Mechanisms regulating resistance to inhibitors of topoisomerase II

Inhibitors of topoisomerase II (topo II) are clinically effective in the management of hematological malignancies and solid tumors. The efficacy of anti-tumor drugs targeting topo II is often limited by resistance and studies with in vitro cell culture models have provided several insights on potential mechanisms. Multidrug transporters that are involved in the efflux and consequently reduced cytotoxicity of diverse anti-tumor agents suggest that they play an important role in resistance to clinically active drugs. However, in clinical trials, modulating the multidrug-resistant phenotype with agents that inhibit the efflux pump has not had an impact. Since reduced drug accumulation per se is insufficient to explain tumor cell resistance to topo II inhibitors several studies have focused on characterizing mechanisms that impact on DNA damage mediated by drugs that target the enzyme. Mammalian topo IIα and topo IIβ isozymes exhibit similar catalytic, but different biologic, activities. Whereas topo IIα is associated with cell division, topo IIβ is involved in differentiation. In addition to site specific mutations that can affect drug-induced topo II-mediated DNA damage, post-translation modification of topo II primarily by phosphorylation can potentially affect enzyme-mediated DNA damage and the downstream cytotoxic response of drugs targeting topo II. Signaling pathways that can affect phosphorylation and changes in intracellular calcium levels/calcium dependent signaling that can regulate site-specific phosphorylation of topoisomerase have an impact on downstream cytotoxic effects of topo II inhibitors. Overall, tumor cell resistance to inhibitors of topo II is a complex process that is orchestrated not only by cellular pharmacokinetics but more importantly by enzymatic alterations that govern the intrinsic drug sensitivity

A parametric study on the buckling of functionally graded material plates with internal discontinuities using the partition of unity method

In this paper, the effect of local defects, viz., cracks and cutouts on the buckling behaviour of functionally graded material plates subjected to mechanical and thermal load is numerically studied. The internal discontinuities, viz., cracks and cutouts are represented independent of the mesh within the framework of the extended finite element method and an enriched shear flexible 4-noded quadrilateral element is used for the spatial discretization. The properties are assumed to vary only in the thickness direction and the effective properties are estimated using the Mori-Tanaka homogenization scheme. The plate kinematics is based on the first order shear deformation theory. The influence of various parameters, viz., the crack length and its location, the cutout radius and its position, the plate aspect ratio and the plate thickness on the critical buckling load is studied. The effect of various boundary conditions is also studied. The numerical results obtained reveal that the critical buckling load decreases with increase in the crack length, the cutout radius and the material gradient index. This is attributed to the degradation in the stiffness either due to the presence of local defects or due to the change in the material composition.Comment: arXiv admin note: text overlap with arXiv:1301.2003, arXiv:1107.390

Application of a Combined Active Control and Fault Detection Scheme to an Active Composite Flexible Structure.

In this paper, the problem of increasing reliability of active control procedure is considered. Indeed, a design method of rejection perturbation in presence of potentially faults, on a flexible structure with integrated piezo-ceramics, is presented. The piezo-ceramics are used as actuators and sensors. A single unit based solution, which handles both control action and fault diagnosis is proposed. The algorithm uses H∞ optimization techniques. A full order model of the structure is first obtained via both finite-element (FE) approach and identification procedure. This model is then reduced in order to be used in our robust approach. By a suitable choice of weightings functions, the provided method is able to reject disturbance robustly and to estimate occurred faults. The case of sensors and actuators faults is discussed. The choice of weightings for diagnosis and control systems is also tackled. Finally, the effectiveness of this integrated method is confirmed by both simulation and experimental results

Pulse Echo Ultrasonic Testing of Adhesive Bonded Joints for Automotive Applications

The growing prominence of adhesive bonding technology in automotive manufacture has necessitated the development of reliable and robust quality assurance techniques. Of the different Nondestructive testing technologies available, Ultrasonic testing has shown itself to be the most promising technique to satisfy the requirements in automobile production. The current work attempts to apply two variations of the Ultrasonic Pulse Echo technique namely Contact and Immersion testing for inspecting typical hem bonded automotive joints. The joints have been tested for disbond at the various metal-adhesive interfaces by using an ultrasonic scan comparison method which compares the acquired signals against a reference scan from the unbonded metal sheet. The results for the above tests have been documented. Detection of the absence of adhesive has been possible at the interfaces using the Contact testing variation. In the case of the Immersion testing, suitable distinction between the echoes from the different interfaces has not been achieved. Based on the results obtained, it has been proposed that the testing frequency be increased to obtain a clear distinction between the adherend and adhesive surface echoes

CUSTOMER SATISFACTION WITH ONLINE FOOD ORDERING PORTALS IN QATAR

The recent boom in online food ordering and delivery in Qatar has led to increased competition among service providers within the industry. Identifying the lack of research in the context of Qatar’s online food industry, this study aims to determine the key success factors that lead to customer satisfaction and loyalty, as well as customers’ satisfaction levels with their respective service providers. Data was collected from 263 random customers through an online questionnaire and analyzed to test the hypotheses of the research model and answer the research questions. By applying multivariate regression analyses to assess the proposed model, this study confirms that while restaurant quality has no direct effect on customer satisfaction and loyalty, service provider quality does. Moreover, this study sheds light on the mediation role of customer satisfaction on the relationship between service provider quality and loyalty. Overall, the study provides valuable insights for the successful operation of online food ordering services in Qatar