Temporal characterization and in vitro comparison of cell survival following the delivery of 3D-conformal, intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT)

A phantom was designed and implemented for the delivery of treatment plans to cells in vitro. Single beam, 3D-conformal radiotherapy (3D-CRT) plans, inverse planned five-field intensity-modulated radiation therapy (IMRT), nine-field IMRT, single-arc volumetric modulated arc therapy (VMAT) and dual-arc VMAT plans were created on a CT scan of the phantom to deliver 3 Gy to the cell layer and verified using a Farmer chamber, 2D ionization chamber array and gafchromic film. Each plan was delivered to a 2D ionization chamber array to assess the temporal characteristics of the plan including delivery time and 'cell's eye view' for the central ionization chamber. The effective fraction time, defined as the percentage of the fraction time where any dose is delivered to each point examined, was also assessed across 120 ionization chambers. Each plan was delivered to human prostate cancer DU-145 cells and normal primary AGO-1522b fibroblast cells. Uniform beams were delivered to each cell line with the delivery time varying from 0.5 to 20.54 min. Effective fraction time was found to increase with a decreasing number of beams or arcs. For a uniform beam delivery, AGO-1552b cells exhibited a statistically significant trend towards increased survival with increased delivery time. This trend was not repeated when the different modulated clinical delivery methods were used. Less sensitive DU-145 cells did not exhibit a significant trend towards increased survival with increased delivery time for either the uniform or clinical deliveries. These results confirm that dose rate effects are most prevalent in more radiosensitive cells. Cell survival data generated from uniform beam deliveries over a range of dose rates and delivery times may not always be accurate in predicting response to more complex delivery techniques, such as IMRT and VMAT.

Neutron diffraction, NMR and molecular dynamics study of glucose dissolved in the ionic liquid 1-ethyl-3-methylimidazolium acetate

beta-D-glucose dissolved in the ionic liquid 1-ethyl-3-methylimidazolium acetate in a 6 : 1 molar ratio (ionic liquid : glucose) has been studied by neutron scattering, NMR and molecular dynamics simulations. Good agreement was found between simulated neutron scattering profiles generated for isotopically substituted liquid systems and those experimentally determined as well as between simulated and experimental diffusion coefficients obtained by Pulsed Field Gradient NMR spectroscopy. The overriding glucose-ionic liquid interactions in the liquid are hydrogen-bonding between acetate oxygens and sugar hydroxyl groups. The ionic liquid cation was found to play only a minor role in the solvation of the sugar and does not participate in hydrogen-bonding with the sugar to any significant degree. NOESY experiments lend further evidence that there is no direct interaction between sugar hydroxyl groups and acidic hydrogens on the ionic liquid cation.

PRELIMINARY STUDIES OF RADIATION COUPLING BETWEEN REMOTE SOFT-X-RAY LASER-AMPLIFIERS

Coupling of a soft X-ray laser beam with a relaying concave mirror in a sequentially pumped amplifier geometry using the Ne-like Ge system has been studied experimentally. Preliminary observations indicate an increase in the spatial coherence of the amplified relayed beam. In addition, near-field imaging of one of the amplifier plasmas shows a double-lobed intensity pattern of the emergent beam indicating refractive guiding of the amplified beam with components both normal and tangential to the target surface.

A computational model of cellular response to modulated radiation fields

Purpose:<br/>To develop a model to describe the response of cell populations to spatially modulated radiation exposures of relevance to advanced radiotherapies.<br/><br/>Materials and Methods:<br/>A Monte Carlo model of cellular radiation response was developed. This model incorporated damage from both direct radiation and intercellular communication including bystander signaling. The predictions of this model were compared to previously measured survival curves for a normal human fibroblast line (AGO1522) and prostate tumor cells (DU145) exposed to spatially modulated fields.<br/><br/>Results:<br/>The model was found to be able to accurately reproduce cell survival both in populations which were directly exposed to radiation and those which were outside the primary treatment field. The model predicts that the bystander effect makes a significant contribution to cell killing even in uniformly irradiated cells. The bystander effect contribution varies strongly with dose, falling from a high of 80% at low doses to 25% and 50% at 4 Gy for AGO1522 and DU145 cells, respectively. This was verified using the inducible nitric oxide synthase inhibitor aminoguanidine to inhibit the bystander effect in cells exposed to different doses, which showed significantly larger reductions in cell killing at lower doses.<br/><br/>Conclusions:<br/>The model presented in this work accurately reproduces cell survival following modulated radiation exposures, both in and out of the primary treatment field, by incorporating a bystander component. In addition, the model suggests that the bystander effect is responsible for a significant portion of cell killing in uniformly irradiated cells, 50% and 70% at doses of 2 Gy in AGO1522 and DU145 cells, respectively. This description is a significant departure from accepted radiobiological models and may have a significant impact on optimization of treatment planning approaches if proven to be applicable in vivo.

A review of studies of ionizing radiation-induced double-strand break clustering

Underpinning current models of the mechanisms of the action of radiation is a central role for DNA damage and in particular double-strand breaks (DSBs). For radiations of different LET, there is a need to know the exact yields and distributions of DSBs in human cells. Most measurements of DSB yields within cells now rely on pulsed-field gel electrophoresis as the technique of choice. Previous measurements of DSB yields have suggested that the yields are remarkably similar for different types of radiation with RBE values less than or equal to1.0. More recent studies in mammalian cells, however, have suggested that both the yield and the spatial distribution of DSBs are influenced by radiation quality. RBE values for DSBs induced by high-LET radiations are greater than 1.0, and the distributions are nonrandom. Underlying this is the interaction of particle tracks with the higher-order chromosomal structures within cell nuclei. Further studies are needed to relate nonrandom distributions of DSBs to their rejoining kinetics. At the molecular level, we need to determine the involvement of clustering of damaged bases with strand breakage, and the relationship between higher-order clustering over sizes of kilobase pairs and above to localized clustering at the DNA level. Overall, these studies will allow us to elucidate whether the nonrandom distributions of breaks produced by high-LET particle tracks have any consequences for their repair and biological effectiveness. (C) 2001 by Radiation Research Society.

A Monte Carlo model of DNA double-strand break clustering and rejoining kinetics for the analysis of pulsed-field gel electrophoresis data

In studies of radiation-induced DNA fragmentation and repair, analytical models may provide rapid and easy-to-use methods to test simple hypotheses regarding the breakage and rejoining mechanisms involved. The random breakage model, according to which lesions are distributed uniformly and independently of each other along the DNA, has been the model most used to describe spatial distribution of radiation-induced DNA damage. Recently several mechanistic approaches have been proposed that model clustered damage to DNA. In general, such approaches focus on the study of initial radiation-induced DNA damage and repair, without considering the effects of additional (unwanted and unavoidable) fragmentation that may take place during the experimental procedures. While most approaches, including measurement of total DNA mass below a specified value, allow for the occurrence of background experimental damage by means of simple subtractive procedures, a more detailed analysis of DNA fragmentation necessitates a more accurate treatment. We have developed a new, relatively simple model of DNA breakage and the resulting rejoining kinetics of broken fragments. Initial radiation-induced DNA damage is simulated using a clustered breakage approach, with three free parameters: the number of independently located clusters, each containing several DNA double-strand breaks (DSBs), the average number of DSBs within a cluster (multiplicity of the cluster), and the maximum allowed radius within which DSBs belonging to the same cluster are distributed. Random breakage is simulated as a special case of the DSB clustering procedure. When the model is applied to the analysis of DNA fragmentation as measured with pulsed-field gel electrophoresis (PFGE), the hypothesis that DSBs in proximity rejoin at a different rate from that of sparse isolated breaks can be tested, since the kinetics of rejoining of fragments of varying size may be followed by means of computer simulations. The problem of how to account for background damage from experimental handling is also carefully considered. We have shown that the conventional procedure of subtracting the background damage from the experimental data may lead to erroneous conclusions during the analysis of both initial fragmentation and DSB rejoining. Despite its relative simplicity, the method presented allows both the quantitative and qualitative description of radiation-induced DNA fragmentation and subsequent rejoining of double-stranded DNA fragments. (C) 2004 by Radiation Research Society.

Evidence for complexity at the nanometer scale of radiation-induced DNA DSBs as a determinant of rejoining kinetics

The rejoining kinetics of double-stranded DNA fragments, along with measurements of residual damage after postirradiation incubation, are often used as indicators of the biological relevance of the damage induced by ionizing radiation of different qualities. Although it is widely accepted that high-LET radiation-induced double-strand breaks (DSBs) tend to rejoin with kinetics slower than low-LET radiation-induced DSBs, possibly due to the complexity of the DSB itself, the nature of a slowly rejoining DSB-containing DNA lesion remains unknown. Using an approach that combines pulsed-field gel electrophoresis (PFGE) of fragmented DNA from human skin fibroblasts and a recently developed Monte Carlo simulation of radiation-induced DNA breakage and rejoining kinetics, we have tested the role of DSB-containing DNA lesions in the 8-kbp-5.7-Mbp fragment size range in determining the DSB rejoining kinetics. It is found that with low-LET X rays or high LET alpha particles, DSB rejoining kinetics data obtained with PFGE can be computer-simulated assuming that DSB rejoining kinetics does not depend on spacing of breaks along the chromosomes. After analysis of DNA fragmentation profiles, the rejoining kinetics of X-ray-induced DSBs could be fitted by two components: a fast component with a half-life of 0.9 +/- 0.5 h and a slow component with a half-life of 16 +/- 9 h. For a particles, a fast component with a half-life of 0.7 +/- 0.4 h and a slow component with a half-life of 12 5 h along with a residual fraction of unrepaired breaks accounting for 8% of the initial damage were observed. In summary, it is shown that genomic proximity of breaks along a chromosome does not determine the rejoining kinetics, so the slowly rejoining breaks induced with higher frequencies after exposure to high-LET radiation (0.37 +/- 0.12) relative to low-LET radiation (0.22 +/- 0.07) can be explained on the basis of lesion complexity at the nanometer scale, known as locally multiply damaged sites. (c) 2005 by Radiation Research Society.

Relative biological effectiveness (RBE) and out-of-field cell survival responses to passive scattering and pencil beam scanning proton beam deliveries

<p>The relative biological effectiveness (RBE) of passive scattered (PS) and pencil beam scanned (PBS) proton beam delivery techniques for uniform beam configurations was determined by clonogenic survival. The radiobiological impact of modulated beam configurations on cell survival occurring in- or out-of-field for both delivery techniques was determined with intercellular communication intact or physically inhibited. Cell survival responses were compared to those observed using a 6 MV photon beam produced with a linear accelerator. DU-145 cells showed no significant difference in survival response to proton beams delivered by PS and PBS or 6 MV photons taking into account a RBE of 1.1 for protons at the centre of the spread out Bragg peak. Significant out-of-field effects similar to those observed for 6 MV photons were observed for both PS and PBS proton deliveries with cell survival decreasing to 50-60% survival for scattered doses of 0.05 and 0.03 Gy for passive scattered and pencil beam scanned beams respectively. The observed out-of-field responses were shown to be dependent on intercellular communication between the in-and out-of-field cell populations. These data demonstrate, for the first time, a similar RBE between passive and actively scanned proton beams and confirm that out-of-field effects may be important determinants of cell survival following exposure to modulated photon and proton fields</p>

A Kinetic-Based Model of Radiation-Induced Intercellular Signalling

It is now widely accepted that intercellular communication can cause significant variations in cellular responses to genotoxic stress. The radiation-induced bystander effect is a prime example of this effect, where cells shielded from radiation exposure see a significant reduction in survival when cultured with irradiated cells. However, there is a lack of robust, quantitative models of this effect which are widely applicable. In this work, we present a novel mathematical model of radiation-induced intercellular signalling which incorporates signal production and response kinetics together with the effects of direct irradiation, and test it against published data sets, including modulated field exposures. This model suggests that these so-called "bystander" effects play a significant role in determining cellular survival, even in directly irradiated populations, meaning that the inclusion of intercellular communication may be essential to produce robust models of radio-biological outcomes in clinically relevant in vivo situations.

Metamaterial as a controllable template for nanoscale field localization

<p>We report that subwavelength localization of light in the near-field of a double-periodic photonic metamaterial may be efficiently controlled by the polarization and wavelength of the incident radiation. A dramatic variation in the periodic near-field landscapes, including a transition from a pattern of isolated subwavelength plasmon hot-spots to a blurred, low contrast pattern, accompanied by a change in the pattern's symmetry has been observed in the proximity of an aluminum nanowire "fish-scale" nanostructure. Hot-spots as small as 0.23 lambda have been achieved and their position has been controlled by tuning the wavelength of incident light across the dipole absorption resonance of the metamaterial. A simple switch of the polarization state can lead to a spatial period doubling in the landscape pattern.</p>

A Neutron Diffraction and Molecular Dynamics Investigation of Acetate-based Ionic Liquids as Solvents for Glucose

<p>The liquid state structure of the ionic liquid, 1-ethyl-3-methylimidazolium acetate, and the solute/solvent structure of glucose dissolved in the ionic liquid at a 1: 6 molar ratio have been investigated at 323 K by molecular dynamics simulations and neutron diffraction experiments using H/D isotopically substituted materials. Interactions between hydrogen-bond donating cation sites and polar, directional hydrogen-bond accepting acetate anions are examined. Ion-ion radial distribution functions for the neat ionic liquid, calculated from both MD and derived from the empirical potential structure refinement model to the experimental data, show the alternating shell-structure of anions around the cation, as anticipated. Spatial probability distributions reveal the main anion-to-cation features as in-plane interactions of anions with imidazolium ring hydrogens and cation-cation planar stacking. Interestingly, the presence of the polarised hydrogen-bond acceptor anion leads to increased anion-anion tail-tail structuring within each anion shell, indicating the onset of hydrophobic regions within the anion regions of the liquid.</p>

Investigating the influence of respiratory motion on the radiation induced bystander effect in modulated radiotherapy

Respiratory motion introduces complex spatio-temporal variations in the dosimetry of radiotherapy and may contribute towards uncertainties in radiotherapy planning. This study investigates the potential radiobiological implications occurring due to tumour motion in areas of geometric miss in lung cancer radiotherapy. A bespoke phantom and motor-driven platform to replicate respiratory motion and study the consequences on tumour cell survival in vitro was constructed. Human non-small-cell lung cancer cell lines H460 and H1299 were irradiated in modulated radiotherapy configurations in the presence and absence of respiratory motion. Clonogenic survival was calculated for irradiated and shielded regions. Direction of motion, replication of dosimetry by multi-leaf collimator (MLC) manipulation and oscillating lead shielding were investigated to confirm differences in cell survival. Respiratory motion was shown to significantly increase survival for out-of-field regions for H460/H1299 cell lines when compared with static irradiation (p &lt;0.001). Significantly higher survival was found in the in-field region for the H460 cell line (p &lt;0.030). Oscillating lead shielding also produced these significant differences. Respiratory motion and oscillatory delivery of radiation dose to human tumour cells has a significant impact on in- and out-of-field survival in the presence of non-uniform irradiation in this in vitro set-up. This may have important radiobiological consequences for modulated radiotherapy in lung cancer. 

Directional modulation transmitter radiation pattern considerations

<p>A pattern synthesis approach is applied to a directional modulation (DM) system. A systematic synthesis procedure is suggested which ensures optimal constellation patterns production along pre-specified communication directions, whereas simultaneously conserving energy dispersal in other directions. In this study, the properties of DM systems synthesised from Gaussian magnitude far-field radiation pattern templates are used to illustrate performance benefits with regards to DM bit error rate response compared with those achieved by a conventional steered array.</p>

Non-targeted effects of ionising radiation-Implications for low dose risk

<p>Non-DNA targeted effects of ionising radiation, which include genomic instability, and a variety of bystander effects including abscopal effects and bystander mediated adaptive response, have raised concerns about the magnitude of low-dose radiation risk. Genomic instability, bystander effects and adaptive responses are powered by fundamental, but not clearly understood systems that maintain tissue homeostasis. Despite excellent research in this field by various groups, there are still gaps in our understandfng of the likely mechanisms associated with non-DNA targeted effects, particularly with respect to systemic (human health) consequences at low and intermediate doses of ionising radiation. Other outstanding questions include links between the different non-targeted responses and the variations. in response observed between individuals and cell lines, possibly a function of genetic background. Furthermore, it is still not known what the initial target and early interactions in cells are that give rise to non-targeted responses in neighbouring or descendant cells. This paper provides a commentary on the current state of the field as a result of the non-targeted effects of ionising radiation (NOTE) Integrated Project funded by the European Union. Here we critically examine the evidence for non-targeted effects, discuss apparently contradictory results and consider implications for low-dose radiation health effects. (C) 2012 Elsevier B.V. All rights reserved.</p>

Directional Modulation Far-field Pattern Separation Synthesis Approach

In this study, a far-field power pattern separation approach is proposed for the synthesis of directional modulation (DM) transmitter arrays. Separation into information patterns and interference patterns is enabled by far-field pattern null steering. Compared with other DM synthesis methods, for example, bit error rate-driven DM optimisation and orthogonal vector injection, the approach developed in this study facilitates manipulation of artificial interference spatial distributions. With such capability more interference power can be projected into those spatial directions most vulnerable to eavesdropping, that is, the information side lobes. In such a fashion, information leaked through radiation side lobes can be effectively mitigated in a transmitter power efficient manner. Furthermore, for the first time, the authors demonstrate how multi-beam DM transmitters can be synthesised via this approach.