Transient disappearance of RAS mutant clones in plasma: A counterintuitive clinical use of EGFR inhibitors in RAS mutant metastatic colorectal cancer

Genomic studies performed through liquid biopsies widely elucidated the evolutionary trajectory of RAS mutant clones under the selective pressure of EGFR inhibitors in patients with wild type RAS primary colorectal tumors. Similarly, the disappearance of RAS mutant clones in plasma has been more recently reported in some patients with primary RAS mutant cancers, supporting for the first time an unexpected negative selection of RAS mutations during the clonal evolution of mCRC. To date, the extent of conversion to RAS wild type disease at the time of progression has not been clarified yet. As a proof of concept, we prospectively enrolled mCRC patients progressing under anti-VEGF based treatments. Idylla™system was used to screen RAS mutations in plasma and the wild type status of RAS was further confirmed through IT-PGM (Ion Torrent Personal Genome Machine) sequencing. RAS was found mutant in 55% of cases, retaining the same plasma mutation as in the primary tumor at diagnosis, while it was found wild-type in 45%. Four patients testing negative for RAS mutations in plasma at the time of progression of disease (PD) were considered eligible for treatment with EGFR inhibitors and treated accordingly, achieving a clinical benefit. We here propose a hypothetical algorithm that accounts for the transient disappearance of RAS mutant clones over time, which might extend the continuum of care of mutant RAS colorectal cancer patients through the delivery of a further line of therapy

The Resource Leveling Problem with multiple resources using an adaptive genetic algorithm

Resource management ensures that a project is completed on time and at cost, and that its quality is as previously defined; nevertheless, resources are scarce and their use in the activities of the project leads to conflicts in the schedule. Resource Leveling Problems consider how to make the resource consumption as efficient as possible. This paper presents a new Adaptive Genetic Algorithm for the Resource Leveling Problem with multiple resources, and its novelty lies in using the Weibull distribution to establish an estimation of the global optimum as a termination condition. The extension of the project deadline with a penalty is allowed, avoiding the increase in the project criticality punishing the shift of activities. The algorithmis tested with the standard Project Scheduling Problem Library PSPLIB, and a complete analysis and benchmarking test instances are presented. The proposed algorithm is implemented using VBA for Excel 2010 in order to provide a flexible and powerful decision support system that enables practitioners to choose between different feasible solutions to a problem, and in addition it is easily adjustable to the constraints and particular needs of each project in realistic environments.This study was partially funded by the Spanish Ministry of Science and Innovation (research project BIA2011-23602).Ponz Tienda, JL.; Yepes Piqueras, V.; Pellicer Armiñana, E.; Moreno Flores, J. (2013). The Resource Leveling Problem with multiple resources using an adaptive genetic algorithm. Automation in Construction. 29(1):161-172. doi:10.1016/j.autcon.2012.10.003S16117229

Crack Front Geometry and Stress Intensity Factor of Semi‑circular Bend Specimens with Straight Through and Chevron Notches

The semi-circular bending (SCB) test is one of the most useful testing methods for determining the mode-I fracture toughness of rocks. An SCB specimen with an artificial notch is loaded at three points including two lower points and a single upper point during the test. In general, there are two types of geometries for artificial notches: straight through and chevron notches. The straight through notch is commonly adopted for the SCB (STNSCB) test as the suggested method for estimating mode-I fracture toughness of rocks in ISRM, while the cracked chevron notch SCB (CCNSCB) test using a specimen with a chevron notch has been performed by some researches. In this paper, by means of the commercial finite-element software ABAQUS, cracking behavior from the tip of an artificial notch during STNSCB and CCNSCB tests is analyzed with Extended Finite-Element Method (XFEM) to clarify crack front geometry in the process of cracking. The relationship between the crack length and the stress intensity factor can be obtained by analyzing stress intensity factors of the specimen with FEM, based on crack front geometries calculated with XFEM during the cracking process. Using this relationship, the minimum stress intensity factor at a critical crack length is determined for estimating mode-I fracture toughness of the rock for the CCNSCB test. Furthermore, by performing the SCB tests using Kimachi sandstone specimens with three different artificial notch geometries, fracture toughness of the sandstone is determined from the SCB test. Consequently, it is concluded that the values of fracture toughness from the test with three notch geometries are almost the same