Abstract
Future concepts in miniaturized HTScreening technologies will concentrate on making optimal use of the two emerging technologies, combinatorial chemistry and functional genomics. To effectively exploit compounds from highly-parallel combinatorial synthesis and the high number of new target proteins from functional genomics, Novartis and Evotec BioSystems developed the CONA-BSP (confocal nanoscanning - bead scanning picking technology) as a novel high throughput - low hit-rate HTS process. In combination with the Novartis proprietary AIDA-Technology, quantitative on-bead confocal fluorescence screening can be combined with off-bead confirmation via a series of fluorescence techniques such as fluorescence anisotropy, or rotational correlation time applied to equilibrium binding studies. Single molecule fluorescence spectroscopy and confocal nanoscanning/AIDA technology provide an optimal combination for a miniaturized automated uHTS process with high mechanistic resolution in functional and coupled assay systems.
Highlights
The presence of autoantibodies directed to citrullinated antigens in serum is highly specific for rheumatoid arthritis (RA)
We discuss the presence of anti-keratin antibodies (AKA) of the IgG class in patients with defined juvenile idiopathic arthritis (JIA)
Our study revealed that AKA was present overall in 18/29 patients (62%) with severe JIA and in 12/26 patients (46,2 %) with non-severe disease, this did not reach statistical significance (P = 0,18)
Summary
The presence of autoantibodies directed to citrullinated antigens in serum is highly specific for RA. Anti-CCP concentrations (expressed in Units per mg total IgG) were on average 1.34 times higher in SF compared to serum (n = 20, P < 0.05) or 1.37 when only positive samples were included (n = 11, P < 0.05) Conclusion: Citrullinated antigens are present in the synovia of both RA and control patients with similar prevalence. At higher concentrations (>1ng/μl) of RNA-oligonucleotides unspecific hybridization-signals prevailed in tissues of all diseases (even in normal controls) The combination of both methods (in situ-hybridization and immunohistochemistry) identifies the single cells inside the synovial lining layer which contains the highly expressed RAB3 “Kreisler” (maf B) gene. Conclusions: These data demonstrates for the first time that statins (and fluvastatin) are able to inhibit an endothelial proadhesive and pro-inflammatory phenotype induced by different stimuli including anti-β2GPI antibodies or pro-inflammatory cytokines These findings suggest a potential usefulness for statins in the prevention of the APS pro-atherothrombotic state
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