Overcoming Multidrug Resistance (MDR): Design,Biological Evaluation and Molecular Modelling Studies of 2,4-Substituted Quinazoline Derivatives

Some 2,4-disubstituted quinazolines were synthesized and studied as multidrug resistance (MDR) reversers. The new derivatives carried the quinazoline-4-amine scaffold found in modulators of the ABC transporters involved in MDR, as the TKIs gefitinib and erlotinib. Their behaviour on the three ABC transporters, P-gp, MRP1 and BCRP, was investigated. Almost all compounds inhibited the P-gp activity in MDCK-MDR1 cells overexpressing P-gp, showing EC₅₀ values in the nanomolar range ( 1 d , 1 e , 2 a , 2 c , 2 e ). Some compounds were active also towards MRP1 and/or BCRP. Docking results obtained by in silico studies on the P-gp crystal structure highlighted common features for the most potent compounds. The P-gp selective compound 1 e was able to increase the doxorubicin uptake in HT29/DX cells and to restore its antineoplastic activity in resistant cancer cells in the same extent of sensitive cells. Compound 2 a displayed a dual inhibitory effect showing good activities towards both P-gp and BCRP.     

Aging and inhibition processes: The case of metaphor treatment.

The inhibitory deficit hypothesis has often been cited as a possible explanation for cognitive changes related to age. The aim of this study was to develop a new procedure for evaluating effortful inhibition on the basis of the comprehension of metaphors. Our experiment was carried out on younger and older adults, in whom we also measured inhibitory capacity, working memory, and processing speed. The results show that older participants required a longer time and made more frequent errors in rejecting metaphors versus literally false statements. The interference effect was predicted by the psychometric tests designed to evaluate inhibition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Design and performance evaluation of ContentPlace,a social-aware data dissemination system for opportunistic networks

In this paper we present and evaluate ContentPlace, a data dissemination system for opportunistic networks, i.e., mobile networks in which stable simultaneous multi-hop paths between communication endpoints cannot be provided. We consider a scenario in which users both produce and consume data objects. ContentPlace takes care of moving and replicating data objects in the network such that interested users receive them despite possible long disconnections, partitions, etc. Thanks to ContentPlace, data producers and consumers are completely decoupled, and might be never connected to the network at the same point in time. The key feature of ContentPlace is learning and exploiting information about the social behaviour of the users to drive the data dissemination process. This allows ContentPlace to be more efficient both in terms of data delivery and in terms of resource usage with respect to reference alternative solutions. The performance of ContentPlace is thoroughly investigated both through simulation and analytical models.     

Session based access control in geographically replicated Internet services

Performance critical services over Internet often rely on geographically distributed architectures of replicated servers. Content Delivery Networks (CDN) are a typical example where service is based on a distributed architecture of replica servers to guarantee resource availability and proximity to final users. In such distributed systems, network links are not dedicated, and may be subject to external traffic. This brings up the need to develop access control policies that adapt to network load changing conditions. Further, Internet services are mainly session based, thus an access control support must take into account a proper differentiation of requests and perform session based decisions while considering the dynamic availability of resources due to external traffic.In this paper we introduce a distributed architecture with access control capabilities at session aware access points. We consider two types of services characterized by different patterns of resource consumption and priorities. We formulate a Markov Modulated Poisson Decision Process for access control that captures the heterogeneity of multimedia services and the variable availability of resources due to external traffic. The proposed model is optimized by means of stochastic analysis, showing the impact of external traffic on service quality. The structural properties of the optimal solutions are studied and considered as the basis for the formulation of heuristics. The performance of the proposed heuristics is studied by means of simulations, showing that in some typical scenario they perform close to the optimum.     

End-of-life decision-making in the hospital: current practice and future prospects

The contributions of the various ulnar-innervated muscles of the hand to the hypothenar compound muscle action potential (CMAP) were estimated by directly stimulating individual muscles and by analyzing CMAP shape changes resulting from manipulations that changed individual muscle lengths. The results show that the first peak of the negative phase of the hypothenar CMAP comes from the hypothenar muscles, but that the second peak is due to a large volume-conducted potential from the interosseous muscles. The interosseous contribution affects both the amplitude and the area of the CMAP, and makes these parameters sensitive to changes in the configuration of the fingers and the temperature gradient in the hand. To reduce the interosseous contribution, a "balanced reference" consisting of two reference electrodes, one over each tendon, is proposed.     

Pathogenic mechanisms in the rheumatoid nodule: comparison of proinflammatory cytokine production and cell adhesion molecule expression in rheumatoid nodules and synovial membranes from the same patient

OBJECTIVE: To investigate the production of proinflammatory cytokines and expression of cell adhesion molecules in the rheumatoid nodule. METHODS: Cytokine content (tumor necrosis factor alpha [TNFalpha], interleukin-1beta [IL-1beta], and IL-1 receptor antagonist [IL-1Ra]), at the messenger RNA (mRNA) and protein levels, and cell adhesion molecule expression were studied in 16 rheumatoid nodules and 6 synovial membranes. RESULTS: Macrophages in the rheumatoid nodules contained TNFalpha, IL-1beta, and IL-1Ra mRNA and protein, particularly in perivascular cells of the stroma and in the palisading layer. All cell adhesion molecules studied were expressed in both the rheumatoid nodules and synovial membranes, with increased expression of E-selectin in the rheumatoid nodule compared with the synovial membrane, and with the absence of vascular cell adhesion molecule 1 expression on cells of the palisading layer in the rheumatoid nodule. CONCLUSION: The presence of similar proinflammatory cytokines and cell adhesion molecules in the rheumatoid nodule and synovial membrane suggests that similar pathogenic processes result in the chronic inflammation and tissue destruction in these lesions.     

Visualizing the dynamics of T cell activation: intracellular adhesion molecule 1 migrates rapidly to the T cell/B cell interface and acts to sustain calcium levels

T cell recognition typically involves both the engagement of a specific T cell receptor with a peptide/major histocompatibility complex (MHC) and a number of accessory interactions. One of the most important interactions is between the integrin lymphocyte function-associated antigen 1 (LFA-1) on the T cell and intracellular adhesion molecule 1 (ICAM-1) on an antigen-presenting cell. By using fluorescence video microscopy and an ICAM-1 fused to a green fluorescent protein, we find that the elevation of intracellular calcium in the T cell that is characteristic of activation is followed almost immediately by the rapid accumulation of ICAM-1 on a B cell at a tight interface between the two cells. This increased density of ICAM-1 correlates with the sustained elevation of intracellular calcium in the T cell, known to be critical for activation. The use of peptide/MHC complexes and ICAM-1 on a supported lipid bilayer to stimulate T cells also indicates a major role for ICAM-1/LFA-1 in T cell activation but, surprisingly, not for adhesion, as even in the absence of ICAM-1 the morphological changes and adhesive characteristics of an activated T cell are seen in this system. We suggest that T cell antigen receptor-mediated recognition of a very small number of MHC/peptide complexes could trigger LFA-1/ICAM-1 clustering and avidity regulation, thus amplifying and stabilizing the production of second messengers.