Pharmacogenetic profiling and cetuximab outcome in patients with advanced colorectal cancer

<p>Abstract</p> <p>Background</p> <p>We analyzed the influence of 8 germinal polymorphisms of candidate genes potentially related to EGFR signalling (<it>EGFR</it>, <it>EGF</it>, <it>CCND1</it>) or antibody-directed cell cytotoxicity (<it>FCGR2A </it>and <it>FCGR3A</it>) on outcome of colorectal cancer (CRC) patients receiving cetuximab-based therapy.</p> <p>Methods</p> <p>Fifty-eight advanced CRC patients treated with cetuximab-irinotecan salvage therapy between 2001 and 2007 were analyzed (mean age 60; 50 PS 0-1). The following polymorphisms were analyzed on blood DNA: <it>EGFR </it>(CA repeats in intron 1, -216 G > T, -191C > A, R497K), <it>EGF </it>(A61G), <it>CCND1 </it>(A870G), <it>FCGR2A </it>(R131H), <it>FCGR3A </it>(F158V). Statistical analyses were conducted on the total population and on patients with wt KRas tumors. All SNPs were considered as ternary variables (wt/wt <it>vs </it>wt/mut <it>vs </it>mut/mut), with the exception of -191C > A <it>EGFR </it>polymorphism (AA patient merged with CA patients).</p> <p>Results</p> <p>Analysis of skin toxicity as a function of EGFR intron 1 polymorphism showed a tendency for higher toxicity in patients with a low number of CA-repeats (p = 0.058). <it>CCND1 </it>A870G polymorphism was significantly related to clinical response, both in the entire population and in KRas wt patients, with the G allele being associated with a lack of response. In wt KRas patients, time to progression (TTP) was significantly related to <it>EGFR </it>-191C > A polymorphism with a longer TTP in CC patients as compared to others, and to <it>CCND1 </it>A870G polymorphism with the G allele being associated with a shorter TTP; a multivariate analysis including these two polymorphisms only retained <it>CCND1 </it>polymorphism. Overall survival was significantly related to <it>CCND1 </it>polymorphism with a shorter survival in patients bearing the G allele, and to <it>FCGR3A </it>F158V polymorphism with a shorter survival in VV patients (in the entire population and in KRas wt patients). <it>FCGR3A </it>F158V and <it>CCND1 </it>A870G polymorphisms were significant independent predictors of overall survival.</p> <p>Conclusions</p> <p>Present original data obtained in wt KRas patients corresponding to the current cetuximab-treated population clearly suggest that <it>CCND1 </it>A870G polymorphism may be used as an additional marker for predicting cetuximab efficacy, TTP and overall survival. In addition, <it>FCGR3A </it>F158V polymorphism was a significant independent predictor of overall survival.</p

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M&gt;70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0&lt;e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Mercury distribution in tropical soil profiles related to origin of mercury and soil processes

The aim of the study is to improve our understanding of the vertical and lateral variations in the mercury content [Hg] of tropical soils. In addition to the distance to anthropogenic sources of Hg, the most frequently evoked determining factor is the abundance of Hg-bearing phases. Soil processes (weathering, mass or water transfer) determine the abundance of carrier phases. We assume that soil processes also have a direct impact on the distribution of Hg and that the impact is different according to the lithogenic or atmospheric origin of this element. We compare two types of soil (oxisol and ultisol) in the French Guiana forest, at localities a few tens of metres apart and exhibiting very different Hg contents. We show that vertical profiles of [Hg] are strongly related to the variations of [Hg-atmospheric], whereas [Hg-lithogenic] varies little. The penetration of Hg-atmospheric from the surface deposits is favoured down to a depth of 3 in in the oxisol and limited to the upper horizons of the ultisol because of contrasted hydraulic conductivity between the two soils. Hg is primarily of lithogenic origin in the alteritic horizons of the ultisol. The relative accumulation of Hg-lithogenic during the progressive weathering of parental material is limited near the soil surface by the disequilibrium of secondary minerals. Remobilization of Hg-atmospheric or Hg-lithogenic stored in the soil is a function of the chemical or particulate erosion of Hg-bearing phases, particularly active in the upper horizons of the ultisol, where lateral flow occurs during rain events. The correlations observed between the iron or clay contents and [Hg] can be caused by the affinity of Hg for these carrier phases, but may also reflect the weathering and the transfer processes which affect together the fate of Hg and the mineralogical and chemical composition of the soil

Weathering versus atmospheric contributions to mercury concentrations in French Guiana soils

This work focuses on two possible sources of Hg in tropical soils, (i) lithogenic Hg from in situ weathering of soil parental material, and (ii) exogenic Hg from natural long-term atmospheric inputs and anthropogenic input from past and present industrial activities. The concentration of lithogenic Hg [Hg](lithogenic) was based on comparison of measured Hg concentration with those of elements resistant to weathering such as Nb, U, Zn, Fe. Exogenic Hg was quantified by subtracting [Hg](lithogenic) from total Hg concentrations. This calculation was applied to 4 French Guiana soil profiles, 3 profiles on the same toposequence (ferralsol, acrisol, hydromorphic soil) and one acrisol close to a Au mine, where elemental Hg is used. In all profiles, [Hg](lithogenic) varied slightly and was always below 40 mu g kg(-1), whereas [Hg](exogenic) varied considerably and reached 500 mu g kg(-1). The highest [Hg](exogmic) was calculated for the upper horizon of the acrisol close to Au mining activity, but also in the ferralsol. Concentrations of Hg were insignificant in the compact alterite in acrisols. It was concluded that pedogenesis processes that affect the natural Hg supply, combined with anthropogenic sources, explain the Hg concentrations in these tropical soils

Research into Social Work in France : A Collaborative Initiative Considered against Referentials of Competence an Example : A Study of Scrap Dealers in the Ile-De-France Region

International audienceLa mise en øeuvre d'une recherche concernant les biffins en Ile-de-France, pour la région, l'association AURORE a dépassé son cøeur de métiers, lié à l'action sociale à visée intégrative. Cette expérience permet de mesurer les compétences mises en øeuvre des professionnels qui l'ont encadré. En utilisant les référentiels de compétences des qualifications des métiers de l'encadrement du travail social (CAFERUIS, CAFDES et DEIS), notre propos consiste à mesurer quelle est la compétence aujourd'hui du travail social à encadrer le développement de la recherche en travail social en France. En fonction de l'amplitude entre le prescrit et le réel, il est alors possible de dégager quelques enjeux en matière de compétences, d'innovation et d'identité professionnelle