Showing papers by "David W. Hogg published in 2019"

Five-year survival with combined nivolumab and ipilimumab in advanced melanoma: New England Journal of Medicine

Abstract: BACKGROUND Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial. METHODS We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group. RESULTS At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted. CONCLUSIONS Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

Towards precise stellar ages: combining isochrone fitting with empirical gyrochronology

Abstract: We present a new age-dating technique that combines gyrochronology with isochrone fitting to infer ages for FGKM main-sequence and subgiant field stars. Gyrochronology and isochrone fitting are each capable of providing relatively precise ages for field stars in certain areas of the Hertzsprung-Russell diagram: gyrochronology works optimally for cool main-sequence stars, and isochrone fitting can provide precise ages for stars near the main-sequence turnoff. Combined, these two age-dating techniques can provide precise and accurate ages for a broader range of stellar masses and evolutionary stages than either method used in isolation. We demonstrate that the position of a star on the Hertzsprung- Russell or color-magnitude diagram can be combined with its rotation period to infer a precise age via both isochrone fitting and gyrochronology simultaneously. We show that incorporating rotation periods with 5% uncertainties into stellar evolution models improves age precision for FGK stars on the main sequence, and can, on average, provide age estimates up to three times more precise than isochrone fitting alone. In addition, we provide a new gyrochronology relation, calibrated to the Praesepe cluster and the Sun, that includes a variance model to capture the rotational behavior of stars whose rotation periods do not lengthen with the square-root of time, and parts of the Hertzsprung-Russell diagram where gyrochronology has not been calibrated. This publication is accompanied by an open source Python package, stardate, for inferring the ages of main-sequence and subgiant FGKM stars from rotation periods, spectroscopic parameters and/or apparent magnitudes and parallaxes.

Synthetic Peptides as Therapeutic Agents: Lessons Learned From Evolutionary Ancient Peptides and Their Transit Across Blood-Brain Barriers.

Abstract: Peptides play a major role in the transmission of information to and from the central nervous system. However, because of their structural complexity, the development of pharmacological peptide-based therapeutics has been challenged by the lack of understanding of endogenous peptide evolution. The teneurin C-terminal associated peptides (TCAP) possess many of the required attributes of a practical peptide therapeutic. TCAPs, associated with the teneurin transmembrane proteins that bind to the latrophilins, members of the Adhesion family of G-protein-coupled receptors (GPCR). Together, this ligand-receptor unit plays an integral role in synaptogenesis, neurological development, and maintenance, and is present in most metazoans. TCAP has structural similarity to corticotropin-releasing factor (CRF), and related peptides, such as calcitonin and the secretin-based peptides and inhibits the (CRF)-associated stress response. Latrophilins are structurally related to the secretin family of GPCRs. TCAP is a soluble peptide that crosses the blood-brain barrier and regulates glucose transport into the brain. We posit that TCAP represents a phylogenetically older peptide system that evolved before the origin of the CRF-calcitonin-secretin clade of peptides and plays a fundamental role in the regulation of cell-to-cell energy homeostasis. Moreover, it may act as a phylogenetically older peptide system that evolved as a natural antagonist to the CRF-mediated stress response. Thus, TCAP's actions on the CNS may provide new insights into the development of peptide therapeutics for the treatment of CNS disorders.

Wobble: a data-driven method for precision radial velocities

Abstract: Extreme-precision radial velocity (EPRV) exoplanet surveys face considerable data analysis challenges in extracting maximally precise RVs from spectra. Chief among these, particularly for the upcoming generation of red-optimized spectrographs targeting M dwarfs, is the presence of telluric absorption features which are not perfectly known. Another major limitation on the achievable RV precision is the need to adopt an imperfect stellar template against which to cross-correlate or otherwise match the observations. In both cases, precision-limiting reliance on external information can be sidestepped using the data directly. Here we propose a data-driven method to simultaneously extract precise RVs and infer the underlying stellar and telluric spectra using a linear model (in the log of flux). The model employs a convex objective and convex regularization to keep the optimization of the spectral components fast. We implement this method in wobble, an open-source python package which uses TensorFlow in one of its first non-neural-network applications to astronomical data. In this work, we demonstrate the performance of wobble on archival HARPS spectra. We recover the canonical exoplanet 51 Pegasi b, detect the secular RV evolution of the M dwarf Barnard's Star, and retrieve the Rossiter-McLaughlin effect for the Hot Jupiter HD 189733b. The method additionally produces extremely high-S/N composite stellar spectra and detailed time-variable telluric spectra, which we also present here.

Activity of the Carboxy-Terminal Peptide Region of the Teneurins and Its Role in Neuronal Function and Behavior in Mammals

Abstract: Teneurin C-terminal associated peptides (TCAPs) are an evolutionarily ancient family of 40- to 41-residue bioactive peptides located on the extracellular end of each of the four teneurin transmembrane proteins. TCAP-1 may exist as a tethered peptide at the teneurin-1 carboxy end or as an independent peptide that is either released via post-transcriptional cleavage from its teneurin-1 pro-protein or independently expressed as its own mRNA. In neurons, soluble TCAP-1 acts as a paracrine factor to regulate cellular activity and neuroplastic interactions. In vitro studies indicate that, by itself, synthetic TCAP-1 promotes neuron growth and protects cells from chemical insult. In vivo, TCAP-1 increases hippocampal neuron spine density, reduces stress-induced behavior and ablates cocaine-seeking behaviors. Together, these studies suggest that the physiological effects of TCAP-1 are a result of an inhibition of corticotropin-releasing factor (CRF) activity leading to increased energy production. This hypothesis is supported by in vivo functional positron emissions tomography studies, which demonstrate that TCAP-1 significantly increases glucose uptake in rat brain. Complimentary in vitro studies show that enhanced glucose uptake is the result of TCAP-1-induced insertion of the glucose transporter into the neuronal plasma membrane, leading to increased glucose uptake and ATP production. Interestingly, TCAP-1-mediated glucose uptake occurs through a novel insulin-independent pathway. This review will focus on examining the role of TCAP on neuronal energy metabolism in the central nervous system.

Applying Liouville's Theorem to Gaia Data

Abstract: The Milky Way is filled with the tidally-disrupted remnants of globular clusters and dwarf galaxies. Determining the properties of these objects -- in particular, initial masses and density profiles -- is relevant to both astronomy and dark matter physics. However, most direct measures of mass cannot be applied to tidal debris, as the systems of interest are no longer in equilibrium. Since phase-space density is conserved during adiabatic phase mixing, Liouville's theorem provides a connection between stellar kinematics as measured by observatories such as Gaia and the original mass of the disrupted system. Accurately recovering the phase-space density is complicated by uncertainties resulting from measurement errors and orbital integration, which both effectively inject entropy into the system, preferentially decreasing the measured density. In this paper, we demonstrate that these two issues can be overcome. First, we measure the phase-space density of the globular cluster M4 in Gaia data, and use Liouville's theorem to derive its mass. We then show that, for tidally disrupted systems, the orbital parameters and thus phase-space density can be inferred by minimizing the phase-space entropy of cold stellar streams. This work is therefore a proof of principle that true phase-space density can be measured and the original properties of the star cluster reconstructed in systems of astrophysical interest.

The Galactic Midplane Is Not a Plane: Implications for Dynamical Analysis with Gaia Data and Beyond

Abstract: Orbital properties of stars, computed from their six-dimensional phase space measurements and an assumed Galactic potential, are used to understand the structure and evolution of the Galaxy. Stellar actions, computed from orbits, have the attractive quality of being invariant under certain assumptions and are therefore used as quantitative labels of a star's orbit. We report a subtle but important systematic error that is induced in the actions as a consequence of local midplane variations expected for the Milky Way. This error is difficult to model because it is non-Gaussian and bimodal, with neither mode peaking on the null value. An offset in the vertical position of the Galactic midplane of $\sim15\,\text{pc}$ for a thin disk-like orbit or $\sim 120\,\text{pc}$ for a thick disk-like orbit induces a $25\%$ systematic error in the vertical action $J_z$. In FIRE simulations of Milky Way-mass galaxies, these variations are on the order of $\sim100\,\text{pc}$ at the solar circle. From observations of the mean vertical velocity variation of $\sim5\text{--}10\,\text{km}\,\text{s}^{-1}$ with radius, we estimate that the Milky Way midplane variations are $\sim60\text{--}170\,\text{pc}$, consistent with three-dimensional dust maps. Action calculations and orbit integrations, which assume the global and local midplanes are identical, are likely to include this induced error, depending on the volume considered. Variation in the local standard of rest or distance to the Galactic center causes similar issues. The variation of the midplane must be taken into account when performing dynamical analysis across the large regions of the disk accessible to Gaia and future missions.

Stellar multiplicity: an interdisciplinary nexus

Abstract: Our uncertainties about binary star systems (and triples and so on) limit our capabilities in literally every single one of the Thematic Areas identified for Astro2020. We need to understand the population statistics of stellar multiplicity and their variations with stellar type, chemistry, and dynamical environment: Correct interpretation of any exoplanet experiment depends on proper treatment of resolved and unresolved binaries; stellar multiplicity is a direct outcome of star and companion formation; the most precise constraints on stellar structure come from well-characterized binary systems; stellar populations heavily rely on stellar and binary evolution modeling; high-redshift galaxy radiation and reionization is controlled by binary-dependent stellar physics; compact objects are the outcomes of binary evolution; the interpretation of multi-messenger astronomy from gravitational waves, light, and neutrinos relies on understanding the products of binary star evolution; near-Universe constraints on the Hubble constant with Type Ia supernovae and gravitational-wave mergers are subject to systematics related to their binary star progenitors; local measures of dark-matter substructure masses are distorted by binary populations. In order to realize the scientific goals in each of these themes over the next decade, we therefore need to understand how binary stars and stellar multiplets are formed and distributed in the space of masses, composition, age, and orbital properties, and how the distribution evolves with time. This white paper emphasizes the interdisciplinary importance of binary-star science and advocates that coordinated investment from all astrophysical communities will benefit almost all branches of astrophysics.