In Silico Models of DNA Damage and Repair in Proton Treatment Planning: A Proof of Concept.

There is strong in vitro cell survival evidence that the relative biological effectiveness (RBE) of protons is variable, with dependence on factors such as linear energy transfer (LET) and dose. This is coupled with the growing in vivo evidence, from post-treatment image change analysis, of a variable RBE. Despite this, a constant RBE of 1.1 is still applied as a standard in proton therapy. However, there is a building clinical interest in incorporating a variable RBE. Recently, correlations summarising Monte Carlo-based mechanistic models of DNA damage and repair with absorbed dose and LET have been published as the Manchester mechanistic (MM) model. These correlations offer an alternative path to variable RBE compared to the more standard phenomenological models. In this proof of concept work, these correlations have been extended to acquire RBE-weighted dose distributions and calculated, along with other RBE models, on a treatment plan. The phenomenological and mechanistic models for RBE have been shown to produce comparable results with some differences in magnitude and relative distribution. The mechanistic model found a large RBE for misrepair, which phenomenological models are unable to do. The potential of the MM model to predict multiple endpoints presents a clear advantage over phenomenological models.

Mechanistic modelling supports entwined rather than exclusively competitive DNA double-strand break repair pathway.

Following radiation induced DNA damage, several repair pathways are activated to help preserve genome integrity. Double Strand Breaks (DSBs), which are highly toxic, have specified repair pathways to address them. The main repair pathways used to resolve DSBs are Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR). Cell cycle phase determines the availability of HR, but the repair choice between pathways in the G2 phases where both HR and NHEJ can operate is not clearly understood. This study compares several in silico models of repair choice to experimental data published in the literature, each model representing a different possible scenario describing how repair choice takes place. Competitive only scenarios, where initial protein recruitment determines repair choice, are unable to fit the literature data. In contrast, the scenario which uses a more entwined relationship between NHEJ and HR, incorporating protein co-localisation and RNF138-dependent removal of the Ku/DNA-PK complex, is better able to predict levels of repair similar to the experimental data. Furthermore, this study concludes that co-localisation of the Mre11-Rad50-Nbs1 (MRN) complexes, with initial NHEJ proteins must be modeled to accurately depict repair choice.

Clinically relevant nanodosimetric simulation of DNA damage complexity from photons and protons.

Relative Biological Effectiveness (RBE), the ratio of doses between radiation modalities to produce the same biological endpoint, is a controversial and important topic in proton therapy. A number of phenomenological models incorporate variable RBE as a function of Linear Energy Transfer (LET), though a lack of mechanistic description limits their applicability. In this work we take a different approach, using a track structure model employing fundamental physics and chemistry to make predictions of proton and photon induced DNA damage, the first step in the mechanism of radiation-induced cell death. We apply this model to a proton therapy clinical case showing, for the first time, predictions of DNA damage on a patient treatment plan. Our model predictions are for an idealised cell and are applied to an ependymoma case, at this stage without any cell specific parameters. By comparing to similar predictions for photons, we present a voxel-wise RBE of DNA damage complexity. This RBE of damage complexity shows similar trends to the expected RBE for cell kill, implying that damage complexity is an important factor in DNA repair and therefore biological effect.

Effect of endurance training on perceived exertion and stress hormones in women.

Fifteen women (20- to 23-yr.-old), engaged in an intensive 6- to 8-wk. endurance running program, progressively increased distance from 20 miles during the first week to 50 miles during the fifth week and thereafter. Before (T1), during (T2), and after training (T3), submaximal treadmill runs of 1-hr. duration subdivided into three successive 20-min. segments were completed at approximately 60, 70, and 80% of maximal oxygen uptake, respectively. Ratings of perceived exertion (RPE) were differentiated to obtain local (L), central (C), and over-all (O) responses during these 20-min. segments. Subjects rated the effort during the final 30 sec. of each 5-min. interval. Upon completion of each exercise segment, blood samples were drawn for analysis of lactate (Hla), epinephrine (E), and norepinephrine (NE) to determine the relationship between the differentiated RPEs and these stress markers. Endurance training significantly lowered central and over-all ratings of perceived exertion between T1 and T3 runs but no change occurred in the L-RPE responses to muscular and joint strain. Significant correlations between the stress markers and RPE pooled across sessions were observed during the three treadmill sessions (Hla vs L-RPE, eta = 0.68; E vs C-RPE, eta = 0.54; and NE vs C-RPE, eta = 0.63). These findings indicate that central and over-all ratings of perceived exertion may be more readily influenced by intensive endurance training than local ratings. In addition, while lactate levels may be related to local ratings of perceived exertion, catecholamine levels appear to be associated with central ratings.