RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)

Activated RAS promotes dimerization of members of the RAF kinase family. ATP-competitive RAF inhibitors activate ERK signalling by transactivating RAF dimers. In melanomas with mutant BRAF(V600E), levels of RAS activation are low and these drugs bind to BRAF(V600E) monomers and inhibit their activity. This tumour-specific inhibition of ERK signalling results in a broad therapeutic index and RAF inhibitors have remarkable clinical activity in patients with melanomas that harbour mutant BRAF(V600E). However, resistance invariably develops. Here, we identify a new resistance mechanism. We find that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kDa variant form of BRAF(V600E), p61BRAF(V600E), which lacks exons 4-8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) shows enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) is expressed endogenously or ectopically, ERK signalling is resistant to the RAF inhibitor. Moreover, a mutation that abolishes the dimerization of p61BRAF(V600E) restores its sensitivity to vemurafenib. Finally, we identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumours of six of nineteen patients with acquired resistance to vemurafenib. These data support the model that inhibition of ERK signalling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identify a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.     

QUADRATIC REPRESENTATION FOR ROADWAY PROFILE THAT MINIMIZES EARTHWORK COST

Roadway design usually involves choices regarding grade selection and earthwork (transportation) that can be solved using linear programming. Previous work considered the road profile as series of interconnected linear segments. In these models, constraints are included in the linear programming formulation to insure continuity of the road, which cause sharp connectivity points at the intersection of the linear segments. This sharp connectivity needs to be smoothed out after l;he linear programming solution is found and the earth in the smoothed portion of the roadway has to be moved to the landfill. In previous research, the smoothing issue is dealt with after an optimal solution is found. This increases the work required by the design engineer and consequently increases the construction cost; furthermore, the optimal solution is violated by this smoothing operation. In this paper, the issue of sharp connectivity points is resolved by representing the road profile by a quadratic function. The continuit     

A MARKOVIAN APPROACH TO DETERMINING PROCESS MEANS WITH DUAL QUALITY CHARACTERISTICS

This paper studies a production system where products are produced continuously and whose specification limits are specified for screening inspection. In this paper, we consider dual quality characteristics and different costs associated with each quality characteristic that falls below a lower specification limit or above an upper specification limit. Due to these different costs, the expected total profit will greatly depend on the process parameters, especially a process mean. This paper develops a Markovian-based model for determining the optimum process means with the consideration of dual quality characteristics in a single-stage system. The proposed model is then illustrated through a numerical example and sensitivity analysis is performed to validate the model. The results showed that the optimum process mean for both quality characteristics have a significant effect on the performance of the system. Since the literature survey shows that dealing with multi-quality characteristics is extremely limited, the proposed model, coupled with the Markovian approach, provides a unique contribution to this field.     

Multiobjective Optimal Water ResourcesManagement for a Large River Basin

1IntroductionTiledesigllalldof)erati()lloftilt.egratedmultiplewatersuppliesandhydroelectricfacilitiestol>ostutilizea1'egi()llalt-c'aterresourcecallcollstituteacolllplexanddifficultoptimizationprohleln.involvingill('tilt(-'r;\('tiollofI)oliti('alalldlegalprocesses,institutiollalregulat,ionsalldengilleerillgecollolllics.Tllolastqllart('rofa(}elltur}'11aswitllessedasigllificantdevelopmelltofoptimizatiollalgol'itllllls.Tillsif('ti\.it}'ilasI>een1llotivatedbytwomajorfactorsftherapidevolutiollofcom…     

The FN3 and BRCT motifs in the exomer component Chs5p define a conserved module that is necessary and sufficient for its function

Chs5p is a component of the exomer, a coat complex required to transport the chitin synthase Chs3p from the trans-Golgi network to the plasma membrane. The Chs5p N-terminal region exhibits fibronectin type III (FN3) and BRCT domains. FN3 domains are present in proteins that mediate adhesion processes, whereas BRCT domains are involved in DNA repair. Several fungi—including Schizosaccharomyces pombe, which has no detectable amounts of chitin—have proteins similar to Chs5p. Here we show that the FN3 and BRCT motifs in Chs5p behave as a module that is necessary and sufficient for Chs5p localization and for cargo delivery. The N-terminal regions of S. cerevisiae Chs5p and S. pombe Cfr1p are interchangeable in terms of Golgi localization, but not in terms of exomer assembly, showing that the conserved function of this module is protein retention in this organelle and that the interaction between the exomer components is organism-specific.     

CT Brain Image: Abnormalities Recognition and Segmentation

In order to develop an automated segmentation system for Computed Tomography (CT) brain images, a new approach which consists of several unsupervised segmentation techniques was introduced. The system segments the CT brain images into three partitions, i. e., abnormalities, cerebrospinal fluid (CSF), and brain matter. Our approach consists of two phase-segmentation methods. In the first phase segmentation, k-means and fuzzy c-means (FCM) methods were implemented to segment and transform the images into the binary images. Based on the connected component in binary images, a decision tree was employed for the annotation of normal or abnormal regions, In the second phase segmentation, the modified FCM with population-diameter independent (PDI) segmentation was applied to segment the images into CSF and brain matter. The experimental results have shown that our proposed system is feasible and yield satisfactory results.     

Cu-Zn-Al2O3 nanocomposites: study of microstructure,corrosion, and wear properties

Alumina nanoparticles were added to a Cu-Zn alloy to investigate their effect on the microstructural, tribological, and corrosion properties of the prepared alloys. Alloying was performed using a mixture of copper and zinc powders with 0vol% and 5vol% of α-Al nanopowder in a satellite ball mill. The results showed that the Cu-Zn solid solution formed after 18 h of mechanical alloying. The mechan-ically alloyed powder was compacted followed by sintering of the obtained green compacts at 750℃ for 30 min. Alumina nanoparticles were uniformly distributed in the matrix of the Cu-Zn alloy. The tribological properties were evaluated by pin-on-disk wear tests, which revealed that, upon the addition of alumina nanoparticles, the coefficient of friction and the wear rate were reduced to 20% and 40%, respectively. The corrosion properties of the samples exposed to a 3.5wt% NaCl solution were studied using the immersion and potentiodynamic polarization methods, which revealed that the addition of alumina nanoparticles reduced the corrosion current of the nanocomposite by 90%.