课程文献中心 更多>>

关键词： HLA   immunopeptidomics   pancreatic cancer   ZenoSWATH DIA   cancer antigens  

摘要： Pancreatic ductal adenocarcinoma (PDAC), with its devastating prognosis and limited treatment options, demands innovative therapeutic strategies. T-cell-based immunotherapy has shown promise for many cancers, including PDAC, but is limited by our knowledge of the breadth of cancer-specific T-cell epitopes available. Thus, a comprehensive assessment of the immunopeptidome of PDAC is essential to pave the way for the effective design of immunotherapy and related interventions. In this study, we immunoaffinity purified Human Leukocyte Antigen (HLA) class I-bound peptides from the Panc1 cell line grown in the absence and presence of cytokine stimulation. These peptides were subjected to an off-line high-pH reversed-phase (HPH-RP) fractionation prior to data acquisition. We demonstrate that HPH-RP fractionation followed by data-dependent acquisition (DDA) is a relatively simple and reliable technique that expands the depth of coverage of the PDAC immunopeptidome, allowing the identification of over 22,500 canonical HLA-bound peptides. In addition, the complementary separation by HPH-RP improved the identification confidence, particularly in the case of co-fragmenting precursors in data-independent acquisition (DIA) workflows. This strategy facilitated the identification of a high number of cancer-testis antigen (CTA)-derived immunopeptides. However, given that fractionation is typically associated with an adsorptive loss, it is impractical to apply HPH-RP on often minuscule clinical specimens and biopsies. Thus, we explored the feasibility of immunopeptidome analysis with cellular inputs as low as 1 million cells (equivalent to approximately 1 mg of tissue) using either a ZenoSWATH DIA interpreted using a spectral library derived from the HPH-RP strategy, or an optimized DDA workflow on the SCIEX ZenoToF 7600 system. Both approaches enabled robust detection of CTA-derived and other potentially clinically actionable immunopeptides even at the lowest cellular inputs. We di

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.

摘要： Objectives: The study objective was to determine if a common single nucleotide polymorphism in the interleukin 6 (IL-6) receptor (rs2228145, ***358Ala) predicted treatment response to tocilizumab in giant cell arteritis (GCA). Methods: Genetic sequencing of the rs2228145 locus was performed in 2 independent cohorts of patients with GCA. Peripheral blood mononuclear cells (PBMCs) from patients and controls were evaluated for expression of the interleukin 6 receptor (IL-6R) and its coreceptor, gp130, using flow cytometry. The same PBMCs were stimulated with IL-6 and evaluated for downstream targets of IL-6: STAT3 phosphorylation (pSTAT3) and IL-17A expression. Results: In total, 100 patients with GCA were included (derivation cohort n = 58;validation cohort n = 42). The rs2228145 variant predicted tocilizumab response in each cohort. In the derivation cohort, a gene dose-dependent response was observed with a 36% response rate in the homozygous patients and 95% response rate in patients without the variant (P = .003). In the validation cohort, tocilizumab response rates were 50% for homozygotes and 85% for patients without the variant (P = .04). pSTAT3 levels were significantly increased in response to IL-6 stimulation in a gene dose-dependent manner in CD4 T cells from patients with GCA but not controls. CD4 T cells from patients with GCA had significantly higher membrane expression of gp130 than healthy controls, and response to IL-6 correlated with gp130 expression. IL-17 producing CD4 T cells were increased in a gene dose-dependent response to IL-6 (P < .01). Conclusions: The rs2228145 variant is associated with decreased treatment response to tocilizumab and worse outcomes in GCA by enhancing CD4 T cell response to IL-6.

关键词： oocyte donation   pre-eclampsia   decidua   HLA   myeloid cells  

摘要： OBJECTIVE: Healthy pregnancy requires local tolerogenic immune mechanisms. Pregnancies after oocyte donation (OD) are related to more fetal-maternal HLA mismatching and to elevated risk of pre-eclampsia. We hypothesize that in OD pregnancies with ...

关键词： Cyclophosphamide   Sakuranetin   Immunosuppression   Cytokines   Immunoglobulin   Interleukins  

摘要： Cyclophosphamide is a widely used chemotherapeutic agent known for its effectiveness in treating various cancers;however, it is associated with significant immunosuppressive side effects. This study investigates the potential of sakuranetin, a natural flavonoid, in mice under cyclophosphamide-induced immunosuppressive conditions. Mice were grouped into four groups: one control group, two treated with cyclophosphamide and two sakuranetin-treated groups receiving different doses (10 and 20 mg/kg). Immune organ indices, lymphocyte proliferation, hematological parameters, nitric oxide levels, cytokines (tumor necrosis factor alpha-TNF-alpha, interferon gamma-IFN-gamma), interleukins (interleukin-1 beta-IL-1 beta, IL-4, IL-6), immunoglobulin G (IgG), IgM levels, plague-forming cells quantification, qualitative hemolysis, and delayed-type hypersensitivity were assessed. Cyclophosphamide significantly (P < 0.05) reduced immune organ indices, lymphocyte proliferation, changes in hematological parameters, and nitric oxide levels. Treatment with both sakuranetin doses restored these parameters and normalized cytokine, IgG, and IgM levels (P < 0.05). Sakuranetin significantly (P < 0.05) improved the immunomodulatory action with elevated immune response with downregulation in immune response mediated by cells. Sakuranetin effectively counteracts cyclophosphamide-induced immunosuppression by modulating the IFN-gamma, TNF-alpha, IgG, and interleukin pathway, suggesting its potential as a protective agent.

关键词： Exosomes   EVT   HLA class I molecules  

摘要： OBJECTIVE: Acceptance and support for the semi-allogeneic embryo and effective protection of both mother and fetus are required for a successful pregnancy. Placenta-derived exosomes have a crucial role in human implantation and pregnancy. Exosomes...

关键词： anxiety   body mass index   cortisol   executive functions   TNF alpha  

摘要： Overweight and obesity are associated with poorer executive functions (EF). The underlying mechanisms contributing to this relationship are not yet conclusive, but cortisol, anxiety, and inflammation are likely among the contributing factors. Our objective was to evaluate whether fibrinogen, tumour necrosis factor alpha (TNF alpha), cortisol, and anxiety significantly mediate the association between body mass index (BMI) z-score and EF (i.e., working memory, inhibition, cognitive flexibility, and a latent EF component) in both adolescents and adults. In this cross-sectional study, 268 participants aged 11-49 years with BMI values ranging from normal-weight to obesity were medically and neuropsychologically evaluated. Moderated multiple mediation analyses with mediators in parallel were conducted (X: BMI z-score;M: cortisol, anxiety, TNF alpha, and fibrinogen;Y: executive functions;Moderator: adolescent and adult groups). Our results suggested that TNF alpha mediated the association between BMI z-score and working memory only in adolescents (indirect effect = 0.09, 95% CI [0.03, 0.19]), whereas in adults, cortisol (indirect effect = -0.06, 95% CI [-0.13, -0.01]) and anxiety (indirect effect = 0.02, 95% CI [0.0001, 0.07]) mediated this association. Additionally, in adults, anxiety also mediated the relationship between BMI z-score and the latent EF component (indirect effect = 0.03, 95% CI [0.004, 0.08]). In the full sample, TNF alpha significantly mediated the relationship between BMI z-score and inhibition (indirect effect = -0.03, 95% CI [-0.06, -0.002]). In conclusion, our study suggests that inflammation, cortisol, and anxiety are biologically and psychologically plausible mechanisms through which BMI may influence cognitive performance. Large-scale longitudinal studies are needed to confirm these findings and to determine whether the observed associations are age-dependent.