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关键词： Psoriasis   biologic therapy   TNF inhibitors   interleukin inhibitors   IL-23  

摘要： IntroductionPsoriasis (PsO) is a common chronic, inflammatory, immune-mediated disease. In 2023, a 4.4% prevalence of PsO was reported in Portugal. Currently, Tumor Necrosis Factor inhibitors (TNFi) are the recommended first-line (1 L) biologic agents in Portugal given their lower cost. However, TNFi may not be suitable for several patients. In these patients, interleukin inhibitors (ILi) should be considered as they provide more effective outcomes and a better safety *** interviews with PsO experts were conducted to identify PsO biologic treatment needs, resulting in an online survey to explore clinical cases focused on subpopulations of PsO. A delphi study evaluated consensus on clinical criteria to initiate non-TNFi therapy in seven predefined subpopulations of *** study highlights the benefit of starting non-TNFi therapy in all PsO predefined subpopulations. Patients with infection risk, mild heart failure and associated comorbidities, autoimmune diseases and family history of demyelinating disease consensually benefit from starting non-TNFi therapy in 1 L. Several risks associated with latent tuberculosis, advanced age and oncological disease were also *** the existence of various risks associated with TNFi usage, this clinical perspective overview of Portuguese experts in PsO treatment emphasizes the need for a tailored therapeutic framework in the management of PsO.

关键词： Cancer   clinical trials   cytokine   High-dose IL-2 (HD IL-2)   IL-2 receptor (IL-2R)   IL-2R agonist   immunotherapy   Interleukin-2 (IL-2)  

摘要： Immune checkpoint blockade (ICB) has significantly improved the survival for many patients with advanced malignancy. However, fewer than 50% of patients benefit from ICB, highlighting the need for more effective immunotherapy options. High-dose interleukin-2 (HD IL-2) immunotherapy, which is approved for patients with metastatic melanoma and renal cell carcinoma, stimulates CD8+ T cells and NK cells and can generate durable responses in a subset of patients. Moreover, HD IL-2 may have potential efficacy in patients whose disease has progressed following ICB and plays a vital role in expanding tumor-infiltrating lymphocyte (TIL) in TIL therapy. Despite its potential, the use of HD IL-2 is limited by severe toxicities such as hypotension and vascular leak syndrome. Additionally, only a few patients achieve a good outcome after HD IL-2 therapy. To address these challenges, numerous next-generation IL-2 receptor (IL-2 R) agonists have been developed to exhibit treatment effects while minimizing adverse events. This review will explore IL-2 biology, the clinical application of HD IL-2 therapy, and the development of novel IL-2 R agonists for cancer immunotherapy.

关键词： Fusobacterium   novel species   pangenome   comparative genomics   intestinal microbiota   colorectal cancer  

摘要： Cancerous tissue is a largely unexplored microbial niche that provides a unique environment for the colonization and growth of specific bacterial communities, and with it, the opportunity to identify novel bacterial species. Here, we report distinct features of a novel Fusobacterium species, F. sphaericum sp. nov. (Fs), isolated from primary colon adenocarcinoma tissue. We acquire the complete closed genome and associated methylome of this organism and phylogenetically confirm its classification into the Fusobacterium genus, with F. perfoetens as its closest neighbor. Fs is phenotypically and genetically distinct, with morphological analysis revealing its coccoid shape, that while similar to F. perfoetens is rare for most Fusobacterium members. Fs displays a metabolic profile and antibiotic resistance repertoire consistent with other Fusobacterium species. In vitro, Fs has adherent and immunomodulatory capabilities, as it intimately associates with human colon cancer epithelial cells and promotes IL-8 secretion. An analysis of the prevalence and abundance of Fs in > 20,000 human metagenomic samples shows that it is a rarely detected member within human stool with variable relative abundance, found in both healthy controls and patients with colorectal cancer (CRC). Our study sheds light on a novel bacterial species isolated directly from the human CRC tumor niche and given its in vitro interaction with cancer epithelial cells suggests that its role in human health and disease warrants further investigation.

关键词： Myocardial ischemia/reperfusion injury   caspase-1   IL-1 beta   pyroptosis   mitochondrial homeostasis   cardiomyocyte injury  

摘要： BackgroundPyroptosis is a novel kind of programmed cell death and Caspase-1 plays key roles in driving pyroptosis. The current study aims to elucidate the molecular mechanism affecting cardiomyocyte pyroptosis in myocardial ischemia/reperfusion (I/R) injury, both in vivo and in *** murine model of myocardial I/R injury was established and then treated with lentivirus-mediated shRNA targeting Caspase-1 to evaluate the effect of Caspase-1 on myocardial I/R injury. Further, Caspase-1 was silenced in the cardiomyocytes following hypoxia-reoxygenation (H/R) to detect the function of Caspase-1 in mitochondrial homeostasis and cardiomyocyte *** of Caspase-1 inhibited the secretion of interleukin-1 beta (IL-1 beta), improved cardiac dysfunction and decreased pyroptosis in vivo. The cardio-protective effect was verified in the H/R-induced cardiomyocyte model. Recombinant IL-1 beta protein reversed the inhibitory effect of Caspase-1 knockdown on ***, activating the Caspase-1/IL-1 beta axis by myocardial I/R injury causes mitochondrial homeostasis imbalance, pyroptosis, and the consequent cardiomyocyte injury.

关键词： Escherichia coli   lymphostatin   Chlamydia   inhibition   lymphocyte   IFN gamma  

摘要： Pathogens frequently produce proteins to evade or inhibit host immune responses. One such protein is lymphostatin from attaching and effacing Escherichia coli (also known as lymphocyte inhibitory factor A;LifA), which influences intestinal colonization and inhibits mitogen- and antigen-activated proliferation of T lymphocytes and pro-inflammatory cytokine synthesis. Here, we report the cloning, purification and characterization of a LifA homologue from Chlamydia pecorum. The predicted 382 KDa protein (CPE2_0552) exhibited 36% identity and 55% similarity over 3171 amino acids to lymphostatin from enteropathogenic E. coli strain E2348/69. CPE2_0552 shares glycosyltransferase and cysteine protease motifs required for lymphostatin activity, including similarity in the tertiary structure of these domains predicted by AlphaFold 3. Purified CPE2_0552 did not share the L-shaped globular structure of lymphostatin when analyzed by transmission electron microscopy. CPE2_0552 inhibited concanavalin A-stimulated proliferation of bovine T cells in a concentration-dependent manner, with an inhibitory dose 50 (ID50) of 812 pg/mL. This was 38-fold higher than the ID50 of E. coli E2348/69 lymphostatin tested in parallel on T cells from the same donors (21 pg/mL), but was similar to another LifA homologue from E. coli O157:H7 (ToxB). Moreover, CPE2_0552 inhibited the secretion of interferon gamma (IFN gamma), a key cytokine that influences the outcome of Chlamydia infections. At the concentrations at which CPE2_0552 inhibited T lymphocyte proliferation and IFN gamma secretion, negligible cytotoxicity was observed after 72 h of stimulation. Our study indicates that E. coli lymphostatin belongs to a wider family of lymphocyte-inhibitory molecules that exist in distantly related bacterial pathogens.

关键词： Obese patients with PCOS   BMP-15   infertility   metabolic disorders  

摘要： Background: Obesity-related polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with infertility and metabolic dysfunction. While bone morphogenetic protein-15 (BMP-15) plays a recognized role in ovarian function, its specific impact on infertility in obese PCOS patients remains unclear Objective: This study aimed to investigate the influence of BMP-15, NOD-like receptor protein 3 (NLRP3), and interleukin-18 (IL-18) on infertility in this population and to evaluate their predictive clinical value. Methods: Clinical data from 185 obese PCOS patients were retrospectively analyzed. Univariate and logistic regression analyses identified infertility-related factors. Results: Results showed an infertility rate of 34.43%, with significant differences in BMP-15, NLRP3, IL-18, Morisky Medication Adherence Scale (MMAS-8), and Connor-Davidson Resilience Scale (CD-RISC) scores between infertility and non-infertility groups. NLRP3, IL-18, and MMAS-8 emerged as risk factors, while BMP-15 and CD-RISC were *** an obese PCOS mouse model, BMP-15 administration improved metabolic parameters, restored hormonal balance, reduced ovarian inflammation, and preserved fertility. Conclusion: These findings suggest that BMP-15 plays a protective role in PCOS-related infertility by modulating metabolic and inflammatory pathways. BMP-15 may serve as a valuable biomarker and therapeutic target for early identification and intervention in obese PCOS patients at risk of infertility.

关键词： cGAS-STING pathway   porcine   apoptosis   interferon   autophagy   caspase  

摘要： The innate immune cGAS-STING signalling pathway recognizes double-stranded DNA and induces the interferon (IFN) response, autophagy and apoptosis, exerting a broad antiviral effect. However, the mechanisms and interrelationship between STING induced downstream IFN, autophagy, and apoptosis in livestock have not been fully elucidated. Our previous study defined porcine STING (pSTING) induced IFN, autophagy and apoptosis, and showed that IFN does not affect autophagy and apoptosis, whereas autophagy inhibits both IFN and apoptosis, likely by promoting pSTING degradation. In this study, we further explored the underlying mechanism of pSTING induced apoptosis and the regulation of IFN and autophagy by apoptosis. First, pSTING induces endoplasmic reticulum (ER) stress and mitochondrial damage to activate caspases 9, 3, and 7, which drive intrinsic apoptosis. Second, pSTING triggered apoptosis inhibits the IFN response by activating caspase 7, which cleaves pIRF3 at the species specific D197/D198 site. Third, pSTING activated apoptotic caspases 9, 3, and 7 reduce the expression of ATG proteins, and cleave the ATG5-ATG12L1 complex, effectively inhibiting autophagy. Fourth, knockout of pSTING activated apoptosis heightens the IFN response and autophagy, while suppressing the replication of Herpes Simplex Virus type 1 (HSV-1), Vesicular Stomatitis Virus (VSV) and Pseudorabies Virus (PRV). This study sheds light on the molecular mechanisms of innate immunity in pigs.

关键词： Platelet transfusion refractoriness   anti-HLA antibody   anti-HLA-C autoantibody   hematologic disorders  

摘要： Objectives Platelet transfusion refractoriness (PTR) is a frustrating clinical problem, and primary and persistent (P/P) PTR who experienced persistent PTR since the first transfusion was failed to be well recognized. This study aims to investigate the incidence and risk factors for P/P PTR. Methods Patients with hematologic disorders who underwent HLA high-resolution genotyping and donor-specific HLA antibody or panel reactive antibody (PRA) testing between January 2019 and March 2023 were reviewed. Clinical data including infection history, splenomegaly, frequency and quantity of blood transfusions, and transfusions response were delineated and subsequently analyzed. Results 114 patients were included retrospectively, and 1071 transfusions were recorded. The overall incidence of PTR was 28.95% (33/114), with 63.63% (21/33) being P/P PTR. Anti class I HLA (anti-HLA-I) antibody was identified as an independent risk factor for ineffective platelet transfusion through multivariate logistic regression analysis (p = .034). Interestingly, anti-HLA-C autoantibodies were first found in six patients, and both anti-HLA-A and C autoantibodies were detected in one case, comprising a total of 10.71% (6/56) of HLA-I antibody-positive patients. Further analysis revealed that anti-HLA-C autoantibody was identified as an independent risk factor for P/P PTR (p = .039). Among patients with positive anti-HLA-C antibodies, significant differences in the effectiveness of ABO, D-matched and cross-matching transfusions were observed between patients with or without anti-HLA-C autoantibodies (p < .001 and p = .017). Notably, platelet transfusions independence was achieved by two of the four patients who received rituximab. Conclusions This work emphasized the significance of anti-HLA-C autoantibody for P/P PTR in hematological patients, and rituximab may therapeutic.

关键词： MHC I   immunopeptidome   colorectal cancer   topoisomerase inhibitor   microsatellite  

摘要： Immunotherapy options for microsatellite stable (MSS) colorectal cancer are currently very limited. The lack of detectably unique or altered immunogens in the tumor microenvironment may be a factor. Radiation and chemotherapy may enhance immunotherapy by increasing cancer cell visibility through Major Histocompatibility Complex I (MHC I) expression. To investigate this, we treated MSS and microsatellite-instable (MSI) colon cancer cells with a topoisomerase inhibitor and analyzed MHC I-associated peptides. Treatment increased peptide numbers by 5% in RKO (MSI) cells and 83% in SW620 (MSS) cells, with 40-50% of peptides being exclusive to treatment. Additionally, clustering analysis revealed a set of peptides with uniquely conserved residues displayed only in treated MSS SW620 cells. Gene Ontology analysis of MHC I-displayed proteins revealed a treatment-induced increase in extracellular vesicle- and nuclear-derived proteins, alongside reduced cytosolic protein sampling. Overall, we present evidence for treatment-inducible differential display of peptides, some of which may affect interactions and functions of immune cells. Given the multitude of factors that modulate the effects of increased MHC I expression and associated peptides, further studies are needed to elucidate the pathophysiological implications of these changes.