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c-Met inhibitor SU11274 enhances the response of the prostate cancer cell line DU145 to ionizing radiation

Highlights: Black-Right-Pointing-Pointer c-Met inhibition could significantly enhance the radiosensitivity of DU145 cells. Black-Right-Pointing-Pointer The mechanisms of the radiosensitization effect of c-Met inhibition on DU145 cells were also presented in this paper. Black-Right-Pointing-Pointer This is the first study demonstrating the effectiveness of c-Met inhibition on treating HRPC cells with radiotherapy. -- Abstract: Hormone-refractory prostate cancer shows substantial resistance to most conventional therapies including radiotherapy, constitutes a key impediment to curing patients with the disease. c-Met overexpression plays a key role in prostate cancer tumorigenesis and disease progression. Here, we demonstrate that c-Met inhibition by SU11274 could significantly suppress cell survival and proliferation as well as enhance the radiosensitivity of DU145 cells. The underlying mechanisms of the effects of SU11274 on DU145 cells may include the inhibition of c-Met signaling, depolarization of the mitochondrial membrane potential, impairment of DNA repair function, abrogation of cell cycle arrest, and enhancement of cell death. Our study is the first to show the effectiveness of combining c-Met inhibition with ionizing radiation to cure hormone-refractory prostate cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Modeling of free electronic state density in hydrogenic plasmas based on nearest neighbor approximation

Most conventional atomic models in a plasma do not treat the effect of the plasma on the free-electron state density. Using a nearest neighbor approximation, the state densities in hydrogenic plasmas for both bound and free electrons were evaluated and the effect of the plasma on the atomic model (especially for the state density of the free electron) was studied. The model evaluates the electron-state densities using the potential distribution formed by the superposition of the Coulomb potentials of two ions. The potential from one ion perturbs the electronic state density on the other. Using this new model, one can evaluate the free-state density without making any ad-hoc assumptions. The resulting contours of the average ionization degree, given as a function of the plasma temperature and density, are shifted slightly to lower temperatures because of the effect of the increasing free-state density.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

THE STELLAR AND GAS KINEMATICS OF THE LITTLE THINGS DWARF IRREGULAR GALAXY NGC 1569

In order to understand the formation and evolution of Magellanic-type dwarf irregular (dIm) galaxies, one needs to understand their three-dimensional structure. We present measurements of the stellar velocity dispersion in NGC 1569, a nearby post-starburst dIm galaxy. The stellar vertical velocity dispersion, {sigma}{sub z}, coupled with the maximum rotational velocity derived from H I observations, V{sub max}, gives a measure of how kinematically hot the galaxy is, and, therefore, indicates its structure. We conclude that the stars in NGC 1569 are in a thick disk with a V{sub max}/{sigma}{sub z} = 2.4 {+-} 0.7. In addition to the structure, we analyze the ionized gas kinematics from O III observations along the morphological major axis. These data show evidence for outflow from the inner starburst region and a potential expanding shell near supermassive star cluster (SSC) A. When compared to the stellar kinematics, the velocity dispersion of the stars increases in the region of SSC A supporting the hypothesis of an expanding shell. The stellar kinematics closely follow the motion of the gas. Analysis of high-resolution H I data clearly reveals the presence of an H I cloud that appears to be impacting the eastern edge of NGC 1569. Also, an ultra-dense H I cloud can be seen extending to the west of the impacting H I cloud. This dense cloud is likely the remains of a dense H I bridge that extended through what is now the central starburst area. The impacting H I cloud was the catalyst for the starburst, thus turning the dense gas into stars over a short timescale, {approx}1 Gyr. We performed a careful study of the spectral energy distribution using infrared, optical, and ultraviolet photometry, producing a state-of-the-art mass model for the stellar disk. This mass modeling shows that stars dominate the gravitational potential in the inner 1 kpc. The dynamical mass of NGC 1569, derived from V{sub max}, shows that the disk may be dark matter deficient in the inner region, although, when compared to the expected virial mass determined from halo abundance matching techniques, the dark matter profile seems to agree with the observed mass profile at a radius of 2.2 kpc.

79 ASTRONOMY AND ASTROPHYSICS↗

Depolarizing collisions with hydrogen: Neutral and singly ionized alkaline earths

Depolarizing collisions are elastic or quasielastic collisions that equalize the populations and destroy the coherence between the magnetic sublevels of atomic levels. In astrophysical plasmas, the main depolarizing collider is neutral hydrogen. We consider depolarizing rates on the lowest levels of neutral and singly ionized alkali earths Mg I, Sr I, Ba I, Mg II, Ca II, and Ba II, due to collisions with H°. We compute ab initio potential curves of the atom-H° system and solve the quantum mechanical dynamics. From the scattering amplitudes, we calculate the depolarizing rates for Maxwellian distributions of colliders at temperatures T ≤ 10,000 K. A comparative analysis of our results and previous calculations in the literature is completed. We discuss the effect of these rates on the formation of scattering polarization patterns of resonant lines of alkali earths in the solar atmosphere, and their effect on Hanle effect diagnostics of solar magnetic fields.

79 ASTRONOMY AND ASTROPHYSICS↗

Low transverse emittance electron bunches from two-color laser-ionization injection

A method is proposed to generate low emittance electron bunches from two color laser pulses in a laser-plasma accelerator. A two-region gas structure is used, containing a short region of a high-Z gas (e.g., krypton) for ionization injection, followed by a longer region of a low-Z gas for post-acceleration. A long-laser-wavelength (e.g., 5 μm) pump pulse excites plasma wake without triggering the inner-shell electron ionization of the high-Z gas due to low electric fields. A short-laser-wavelength (e.g., 0.4 μm) injection pulse, located at a trapping phase of the wake, ionizes the inner-shell electrons of the high-Z gas, resulting in ionization-induced trapping. Compared with a single-pulse ionization injection, this scheme offers an order of magnitude smaller residual transverse momentum of the electron bunch, which is a result of the smaller vector potential amplitude of the injection pulse. © 2013 SPIE.

47 OTHER INSTRUMENTATION↗

TH-C-17A-04: Shining Light On the Implementation of Cherenkov Emission in Radiation Therapy

Purpose: We hypothesize that Cherenkov emission (CE) by radiotherapy beams is correlated with radiation dose, CE detection can be maximized by a spectral shift towards the near-infrared (NIR) window of biological tissue, and in certain tissue types (ex. breast/oropharynx), it could prove superior to mega-voltage (MV) imaging. Therefore, we compare CE imaging to onboard MV imaging. Methods: Dose-CE correlation was investigated via simulation and experiment. A Monte Carlo (MC) CE simulator was designed using Geant4. Experimental phantoms include: water; tissuesimulating phantom composed of water, fat emulsion, and beef blood; plastic phantom with solid water insert. The optical spectrometry system consisted of a multi-mode optical fiber and diffraction-grating spectrometer incorporating a front/back-illuminated charge-coupled device (CCD). CdSe/ZnS quantum dots (QDs), emitting at (650±10) nm, were used to achieve NIR shift of the CE signal. CE and MV images were acquired with a complementary metal-oxide-semiconductor (CMOS) camera and an electronic portal imaging device (EPID), respectively. Results: MC and experimental studies indicate a strong linear correlation between radiation dose and CE (Pearson coefficient > 0.99). CE by an 18 MeV beam was effectively shifted towards the NIR in water and in a tissue-simulating phantom, exhibiting a 50% increase at 650 nm for QD depths of ∼3 mm. CE images exhibited relative contrast superior to EPID images by a factor of 30. Conclusion: Our work supports the potential for application of CE in radiotherapy online imaging for patient setup and treatment verification, since CE is intrinsic to the beam and non-ionizing, and QDs can be used to improve CE detectability, yielding image quality superior to MV imaging for the case of low density variability, low optical attenuation materials, such as breast or oropharyngeal cavities. Ongoing work involves microenvironment functionalization of QDs and application of multichannel spectrometry for simultaneous acquisition of dosimetric and tumor oxygenation signals. Funding received from the following organizations: Natural Sciences and Engineering Research Council of Canada, McGill University. YZ acknowledges partial support by the CREATE Medical Physics Research Training Network grant of the Natural Sciences and Engineering Research Council (Grant number: 432290)

07 ISOTOPE AND RADIATION SOURCES↗

Inference of Causal Networks from Time-Varying Transcriptome Data via Sparse Coding

Temporal analysis of genome-wide data can provide insights into the underlying mechanism of the biological processes in two ways. First, grouping the temporal data provides a richer, more robust representation of the underlying processes that are co-regulated. The net result is a significant dimensional reduction of the genome-wide array data into a smaller set of vocabularies for bioinformatics analysis. Second, the computed set of time-course vocabularies can be interrogated for a potential causal network that can shed light on the underlying interactions. The method is coupled with an experiment for investigating responses to high doses of ionizing radiation with and without a small priming dose. From a computational perspective, inference of a causal network can rapidly become computationally intractable with the increasing number of variables. Additionally, from a bioinformatics perspective, larger networks always hinder interpretation. Therefore, our method focuses on inferring the simplest network that is computationally tractable and interpretable. The method first reduces the number of temporal variables through consensus clustering to reveal a small set of temporal templates. It then enforces simplicity in the network configuration through the sparsity constraint, which is further regularized by requiring continuity between consecutive time points. We present intermediate results for each computational step, and apply our method to a time-course transcriptome dataset for a cell line receiving a challenge dose of ionizing radiation with and without a prior priming dose. Our analyses indicate that (i) the priming dose increases the diversity of the computed templates (e.g., diversity of transcriptome signatures); thus, increasing the network complexity; (ii) as a result of the priming dose, there are a number of unique templates with delayed and oscillatory profiles; and (iii) radiation-induced stress responses are enriched through pathway and subnetwork studies.

59 BASIC BIOLOGICAL SCIENCES↗

The Determination of Radiation Hardness of Semiconductor Materials and Devices with Ion Beams

lon accelerator based techniques provide unique tools to gain insight into the phenomena underlying the formation of defects induced by energetic particles in semiconductor materials and their effects on the electronic features of the device. In recognition of the potential of these techniques, with the aim of enhancing the understanding of the mechanisms underlying the degradation of the performances of semiconductor devices induced by ionizing radiation, the IAEA established a Research Project, coordinated by the Physics Section (CRP F11016) entitled "Utilization of ion accelerators for studying and modelling of radiation induced defects in semiconductors and insulators" at the end of 2011. The objective of this IAEA Coordinated Research Project (CRP) was to enhance the capabilities of the interested Member States by facilitating their collective efforts to use accelerator-based ion irradiation of electronic materials in conjunction with available advanced characterization techniques to gain a deeper understanding of how different types of radiation influences the electronic properties of materials and devices, leading to an improved radiation hardness. A dynamic and productive research was stimulated by this CRP among collaborating partners, resulting in publications in scientific journals [CRP2016], educational and scientific software packages [W8, Forneris2014], and a number of collaborations among the participating research groups. Two of the most significant outcomes of this project are i) the experimental protocol, which rationalizes the use of the many existing characterization techniques adopted to investigate radiation effects in semiconductor devices and ii) the relevant theoretical approach to interpret the experimental data [Vittone2016 and references therein]. This publication integrates output of research articles published by the partners of the CRP and is aimed to provide an exhaustive description of the experimental protocol, the theoretical model with the relevant limits of application, the data analysis procedure, and the physical observables which can be effectively measured and which can be used for assessment of the radiation hardness of semiconductor devices. The intended audience of this report includes all those professionals and technologists working in ion beam functional analysis of semiconductor materials, solid-state physicists and engineers involved in the design of electronic devices working in radiation harsh environments.

36 MATERIALS SCIENCE↗

All-aluminum optical system for a large cryogenically cooled far infrared echelle spectrometer

In the past few years, NASA's Kuiper Airborne Observatory (KAO) has made it possible to conduct pioneering observations of far infrared lines from astronomical sources. Such observations, in the case of wavelengths in the approximate range from 20 to 350 microns, cannot be performed from ground-based sites, because of telluric water absorption effects. Lines in the considered range provide information about the interstellar gas in molecular, neutral atomic, and ionized form of occurrence. The present paper provides a description of the development of the cryogenic optical system of a spectrometer designed to exploit the potential of the KAO for observing the far infrared lines. Attention is given to design goals and considerations, details of optical design, the fabrication of the optical system, the cryostat, and performance.

Erickson, E. F.↗

Bremsstrahlung X-rays from Jovian auroral electrons

The spectrum of X-rays from the planet Jupiter is calculated according to an auroral electron beam model. The electrons are assumed to be accelerated by a field-aligned potential drop and penetrate into the atmosphere as a Maxwellian beam of primaries which are scattered, degraded in energy, and merged with a population of ionization secondaries having a power law energy distribution. The soft X-rays observed by the Einstein Observatory satellite are due to bremsstrahlung from the secondary electrons in the H2 atmosphere. The X-ray intensity is best reconciled with a beam of primaries having a characteristic energy 30-100 keV and penetrating the homopause with an auroral energy flux typically of 10-20 ergs/sq cm s but no greater than 50 ergs/sq cm s.

Barbosa, D. D.↗

Environmental interactions of the Space Station Freedom electric power system

The Space Station Freedom operates in a low earth orbit (LEO) environment. Such operation results in different potential interactions with the Space Station systems including the Electric Power System (EPS). These potential interactions result in environmental effects which include neutral species effects such as atomic oxygen erosion, effects of micrometeoroid and orbital debris impacts, plasma effects, ionizing radiation, and induced contamination degradation effects. The EPS design and its interactions with the LEO environment are briefly described and the results of analyses and testing programs planned and performed thus far to resolve environmental concerns related to the EPS and its function in LEO environment.

Nahra, Henry K.↗

Environmental interactions of the Space Station Freedom electric power system

The Space Station Freedom will be operating in the Low Earth Orbit (LEO) environment. LEO environment operation results in different potential interactions with the Space Station systems including the Electric Power Systems (EPS). These potential interactions result in environmental effects which include neutral species effects such as atomic oxygen erosion, effects of micrometeroid and orbital debris impacts, plasma effects, ionizing radiation effects, and induced contamination degradation effects. The EPS design and its interactions with the LEO environment are described. The results of analyses and testing programs planned and performed thus far to resolve the environmental concerns related to the EPS and its function in the LEO environment are discussed.

Nahra, Henry K.↗

Superconducting Accelerators for High-Power X-ray production

To date, linear accelerators (linacs) as electron sources used to produce ionizing radiation for industrial purposes have been limited to less than 100 kW. When the electron beam is used directly, this is sufficient for most potential applications. However, when the electron beam is used for the production of photons (x-rays) which are then to be used in an application, this is not sufficient to compete with other sources of photons (gamma rays from cobalt-60). This paper will discuss acompact superconducting RF (CSRF) accelerator system that relies on emerging technologies that will be able to produce electron beam powers into the 100s of kW with efficiencies much better than present linacs. The focus is to produce x-ray beams for medical device sterilization to provide alternatives for the present use of cobalt-60 for this purpose.

43 PARTICLE ACCELERATORS↗

Sheath transitions in a cylindrical filament discharge: Axisymmetric 1D3V PIC-MCC simulations

We present the first nonplanar hot cathode discharge simulations that capture the role of the trapped-ions plasma, elucidating new phenomena unobservable in planar geometric discharges. A discharge struck between a single emitting wire filament cathode and a bounding anode is simulated in cylindrical geometry using an axisymmetric (radial) particle-in-cell Monte-Carlo collisions code. Operating the discharge near its ionization energy threshold can lead to the formation of a two plasma mode (TPM). One plasma forms in the conventional upstream region through electron impact ionization of background neutrals. A second plasma, whose global effect on the discharge was not previously well understood, forms downstream through the trapping of cold ions in the potential well of the filament’s virtual cathode, a process enabled by ion-neutral charge exchange collisions. Three space charge regions intersperse the electrode gap—an emissive sheath between the cathode filament and trapped-ions plasma, a double layer between the two plasmas, and a classical sheath between the upstream plasma and the outer anode. Simulations exhibit mode transitions and quenching instabilities that transform the discharge between the TPM and other single-plasma sheath modes that include classical (temperature-limited), space charge limited, and inverse (anode glow) modes. The transitions are explained via “aid-and-compete” dynamics wherein the growth of one plasma enhances growth in the other while concurrently exhibiting expansion dynamics antagonistic to each other. The system exhibits strong hysteresis memory during the mode transitions. Improved understanding and control of these sheath mode transitions are expected to benefit plasma applications with hot cathodes.

Electrical hysteresis↗

Ultrafast isomerization in acetylene dication after carbon K-shell ionization

Ultrafast proton migration and isomerization are key processes for acetylene and its ions. However, the mechanism for ultrafast isomerization of acetylene [HCCH]2+ to vinylidene [H2CC]2+ dication remains nebulous. Theoretical studies show a large potential barrier ( > 2 eV) for isomerization on low-lying dicationic states, implying picosecond or longer isomerization timescales. However, a recent experiment at a femtosecond X-ray free-electron laser suggests sub-100 fs isomerization. Here we address this contradiction with a complete theoretical study of the dynamics of acetylene dication produced by Auger decay after X-ray photoionization of the carbon atom K shell. We find no sub-100 fs isomerization, while reproducing the salient features of the time-resolved Coulomb imaging experiment. This work resolves the seeming contradiction between experiment and theory and also calls for careful interpretation of structural information from the widely applied Coulomb momentum imaging method.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

WE-EF-207-11: Energy and Depth Response of Thermoluminescent Dosimeters and Ionization Chambers in Water for Kilovoltage X-Ray Beams

Purpose: To assess the effects of changes in beam quality on detector response in the kilovoltage energy range by modulating the x-ray tube voltage and the measurement depth in water. Methods: Measurements were performed with TLD-100 and TLD-100H thermoluminescent dosimeters and an A12 farmer-type ionization chamber. To assess the energy response of the detectors, irradiations were performed at a depth of 3 cm in a custom-built thin-window water phantom using the moderately filtered x-ray beams at the UWADCL (20 kVp-250 kVp) and a Co-60 beam.The x-ray beams and detectors were modeled using the EGSnrc Monte Carlo code. The model was validated by simulating dose to the collecting volume of an A12 farmer chamber and comparing it with measured A12 signal as a function of depth. Dose was tallied to each detector and to water for comparison with measurements. Simulations were used to calculate the predicted energy response, which was compared to the measured response of each detector. Dose to each detector and dose to water as a function of depth were also simulated. Results: Detector output per dose to water was found to deviate by up to 15%, 20% and 30% as a function of energy relative to Co-60 for the A12, TLD-100H and TLD-100, respectively. The EGSnrc simulations produced results similar to the measurements for ionization chambers, but discrepancies of up to 30% were observed for TLD-100H. Simulated detector response as a function of depth was found to vary by up to 3%. Conclusion: These results suggest that changes in beam quality in kilovoltage x-ray beams can have a significant impact on detector response. In-water detector response was found to differ from the previously investigated in-air response. Deviations in detector response as a function of depth were less significant, but could potentially cause dosimetric errors if ignored.

60 APPLIED LIFE SCIENCES↗

Detection of microcalcifications by characteristic magnetic susceptibility effects using MR phase image cross-correlation analysis

Purpose: To develop and evaluate a new method for detecting calcium deposits using their characteristic magnetic susceptibility effects on magnetic resonance (MR) images at high fields and demonstrate its potential in practice for detecting breast microcalcifications. Methods: Characteristic dipole signatures of calcium deposits were detected in magnetic resonance phase images by computing the cross-correlation between the acquired data and a library of templates containing simulated phase patterns of spherical deposits. The influence of signal-to-noise ratio and various other MR parameters on the results were assessed using simulations and validated experimentally. The method was tested experimentally for detection of calcium fragments within gel phantoms and calcium-like inhomogeneities within chicken tissue at 7 T with optimized MR acquisition parameters. The method was also evaluated for detection of simulated microcalcifications, modeled from biopsy samples of malignant breast cancer, inserted in silico into breast magnetic resonance imaging (MRIs) of healthy subjects at 7 T. For both assessments of calcium fragments in phantoms and biopsy-based simulated microcalcifications in breast MRIs, receiver operator characteristic curve analyses were performed to determine the cross-correlation index cutoff, for achieving optimal sensitivity and specificity, and the area under the curve (AUC), for measuring the method’s performance. Results: The method detected calcium fragments with sizes of 0.14–0.79 mm, 1 mm calcium-like deposits, and simulated microcalcifications with sizes of 0.4–1.0 mm in images with voxel sizes between (0.2 mm){sup 3} and (0.6 mm){sup 3}. In images acquired at 7 T with voxel sizes of (0.2 mm){sup 3}–(0.4 mm){sup 3}, calcium fragments (size 0.3–0.4 mm) were detected with a sensitivity, specificity, and AUC of 78%–90%, 51%–68%, and 0.77%–0.88%, respectively. In images acquired with a human 7 T scanner, acquisition times below 12 min, and voxel sizes of (0.4 mm){sup 3}–(0.6 mm){sup 3}, simulated microcalcifications with sizes of 0.6–1.0 mm were detected with a sensitivity, specificity, and AUC of 75%–87%, 54%–87%, and 0.76%–0.90%, respectively. However, different microcalcification shapes were indistinguishable. Conclusions: The new method is promising for detecting relatively large microcalcifications (i.e., 0.6–0.9 mm) within the breast at 7 T in reasonable times. Detection of smaller deposits at high field may be possible with higher spatial resolution, but such images require relatively long scan times. Although mammography can detect and distinguish the shape of smaller microcalcifications with superior sensitivity and specificity, this alternative method does not expose tissue to ionizing radiation, is not affected by breast density, and can be combined with other MRI methods (e.g., dynamic contrast-enhanced MRI and diffusion weighted MRI), to potentially improve diagnostic performance.

60 APPLIED LIFE SCIENCES↗

Raman scattering of photons by hydrogenlike ions I: A semirelativistic and nondipole approach

Going beyond the usual nonrelativistic treatments of Raman scattering of light by a ground-state electron in hydrogenic ions, we propose in this work a semirelativistic and nondipole approach in the case of inelastic process under the ionization threshold. This scheme is based, on the one hand, on the discrete semirelativistic Coulomb Sturmian basis sets, and on the other hand, on the direct Foldy–Wouthuysen interaction Hamiltonian derived recently from the Dirac equation with electromagnetic potentials (Hinschberger and Hervieux 2012) and confirmed by us to seventh order in powers of 1∕m. It includes the paramagnetic, the diamagnetic, the magnetic field–spin and the electric field–spin interactions. Moreover, the photon fields are expanded in electric and magnetic multipoles and nondipole effects are fully taken into account. On utilizing these ingredients, we build in detail the multipole expansion of the semirelativistic Raman scattering cross section when the photon energy is under the ionization threshold. For each type of the allowed multipole components, namely EE, MM and EM in the standard notations, suitable closed forms of total scattering cross sections are calculated for numerical computations. Such analytical expressions enable the evaluation of the contribution of each of these interaction operators and field multipoles in the scattering process.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗