TY - GEN A1 - Maier, Corinna A1 - Hartung, Niklas A1 - de Wiljes, Jana A1 - Kloft, Charlotte A1 - Huisinga, Wilhelm T1 - Bayesian Data Assimilation to Support Informed Decision Making in Individualized Chemotherapy T2 - Postprints der Universität Potsdam : Mathematisch Naturwissenschaftliche Reihe N2 - An essential component of therapeutic drug/biomarker monitoring (TDM) is to combine patient data with prior knowledge for model-based predictions of therapy outcomes. Current Bayesian forecasting tools typically rely only on the most probable model parameters (maximum a posteriori (MAP) estimate). This MAP-based approach, however, does neither necessarily predict the most probable outcome nor does it quantify the risks of treatment inefficacy or toxicity. Bayesian data assimilation (DA) methods overcome these limitations by providing a comprehensive uncertainty quantification. We compare DA methods with MAP-based approaches and show how probabilistic statements about key markers related to chemotherapy-induced neutropenia can be leveraged for more informative decision support in individualized chemotherapy. Sequential Bayesian DA proved to be most computationally efficient for handling interoccasion variability and integrating TDM data. For new digital monitoring devices enabling more frequent data collection, these features will be of critical importance to improve patient care decisions in various therapeutic areas. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 827 KW - Induced neutropenia KW - Model KW - Myelosuppression KW - Prediction Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-445500 SN - 1866-8372 IS - 827 ER - TY - GEN A1 - Hartung, Niklas A1 - Benary, Uwe A1 - Wolf, Jana A1 - Kofahl, Bente T1 - Paracrine and autocrine regulation of gene expression by Wnt-inhibitor Dickkopf in wild-type and mutant hepatocytes T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Background Cells are able to communicate and coordinate their function within tissues via secreted factors. Aberrant secretion by cancer cells can modulate this intercellular communication, in particular in highly organised tissues such as the liver. Hepatocytes, the major cell type of the liver, secrete Dickkopf (Dkk), which inhibits Wnt/ β-catenin signalling in an autocrine and paracrine manner. Consequently, Dkk modulates the expression of Wnt/ β-catenin target genes. We present a mathematical model that describes the autocrine and paracrine regulation of hepatic gene expression by Dkk under wild-type conditions as well as in the presence of mutant cells. Results Our spatial model describes the competition of Dkk and Wnt at receptor level, intra-cellular Wnt/ β-catenin signalling, and the regulation of target gene expression for 21 individual hepatocytes. Autocrine and paracrine regulation is mediated through a feedback mechanism via Dkk and Dkk diffusion along the porto-central axis. Along this axis an APC concentration gradient is modelled as experimentally detected in liver. Simulations of mutant cells demonstrate that already a single mutant cell increases overall Dkk concentration. The influence of the mutant cell on gene expression of surrounding wild-type hepatocytes is limited in magnitude and restricted to hepatocytes in close proximity. To explore the underlying molecular mechanisms, we perform a comprehensive analysis of the model parameters such as diffusion coefficient, mutation strength and feedback strength. Conclusions Our simulations show that Dkk concentration is elevated in the presence of a mutant cell. However, the impact of these elevated Dkk levels on wild-type hepatocytes is confined in space and magnitude. The combination of inter- and intracellular processes, such as Dkk feedback, diffusion and Wnt/ β-catenin signal transduction, allow wild-type hepatocytes to largely maintain their gene expression. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 886 KW - Wnt/ β-catenin signalling pathway KW - Dickkopf diffusion and feedback regulation KW - APC concentration gradient KW - mathematical model KW - paracrine and autocrine regulation KW - reaction-diffusion system Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-430778 SN - 1866-8372 IS - 886 ER -