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关键词： IL-17   Bone healing   Tendon ossification   Tendon aging  

摘要： The interleukin-17 (IL-17) family, encompassing IL-17A to IL-17F, plays pivotal roles across various biomedical fields. IL-17A, a prominent cytokine, has garnered significant attention. However, the pathological effects of IL17 can often be unpredictable. This review delves into the multifaceted roles of IL-17 family members in bone healing, tendon ossification, and aging. IL-17 is central in modulating the inflammatory response during bone healing, influencing osteoblast and osteoclast activities, and promoting bone regeneration. In the context of tendon ossification, IL-17 orchestrates the proliferation, differentiation, and apoptosis of fibroblasts, instigating inflammatory responses. It also impacts the functionality of tendon stem cells and the composition of the extracellular matrix, correlating with indicators of tendon senescence. By understanding these dynamic changes, we gain deeper insights into IL-17's crucial function in bone and tendon tissues, highlighting its potential in modulating inflammatory responses. As research continues to evolve, promising therapeutic interventions targeting IL-17 are on the horizon, addressing disease challenges and paving the way for new, effective treatments.

关键词： HLA novel allele   HLA-DPB1*1781:01   nanopore sequencing  

摘要： HLA-DPB1*1781:01 differs from HLA-DPB1*03:01:01:01 by one nonsynonymous nucleotide substitution in codon 5 in exon 1.

关键词： Autoantibodies   Diagnosis   Endotype   Genetics   Genotype   Heterogeneity   HLA   Immunologic   Phenotype   Precision medicine   Preclinical   Prediction   Screening   TrialNet   Type 1 diabetes  

摘要： Aims/hypothesis Many studies of type 1 diabetes pathogenesis focus on individuals with high-risk HLA haplotypes. We tested the hypothesis that, among islet autoantibody-positive individuals, lacking HLA-DRB1*04-DQA1*03-DQB1*0302 (HLA-DR4-DQ8) and/or HLA-DRB1*0301-DQA1*0501-DQB1*0201 (HLA-DR3-DQ2) is associated with phenotypic differences, compared with those who have these high-risk HLA haplotypes. Methods We classified autoantibody-positive relatives of individuals with type 1 diabetes into four groups based on having both HLA-DR4-DQ8 and HLA-DR3-DQ2 (DR3/DR4;n=1263), HLA-DR4-DQ8 but not HLA-DR3-DQ2 (DR4/non-DR3;n=2340), HLA-DR3-DQ2 but not HLA-DR4-DQ8 (DR3/non-DR4;n=1607) and neither HLA-DR3-DQ2 nor HLA-DR4-DQ8 (DRX/DRX;n=1294). Group comparisons included demographics, metabolic markers and the prevalence of autoantibodies against GAD65 (GADA%), IA-2 (IA-2A%) or insulin (IAA%) at enrolment. A p value <0.01 was considered statistically significant. Results IA-2A% was lower in the DRX/DRX group (20.9%) than in the DR4/non-DR3 (38.5%, p<0.001) and DR3/DR4 (44.8%, p<0.001) groups, but similar to the DR3/non-DR4 group (20.0%). Conversely, IAA% was similar in the DRX/DRX (43.4%), DR4/non-DR3 (41.1%) and DR3/DR4 (41.0%) groups, but lower in the DR3/non-DR4 group (30.1%, p<0.001). Participants in the DRX/DRX group were older, with a lower prevalence of White participants and a higher prevalence of overweight/obesity, and higher preserved C-peptide (as measured by a lower Index60) than those in the DR3/DR4 group (all comparisons, p<0.005), a lower prevalence of White or non-Hispanic participants and a lower Index60 than those in the DR4/non-DR3 group, and younger age, a higher prevalence of Hispanic participants and a lower Index60 than those in the DR3/non-DR4 group (all comparisons, p<0.005). Among the 1292 participants who progressed to clinical type 1 diabetes, those in the DR3/non-DR4 group had higher GADA%, lower IA-2A% and lower IAA% than the other groups (all compa

关键词： Glutamine metabolism   IFN-gamma signaling   Non-small cell lung cancer   Autophagy   Immunotherapy   V9302  

摘要： Glutamine metabolism is emerging as a target for improving immunotherapy efficacy. However, the outcomes remain inconclusive. Given that the tumor-intrinsic response to interferon-gamma (IFN-gamma) is a key determinant of immunotherapy efficacy, we investigated whether and how glutamine deprivation in cancer cells affects their response to IFN-gamma. By using human lung cancer cell lines, patient-derived tumor explants, and a syngeneic mouse model of lung cancer, we demonstrated that glutamine deprivation reduced the IFN-gamma-driven response in cancer cells by promoting autophagy-dependent IFN-gamma receptor (IFNGR1) degradation and rendering tumors resistant to anti-PD-1 or anti-PD-L1 therapy. Treatment with V9302, an inhibitor of the alanine-serine-cysteine transporter (ASCT2), enhanced the IFN-gamma-driven response of cancer cells and increased the efficacy of PD-1 blockade therapy. Mechanistic analysis revealed that V9302 inhibited autophagy by impairing lysosomal activity independent of glutamine deprivation, likely because of its physiochemical properties, thereby preventing IFNGR1 degradation. Moreover, V9302 also increased Glut1 expression through the inhibition of lysosomal pathway-dependent degradation of Glut1 and consequently increased cancer cell glucose uptake, in turn retaining the levels of intracellular alpha-ketoglutarate (alpha-KG) and ATP, which are involved in maintaining IFN-gamma signal transduction in cancer cells. In support of these findings, targeting lysosomal activity with chloroquine (CQ) also increased IFNGR1 expression and the IFN-gamma-driven response in cancer cells. The administration of CQ increased the sensitivity of ASCT2-deficient tumors to anti-PD-L1 therapy. Glutamine deprivation per se leads to resistance to immunotherapy, whereas V9302 treatment results in increased immunotherapy efficacy through impaired lysosomal activity, which is independent of glutamine deprivation.

关键词： Fatigue   Cancer   Oncology   Cytokines   Hemoglobin   Latent growth curve model  

摘要： PurposeThe present study aimed to examine (a) how fatigue severity changes during the course of chemotherapy in patients with hematologic cancer and (b) whether cytokines (IL-1 alpha, IL-1 beta, IL-6) are associated with fatigue change after controlling for demographic and clinical factors (e.g., hemoglobin/hematocrit, medications, comorbid conditions).MethodsThis observational cohort study used data from 148 hematological cancer patients four times: prior to chemotherapy, on the last day of chemotherapy, 1 week after the chemotherapy completion, and 1 month after baseline assessment. Latent growth curve modeling was used to examine the longitudinal association of fatigue severity with cytokines and *** quadratic growth curve model fit the data well, indicating model tenability, and explained a large amount of variance in fatigue across measurement time points. Fatigue slightly increased toward the end of chemotherapy and decreased with time after chemotherapy completion. The influence of IL-6 on fatigue was significant at all time points except at the last assessment occasion (i.e., 1 month after the baseline assessment). The influence of IL-6 on fatigue was independent (unique) from the impact of hemoglobin level. Age and chemotherapy given for the first line of treatment significantly influenced the rate of fatigue change over time. Age also influenced the change pattern's *** severity changes across the course of chemotherapy within the context of IL-6 activity, not the hemoglobin level. The influence of IL-6 may be limited during and shortly after chemotherapy. These findings inform the development of new symptom management strategies.

摘要： Hypoimmunogenic universal induced pluripotent stemn (iPS) cells were generated through the targeted disruption of key genes, including human leukocyte antigen (HLA)-A, HLA-B and HLA-DR alpha (DRA), using the CRISPR-Cas9 system. This approach aimed to minimize immune recognition and enhance the potential of iPS cells for allogeneic therapy. Heterozygous iPS cells were used for guide RNA design and validation to facilitate the knockout (KO) of the HLA-A, HLA-B and HLA-DRA genes. The electroporation of iPS cells using the selected guide RNAs enabled the generation of triple-KO iPS cells, followed by single-cell cloning for clone selection. Clone A7, an iPS cell with targeted KOs of the HLA-A, HLA-B and HLA-DRA genes, was identified as the final candidate. Messenger RNA analysis revealed robust expression of pluripotency markers, such as octamer-binding transcription factor 4, sex-determining region Y box 2, Kr & uuml;ppel-like factor 4, Lin-28 homolog A and Nanog homeobox, while protein expression assays confirmed the presence of octamer-binding transcription factor 4, stage-specific embryonic antigen 4, Nanog homeobox and tumor rejection antigen 1-60. A karyotype examination revealed no anomalies, and three-germ layer differentiation assays confirmed the differentiation potential. After interferon gamma stimulation, the gene-corrected clone A7 lacked HLA-A, HLA-B and HLA-DR protein expression. Immunogenicity testing further confirmed the hypoimmunogenicity of clone A7, which was evidenced by the absence of proliferation in central memory T cells and effector memory T cells. In conclusion, clone A7, a triple-KO iPS cell clone that demonstrates immune evasion properties, retained its intrinsic iPS cell characteristics and exhibited no immunogenicity.

关键词： Anti-TNF   antibody formation   inflammatory bowel disease   loss of response   Saudi Arabia  

摘要： Background: The emergence of tumor necrosis factor inhibitors (anti-TNF) has considerably changed the management of inflammatory bowel disease (IBD) in patients who do not respond to traditional therapies. This study assesses the prevalence of anti-TNF drug levels (DLs) and antibodies (ATAbs) in patients with IBD in Saudi Arabia and explores their associations with IBD type and prior anti-TNF failure. Methods: This cross-sectional study included patients aged 14-75 years diagnosed with Crohn's disease (CD) or ulcerative colitis (UC), treated with anti-TNF medications at King Fahad Medical City over January 2016 to December 2022. Data were analyzed using descriptive statistics, Mann-Whitney U test, Kruskal-Wallis test, Pearson's Chi-squared test, and multinomial logistic regression. Results: Among 392 patients with IBD (median age, 31 years), 75.8% were diagnosed with CD and 24.2% with UC. Anti-TNF levels were subtherapeutic in 27.0% patients, therapeutic in 21.5%, and supratherapeutic in 51.5%. ATAbs were negative in 73.1% patients, weakly positive in 9.8%, and positive in 17.1%. Subtherapeutic anti-TNF levels were significantly associated with positive ATAbs (P < 0.001). Prior anti-TNF therapy failure was observed in 37.2% cases, with 15.3% showing immunogenicity. No significant demographic differences were noted across ATAbs groups. Conclusion: We highlight the prevalence of subtherapeutic and supratherapeutic anti-TNF levels among patients with IBD in Saudi Arabia and their association with ATAbs. The findings underscore the importance of monitoring anti-TNF DLs and ATAbs to optimize treatment outcomes in IBD management. Future research should focus on the longitudinal impact of these factors and explore genetic predictors of treatment response.

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： aspergillosis   Candida spp.   candidemia   cryptococcosis   deep fungal infection   immunodeficiency   pityriasis versicolor   systemic infection  

摘要： TNF-alpha inhibitors, including infliximab, adalimumab and etanercept, are used to treat various inflammatory diseases, such as arthritis, psoriasis and ankylosing spondylitis. However, these treatments may predispose patients to fungal infections, including histoplasmosis, candidiasis and aspergillosis. In this study, we systematically reviewed case reports to critically examine the correlations between anti-TNF-alpha therapies and the occurrence of invasive and superficial fungal infections. Infliximab was the most commonly used TNF-alpha inhibitor (50.65%). The highest number of fungal infections during anti-TNF34 alpha therapy was reported in the USA (84.25%). The conditions treated primarily included rheumatoid arthritis. A total of 517 invasive fungal infections were identified, including histoplasmosis, invasive candidiasis and aspergillosis, with histoplasmosis being the most common. Most studies were conducted in higher-income countries, highlighting the critical lack of research on the use of immunobiologicals in relation to fungal diseases in African countries, which requires further attention. Logistic regression analysis revealed significant associations between adalimumab use and increased risks of candidiasis, coccidioidomycosis, onychomycosis and pityriasis versicolor. For etanercept, significant associations were found with aspergillosis, coccidioidomycosis, cryptococcosis, dermatophytosis, invasive candidiasis, pityriasis versicolor and onychomycosis. Infliximab use was significantly associated with coccidioidomycosis, onychomycosis, aspergillosis, cryptococcosis, histoplasmosis and invasive candidiasis. The data presented in this study clearly demonstrate an association between the use of TNF-alpha inhibitors and an increased risk of fungal infections. It is imperative that healthcare professionals maintain a high level of vigilance when managing patients on these medications. Regular monitoring and proactive management strategies are essential to