A generalizable data-driven multicellular model of pancreatic ductal adenocarcinoma.

BACKGROUND: Mechanistic models, when combined with pertinent data, can improve our knowledge regarding important molecular and cellular mechanisms found in cancer. These models make the prediction of tissue-level response to drug treatment possible, which can lead to new therapies and improved patient outcomes. Here we present a data-driven multiscale modeling framework to study molecular interactions between cancer, stromal, and immune cells found in the tumor microenvironment. We also develop methods to use molecular data available in The Cancer Genome Atlas to generate sample-specific models of cancer. RESULTS: By combining published models of different cells relevant to pancreatic ductal adenocarcinoma (PDAC), we built an agent-based model of the multicellular pancreatic tumor microenvironment, formally describing cell type-specific molecular interactions and cytokine-mediated cell-cell communications. We used an ensemble-based modeling approach to systematically explore how variations in the tumor microenvironment affect the viability of cancer cells. The results suggest that the autocrine loop involving EGF signaling is a key interaction modulator between pancreatic cancer and stellate cells. EGF is also found to be associated with previously described subtypes of PDAC. Moreover, the model allows a systematic exploration of the effect of possible therapeutic perturbations; our simulations suggest that reducing bFGF secretion by stellate cells will have, on average, a positive impact on cancer apoptosis. CONCLUSIONS: The developed framework allows model-driven hypotheses to be generated regarding therapeutically relevant PDAC states with potential molecular and cellular drivers indicating specific intervention strategies

Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height.

The biological processes controlling human growth are diverse, complex and poorly understood. Genetic factors are important and human height has been shown to be a highly polygenic trait to which common and rare genetic variation contributes. Weaver syndrome is a human overgrowth condition characterised by tall stature, dysmorphic facial features, learning disability and variable additional features. We performed exome sequencing in four individuals with Weaver syndrome, identifying a mutation in the histone methyltransferase, EZH2, in each case. Sequencing of EZH2 in additional individuals with overgrowth identified a further 15 mutations. The EZH2 mutation spectrum in Weaver syndrome shows considerable overlap with the inactivating somatic EZH2 mutations recently reported in myeloid malignancies. Our data establish EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth

Dynamical Measurements of Black Hole Masses in Four Brightest Cluster Galaxies at 100 Mpc

We present stellar kinematics and orbit superposition models for the central regions of four Brightest Cluster Galaxies (BCGs), based upon integral-field spectroscopy at Gemini, Keck, and McDonald Observatories. Our integral-field data span radii from < 100 pc to tens of kpc. We report black hole masses, M_BH, of 2.1 +/- 1.6 x 10^10 M_Sun for NGC 4889, 9.7 + 3.0 - 2.6 x 10^9 M_Sun for NGC 3842, and 1.3 + 0.5 - 0.4 x 10^9 M_Sun for NGC 7768. For NGC 2832 we report an upper limit of M_BH < 9 x 10^9 M_Sun. Stellar orbits near the center of each galaxy are tangentially biased, on comparable spatial scales to the galaxies' photometric cores. We find possible photometric and kinematic evidence for an eccentric torus of stars in NGC 4889, with a radius of nearly 1 kpc. We compare our measurements of M_BH to the predicted black hole masses from various fits to the relations between M_BH and stellar velocity dispersion, luminosity, or stellar mass. The black holes in NGC 4889 and NGC 3842 are significantly more massive than all dispersion-based predictions and most luminosity-based predictions. The black hole in NGC 7768 is consistent with a broader range of predictions.Comment: 24 pages, 18 figures. Accepted for publication in Ap

The Global Magneto-Ionic Medium Survey: A Faraday Depth Survey of the Northern Sky Covering 1280-1750 MHz

The Galactic interstellar medium hosts a significant magnetic field, which can be probed through the synchrotron emission produced from its interaction with relativistic electrons. Linearly polarized synchrotron emission is generated throughout the Galaxy, and at longer wavelengths, modified along nearly every path by Faraday rotation in the intervening magneto-ionic medium. Full characterization of the polarized emission requires wideband observations with many frequency channels. We have surveyed polarized radio emission from the Northern sky over the the range 1280-1750 MHz, with channel width 236.8 kHz, using the John A. Galt Telescope (diameter 25.6 m) at the Dominion Radio Astrophysical Observatory, as part of the Global Magneto-Ionic Medium Survey. The survey covered 72% of the sky, declinations -30 to +87 degrees at all right ascensions. The intensity scale was absolutely calibrated, based on the flux density and spectral index of Cygnus A. Polarization angle was calibrated using the extended polarized emission of the Fan Region. Data are presented as brightness temperatures with angular resolution 40'. Sensitivity in Stokes Q and U is 45 mK rms in a 1.18 MHz band. We have applied rotation measure synthesis to the data to obtain a Faraday depth cube of resolution 150 radians per square metre and sensitivity 3 mK rms of polarized intensity. Features in Faraday depth up to a width of 110 radians per square metre are represented. The maximum detectable Faraday depth is +/- 20,000 radians per square metre. The survey data are available at the Canadian Astronomy Data Centre.Comment: Accepted for publication in the Astronomical Journa

GASKAP -- The Galactic ASKAP Survey

A survey of the Milky Way disk and the Magellanic System at the wavelengths of the 21-cm atomic hydrogen (HI) line and three 18-cm lines of the OH molecule will be carried out with the Australian Square Kilometre Array Pathfinder telescope. The survey will study the distribution of HI emission and absorption with unprecedented angular and velocity resolution, as well as molecular line thermal emission, absorption, and maser lines. The area to be covered includes the Galactic plane (|b|< 10deg) at all declinations south of delta = +40deg, spanning longitudes 167deg through 360deg to 79deg at b=0deg, plus the entire area of the Magellanic Stream and Clouds, a total of 13,020 square degrees. The brightness temperature sensitivity will be very good, typically sigma_T ~ 1 K at resolution 30arcsec and 1 km/s. The survey has a wide spectrum of scientific goals, from studies of galaxy evolution to star formation, with particular contributions to understanding stellar wind kinematics, the thermal phases of the interstellar medium, the interaction between gas in the disk and halo, and the dynamical and thermal states of gas at various positions along the Magellanic Stream.Comment: 45 pages, 8 figures, Pub. Astron. Soc. Australia (in press

The Rapid ASKAP Continuum Survey I: Design and First Results

The Rapid ASKAP Continuum Survey (RACS) is the first large-area survey to be conducted with the full 36-antenna Australian Square Kilometre Array Pathfinder (ASKAP) telescope. RACS will provide a shallow model of the ASKAP sky that will aid the calibration of future deep ASKAP surveys. RACS will cover the whole sky visible from the ASKAP site in Western Australia, and will cover the full ASKAP band of $700-1800$ MHz. The RACS images are generally deeper than the existing NRAO VLA Sky Survey (NVSS) and Sydney University Molonglo Sky Survey (SUMSS) radio surveys and have better spatial resolution. All RACS survey products will be public, including radio images (with $\sim 15$ arcsecond resolution) and catalogues of about three million source components with spectral index and polarisation information. In this paper, we present a description of the RACS survey and the first data release of 903 images covering the sky south of declination $+41^\circ$ made over a 288 MHz band centred at 887.5 MHz.Comment: 24 pages, 17 figures, 4 tables. For associated data see https://data.csiro.au/collections/domain/casdaObservation/results/PRAS110%20-%20The%20Rapid%20ASKAP%20Continuu