Comparing independent high-throughput gene-expression experiments can generate hypotheses about which gene-expression programs are shared between particular biological processes. Current techniques to compare expression profiles typically involve choosing a fixed differential expression threshold to summarize results, potentially reducing sensitivity to small but concordant changes. We present a threshold-free algorithm called Rank–rank Hypergeometric Overlap (RRHO). This algorithm steps through two gene lists ranked by the degree of differential expression observed in two profiling experiments, successively measuring the statistical significance of the number of overlapping genes. The output is a graphical map that shows the strength, pattern and bounds of correlation between two expression profiles. To demonstrate RRHO sensitivity and dynamic range, we identified shared expression networks in cancer microarray profiles driving tumor progression, stem cell properties and response to targeted kinase inhibition. We demonstrate how RRHO can be used to determine which model system or drug treatment best reflects a particular biological or disease response. The threshold-free and graphical aspects of RRHO complement other rank-based approaches such as Gene Set Enrichment Analysis (GSEA), for which RRHO is a 2D analog. Rank–rank overlap analysis is a sensitive, robust and web-accessible method for detecting and visualizing overlap trends between two complete, continuous gene-expression profiles. A web-based implementation of RRHO can be accessed at http://systems.crump.ucla.edu/rankrank/.

In contrast to normal cells, cancer cells avidly take up glucose and metabolize it to lactate even when oxygen is abundant, a phenomenon referred to as the Warburg effect. This fundamental alteration in glucose metabolism in cancer cells enables their specific detection by Positron Emission Tomography (PET) following intravenous injection of the glucose analogue 18F-fluorodeoxy-glucose (18FDG). However, this useful imaging technique is limited by the fact that not all cancers avidly take up FDG. To identify molecular determinants of 18FDG-retention, we interogated the transcriptomes of human cancer cell lines and primary tumors for metabolic pathways associated with 18FDG radiotracer uptake. From 95 metabolic pathways that were interrogated, the glycolysis and several glycolysis-related pathways (pentose-phosphate, carbon fixation, aminoacyl-tRNA biosynthesis, one-carbon-pool by folate) showed the greatest transcriptional enrichment. This “FDG signature” predicted FDG-uptake in breast cancer cell lines and overlapped with established gene expression signatures for the “basal-like” breast cancer subtype and MYC-induced tumorigenesis in mice. Human breast cancers with nuclear MYC staining and high RNA expression of MYC target genes showed high 18FDG-PET uptake (p < 0.005). Presence of the FDG signature was similarly associated with MYC gene copy gain, increased MYC transcript levels, and elevated expression of metabolic MYC target genes in a human breast cancer genomic dataset. Together, our findings link clinical observations of glucose uptake with a pathologic and molecular subtype of human breast cancer. Further, they suggest related approaches to derive molecular determinants of radiotracer retention for other PET-imaging probes.

The purpose of this work was to calculate radiation dose and its organ distribution in a realistic mouse phantom from micro-computed tomography (microCT) imaging protocols. CT dose was calculated using GATE and a voxelized, realistic phantom. The x-ray photon energy spectra used in simulations were precalculated with GATE and validated against previously published data. The number of photons required per simulated experiments was determined by direct exposure measurements. Simulated experiments were performed for three types of beams and two types of mouse beds. Dose-volume histograms and dose percentiles were calculated for each organ. For a typical microCT screening examination with a reconstruction voxel size of 200 μm, the average whole body dose varied from 80 mGy (at 80 kVp) to 160 mGy (at 50 kVp), showing a strong dependence on beam hardness. The average dose to the bone marrow is close to the soft tissue average. However, due to dose nonuniformity and higher radiation sensitivity, 5% of the marrow would receive an effective dose about four times higher than the average. If CT is performed longitudinally, a significant radiation dose can be given. The total absorbed radiation dose is a function of milliamperes-second, beam hardness, and desired image quality (resolution, noise and contrast). To reduce dose, it would be advisable to use the hardest beam possible while maintaining an acceptable contrast in the image.

Abstract. We are developing a simulation of needle insertion and radioactive seed implantation to facilitate surgeon training and planning for brachytherapy for treating prostate cancer. Inserting a needle into soft tissues causes the tissues to displace and deform: ignoring these effects during seed implantation leads to imprecise seed placements. Surgeons should learn to compensate for these effects so seeds are implanted close to their pre-planned locations. We describe a new 2-D dynamic FEM model based on a 7-phase insertion sequence where the mesh is updated to maintain element boundaries along the needle shaft. The locations of seed implants are predicted as the tissue deforms. The simulation, which achieves 24 frames per second using a 1250 triangular element mesh on a 750Mhz Pentium III PC, is available for surgeon testing by contacting ron@ieor.berkeley.edu.

It has been observed that microfluidic chips used for synthesizing 18F-labeled compounds demonstrate visible light emission without nearby scintillators or fluorescent materials. The origin of the light was investigated and found to be consistent with the emission characteristics from Cerenkov radiation. Since 18F decays through the emission of high-energy positrons, the energy threshold for beta particles, i.e., electrons or positrons, to generate Cerenkov radiation was calculated for water and polydimethylsiloxane (PDMS), the most commonly used polymer-based material for microfluidic chips. Beta particles emitted from 18F have a continuous energy spectrum, with a maximum energy that exceeds this energy threshold for both water and PDMS. In addition, the spectral characteristics of the emitted light from 18F in distilled water were also measured, yielding a broad distribution from 300 nm to 700 nm, with higher intensity at shorter wavelengths. A photograph of the 18F solution showed a bluish-white light emitted from the solution, further suggesting Cerenkov radiation. In this study, the feasibility of using this Cerenkov light emission as a method for quantitative measurements of the radioactivity within the microfluidic chip in situ was evaluated. A detector previously developed for imaging microfluidic platforms was used. The detector consisted of a charge coupled device (CCD) optically coupled to a lens. The system spatial resolution, minimum detectable activity and dynamic range were evaluated. In addition, a calibration of Cerenkov signal versus activity concentration in the microfluidic chip was determined. This novel method of Cerenkov radiation measurements will provide researchers with a simple yet robust quantitative imaging tool for microfluidic applications utilizing beta particles.

PETbox4 is a new, fully tomographic bench top PET scanner dedicated to high sensitivity and high resolution imaging of mice. This manuscript characterizes the performance of the prototype system using the National Electrical Manufacturers Association (NEMA) NU 4–2008 standards, including studies of sensitivity, spatial resolution, energy resolution, scatter fraction, count-rate performance and image quality. The PETbox4 performance is also compared with the performance of PETbox, a previous generation limited angle tomography system. PETbox4 consists of four opposing flat-panel type detectors arranged in a box like geometry. Each panel is made by a 24 × 50 pixelated array of 1.82 × 1.82 × 7mm bismuth germanate (BGO) scintillation crystals with a crystal pitch of 1.90mm. Each of these scintillation arrays is coupled to two Hamamatsu H8500 photomultiplier tubes via a glass light guide. Volumetric images for a 45 × 45 × 95 mm field of view (FOV) are reconstructed with a maximum likelihood expectation maximization (ML-EM) algorithm incorporating a system model based on a parameterized detector response. With an energy window of 150–650 keV, the peak absolute sensitivity is approximately 18% at the center of FOV. The measured crystal energy resolution ranges from 13.5% to 48.3% full width at half maximum (FWHM), with a mean of 18.0%. The intrinsic detector spatial resolution is 1.5mm FWHM in both transverse and axial directions. The reconstructed image spatial resolution for different locations in the FOV ranges from 1.32mm to 1.93 mm, with an average of 1.46 mm. The peak noise equivalent count rate for the mouse-sized phantom is 35 kcps for a total activity of 1.5 MBq (40 µCi) and the scatter fraction is 28%. The standard deviation in the uniform region of the image quality phantom is 5.7%. The recovery coefficients range from 0.10 to 0.93. In comparison to the first generation two panel PETbox system, PETbox4 achieves substantial improvements on sensitivity and spatial resolution. The overall performance demonstrates that the PETbox4 scanner is suitable for producing high quality images for molecular imaging based biomedical research.

The purpose of this study was to calculate internal absorbed dose distribution in mice from pre-clinical small animal PET imaging procedures with fluorine-18 labeled compounds (18FDG, 18FLT, and fluoride ion). The GATE Monte Carlo software and a realistic, voxel-based mouse phantom that included a subcutaneous tumor were used to perform simulations. Discretized time-activity curves obtained from dynamic in vivo studies with each of the compounds were used to set the activity concentration in the simulations. For 18FDG, a realistic range of uptake ratios was considered for the heart and tumor. For each simulated time frame, the biodistribution of the radionuclide in the phantom was considered constant, and a sufficient number of decays were simulated to achieve low statistical uncertainty. Absorbed dose, which was scaled to take into account radioactive decay, integration with time, and changes in biological distribution was reported in mGy per MBq of administered activity for several organs and uptake scenarios. The mean absorbed dose ranged from a few mGy/MBq to hundreds of mGy/MBq. Major organs receive an absorbed dose in a range for which biological effects have been reported. The effects on a given investigation are hard to predict; however, investigators should be aware of potential perturbations especially when the studied organ receives high absorbed dose and when longitudinal imaging protocols are considered.

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