The role of cisplatin and NAMI-A plasma-protein interactions in relation to combination therapy

The aim of the study is to evaluate the differences of protein binding of NAMI-A, a new ruthenium drug endowed with selective antimetastatic properties, and of cisplatin and to ascertain the possibility to use two drugs based on heavy metals in combination to treat solid tumour metastases. For this purpose, we have developed a technique that allows the proteins, to which metal drugs bind, to be identified from real protein mixtures. Following incubation with the drugs, the bands containing platinum and/or ruthenium are separated by native PAGE, SDS-PAGE and 2D gel electrophoresis, and identified using laser ablation inductively coupled plasma mass spectrometry. Both drugs interact with essentially the same proteins which, characterised by proteomics, are human serum albumin precursor, macroglobulin alpha 2 and human serotransferrin precursor. The interactions of NAMI-A are largely reversible whereas cisplatin forms stronger interactions that are less reversible. These data correlate well with the MCa mammary carcinoma model on which full doses of NAMI-A combined with cisplatin show additive effects as compared to each treatment taken alone, independently of whether NAMI-A precedes or follows cisplatin. Furthermore, the implication from this study is that the significantly lower toxicity of NAMI-A, compared to cisplatin, could be a consequence of differences in the mode of binding to plasma proteins, involving weaker interactions compared to cisplatin.

Relation between plaque type, plaque thickness, blood shear stress, and plaque stress in coronary arteries assessed by X-ray Angiography and Intravascular Ultrasound

Purpose: Atheromatic plaque progression is affected, among others phenomena, by biomechanical, biochemical, and physiological factors. In this paper, the authors introduce a novel framework able to provide both morphological (vessel radius, plaque thickness, and type) and biomechanical (wall shear stress and Von Mises stress) indices of coronary arteries. Methods: First, the approach reconstructs the three-dimensional morphology of the vessel from intravascular ultrasound(IVUS) and Angiographic sequences, requiring minimal user interaction. Then, a computational pipeline allows to automatically assess fluid-dynamic and mechanical indices. Ten coronary arteries are analyzed illustrating the capabilities of the tool and confirming previous technical and clinical observations. Results: The relations between the arterial indices obtained by IVUS measurement and simulations have been quantitatively analyzed along the whole surface of the artery, extending the analysis of the coronary arteries shown in previous state of the art studies. Additionally, for the first time in the literature, the framework allows the computation of the membrane stresses using a simplified mechanical model of the arterial wall. Conclusions: Circumferentially (within a given frame), statistical analysis shows an inverse relation between the wall shear stress and the plaque thickness. At the global level (comparing a frame within the entire vessel), it is observed that heavy plaque accumulations are in general calcified and are located in the areas of the vessel having high wall shear stress. Finally, in their experiments the inverse proportionality between fluid and structural stresses is observed.

Sedimentation of macroscopic rigid knots and its relation to gel electrophoretic mobility of DNA knots.

We address the general question of the extent to which the hydrodynamic behaviour of microscopic freely fluctuating objects can be reproduced by macrosopic rigid objects. In particular, we compare the sedimentation speeds of knotted DNA molecules undergoing gel electrophoresis to the sedimentation speeds of rigid stereolithographic models of ideal knots in both water and silicon oil. We find that the sedimentation speeds grow roughly linearly with the average crossing number of the ideal knot configurations, and that the correlation is stronger within classes of knots. This is consistent with previous observations with DNA knots in gel electrophoresis.

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

Rationale Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine. Objective The major aims were to investigate the pharmacokineticsa and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model. Methods Mephedrone was administered to male SpragueDawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180240 min. Results Mephedrone plasma concentrations after i.v. administration fit a two-compartment model (α=10.23 h−1, β=1.86 h−1). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10 % and the percentage of mephedrone protein binding was 21.59±3.67%. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85±0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokineticpharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect. Conclusions We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude,and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity.

Intra-specific variation in cell wall constituents of needle age classes of Pinus sylvestris in relation to soil fertility status in Southwest England

Abstract

Adaptability and stability of white oat cultivars in relation to chemical composition of the caryopsis

The objective of this work was to characterize the chemical properties of white oat (Avena sativa) caryopsis and to determine the adaptability and stability of cultivars recommended for cultivation in the state of Rio Grande do Sul, Brazil. The trials were carried out in the 2007, 2008 and 2009 crop seasons, in three municipalities: Augusto Pestana, Capão do Leão, and Passo Fundo. Fifteen cultivars were evaluated in a randomized block design, with four replicates. The contents of protein, lipid, and nitrogen-free extract were evaluated in the caryopsis. Cultivar performances for the measured characters varied according to location and year of cultivation. The cultivar URS Guapa showed high content of nitrogen-free extract and low contents of protein and lipid in the caryopsis. 'FAPA Louise' showed high content of lipid, whereas 'Albasul', 'UPF 15', and 'UPF 18' showed high content of protein and low content of nitrogen-free extract. There is no evidence of an ideal biotype for the evaluated characters, which could simultaneously show high average performance, adaptability to favorable and unfavorable environments, and stability.

Size and fat content of gynes in relation to the mode of colony founding in ants (Hymenoptera; Formicidae)

In ants, there are two main processes of colony founding, the independent and the dependent modes. In the first case young queens start colony founding without the help of workers, whereas in the second case they are accompanied by workers. To determine the relation between the mode of colony founding and the physiology of queens, we collected mature gynes of 24 ant species. Mature gynes of species utilizing independent colony founding had a far higher relative fat content than gynes of species employing dependent colony founding. These fat reserves are stored during the period of maturation, i.e. between the time of emergence and mating, and serve as fuel during the time of colony founding to nurture the queen and the brood. Gynes of species founding independently but non claustrally were found to have a relative fat content intermediate between the values found for gynes founding independently and those founding dependently. This suggests that such gynes rely partially on their fat reserves and partially on the energy provided by prey they collect to nurture themselves and the first brood during the time of colony founding. Study of the fat content of mature gynes of all species has shown that it gives a good indication of the mode of colony founding.

Relation between sequence and structure of HIV-1 protease inhibitor complexes: a model system for the analysis of protein flexibility.

The flexibility of different regions of HIV-1 protease was examined by using a database consisting of 73 X-ray structures that differ in terms of sequence, ligands or both. The root-mean-square differences of the backbone for the set of structures were shown to have the same variation with residue number as those obtained from molecular dynamics simulations, normal mode analyses and X-ray B-factors. This supports the idea that observed structural changes provide a measure of the inherent flexibility of the protein, although specific interactions between the protease and the ligand play a secondary role. The results suggest that the potential energy surface of the HIV-1 protease is characterized by many local minima with small energetic differences, some of which are sampled by the different X-ray structures of the HIV-1 protease complexes. Interdomain correlated motions were calculated from the structural fluctuations and the results were also in agreement with molecular dynamics simulations and normal mode analyses. Implications of the results for the drug-resistance engendered by mutations are discussed briefly.