[Show abstract][Hide abstract] ABSTRACT: In press (2014) - One of the main issues of low-energy internal emitters concerns the very short ranges of beta particles, comparable to the dimensions of the biological targets. Depending on the chemical form, the radionuclide may be more concentrated either in the cytoplasm or in the nucleus of the target cell. Consequently, the conventional dosimetry - neglecting this issue - may overestimate or underestimate the dose to the nucleus and hence the biological effects. To assess the magnitude of these deviations and to provide a realistic evaluation of the localized energy deposition by low-energy internal emitters, the biophysical track-structure code PARTRAC was used to calculate nuclear doses, DNA damage yields and fragmentation patterns for different localizations of radionuclides in human interphase fibroblasts. The nuclides considered in the simulations were tritium and nickel-63, emitting electrons with average energies of 5.7 keV (range in water of 0.42 µm) and 17 keV (range of 5 µm), respectively, covering both very short and medium ranges of beta-decay products. The simulations results show that the largest deviations from the conventional dosimetry occur for inhomogeneously distributed short-range emitters. For uniformly distributed radionuclides selectively in the cytoplasm but excluded from the cell nucleus, the dose in the nucleus is 15% of the average dose in the cell in the case of tritium but 64% for nickel-63. Also the numbers of double-strand breaks (DSB) and the distributions of DNA fragments depend on sub-cellular localization of the radionuclides; in the investigated low- and medium-dose regions, DSB numbers are proportional to the nuclear dose, with about 50 DSB/Gy for both studied nuclides. DSB numbers on specific chromosomes depend on the radionuclide localization in the cell too, with chromosomes located more peripherally in cell nucleus being more damaged by short-ranged emitters in cytoplasm as compared with chromosomes located more centrally. These results illustrate the potential overestimation or underestimation of the risk associated with low-energy emitters, particularly for tritium intake, when their distribution at sub-cellular levels is not considered appropriately.
[Show abstract][Hide abstract] ABSTRACT: Nowadays the Pavia TRIGA reactor is available for national and international collaboration in various research field. The TRIGA Mark II nuclear research reactor of the Pavia University offers different in- and out-core neutron irradiation channels, each characterized by different integral and differential (in energy) neutron spectra. In the last two years a campaign of measurements and simulations have been performed in order to guarantee a better characterization of these different fluxes to meet the demands of irradiations that required precise information on these spectra, as radiobiological and microdosimetric studies. Experimental data on neutron fluxes have been collected analyzing and measuring the induced gamma activity in thin target foils of different materials irradiated in different TRIGA experimental channels. The data on the induced gamma activities have been processed with the SAND II deconvolution code and finally compared with the spectra obtained with Monte Carlo simulation. The comparison between simulated and measured spectra showed good agreement allowing a more precise characterization of neutron spectra and a validation of the method adopted.
[Show abstract][Hide abstract] ABSTRACT: The number of small radiation-induced DNA fragments can be heavily underestimated when determined from measurements of DNA mass fractions by gel electrophoresis, leading to a consequent underestimation of the initial DNA damage induction. In this study we reanalyzed the experimental results for DNA fragmentation and DNA double-strand break (DSB) yields in human fibroblasts irradiated with γ rays and nitrogen ion beams with linear energy transfer (LET) equal to 80, 125, 175 and 225 keV/μm, originally measured by Höglund et al. (Radiat Res 155, 818-825, 2001 and Int J Radiat Biol 76, 539-547, 2000). In that study the authors converted the measured distributions of fragment masses into DNA fragment distributions using mid-range values of the measured fragment length intervals, in particular they assumed fragments with lengths in the interval of 0-48 kbp had the mid-range value of 24 kbp. However, our recent detailed simulations with the Monte Carlo code PARTRAC, while reasonably in agreement with the mass distributions, indicate significantly increased yields of very short fragments by high-LET radiation, so that the actual average fragment lengths, in the interval 0-48 kbp, 2.4 kbp for 225 keV/μm nitrogen ions were much shorter than the assumed mid-range value of 24 kbp. When the measured distributions of fragment masses are converted into fragment distributions using the average fragment lengths calculated by PARTRAC, significantly higher yields of DSB related to short fragments were obtained and resulted in a constant relative biological effectiveness (RBE) for DSB induction yield of 2.3 for nitrogen ions at 125-225 keV/μm LET. The previously reported downward trend of the RBE values over this LET range for DSB induction appears to be an artifact of an inadequate average fragment length in the smallest interval.
[Show abstract][Hide abstract] ABSTRACT: Radiation therapy is one of the most common and effective strategies used to treat cancer. The irradiation is usually performed with a fractionated scheme, where the dose required to kill tumour cells is given in several sessions, spaced by specific time intervals, to allow healthy tissue recovery. In this work, we examined the DNA repair dynamics of cells exposed to radiation delivered in fractions, by assessing the response of histone-2AX (H2AX) phosphorylation (γ-H2AX), a marker of DNA double strand breaks. γ-H2AX foci induction and disappearance were monitored following split dose irradiation experiments in which time interval between exposure and dose were varied. Experimental data have been coupled to an analytical theoretical model, in order to quantify key parameters involved in the foci induction process. Induction of γ-H2AX foci was found to be affected by the initial radiation exposure with a smaller number of foci induced by subsequent exposures. This was compared to chromatin relaxation and cell survival. The time needed for full recovery of γ-H2AX foci induction was quantified (12 hours) and the 1:1 relationship between radiation induced DNA double strand breaks and foci numbers was critically assessed in the multiple irradiation scenarios.
PLoS ONE 01/2013; 8(11):e79541. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aims and background. To calculate peripheral radiation dose to the second primary site in patients who have developed a second malignancy after breast cancer radiotherapy (index cases) and to compare it with dose in the analogous anatomical site in radiotherapy-treated breast cancer patients who did not experience a second malignancy (controls). To evaluate the feasibility of Peridose-software peripheral dose calculation in retrospective case-control studies. Material and study design. A case-control study on 12,630 patients who underwent adjuvant breast radiotherapy was performed. Minimum 5-year follow-up was required. Each index case was matched with 5 controls by 1) year of birth, 2) year of radiotherapy and 3) follow-up duration. Peridose-software was used to calculate peripheral dose. Results. 195 second cancers were registered (0.019% of all patients treated with adjuvant irradiation). Several methodological limitations of the Peridose calculation were encountered including impossibility to calculate the peripheral dose in the patients treated with intraoperative or external electron beam radiotherapy, in case of second tumors located at <15 cm from the radiotherapy field etc. Moreover, Peridose requires full radiotherapy data and the distance between radiotherapy field and second primary site. Due to these intrinsic limitations, only 6 index cases were eligible for dose calculation. Calculated doses at the second cancer site in index cases and in an analogous site in controls ranged between 7.5 and 145 cGy. The mean index-control dose difference was -3.15 cGy (range, -15.8 cGy and +2.7 cGy).Conclusions. The calculated peripheral doses were low and the index-control differences were small. However, the small number of eligible patients precludes a reliable analysis of a potential dose-response relationship. Large patient series followed for a long period and further improvement in the methodology of the peripheral dose calculation are necessary in order to overcome the methodological challenges of the study.
[Show abstract][Hide abstract] ABSTRACT: The normal tissue complication probability (NTCP) models that are currently being proposed for estimation of risk of harm following radiotherapy are mainly based on simplified empirical models, consisting of dose distribution parameters, possibly combined with clinical or other treatment-related factors. These are fitted to data from retrospective or prospective clinical studies. Although these models sometimes provide useful guidance for clinical practice, their predictive power on individuals seems to be limited. This paper examines the radiobiological mechanisms underlying the most important complications induced by radiotherapy, with the aim of identifying the essential parameters and functional relationships needed for effective predictive NTCP models. The clinical features of the complications are identified and reduced as much as possible into component parts. In a second step, experimental and clinical data are considered in order to identify the gross anatomical structures involved, and which dose distributions lead to these complications. Finally, the pathogenic pathways and cellular and more specific anatomical parameters that have to be considered in this pathway are determined. This analysis is carried out for some of the most critical organs and sites in radiotherapy, i.e. spinal cord, lung, rectum, oropharynx and heart. Signs and symptoms of severe late normal tissue complications present a very variable picture in the different organs at risk. Only in rare instances is the entire organ the critical target which elicits the particular complication. Moreover, the biological mechanisms that are involved in the pathogenesis differ between the different complications, even in the same organ. Different mechanisms are likely to be related to different shapes of dose effect relationships and different relationships between dose per fraction, dose rate, and overall treatment time and effects. There is good reason to conclude that each type of late complication after radiotherapy depends on its own specific mechanism which is triggered by the radiation exposure of particular structures or sub-volumes of (or related to) the respective organ at risk. Hence each complication will need the development of an NTCP model designed to accommodate this structure.
Radiotherapy and Oncology 06/2012; · 4.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Purpose: To investigate the mechanisms regulating the pathways of the bystander transmission in vitro, focusing on the radiation-perturbed signalling (via Interleukine 6, IL-6) of the irradiated cells after exposure to low doses of different radiation types. Materials and methods: An integrated 'systems radiation biology' approach was adopted. Experimentally the level of the secreted cytokine from human fibroblasts was detected with ELISA (Enzyme-Linked ImmunoSorbent Assay) method and subsequently the data were analyzed and coupled with a phenomenological model based on differential equations to evaluate the single-cell release mechanisms. Results: The data confirmed the important effect of radiation on the IL-6 pathway, clearly showing a crucial role of the ROS (Reactive Oxygen Species) in transducing the effect of initial radiation exposure and the subsequent long-term release of IL-6. Furthermore, a systematic investigation of radiation dose/radiation quality dependence seems to indicate an increasing efficiency of high LET (Linear Energy Transfer) irradiation in the release of the cytokine. Basic hypotheses were tested, on the correlation between direct radiobiological damage and signal release and on the radiation target for this endpoint (secretion of IL-6) Conclusions: The results demonstrate the role of reactive oxygen and nitrogen species in the signaling pathways of IL-6. Furthermore the systems radiation biology approach here adopted, allowed us to test and verify hypotheses on the behavior of the single cell in the release of cytokine, after the exposure to different doses and different qualities of ionizing radiation.
International Journal of Radiation Biology 06/2012; 88(10):751-62. · 1.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is well known that mammalian cells exposed to ionizing radiation can
show different types of chromosome aberrations (CAs) including
dicentrics, translocations, rings, deletions and complex exchanges.
Chromosome aberrations are a particularly relevant endpoint in
radiobiology, because they play a fundamental role in the pathways
leading either to cell death, or to cell conversion to malignancy. In
particular, reciprocal translocations involving pairs of specific genes
are strongly correlated (and probably also causally-related) with
specific tumour types; a typical example is the BCR-ABL translocation
for Chronic Myeloid Leukaemia. Furthermore, aberrations can be used for
applications in biodosimetry and more generally as biomarkers of
exposure and risk, that is the case for cancer patients monitored during
Carbon-ion therapy and astronauts exposed to space radiation. Indeed
hadron therapy and astronauts' exposure to space radiation represent two
of the few scenarios where human beings can be exposed to heavy ions.
After a brief introduction on the main general features of chromosome
aberrations, in this work we will address key aspects of the current
knowledge on chromosome aberration induction, both from an experimental
and from a theoretical point of view. More specifically, in vitro data
will be summarized and discussed, outlining important issues such as the
role of interphase death/mitotic delay and that of complex-exchange
scoring. Some available in vivo data on cancer patients and astronauts
will be also reported, together with possible interpretation problems.
Finally, two of the few available models of chromosome aberration
induction by ionizing radiation (including heavy ions) will be described
and compared, focusing on the different assumptions adopted by the
authors and on how these models can deal with heavy ions.
Radiation Damage in Biomolecular Systems. 01/2012;
[Show abstract][Hide abstract] ABSTRACT: The role of track structures for understanding the biological effects of radiation has been the subject of research activities for decades. The physics that describes such processes is the core Monte Carlo codes, such as the biophysical PARTRAC (PARticle TRACks) code described in this review, which follow the mechanisms of radiation-matter interaction from the early stage. In this paper a review of the track structure theory (and of its possible extension concerning non-DNA targets) is presented.
The role of radiation quality and track structure is analyzed starting from the heavy ions results obtained with the biophysical Monte Carlo code PARTRAC (PARticles TRACks). PARTRAC calculates DNA damage in human cells based on the superposition of simulated track structures in liquid water to an 'atom-by-atom' model of human DNA.
Calculations for DNA fragmentation compared with experimental data for different radiation qualities are illustrated. As an example, the strong dependence of the complexity of DNA damage on radiation track structure, and the very large production of very small DNA fragments (lower than 1 kbp (kilo base pairs) usually not detected experimentally) after high LET (high-Linear Energy Transfer) irradiation is shown. Furthermore the possible importance of non-nuclear/non-DNA targets is discussed in the particular case of cellular membrane and mitochondria.
The importance of the track structure is underlined, in particular the dependence of a given late cellular effect on the spatial distribution of DNA double-strand breaks (DSB) along the radiation track. These results show that the relative biological effectiveness (RBE) for DSB production can be significantly larger than 1. Moreover the cluster properties of high LET radiation may determine specific initial targets and damage evolution.
International Journal of Radiation Biology 09/2011; 88(1-2):77-86. · 1.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: As radical radiotherapy treatments become more effective, more and more cancer patients are becoming cured of their disease and surviving for decades. Damage to exposed healthy tissues that becomes manifest in the medium-to-long-term is becoming a more significant factor in the choice of individual treatment plans and treatment modality. However, currently there are no reliable objective methods for predicting in an individual patient the occurrence of normal tissue complications, or second cancers caused by radiation. This is especially needed as new competing techniques and modalities become available, such as IMRT, protons, carbon ions, etc., all advancing the ability to focus the radiation dose on the target while sparing normal tissue. ALLEGRO is a Euratom-funded project that is currently investigating the current state of knowledge, and attempting to define the priority research areas. Preliminary considerations of the problems to be solved and research priorities are presented.
[Show abstract][Hide abstract] ABSTRACT: The importance of research to reduce uncertainties in risk assessment of low and protracted exposures is now recognised globally. In Europe a new initiative, called 'Multidisciplinary European LOw Dose Initiative' (MELODI), has been proposed by a 'European High Level and Expert Group on low-dose risk research' (www.hleg.de), aimed at integrating national and EC (Euratom) efforts. Five national organisations: BfS (DE), CEA (FR), IRSN (FR), ISS (IT) and STUK (FI), with the support of the EC, have initiated the creation of MELODI by signing a letter of intent. In the forthcoming years, MELODI will integrate in a step-by-step approach EU institutions with significant programmes in the field and will be open to other scientific organisations and stakeholders. A key role of MELODI is to develop and maintain over time a strategic research agenda (SRA) and a road map of scientific priorities within a multidisciplinary approach, and to transfer the results for the radiation protection system. Under the coordination of STUK a network has been proposed in the 2009 Euratom Programme, called DoReMi (Low-Dose Research towards Mutidisciplinary Integration), which can help the integration process within the MELODI platform. DoReMi and the First MELODI Open Workshop, organised by BfS in September 2009, are now important inputs for the European SRA.
[Show abstract][Hide abstract] ABSTRACT: The investigation of the bystander phenomena (i.e. the induction of damage in cells not directly traversed by radiation) is strictly related to the study of the mechanisms of intercellular communication and of the perturbative effects of radiation. A new possible way to try to solve the bystander puzzle is through a 'systems radiation biology' approach with the total integration of experimental and theoretical activities. In particular, this contribution will focus on: (1) 'ad hoc' experiments designed to quantify key parameters involved in intercellular signalling (focusing, as a pilot study, on release, decay and internalization of interleukine-6 molecules, their modulation by radiation, and possible differences between in vivo/in vitro behaviour); (2) the implementation and the development of two different modelling approaches: a stochastic model (based on a Monte Carlo code) that takes account of the local mechanisms of release and internalization of signalling molecules (e.g. cytokines) and an analytical model where signal molecules are treated as a population and their temporal behaviour is described by differential equations. This approach provided instruments to investigate the complex phenomena of signal transmission and the role of cell communication to guarantee (maintain) the robustness of the in vitro experimental systems against the effects of perturbations.
[Show abstract][Hide abstract] ABSTRACT: The PARTRAC code has been developed constantly in the last several years. It is a Monte Carlo code based on an event-by-event description of the interactions taking place between the ionising radiation and liquid water, and in the present version simulates the transport of photons, electrons, protons, helium and heavier ions. This is combined with an atom-by-atom representation of the biological target, i.e. the DNA target model of a diploid human fibroblast in its interphase (genome of 6 Gigabase pairs). DNA damage is produced by the events of energy depositions, either directly, if they occur in the volume occupied by the sugar-phosphate backbone, or indirectly, if this volume is reached by radiation-induced radicals. This requires the determination of the probabilities of occurrence of DNA damage. Experimental data are essential for this determination. However, after the adjustment of the relevant parameters through the comparison of the simulation data with the DNA fragmentation induced by photon irradiation, the code has been used without further parameter adjustments, and the comparison with the fragmentation induced by charged particle beams has validated the code. In this paper, the results obtained for the DNA fragmentation induced by gamma rays and by charged particle beams of various LET are shown, with a particular attention to the production of very small fragments that are not detected in experiments.
[Show abstract][Hide abstract] ABSTRACT: Cell-to-cell signaling has become a significant issue in radiation biology due to experimental evidence, accumulated primarily since the early 1990s, of radiation-induced bystander effects. Several candidate mediators involved in cell-to-cell communication have been investigated and proposed as being responsible for this phenomenon, but the current investigation techniques (both theoretical and experimental) of the mechanisms involved, due to the particular set-up of each experiment, result in experimental data that often are not directly comparable. In this study, a comprehensive approach was adopted to describe cell-to-cell communication (focusing on cytokine signaling) and its modulation by external agents such as ionizing radiation. The aim was also to provide integrated theoretical instruments and experimental data to help in understanding the peculiarities of in vitro experiments. Theoretical/modeling activities were integrated with experimental measurements by (1) redesigning a cybernetic model (proposed in its original form in the 1950s) to frame cell-to-cell communication processes, (2) implementing and developing a mathematical model, and (3) designing and carrying out experiments to quantify key parameters involved in intercellular signaling (focusing as a pilot study on the release and decay of IL-6 molecules and their modulation by radiation). This formalization provides an interpretative framework for understanding the intercellular signaling and in particular for focusing on the study of cell-to-cell communication in a "step-by-step" approach. Under this model, the complex phenomenon of signal transmission was reduced where possible into independent processes to investigate them separately, providing an evaluation of the role of cell communication to guarantee and maintain the robustness of the in vitro experimental systems against the effects of perturbations.
Radiation Research 09/2010; 174(3):280-9. · 2.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Health effects of exposures at low doses and/or low dose rates are recognized as requiring intensive research activity to answer several questions. To address these issues at a strategic level in Europe, with the perspective of integrating national and EC efforts (in particular those within the Euratom research programmes), a "European High Level and Expert Group (HLEG) on low dose risk research" was formed and carried out its work during 2008. The Group produced a report published by the European Commission in 2009 and available on the website http://www.hleg.de . The more important research issues identified by the HLEG were as follows: (a) the shape of dose-response for cancer; (b) the tissue sensitivities for cancer induction; (c) the individual variability in cancer risk; (d) the effects of radiation quality (type); (e) the risks from internal radiation exposure; and (f) the risks of, and dose response relationships for, non-cancer diseases. In this paper, the radiation quality issues are especially considered, since they are closely linked to health problems and related radioprotection in space and in emerging radiotherapeutic techniques (i.e., hadrontherapy). The peculiar features of low-fluence, high-LET radiation exposures can question in particular the validity of the radiation-weighting factor (w ( R )) approach. Specific strategies are therefore needed to assess such risks. A multi-scale/systems biology approach, based on mechanistic studies coordinated with molecular-epidemiological studies, is considered essential to elucidate differences and similarities between specific effects of low- and high-LET radiation.
[Show abstract][Hide abstract] ABSTRACT: We simulated the irradiation of human fibroblasts with gamma rays, protons and helium, carbon and iron ions at a fixed dose of 5 Gy. The simulations were performed with the biophysical Monte Carlo code PARTRAC. From the output of the code, containing in particular the genomic positions of the radiation-induced DNA double-strand breaks (DSBs), we obtained the DNA fragmentation spectra. Very small fragments, in particular those related to "complex lesions" (few tens of base pairs), are probably very important for the late cellular consequences, but their detection is not possible with the common experimental techniques. We paid special attention to the differences among the various ions in the production of these very small fragments; in particular, we compared the fragmentation spectra for ions of the same specific energy and for ions of the same LET (linear energy transfer). As found previously for iron ions, we found that the RBE (relative biological effectiveness) for DSB production was considerably higher than 1 for all high-LET radiations considered. This is at variance with the results obtainable from experimental data, and it is due to the ability to count the contribution of small fragments. It should be noted that for a given LET this RBE decreases with increasing ion charge, due mainly to the increasing mean energy of secondary electrons. A precise quantification of the DNA initial damage can be of great importance for both radiation protection, particularly in open-space long-term manned missions, and hadrontherapy.
Radiation Research 03/2010; 173(3):263-71. · 2.70 Impact Factor