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关键词： Biosimilars   Effectiveness   Inflammatory bowel disease   Switch  

摘要： Background: Data on nonmedical switching from one anti-Tumor Necrosis Factor (TNF)- alpha biosimilar to another in inflammatory bowel disease (IBD) are relatively sparse. We aimed to study the effects of nonmedical switch from infliximab biosimilar CT-P13 to SB2 and from adalimumab biosimilar ABP 501 to SB5. Methods: In this observational study, consecutive IBD patients receiving nonmedical switch were prospectively followed-up for 12 months. The primary outcome was treatment persistence;other outcomes included: secondary effectiveness outcomes, saf ety, immunogenicity, inflammatory makers levels and psychometric assessments. Results: A total of 119 and 76 patients were enrolled in the SB2 and SB5 cohorts. Persistence on treatment at 12 months was 84.0 % in the SB2 cohort and 78.9 % in the SB5 cohort. No clinically meaningful changes in other secondary effectiveness outcomes were recorded. Rates of 0.38 and 0.63 adverse events of interest per 100 patient-years were observed in the SB2 and SB5 cohorts. The pharmacokinetics and immunogenicity of either drug were unaffected by nonmedical switch;similarly, levels of inflammatory cytokines remained largely unchanged. No changes in psychometric assessments were recorded. Conclusion: Nonmedical switch of infliximab and adalimumab biosimilars does not significantly affect treatment effectiveness, safety and pharmacokinetics, nor does it have major psychological implications for patients. (c) 2025 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： All-trans retinoid acid (atRA)   Regulatory T cells (Treg cells)   Experimental autoimmune encephalomyelitis (EAE)   Interleukin-23 receptor (IL-23R)   Th17 cells   Dendritic cells   Serum- and glucocorticoid-regulated kinase 1-dependent (SGK1)  

摘要： High salt diet (HSD) is implicated in numerous disorders, which boosts Th17 cell development and weakens immunosuppressive function of regulatory T cells (Treg cells) Treg cells, leading to the exacerbation of EAE. However, little is known regarding the harness of excessive proinflammatory responses evoked by HSD. Here we show that atRA, a key vitamin A metabolite with multifaceted immunoregulatory properties has the potential in inhibiting the proinflammatory reaction of high salt. Treatment with atRA in vivo elicited the Treg generation in cervical and axillary lymph nodes (CALs), and in CNS of experimental autoimmune encephalomyelitis (EAE). Meanwhile, the proportion of Th17-like Treg cells (ROR gamma t-positive or GM-CSF-positive Treg cells) decreased in CALs. atRA also inhibited IL-17A expression in CD4(+) effector T cells. In-vitro mechanistic studies showed that atRA inhibit IL-23R but not SGK1 expression in Treg cells and this results in maintained immunosuppressive function of Treg cells even in the presence of IL-6 and high salt. Furthermore, treatment of EAE with anti-IL-23R mAb attenuated HSD-provoked EAE progress. This was associated with a reduction in the number of CNS-infiltrating Th17 cells and an increase of CAL-Treg cells. Mechanically, treatment with atRA significantly promoted LP-CD103(+)CD11c(+) dendritic cells, a subgroup of cells most closely involved in endogenous retinoic acid metabolism, and enhanced intestinal Aldh1a1 and Rdh10 expression from HSD-fed EAE mice. Interestingly, anti-IL-23R mAb administration also reduced IL-23R expression in Treg cells, along with the increased proportion of LP-CD103(+)CD11c(+) dendritic cells and Rdh10 mRNA expression. In conclusion, administration of atRA might be a way to combat the proinflammatory effects of HSD. Meanwhile, systematic inhibition of IL-23R also had a moderate therapeutic potential in inhibiting inflammatory effects of high salt, which may serve as a basis for the identification of novel

关键词： Diabetes mellitus   metabolic syndrome   cardiorenal syndrome   natriuretic peptides   biomarkers  

摘要： Introduction Diabetes Mellitus (DM) is a metabolic disorder characterized by persistent hyperglycemia and/or insulin resistance. If left uncontrolled, it can lead to a combination of cardiac and renal alterations known as cardiorenal syndrome. Additionally, oxidative stress and inflammation contribute to tissue damage, thereby reducing the life expectancy of individuals with diabetes. Aim The aim of this study was to identify early molecular markers associated with cardiorenal syndrome, oxidative stress, and inflammation, and to investigate their correlation with the duration of exposure to DM. Methods An experimental DM model was employed using Wistar rats. The rats were divided into four groups: diabetic rats at 7 days (DM7), diabetic rats at 30 days (DM30), control sham at 7 days (CS7), and control sham at 30 days (CS30). Blood and brain tissue from the brainstem region were collected at 7 and 30 days after confirming DM induction. Gene expression analysis of Bnp, Anp, Cat, Gpx, Sod, Tnf-alpha, and Il-6 was performed. Results The analysis revealed lower expression values of Cat in the brainstem tissue of the DM7 group compared to the NDS7 group. Moreover, diabetic animals exhibited statistically lower levels of Tnf-alpha in their peripheral blood compared to the control animals. Conclusion This study concluded that DM alters the oxidative balance in the brainstem after 7 days of DM induction, resulting in lower Cat expression levels. Although some genes did not show statistical differences after 30 days of DM induction, other genes exhibited no expression values, indicating possible gene silencing. The study identified an imbalance in the studied pathways and concluded that the organism undergoes a compensatory state in response to the initial metabolic alterations caused by DM.

关键词： Schizophrenia   tumor necrosis factor-alpha   rs1800629   polymorphism   meta-analysis   genetics  

摘要： Objective: Schizophrenia is a multifaceted psychiatric disorder that affects about 1% of the world's population and arises from a combination of genetic, environmental, and neurodevelopmental influences. Recent studies highlight the role of immune system disturbances and neuroinflammation in its development, with tumor necrosis factor-alpha (TNF-alpha) identified as a pivotal cytokine. This meta-analysis aims to clarify the relationship between the TNF-alpha rs180062 9 genetic variant and the risk of schizophrenia by synthesizing data from published research. Methods: Two independent reviewers systematically searched PubMed, Web of Science, Embase, Cochrane Library, and Chinese National Knowledge Infrastructure for studies published up to January 19, 2024. Odds ratios and 95% confidence intervals were computed using a fixed-effects model, taking into accountthe absence of significant heterogeneity. Results: A total of 33 case-control studies were included, encompassing 7,624 individuals with schizophrenia and 8,933 healthy controls from diverse backgrounds (21 studies on Asian populations,11 on Caucasian, and one on a mixed group) conducted between 2001 and 2020. The pooled analysis did not reveal a significant link between the TNF-alpha rs1800629 polymorphism and susceptibility to schizophrenia under any genetic model. Further subgroup analyses by ethnicity (Asian, Caucasian), country (China, Poland), genotyping technique, and publication year also yielded no notable associations. Conclusions: This comprehensive meta-analysis offers strong evidence that the TNF-alpha rs180062 9 variant is not significantly associated with schizophrenia risk, either globally or within specific ethnic groups. These findings indicate that this polymorphism likely does not play a major role in schizophrenia susceptibility, underscoring the importance of future investigations into other TNF-alpha variants, gene-gene interactions, or alternative inflammatory mechanisms.

关键词： IL-4   IL-15   RNA sequencing   type I interferon   virtual memory CD8 T cells  

摘要： The development of virtual memory CD8 T cells is dependent on IL-4, type I interferon, and IL-15. However, it remains unclear whether these cytokines individually contribute to the generation of specific subsets of virtual memory CD8 T cells. In this study, virtual memory CD8 T cells were categorized into four subsets based on Ly6C and Sca-1 expression, and their development was examined using knock-out mice lacking IFNAR1, IL-4, or IL-15R alpha. Notably, both Ly6C+ Sca-1+ and Ly6C- Sca-1+ subsets were significantly reduced in the spleen of IFNAR1 knock-out mice, while the proportion of Ly6C+ Sca-1- VM CD8 T cells was reduced in IL-4-deficient mice. In IL-15R alpha knock-out mice, both the Ly6C+ Sca-1- and Ly6C- Sca-1- subsets were significantly reduced. Bulk RNA sequencing analysis revealed distinct gene expression patterns in na & iuml;ve cells, true memory cells, and the four virtual memory cell subsets. Specifically, Ly6C+ subsets were enriched with IL-15 signal-related genes, whereas Ly6C- subsets and true memory cells were enriched for cell cycle-related genes. Functionally, the Ly6C+ and/or Sca-1+ subsets exhibited higher production of IFN-gamma and TNF-alpha compared with the Ly6C- Sca-1- subsets. Overall, this study demonstrates the heterogeneity of virtual memory CD8 T cells and highlights the cytokine-dependent nature of their development.

关键词： Nadunolimab   Solid tumors   Efficacy   Safety   Pharmacokinetics   Biomarkers  

摘要： Interleukin (IL)-1 signaling has an essential role in tumor progression and immunosuppression and is linked to acquired resistance to anti-PD-1/PD-L1 treatment. Nadunolimab is an IL1RAP (IL-1 receptor accessory protein)-targeting antibody that blocks IL-1 alpha/IL-1 beta signaling and has enhanced antibody-dependent cellular cytotoxicity. We investigated the safety and preliminary efficacy of nadunolimab with pembrolizumab in patients with metastatic solid tumors who had progressed on previous checkpoint inhibitor treatment, suggesting acquired checkpoint inhibitor resistance (NCT04452214). This phase 1b trial enrolled patients with metastatic disease who had exhausted or declined standard-of-care alternatives. Patients received nadunolimab (5 mg/kg) and standard-dose pembrolizumab. The primary objective was to assess safety. Secondary objectives were anti-tumor response as per iRECIST, pharmacokinetics, and changes in immune mediators. Fifteen patients with stage IV cancer (head and neck squamous cell carcinoma, non-small cell lung cancer, melanoma) entered the trial. Grade >= 3 adverse events were reported for 7 patients (47%). There was one dose-limiting toxicity of febrile neutropenia. The most frequent grade >= 3 adverse event was dysphagia (two patients). Seven patients (47%) had reductions in target lesion size. Median iPFS was 3.4 months (95% CI 1.4-8.6). Median OS was 19.7 months (95% CI 4.3-28.7) with 67% 1-year survival. Survival was significantly longer in patients with higher baseline tumor infiltration of CD163 + macrophages and natural killer cells and in patients with reduced on-treatment circulating IL-6 levels or neutrophil-to-lymphocyte ratio. Nadunolimab with pembrolizumab had an acceptable safety profile, and prolonged disease control was observed in a subset of patients. The results support further development of nadunolimab in combination with checkpoint inhibitors.

关键词： dorsal root ganglion   IL-10   lipopolymer nanoparticle   mRNA   paclitaxel-induced peripheral neuropathy  

摘要： Paclitaxel (PTX) is a commonly used chemotherapeutic agent for treating various solid tumors;however, it often leads to a severe side effect known as paclitaxel-induced peripheral neuropathy (PIPN), for which effective treatments are limited. Although mRNA therapies have shown promise in addressing central nervous system (CNS) disorders, the successful delivery of mRNA therapeutics to the nervous system is still hindered by many biological barriers. In this study, it is demonstrated that, compared with commercial MC3 lipid nanoparticles (MC3 LNPs), mRNA-loaded P6CIT-derived lipopolymer nanoparticles (P6CIT LPNPs), which are delivered via intrathecal injection, achieve effective penetration through the pia mater. More importantly, this P6CIT LPNP demonstrates the ability to achieve highly targeted mRNA transfection in gliocytes within the spinal cord and dorsal root ganglia (DRG), which is essential for the regulation of neuroinflammation. Furthermore, two intrathecal injections of P6CIT LPNPs encapsulating mIL-10 (P6CIT/mIL-10) significantly alleviate PIPN by reducing proinflammatory cytokine production, gliocyte activation, and presynaptic NMDA receptor hyperactivity in both male and female mice. This study presents a promising and clinically translatable platform for using mRNA-loaded LPNPs to treat PIPN.

关键词： Sporotrichosis   Lesions   T helper cells   Keratinocytes   Immune response   Cytokines   Skin diseases   Fungal diseases  

摘要： Background Sporotrichosis is a subcutaneous mycosis caused by members of the genus Sporothrix, among which Sporothrix globosa (S. globosa) is the predominant etiological agent in Asia. T cell immunity plays crucial roles in fungal infections, yet the local T cell immune profile in sporotrichosis lesions remains unclear. IL-18, a pleiotropic cytokine capable of modulating T cell responses, is also poorly understood in host defense against S. ***/principal findings qPCR, western blot, and IHC/mIHC were employed to profile IL-18, IL-18 BP, caspase-1 and IL-18R axis, along with Th1,Th2, and Th17 cells and their specific cytokines in sporotrichosis lesions versus healthy skin. Cellular sources of IL-18 in the lesions were identified via mIHC, and IL-18 production from keratinocyte/PBMCs exposed to S. globosa in vitro was tested by qPCR and western blot. Flow cytometry was performed to evaluate the role of IL-18 in Th2 polarization in the PBMCs-S. globosa coculture system. Lesional skin exhibited hyperactivated IL-18 signaling, marked by upregulated IL-18, caspase-1, and IL-18R, alongside decreased IL-18 BP. IL-18 was primarily released by dermal dendritic cells and Langerhans cells, rather than keratinocytes. A mixed Th1/Th2/Th17 microenvironment with Th2 predominance correlated strongly with prolonged disease duration. Strikingly, IL-18 synergistically interacted with Th1-derived IL-2 to establish a self-reinforcing Th2 loop, as evidenced by the strong correlation between lesional IL-4 and IL-18 levels (r = 0.70) and the concomitant upregulation of IL-18/IL-2 during S. globosa-induced Th2 expansion in PBMCs-an effect reversed by IL-18/IL-2 neutralizing antibodies. Critically, this Th2 skewing was mechanistically dependent on NF-kappa B signaling, as demonstrated through pharmacological pathway ***/significance This study unveils the dual role of IL-18 in human sporotrichosis caused by S. globosa-amplifying both Th1 and Th2 responses bu

关键词： ADMET   Eczema   IL-4R alpha   Molecular Docking   Molecular Dynamics   Phytochemicals  

摘要： Eczema, a chronic inflammatory skin disorder, affects a significant portion of the global population, leading to itching, redness, and skin damage. This study investigates the potential of 39 phytochemicals derived from Atractylis cancellata, Helianthemum sessiliflorum, and Euphorbia guyoniana as IL-4R alpha modulators for the development of plant-derived therapeutics against eczema. Using advanced molecular docking and molecular dynamics simulations, we evaluated the binding affinity, stability, and potential efficacy of these compounds in targeting IL-4R alpha. Our results demonstrate that 10 compounds show strong binding affinity, with values ranging from -12.421 kcal/mol to -8.157 kcal/mol. Among these, Isoolivil and Catechin stood out as particularly promising compounds. Both demonstrated favorable ADMET properties for topical administration, suggesting minimal irritation and optimal skin penetration. In terms of stability, both compounds exhibited RMSD fluctuations below 2 & Aring;during 100 ns molecular dynamics simulations, indicating stable and effective binding to IL-4R alpha. The study also highlights the anti-inflammatory and immunomodulatory properties of these compounds, suggesting their potential use in topical therapeutic formulations for eczema treatment. These findings provide a foundation for further experimental studies and the development of novel, plant-derived therapies for inflammatory skin diseases.

关键词： genomic full length   HLA-DRB1*14:84   PacBio sequencing  

摘要： The genomic full-length sequence of the HLA-DRB1*14:84 allele was identified using a PacBio sequencing approach from China.