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The ErbB2ΔEx16 splice variant is a major oncogenic driver in breast cancer that promotes a pro-metastatic tumor microenvironment.
Amplification and overexpression of erbB2/neu proto-oncogene is observed in 20-30% human breast cancer and is inversely correlated with the survival of the patient. Despite this, somatic activating mutations within erbB2 in human breast cancers are rare. However, we have previously reported that a splice isoform of erbB2, containing an in-frame deletion of exon 16 (herein referred to as ErbB2ΔEx16), results in oncogenic activation of erbB2 because of constitutive dimerization of the ErbB2 receptor. Here, we demonstrate that the ErbB2ΔEx16 is a major oncogenic driver in breast cancer that constitutively signals from the cell surface. We further show that inducible expression of the ErbB2ΔEx16 variant in mammary gland of transgenic mice results in the rapid development of metastatic multifocal mammary tumors. Genetic and biochemical characterization of the ErbB2ΔEx16-derived mammary tumors exhibit several unique features that distinguish this model from the conventional ErbB2 ones expressing the erbB2 proto-oncogene in mammary epithelium. Unlike the wild-type ErbB2-derived tumors that express luminal keratins, ErbB2ΔEx16-derived tumors exhibit high degree of intratumoral heterogeneity co-expressing both basal and luminal keratins. Consistent with these distinct pathological features, the ErbB2ΔEx16 tumors exhibit distinct signaling and gene expression profiles that correlate with activation of number of key transcription factors implicated in breast cancer metastasis and cancer stem cell renewal
Methane storms as a driver of Titan's dune orientation
Titan's equatorial regions are covered by eastward propagating linear dunes.
This direction is opposite to mean surface winds simulated by Global Climate
Models (GCMs), which are oriented westward at these latitudes, similar to trade
winds on Earth. Different hypotheses have been proposed to address this
apparent contradiction, involving Saturn's gravitational tides, large scale
topography or wind statistics, but none of them can explain a global eastward
dune propagation in the equatorial band. Here we analyse the impact of
equinoctial tropical methane storms developing in the superrotating atmosphere
(i.e. the eastward winds at high altitude) on Titan's dune orientation. Using
mesoscale simulations of convective methane clouds with a GCM wind profile
featuring superrotation, we show that Titan's storms should produce fast
eastward gust fronts above the surface. Such gusts dominate the aeolian
transport, allowing dunes to extend eastward. This analysis therefore suggests
a coupling between superrotation, tropical methane storms and dune formation on
Titan. Furthermore, together with GCM predictions and analogies to some
terrestrial dune fields, this work provides a general framework explaining
several major features of Titan's dunes: linear shape, eastward propagation and
poleward divergence, and implies an equatorial origin of Titan's dune sand.Comment: Published online on Nature Geoscience on 13 April 201
Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling
Large brain size is one of the defining characteristics of modern humans. Seckel syndrome (MIM 210600), a disorder of markedly reduced brain and body size, is associated with defective ATR-dependent DNA damage signaling. Only a single hypomorphic mutation of ATR has been identified in this genetically heterogeneous condition. We now report that mutations in the gene encoding pericentrin (PCNT)--resulting in the loss of pericentrin from the centrosome, where it has key functions anchoring both structural and regulatory proteins--also cause Seckel syndrome. Furthermore, we find that cells of individuals with Seckel syndrome due to mutations in PCNT (PCNT-Seckel) have defects in ATR-dependent checkpoint signaling, providing the first evidence linking a structural centrosomal protein with DNA damage signaling. These findings also suggest that other known microcephaly genes implicated in either DNA repair responses or centrosomal function may act in common developmental pathways determining human brain and body size
Vascular complications of prosthetic inter-vertebral discs
Five consecutive cases of prosthetic inter-vertebral disc displacement with severe vascular complications on revisional surgery are described. The objective of this case report is to warn spinal surgeons that major vascular complications are likely with anterior displacement of inter-vertebral discs. We have not been able to find a previous report on vascular complications associated with anterior displacement of prosthetic inter-vertebral discs. In all five patients the prosthetic disc had eroded into the bifurcation of the inferior vena cava and the left common iliac vein. In three cases the aortic bifurcation was also involved. The fibrosis was so severe that dissecting out the arteries and veins to provide access to the relevant disc proved impossible. Formal division of the left common iliac vein and artery with subsequent repair was our solution. Anterior inter-vertebral disc displacement was associated with severe vascular injury. Preventing anterior disc displacement is essential in disc design. In the event of anterior displacement, disc removal should be planned with a Vascular Surgeon
Neutron Electric Dipole Moment Constraint on Scale of Minimal Left-Right Symmetric Model
Using an effective theory approach, we calculate the neutron electric dipole
moment (nEDM) in the minimal left-right symmetric model with both explicit and
spontaneous CP violations. We integrate out heavy particles to obtain
flavor-neutral CP-violating effective Lagrangian. We run the Wilson
coefficients from the electroweak scale to the hadronic scale using one-loop
renormalization group equations. Using the state-of-the-art hadronic matrix
elements, we obtain the nEDM as a function of right-handed W-boson mass and
CP-violating parameters. We use the current limit on nEDM combined with the
kaon-decay parameter to provide the most stringent constraint yet on
the left-right symmetric scale TeV.Comment: 20 pages and 8 figure
The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic and macrophage infiltration, microvessel density and survival in patients with primary operable breast cancer
The significance of the inter-relationship between tumour and host local/systemic inflammatory responses in primary operable invasive breast cancer is limited. The inter-relationship between the systemic inflammatory response (pre-operative white cell count, C-reactive protein and albumin concentrations), standard clinicopathological factors, tumour T-lymphocytic (CD4+ and CD8+) and macrophage (CD68+) infiltration, proliferative (Ki-67) index and microvessel density (CD34+) was examined using immunohistochemistry and slide-counting techniques, and their prognostic values were examined in 168 patients with potentially curative resection of early-stage invasive breast cancer. Increased tumour grade and proliferative activity were associated with greater tumour T-lymphocyte (P<0.05) and macrophage (P<0.05) infiltration and microvessel density (P<0.01). The median follow-up of survivors was 72 months. During this period, 31 patients died; 18 died of their cancer. On univariate analysis, increased lymph-node involvement (P<0.01), negative hormonal receptor (P<0.10), lower albumin concentrations (P<0.01), increased tumour proliferation (P<0.05), increased tumour microvessel density (P<0.05), the extent of locoregional control (P<0.0001) and limited systemic treatment (Pless than or equal to0.01) were associated with cancer-specific survival. On multivariate analysis of these significant covariates, albumin (HR 4.77, 95% CI 1.35–16.85, P=0.015), locoregional treatment (HR 3.64, 95% CI 1.04–12.72, P=0.043) and systemic treatment (HR 2.29, 95% CI 1.23–4.27, P=0.009) were significant independent predictors of cancer-specific survival. Among tumour-based inflammatory factors, only tumour microvessel density (P<0.05) was independently associated with poorer cancer-specific survival. The host inflammatory responses are closely associated with poor tumour differentiation, proliferation and malignant disease progression in breast cancer
First-principles design and subsequent synthesis of a material to search for the permanent electric dipole moment of the electron
We describe the first-principles design and subsequent synthesis of a new
material with the specific functionalities required for a solid-state-based
search for the permanent electric dipole moment of the electron. We show
computationally that perovskite-structure europium barium titanate should
exhibit the required large and pressure-dependent ferroelectric polarization,
local magnetic moments, and absence of magnetic ordering even at liquid helium
temperature. Subsequent synthesis and characterization of
EuBaTiO ceramics confirm the predicted desirable
properties.Comment: Nature Materials, in pres
NF-κB targeting by way of IKK inhibition sensitizes lung cancer cells to adenovirus delivery of TRAIL
<p>Abstract</p> <p>Background</p> <p>Lung cancer causes the highest rate of cancer-related deaths both in men and women. As many current treatment modalities are inadequate in increasing patient survival, new therapeutic strategies are required. TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in tumor cells but not in normal cells, prompting its current evaluation in a number of clinical trials. The successful therapeutic employment of TRAIL is restricted by the fact that many tumor cells are resistant to TRAIL. The goal of the present study was to test a novel combinatorial gene therapy modality involving adenoviral delivery of TRAIL (Ad5hTRAIL) and IKK inhibition (AdIKKβKA) to overcome TRAIL resistance in lung cancer cells.</p> <p>Methods</p> <p>Fluorescent microscopy and flow cytometry were used to detect optimum doses of adenovirus vectors to transduce lung cancer cells. Cell viability was assessed via a live/dead cell viability assay. Luciferase assays were employed to monitor cellular NF-κB activity. Apoptosis was confirmed using Annexin V binding.</p> <p>Results</p> <p>Neither Ad5hTRAIL nor AdIKKβKA infection alone induced apoptosis in A549 lung cancer cells, but the combined use of Ad5hTRAIL and AdIKKβKA significantly increased the amount of A549 apoptosis. Luciferase assays demonstrated that both endogenous and TRAIL-induced NF-κB activity was down-regulated by AdIKKβKA expression.</p> <p>Conclusions</p> <p>Combination treatment with Ad5hTRAIL and AdIKKβKA induced significant apoptosis of TRAIL-resistant A549 cells, suggesting that dual gene therapy strategy involving exogenous TRAIL gene expression with concurrent IKK inhibition may be a promising novel gene therapy modality to treat lung cancer.</p
Methane drizzle on Titan
Saturn's moon Titan shows landscapes with fluvial features(1) suggestive of hydrology based on liquid methane. Recent efforts in understanding Titan's methane hydrological cycle have focused on occasional cloud outbursts near the south pole(2-4) or cloud streaks at southern mid-latitudes(5,6) and the mechanisms of their formation. It is not known, however, if the clouds produce rain or if there are also non-convective clouds, as predicted by several models(7-11). Here we show that the in situ data on the methane concentration and temperature profile in Titan's troposphere point to the presence of layered optically thin stratiform clouds. The data indicate an upper methane ice cloud and a lower, barely visible, liquid methane-nitrogen cloud, with a gap in between. The lower, liquid, cloud produces drizzle that reaches the surface. These non-convective methane clouds are quasi-permanent features supported by the global atmospheric circulation, indicating that methane precipitation occurs wherever there is slow upward motion. This drizzle is a persistent component of Titan's methane hydrological cycle and, by wetting the surface on a global scale, plays an active role in the surface geology of Titan.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62668/1/nature04948.pd
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