Colorectal cancer (CRC) is a genetic disease governed by clonal evolution1. Genotyping CRC tissue is employed for therapeutic purposes but this approach has significant limitations. A tissue sample represents a single snapshot in time, is subjected to selection bias due to tumor heterogeneity, and can be difficult to obtain. We exploited circulating DNA (ctDNA) to genotype colorectal tumors and track clonal evolution during therapies with the anti-EGFR antibodies cetuximab or panitumumab. We identified genomic alterations in KRAS, NRAS, MET, ERBB2, FLT3, EGFR and MAP2K1 in ctDNA of patients with primary or acquired resistance to EGFR blockade. Mutant RAS clones, which rise in blood during EGFR blockade, decline upon withdrawal of anti-EGFR antibodies indicating that clonal evolution continues beyond clinical progression. Pharmacogenomic analysis of CRC cells, which had acquired resistance to cetuximab, reveals that upon antibody withdrawal KRAS clones decay, while the population regains drug sensitivity. ctDNA profiles of patients who benefit from multiple challenging with anti-EGFR antibodies exhibit pulsatile levels of mutant KRAS. These results reveal that the CRC genome adapts dynamically to intermittent drug schedules and provide a molecular explanation for the efficacy of re-challenge therapies based on EGFR blockade.

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et al.. Dynamics of a hybrid morphing wing with active open loop vibrating trailing edge by Time-Resolved PIV and force measures.This is an author-deposited version published in: http://oatao.univ-toulouse.fr/ Eprints ID: 16095Open Archive Toulouse Archive Ouverte (OATAO)OATAO is an open access repository that collects the work of Toulouse researchers and makes it freely available over the web where possible. Keywords:Morphing Smart materials Wind tunnel experiments Vortex breakdown Harmonic forcing a b s t r a c t A quantitative characterization of the effects obtained by high frequency-low amplitude trailing edge actuation is presented. Particle image velocimetry, pressure and aerodynamic forces measurements are carried out on a wing prototype equipped with shape memory alloys and trailing edge piezoelectric-actuators, allowing simultaneously high deformations (bending) in low frequency and higher-frequency vibrations. The effects of this hybrid morphing on the forces have been quantified and an optimal actuation range has been identified, able to increase lift and decrease drag. The present study focuses more specifically on the effects of the higher-frequency vibrations of the trailing edge region. This actuation allows manipulation of the wake turbulent structures. It has been shown that specific frequency and amplitude ranges achieved by the piezoelectric actuators are able to produce a breakdown of larger coherent eddies by means of upscale energy transfer from smaller-scale eddies in the near wake. It results a thinning of the shear layers and the wake's width, associated to reduction of the form drag, as well as a reduction of predominant frequency peaks of the shear-layer instability. These effects have been shown by means of frequency domain analysis and Proper Orthogonal Decomposition.

ABCB4 mutations are responsible for a chronic liver disease in more than one-third of patients with chronic intrahepatic cholestasis and elevated γ-GT activity. In patients with severe ABCB4 genotype, the disease is often progressive with risk of developing cirrhosis and liver failure during the first 2 decades of life. Patients with mild genotypes, including single heterozygous mutations, have variable expressions of liver disease that may be influenced by comorbidity factors and modulated by still unknown genetic modifiers.

Since the advent of monoclonal antibodies against epidermal growth factor receptor (EGFR) in colorectal cancer therapy, the determination of RAS mutational status is needed for therapeutic decision-making. Most prevalent in colorectal cancer are KRAS exon 2 mutations (40% prevalence); lower prevalence is observed for KRAS exon 3 and 4 mutations (6%) and NRAS exon 2, 3, and 4 mutations (5%). The Idylla™ KRAS Mutation Test on the molecular diagnostics Idylla™ platform is a simple (<2 minutes hands-on time), highly reliable, and rapid (approximately 2 hours turnaround time) in vitro diagnostic sample-to-result solution. This test enables qualitative detection of 21 mutations in codons 12, 13, 59, 61, 117, and 146 of the KRAS oncogene being clinically relevant according to the latest clinical guidelines. Here, the performance of the Idylla™ KRAS Mutation Assay, for Research Use Only, was assessed on archived formalin-fixed paraffin-embedded (FFPE) tissue sections by comparing its results with the results previously obtained by routine reference approaches for KRAS genotyping. In case of discordance, samples were assessed further by additional methods. Among the 374 colorectal cancer FFPE samples tested, the overall concordance between the Idylla™ KRAS Mutation Assay and the confirmed reference routine test results was found to be 98.9%. The Idylla™ KRAS Mutation Assay enabled detection of 5 additional KRAS-mutated samples not detected previously with reference methods. As conclusion the Idylla™ KRAS Mutation Test can be applied as routine tool in any clinical setting, without needing molecular infrastructure or expertise, to guide the personalized treatment of colorectal cancer patients.

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