Virtual clinical trials in medical imaging: a review

The accelerating complexity and variety of medical imaging devices and methods have outpaced the ability to evaluate and optimize their design and clinical use. This is a significant and increasing challenge for both scientific investigations and clinical applications. Evaluations would ideally be done using clinical imaging trials. These experiments, however, are often not practical due to ethical limitations, expense, time requirements, or lack of ground truth. Virtual clinical trials (VCTs) (also known as in silico imaging trials or virtual imaging trials) offer an alternative means to efficiently evaluate medical imaging technologies virtually. They do so by simulating the patients, imaging systems, and interpreters. The field of VCTs has been constantly advanced over the past decades in multiple areas. We summarize the major developments and current status of the field of VCTs in medical imaging. We review the core components of a VCT: computational phantoms, simulators of different imaging modalities, and interpretation models. We also highlight some of the applications of VCTs across various imaging modalities

The magic bullet: Creating Indium-111 bombesin targeting vectors for use in diagnostic imaging of prostate and breast cancer [abstract]

Abstract only availableBackground: According to the American Cancer Society, over 68,000 men and women will die from prostate and breast cancer in this year alone. Prostate, breast and other cancers have been shown to express the BB2 receptor. For the past decade the Hoffman laboratory has been synthesizing radiopharmaceutical conjugates based on the Bombesin (BBN) peptide (Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2) that target the BB2 receptor for diagnosis and treatment of cancer. The radioconjugates are composed of a bombesin targeting vector, linking group, chelation moiety and a radioactive metal. One focus of our group is to investigate the efficacy of new Bombesin Targeting Vectors (BTV) which are derivatives of the BBN peptide. In the sixth position of the BTV is a D-phenylalanine amino acid. Our hypothesis is that the D-phenylalanine is responsible for significantly reducing kidney retention. Reduction of kidney retention is crucial for clinical radiotherapeutic applications because the kidney is often the dose limiting organ. In order to understand the structure function relationship of the D-phenylalanine in the BTV targeting vectors, we synthesized and evaluated the BTV peptide with the L-phenylalanine in the sixth position to determine what effect the stereochemistry has upon the in vitro receptor binding and in vivo pharmacokinetic properties of the peptide. Methods: The peptides were synthesized using solid phase peptide synthesis, purified using RP-HPLC, and characterized using electrospray mass spectrometry. Radiolabeling of the peptides was performed using 111InCl3. In vitro cell binding assays and internalization and efflux studies were performed using the PC-3 human cancer cell line. In vivo pharmacokinetic studies were performed using CF-1 mice. Micro-SPECT (single photon emission computed tomography) imaging studies were performed in PC-3 SCID mice. Results: In vivo pharmacokinetic studies at 15 min post-injection gave 39.85 ± 5.07 %ID/g in the BB2 receptor expressing mouse pancreas for the L-Phe-BTV radioconjugate compared to 10.30 ± 0.34 for the D-Phe-BTV. Surprisingly, the kidney clearance for both radioconjugates was statistically identical. Conclusion: Incorporation of the L-Phe instead of the D-Phe into the sixth position of the BTV had no statistically significant effect upon the renal clearance of the radioconjugate. However, the change in stereochemistry from the L to the D-form had significant effects upon the in vivo uptake and retention of the radioconjugate. Further investigations will be conducted to understand the mechanism responsible for the difference in uptake and retention of the two Bombesin radioconjugates

Investigating the bifunctional chelate approach for radiopharmaceutical development

The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract, appears in the public.pdf file.Title from PDF of title page (University of Missouri--Columbia, viewed on August 20, 2010)Thesis advisors: Dr. Silvia Jurisson and Dr. Timothy Hoffman.Vita.Ph. D. University of Missouri--Columbia 2010.[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Radiopharmaceuticals are drugs that contain a radioactive atom for the purpose of imaging or therapy of disease. The type of emission determines the applicability for each drug. For instance, alpha and beta particles are used for treatment of disease, while gamma and positron emissions are useful for disease detection. There are three main ways to develop a radiopharmaceutical drug; 1) through direct administration of a radionuclide, 2) incorporating a radiolabel directly into a small molecule, or 3) using the bifunctional chelate approach to indirectly label peptides or antibodies. The final model is the focus of this work. The bifunctional chelate approach involves using a chelate that forms thermodynamically and kinetically inert complexes and also has the ability to couple to the targeting moiety. The work involved with this project is three pronged 1) chelate development for Au-198/199, 2) peptide optimization for Ga-67/68, and 3) comparing in vitro/in vivo behavior of Ga-67 and In-111. In the first project, possible chelates using a bis-thiosemicarbazide chelate backbone were investigated for their ability to form stable complexes with gold. Au-198/199 isotopes offer potential uses for both imaging and therapy. Gold(III) chemistry, however, creates pitfalls to the applicability of these isotopes. Gold(III) has the problem of oxidizing donor ligands, or being reduced to Au(0). The benefit of using bis-thiosemicarbazides based chelates was that there are two non-oxidizable imine nitrogen donor atoms and two stable thiol donor atoms. A variety of gold complexes were made at the macroscopic level, and further studied at the radiotracter level for in vitro and in vivo stability. Results demonstrated that the chelates tested did not provide the necessary stability at the radiotracer level, however, insight into possible reasons for this instability were elucidated. The second project involved optimizing the targeting peptide, bombesin, as an antagonist for in vivo imaging of GRP receptor positive tumors. A series of peptides that differed in their C-terminal ends or 6th position amino acid, were synthesized and coupled to the chelate, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and labeled with Ga-67. Gallium-67 is a useful isotope for single photon emission computed tomography (SPECT) and has been found to form thermodynamically stable complexes with DOTA. This project involved comparing the imaging potential of each peptide analogue by first determining in vitro binding affinity and stability, and then comparing in vivo biodistribution profiles. Results demonstrated that analogues with more electron donating groups on the C-terminus generated greater binding affinity, the addition of (D) amino acids in the 6th position aided in background tissue clearance, and the highest tumor accumulation was demonstrated with the 67Ga-DOTA-8-aminooctanoic acid-[(D)Trp6]BBN(6-13)NHC2H5 conjugate. The final project was to compare the in vitro and in vivo behavior of the same peptide conjugates previously discussed when labeled with Ga-67 or In-111. Gallium and indium both share similar chemistries, however, differences in coordination and size could have dramatic effects on in vitro binding affinity and stability, as well as in vivo clearance rates and pathways. Therefore, the lead compounds from the previous project were further evaluated when labeled with In-111 and compared to the results determined for the Ga-67 conjugates. Results demonstrated that in general Ga-67 conjugates had higher binding affinity, similar stability in human serum, and vast differences in both hydrophobicity and in vivo biodistribution profiles.Includes bibliographical reference

Ubiquitous influence of wildfire emissions and secondary organic aerosol on summertime atmospheric aerosol in the forested Great Lakes region

Long-range aerosol transport affects locations hundreds of kilometers from the point of emission, leading to distant particle sources influencing rural environments that have few major local sources. Source apportionment was conducted using real-time aerosol chemistry measurements made in July 2014 at the forested University of Michigan Biological Station near Pellston, Michigan, a site representative of the remote forested Great Lakes region. Size-resolved chemical composition of individual 0.5–2.0 µm particles was measured using an aerosol time-of-flight mass spectrometer (ATOFMS), and non-refractory aerosol mass less than 1 µm (PM1) was measured with a high-resolution aerosol mass spectrometer (HR-AMS). The field site was influenced by air masses transporting Canadian wildfire emissions and urban pollution from Milwaukee and Chicago. During wildfire-influenced periods, 0.5–2.0 µm particles were primarily aged biomass burning particles (88 % by number). These particles were heavily coated with secondary organic aerosol (SOA) formed during transport, with organics (average O∕C ratio of 0.8) contributing 89 % of the PM1 mass. During urban-influenced periods, organic carbon, elemental carbon–organic carbon, and aged biomass burning particles were identified, with inorganic secondary species (ammonium, sulfate, and nitrate) contributing 41 % of the PM1 mass, indicative of atmospheric processing. With current models underpredicting organic carbon in this region and biomass burning being the largest combustion contributor to SOA by mass, these results highlight the importance for regional chemical transport models to accurately predict the impact of long-range transported particles on air quality in the upper Midwest, United States, particularly considering increasing intensity and frequency of Canadian wildfires

Acoustical structured illumination for super-resolution ultrasound imaging

Tali Ilovitsh et al. describe a new method, acoustical structured illumination, for generating super-resolution ultrasound images. The method applies principles from structured illumination microscopy and can be adapted to existing ultrasound systems without the need for additional components