NEXT-FLUX (Neural-net EXtracellular Trained Flux Constraints)

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First-in-Human Phase I Study to Evaluate the Brain-Penetrant PI3K/mTOR Inhibitor GDC-0084 in Patients with Progressive or Recurrent High-Grade Glioma.

PurposeGDC-0084 is an oral, brain-penetrant small-molecule inhibitor of PI3K and mTOR. A first-in-human, phase I study was conducted in patients with recurrent high-grade glioma.Patients and methodsGDC-0084 was administered orally, once daily, to evaluate safety, pharmacokinetics (PK), and activity. Fluorodeoxyglucose-PET (FDG-PET) was performed to measure metabolic responses.ResultsForty-seven heavily pretreated patients enrolled in eight cohorts (2-65 mg). Dose-limiting toxicities included 1 case of grade 2 bradycardia and grade 3 myocardial ischemia (15 mg), grade 3 stomatitis (45 mg), and 2 cases of grade 3 mucosal inflammation (65 mg); the MTD was 45 mg/day. GDC-0084 demonstrated linear and dose-proportional PK, with a half-life (∼19 hours) supportive of once-daily dosing. At 45 mg/day, steady-state concentrations exceeded preclinical target concentrations producing antitumor activity in xenograft models. FDG-PET in 7 of 27 patients (26%) showed metabolic partial response. At doses ≥45 mg/day, a trend toward decreased median standardized uptake value in normal brain was observed, suggesting central nervous system penetration of drug. In two resection specimens, GDC-0084 was detected at similar levels in tumor and brain tissue, with a brain tissue/tumor-to-plasma ratio of >1 and >0.5 for total and free drug, respectively. Best overall response was stable disease in 19 patients (40%) and progressive disease in 26 patients (55%); 2 patients (4%) were nonevaluable.ConclusionsGDC-0084 demonstrated classic PI3K/mTOR-inhibitor related toxicities. FDG-PET and concentration data from brain tumor tissue suggest that GDC-0084 crossed the blood-brain barrier

The Star Formation and Extinction Co-Evolution of UV-Selected Galaxies over 0.05<z<1.2

We use a new stacking technique to obtain mean mid IR and far IR to far UV flux ratios over the rest near-UV/near-IR color-magnitude diagram. We employ COMBO-17 redshifts and COMBO-17 optical, GALEX far and near UV, Spitzer IRAC and MIPS Mid IR photometry. This technique permits us to probe infrared excess (IRX), the ratio of far IR to far UV luminosity, and specific star formation rate (SSFR) and their co-evolution over two orders of magnitude of stellar mass and redshift 0.1<z<1.2. We find that the SSFR and the characteristic mass (M_0) above which the SSFR drops increase with redshift (downsizing). At any given epoch, IRX is an increasing function of mass up to M_0. Above this mass IRX falls, suggesting gas exhaustion. In a given mass bin below M_0 IRX increases with time in a fashion consistent with enrichment. We interpret these trends using a simple model with a Schmidt-Kennicutt law and extinction that tracks gas density and enrichment. We find that the average IRX and SSFR follows a galaxy age parameter which is determined mainly by the galaxy mass and time since formation. We conclude that blue sequence galaxies have properties which show simple, systematic trends with mass and time such as the steady build-up of heavy elements in the interstellar media of evolving galaxies and the exhaustion of gas in galaxies that are evolving off the blue sequence. The IRX represents a tool for selecting galaxies at various stages of evolution.Comment: Accepted for publication in GALEX Special Ap.J.Suppl., December, 200

Ultraviolet through Infrared Spectral Energy Distributions from 1000 SDSS Galaxies: Dust Attenuation

The meaningful comparison of models of galaxy evolution to observations is critically dependent on the accurate treatment of dust attenuation. To investigate dust absorption and emission in galaxies we have assembled a sample of ~1000 galaxies with ultraviolet (UV) through infrared (IR) photometry from GALEX, SDSS, and Spitzer and optical spectroscopy from SDSS. The ratio of IR to UV emission (IRX) is used to constrain the dust attenuation in galaxies. We use the 4000A break as a robust and useful, although coarse, indicator of star formation history (SFH). We examine the relationship between IRX and the UV spectral slope (a common attenuation indicator at high-redshift) and find little dependence of the scatter on 4000A break strength. We construct average UV through far-IR spectral energy distributions (SEDs) for different ranges of IRX, 4000A break strength, and stellar mass (M_*) to show the variation of the entire SED with these parameters. When binned simultaneously by IRX, 4000A break strength, and M_* these SEDs allow us to determine a low resolution average attenuation curve for different ranges of M_*. The attenuation curves thus derived are consistent with a lambda^{-0.7} attenuation law, and we find no significant variations with M_*. Finally, we show the relationship between IRX and the global stellar mass surface density and gas-phase-metallicity. Among star forming galaxies we find a strong correlation between IRX and stellar mass surface density, even at constant metallicity, a result that is closely linked to the well-known correlation between IRX and star-formation rate.Comment: 12 pages, 8 figures, 2 tables, appearing in the Dec 2007 GALEX special issue of ApJ Supp (29 papers

A GALEX Ultraviolet Imaging Survey of Galaxies in the Local Volume

We present results from a GALEX ultraviolet (UV) survey of a complete sample of 390 galaxies within ~11 Mpc of the Milky Way. The UV data are a key component of the composite Local Volume Legacy (LVL), an ultraviolet-to-infrared imaging program designed to provide an inventory of dust and star formation in nearby spiral and irregular galaxies. The ensemble dataset is an especially valuable resource for studying star formation in dwarf galaxies, which comprise over 80% of the sample. We describe the GALEX survey programs which obtained the data and provide a catalog of far-UV (~1500 Angstroms) and near-UV (~2200 Angstroms) integrated photometry. General UV properties of the sample are briefly discussed. We compute two measures of the global star formation efficiency, the SFR per unit HI gas mass and the SFR per unit stellar mass, to illustrate the significant differences that can arise in our understanding of dwarf galaxies when the FUV is used to measure the SFR instead of H-alpha. We find that dwarf galaxies may not be as drastically inefficient in coverting gas into stars as suggested by prior H-alpha studies. In this context, we also examine the UV properties of late-type dwarf galaxies that appear to be devoid of star formation because they were not detected in previous H-alpha narrowband observations. Nearly all such galaxies in our sample are detected in the FUV, and have FUV SFRs that fall below the limit where the H-alpha flux is robust to Poisson fluctuations in the formation of massive stars. The UV colors and star formation efficiencies of H-alpha-undetected, UV-bright dwarf irregulars appear to be relatively unremarkable with respect to those exhibited by the general population of star-forming galaxies.Comment: submitted to ApJS, revised per referee's comments; accepted Oct. 30 w/o further revision; 37 pages; figure 6 omitted due to size; figure available from http://users.obs.carnegiescience.edu/jlee/paper

The Young and the Dustless: Interpreting Radio Observations of UltraViolet Luminous Galaxies

Ultraviolet Luminous Galaxies (UVLGs) have been identified as intensely star-forming, nearby galaxies. A subset of these, the supercompact UVLGs, are believed to be local analogs of high redshift Lyman Break Galaxies. Here we investigate the radio continuum properties of this important population for the first time. We have observed 42 supercompact UVLGs with the VLA, all of which have extensive coverage in the UV/optical by GALEX and SDSS. Our analysis includes comparison samples of multiwavelength data from the Spitzer First Look Survey and from the SDSS-Galex matched catalogs. In addition we have Spitzer MIPS data for 24 of our galaxies and find that they fall on the radio-FIR correlation of normal star-forming galaxies. We find that our galaxies have lower radio-to-UV ratios and lower Balmer decrements than other local galaxies with similar (high) star formation rates. Optical spectra show they have lower Dn(4000) and HdeltaA indices, higher Hbeta emission-line equivalents widths, and higher [OIII]5007/Hbeta emission-line ratios than normal star forming galaxies. Comparing these results to galaxy spectral evolution models we conclude that supercompact UVLGs are distinguished from normal star forming galaxies firstly by their high specific star formation rates. Moreover, compared to other types of galaxies with similar star formation rates, they have significantly less dust attenuation. In both regards they are similar to Lyman Break Galaxies. This suggests that the process that causes star formation in the supercompact UVLGs differs from other local star forming galaxies, but may be similar to Lyman Break Galaxies.Comment: 37 pages, 13 figures, accepted and scheduled to appear in ApJS December 2007 (GALEX Special Issue

Science based tools informing coastal management in a changing climate

To better inform decisions associated with coastal management a database of numerical simulations has been generated using publically available data to populate an online decision-support tool (DST). This research is part of the Adaptation and Resilience of Coastal Energy Supply (ARCoES) project that focuses on areas of critical coastal energy infrastructure within the UK, such as nuclear power station locations. This web-based tool has been developed with coastal and energy sector practitioners to produce a system that visualizes plausible future changes in flood hazard to assess when ‘tipping points’ in a location’s management strategy may be required in response to rising sea levels and storms over the next 500 years. Although the main product is focused on vulnerability to flooding, additional research on the natural resilience of shorelines has also been considered in relation to future adaptation strategies. These findings are fed into economic models developed through ARCoES to assess the cost-benefit impacts or real option

UV Star Formation Rates in the Local Universe

We measure star formation rates of ~50,000 optically-selected galaxies in the local universe (z~0.1), spanning a range from gas-rich dwarfs to massive ellipticals. We obtain dust-corrected SFRs by fitting the GALEX (UV) and SDSS (optical) photometry to a library of population synthesis models that include dust attenuation. For star-forming galaxies, our UV-based SFRs compare remarkably well with those derived from SDSS H alpha. Deviations from perfect agreement between these two methods are due to differences in the dust attenuation estimates. In contrast to H alpha, UV provides reliable SFRs for galaxies with weak or no H alpha emission, and where H alpha is contaminated with an emission from an AGN. We use full-SED SFRs to calibrate a simple prescription that uses GALEX UV magnitudes to produce good SFRs for normal star-forming galaxies. The specific SFR is considered as a function of stellar mass for (1) star-forming galaxies with no AGN, (2) those hosting an AGN, and for (3) galaxies without H alpha emission. We find that the three have distinct star formation histories, with AGN lying intermediate between the star-forming and the quiescent galaxies. Normal star forming galaxies (without an AGN) lie on a relatively narrow linear sequence. Remarkably, galaxies hosting a strong AGN appear to represent the massive continuation of this sequence. Weak AGN, while also massive, have lower SFR, sometimes extending to the realm of quiescent galaxies. We propose an evolutionary sequence for massive galaxies that smoothly connects normal star-forming galaxies to quiescent (red sequence) galaxies via strong and weak AGN. We confirm that some galaxies with no H alpha emission show signs of SF in the UV. We derive a UV-based cosmic SFR density at z=0.1 with smaller total error than previous measurements (abridged).Comment: Accepted for publication in ApJ (Special GALEX Supplement issue - Dec 2007). v2: Typo in Eq. 2 correcte