Indiana Consortium for Innovation in Biomedical Imaging

poster abstractThe Indiana Consortium for Innovation in Biomedical Imaging (Indiana-CIBI) has been established to leverage the biomedical imaging strengths of several major academic institutions throughout Indiana. This initiative provides the environment, infrastructure, and resources necessary for establishing one of the premier translational, research and educational imaging networks in the United States. The Indiana-CIBI will facilitate the identification of crucial clinical problems and unmet research needs; stimulate the development of innovative solutions; and help translate optimized patient care services into practice at partner health-care delivery facilities. The objectives of the Indiana-CIBI include: Providing national leadership in translation from concept to practice. Encouraging targeted problem-driven technology development. Nurturing innovation and progress through facile access to advanced resources. Focusing Indiana state-wide interdisciplinary partnerships in the development of new, innovative imaging technologies and the utilization of imaging resources. Cultivating investigator engagement and channeling intrinsic motivation. The stated objectives of the Indiana-CIBI define the operational model for the consortium. Key steps in the innovation-focused process include: 1) Identification of critical clinical or biomedical research needs by physician or biomedical investigator(s); 2) Creation of innovative solutions through innovation incubator teams, imaging innovation marathons, and crowdsourcing solicitations; 3) Translation to practice through a large medical physics/radiology network; and 4) Translation to advanced core services through the Indiana-CTSI core resource network. Critical success factors for the Indiana-CIBI include tight integration within academic health care facilities, consolidation of fragmented resources, and expansion of critical support resources, eliminating the need to duplicate some types of services across multiple sites in Indiana. For further information regarding the Indiana Consortium for Innovation in Biomedical Imaging and its programs please contact Mark Holland or Gary Hutchins at [email protected]. The Indiana-CIBI is supported, in part, by contributions from the IUPUI Office of the Vice Chancellor for Research

Research Center for Quantitative Renal Imaging

poster abstractMission: The mission of the Research Center for Quantitative Renal Imaging is to provide a focused research environment and resource for the development, implementation, and dissemination of innovative, quantitative imaging methods designed to assess the status of and mechanisms associated with acute and chronic kidney disease and evaluate efficacy of therapeutic interventions. Nature of the Center: This Research Center provides a formal mechanism to link research programs focused on understanding the fundamental mechanisms associated with kidney diseases with those associated with the development of advanced imaging methods and quantitative analyses into a focused effort dedicated toward the development and implementation of quantitative renal imaging methods. Goals of the IUPUI Research Center for Quantitative Renal Imaging: Identify, develop, and implement innovative imaging methods that provide quantitative imaging biomarkers for assessing and inter-relating renal structure, function, hemodynamics and underlying tissue micro-environmental factors contributing to kidney disease. Establish an environment that facilitates and encourages interdisciplinary collaborations among investigators and offers research support to investigators focused on developing and utilizing innovative quantitative imaging methods in support of kidney disease research. Provide a resource to inform the greater research and healthcare communities of advances in quantitative renal imaging and its potential for enhanced patient management and care. Offer an imaging research resource to companies engaged in product development associated with the diagnosis and treatment of kidney diseases. Further Information: For further information regarding the IUPUI Research Center for Quantitative RenalImaging and its funding programs please visit http://www.renalimaging.iupui.edu/ or contact the Center at [email protected]. Acknowledgments: The IUPUI Research Center for Quantitative Renal Imaging is supported by contributions from the IUPUI Signature Center Initiative, the Department of Radiology & Imaging Sciences; the Division of Nephrology, the IUPUI School of Science, the IUPUI School of Engineering & Technology, and the Indiana Clinical and Translational Sciences Institute (CTSI)

Joint Maxiniurn Likelihood Estimation of Emission and Attenuation Densities in PET

Accurate attenuation correction can be performed in PET (positron emission tomography) using transmission scanning to estimate the survival probabilities along each coincidence line. However, since these measurements are typically corrupted by Poisson counting noise, they propagate additional uncertainty into reconstructed images and kinetic parameter estimates. This can be especially true in the thorax where the attenuating medium is heterogeneous and the statistical precision of the transmission scan may be approximately the same as that of the emission data. To account for the Poisson noise in the transmission measurement, the authors have developed a sieve-constrained maximum likelihood algorithm that jointly estimates both the survival probability and the emission intensity. They present some of their initial experiences in using the joint alternate and maximize algorithm with simulated PET data.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/85813/1/Fessler119.pd

Synthesis of [11C]GSK1482160 as a new PET agent for targeting P2X7 receptor

The authentic standards GSK1482160 and its isomer, as well as the radiolabeling precursors desmethyl-GSK1482160 and Boc-protected desmethyl-GSK1482160 were synthesized from l-pyroglutamic acid, methyl l-pyroglutamate and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 27–28% in 3 steps, 58% in 4 steps, 76% in 1 step and 33% in 2 steps, respectively. [11C]GSK1482160 was prepared from either desmethyl-GSK1482160 or Boc-protected desmethyl-GSK1482160 with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with SPE in 40–50% and 30–40% radiochemical yield, respectively, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity at EOB was 370–1110 GBq/μmol with a total synthesis time of ∼40-min from EOB

Combination GLP-1 and Insulin Treatment Fails to Alter Myocardial Fuel Selection Versus Insulin Alone in Type 2 Diabetes

Context Glucagon-like peptide-1 (GLP-1) and the clinically available GLP-1 agonists have been shown to exert effects on the heart. It is unclear whether these effects occur at clinically used doses in vivo in humans, possibly contributing to CVD risk reduction. Objective To determine whether liraglutide at clinical dosing augments myocardial glucose uptake alone or in combination with insulin compared to insulin alone in metformin-treated Type 2 diabetes mellitus. Design Comparison of myocardial fuel utilization after 3 months of treatment with insulin detemir, liraglutide, or combination detemir+liraglutide. Setting Academic hospital Participants Type 2 diabetes treated with metformin plus oral agents or basal insulin. Interventions Insulin detemir, liraglutide, or combination added to background metformin Main Outcome Measures Myocardial blood flow, fuel selection and rates of fuel utilization evaluated using positron emission tomography, powered to demonstrate large effects. Results We observed greater myocardial blood flow in the insulin-treated groups (median[25th, 75th percentile]: detemir 0.64[0.50, 0.69], liraglutide 0.52[0.46, 0.58] and detemir+liraglutide 0.75[0.55, 0.77] mL/g/min, p=0.035 comparing 3 groups and p=0.01 comparing detemir groups to liraglutide alone). There were no evident differences between groups in myocardial glucose uptake (detemir 0.040[0.013, 0.049], liraglutide 0.055[0.019, 0.105], detemir+liraglutide 0.037[0.009, 0.046] µmol/g/min, p=0.68 comparing 3 groups). Similarly there were no treatment group differences in measures of myocardial fatty acid uptake or handling, and no differences in total oxidation rate. Conclusions These observations argue against large effects of GLP-1 agonists on myocardial fuel metabolism as mediators of beneficial treatment effects on myocardial function and ischemia protection

Functional MRI Assessment of Renal Fibrosis in Rat Models

poster abstractIntroduction Renal fibrosis is a common consequence of chronic kidney diseases which affects a large population. Therefore, it is important to establish imaging based noninvasive biomarkers to monitor the progression or regression of renal fibrosis instead of biopsy. Magnetic resonance imaging (MRI) could provide both high spatial resolution and excellent tissue contrast for visualization of kidney morphology. Moreover, MRI is capable of assessing pseudo perfusion (Df) and perfusion fraction (Pf) with intra-voxel incoherent motion (IVIM) imaging (1), tissue oxygenation with T2* mapping (2), macromolecular composition with T1rho imaging (3) and kidney function (eGFR) with dynamic contrast enhanced (DCE) imaging (4). This study is aimed to evaluate the sensitivity of these MRI techniques to the renal fibrotic changes in a rat model. Methods A total of 4 rats were scanned at early (2-5 days) and late (25-35 days) time points after surgical intervention (unilateral ureteral obstruction to induce renal fibrosis) on a Siemens Tim Trio 3T scanner using an 80mm inner diameter 8-channel rat body coil (RAPID, USA) under a stable anesthetized condition. Axial images of 80mm FOV, 2mm slice thick and sub-millimeter in-place resolution were acquired for different functional MRI techniques with following parameters, respectively: IVIM with10 b-values of 0 - 750 s/mm2. T2*: with 10 TEs of 8 - 66 ms; T1rho: with 9 TSL times of 5 - 80 ms; DCE: with150 dynamic measurements at a temporal resolution of 1.01 s. before and after a 15s injection of 1.1 ml GD-DTPA through rat tail with a power injector. Functional data were processed and analyzed using custom MATLAB programs or analysis tools installed in the MRI console workstation. Results Figure 1 shows an anatomical image of the obstructed (R) and healthy (L) rat kidneys. Figures 2-4 show example T1rho map, IVIM Df map, and T2* map, respectively. Quantitative results based on ROI measurements are summarized in table 1. Changes consistent with the expected progression of fibrosis were observed in the obstructed kidney (R) while the healthy kidney (L) and muscle region remained stable. Figure 5 shows the DCE-MRI images at baseline as well as 45s, 95s and 240s after contrast infusion. The timing and intensity of signal changes are clearly different between two kidneys. Quantitative results of DCE-MRI data and comparison with PET study is reported in a separate abstract. Discussion High quality anatomical and functional images of rat kidney can be obtained on a clinical 3.0T MR scanner with dedicated small animal coils and optimized imaging techniques. The findings suggest that IVIM, T2*, T1rho and DCE can be used to assess and monitor different aspects of physiological changes in kidney fibrosis

Using Flow Feature to Extract Pulsatile Blood Flow from 4D Flow MRI Images

4D flow MRI images make it possible to measure pulsatile blood flow inside deforming vessel, which is critical in accurate blood flow visualization, simulation, and evaluation. Such data has great potential to overcome problems in existing work, which usually does not reflect the dynamic nature of elastic vessels and blood flows in cardiac cycles. However, the 4D flow MRI data is often low-resolution and with strong noise. Due to these challenges, few efforts have been successfully conducted to extract dynamic blood flow fields and deforming artery over cardiac cycles, especially for small artery like carotid. In this paper, a robust flow feature, particularly the mean flow intensity is used to segment blood flow regions inside vessels from 4D flow MRI images in whole cardiac cycle. To estimate this flow feature more accurately, adaptive weights are added to the raw velocity vectors based on the noise strength of MRI imaging. Then, based on this feature, target arteries are tracked in at different time steps in a cardiac cycle. This method is applied to the clinical 4D flow MRI data in neck area. Dynamic vessel walls and blood flows are effectively generated in a cardiac cycle in the relatively small carotid arteries. Good image segmentation results on 2D slices are presented, together with the visualization of 3D arteries and blood flows. Evaluation of the method was performed by clinical doctors and by checking flow volume rates in the vertebral and carotid arteries

Equivalence of arterial and venous blood for [11C]CO2-metabolite analysis following intravenous administration of 1-[11C]acetate and 1-[11C]palmitate

PURPOSE: Sampling of arterial blood for metabolite correction is often required to define a true radiotracer input function in quantitative modeling of PET data. However, arterial puncture for blood sampling is often undesirable. To establish whether venous blood could substitute for arterial blood in metabolite analysis for quantitative PET studies with 1-[(11)C]acetate and 1-[(11)C]palmitate, we compared the results of [(11)C]CO2-metabolite analyses performed on simultaneously collected arterial and venous blood samples. METHODS: Paired arterial and venous blood samples were drawn from anesthetized pigs at 1, 3, 6, 8, 10, 15, 20, 25 and 30min after i.v. administration of 1-[(11)C]acetate and 1-[(11)C]palmitate. Blood radioactivity present as [(11)C]CO2 was determined employing a validated 10-min gas-purge method. Briefly, total blood (11)C radioactivity was counted in base-treated [(11)C]-blood samples, and non-[(11)C]CO2 radioactivity was counted after the [(11)C]-blood was acidified using 6N HCl and bubbled with air for 10min to quantitatively remove [(11)C]CO2. RESULTS: An excellent correlation was found between concurrent arterial and venous [(11)C]CO2 levels. For the [(11)C]acetate study, the regression equation derived to estimate the venous [(11)C]CO2 from the arterial values was: y=0.994x+0.004 (r(2)=0.97), and for the [(11)C]palmitate: y=0.964x-0.001 (r(2)=0.9). Over the 1-30min period, the fraction of total blood (11)C present as [(11)C]CO2 rose from 4% to 64% for acetate, and 0% to 24% for palmitate. The rate of [(11)C]CO2 appearance in venous blood appears similar for the pig model and humans following i.v. [(11)C]-acetate administration. CONCLUSION: Venous blood [(11)C]CO2 values appear suitable as substitutes for arterial blood samples in [(11)C]CO2 metabolite analysis after administration of [(11)C]acetate or [(11)C]palmitate ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Quantitative PET studies employing 1-[(11)C]acetate and 1-[(11)C]palmitate can employ venous blood samples for metabolite correction of an image-derived tracer arterial input function, thereby avoiding the risks of direct arterial blood sampling

Synthesis and in vitro biological evaluation of new P2X7R radioligands [11C]halo-GSK1482160 analogs

The reference standards halo-GSK1482160 (F-, Br-, and I-) and their corresponding precursors desmethyl-halo-GSK1482160 (F-, Br-, and I-) were synthesized from (S)-1-methyl-5-oxopyrrolidine-2-carboxylic acid or (S)-5-oxopyrrolidine-2-carboxylic acid and 2-halo-3-(trifluoromethyl)benzylamine (F-, Br-, and I-) in one step with 45–93% yields. The target tracers [11C]halo-GSK1482160 (F-, Br-, and I-) were prepared from desmethyl-halo-GSK1482160 (F-, Br-, and I-) with [11C]CH3OTf under basic conditions (NaOH-Na2CO3, solid, w/w 1:2) through N-[11C]methylation and isolated by HPLC combined with SPE in 40–50% decay corrected radiochemical yield. The radiochemical purity was >99%, and the molar activity (AM) at end of bombardment (EOB) was 370–740 GBq/μmol. The potency of halo-GSK1482160 (F-, Br-, and I-) in comparison with GSK1482160 (Cl-) was determined by a radioligand competitive binding assay using [11C]GSK1482160, and the binding affinity Ki values for halo-GSK1482160 (F-, Br-, and I-) and GSK1482160 (Cl-) are 54.2, 2.5, 1.9 and 3.1 nM, respectively

Knockdown of the DNA repair and redox signaling protein Ape1/ Ref-1 blocks ovarian cancer cell and tumor growth

Apurinic endonuclease 1/redox effector factor-1 (Ape1/Ref-1 or Ape1) is an essential protein with two distinct functions. It is a DNA repair enzyme in the base excision repair (BER) pathway and a reduction–oxidation (redox) signaling factor maintaining transcription factors in an active reduced state. Our laboratory previously demonstrated that Ape1 is overexpressed in ovarian cancer and potentially contributes to resistance. Therefore, we utilized siRNA technology to knockdown protein levels of Ape1 in ovarian cancer cell line, SKOV-3x. Knocking Ape1 down had dramatic effects on cell growth in vitro but was not due to an increase in apoptosis and at least partially due to an extension in transit time through S-phase. Similarly, human ovarian tumor xenografts with reduced levels of Ape1 protein demonstrated a dramatic reduction in tumor volume (p < 0.01) and also statistically significant (p = 0.02) differences in 18F-fluorodeoxyglucose (FDG) uptake indicating reduced glucose metabolism and cellular proliferation. Ape1's role in DNA repair and redox signaling is important to our basic understanding of ovarian cancer cell growth and these findings strongly support Ape1 as a therapeutic target