Rationale and design of LUX-Head & Neck 1: a randomised, Phase III trial of afatinib versus methotrexate in patients with recurrent and/or metastatic head and neck squamous cell carcinoma who progressed after platinum-based therapy

Background: Patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) receiving platinum-based chemotherapy as their first-line treatment have a dismal prognosis, with a median overall survival (OS) of ~7 months. Methotrexate is sometimes used following platinum failure or in patients not fit enough for platinum therapy, but this agent has not demonstrated any OS improvement. Targeted therapies are a novel approach, with the EGFR-targeting monoclonal antibody cetuximab (plus platinum-based chemotherapy) approved in the US and Europe in the first-line R/M setting, and as monotherapy following platinum failure in the US. However, there is still a high unmet medical need for new treatments that improve outcomes in the second-line R/M setting following failure on first-line platinum-containing regimens. Afatinib, an irreversible ErbB family blocker, was recently approved for the first-line treatment of EGFR mutation-positive metastatic non-small cell lung cancer. Afatinib has also shown clinical activity similar to cetuximab in a Phase II proof-of-concept HNSCC trial. Based on these observations, the Phase III, LUX-Head & Neck 1 study is evaluating afatinib versus methotrexate in R/M HNSCC patients following progression on platinum-based chemotherapy in the R/M setting. Methods/Design Patients with progressive disease after one first-line platinum-based chemotherapy are randomised 2:1 to oral afatinib (starting dose 40 mg once daily) or IV methotrexate (starting dose 40 mg/m2 once weekly) administered as monotherapy with best supportive care until progression or intolerable adverse events. Efficacy of afatinib versus methotrexate will be assessed in terms of progression-free survival (primary endpoint). Disease progression will be evaluated according to RECIST v1.1 by investigator and independent central review. Secondary endpoints include OS, tumour response and safety. Health-related quality of life and biomarker assessments will also be performed. Discussion If the LUX-Head & Neck 1 trial meets its primary endpoint, it will demonstrate the ability of afatinib to elicit an improved treatment benefit versus a commonly used chemotherapy agent in the second-line treatment of R/M HNSCC patients who have failed on first-line platinum-based therapy, confirm the clinical efficacy of afatinib observed in the Phase II proof-of-concept study, and establish a new standard of care for this patient population

Thermal quantum electrodynamics of nonrelativistic charged fluids

The theory relevant to the study of matter in equilibrium with the radiation field is thermal quantum electrodynamics (TQED). We present a formulation of the theory, suitable for non relativistic fluids, based on a joint functional integral representation of matter and field variables. In this formalism cluster expansion techniques of classical statistical mechanics become operative. They provide an alternative to the usual Feynman diagrammatics in many-body problems which is not perturbative with respect to the coupling constant. As an application we show that the effective Coulomb interaction between quantum charges is partially screened by thermalized photons at large distances. More precisely one observes an exact cancellation of the dipolar electric part of the interaction, so that the asymptotic particle density correlation is now determined by relativistic effects. It has still the $r^{-6}$ decay typical for quantum charges, but with an amplitude strongly reduced by a relativistic factor.Comment: 32 pages, 0 figures. 2nd versio

Effect of C282Y genotype on self-reported musculoskeletal complications in hereditary hemochromatosis

Objective Arthropathy that mimics osteoarthritis (OA) and osteoporosis (OP) is considered a complication of hereditary hemochromatosis (HH). We have limited data comparing OA and OP prevalence among HH patients with different hemochromatosis type 1 (HFE) genotypes. We investigated the prevalence of OA and OP in patients with HH by C282Y homozygosity and compound heterozygosity (C282Y/H63D) genotype. Methods A total of 306 patients with HH completed a questionnaire. Clinical and demographic characteristics and presence of OA, OP and related complications were compared by genotype, adjusting for age, sex, body mass index (BMI), current smoking and menopausal status. Results In total, 266 of the 306 patients (87%) were homozygous for C282Y, and 40 (13%) were compound heterozygous. The 2 groups did not differ by median age [60 (interquartile range [IQR] 53 to 68) vs. 61 (55 to 67) years, P=0.8], sex (female: 48.8% vs. 37.5%, P=0.18) or current smoking habits (12.4% vs. 10%, P=0.3). As compared with compound heterozygous patients, C282Y homozygous patients had higher median serum ferritin concentration at diagnosis [1090 (IQR 610 to 2210) vs. 603 (362 to 950) mu g/L, P<0.001], higher median transferrin saturation [80% (IQR 66 to 91%) vs. 63% (55 to 72%), P<0.001]) and lower median BMI [24.8 (22.1 to 26.9) vs. 26.2 (23.5 to 30.3) kg/m2, P<0.003]. The overall prevalence of self-reported OA was significantly higher with C282Y homozygosity than compound heterozygosity (53.4% vs. 32.5%; adjusted odds ratio [aOR] 2.4 [95% confidence interval 1.2-5.0]), as was self-reported OP (25.6% vs. 7.5%; aOR 3.5 [1.1-12.1]). Conclusion Patients with C282Y homozygosity may be at increased risk of musculoskeletal complications of HH.Association Rhumatisme et Travail (Centre Viggo Petersen, Hospital Lariboisiere, Paris

Equilibrium correlations in charged fluids coupled to the radiation field

We provide an exact microscopic statistical treatment of particle and field correlations in a system of quantum charges in equilibrium with a classical radiation field. Using the Feynman-Kac-Ito representation of the Gibbs weight, the system of particles is mapped onto a collection of random charged wires. The field degrees of freedom can be integrated out, providing an effective pairwise magnetic potential. We then calculate the contribution of the transverse field coupling to the large-distance particle correlations. The asymptotics of the field correlations in the plasma are also exactly determined.Comment: 31 pages, 0 figures. PACS 05.30.-d, 05.40.-a, 11.10.Wx. Changes: Improved comparison with existing literature on field correlations. Added Concluding Remarks. References update

InfraPhenoGrid: A scientific workflow infrastructure for Plant Phenomics on the Grid

International audiencePlant phenotyping consists in the observation of physical and biochemical traits of plant genotypes in response to environmental conditions. Challenges , in particular in context of climate change and food security, are numerous. High-throughput platforms have been introduced to observe the dynamic growth of a large number of plants in different environmental conditions. Instead of considering a few genotypes at a time (as it is the case when phenomic traits are measured manually), such platforms make it possible to use completely new kinds of approaches. However, the data sets produced by such widely instrumented platforms are huge, constantly augmenting and produced by increasingly complex experiments, reaching a point where distributed computation is mandatory to extract knowledge from data. In this paper, we introduce InfraPhenoGrid, the infrastructure we designed and deploy to efficiently manage data sets produced by the PhenoArch plant phenomics platform in the context of the French Phenome Project. Our solution consists in deploying scientific workflows on a Grid using a middle-ware to pilot workflow executions. Our approach is user-friendly in the sense that despite the intrinsic complexity of the infrastructure, running scientific workflows and understanding results obtained (using provenance information) is kept as simple as possible for end-users

Inelastic X-ray Scattering by Electronic Excitations in Solids at High Pressure

Investigating electronic structure and excitations under extreme conditions gives access to a rich variety of phenomena. High pressure typically induces behavior such as magnetic collapse and the insulator-metal transition in 3d transition metals compounds, valence fluctuations or Kondo-like characteristics in $f$-electron systems, and coordination and bonding changes in molecular solids and glasses. This article reviews research concerning electronic excitations in materials under extreme conditions using inelastic x-ray scattering (IXS). IXS is a spectroscopic probe of choice for this study because of its chemical and orbital selectivity and the richness of information it provides. Being an all-photon technique, IXS has a penetration depth compatible with high pressure requirements. Electronic transitions under pressure in 3d transition metals compounds and $f$-electron systems, most of them strongly correlated, are reviewed. Implications for geophysics are mentioned. Since the incident X-ray energy can easily be tuned to absorption edges, resonant IXS, often employed, is discussed at length. Finally studies involving local structure changes and electronic transitions under pressure in materials containing light elements are briefly reviewed.Comment: submitted to Rev. Mod. Phy

Reddening and Extinction Toward the Galactic Bulge from OGLE-III: The Inner Milky Way's Rv ~ 2.5 Extinction Curve

We combine VI photometry from OGLE-III with VVV and 2MASS measurements of E(J-K_{s}) to resolve the longstanding problem of the non-standard optical extinction toward the Galactic bulge. We show that the extinction is well-fit by the relation A_{I} = 0.7465*E(V-I) + 1.3700*E(J-K_{s}), or, equivalently, A_{I} = 1.217*E(V-I)(1+1.126*(E(J-K_{s})/E(V-I)-0.3433)). The optical and near-IR reddening law toward the inner Galaxy approximately follows an R_{V} \approx 2.5 extinction curve with a dispersion {\sigma}_{R_{V}} \approx 0.2, consistent with extragalactic investigations of the hosts of type Ia SNe. Differential reddening is shown to be significant on scales as small as as our mean field size of 6', with the 1{\sigma} dispersion in reddening averaging 9% of total reddening for our fields. The intrinsic luminosity parameters of the Galactic bulge red clump (RC) are derived to be (M_{I,RC}, \sigma_{I,RC,0}, (V-I)_{RC,0}, \sigma_{(V-I)_{RC}}, (J-K_{s})_{RC,0}) = (-0.12, 0.09, 1.06, 0.121, 0.66). Our measurements of the RC brightness, brightness dispersion and number counts allow us to estimate several Galactic bulge structural parameters. We estimate a distance to the Galactic center of 8.20 kpc, resolving previous discrepancies in distance determinations to the bulge based on I-band observations. We measure an upper bound on the tilt {\alpha} \approx 40{\deg}. between the bar's major axis and the Sun-Galactic center line of sight, though our brightness peaks are consistent with predictions of an N-body model oriented at {\alpha} \approx 25{\deg}. The number of RC stars suggests a total stellar mass for the Galactic bulge of 2.0*10^{10} M_{\odot}, if one assumes a Salpeter IMF.Comment: 61 Pages, 21 Figures, 4 Tables, Submitted to The Astrophysical Journal and modified as per a referee report. Includes reddening, reddening law, differential reddening, mean distance, dispersion in distance, surface density of stars and errors thereof for ~9,000 bulge sightlines. For a brief video explaining the key result of this paper, see http://www.youtube.com/user/OSUAstronom

Investigation of bone resorption within a cortical basic multicellular unit using a lattice-based computational model

In this paper we develop a lattice-based computational model focused on bone resorption by osteoclasts in a single cortical basic multicellular unit (BMU). Our model takes into account the interaction of osteoclasts with the bone matrix, the interaction of osteoclasts with each other, the generation of osteoclasts from a growing blood vessel, and the renewal of osteoclast nuclei by cell fusion. All these features are shown to strongly influence the geometrical properties of the developing resorption cavity including its size, shape and progression rate, and are also shown to influence the distribution, resorption pattern and trajectories of individual osteoclasts within the BMU. We demonstrate that for certain parameter combinations, resorption cavity shapes can be recovered from the computational model that closely resemble resorption cavity shapes observed from microCT imaging of human cortical bone.Comment: 17 pages, 11 figures, 1 table. Revised version: paper entirely rewritten for a more biology-oriented readership. Technical points of model description now in Appendix. Addition of two new figures (Fig. 5 and Fig. 9) and removal of former Fig.

Nonlinear modulational stability of periodic traveling-wave solutions of the generalized Kuramoto-Sivashinsky equation

In this paper we consider the spectral and nonlinear stability of periodic traveling wave solutions of a generalized Kuramoto-Sivashinsky equation. In particular, we resolve the long-standing question of nonlinear modulational stability by demonstrating that spectrally stable waves are nonlinearly stable when subject to small localized (integrable) perturbations. Our analysis is based upon detailed estimates of the linearized solution operator, which are complicated by the fact that the (necessarily essential) spectrum of the associated linearization intersects the imaginary axis at the origin. We carry out a numerical Evans function study of the spectral problem and find bands of spectrally stable periodic traveling waves, in close agreement with previous numerical studies of Frisch-She-Thual, Bar-Nepomnyashchy, Chang-Demekhin-Kopelevich, and others carried out by other techniques. We also compare predictions of the associated Whitham modulation equations, which formally describe the dynamics of weak large scale perturbations of a periodic wave train, with numerical time evolution studies, demonstrating their effectiveness at a practical level. For the reader's convenience, we include in an appendix the corresponding treatment of the Swift-Hohenberg equation, a nonconservative counterpart of the generalized Kuramoto-Sivashinsky equation for which the nonlinear stability analysis is considerably simpler, together with numerical Evans function analyses extending spectral stability analyses of Mielke and Schneider.Comment: 78 pages, 11 figure