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关键词： anti-interferon-gamma autoantibody   autoimmunity   secondary immunodeficiency   urothelial carcinoma   papillary thyroid carcinoma   autoimmune thyroiditis  

摘要： Background Opportunistic intramacrophagic infections are well-characterized in adult-onset immunodeficiency associated with neutralizing anti-IFN-gamma autoantibodies (nAIGA).Objective Concomitant autoimmune and neoplastic diseases are rarely *** This study included 50 patients diagnosed with adult-onset immunodeficiency due to nAIGA between 2014-2024. Thirty-three were retrospectively included before January 2022, and 17 out of 295 screened patients were enrolled prospectively since January 2022. Ten patients were excluded due to missing records. All patients had regular follow-ups;anti-IFN-gamma titers, autoimmune markers and cancer survey were conducted according to the primary physician's *** The median age at diagnosis of adult-onset immunodeficiency was 57 years, and 53% were men. Malignancy occurred in 25%;genitourinary cancer predominated (n=4). Most (93%) patients had at least one positive autoimmune marker. Fifty-eight percent of patients were diagnosed with concomitant autoimmune diseases, and women (65%) predominated. Anti-nuclear antibody was positive in 61%, lupus anticoagulant in 50%, whilst autoimmune thyroiditis markers in 43%. Twenty-two percent of patients required long-term immunomodulation including biologic agents such as rituximab and daratumumab. Three patients (8%) died after a median interval of 9.4 years due to sepsis (n=2) and aggressive urothelial cancer (n=1). Most patients had decreasing nAIGA titers over time;two outliers with persistently high neutralizing antibodies developed late-onset *** Adult-onset immunodeficiency due to nAIGA is a syndrome associated with concomitant autoimmunity. Chronic infection and autoimmune-mediated inflammation may foster neoplastic changes, but the underlying mechanism is still undetermined. Autoimmune disease and cancer surveillance for patients with nAIGA is advised.

摘要： The third-generation mutation-selective EGFR tyrosine kinase inhibitor (EGFR-TKI) osimertinib (or AZD9291) effectively induces apoptosis in EGFR mutant (EGFRm) non-small cell lung cancer (NCSLC) cells. However, the underlying mechanisms have not been fully elucidated. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or TNFSF10) is known as a death ligand that initiates apoptosis via binding to its cell surface death receptors such as DR5. In this study, we found that osimertinib and other EGFR-TKIs increased the expression of TRAIL primarily in EGFRm NSCLC cell lines. This effect was accompanied with increased IL6 expression and STAT3 activation. Inhibition of STAT3 with either protein degradation or gene knockout abrogated the ability of osimertinib or recombinant human IL6 to elevate TRAIL levels. Moreover, osimertinib increased STAT3-dependent transcription of TRAIL via two STAT3 novel binding sites present in the TRAIL 5'flanking region. Hence, osimertinib induces IL6/STAT3-mediated TRAIL expression in EGFRm NSCLC cells. While osimertinib lost the ability to induce TRAIL expression in osimertinib-resistant EGFRm NSCLC, knockdown or knockout of TRAIL in sensitive EGFRm NSCLC cells rendered them less sensitive to osimertinib both in vitro and in vivo. Thus, TRAIL elevation contributes to the induction of apoptosis by osimertinib in EGFRm NSCLC cells. Furthermore, osimertinib increased membrane-bound TRAIL and DR5 membrane clustering and DR5 knockdown significantly compromised the cell-killing effect of osimertinib, together suggesting a DR5-dependent effect. Collectively, this study has revealed a previously undiscovered connection between TRAIL induction and osimertinib-induced apoptosis in EGFRm NSCLC cells, increasing our understanding of mechanisms accounting for apoptosis induced by osimertinib.

关键词： age donor kidney   antibody-mediated rejection   donor-specific anti-HLA antibodies   graft survival   kidney transplantation  

摘要： Background and hypothesis: The presence of donor-specific anti-HLA antibodies before kidney transplantation (preDSAs) is associated with decreased graft survival. The hypothesis that increasing donor kidney age is negatively associated with the impact of preDSA on graft survival was investigated. Methods: Outcome of kidney transplantation in a single center cohort of 2,024 patients transplanted between 2010 and 2020 with a follow-up of at least 3 years was analyzed to assess this relation. Results: DSAs before transplantation were present in 14% of recipients and showed an independent association with graft loss. The preDSA against HLA class I (2%) or class II (7%) had an adjusted hazard ratio (HR) for death censored graft failure of 5.8 (95% CI 4.4-7.7), while the combination (5%) had an HR of 18.6 (95% CI 13.8-25.1). The preDSA-associated increase in graft failure was caused primarily by an increase in the incidence of antibody-mediated rejection (ABMR), intragraft thrombosis, and primary non-function. These effects were observed more frequently in the deceased donor kidney transplantations compared to living donor kidney transplantations. The incidence of ABMR was not associated with donor kidney age. However, increasing donor kidney age significantly aggravated the negative effect of preDSA on graft survival. For instance, recipients aged >= 65 years transplanted with a deceased donor kidney aged >= 65 years had an uncensored 1- and 3-year graft survival of 83% and 67%, respectively, if transplanted without DSA. This decreased to 56% and 35% if transplanted in the presence of DSA. For comparison, recipients aged >= 65 years of a deceased donor kidney aged <65 years had an uncensored 1- and 3-year graft survival of 92% and 78%, respectively, without preDSA, and if transplanted with preDSA, this decreased to 77% and 69%, respectively. Conclusions: The negative effect of circulating DSA at the time of transplantation on both early and late death-censored graft surv

关键词： osteoporotic fractures   bacterial extracellular vesicle   synthetic biology   osteogenic differentiation   bone organoid  

摘要： Osteoporosis (OP) is a systemic disease characterized by decreased bone density and quality, leading to fragile bones and osteoporotic fractures (OPF). Conventional treatments for OPF often exhibit limited therapeutic efficacy and significant side effects. Synthetic biology-based bacterial extracellular vesicles (BEVs) offer a safe and effective alternative for OPF treatment. Here, we constructed bioengineered BEVs loaded with pBMP-2-VEGF (BEVs-BP) and encapsulated them together with IL-4 in GelMA hydrogels to form IL-4/BEVs-BP@GelMA. Initially, IL-4 alleviated chronic inflammation by modulating immune cells, while BEVs-BP subsequently enhanced osteogenesis and vascularization by upregulating BMP-2 and VEGF expression. In vitro, IL-4/BEVs-BP@GelMA polarized M1 macrophages toward the M2 phenotype, enhanced osteogenesis, and increased angiogenesis. Moreover, BEVs-BP effectively promoted the maturation and mineralization of bone organoids in vivo. Finally, IL-4/BEVs-BP@GelMA successfully accelerated osteoporotic fracture repair in mice. In summary, we developed an easy-to-build and powerful bone repair biomaterial, IL-4/BEVs-BP@GelMA, which offers a therapeutic strategy for osteoporotic fracture management.

关键词： Oleanolic acid   Mesangial proliferative glomerulonephritis   Mesangial cells proliferation   Inflammatory response   Network pharmacology   IL-17/ERK/AKT pathway  

摘要： Background: Mesangial proliferative glomerulonephritis (MsPGN) is a common form of glomerulonephritis characterized by mesangial cell proliferation and inflammatory responses. However, current clinical treatment options for MsPGN are rather limited. Oleanolic acid (OA), a natural pentacyclic triterpenoid compound, exhibits anti-tumor and anti-inflammatory properties and has been proven to have renal protective effects. We speculate that OA could potentially serve as an alternative therapy for MsPGN. Objective: This study aimed to investigate the therapeutic efficacy and mechanism of OA against MsPGN. Methods: Tail vein injection of anti-Thy1 antibody was used to establish the MsPGN model, followed by a comprehensive assessment of the effects of OA on renal function, histopathological changes, and inflammatory responses in anti-Thy1 nephritis rats. Subsequently, network pharmacology was employed to predict the key targets and pathways of OA in treating MsPGN. Finally, in vivo and in vitro experiments were conducted to validate the results of network pharmacology. Results: OA significantly improved renal function, and attenuated mesangial cell proliferation and inflammatory reactions in anti-Thy1 nephritis rats. Network pharmacology analysis identified TNF-alpha, IL-6, IL-1 beta, MAPK3, and AKT1 as key targets of OA in the treatment of MsPGN, and involved the IL-17 signaling pathway. Additionally, we observed increased phosphorylation levels of ERK and AKT, as well as activation of downstream inflammatory responses, in both anti-Thy1 nephritis rats and mesangial cells stimulated with IL-17. In contrast, treatment with OA and the ERK inhibitor PD98059 reversed these effects. Furthermore, we identified IL17RA within this pathway as a potential target of OA. Conclusions: Our study demonstrates that OA can modulate the IL-17/ERK/AKT signaling pathway, thereby improving anti-Thy1 antibody-induced MsPGN. This establishes a theoretical basis for OA to potentially serve as a

关键词： Stromal cell-derived factor 1   Ferroptosis   Chondrocyte   Osteoarthritis   Interleukin 6   Hypoxia-inducible factor 1 alpha  

摘要： Background: Osteoarthritis (OA) is a common joint disease with an incompletely understood pathogenesis. SDF-1, a key factor in cartilage matrix degradation, is involved in OA cartilage degeneration, yet its mechanism, especially regarding ferroptosis, remains unclear. This study focuses on elucidating the role of SDF-1-induced chondrocyte ferroptosis and the IL6/HIF-1 alpha signalling axis in OA. Methods: A rabbit OA model was created via SDF-1 induction. Knee cartilage tissues were sequenced and analyzed bioinformatically to identify key genes, and explore critical pathways. Clinical tissue samples were utilized to validate their clinical relevance. Furthermore, cell and rabbit models were constructed through gene interference and pathway blocking. The expression of related genes and proteins was detected by QPCR, ELISA, Western blot, and immunofluorescence. Additionally, OA and ferroptosis indicators such as cell viability, immunohistochemistry, ROS, lipid ROS, Fe2+, MDA, and mitochondrial morphology were evaluated to uncover the molecular mechanism by which SDF-1 regulates the IL6/HIF-1 alpha signalling axis to mediate chondrocyte ferroptosis. Results: Bioinformatics revealed that ferroptosis was significantly activated in SDF-1-induced OA, with IL6 and HIF-1 pathways implicated. In vitro and in vivo, SDF-1 increased the expression and secretion of MMP13 but decreased COL2A1 and ACAN in chondrocytes, leading to OA-like changes. It also suppressed the expression levels of SLC7A11 and GPX4, upregulated the gene and protein levels of ACSL4, promoted the accumulation of MDA, Fe2+, and ROS, and caused mitochondrial morphological changes. These ferroptosis manifestations could be alleviated by the ferroptosis inhibitor Fer-1. IL6 was an important mediator of SDF-1-induced ferroptosis, and knocking down IL6 also inhibited chondrocyte ferroptosis changes. Overexpressing IL6 (oeIL6) and using PX478 to inhibit the HIF-1 signalling pathway showed that PX478 could significan

关键词： IL-20 family   Neuroinflammation   Neurodegenerative diseases   Cytokines   Therapeutic targets  

摘要： The IL-20 cytokine family, comprising IL-19, IL-20, IL-22, IL-24, and IL-26, has emerged as a critical player in the pathogenesis of neurodegenerative diseases due to its multiple roles in inflammation, tissue repair, and immune modulation. These cytokines signal through IL-20 receptor complexes (IL-20RA/IL-20RB and IL-22RA1/IL20RB), triggering diverse immune processes. Recent evidence highlights their significant contributions to neuroinflammation and neurodegeneration in central nervous system disorders. IL-20 family cytokines impact microglial activation, which, when dysregulated, exacerbates neuronal damage. Specifically, IL-20 and IL-24 are linked to elevated pro-inflammatory markers in glial cells, promoting neurodegeneration. In contrast, IL-22 exhibits dual functionality, exerting protective and pathological roles depending on the inflammatory milieu. Key mechanisms involve the regulation of blood-brain barrier integrity, oxidative stress, and autophagy. IL-22 and IL-24 also protect neurons by enhancing antioxidant defenses and maintaining epithelial barrier function, while their dysregulation contributes to blood-brain barrier disruption and protein aggregate accumulation, hallmark features of Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Elevated IL-22 levels in Alzheimer's disease and IL-19's regulatory role in multiple sclerosis suggest they may serve as potential biomarkers and therapeutic targets. IL-26's role in amplifying inflammatory cascades further underscores the complexity of this cytokine family in neurodegenerative pathology. Therapeutically, strategies targeting IL-20 cytokines include monoclonal antibodies, receptor modulation, and recombinant cytokine administration. These approaches aim to mitigate neuroinflammation, restore immune balance, and protect neuronal integrity. This review underscores the IL-20 family's emerging relevance in neurodegenerative diseases, highlighting its potential for novel diagnostic and thera

关键词： Decitabine   PDGC   Differentiation therapy   Immunity   NK cells  

摘要： Poorly differentiated gastric cancer (PDGC) is characterized by high invasiveness, rapid progression, and poor prognosis for patients. Differentiation therapy has long been a promising approach by manipulating the differentiation state of tumor cells to inhibit tumor growth, offering fewer side effects. Decitabine (DAC), is known as an inhibitor of DNA methylation, thus reactivating the transcription of previously methylated silenced genes associated with differentiation to induce a more differentiated state. This study used the differentiation-inducing agents DAC to treat two PDGC cell lines, MKN45 and NUGC4, and explored the impact of DAC on cell proliferation and influence of their sensitivity to Natural Killer cells (NK cells) mediated cytotoxicity. The results demonstrated a significant reduction in cell proliferation, migration, and invasion without affecting cell viability after DAC treatment. Additionally, transcriptomic analysis revealed that DAC-treated PDGC cells upregulated multiple immune-related genes, including the gene encoding for tumor necrosis factor alpha (TNF-alpha). Co-culture study of NK cells and PDGC cells showed that DAC treatment enhanced the sensitivity of these cancer cells to NK cell-mediated cytotoxicity, and TNF-alpha played a crucial role in promoting NK cell cytotoxicity. Following the subcutaneous implantation of tumors in nude mice, DAC administration significantly inhibited the growth of PDGC tumors and induced the upregulation of differentiation related genes. In summary, DAC effectively reduces the malignant characteristics of the PDGC cells by promoting their transition towards a higher state of differentiation and enhancing their sensitivity to NK cell-mediated killing, providing new insights for the mechanisms of the antitumor effects of DAC.

关键词： AP1-S1   AP1-B1   AP1-G1   AP1-M1   Prognosis   HLA-loss   Immunological regulation  

摘要： The clathrin adaptor protein 1 (AP1) plays a pivotal role in the endocytosis of cell surface proteins and transportation between the golgi apparatus and lysosomes. Despite its critical functions, the implications of AP1 dysregulation in human cancers have yet to be elucidated. The structural analysis of AP1 subunits was conducted utilizing data from the Protein Data Bank (PDB), which is composed of four subunits: AP1-S1, AP1-B1, AP1-G1, and AP1-M1. Notably, the expression levels of AP1 subunits exhibit significant variability between tumor and normal tissues across different cancer types using data from the CPTAC, GEO, and TCGA databases. Kaplan-Meier (K-M) curve analysis has revealed that certain AP1 subunits are correlated with patient prognosis in various cancers. For instance, the AP1-S1 subunit is related to poor survival outcomes in head and neck squamous carcinoma, clear cell renal cell carcinoma, and lung adenocarcinoma. Furthermore, the aberrant expression of AP1-S1 demonstrated a negative correlation with immune cells infiltration, particularly in lung adenocarcinoma. Concurrently, a significant negative relationship between AP1-S1 and HLA molecules was observed, indicating a potential mechanism for AP1-induced HLA degradation. In vitro experiments demonstrated that the knockdown of AP1-S1 led to an upregulation of HLA-B protein expression and inhibited the viability, migration, and invasion capabilities of tumor cells in lung adenocarcinoma cell lines, specifically A549 and H1299. Immunohistochemical staining further revealed the abnormal expression of AP1-S1 in lung adenocarcinoma specimens. Through a comprehensive pan-cancer multi-omics analysis and experimental validation, this study explored the prognostic significance of four AP1 subunits. Additionally, it examined the regulatory relationship between AP1S1 and HLA-B, which may play a role in immune escape. Additionally, the research identified AP1-S1 as a valuable biomarker and a potential target for

摘要： Diffuse large B-cell lymphoma (DLBCL) remains a major clinical challenge and requires the development of new therapeutic approaches. The identification of cuproptosis, a newly defined form of copper-induced cell death, has provided innovative insights for cancer therapy. Here, we report that loss of the mitochondrial matrix reductase FDX1 in DLBCL cells impairs the antitumor effect of elesclomol (ES), which performs its function by transporting excess copper into cells. Overexpressing (OE) FDX1 significantly sensitized DLBCL cells to ES-induced cell death in vitro and enhanced the anticancer activity of ES in vivo. Furthermore, treatment with ES in FDX1-high expression patient-derived xenograft (PDX) showed a significantly greater inhibitory effect than in FDX1-low expression PDX. Mechanistically, FDX1 promotes the induction of IFN-beta-dependent PANoptosis by increasing IRF3 phosphorylation in DLBCL cells upon ES treatment. Consistent with this finding, patient cohort analysis revealed that FDX1 expression correlated positively with enhanced IRF3 phosphorylation. Together, our findings are the first to identify the central role of FDX1 in synergizing with ES to activate IFN-beta signaling and induce PANoptosis. This study enables us to re-explore the clinical anticancer potential of ES as a novel therapeutic strategy for DLBCL.