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关键词： Oncolytic Virus   Neoantigen Vaccines   Peptide-MHC Complexes   Tumor Immunotherapy  

摘要： Neoantigen vaccine is a promising breakthrough in tumor immunotherapy. However, the application of this highly personalized strategy in the treatment of solid tumors is hindered by several obstacles, including very costly and time-consuming preparation steps, uncertainty in prediction algorithms and tumor heterogeneity. Universalization of neoantigen vaccine is an ideal yet currently unattainable solution to such limitations. To overcome these limitations, we engineered oncolytic viruses co-expressing neoantigens and neoantigen-binding major histocompatibility complex (MHC) molecules to force ectopic delivery of peptide-MHC ligands to T cell receptors (TCRs), enabling specific targeting by neoantigen vaccine-primed host immunity. When integrated with neoantigen vaccination, the engineered viruses exhibited potent cytolytic activity in a variety of tumor models irrespective of the neoantigen expression profiles, eliciting robust systemic antitumor immunity to reject tumor rechallenge and inhibit abscopal tumor growth with a favorable safety profile. Thus, this study provides a powerful approach to enhance the universality and efficacy of neoantigen vaccines, meeting the urgent need for universal neoantigen vaccines in the clinic to facilitate the further development of tumor immunotherapy.

关键词： anti-citrullinated peptide antibody (ACPA)   HLA-DRB1/DQB1   rheumatoid arthritis   treatment response  

摘要： The present study aimed to determine the association of HLA-DRB1/-DQB1 alleles with response to treatment and anti-citrullinated peptide antibody (ACPA) status in Iranian rheumatoid arthritis (RA) patients. A total of 167 RA patients, including 114 good responders (GRs) and 53 poor responders (PRs) as well as 330 ethnic-matched healthy controls, participated in this study. Disease activity and treatment response were assessed using the Disease Activity Score 28-joint (DAS28) scores during the 9-month post-treatment. HLA-DRB1/-DQB1 alleles were identified using polymerase chain reaction with a sequence-specific primers (PCR-SSP) method and compared between the study groups. Of the patients, 106 (63.5%) were ACPA-positive, 88 (52.7%) human leucocyte antigen (HLA)-shared epitope (SE)-positive, 64 (38.3%) ACPA+SE+ and 37 (22.2%) ACPA-SE-. HLA-SE alleles were significantly more frequent in patients (p = 3.2e - 05), in PR versus GR patients (p = 0.01) and in ACPA+ versus ACPA- patients (p = 0.009). PR patients had a higher prevalence of ACPA+SE+ compared to GR patients (p = 0.02). Higher frequencies of DRB1*04:02 (pc = 0.03), *04:04 (pc = 0.007), *04:05 (pc = 5.0e - 05), *10:01 (pc = 1.0e - 04), DQB1*03:02 (pc = 0.002) and *05:01 (pc = 0.002) alleles, and lower frequencies of DRB1*04:01 (pc = 0.007), *11:01 (pc = 0.03), *13:01 (pc = 0.03) and DQB1*06:03 (pc = 0.03) alleles were observed in patients compared to healthy controls. These findings suggest a relationship between HLA-SE alleles and ACPA development and a potential link between HLA-SE/non-SE alleles and therapeutic responses in RA patients.

关键词： Immortalized human minor salivary gland cell line   Human telomerase reverse transcriptase   SV40 large T antigen   Inflammatory cytokines   Chemokines  

摘要： The role of inflammatory response by salivary gland cells is considered to be important in the pathogenesis of salivary gland chronic inflammation, as seen in Sj & ouml;gren's syndrome patients. The primary salivary gland cell cultures are required to investigate such inflammatory responses, though primary cells exhibit a limited replicative short lifespan with only a few passages. An immortalized human minor salivary gland cell line, NSG cells, was established by transfection with human telomerase reverse transcriptase (hTERT) and SV40 large T antigen (SV40LT). The effects of IFN-gamma, TNF-alpha, and IL-1 beta on chemokine expression in those cells were then examined. Following hTERT expression vector and SV40LT vector transfections into minor salivary gland cells with a non-viral method, real-time PCR was employed to examine the effects of IFN-gamma, TNF-alpha, and IL-1 beta on chemokine mRNA expression. Additionally, ELISA was used to examine the effects of combinations of IFN-gamma, TNF-alpha, and IL-1 beta on CXCL10 and CXCL1 protein expressions. NSG cell growth was found to continue for more than 100 population doublings and the cells constitutively expressed immortalized-related and salivary gland-associated genes. IFN-gamma, TNF-alpha, and IL-1 beta each increased the examined chemokines by various levels. Both TNF-alpha and IL-1 beta separately increased IFN-gamma-induced CXCL10 in the NSG cells, whereas IFN-gamma decreased CXCL1 induced by TNF-alpha or IL-1 beta. An immortalized human minor salivary gland cell line was established by hTERT and SV40LT transfection. The examinations showed that IFN-gamma, TNF-alpha, and IL-1 beta have important roles for development of salivary gland inflammation, such as Sj & ouml;gren's syndrome.

关键词： Biological therapy   Clinical remission   Recurrence   Rheumatoid arthritis   Withdrawing treatment  

摘要： BACKGROUND:This study evaluates the long-term effectiveness and safety of methotrexate-tacrolimus combination therapy compared to methotrexate monotherapy in maintaining successful tumor necrosis factor (TNF) inhibitor discontinuation in rheumatoid arthritis (RA) patients. METHODS:We retrospectively analyzed consecutive RA patients who discontinued TNF inhibitors after achieving disease control by October 2022 and received either methotrexate monotherapy or methotrexate-tacrolimus combination therapy for up to 10 years. Per-observation time-to-event analyses assessed treatment failure, treatment intensification, first disease flare, and irreversible functional deterioration. Mixed-effects Cox models, time-dependent Cox models without random effects, and Kaplan-Meier estimates with inverse probability weighting were applied. Safety assessment included treatment-limiting adverse events and renal function trends. RESULTS:A total of 147 treatment lines (96 methotrexate monotherapy and 51 combination therapy) in 116 patients were analyzed. The combination therapy significantly reduced treatment failure (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.24-0.72), treatment intensification with the index drugs (HR, 0.38; 95% CI, 0.22-0.67) and with biologics or Janus kinase inhibitors (HR, 0.39; 95% CI, 0.22-0.71), and first flare (HR, 0.55; 95%CI 0.36-0.84), with consistent findings across models. The benefit was most pronounced in patients with prior flares during methotrexate monotherapy after TNF inhibitor discontinuation, with HRs as low as 0.04-0.12 across outcomes. No significant differences in treatment-limiting adverse events were observed. The annual increase in serum creatinine for tacrolimus users was 0.0032 mg/dL, suggesting minimal long-term renal impact. CONCLUSIONS:Methotrexate-tacrolimus combination therapy significantly reduces relapse risk following TNF inhibitor discontinuation without compromising safety, offering a potentially sustainable treat

关键词： IL-17 inhibitors   inflammatory bowel disease   Secukinumab  

摘要： IL-17 inhibitors effectively treat psoriasis and psoriatic arthritis but may increase the risk of inflammatory bowel disease (IBD). We assessed their association with IBD compared to apremilast. Utilising the TriNetX database, we analysed patients with psoriasis or ankylosing spondylitis initiating IL-17 inhibitors or apremilast. We used propensity score matching and Cox models to estimate IBD risk. Among 13,216 matched patients per group, 142 developed IBD with IL-17 inhibitors versus 60 with apremilast (aHR = 2.50, 95% CI: 1.85-3.39). IL-17 inhibitors increase IBD risk, necessitating careful patient selection and monitoring.

关键词： Refractory hemophagocytic lymphohistiocytosis (r-HLH)   Emapalumab   Ruxolitinib   Cytokines   Epstein-Barr virus (EBV)   Salvage therapy  

摘要： Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory disorder characterized by excessive cytokine release. More than 30% of HLH cases are refractory to frontline therapy. Unfortunately, there is no universally accepted second-line regimen, and about 30% of patients fail to respond to current salvage treatments. Moreover, evidence guiding alternative therapies and the optimal timing for switching to new treatments in refractory patients is limited. This study retrospectively analyzed the efficacy and safety of the RED regimen (ruxolitinib, emapalumab, and dexamethasone) in 15 refractory HLH patients who had failed at least two previous salvage therapies. Overall, eight (53.3%) patients achieved partial remission, and four of those eight proceeded to hematopoietic stem cell transplantation (HSCT). Notably, pre-RED levels of C-X-C motif chemokine 9 (CXCL9) and interleukin-18 (IL-18) were significantly higher in patients who later responded to RED, suggesting that these biomarkers may predict a better response. We also observed that, for eight partial-remission patients, hemoglobin, fibrinogen, aspartate aminotransferase, calcium, and CXCL9 levels tracked well with early therapeutic responses (one to two weeks). No grade 3 or higher adverse effects were linked to the RED regimen. This comprehensive investigation of the RED approach in HLH, although small in sample size, supports the possibility that RED can serve as an effective and relatively safe salvage therapy for refractory HLH.

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： Infant   Initiative   Monoclonal antibody   Prevention   Respiratory syncytial virus  

摘要： Respiratory syncytial virus (RSV) is the leading viral pathogen for the hospitalization of infants with respiratory infection, and all-infant protection (AIP) from severe RSV infection has been identified as a major global ***-world evidence has shown that prophylactic monoclonal antibodies (mAbs) represent an avenue for effectively addressing this leading cause of hospitalization of *** Global Pediatric Pulmonology Alliance (GPPA) recommends prophylactic mAbs for all infants who are born during or just prior to entering their first RSV *** settings where RSV seasonality exists, GPPA also advocates for a seasonal offering of prophylactic RSV mAbs to promote high uptake and operational effectiveness. © 2025 Chinese Medical Journals Publishing House ***. All rights reserved.

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.