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关键词： CD8(+) T-lymphocytes   dendritic cells   epitopes   HCC   T-lymphocyte   tumor-associated antigen  

摘要： Background: HCC is the most common form of primary liver cancer, and despite recent advances in cancer treatment, it remains associated with poor prognosis and a lack of response to conventional therapies. Immunotherapies have emerged as a promising approach for cancer treatment, especially through the identification of tumor-specific immunogenic epitopes that can trigger a targeted immune response. This study aimed to identify immunogenic epitopes associated with HCC for the development of specific immunotherapies. Methods: We used high-throughput data screening and bioinformatics tools for antigens and epitope selection. The immunogenicity of the selected epitopes was studied after coculture of peripheral blood mononuclear cells obtained from healthy donors or HCC patients with a plasmacytoid dendritic cell line loaded with the selected peptides. Specific CD8(+) T cell amplification and functionality were determined by labeling with tetramers and by IFN-gamma and CD107a expression (flow cytometry and ELISpot). Results: We analyzed the transcriptional gene expression landscape of HCC to screen for a set of 16 ectopically expressed genes in a majority of HCC samples. Epitopes predicted to bind to HLA-A*02:01 with high affinity were further validated for their immunogenicity using the previously described plasmacytoid dendritic cell line in ex vivo CD8(+) activation assays using patient immune cells. Three out of the 30 tested epitopes, namely FLWGPRALV (MAGE-A3), FMNKFIYEI (AFP), and KMFHTLDEL (LRRC46), elicited a strong T-cell response, in activation assays, degranulation assays, and IFN-gamma secretion assays. Conclusions: These results highlight the potential of these peptides to be considered as targets for immunotherapies. The discovery of such immunogenic epitopes should improve immune-based treatments for liver cancer in combination with the current treatment approach.

关键词： AVL9   Chemoresistance   NF-κB   KPC   PDAC   AG   gemcitabine combined with albumin-paclitaxel (Abraxane)   AUC   area under the curve   ChIP   chromatin immunoprecipitation   dCDA   dCyd deaminase   dCK   dCyd kinase   DEGs   differentially expressed genes   FNA   fine-needle aspiration   GEM   gemcitabine   HRE   hypoxia response element   IC50   half maximal inhibitory concentration   IFN   interferon   IHC   immunohistochemistry   IKK   inhibitor of kappa B kinase   IκB   inhibitory-κB   KPC   Kras G12D Trp53 R172H Pdx1-Cre   KPCA   Kras G12D Trp53 R172H Pdx1-Cre AVL9 fl/fl   mRNA   messenger RNA   NF-κB   nuclear factor–κB   p-   phosphorylated   PCA   principal components analysis   PDAC   pancreatic ductal adenocarcinoma   PDO   patient-derived organoid   PDX   patient-derived xenograft   scRNA-seq   single cell transcriptomic sequencing   SKP1   S-Phase Kinase Associated Protein 1   TCGA   The Cancer Genome Atlas   tSNE   t-distributed stochastic neighbor embedding  

摘要： BACKGROUND & AIMS: Gemcitabine combined with albumin-paclitaxel (AG) is a crucial therapeutic option for pancreatic ductal adenocarcinoma (PDAC). However, the response to chemotherapy is relatively poor, with rapid development of resistance. The aim of this study was to explore the mechanism of resistance to AG and to develop strategies that can sensitize the AG regimen. METHODS: We used organoid models, patient-derived xenografts, and genetically engineered mouse models in our study. Chromatin immunoprecipitat ion, double luciferase assay, coimmunoprecipitation, and far-western blotting analysis were performed to investigate the mechanism. The AVL9 inhibitors were identified through protein structure analysis and molecular docking analysis, and their efficacy was verified in patient-derived xenografts, patient-derived organoids-based xenograft, and KPC models. RESULTS: Through multistrategy screening, we identified AVL9 as a key target for AG resistance in PDAC. Its tumor-promoting effects were confirmed in our clinical cohorts. Mechanistically, HIF-1a, a hypoxia-related transcription factor, drives the expression of AVL9. AVL9 acts as a scaffold that facilitates the binding of IkBa to SKP1, leading to enhanced ubiquitination and degradation of IkBa, which further activates the nuclear factor-kB pathway. The potential AVL9targeting inhibitor, Edotecarin, was shown to reverse AG chemo-resistance in PDAC. CONCLUSION: AVL9 expression is driven by HIF-1a in PDAC. The physical interaction of AVL9, IkBa, and SKP1 provides a novel molecular mechanism for the abnormal activation of the nuclear factor-kB pathway. Therefore, the AVL9-targeting drug Edotecarin could be a promising therapeutic strategy for sensitizing PDAC to AG.

关键词： TB   tuberculosis   TNF   tumor necrosis factor  

关键词： Clear aligner   Cytokines   Gingival crevicular fluid   Interleukin-8   Interleukin-6  

摘要： Objectives: To compare short-term changes in the levels of interleukin-8 (IL-8) and interleukin-6 (IL-6) in the gingival crevicular fluid (GCF) of individuals undergoing orthodontic treatment with clear aligners. Materials and Methods: This study included 15 individuals. Each patient used clear aligners designed not to cause tooth movement in the GCF sampled teeth, to be changed every 10 days. GCF samples were collected from teeth 16 (upper right first molar) and 31 (lower left central incisor) at baseline and after the procedure at the first hour, third, seventh, 14th, and 21st days. In addition, clinical periodontal parameters for the full mouth and the teeth from which GCF was collected were recorded initially and on the 21st day. Results: A statistically significant difference was observed between the levels of IL-8 before the procedure, on the third and seventh days, and on the 21st day (P < .01). The increase in IL-6 levels on the 14th and 21st days was significantly different compared to the levels before the procedure (P < .01). A positive correlation was detected between IL-8 and IL-6 levels at the first hour, a negative correlation on the third day, and a lower level of positive correlation on the seventh, 14th, and 21st days. Conclusions: Within 21 days, the levels of IL-8 and IL-6 significantly increased in individuals undergoing orthodontic treatment with clear aligners. Within the limits of this study, the clear aligner material may affect the levels of IL-8 and IL-6 in the GCF.

关键词： Transmembrane TNF-alpha   Reverse signaling   LPS/TLR4 signaling pathway   MCPIP1   SIRT1  

摘要： Background: Studies have demonstrated that transmembrane tumor necrosis factor-alpha (tmTNF-alpha) plays an anti-inflammatory role. tmTNF-alpha has a dual function, acting as both a signaling ligand and a receptor that transmits reverse signaling to cells expressing tmTNF-alpha. However, the role and mechanisms of tmTNF-alpha reverse signaling in sepsis are not fully understood. Objective: To explore the potential role and mechanisms of tmTNF-alpha reverse signaling in lipopolysaccharide (LPS)-induced inflammation. Methods: The expression levels of tmTNF-alpha and TNF-alpha mRNA were evaluated using flow cytometry and real-time PCR, respectively. We employed the anti-TNF-alpha drug infliximab to stimulate tmTNF-alpha reverse signaling and measured interleukin-6 (IL-6) and monocyte chemoattractant protein (MCP)-1 production through real-time PCR and ELISA in THP-1-derived macrophages. The location of p65 was determined through immunofluorescence assay. The phosphorylation and acetylation of p65, as well as the expression levels of MCP-induced protein 1 (MCPIP1) and Sirtuin 1 (SIRT1), were evaluated using western blotting. Results: Our findings revealed that tmTNF-alpha reverse signaling reduced the expression of IL-6 and MCP-1 triggered by LPS. tmTNF-alpha reverse signaling inhibited the nucleartranslocation of p65, suppressed p65 phosphorylation and acetylation, and upregulated the expression of negative regulatory molecules MCPIP1 and SIRT1 in the LPS/ toll-like receptor 4 (TLR4) signaling pathway . Conclusion: This study demonstrates that tmTNF-alpha reverse signaling plays a negative regulatory role in inflammation triggered by LPS by inhibiting the TLR4/ nuclear factor kappa B (NF-kappa B) signaling pathway. This study helps to further understand the function of tmTNF-alpha reverse signaling and offers new therapeutic possibilities for sepsis and other inflammatory diseasesconditions.

关键词： HLA-B*18:01:56   NGS HLA typing novel   novel HLA-B allele  

摘要： HLA-B*18:01:56 showed two synonymous nucleotide differences compared to the HLA-B*18:01:01:01 allele in codons 224 and 225.

关键词： l-DOPA-induced dyskinesia   neuroinflammation   NF-kappa B signalling pathway   TNF-alpha  

摘要： Levodopa-induced dyskinesia (LID) is a common and debilitating complication of long-term Parkinson's disease treatment. This review explores the roles of NF-kappa B and TNF-alpha signalling pathways in LID pathophysiology and potential therapeutic approaches targeting these mechanisms. Chronic levodopa treatment leads to aberrant neuroplasticity and neuroinflammation, involving activation of NF-kappa B and increased production of pro-inflammatory cytokines like TNF-alpha. NF-kappa B activation in glial cells contributes to sustained neuroinflammation and exacerbates dopaminergic neuron loss. TNF-alpha levels are elevated in brain regions affected by LID and correlate with dyskinesia severity. Several compounds are involved in mitigating LID by modulating these pathways. Agmatine reduces NF-kappa B activation and NMDA receptor expression while protecting dopaminergic neurons. Resveratrol and doxycycline demonstrate antidyskinetic effects by attenuating neuroinflammation and TNF-alpha production. The Rho-kinase (ROCK) inhibitor fasudil and cannabinoid receptor 2 (CB2) receptor agonists also show efficacy in reducing LID severity and neuroinflammation. Hydrogen gas inhalation decreases pro-inflammatory cytokine levels associated with LID. These findings highlight the complex interplay between NF-kappa B, TNF-alpha and other neurotransmitter systems in LID pathogenesis. Targeting neuroinflammation and glial activation through these pathways represents a promising strategy for developing novel LID treatments. Further research is needed to fully elucidate the mechanisms and optimize therapeutic approaches targeting NF-kappa B and TNF-alpha signalling in LID.

摘要： COVID-19 is associated with diverse neurological abnormalities, but the underlying mechanisms are unclear. We hypothesized that microglia, the resident immune cells of the brain, are centrally involved in this process. To study this, we developed an autopsy platform allowing the integration of molecular anatomy, protein and mRNA datasets in postmortem mirror blocks of brain and peripheral organ samples from cases of COVID-19. We observed focal loss of microglial P2Y12R, CX3CR1-CX3CL1 axis deficits and metabolic failure at sites of virus-associated vascular inflammation in severely affected medullary autonomic nuclei and other brain areas. Microglial dysfunction is linked to mitochondrial injury at sites of excessive synapse and myelin phagocytosis and loss of glutamatergic terminals, in line with proteomic changes of synapse assembly, metabolism and neuronal injury. Furthermore, regionally heterogeneous microglial changes are associated with viral load and central and systemic inflammation related to interleukin (IL)-1 or IL-6 via virus-sensing pattern recognition receptors and inflammasomes. Thus, SARS-CoV-2-induced inflammation might lead to a primarily gliovascular failure in the brain, which could be a common contributor to diverse COVID-19-related neuropathologies.

关键词： ALT   alanine aminotransferase   ASO   antisense oligonucleotide   DCA   deoxycholic acid   FDA   US Food and Drug Administration   FGF   fibroblast growth factor   FMT   fecal microbiota transplantation   FXR   farnesoid X receptor   GIP   glucose-dependent insulinotropic polypeptide   GLP-1   glucagon-like peptide 1   HCC   hepatocellular carcinoma   HFD   high-fat diet   HSD17B13   hydroxysteroid 17-   β   dehydrogenase-13   IL   interleukin   LDL   low-density lipoprotein   LPS   lipopolysaccharide   MASH   metabolic dysfunction–associated steatohepatitis   MASLD   metabolic dysfunction–associated steatotic liver disease   NAFLD   nonalcoholic fatty liver disease   NASH   nonalcoholic steatohepatitis   NF-   κ   B   nuclear factor kappa B   PAMP   pathogen-associated molecular pattern   PNPLA3   patatin-like phospholipase domain-containing 3   PPAR   peroxisome proliferator–activated receptor   RCT   randomized controlled trial   RNAi   RNA interference   ROS   reactive oxygen species   SCD-1   stearoyl-CoA desaturase 1   SCFA   short-chain fatty acid   siRNA   small interfering RNA   T2DM   type 2 diabetes mellitus   THR   thyroid hormone receptor   TLR   toll-like receptor   TMAO   trimethylamine N-oxide   VLDL   very low–density lipoprotein  

摘要： Metabolic dysfunction-associated steatotic liver disease (MASLD;formerly known as nonalcoholic fatty liver disease) is a chronic liver disease affecting over a billion individuals worldwide. MASLD can gradually develop into more severe liver pathologies, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and liver malignancy. Notably, although being a global health problem, there are very limited therapeutic options against MASLD and its related diseases. While a thyroid hormone receptor agonist (resmetirom) is recently approved for MASH treatment, other efforts to control these diseases remain unsatisfactory. Given the projected rise in MASLD and MASH incidence, it is urgent to develop novel and effective therapeutic strategies against these prevalent liver diseases. In this article, the pathogenic mechanisms of MASLD and MASH, including insulin resistance, dysregulated nuclear receptor signaling, and genetic risk factors (eg, patatin-like phospholipase domain-containing 3 and hydroxysteroid 17-b dehydrogenase-13), are introduced. Various therapeutic interventions against MASH are then explored, including approved medication (resmetirom), drugs that are currently in clinical trials (eg, glucagon-like peptide 1 receptor agonist, fibroblast growth factor 21 analog, and PPAR agonist), and those failed in previous trials (eg, obeticholic acid and stearoyl-CoA desaturase 1 antagonist). Moreover, given that the role of gut microbes in MASLD is increasingly acknowledged, alterations in the gut microbiota and microbial mechanisms in MASLD development are elucidated. Therapeutic approaches that target the gut microbiota (eg, dietary intervention and probiotics) against MASLD and related diseases are further explored. With better understanding of the multifaceted pathogenic mechanisms, the development of innovative therapeutics that target the root causes of MASLD and MASH is greatly facilitated. The possibility of alleviating MASH and achieving be

关键词： thymic stromal lymphopoietin (TSLP)   interleukin-4   chronic rhinosinusitis (CRS)   chronic rhinosinusitis with nasal polyps (CRSwNP)   patient reported outcome measures (PROMs)   fractional exhaled nitric oxide   SNOT-22   UPSIT   endotype   functional endoscopic sinus surgery  

摘要： Background Thymic stromal lymphopoietin (TSLP) plays an important role in mediating the type-2-inflammatory response. This study examined how TSLP and interleukin (IL)-4 levels in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) correlated with clinical and postoperative outcomes. Methods Solid-phase sandwich ELISA was used to analyze TSLP and IL-4 levels in mucus (n = 47), plasma (n = 17), polyp (n = 30), inferior (n = 25), and middle (n = 26) turbinate tissue collected during functional endoscopic sinus surgery (FESS) in CRSwNP patients (n = 76) and controls (n = 11). Inclusion criteria includes patients with medical treatment refractory CRSwNP confirmed by endoscopy or maxillofacial CT. Exclusion criteria include history of immunodeficiency, coagulation disorders, fungal sinusitis, or cystic fibrosis. Levels of TSLP and IL-4 were correlated with SNOT-22, UPSIT, and fractional exhaled nitric oxide (FeNO) using MannWhitney U two-tailed test and linear regression with Spearman correlation coefficient test. Results TSLP is elevated in the inferior turbinates (effect size = 2.695, p = 0.0007) of CRSwNP patients compared to controls. IL-4 is expressed at elevated levels in the inferior (effect size = 3.092, p < 0.0001) and middle turbinates (effect size = 2.041, p = 0.019) compared to controls. Mucus TSLP (r = 0.4013, p = 0.0153) and IL-4 (r = 0.6138, p < 0.0001) positively correlate with preoperative FeNO levels. Lower TSLP in the inferior (r = -0.5179, p = 0.0231) and middle turbinates (r = -0.5075, p = 0.0224) and lower IL-4 in the inferior turbinates (r = -0.5205, p = 0.0223) correlate with a greater improvement in SNOT-22 post-FESS. Conclusion TSLP and IL-4 are elevated in patients with CRSwNP and correlated with increased preoperative FeNO levels and decreased sinonasal quality of life benefit after FESS. Expression of TSLP and IL-4 may play a role in guiding postoperative expectations in patients with treatment refractory CRSwNP.