Regulation of IFN response gene activity during infliximab treatment in rheumatoid arthritis is associated with clinical response to treatment

ABSTRACT: INTRODUCTION: Cross-regulation between tumor necrosis factor (TNF) and type I interferon (IFN) has been postulated to play an important role in autoimmune diseases. Therefore we determined the effect of TNF-blockade in rheumatoid arthritis (RA) on the type I IFN-response gene activity in relation to clinical response. METHODS: Peripheral blood from 33 RA patients was collected in PAXgene tubes before and after the start of infliximab treatment. In a first group of 15 patients the baseline expression of type I IFN-regulated genes was determined using cDNA-microarrays and compared to levels one month after treatment. The remaining 18 patients were studied as an independent group for validation using quantitative (q)PCR. RESULTS: Gene expression analysis revealed that anti-TNF antibody treatment induced a significant increase in type I IFN-response activity in a subset of RA patients, whereas expression levels remained similar or were slightly decreased in others. The findings appear clinically relevant since patients with an increased IFN-response gene activity after anti-TNF therapy had a poor clinical outcome. This association was confirmed and extended for an IFN-response gene set consisting of OAS1, LGALS3BP, Mx2, OAS2 and SERPING1 in five EULAR good and five EULAR poor responders, by qPCR. CONCLUSIONS: Regulation of IFN-response gene activity upon TNF-blockade in RA is not as consistent as previously described, but varies between patients. The differential changes in IFN-response gene activity appear relevant to the clinical outcome of TNF-blockade in R

Co-chaperones are limiting in a depleted chaperone network

To probe the limiting nodes in the chaperoning network which maintains cellular proteostasis, we expressed a dominant negative mutant of heat shock factor 1 (dnHSF1), the regulator of the cytoplasmic proteotoxic stress response. Microarray analysis of non-stressed dnHSF1 cells showed a two- or more fold decrease in the transcript level of 10 genes, amongst which are the (co-)chaperone genes HSP90AA1, HSPA6, DNAJB1 and HSPB1. Glucocorticoid signaling, which requires the Hsp70 and the Hsp90 folding machines, was severely impaired by dnHSF1, but fully rescued by expression of DNAJA1 or DNAJB1, and partially by ST13. Expression of DNAJB6, DNAJB8, HSPA1A, HSPB1, HSPB8, or STIP1 had no effect while HSP90AA1 even inhibited. PTGES3 (p23) inhibited only in control cells. Our results suggest that the DNAJ co-chaperones in particular become limiting in a depleted chaperoning network. Our results also suggest a difference between the transcriptomes of cells lacking HSF1 and cells expressing dnHSF1

Apelin: A putative novel predictive biomarker for bevacizumab response in colorectal cancer

Bevacizumab (bvz) is currently employed as an anti-angiogenic therapy across several cancer indications. Bvz response heterogeneity has been well documented, with only 10-15% of colorectal cancer (CRC) patients benefitting in general. For other patients, clinical efficacy is limited and side effects are significant. This reinforces the need for a robust predictive biomarker of response. To identify such a biomarker, we performed a DNA microarray-based transcriptional profiling screen with primary endothelial cells (ECs) isolated from normal and tumour colon tissues. Thirteen separate populations of tumour-associated ECs and 10 of normal ECs were isolated using fluorescence-activated cell sorting. We hypothesised that VEGF-induced genes were overexpressed in tumour ECs; these genes could relate to bvz response and serve as potential predictive biomarkers. Transcriptional profiling revealed a total of 2,610 differentially expressed genes when tumour and normal ECs were compared. To explore their relation to bvz response, the mRNA expression levels of top-ranked genes were examined using quantitative PCR in 30 independent tumour tissues from CRC patients that received bvz in the adjuvant setting. These analyses revealed that the expression of MMP12 and APLN mRNA was significantly higher in bvz non-responders compared to responders. At the protein level, high APLN expression was correlated with poor progression-free survival in bvz-treated patients. Thus, high APLN expression may represent a novel predictive biomarker for bvz unresponsiveness.</p

Tumor-Educated Platelet RNA for the Detection and (Pseudo)progression Monitoring of Glioblastoma

Tumor-educated platelets (TEPs) are potential biomarkers for cancer diagnostics. We employ TEP-derived RNA panels, determined by swarm intelligence, to detect and monitor glioblastoma. We assessed specificity by comparing the spliced RNA profile of TEPs from glioblastoma patients with multiple sclerosis and brain metastasis patients (validation series, n = 157; accuracy, 80%; AUC, 0.81 [95% CI, 0.74–0.89; p < 0.001]). Second, analysis of patients with glioblastoma versus asymptomatic healthy controls in an independent validation series (n = 347) provided a detection accuracy of 95% and AUC of 0.97 (95% CI, 0.95–0.99; p < 0.001). Finally, we developed the digitalSWARM algorithm to improve monitoring of glioblastoma progression and demonstrate that the TEP tumor scores of individual glioblastoma patients represent tumor behavior and could be used to distinguish false positive progression from true progression (validation series, n = 20; accuracy, 85%; AUC, 0.86 [95% CI, 0.70–1.00; p < 0.012]). In conclusion, TEPs have potential as a minimally invasive biosource for blood-based diagnostics and monitoring of glioblastoma patients