The androgen receptor and signal-transduction pathways in hormone-refractory prostate cancer. Part 2: androgen-receptor cofactors and bypass pathways

Prostate cancer is the second leading cause of cancer related deaths in men from the western world. Treatment of prostate cancer has relied on androgen deprivation therapy for the past 50 years. Response rates are initially high (70-80%), however almost all patients develop androgen escape and subsequently die within 1-2 years. Unlike breast cancer, alternative approaches (chemotherapy and radiotherapy) do not increase survival time. The high rate of prostate cancer mortality is therefore strongly linked to both development of androgen escape and the lack of alternate therapies. AR mutations and amplifications can not explain all cases of androgen escape and post-translational modification of the AR has become an alternative theory. However recently it has been suggested that AR co-activators e.g. SRC-1 or pathways the bypass the AR (Ras/MAP kinase or PI3K/Akt) may stimulated prostate cancer progression independent of the AR. This review will focus on how AR coactivators may act to increase AR transactivation during sub-optimal DHT concentrations and also how signal transduction pathways may promote androgen escape via activation of transcription factors, e.g. AP-1, c-Myc and Myb, that induce cell proliferation or inhibit apoptosis

Mott physics and band topology in materials with strong spin-orbit interaction

Recent theory and experiment have revealed that strong spin-orbit coupling can have dramatic qualitative effects on the band structure of weakly interacting solids. Indeed, it leads to a distinct phase of matter, the topological band insulator. In this paper, we consider the combined effects of spin-orbit coupling and strong electron correlation, and show that the former has both quantitative and qualitative effects upon the correlation-driven Mott transition. As a specific example we take Ir-based pyrochlores, where the subsystem of Ir 5d electrons is known to undergo a Mott transition. At weak electron-electron interaction, we predict that Ir electrons are in a metallic phase at weak spin-orbit interaction, and in a topological band insulator phase at strong spin-orbit interaction. Very generally, we show that with increasing strength of the electron-electron interaction, the effective spin-orbit coupling is enhanced, increasing the domain of the topological band insulator. Furthermore, in our model, we argue that with increasing interactions, the topological band insulator is transformed into a "topological Mott insulator" phase, which is characterized by gapless surface spin-only excitations. The full phase diagram also includes a narrow region of gapless Mott insulator with a spinon Fermi surface, and a magnetically ordered state at still larger electron-electron interaction.Comment: 10+ pages including 3+ pages of Supplementary Informatio

Potential application of mesh-free SPH method in turbulent river flows

A comprehensive review has been completed on the simulation of turbulent flow over rough beds using mesh-free particle models. Based on the outcomes of this review, an improved Smoothed Particle Hydrodynamics (SPH) method has been developed for open channel flows over a rough bed, in which a mixing length model is used for modeling the 2D turbulence and a drag force equation is proposed for treating the boundary shear. The proposed model was applied to simulate a depth-limited open channel flow over a rough bed surface. The results of the velocity profile and shear stress distribution show a good agreement with the experimental data and existing analytical solutions. This work reveals that in order to correctly model turbulent open channel flow over a rough bed, the treatment of both flow turbulence and bed roughness effect is equally important

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

The effect of turbulent viscous shear stress on red blood cell hemolysis

[[abstract]]Non-physiologic turbulent flow occurs in medical cardiovascular devices resulting in hemodynamic stresses that may damage red blood cells (RBC) and cause hemolysis. Hemolysis was previously thought to result from Reynolds shear stress (RSS) in turbulent flows. A more recent hypothesis suggests that turbulent viscous shear stresses (TVSS) at spatial scales similar in size to RBCs are related to their damage. We applied two-dimensional digital particle image velocimetry to measure the flow field of a free-submerged axisymmetric jet that was utilized to hemolyze porcine RBCs in selected locations. Assuming a dynamic equilibrium for the sub-grid scale (SGS) energy flux between the resolved and the sub-grid scales, the SGS energy flux was calculated from the strain rate tensor computed from the resolved velocity fields. The SGS stress was determined by the Smagorinsky model, from which the turbulence dissipation rate and then TVSS were estimated. Our results showed the hemolytic threshold of the Reynolds stresses was up to 517 Pa, and the TVSSs were at least an order of magnitude less than the RSS. The results provide further insight into the relationship between turbulence and RBC damage.[[incitationindex]]SCI[[booktype]]紙本[[countrycodes]]JP

NPR3 and NPR4 are receptors for the immune signal salicylic acid in plants

Salicylic acid (SA) is a plant immune signal produced upon pathogen challenge to induce systemic acquired resistance (SAR). It is the only major plant hormone for which the receptor has not been firmly identified. SAR in Arabidopsis requires the transcription cofactor NPR1 (nonexpresser of PR genes 1), whose degradation serves as a molecular switch for SAR. Here we show that NPR1 paralogues, NPR3 and NPR4, are SA receptors that bind SA with different affinities and function as adaptors of the Cullin 3 ubiquitin E3 ligase to mediate NPR1 degradation in an SA-regulated manner. Accordingly, the npr3 npr4 mutant accumulates higher levels of NPR1 and is insensitive to SAR induction. Moreover, this mutant is defective in pathogen effector-triggered programmed cell death and immunity. Our study reveals the mechanism of SA perception in determining cell death and survival in response to pathogen challenge

Health status, use of healthcare, and socio-economic implications of cancer survivorship in Portugal : results from the fourth national health survey

Health status, use of healthcare, and socio-economic implications of cancer survivorship in Portugal: results from the Fourth National Health SurveyUnderstanding the morbidity and socio-economic implications of cancer survivorship is essential for a comprehensive management of oncological diseases. We compared cancer survivors (CS) with the general population regarding health status, use of healthcare resources and socio-economic condition. We analyzed data from a representative sample of the Portuguese population aged a parts per thousand yen15 years (n = 35,229). We defined three groups of CS, according to the time since diagnosis and the latest cancer treatment: CS 1 diagnosis within 12 months of interview; CS 2 diagnosis more than 12 months before and treatment in the previous 12 months; CS 3 diagnosis and treatment more than 12 months before. These were compared with the general population, adjusting for differences in sex, age, and place of residence. The prevalence of CS was 2.2 % (CS 1: 0.2 %; CS 2: 0.9 %, CS 3: 1.1 %). Self-perceived health status was worse among CS and short-time incapacity more frequent among CS 1 and CS 2. Health expenses were higher in the early stages of survivorship. Lower household income and financial difficulties were more frequent in CS 1 and CS 3 men, respectively. This study confirmed the higher consumption of healthcare resources and worse financial situation among CS. Our study provides valuable information for understanding the global impact of cancer survivorship.The authors thank the National Health Systems Observatory (Observatorio Nacional de Saude), National Institute of Health Dr. Ricardo Jorge (INSA), Ministry of Health and the National Institute of Statistics (INE) for providing the data (Ministerio da Saude, Instituto Nacional de Saude Dr. Ricardo Jorge; IP, Departamento de Epidemiologia/Instituto Nacional de Estatistica: Inquerito Nacional de Saude 2005/2006). Luis Pacheco-Figueiredo received a grant from the Fundacao para a Ciencia e a Tecnologia (SFRH/SINTD/60124/2009)

Observation of a ppb mass threshoud enhancement in \psi^\prime\to\pi^+\pi^-J/\psi(J/\psi\to\gamma p\bar{p}) decay

The decay channel $\psi^\prime\to\pi^+\pi^-J/\psi(J/\psi\to\gamma p\bar{p})$ is studied using a sample of $1.06\times 10^8$ $\psi^\prime$ events collected by the BESIII experiment at BEPCII. A strong enhancement at threshold is observed in the $p\bar{p}$ invariant mass spectrum. The enhancement can be fit with an $S$-wave Breit-Wigner resonance function with a resulting peak mass of $M=1861^{+6}_{-13} {\rm (stat)}^{+7}_{-26} {\rm (syst)} {\rm MeV/}c^2$ and a narrow width that is $\Gamma<38 {\rm MeV/}c^2$ at the 90% confidence level. These results are consistent with published BESII results. These mass and width values do not match with those of any known meson resonance.Comment: 5 pages, 3 figures, submitted to Chinese Physics

Long-term functional outcomes and the patient perspective following altered fractionation with concomitant boost for oropharyngeal cancer

With no long-term data available in published research to date, this study presents details of the swallowing outcomes as well as barriers to and facilitators of oral intake and weight maintenance at 2 years after altered fractionation radiotherapy with concomitant boost (AFRT-CB). Twelve patients with T1-T3 oropharyngeal cancer who received AFRT-CB were assessed at baseline, 6 months, and 2 years post-treatment for levels of dysphagia and salivary toxicity, food and fluid tolerance, functional swallowing outcomes, patient-reported function, and weight. At 2 years, participants were also interviewed to explore barriers and facilitators of oral intake. Outcomes were significantly worse at 2 years when compared to baseline for late toxicity, functional swallowing, and patient-rated physical aspects of swallowing. Most patients (83%) tolerated a full diet pretreatment, but the rate fell to 42% (remainder tolerated soft diets) at 2 years. Multiple barriers to oral intake that impacted on activity and participation levels were identified. Participants lost 11 kg from baseline to 2 years, which was not regained between 6 months and 2 years. Global, social, and emotional domains of patient-reported function returned to pretreatment levels. At 2 years post AFRT-CB, worsening salivary and dysphagia toxicity, declining functional swallowing, and multiple reported ongoing barriers to oral intake had a negative impact on participants' activity and participation levels relating to eating. These ongoing deficits contributed to significant deterioration in physical swallowing functioning determined by the MDADI. In contrast, patients perceived their broader functioning had improved at 2 years, suggesting long-term adjustment to ongoing swallowing deficits