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.     

Diffusive motion of iron microcrystals studied by Mössbauer spectroscopy

A new model is presented which explains well the dramatic decrease of the Mössbauer line intensities with raising temperatures for freely dispersed iron microscrystals. In contrast to other theories which consider mainly vibration to be responsible we discuss here the decrease in terms of large amplitude diffusive rotational or translational jumps of the particles. Such diffusive jumps lead — in agreement with the observation — to a strong reduction of the Mössbauer-intensity without broadening the line width in a noticeable way. The typical potential well for a diffusing particle in an equilibrium position is derived quantitatively to be 13 meV. The model might be important also for a new understanding of the dynamics of catalytic clusters either in contact with each other or with larger solid surfaces.Part of this work was supported by the DFG Sonderforschungsbereich 306, Konstanz     

Elliott-Morse measures and Kakutani's dichotomy theorem

Dedicated to the memory of John Oxtoby     

Time interval distributions of atoms in atomic beams

We report an experimental investigation of two-particle correlations between neutral atoms in a Hanbury Brown and Twiss experiment. Both an atom laser beam and a pseudo-thermal atomic beam are extracted from a Bose–Einstein condensate and the atom flux is measured with a single atom counter. We determine the conditional and the unconditional detection probabilities for the atoms in the beam and find good agreement with the theoretical predictions. PACS 03.75.Pp; 05.30.Jp; 07.77.Gx; 42.50.Pq     

Bayesian Object Identification: Variants

We present a Bayesian theory of object identification. Here, identifying an object means selecting a particular observation from a group of observations (variants), this observation (the regular variant) being characterized by a distributional model. In this sense, object identification means assigning a given model to one of several observations. Often, it is the statistical model of the regular variant, only, that is known. We study an estimator which relies essentially on this model and not on the characteristics of the “irregular” variants. In particular, we investigate under what conditions this variant selector is optimal. It turns out that there is a close relationship with exchangeability and Markovian reversibility. We finally apply our theory to the case of irregular variants generated from the regular variant by a Gaussian linear model.     

Local radial Phragmén-Lindelöf estimates for plurisubharmonic functions on analytic varieties

We give a sufficient condition for a local radial Phragmén-Lindelöf principle on analytic varieties. This condition is expressed in terms of existence of hyperbolic directions.

     

Nonclassical multidimensional singular integral operators on R + n+1

Banach algebras of certain bounded operators acting on the half-spaceL _p (R ₊ ⁿ⁺¹ ,x ₀ ) (1<p<, –1<<p–1) are defined which contain for example Wiener-Hopf operators, defined by multidimensional singular convolution integral operators, as well as certain singular integral operators with fixed singularities. Moreover the symbol may be a positive homogeneous function only piecewise continuous on the unit sphere. Actually these multidimensional singular integral operators may be not Calderón-Zygmund operators but are built up by those in lower dimensions. This paper is a continuation of a joint paper of the author together with R.V. Duduchava [10]. The purpose is to investigate invertibility or Fredholm properties of these operators, while the continuity is given by definition. This is done in [10] forp=2 and –1<<1, and in the present paper forL _p (R ₊ ⁿ⁺¹ ,x ₀ ) with 1<p< and –1<<p–1.