课程文献中心 更多>>

关键词： TACC3   radiotherapy resistance   HCC   Macrophage   XRCC5/6  

摘要： Radiotherapy plays an increasingly crucial role in the treatment of hepatocellular carcinoma (HCC). However, resistance to radiotherapy remains a significant obstacle to achieving optimal treatment outcomes. Our objective is to elucidate the mechanisms underlying radiotherapy resistance. Through proteomic sequencing of radiotherapy-resistant cell lines and patient-derived xenograft tissues from HCC patients, we identified that Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) is upregulated in both radiotherapy-resistant cell lines and tissues. After radiotherapy treatment, DNAPK phosphorylates TACC3 at 315 threonine, leading to enhanced protein stability of TACC3. TACC3 facilitated the proliferative capacity and radiotherapy resistance of HCC cells by promoting the interaction between XRCC5 and XRCC6 through specific residues within its coiledcoil domain, namely ILE736, ASN742 and GLU773. This interaction facilitates DNA damage repair via the nonhomologous end joining pathway in response to radiation, thereby contributing to the radiotherapy resistance in HCC cells. Furthermore, TACC3 increases the production of IL-4 and IL-10 within HCC cells, inducing the differentiation of M0 macrophages to M2 macrophages within the immune microenvironment, leading to the suppression of CD8+T cell cytotoxic functions and creating an immunosuppressive microenvironment in HCC. Targeting TACC3 with inhibitor KHS101 significantly inhibit the proliferation of HCC and improve the immune microenvironment of HCC.

关键词： Tumor progression   Autophagy modulation   Cancer cell survival   IL-6/STAT3 pathway   Proteasome  

摘要： Aims: This study aims to investigate the expression, clinical relevance, and functional roles of PSME2 in esophageal squamous cell carcinoma (ESCC). Materials and methods: The biomarkers for ESCC were identified through comprehensive analysis of publicly available mRNA transcriptome data obtained from TCGA and GEO databases. The mRNA and protein expression levels of PSME2 in ESCC were validated using two independent cohorts of ESCC samples. The proliferation, migration, invasion, and autophagy activity of ESCC cells were evaluated in vitro through the knockdown of PSME2 or PR171. The effects of the knockdown of PSME2, STAT3 inhibitor WP1066, and autophagy inhibitor chloroquine on the tumorigenic potential of ESCC cells were also assessed through an in vivo subcutaneous tumor model established in nude mice. Key findings: The result obtained indicates the upregulation of PSME2 in ESCC, suggesting poor prognosis. The result also shows that the knockdown of PSME2 and PR171 triggers the reduction in ESCC cell proliferation, migration, and invasion. Thus, it buttresses the fact that PSME2 knockdown induced autophagy through the IL6/ STAT3 pathway, leading to cell death resistance. The result also linked the suppression of tumor growth to the knockdown of PSME2 and WP1066 or chloroquine, suggesting that targeting these proteins may be a potential therapeutic strategy for inhibiting tumor progression. Significance: The study shows the promising role of PSME2 as a therapeutic target in ESCC management. The combined inhibition of PSME2 and activated pathways ensures effective suppression of tumor growth and proliferation, thus offering a novel strategy for better treatment outcomes in ESCC patients.

关键词： Chronic hepatitis B   Functional cure   Machine learning  

摘要： Background: Functional cure is the ideal treatment goal for chronic hepatitis B (CHB) treatment. We developed and validated machine learning (ML) models to predict functional cure in CHB patients. Methods: This study retrospectively recruited 534 CHB patients who received Peg-IFN treatment to construct model and 269 patients for external validation. We analyzed three strategies: baseline, week 12, week 24. Seven ML models were constructed using selected variables by Boruta and least absolute shrinkage and selection operator regression algorithm, and performance metrics, including area under the curve (AUC), sensitivity, specificity, and F1 score were applied to determine the best model. We utilized SHapley Additive exPlanation to visualize and interpret the best model and built a website to conveniently predict functional cure of CHB. Results: A total of 272 participants were cured in our study. Compared to baseline and week 12 strategies, week 24 using Support Vector Machine (SVM) model can better predict functional cure of CHB, with reliable predictive performance (AUC = 0.981), calibration and clinical applicability in external validation cohort. Age, ALT ratio at week 12, HBsAg at week 24 and HBsAg ratio at week 24 were important features. In order to enhance clinical convenience and effectiveness of the constructed model, a web-based dynamic nomogram was created (Dynamic Nomogram (***)). Conclusion: This study developed SVM model to predict functional cure in CHB patients treated with Peg-IFN. Furthermore, we also built a website that clinicians can individualized predict the efficacy of Peg-IFN therapy in CHB patients.

关键词： Helicobacter pylori   IL-17   IL-23   Gastric ulcer and gastric cancer  

摘要： Background: Helicobacter pylori (H. pylori) infection is associated with various gastric diseases, including gastric ulcer (GU) and gastric cancer (GC). Objective: The research examines the levels of IL-17 and IL-23 in patients with H. pylori-induced gastric diseases and evaluates the correlation between these cytokines. Subjects and methods: This cross-sectional study was conducted from September 2020 to August 2022. A total of 96 patients were recruited and diagnosed with H. pylori. They were grouped into 56 with GU and 40 with GC. A health control (HC) group of 30 individuals without H. pylori was included. Serum levels of IL-17 and IL-23 were measured in all participants. Results: H. pylori-positive patients showed significantly higher IL-17 and IL-23 levels in GU and GC compared to negative groups (P < 0.001). Post-hoc analysis showed the highest level of both cytokines IL-17 and IL-23 difference between H. pylori-positive GC and control (-48.14, p < 0.001 and -36.75, p < 0.001, respectively). There was a positive correlation between IL-17 and IL-23 in both H. pylori-positive (r = 0.573, P < 0.05) and H. pylori-negative (r = 0.452, P < 0.05). High levels of IL-23 were found to increase the risk of GC significantly. Conclusion: The serum levels of IL-17 and IL-23 are significantly elevated in patients with GU and GC, regardless of H. pylori status, compared to healthy controls. This suggests their potential role as biomarkers for inflammation and disease progression in gastric conditions associated with H. pylori.

关键词： Sarcopenia   Ursolic acid   Skeletal atrophy   Gut microbiota   IL-17a pathway.  

摘要： Sarcopenia significantly impairs quality of life, especially in diabetic patients, where effective treatment options remain limited. The IL-17a-related gutmuscle axis suggests a potential role of the gut microbiota in the development of sarcopenia. Ursolic acid (UA) has shown promise as an anti-sarcopenic agent. Nevertheless, the relationship between UA and the IL-17a-related gut-muscle axis remains unclear. In this research, sarcopenia model was established using streptozotocin in vivo and in vitro with TNF- alpha-managed C2C12 myotubes. UA significantly altered the gut microbiota, notably increasing observed OTUs and the Shannon index of sarcopenic mice. Specifically, UA effectively mitigated the decrease of Bacteroides thetaiotaomicron and restored the total level of short-chain fatty acids, particularly reducing propionic acid and increasing isovaleric acid. Additionally, UA markedly improved muscle quality and function, as evidenced by increased body weight, grip strength, and muscle weight, as well as significantly decreased expression of Atrogin-1 and MuRF-1. Moreover, RNA sequencing results clearly indicated that UA suppressed the IL-17 signaling pathway in sarcopenic mice. Furthermore, UA alleviated oxidative stress and apoptosis in sarcopenic mice. Notably, UA inhibited the IL-17a pathway in sarcopenic mice by suppressing the heightened expression of the proteins. In vitro experiments further confirmed that UA inhibited TNF- alpha-induced myotube atrophy, reduced Atrogin-1 and MuRF-1 expression, and strongly suggested that IL-17a may be a key target of UA in combating myotube atrophy. The study emphasizes the importance of UA in alleviating

关键词： Infliximab   biosimilars   TNF   psoriasis   inflammation   infusion therapy   PASI  

摘要： Infliximab (INF), a murine human monoclonal antibody, is a substantially more successful biologic than topical drugs for treating mild to severe psoriasis because it clears the skin rapidly due to its fast onset of action. Loss of responsiveness over time and some adverse effects, especially the experience of infusion reactions, are the major causes of non-compliance with INF medication. Therefore, evaluation of the long-term reliability of anti-tumor necrosis factor (TNF) medications is necessary for the assessment of the risks associated with long-term anti-TNF therapy. For psoriasis, there are registered safety statistics;however, these individuals might not receive the same level of care as those in a randomized study. Few assessments of the safety of anti-TNF medications across indications, including their biosimilars, are present, but it's still unknown how anti-infliximab antibodies arise and produce harmful effects. INF biosimilars, when subjected to human studies to reduce cost and improve access, provide therapeutic benefits with associated adverse events, showing variations in incidence depending upon varying patient populations and no new safety indications. During therapy, certain individuals develop antibodies against INF, which are believed to be linked to a loss of response (LOR). Additional research aimed at identifying individuals who are susceptible to treatment resistance is likely to assist doctors in accurately selecting the appropriate candidates for anti-TNF-alpha therapy and enhancing the long-term effectiveness of the treatment. From clinical studies, we expect to learn about how to utilize INF or its biosimilars more effectively in the management of psoriasis. Therefore, the paper focuses on the efficacy and safety monitoring of INF and developed biological therapies.

关键词： Colorectal cancer   Immunotherapy resistance   CD8+T cells   IL32   Nano-selenium   Engineered probiotics   Extracellular vesicles   Tumor microenvironment   Biomaterial therapy  

摘要： Background and objective: Colorectal cancer (CRC) is a major global health burden, with immunotherapy often limited by immune tolerance and resistance. This study introduces an innovative approach using Selenium Nanoparticles-Loaded Extracellular Vesicles combined with Interleukin-32 and Engineered Probiotic Escherichia coli Nissle 1917 (SeNVs@NE-IL32-EcN) to enhance CD8+ T cell-mediated immune responses and overcome immunotherapy resistance. Methods: Single-cell RNA sequencing (scRNA-seq) and transcriptomic analyses were performed to identify key immune cells and regulators involved in CRC immunotherapy resistance, focusing on CD8+ T cells and the regulatory factor IL32. A humanized xenograft mouse model was used to evaluate the impact of IL32 and SeNVs@NE-IL32-EcN on tumor growth and immune responses. The SeNVs@NE-IL32-EcN complex was synthesized through a reverse micelle method and functionalized using extracellular vesicles. Its morphology, size, antioxidant activity, and safety were characterized using electron microscopy, dynamic light scattering (DLS), and in vitro co-culture assays. Results: Single-cell analyses revealed a significant reduction in CD8+ T cell infiltration in immunotherapyresistant CRC patients. IL32 was identified as a key regulator enhancing CD8+ T cell cytotoxic activity through granzyme B and IFN-gamma secretion. Treatment with SeNVs@NE-IL32-EcN significantly improved the proliferation and activity of CD8+ T cells and reduced tumor progression in humanized mouse models. In vitro and in vivo results demonstrated the complex's biocompatibility, antioxidant properties, and ability to enhance CRC immunotherapy while mitigating immune tolerance. Conclusion: SeNVs@NE-IL32-EcN offers a novel nano-biomaterial strategy that integrates nanotechnology and probiotic therapy to enhance CD8+ T cell-mediated immunity and overcome CRC immunotherapy resistance. This study lays the foundation for future therapeutic applications in cancer treatment by advan

关键词： Autoimmune   HLA   Immunogenetics   Stevens-Johnson syndrome   Toxic epidermal necrolysis  

摘要： Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are very rare dermatologic disorders characterized by extensive detachment of the epidermis. Although some drugs, infectious agents, HLA genes, malignancy and connective tissue diseases are thought to play a role in the development of the disease, the pathogenesis has not been fully elucidated. Type IV hypersensitivity reactions are thought to be the underlying cause of these diseases. Inflammatory changes such as purulent erosion, ulcers and crusting can be seen in the gastrointestinal system, urinary tract and genital mucosa. Some immunologic biyomarkers like as HLA-B* 1502, Granulysin and CCL-27 are used in clinical diagnosis, prognosis, treatment, and personalized new drug development that could further explain the pathogenesis of SJS and TEN. This review focuses on the pathophysiology of the SJS and TEN and presents it in light of current data on this subject. We recommend further in vivo and in vitro studies to unravel the underlying immunological mechanisms to determine appropriate intervention strategies.

关键词： Inflammatory signaling   oxidative stress signaling   immune signaling   myocardial cell injury   elderly  

摘要： Introduction The mutual activations of multiple signaling pathways are the key factors in the development and progression of myocardial cell injuries. Objective This research aimed to compare the different degrees of myocardial injury after coronary stenting, permanent pacemaker implantations, or cardiac radiofrequency ablation and to investigate the effects of the mutual activation of TNF-alpha/NF-kappa B, TLR2/TLR4, and ROS/MDA signaling pathways on myocardial injury in elderly patients after coronary stents or permanent pacemakers or radiofrequency ablation. Methods We determined reactive oxygen species (ROS), malondialdehyde (MDA), toll-like receptor 2 (TLR2), toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-kappa B), tumor necrosis factor-alpha (TNF-alpha) and high-sensitive cardiac troponin T (hs-cTnT) as a marker of myocardial injury in patients. Results The levels of ROS, MDA, TLR2, TLR4, NF-kappa B, TNF-alpha, and hs-cTnT were increased in patients with permanent pacemaker implantations when compared to patients with cardiac radiofrequency ablation (P < 0.01) at 6 months and were further increased in patients with coronary stenting compared to patients with cardiac radiofrequency ablation and permanent pacemaker implantations at 6 months, respectively (P < 0.01). This research confirmed that ROS, MDA, TLR2, TLR4, NF-kappa B, and TNF-alpha predicted myocardial injury severity. Conclusion Oxidative stress (ROS/MDA signaling pathway) may be linked to immune response (TLR2/TLR4 signaling pathway) and pro-inflammatory response (TNF-alpha/NF-kappa B signaling pathway) in myocardial injury, and ROS/MDA signaling may play a dominant role.