183 research outputs found
Mechanistic interrogation of combination Bevacizumab/dual PI3K/mTOR inhibitor response in Glioblastoma implementing novel MR and PET imaging biomarkers.
Purpose:
Resistance to bevacizumab (BEV) in glioblastoma (GBM) is believed to occur via activation of molecular networks including the mTOR/PI3K pathway. Implementing an MRI/PET molecular imaging biomarker approach, we sought to interrogate response to combining BEV with the mTOR/PI3K inhibitor BEZ235.
Methods:
Tumors were established by orthotopically implanting U87MG-luc2 in mice. Animals were treated with BEZ235 and/or BEV, and imaged using diffusion weighted-MRI, T2 weighted (T2w), and T2* weighted (T2*w) before and following delivery of superparamagnetic iron oxide (SPIO) contrast. Maps for changes in relaxation rates: ΔR2, ΔR2* and apparent diffusion coefficient (ADC) were calculated. Vessel Size Index (VSI) and micro vessel density index (MDI) were derived. 3´-deoxy-3´-[18F]fluorothymidine ([18F]FLT)- and O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) PET was further performed and tumor endothelium/proliferation markers assessed by immunohistochemistry.
Results:
Treatment with BEV resulted in a pronounced decrease in tumor volume (T2w MRI). No additive effect on tumour volume was observed in BEV/BEZ235 combination compared with BEV monotherapy. Ki67 proliferation index staining and [18F]FLT uptake studies were used to support observations. Using ΔR2* and ΔR2 values respectively, BEZ235 + BEV combination significantly reduced tumor microvessel volume in comparison to BEV alone. Decreased MDI was further observed in the combination group; supported by von Willebrand Factor (vWF) immunohistochemistry. We observed decreased [18F]FET uptake following BEV, but failed to observe further reduced [18F]FET uptake in the combination cohort. vWF IHC analysis showed mean tumor vessel size increased in all cohorts. Conclusions: Assessing MR imaging biomarker parameters together with [18F]FET and [18F]FLT PET, informed drug combination mechanism of action and provided clues as to potential clinical response. Translation of a BEZ35/BEV combination regimen could support reduction of peritumoral edemaobviating the requirement for steroids. Implementing hypothesis driven molecular imaging studies facilitates the interrogation of drug response in the pre-clinic. These data may more accurately predict the clinical potential of novel therapeutic approaches in oncology
The Atacama Cosmology Telescope: Sunyaev-Zel'dovich Selected Galaxy Clusters at 148 GHz from Three Seasons of Data
[Abridged] We present a catalog of 68 galaxy clusters, of which 19 are new
discoveries, detected via the Sunyaev-Zel'dovich effect (SZ) at 148 GHz in the
Atacama Cosmology Telescope (ACT) survey of 504 square degrees on the celestial
equator. A subsample of 48 clusters within the 270 square degree region
overlapping SDSS Stripe 82 is estimated to be 90% complete for M_500c > 4.5e14
Msun and 0.15 < z < 0.8. While matched filters are used to detect the clusters,
the sample is studied further through a "Profile Based Amplitude Analysis"
using a single filter at a fixed \theta_500 = 5.9' angular scale. This new
approach takes advantage of the "Universal Pressure Profile" (UPP) to fix the
relationship between the cluster characteristic size (R_500) and the integrated
Compton parameter (Y_500). The UPP scalings are found to be nearly identical to
an adiabatic model, while a model incorporating non-thermal pressure better
matches dynamical mass measurements and masses from the South Pole Telescope. A
high signal to noise ratio subsample of 15 ACT clusters is used to obtain
cosmological constraints. We first confirm that constraints from SZ data are
limited by uncertainty in the scaling relation parameters rather than sample
size or measurement uncertainty. We next add in seven clusters from the ACT
Southern survey, including their dynamical mass measurements based on galaxy
velocity dispersions. In combination with WMAP7 these data simultaneously
constrain the scaling relation and cosmological parameters, yielding \sigma_8 =
0.829 \pm 0.024 and \Omega_m = 0.292 \pm 0.025. The results include
marginalization over a 15% bias in dynamical mass relative to the true halo
mass. In an extension to LCDM that incorporates non-zero neutrino mass density,
we combine our data with WMAP7+BAO+Hubble constant measurements to constrain
\Sigma m_\nu < 0.29 eV (95% C. L.).Comment: 32 pages, 21 figures To appear in J. Cosmology and Astroparticle
Physic
The Atacama Cosmology Telescope: Temperature and Gravitational Lensing Power Spectrum Measurements from Three Seasons of Data
We present the temperature power spectra of the cosmic microwave background
(CMB) derived from the three seasons of data from the Atacama Cosmology
Telescope (ACT) at 148 GHz and 218 GHz, as well as the cross-frequency spectrum
between the two channels. We detect and correct for contamination due to the
Galactic cirrus in our equatorial maps. We present the results of a number of
tests for possible systematic error and conclude that any effects are not
significant compared to the statistical errors we quote. Where they overlap, we
cross-correlate the ACT and the South Pole Telescope (SPT) maps and show they
are consistent. The measurements of higher-order peaks in the CMB power
spectrum provide an additional test of the Lambda CDM cosmological model, and
help constrain extensions beyond the standard model. The small angular scale
power spectrum also provides constraining power on the Sunyaev-Zel'dovich
effects and extragalactic foregrounds. We also present a measurement of the CMB
gravitational lensing convergence power spectrum at 4.6-sigma detection
significance.Comment: 21 pages; 20 figures, Submitted to JCAP, some typos correcte
The Atacama Cosmology Telescope: Cosmological parameters from three seasons of data
We present constraints on cosmological and astrophysical parameters from
high-resolution microwave background maps at 148 GHz and 218 GHz made by the
Atacama Cosmology Telescope (ACT) in three seasons of observations from 2008 to
2010. A model of primary cosmological and secondary foreground parameters is
fit to the map power spectra and lensing deflection power spectrum, including
contributions from both the thermal Sunyaev-Zeldovich (tSZ) effect and the
kinematic Sunyaev-Zeldovich (kSZ) effect, Poisson and correlated anisotropy
from unresolved infrared sources, radio sources, and the correlation between
the tSZ effect and infrared sources. The power ell^2 C_ell/2pi of the thermal
SZ power spectrum at 148 GHz is measured to be 3.4 +\- 1.4 muK^2 at ell=3000,
while the corresponding amplitude of the kinematic SZ power spectrum has a 95%
confidence level upper limit of 8.6 muK^2. Combining ACT power spectra with the
WMAP 7-year temperature and polarization power spectra, we find excellent
consistency with the LCDM model. We constrain the number of effective
relativistic degrees of freedom in the early universe to be Neff=2.79 +\- 0.56,
in agreement with the canonical value of Neff=3.046 for three massless
neutrinos. We constrain the sum of the neutrino masses to be Sigma m_nu < 0.39
eV at 95% confidence when combining ACT and WMAP 7-year data with BAO and
Hubble constant measurements. We constrain the amount of primordial helium to
be Yp = 0.225 +\- 0.034, and measure no variation in the fine structure
constant alpha since recombination, with alpha/alpha0 = 1.004 +/- 0.005. We
also find no evidence for any running of the scalar spectral index, dns/dlnk =
-0.004 +\- 0.012.Comment: 26 pages, 22 figures. This paper is a companion to Das et al. (2013)
and Dunkley et al. (2013). Matches published JCAP versio
The Atacama Cosmology Telescope: Cosmology from Galaxy Clusters Detected via the Sunyaev-Zel'dovich Effect
We present constraints on cosmological parameters based on a sample of
Sunyaev-Zel'dovich-selected galaxy clusters detected in a millimeter-wave
survey by the Atacama Cosmology Telescope. The cluster sample used in this
analysis consists of 9 optically-confirmed high-mass clusters comprising the
high-significance end of the total cluster sample identified in 455 square
degrees of sky surveyed during 2008 at 148 GHz. We focus on the most massive
systems to reduce the degeneracy between unknown cluster astrophysics and
cosmology derived from SZ surveys. We describe the scaling relation between
cluster mass and SZ signal with a 4-parameter fit. Marginalizing over the
values of the parameters in this fit with conservative priors gives sigma_8 =
0.851 +/- 0.115 and w = -1.14 +/- 0.35 for a spatially-flat wCDM cosmological
model with WMAP 7-year priors on cosmological parameters. This gives a modest
improvement in statistical uncertainty over WMAP 7-year constraints alone.
Fixing the scaling relation between cluster mass and SZ signal to a fiducial
relation obtained from numerical simulations and calibrated by X-ray
observations, we find sigma_8 = 0.821 +/- 0.044 and w = -1.05 +/- 0.20. These
results are consistent with constraints from WMAP 7 plus baryon acoustic
oscillations plus type Ia supernoava which give sigma_8 = 0.802 +/- 0.038 and w
= -0.98 +/- 0.053. A stacking analysis of the clusters in this sample compared
to clusters simulated assuming the fiducial model also shows good agreement.
These results suggest that, given the sample of clusters used here, both the
astrophysics of massive clusters and the cosmological parameters derived from
them are broadly consistent with current models.Comment: 12 pages, 7 figures. Submitted to Ap
The Atacama Cosmology Telescope: Extragalactic Sources at 148 GHz in the 2008 Survey
We report on extragalactic sources detected in a 455 square-degree map of the
southern sky made with data at a frequency of 148 GHz from the Atacama
Cosmology Telescope 2008 observing season. We provide a catalog of 157 sources
with flux densities spanning two orders of magnitude: from 15 to 1500 mJy.
Comparison to other catalogs shows that 98% of the ACT detections correspond to
sources detected at lower radio frequencies. Three of the sources appear to be
associated with the brightest cluster galaxies of low redshift X-ray selected
galaxy clusters. Estimates of the radio to mm-wave spectral indices and
differential counts of the sources further bolster the hypothesis that they are
nearly all radio sources, and that their emission is not dominated by
re-emission from warm dust. In a bright (>50 mJy) 148 GHz-selected sample with
complete cross-identifications from the Australia Telescope 20 GHz survey, we
observe an average steepening of the spectra between 5, 20, and 148 GHz with
median spectral indices of , , and . When the
measured spectral indices are taken into account, the 148 GHz differential
source counts are consistent with previous measurements at 30 GHz in the
context of a source count model dominated by radio sources. Extrapolating with
an appropriately rescaled model for the radio source counts, the Poisson
contribution to the spatial power spectrum from synchrotron-dominated sources
with flux density less than 20 mJy is C^{\rm Sync} = (2.8 \pm 0.3) \times
10^{-6} \micro\kelvin^2.Comment: Accepted to Ap
The Atacama Cosmology Telescope: A Measurement of the Cosmic Microwave Background Power Spectrum at 148 and 218 GHz from the 2008 Southern Survey
We present measurements of the cosmic microwave background (CMB) power
spectrum made by the Atacama Cosmology Telescope at 148 GHz and 218 GHz, as
well as the cross-frequency spectrum between the two channels. Our results
clearly show the second through the seventh acoustic peaks in the CMB power
spectrum. The measurements of these higher-order peaks provide an additional
test of the {\Lambda}CDM cosmological model. At l > 3000, we detect power in
excess of the primary anisotropy spectrum of the CMB. At lower multipoles 500 <
l < 3000, we find evidence for gravitational lensing of the CMB in the power
spectrum at the 2.8{\sigma} level. We also detect a low level of Galactic dust
in our maps, which demonstrates that we can recover known faint, diffuse
signals.Comment: 19 pages, 13 figures. Submitted to ApJ. This paper is a companion to
Hajian et al. (2010) and Dunkley et al. (2010
The Atacama Cosmology Telescope: Two-Season ACTPol Spectra and Parameters
We present the temperature and polarization angular power spectra measured by
the Atacama Cosmology Telescope Polarimeter (ACTPol). We analyze night-time
data collected during 2013-14 using two detector arrays at 149 GHz, from 548
deg of sky on the celestial equator. We use these spectra, and the spectra
measured with the MBAC camera on ACT from 2008-10, in combination with Planck
and WMAP data to estimate cosmological parameters from the temperature,
polarization, and temperature-polarization cross-correlations. We find the new
ACTPol data to be consistent with the LCDM model. The ACTPol
temperature-polarization cross-spectrum now provides stronger constraints on
multiple parameters than the ACTPol temperature spectrum, including the baryon
density, the acoustic peak angular scale, and the derived Hubble constant.
Adding the new data to planck temperature data tightens the limits on damping
tail parameters, for example reducing the joint uncertainty on the number of
neutrino species and the primordial helium fraction by 20%.Comment: 23 pages, 25 figure
The Atacama Cosmology Telescope: Physical Properties and Purity of a Galaxy Cluster Sample Selected via the Sunyaev-Zel'dovich Effect
We present optical and X-ray properties for the first confirmed galaxy
cluster sample selected by the Sunyaev-Zel'dovich Effect from 148 GHz maps over
455 square degrees of sky made with the Atacama Cosmology Telescope. These
maps, coupled with multi-band imaging on 4-meter-class optical telescopes, have
yielded a sample of 23 galaxy clusters with redshifts between 0.118 and 1.066.
Of these 23 clusters, 10 are newly discovered. The selection of this sample is
approximately mass limited and essentially independent of redshift. We provide
optical positions, images, redshifts and X-ray fluxes and luminosities for the
full sample, and X-ray temperatures of an important subset. The mass limit of
the full sample is around 8e14 Msun, with a number distribution that peaks
around a redshift of 0.4. For the 10 highest significance SZE-selected cluster
candidates, all of which are optically confirmed, the mass threshold is 1e15
Msun and the redshift range is 0.167 to 1.066. Archival observations from
Chandra, XMM-Newton, and ROSAT provide X-ray luminosities and temperatures that
are broadly consistent with this mass threshold. Our optical follow-up
procedure also allowed us to assess the purity of the ACT cluster sample.
Eighty (one hundred) percent of the 148 GHz candidates with signal-to-noise
ratios greater than 5.1 (5.7) are confirmed as massive clusters. The reported
sample represents one of the largest SZE-selected sample of massive clusters
over all redshifts within a cosmologically-significant survey volume, which
will enable cosmological studies as well as future studies on the evolution,
morphology, and stellar populations in the most massive clusters in the
Universe.Comment: 20 pages, 15 figures, 6 tables. Accepted for publication in ApJ.
Higher resolution figures available at:
http://peumo.rutgers.edu/~felipe/e-prints
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