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关键词： Advanced cancer   HLA subtype   immune checkpoint   predictive biomarkers  

摘要： Specific shared HLA-I alleles were linked to the response to immune checkpoint blockade (ICB). We aimed to identify the HLA-A subtypes associated with maximum benefit from ICB. We compiled a clinical dataset of patients who underwent a CLIA-approved germline HLA status testing as part of various advanced immune and cell therapy trials undertaken at the Christie NHS Foundation Trust. A total of 285 patients were eligible for final analysis. We identified 15 HLA-A subtypes, the most common alleles being HLA-A02, HLA-A01, and HLA-A03. A02:01 showed a tumor lineage-specific distribution. One hundred and forty patients received ICB and had evaluable response status. Patients with A01 were associated with better clinical outcomes. No significant associations were observed between HLA-A subtypes and the incidence of immune-related adverse effects. HLA genotyping should be incorporated early in the diagnostic work-up of patients with solid cancers as a predictive and selective biomarker.

关键词： S100A8/A9   S100A12   Autoimmune disease   Inflammation   Biomarkers   Targeted therapy   AID   autoimmune diseases   AIA   antigen-induced arthritis   AS   atherosclerosis   AAV   antibody-associated vasculitis   BAFF   B cell activating factor   CRP   C-reactive protein   CNS   central nervous   CCL18   C-C motif chemokine ligand 18   DC   dendritic cells   DAMPs   damage-associated molecular patterns   DMARDs   disease-modifying anti-rheumatic drugs   ERAP1   endoplasmic reticulum aminopeptidase   Fli1   friend leukemia virus integration 1   GPCRs   G-protein-coupled receptors   GPP   generalized pustular PsO   HLA   human leukocyte antigen   IBD   inflammatory bowel disease   IκBα   inhibitor of κB-α   ILD   interstitial lung disease   LN   lupus nephritis   LPS   lipopolysaccharide   MD-2   myeloid differential protein-2   MMF   mycophenolate mofetil   MAPK   mitogen-activated protein kinas   MMPs   matrix metalloproteinases   MHC   major histocompatibility complex   NF-κB   nuclear factor kappa-B   NLRP3   NOD-like receptor family pyrin domain containing 3   p38 MAPK   p38 mitogen-activated protein kinase   PRRs   Pattern Recognition Receptors   PPP   palmoplantar pustulosis   PsA   psoriatic arthritis   PsO   Psoriasis   PAMPs   pathogen-associated molecular patterns   RRMS   relapsing-remitting multiple sclerosis   RAGE   receptors for advanced glycation end-products   ROS   reactive oxygen species   RA   Rheumatoid arthritis   SLE   Systemic Lupus Erythematosus   SLEDAI   Systemic Lupus Erythematosus Disease Activity Index   SSc   systemic sclerosis   SpA   spondylarthritis   TLR4   toll-like receptors-4   TGF-β   transforming growth factor-β   UC   ulcerative colitis  

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关键词： Chronic wound   Inflammation   Oxidative stress   Purinergic signaling  

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摘要： We read with great interest the recent study by Dwt et al. [ 1], which investigated the associations of interleukin-1 receptor antagonist (IL-1RA), interleukin-1 receptor type 2 (IL-1R2), and IL-1 receptor accessory protein (IL-1RAcP) with adverse...

关键词： AMD   Aqueous humor   Assay qualification   Biomarker   IL-33   Immuno-PCR  

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摘要： We found that interleukin-1 receptor antagonist (IL-1RA) was an independent risk factor for 2- and 5-year mortality in our recently published paper in IJC [ 1]. However, as underscored in the letter by Wan et al. , some aspects may require additio...

关键词： Methamphetamine   TNF   Blood-brain barrier   Neuroinflammation   Cytokines   Addiction  

摘要： Methamphetamine use disorder remains a significant public health concern, impacting neuronal function, immune responses, and vascular integrity. Of particular interest is methamphetamine's disruption of the blood-- brain barrier (BBB), a key event that triggers neuroimmune dysfunction and the development of neurodegenerative conditions. While the systemic effects of methamphetamine are well-characterized, the mechanism(s) governing its dysregulation of BBB physiology remain poorly understood. Emerging evidence suggests that the methamphetamine-induced production of tumor necrosis factor (TNF), occurring both in the periphery and within the central nervous system, triggers a cascade of molecular events that compromises BBB permeability. This review provides a comprehensive overview of current findings on the cross interaction between methamphetamine and the BBB, with particular emphasis on the potential role of TNF in dysregulation of BBB permeability and dysfunction. By elucidating the complex interplay between methamphetamine, TNF, and the BBB, we aim to inform the development of targeted interventions and preventative strategies to mitigate methamphetamine-induced neurovascular and neuroimmune dysfunction.

关键词： Pyridone   Apoptosis   Anticancer   Flow cytometry   ADMET   DFT  

摘要： Epidermal Growth Factor Receptor (EGFR) is crucial for cancer cell growth, survival, and resistance. Inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) also help tumors grow and evade the immune system. Developing multi-targeted inhibitors that hit both cancerous and inflammatory pathways has strong therapeutic potential. This study aims to design, create, and test novel series of pyridonebased derivatives serving as dual inhibitors of EGFR signaling pathways with anti-inflammatory effects by suppressing IL-6 and TNF-alpha. We synthesized and structurally characterized a set of novel pyridone derivatives. We checked their physicochemical and pharmacokinetic properties using in silico ADMET profiling. We evaluated the anticancer activity of the compounds through the MTT assay, testing viability and cytotoxicity in MCF-7 (breast) and A549 (lung) cancer cell lines. We further assessed selected compounds for their EGFR inhibitory effects and cytokine suppression. We conducted flow cytometry (Annexin V/PI staining) to evaluate apoptosis induction. Some of the novel compounds showed high binding affinity to EGFR in docking studies. Among these, compound 5h showed potent anticancer activity on both tested cell lines A549 and MCF7 with an IC50 of 9.2 mu M and 8.2 mu M respectively also it significantly reduced IL-6 and TNF-alpha levels in A549 cells, also showed promising ADMET profiles. Flow cytometry confirmed apoptosis induction in a dose-dependent manner. We performed molecular docking to evaluate the binding affinity against EGFR and related inflammatory targets. DFT calculations were performed to analyze molecular reactivity through HOMO/LUMO and molecular electrostatic potential (ESP) studies. ESP map analysis supports theoretical descriptors and confirms that compound 5h is the most biologically active candidate among the synthesized derivatives.

关键词： Photodynamic therapy  

摘要： Major histocompatibility complex I (MHC-I) has significant potential for augmenting cancer immunogenicity and immune recognition. Here, we report an innovative therapeutic strategy that synergistically integrates blue light-upregulated MHC-I expression with blue light-induced ferroptosis and cuproptosis. Blue light promoted MHC-I expression in mouse melanoma cells by modulating the NF-κB-SUSD6 signaling axis. Subsequently, an MHC-I-enriched melanoma cytomembrane was used to encapsulate the photoresponsive Cu@ferrihydrite (Cu@Fh) nanoparticles, forming M-Cu@Fh. MHC-I facilitated dendritic cells (DCs) maturation and CD8+/CD4+ T cells activation. M-Cu@Fh also triggered oxidative stress and concurrent ferroptosis/cuproptosis through the controllable release of Fe/Cu ions under blue-light irradiation. In vivo experiments demonstrated that the combination of blue light and M-Cu@Fh converted immune "cold" tumors into "hot" tumors, suppressed in situ melanoma growth through oxidative damages and enhanced immunogenicity. Furthermore, systemic activation of DCs and CD8+/CD4+ T cells in lymphoid organs (lymph nodes and spleen) and lungs conferred prophylactic efficacy against abscopal metastasis. Our study elucidates the photoregulatory mechanism of MHC-I in melanoma cells and presents a transformative combinatorial strategy that synergizes blue light-driven photoimmunotherapy (PIT) with blue light-activated photodynamic therapy (PDT) for melanoma management and metastasis prevention. © 2024