Inhibition of the multidrug resistance P-glycoprotein: Time for a change of strategy?

P-glycoprotein (P-gp) is a key player in the multidrug-resistant phenotype in cancer. The protein confers resistance by mediating the ATP-dependent efflux of an astonishing array of anticancer drugs. Its broad specificity has been the subject of numerous attempts to inhibit the protein and restore the efficacy of anticancer drugs. The general strategy has been to develop compounds that either compete with anticancer drugs for transport or act as direct inhibitors of P-gp. Despite considerable in vitro success, there are no compounds currently available to "block" P-gp-mediated resistance in the clinic. The failure may be attributed to toxicity, adverse drug interaction, and numerous pharmacokinetic issues. This review provides a description of several alternative approaches to overcome the activity of P-gp in drug-resistant cells. These include 1) drugs that specifically target resistant cells, 2) novel nanotechnologies to provide high-dose, targeted delivery of anticancer drugs, 3) compounds that interfere with nongenomic transfer of resistance, and 4) approaches to reduce the expression of P-gp within tumors. Such approaches have been developed through the pursuit of greater understanding of resistance mediators such as P-gp, and they show considerable potential for further application. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics

Microparticles mediate the intercellular regulation of microRNA-503 and proline-rich tyrosine kinase 2 to alter the migration and invasion capacity of breast cancer cells

The successful treatment of cancer is hampered by drug resistance and metastasis. While these two obstacles were once considered separately, recent evidence associates resistance with an enhanced metastatic capacity. However, the underlying mechanisms remain undefined. We previously described the intercellular transfer of drug resistance via submicron vesicles called microparticles (MPs). We now propose that MPs derived from drug-resistant cells are also involved in the intercellular transfer of components to enhance the migration and invasion capacity of cells. Thus, MPs may be a conduit between resistance and metastasis. We used microarray analysis to identify regulatory microRNAs (miRNAs), which contribute to the dissemination of metastatic traits. miR-503 was downregulated in recipient cells following co-culture with MPs isolated from drug-resistant cells. miR-503 was inversely associated with metastasis, as demonstrated using wound healing/scratch migration assays and Matrigel®-coated transwell invasion assays. Proline-rich tyrosine kinase 2 (PYK2) was upregulated in recipient cells and associated with increased migration and invasion, with these phenotypes being reversed using a pharmacological inhibitor of PYK2 phosphorylation, tyrphostin A9. However, the MP-mediated promotion of metastatic traits was not due to the presence of these effectors in the MP cargo but rather due to down stream effector molecules in these pathways. This is the first demonstration that the role of MPs in trait acquisition extends beyond the direct transfer of vesicle components and also includes transfer of intermediary regulators that induce down stream mediators following transfer to recipient cells. This implicates an expanding role of MPs in cancer pathogenesis. © 2014 Gong, Luk, Jaiswal and Bebawy

Sampling Distributions of Random Electromagnetic Fields in Mesoscopic or Dynamical Systems

We derive the sampling probability density function (pdf) of an ideal localized random electromagnetic field, its amplitude and intensity in an electromagnetic environment that is quasi-statically time-varying statistically homogeneous or static statistically inhomogeneous. The results allow for the estimation of field statistics and confidence intervals when a single spatial or temporal stochastic process produces randomization of the field. Results for both coherent and incoherent detection techniques are derived, for Cartesian, planar and full-vectorial fields. We show that the functional form of the sampling pdf depends on whether the random variable is dimensioned (e.g., the sampled electric field proper) or is expressed in dimensionless standardized or normalized form (e.g., the sampled electric field divided by its sampled standard deviation). For dimensioned quantities, the electric field, its amplitude and intensity exhibit different types of Bessel $K$ sampling pdfs, which differ significantly from the asymptotic Gauss normal and $\chi^{(2)}_{2p}$ ensemble pdfs when $\nu$ is relatively small. By contrast, for the corresponding standardized quantities, Student $t$, Fisher-Snedecor $F$ and root-$F$ sampling pdfs are obtained that exhibit heavier tails than comparable Bessel $K$ pdfs. Statistical uncertainties obtained from classical small-sample theory for dimensionless quantities are shown to be overestimated compared to dimensioned quantities. Differences in the sampling pdfs arising from de-normalization versus de-standardization are obtained.Comment: 12 pages, 15 figures, accepted for publication in Phys. Rev. E, minor typos correcte

Receptive vocabulary differences in monolingual and bilingual children

Studies often report that bilingual participants possess a smaller vocabulary in the language of testing than monolinguals, especially in research with children. However, each study is based on a small sample so it is difficult to determine whether the vocabulary difference is due to sampling error. We report the results of an analysis of 1,738 children between 3 and 10 years old and demonstrate a consistent difference in receptive vocabulary between the two groups. Two preliminary analyses suggest that this difference does not change with different language pairs and is largely confined to words relevant to a home context rather than a school context

Lifelong Bilingualism Maintains White Matter Integrity in Older Adults

Previous research has shown that bilingual speakers have higher levels of cognitive control than comparable monolinguals, especially at older ages. The present study investigates a possible neural correlate of this behavioral effect. Given that white matter (WM) integrity decreases with age in adulthood, we tested the hypothesis that bilingualism is associated with maintenance of WM in older people. Using diffusion tensor imaging, we found higher WM integrity in older people who were lifelong bilinguals than in monolinguals. This maintained integrity was measured by fractional anisotropy (FA) and was found in the corpus callosum extending to the superior and inferior longitudinal fasciculi. We also hypothesized that stronger WM connections would be associated with more widely distributed patterns of functional connectivity in bilinguals. We tested this by assessing the resting-state functional connectivity of frontal lobe regions adjacent to WM areas with group differences in FA. Bilinguals showed stronger anterior to posterior functional connectivity compared to monolinguals. These results are the first evidence that maintained WM integrity is related to lifelong naturally occurring experience; the resulting enhanced structural and functional connectivity may provide a neural basis for “brain reserve.

Structural Color Printing Based on Plasmonic Metasurfaces of Perfect Light Absorption

Subwavelength structural color filtering and printing technologies employing plasmonic nanostructures have recently been recognized as an important and beneficial complement to the traditional colorant-based pigmentation. However, the color saturation, brightness and incident angle tolerance of structural color printing need to be improved to meet the application requirement. Here we demonstrate a structural color printing method based on plasmonic metasurfaces of perfect light absorption to improve color performances such as saturation and brightness. Thin-layer perfect absorbers with periodic hole arrays are designed at visible frequencies and the absorption peaks are tuned by simply adjusting the hole size and periodicity. Near perfect light absorption with high quality factors are obtained to realize high-resolution, angle-insensitive plasmonic color printing with high color saturation and brightness. Moreover, the fabricated metasurfaces can be protected with a protective coating for ambient use without degrading performances. The demonstrated structural color printing platform offers great potential for applications ranging from security marking to information storage

A histological grading system for evaluating disc degeneration in the mouse

Poster no. 1634INTRODUCTION: Previously we have created a simple mouse model to study the disc degeneration in mice, using the technique of annular puncture in the mouse tail. The punctured mouse disc undergoes the progressive morphological changes over a period of 12 weeks. Degenerative changes were observed in both annulus fibrosus (AF) and nucleus pulposus (NP), such as appearance of cell clusters in NP and formation of cracks in AF. The objective of the current study is to establish a histological grading system to describe these degenerative changes and evaluate the severity of the degeneration in the punctured murine discs. We hope that this histological grading system can be useful in future study to evaluate the disc degeneration in the mouse …postprin

Waste reduction and recycling strategies for the in-flight services in the airline industry

Author name used in this publication: X. D. LiAuthor name used in this publication: S. C. Lee2002-2003 > Academic research: refereed > Publication in refereed journalAccepted ManuscriptPublishe