Ras/Raf-1/MAPK pathway mediates response to tamoxifen but not chemotherapy in breast cancer patients

<b>Purpose</b>: The expression and activation of the Ras/Raf-1/mitogen-activated protein kinase (MAPK) pathway plays an important role in the development and progression of cancer, and may influence response to treatments such as tamoxifen and chemotherapy. In this study we investigated whether the expression and activation of the key components of this pathway influenced clinical outcome, to test the hypothesis that activation of the MAPK pathway drives resistance to tamoxifen and chemotherapy in women with breast cancer. <b>Experimental Design</b>: Breast tumors from patients at the Glasgow Royal Infirmary and others treated within the BR9601 trial were analyzed for expression of the three Ras isoforms, total Raf-1, active and inactive forms of Raf-1 [pRaf(ser338) and pRaf(ser259), respectively], MAPK, and phospho-MAPK using an immunohistochemical approach. Analyses were done with respect to disease free-survival and overall survival. <b>Results</b>: Expression and activation of the Ras pathway was associated with loss of benefit from treatment with tamoxifen but not chemotherapy. Overexpression of pRaf(ser338) was associated with shortened disease-free and overall survival time in univariate analyses. Multivariate analysis suggested pRaf(ser338) was independent of known prognostic markers in predicting outcome following tamoxifen treatment (<i>P</i>=0.03). <b>Conclusion</b>: This study suggests that activation of the Ras pathway predicts for poor outcome on tamoxifen but not chemotherapy, and identifies pRaf(ser338) as a potential marker of resistance to estrogen receptor–targeted therapy. In addition, it suggests that expression of pRaf(ser338) could identify patients for whom tamoxifen alone is insufficient adjuvant systemic therapy, but for whom the addition of chemotherapy may be of benefit

Design optimisation of air-fed full pressurised suits

This article is a post-print version of the published article which may be accessed at the link below.The JET machine and associated facilities require significant maintenance and enhancement installation activities in support of the experimental exploitation programme. A proportion of these activities are within radiological and respiratory hazardous environments. As such, breathing air-fed one-piece pressurised suits provide workers with protection from the inhalation of both airborne tritium and beryllium dust. The design of these suits has essentially developed empirically. There is a practical necessity to improve the design to optimise worker performance, protection and thermal comfort. This paper details the complexity of modeling the three-dimensional thermofluid domain between the inner surface of the suit and under garments that includes mass as well as heat transfer, suiting geometry, human metabolism and respiration and effects of limb movements. The methods used include computational fluid dynamics (CFD), theoretical adaptations of mixed-phase turbulent flow, profile scanning of a suit and actuating life size mannequin and data processing of the images and experimental validation trials. The achievements of the current programme and collaborations are presented in the paper and future endeavors are discussed.The author gratefully acknowledges the loan of the articulated mannequin from the Defence Science and Technology Laboratories. This work was funded jointly by EPSRC and by the European Communities under the contract of Association between EURATOM and UKAEA. The views and opinions expressed herein do not necessarily reflect those of the European Commission. This work was carried out within the framework of EFDA

Geometry of Frictionless and Frictional Sphere Packings

We study static packings of frictionless and frictional spheres in three dimensions, obtained via molecular dynamics simulations, in which we vary particle hardness, friction coefficient, and coefficient of restitution. Although frictionless packings of hard-spheres are always isostatic (with six contacts) regardless of construction history and restitution coefficient, frictional packings achieve a multitude of hyperstatic packings that depend on system parameters and construction history. Instead of immediately dropping to four, the coordination number reduces smoothly from $z=6$ as the friction coefficient $\mu$ between two particles is increased.Comment: 6 pages, 9 figures, submitted to Phys. Rev.

Expression of tumor necrosis factor [alpha] converting enzyme in endocrine cancers

Tumor necrosis factor [alpha] converting enzyme (TACE) mediates shedding of human epidermal growth factor receptor-4 (HER4). Recent data suggest that released HER4 intracellular domain (4ICD) induces apoptosis in breast cancer. TACE expression, as measured by immunohistochemical analysis, was observed in 183 of 383 breast carcinomas, 39 of 217 ovarian carcinomas, and 16 of 24 and 17 of 24 hormone-sensitive and hormone-insensitive prostate carcinomas, respectively. HER4 expression was detected in breast carcinomas by using 2 antibodies recognizing an extracellular or intracellular epitope. TACE expression was predominantly seen in tumors with high levels of 4ICD and membranous HER4. Apoptotic activity was measured by the terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay and cleaved caspase-3 staining in breast carcinomas. There was no significant association between cleaved caspase-3 or TUNEL positivity and 4ICD, whereas TUNEL positivity was seen predominantly in tumors with high levels of internalized HER4. The data presented herein show TACE expression in endocrine cancers and further support a role for TACE in breast cancer apoptosis

Stress Transmission through Three-Dimensional Ordered Granular Arrays

We measure the local contact forces at both the top and bottom boundaries of three-dimensional face-centered-cubic and hexagonal-close-packed granular crystals in response to an external force applied to a small area at the top surface. Depending on the crystal structure, we find markedly different results which can be understood in terms of force balance considerations in the specific geometry of the crystal. Small amounts of disorder are found to create additional structure at both the top and bottom surfaces.Comment: 9 pages including 9 figures (many in color) submitted to PR

Bulk dynamics for interfacial growth models

We study the influence of the bulk dynamics of a growing cluster of particles on the properties of its interface. First, we define a {\it general bulk growth model} by means of a continuum Master equation for the evolution of the bulk density field. This general model just considers arbitrary addition of particles (though it can be easily generalized to consider substraction) with no other physical restriction. The corresponding Langevin equation for this bulk density field is derived where the influence of the bulk dynamics is explicitly shown. Finally, when it is assumed a well-defined interface for the growing cluster, the Langevin equation for the height field of this interface for some particular bulk dynamics is written. In particular, we obtain the celebrated Kardar-Parisi-Zhang (KPZ) equation. A Monte Carlo simulation illustrates the theoretical results.Comment: 6 pages, 2 figure

Constraints on R-parity violating supersymmetry from leptonic and semileptonic tau, B_d and B_s decays

We put constraints on several products of R-parity violating lambda lambda' and lambda' lambda' type couplings from leptonic and semileptonic tau, B_d and B_s decays. Most of them are one to two orders of magnitude better than the existing bounds, and almost free from theoretical uncertainties. A significant improvement of these bounds can be made in high luminosity tau-charm or B factories.Comment: 14 pages, latex. A few references added, two typos corrected. Version to be published in Physical Review

Monopole characteristics in various Abelian gauges

Renormalization group (RG) smoothing is employed on the lattice to investigate and to compare the monopole structure of the SU(2) vacuum as seen in different gauges (maximally Abelian (MAG), Polyakov loop (PG) and Laplacian gauge (LG)). Physically relevant types of monopoles (LG and MAG) are distinguished by their behavior near the deconfining phase transition. For the LG, Abelian projection reproduces well the gauge independent monopole structure encoded in an auxiliary Higgs field. Density and localization properties of monopoles, their non-Abelian action and topological charge are studied. Results are presented confirming the Abelian dominance with respect to the non-perturbative static potential for all gauges considered.Comment: 36 pages, 12 figure

Partonic flow and ϕ\phi-meson production in Au+Au collisions at sNN\sqrt{s_{NN}} = 200 GeV

We present first measurements of the $\phi$-meson elliptic flow ($v_{2}(p_{T})$) and high statistics $p_{T}$ distributions for different centralities from $\sqrt{s_{NN}}$ = 200 GeV Au+Au collisions at RHIC. In minimum bias collisions the $v_{2}$ of the $\phi$ meson is consistent with the trend observed for mesons. The ratio of the yields of the $\Omega$ to those of the $\phi$ as a function of transverse momentum is consistent with a model based on the recombination of thermal $s$ quarks up to $p_{T}\sim 4$ GeV/$c$, but disagrees at higher momenta. The nuclear modification factor ($R_{CP}$) of $\phi$ follows the trend observed in the $K^{0}_{S}$ mesons rather than in $\Lambda$ baryons, supporting baryon-meson scaling. Since $\phi$-mesons are made via coalescence of seemingly thermalized $s$ quarks in central Au+Au collisions, the observations imply hot and dense matter with partonic collectivity has been formed at RHIC.Comment: 6 pages, 4 figures, submit to PR