ABSTRACT
PURPOSE: In this work, we develop a methodology for using Fricke gel dosimeters for dose distribution measurements surrounding high-density implants which circumvents artifact production by removing the obstruction during imaging. METHODS: Custom 3D printed molds were used to set cavities in Fricke gel phantoms to allow for the suspension of high-density implants in different geometries. This allowed for the metal valve extracted from a temporary tissue expander to be suspended during irradiation, and removed during optical-CT scanning. RESULTS: The removal of the metal implant and subsequent backfilling of the remaining cavity with optically matched fluid prior to dose evaluation enables accurate optical-CT scanning of the gel dosimeters. Results have shown very good agreement between measured and calculated doses within 2 mm from the surface of the implant. Slight deviations are present within 1 mm of the interface. CONCLUSIONS: Artifacts in the form of radial streaking, cold spots, and hot spots were all reduced using this technique, enabling the broader and more accurate use of optical-CT for the imaging of gels containing opaque objects.
Subject(s)
Prostheses and Implants , Radiation Dosimeters , Artifacts , Gels , Optical Phenomena , Phantoms, Imaging , Printing, Three-Dimensional , Tomography, X-Ray ComputedABSTRACT
Isoindoline nitroxides are potentially useful probes for viable biological systems, exhibiting low cytotoxicity, moderate rates of biological reduction and favorable Electron Paramagnetic Resonance (EPR) characteristics. We have evaluated the anionic (5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl; CTMIO), cationic (5-(N,N,N-trimethylammonio)-1,1,3,3-tetramethylisoindolin-2-yloxyl iodide, QATMIO) and neutral (1,1,3,3-tetramethylisoindolin-2-yloxyl; TMIO) nitroxides and their isotopically labeled analogs ((2)H(12)- and/or (2)H(12)-(15)N-labeled) as potential EPR oximetry probes. An active ester analogue of CTMIO, designed to localize intracellularly, and the azaphenalene nitroxide 1,1,3,3-tetramethyl-2,3-dihydro-2-azaphenalen-2-yloxyl (TMAO) were also studied. While the EPR spectra of the unlabeled nitroxides exhibit high sensitivity to O(2) concentration, deuteration resulted in a loss of superhyperfine features and a subsequent reduction in O(2) sensitivity. Labeling the nitroxides with (15)N increased the signal intensity and this may be useful in decreasing the detection limits for in vivo measurements. The active ester nitroxide showed approximately 6% intracellular localization and low cytotoxicity. The EPR spectra of TMAO nitroxide indicated an increased rigidity in the nitroxide ring, due to dibenzo-annulation.
Subject(s)
Cyclic N-Oxides/chemistry , Electron Spin Resonance Spectroscopy/methods , Isoindoles/chemistry , Oximetry/methods , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , CHO Cells , Chromatography, Thin Layer , Clone Cells , Cricetinae , Cricetulus , Deuterium , Indicators and Reagents , Indoles , Isotope Labeling , Methylamines , Nitrogen Oxides/chemistry , Nitrogen Radioisotopes , Oxygen/chemistry , Oxygen Consumption/drug effects , Trypan BlueABSTRACT
Mutations in the ATM gene (mutated in ataxia telangiectasia) in both humans and mice predispose to lymphoid tumors. A defect in this gene also causes neurodegeneration in humans and a less severe neurological phenotype in mice. There is some evidence that oxidative stress contributes to these defects, suggesting that antioxidants could alleviate the phenotype. We demonstrate here that the antioxidant 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO) dramatically delays the onset of thymic lymphomas in Atm(-/-) mice which is not due to an enhancement of apoptosis by CTMIO. We also show that this compound corrects neurobehavioral deficits in these mice and reduces oxidative damage to Purkinje cells. The likely mechanism of action of CTMIO is due to a reduction in oxidative stress, which is protective against both the tumor progression and the development of neurological abnormalities. These data suggest that antioxidant therapy has considerable potential in the management of ataxia telangiectasia and possibly other neurodegenerative disorders where oxidative stress is implicated.
Subject(s)
Antioxidants/therapeutic use , Ataxia Telangiectasia/genetics , Behavior, Animal/drug effects , Cell Cycle Proteins/genetics , DNA-Binding Proteins/genetics , Indoles/therapeutic use , Lymphoma/genetics , Mutation , Protein Serine-Threonine Kinases/genetics , Tumor Suppressor Proteins/genetics , Animals , Apoptosis , Ataxia Telangiectasia Mutated Proteins , Cell Line, Tumor , DNA-Binding Proteins/deficiency , Disease Models, Animal , Genotype , Humans , Lymphoma/prevention & control , Mice , Mice, Knockout , Mice, Mutant Strains , Motor Activity/drug effects , Polymerase Chain Reaction , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Protein Serine-Threonine Kinases/deficiency , Tumor Suppressor Proteins/deficiencyABSTRACT
Three water-soluble carboxy nitroxide antioxidants, 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl, 4-carboxy-2,2,6,6-tetramethylpiperidin-1-yloxyl, and 3-carboxy-2,2,5,5-tetramethylpyrrolidin-1-yloxyl, show significant impact on the postirradiation survival rates of ataxia telangiectasia (A-T) cells compared to normal cells, an assay which represents a model for understanding the impact of ROS damage on the A-T phenotype. The effects of these antioxidants are much more significant than those of vitamin E or Trolox (a water-soluble vitamin E analog), studied using the same cell survival model.
