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关键词： hepatitis B virus   hepatocellular carcinoma   HLA-DR+ tumor cells   immunosuppressive   tumor microenvironment  

摘要： Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with hepatitis B virus (HBV) as a major driver. Despite the pivotal role of viral infections in shaping the tumor microenvironment (TME), the mechanistic differences among HBV-, hepatitis C virus (HCV)-, and non-B non-C (NBNC)-associated HCC remain poorly understood. By integrating the largest publicly available single-cell RNA sequencing (scRNA-seq) dataset of HCC (160 samples from 124 patients) with multi-scale protein-level validation using multiplex immunofluorescence and tissue microarrays (198 HCC specimens), HLA-DR+ tumor cells are identified as a distinctive feature of HBV+HCC. These tumor cells uniquely express MHC class II molecules, typically restricted to antigen-presenting cells, and correlate with immune checkpoint activation and PD-L1 expression, potentially contributing to an immunosuppressive microenvironment specific to HBV+HCC. Trajectory analysis revealed distinct CD8(+) T-cell differentiation pathways in HBV+HCC, characterized by enhanced exhaustion and stem-like phenotypes. HLA-DR+ tumor cells are associated with increased recruitment of CD8(+) T cells and correlated with T-cell exhaustion, potentially contributing to a suppressive TME. Clinically, high proportions of HLA-DR+ tumor cells are linked to poor survival outcomes, especially when accompanied by elevated PD-L1 expression, suggesting that HLA-DR+ tumor cells may serve as a potential predictive biomarker for immunotherapy efficacy in HCC. Collectively, the findings highlight HLA-DR+ tumor cells as a distinctive feature of HBV-associated HCC (HBV+HCC), providing novel insights into possible immunosuppressive mechanisms and therapeutic targets for immunotherapy in this disease context.

关键词： RNA sequencing   DPSCs   TNF alpha   inflammation   dentinogenesis   regeneration TNF alpha stimulates DPSCs odontoblastic differentiation  

摘要： Introduction Inflammation is a complex host response to harmful infections or injuries, playing beneficial and detrimental roles in tissue regeneration. Notably, clinical dentinogenesis associated with caries development occurs within an inflammatory environment. Reparative dentinogenesis is closely linked to intense inflammation, which triggers the recruitment and differentiation of dental pulp stem cells (DPSCs) into the dentin lineage. Understanding how inflammatory responses influence DPSCs is essential for elucidating the mechanisms underlying dentin and pulp *** Given the limited data on this process, a broad approach is employed here to understand better the complex mechanisms involved and identify downstream signaling targets. This study investigates the role of inflammation and the complement receptor C5L2 in the odontoblastic differentiation of DPSCs and the associated transcriptomic changes using poly-A RNA sequencing (RNA-seq). RNA-seq techniques provide insight into the transcriptome of a cell, offering higher coverage and greater resolution of its dynamic *** Following inflammatory stimulation, DPSCs exhibit significantly altered gene profiles, including marked up-regulation of key odontogenic genes, highlighting the critical role of inflammation in dentinogenesis. We demonstrate that TNF alpha-treated, odontoblast-like differentiating DPSCs, under C5L2 modulation, show differentially expressed gene profiles and transcriptomic *** Beyond quantifying gene expression, RNA-seq data also enable the discovery of novel transcripts, the identification of alternatively spliced genes, and the detection of allele-specific expression. The data presented may offer new avenues for experimental approaches to uncovering pathways in dentinogenesis by identifying specific transcription factors and gene profiles.

关键词： CSF1   mast cell   mast cell mediator   melanoma   proteome   MC   mast cell   PRR   pattern recognition receptors   PAMS   pathogen-associated molecular patterns   DAMP   damage-associated molecular pattern   MCG   Mast cell granules   DC   dendritic cell   CSF1   colony-stimulating factor 1   cPMC   cultured (mouse) peritoneal mast cells   DNP   2,4-Dinitrophenyl   HSA   human serum albumin   FCER1A   Fc epsilon receptor I alpha   SNAP23   synaptosomal-associated protein 23   ActD   Actinomycin D   CHX   Cycloheximide   rCSF1   recombinant colony stimulating factor 1   MCp   mast cell progenitor   IgE   immunglobulin E   SP   substance P   IL   interleukin   LPS   lipopolysaccharide   C48/80   compound 48/80   BM   bone marrow   MACS   Magnetic Activated Cell Sorting  

摘要： Background Mast cells are tissue-resident immune cells present in connective tissues throughout the body. They exert diverse functions in immunity by rapidly releasing a plethora of preformed mediators, including proteoglycans, cytokines, and proteases, which are stored in cytoplasmic granules. Objective Our aim was to systematically and globally identify mast cell-released protein mediators and elucidate their functions. Methods We analysed the secretomes of antigen-activated primary mouse mast cells using quantitative mass spectrometry-based proteomics and conducted follow-up studies in vitro, ex vivo and using mast cell-specific genetic mouse models. Results We identified CSF1 as a novel preformed mast cell mediator present in the granules of all connective tissue-type mast cells. We further show that the mast cell secretome can induce macrophage differentiation and a unique polarisation pattern via CSF1 and other mediators. Mast cell-derived CSF1 has systemic functions, as mast cell-specific CSF1-deficient mice have lower serum CSF1 levels and reduced numbers of circulating monocytes. In addition, using an orthotopic transplantation-based melanoma mouse model, we show that loss of mast cell-derived CSF1 promotes cancer cell expansion. Finally, we demonstrate that CSF1 is also prestored and released by human mast cells. Conclusion CSF1 is an evolutionarily conserved, constitutive mast cell granule component. Mast cell degranulation induces macrophage differentiation and a unique polarisation state, the former being completely dependent on CSF1, while the latter is only modulated.

关键词： curcumin   pancreatic cancer   machine learning   transcriptome sequencing   cellular experiments   computer simulation  

摘要： Purpose Pancreatic cancer is a highly aggressive malignancy characterised by a complex tumour microenvironment and chronic inflammation. Studies found curcumin inhibited with inflammatory responses and tumour proliferation by interfering with production and activation of pro-inflammatory factors. This study investigated curcumin treated pancreatic cancer by modulating key targets in the inflammatory response and their signalling *** The human pancreatic cancer PL45 cells and SUIT-2 cells were utilized to establish cellular experiments, and the effects of curcumin on proliferation, apoptosis and cell migration of PL45 cells and SUIT-2 cells were detected by CCK-8, Annexin V-FITC/PI and cell scratching experiment. PL45 cells RNA from experimental and control groups was also analyzed by transcriptome sequencing. Bioinformatics screening of differential gene targets in transcriptome sequencing was performed. Gene Ontology, KEGG and Protein-protein interaction were used to analyze the differentially expressed targets at the gene level and protein level, respectively. We validated the differential gene targets by machine learning analysis of GSE28735 data, and performed survival analysis, pan-tumor analysis, immune infiltration analysis and single-cell transcriptional analysis on the differentially expressed targets. Computer simulations were utilized to verify the stability of curcumin binding to key *** Results of cellular experiments suggested 30 mu g/mL curcumin and 50 mu g/mL curcumin significantly inhibited the proliferation and growth of PL45 and SUIT-2, respectively. The transcriptome results indicated that 2,676 genes showed differential expression in curcumin-treated group compared to control group. Bioinformatics and machine learning analyses screened 14 key targets that are closely related to the inflammatory response in pancreatic cancer. Molecular dynamics showed binding free energies for IL1B/Curcumin, IL10RA/Curcumin, NLRP3/Curcum

摘要： is the major causative agent of leptospirosis. Humans, canines and livestock animals are susceptible to species and can develop fulminant disease. Rodents serve as reservoir hosts in which the bacteria colonize the renal tubules and are excreted in the urine. The host immune response to spp. remains poorly defined. We show that induces a robust type I interferon (IFN) response in human and murine macrophages that is dependent on the cytosolic dsDNA sensor Cyclic GMP-AMP Synthase (cGAS) and the Stimulator of IFN Genes (STING) signaling pathway. Further, we show that mice deficient in the IFNα/β receptor subunit 1 (IFNAR1) or STING had higher bacterial burdens and increased renal colonization following infection suggesting that cGAS-STING-driven type I IFN is required for the host defense against . These findings demonstrate the significance of cGAS-STING- dependent type I IFN signaling in mammalian innate immune responses to .

关键词： alarmin   atopic dermatitis   interleukin-36 alpha   inflammation   psoriasis  

摘要： (1) Background: The IL-36 cytokines have been identified as key contributors to pustular psoriasis, and their inhibitor is already in clinical use. However, few studies have explored them in atopic dermatitis. (2) Methods: The role of IL-36 alpha was investigated in various atopic dermatitis models using wild-type, keratin 14-specific IL-33 transgenic, IL-18 transgenic, caspase-1 transgenic, and caspase-1 transgenic mice with IL-17AF deletion, reflecting diverse aspects of human skin inflammation. IL-36 alpha was administered subcutaneously in five doses on alternate days across the five strains to examine cellular infiltration patterns and cytokine expression levels. (3) Results: The skin phenotype was exacerbated, accompanied by worsening edema and skin thickness in all mouse groups upon IL-36 alpha administration. An increase in infiltrating cells was observed among innate immune cells, while lymphocyte counts, including T cells and innate lymphoid cells, did not rise. Additionally, anti-inflammatory cytokines were induced simultaneously with inflammatory cytokines and downstream cytokines of IL-36 alpha as well. Infiltrating lymphocytes in the skin displayed a distinct Type 2 cytokine-dominant profile for innate lymphoid cells and a Type 3 cytokine-dominant profile for T helper cells and gamma delta T cells, contrasting with the Type 1-dominant cell profile in draining lymph nodes. Type 1, Type 2, and Type 3 cytokine dominance patterns were not affected by the administration of IL-36 alpha. (4) Conclusions: IL-36 alpha triggers inflammatory responses in atopic dermatitis by activating innate immunity. The infiltrating lymphocytes in the skin have different cytokine production profiles between innate lymphoid cells and T cells, as well as different patterns of cytokine production in their draining lymph nodes.

关键词： Guselkumab   IL-23 inhibitors   phase 3 clinical trial   QUASAR   mirikizumab   risankizumab   ulcerative colitis  

摘要： IntroductionUlcerative colitis (UC) includes a dysregulated immune response. The conventional therapy includes immunosuppressants, and biologics targeting inflammatory mediators, but these are often inadequate, or subjects become unable to tolerate *** coveredQUASAR: the induction and maintenance components of the phase 3 trial of guselkumab, which inhibits IL-23 by dual mechanisms, in subjects with moderate-to-severe UC. QUASAR enrolled those that had an inadequate response and/or intolerance to corticosteroids, immunosuppressants, biologics, or Janus kinase (JAK) inhibitors. In both parts of the trial, guselkumab improved clinical remission with no excess of adverse *** opinionFor those enrolled throughout, after the maintenance part, the benefit with guselkumab on clinical remission was 24% percentage points (45 vs 21%), which is relatively small. There is no direct comparison of guselkumab with other IL-23 inhibitors in UC. Indirectly comparing trials suggests the clinical remission rates at the end of the trials was higher with guselkumab than with the other approved IL-23, inhibitors, mirikizumab or risankizumab (17 or 15% points, respectively). Thus, guselkumab may be more efficacious than the other 1 L-23 antagonists, possibly due to its additional action to block the CD64 receptor. However, this needs to be tested in a direct comparison trial.

关键词： Single filamentous bacteria   Th17 cells   IL-17A   Retinoic acid receptor   Rotavirus vaccine   Shedding  

摘要： Single filamentous bacteria (SFB) have been shown to prevent murine rotavirus (RV) and other mammalian enteric infections, independent of type I and II interferons, by promoting adaptive and innate immunity through differentiation of intestinal Th17 cells, production of immunoglobulin A and retinoic acid receptor (RAR) signaling. Here, we assessed whether the abundance of the bacterium at the time of oral RV vaccination would impede the vaccine performance. Stool samples were collected from infants a week after RV vaccination to determine vaccine shedders (n = 20) and non-shedders (n = 20). The abundance of SFB and expression of Cathepsin L (CTSL, a biomarker for differentiated Th17 cells), cytokines 17 A and IL-22, and retinoic acid receptor (RAR) were assayed using quantitative PCR. The abundance of SFB was significantly high in non-shedders compared to vaccine shedders, p = 0.042, and correlated negatively with vaccine virus shedding load (R = - 0.69). The expression of CTSL was increased 3.5-fold in non-shedders compared to vaccine shedders, p = 0.035. Similarly, the expression of IL-17 A and IL-22 was increased 8.5- and 12-fold, respectively, in non-shedders versus shedders. The expression of RAR was also consistent with the abundance of SFB, as it increased 5.9-fold in non-shedders compared to vaccine shedders, p = 0.034. Logistic regression analysis indicated that Infants possessing increased abundance of SFB were less likely to shed the vaccine in stool samples (OR = 0.31, 95% CI = 0.102-0.962), p = 0.043. Taken together, our observations suggest that the abundance of SFB at the time of vaccination may impede the oral RV vaccine take in the study population.

关键词： Lipid metabolism   Cutaneous malignant melanoma   Oncogene   Risk model  

摘要： BackgroundCutaneous malignant melanoma (CMM) ranks among the deadliest forms of cancer. Abnormalities in lipid metabolism may have a connection with the risk of CMM *** metabolism-related genes were selected in MSigDB. A lipid metabolism-related predictive model was constructed in The Cancer Genome Atlas-skin cutaneous melanoma (TCGA-SKCM) using univariate Cox regression analysis, non-negative matrix factorization (NMF) clustering analysis, Weighted correlation network analysis (WGCNA), least absolute shrinkage and selection operator regression (LASSO) analysis, and outcomes-related genes were identified. The roles of candidate genes in CMM were determined using in vivo and in vitro experiments, and the pathway mechanism of the candidate gene was studied using transcriptomics, proteomics, lipid metabolomics, and other molecular biological *** predictive model was established, Risk Score = -0.009 * UBE2L6 + 0.033 * PLEKHA5 + 0.024 * LHB + 0.036 * CARM1 + 0.016 * PRXL2B + 0.131 * PLA2G4D. The pleckstrin homology domain-containing A5 (PLEKHA5) was identified as an essential gene and positively correlated with poor outcomes in CMM. Fc receptor-like A (FCRLA) is the downstream gene of PLEKHA5, upregulated in CMM, and tumor necrosis factor alpha (TNF alpha) is also an essential cytokine that promotes CMM proliferation and metastasis. Lipid metabolomics showed that PLEKHA5 knockdown increased ceramide and sphingosine levels while decreasing cholesterol ester and triglyceride levels in CMM cells, possibly related to disease *** predictive model of CMM related to lipid metabolism was constructed. TNF alpha activates the PLEKHA5-FCRLA axis to enhance neutral lipid storage and energy metabolism in CMM cells, promoting malignant behavior.