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关键词： Cancer immunotherapy   Epitope prediction   HLA   Machine learning   MHC  

摘要： Cancer immunotherapy hinges on accurate epitope prediction for advancing vaccine development. VaxOptiML (available at https://***/) is an integrated pipeline designed to enhance epitope prediction and prioritization. This study aims to develop and deploy a robust tool for accurate prediction and prioritization of highly immunogenic and optimized MHC-I and MHC-II T-cell epitopes for cancer vaccine development and immunotherapy. Utilizing a curated dataset of experimentally validated epitopes and employing sophisticated machine learning techniques, VaxOptiML features three models: epitope prediction from target sequences, personalized HLA typing, and prioritization the predicted epitopes based on immunogenicity scores. Our rigorous data extraction, cleaning, and feature extraction processes, coupled with model building, yield exceptional accuracy, sensitivity, specificity, and F1 score, surpassing existing prediction methods. Comprehensive visual representations underscore VaxOptiML's robustness and efficacy in accelerating epitope discovery and vaccine design for cancer immunotherapy. Deployed via Streamlit for public use, VaxOptiML enhances accessibility and usability for researchers and clinicians, demonstrating significant potential in cancer immunotherapy.

关键词： IL-2R beta   Inborn errors of immunity   Immunodeficiency   Autoimmunity   Hematopoietic stem cell transplantation   Conditioning  

关键词： Anti-inflammatory therapy   Colchicine   Coronary artery disease   Interleukin-1 inhibitors   Interleukin-6 inhibitors   Methotrexate   NLRP3/IL-1 beta/IL-6/CRP pathway  

摘要： Background Treatment effects of anti-inflammatory therapies inhibiting the NLRP3/IL-1 beta/IL-6/CRP pathway in coronary artery disease (CAD) had conflicting results. The study aims to evaluate efficacy and safety outcomes of treatments inhibiting this pathway. Methods Cochrane Library, Embase, Pubmed, and *** were searched for randomized controlled trials evaluating therapies inhibiting the NLRP3/IL-1 beta/IL-6/CRP pathway in CAD patients. Relative risks (RR) with 95% confidence intervals (CI) were calculated. Results 32 studies and 37,056 individuals were included. Anti-inflammatory therapies inhibiting the pathway reduced the risks of myocardial infarction (MI) (RR 0.85, 95% CI 0.78-0.93) and coronary revascularization (RR 0.80, 95% CI 0.74-0.86), with no benefits in major adverse cardiovascular events (MACE), heart failure (HF), stroke, cardiovascular or all-cause mortality. Colchicine reduced the risks of MACE, MI, and coronary revascularization. IL-1 inhibitors reduced the risks of coronary revascularization, with potential benefits in MI and HF. Increased risks of infections, gastrointestinal adverse effects, and injection site reactions were found. Meta-regression analysis demonstrated that post-treatment hsCRP/CRP was correlated with MACE (p < 0.001) and MI (p = 0.048) and post-treatment IL-6 was associated with MI (p = 0.033). Conclusion Anti-inflammatory therapies inhibiting the NLRP3/IL-1 beta/IL-6/CRP pathway had satisfying safety profiles and were beneficial in preventing MI and coronary revascularization in CAD patients despite no benefits in stroke, cardiovascular, or all-cause mortality.

关键词： IL-21   Inflammation   Lymphocytes   S. aureus   Septic arthritis   TGF-beta   Th17/Treg  

摘要： Septic arthritis (SA) caused by Staphylococcus aureus is a severe inflammatory joint disease, characterized by synovitis accompanied with cartilage destruction and bone erosion. The available antibiotic treatment alone is insufficient to resolve the inflammation that leads to high rates of morbidity and mortality. Among the CD4+ T helper lymphocytes, the Th17 and Tregs are key regulators of immune homeostasis. A high Th17 could lead to autoimmunity, whereas an increase in Tregs indicates immunosuppression. Depending on the external cytokine milieu, na & iuml;ve CD4+ T cells transform into either Th17 or Treg cell lineage. TGF-beta in the presence of IL-21 produces Th17 cells and drives the inflammatory cascade of reactions. We studied the effects of in vivo neutralization of TGF-beta and IL-21 in septic arthritic mice to control arthritic inflammation, which has not been studied before. The arthritic index showed maximum severity in the SA group which substantially reduced in the Ab-treated groups. Flow cytometric analyses of peripheral blood collected from mice at 9DPI revealed the highest Th17/Treg ratio in the SA group but least in the combined-antibody-treated group. TGF-beta 1 and IL-21 cytokine production from serum, spleen, and synovial tissue homogenates was significantly reduced in the dual Ab-treated group than in the untreated SA group. From the Western blot analyses obtained from splenic lymphocytes at 9 DPI, we elucidated the possible underlying mechanism of interplay in downstream signalling involving the interaction between different STAT proteins and SOCS, NF-kappa B, RANKL, mTOR, iNOS, and COX-2 in regulating inflammation and osteoclastogenesis. On endogenous blockade with TGF-beta and IL-21, the Th17/Treg ratio and resultant arthritic inflammation in SA were found to be reduced. Therefore, maintaining the Th17/Treg balance is critical to eradicate infection as well as suppress excessive inflammation and neutralization of TGF-beta and IL-21 could pr

关键词： Type 1 diabetes   Islet antigen-specific T cells   T cell epitopes   Islet-specific autoantibodies  

摘要： A proportion of patients with new-onset diabetes share similar symptoms with type 1 diabetes (T1D) patients but they are negative for islet antigen-specific autoantibodies. This study was to develop an islet antigen-specific CD8(+) T-cell assay to provide autoimmune evidence regarding these "suspected" T1D patients. HLA-A*0201 individuals with autoAbs(+) T1D, autoAbs(-) suspected T1D, and type 2 diabetes, along with HLA-A*0201 healthy controls were recruited. Using interferon-gamma enzyme-linked immunospot assays, the percentages of participants in each group with various islet antigen-specific CD8(+) T cells were determined. Sixteen out of the 28 islet antigen-specific epitopes tested were T1D specific, meaning that there was a significantly (P < 0.05) greater epitope positivity rate in the autoAbs(+) T1D cohort than in the healthy controls. Using a cutoff value of two positive epitopes, the 16-epitope panel led to a sensitivity of 75.0% and a specificity of 94.4% regarding the autoAbs(+) T1D patients. Even when using an optimized five-epitope panel, the results were highly accurate. Notably, in the application phase of the study, 77.8% of a new cohort of autoAbs(-) suspected T1D patients exhibited positivity when using the five-epitope optimized panel. This highly accurate method, especially for pediatric patients, will improve clinical diagnosis and etiological classification of autoimmune T1D.

关键词： ADAMTS-8   Colorectal cancer   Transcriptional regulation   Inflammation   IL-6  

摘要： BackgroundADAMTSs are extracellular matrix metalloproteinases that mainly process extracellular matrix components and closely related tumorigenesis. ADAMTS-8 is an anti-angiogenic member of the family and is dysregulated in common cancers. The tumor suppressor function of the ADAMTS-8 has been demonstrated in colorectal cancer. Although ADAMTS-8 plays a critical role in tumor progression, transcriptional regulatory features haven't been studied *** and methodsThe human ADAMTS-8 promoter was cloned into the pMetLuc Reporter vector. Basal promoter activity and the effect of the IL-6 on ADAMTS-8 promoter activity were determined by transient transfection assays in SW480 cells. QRT-PCR and Western blot analyses assessed the impact of IL-6 on ADAMTS-8 mRNA and protein expressions. Functional binding of the specific transcription factors to the ADAMTS-8 promoter region was evaluated by ChIP qPCR and *** results demonstrated that the ADAMTS-8 promoter includes multiple binding sites for transcription factors that could be activated in the inflammatory pathways. IL-6 stimulation increased ADAMTS-8 promoter activity, also mRNA, and protein expressions. Pathway inhibition studies showed that IL-6-mediated induction of ADAMTS-8 was achieved through p38/MAPK, NF-kappa B, PI3K, and SAPK/JNK pathways. STATs, Elk-1, and c-Jun functionally bind to the ADAMTS-8 promoter *** can be concluded that inflammation is a strong positive regulator of the ADAMTS-8 gene.

关键词： Microchimerism   HLA   Autoimmune disease  

摘要： Naturally acquired microchimerism (Mc) is increasingly recognized as an aspect of normal biology. Maternal-fetal bi-directional exchange during pregnancy creates a Mc legacy for the long-term in both individuals. Maternal Mc in her offspring and Mc of fetal origin in women with previous births are best studied. Other sources include from a known or vanished twin, miscarriage or pregnancy termination, older sibling, or previous maternal pregnancy loss. Mc is pleotropic and protean, present in diverse forms, and changing over time as other aspects of biology. Mc acquired from multiple sources, at different lifespan times, and taking on an array of diverse forms, creates a "forward, reverse, and horizontal inheritance" Mc landscape. Mc is found in adaptive and innate immune cells, as resident tissue-specific cells in a wide variety of human tissues, and among other forms as extracellular vesicles. HLA molecules function in a myriad of ways as key determinants for health and are of central importance in interactions between genetically disparate individuals. Studies of autoimmune disease have firmly established a primary role of HLA molecules. Studies of iatrogenic chimerism have established benefit of donor-recipient HLA-disparity against recurrent malignancy after transplantation. HLA molecules and HLA-relationships of families are therefore of particular interest in seeking to understand the role(s) of Mc at the interface of auto-immunity and healthy allo-immunity. This review will begin by providing perspective on Mc in biology followed by a primary focus on persistent Mc according to the human lifespan, in healthy individuals and with illustrative examples of autoimmune diseases.

关键词： MHC polymorphism   Evolution   Bioinformatics   Primates   Selective sweep  

摘要： T cells recognize peptides displayed on the surface of cells on MHC molecules. Genetic variation in MHC genes alters their peptide-binding repertoire and thus influences the potential immune response generated against pathogens. Both gorillas and chimpanzees show reduced diversity at their MHC class I A (MHC-A) locus compared to humans, which has been suggested to be the result of a pathogen-mediated selective sweep. More specifically, gorillas lack A3 lineage alleles while chimpanzees seem to have lost the A2 lineage. While previous studies showed this using phylogenetic analysis, here, we take an in silico functional approach and use the peptide-MHC binding prediction software NetMHCpan to examine the peptide-binding repertoires of common human, chimpanzee, and gorilla MHC-A molecules. We find that both gorillas and chimpanzees lack the A02 peptide binding specificity (supertype) despite gorillas being expected to have this specificity since they kept the A2 lineage. Additionally, we show that human MHC molecules with the A02 specificity bind fewer virus-derived peptides than other MHC molecules. We also do not find differential presentation of self-peptides by the A02 supertype, making the purpose of maintaining this specificity in high frequencies in the human population unclear. Taken together, we hypothesize that poor presentation of viral peptides by A02 supertype MHC molecules could have resulted in a selective sweep in chimpanzees and/or gorillas, though we could not identify a specific virus that may have caused this sweep.

关键词： Kidney Transplantation   HLA   Fairness   Kidney Exchange Programs (KEP)   Multi-Agent Kidney Exchange (MKEP)  

摘要： This paper presents a comprehensive review of the last two decades of research on Kidney Exchange Programs (KEPs), systematically categorizing and classifying key contributions to provide readers with a structured understanding of advancements in the field. The review highlights the evolution of KEP methodologies and lays the foundation for our contribution. We propose three mathematical models aimed at improving both the quantity and quality of kidney transplants. Model 1 maximizes the number of transplants by focusing on compatibility based on blood type and PRA, without additional constraints. Model 2 introduces a minimum Human Leukocyte Antigen (HLA) compatibility threshold to enhance transplant quality, though this leads to fewer matches. Model 3 extends the problem to a Multi-Agent Kidney Exchange Program (MKEP), pooling incompatible donor-recipient pairs across multiple agents, resulting in a higher number of successful transplants while ensuring fairness across agents. Sensitivity analyses demonstrate tradeoffs between transplant quantity and quality, with Model 3 striking the optimal balance by leveraging multi-agent collaboration to improve both the number and quality of transplants. These findings underscore the potential benefits of more integrated kidney exchange systems. (c) 2025 by the authors;licensee Growing Science, Canada

关键词： YB1   lipid metabolism   nonalcoholic fatty liver disease   NAFLD   inhibin Beta E   INHBE   TNF-beta signaling pathway   Y-box binding protein-1  

摘要： Nonalcoholic fatty liver disease (NAFLD) is a prevalent liver disorder that has emerged as a significant public health concern. This study aimed to investigate the mechanisms by which Y-box binding protein-1 (YB1) knockdown influences lipid metabolism and oxidative stress in palmitic acid (PA)-induced NAFLD LO2 cells. The expression of YB1 was analyzed using the GSE89632 dataset from the Gene Expression Omnibus (GEO) database. RNA sequencing was performed, followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, and proteinprotein interaction (PPI) network analyses to identify differentially expressed genes (DEGs). Quantitative Real-Time PCR (QRT-PCR), Western blotting, flow cytometry, and various biochemical assays were used to evaluate gene expression, lipid accumulation, and oxidative stress. Our results demonstrated that YB1 is highly expressed in NAFLD. RNA sequencing revealed 798 DEGs between the shCtrl and shYB1 groups, with 190 genes upregulated and 608 genes downregulated. Notably, we observed an increase in INHBE (Inhibin Beta E) expression, while EGR1, GDF15, NUPR1, and FOSB were decreased in NAFLD LO2 cells. YB1 knockdown, particularly when combined with INHBE suppression, significantly enhanced cell viability, improved lipid metabolism, and reduced reactive oxygen species (ROS) accumulation and malondialdehyde (MDA) content. The downstream mechanism was primarily associated with TNF-beta signaling. Specifically, we observed decreased levels of TGF-beta 1, p-Smad2, and p-Smad3 following YB1 and INHBE knockdown. Furthermore, INHBE overexpression reversed the beneficial effects induced by YB1 knockdown. In conclusion, YB1 knockdown improves lipid metabolism and reduces oxidative stress in NAFLD LO2 cells, largely through the INHBE/TNF-beta signaling pathway. These findings provide valuable insights into novel therapeutic strategies for managing NAFLD.