Browsing by Author "Timmer, J."

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Mathematical modeling of drug-induced receptor internalization in the HER2-positive SKBR3 breast cancer cell-line
    (Berlin : Springer Nature, 2019) Fehling-Kaschek, M.; Peckys, D.B.; Kaschek, D.; Timmer, J.; Jonge, N.
    About 20% of breast cancer tumors over-express the HER2 receptor. Trastuzumab, an approved drug to treat this type of breast cancer, is a monoclonal antibody directly binding at the HER2 receptor and ultimately inhibiting cancer cell growth. The goal of our study was to understand the early impact of trastuzumab on HER2 internalization and recycling in the HER2-overexpressing breast cancer cell line SKBR3. To this end, fluorescence microscopy, monitoring the amount of HER2 expression in the plasma membrane, was combined with mathematical modeling to derive the flux of HER2 receptors from and to the membrane. We constructed a dynamic multi-compartment model based on ordinary differential equations. To account for cancer cell heterogeneity, a first, dynamic model was expanded to a second model including two distinct cell phenotypes, with implications for different conformational states of HER2, i.e. monomeric or homodimeric. Our mathematical model shows that the hypothesis of fast constitutive HER2 recycling back to the plasma membrane does not match the experimental data. It conclusively describes the experimental observation that trastuzumab induces sustained receptor internalization in cells with membrane ruffles. It is also concluded that for rare, non-ruffled (flat) cells, HER2 internalization occurs three orders of magnitude slower than for the bulk, ruffled cell population. © 2019, The Author(s).
  • Thumbnail Image
    Item
    Tempting long-memory - on the interpretation of DFA results
    (Göttingen : Copernicus GmbH, 2004) Maraun, D.; Rust, H.W.; Timmer, J.
    We study the inference of long-range correlations by means of Detrended Fluctuation Analysis (DFA) and argue that power-law scaling of the fluctuation function and thus long-memory may not be assumed a priori but have to be established. This requires the investigation of the local slopes. We account for the variability characteristic for stochastic processes by calculating empirical confidence regions. Comparing a long-memory with a short-memory model shows that the inference of long-range correlations from a finite amount of data by means of DFA is not specific. We remark that scaling cannot be concluded from a straight line fit to the fluctuation function in a log-log representation. Furthermore, we show that a local slope larger than α=0.5 for large scales does not necessarily imply long-memory. We also demonstrate, that it is not valid to conclude from a finite scaling region of the fluctuation function to an equivalent scaling region of the autocorrelation function. Finally, we review DFA results for the Prague temperature data set and show that long-range correlations cannot not be concluded unambiguously.