http://precedings.nature.com/users/daebe2d980c304e6834714ad48d79519/ Documents posted by Trevor Marshall Nature Publishing Group en Nature Precedings http://precedings.nature.com/images/header_logo.gif http://precedings.nature.com http://dx.doi.org/10.1038/npre.2007.164.1 The US CDC believes that 65% of all infections in developed countries may be caused by pathogens in biofilms. Electron Microscopy has shown that these bacterial communities can evade phagocytosis, and persist in the cytoplasm of monocytes, macrophages, lymphocytes and neutrophils. Three decades ago, Wirostko et al. found such intraphagocytic communities in Crohn’s disease, Juvenile Rheumatoid Arthritis and Sarcoidosis. However, the mechanism(s) by which such persistent bacteria could evade the immune system have remained elusive. Recently, 16S RNA from species of gliding bacteria never thought to be able to survive in vivo, have been found in surgically removed biofilms. This study set out to identify whether the genomes of these gliding bacteria might yield insight into mechanisms by which such persistent pathogens could evade phagocytosis. http://dx.doi.org/10.1038/npre.2007.164.1 Fri, 22 Jun 2007 13:17:53 UTC Bacterial Capnine Blocks Transcription of Human Antimicrobial Peptides doi:10.1038/npre.2007.164.1 2007-06-22 Trevor G. Marshall Nature Precedings 2007-06-22T13:17:53Z Poster Immunology Microbiology Bioinformatics http://creativecommons.org/licenses/by/2.5/ http://dx.doi.org/10.1038/npre.2007.52.1 The US FDA currently accepts carcinogenicity studies of pharmaceutical drugs based on murine models. In addition to 6 month studies with p53(+/-) and ras.H2 transgenic mice, lifetime studies (typically 2 years) in WT mice or rats are also considered as evidence that a drug lacks carcinogenic activity. This model is not always exhaustive. For example, during the acceptance testing of the ARB Olmesartan1, possible carcinogenicity observed in hamsters was not able to be duplicated in rats, or in transgenic mice. We have previously used the static molecular modeling of AutoDock to demonstrate that Olmesartan has agonostic activity in the PDB:1DB1 model of the human VDR Nuclear Receptor2, while it has antagonistic activity in the PDB:1RK3 model of the rat VDR. This agonism has now been confirmed with Molecular Dynamics, using GROMACS. The murine VDR indeed lost its ability to bind the DRIP-205 co-activator when Olmesartan was the ligand, while the human VDR was activated by Olmesartan similarly to its native ligand (1,25-dihydroxyvitamin-D). Since the VDR is believed to express 913 genes3, many of which are known to be associated with cancer pathogenesis, good homology between human VDR, and the animal model VDR, is exceedingly important. CONCLUSION: The murine environment is inadequate to accurately model drug carcinogenic activity in humans. A species should be chosen which has a VDR LBP homology closer to that of man. AutoDock and GROMACS molecular analyses are useful in resolving any remaining anomalies in the observed data.References:1. FDA CDER: NDA-21-286, Sankyo Pharma Inc Available from URL http://www.fda.gov/cder/foi/nda/2002/21-286_Benicar.htm2. Marshall TG: VDR Nuclear Receptor Competence is the Key to Recovery from Chronic Inflammatory and Autoimmune Disease. Abstract presentation, DMM2006.Available from URL http://AutoimmunityResearch.org/karolinska-handout.pdf3. Wang TT, et al: Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin-D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95. http://dx.doi.org/10.1038/npre.2007.52.1 Fri, 15 Jun 2007 15:05:40 UTC Molecular Static and Dynamic Analyses reveal Flaw in Murine Model used by US FDA to Detect Drug Carcinogenicity doi:10.1038/npre.2007.52.1 2007-06-15 Trevor Marshall Nature Precedings 2007-06-15T15:05:40Z Poster Biotechnology Cancer Immunology Pharmacology Bioinformatics http://creativecommons.org/licenses/by/2.5/