Patient and researcher perspectives on facilitating patient and public involvement in rheumatology research

No abstract available

Analysis of early changes in DNA methylation in synovial fibroblasts of RA patients before diagnosis

DNA methylation is an important epigenetic modification that is known to be altered in rheumatoid arthritis synovial fibroblasts (RASF). Here, we compared the status of promoter DNA methylation of SF from patients with very early RA with SF from patients with resolving arthritis, fully established RA and from non-arthritic patients. DNA was hybridized to Infinium Human methylation 450k and 850k arrays and differential methylated genes and pathways were identified. We could identify a significant number of CpG sites that differed between the SF of different disease stages, showing that epigenetic changes in SF occur early in RA development. Principal component analysis confirmed that the different groups of SF were separated according to their DNA methylation state. Furthermore, pathway analysis showed that important functional pathways were altered in both very early and late RASF. By focusing our analysis on CpG sites in CpG islands within promoters, we identified genes that have significant hypermethylated promoters in very early RASF. Our data show that changes in DNA methylation differ in RASF compared to other forms of arthritis and occur at a very early, clinically yet unspecific stage of disease. The identified differential methylated genes might become valuable prognostic biomarkers for RA development

CD151 Regulates Tumorigenesis by Modulating the Communication between Tumor Cells and Endothelium

The tetraspanin CD151 forms stoichiometric complexes with laminin-binding integrins (e.g., alpha 3 beta 1, alpha 6 beta 1, and alpha 6 beta 4) and regulates their ligand-binding and signaling functions. We have found that high expression of CD151 in breast cancers is associated with decreased overall survival (3.44-fold higher risk of death). Five-year estimated survival rates were 45.8% (95% confidence interval, 16.4-71.4%) for CD151-positive Patients and 79.9% (95% confidence interval, 62.2-90.0%) for CD151-negative Patients. Furthermore, CD151 was positively associated with axillary lymph node involvement. To study the biological significance of this observation, we investigated the contribution of CD151 in breast cancer tumorigenesis using MDA-MB-231 cells as a model system. Stable down-regulation of this tetraspanin by short-hairpin RNA decreased the tumorigenicity of these cells in mice. Detailed immunohistologic analysis of CD151 (+) and CD151(-) xenografts showed differences in tumor vascular pattern. Vascularization observed at the subcutaneous border of the CD151 (+) tumors was less pronounced or absent in the CD151(-) xenografts. In vitro experiments have established that depletion of CD151 did not affect the inherent proliferative capacity of breast cancer cells in three-dimensional extracellular matrices, but modified their responses to endothelial cells in coculture experiments. The modulatory activity of CD151 was dependent on its association with both alpha 3 beta 1 and alpha 6 beta 4 integrins. These data point to a new role of CD151 in tumorigenesis, whereby it functions as an important regulator of communication between tumor cells and endothelial cells. These results also identify CD151 as a potentially novel prognostic marker and target for therapy in breast cancer

Optimizing the Environmental and Economic Sustainability of Remote Community Infrastructure

Remote communities such as rural villages, post-disaster housing camps, and military forward operating bases are often located in remote and hostile areas with limited or no access to established infrastructure grids. Operating these communities with conventional assets requires constant resupply, which yields a significant logistical burden, creates negative environmental impacts, and increases costs. For example, a 2000-member isolated village in northern Canada relying on diesel generators required 8.6 million USD of fuel per year and emitted 8500 tons of carbon dioxide. Remote community planners can mitigate these negative impacts by selecting sustainable technologies that minimize resource consumption and emissions. However, the alternatives often come at a higher procurement cost and mobilization requirement. To assist planners with this challenging task, this paper presents the development of a novel infrastructure sustainability assessment model capable of generating optimal tradeoffs between minimizing environmental impacts and minimizing life-cycle costs over the community’s anticipated lifespan. Model performance was evaluated using a case study of a hypothetical 500-person remote military base with 864 feasible infrastructure portfolios and 48 procedural portfolios. The case study results demonstrated the model’s novel capability to assist planners in identifying optimal combinations of infrastructure alternatives that minimize negative sustainability impacts, leading to remote communities that are more self-sufficient with reduced emissions and costs

Cytokines and Inflammatory Mediators [30-39]: 30. The LPS Stimulated Production of Interleukin-10 is not Associated with -819C/T and -592C/A Promoter Polymorphisms in Healthy Indian Subjects

Background: Interleukin-10 is a pivotal immunoregulatory cytokine with pleiotropic effects on the immune system. IL-10 promoter polymorphisms have been associated with disease susceptibility and the ability to secrete IL-10 in vitro. We suspected that the association of the widely studied -819C/T and -592C/A polymorphisms with the IL-10 production might vary between ethnic groups. Therefore, we examined the association of -819 C/T and -592 C/A promoter polymorphisms with in vitro LPS stimulated secretion of IL-10 in normal healthy Indian volunteers. Methods: Peripheral blood was collected from 103 healthy volunteers and diluted whole blood cultures were set up with 100 ng/ml of LPS as stimulant: supernatant was collected at 24 h and IL-10 levels were assayed by ELISA. Genotyping was done for -819C/T polymorphism in 101 individuals and -592C/A polymorphism in 68 individuals by polymerase chain reaction followed by RFLP. The differences in IL-10 production between the genotypes were analysed by ANOVA. Results: There were 30, 47 and 24 individuals with the CC, CT and TT genotypes with a minor allele (T) frequency of 47% for the -819C/T polymorphism. The CC and TT genotypes at position -819 were strongly associated with CC and AA genotypes at -592 position suggestive of strong linkage disequilibrium. There was no association between the -819 genotype and the in vitro LPS stimulated IL-10 levels. Conclusions: The -819C/T and the -592 C/A polymorphisms of the IL-10 promoter region are not significantly associated with LPS stimulated IL-10 production healthy Indian subjects. Disclosure statement: All authors have declared no conflicts of interes

What can rheumatologists learn from translational cancer therapy?

It is well established that an intimate connection exists between inflammation and neoplasia. Indeed, particular chronic infections and autoimmune processes giving rise to prolonged site-specific inflammation are known to increase the probability of the development of specific cancers. Molecular characterisation of these processes has revealed profound similarities in the specific molecules involved in persistence of inflammation and in both the primary induction of neoplastic processes and in specification of the preferred anatomic sites of metastatic spread. The therapeutic importance of these findings is underscored by the remarkable success in the treatment of autoimmune pathology using medications initially developed for use in oncology and this arena is one of considerable therapeutic promise for rheumatologists