Cytochrome P450 pharmacogenetics : implications for anticancer and warfarin therapy

There is a pronounced interindividual variability in the drug disposition, response and toxicity. Pharmacogenetics aims at identifying genetic biomarkers that could help to increase the drug efficacy, reduce adverse drug reactions and contribute to the development of personalized medicine. Polymorphic cytochrome P450 genes encoding heme-containing ER membrane bound monooxygenases that metabolize xenobiotics, drugs and also endogenous compounds, strongly contribute to interindividual variations in drug response. In the present work we have investigated molecular mechanisms of the adverse drug reactions caused by the polymorphic changes in the cytochrome P450 2C8 (CYP2C8), CYP2C9 and CYP3A4 genes and, in addition developed a novel enzymatic assay for CYP2W1. CYP2W1, a P450 enzyme mainly expressed in colon cancer, has an unknown function and no specific substrates were previously identified. Despite the unusual inverse membrane topology of CYP2W1 that allows its glycosylation but prevents interaction with the redox partner, P450 oxidoreductase (POR), we discovered specific CYP2W1-mediated metabolism of indolines, which indicates the presence of a yet unknown electron transport chain in the lumen of ER. CYP2C9 catalyzes the metabolism of anticoagulant drug warfarin. We characterized the newly discovered rare CYP2C9*35 allele encoding an enzyme with two amino acid changes including Arg125Leu that was found in a patient with warfarin hypersensitivity. The expression of the variant proteins in the mammalian HEK293 cell system showed abolished activity of the CYP2C9.35 enzyme towards warfarin in NADPH supported reaction, but the enzyme could be activated when NADPH was replaced by hydroperoxides. This indicates that CYP2C9.35 is unable to receive electrons from POR because of the impaired interaction with this redox partner. Indeed, in silico modeling confirmed this conclusion showing disrupted salt bridges between CYP2C9.35 and POR due to the mutation of key residues involved in such interaction. CYP3A4 is one of the key enzymes, which metabolizes the anticancer drug paclitaxel. In a cohort of 236 Spanish patients with a paclitaxel induced neuropathy whole exome sequencing revealed the presence of different rare CYP3A4 gene variants, CYP3A4*8, CYP3A4*20, CYP3A4*25 (p.Pro389Ser) and CYP3A4*27 (p.Leu475Val), the latter two previously not described. The expression of these two novel gene variants in HEK293 cells revealed that the corresponding enzymes are more unstable than the CYP3A4.1 enzyme and carriers of these rare CYP3A4 variants had much higher risk for neuropathy and a need in paclitaxel treatment modifications. The data indicate enrichment of these rare defect CYP3A4 alleles in the group of the paclitaxel induced neuropathy patients and suggest that genotyping of CYP3A4 defective variants may provide a basis for paclitaxel treatment individualization. Based on previous data indicating a role for the defective CYP2C8*3 allele for paclitaxel induced neuropathy, we also investigated the influence of this polymorphism on paclitaxel induced neuropathy and neuropathy risk in 148 patients receiving paclitaxel as well as the CYP2C8.3 catalyzed metabolism of paclitaxel in a mammalian expression system. However, in contrast to many other studies we found no significant effect of this allele on paclitaxel induced neuropathy or paclitaxel metabolism in vitro. In conclusion, our data indicate the importance of rare genetic CYP variants for induction of selective drug induced adverse reactions and emphasize the necessity of more extensive genetic analyses, e.g. whole exome sequencing, before fully individualized drug therapy can be achieved

Discrete diffraction managed solitons: Threshold phenomena and rapid decay for general nonlinearities

We prove a threshold phenomenon for the existence/non-existence of energy minimizing solitary solutions of the diffraction management equation for strictly positive and zero average diffraction. Our methods allow for a large class of nonlinearities, they are, for example, allowed to change sign, and the weakest possible condition, it only has to be locally integrable, on the local diffraction profile. The solutions are found as minimizers of a nonlinear and nonlocal variational problem which is translation invariant. There exists a critical threshold ?cr such that minimizers for this variational problem exist if their power is bigger than ?cr and no minimizers exist with power less than the critical threshold. We also give simple criteria for the finiteness and strict positivity of the critical threshold. Our proof of existence of minimizers is rather direct and avoids the use of Lions' concentration compactness argument. Furthermore, we give precise quantitative lower bounds on the exponential decay rate of the diffraction management solitons, which confirm the physical heuristic prediction for the asymptotic decay rate. Moreover, for ground state solutions, these bounds give a quantitative lower bound for the divergence of the exponential decay rate in the limit of vanishing average diffraction. For zero average diffraction, we prove quantitative bounds which show that the solitons decay much faster than exponentially. Our results considerably extend and strengthen the results of [15] and [16].Comment: 49 pages, no figure

Cross-cultural study of obesity regarding socio-cultural attitudes on appearance involvement and appearance management behaviors through clothing: 20s-30s female plus-size consumers

Socio-cultural attitudes on obesity differently influence on formation of individual person\u27s body image, attitudes, and appearance management and involvement. Recently consumer market research on young female plus-size consumers clearly shows the increasing population of obesity and the changing social perception on the plus-size market from being negative to being somewhat positive

Internal Peace in Life

The design, Internal Peace in Life, consisting of sleeveless top and high waist skirt, reflects designers’ current life journey with challenge, hope, and wish. This piece is unique in terms of application of Korean traditional clothing, called Hanbok, into contemporary apparel design, simple pattern development using geometric shapes, and the visual experimentation of relationships between 2D shape and the evolving 3D structures. This design also presents the delicacy and beauty of hand overcasting and opens a new way to integrate 3D printed objects into wearable fashion products considering wearers’ functionality

Optimizing pentose utilization in yeast: the need for novel tools and approaches

Hexose and pentose cofermentation is regarded as one of the chief obstacles impeding economical conversion of lignocellulosic biomass to biofuels. Over time, successful application of traditional metabolic engineering strategy has produced yeast strains capable of utilizing the pentose sugars (especially xylose and arabinose) as sole carbon sources, yet major difficulties still remain for engineering simultaneous, exogenous sugar metabolism. Beyond catabolic pathways, the focus must shift towards non-traditional aspects of cellular engineering such as host molecular transport capability, catabolite sensing and stress response mechanisms. This review highlights the need for an approach termed 'panmetabolic engineering', a new paradigm for integrating new carbon sources into host metabolic pathways. This approach will concurrently optimize the interdependent processes of transport and metabolism using novel combinatorial techniques and global cellular engineering. As a result, panmetabolic engineering is a whole pathway approach emphasizing better pathways, reduced glucose-induced repression and increased product tolerance. In this paper, recent publications are reviewed in light of this approach and their potential to expand metabolic engineering tools. Collectively, traditional approaches and panmetabolic engineering enable the reprogramming of extant biological complexity and incorporation of exogenous carbon catabolism

Das Rätsel von SVO beim Erlernen des Deutschen - Warum ist SVO so leicht, SOV dagegen so schwer produzierbar?

Der Erwerb der deutschen Wortstellungsregeln ist eines der besonders intensiv erforschten Themen. In diesem Artikel sollen zunächst die Grenzen der in der Forschung diskutierten Erklärungsansätze (Erwerbssequenzen einerseits, Transfer andererseits) gezeigt und anschließend ein psycholinguistisches Konzept „Entstehung eines morphosyntaktischen Spannungsfelds“ zur Erklärung der mit Wortstellungen verbundenen Produktionsschwierigkeiten beim Erlernen des Deutschen vorgestellt werden. Ferner werden Zusammenhänge zwischen Morphosyntax und Prosodie sowie deren Nutzungsmöglichkeiten zur Vermittlung der als besonders schwierig geltenden Nebensatzstruktur für DaF-Lernende aufgezeigt

Characterization of thiobarbituric acid derivatives as inhibitors of hepatitis C virus NS5B polymerase

In an effort to find chemicals inhibiting the enzymatic activity of the hepatitis C virus (HCV) NS5B polymerase, a series of thiobarbituric acid derivatives were selected from a library provided by Korea Research Institute of Chemical Technology and characterized. The selected compounds exhibited IC50 values ranging from 1.7 to 3.8 μM, and EC50 values ranging from 12.3 to 20.7 μM against NS5B polymerase of type 1b strain. They showed little effect against type 2a polymerase. One of the compounds, G05, was selected and further characterized. It inhibited the synthesis of RNA by recombinant HCV NS5B polymerase in a dose dependent manner. The CC50 value was 77 μM. The inhibition was in a noncompetitive manner with the substrate UTP. The compound did not inhibit the elongation step of RNA synthesis in a single-cycle processive polymerization assay. It inhibited the binding of NS5B polymerase to the template RNA in a dose-dependent manner