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关键词： rheumatoid arthritis   anti-TNF   Nrf2   reverse signaling   biotherapy   monoclonal antibodies   monocytes   prediction  

摘要： (1) Background: TNF inhibitors (TNFis) have revolutionized the treatment of rheumatoid arthritis (RA). However, 30-40% of RA patients do not respond adequately to those biologics. In addition to neutralizing soluble TNF, TNFis have the ability to bind the transmembrane form of TNF, tmTNF. Importantly, tmTNF can act itself as a receptor that induces "Reverse Signaling" (RS) in cells. We previously showed that certolizumab, a Fab' TNFi, activates RS in human primary monocytes, at least in part through the transcription factor Nrf2 that is known to regulate the expression of genes involved in anti-inflammatory response and oxidative stress. (2) Methods: Here, we have developed an assay for the prediction of clinical response of RA patients to TNF inhibitors. This assay is based on mRNA quantitation of CD36 activation and of six genes induced by Nrf2 following tmTNF RS in fresh monocytes. (3) Results: We could predict the response to anti-TNF monoclonal antibodies (mAbs) with 93.3% accuracy. However, our method was not suitable for the prediction of the response to TNF soluble receptor etanercept. (4) Conclusions: We have developed a rather simple, short-term test that can be standardized. Predicting the response to TNF mAbs will help physicians offer the best available treatment and provide patients with personalized medicine.

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

关键词： soluble CD95L   PTLD   CNS-PTLD   survival outcomes   CNS   Central Nervous System   CR   Complete Response   CI   Confidence Interval   EBV   Epstein-Barr Virus   HD   Healthy Donor   HR   Hazard ratio   HSC   Hematopoietic Stem Cells   mCD95L   membrane-bound CD95 Ligand   IQR   Inter Quartile Range   ORR   Overall Response Rate   OS   Overall Survival   PFS   Progression-Free Survival   PTLD   Post-Transplant Lymphoproliferative Disorder   PR   Partial Response   ROC   Receiver-Operating Characteristic   sCD95L   soluble CD95 Ligand   SOT   Solid Organ Transplantation   TC   Transplant Control   TNF   Tumor Necrosis Factor  

摘要： CD95L is a transmembrane cytokine mainly expressed by activated T and NK cells to contract the immune response through cell-cell contact. Conversely, after cleavage by metalloproteases, this ligand releases a soluble CD95L (sCD95L) that stimulates the immune response and its antitumor activity. In Post-Transplant Lymphoproliferative Disorders (PTLDs), we hypothesized that the concentration of sCD95L could exert a biological function and affect clinical outcomes by modulating the immune response. Using the K-VIROGREF biobank, we quantified sCD95L in 163 patients with PTLD, 16 transplant controls and 28 healthy donors. Transplant recipients had higher plasma levels of sCD95L than healthy donors. More interestingly, patients with PTLD and high concentration of sCD95L had better clinical outcomes than patients with lower concentration, particularly those with central nervous system (CNS) involvement known to have poor survivals. At the cellular level, only NK and NKT-like cells fractions were reduced in the blood of patients with CNS-PTLD and high concentration of sCD95L, suggesting that sCD95L may either promote the trafficking of these cells within tumors or modulate their differentiation/survival. In conclusion, we showed in this exploratory analysis that plasma concentration of sCD95L might be a prognostic marker in patients with PTLD, particularly in those with CNS involvement.

关键词： Glioblastoma   Monocyte-derived macrophages   Temozolomide resistance   Hypoxia   Lactylation  

摘要： Introduction Temozolomide (TMZ) resistance poses a significant challenge to the treatment of aggressive and highly lethal glioblastomas (GBM). Monocyte-derived Macrophages (MDM) within the tumor microenvironment are key factors contributing to TMZ resistance in GBM. Lactate-mediated histone lysine lactylation (Kla) plays a crucial role in the regulation of tumor progression. However, the mechanism through which MDM-induced Kla expression promotes TMZ resistance in GBM remains unclear. Objectives The objective of this study s to identify a subtype of MDM with therapeutic potential target and to elucidate the mechanisms through which this subtype of MDM contributes to tumor malignant progression and TMZ resistance. Methods We integrated single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics data to evaluate whether mesenchymal (MES) MDM is associated with poor prognosis. By establishing a subtype model of GBM cells for the first time, we validated the mechanism by which MES-MDM promotes subtype conversion of tumor cells. Using patient-derived GBM organoids and an intracranial orthotopic GBM model, we demonstrated that targeting MES-MDMs increased GBM sensitivity to TMZ treatment. Results We identified a novel MDM subtype, MES-MDM, in the hypoxic niches of the perinecrotic region characterized by high TREM1 expression, which fueled GBM progression. Hypoxia drived MES-MDM signatures by activating ATF3 transcription. MES-MDM facilitated the transition from the NPC to the MES subtype in GBM cells, in which Histone Deacetylase 1 (HDAC1) Kla, induced by the TNF-CELSR2/p65 signaling pathway, promoted this conversion, thereby promoting TMZ resistance. Targeting MES-MDM with TREM1 inhibitory peptides amplified TMZ sensitivity, offering a potential strategy for overcoming resistance to therapy in GBM. Targeting TREM1 enhanced the effectiveness of anti-PD-1 immunotherapy. Conclusion This study provides a potential therapeutic strategy for patients with MES-subtype GB

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： 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.

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.

关键词： esophageal squamous cell carcinoma   IL-6   PD-1 inhibitor   tumor microenvironment   prognosis  

摘要： Background Due to the low efficacy rates, effective biomarkers are desperately needed to determine populations of advanced esophageal squamous cell carcinoma (ESCC) that may benefit from immune checkpoint inhibitor (ICI) *** To explore the relationship between IL-6 and the esophageal cancer tumor immune microenvironment using online databases and esophageal cancer tissue microarrays and to investigate the predictive role of IL-6 for immunotherapy in esophageal squamous carcinoma patients through clinical study *** RNA-seq datasets of ESCC patients were obtained from TCGA, and the relationship between IL-6 and immune cells was discovered using TIMER 2.0 databases. CD8, IL-6, and PD-L1 expression in ESCC tissue microarrays were measured using immunohistochemistry, and then the tumor microenvironment was classified. Furthermore, blood specimens were collected from advanced ESCC patients before they received PD-1 inhibitors, and follow-up was conducted to gather clinical survival data. Based on IL-6 levels. We divided the population into the high and low IL-6 groups, comparing the efficacy and survival of the two *** IL-6 positively correlated with mRNA levels of PD-L1, negatively correlated with immune cells, and positively correlated with immunosuppressive cells. High IL-6 expression in tissues might make PD-1/L1 blockade therapy less effective. Individuals with higher baseline plasma IL-6 levels had significantly lower objective remission rates and inferior PFS and OS. Elevated baseline IL-6 was demonstrated to be an independent risk factor for the prognosis of advanced ESCC patients using PD-1 inhibitors, according to COX regression *** IL-6 overexpression correlates with the immunosuppressive tumor microenvironment in ESCC, and it can be a predictive biomarker in ESCC patients received with PD-1 inhibitors.