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ABSTRACT: The intention of this review is to provide information about the rapidly evolving field of molecular imaging and its potential impact on the clinical practice of nuclear medicine. On completing this article the reader should be able to define molecular imaging, describe the ways in which molecular imaging can be used, identify some of the biologic processes that can be targeted with molecular imaging agents, and list the modalities that can be used for molecular imaging, along with the strengths and weaknesses of each.
Journal of Nuclear Medicine Technology 09/2009; 37(3):151-61.
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ABSTRACT: Silicon double-sided strip detectors offer outstanding instrinsic spatial resolution with reasonable detection efficiency for iodine-125 emissions. This spatial resolution allows for multiple-pinhole imaging at low magnification, minimizing the problem of multiplexing. We have conducted imaging studies using a prototype system that utilizes a detector of 300-micrometer thickness and 50-micrometer strip pitch together with a 23-pinhole collimator. These studies include an investigation of the synthetic-collimator imaging approach, which combines multiple-pinhole projections acquired at multiple magnifications to obtain tomographic reconstructions from limited-angle data using the ML-EM algorithm. Sub-millimeter spatial resolution was obtained, demonstrating the basic validity of this approach.
IEEE Transactions on Nuclear Science 06/2009; 56(3):646-652. · 1.45 Impact Factor
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ABSTRACT: This work presents characterization studies of thick silicon double-sided strip detectors for a high-resolution small-animal SPECT. The dimension of these detectors is 60.4 mm × 60.4 mm × 1 mm. There are 1024 strips on each side that give the coordinates of the photon interaction, with each strip processed by a separate ASIC channel. Our measurement shows that intrinsic spatial resolution equivalent to the 59 μm strip pitch is attainable. Good trigger uniformity can be achieved by proper setting of a 4-bit DAC in each ASIC channel to remove trigger threshold variations. This is particularly important for triggering at low energies. The thick silicon DSSD (Double-sided strip detector) shows high potential for small-animal SPECT.
IEEE Transactions on Nuclear Science 06/2009; 56(3):557-564. · 1.45 Impact Factor
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ABSTRACT: The limitations on the sensitivity for detecting small changes in MRI, CT, and ultrasound pulse-echo images are used to estimate the practical requirements for molecular imaging and targeted contrast enhancement for these modalities. These types of imaging are highly unlikely to approach the sensitivity for detecting molecular processes of radionuclear methods, and the prospects for achieving sufficient concentrations of appropriate agents in vivo are poor for several types of applications such as small-molecule targeting of specific receptors. However, using relatively large carrier systems such as particles and liposomes, sufficient concentrations of paramagnetic agents may be delivered to achieve MR-signal changes adequate for detection. The use of higher-resolution MR images will aid the prospects for molecular imaging in small animals. Theoretic considerations also predict that a similar approach, using rather large particles or carriers of materials with a high atomic number, may also be successful for CT, especially with additional developments such as the use of monochromatic x-rays. The prospects of molecular imaging by x-ray imaging may not be as bleak as has been predicted. For ultrasound detection, gas-filled bubbles can provide a sufficient backscattered sound intensity to be detectable at concentrations and sizes not much different from agents designed for these other modalities.
Journal of Nuclear Medicine 06/2009; 50(6):999-1007. · 6.38 Impact Factor
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H Charles Manning,
Nipun B Merchant,
A Coe Foutch,
John M Virostko,
Shelby K Wyatt,
Chirayu Shah,
Eliot T McKinley,
Jingping Xie,
Nathan J Mutic,
M Kay Washington,
Bonnie LaFleur,
Mohammed Noor Tantawy, Todd E Peterson,
M Sib Ansari,
Ronald M Baldwin,
Mace L Rothenberg,
Darryl J Bornhop,
John C Gore,
Robert J Coffey
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ABSTRACT: To evaluate noninvasive molecular imaging methods as correlative biomarkers of therapeutic efficacy of cetuximab in human colorectal cancer cell line xenografts grown in athymic nude mice. The correlation between molecular imaging and immunohistochemical analysis to quantify epidermal growth factor (EGF) binding, apoptosis, and proliferation was evaluated in treated and untreated tumor-bearing cohorts.
Optical imaging probes targeting EGF receptor (EGFR) expression (NIR800-EGF) and apoptosis (NIR700-Annexin V) were synthesized and evaluated in vitro and in vivo. Proliferation was assessed by 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) positron emission tomography. Assessment of inhibition of EGFR signaling by cetuximab was accomplished by concomitant imaging of NIR800-EGF, NIR700-Annexin V, and [18F]FLT in cetuximab-sensitive (DiFi) and insensitive (HCT-116) human colorectal cancer cell line xenografts. Imaging results were validated by measurement of tumor size and immunohistochemical analysis of total and phosphorylated EGFR, caspase-3, and Ki-67 immediately following in vivo imaging.
NIR800-EGF accumulation in tumors reflected relative EGFR expression and EGFR occupancy by cetuximab. NIR700-Annexin V accumulation correlated with cetuximab-induced apoptosis as assessed by immunohistochemical staining of caspase-3. No significant difference in tumor proliferation was noted between treated and untreated animals by [18F]FLT positron emission tomography or Ki-67 immunohistochemistry.
Molecular imaging can accurately assess EGF binding, proliferation, and apoptosis in human colorectal cancer xenografts. These imaging approaches may prove useful for serial, noninvasive monitoring of the biological effects of EGFR inhibition in preclinical studies. It is anticipated that these assays can be adapted for clinical use.
Clinical Cancer Research 12/2008; 14(22):7413-22. · 7.74 Impact Factor
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ABSTRACT: Crossed-strip gamma-ray detectors are an attractive option for small-animal SPECT imagers due to their high space-bandwidth product. In systems with independent triggering of the two sides of the detector, advanced data-processing techniques are required to accurately determine gamma-ray interaction locations and energy deposition. Optimal detector operation further relies on rigorous detector characterization in order to achieve detector triggering uniformity and best timing resolution and to permit position and energy estimation with maximum-likelihood methods. We describe algorithms and methods developed for calibrating and characterizing a recently fabricated system based on 1024-strips-per-side 1-mm-thick silicon detectors.
Nuclear Science Symposium Conference Record, 2008. NSS '08. IEEE; 11/2008
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Carrie K Jones,
Ashley E Brady,
Albert A Davis,
Zixiu Xiang,
Michael Bubser,
Mohammed Noor Tantawy,
Alexander S Kane,
Thomas M Bridges,
J Phillip Kennedy,
Stefania R Bradley, Todd E Peterson,
M Sib Ansari,
Ronald M Baldwin,
Robert M Kessler,
Ariel Y Deutch,
James J Lah,
Allan I Levey,
Craig W Lindsley,
P Jeffrey Conn
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ABSTRACT: Recent studies suggest that subtype-selective activators of M(1)/M(4) muscarinic acetylcholine receptors (mAChRs) may offer a novel approach for the treatment of psychotic symptoms associated with schizophrenia and Alzheimer's disease. Previously developed muscarinic agonists have provided clinical data in support of this hypothesis, but failed in clinical development because of a lack of true subtype specificity and adverse effects associated with activation of other mAChR subtypes. We now report characterization of a novel highly selective agonist for the M(1) receptor with no agonist activity at any of the other mAChR subtypes, termed TBPB [1-(1'-2-methylbenzyl)-1,4'-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one]. Mutagenesis and molecular pharmacology studies revealed that TBPB activates M(1) through an allosteric site rather than the orthosteric acetylcholine binding site, which is likely critical for its unprecedented selectivity. Whole-cell patch-clamp recordings demonstrated that activation of M(1) by TBPB potentiates NMDA receptor currents in hippocampal pyramidal cells but does not alter excitatory or inhibitory synaptic transmission, responses thought to be mediated by M(2) and M(4). TBPB was efficacious in models predictive of antipsychotic-like activity in rats at doses that did not produce catalepsy or peripheral adverse effects of other mAChR agonists. Finally, TBPB had effects on the processing of the amyloid precursor protein toward the non-amyloidogenic pathway and decreased Abeta production in vitro. Together, these data suggest that selective activation of M(1) may provide a novel approach for the treatment of symptoms associated with schizophrenia and Alzheimer's disease.
Journal of Neuroscience 11/2008; 28(41):10422-33. · 7.11 Impact Factor
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ABSTRACT: Three-dimensional intra- and intersubject registration of image volumes is important for tasks that include quantification of temporal/longitudinal changes, atlas-based segmentation, computing population averages, or voxel and tensor-based morphometry. While a number of methods have been proposed to address this problem, few have focused on the problem of registering whole body image volumes acquired either from humans or small animals. These image volumes typically contain a large number of articulated structures, which makes registration more difficult than the registration of head images, to which the majority of registration algorithms have been applied. This article presents a new method for the automatic registration of whole body computed tomography (CT) volumes, which consists of two main steps. Skeletons are first brought into approximate correspondence with a robust point-based method. Transformations so obtained are refined with an intensity-based nonrigid registration algorithm that includes spatial adaptation of the transformation's stiffness. The approach has been applied to whole body CT images of mice, to CT images of the human upper torso, and to human head and neck CT images. To validate the authors method on soft tissue structures, which are difficult to see in CT images, the authors use coregistered magnetic resonance images. They demonstrate that the approach they propose can successfully register image volumes even when these volumes are very different in size and shape or if they have been acquired with the subjects in different positions.
Medical Physics 05/2008; 35(4):1507-20. · 2.83 Impact Factor
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ABSTRACT: The ability to estimate absorbed doses in experimental animals to which radiolabeled material has been administered may be important in explaining and controlling potential radiation toxicity observed during preclinical trials. Most previously reported models for establishing doses to small animals have been stylized and mathematically based. This study establishes dose factors for internal sources in realistic models of a typical mouse and a typical rat, based on image data obtained using a dedicated small-animal CT scanner.
A transgenic mouse (body mass, 27 g) and a Sprague-Dawley rat (body mass, 248 g) were imaged using the dedicated small-animal CT scanner. Identified organs were segmented using computer tools that Vanderbilt University applies to process human images for 3-dimensional dosimetry. Monte Carlo N-particle transport code (MCNP) input files were prepared from the 3-dimensional, voxel-based image data. Using methods established for human studies, radiation transport calculations of absorbed fractions (AFs) were performed using MCNP, version 4C, on the segmented images, and dose conversion factors for several radionuclides were developed.
AFs were established at discrete energies for electron and photon sources assumed to be uniformly distributed throughout approximately 10 source and target regions in both models. Electron self-irradiation AFs were significantly less than 1.0 for many organs, at energies above 0.5 MeV, and significant cross irradiation was observed for high-energy electrons, such as those from (90)Y or (188)Re, in many organs. Calculated dose conversion factors reflected these trends and agreed well with the results of other authors who have undertaken similar investigations.
The AFs calculated in this study will be useful in determining the dose to organs for mice and rats similar in size to those studied here. The segmented, voxel-based models developed here can be used for external dose calculations as well.
Journal of Nuclear Medicine 05/2006; 47(4):655-9. · 6.38 Impact Factor
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Georgios T Stathopoulos,
Zhiwen Zhu,
M Brett Everhart,
Ioannis Kalomenidis,
William E Lawson,
Semra Bilaceroglu, Todd E Peterson,
Daphne Mitchell,
Fiona E Yull,
Richard W Light,
Timothy S Blackwell
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ABSTRACT: We developed a novel mouse model of malignant pleural effusion (MPE) by injecting Lewis lung cancer (LLC) cells directly into the pleural space of syngeneic C57B/6 mice. The pleural effusions in this model share common cellular and biochemical features with human MPEs. Implantation and growth of pleural tumors triggers a host inflammatory response characterized by a mixed inflammatory cell influx into the pleural fluid. LLC cells exhibited high basal nuclear factor (NF)-kappaB activity in vitro and in vivo, which we used to drive expression of a NF-kappaB-dependent green fluorescent protein-firefly luciferase fusion reporter construct. NF-kappaB-dependent reporter expression allowed intravital tracing of pleural tumors. Inhibition of NF-kappaB in LLC cells did not affect cell viability in culture; however, injection of LLC cells expressing a dominant NF-kappaB inhibitor resulted in decreased tumor burden, decreased pleural effusion volume, and decreased pleural effusion TNF-alpha levels. These studies indicate that tumor NF-kappaB activity regulates pleural tumor progression. This reproducible model of MPE can be used to further study the influence of specific host and tumor factors on the pathogenesis of MPE and evaluate new therapeutic strategies.
American Journal of Respiratory Cell and Molecular Biology 03/2006; 34(2):142-50. · 5.13 Impact Factor
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ABSTRACT: The first full single-photon emission computed tomography (SPECT) imager to exploit eight compact high-intrinsic-resolution cadmium zinc telluride (CZT) detectors, called SemiSPECT, has been completed. Each detector consists of a CZT crystal and a customized application-specific integrated circuit (ASIC). The CZT crystal is a 2.7 cm x 2.7 cm x -0.2 cm slab with a continuous top electrode and a bottom electrode patterned into a 64 x 64 pixel array by photolithography. The ASIC is attached to the bottom of the CZT crystal by indium-bump bonding. A bias voltage of -180 V is applied to the continuous electrode. The eight detectors are arranged in an octagonal lead-shielded ring. Each pinhole in the eight-pinhole aperture placed at the center of the ring is matched to each individual detector array. An object is imaged onto each detector through a pinhole, and each detector is operated independently with list-mode acquisition. The imaging subject can be rotated about a vertical axis to obtain additional angular projections. The performance of SemiSPECT was characterized using 99mTc. When a 0.5 mm diameter pinhole is used, the spatial resolution on each axis is about 1.4 mm as estimated by the Fourier crosstalk matrix, which provides an algorithm-independent average resolution over the field of view. The energy resolution achieved by summing neighboring pixel signals in a 3 x 3 window is about 10% full-width-at-half-maximum of the photopeak. The overall system sensitivity is about 0.5 x 10(-4) with the energy window of +/-10% from the photopeak. Line-phantom images are presented to visualize the spatial resolution provided by SemiSPECT, and images of bone, myocardium, and human tumor xenografts in mice demonstrate the feasibility of preclinical small-animal studies with SemiSPECT.
Medical Physics 03/2006; 33(2):465-74. · 2.83 Impact Factor
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Proceedings of the 2006 IEEE International Symposium on Biomedical Imaging: From Nano to Macro, Arlington, VA, USA, 6-9 April 2006; 01/2006
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Biomedical Image Registration, Third International Workshop, WBIR 2006, Utrecht, The Netherlands, July 9-11, 2006, Proceedings; 01/2006
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Conor C Lynch,
Atsuya Hikosaka,
Heath B Acuff,
Michelle D Martin,
Noriyasu Kawai,
Rakesh K Singh,
Tracy C Vargo-Gogola,
Jennifer L Begtrup, Todd E Peterson,
Barbara Fingleton,
Tomoyuki Shirai,
Lynn M Matrisian,
Mitsuru Futakuchi
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ABSTRACT: We developed a rodent model that mimics the osteoblastic and osteolytic changes associated with human metastatic prostate cancer. Microarray analysis identified MMP-7, cathepsin-K, and apolipoprotein D as being upregulated at the tumor-bone interface. MMP-7, which was produced by osteoclasts at the tumor-bone interface, was capable of processing RANKL to a soluble form that promoted osteoclast activation. MMP-7-deficient mice demonstrated reduced prostate tumor-induced osteolysis and RANKL processing. This study suggests that inhibition of MMP-7 will have therapeutic benefit in the treatment of prostate cancer-induced osteolysis.
Cancer Cell 06/2005; 7(5):485-96. · 26.57 Impact Factor
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Proceedings of the 2002 IEEE International Symposium on Biomedical Imaging, Ritz-Carlton Hotel, Washington, DC, USA, 7-10 June 2002; 01/2002
