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关键词： botulinum toxin A   immunogenicity   HLA polymorphism   computational immunogenetics   neurotoxin-associated proteins   molecular docking   epitope mapping  

摘要： Botulinum toxin A (BoNT-A) is widely used in both therapeutic and aesthetic settings;however, the formation of neutralizing antibodies (NAbs) remains a critical concern, leading to treatment failure. Immunogenic responses are known to vary between individuals due to HLA polymorphisms. Although some claim that neurotoxin-associated proteins (NAPs) shield BoNT-A from immune detection or are themselves immunogenic, there is limited molecular evidence supporting either view. This study applies computational immunogenetics to explore BoNT-A immunogenicity, focusing on HLA binding and the influence of accessory proteins. Epitope mapping, molecular docking, and HLA binding predictions were used to evaluate interactions between BoNT-A epitopes and selected class II HLA alleles (HLA-DQA1*01:02, HLA-DQA1*03:03, HLA-DQB1*06:04, HLA-DQB1*03:01, and HLA-DRB1*15:01). To assess the potential immunomodulatory role of NAPs, molecular dynamics (MD) simulations, solvent-accessible surface area (SASA) analysis, and electrostatic potential mapping were also conducted. Key epitopes-L11, N25, and C10-showed strong binding affinities to HLA-DQA1*01:02, HLA-DQB1*06:04, and HLA-DQA1*03:03, indicating a potential immunodominant role. NAPs did not obstruct these epitopes but slightly increased their exposure and appeared to stabilize the toxin structure. Electrostatic mapping and binding free energy calculations suggested no significant immunogenic shift in the presence of NAPs. BoNT-A immunogenicity appears to be influenced by HLA allele variability, reinforcing the value of patient-specific genetic profiling. The presumed immunogenic role of NAPs remains unsubstantiated at the molecular level, underscoring the need for evidence-based evaluation over commercial rhetoric. While these findings provide valuable molecular insight, it is important to acknowledge that they are derived entirely from in silico analyses. As such, experimental validation remains essential to confirm the immunological r

关键词： Immune checkpoint inhibitors (ICI)   HLA   Genomic mutation profile   Retrotransposition   LINE-1   TMB  

摘要： BackgroundImmune checkpoint inhibitors (ICI) have revolutionized cancer treatment, particularly in advanced non-small cell lung cancer (NSCLC) and muscle-invasive bladder cancer (MIBC). However, identifying reliable predictive biomarkers for ICI response remains a significant challenge. In this study, we analyzed real-world cohorts of advanced NSCLC and MIBC patients treated with ICI as first-line *** samples underwent Whole Genome Sequencing (WGS) to identify specific somatic variants and assess tumor mutational burden (TMB). Additionally, mutational signature extraction and pathway enrichment analyses were performed to uncover the underlying mechanisms of ICI response. We also characterized HLA-I haplotypes and investigated LINE-1 *** mutation patterns were identified in patients who responded to treatment, suggesting potential biomarkers for predicting ICI effectiveness. In NSCLC, tumor mutational burden (TMB) did not differ significantly between responders and non-responders, while in MIBC, higher TMB was linked to better responses. Specific mutational signatures and HLA haplotypes were associated with ICI response in both cancers. Pathway analysis showed that NSCLC responders had active inflammatory and immune pathways, while pathways enriched in non-responders related to FGFR3 and neural crest differentiation, associated to resistance mechanisms. In MIBC, responders had alterations in DNA repair, leading to more neoantigens and a stronger ICI response. Importantly, for the first time, we found that LINE-1 activation was positively linked to ICI response, especially in *** findings reveal promising biomarkers and mechanistic insights, offering a new perspective on predicting ICI response and opening up exciting possibilities for more personalized immunotherapy strategies in NSCLC and MIBC.

关键词： COVID-19   cytokines   oxidative stress   SARS-CoV-2 virus  

摘要： Background: The coronavirus-caused disease (COVID-19), first identified in China in December 2019, has spread worldwide becoming a global pandemic. Although people infected with the SARS-CoV-2 virus presented mainly respiratory and gastrointestinal symptoms, an increase in cardiovascular incidents was observed in several scientific studies. SARS-CoV-2 virus has been shown to disrupt the normal immune response leading to a dysregulation of immune system function and massive production of inflammatory cytokines commonly known as "cytokine storm". Methods: 57 patients eventually participated in the study, assigned to non-COVID (24 patients) and COVID (33 patients) groups. After signing consent to participate in the study, each patient was given a self-administered questionnaire to fill out prior to specimen collection, anthropometric measurements were taken and venous blood was collected for the following determinations: pro- and anti-inflammatory cytokines using a Bio-Plex 200 system, oxidative stress markers and basic hematological blood parameters. Results: showed statistically significant higher values of IL-1Ra and IL-1 beta in the COVID-19 group. Of the oxidative stress markers, only MDA levels were higher in the COVID-19 group. Conclusions: the results of our study provide evidence and support the occurrence of elevated levels of IL-1Ra, IL-1 beta and MDA in the COVID-19 group of patients, which are associated with a worse course and prognosis of COVID-19. A better understanding of the pathophysiology and dysregulation of the immune system associated with the cytokine storm is essential to select patients at risk and develop effective drugs and vaccines.

关键词： Immunotherapy   Natural killer cells   Ovarian cancer  

摘要： Objective To demonstrate the significance of supercharged natural killer (sNK) cells to target aggressive gynecological tumours. Methods and analysis We used cell cultures of peripheral blood-derived mononuclear cells (PBMCs) and purified NK cells alone and in the presence of tumours. MHC-class gene expression assessments of ovarian tumours were performed using gene set enrichment analysis (GSEA). Secretion and expression levels of cytokines in PBMCs and NK cells were determined using ELISA and scRNA seq analysis, respectively. A flow cytometer was used for surface marker analysis. 51 Cr and eSight were used to determine the killing activity of NK cells. Results We have observed a significant decrease in the numbers and functions of NK cells in patients with ovarian cancer. GSEA revealed differently expressed genes, decreased differentiation- and immune-related genes, and increased genes for cell cycle analysis in recurrent tumours compared with chemo-naive ovarian tumours. Increased gene expression as well as secretion of interferon-γand tumour necrosis factor-α and increased avidity in binding to tumour cells by sNK cells was observed. Unlike primary interleukin (IL)-2-activated NK cells, sNK cells effectively lysed OVCAR8 ovarian poorly differentiated cancer stem-like cells (PDCSCs) and well-differentiated OVCAR4 tumours. Primary ovarian tumours with lower MHC-class I expression were highly susceptible to both primary IL-2-activated NK and sNK cells, whereas the well-differentiated tumours with high expression of MHC-class I were only susceptible to sNK cells. Conclusion The use of sNK cells in immunotherapy emerges as a potentially effective strategy to target and eliminate the majority of ovarian tumour clones, thereby providing a potential therapeutic opportunity in preventing the recurrence of the disease. © Author(s) (or their employer(s)) 2025.

关键词： oncolytic virus   vaccinia virus   GM-CSF   IL-7   pancreatic cancer  

摘要： Objectives: Pancreatic cancer remains a therapeutic challenge due to its immunosuppressive microenvironment and treatment resistance. This study aimed to develop a novel recombinant oncolytic vaccinia virus (VVL-GL7) co-expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-7 (IL-7), designed to enhance anti-tumor immunity and synergize with immune checkpoint inhibitors. Methods: VVL-GL7 was constructed through CRISPR/Cas9-mediated knockout of TK and A49 genes, combined with the simultaneous insertion of dual cytokine-encoding cassettes. Anti-tumor efficacy was evaluated in vitro and in vivo using C57BL/6 mouse and Syrian hamster pancreatic cancer models. Comprehensive immune profiling evaluated CD8+ T-cell and macrophage infiltration dynamics while simultaneously assessing memory T-cell differentiation patterns using flow cytometry. Preclinical combination studies of VVL-GL7 and the PD-1 immune checkpoint inhibitor were systematically evaluated in a syngeneic pancreatic cancer model. Results: VVL-GL7 exhibited potent oncolytic activity, inducing significant tumor regression in both preclinical models. VVL-GL7 therapy significantly augmented CD8+ T-cell and macrophage infiltration within the tumor microenvironment, while concomitantly driving memory T-cell differentiation. The synergistic effects of VVL-GL7 and the PD-1 blockade further improved therapeutic outcomes, resulting in significantly higher tumor remission rates compared to monotherapy and achieving complete tumor regression in pancreatic cancer models. Conclusions: VVL-GL7 reprograms the immunosuppressive tumor microenvironment and synergizes with anti-PD-1 antibodies to overcome resistance in pancreatic cancer.

关键词： Interleukin inhibitors   Biologics   Fungal infections   Candidiasis   Dermatophytosis   Invasive candidiasis   Psoriasis   Invasive fungal infection   Immunosuppression   Diabetes  

关键词： Antibody   B cell   Tumor microenvironment - TME   T cell   Major histocompatibility complex - MHC  

摘要： Background Cancers persist despite expression of immunogenic neoantigens and ongoing antitumor immune responses. While some occult tumors likely are cleared by effective antitumor immune responses, the targeted antigens are not easily identifiable as those tumors spontaneously *** We used mouse models with a defined antigenic protein mimicking tumor-specific neoantigens to address the nature of these spontaneous anti-tumor immune *** BALB/c (H-2d) mice challenged with BALB/c breast tumors expressing the rat-erbB2 oncoprotein succumb to their tumors despite ongoing immune responses targeting tumor-specific model antigens. Meanwhile, congenic BALB.B (H-2b) and H-2d/H-2b F1 hybrid mice spontaneously eliminate genetically matched tumors in a major histocompatibility complex (MHC)-II dependent manner. Adoptive transfer and immune cell depletion strategies revealed CD4+ T cells and CD20+ B cells are crucial mediators of the protective response in H-2b mice. Furthermore, passive transfer of immune serum from mice rejecting their tumors confers resistance in tumor antigen-tolerant animals with an inversely proportional relationship between tumor outgrowth and the amount of rat-erbB2 specific antibody present in tumor-bearing mice. Introduction of the rat-erb2 ectodomain into other H-2b tumor models also promotes their spontaneous tumor rejection. Notably, the tumor microenvironments differ in rat-erbB2+ tumor-bearing BALB.B and BALB/c mice at the time of fate decision in the models reflecting the differences between effective and ineffective tumor immune *** We find that the effective antitumor immunity targeting neoantigens in these breast cancer models is determined by MHC-II-restricted presentation of optimal cancer-associated antigens. These responses are dependent on CD4+ T cells, B cells, and antigen-specific antibodies.

关键词： Genetic variations   haplotypes   IL-23/IL-17 pathway   polymorphisms   scleritis  

摘要： PurposeTo examine the relationship between IL-23/IL-17 pathway gene polymorphisms and scleritis susceptibility in the Chinese Han *** assessed IL-23/IL-17 pathway-related SNPs in 898 scleritis cases and 1,573 controls, employing stratified analysis to evaluate subtype-specific impacts and a discovery-validation cohort strategy to ensure genetic association ***-23 R/rs10789229 TC genotype and C allele, and the IL-21/rs2221903 TT genotype and T allele were more frequent in scleritis patients (Pc = 2.07 x 10-3-2.77 x 10-6, OR = 1.497-2.327, 95% CI = 1.216-3.219), particularly anterior scleritis (Pc = 3.88 x 10-3-2.95 x 10-6, OR = 1.507-2.378, 95% CI = 1.209-3.321). The IL-23 R/rs10789229 TT genotype and T allele, and the IL-21/rs2221903 TC genotype and C allele were found less common among scleritis patients overall (Pc = 2.07 x 10-3-4.18 x 10-6, OR = 0.436-0.668, 95% CI = 0.316-0.822) and in the anterior scleritis subgroups (Pc = 3.88 x 10-3-4.43 x 10-6, OR = 0.427-0.664, 95% CI = 0.306-0.827). The analysis of haplotypes showed a noteworthy surge of IL-23 R CCCG haplotype in both scleritis patients in general (Pc = 1.91 x 10-4) and those with anterior scleritis (Pc = 1.15 x 10-4). Conversely, the frequency of the IL-17A GAA haplotype was significantly lower among scleritis patients overall (Pc = 4.17 x 10-12) and in the anterior or posterior scleritis subgroups (Pc = 7.41 x 10-11;Pc = 0.021). Only the IL-23 R/rs10789229 variant demonstrated consistent replication in the validation *** findings suggest that specific polymorphisms of IL-23/IL-17 pathway-related genes could confer risk to the development of scleritis in the Chinese Han population. Patients with varying subtypes of scleritis exhibit somewhat similar genetic profiles.

关键词： Bronchopulmonary dysplasia   Apoptosis   Sodium propionate   IL-17   Alveolar epithelial cells  

摘要： Sodium propionate (SP) has been shown to enhance alveolar growth retardation in Bronchopulmonary Dysplasia (BPD), but the mechanism remains unclear. The aim of this study is to explore the potential mechanism of SP in the treatment of BPD by utilizing animal and cell models along with bioinformation analysis. Neonatal mice were exposed to either air (21% O2) or hyperoxia (85% O2) from the first day after birth to establish the BPD model. The neonatal mice were intraperitoneally injected with normal saline (control group) or SP (500 mg/kg, SP group) from day 8 to day 14. SP significantly reduced the inflammatory condition of alveolar septal thickening, and decreased the alveolar fusion and mitigated weight loss in BPD mice. ELISA results demonstrated that SP significantly inhibited the secretion of IL-17, IL-6 and TNF alpha. Transcriptome analysis confirmed that IL-17 signaling pathway is closely related to the therapeutic effects of SP on BPD. In addition, MX2, MMP10, IL-11, ZMAT4 and SEC1 genes were identified as key and potential targets involved in the mechanism of SP treating BPD. Meanwhile, in mouse alveolar epithelial cells, apoptosis was induced by hyperoxia, but it was reduced following SP intervention. The expression of IL-17 pathway related genes: IL-17A, IL-6, TNF alpha and cox2 was decreased in hyperoxia treated cells after SP intervention. In conclusion, through transcriptome analysis, animal and cell experiments, we explored the role of sodium propionate in attenuating apoptosis in a BPD model through IL-17 pathway.

关键词： Sweroside   Psoriasis   NLRP3/Caspase-1   IL-1 beta   Anti-inflammatory  

摘要： Psoriasis is a chronic autoimmune skin disorder with no cure, posing challenges in long-term therapy and economic burden. Sweroside (SOS), an iridoid compound from Gentiana, shows promise for treatment due to its anti-inflammatory properties. In this study, SOS significantly reduced erythema, thickening, and scaling in IMQinduced psoriasiform mice, lowered serum TNF-alpha and IL-1 beta levels, and suppressed inflammatory marker expression. Molecular docking revealed strong binding to IL-1 beta and NLRP3 proteins. Western blot and RT-PCR confirmed that SOS inhibited NLRP3, Cleaved-Caspase-1, ASC, and IL-1 beta expression. SOS's inhibition of IL-1 beta production is mediated through the NLRP3/Caspase-1 pathway. Additionally, SOS regulates IL-1 beta signal transduction and precursor production, exhibiting anti-inflammatory effects linked to NF-kappa B signaling inhibition in HaCaT cells. Thus, SOS has potential as a psoriasis treatment.