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关键词： HBV   HBsAg loss   Peg-IFN alpha   Machine learning   Functional cure  

摘要： Objective: Functional cure is currently the highest goal of hepatitis B virus(HBV) *** interferon (Peg-IFN) alpha is an important drug for this purpose,but even in the hepatitis B e antigen(HBeAg)-negative population,there is still a portion of the population respond poorly to ***,it is important to explore the influencing factors affecting the response rate of Peg-IFN alpha and establish a prediction model to further identify advantaged populations. Methods: We retrospectively analyzed 382 patients.297 patients were in the training set and 85 patients from another hospital were in the test *** intersect features were extracted from all variables using the recursive feature elimination(RFE) algorithm, Boruta algorithm, and least absolute shrinkage and selection operator (LASSO) regression algorithm in the training ***,we employed six machine learning(ML) algorithms- Logistic Regression(LR),Random Forest(RF),Support Vector Machines(SVM),K Nearest Neighbors(KNN),Light Gradient Boosting Machine(LightGBM) and Extreme Gradient Boosting(XGBoost)-to develop the *** 10-fold cross-validation helped determine the best-performing model,which was then tested *** performance was assessed using metrics such as area under the curve(AUC) and other *** Additive exPlanations(SHAP) plots were used to interpret variable significance. Results: 138/382(36.13 %) patients achieved functional *** at baseline,HBsAg decline at week12,nonalcoholic fatty liver disease(NAFLD) and age were identified as significant *** performed the best, with AUC value of 0.988,and maintained good performance in test *** SHapley Additive exPlanations(SHAP) plot highlighted HBsAg at baseline and HBsAg decline at week 12 are the top two *** web-calculator was designed to predict functional cure more conveniently(https://***/model/list/predi ct/model/html?mid = 17054&symbol = 317ad245Hx628ko3u

关键词： IL-2   Type 2 diabetes   Immunotherapy   Regulatory T cells   Macrophage polarization   Th17 T cells   Gut microbiota  

摘要： Interleukin-2 (IL-2) is pivotal in immune regulation, particularly in the promotion of regulatory T (Treg) cells and the maintenance of immune tolerance. While its efficacy in autoimmune diseases is well established, its role in type 2 diabetes (T2D) remains largely unexplored. This study investigates the effects of low-dose IL-2 in a KM mouse model of T2D induced by streptozotocin (STZ) and a high-fat, high-sugar (HFHS) diet. We found that lowdose IL-2 administration significantly improved fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c) levels, and glucose tolerance, indicating better glycemic control. Additionally, IL-2 treatment improved insulin sensitivity, enhanced insulin secretion, and ameliorated lipid metabolism, as evidenced by reduced cholesterol and triglyceride levels. These metabolic improvements were associated with a modulation of inflammation, including a reduction in pro-inflammatory cytokines (TNF-alpha, IL-113) and an increase in anti-inflammatory cytokines (IL-10). Importantly, IL-2 also altered the gut microbiome, reducing intestinal inflammation and endotoxin levels, which suggests a broader impact on metabolic health beyond immune regulation. These findings support the potential of low-dose IL-2 as an immunotherapeutic approach for improving metabolic dysfunction and inflammation in T2D.

关键词： IL-17A   Radiation-induced lung injury   mTOR   PP2A B56 alpha   Autophagy  

摘要： Objective: Radiation-induced lung injury (RILI) is a serious complication of radiotherapy, and the role of IL-17A in this process is not well understood. While IL-17A has been shown to modulate autophagy, conflicting reports exist regarding its activation or inhibition of autophagy. This study investigates the role of IL-17A in RILI and its effects on autophagy via the PP2A-mTOR pathway, with a focus on the PP2A B56 alpha subunit. Methods: C57BL/6J mice and human lung epithelial cells (BEAS-2B) were exposed to radiation with or without recombinant IL-17A. Autophagy markers were analyzed using Western blotting, immunofluorescence, and autophagy flux assays. PP2A activity, specifically the B56 alpha subunit, was measured. A PP2A agonist (DT-061) was used to verify its role in reversing IL-17A-mediated autophagy inhibition. Results: IL-17A inhibited autophagy in lung epithelial cells exposed to radiation by suppressing PP2A activity, particularly through downregulation of the B56 alpha subunit, leading to mTOR activation and reduced autophagosome formation. Treatment with DT-061 restored autophagic activity and improved cell viability. These findings align with reports suggesting that IL-17A inhibits autophagy in certain contexts, while other studies have shown opposing effects. Conclusion: IL-17A inhibits autophagy in RILI through the PP2A B56 alpha-mTOR pathway, exacerbating lung damage. Further research is needed to clarify the role of IL-17A in different cell types and conditions. Targeting the IL-17A-PP2A B56 alpha-mTOR axis may offer new therapeutic strategies for RILI management.

关键词： T-cells  

摘要： Interleukin-2 (IL-2) is a T cell growth factor that is essential for the proliferation of T cells and the generation of effector and memory cells. The antitumor activity of high-dose IL-2 therapy requires maintaining the affinity between IL-2 and IL2-R alpha, which can also bring serious toxic side effects. To address this issue, we designed ZGP-Cysteamine-IL-2-K64C and (ZGP-Cysteamine)2-IL-2-(K43C, K64C) based on the strategy of FAP alpha enzyme-activated prodrugs, and investigated their anti-tumour activity and side effects. In vitro FAP alpha enzyme cleavage results indicated that the side-chain modified ZGP-Cysteamine moiety could be precisely recognized and cleaved by FAP alpha, thereby restoring the activity of native IL-2 capable of binding to IL-2R alpha in the tumour microenvironment, where it promotes the expansion of CD8+ T cells. Meanwhile, surface plasmon resonance analysis revealed that, compared to wt-IL-2, both ZGP-Cysteamine-IL-2-K64C and (ZGP-Cysteamine)2-IL-2-(K43C, K64C) exhibited significantly reduced affinity for IL-2R alpha, while their affinity for IL-2R beta gamma remained unchanged. Remarkably, ZGP-Cysteamine-IL-2-K64C and (ZGPCysteamine)2-IL-2-(K43C, K64C) almost completely eliminated the pulmonary edema and vascular permeability. Furthermore, the combination of ZGP-CysteamineIL-2-K64C and PD-1 blockade showed robust anti-tumour activity in mice tumour models. Our study provides new insights into the structural design of IL-2 prodrug with low side effect and robust anti-tumour efficacy.

关键词： Decellularization   Criteria of decellularization   Human Leucocyte antigen   Major histocompatibility complex   Immunization   Rejection  

摘要： Last twenties, tissue engineering has rapidly advanced to address the shortage of organ donors. Decellularization techniques have been developed to mitigate immune rejection and alloresponse in transplantation. However, a clear definition of effective decellularization remains elusive. This study compares various decellularization protocols using the human fascia lata model. Morphological, structural and cytotoxicity/viability analyses indicated that all the five tested protocols were equivalent and met Crapo's criteria for successful decellularization. Interestingly, only the in vivo immunization test on rats revealed differences. Only one protocol exhibited Human Leucocyte Antigen (HLA) content below 1% residual threshold, the only criterion preventing rat immunization with an absence of rat anti-human IgG switch after one month (N=4 =4 donors for each of the 7 groups, added by negative and positive controls, n=28). =28). By respecting a refined set of criteria, i.e. lack of visible nuclear material, <50ng DNA/mg dry weight of extracellular matrix, and <1% residual HLA content, the potential for adverse host reactions can be drastically reduced. In conclusion, this study emphasizes the importance of considering not only nuclear components but also major histocompatibility complex in decellularization protocols and proposes new guidelines to promote safer clinical development and use of bioengineered scaffolds.

关键词： TNF-alpha/IL-1 beta/IL-1 alpha/IL-12 axes   TLR1/TLR3/TLR5/MYD88 signaling pathway   Carotid artery occlusion   Coronary artery occlusion   Elderly patients  

摘要： Background: It remains difficult to evaluate the risk factors for concomitant carotid artery as well as coronary artery diseases in elderly patients. The aim of this research was to determine the TNF-alpha/IL-1 beta/IL-1 alpha/IL-12 axesTLR1/TLR3/TLR5/MYD88 immune signaling pathway interactions in coexistent carotid artery occlusion and coronary artery occlusion in elderly patients. Methods: Elderly patients, who underwent carotid ultrasonography and coronary computed tomography angiography, were consecutively included in this research. The analyzed groups consisted of those with coexistent carotid artery occlusion and coronary artery occlusion as well as healthy individuals were enrolled as control group. The circulating levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-1 alpha (IL-1 alpha), interleukin-12 (IL-12), toll-like receptor 1 (TLR1), toll-like receptor 3 (TLR3), toll-like receptor 5 (TLR5) and myeloid differentiation factor 88 (MYD88) were measured. Results: The biomarkers (TNF-alpha, IL-1 beta, IL-1 alpha, IL-12, TLR1, TLR3, TLR5 and MYD88) were significantly increased in carotid artery occlusion + left circumflex coronary artery occlusion group when compared with control group and carotid artery occlusion + right coronary artery occlusion group, respectively (P < 0.001), and were further elevated in carotid artery occlusion + left anterior descending coronary artery occlusion group when compared to carotid artery occlusion + right coronary artery occlusion group and carotid artery occlusion + left circumflex coronary artery occlusion group, respectively (P < 0.001). Conclusion: This research demonstrated that the TNF-alpha/IL-1 beta/IL-1 alpha/IL-12 axes and TLR1/TLR3/TLR5/MYD88 immune signaling pathway implicated in the pathogenesis of carotid artery occlusion with coronary artery occlusion in elderly patients.

关键词： Granuloma annulare   Granulomas   IFN-gamma   Macrophage   TNF  

摘要： Granuloma annulare (GA) is an idiopathic condition characterized by granulomatous inflammation in the skin. Prior studies have suggested that GA develops from various triggers, leading to a complex interplay involving innate and adaptive immunity, tissue remodeling, and fibrosis. Macrophages are the major immune cells comprising GA granulomas;however, the molecular drivers and inflammatory signaling cascade behind macrophage activation are poorly understood. Histologically, GA exhibits both palisaded and interstitial patterns on histology;however, the molecular composition of GA at the spatial level remains unexplored. GA is a condition without Food and Drug Administration- approved therapies despite the significant impact of GA on QOL. Spatial transcriptomics is a valuable tool for profiling localized, genome-wide gene expression changes across tissues, with emerging applications in clinical medicine. To improve our understanding of the spatially localized gene expression patterns underlying GA, we profiled the spatial gene expression landscape from 6 patients with GA. Our findings revealed mixed T helper 1 and T helper 2 signals comprising the GA micro- environment and spatially distinct M1 and M2 macrophage polarization characteristics. IFN-g and TNF signals emerged as important regulators of GA granulomatous inflammation, and IL-32 emerged as a key driver of granulomatous inflammation. Overall, our spatial transcriptomics data indicate that GA exhibits mixed immune and macrophage polarization.

摘要： BACKGROUND:Metastatic colorectal cancer (mCRC) is the main cause of CRC mortality, with limited treatment options. Although immunotherapy has benefited some cancer patients, mCRC typically lacks the molecular features that respond to this treatment. However, recent studies indicate that the immune microenvironment of mCRC may be modified to enhance the effect of immune checkpoint inhibitors. This study aimed to explore the metastatic tumor microenvironment (TME) by comparing cell populations in colorectal liver (CLM), lung (mLu), and peritoneal (PM) metastases. METHODS:RNA isolated from 20 CLM, 15 mLu, and 35 PM samples was subjected to mRNA sequencing and explored through TME deconvolution tools, consensus molecular subtyping (CMS), and differential gene expression and gene set enrichment analysis, with respect to the metastatic sites. Clinical data and KRAS/BRAF hotspot mutation status were also obtained for all the cases. RESULTS:The cell type fractions in the TME were relatively similar between the metastatic sites, except for cancer-associated fibroblasts (CAFs), B cells, endothelial cells, and CD4+ T cells. Notably, PM showed enrichment for CAFs and endothelial cells, consistent with distinct pathways associated with metastatic growth and progression in the peritoneal cavity. PM with the mesenchymal subtype, CMS4, had increased CAFs, endothelial cells, and macrophages, along with up-regulated genes related to TNF-α signaling via NF-κB, EMT, and angiogenesis. CONCLUSIONS:Tumor samples from different metastatic sites exhibited a broadly similar TME in terms of immune cell composition, with some intriguing differences. Targeting CAF-associated pathways, macrophages, and TNF-α signaling through NR4A could represent potential novel therapeutic approaches in CMS4 PM.

关键词： Biomolecular spectroscopic profiling   Cardiovascular disease macromolecular markers   Non-invasive   Label-free spectroscopy-AI technique  

摘要： Cardiovascular disease (CVD) remains a major global health concern and a leading cause of morbidity and mortality worldwide. Early-diagnosis and prompt medical attention are crucial in managing and reducing overall impact on health-and-wellbeing, necessitating the development of innovative diagnostics, which transcend traditional methodologies. Raman spectroscopy uniquely provides molecular fingerprinting and structural information, offering insights into biochemical composition. Integration of Raman spectroscopy with advanced machine learning is established as a powerful clinical adjunct for point-of-care detection of CVDs. A non-invasive, label-free spectroscopic platform coupled with neural network algorithm, 'SKiNET' has been developed to accurately detect the biomolecular changes within plasma of CVD versus healthy cohorts, enabling rapid diagnosis and longer-term monitoring, where the real-time capabilities provide dynamic assessment of progression, aligning treatment strategies with evolving states. CVD has been detected and classified via SKiNET with 88.6 %-accuracy, 92.9 %-specificity and 85.1 %-sensitivity and with 83.8 %-accuracy. The hybrid RS-SKiNET biomolecularly specific detection signposted a comprehensive panel of CVD-indicative biomarkers, including SIL-6, IL-9, LpA, ApoB, PCSK9 and NT-ProBNP, offering important insights into disease mechanisms and risk- stratification. This multidimensional technique holds potential for improved patient-and-healthcare management for CVDs, laying the platform toward high-throughput biomolecular profiling of CVD-indicative macro- molecular biomarkers, particularly vital for widespread point-of-care diagnostics and monitoring.