Showing papers by "David W. Hogg published in 2015"

Finding, characterizing and classifying variable sources in multi-epoch sky surveys: QSOs and RR Lyrae in PS1 3$\pi$ data

Abstract: In area and depth, the Pan-STARRS1 (PS1) 3$\pi$ survey is unique among many-epoch, multi-band surveys and has enormous potential for all-sky identification of variable sources. PS1 has observed the sky typically seven times in each of its five bands ($grizy$) over 3.5 years, but unlike SDSS not simultaneously across the bands. Here we develop a new approach for quantifying statistical properties of non-simultaneous, sparse, multi-color lightcurves through light-curve structure functions, effectively turning PS1 into a $\sim 35$-epoch survey. We use this approach to estimate variability amplitudes and timescales $(\omega_r, \tau)$ for all point-sources brighter than $r_{\mathrm{P1}}=21.5$ mag in the survey. With PS1 data on SDSS Stripe 82 as ``ground truth", we use a Random Forest Classifier to identify QSOs and RR Lyrae based on their variability and their mean PS1 and WISE colors. We find that, aside from the Galactic plane, QSO and RR Lyrae samples of purity $\sim$75\% and completeness $\sim$92\% can be selected. On this basis we have identified a sample of $\sim 1,000,000$ QSO candidates, as well as an unprecedentedly large and deep sample of $\sim$150,000 RR Lyrae candidates with distances from $\sim$10 kpc to $\sim$120 kpc. Within the Draco dwarf spheroidal, we demonstrate a distance precision of 6\% for RR Lyrae candidates. We provide a catalog of all likely variable point sources and likely QSOs in PS1, a total of $25.8\times 10^6$ sources.

A phase 2 study of tremelimumab in patients with advanced uveal melanoma.

Abstract: Similar to cutaneous melanoma, several strategies of immune escape have been documented in uveal melanomas (UMs). We hypothesized that these cancers could respond to cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibition with tremelimumab by potentiating T-cell activation. This was an open-label, multicentre phase 2 study in patients with advanced UM who had not received prior immunotherapy. Patient received tremelimumab at 15 mg/kg administered every 90 days for up to four cycles. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints were safety, durable response rate, objective response rate, duration of objective response, duration of complete response, and median overall survival (OS). Eleven patients, all with M1c disease, were enrolled with no responses observed. The median follow-up was 11 months (range 2-36 months). The median PFS was 2.9 months (95% confidence interval 2.8-3.0) and the 6-month PFS rate was 9.1%. The median OS was 12.8 months (95% confidence interval 3.8-19.7). Toxicities were consistent with CTLA-4 blockade and were manageable. Although the median OS of 12.8 months and the manageable toxicity profile of tremelimumab observed in this study seem promising, the modest 6-month PFS and the lack of responses observed resulted in the study being stopped due to futility at the first interim stage. To date, no systemic treatment has demonstrated a survival benefit in patients with advanced UM. The standard treatment for patients with advanced UM should be a clinical trial.

Decreases in mitochondrial reactive oxygen species initiate GABAA receptor-mediated electrical suppression in anoxia-tolerant turtle neurons

Abstract: Key points Anoxia induces hyper-excitability and cell death in mammalian brain but in the western painted turtle (Chrysemys picta bellii) enhanced GABA transmission prevents injury. The mechanism responsible for increased GABA transmission is unknown; however, reactive oxygen species (ROS) generated by mitochondria may play a role because this is an oxygen-sensitive process. In this study, we show that inhibition of mitochondrial ROS production is sufficient to initiate a redox-sensitive GABA signalling cascade that suppresses pyramidal neuron action potential frequency. These results further our understanding of the turtle's unique strategy for reducing ATP consumption during anoxia and highlights a natural mechanism in which to explore therapies to protect mammalian brain from low-oxygen insults (e.g. cerebral stroke). Abstract Anoxia induces hyper-excitability and cell death in mammalian brain but in the anoxia-tolerant western painted turtle (Chrysemys picta bellii) neuronal electrical activity is suppressed (i.e. spike arrest), adenosine triphosphate (ATP) consumption is reduced, and cell death does not occur. Electrical suppression is primarily the result of enhanced γ-aminobutyric acid (GABA) transmission; however, the underlying mechanism responsible for initiating oxygen-sensitive GABAergic spike arrest is unknown. In turtle cortical pyramidal neurons there are three types of GABAA receptor-mediated currents: spontaneous inhibitory postsynaptic currents (IPSCs), giant IPSCs and tonic currents. The aim of this study was to assess the effects of reactive oxygen species (ROS) scavenging on these three currents since ROS levels naturally decrease with anoxia and may serve as a redox signal to initiate spike arrest. We found that anoxia, pharmacological ROS scavenging, or inhibition of mitochondrial ROS generation enhanced all three types of GABA currents, with tonic currents comprising ∼50% of the total current. Application of hydrogen peroxide inhibited all three GABA currents, demonstrating a reversible redox-sensitive signalling mechanism. We conclude that anoxia-mediated decreases in mitochondrial ROS production are sufficient to initiate a redox-sensitive inhibitory GABA signalling cascade that suppresses electrical activity when oxygen is limited. This unique strategy for reducing neuronal ATP consumption during anoxia represents a natural mechanism in which to explore therapies to protect mammalian brain from low-oxygen insults.

Proteomic changes in the brain of the western painted turtle (Chrysemys picta bellii) during exposure to anoxia.

Abstract: During anoxia, overall protein synthesis is almost undetectable in the brain of the western painted turtle. The aim of this investigation was to address the question of whether there are alterations to specific proteins by comparing the normoxic and anoxic brain proteomes. Reductions in creatine kinase, hexokinase, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate kinase reflected the reduced production of adenosine triphosphate (ATP) during anoxia while the reduction in transitional endoplasmic reticulum ATPase reflected the conservation of ATP or possibly a decrease in intracellular Ca(2+). In terms of neural protection programed cell death 6 interacting protein (PDCD6IP; a protein associated with apoptosis), dihydropyrimidinase-like protein, t-complex protein, and guanine nucleotide protein G(o) subunit alpha (Go alpha; proteins associated with neural degradation and impaired cognitive function) also declined. A decline in actin, gelsolin, and PDCD6IP, together with an increase in tubulin, also provided evidence for the induction of a neurological repair response. Although these proteomic alterations show some similarities with the crucian carp (another anoxia-tolerant species), there are species-specific responses, which supports the theory of no single strategy for anoxia tolerance. These findings also suggest the anoxic turtle brain could be an etiological model for investigating mammalian hypoxic damage and clinical neurological disorders.

Patterns of response to anti-PD1 treatment: Comparison of three radiological response criteria and effect on overall survival (OS) in metastatic melanoma patients (MM).

Abstract: 9073 Background: Radiological assessment of patterns of response (R) to checkpoint inhibitors remain imperfect. irRC accounts for pseudoprogression but does not evaluate change in density. We aimed...