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摘要： Introduction: Cerebrospinal fluid (CSF) cytokines may contribute to immune-mediated processes affecting the central nervous system (CNS). We evaluated CSF cytokine profiles in children with suspected neuroinflammatory conditions to explore their clinical relevance. Methods: Between 2019 and 2024, CSF from children <18 years were analyzed using BD Biosciences cytokine bead array for interleukin-2 (IL-2), IL-4, IL-6, IL-10, interferon-alpha (IFN-alpha), and tumour necrosis-factor-alpha (TNF-alpha). Clinical phenotyping was conducted. Serum cytokine levels were measured in cases with abnormal CSF, when available. Results: 112 patients were included (median age 6 years [IQR 3.6-11.2];54 % male). CSF IL-6 was raised in 35/112 (31 %;median 107 pg/ml, IQR 24-329). No other cytokine was raised without concurrent IL-6. Raised CSF IL-6 occurred in 16/50 acquired neuroimmune conditions (including myelin oligodendrocyte glycoprotein antibody-associated disease, seronegative demyelination, seronegative autoimmune encephalitis, and febrile-infection-related epilepsy syndrome), 5/9 CNS infections;9/17 monogenic autoinflammatory syndromes, and 5/7 cancer treatment-related neurotoxicities. Of the 35 patients with raised CSF IL-6, 21 had serum cytokines tested;13 (62 %) showed elevated serum IL-6. In demyelinating cases, higher IL-6 was associated with increased CSF protein (p = 0.007). Follow-up CSF samples (n = 16, median 34 days) showed persistent elevation in 7 and normalisation in 9. IL-6 inhibitors (tocilizumab and/or siltuximab) were used in 10 patients with variable outcomes, depending on the underlying etiology. Conclusions: CSF IL-6 was the most frequently elevated cytokine in our cohort, observed across a range of primary and secondary neuroinflammatory disorders. While not diagnostic of a specific condition, its elevation may help guide treatment decisions.

关键词： Infliximab   biosimilars   TNF   psoriasis   inflammation   infusion therapy   PASI  

摘要： Infliximab (INF), a murine human monoclonal antibody, is a substantially more successful biologic than topical drugs for treating mild to severe psoriasis because it clears the skin rapidly due to its fast onset of action. Loss of responsiveness over time and some adverse effects, especially the experience of infusion reactions, are the major causes of non-compliance with INF medication. Therefore, evaluation of the long-term reliability of anti-tumor necrosis factor (TNF) medications is necessary for the assessment of the risks associated with long-term anti-TNF therapy. For psoriasis, there are registered safety statistics;however, these individuals might not receive the same level of care as those in a randomized study. Few assessments of the safety of anti-TNF medications across indications, including their biosimilars, are present, but it's still unknown how anti-infliximab antibodies arise and produce harmful effects. INF biosimilars, when subjected to human studies to reduce cost and improve access, provide therapeutic benefits with associated adverse events, showing variations in incidence depending upon varying patient populations and no new safety indications. During therapy, certain individuals develop antibodies against INF, which are believed to be linked to a loss of response (LOR). Additional research aimed at identifying individuals who are susceptible to treatment resistance is likely to assist doctors in accurately selecting the appropriate candidates for anti-TNF-alpha therapy and enhancing the long-term effectiveness of the treatment. From clinical studies, we expect to learn about how to utilize INF or its biosimilars more effectively in the management of psoriasis. Therefore, the paper focuses on the efficacy and safety monitoring of INF and developed biological therapies.

关键词： Colorectal cancer   Immunotherapy resistance   CD8+T cells   IL32   Nano-selenium   Engineered probiotics   Extracellular vesicles   Tumor microenvironment   Biomaterial therapy  

摘要： Background and objective: Colorectal cancer (CRC) is a major global health burden, with immunotherapy often limited by immune tolerance and resistance. This study introduces an innovative approach using Selenium Nanoparticles-Loaded Extracellular Vesicles combined with Interleukin-32 and Engineered Probiotic Escherichia coli Nissle 1917 (SeNVs@NE-IL32-EcN) to enhance CD8+ T cell-mediated immune responses and overcome immunotherapy resistance. Methods: Single-cell RNA sequencing (scRNA-seq) and transcriptomic analyses were performed to identify key immune cells and regulators involved in CRC immunotherapy resistance, focusing on CD8+ T cells and the regulatory factor IL32. A humanized xenograft mouse model was used to evaluate the impact of IL32 and SeNVs@NE-IL32-EcN on tumor growth and immune responses. The SeNVs@NE-IL32-EcN complex was synthesized through a reverse micelle method and functionalized using extracellular vesicles. Its morphology, size, antioxidant activity, and safety were characterized using electron microscopy, dynamic light scattering (DLS), and in vitro co-culture assays. Results: Single-cell analyses revealed a significant reduction in CD8+ T cell infiltration in immunotherapyresistant CRC patients. IL32 was identified as a key regulator enhancing CD8+ T cell cytotoxic activity through granzyme B and IFN-gamma secretion. Treatment with SeNVs@NE-IL32-EcN significantly improved the proliferation and activity of CD8+ T cells and reduced tumor progression in humanized mouse models. In vitro and in vivo results demonstrated the complex's biocompatibility, antioxidant properties, and ability to enhance CRC immunotherapy while mitigating immune tolerance. Conclusion: SeNVs@NE-IL32-EcN offers a novel nano-biomaterial strategy that integrates nanotechnology and probiotic therapy to enhance CD8+ T cell-mediated immunity and overcome CRC immunotherapy resistance. This study lays the foundation for future therapeutic applications in cancer treatment by advan

关键词： Myofascial pain syndrome   Myofascial trigger points   Isoliquiritigenin   IL-17   Inflammation  

摘要： Background: Myofascial trigger points (MTrPs) are a primary cause of myofascial pain syndrome. Current studies suggest that MTrPs consist of persistent sarcomere contraction and an inflammatory microenvironment. IL-17 has been implicated in the progression of inflammation. However, its expression of IL-17 in MTrPs and the underlying mechanisms remain unclear. Purpose: This study aimed to characterise IL-17 signalling and elucidate the associated molecular mechanisms in the context of MTrPs, and evaluate the therapeutic effects of isoliquiritigenin (ISL) on MTrPs. Methods: We examined IL-17A signalling expression using immunohistochemistry, reverse transcription-quantitative polymerase chain reaction and western blot analysis in MTrPs rat. Haematoxylin and eosin staining and transmission electron microscopy were used to assess muscle fibre and sarcomere morphology. The Randall-Selitto test was employed to evaluate pain-like behaviours in rats. Dihydroethidium staining, JC-1 assay, and ATP quantification were used to assess inflammation-associated mitochondrial function in vitro and in vivo. Additionally, molecular docking, cellular thermal shift, and drug affinity responsive target stability assays were conducted to examine the interaction between ISL and the IL-17 receptor subunit A (IL-17RA) protein. Results: IL-17A and IL-17RA were significantly expressed in rats with MTrPs. These rats exhibited elevated oxidative stress level and reduced ATP production. Studies on IL-17A stimulated myotubes and gastrocnemius muscle indicated that IL-17RA signalling contributes to inflammation, abnormal sarcomere contraction and mitochondrial dysfunction in MTrPs. Lentivirus-mediated IL-17RA knockdown in the rats further confirmed these findings. Inhibition of the mitogen-activated protein kinase p38 and subsequent rescue experiments highlighted the critical role of IL-17RA/Act1/p38 signalling. Notably, molecular docking and validation experiments revealed that ISL binds to and in

关键词： Autoimmune   HLA   Immunogenetics   Stevens-Johnson syndrome   Toxic epidermal necrolysis  

摘要： Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are very rare dermatologic disorders characterized by extensive detachment of the epidermis. Although some drugs, infectious agents, HLA genes, malignancy and connective tissue diseases are thought to play a role in the development of the disease, the pathogenesis has not been fully elucidated. Type IV hypersensitivity reactions are thought to be the underlying cause of these diseases. Inflammatory changes such as purulent erosion, ulcers and crusting can be seen in the gastrointestinal system, urinary tract and genital mucosa. Some immunologic biyomarkers like as HLA-B* 1502, Granulysin and CCL-27 are used in clinical diagnosis, prognosis, treatment, and personalized new drug development that could further explain the pathogenesis of SJS and TEN. This review focuses on the pathophysiology of the SJS and TEN and presents it in light of current data on this subject. We recommend further in vivo and in vitro studies to unravel the underlying immunological mechanisms to determine appropriate intervention strategies.

关键词： Ultrasound   Piezoelectric   Programmed immunomodulation   Macrophage polarization   Boneregeneration  

摘要： In craniomaxillofacial bone defect repair, both classically (M1) and alternatively (M2) activated macrophages coexist and are crucial to the repair process. However, recent studies focus on regulating macrophage M2 repolarization to promote osteogenic differentiation, overlooking the significant role of the M1 phenotype in bone marrow-derived mesenchymal stem cells (BMSCs) recruitment. Consequently, this research reports a programmed macrophage polarization therapy that is based on natural immunoregulatory. First, ultrasounddriven piezoelectric potential from beta-phase polyvinylidene fluoride (beta-PVDF) film activates M1 polarization. In vitro results show that the M1 phenotype exhibits a remarkable ability to recruit BMSCs and promote osteogenic differentiation. Subsequently, the rapid and potent M2 repolarization was achieved after interleukin-4 (IL-4) treatment, which promoted osteogenic differentiation. In vivo results indicate that the piezo-IL-4 programmed immunomodulatory system effectively facilitated the rapid repair of bone defects. This study first combined ultrasound piezoelectricity with IL-4 to promote programmed regulation of macrophage polarization and promote BMSCs recruitment and differentiation. This approach offers an effective strategy based on natural immunoregulatory for modulating the immune microenvironment, which is essential for the design and development of bone repair materials, provides a significant theoretical foundation for the optimisation of immune regulation strategies in the field of bone tissue engineering.

关键词： Molecular dynamics  

摘要： Tumor Necrosis Factor-alpha (TNF-α) is a key pro-inflammatory cytokine that plays a central role in the development and progression of several inflammatory and autoimmune disorders, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. Targeting TNF-α has become a crucial therapeutic strategy for managing these conditions. In this study, a virtual screening approach was employed to identify potential TNF-α inhibitors from an in-house natural compound library maintained at CSIR-IIIM, Jammu. Molecular docking analyses were performed to evaluate the binding affinities of these natural compounds to the TNF-α protein. The top-ranked compounds were further refined through a similarity search against known natural product TNF-α inhibitors to identify promising candidates. Based on molecular docking and similarity search analyses, 13 potential compounds were identified and subjected to in vitro validation. The experimental results confirmed that compounds IN00569 and IN00007 exhibited strong inhibitory activity by significantly reducing TNF-α secretion in LPS-stimulated RAW 264.7 macrophages, supporting their potential as lead anti-inflammatory agents. Molecular dynamics simulations and MM/GBSA analyses further validated the stability and binding potential of IN00007 and IN00569 with TNF-α, reinforcing their in vitro anti-inflammatory activity. These findings suggest that natural product-based inhibitors may serve as promising candidates for TNF-α-targeted drug development. © 2025 Elsevier B.V.

关键词： HLA‐DQB1*06   new alleles   next‐generation sequencing  

摘要： Genomic sequences of the HLA-DQB1*06:02:01:38, -DQB1*06:02:01:39, -DQB1*06:03:01:25, -DQB1*06:03:01:27, -DQB1*06:04:01:09 and -DQB1*06:529 alleles.

摘要： The HLA-DQA1*05:121 allele differs from the HLA-DQA1*05:05:01:01 allele by a single nucleotide in exon 3.

关键词： Autophagy   LAMP1   MHC-1   Ovarian cancer   XPR1  

摘要： Immune checkpoint inhibitors have a poor effect in treating ovarian cancer, and the specific mechanism is unknown. The purpose of this research was to investigate the impact of XPR1 on controlling autophagy in ovarian cancer. The findings suggested an increase in XPR1 expression in ovarian cancer tissues. The elevated level of its expression was linked to the stage of ovarian cancer, as well as overall survival and progression-free survival. XPR1 enhanced the growth and spread of ovarian cancer while suppressing autophagy. Moreover, XPR1 suppressed autophagy flux by interacting with LAMP1 and the PI3K/Akt/mTOR pathway. XPR1 controlled the positioning and production of MHC-I molecules on the surfaces of ovarian cancer cells via autophagy. Silencing XPR1 combined with the autophagy inhibitor chloroquine significantly inhibited tumor growth in mouse ovarian cancer models. In conclusion, the findings indicate that XPR1 could serve as a promising target for the diagnosis and treatment of ovarian cancer. Combined autophagy inhibitors may improve the sensitivity of ovarian cancer immunotherapy. (c) 2024 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY license (http://***/ licenses/by/4.0/).