Because understanding of the inventory, connectivity and dynamics of the components characterizing the process of coagulation is relatively mature, it has become an attractive target for physiochemical modeling. Such models can potentially improve the design of therapeutics. The prothrombinase complex (composed of the protease factor (F)Xa and its cofactor FVa) plays a central role in this network as the main producer of thrombin, which catalyses both the activation of platelets and the conversi ...[more]
Project description:Blood coagulation model investigating effects of Xa-inhibitors (Rivaroxaban and Apixaban). Model is an extension of Pohl1994 and reduced from Wajima2009.
Encoding the model from the supplementary files results in 43 species, 82 reactions and 111 parameters. Including the drug (Xa-inhibitor) and drug-Xa complexes results in 46 species, 84 reactions and 115 parameters (+1 dummy variable to change inhibitory kinetic parameters depending on which drug is simulated). The publication lists there being 45 species, 84 reactions and 116 parameters. Publication figure 2 has 45 species present however the complex VIIa:Xa (reaction 51 involving Xa and VIIa) is not shown. This figure also has numerous small errors such as listing IXa:ATIII complex twice (instead of one being XIa:ATIII), not showing XIa:ATIII, typo ('Va' -> Va), typo (IXa + VIIIa -> IXA:'VIIa').
Rate laws for Xa-drug interactions were assumed to be mass action.
Project description:Mathematical model of blood coagulation. Reused Wajima2009 model with modifications to reactions 27 (formation of Va:Xa complex), 32 (Xa inhibition by TFPI) and 45 (Xa inhibition by TFPI-Heparin complex) as described in publication equations 2,3 and 4. Publication lists parameter sets to simulate Rivaroxaban, VKA and Enoxaparin (supplementary files).
Project description:Reused mathematical model (Hockin et al., 2002) of blood coagulation simulating the effects of coagulation factor inhibitors, fondaparinux (synthetic heparin) and Rivaroxaban. Fondaparinux (Fpx) simulated to reversibly bind with ATIII before irreversibly binding to Xa, IXa, mIIa, TF:VIIa, Xa:Va and IIa. Rivaroxaban simulated to bind reversibly to Xa and Xa:Va.
Project description:Mathematical model of blood coagulation to simulate factor IIa, Va and Xa concentration profiles. Publication also illustrates the effect of hirudin on factor IIa, Va and Xa generation.
Project description:Inactivation of TGF-beta family signaling is implicated in colorectal tumor progression. Using the cis-Apc/Smad4 mutant mice, a model of invasive colorectal cancer whose TGF-beta family signaling is blocked, we demonstrate here that a novel type of immature myeloid cells (iMCs) is recruited from the bone marrow to the tumor invasion front. These CD34+ iMCs express MMP9/2 and CC-chemokine receptor 1 (CCR1), and migrate toward its ligand CCL9. In the adenocarcinomas, expression of CCL9 is increased in the tumor epithelium. Such changes in the chemokine expression or the CD34+ iMC recruitment are not observed in the Apc (+/–) mice, a model of adenomatous polyposis. By knocking out Ccr1 gene in the cis-Apc/Smad4 mutant mice, we further demonstrate that lack of CCR1 prevents the accumulation of CD34+ iMCs at the invasion front and suppresses tumor invasion. These results indicate that loss of the TGF-beta family signaling in tumor epithelium causes accumulation of iMCs that help tumor invasion. Keywords: disease state analysis Overall design: We compared the gene expression profile of the cis-Apc/Smad4 adenocarcinomas with that of the Apc (+/–) adenomas to look for chemokines that were increased in the adenocarcinomas. To this end, we used DNA Chip Consortium Mouse Microarray v2.0 (oligonucleotide microarray) that contains 65-mer oligonuleotide probes for 21,997 mouse transcripts for three individual analyses.