1,721,041 research outputs found
A Model of Radiation-Induced Cell Killing: Insights into Mechanisms and Applications for Hadron Therapy
No full textA mechanism-based, two-parameter biophysical model of cell killing was developed, with the aim of elucidating the mechanisms underlying radiation-induced cell death and predicting cell killing by different radiation types, including protons and carbon ions at energies and doses of interest for cancer therapy. It was assumed that certain chromosome aberrations (dicentrics, rings and large deletions, called “Lethal Aberrations”) lead to clonogenic inactivation, and that aberrations derive from μm-scale misrejoining of chromatin fragments, which in turn are produced by “dirty” double-strand breaks called “Cluster Lesions” (CLs); the average number of CLs per Gy and per cell was left as a semi-free parameter, whereas the threshold distance for chromatin-fragment rejoining was the second parameter. The model, “translated” into a Monte Carlo code providing simulated survival curves, was compared with survival data on V79 cells exposed to protons and carbon ions, as well as X-rays. The agreement between simulations and data validated the model and supported the assumptions; in particular, at least for doses up to few Gy, dicentrics, rings and large deletions were found to be lethal not only for AG1522 cells exposed to X-rays, as already reported by others, but also for V79 cells exposed to protons and carbon ions of different energies. Furthermore, the derived CL yields suggest that the critical DNA lesions leading to clonogenic inactivation are more complex than “clean” DSBs.
Following validation, the model was applied to characterize the particle- and LET-dependence of proton and carbon cell-killing. Consistent with the proton data, the predicted fraction of inactivated cells after 2-Gy protons was 40-50% below 7.7 keV/μm, increased by a factor 1.6 between 7.7 and 30.5 keV/μm, and decreased by a factor 1.1 between 30.5 and 34.6 keV/μm. These LET values correspond to proton energies below a few MeV, which are always present in the distal region of hadrontherapy Spread-Out Bragg Peaks (SOBP); especially when critical organs are present beyond the tumour, this should be taken into account in clinics. Consistent with the carbon data, the predicted fraction of inactivated cells after 2-Gy carbon was 40-50% between 13.7 and 32.4 keV/μm, it increased by a factor 1.7 between 32.4 and 153.5 keV/μm, and decreased by a factor 1.1 between 153.5 and 339.1 keV/μm. Finally, the model was applied to predict cell death at different depths along a carbon SOBP used for pre-clinical experiments at HIMAC in Chiba (Japan); the predicted fraction of inactivated cells was found to be roughly constant (less than 10%) along the SOBP, suggesting that this approach may be applied to predict cell killing by therapeutic beams and that, more generally, dicentrics, rings and deletions at the first mitosis may be regarded as a “biological dose”.
This work allowed to shed light on the mechanisms of radiation-induced cell death, to characterize the particle- and LET-dependence of proton and carbon cell-killing, and to predict cell death along a carbon SOBP. More generally, a mechanism-based tool was developed that in some minutes can predict cell inactivation by protons or carbon ions of a given energy and dose, basing on an experimental photon curve and, in principle, a single (experimental) survival point for the considered ion type and energy. The model does not use RBE values, which can be a source of uncertainties
A BIOPHYSICAL MODEL LINKING RADIATION-INDUCED CHROMOSOME ABERRATIONS AND CELL DEATH
No full textA mechanism-based model of radiation cell death will be presented, assuming that dicentrics, rings and large deletions (“lethal aberrations” or LA) lead to clonogenic inactivation, and that chromosome aberrations derive from DNA cluster lesions (CL) interacting at the m scale. The CL yield and the threshold distance governing chromosome free-end rejoining are the only model parameters.
The model, implemented as a MC code called BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations), was applied to AG1522 and V79 cells exposed to photons, alpha particles and heavy ions including Carbon. The agreement with data taken from the literature validated the model and supported the assumptions, suggesting that lethal aberrations lead to cell death 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 supported the idea that the critical DNA lesions leading to cell death (via chromosome aberrations) are a sub-class of DSB showing LET-dependent yields, and that the effects of energy-deposition clustering at the nm scale are modulated by m-scale proximity effects. The model was then applied to predict the fraction of inactivated cells, as well as the yields of lethal aberrations and DNA cluster lesions, as a function of LET; the maximum shown by CL and LA was much higher than that shown by cell inactivation.
Acknowledgements: work supported by INFN (project “MiMo-Bragg”)
Neutron Spectrometry for the University of Pavia TRIGA Thermal Neutron Source Facility
No full textThe University of Pavia and the Idaho National
Laboratory (INL) are collaborating in the field of
medical neutron dosimetry specific to Neutron
Capture Therapy (NCT) radiobiological research
applications. Recognizing the importance of
accurate and reproducible radiation dosimetry as an
essential tool for interpretation and combination of
preclinical and clinical results from different research
facilities that are active in this field, we have
conducted an experimental characterization of the
neutronic performance of the reactor based thermal
neutron source for nuclear medical research at the
University of Pavia TRIGATM research reactor. This
activity is part of a larger dosimetry intercomparison
exercise, based on a common experimental protocol
that also includes the thermal neutron irradiation
facilities used for medical research at the Missouri
University Research Reactor (MURR) and the RA-3
Research Reactor in Buenos Aires, Argentina
Physical Neutron Dosimetry for the University of Pavia Thermal Neutron Source for BNCT Research
No full textA compact scintillator-based detector with collimator and shielding for dose monitoring in boron neutron capture therapy
No full textBoron neutron capture therapy exploits 10B(n,alpha)7Li reactions for targeted tumor destruction. In this work, we aimed at developing a dose monitoring system based on the detection of 478 keV gamma rays emitted by the reactions, which is very challenging due to the severe background present. We investigated a compact gammaray detector with a pinhole collimator and shielding housing. Experimental nuclear reactor measurements involved varying boron concentrations and artificial shifts of the sources. The system successfully resolved the 478 keV photopeak and detected 1 cm lateral displacements, confirming its suitability for precise boron dose monitoring
From radiation-induced chromosome damage to cell death: modelling basic mechanisms and applications to Boron Neutron Capture Therapy
No full textCell death is a crucial endpoint in radiation-induced biological damage, since any cancer therapy aims to kill tumour cells and cell death is a reference endpoint to characterize the radiation action in biological targets. Starting from Lea’s target theory, many models have been proposed to interpret radiation-induced cell killing. After discussing the main models of cell survival, in this paper we will present a theoretical approach based on the experimentally observed link between chromosome aberrations and cell death [1]. A mechanistic model and a Monte Carlo code originally developed for chromosome aberrations were extended to simulate radiation-induced cell death adopting a one-to-one relationship between the average number of “lethal aberrations” (dicentrics, rings and deletions) per cell and –lnS, being S the fraction of surviving cells. Although the observation by Cornforth and Bedford was related to normal fibroblasts exposed to X rays, in the present work the approach was applied also to intermediate- and high-LET radiation. The good agreement between simulation outcomes and literature data provided a model validation for normal cells exposed to different radiation types. The same approach was then successfully applied to simulate the survival of cells enriched with Boron and irradiated with thermal neutrons at the Triga Mark II reactor in Pavia, to mimic a typical BNCT treatment
A compact gamma-ray detector coupled with a pinhole collimator for real-time dose monitoring in BNCT
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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
The design of a promp gamma neutron activation analysis beam for BNCT purpose at the TRIGA Mark II reactor in Pavia.
No full textIn preclinical and clinical Boron Neutron Capture Therapy studies the knowledge of the amount of 10B in blood and tissues is very important. The boron concentration measurements method used in Pavia (Italy) is based on the charged particles spectrometry of thin tissue cuts irradiated in the Thermal Column of the TRIGA reactor of the University. In order to perform measurements in biological liquids such as blood and urine, or in other tissue that cannot be cut in slices, a Prompt Gamma Neutron Activation Analysis (PGNAA) [1] facility is being designed, which measures 10B concentration detecting the prompt gamma from boron nuclear capture reaction.
At the TRIGA reactor in Pavia, there are four horizontal channels, potentially available for PGNAA. The choice of the suitable channel, and the design of its configuration, were achieved using the Monte Carlo neutron transport code MCNP4c2. To perform the simulations, an input code already validated, describing the reactor structure and the neutron source, was used. The calculations were implemented applying non-analog techniques for the neutron transport, that are necessary to obtain a sufficient statistic in every positions along the channel and especially at its end.
The selection of the channel for PGNAA installation was carried out by comparing the simulated fluxes obtained in the different channels at the present configuration. The channel shielded by the core reflector was chosen, because the graphite lowers the fast component of the neutrons, with no need to insert additional material in the facility. The thermal flux at its end is 1.7 x108 n/cm2 s with thermal-to-total neutron flux ratio around 0.8.
Subsequently a bismuth block for gamma radiation shielding and blocks of single crystal sapphire as filter for fast neutron component were inserted in the channel. Other components of the facility that are under study are a collimator and the beam catcher
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