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     

Inclusive production of neutral vector mesons in hadronic Z decays

A data sample of about 3.0 million hadronicZ decays collected by the ALEPH experiment at LEP in the years 1991 through 1994 is used to make an inclusive selection of B hadron events. In this event sample 4227±140±252B* mesons in the decayB*→Bγ and 1944±108±161B** _u,d mesons decaying into a B meson and a charged pion are reconstructed. Here and in the followingB** _u,d denotes the eightL=1(bū) and (bd) states and their charge conjugate. For the well establishedB* meson the following quantities are obtained:ΔM=M _B*−M_B=(45.30±0.35±0.87) MeV/c² andN _B*/(N _B+N _B*)=(77.1±2.6±7.0)%. The angular distribution of the photons in theB* rest frame is used to measure the relative contribution of longitudinalB* polarization states to beσ _L/(σ _L+σ _T)=(33±6±5)%.     

Fourier transform spectroscopy of CH3OH: rotation-torsion-vibration structure for the CH3-rocking and OH-bending modes

High-resolution Fourier transform spectra of CH₃OH have been investigated in the infrared region from 930 to 1450 cm⁻¹ in order to map the torsion-rotation energy manifolds associated with the ν₇ in-plane CH₃ rock, the ν₁₁ out-of-plane CH₃ rock, and the ν₆ OH bend. Upper-state term values have been determined from the assigned spectral subbands, and have been fitted to power-series expansions to obtain substate origins and effective B-values for the three modes. The substate origins have been grouped into related families according to systematic trends observed in the torsion-vibration energy map, but there are substantial differences from the traditional torsional patterns. There appears to be significant torsion-mediated spectral mixing, and a variety of “forbidden” torsional combination subbands with |Δυ_t|>1 have been observed, where υ_t denotes the torsional quantum number (equivalent to υ₁₂). For example, coupling of the (υ₆,υ_t)=(1,0) OH bend to nearby torsionally excited (υ₇,υ_t)=(1,1) CH₃-rock and (υ₈,υ_t)=(1,1) CO-stretch states introduces (υ₆,υ_t)=(1,0)←(0,1) subbands into the spectrum and makes the ν₇+ν₁₂−ν₁₂ torsional hot band stronger than the ν₇ fundamental. The results suggest a picture of strong coupling among the OH-bending, CH₃-rocking, and CO-stretching modes that significantly modifies the traditional energy structure and raises interesting and provocative questions about the torsion-vibration identity of a number of the observed states.     

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.