RB loss contributes to aggressive tumor phenotypes in MYC-driven triple negative breast cancer

Triple negative breast cancer (TNBC) is characterized by multiple genetic events occurring in concert to drive pathogenic features of the disease. Here we interrogated the coordinate impact of p53, RB, and MYC in a genetic model of TNBC, in parallel with the analysis of clinical specimens. Primary mouse mammary epithelial cells (mMEC) with defined genetic features were used to delineate the combined action of RB and/or p53 in the genesis of TNBC. In this context, the deletion of either RB or p53 alone and in combination increased the proliferation of mMEC; however, the cells did not have the capacity to invade in matrigel. Gene expression profiling revealed that loss of each tumor suppressor has effects related to proliferation, but RB loss in particular leads to alterations in gene expression associated with the epithelial-to-mesenchymal transition. The overexpression of MYC in combination with p53 loss or combined RB/p53 loss drove rapid cell growth. While the effects of MYC overexpression had a dominant impact on gene expression, loss of RB further enhanced the deregulation of a gene expression signature associated with invasion. Specific RB loss lead to enhanced invasion in boyden chambers assays and gave rise to tumors with minimal epithelial characteristics relative to RB-proficient models. Therapeutic screening revealed that RB-deficient cells were particularly resistant to agents targeting PI3K and MEK pathway. Consistent with the aggressive behavior of the preclinical models of MYC overexpression and RB loss, human TNBC tumors that express high levels of MYC and are devoid of RB have a particularly poor outcome. Together these results underscore the potency of tumor suppressor pathways in specifying the biology of breast cancer. Further, they demonstrate that MYC overexpression in concert with RB can promote a particularly aggressive form of TNB

Einfluss der Sakrumfraktur auf das funktionelle Langzeitergebnis von Beckenringverletzungen

Zusammenfassung: In der Akutphase umfasst die Behandlung der Beckenringverletzung mit Beteiligung des iliosakralen Komplexes die effiziente Blutungskontrolle und Stabilisierung des Beckenrings. Für das Langzeitresultat sind jedoch neurologische Ausfälle, Fehlverheilungen des hinteren Beckenrings mit tieflumbalen Schmerzen und urologische Komplikationen entscheidend. Zwischen 1991 und 2000 wurden in unserer Klinik 173Patienten mit Sakrumfrakturen behandelt. Diese wurden im Rahmen einer lateralen Kompressionsfraktur (AO-Klassifikation TypB2) oder einer "vertical-shear-" (Typ-C-)Verletzung mit einer Dislokation von 1cm wurden operativ (n=33, 19%) versorgt. 112Patienten wurden nach durchschnittlich 4,9Jahren nachkontrolliert. Von den 39Patienten mit neurologischen Ausfällen (35%) zeigten lediglich 4 eine vollständige neurologische Erholung. Chronische tieflumbale Schmerzen traten selten (n=8, 7%) und nur bei einer Typ-C-Verletzung auf. Die geringe Inzidenz an lumbalen Schmerzen rechtfertigt die konservative Therapie wenig dislozierter (<1cm) Sakrumfrakturen. Entscheidend für das Langzeitergebnis sind neurologische Defizite, die bei 30% aller Patienten persistiere

J004457+4123 (Sharov 21): not a remarkable nova in M31 but a background quasar with a spectacular UV flare

We announce the discovery of a quasar behind the disk of M31, which was previously classified as a remarkable nova in our neighbour galaxy. The paper is primarily aimed at the outburst of J004457+4123 (Sharov 21), with the first part focussed on the optical spectroscopy and the improvement in the photometric database. Both the optical spectrum and the broad band spectral energy distribution of Sharov 21 are shown to be very similar to that of normal, radio-quiet type 1 quasars. We present photometric data covering more than a century and resulting in a long-term light curve that is densely sampled over the past five decades. The variability of the quasar is characterized by a ground state with typical fluctuation amplitudes of ~0.2 mag around B~20.5, superimposed by a singular flare of ~2 yr duration (observer frame) with the maximum at 1992.81 where the UV flux has increased by a factor of ~20. The total energy in the flare is at least three orders of magnitudes higher than the radiated energy of the most luminous supernovae, provided that it comes from an intrinsic process and the energy is radiated isotropically. The profile of the flare light curve appears to be in agreement with the standard predictions for a stellar tidal disruption event where a ~10 M_sun giant star was shredded in the tidal field of a ~2...5 10^8 M_sun black hole. The short fallback time derived from the light curve requires an ultra-close encounter where the pericentre of the stellar orbit is deep within the tidal disruption radius. Gravitational microlensing provides an alternative explanation, though the probability of such a high amplification event is very low.Comment: Accepted for publication in Astronomy and Astrophysics, 14 pages, 11 figure

<i>Herschel</i> observations of the debris disc around HIP 92043

Context. Typical debris discs are composed of particles ranging from several micron sized dust grains to km sized asteroidal bodies, and their infrared emission peaks at wavelengths 60-100 μm. Recent Herschel DUNES observations have identified several debris discs around nearby Sun-like stars (F, G and K spectral type) with significant excess emission only at 160 μm. Aims. We observed HIP 92043 (110 Her, HD 173667) at far-infrared and sub-millimetre wavelengths with Herschel PACS and SPIRE. Identification of the presence of excess emission from HIP 92043 and the origin and physical properties of any excess was undertaken through analysis of its spectral energy distribution (SED) and the PACS images. Methods. The PACS and SPIRE images were produced using the HIPE photProject map maker routine. Fluxes were measured using aperture photometry. A stellar photosphere model was scaled to optical and near infrared photometry and subtracted from the far-infared and sub-mm fluxes to determine the presence of excess emission. Source radial profiles were fitted using a 2D Gaussian and compared to a PSF model based on Herschel observations of α Boo to check for extended emission. Results. Clear excess emission from HIP 92043 was observed at 70 and 100 μm. Marginal excess was observed at 160 and 250 μm. Analysis of the images reveals that the source is extended at 160 μm. A fit to the source SED is inconsistent with a photosphere and single temperature black body. Conclusions. The excess emission from HIP 92043 is consistent with the presence of an unresolved circumstellar debris disc at 70 and 100 μm, with low probability of background contamination. The extended 160 μm emission may be interpreted as an additional cold component to the debris disc or as the result of background contamination along the line of sight. The nature of the 160 μm excess cannot be determined absolutely from the available data, but we favour a debris disc interpretation, drawing parallels with previously identified cold disc sources in the DUNES sample

Lagrangian particle paths and ortho-normal quaternion frames

Experimentalists now measure intense rotations of Lagrangian particles in turbulent flows by tracking their trajectories and Lagrangian-average velocity gradients at high Reynolds numbers. This paper formulates the dynamics of an orthonormal frame attached to each Lagrangian fluid particle undergoing three-axis rotations, by using quaternions in combination with Ertel's theorem for frozen-in vorticity. The method is applicable to a wide range of Lagrangian flows including the three-dimensional Euler equations and its variants such as ideal MHD. The applicability of the quaterionic frame description to Lagrangian averaged velocity gradient dynamics is also demonstrated.Comment: 9 pages, one figure, revise

Lagrangian analysis of alignment dynamics for isentropic compressible magnetohydrodynamics

After a review of the isentropic compressible magnetohydrodynamics (ICMHD) equations, a quaternionic framework for studying the alignment dynamics of a general fluid flow is explained and applied to the ICMHD equations.Comment: 12 pages, 2 figures, submitted to a Focus Issue of New Journal of Physics on "Magnetohydrodynamics and the Dynamo Problem" J-F Pinton, A Pouquet, E Dormy and S Cowley, editor

Ghost excitonic insulator transition in layered graphite

Some unusual properties of layered graphite, including a linear energy dependence of the quasiparticle damping and weak ferromagnetism at low doping, are explained as a result of the proximity of a single graphene sheet to the excitonic insulator phase which can be further stabilized in a doped system of many layers stacked in the staggered ($ABAB...$) configuration

The HOSTS Survey for Exozodiacal Dust: Preliminary results and future prospects

[abridged] The presence of large amounts of dust in the habitable zones of nearby stars is a significant obstacle for future exo-Earth imaging missions. We executed an N band nulling interferometric survey to determine the typical amount of such exozodiacal dust around a sample of nearby main sequence stars. The majority of our data have been analyzed and we present here an update of our ongoing work. We find seven new N band excesses in addition to the high confidence confirmation of three that were previously known. We find the first detections around Sun-like stars and around stars without previously known circumstellar dust. Our overall detection rate is 23%. The inferred occurrence rate is comparable for early type and Sun-like stars, but decreases from 71% [+11%/-20%] for stars with previously detected mid- to far-infrared excess to 11% [+9%/-4%] for stars without such excess, confirming earlier results at high confidence. For completed observations on individual stars, our sensitivity is five to ten times better than previous results. Assuming a lognormal luminosity function of the dust, we find upper limits on the median dust level around all stars without previously known mid to far infrared excess of 11.5 zodis at 95% confidence level. The corresponding upper limit for Sun-like stars is 16 zodis. An LBTI vetted target list of Sun-like stars for exo-Earth imaging would have a corresponding limit of 7.5 zodis. We provide important new insights into the occurrence rate and typical levels of habitable zone dust around main sequence stars. Exploiting the full range of capabilities of the LBTI provides a critical opportunity for the detailed characterization of a sample of exozodiacal dust disks to understand the origin, distribution, and properties of the dust.Comment: To appear in SPIE Astronomical Telescopes + Instrumentation 2018 proceedings. Some typos fixed, one reference adde

A peculiar class of debris disks from Herschel/DUNES - A steep fall off in the far infrared

Aims. We present photometric data of debris disks around HIP 103389 (HD 199260), HIP 107350 (HN Peg, HD206860), and HIP 114948 (HD 219482), obtained in the context of our Herschel Open Time Key Program DUNES (DUst around NEarby Stars). Methods. We used Herschel/PACS to detect the thermal emission of the three debris disks with a 3 sigma sensitivity of a few mJy at 100 um and 160 um. In addition, we obtained Herschel/PACS photometric data at 70 um for HIP 103389. Two different approaches are applied to reduce the Herschel data to investigate the impact of data reduction on the photometry. We fit analytical models to the available spectral energy distribution (SED) data. Results. The SEDs of the three disks potentially exhibit an unusually steep decrease at wavelengths > 70 um. We investigate the significance of the peculiar shape of these SEDs and the impact on models of the disks provided it is real. Our modeling reveals that such a steep decrease of the SEDs in the long wavelength regime is inconsistent with a power-law exponent of the grain size distribution -3.5 expected from a standard equilibrium collisional cascade. In contrast, a very distinct range of grain sizes is implied to dominate the thermal emission of such disks. However, we demonstrate that the understanding of the data of faint sources obtained with Herschel is still incomplete and that the significance of our results depends on the version of the data reduction pipeline used. Conclusions. A new mechanism to produce the dust in the presented debris disks, deviations from the conditions required for a standard equilibrium collisional cascade (grain size exponent of -3.5), and/or significantly different dust properties would be necessary to explain the potentially steep SED shape of the three debris disks presented. (abridged)Comment: 14 pages, 4 figures, accepted by A&