Discovery of Novel Symmetrical 1,4-Dihydropyridines as Inhibitors of Multidrug-Resistant Protein (MRP4) Efflux Pump for Anticancer Therapy

Despite the development of targeted therapies in cancer, the problem of multidrug resistance (MDR) is still unsolved. Most patients with metastatic cancer die from MDR. Transmembrane efflux pumps as the main cause of MDR have been addressed by developed inhibitors, but early inhibitors of the most prominent and longest known efflux pump P-glycoprotein (P-gp) were disappointing. Those inhibitors have been used without knowledge about the expression of P-gp by the treated tumor. Therefore the use of inhibitors of transmembrane efflux pumps in clinical settings is reconsidered as a promising strategy in the case of the respective efflux pump expression. We discovered novel symmetric inhibitors of the symmetric efflux pump MRP4 encoded by the ABCC4 gene. MRP4 is involved in many kinds of cancer with resistance to anticancer drugs. All compounds showed better activities than the best known MRP4 inhibitor MK571 in an MRP4-overexpressing cell line assay, and the activities could be related to the various substitution patterns of aromatic residues within the symmetric molecular framework. One of the best compounds was demonstrated to overcome the MRP4-mediated resistance in the cell line model to restore the anticancer drug sensitivity as a proof of concept.     

Long-wavelength Ultraviolet A1 and Visible Light Photoprotection: A Multimodality Assessment of Dose and Response

Human skin is exposed to visible light (VL; 400–700 nm) and long-wavelength ultraviolet A1 (UVA1) radiation (370–400 nm) after the application of organic broad-spectrum sunscreens. The biologic effects of these wavelengths have been demonstrated; however, a dose–response has not been investigated. Ten subjects with Fitzpatrick skin phototype IV-VI were enrolled. Subjects were irradiated with 2 light sources (80–480 J cm⁻²): one comprising VL with less than 0.5% UVA1 (VL+UVA1) and the other pure VL. Skin responses were evaluated for 2 weeks using clinical and spectroscopic assessments. 4-mm punch biopsies were obtained from nonirradiated skin and sites irradiated with 480 J cm⁻² of VL+UVA1 and pure VL 24 h after irradiation. Clinical and spectroscopic assessments demonstrated a robust response at VL+UVA1 sites compared with pure VL. Histology findings demonstrated a statistically significant increase in the marker of inflammation (P < 0.05) and proliferation (P < 0.05) at the irradiated sites compared with nonirradiated control. Threshold doses of VL+UVA1 resulting in biologic responses were calculated. Results indicate that approximately 2 h of sun exposure, which equates to VL+UVA1 dose (~400 J cm⁻²), is capable of inducing inflammation, immediate erythema and delayed tanning. These findings reinforce the need of photoprotection beyond the UV range.     

Real-time recursive estimation of statistical parameters

Recursive algorithms for the computation of standard deviation and average deviation are derived and their applications in data acquisition are discussed. The relative speeds and accuracies of the two algorithms are compared for synthetic data. The performance of recursive estimation under shot and proportional noise limitations is also described. As an example of the utility of these algorithms, absorbance data with constant confidence intervals are collected regardless of incident and transmitted intensities. The desired precision is specified prior to data acquisition and used to control signal-averaging of the data in real time.     

S 1 actions and elliptic genera

A proof is given of Witten's conjectures for the rigidity of the index of the Dirac-Ramond operator on the loop space of a spin manifold which admits anS ¹ symmetry.Research supported in part by the National Science Foundation     

On division rings with algebraic commutators of bounded degree

We shall answer several questions concerning additive or multiplicative commutators in a division ring which are algebraic of bounded degree over its center.     

Self-organized ZnAl2O4 nanostructures grown on -sapphire

Self-organized ZnAl₂O₄ nanostructures with the appearance (in SEM) of high aspect ratio horizontal nanowires are grown on uncatalysed c-sapphire by vapour phase transport. The nanostructures grow as three equivalent crystallographic variants on c-sapphire. Raman and cathodoluminescence spectroscopy confirm that the nanostructures are not ZnO and TEM shows that they are the cubic spinel, zinc aluminate, ZnAl₂O₄, formed by the reaction of Zn and O with the sapphire substrate.     

A high sensitivity titration calorimeter using pyroelectric sensor

A new sensitive isothermal titration microcalorimeter using polyvinylidene difluoride (PVDF) as detector has been developed. Heat pulses of less than 0.4 μJ can be detected and the baseline noise level (p-p) is 40 nW. The calorimeter is constructed with one reaction cell (0.7 ml) insulated by several radiation shields inside a vacuum chamber. The performance of the instrument was examined by measuring the heat of protonation of Tris with HCl. The enthalpy of reaction was found to be ?49±1 kJ·mol^?1, in good agreement with the reported value of ?47.5 kJ·mol^?1.     

Profile empirical likelihood for parametric and semiparametric models

This paper introduces a profile empirical likelihood and a profile conditionally empirical likelihood to estimate the parameter of interest in the presence of nuisance parameters respectively for the parametric and semiparametric models. It is proven that these methods propose some efficient estimators of parameters of interest in the sense of least-favorable efficiency. Particularly, for the decomposable semiparametric models, an explicit representation for the estimator of parameter of interest is derived from the proposed nonparametric method. These new estimations are different from and more efficient than the existing estimations. Some examples and simulation studies are given to illustrate the theoretical results. The first author is supported by NNSF projects (10371059 and 10171051) of China. The second author is supported by a grant from The Research Grants Council of the Hong Kong Special Administrative Region, China (#HKU7060/04P). The third author is supported by the University Research Committee of the University of Hong Kong and a grant from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. HKU7323/01M).