1,720,972 research outputs found
Chromosome aberrations and cell death by ionizing radiation: Evolution of a biophysical model
No full textUn modello biofisico di morte cellulare basato sulle lesioni a cluster del DNA e le aberrazioni cromosomiche: implicazioni sui meccanismi e applicazioni nell’ambito dell’adroterapia
No full text
Prediction of normal tissue complication probability for rat spinal cord tolerance following ion irradiations
No full textObjective. Currently, treatment planning in cancer hadrontherapy relies on dose-volume criteria and physical quantities constraints. However, incorporating biologically related models of tumor control probability and of normal tissue complication probability (NTCP) would help further minimizing adverse tissue reactions, and would allow achieving a more patient-specific strategy. The aim of this work was therefore the development of a mechanistic approach to predict NTCP for late tissue reactions following ion irradiation. Approach. A dataset on the tolerance of the rat spinal cord was considered, providing NTCP (for paresis of at least grade II) experimental data following irradiation by photons, protons, helium and carbon ions, under different fractionation schemes. The photon data were fit by a mechanistic NTCP model with four parameters, called Critical Element Model; this allowed fixing the two parameters that only depend on the tissue features. Afterwards, the two parameters depending on radiation quality were predicted by applying the BIophysical ANalysis of Cell death and chromosome Aberrations biophysical model, for each ion type and dose-averaged linear energy transfer value. Main results. The predicted NTCP curves for ion irradiation were tested against the ion experimental data, by Chi-Square and p-value calculations. The model passed a significance test at 1% for all the datasets, and 5% for 13 out of 16 datasets, thus showing a good predictive power. The Relative biological effectiveness (RBE) was also calculated and compared with the data for the endpoint of NTCP equal to 50 % , and a considerable discrepancy with the commonly calculated RBE for cell survival was shown. Significance. This study highlights the importance of considering the endpoint of interest when computing the RBE, through the application of a NTCP model, and it represents a first step towards the development of an approach to improve treatment plan optimization in therapy. To this aim, the approach needs to be extended to other endpoints and to be applied to patients’ data
The role of DNA cluster damage and chromosome aberrations in radiation-induced cell killing: a theoretical approach
No full textThe role played by DNA cluster damage and chromosome aberrations in radiation-induced cell killing was investigated, assuming that certain chromosome aberrations (dicentrics, rings and large deletions, or 'lethal aberrations') lead to clonogenic inactivation and that chromosome aberrations are due to micrometre-scale rejoining of chromosome fragments derived from DNA cluster lesions (CLs). The CL yield and the threshold distance governing fragment rejoining were left as model parameters. The model, implemented as a Monte Carlo code called BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations), provided simulated survival curves that were compared with survival data on AG1522 and V79 cells exposed to different radiation types, including heavy ions. The agreement between simulation outcomes and experimental data suggests that lethal aberrations are likely to play an important role in cell killing not only for AG1522 cells exposed to X rays, as already reported by others, but also for other radiation types and other cells. Furthermore, the results are consistent with the hypothesis that the critical DNA lesions leading to cell death and chromosome aberrations are double-strand break clusters (possibly involving the ∼1000-10 000 bp scale) and that the effects of such clusters are modulated by micrometre-scale proximity effects during DNA damage processing
Modeling radiation-induced cell death: role of different levels of DNA damage clustering
No full textSome open questions on the mechanisms underlying radiation-induced cell death were addressed by a biophysical model, focusing on DNA damage clustering and its consequences. DNA "cluster lesions" (CLs) were assumed to produce independent chromosome fragments that, if created within a micrometer-scale threshold distance (d), can lead to chromosome aberrations following mis-rejoining; in turn, certain aberrations (dicentrics, rings and large deletions) were assumed to lead to clonogenic cell death. The CL yield and d were the only adjustable parameters. The model, implemented as a Monte Carlo code called BIophysical ANalysis of Cell death and chromosome Aberrations (BIANCA), provided simulated survival curves that were directly compared with experimental data on human and hamster cells exposed to photons, protons, α-particles and heavier ions including carbon and iron. d = 5 μm, independent of radiation quality, and CL yields in the range ~2-20 CLs Gy(-1) cell(-1), depending on particle type and energy, led to good agreement between simulations and data. This supports the hypothesis of a pivotal role of DNA cluster damage at sub-micrometric scale, modulated by chromosome fragment mis-rejoining at micrometric scale. To investigate the features of such critical damage, the CL yields were compared with experimental or theoretical yields of DNA fragments of different sizes, focusing on the base-pair scale (related to the so-called local clustering), the kbp scale ("regional clustering") and the Mbp scale, corresponding to chromatin loops. Interestingly, the CL yields showed better agreement with kbp fragments rather than bp fragments or Mbp fragments; this suggests that also regional clustering, in addition to other clustering levels, may play an important role, possibly due to its relationship with nucleosome organization in the chromatin fiber
The BIANCA model/code of radiation-induced cell death: application to human cells exposed to different radiation types
No full textThis paper presents a biophysical model of radiation-induced cell death,
implemented as a Monte Carlo code called BIophysical ANalysis of Cell
death and chromosome Aberrations (BIANCA), based on the assumption
that some chromosome aberrations (dicentrics, rings, and large deletions,
called "lethal aberrations") lead to clonogenic inactivation. In turn,
chromosome aberrations are assumed to derive from clustered, and thus
severe, DNA lesions (called "cluster lesions," or CL) interacting at the
micrometer scale; the CL yield and the threshold distance governing CL
interaction are the only model parameters. After a pilot study on V79
hamster cells exposed to protons and carbon ions, in the present work the
model was extended and applied to AG1522 human cells exposed to
photons, He ions, and heavier ions including carbon and neon. The
agreement with experimental survival data taken from the literature
supported the assumptions. In particular, the inactivation of AG1522 cells
was explained by lethal aberrations not only for X-rays, as already
reported by others, but also for the aforementioned radiation types.
Furthermore, the results are consistent with the hypothesis that the critical
initial lesions leading to cell death are DNA cluster lesions having yields in
the order of similar to 2 CL Gy(-1) cell(-1) at low LET and similar to 20 CL
Gy(-1) cell(-1) at high LET, and that the processing of these lesions is
modulated by proximity effects at the micrometer scale related to
interphase chromatin organization. The model was then applied to
calculate the fraction of inactivated cells, as well as the yields of lethal
aberrations and cluster lesions, as a function of LET; the results showed a
maximum around 130 keV/mu m, and such maximum was much higher for
cluster lesions and lethal aberrations than for cell inactivation
- …
