot和IFA结果显示，制备的多克隆抗体特异性识别PRRSV NSP1α蛋白。Western blot和激光共聚焦结果显示，NSP1α蛋白主要定位在细胞核内。【结论】成功表达、纯化了PRRSV NSP1α蛋白并制备了鼠源多克隆抗体，该多克隆抗体与PRRSV NSP1α蛋白具有良好的反应活性和特异性。

摘要： In unrelated allogeneic hematopoietic cell transplantation (allo-HCT), older and/or HLAmismatched donors are known risk factors for survival outcomes. In healthy individuals, cytomegalovirus (CMV) seropositivity is associated with impaired adaptive immune systems. We assessed whether the adverse effects of donor risk factors are influenced by the donor CMV serostatus. We analyzed 5836 patients with CMV seropositivity who received unrelated allo-HCT. We divided the entire cohort into 2 cohorts according to the donor CMV serostatus: CMV positive (DP) and negative (DN). We also stratified each cohort into 4 groups based on donor age (aged >= 40 or <40 years) and HLA parity (8/8 or 7/8): Young88 and Old88, and Young78 and Old78, respectively. In the CMV-DP cohort, the Old88 (hazard ratio [HR], 1.20;P = .012), Young78 (HR, 1.35;P < .001), and Old78 (HR, 1.60;P < .001) groups were associated with inferior overall survival (OS) than the Young88 group. In contrast, in the CMV-DN cohort, neither donor age nor HLA disparity was associated with inferior OS. The adverse impact of donor age was different between the cohorts (CMV-DP: HR, 1.19;P = .001;CMV-DN: HR, 1.04;P = .53;P for interaction, .070), as was the impact of HLA (CMV-DP: HR, 1.34;P < .001;CMV-DN: HR, 1.08;P = .23;P for interaction, .012). The impacts of donor age and HLA mismatch on OS might differ according to the donor CMV serostatus. In unrelated allo-HCT from a CMV-seronegative donor, an HLA-mismatched older donor may be able to be selected without affecting OS.

关键词： autoimmune diseases   lupus   mathematical modeling   quantitative systems pharmacology   type 1 interferon  

摘要： Type I interferon (IFN1) pathway-targeting therapies represent a highly promising class of remedies for the treatment of systemic lupus erythematosus. However, the overall clinical benefit of these compounds is afflicted by marked variability. In this study, we developed a quantitative systems pharmacology model of type I IFN-mediated inflammation and applied it for an indirect comparison of anifrolumab, sifalimumab, daxdilimab, and litifilimab pharmacodynamic response, represented in the model by the change in IFN1 gene signature (IFNGS). The model consists of 20 ordinary differential equations and 68 parameters, among which four systemic parameters (including one random effect) were estimated using patient-level data from Phase IIb anifrolumab clinical trial. Within-target and within-pathway validation was performed using study-level pharmacokinetics, IFN alpha, and/or IFNGS data from five anifrolumab, four sifalimumab, one daxdilimab, and one litifilimab trials. The model successfully captured overall trends in IFNGS at clinically relevant doses of these compounds and discriminated IFNGS response between patients with low (< 2.75) and high (>= 2.75) baseline IFNGS. Overprediction of treatment benefit was observed for the low range of anifrolumab doses (100-150 mg every 4 weeks). In contrast, IFNGS response under 150 mg of daxdilimab was underpredicted, despite the accurate description of plasmacytoid dendritic cells and IFN alpha biomarkers. Results of the global sensitivity analysis revealed baseline IFNGS, IFN alpha, and IFN alpha fraction as key factors affecting treatment benefit the most. In terms of maximum IFNGS reduction, anifrolumab showed superior potential compared to sifalimumab, daxdilimab, and litifilimab (Delta IFNGS similar to 25%), which was further enhanced in patients with high baseline IFNGS or IFN alpha (Delta IFNGS similar to 50%-60%).

关键词： 银屑病   克银合剂   凉血除湿法   IL-23/Th17细胞轴   临床疗效  

摘要： 目的：观察克银合剂治疗血热证中重度寻常型银屑病的临床疗效及安全性，初步探讨其对IL-23/辅助性T细胞17（Th17）细胞轴的干预作用。方法：收集门诊的血热证中重度寻常型银屑病患者30例作为研究组，选取健康体检的正常人30例作为对照组，研究组予克银合剂口服，30 mL/次，每日3次，疗程12周。比较研究组患者治疗前后的银屑病皮损面积与严重程度指数（psoriasis area and severity index，PASI）评分、体表皮损面积（body surface area，BSA）评分、皮肤病生活质量指数（dermatology life quality index，DLQI）评分，并比较治疗前两组间与研究组治疗前后血清中IL-17、IL-22、IL-23、IL-6、TNF-α的表达水平。结果：银屑病症状评分方面，治疗12周后，研究组患者的PASI评分、BSA评分、DLQI评分较治疗前均显著下降(P均＜0.01)，其中PASI 50及PASI 75的应答率分别为63.3%和16.7%。IL-23/Th17细胞轴相关因子方面，研究组患者的血清IL-17、IL-22、IL-6、IL-23、TNF-α水平显著高于健康对照组(均＜0.01)。研究组治疗12周后，患者的血清IL-22、IL-6、IL-17、IL-23、TNF-α 水平较治疗前均显著降低(P均＜0.01)。结论：克银合剂治疗血热证中重度寻常型银屑病疗效显著，安全性高，可以显著降低IL-23/Th17轴相关因子（IL-23、IL-22、IL-17、IL-6、TNF-α）水平。