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

Genome-wide redistribution of MeCP2 in dorsal root ganglia after peripheral nerve injury.

BACKGROUND: Methyl-CpG-binding protein 2 (MeCP2), a protein with affinity for methylated cytosines, is crucial for neuronal development and function. MeCP2 regulates gene expression through activation, repression and chromatin remodeling. Mutations in MeCP2 cause Rett syndrome, and these patients display impaired nociception. We observed an increase in MeCP2 expression in mouse dorsal root ganglia (DRG) after peripheral nerve injury. The functional implication of increased MeCP2 is largely unknown. To identify regions of the genome bound by MeCP2 in the DRG and the changes induced by nerve injury, a chromatin immunoprecipitation of MeCP2 followed by sequencing (ChIP-seq) was performed 4 weeks after spared nerve injury (SNI). RESULTS: While the number of binding sites across the genome remained similar in the SNI model and sham control, SNI induced the redistribution of MeCP2 to transcriptionally relevant regions. To determine how differential binding of MeCP2 can affect gene expression in the DRG, we investigated mmu-miR-126, a microRNA locus that had enriched MeCP2 binding in the SNI model. Enriched MeCP2 binding to miR-126 locus after nerve injury repressed miR-126 expression, and this was not mediated by alterations in methylation pattern at the miR-126 locus. Downregulation of miR-126 resulted in the upregulation of its two target genes Dnmt1 and Vegfa in Neuro 2A cells and in SNI model compared to control. These target genes were significantly downregulated in Mecp2-null mice compared to wild-type littermates, indicating a regulatory role for MeCP2 in activating Dnmt1 and Vegfa expression. Intrathecal delivery of miR-126 was not sufficient to reverse nerve injury-induced mechanical and thermal hypersensitivity, but decreased Dnmt1 and Vegfa expression in the DRG. CONCLUSIONS: Our study shows a regulatory role for MeCP2 in that changes in global redistribution can result in direct and indirect modulation of gene expression in the DRG. Alterations in genome-wide binding of MeCP2 therefore provide a molecular basis for a better understanding of epigenetic regulation-induced molecular changes underlying nerve injury

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

Maternal depression and childhood obesity: A systematic review

Objective. Maternal depression is prevalent and has been associated with parenting practices that influence child weight. In this systematic review we aimed to examine the prospective association between maternal depression and child overweight.Methods. We searched four databases (PsycINFO, PubMed, Embase, and Academic Search Premier) to identify studies for inclusion. We included studies with a prospective design with at least one year follow-up, measuring maternal depression at any stage after childbirth, and examining child overweight or obesity status, body mass index z-score or percentile, or adiposity. Two authors extracted data independently and findingswere qualitatively synthesized.Results. We identified nine prospective studies for inclusion. Results were examined separately for episodic depression (depression at a single measurement occasion) and chronic depression (depression on multiple measurement occasions). Mixed results were observed for the relationship between episodic depression and indicators of child adiposity. Chronic depression, but not episodic depression,was associated with greater risk for child overweight.Conclusions.While chronic depression may be associated with child overweight, further research is needed. Research is also needed to determine whether maternal depression influences child weight outcomes in adolescence and to investigate elements of the family ecology that may moderate the effect of maternal depression on child overweight

The potential role of T-cells and their interaction with antigen-presenting cells in mediating immunosuppression following trauma-hemorrhage

Objective: Trauma-hemorrhage results in depressed immune responses of antigen-presenting cells (APCs) and T-cells. Recent studies suggest a key role of depressed T-cell derived interferon (IFN)-g in this complex immune cell interaction. The aim of this study was to elucidate further the underlying mechanisms responsible for dysfunctional T-cells and their interaction with APCs following trauma-hemorrhage. Design: Adult C3H/HeN male mice were subjected to trauma-hemorrhage (3-cm midline laparotomy) followed by hemorrhage (blood pressure of 35�5mmHg for 90 min and resuscitation) or sham operation. At 24 h thereafter, spleens were harvested and T-cells (by Microbeads) and APCs (via adherence) were Isolated. Co-cultures of T-cells and APCs were established for 48 h and stimulated with concanavalin A and lipopolysaccharide. T-Cell specific cytokines known to affect APC function (i.e. interleukin(IL)-2, IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF)) were measured in culture supernatants by Multiplex assay. The expression of MHC class II as well as co-stimulatory surface molecules on T-cells and APCs was determined by flow cytometry. Results: The release of IL-4 and GM-CSF by T-cells was suppressed following trauma-hemorrhage, irrespective of whether sham or trauma-hemorrhage APCs were present. Antigen-presenting cells from animals subjected to trauma-hemorrhage did not affect T-cell derived cytokine release by sham T-cells. In contrast, T-cells from traumahemorrhage animals depressed MHC class II expression of CD11c(þ) cells, irrespective of whether APCs underwent sham or trauma-hemorrhage procedure. Surprisingly, co-stimulatory molecules on APCs (CD80, CD86) were not affected by trauma-hemorrhage. Conclusions: These results suggest that beside IFN-g other T-cell derived cytokines contribute to immunosuppression following trauma-hemorrhage causing diminished MHC II expression on APCs. Thus, T-cells appear to play an important role in this interaction at the time-point examined. Therapeutic approaches should aim at maintenance of T-cell function and their interaction with APCs to prevent extended immunosuppression following trauma-hemorrhage

<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 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

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