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

A NEWLY FORMING COLD FLOW PROTOGALACTIC DISK, A SIGNATURE of COLD ACCRETION from the COSMIC WEB

How galaxies form from, and are fueled by, gas from the intergalactic medium (IGM) remains one of the major unsolved problems in galaxy formation. While the classical Cold Dark Matter paradigm posits galaxies forming from cooling virialized gas, recent theory and numerical simulations have highlighted the importance of cold accretion flows - relatively cool (T ∼ few × 104 K) unshocked gas streaming along filaments into dark matter halos, including hot, massive, high-redshift halos. These flows are thought to deposit gas and angular momentum into the circumgalactic medium resulting in disk- or ring-like structures, eventually coalescing into galaxies forming at filamentary intersections. We earlier reported a bright, Lyα emitting filament near the QSO HS1549+19 at redshift z = 2.843 discovered with the Palomar Cosmic Web Imager. We now report that the bright part of this filament is an enormous (R > 100 kpc) rotating structure of hydrogen gas with a disk-like velocity profile consistent with a 4 × 1012 M o halo. The orbital time of the outer part of the what we term a "protodisk" is comparable to the virialization time and the age of the universe at this redshift. We propose that this protodisk can only have recently formed from cold gas flowing directly from the cosmic we

The Star Formation Rate Function of the Local Universe

We have derived the bivariate luminosity function for the far ultraviolet (1530Angstroms) and far infrared (60 microns). We used matched GALEX and IRAS data, and redshifts from NED and PSC-z. We have derived a total star formation luminosity function phi(L_{tot}), with L_{tot} = L_{FUV}+L_{FIR}. Using these, we determined the cosmic ``star formation rate'' function and density for the local universe. The total SFR function is fit very well by a log-normal distribution over five decades of luminosity. We find that the bivariate luminosity function phi(L_{FUV},L_{FIR}) shows a bimodal behavior, with L_{FIR} tracking L_{FUV} for L_{TOT}< 10^10 L_sun, and L_{FUV} saturating at 10^10 L_sun, while L_{TOT} L_{FIR} for higher luminosities. We also calculate the SFR density and compare it to other measurements.Comment: This paper will be published as part of the Galaxy Evolution Explorer (GALEX) Astrophysical Journal Letters Special Issue. Links to the full set of papers will be available at http:/www.galex.caltech.edu/PUBLICATIONS/ after November 22, 200

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

Extinction Corrected Star Formation Rates Empirically Derived from Ultraviolet-Optical Colors

Using a sample of galaxies from the Sloan Digital Sky Survey spectroscopic catalog with measured star-formation rates (SFRs) and ultraviolet (UV) photometry from the GALEX Medium Imaging Survey, we derived empirical linear correlations between the SFR to UV luminosity ratio and the UV-optical colors of blue sequence galaxies. The relations provide a simple prescription to correct UV data for dust attenuation that best reconciles the SFRs derived from UV and emission line data. The method breaks down for the red sequence population as well as for very blue galaxies such as the local ``supercompact'' UV luminous galaxies and the majority of high redshift Lyman Break Galaxies which form a low attenuation sequence of their own.Comment: 20 pages, 11 figures, accepted for publication in the ApJS GALEX special issu

Clustering Properties of restframe UV selected galaxies I: the correlation length derived from GALEX data in the local Universe

We present the first measurements of the angular correlation function of galaxies selected in the far (1530 A) and near (2310 A) Ultraviolet from the GALEX survey fields overlapping SDSS DR5 in low galactic extinction regions. The area used covers 120 sqdeg (GALEX - MIS) down to magnitude AB = 22, yielding a total of 100,000 galaxies. The mean correlation length is ~ 3.7 \pm 0.6 Mpc and no significant trend is seen for this value as a function of the limiting apparent magnitude or between the GALEX bands. This estimate is close to that found from samples of blue galaxies in the local universe selected in the visible, and similar to that derived at z ~ 3 for LBGs with similar rest frame selection criteria. This result supports models that predict anti-biasing of star forming galaxies at low redshift, and brings an additional clue to the downsizing of star formation at z<1.Comment: Accepted for publication in GALEX Special ApJs, December 200

UV emission and Star Formation in Stephan's Quintet

we present the first GALEX UV images of the well known interacting group of galaxies, Stephan's Quintet (SQ). We detect widespread UV emission throughout the group. However, there is no consistent coincidence between UV structure and emission in the optical, H\alpha, or HI. Excluding the foreground galaxy NGC7320 (Sd), most of the UV emission is found in regions associated with the two spiral members of the group, NGC7319 and NGC7318b, and the intragroup medium starburst SQ-A. The extinction corrected UV data are analyzed to investigate the overall star formation activity in SQ. It is found that the total star formation rate (SFR) of SQ is 6.69+-0.65 M_\sun/yr. Among this, 1.34+-0.16 M_sun/yr is due to SQ-A. This is in excellent agreement with that derived from extinction corrected H\alpha luminosity of SQ-A. The SFR in regions related to NGC 7319 is 1.98+-0.58 M_\sun/yr, most of which(68%) is contributed by the disk. The contribution from the 'young tail' is only 15%. In the UV, the 'young tail' is more extended (~100 kpc) and shows a loop-like structure, including the optical tail, the extragalactic HII regions recently discovered in H\alpha, and other UV emission regions discovered for the first time. The UV and optical colors of the 'old tail' are consistent with a single stellar population of age t ~10^{8.5+-0.4} yrs. The UV emission associated with NGC 7318b is found in a very large (~80 kpc) disk, with a net SFR of 3.37+-0.25 M_sun/yr. Several large UV emission regions are 30 -- 40 kpc away from the nucleus of NGC7318b. Although both NGC7319 and NGC7318b show peculiar UV morphology, their SFR is consistent with that of normal Sbc galaxies, indicating that the strength of star formation activity is not enhenced by interactions.Comment: This paper will be published as part of the Galaxy Evolution Explorer(GALEX) Astrophysical Journal Letters Special Issue. Links to the full set of papers will be available at http:/www.galex.caltech.edu/PUBLICATIONS/ after November 22, 200

Recent star formation in nearby galaxies from GALEX imaging:M101 and M51

The GALEX (Galaxy Evolution Explorer) Nearby Galaxies Survey is providing deep far-UV and near-UV imaging for a representative sample of galaxies in the local universe. We present early results for M51 and M101, from GALEX UV imaging and SDSS optical data in five bands. The multi-band photometry of compact stellar complexes in M101 is compared to population synthesis models, to derive ages, reddening, reddening-corrected luminosities and current/initial masses. The GALEX UV photometry provides a complete census of young compact complexes on a approximately 160pc scale. A galactocentric gradient of the far-UV - near-UV color indicates younger stellar populations towards the outer parts of the galaxy disks, the effect being more pronounced in M101 than in M51.Comment: This paper will be published as part of the Galaxy Evolution Explorer (GALEX) Astrophysical Journal Letters Special Issue. Full paper available from http://dolomiti.pha.jhu.edu . Links to full set of papers will be available at http://www.galex.caltech.edu/PUBLICATIONS/ after November 22, 200