Holistic View on Cell Survival and DNA Damage: How Model-Based Data Analysis Supports Exploration of Dynamics in Biological Systems

Abstract

<jats:p>In this work, a method is established to calibrate a model that describes the basic dynamics of DNA damage and repair. The model can be used to extend planning for radiotherapy and hyperthermia in order to include the biological effects. In contrast to “syntactic” models (e.g., describing molecular kinetics), the model used here describes radiobiological semantics, resulting in a more powerful model but also in a far more challenging calibration. Model calibration is attempted from clonogenic assay data (doses of 0–6 Gy) and from time-resolved comet assay data obtained within 6 h after irradiation with 6 Gy. It is demonstrated that either of those two sources of information alone is insufficient for successful model calibration, and that both sources of information combined in a holistic approach are necessary to find viable model parameters. Approximate Bayesian computation (ABC) with simulated annealing is used for parameter search, revealing two aspects that are beneficial to resolving the calibration problem: (1) assessing posterior parameter distributions instead of point-estimates and (2) combining calibration runs from different assays by joining posterior distributions instead of running a single calibration run with a combined, computationally very expensive objective function.</jats:p>

Cinnamaldehyde-Rich Cinnamon Extract Induces Cell Death in Colon Cancer Cell Lines HCT 116 and HT-29

“…Moreover, we have shown by clonogenic assay that CRCE decreased the proliferation ability of viable cells. This also suggests that the proliferation ability might have been impaired by DNA damage, while we cannot rule out the possibility that the cytotoxic effect of CRCE impaired the seeded cells' viability [46]. We assume that the activity of CRCE is exerted via different pathways, which still need to be explored, as both the increase in sub-G 1 and Annexin V/PI assays confirmed that CRCE induces apoptosis and that cell cycle arrest is an intermediate step prior to apoptotic death.…”

Biological modeling in thermoradiotherapy: present status and ongoing developments toward routine clinical use

“…Since the state variable N 0 is tracking clonogenic cells, the MHR model can be used to fit experimental cell survival curves. Although good quality fits of cell survival curves were obtained, unambiguous interpretation of the results can be quite challenging, since very different sets of parameters, representing very different repair dynamics, can fit a set of experimental results almost equally well [57,58]. Furthermore, sometimes unexpected parameter values were found; calibration and validation of the model are thus quite challenging.…”

“…Since the MHR model has 8 free parameters and clonogenic assays typically have only 5 data points, additional data are needed for reliable model calibration. To this end, Weyland et al implemented methods to map the model to comet assay readouts to be combined with clonogenic assay data [58]. Results showed that unambiguous model parameters can only be obtained by combining information from both assays in a holistic approach.…”

“…cytotoxicity by hyperthermia and does not correctly describe inhibition of DNA damage repair at higher temperatures [58].…”