Analysis of Multiple Sarcoma Expression Datasets: Implications for Classification, Oncogenic Pathway Activation and Chemotherapy Resistance

Background: Diagnosis of soft tissue sarcomas (STS) is challenging. Many remain unclassified (not-otherwise-specified, NOS) or grouped in controversial categories such as malignant fibrous histiocytoma (MFH), with unclear therapeutic value. We analyzed several independent microarray datasets, to identify a predictor, use it to classify unclassifiable sarcomas, and assess oncogenic pathway activation and chemotherapy response. Methodology/Principal Findings: We analyzed 5 independent datasets (325 tumor arrays). We developed and validated a predictor, which was used to reclassify MFH and NOS sarcomas. The molecular “match” between MFH and their predicted subtypes was assessed using genome-wide hierarchical clustering and Subclass-Mapping. Findings were validated in 15 paraffin samples profiled on the DASL platform. Bayesian models of oncogenic pathway activation and chemotherapy response were applied to individual STS samples. A 170-gene predictor was developed and independently validated (80-85% accuracy in all datasets). Most MFH and NOS tumors were reclassified as leiomyosarcomas, liposarcomas and fibrosarcomas. “Molecular match” between MFH and their predicted STS subtypes was confirmed both within and across datasets. This classification revealed previously unrecognized tissue differentiation lines (adipocyte, fibroblastic, smooth-muscle) and was reproduced in paraffin specimens. Different sarcoma subtypes demonstrated distinct oncogenic pathway activation patterns, and reclassified MFH tumors shared oncogenic pathway activation patterns with their predicted subtypes. These patterns were associated with predicted resistance to chemotherapeutic agents commonly used in sarcomas. Conclusions/Significance: STS profiling can aid in diagnosis through a predictor tracking distinct tissue differentiation in unclassified tumors, and in therapeutic management via oncogenic pathway activation and chemotherapy response assessment

Measuring the mass of the central black hole in the bulgeless galaxy ngc 4395 from gas dynamical modeling

NGC 4395 is a bulgeless spiral galaxy, harboring one of the nearest known type 1 Seyfert nuclei. Although there is no consensus on the mass of its central engine, several estimates suggest it is one of the lightest massive black holes (MBHs) known. We present the first direct dynamical measurement of the mass of this MBH from a combination of two-dimensional gas kinematic data, obtained with the adaptive optics assisted near-infrared integral field spectrograph Gemini/NIFS and high-resolution multiband photometric data from Hubble Space Telescope's Wide Field Camera 3. We use the photometric data to model the shape and stellar mass-to-light ratio of the nuclear star cluster (NSC). From the Gemini/NIFS observations, we derive the kinematics of warm molecular hydrogen gas as traced by emission through the H2 1–0 S(1) transition. These kinematics show a clear rotational signal, with a position angle orthogonal to NGC 4395's radio jet. Our best-fitting tilted ring models of the kinematics of the molecular hydrogen gas contain a black hole with mass M={4}-3+8× {10}5 M⊙ (3σ uncertainties) embedded in an NSC of mass M=2× {10}6 M⊙. Our black hole mass measurement is in excellent agreement with the reverberation mapping mass estimate of Peterson et al. but shows some tension with other mass measurement methods based on accretion signals

HST/ACS Emission Line Imaging of Low Redshift 3CR Radio Galaxies I: The Data

We present 19 nearby (z<0.3) 3CR radio galaxies imaged at low- and high-excitation as part of a Cycle 15 Hubble Space Telescope snapshot survey with the Advanced Camera for Surveys. These images consist of exposures of the H-alpha (6563 \AA, plus [NII] contamination) and [OIII] 5007 \AA emission lines using narrow-band linear ramp filters adjusted according to the redshift of the target. To facilitate continuum subtraction, a single-pointing 60 s line-free exposure was taken with a medium-band filter appropriate for the target's redshift. We discuss the steps taken to reduce these images independently of the automated recalibration pipeline so as to use more recent ACS flat-field data as well as to better reject cosmic rays. We describe the method used to produce continuum-free (pure line-emission) images, and present these images along with qualitative descriptions of the narrow-line region morphologies we observe. We present H-alpha+[NII] and [OIII] line fluxes from aperture photometry, finding the values to fall expectedly on the redshift-luminosity trend from a past HST/WFPC2 emission line study of a larger, generally higher redshift subset of the 3CR. We also find expected trends between emission line luminosity and total radio power, as well as a positive correlation between the size of the emission line region and redshift. We discuss the associated interpretation of these results, and conclude with a summary of future work enabled by this dataset.Comment: 18 pages, 12 figures, accepted for publication in ApJ

MicroRNA paraffin-based studies in osteosarcoma reveal reproducible independent prognostic profiles at 14q32

Background: Although microRNAs (miRNAs) are implicated in osteosarcoma biology and chemoresponse, miRNA prognostic models are still needed, particularly because prognosis is imperfectly correlated with chemoresponse. Formalin-fixed, paraffin-embedded tissue is a necessary resource for biomarker studies in this malignancy with limited frozen tissue availability. Methods: We performed miRNA and mRNA microarray formalin-fixed, paraffin-embedded assays in 65 osteosarcoma biopsy and 26 paired post-chemotherapy resection specimens and used the only publicly available miRNA dataset, generated independently by another group, to externally validate our strongest findings (n = 29). We used supervised principal components analysis and logistic regression for survival and chemoresponse, and miRNA activity and target gene set analysis to study miRNA regulatory activity. Results: Several miRNA-based models with as few as five miRNAs were prognostic independently of pathologically assessed chemoresponse (median recurrence-free survival: 59 months versus not-yet-reached; adjusted hazards ratio = 2.90; P = 0.036). The independent dataset supported the reproducibility of recurrence and survival findings. The prognostic value of the profile was independent of confounding by known prognostic variables, including chemoresponse, tumor location and metastasis at diagnosis. Model performance improved when chemoresponse was added as a covariate (median recurrence-free survival: 59 months versus not-yet-reached; hazard ratio = 3.91; P = 0.002). Most prognostic miRNAs were located at 14q32 - a locus already linked to osteosarcoma - and their gene targets display deregulation patterns associated with outcome. We also identified miRNA profiles predictive of chemoresponse (75% to 80% accuracy), which did not overlap with prognostic profiles. Conclusions: Formalin-fixed, paraffin-embedded tissue-derived miRNA patterns are a powerful prognostic tool for risk-stratified osteosarcoma management strategies. Combined miRNA and mRNA analysis supports a possible role of the 14q32 locus in osteosarcoma progression and outcome. Our study creates a paradigm for formalin-fixed, paraffin-embedded-based miRNA biomarker studies in cancer

Precise Black Hole Masses From Megamaser Disks: Black Hole-Bulge Relations at Low Mass

The black hole (BH)-bulge correlations have greatly influenced the last decade of effort to understand galaxy evolution. Current knowledge of these correlations is limited predominantly to high BH masses (M_BH> 10^8 M_sun) that can be measured using direct stellar, gas, and maser kinematics. These objects, however, do not represent the demographics of more typical L< L* galaxies. This study transcends prior limitations to probe BHs that are an order of magnitude lower in mass, using BH mass measurements derived from the dynamics of H_2O megamasers in circumnuclear disks. The masers trace the Keplerian rotation of circumnuclear molecular disks starting at radii of a few tenths of a pc from the central BH. Modeling of the rotation curves, presented by Kuo et al. (2010), yields BH masses with exquisite precision. We present stellar velocity dispersion measurements for a sample of nine megamaser disk galaxies based on long-slit observations using the B&C spectrograph on the Dupont telescope and the DIS spectrograph on the 3.5m telescope at Apache Point. We also perform bulge-to-disk decomposition of a subset of five of these galaxies with SDSS imaging. The maser galaxies as a group fall below the M_BH-sigma* relation defined by elliptical galaxies. We show, now with very precise BH mass measurements, that the low-scatter power-law relation between M_BH and sigma* seen in elliptical galaxies is not universal. The elliptical galaxy M_BH-sigma* relation cannot be used to derive the BH mass function at low mass or the zeropoint for active BH masses. The processes (perhaps BH self-regulation or minor merging) that operate at higher mass have not effectively established an M_BH-sigma* relation in this low-mass regime.Comment: 21 pages, 14 figures, accepted for publication in the Astrophysical Journa

Observations of Arp 220 using Herschel-SPIRE: An Unprecedented View of the Molecular Gas in an Extreme Star Formation Environment

We present Herschel SPIRE-FTS observations of Arp~220, a nearby ULIRG. The FTS continuously covers 190 -- 670 microns, providing a good measurement of the continuum and detection of several molecular and atomic species. We detect luminous CO (J = 4-3 to 13-12) and water ladders with comparable total luminosity; very high-J HCN absorption; OH+, H2O+, and HF in absorption; and CI and NII. Modeling of the continuum yields warm dust, with T = 66 K, and an unusually large optical depth of ~5 at 100 microns. Non-LTE modeling of the CO shows two temperature components: cold molecular gas at T ~ 50 K and warm molecular gas at T ~1350 K. The mass of the warm gas is 10% of the cold gas, but dominates the luminosity of the CO ladder. The temperature of the warm gas is in excellent agreement with H2 rotational lines. At 1350 K, H2 dominates the cooling (~20 L_sun/M_sun) in the ISM compared to CO (~0.4 L_sun/M_sun). We found that only a non-ionizing source such as the mechanical energy from supernovae and stellar winds can excite the warm gas and satisfy the energy budget of ~20 L_sun/M_sun. We detect a massive molecular outflow in Arp 220 from the analysis of strong P-Cygni line profiles observed in OH+, H2O+, and H2O. The outflow has a mass > 10^{7} M_sun and is bound to the nuclei with velocity < 250 km/s. The large column densities observed for these molecular ions strongly favor the existence of an X-ray luminous AGN (10^{44} ergs/s) in Arp 220.Comment: Accepted in ApJ on September 1, 201

Gemini/GMOS Imaging of Globular Cluster Systems in Five Early-type Galaxies

This paper presents deep high quality photometry of globular cluster (GC) systems belonging to five early-type galaxies covering a range of mass and environment. Photometric data were obtained with the Gemini North and Gemini South telescopes in the filter passbands g', r', and i'. The combination of these filters with good seeing conditions allows an excellent separation between GC candidates and unresolved field objects. Bimodal GC colour distributions are found in all five galaxies. Most of the GC systems appear bimodal even in the (g' -r') vs (r' -i') plane. A population of resolved/marginally resolved GC and Ultra Compact Dwarf candidates was found in all the galaxies. A search for the so-called "blue tilt" in the colour-magnitude diagrams reveals that NGC 4649 clearly shows that phenomenon although no conclusive evidence was found for the other galaxies in the sample. This "blue tilt" translates into a mass-metallicity relation given by Z \propto M^0.28\pm0.03 . This dependence was found using a new empirical (g' -i') vs [Z/H] relation which relies on an homogeneous sample of GC colours and metallicities. This paper also explores the radial trends in both colour and surface density for the blue (metal-poor) and red (metal-rich) GC subpopulations. As usual, the red GCs show a steeper radial distribution than the blue ones. Evidence of galactocentric colour gradients is found in some of the GC systems, being more significant for the two S0 galaxies in the sample. Red GC subpopulations show similar colours and gradients to the galaxy halo stars in their inner region. A GC mean colour-galaxy luminosity relation, consistent with [Z/H] \propto L_B ^0.26\pm0.08, is present for the red GCs. An estimate of the total GC populations and specific frequency SN values is presented for NGC 3115, NGC 3379, NGC 3923 and NGC 4649.Comment: 23 pages, 13 figures and 9 tables. Tables A1 and A2 will be published in full online only. Accepted for publication in MNRA

Eight-Dimensional Mid-Infrared/Optical Bayesian Quasar Selection

We explore the multidimensional, multiwavelength selection of quasars from mid-IR (MIR) plus optical data, specifically from Spitzer-IRAC and the Sloan Digital Sky Survey (SDSS). We apply modern statistical techniques to combined Spitzer MIR and SDSS optical data, allowing up to 8-D color selection of quasars. Using a Bayesian selection method, we catalog 5546 quasar candidates to an 8.0 um depth of 56 uJy over an area of ~24 sq. deg; ~70% of these candidates are not identified by applying the same Bayesian algorithm to 4-color SDSS optical data alone. Our selection recovers 97.7% of known type 1 quasars in this area and greatly improves the effectiveness of identifying 3.5<z<5 quasars. Even using only the two shortest wavelength IRAC bandpasses, it is possible to use our Bayesian techniques to select quasars with 97% completeness and as little as 10% contamination. This sample has a photometric redshift accuracy of 93.6% (Delta Z +/-0.3), remaining roughly constant when the two reddest MIR bands are excluded. While our methods are designed to find type 1 (unobscured) quasars, as many as 1200 of the objects are type 2 (obscured) quasar candidates. Coupling deep optical imaging data with deep mid-IR data could enable selection of quasars in significant numbers past the peak of the quasar luminosity function (QLF) to at least z~4. Such a sample would constrain the shape of the QLF and enable quasar clustering studies over the largest range of redshift and luminosity to date, yielding significant gains in our understanding of quasars and the evolution of galaxies.Comment: 49 pages, 14 figures, 7 tables. AJ, accepte

Variability and Multiwavelength Detected AGN in the GOODS Fields

We identify 85 variable galaxies in the GOODS North and South fields using 5 epochs of HST ACS V-band (F606W) images spanning 6 months. The variables are identified through significant flux changes in the galaxy's nucleus and represent ~2% of the survey galaxies. With the aim of studying the active galaxy population in the GOODS fields, we compare the variability-selected sample with X-ray and mid-IR AGN candidates. Forty-nine percent of the variables are associated with X-ray sources identified in the 2Ms Chandra surveys. Twenty-four percent of X-ray sources likely to be AGN are optical variables and this percentage increases with decreasing hardness ratio of the X-ray emission. Stacking of the non-X-ray detected variables reveals marginally significant soft X-ray emission. Forty-eight percent of mid-IR power-law sources are optical variables, all but one of which are also X-ray detected. Thus, about half of the optical variables are associated with either X-ray or mid-IR power-law emission. The slope of the power-law fit through the Spitzer IRAC bands indicates that two-thirds of the variables have BLAGN-like SEDs. Among those galaxies spectroscopically identified as AGN, we observe variability in 74% of broad-line AGNs and 15% of NLAGNs. The variables are found in galaxies extending to z~3.6. We compare the variable galaxy colors and magnitudes to the X-ray and mid-IR sample and find that the non-X-ray detected variable hosts extend to bluer colors and fainter intrinsic magnitudes. The variable AGN candidates have Eddington ratios similar to those of X-ray selected AGN.Comment: 36 pages, 12 figures, ApJ accepte