@article{EhmannZollerMinichmayretal.2017,
  author    = {Ehmann, Lisa and Zoller, Michael and Minichmayr, Iris K. and Scharf, Christina and Maier, Barbara and Schmitt, Maximilian V. and Hartung, Niklas and Huisinga, Wilhelm and Vogeser, Michael and Frey, Lorenz and Zander, Johannes and Kloft, Charlotte},
  title     = {Role of renal function in risk assessment of target non-attainment after standard dosing of meropenem in critically ill patients},
  series = {Critical care},
  volume    = {21},
  journal   = {Critical care},
  publisher = {BioMed Central},
  address   = {London},
  issn      = {1466-609X},
  doi       = {10.1186/s13054-017-1829-4},
  pages     = {14},
  year      = {2017},
  abstract  = {Background: Severe bacterial infections remain a major challenge in intensive care units because of their high prevalence and mortality. Adequate antibiotic exposure has been associated with clinical success in critically ill patients. The objective of this study was to investigate the target attainment of standard meropenem dosing in a heterogeneous critically ill population, to quantify the impact of the full renal function spectrum on meropenem exposure and target attainment, and ultimately to translate the findings into a tool for practical application. Methods: A prospective observational single-centre study was performed with critically ill patients with severe infections receiving standard dosing of meropenem. Serial blood samples were drawn over 4 study days to determine meropenem serum concentrations. Renal function was assessed by creatinine clearance according to the Cockcroft and Gault equation (CLCRCG). Variability in meropenem serum concentrations was quantified at the middle and end of each monitored dosing interval. The attainment of two pharmacokinetic/pharmacodynamic targets (100\% T->MIC, 50\% T->4xMIC) was evaluated for minimum inhibitory concentration (MIC) values of 2 mg/L and 8 mg/L and standard meropenem dosing (1000 mg, 30-minute infusion, every 8 h). Furthermore, we assessed the impact of CLCRCG on meropenem concentrations and target attainment and developed a tool for risk assessment of target non-attainment. Results: Large inter-and intra-patient variability in meropenem concentrations was observed in the critically ill population (n = 48). Attainment of the target 100\% T->MIC was merely 48.4\% and 20.6\%, given MIC values of 2 mg/L and 8 mg/L, respectively, and similar for the target 50\% T->4xMIC. A hyperbolic relationship between CLCRCG (25-255 ml/minute) and meropenem serum concentrations at the end of the dosing interval (C-8h) was derived. For infections with pathogens of MIC 2 mg/L, mild renal impairment up to augmented renal function was identified as a risk factor for target non-attainment (for MIC 8 mg/L, additionally, moderate renal impairment). Conclusions: The investigated standard meropenem dosing regimen appeared to result in insufficient meropenem exposure in a considerable fraction of critically ill patients. An easy-and free-to-use tool (the MeroRisk Calculator) for assessing the risk of target non-attainment for a given renal function and MIC value was developed.},
  language  = {en}
}
@article{HartungHuynhGaudyMarquesteetal.2017,
  author    = {Hartung, Niklas and Huynh, Cecilia T. -K. and Gaudy-Marqueste, Caroline and Flavian, Antonin and Malissen, Nausicaa and Richard-Lallemand, Marie-Aleth and Hubert, Florence and Grob, Jean-Jacques},
  title     = {Study of metastatic kinetics in metastatic melanoma treated with B-RAF inhibitors: Introducing mathematical modelling of kinetics into the therapeutic decision},
  series = {PLoS one},
  volume    = {12},
  journal   = {PLoS one},
  publisher = {PLoS},
  address   = {San Fransisco},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0176080},
  pages     = {11},
  year      = {2017},
  abstract  = {Background Evolution of metastatic melanoma (MM) under B-RAF inhibitors (BRAFi) is unpredictable, but anticipation is crucial for therapeutic decision. Kinetics changes in metastatic growth are driven by molecular and immune events, and thus we hypothesized that they convey relevant information for decision making. Patients and methods We used a retrospective cohort of 37 MM patients treated by BRAFi only with at least 2 close CT-scans available before BRAFi, as a model to study kinetics of metastatic growth before, under and after BRAFi. All metastases (mets) were individually measured at each CT-scan. From these measurements, different measures of growth kinetics of each met and total tumor volume were computed at different time points. A historical cohort permitted to build a reference model for the expected spontaneous disease kinetics without BRAFi. All variables were included in Cox and multistate regression models for survival, to select best candidates for predicting overall survival. Results Before starting BRAFi, fast kinetics and moreover a wide range of kinetics (fast and slow growing mets in a same patient) were pejorative markers. At the first assessment after BRAFi introduction, high heterogeneity of kinetics predicted short survival, and added independent information over RECIST progression in multivariate analysis. Metastatic growth rates after BRAFi discontinuation was usually not faster than before BRAFi introduction, but they were often more heterogeneous than before. Conclusions Monitoring kinetics of different mets before and under BRAFi by repeated CT-scan provides information for predictive mathematical modelling. Disease kinetics deserves more interest},
  language  = {en}
}
@article{HartungBenaryWolfetal.2017,
  author    = {Hartung, Niklas and Benary, Uwe and Wolf, Jana and Kofahl, Bente},
  title     = {Paracrine and autocrine regulation of gene expression by Wnt-inhibitor Dickkopf in wild-type and mutant hepatocytes},
  series = {BMC systems biology},
  volume    = {11},
  journal   = {BMC systems biology},
  publisher = {BioMed Central},
  address   = {London},
  issn      = {1752-0509},
  doi       = {10.1186/s12918-017-0470-9},
  pages     = {16},
  year      = {2017},
  abstract  = {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/beta-catenin signalling in an autocrine and paracrine manner. Consequently, Dkk modulates the expression of Wnt/beta-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/beta-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/beta-catenin signal transduction, allow wild-type hepatocytes to largely maintain their gene expression.},
  language  = {en}
}
@misc{HartungBenaryWolfetal.2017,
  author    = {Hartung, Niklas and Benary, Uwe and Wolf, Jana and Kofahl, Bente},
  title     = {Paracrine and autocrine regulation of gene expression by Wnt-inhibitor Dickkopf in wild-type and mutant hepatocytes},
  series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  journal   = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  number    = {886},
  issn      = {1866-8372},
  doi       = {10.25932/publishup-43077},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-430778},
  pages     = {18},
  year      = {2017},
  abstract  = {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.},
  language  = {en}
}