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关键词： 血小板/淋巴细胞比值   肝脏疾病   Platelet-to-Lymphocyte Ratio   Liver Disease  

摘要： 血小板/淋巴细胞比值(Platelet-to-Lymphocyte Ratio, PLR)作为一种反映全身性炎症标志物，因其易于获取、计算方法简便以及成本较低等优势，在肝脏疾病的研究中受到广泛关注。本文综述了PLR在病毒性肝炎、非酒精性脂肪性肝病、肝硬化以及原发性肝癌等方面的研究进展，重点关注其在疾病监测和预后评估中的潜在应用价值。

关键词： 冠心病   非罪犯血管病变   冠脉介入治疗技术   C-反应蛋白   淋巴细胞   Coronary Heart Disease   Non-Culprit Coronary Lesions   Percutaneous Coronary Intervention   C-Reactive Protein   Lymphocytes  

摘要： 随着冠脉介入治疗技术(Percutaneous Coronary Intervention, PCI)的发展和进步，以及术后新型抗血小板聚集药物和抗凝药物的广泛使用，冠状动脉性心脏病(简称冠心病，coronary heart disease, CHD)患者的临床预后得到显著改善，CHD相关的并发症也显著降低。然而，PCI术后非罪犯血管(non-culprit coronary lesions, NCCLs)病变进展的问题，仍是影响患者长期生存率和预后的重要挑战。因此，深入探讨和解决NCCLs病变进展的机制、病理生理过程、影响因素，并在此基础上制定有效的治疗和预防策略，对进一步改善患者预后，进一步降低死亡率具有一定的临床意义和研究价值。

关键词： neutrophil   diagnosis   early progression   myocardial infarction   mouse model   single cell RNA analysis  

摘要： Introduction Myocardial infarction (MI) is a leading cause of death worldwide. Immune cells play a significant role in the MI development. This study aims to identify a marker related to neutrophil for the diagnosis and early progression of *** Key genes were screened using three machine learning algorithms to establish a diagnostic model. A gene associated with the early progression of MI was identified based on single cell RNA sequencing data. To further validate the predictive value of the gene, the mouse models of MI were constructed. Immunofluorescence (IF) analysis demonstrated the co-expression of the gene with neutrophils. Immunohistochemistry (IHC) was performed to validate the role of the gene in the progression of *** Neutrophils were identified and verified as the key infiltrating immune cells (IICs) involved in the onset of MI. A diagnostic panel with superior performance was developed using five key genes related to neutrophils in MI (AUC = 0.887). Among the panel, IL1R2 was found to early phase of MI, which was further corroborated by IHC in mouse models of *** This study suggests that IL1R2, which is specific to neutrophils, can predict the diagnosis and early progression of MI, providing new insights into the clinical management of MI.

关键词： 亮氨酸   生长   非特异性免疫   抗氧化能力   肝脏健康   鳜  

摘要： 实验以鳜(Siniperca chuatsi)为研究对象,选择初始体重为(37.26±0.22)g的健康鳜216尾,随机分为6个处理组,分别饲喂亮氨酸(Leu)水平为1.88%、2.49%、3.13%、3.73%、4.29%和4.90%的实验饲料(记作L1.88、L2.49、L3.13、L3.73、L4.29、L4.90)8周,探究不同Leu水平饲料对鳜幼鱼生长、抗氧化能力、肝脏健康及非特异性免疫功能的影响。实验结果表明,鳜肝体比及脏体比与Leu水平呈线性正相关,鳜的增重率、特定生长率均在L3.13组达到最大值,其中Leu缺乏组(L1.88)和过量组(L4.90)的增重率及特定生长率均显著低于其余各组(P<0.05)。此外, L3.13组饲料系数显著低于L1.88、L2.49、L4.29和L4.90组(P<0.05)。随着Leu水平的升高,全鱼粗蛋白和粗脂肪整体呈先升高后降低的趋势,其中L3.13、L3.73和L4.29组全鱼粗脂肪显著高于其余各组(P<0.05), L3.19和L4.90组肝脏粗蛋白显著低于L3.13组。Leu水平的升高引起肝脏中超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)活性先升高后降低,且均在L1.88组最低。L3.13组和L3.73组SOD、GSH-Px活性都显著高于其余各组(P<0.05)。L3.13和L3.73组血清溶菌酶(LYZ)和补体成分3(C3)含量均显著高于其余各组(P<0.05);随着Leu水平的升高,血清谷丙转氨酶(ALT)和谷草转氨酶(AST)活性,展现出先下降后上升趋势, L3.13组ALT活性最低, L3.73组AST活性最低; L1.88组AST活性显著高于其余各组(P<0.05)。L3.13组与L3.73组nf-κb-p65、tnf-α表达显著低于其余各组(P<0.05)。L3.13、L3.73和L4.29组il-1β、pai的基因表达量显著低于其他组(P<0.05)。L3.13和L3.73组肝脏细胞的空泡化程度明显低于其余各组,这与血清中ALT和AST水平变化趋势和免疫基因表达的结果是一致的。以上结果表明,适宜水平的饲料Leu能够提高饲料效率和蛋白沉积以增进鳜的生长,改善肝脏健康并且显著增强鳜的非特异免疫能力;而过高或者过低的Leu水平均不利于鳜的生长和免疫。此外,基于增重率的二次回归分析显示,鳜幼鱼饲料最佳Leu水平为3.28%,占蛋白水平的6.92%。

关键词： Radiomics   High-grade glioma   IL7R   Prognosis  

摘要： BackgroundHigh-grade gliomas are among the most aggressive and deadly brain tumors, highlighting the critical need for improved prognostic markers and predictive models. Recent studies have identified the expression of IL7R as a significant risk factor that affects the prognosis of patients diagnosed with high-grade gliomas (HGG). This research focuses on investigating the prognostic significance of Interleukin 7 Receptor (IL7R) expression and aims to develop a noninvasive predictive model based on radiomics for *** conducted an analysis using data from The Cancer Genome Atlas (TCGA) and The Cancer Imaging Archive (TCIA), focusing on a group of 310 patients diagnosed with high-grade gliomas. To evaluate prognosis, we applied both univariate and multivariate Cox regression analyses alongside Kaplan-Meier survival analysis. Radiomics features were extracted from specific regions of interest, which were outlined by two physicians using 3D Slicer software. For selecting the most relevant features, we utilized the Minimum Redundancy Maximum Relevance (mRMR) and Recursive Feature Elimination (RFE) algorithms. Following this, we developed and assessed Support Vector Machine (SVM) and Logistic Regression (LR) models, measuring their performance through various metrics such as accuracy, specificity, sensitivity, positive predictive value, calibration curves, the Hosmer-Lemeshow goodness-of-fit test, decision curve analysis (DCA), and Kaplan-Meier survival *** survival analysis encompassed a total of 310 patients diagnosed with high-grade glioma, sourced from the TCGA database. Patients were stratified into high and low expression groups based on the levels of IL7R expression. Kaplan-Meier survival curves and Cox regression analysis revealed that an increase in IL7R expression correlated with a decline in overall survival (OS). The median Intraclass Correlation Coefficient (ICC) for the assessed radiomic features was determined to be 0.869, with 93 f

关键词： GB05   IFN alpha 1b   Inhalation solution   HRSV   HSA   Safety   Pharmacokinetics  

摘要： Human respiratory syncytial virus (HRSV) infection is linked to significant morbidity and mortality in infants and young children worldwide, yet no effective treatment is available. Interferon alpha (IFN alpha), a major subtype among the IFN family, has demonstrated antiviral effects by activating the human immune system. Aerosol inhalation is a way of IFN administration that can enhance efficacy while decreasing serum IFN alpha concentrations and systemic exposure, thereby minimizing the risk of systemic toxicity. However, at present, human interferon alpha 1b (IFN alpha 1b) injection solution is used off-label for inhalation, raising safety concerns for infants. Additionally, natural IFN alpha 1b contains a free sulfhydryl group from cysteine residue, increasing the risk of structural instability. Human serum albumin (HSA), an excipient in IFN alpha 1b formulations, may pose safety risks to infants. To address these concerns, we developed GB05-human IFN alpha 1b inhalation solution with optimized molecular design, expression system and formulation. First, GB05 protein was expressed in the periplasmic space to achieve easier purification. GB05 was engineered with a C86S mutation to prevent the formation of intermolecular disulfide bonds. Furthermore, GB05 was formulated according to regulations for inhalation solution, with a minimal HSA of 0.1 %, to ensure safety while preserving biological activity and stability. Plasma concentrations of GB05 following nebulization in cynomolgus macaques were significantly lower than those in the lungs, suggesting a reduced risk of systemic adverse events. Finally, GB05 showed good efficacy against HRSV infection in vitro and in vivo. In summary, GB05 is the first reported IFN inhalation solution manufactured in compliance with regulatory standards, to our knowledge, exhibiting safety and efficacy due to effectively local delivery. GB05 will fill the gap in the treatment of HRSV infection.

关键词： Estrogen receptor (ER(3)   breast cancer   interleukin-8 (IL-8)   NF-xB  

摘要： Background: Estrogen receptor (3 (ER(3) has been confirmed to play a tumor suppressor effect in various cancers, but its role in breast cancer is still unclear, especially in triple-negative breast cancer. In this study, we aim to explore the expression of ER(3 in breast cancer and its influence on the biological behavior of breast cancer cells, including its potential mechanisms of action. Methods: MCF-7 and MDA-MB-231 breast cancer cell lines were transfected with ER(3-overexpressing lentivirus and treated with pyrrolidinedithiocarbamate ammonium, a specific inhibitor of NF-xB. Cell Counting Kit-8, colony formation, and apoptosis assays were used to examine breast cancer cells viability in vitro. We further investigated breast cancer cells mobility and migration through wound healing and transwell assays. Western blot and quantitative real-time polymerase chain reaction analysis determined the expression of related genes at the protein and messenger RNA levels. Results: Breast cancer tissues displayed significantly lower ER(3 messenger RNA and protein levels compared to adjacent healthy tissues. Conversely, interleukin-8 (IL-8) messenger RNA and protein levels were significantly higher in cancer tissues. ER(3 overexpression led to a reduction in the expression of NF-xB pathway proteins like p-IxBa and p-P65, thereby inhibiting the pathway and consequently decreasing the expression of the inflammatory factor IL-8. This resulted in decreased mobility and migration of breast cancer cells, accompanied by increased apoptosis. Conclusions: This study demonstrates that ER(3 suppresses the NF-xB/IL-8 signaling axis by inhibiting the phosphorylation of IxBa and P65, consequently restricting breast cancer cell mobility and migration while promoting apoptosis.

关键词： protective vaccination   blood-stage malaria   liver response   genes expressing plasma proteins   coagulation   fibrinolysis   complement   IL-6 trans-signaling  

摘要： In response to vaccination and/or infectious agents, the liver produces acute-phase proteins (APPs) driven by IL-6, which circulate in blood plasma as components of the humoral innate defense. This study investigates the liver of mice for possible effects of protective vaccination against primary blood-stage infections of Plasmodium chabaudi malaria on the expression of genes encoding APPs and IL-6 family members. Female Balb/c mice were vaccinated with a non-infectious vaccine prior to challenge with 10(6) P. chabaudi-infected erythrocytes, resulting in about 80% survival of otherwise lethal infections. Gene expression microarrays were used to determine the relative transcript levels of genes in the livers of vaccinated and unvaccinated mice on days 0, 1, 4, 8, and 11 p.i. (post infectionem). Vaccination induced significant (p-value < 0.05) differences in the expression of malaria-responsive genes toward the end of crisis on day 11 p.i., when mice recovered from infections. These genes include Saa4, Apcs, Cp, and Crp, encoding APPs described to inhibitorily interact with parasitic blood stages;the genes F2, F7, F8, F9, F10, and F13b, and Plg, Plat, and Serpina5, encoding proteins balancing coagulation vs. fibrinolysis dysregulated by malaria, respectively;the genes Hc, C8a, C8b, C8g, and C9, encoding components of lytic complement membrane attack complex (MAC);and Cfh, Cfi, and C4bp, encoding complement-regulatory proteins. Vaccination accelerated, albeit differently, the malaria-induced activation of all three complement pathways, evidenced as higher transcript levels of C1qa, C1qb, C1qc, Fcna, Cfp, C3, Cfh, C8a, and C9 on day 4 p.i., C1ra, C1s, and C2 on day 1 p.i., and Serping1, encoding the multifunctional protease inhibitor C1INH, on day 0 p.i. Protective vaccination may also accelerate downregulation of the malaria-promoting lethality of IL-6 trans-signaling, which may contribute to an overall accelerated recovery of mice from otherwise lethal blood-stage mal

关键词： immunotherapy   cancer   Merkel cell carcinoma   antiviral immunity   cytokines  

摘要： Previously, we reported on the peptide-HLA-I fusion protein EpCAM-ReTARG(TPR), which allows us to redirect the cytotoxic activity of pre-existing anti-CMV CD8(pos) T cell immunity to selectively eliminate EpCAM(pos) cancer cells. EpCAM-ReTARG(TPR) consists of the CMV pp65-derived peptide TPRVTGGGAM (TPR) fused in tandem with a soluble HLA-B*07:02/beta 2-microglobulin (beta 2M) molecule and an EpCAM-directed Fab antibody fragment. To further enhance its anticancer activity, we equipped EpCAM-ReTARG(TPR) with the immune-potentiating cytokine muteins IL2((H16A,F42A)) and IFN alpha(R149A), respectively. Both cytokines are engineered to have attenuated affinity for their respective cytokine receptors. Compared to EpCAM-ReTARG(TPR), in vitro treatment of EpCAM(pos) carcinoma cell lines with EpCAM-ReTARG(TPR)vIL2 for 24 h increased the cytotoxic activity of PBMCs containing low levels of TPR-specific CD8(pos) T cells by similar to 15%, whereas EpCAM-ReTARG(TPR)IFN alpha(R149A) induced an increase of similar to 50%. Moreover, treatment for 120 h with EpCAM-ReTARG(TPR)IFN alpha(R149A) inhibited the proliferative capacity of the cancer cell lines OvCAR3 and PC3M by similar to 91% without compromising the viability of the TPR-specific CD8(pos) T cells and increased their capacity for IFN gamma secretion. Importantly, EpCAM-ReTARG(TPR)IFN alpha(R149A) potently induced the elimination of primary EpCAM(pos) refractory carcinoma cells from a Merkel cell carcinoma (MCC) patient. Taken together, the armoring of the carcinoma-directed peptide-HLA-I fusion protein EpCAM-ReTARG(TPR) with IFN alpha(R149A) potently enhanced the efficacy of pre-existing anti-CMV CD8(pos) T cell immunity to selectively eliminate EpCAM(pos) cancer cells.

关键词： extrinsic allergic alveolitis   BAFF   cytokine   TLR9   ozanimod   S1P   S1P(1)   S1P(5)   CD69   TNF  

摘要： Lymphocytes are central to the pathogenesis of hypersensitivity pneumonitis and a strong body of evidence supports that lymphocytes are modulated by sphingosine-1-phosphate receptor-modifying drugs. This exploratory study aimed to determine if a pharmacological sphingosine-1-phosphate receptor ligand interfered with the activation of lymphocytes obtained from fibrotic hypersensitivity pneumonitis patients. Peripheral blood mononuclear cells of 12 patients and 10 control subjects were submitted to CD3/CD28 stimulation, isolated B cells were incubated with a TLR9 ligand;and we tested how these stimulations were impacted by ozanimod, a sphingosine-1-phosphate receptor ligand. T cell and B cell subsets from patients overexpressed CD69 and cytokines such as TNF and IL-4 in response to CD3/CD28 stimulation, compared to controls. In patients with fibrotic hypersensitivity pneumonitis, ozanimod alleviated CD3/CD28 induction of CD69, IL-4, and TNF in CD8, but not CD4 T cells. In isolated B cells stimulated with a TLR9 ligand, ozanimod reduced cell surface expression of CD69, CD86, and CD40, as well as TNF and IL-6 accumulation in supernatant. We conclude that lymphocyte subsets are functionally impacted in patients with fibrotic hypersensitivity pneumonitis and that ozanimod can interfere ex vivo with the overactivation of B cells and CD8 T cells in response to specific stimuli.