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摘要： N7-methylguanosine (m7G) modification of transfer RNA (tRNA) is essential for the biological functions of tRNAs and has been found to play a regulatory role in a variety of human cancers. However, the biological function of METTL1-mediated m7G tRNA modification in papillary thyroid cancer (PTC) is unclear. Here, we found that METTL1 is significantly upregulated in PTC tissues compared to normal control tissues and is associated with poor PTC prognosis. Functional analysis confirmed that METTL1 promotes the proliferation and metastasis of PTC cells in a manner dependent on its tRNA methyltransferase activity. Mechanistically, METTL1 knockdown leads to a decrease in the abundance of certain m7G-modified tRNAs, which suppresses the m7G tRNA modification-mediated codon-specific translation of TNF-alpha. Furthermore, exogenous supplementation with TNF-alpha partially reversed the decrease in the proliferation and metastasis of PTC cells induced by METTL1 deletion. Positive correlations between METTL1, WDR4, and TNF-alpha expression, which affect the proliferation and metastasis of PTC, were confirmed via analysis of microarrays containing PTC tissues. These results demonstrate the oncogenic role of METTL1-mediated m7G tRNA modification in regulating codon-specific translation efficiency in PTC and suggest that targeting METTL1 may be a promising therapeutic approach for overcoming PTC progression by inhibiting PTC cell proliferation and metastasis.

关键词： endothelial function   RA   cardiovascular disease   PET/CT  

摘要： Objectives: Cardiovascular risk in RA is multifactorial, with endothelial dysfunction being a significant, but not exclusive contributor. This risk is further worsened by accelerated atherosclerosis, increased arterial stiffness, and other inflammation-associated pathophysiological mechanisms, alongside traditional cardiovascular risk factors. This study evaluated the effects of 6 months of anti-inflammatory therapy on endothelial biomarkers, including E-selectin, vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and IL-8. Additionally, correlations between changes in biomarker concentrations and FDG-PET/CT arterial uptake were examined. Methods: Patients with active RA receiving anti-inflammatory therapy were compared with age- and sex-matched controls with OA. Endothelial biomarkers were measured at baseline, 6 months and 48 months of treatment. FDG-PET/CT was performed at baseline and 6 months after anti-inflammatory treatment to assess arterial inflammation, quantified as the maximal standard uptake value (SUVmax) in the aorta. The longitudinal impact of therapy was assessed across the RA cohort, with additional stratification by disease duration and treatment response. Results: Final assessment included 40 RA patients (18 early RA, 22 established RA) and 19 OA controls. In the RA cohort, E-selectin (Delta 6M-BL= -4 ng/ml +/- 3.17;P = 0.006) and IL-8 (Delta 6M-BL= -10 pg/ml +/- 4.2;P< 0.001) significantly decreased over 6 months. IL-8 decreased in both early (Delta 6M-BL= -8 pg/ml +/- 4.16;P = 0.022) and established RA (Delta 6M-BL= -12 pg/ml +/- 4.17;P = 0.004), while E-selectin decreased only in established RA (Delta 6M-BL= -5 ng/ml +/- 5.22;P = 0.012). Responders to therapy showed reductions in both endothelial markers. PET/CT analysis revealed positive correlations between Delta SUVmax and Delta IL-8, as well as Delta E-selectin. Conclusion: Anti-inflammatory therapy in RA gives early and sustained reductions in endotheli

摘要： Background: Crohn's disease (CD) is a chronic inflammatory bowel disease leading to symptoms such as abdominal pain, diarrhea, weight loss, fatigue, and complications such as strictures and fistulas. Ustekinumab (CNTO 1275) and briakinumab (ABT-874) are monoclonal antibodies that target the standard p40 subunit of the cytokines interleukin-12 and interleukin-23 (IL-12/23p40), which are involved in the pathogenesis of CD. Briakinumab has been withdrawn for the treatment of CD, making ustekinumab the only available antibody against the p40 subunit of interleukin-12 and interleukin-23 approved for this purpose. Objectives: To assess the benefits and harms of anti-IL-12/23p40 antibodies for induction of remission in CD, as compared to no treatment, placebo, other drug treatment, or varying dosing schedules. Search methods: We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and MEDLINE (from inception to 2 February 2024) and Embase (from inception until 12 August 2022). We also searched ***, WHO ICTRP, references, and conference abstracts to identify additional studies. Selection criteria: We included randomized controlled trials (RCTs) of at least four weeks' duration in which monoclonal antibodies against IL-12/23p40 were compared to placebo, no treatment, or another active comparator in people with active CD. We also included trials examining different doses of antibodies against IL-12/23p40. Data collection and analysis: Two review authors independently screened studies for inclusion and extracted data. We assessed the methodological quality of the included studies using Cochrane's RoB 2 tool. The primary outcome was failure to induce clinical remission by week 8, or 6 to 12 as available. Secondary outcomes included failure to induce clinical improvement (clinical response), induction of endoscopic remission, quality of life, and adverse events, serious adverse events, and withdrawals due to adverse e

关键词： Distemper   Neurological signs   Cerebrospinal fluids   Pro-inflammatory cytokines  

摘要： BackgroundCanine distemper virus (CDV) is a multisystemic disease in dogs that causes severe neurological signs due to viral replication in neurons and glial cells;this leads to gray matter lesions and demyelination. The resulting inflammation causes additional harm to the affected tissues. This study aimed to investigate the relationship between pro-inflammatory cytokines Tumor Necrosis Factor (TNF-alpha) and interleukin (IL-6) levels in Cerebrospinal fluid (CSF) and the neurological form of distemper disease in *** study included 23 CDV-infected dogs with neurological signs, 10 diseased but CDV-negative (non-infected) dogs, and 12 healthy controls. CSF samples were analyzed using Reverse Transcription Polymerase Chain Reaction (RT-PCR) for CDV sequences and the sandwich enzyme-linked immunosorbent assay (ELISA) method for quantifying IL-6 and TNF-alpha levels. While a significant increase in CSF cytokine levels was observed between the CDV-infected and healthy controls, no significant differences were detected between the CDV-infected and non-infected diseased *** elevated levels of IL-6 and TNF-alpha in the CSF of dogs with nervous distemper suggest their involvement in disease pathogenesis. However, their lack of specificity limits their use as reliable diagnostic biomarkers for distinguishing nervous distemper from other neurological conditions in dogs. Further research is needed to identify more accurate and specific biomarkers for the precise diagnosis and effective management of CDV infection.

关键词： IL-10   病毒样颗粒   SpyCatcher/SpyTag系统   肿瘤免疫治疗   细胞因子递送  

摘要： 为了研究免疫调节细胞因子IL-10在肿瘤免疫中的作用，本研究构建了一个全新的IL-10递送平台，对其抑制肿瘤的能力进行了分析.结果发现，皮下注射病毒样颗粒呈递的IL-10(VLP-IL10)在荷瘤小鼠模型中显著抑制了肿瘤生长（P<0.001）.活体成像的结果也进一步发现病毒样颗粒呈递的IL-10靶向并驻留淋巴结的能力要优于游离IL-10；通过流式细胞术对淋巴结中的树突状细胞进行分析，发现病毒样颗粒呈递的IL-10相较于游离IL-10可以更好地激活树突状细胞的成熟，其中CD80、CD86和MHCⅠ的比例相较于PBS组均有显著的增加（P <0.05），更好地实现效应T细胞的活化及抗原呈递，达到肿瘤的免疫治疗.因此，该平台实现了IL-10的稳定递送和良好的靶向性，展现了病毒样颗粒递送的IL-10在肿瘤免疫治疗中的良好效果.

关键词： biomarkers   treatment response   corticosteroids   refractoriness   interleukin-10   non-infectious uveitis  

摘要： Uveitis, a group of heterogeneous diseases causing ocular inflammation, is a major contributor to vision loss globally. While systemic corticosteroids (CS) are the mainstay treatment, identifying CS-refractory patients remains a significant challenge. This study aimed to explore cytokine expression and Glucocorticoid Receptor (GR) levels as biomarkers for the early detection of CS-refractory cases in non-infectious uveitis. We assayed blood samples from 19 patients with non-infectious uveitis, for the expression of IL-6, IL-17A, TNF-alpha, IL-10 and GR alpha. The cohort included 11 refractory and 8 sensitive patients, categorized based on their clinical response to corticosteroids (prednisone 1 mg/kg/day). Blood draws were conducted at three time points (at baseline, day 7- and day 14 after CS initiation), and peripheral blood mononuclear cells (PBMCs) were isolated to measure cytokine and GR alpha transcript levels via real-time PCR. The expression levels of GR alpha and cytokines IL-6, IL-17A and TNF-alpha did not show significant changes between CS-sensitive and CS-refractory patients on the different days of treatment. However, IL-10 expression levels as the day14-to-day7 ratio were significantly higher in patients sensitive to CS therapy. A higher day14-to-day7 ratio was also found for the IL-6/IL-10, IL-17A/IL-10 and GR alpha/IL-10 ratios. ROC curve analysis demonstrated a robust predictive performance of IL-10 mRNA expression and the IL-6/IL-10 ratio for identifying CS-refractory patients. In conclusion, the expression of IL-10 and the IL-6/IL-10 ratio hold promise as early predictive biomarkers for CS treatment refractoriness in patients with non-infectious uveitis. These findings offer valuable insights into personalized treatment strategies, potentially leading to improved clinical outcomes.

关键词： rheumatoid arthritis   HLA-DRB1 alleles   shared epitope   anti-CCP antibodies   Chilean cohort  

摘要： Introduction Rheumatoid arthritis (RA) is an autoimmune disease influenced by genetic factors, particularly HLA-DRB1 alleles. The objective of this study was to characterize the distribution of HLA-DRB1 alleles in Chilean RA patients and healthy controls (HC) and evaluate associations with susceptibility or protection, autoantibody seropositivity, and disease *** We genotyped 367 RA patients and 623 HC for HLA-DRB1 using PCR-SSO. Then, we examined allele frequencies and distribution, including known RA risk alleles of the "Shared Epitope" (SE) of HLA-DRB1 and protective (PR) alleles, using the Chi-square or Fisher's exact tests. Odds ratios with 95% confidence intervals were calculated to measure the degree of association, and unpaired T-tests were used to compare continuous *** The most frequent SE alleles among RA patients were *04:01 (16.1%), *04:04 (13.9%), and *14:02 (11.7%). SE alleles *04:01, *04:04, *04:05, *04:08, and *10:01, along with non-SE alleles *09:01 and *15:02, were associated with RA susceptibility. In addition, allele *14:02 showed an association with the presence of anti-cyclic citrullinated peptides (anti-CCP) antibodies. Meanwhile, PR alleles *11:01 (14.8%) and *16:02 (9.8%) were observed most frequently in HC and RA patients, respectively. PR alleles *11:01, *11:04, and *13:01, as well as the non-PR alleles *15:01, *04:07, *03:01, *07:01, and *08:02, were associated with protection from RA, and showed no significant associations with autoantibody *** This study provides a comprehensive overview of HLA-DRB1 allele distribution in the Chilean population, identifying both well-known and novel allele associations with RA susceptibility, protection, and disease activity.

关键词： Alzheimer disease   Cellular immune response   Immunology   Microbiology   Neuroscience  

摘要： Accumulating evidence implicates the gut microbiome (GMB) in the pathogenesis and progression of Alzheimer's disease (AD). We recently showed that the GMB regulates reactive astrocytosis and Aβ plaque accumulation in male APPPS1-21 AD model mice. Yet, the mechanism(s) by which GMB perturbation alters reactive astrocytosis in a manner that reduces Aβ deposition remain unknown. Here, we performed metabolomics on plasma from mice treated with antibiotics (abx) and identified a significant increase in plasma propionate, a gut-derived short chain fatty acid, only in male mice. Administration of sodium propionate reduced reactive astrocytosis and Aβ plaques in APPPS1-21 mice, phenocopying the abx-induced phenotype. Astrocyte-specific RNA sequencing on abx and propionate treated mice showed reduced expression of pro-inflammatory and increased expression of neurotrophic genes. Next, we performed flow cytometry experiments where we found abx and propionate decreased peripheral RAR-related orphan receptor-γ (Rorγt)+ CD4+ (Th17) cells and IL-17 secretion, which positively correlated with reactive astrocytosis. Lastly, using an IL-17 monoclonal antibody to deplete IL-17, we found that propionate reduces reactive astrocytosis and Aβ plaques in an IL-17-dependent manner. Together, these results suggest that gut-derived propionate regulates reactive astrocytosis and Aβ amyloidosis by decreasing peripheral Th17 cells and IL-17 release. Thus, propionate treatment or strategies boosting propionate production may represent novel therapeutic strategies for AD.

摘要： Osteoarthritis (OA) is a multifactorial degenerative disease involved subchondral bone remodeling, cartilage destruction and synovium inflammation. While receptor activator of nuclear factor-kappa B ligand (RANKL), a tumor necrosis factor (TNF) superfamily protein, is the critical regulator in bone metabolism associated with subchondral bone resorption, TNF-alpha is also an important inflammatory factor involved in the OA inflammation and cartilage destruction. Based on previous compound Y1599, we identified a novel tetrahydro-beta-carboline derivative Y2641 with both RANKL and TNF-alpha inhibition in this study. Y2641 exhibited potent RANKL-induced osteoclastogenic inhibition (IC50 = 109.1 nM), and had anti-inflammatory and cartilage destruction inhibiting effects at 10 mu M with low cytotoxicity. SPR assays demonstrated the binding affinity of Y2641 to RANKL (K d = 3.984 mu M) and TNF-alpha (K d = 18.59 mu M). In vivo assay further revealed the disease-modifying effects of Y2641 in OA rats, establishing Y2641 as a promising lead compound for the development of disease-modifying osteoarthritis drugs.