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

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 IL-17 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： Acute severe ulcerative colitis   Anti-TNF   Biomarkers   Infliximab   Predictors  

摘要： Acute severe ulcerative colitis (ASUC) affects up to 25% of patients with UC and is associated with an increased risk of colectomy. Despite improvements in medical management, individual patient prognostication and risk stratification in ASUC remains challenging. We explored clinical, biochemical, and endoscopic factors as potential predictors for colectomy in patients hospitalized with ASUC. A retrospective analysis of patients with ASUC as defined by Truelove and Witts criteria admitted to the Mount Sinai Hospital between 2011 and 2020 was conducted. Data on disease history, medication use, clinical symptoms, and laboratory results during admission for ASUC were included. Colectomy risk during hospitalization and within one year was assessed. We included 158 patients; 34 (21.5%) underwent colectomy during hospital admission and 41 (25.9%) within a year. On multivariable analysis, prior anti-TNF exposure (odds ratio [OR] 4.59, 95% confidence interval [CI] 1.57–13.4, P = 0.005), and biologic use at admission (OR 3.31, 95%CI 1.14–9.63, P = 0.028) were associated with an increased risk of 1-year colectomy. Conversely, mesalamine use at admission decreased this risk (OR 0.31, 95%CI 0.13–0.72, P = 0.006). Other risk factors included recent UC-related hospitalization (< 1 year of admission), higher bowel movement frequency after 3 days of treatment, low hemoglobin and albumin levels, and elevated CRP. Infliximab treatment was associated with decreased risk of urgent (OR 0.30, 95%CI 0.13–0.73, P = 0.007) and 1-year colectomy (OR 0.31, 95%CI 0.14–0.73, P = 0.007). In patients with ASUC, prior anti-TNF exposure is linked to a higher risk of both short- and long-term colectomy, while recycling infliximab may reduce colectomy risk.

关键词： CLIP   CP: Cancer   CP: Immunology   MHC class II   antigen presentation   dendritic cells   invariant chain   tumor immunology   tumor-draining lymph node  

摘要： Tumor-draining lymph node dendritic cells (DCs) are poor stimulators of tumor antigen-specific CD4 T cells; however, the mechanism behind this defect is unclear. We now show that, in tumor-draining lymph node DCs, a large proportion of major histocompatibility complex class II (MHC-II) molecules retains the class II-associated invariant chain peptide (CLIP) fragment of the invariant chain bound to the MHC-II peptide binding groove due to reduced expression of the peptide editor H2-M and enhanced activity of the CLIP-generating proteinase cathepsin S. The net effect of this is that MHC-II molecules are unable to efficiently bind antigenic peptides. DCs in mice expressing a mutation in the invariant chain sequence that results in enhanced MHC-II-CLIP accumulation are poor stimulators of CD4 T cells and have diminished anti-tumor responses. Our data reveal a previously unknown mechanism of immune evasion in which enhanced expression of MHC-II-CLIP complexes on tumor-draining lymph node DCs limits MHC-II availability for tumor peptides.

摘要： Despite the promising clinical applications of immunotherapy, its effectiveness is often limited by low immune responses and tumor immune escape. In this study, we introduce a simple and drug-free inorganic nanomaterial, sodium succinate (CHNaO NPs), prepared using a rapid microemulsion method to enhance cancer immunotherapy. The synthesized CHNaO NPs can release high concentrations of Na and succinate ions into tumor cells, leading to an increase in intracellular osmolarity. This triggers the pyroptosis pathway, resulting in the release of cellular contents, inflammatory factors, and damage-associated molecular patterns, which ultimately boost immune responses. Furthermore, CHNaO NPs inhibit tumor immune escape through upregulating major histocompatibility complex-I (MHC-I) expression. Collectively, CHNaO NPs significantly inhibit tumor growth and metastasis by pyroptosis-induced immune activation and MHC-I expression upregulation-remitted tumor immune escape. This research offers a novel approach to tumor treatment that leverages MHC-I expression and pyroptosis, demonstrating the potential for clinical application in cancer immunotherapy.

关键词： Hyperprogressive disease   IFN-γ   Immune checkpoint inhibitors   Non-Small Cell Lung Cancer   PD-L1   Tumor plasticity  

摘要： Non-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer death worldwide. Although immune checkpoint inhibitors (ICIs) have shown remarkable clinical efficacy, they can also induce a paradoxical cancer acceleration, known as hyperprogressive disease (HPD), whose causative mechanisms are still unclear. This study investigated the mechanisms of ICI resistance in an HPD-NSCLC model. Two primary cell cultures were established from samples of a NSCLC patient, before ICI initiation (“baseline”, NSCLC-B) and during HPD (“hyperprogression”, NSCLC-H). The cell lines were phenotypically and molecularly characterized through immunofluorescence, Western Blotting and RNA-Seq analysis. To assess cell plasticity and aggressiveness, cellular growth patterns were evaluated both in vitro and in vivo through 2D and 3D cell growth assays and patient-derived xenografts establishment. In vitro investigations, including the evaluation of cell sensitivity to interferon-gamma (IFN-γ) and cell response to PD-L1 modulation, were conducted to explore the influence of these factors on cell plasticity regulation. NSCLC-H exhibited increased expression of specific CD44 isoforms and a more aggressive phenotype, including organoid formation ability, compared to NSCLC-B. Plastic changes in NSCLC-H were well described by a deep transcriptome shift, that also affected IFN-γ–related genes, including PD-L1. IFN-γ–mediated cell growth inhibition was compromised in both 2D-cultured NSCLC-B and NSCLC-H cells. Further, the cytokine induced a partial activation of both type I and type II IFN-pathway mediators, together with a striking increase in NSCLC-B growth in 3D cell culture systems. Finally, low IFN-γ doses and PD-L1 modulation both promoted plastic changes in NSCLC-B, increasing CD44 expression and its ability to produce spheres. Our findings identified plasticity as a relevant hallmark of ICI-mediated HPD by demonstrating that ICIs can modulate the IFN-γ and PD-L1 pathways, driving tumor cel

摘要： BACKGROUND:Antibody-mediated rejection (ABMR) has become one of the leading causes of chronic lung graft dysfunction. However, in lung transplantation, this entity is sometimes difficult and controversial to diagnose. It is mainly caused by the appearance of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA), although there are situations with C4d deposits in biopsy in the absence of circulating DSA. The aim of this work was to study the potential role of non-HLA antibodies in the development of ABMR without DSA after lung transplantation. METHODS:A case-control study was designed with a cohort of lung transplant recipients at our institution. Twenty-seven patients with ABMR and without anti-HLA antibodies were identified after lung transplantation, and a control group of 21 transplant recipients was selected with the same post-transplant follow-up without evidence of rejection. Non-HLA antibodies were studied pretransplant using Luminex (ThermoFisher, One Lambda). RESULTS:The median of the pretransplant non-HLA-positive antibodies in the group with ABMR without DSA is significantly higher than in the control group: 2 (interquartile range, 0-16) vs 0 (interquartile range, 0-1; P < .01). Patients with >1.5 pretransplant non-HLA antibodies were more likely to develop ABMR without DSA (sensitivity, 80.95%; specificity, 55.55%; area under the curve, 71.3%). CONCLUSION:The increase of non-HLA antibodies before lung transplantation has recently been shown to increase the risk of chronic lung allograft dysfunction. These results confirm that patients with a higher number of non-HLA antibodies could be at risk of developing ABMR without DSA. These results point out the possible usefulness of pre-lung transplant non-HLA antibodies to identify patients with end-stage lung disease at risk of developing ABMR without DSA.

摘要： Norovirus (NoV) infection is a leading cause of gastroenteritis and poses global health threats, with increasing incidence reported in immunocompromised individuals, which is further exacerbated by the globalization of the food industry. Eumelanin has demonstrated its potential in antiviral treatments, but its role in preventing viral infections remains underexplored. Therefore, in this study, we investigated the antiviral properties and potential mechanisms of self-assembled eumelanin nanoparticles (EmNPs) against Tulane virus (TuV), a surrogate with a similar infection mechanism to NoVs. EmNPs exhibited low cytotoxicity and strong antiviral activity in pre-incubated cells. Additionally, EmNPs stimulated the growth and endocytosis of cilia on the cell surface, exposing internal long-nanoparticle chains to interact with the cell membrane while promoting cilia growth and enhancing intercellular connections in cells. EmNPs were then transported to lysosomes vesicles, leading to a perinuclear lysosome clustering. EmNPs activated several key intracellular signaling pathways, including Toll-like receptor (TLR) and C-type lectin receptor (CLR) pathways, along with activating NF-κB, Rap1, TNF, and Hippo pathways. This regulatory action initiated innate cellular immunity, significantly enhancing the production of type I interferons (IFN-α/β) and promoting the localization of lysosomes to the perinuclear region. Therefore, this study illustrated that EmNPs effectively stimulated immune responses, improved intercellular communication, and facilitated transport mechanisms, thereby bolstering resistance to subsequent viral infections. These findings position EmNPs as promising candidates for the prevention of norovirus infections.

关键词： Gastric cancer   Helicobacter pylori   Oxidative stress   Pepsinogen-I   Pepsinogen-I, PG-I/PG-II interleukin-8  

摘要： Helicobacter pylori (***), a gram-negative bacterial pathogen associated with an increased risk of gastric cancer. This study investigates potential factors in the incidence of gastric cancer in patients with ***, including oxidative stress, inflammatory biomarkers, serum pepsinogens (PG) of I and II, and PG-I/PG-II ratio. The study comprised individuals with Helicobacter pylori (***) infection, gastric cancer patients, and healthy individuals. Biochemical parameters such as FBS (fasting blood sugar), lipid profile, and liver and kidney functional factors were evaluated using colorimetric techniques. Oxidative markers such as total oxidant status (TOS) and malondialdehyde (MDA) were quantified through colorimetric methods. IL-8, PG-II, and PG-II levels were also determined using the ELISA technique. Individuals with H. pylori infection exhibited elevated levels of IL-8 (940.5 ± 249.7 vs. 603.4 ± 89.1 pg/ml, P < 0.0001) and oxidative species (5.47 ± 0.7 vs. 1.64 ± 0.7 nM, P < 0.05) compared to gastric cancer patients, who, despite having lower levels of IL-8 and oxidative species, showed higher levels of MDA. *** patients exhibited significantly higher levels of PG-I (7.28 ± 2.1 vs. 2.61 ± 1.4 ng/ml, P < 0.001), PG-II (3.21 ± 1 vs. 2.6 ± 0.6 ng/ml, P < 0.001), and the PG-I/PG-II ratio (2.27 ± 1.2 vs. 1 ± 0.4, P < 0.001) compared to gastric cancer patients. The findings were substantiated using various data analysis platforms such as Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN (The University of ALabama at Birmingham CANcer data analysis), cBioPortal, and TIMER (Tumor IMmune Estimation Resource). These parameters could serve as potential diagnostic biomarkers for screening and therapeutic interventions based on the cut-off values derived from ROC (receiver operating characteristic) curves for IL-8, PGI, PGII, and PGI/PGII across the three groups. IL-8, PGI, PGII, and PGI/PGII parameters could serve as potential dia