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The measurement of MN size did not reveal any differences between the effect of alpha particles and mixed beam. In conclusion, a combined exposure of PBL to alpha particles and X-rays leads to a synergistic effect as measured by the frequency of MN.
Natural nitrogen is comprises of two isotopes The primary and secondary nuclear reactions between the proton beam and the boron-nitride target are shown in Fig.
More nuclear reactions are possible in this context, but we do not consider them in a first approach because either their cross section is too small at the involved energies or the proportion of present elements is too small to contribute significantly to the observations. An example of the high-energy spectrum measured in the magnetic spectrometer for a solid boron target is shown in Fig. The error bars take into account the variation of the number of impacts across the direction perpendicular to the magnetic field.
Examples of the time evolution of the normalized activation for B and BN targets are shown in Fig. A very interesting feature appears at late times in the BN curve. This is not observed in the B target case. We calculated a fit of this curve using the sum of the two exponentials,.
The inset of part a is an enlargement of the beginning of the curve for the B target. This is shown in the insert of Fig. This must be due to the contribution of a short-lived component that, for our conditions, could be Nitrogen We observed that its proportion was larger in the B than in the BN targets, but it was not possible with the actual precision of our instrumentation to deduce an accurate yield of 13 N. We made a few tests, either by changing the proton energy spectrum or the irradiated target, to unequivocally identify the involved nuclear reactions.
The proton spectrum was modified by changing the thin foil thickness or nature irradiated by the picosecond beam or by varying the intensity of the pulse. We first consider reactions producing 11 C in B targets. The activation level was then reduced by a factor ten. In both cases, as expected from its cross section 15 , the efficiency of the reaction 11 B p,n 11 C was reduced, explaining the observed reduction of the activity. The high-energy cutoff is modified by the conditions of interaction: nature of the target, intensity of the short pulse.
An interesting part of the experiment was comparing the results from B and BN targets where both solid and plasma targets were explored. The contributions of 13 N and 18 F are considered as negligible in a first approach. Most likely, this result simply reflects the fact that the number of active atoms is reduced by a factor 2 in BN targets compared to B targets. So, most of the observed 11 C was produced by reaction 4.
The surprising result was the increase of activation in the case where the BN targets were conditioned in the plasma state by the nanosecond beam. From the temporal analysis, the activation corresponds again mainly to 11 C production. In previous studies 6 , we already observed that the number of nuclear reactions was enhanced by plasma formation of the irradiated target.
The interesting fact in this experiment is that the increase of activation is significantly greater in BN than in B plasmas. In Fig. This latter result is likely due to the reaction 13 becoming active because of higher energy protons available with gold target. The rectangles show the plasma forming pulses for the three time-delays. Looking at the possible reactions in our experiment Fig.
In the same way, secondary protons are likely produced by reactions 8 and 11 with an energy large enough to induce new reactions with 11 B. In our BN targets, the observation of 18 F radioactivity can be used as a diagnostic tool to estimate the yield of secondary protons produced in reaction 11 : typically for each reaction of the type 12 , where an observable radioactive isotope 18 F is produced, there are up to reactions 11 that produce an energetic proton.
A similar diagnostic role is played by 13 N activity. It is generated in reaction 9 which occurs also as a fraction of reaction 8 The proton beam spectrum shown in Fig. However, non-laser, non-plasma beam stopping power wisdom suggests that primary reactions dominate secondary by a factor 10, In addition we use 18 F as diagnostic, which is suppressed by its electromagnetic production process, thus one can easily argue that one 18 F is suppressed by a factor million and this suppression is reduced to —10, by the structure of the primary proton beam.
We conceived this experiment in order to establish the strength of this effect. The second and equally important point is the observation of the modification of the 11 C production in BN plasma as compared to B plasma.
This result means that, beyond the plasma action, new effects occur that we attributed to the reaction cycles induced by the secondary reactions described above.
It appears that in the plasma state the reaction rates are increased and this also applies to the secondary reactions. The effect of the time delay between the two laser pulses further demonstrates that the temperature and the ionization state of the target affects the nuclear reaction rates.
This means that the plasma entered the recombination phase with a temperature which decreases rapidly. The results are nevertheless different from those of the solid state. In summary, our results demonstrate that it is possible to produce a charged particle chain of reactions using boron-nitride targets irradiated by a laser-accelerated proton beam. We believe that this result is an important stepping stone towards energy production by laser fusion as well as to the production of required yields of medical radio-isotopes by laser.
Our experimental conditions were not optimized for the 18 F and 11 C productions, which explains the relatively low yields that are observed.
In the future, improvements can be expected by optimization of isotope mixture, of the proton spectra as was observed with gold , of the plasma formation and of the target characteristics. Experiments were conducted on the Elfie laser facility at Ecole Polytechnique.
The scheme of the experimental set up is shown in Fig. The short laser pulse, with 10 J in 0. The energy spectrum of the proton beam was characterized using Thomson parabola and CR39 track-detector covered with Aluminum foils of different thickness to select the proton energy ranges. There is growing concern regarding exposure of cancer patients to mixed beams of low and high LET radiation during radiation therapy.
In external beam radiation therapy background neutrons are generated in linear accelerators operating at energies above 10 MeV [ 8 , 9 ], giving rise to neutron equivalent doses per unit photon tumour dose from 0. Mixed beam exposures are also not uncommon in our environment. There are urban areas where high indoor radon levels are combined with elevated background gamma radiation to generate absorbed doses of 20 mSv y -1 or more, well above the average of 2. Finally, during airplane- and spaceflights high LET cosmic radiation interacts with the shielding material of the cabin to produce gamma background radiation that acts in combination with the high LET particles [ 15 , 16 ].
In the studies on the effect of mixed beam irradiation published so far, both additivity [ 17 — 21 ] and synergism [ 22 — 29 ] have been observed. The main endpoints employed in these studies were clonogenic survival [ 17 , 18 , 21 — 25 , 27 , 28 ], the micronucleus assay [ 19 , 26 ] and the chromosomal aberration test [ 20 , 29 ].
Interestingly, no studies investigating DNA damage and repair after mixed beam exposure were performed. The number of gamma-H2AX ionizing radiation induced foci IRIF has been observed to be proportional to the number of double-strand breaks produced [ 30 — 33 ]. The existing differences in ionization density and track structure for the actions of radiations of high and low LET [ 34 ] are reflected in IRIF characteristics.
It should be noted that alpha particles induce low as well as high LET damage in cells, due to the presence of delta electrons. In addition to the particle track itself, observed as a string of IRIF if viewed from the side [ 36 , 40 ], the delta electrons induce less complex damage at a distance from the track [ 41 , 42 ], giving rise to smaller IRIF.
We have recently developed a dedicated exposure facility that allows studying the cellular effects of mixed beam exposure [ 45 ]. The facility allows a simultaneous irradiation of cells with alpha particles from above and X-rays from below and we use it to investigate the formation and disappearance of IRIF in cells exposed to mixed beams.
The results indicate a difference in repair kinetics of IRIF induction and repair between the three types of irradiation. However, since the IRIF level after 24 h was similar for all irradiation schemes, long-term effects were not clear. The dose response to mixed beam irradiation was additive. For dose response analysis, cells were exposed to 0. The rational for using these doses was that in our earlier study we saw a synergistic effect of mixed beams in this dose range [ 46 ].
For analysis of repair kinetics 0. Predicted mixed beam values were obtained by dividing the alpha particle- and X-ray values by half and adding them. The same approach was applied for the lowest dose in the dose response curve 0.
Since irradiations as well as image capture were carried out perpendicularly to the glass slide to which cells were attached, one particle traversal was visualized as one large IRIF. See Methods for further information. In Figure 1 original images as well as output images from the analysis are presented.
Mixed beam-irradiated cells exhibited an intermediate response Figure 1D -F. Original and program output sample images for X-ray, mixed beam and alpha-particle irradiated VH10 cells. Images were captured 1 h after irradiation. A - C : Original images. D : Analysis image from A, X-rays. E : Analysis image from B , alpha particles. F : Analysis image from C , mixed beams. The dose response at 1 h post exposure revealed no significant differences between the exposure schemes.
A relative biological effectiveness RBE of 0. The relatively low RBE originates from the characteristics of the irradiation setup, where one particle track will be viewed as one LF, thereby underestimating the number of IRIF after alpha particle exposure.
Dose response and repair kinetics for summarized gamma-H2AX foci number and total area per nucleus. A : number of IRIF per nucleus for dose response. B : IRIF area per nucleus for dose response.
C : number of IRIF per nucleus for repair kinetics. D : IRIF area per nucleus for repair kinetics. Error bars represent standard deviations.
Dose response was scored 1 h after irradiation. For repair kinetics, analysis was carried out 0. The number and area of IRIF per nucleus in X-ray-irradiated cells decreased steadily with time, significantly so for 0. In mixed beam-irradiated cells a significant decrease from 0. There were no significant changes after alpha particle exposures during the first three time points Figure 2C -D. The number and area of IRIF per nucleus in mixed beam-irradiated cells were predicted to decrease from 0.
However, due to overlapping standard deviations this difference was not significant. The total IRIF area per nucleus for alpha particle and mixed beam-irradiated cells was very similar to that of X-rays, indicating that each IRIF, on average, was larger when alpha particles had contributed to the dose Figure 2D.
The results for number and area of SF per nucleus were very similar to those depicted in Figure 2 since the majority of IRIF were small. The same was true for intensity, which was always directly proportional to area. The results for SF and intensity were therefore not shown.
Results for mixed beam-irradiated cells were intermediate, with overlapping observed and predicted values, indicating an additive response. The R 2 for LF linear fit was 0. Dose response and repair kinetics for large gamma-H2AX foci number and total area per nucleus. A : number of LF per nucleus for dose response.
D : LF area per nucleus for repair kinetics. Due to large overlapping standard deviations there were no significant differences in the LF kinetics. At the 24 h time point the numbers of LF were at low, comparable levels for all irradiation schemes. However, two trends could be seen.
Second, in mixed beam irradiated cells the number and area of LF were predicted to decrease slightly during the first three time points, while the observed data instead indicated an increase. Due to the configuration of the setup alpha particle irradiation from above, and image capture from the same viewpoint , a LF observed in a cell irradiated with alpha particles was expected to depict one particle track. To validate this claim, the fluence was utilized.
This corresponded well with the number of LF observed in alpha particle-irradiated cells for repair kinetics Figure 3C , but the LF numbers for dose response was significantly lower Figure 3A. In the repair kinetics study an individual SF was generally largest in alpha particle-irradiated cells, intermediate in mixed beam- and smallest in X-ray-irradiated cells for the first three time points Figure 4B.
Average area per individual ionizing radiation-induced gamma-H2AX focus small, large and summarized. A : average area per LF for dose response. B : average area per SF for repair kinetics. C : average area per LF for dose response. D : average area per LF for repair kinetics. E : average area per IRIF for dose response. F : average area per IRIF for repair kinetics.
Significant differences were observed for alpha particle- and X-ray-irradiated cells at 0. Mixed beam-irradiated cells generally had smaller LF that alpha particle-irradiated cells significant for 0.
Details of the physical, chemical, and biological modules that were used to model the level of chromosomal aberrations are described elsewhere [ 19 , 27 ]. The parameters of the CA model were taken from Friedland et al. The CA induction model starts from radiation-induced DNA damage assessed by overlapping radiation track structures with the DNA molecule as described above.
The use of nonhomologous end joining and not of homologous recombination repair is considered because the simulations were carried out for unstimulated peripheral blood lymphocytes that are in the G 0 phase of the cell cycle. Additionally, to the initial spatial distribution and complexity, the simulation includes diffusive motion, enzymatic processing, synapsis, and ligation of individual DSB ends. Improper joining of DNA fragments results in different chromosome aberration types simulated with the PARTRAC repair module by tracking the chromosome origin of the ligated fragments and the positions of centromeres.
The motion of DNA ends is modeled considering chromatin mobility within time scales of a few hours. High-energy helium nuclei ionize densely along their tracks when they pass the cell nucleus, giving rise to highly clustered and complex DNA lesions. High-energy photons and the energetic electrons liberated via photoelectric and Compton effect interact sparsely with electrons of atoms and can travel long distances inside a cell nucleus before they interact.
Examples of simulated ionization events for X-rays and alpha particles are shown in Figure 1 the simulations of early DNA damage take also into account excitation of the water medium, but they are not shown in the figure.
The simulated spatial ionization distribution within an exemplary lymphocyte nucleus after X-ray left panel and alpha irradiation right panel with the dose equal 1 Gy. The geometrical information about the interactions with the DNA can be translated into genomic distances given as numbers of base pairs from the end of the hit chromosomes and thus used to define the DNA damage size and position.
The linear dependence of the dose of X-rays and alpha particles and the amount of SSB and DSB formation after physical and chemical stages are shown in Figure 2. Taking into account the uncertainties of performed simulations, it can be assumed that the simulated mean values of SSB and DSB are in line with experimental data and calculations performed with independent MC tools.
The uncertainties are given as standard deviations. Both sets of results are shown in Figure 3. TABLE 1. Error bars indicate standard deviations. The determined p value was 0. The difference between low- and high-LET radiation interactions within cells is described by spatial distributions of ionization acts inside a nucleus.
As shown in Figure 4 , DSB clusters appear more often for densely ionizing alpha particles as compared with X-ray irradiation. Dose—response curves for simulated DSB clusters in lymphocytes exposed to X-rays, alpha particles, and mixed beams: A comparison between alpha particles and X-rays, B calculated values for a mixed beam simulation compared with expected values if additivity is preserved. The calculated total numbers of CA formation in spherical cells human peripheral blood lymphocytes were compared with experimental data [ 12 ] collected previously in our laboratory for cells exposed to X-rays, alpha particles, and mixed beams.
The results are shown in Figures 5 and 6. The uncertainties of data points scored during the experiment were calculated as square roots of variations based on Poisson distribution.
Comparison of modeled and experimental results. Linear quadratic and linear relationships between the number of chromosomal aberrations CA scored for a cell induced by X-rays A and alpha particles B and the dose for experimental data and MC simulations. The number of chromosomal aberrations scored for a cell induced by mixed beams as a function of the dose for experimental data and MC simulations.
Comparison of CA dose responses of cells irradiated with X-rays shows different trends obtained with experimental data and MC simulations. However, CA was scored experimentally only up to 0. The scaling factor equal to 3. Number of chromosomal aberrations induced by mixed beam radiation and modeled with PARTRAC was comparable to the experimental data, and no scaling factor was needed. However, simulated data points are in agreement with the experimental data because the experimental uncertainties are large with respect to error bars of simulations.
Analogous to the approach taken by Staaf et al. In the experimental study [ 12 ], exposure to alpha particles and X-rays always started simultaneously, with X-ray irradiation source remaining on for a few minutes after the alpha exposure was stopped.
There is no dose-rate model implemented in the PARTRAC codes, so simulations of X-ray and alpha particle irradiation were performed separately and combined for mixed beam calculations. It is assumed that cells need 48 h to repair the damage before they reach the first posttreatment mitosis. The results are shown in Figure 7. Envelopes of additivity calculated for 4 selected frequencies of chromosomal aberrations CA , from mixed beams composed of alpha particles and X-rays: A: 3.
The mixed beam doses were 0. Data points showing simulated numbers of CA induced by mixed beam radiation are located outside of the left envelope borders, indicating an interaction of alpha particles and X-rays leading to CA frequencies higher than predicted based on assuming additivity. The results are shown in Figure 8. The mixed beam doses for 4. The data points representing mixed beam-induced CA were again outside the left envelope borders, indicating synergism.
The characteristics of the physical features of the interaction of ionizing radiations with living matter and accompanying chemical reactions are a major determinant of their final biological consequences.
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