We use Chandra data to map the gas temperature in the central region of the merging cluster A2142. The cluster is markedly nonisothermal; it appears that the central cooling flow has been disturbed but not destroyed by a merger. The X-ray image exhibits two sharp, bow-shaped, shock-like surface brightness edges or gas density discontinuities. However, temperature and pressure profiles across these edges indicate that these are not shock fronts. The pressure is reasonably continuous across these edges, while the entropy jumps in the opposite sense to that in a shock (i.e. the denser side of the edge has lower temperature, and hence lower entropy). Most plausibly, these edges delineate the dense subcluster cores that have survived a merger and ram pressure stripping by the surrounding shock-heated gas.

We present multiband photometry of 185 type-Ia supernovae (SNe Ia), with over 11,500 observations. These were acquired between 2001 and 2008 at the F. L. Whipple Observatory of the Harvard-Smithsonian Center for Astrophysics (CfA). This sample contains the largest number of homogeneously observed and reduced nearby SNe Ia (z 0.08) published to date. It more than doubles the nearby sample, bringing SN Ia cosmology to the point where systematic uncertainties dominate. Our natural system photometry has a precision of 0.02 mag in BV RI r i and 0.04 mag in U for points brighter than 17.5 mag. We also estimate a systematic uncertainty of 0.03 mag in our SN Ia standard system BV RI r i photometry and 0.07 mag for U. Comparisons of our standard system photometry with published SN Ia light curves and comparison stars, where available for the same SN, reveal agreement at the level of a few hundredths mag in most cases. We find that 1991bg-like SNe Ia are sufficiently distinct from other SNe Ia in their color and light-curve-shape/ luminosity relation that they should be treated separately in light-curve/distance fitter training samples. The CfA3 sample will contribute to the development of better light-curve/distance fitters, particularly in the few dozen cases where near-infrared photometry has been obtained and, together, can help disentangle host-galaxy reddening from intrinsic supernova color, reducing the systematic uncertainty in SN Ia distances due to dust.

Physiologically based pharmacokinetic (PBPK) modeling and simulation is a tool that can help predict the pharmacokinetics of drugs in humans and evaluate the effects of intrinsic (e.g., organ dysfunction, age, genetics) and extrinsic (e.g., drug-drug interactions) factors, alone or in combinations, on drug exposure. The use of this tool is increasing at all stages of the drug development process. This report reviews recent instances of the use of PBPK in decision-making during regulatory review. The examples are based on Center for Drug Evaluation and Research reviews of several submissions for investigational new drugs (INDs) and new drug applications (NDAs) received between July 2008 and June 2010. The use of PBPK modeling and simulation facilitated the following types of decisions: the need to conduct specific clinical pharmacology studies, specific study designs, and appropriate labeling language. The report also discusses the challenges encountered when PBPK modeling and simulation were used in these cases and recommends approaches to facilitating full utilization of this tool.

We present 1210 Johnson/Cousins B, V , R, and I photometric observations of 22 recent Type Ia supernovae (SNe Ia) : SNe 1993ac, 1993ae, 1994M, 1994S, 1994T, 1994Q, 1994ae, 1995D, 1995E, 1995al, 1995ac, 1995ak, 1995bd, 1996C, 1996X, 1996Z, 1996ab, 1996ai, 1996bk, 1996bl, 1996bo, and 1996bv. Most of the photometry was obtained at the Fred Lawrence Whipple Observatory of the HarvardSmithsonian Center for Astrophysics in a cooperative observing plan aimed at improving the database for SNe Ia. The redshifts of the sample range from cz \ 1200 to 37,000 km s~1 with a mean of cz \ 7000 km s~1.

Optical spectroscopic observations of the companion star (type G8IV to K4III) in the microquasar system XTE J1550-564 reveal a radial velocity curve with a best fitting spectroscopic period of P sp = 1.552 ± 0.010 days and a semiamplitude of K 2 = 349 ± 12 km s −1 . The optical mass function is f (M) = 6.86 ± 0.71 M ⊙ (1σ). We tentatively measure the rotational velocity of the companion star to be V rot sin i = 90 ± 10 km s −1 , which when taken at face value implies a mass ratio of Q ≡ M 1 /M 2 = 6.6 +2.5 −1.6 (1σ), using the above value of K 2 . We derive constraints on the binary parameters from simultaneous modelling of the ellipsoidal light and radial velocity curves. We find 1σ ranges for the photometric period (1.5430 d ≤ P ph ≤ 1.5440 d), K−velocity (350.2 ≤ K 2 ≤ 368.6 km s −1 ), inclination (67.0 • ≤ i ≤ 77.4 • ), mass ratio (Q ≥ 12.0), and orbital separation (11.55 R ⊙ ≤ a ≤ 12.50 R ⊙ ). Given these geometrical constraints we find the most likely value of the mass of the compact object is 9.41 M ⊙ with a 1σ range of 8.36 M ⊙ ≤ M 1 ≤ 10.76 M ⊙ . If we apply our tentative value of V rot sin i = 90 ± 10 km s −1 as an additional constraint in the ellipsoidal modelling, we find 1σ ranges of 1.5432 d ≤ P ph ≤ 1.5441 d for the photometric period, 352.2 ≤ K 2 ≤ 370.1 km s −1 for the K−velocity, 70.8 • ≤ i ≤ 75.4 • for the inclination, 6.7 ≤ Q ≤ 11.0 for the mass ratio, and 12.35 R ⊙ ≤ a ≤ 13.22 R ⊙ for the orbital separation. These geometrical constraints imply the most likely value of the mass of the compact object of 10.56 M ⊙ with a 1σ range of 9.68 M ⊙ ≤ M 1 ≤ 11.58 M ⊙ . In either case the mass of the compact object is well above the maximum mass of a stable neutron star, and we therefore conclude XTE J1550-564 contains a black hole.

The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine. However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date. The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells including biosynthesis, cell signaling, and oxidative protection. Herein, we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux, that selectively and potently targets the amino acid transporter ASCT2 (SLC1A5). Pharmacological blockade of ASCT2 with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively, contributed to anti-tumor responses in vitro and in vivo. Representing a new class of targeted therapy, this is the first study to demonstrate the utility of a pharmacological inhibitor of glutamine transport in oncology, laying a framework for paradigm-shifting therapies targeting cancer cell metabolism.

We present UBVRI photometry of 44 type-Ia supernovae (SN Ia) observed from 1997 to 2001 as part of a continuing monitoring campaign at the Fred Lawrence Whipple Observatory of the Harvard-Smithsonian Center for Astrophysics. The data set comprises 2190 observations and is the largest homogeneously observed and reduced sample of SN Ia to date, nearly doubling the number of well-observed, nearby SN Ia with published multicolor CCD light curves. The large sample of U-band photometry is a unique addition, with important connections to SN Ia observed at high redshift. The decline rate of SN Ia U-band light curves correlates well with the decline rate in other bands, as does the U −B color at maximum light. However, the U-band peak magnitudes show an increased dispersion relative to other bands even after accounting for extinction and decline rate, amounting to an additional ∼40% intrinsic scatter compared to B-band.Subject headings: supernovae: general -techniques: photometric Data and Reduction DiscoveryOur program of supernova photometry consists solely of follow-up; we search only our email, not the sky, to find new supernovae. A number of observers, both amateur and professional, are engaged in searching for supernovae. We rely on these searches, as well as prompt notification of candidates, coordinated by Dan Green and Brian Marsden of the IAU's Central Bureau for Astronomical Telegrams (CBAT), with confirmed SN reported in the IAU Circulars. In some cases the SN discoverers provide spectroscopic classification of the new objects, but generally spectroscopy is obtained by others, and reported separately in the IAU Circulars. With our spectroscopic SN follow-up program at the F. L. Whipple Observatory 1.5m telescope and FAST spectrograph (Fabricant et al. 1998), we have classified a large fraction of the new, nearby supernovae reported over the last several years and compiled a large spectroscopic database (Matheson et al. 2005, in preparation).Given a newly discovered and classified supernova, several factors help determine whether or not we include it in our monitoring program. Because of their importance, SN Ia are often given higher priority over other types, but factors such as ease of observability (southern targets and those discovered far to the west are less appealing), supernova phase (objects whose spectra indicate they are after maximum light are given lower priority), redshift (more nearby objects are favored), as well as the number of objects we are already monitoring are significant. Our final sample of well-observed SN Ia is not obtained from a single well-defined set of criteria, and selection effects in both the searches and follow-up may make this sample unsuitable for some applications (such as determining the intrinsic luminosity function of SN Ia, for example). A thorough discussion of the selection biases in the Calán/Tololo supernova search and follow-up campaign can be found in Hamuy & Pinto (1999).The discovery data for the sample of SN Ia presented here are given in Table 1. All of the ...

On December 3, 2014, the FDA granted accelerated approval of blinatumomab (Blincyto; Amgen, Inc.) for treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia (R/R ALL). Blinatumomab is a recombinant murine protein that acts as a bispecific CD19-directed CD3 T-cell engager. The basis for the approval was a single-arm trial with 185 evaluable adults with R/R ALL. The complete remission (CR) rate was 32% [95% confidence interval (CI), 26%-40%], and the median duration of response was 6.7 months. A minimal residual disease response was achieved by 31% (95% CI, 25%-39%) of all patients. Cytokine release syndrome and neurologic events were serious toxicities that occurred. Other common (>20%) adverse reactions were pyrexia, headache, edema, febrile neutropenia, nausea, tremor, and rash. Neutropenia, thrombocytopenia, and elevated transaminases were the most common (>10%) laboratory abnormalities related to blinatumomab. A randomized trial is required in order to confirm clinical benefit. Clin Cancer Res; 21(18); 4035-9. Ó2015 AACR. Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed. Editor's DisclosuresThe following editor(s) reported relevant financial relationships: J.L. Abbruzzese is a consultant/advisory board member for Celgene and Halozyme. CME Staff Planners' DisclosuresThe members of the planning committee have no real or apparent conflict of interest to disclose. Learning ObjectivesUpon completion of this activity, the participant should have a better understanding of the mechanism of action of blinatumomab, how the toxicities of blinatumomab reflect the mechanism of action, and the level of evidence supporting use of blinatumomab for the treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia.