Endobronchial phototoxicity of WST 09 (Tookad), a new fast-acting photosensitizer for photodynamic therapy: preclinical study in the pig

Photodynamic therapy (PDT) has been used for many years for both palliative and curative treatment of bronchial carcinomas. However, prolonged skin phototoxicity and reduced depth of penetration has limited the widespread use of PDT. We studied the endobronchial phototoxicity of a novel photosensitizer, WST 09 (Tookad). Fourteen pairs of Large White-Landrace male piglets were given intravenous WST 09 followed by laser light illumination of the left mainstem bronchus. Different settings for light dose (fluence), fluence rate (FR), drug dose (D) and drug-light interval (DLI) were applied to each pair. Bronchial toxicity was assessed with repeat bronchoscopic photographic evaluation as well as by pathologic examination following autopsy. Animals developed no toxicity, moderate toxicity or severe toxicity. Increased toxicity was seen with increasing D and fluence and decreasing DLI, whereas no increased toxicity was seen with higher FR. PDT-related histological changes in the normal bronchus confirm the vascular effect of WST 09. Depending on the parameter settings for fluence, D and DLI, the lesions ranged from focal intramucosal ischemia to transmural infarction with subsequent acute inflammation and fibrosis. Clinically feasible parameters for drug and light dosimetry were documented. These data will be important in determining safe starting doses for human phase I/II studies.     

Flow microcalorimetry: Experimental development and application to adsorption of heavy metal cations on silica

Sorption of metal ions at the oxide mineral-water interfaces is a complex process involving many various contributions that can be explained using thermodynamics. The aim of this study is to obtain experimental thermodynamic data on adsorption of two heavy metal ions (Cd(II) and Pb(II)) on macroporous silica. Thermal signals of adsorption are studied by flow microcalorimetry which has been preferred because physico-chemicals conditions (pH, equilibrium concentration,…) can be controlled (the routine configuration was optimized in order to get a very stable pressure baseline and avoid important fluctuations in the determination of heat). Mechanisms driving the adsorption have been explained. The calculation of the effective charge of ions determined from the speciation diagrams and of the surface charges shows that the interactions between the two metals and the silica surface are mainly electrostatic. The differential enthalpies of adsorption Δ_adsH have been experimentally measured. The heat of cadmium adsorption is low, endothermic and quantitatively equivalent to that of desorption. In the case of lead, the adsorption is athermal. Free energies and entropic effects related to cation adsorption have then been deduced according to the Gibbs’law. The entropy is positive during the adsorption process and at this temperature (298 K) is quite equivalent to free energy. This entropy is due to modification of hydration shell of the ions during their insertion into the interfacial region.     

High order harmonic balance formulation of free and encapsulated microbubbles

The radial responses of free and encapsulated microbubbles excited by an ultrasonic plane wave with a large wavelength in comparison with the bubble size are governed by NonLinear Ordinary Differential Equations (NL-ODEs). The nonlinear frequency response gives the harmonic content of the time response and constitutes the expected outcome of a high order harmonic analysis. In this paper, high order harmonic balance analysis of modified “RPNNP” (bubble), Hoff and Marmottant (contrast agents) models is performed with an open-source software program. For this purpose, the original NL-ODEs are recast into nonlinear systems in which the nonlinearities are at most quadratic. In the spectral domain, this recast provides close form and aliasing-free solutions of arbitrarily large numbers of harmonics. Relevant quantities such as primary and secondary resonances and the nonlinear amplitude threshold of the excitation wave are evaluated. The frequency curves drawn up characterize the bending and quantify the jump frequencies and amplitudes of each harmonic component. The results obtained with this predictive method confirm that it should provide a useful tool for nonlinear bubble detection and sizing and for contrast agent designing.     

Edge cover by connected bipartite subgraphs

We consider the problem of covering the edge set of an unweighted, undirected graph with the minimum number of connected bipartite subgraphs (where the subgraphs are not necessarily bicliques). We show that this is an NP-hard problem, provide lower bounds through an integer programming formulation, propose several constructive heuristics and a local search, and discuss computational results. Finally, we consider a constrained variant of the problem which we show to be NP-hard, and provide an integer programming formulation for the variant.     

Synthesis of a benzomacrolactone-based somatostatin mimetic

The benzomacrolactone is a framework found in numerous natural products. The synthesis of an orthogonally functionalized benzomacrolactone from D-glucosamine and a salicylic acid derivative is described. This macrolactone was used for the synthesis of a somatostatin mimetic that has submicromolar affinity for the human somatostatin receptor 4 (hSSTR4).     

Experimental and numerical analysis of fretting crack formation based on 3D X-FEM frictional contact fatigue crack model

Nowadays, numerical simulation of 3D fatigue crack growth is easily handled using the eXtended Finite Element Method coupled with level set techniques. The finite element mesh does not need to conform to the crack geometry. Most difficulties associated to complex mesh generation around the crack and the re-meshing steps during the possible propagation are hence avoided. A 3D two-scale frictional contact fatigue crack model developed within the X-FEM framework is presented in this article. It allows the use of a refined discretization of the crack interface independent from the underlying finite element mesh and adapted to the frictional contact crack scale. A stabilized three-field weak formulation is also proposed to avoid possible oscillations in the local solution linked to the LBB condition when tangential slip is occurring. Two basic three-dimensional numerical examples are presented. They aim at illustrating the capacities and the high level of accuracy of the proposed X-FEM model. Stress intensity factors are computed along the crack front. Finally an experimental 3D ball/plate fretting fatigue test with running conditions inducing crack nucleation and propagation is modeled. 3D crack shapes defined from actual experimental ones and fretting loading cycle are considered. This latter numerical simulation demonstrates the model ability to deal with challenging actual complex problems and the possibility to achieve tribological fatigue prediction at a design stage based on the fatigue crack modeling.     

A continuous variant for Grünwald-Letnikov fractional derivatives

The names of Grünwald and Letnikov are associated with discrete convolutions of mesh h, multiplied by h^−α. When h tends to zero, the result tends to a Marchaud’s derivative (of the order of α) of the function to which the convolution is applied. The weights of such discrete convolutions form well-defined sequences, proportional to k^−α−1 near infinity, and all moments of integer order r<α are equal to zero, provided α is not an integer. We present a continuous variant of Grünwald-Letnikov formulas, with integrals instead of series. It involves a convolution kernel which mimics the above-mentioned features of Grünwald-Letnikov weights. A first application consists in computing the flux of particles spreading according to random walks with heavy-tailed jump distributions, possibly involving boundary conditions.     

Nano-scale metallodendritic complexes in electron-transfer processes and catalysis

Nano-sized metallodendrimers in which the equivalent metal fragments are located at the periphery can be assembled covalently, by H-bonding (supramolecular) or onto dendronized nanoparticles. They can be used as electron-reservoirs, i.e. molecular batteries, redox catalysts and sensors for the recognition of biologically relevant anions. They can also be deposited on metal surfaces or electrodes, which optimizes their use as recoverable sensors.