Cell cycle progression can be studied with computational models that allow to describe and predict its perturbation by agents as ionizing radiation or drugs. Such models can then be integrated in tools for pre-clinical/clinical use, e.g. to optimize kinetically-based administration protocols of radiation therapy and chemotherapy. We present a deterministic compartmental model, specifically reproducing how cells that survive radiation exposure are distributed in the cell cycle as a function of dose and time after exposure. Model compartments represent the four cell-cycle phases, as a fuction of DNA content and time. A system of differential equations, whose parameters represent transition rates, division rate and DNA synthesis rate, describes the temporal evolution. Initial model inputs are data from unexposed cells in exponential growth. Perturbation is implemented as an alteration of model parameters that allows to best reproduce cell-cycle profiles post-irradiation. The model is validated with dedicated in vitro measurements on human lung fibroblasts (IMR90). Cells were irradiated with 2 and 5 Gy with a Varian 6 MV Clinac at IRCCS Maugeri. Flow cytometry analysis was performed at the RadBioPhys Laboratory (University of Pavia), obtaining cell percentages in each of the four phases in all studied conditions up to 72 hours post-irradiation. Cells show early G2-phase block (increasing in duration as dose increases) and later G1-phase accumulation. For each condition, we identified the best sets of model parameters that lead to a good agreement between model and experimental data, varying transition rates from G1- to S- and from G2- to M-phase. This work offers a proof-of-concept validation of the new computational tool, opening to its future development and, in perspective, to its integration in a wider framework for clinical use.

中文翻译：

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辐射诱导的细胞周期扰动：一种通过流式细胞仪数据验证的计算工具

可以使用计算模型研究细胞周期进程，该模型允许描述和预测诸如电离辐射或药物之类的物质对其的扰动。然后可以将此类模型集成到临床前/临床使用的工具中，例如以优化基于动力学的放射疗法和化学疗法的给药方案。我们提出了确定性的区室模型，特别是重现了如何在辐射暴露后存活下来的细胞在细胞周期中作为剂量和暴露后时间的函数而分布。模型区室代表四个细胞周期阶段，作为DNA含量和时间的函数。一个微分方程系统描述了时间演化，该系统的参数代表过渡速率，分裂速率和DNA合成速率。初始模型输入是来自未暴露细胞呈指数增长的数据。扰动是通过更改模型参数来实现的，该参数允许最佳地复制辐照后的细胞周期概况。该模型通过在人肺成纤维细胞（IMR90）上进行的专门体外测量得到验证。在IRCCS Maugeri上用Varian 6 MV Clinac用2和5 Gy照射细胞。流式细胞仪分析是在RadBioPhys实验室（帕维亚大学）进行的，在照射后直至72小时的所有研究条件下，均获得了四个阶段中每个阶段的细胞百分比。细胞显示出早期的G2期阻滞（随着剂量增加持续时间增加）和后来的G1期积聚。对于每种情况，我们确定了最佳模型参数集，这些模型参数可以使模型数据与实验数据保持良好的一致性，并且可以改变从G1到S和从G2到M相的转变速率。