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Purpose: The presence and functional competence of intratumoral CD8+ T cells is often a barometer for successful immunotherapeutic responses in cancer. Despite this understanding and the extensive number of clinical-stage immunotherapies focused on potentiation (co-stimulation) or rescue (checkpoint blockade) of CD8+ T cell antitumor activity, dynamic biomarker strategies are often lacking. To help fill this gap, immuno-PET nuclear imaging has emerged as a powerful tool for in vivo molecular imaging of antibody targeting. Here, we took advantage of immuno-PET imaging using 89Zr-IAB42M1-14, anti-mouse CD8 minibody, to characterize CD8+ T-cell tumor infiltration dynamics following ICOS (inducible T-cell co-stimulator) agonist antibody treatment alone and in combination with PD-1 blocking antibody in a model of mammary carcinoma. Procedures. Female BALB/c mice with established EMT6 tumors received 10 µg, IP of either IgG control antibodies, ICOS agonist monotherapy, or ICOS/PD-1 combination therapy on days 0, 3, 5, 7, 9, 10, or 14. Imaging was performed at 24 and 48 h post IV dose of 89Zr IAB42M1-14. In addition to 89Zr-IAB42M1-14 uptake in tumor and tumor-draining lymph node (TDLN), 3D radiomic features were extracted from PET/CT images to identify treatment effects. Imaging mass cytometry (IMC) and immunohistochemistry (IHC) was performed at end of study. Results: 89Zr-IAB42M1-14 uptake in the tumor was observed by day 11 and was preceded by an increase in the TDLN as early as day 4. The spatial distribution of 89Zr-IAB42M1-14 was more uniform in the drug treated vs. control tumors, which had spatially distinct tracer uptake in the periphery relative to the core of the tumor. IMC analysis showed an increased percentage of cytotoxic T cells in the ICOS monotherapy and ICOS/PD-1 combination group compared to IgG controls. Additionally, temporal radiomics analysis demonstrated early predictiveness of imaging features. Conclusion: To our knowledge, this is the first detailed description of the use of a novel immune-PET imaging technique to assess the kinetics of CD8+ T-cell infiltration into tumor and lymphoid tissues following ICOS agonist and PD-1 blocking antibody therapy. By demonstrating the capacity for increased spatial and temporal resolution of CD8+ T-cell infiltration across tumors and lymphoid tissues, these observations underscore the widespread potential clinical utility of non-invasive PET imaging for T-cell-based immunotherapy in cancer. [ABSTRACT FROM AUTHOR]

Objectives: In our laboratory we evaluated the use of micro‐computed tomography (micro‐CT) using a high resolution acquisition protocol and fetuses obtained on Gestation Day (GD) 29 (mating = GD 0). Methods: To show concordance between traditional Alizarin Red S stain and micro‐CT skeletal examination methods, 103 fetuses from 19 untreated Dutch belted rabbits were obtained by cesarean section and stored frozen. The fetuses were thawed, imaged and examined digitally by micro‐CT, then stained and re‐examined using traditional methods. Results: A total of 12 individual malformations and 35 unique variations were detected by both methods. Differences in the extent of ossification were found in only 51 of 26,196 bones while 99.8% of the observations were identical. Of the 51 differences, 31 were an unossified fifth medial phalanx of the forepaw indicating that very low‐density skeletal bones may be visible by Alizarin Red stain but not by micro‐CT scan. To establish this methodology under pharmaceutical testing conditions, we obtained and imaged by micro‐CT Alizarin Red S stained abnormal fetal rabbit skeletons previously exposed to a drug candidate associated with craniofacial malformations in humans. All of the types of skeletal abnormalities first identified by staining were also detected by micro‐CT examination. Representative images of these 66 different fetal skeletal abnormalities were characterized, and compiled to illustrate visual concordance between micro‐CT scanned and traditional Alizarin Red S stained skeletons. Conclusion: Micro‐CT imaging is an accurate, reliable and robust method that can be used as an alternative to stain when examining fetal rabbit skeletons in developmental toxicity studies. [ABSTRACT FROM AUTHOR]

Background: The cardioprotective effects of glucagon-like peptide-1 (GLP-1) and analogs have been previously reported. We tested the hypothesis that albiglutide, a novel long half-life analog of GLP-1, may protect the heart against I/R injury by increasing carbohydrate utilization and improving cardiac energetic efficiency. Methods/Principal Findings: Sprague-Dawley rats were treated with albiglutide and subjected to 30 min myocardial ischemia followed by 24 h reperfusion. Left ventricle infarct size, hemodynamics, function and energetics were determined. In addition, cardiac glucose disposal, carbohydrate metabolism and metabolic gene expression were assessed. Albiglutide significantly reduced infarct size and concomitantly improved post-ischemic hemodynamics, cardiac function and energetic parameters. Albiglutide markedly increased both in vivo and ex vivo cardiac glucose uptake while reducing lactate efflux. Analysis of metabolic substrate utilization directly in the heart showed that albiglutide increased the relative carbohydrate versus fat oxidation which in part was due to an increase in both glucose and lactate oxidation. Metabolic gene expression analysis indicated upregulation of key glucose metabolism genes in the non-ischemic myocardium by albiglutide. Conclusion/Significance: Albiglutide reduced myocardial infarct size and improved cardiac function and energetics following myocardial I/R injury. The observed benefits were associated with enhanced myocardial glucose uptake and a shift toward a more energetically favorable substrate metabolism by increasing both glucose and lactate oxidation. These findings suggest that albiglutide may have direct therapeutic potential for improving cardiac energetics and function. [ABSTRACT FROM AUTHOR]

Epidemiological and toxicological studies have provided evidence that accidentally inhaled nanosize ultrafine particles can induce chronic or acute health damage. MRI, being noninvasive, is able to assess the biodistribution and clearance of magnetically labeled nanoparticles induced by instillation or inhalation. We report 3He and proton MRI follow-up of lung, liver, spleen, and kidney distribution of USPIO (ultrasmall superparamagnetic iron oxide) in a rat model. The sensitivity of the imaging technique to various concentrations of instilled magnetite suspension was first assessed in vivo ( n = 12). A 2-week longitudinal imaging study was then performed on animals ( n = 7) instilled with a 0.5 mg magnetite solution. Hypointense and void signal regions associated with intrapulmonary USPIO were observed in the 3He ventilation images throughout the study, whereas no USPIO-related proton signal intensity changes were found. Intrapulmonary magnetite nanoparticle confinement was confirmed by ex vivo iron assay and histological analysis. This study demonstrates that combined 3He and proton MRI enables noninvasive assessment of the distribution and clearance of magnetically labeled instilled nanoparticles. Magn Reson Med 59:1298-1303, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Spatial and temporal variations in oxygen partial pressure ( pO2) during breath-hold can be exploited to obtain important regional parameters of lung function. In the course of apnea, the oxygen concentration is known to decay exponentially. Therefore, the initial pO2 ( p0) can be used to represent local ventilation, and the oxygen depletion time constant can characterize perfusion. The protocol, based on a nonlinear model of pO2 decay, was validated in six healthy mice. Parametric maps of p0 and oxygen depletion time constant were obtained for pure 3He and 3He/air mixture. The mean measured values of p0 were 77 ± 9 mbar for the pure 3He insufflation and 107 ± 5 mbar for 3He/air mixture, in agreement with the predefined p0 values: 75 ± 15 mbar and 123 ± 15 mbar, respectively. The mean measured oxygen depletion time constants were 6.5 ± 0.2 s for pure 3He and 7.1 ± 0.8 s for the 3He/air mixture, in agreement with physiology. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A non-invasive and free-breathing hyperpolarized (HP) 3He imaging protocol for small animals was implemented and validated on rats for lung function imaging. Animals were allowed to breathe a mixture of air and 3He from a mask and a gas reservoir fitted to their heads. Radial imaging sequences were used, and MRI signal intensity changes were monitored for retrospective cine image reconstruction. The ventilation cycle of the animals was imaged with a 100 ms temporal resolution. The sliding window imaging technique was applied to reconstruct 5 ms time-shifted image series covering the complete breathing cycle. Image series were processed to extract quantitative ventilation parameters such as the gas arrival time. The reproducibility and the non-invasiveness of this ventilation imaging protocol were evaluated by multiple acquisitions on the same animals. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: It is essential to evaluate new stent designs before in vivo testing. The purpose of this study was to develop and validate a controlled and reproducible patient-derived process to produce a life-size in vitro model of aortic arch aneurysm for endovascular procedure simulation. Methods: A three-dimensional magnetic resonance angiography (3D MRA) image derived from a 60-year-old patient with aortic arch aneurysm was segmented using a home-made software package which allows one-click automatic segmentation of the aorta, meshing, and conversion to standard tessellation language (STL) format. A rapid prototyping technique established a stereolithographic model to produce a replica of the whole aorta, including the arch aneurysm and supra-aortic arteries. Results: The final model was made by pouring silicone rubber to obtain a sturdy, life-size, soft, transparent, plastic cast, accurately reproducing both the internal and external anatomy of the aortic aneurysm. This model was used under perfusion by an extracorporeal circulation pump, to test ex vivo stent deployment. Conclusion: The combination of easy segmentation and conversion to the STL format with industrial stereolithography techniques enabled a realistic silicon vascular phantom to be created for endovascular procedure simulation, image modality calibration, and new stent design. [Copyright &y& Elsevier]

Spatial and temporal variations in oxygen partial pressure (pO(2)) during breath-hold can be exploited to obtain important regional parameters of lung function. In the course of apnea, the oxygen concentration is known to decay exponentially. Therefore, the initial pO(2) (p(0)) can be used to represent local ventilation, and the oxygen depletion time constant can characterize perfusion. The protocol, based on a nonlinear model of pO(2) decay, was validated in six healthy mice. Parametric maps of p(0) and oxygen depletion time constant were obtained for pure (3)He and (3)He/air mixture. The mean measured values of p(0) were 77 +/- 9 mbar for the pure (3)He insufflation and 107 +/- 5 mbar for (3)He/air mixture, in agreement with the predefined p(0) values: 75 +/- 15 mbar and 123 +/- 15 mbar, respectively. The mean measured oxygen depletion time constants were 6.5 +/- 0.2 s for pure (3)He and 7.1 +/- 0.8 s for the (3)He/air mixture, in agreement with physiology., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

A non-invasive and free-breathing hyperpolarized (HP) (3)He imaging protocol for small animals was implemented and validated on rats for lung function imaging. Animals were allowed to breathe a mixture of air and (3)He from a mask and a gas reservoir fitted to their heads. Radial imaging sequences were used, and MRI signal intensity changes were monitored for retrospective cine image reconstruction. The ventilation cycle of the animals was imaged with a 100 ms temporal resolution. The sliding window imaging technique was applied to reconstruct 5 ms time-shifted image series covering the complete breathing cycle. Image series were processed to extract quantitative ventilation parameters such as the gas arrival time. The reproducibility and the non-invasiveness of this ventilation imaging protocol were evaluated by multiple acquisitions on the same animals., (c 2006 John Wiley & Sons, Ltd.)