Weldability and liquation cracking behavior of ZhS6U superalloy during electron-beam welding

The weldability of the ZhS6U nickel-based superalloy, which is prone to solidification cracking during electron-beam welding(EBW) repair processes, was investigated. The effects of two different pre-weld heat-treatment cycles on the final microstructure before and after welding were examined. Welds were made on flat coupons using an EBW machine, and the two heat-treatment cycles were designed to reduce γ′ liquation before welding. Microstructural features were also examined by optical and scanning electron microscopy. The results showed that the change in the morphology and size of the γ′ precipitates in the pre-weld heat-treatment cycles changed the ability of the superalloy to release the tensile stresses caused by the matrix phase cooling after EBW. The high hardness in the welded coupons subjected to the first heat-treatment cycle resulted in greater resistance to stress release by the base alloy, and the concentration of stress in the base metal caused liquation cracks in the heat-affected zone and solidification cracks in the weld area.     

COT drives resistance to RAF inhibition through MAP kinase pathway reactivation

Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma-an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance. Identification of resistance mechanisms in a manner that elucidates alternative 'druggable' targets may inform effective long-term treatment strategies. Here we expressed ～600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.     

A single-nucleotide polymorphism tagging set for human drug metabolism and transport

Interindividual variability in drug response, ranging from no therapeutic benefit to life-threatening adverse reactions, is influenced by variation in genes that control the absorption, distribution, metabolism and excretion of drugs. We genotyped 904 single-nucleotide polymorphisms (SNPs) from 55 such genes in two population samples (European and Japanese) and identified a set of tagging SNPs that represents the common variation in these genes, both known and unknown. Extensive empirical evaluations, including a direct assessment of association with candidate functional SNPs in a new, larger population sample, validated the performance of these tagging SNPs and confirmed their utility for linkage-disequilibrium mapping in pharmacogenetics. The analyses also suggest that rare variation is not amenable to tagging strategies.     

Production planning problem with pricing under random yield: CVaR criterion

In this paper, we address a basic production planning problem with price dependent demand and stochastic yield of production. We use price and target quantity as decision variables to lower the risk of low yield. The value of risk control becomes more important especially for products with short life cycle. This is because, the profit implications of low yield might be unbearable in the short run. We apply Conditional Value at Risk （CVaR） to model the, risk. CVaR measure is a coherent risk measure and thereby having nice conceptual and mathematical underpinnings. It is also widely used in practice. We consider the problem under general demand function and general distribution function of yield and find sufficient conditions under which the problem has a unique local maximum. We also both analytically and numerically analyze the impact of parameter change on the optimal solution. Among our results, we analytically show that with increasing risk aversion, the optimal price increases. This relation is opposite to that of in Newsvendor problem where the uncertainty lies in demand side.