Identification of immunologic subtype and prognosis of GBM based on TNFSF14 and immune checkpoint gene expression profiling.

Immune-checkpoint therapy has failed to show significant benefit in glioblastoma (GBM) patients. Immunologic subtypes of GBM are necessary to identify patients who might benefit from immune-checkpoint therapy. This study reviewed 152 GBM samples from The Cancer Genome Atlas (TCGA) and 214 GBM samples from Chinese Glioma Genome Atlas (CGGA). Correlation analysis showed that immune checkpoint genes (ICGs) were mainly positively correlated. The prognostic analysis of the overall survival showed that there was a significant correlation between the overall survival (OS) and the prognosis of ICGs, in which the TNFSF14 gene was a significant adverse prognostic factor. Combined with TMB and neoantigens, we found that TNFSF9 and CD27 were significantly negatively correlated with TMB and neoantigens. The association between adaptive immune pathway genes and ICG expression showed that they were positively correlated with ICGs, indicating that adaptive immune pathway genes have a certain regulatory effect on the expression of ICGs. The analysis of clinical features of the samples showed that the higher the expression of ICGs, the more likely to be correlated with mutant isocitrate dehydrogenase (IDH), while the lower the expression level of IDH, the more likely to be significantly correlated with the primary GBM. Survival analysis showed that low expression of PD-L1, IDO1, or CTLA4 with TNFSF14 in the low expression group had the best prognosis, while high expression of IDO1 or CD274 with TNFSF14 in the high expression group and low expression of CTLA4 with TNFSF14 in the high expression group had the worst prognosis. We conclude that TNFSF14 is a biomarker to identify immunologic subtype and prognosis with other ICGs in GBM and may serve as a potential therapeutic target.

Soluble biomarkers differentiate patients with psoriatic arthritis from those with psoriasis without arthritis.

OBJECTIVE: Biomarkers may be helpful in screening patients with psoriasis for PsA. Our purpose was to identify serum biomarkers for psoriasis and PsA. METHODS: Fifty-two patients with psoriasis (26 satisfying CASPAR classification criteria for PsA) and 26 healthy controls were recruited for our study. Patients with psoriasis and PsA were group matched for age, sex and psoriasis duration, whereas controls were matched for age and sex. Blood samples were drawn at the time of assessment and serum was analysed for the following: IL-12, IL-12p40, IL-17, TNF super family member 14 (TNFSF14), MMP-3, RANK ligand (RANKL), osteoprotegerin (OPG), cartilage oligomeric matrix protein (COMP), C-propeptide of Type II collagen (CPII), collagen fragment neoepitopes Col2-3/4(long mono) (C2C) and Col2-3/4(short) (C1-2C) and highly sensitive CRP (hsCRP). Data were analysed using logistic regression and receiver operating characteristic curves were plotted. RESULTS: Fifty-two patients with psoriatic disease had a mean age of 46 years and psoriasis duration of 16.8 years. Compared with controls, increased serum levels of RANKL, TNFSF14, MMP-3 and COMP independently associated with psoriatic disease (P < 0.05). Twenty-six PsA patients (mean swollen and/or tender joint count 16, swollen joint count 5) were then compared with 26 patients who had psoriasis alone. Increased levels of hsCRP, OPG, MMP-3 and the CPII : C2C ratio were independently associated with PsA (P < 0.03). CONCLUSION: This pilot study indicates that hsCRP, OPG, MMP-3 and the CPII : C2C ratio are biomarkers for PsA in patients with psoriasis.

Raised LIGHT levels in pulmonary arterial hypertension: potential role in thrombus formation.

RATIONALE: Thrombus formation and inflammation are involved in the pathogenesis of pulmonary arterial hypertension (PAH), and LIGHT (Lymphotoxin-like Inducible protein that competes with Glycoprotein D for Herpesvirus entry mediator on T lymphocytes) has been shown to promote vascular inflammation. OBJECTIVES: We sought to investigate the role of the tumor necrosis factor superfamily ligand LIGHT in the pathogenesis of PAH. METHODS: We studied 73 patients with severe PAH and 10 control subjects. LIGHT and pro- and antithrombotic markers were assessed by enzyme immunoassays. MEASUREMENTS AND MAIN RESULTS: (1) Patients with idiopathic PAH (n = 21), patients with PAH related to risk factors or associated conditions (n = 31), and those with chronic thromboembolic PAH (n = 21) all had raised serum levels of LIGHT compared with control subjects (n = 10). (2) LIGHT levels in femoral artery were significantly related to mortality in the patients with PAH. (3) Immunostaining of LIGHT and its receptors was seen in alveolar macrophages, vascular smooth muscle cells, and endothelial cells in lungs from patients with PAH. (4) Thirteen patients received prostacyclin infusion (3 mo), and all showed hemodynamic improvement, accompanied by decreased LIGHT levels. (5) Prostacyclin abolished the release of LIGHT from activated platelets in vitro, suggesting that the decrease in LIGHT during prostacyclin therapy could involve direct effects on platelets. (6) LIGHT increased tissue factor and plasminogen activator inhibitor type 1 and decreased thrombomodulin levels in endothelial cells, inducing a prothrombotic state in these cells. CONCLUSIONS: Our findings suggest prothrombotic effects of LIGHT in PAH involving endothelium-related mechanisms, potentially contributing to the progression of this disorder.

LIGHT--a new member of the TNF superfamily in the plasma, dialysate and urine of uremic patients; the impact of residual diuresis and presence of viral hepatitis.

OBJECTIVES: LIGHT is a cytokine involved in atherosclerosis and cardiovascular disease in general population. DESIGN AND METHODS: We determined the levels of LIGHT in the plasma, dialysate and urine of uremic patients undergoing hemodialysis (HD) and healthy controls. RESULTS: There were no significant differences in the pre and post-HD plasma levels of LIGHT between HD patients with residual diuresis (HD-RD) and HD anuric group (HD-A) compared to controls. HD-RD patients had the lower LIGHT values in dialysate compared to HD-A patients (p<0.001), and higher urinary LIGHT excretion compared to controls (p<0.05). Moreover, the presence of RD and chronic viral hepatitis were independent factors influencing the levels of this cytokine in dialysate. CONCLUSIONS: The plasma levels of LIGHT seem to be similar in HD patients and healthy subjects and were not affected by gender, age, the mean period of HD history, disease etiology, type of medication and type of using dialysis membrane.

The TNF superfamily member LIGHT contributes to survival and activation of synovial fibroblasts in rheumatoid arthritis.

OBJECTIVES: The TNF superfamily member LIGHT has a T-cell co-stimulatory role and has previously been associated with inflammation and autoimmunity. To investigate its role in rheumatoid arthritis (RA), a disease where activated T cells contribute in a prominent way, we have analysed the expression of LIGHT and its receptors in RA and analysed its effects on synovial fibroblasts in vitro. METHODS: The expression of LIGHT was measured in synovial tissues and fluids and the receptors of LIGHT were detected on synovial fibroblasts derived from patients with RA and osteoarthritis (OA). The effects of recombinant LIGHT on the production of proinflammatory cytokines and proteases and on the apoptosis of synovial fibroblasts was assessed. RESULTS: LIGHT mRNA was present in synovial tissues of patients with RA but not with OA. Correspondingly, soluble LIGHT protein could be detected in RA synovial fluid samples at much higher levels than in synovial fluid from patients with OA. Immunohistochemical detection of LIGHT and analysis of synovial fluid cells by flow cytometry revealed CD4 T cells as the major source of LIGHT in the rheumatoid joint. Synovial fibroblasts from RA patients were found to express the LIGHT receptors HVEM and LTbetaR. Recombinant LIGHT induced RA synovial fibroblasts to upregulate MMP-9 mRNA, CD54 and IL-6 in an NF-kappaB-dependent fashion. In vitro, exposure of cultured synovial fibroblasts to LIGHT reduced FAS-mediated apoptosis significantly, without affecting the rate of spontaneous apoptosis. CONCLUSIONS: The results provide evidence for a novel T-cell-dependent activation of synovial fibroblasts by LIGHT in joints of patients with RA, contributing to an inflammatory and destructive phenotype.