According to the number and localization of lesions created in a cell nucleus. We here further improve the DSMK model to be capable of explicitly describing cell inactivation related to the Bcl-2 effect. The nontargeted effect was expressed by improving our original model, which assumed that a cell is potentially inactivated when receiving an apoptotic signal from irradiated cells. In this study, the parameters used in the model assembly were determined by the least-square fitting of the experimentally determined SF of Bcl-2 cells and Neo cells irradiated with microbeam or broadbeam of heavy ions, as well as the WI-38 normal human fibroblasts irradiated with X-ray microbeam. The details of the calculation procedures together with the comparison results between the computationally and experimentally determined SF are given below. The most important difference between the DSMK and MK models is that the DSMK model fully ABT-199 1257044-40-8 considers the stochastic nature of both domain and cellnucleus specific energies, while the MK model represents the stochastic nature by their approximated mean values and variances. Besides, the DSMK model considers the saturation in the production rates of lethal and sublethal lesions per specific energy z in a domain for expressing an overkill effect of high-LET irradiation. Owing to these profiles, the DSMK model can reproduce the experimentally determined SF for high-LET and high-dose irradiation, whereas the original MK model tends to underestimate the data. Calculation procedures for the DSMK model are outlined below, details of which have been previously described. Radioresistance caused by Bcl-2 overexpression was also considered by introducing the concept of the adaptive response. The model assembly reproduced the experimentally determined SF of Bcl-2 cells and Neo cells irradiated with microbeam or broadbeam very well. However, large uncertainty still remains in the fitting parameters as well as the model concept due to the lack of experimental data. The consideration of the Bcl-2 effect results in the increase of the RBE-weighted doses for both mono-energetic and SOBP carbon-ion beams, indicating that the developed model assembly can play an important role in the treatment planning for heavy-ion therapy. On the other hand, the consideration of the nontargeted effect is not so important in the estimate of the RBE-weighted doses for heavy-ion therapy, but it is expected to be beneficial to the treatment planning for brachytherapy and boron neutron capture therapy where irradiated and nonirradiated cells coexist. For more quantitative analyses, further studies are necessary for precisely determining the model parameters for various cell lines. Cataract has been a major cause of visual impairment among senior citizens worldwide. According to data provided by the World Health Organization, cataract is responsible for nearly 50% of blindness across the world. With the coming of aging society, the prevalence of cataract increases rapidly. The importance of risk factors identification for cataract is therefore evident. In the past decades, researchers have performed numerous in-depth epidemiologic studies to understand the pathogenesis of cataract.