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摘要： Low back pain is the leading cause of global disability with intervertebral disc (IVD) degeneration a major cause. However, no current treatments target the underlying pathophysiological causes. PCRX-201 presents a novel gene therapy approach that addresses this issue. PCRX-201 codes for interleukin-1 receptor antagonist, the signalling inhibitor of the pro-inflammatory cytokine interleukin-1, which orchestrates the catabolic degeneration of the IVD. Here, the ability of PCRX-201 to transduce human nucleus pulposus cells to increase IL-1Ra production was assessed together with effects on catabolic pathways. When transduced with PCRX-201, the production and release of IL-1Ra was increased in degenerate human nucleus pulposus cells and tissue. Whereas, the production of downstream proteins, including IL-1 beta, IL-6, MMP3, ADAMTS4 and VEGF were decreased in both cells and tissue, indicating a reduction in IL-1-induced catabolic signalling. Here, a novel gene therapy vector, PCRX-201, was shown to transduce degenerate NP cells and tissue, increasing the production of IL-1Ra. The increased IL-1Ra resulted in decreased production of catabolic cytokines, enzymes and angiogenic factors, whilst also increasing aggrecan expression. This demonstrates PCRX-201 enables the inhibition of IL-1-driven IVD degeneration. The ability of PCRX-201 to elicit anti-catabolic responses is promising and warrants further development to determine the efficacy of this exciting, novel gene therapy.

摘要： Background:Three biologics targeting interleukin 5 (anti-IL-5) or its receptor-α (anti-IL-5Rα) are approved for patients with severe asthma. Methods:We systematically searched the literature published in Medline and Embase up to 1 May 2023 to identify observational studies and nonrandomised trials that assess the response to anti-IL-5/5Rα in real-life patients with severe eosinophilic asthma. We also performed random-effects meta-analyses. Results:We identified 6401 studies, of which 92 with 9546 patients were analysed. Biologics use was associated with a 62% reduction in severe exacerbations (risk ratio 0.38, 95% CI 0.29-0.50) and a 54% reduction in hospitalisations (risk ratio 0.46, 95% CI 0.35-0.61) at 12 months of treatment, compared to pre-treatment. Biologics improved asthma control (decrease in asthma control questionnaire score by 1.11 points (95% CI -1.29--0.94) and increase in asthma control test score by 6.41 points (95% CI 5.66-7.16)) and increased the asthma quality of life questionnaire score by 1.08 points (95% CI 0.88-1.28) and forced expiratory volume in 1 s by 0.21 L (95% CI 0.15-0.27) at 12 months. There was a significant reduction in oral corticosteroids use of 51% (risk ratio 0.49, 95% CI 0.42-0.56), with a mean dose reduction of 6.01 mg·day (95% CI -7.55--4.48) at 12 months of treatment. Similar findings were observed at 3-4, 6 and 24 months. A biomarker-related response to treatment was also noted. Conclusions:This comprehensive meta-analysis summarises the significant clinical response to anti-IL-5/5Rα biologics in real-life studies, providing important insights for their use in clinical practice.

关键词： immunohistochemistry   interleukin-10   interleukin-4   intervertebral disc   low back pain   secretome proteomics  

摘要： BackgroundThis study investigates the native presence and potential anabolic effects of interleukin (IL)-4 and IL-10 in the human intervertebral disc (IVD).MethodsHuman nucleus pulposus (NP) cells cultured in 3D from trauma and degenerate IVDs and NP explants were stimulated with 10 ng/mL IL-4, IL-10, or each in combination with 1 ng/mL IL-1 beta stimulation. The role of IL-4 and IL-10 in the IVD was evaluated using immunohistochemistry, gene expression, and Luminex multiplex immunoassay proteomics (73 secreted) and phosphoproteomics (21 phosphorylated proteins).ResultsIL-4, IL-4R, and IL-10R expression and localization in human cartilage endplate tissue were demonstrated for the first time. No significant gene expression changes were noted under IL-4 or IL-10 stimulation. However, IL-1 beta stimulation significantly increased MMP3, COX2, TIMP1, and TRPV4 expression in NP cells from trauma IVDs. Combined IL-4 and IL-1 beta treatment induced a significant increase in protein secretion of IL-1 alpha, IL-7, IL-16, IL-17F, IL-18, IFN gamma, TNF, ST2, PROK1, bFGF2, and stem cell factor exclusively in NP cells from degenerated IVDs. Conversely, the secretome profile of explants revealed an IL-4-mediated decrease in CXCL13 following treatment with IL-1 beta. Combined IL-10 and IL-1 beta treatment increased neurotrophic growth factor secretion compared with IL-10 *** NP cell phenotype affects the pleiotropic role of IL-4, which can induce a pro-inflammatory response in the presence of catabolic stimuli and enhance the effects of IL-1 beta in degenerated IVDs. Environmental factors, including 3D culture and hypoxia, may alter IL-4's role. Finally, IL-10's potential neurotrophic effects under catabolic stimuli warrant further investigation to clarify its role in IVD degeneration.

关键词： COVID-19   IL-6   Polymorphism   rs1800795   rs1800796   Severity of disease   Turkish population  

摘要： Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is exacerbated by cytokine storms, leading to severe inflammation. Interleukin-6 (IL-6) plays a critical role in this process, and variations in its promoter may influence disease severity. This study aims to investigate the relationship between IL6 promoter polymorphisms rs1800795 (G > C) and rs1800796 (G > C) and the severity of COVID-19 in the Turkish population. A total of 332 participants were included: 84 control, 80 with mild COVID-19, and 168 with severe COVID-19. IL6 polymorphisms were genotyped using the restriction fragment length polymorphism (RFLP) method. The genotypes rs1800795 GC (OR = 3.00, 95% CI: 1.669-5.398, p < 0.000), CC (OR = 7.44, 95% CI: 2.899-19.131, p < 0.000), and rs1800796 GC (OR = 2.76, 95% CI: 1.603-4.761, p < 0.000), as well as the alleles rs1800795 C (OR = 3.01, p < 0.000) and rs1800796 C (OR = 1.97, p = 0.002), may be associated with the severity of COVID-19. According to the Jonckheere-Terpstra (J-T) test, the most significant trends that vary linearly with disease severity were observed for D-dimer [J-T = 15.896, Effect size = 0.68 (0.61 to 0.76), p < 0.000] and CRP [J-T = 15.389, Effect size = 0.66 (0.59 to 0.73), p < 0.000]. The distribution of clinical parameters across genotype combinations (rs1800796/rs1800795*) showed that GC/GC* and GC/CC* were linked to a higher risk of severe inflammation, clotting, and organ damage. Additionally, it has been determined that the G-C and C-C haplotypes may be associated with increased severity of COVID-19. The rs1800795 and rs1800796 polymorphisms are linked to COVID-19 severity and could help guide future treatment strategies.

关键词： Age-related patterns   Gender differences   HLA-B27   Prevalence   Slovak population   Spondyloarthritis  

摘要： Background and objectives: HLA-B27 is a genetic marker associated with spondyloarthropathies, particularly ankylosing spondylitis and axial spondyloarthritis. While its prevalence varies across populations, no data exist for Slovak patients. This study aimed to determine HLA-B27 prevalence in Slovak patients with suspected spondyloarthropathies and assess differences by sex and age. Methods: A retrospective cohort of 1,614 patients (888 females and 726 males) was analyzed for HLA-B27 status (positive/negative) using reverse hybridisation (HLA-B27 StripAssay). Statistical analyses included Pearson's Chi-square test and non-parametric Mann- Whitney U and Kruskal-Wallis tests for sex- and age-related differences. Results: HLA-B27 positivity was 20.57%, with a higher proportion in males (23.28%) than females (18.36%, p = 0.0177). The <20 age group had the highest absolute number of positive cases (126 cases;17.80%), while the 21-40 group had the highest relative positivity (119 cases;29.38%). The lowest positivity was in the >61 age group (17 cases;13.08%), though age distribution differences were not statistically significant (p = 0.7765). Positivity varies across diagnoses, peaking in musculoskeletal (M) and eye disorders (H), where it exceeds 29%. Conclusion: HLA-B27 positivity is strongly associated with rheumatologic and ophthalmologic conditions and exhibits age- and sex-related variability. These findings emphasize the diagnostic significance of HLA-B27 testing in Slovak patients, especially for early detection and management of spondyloarthropathies. Further research on HLA-B27 variability and its clinical implications is needed to optimize diagnostic strategies and patient care.

关键词： Aescin   Alcoholic liver disease   Inflammation   Oxidative stress   p38 MAPK   TNF-alpha  

摘要： Alcoholic liver disease (ALD) is a commonly known liver disease mediated by prolonged alcohol consumption. Aescin is a triterpene saponin that can manage several conditions, including brain trauma, arthritis, venous congestion, stroke, and thrombophlebitis. Even so, studies illustrating the aescin role in ALD are scarce. Our study explored the potential effect of aescin in ALD in mice. In the current experiment, forty mice were utilized and sorted randomly into four groups: the control group received only vehicles, the alcohol group was given 5% alcohol in drinking water for four weeks, and the aescin-treated groups were given 5% alcohol in drinking water and aescin (10 and 20 mg/kg/day) for four weeks, then two doses of 60% alcohol (3g/kg) were given in the 29th and 30th day of the experiment. Our study revealed that aescin ameliorated alcohol-mediated liver damage, including reducing inflammatory cell infiltration and vascular dilatation. The serum concentrations of liver enzymes (ALT and AST) decreased in the aescin-treated groups. The apoptosis and oxidative stress also decreased, and the antioxidant enzyme activities were restored by aescin in alcohol-treated mice. Additionally, aescin decreased ethanol-induced inflammation by downregulating p38 MAPK and tumor necrosis factor-alpha (TNF alpha), suggesting that aescin positively reduces alcohol-caused inflammation and oxidative stress. Consequently, aescin could ameliorate alcohol-induced hepatic damage by targeting the p38 MAPK/TNF-alpha signalling and could be developed as a novel health product that potentially ameliorates ALD.

关键词： CAR Treg   IL23R   Crohn's disease   cell therapy   IBD  

摘要： Background and Aims Regulatory T cells (Tregs) are key regulators in maintaining tissue homeostasis. Disrupted immune homeostasis is associated with Crohn's disease (CD) pathogenesis. Thus, Treg therapy represents a promising long-acting treatment to restore immune balance in the diseased intestine. Chimeric antigen receptor (CAR) T-cell therapy has revolutionized cancer treatment. This innovative approach also provides the opportunity to improve therapy for CD. By targeting a disease-relevant protein, interleukin-23 receptor (IL23R), we engineered Tregs expressing IL23R-CAR for treating active *** Intestinal IL23R expression from active CD was verified by immunohistochemical analysis. Phenotypic and functional characteristics of IL23R-CAR Tregs were assessed using in vitro assays and their migration capacity was monitored in a xenograft tumor model. Transcriptomic and proteomic analyses were performed to associate molecular profiles with IL23R-CAR Treg activation against colon biopsy-derived cells from active CD *** Our study showed that IL23R-CAR displayed negligible tonic signaling and a strong signal-to-noise ratio. IL23R-CAR Tregs maintained regulatory phenotype during in vitro expansion, even when chronically exposed to proinflammatory cytokines and target antigen. IL23R engagement on IL23R-CAR Tregs triggered CAR-specific activation and significantly enhanced their suppressive activity. Also, IL23R-CAR Tregs migrated to IL23R-expressing tissue in humanized mice. Finally, IL23R-CAR Tregs elicited a specific activation against colon biopsy-derived cells from active CD, suggesting an efficient CAR engagement in active CD. Molecular profiling of CD patient biopsies also revealed transcriptomic and proteomic patterns associated with IL23R-CAR *** Overall, our results demonstrate that IL23R-CAR Tregs represent a promising therapy for active CD. Graphical Abstract

关键词： chimerism testing   haematological malignancies   peripheral blast   somatic alterations  

摘要： Tumour cells, which are often found in the peripheral blood of patients with acute leukaemia, may harbour multiple somatic alterations throughout the genome, including changes in the HLA region and short tandem repeat (STR) regions. We investigated whether such somatic alterations interfere with HLA and chimerism diagnostics conducted in preparation for an allogeneic haematopoietic stem cell transplantation (allo-HSCT). This study describes 10 patient-based cases for which laboratory diagnostics were performed prior to a possible stem cell transplant in the Maastricht University Medical Center. In three acute leukaemia patients, somatic alterations were detected within the HLA region in peripheral blood samples: one case showed a complete loss of an HLA haplotype, while two cases exhibited somatic mutations affecting a single HLA class I gene. Additionally, seven patients with haematological malignancies revealed somatic variations within the STR regions, indicated by the presence of a third allele or the partial or complete loss of an allele in pre-transplant peripheral blood samples. In all patients, these somatic variations were confirmed by repeating the tests using buccal swab samples from patients or samples from family members. Furthermore, our study demonstrated that somatic alterations within STR regions used for chimerism testing occurred in 6% of the 176 patients who received an allo-HSCT between 2017 and 2022. This study underscores the clinical relevance of detecting somatic alterations prior to allo-HSCT, as they may interfere with HLA and STR analysis, potentially leading to HLA mistyping or incorrect chimerism detection. Additionally, it highlights the frequency with which genetic changes in tumour cells can affect chimerism diagnostics. The findings emphasise the vital importance of selecting the appropriate sample source for typing purposes and considering the patient's karyotype when choosing STRs, especially when tumour cells are present in the p

关键词： Unresectable hepatocellular carcinoma   Atezolizumab plus bevacizumab   Interleukin-6  

摘要： Background This study aims to identify biomarkers for treatment response of atezolizumab plus bevacizumab (Atezo+Bev) in patients with hepatocellular carcinoma (HCC). Methods 96 patients who received Atezo+Bev or lenvatinib as a first-line systemic therapy were enrolled as the training group after propensity score matching (PSM), and 42 patients treated with Atezo+Bev were enrolled as the validation group. 17 serum cytokines were measured by Luminex multiplex assay at the start of treatment. For further assessment of the association between cytokine levels and the tumor microenvironment (TME), immunohistochemistry (IHC) was performed on pre-treatment liver biopsy specimens. Results In the derivation set, multivariate analysis identified elevated IL-6 as an independent risk factor in the Atezo+Bev group (HR 5.80: p<0.01), but not in the lenvatinib group;in a subset analysis of patients with low IL-6, PFS was longer in the Atezo+Bev training group than in the lenvatinib group (p = 0.02). A validation study also showed a significantly longer prognosis in the low IL-6 group for both PFS (p = 0.0001) and OS (p = 0.03). Serum IL-6 had a positive correlation with tumor IL-6 expression (rho = 0.56, p < 0.0001) and an inverse correlation with the CD8/CD163-positive cell count ratio (rho = -0.4, p < 0.01). Conclusion Serum IL-6 levels are thought to be involved in the suppression of tumor immunity and are useful in predicting the therapeutic effect of Atezo+Bev treatment.