Pixel-Based Absorption Correction for Dual-Tracer Fluorescence Imaging of Receptor Binding Potential

Ratiometric approaches to quantifying molecular concentrations have been used for decades in microscopy, but have rarely been exploited in vivo until recently. One dual-tracer approach can utilize an untargeted reference tracer to account for non-specific uptake of a receptor-targeted tracer, and ultimately estimate receptor binding potential quantitatively. However, interpretation of the relative dynamic distribution kinetics is confounded by differences in local tissue absorption at the wavelengths used for each tracer. This study simulated the influence of absorption on fluorescence emission intensity and depth sensitivity at typical near-infrared fluorophore wavelength bands near 700 and 800 nm in mouse skin in order to correct for these tissue optical differences in signal detection. Changes in blood volume [1-3%] and hemoglobin oxygen saturation [0-100%] were demonstrated to introduce substantial distortions to receptor binding estimates (error \u3e 30%), whereas sampled depth was relatively insensitive to wavelength (error \u3c 6%). In response, a pixel-by-pixel normalization of tracer inputs immediately post-injection was found to account for spatial heterogeneities in local absorption properties. Application of the pixel-based normalization method to an in vivo imaging study demonstrated significant improvement, as compared with a reference tissue normalization approach

Signal Intensity Analysis and Optimization for in Vivo Imaging of Cherenkov and Excited Luminescence.

During external beam radiotherapy (EBRT), in vivo Cherenkov optical emissions can be used as a dosimetry tool or to excite luminescence, termed Cherenkov-excited luminescence (CEL) with microsecond-level time-gated cameras. The goal of this work was to develop a complete theoretical foundation for the detectable signal strength, in order to provide guidance on optimization of the limits of detection and how to optimize near real time imaging. The key parameters affecting photon production, propagation and detection were considered and experimental validation with both tissue phantoms and a murine model are shown. Both the theoretical analysis and experimental data indicate that the detection level is near a single photon-per-pixel for the detection geometry and frame rates commonly used, with the strongest factor being the signal decrease with the square of distance from tissue to camera. Experimental data demonstrates how the SNR improves with increasing integration time, but only up to the point where the dominance of camera read noise is overcome by stray photon noise that cannot be suppressed. For the current camera in a fixed geometry, the signal to background ratio limits the detection of light signals, and the observed in vivo Cherenkov emission is on the order of 100×  stronger than CEL signals. As a result, imaging signals from depths  \u3c 15 mm is reasonable for Cherenkov light, and depths  \u3c 3 mm is reasonable for CEL imaging. The current investigation modeled Cherenkov and CEL imaging of two oxygen sensing phosphorescent compounds, but the modularity of the code allows for easy comparison of different agents or alternative cameras, geometries or tissues

Cherenkov Excited Short-Wavelength Infrared Fluorescence Imaging in vivo with External Beam Radiation

Cherenkov emission induced by external beam radiation therapy from a clinical linear accelerator (LINAC) can be used to excite phosphors deep in biological tissues. As with all luminescence imaging, there is a desire to minimize the spectral overlap between the excitation light and emission wavelengths, here between the Cherenkov and the phosphor. Cherenkov excited short-wavelength infrared (SWIR, 1000 to 1700 nm) fluorescence imaging has been demonstrated for the first time, using long Stokes-shift fluorophore PdSe quantum dots (QD) with nanosecond lifetime and an optimized SWIR detection. The 1  /  λ2 intensity spectrum characteristic of Cherenkov emission leads to low overlap of this into the fluorescence spectrum of PdSe QDs in the SWIR range. Additionally, using a SWIR camera itself inherently ignores the stronger Cherenkov emission wavelengths dominant across the visible spectrum. The SWIR luminescence was shown to extend the depth sensitivity of Cherenkov imaging, which could be used for applications in radiotherapy sensing and imaging in human tissue with targeted molecular probes

Mapping the stellar structure of the Milky Way thick disk and halo using SEGUE photometry

We map the stellar structure of the Galactic thick disk and halo by applying color-magnitude diagram (CMD) fitting to photometric data from the SEGUE survey, allowing, for the first time, a comprehensive analysis of their structure at both high and low latitudes using uniform SDSS photometry. Incorporating photometry of all relevant stars simultaneously, CMD fitting bypasses the need to choose single tracer populations. Using old stellar populations of differing metallicities as templates we obtain a sparse 3D map of the stellar mass distribution at |Z|>1 kpc. Fitting a smooth Milky Way model comprising exponential thin and thick disks and an axisymmetric power-law halo allows us to constrain the structural parameters of the thick disk and halo. The thick-disk scale height and length are well constrained at 0.75+-0.07 kpc and 4.1+-0.4 kpc, respectively. We find a stellar halo flattening within ~25 kpc of c/a=0.88+-0.03 and a power-law index of 2.75+-0.07 (for 7<R_{GC}<~30 kpc). The model fits yield thick-disk and stellar halo densities at the solar location of rho_{thick,sun}=10^{-2.3+-0.1} M_sun pc^{-3} and rho_{halo,sun}=10^{-4.20+-0.05} M_sun pc^{-3}, averaging over any substructures. Our analysis provides the first clear in situ evidence for a radial metallicity gradient in the Milky Way's stellar halo: within R<~15 kpc the stellar halo has a mean metallicity of [Fe/H]=-1.6, which shifts to [Fe/H]=-2.2 at larger radii. Subtraction of the best-fit smooth and symmetric model from the overall density maps reveals a wealth of substructures at all latitudes, some attributable to known streams and overdensities, and some new. A simple warp cannot account for the low latitude substructure, as overdensities occur simultaneously above and below the Galactic plane. (abridged)Comment: 13 pages, 10 figures, accepted for publication in Astrophysical Journa

Binary Contamination in the SEGUE sample: Effects on SSPP Determinations of Stellar Atmospheric Parameters

Using numerical modeling and a grid of synthetic spectra, we examine the effects that unresolved binaries have on the determination of various stellar atmospheric parameters for SEGUE targets measured using the SEGUE Stellar Parameter Pipeline (SSPP). To model undetected binaries that may be in the SEGUE sample, we use a variety of mass distributions for the primary and secondary stars in conjunction with empirically determined relationships for orbital parameters to determine the fraction of G-K dwarf stars, as defined by SDSS color cuts, that will be blended with a secondary companion. We focus on the G-K dwarf sample in SEGUE as it records the history of chemical enrichment in our galaxy. To determine the effect of the secondary on the spectroscopic parameters, we synthesize a grid of model spectra from 3275 to 7850 K (~0.1 to 1.0 \msun) and [Fe/H]=-0.5 to -2.5 from MARCS model atmospheres using TurboSpectrum. We analyze both "infinite" signal-to-noise ratio (S/N) models and degraded versions, at median S/N of 50, 25 and 10. By running individual and combined spectra (representing the binaries) through the SSPP, we determine that ~10% of the blended G-K dwarf pairs with S/N>=25 will have their atmospheric parameter determinations, in particular temperature and metallicity, noticeably affected by the presence of an undetected secondary. To account for the additional uncertainty from binary contamination at a S/N~10, uncertainties of ~140 K and ~0.17 dex in [Fe/H] must be added in quadrature to the published uncertainties of the SSPP. (Abridged)Comment: 68 pages, 20 figures, 9 table

Single or Double Degenerate Progenitors? Searching for Shock Emission in the SDSS-II Type Ia Supernovae

From the set of nearly 500 spectroscopically confirmed type~Ia supernovae and around 10,000 unconfirmed candidates from SDSS-II, we select a subset of 108 confirmed SNe Ia with well-observed early-time light curves to search for signatures from shock interaction of the supernova with a companion star. No evidence for shock emission is seen; however, the cadence and photometric noise could hide a weak shock signal. We simulate shocked light curves using SN Ia templates and a simple, Gaussian shock model to emulate the noise properties of the SDSS-II sample and estimate the detectability of the shock interaction signal as a function of shock amplitude, shock width, and shock fraction. We find no direct evidence for shock interaction in the rest-frame $B$-band, but place an upper limit on the shock amplitude at 9% of supernova peak flux ($M_B > -16.6$ mag). If the single degenerate channel dominates type~Ia progenitors, this result constrains the companion stars to be less than about 6 $M_{\odot}$ on the main sequence, and strongly disfavors red giant companions.Comment: 28 pages, 3 figure

Mass Models and Sunyaev-Zeldovich Effect Predictions for a Flux Limited Sample of 22 Nearby X-Ray Clusters

We define a 90% complete, volume-limited sample of 31 z<0.1 x-ray clusters and present a systematic analysis of public ROSAT PSPC data on 22 of these objects. Our efforts are undertaken in support of the Penn/OVRO SZE survey, and to this end we present predictions for the inverse Compton optical depth towards all 22 of these clusters. We have performed detailed Monte Carlo simulations to understand the effects of the cluster profile uncertainties on the SZE predictions given the OVRO 5.5-meter telescope beam and switching patterns; we find that the profile uncertainties are one of the least significant components of our error budget for SZE-based distance measurements. We also present baryonic masses and baryon mass fractions derived under the assumption of hydrostatic equilibrium for these 22 clusters. The mean baryonic mass fraction within R_500 \sim 500 h^-1 kpc is (7.02 \pm 0.28) x 10^-2 h^-3/2, or (19.8 \pm 0.8) x 10^-2 for h=0.5. We confirm the Allen et al. (1993) claim of an excess absorbing column density towards Abell 478, but do not find similar anomalies in the other 21 clusters in our sample. We also find some evidence for an excess of soft counts in the ROSAT PSPC data. A measurement of H_o using these models and OVRO SZE determinations will be presented in a second paper.Comment: 51 pages, 6 figures included in text. Added comparison of different cosmologies; accepted for publication in Ap

Dynamic Dual-Tracer MRI-Guided Fluorescence Tomography to Quantify Receptor Density In Vivo

The up-regulation of cell surface receptors has become a central focus in personalized cancer treatment; however, because of the complex nature of contrast agent pharmacokinetics in tumor tissue, methods to quantify receptor binding in vivo remain elusive. Here, we present a dual-tracer optical technique for noninvasive estimation of specific receptor binding in cancer. A multispectral MRI-coupled fluorescence molecular tomography system was used to image the uptake kinetics of two fluorescent tracers injected simultaneously, one tracer targeted to the receptor of interest and the other tracer a nontargeted reference. These dynamic tracer data were then fit to a dual-tracer compartmental model to estimate the density of receptors available for binding in the tissue. Applying this approach to mice with deep-seated gliomas that overexpress the EGF receptor produced an estimate of available receptor density of 2.3 ± 0.5 nM (n = 5), consistent with values estimated in comparative invasive imaging and ex vivo studies

Dual-Tracer Background Subtraction Approach for Fluorescent Molecular Tomography

Diffuse fluorescence tomography requires high contrast-to-background ratios to accurately reconstruct inclusions of interest. This is a problem when imaging the uptake of fluorescently labeled molecularly targeted tracers in tissue, which can result in high levels of heterogeneously distributed background uptake. We present a dual-tracer background subtraction approach, wherein signal from the uptake of an untargeted tracer is subtracted from targeted tracer signal prior to image reconstruction, resulting in maps of targeted tracer binding. The approach is demonstrated in simulations, a phantom study, and in a mouse glioma imaging study, demonstrating substantial improvement over conventional and homogenous background subtraction image reconstruction approaches

A Photometric Metallicity Estimate of the Virgo Stellar Overdensity

We determine photometric metal abundance estimates for individual main-sequence stars in the Virgo Overdensity (VOD), which covers almost 1000 deg^2 on the sky, based on a calibration of the metallicity sensitivity of stellar isochrones in the gri filter passbands using field stars with well-determined spectroscopic metal abundances. Despite the low precision of the method for individual stars, we derive [Fe/H] = -2.0 +/-0.1 (internal) +/-0.5 (systematic) for the metal abundance of the VOD from photometric measurements of 0.7 million stars in the Northern Galactic hemisphere with heliocentric distances from ~10 kpc to ~20 kpc. The metallicity of the VOD is indistinguishable, within Delta [Fe/H] < 0.2, from that of field halo stars covering the same distance range. This initial application suggests that the SDSS gri passbands can be used to probe the properties of main-sequence stars beyond ~10 kpc, complementing studies of nearby stars from more metallicity-sensitive color indices that involve the u passband.Comment: 5 pages, 3 figures, Accepted for publication in ApJ Letter