Theoretical optimization of Irinotecan-based anticancer strategies in the case of drug-induced efflux

The anticancer drug Irinotecan (CPT11) is known to trigger the induction of ATP-Binding Cassette (ABC) transporters, responsible for the efflux of the drug and its metabolites outside of the cells. The drug-modulated overexpression of those transporters prevents its accumulation in the intracellular medium, therefore decreasing its efficacy. A critical clinical concern lies in the design of CPT11-based therapeutic strategies which eradicate a maximum number of cancer cells despite their ability to become resistant. In order to address this issue, we supplemented an existing mathematical model of CPT11 molecular pharmacokinetics–pharmacodynamics (PK–PD) with a new model of CPT11-induced overexpression of ABC transporters. We then theoretically optimized exposure to CPT11 given as a single agent or combined either with ABC transporter inhibitors, or with inhibitors of nuclear factors whose activation is responsible for transporter overexpression. We firstly considered a cancer cell population endowed with the ability of inducing their transporters. For any drug combination, we concluded that the highest concentration of CPT11 should be administered in order to kill a maximum number of cancer cells, despite the triggering of resistance. We then considered a population of healthy cells which were assumed to be identical to cancer cells except that they were not able to become resistant. Optimal schemes were defined as the ones which maximized DNA damage in cancer cells under the constraint of DNA damage in healthy cells not exceeding a tolerability threshold. The optimal therapeutic strategy consisted in combining CPT11 with ABC transporter inhibitors as it achieved a complete reversal of resistance by means of the lowest concentrations of CPT11.     

Periodic homogenization of nonlinear non-monotone parabolic operators with three time scales

Multiscale homogenization of nonlinear non-monotone degenerated parabolic operators is investigated. Under a periodicity assumption on the coefficients of the operators under consideration, we obtain by means of multiscale convergence method, an accurate homogenization result. It is also shown that in spite of the presence of several time scales the global homogenized problem is not a reiterated one.     

Cauchy problem on a characteristic cone for the Einstein–Vlasov system: (I) The initial data constraints

In this paper, one considers a Cauchy problem with data on a characteristic cone for the Einstein–Vlasov system in temporal gauge. One highlights gauge-dependent constraints that, supplemented by the standard constraints i.e. the Hamiltonian and the momentum constraints, define the full set of constraints for the considered setting. One studies their global resolution from a suitable choice of some free data, the behavior of the deduced initial data at the vertex of the cone, and the preservation of the gauge.     

Generalization of Selberg’s $$ frac{3}{{16}} $$ theorem and affine sieve

An analogue of the well-known frac316 frac{3}{{16}} lower bound for the first eigenvalue of the Laplacian for a congruence hyperbolic surface is proven for a congruence tower associated with any non-elementary subgroup L of SL(2,Z). The proof in the case that the Hausdorff of the limit set of L is bigger than frac12 frac{1}{2} is based on a general result which allows one to transfer such bounds from a combinatorial version to this archimedian setting. In the case that delta is less than frac12 frac{1}{2} we formulate and prove a somewhat weaker version of this phenomenon in terms of poles of the corresponding dynamical zeta function. These “spectral gaps” are then applied to sieving problems on orbits of such groups.     

Synthesis and luminescence properties of new red-shifted absorption lanthanide(III) chelates suitable for peptide and protein labelling

The synthesis and photo-physical properties of an original bis-pyridinylpyrazine chromophore efficiently sensitising europium(III) and samarium(III) are described. The corresponding lanthanide(III) complexes display in aqueous solutions a maximum excitation wavelength which is significantly red-shifted compared to the usual terpyridine-based chelates, and a valuable luminescence brightness above 2,000 dm(3) mol(-1) cm(-1) at 345 nm was obtained with a europium(III) derivative. Further functionalisation with three different bioconjugatable handles was also investigated and their ability to efficiently label a model hexapeptide was evaluated and compared. Finally, the best bioconjugatable europium(III) chelate was used in representative labelling experiments involving monoclonal antibodies and the luminescence features of the corresponding bioconjugates remained satisfactory.     

Structural modulation of internal charge transfer in small molecular donors for organic solar cells

Donor-acceptor molecules with small chain extension have been synthesized and used as active material in organic solar cells. The effect of fusion of a phenyl group on the end dicyanovinylene acceptor is discussed.     

Ionic Liquid Crystals Formed by Self‐Assembly around an Anionic Anthracene Core

We have designed and synthesised a series of modular, mesogenic complexes based on anthracene‐2,6‐disulfonate and trialkoxybenzyl‐functionalised imidazolium cations. Each complex contains a central, rigid, dianionic anthracene core and two flexible monocations bearing paraffin chains anchored on imidazolium rings. Anthracene‐2,6‐disulfonate can be crystallised with various simple alkylammonium ions and, in the case of ⁺N(CH₃)₂(C₁₆H₃₃)₂, a crystal structure determination has shown that the long paraffinic chains are intercalated between the anthracene moieties. The dianion forms columnar mesophases with trialkoxybenzylimidazolium cations, as identified by polarising optical microscopy and X‐ray scattering measurements. Differential scanning calorimetry studies confirmed mesomorphic behaviour from room temperature to about 200 °C for alkyl chains containing 8, 12 and 16 carbon atoms. The strong luminescence of anthracene is maintained in the mesophase and fluorescence measurements confirmed the presence of J aggregates in all cases. The new functional materials described herein provide an easy access to stable and luminescent mesomorphic materials engineered by an ionic self‐assembly process.     

Positive Solutions to Boundary Value Problems for Second Order Ordinary Differential Equations with Singular Nonlinearities

This paper deals with the existence of solutions to the periodic and the Sturm-Liouville boundary value problems for second order ordinary differential equations with singular nonlinearity. The results are obtained by use of some continuation theorems in the absence of a priori bounds of Capietto-Mawhin-Zanolin.     

Synthesis of PEDOT Nanoparticles and Vesicles by Dispersion Polymerization in Alcoholic Media

Summary: The synthesis of PEDOT nanoparticles and vesicles by dispersion polymerization in a methanol/water mixture (3/2, v/v) is reported, using either ammonium persulfate or iron(III) p‐toluenesulfonate as oxidants and α‐EDOT‐PEO as a reactive stabilizer. The influence of the oxidant as well as the α‐EDOT‐PEO molar mass and concentration on the core‐shell particle morphology and conductivity properties have been investigated. PEDOT particles with conductivities up to 1.5 × 10⁻² S · cm⁻¹ have been obtained in high yield.

TEM image of PEDOT vesicles prepared using PEO‐based stabilizers of 25 000 g · mol⁻¹ in water/methanol mixture (2:3 v/v) at room temperature using ammonium persulfate as an oxidant.