Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer.

IntroductionThe purpose of this study was to retrospectively explore the relationship between human epidermal growth factor receptor 2 (HER2) messenger RNA (mRNA) expression and efficacy in patients receiving trastuzumab plus docetaxel (HT) or trastuzumab emtansine (T-DM1).MethodsPatients with HER2-positive, locally advanced or metastatic breast cancer (MBC) were randomly assigned to HT (n=70) or T-DM1 (n=67). HER2 status was assessed locally using immunohistochemistry or fluorescence in situ hybridization and confirmed retrospectively by central testing. HER2 mRNA expression was assessed using quantitative reverse transcriptase polymerase chain reaction.ResultsHER2 mRNA levels were obtained for 116/137 patients (HT=61; T-DM1=55). Median pretreatment HER2 mRNA was 8.9. The risk of disease progression in the overall population was lower with T-DM1 than with HT (hazard ratio (HR)=0.59; 95% confidence interval (CI) 0.36 to 0.97). This effect was more pronounced in patients with HER2 mRNA≥median (HR=0.39; 95% CI 0.18 to 0.85) versus ConclusionsThis exploratory analysis suggests that while overall, patients with HER2-positive MBC show improved PFS with T-DM1 relative to HT, the effect is enhanced in patients with tumor HER2 mRNA ≥ median.Trial registrationClinicalTrials.gov NCT00679341

NuSTAR Tests of Sterile-Neutrino Dark Matter: New Galactic Bulge Observations and Combined Impact

We analyze two dedicated NuSTAR observations with exposure ${\sim}190$ ks located ${\sim}10^\circ$ from the Galactic plane, one above and the other below, to search for x-ray lines from the radiative decay of sterile-neutrino dark matter. These fields were chosen to minimize astrophysical x-ray backgrounds while remaining near the densest region of the dark matter halo. We find no evidence of anomalous x-ray lines in the energy range 5--20 keV, corresponding to sterile neutrino masses 10--40 keV. Interpreted in the context of sterile neutrinos produced via neutrino mixing, these observations provide the leading constraints in the mass range 10--12 keV, improving upon previous constraints in this range by a factor ${\sim}2$. We also compare our results to Monte Carlo simulations, showing that the fluctuations in our derived limit are not dominated by systematic effects. An updated model of the instrumental background, which is currently under development, will improve NuSTAR's sensitivity to anomalous x-ray lines, particularly for energies 3--5 keV.Comment: 16 pages, 5 figures. Text updated to match published version in PRD. Conclusions unchange

Mechanomodulation of Lipid Membranes by Weakly Aggregating Silver Nanoparticles

Silver nanoparticles (AgNPs) have wide-ranging applications, including as additives in consumer products and in medical diagnostics and therapy. Therefore, understanding how AgNPs interact with biological systems is important for ascertaining any potential health risks due to the likelihood of high levels of human exposure. Besides any severe, acute effects, it is desirable to understand more subtle interactions that could lead to milder, chronic health impacts. Nanoparticles are small enough to be able to enter biological cells and interfere with their internal biochemistry. The initial contact between the nanoparticle and cell is at the plasma membrane. To gain fundamental mechanistic insight into AgNP–membrane interactions, we investigate these phenomena in minimal model systems using a wide range of biophysical approaches applied to lipid vesicles. We find a strong dependence on the medium composition, where colloidally stable AgNPs in a glucose buffer have a negligible effect on the membrane. However, at physiological salt concentrations, the AgNPs start to weakly aggregate and sporadic but significant membrane perturbation events are observed. Under these latter conditions, transient poration and structural remodeling of some vesicle membranes are observed. We observe that the fluidity of giant vesicle membranes universally decreases by an average of 16% across all vesicles. However, we observe a small population of vesicles that display a significant change in their mechanical properties with lower bending rigidity and higher membrane tension. Therefore, we argue that the isolated occurrences of membrane perturbation by AgNPs are due to low-probability mechanomodulation by AgNP aggregation at the membrane

Almost closing the νMSM sterile neutrino dark matter window with NuSTAR

We use NuSTAR observations of the Galactic center to search for x-ray lines from the radiative decay of sterile neutrino dark matter. Finding no evidence of unknown lines, we set limits on the sterile neutrino mass and mixing angle. In most of the mass range 10–50 keV, these are now the strongest limits, at some masses improving upon previous limits by a factor of ∼10. In the νMSM framework, where additional constraints from dark matter production and structure formation apply, the allowed parameter space is reduced by more than half. Future NuSTAR observations may be able to cover much of the remaining parameter space

Evolution of plasma turbulence excited with particle beams

Particles ejected from the Sun that stream through the surrounding plasma of the solar wind are causing instabilities. These generate wavemodes in a certain frequency range especially within shock regions, where particles are accelerated. The aim of this paper is to investigate of amplified Alfvenic wavemodes in driven incompressible magnetohydrodynamic turbulence. Results of different heliospheric scenarios from isotropic and anisotropic plasmas, as well as turbulence near the critical balance are shown. The energy transport of the amplified wavemode is governed by the mechanisms of diffusion, convection and dissipation of energy in wavenumber space. The strength of these effects varies with energy and wavenumber of the mode in question. Two-dimensional energy spectra of spherical k-space integration that permit detailed insight into the parallel and perpendicular development are presented. The evolution of energy injected through driving shows a strong energy transfer to perpendicular wavemodes. The main process at parallel wavemodes is the dissipation of energy in wavenumber space. The generation of higher harmonics along the parallel wavenumber axis is observed. We find evidence for a critical balance in our simulations.Comment: Accepted for publication in A&

Sarcopenia in Children With End-Stage Liver Disease on the Transplant Waiting List

Sarcopenia predicts morbidity and mortality in adults with end-stage liver disease (ESLD) and is determined by total psoas muscle area (tPMA) measurement from computed tomography (CT) imaging. Recently developed pediatric age- and sex-specific tPMA growth curves provide the opportunity to ascertain prevalence and impact of sarcopenia in children awaiting liver transplantation (LT). This retrospective single-center study evaluated sarcopenia in children between 1 and 16 years with ESLD and a clinically indicated abdominal CT less than 3 months before first isolated LT. Sarcopenia was defined as tPMA z score less than −2 measured at the intervertebral L4-5 level. Patient demographic, biochemical, and outcome data were recorded. tPMA was compared with other measures of nutritional status using univariate and multivariate logistic analyses. Outcome measures included 1-year morbidity events and mortality after LT. CT images from 25 (64% female) children with median age of 5.50 (interquartile range [IQR], 3.75-11.33) years were reviewed. Ten children (40%) had a tPMA z score less than −2. Sarcopenia was associated with lower z scores for weight (odds ratio [OR], 0.38; P = 0.02), height (OR, 0.32; P = 0.03), and nutritional support before LT (OR, 12.93; P = 0.01). Sarcopenic children had a longer duration of pediatric intensive care unit (PICU) stay (3.50 [IQR, 3.00-6.00] versus 2.00 [IQR, 2.00-3.50] days; P = 0.03). Sarcopenia was prevalent in 40% of children with ESLD awaiting LT, and lower tPMA z score was associated with deficient anthropometrics and need for nutritional support before LT. Post-LT PICU duration was increased in children with sarcopenia, reflecting adverse outcomes associated with muscle loss. Further studies are needed to elucidate the underlying mechanisms of sarcopenia in children with ESLD

About Lorentz invariance in a discrete quantum setting

A common misconception is that Lorentz invariance is inconsistent with a discrete spacetime structure and a minimal length: under Lorentz contraction, a Planck length ruler would be seen as smaller by a boosted observer. We argue that in the context of quantum gravity, the distance between two points becomes an operator and show through a toy model, inspired by Loop Quantum Gravity, that the notion of a quantum of geometry and of discrete spectra of geometric operators, is not inconsistent with Lorentz invariance. The main feature of the model is that a state of definite length for a given observer turns into a superposition of eigenstates of the length operator when seen by a boosted observer. More generally, we discuss the issue of actually measuring distances taking into account the limitations imposed by quantum gravity considerations and we analyze the notion of distance and the phenomenon of Lorentz contraction in the framework of ``deformed (or doubly) special relativity'' (DSR), which tentatively provides an effective description of quantum gravity around a flat background. In order to do this we study the Hilbert space structure of DSR, and study various quantum geometric operators acting on it and analyze their spectral properties. We also discuss the notion of spacetime point in DSR in terms of coherent states. We show how the way Lorentz invariance is preserved in this context is analogous to that in the toy model.Comment: 25 pages, RevTe