Purpose A novel Megavoltage (MV) multi-layer imager (MLI) design featuring higher detective quantum efficiency and lower noise than current conventional MV imagers in clinical use has been recently reported. Optimization of the MLI design for multiple applications including tumor tracking, MV-CBCT and portal dosimetry requires a computational model that will provide insight into the physics processes that affect the overall and individual components’ performance. The purpose of the current work was to develop and validate a comprehensive computational model that can be used for MLI optimization. Methods The MLI model was built using the Geant4 Application for Tomographic Emission (GATE) application. The model includes x-ray and charged particle interactions as well as the optical transfer within the phosphor. A first prototype MLI device featuring a stack of four detection layers was used for model validation. Each layer of the prototype contains a copper buildup sheet, a phosphor screen and photodiode array. The model was validated against measured data of Modulation Transfer Function (MTF), Noise Power Spectrum (NPS) and Detective Quantum Efficiency (DQE). MTF was computed using a slanted slit with 2.3° angle and 0.1 mm width. NPS was obtained using the autocorrelation function technique. DQE was calculated from MTF and NPS data. The comparison metrics between simulated and measured data were the Pearson’s correlation coefficient (r) and the normalized root-mean-square error (NRMSE). Results Good agreement between measured and simulated MTF and NPS values was observed. Pearson’s correlation coefficient for the combined signal from all layers of the MLI was equal to 0.9991 for MTF and 0.9992 for NPS; NRMSE was 0.0121 for MTF and 0.0194 for NPS. Similarly, the DQE correlation coefficient for the combined signal was 0.9888 and the NRMSE was 0.0686. Conclusions A comprehensive model of the novel MLI design was developed using the GATE toolkit and validated against measured MTF, NPS and DQE data acquired with a prototype device featuring four layers. This model will be used for further optimization of the imager components and configuration for clinical radiotherapy applications.
Selection of pixel size and thickness depends on the imaging application and photon energy utilized. For systems that integrate two nuclear imaging modalities (i.e., combined SPECT/PET), the pixel size should offer an appropriate balance of the effects that take place in the detector, based on the results of the current work. This allows for a system to be designed with the same detector material and the same geometrical configuration for both modalities.
Radiation therapy is widely used to treat human malignancies, but many tumor types, including gliomas, exhibit significant radioresistance. Radiation therapy creates DNA double-strand breaks (DSBs), and DSB repair is linked to rapid changes in epigenetic modifications, including increased histone methylation. This increased histone methylation recruits DNA repair proteins which can then alter the local chromatin structure and promote repair. Consequently, combining inhibitors of specific histone methyltransferases with radiation therapy may increase tumor radiosensitivity, particularly in tumors with significant therapeutic resistance. Here, we demonstrate that inhibitors of the H4K20 methyltransferase SETD8 (UNC-0379) and the H3K9 methyltransferase G9a (BIX-01294) are effective radiosensitizers of human glioma cells. UNC-0379 blocked H4K20 methylation and reduced recruitment of the 53BP1 protein to DSBs, although this loss of 53BP1 caused only limited changes in radiosensitivity. In contrast, loss of H3K9 methylation through G9a inhibition with BIX-01294 increased radiosensitivity of a panel of glioma cells (SER2Gy range: 1.5 - 2.9). Further, loss of H3K9 methylation reduced DSB signaling dependent on H3K9, including reduced activation of the Tip60 acetyltransferase, loss of ATM signaling and reduced phosphorylation of the KAP-1 repressor. In addition, BIX-0194 inhibited DSB repair through both the homologous recombination and nonhomologous end-joining pathways. Inhibition of G9a and loss of H3K9 methylation is therefore an effective approach for increasing radiosensitivity of glioma cells. These results suggest that combining inhibitors of histone methyltransferases which are critical for DSB repair with radiation therapy may provide a new therapeutic route for sensitizing gliomas and other tumors to radiation therapy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.