Microtubule Destabilizing Sulfonamides as an Alternative to Taxane-Based Chemotherapy

Pan-Gyn cancers entail 1 in 5 cancer cases worldwide, breast cancer being the most commonly diagnosed and responsible for most cancer deaths in women. The high incidence and mortality of these malignancies, together with the handicaps of taxanes—first-line treatments—turn the development of alternative therapeutics into an urgency. Taxanes exhibit low water solubility that require formulations that involve side effects. These drugs are often associated with dose-limiting toxicities and with the appearance of multi-drug resistance (MDR). Here, we propose targeting tubulin with compounds directed to the colchicine site, as their smaller size offer pharmacokinetic advantages and make them less prone to MDR efflux. We have prepared 52 new Microtubule Destabilizing Sulfonamides (MDS) that mostly avoid MDR-mediated resistance and with improved aqueous solubility. The most potent compounds, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methylaminobenzenesulfonamide 38, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 42, and N-benzyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 45 show nanomolar antiproliferative potencies against ovarian, breast, and cervix carcinoma cells, similar or even better than paclitaxel. Compounds behave as tubulin-binding agents, causing an evident disruption of the microtubule network, in vitro Tubulin Polymerization Inhibition (TPI), and mitotic catastrophe followed by apoptosis. Our results suggest that these novel MDS may be promising alternatives to taxane-based chemotherapy in chemoresistant Pan-Gyn cancers.     

Biodegradability Study of the Biosurfactant Contained in a Crude Extract from Corn Steep Water

Over the last few years, the global biosurfactant market has raised due to the increasing awareness among consumers, for the use of biological or bio-based products. Because of their composition, it can be speculated that these are more biocompatible and more biodegradable than their chemical homologous. However, at the moment, no studies exist in the literature about the biodegradability of biosurfactants. In this work, a biosurfactant contained in a crude extract, obtained from a corn wet-milling industry stream that ferments spontaneously in the presence of lactic acid bacteria, was subjected to a biodegradation study, without addition of external microbial biomass, under different conditions of temperature (5–45 °C), biodegradation time (15–55 days), and pH (5–7). For that, a Box–Behnken factorial design was applied, which allowed to predict the percentage of biodegradation for the biosurfactant contained in the crude extract, between the range of the independent variables selected in the study, obtaining biodegradation values between 3 and 80%. The percentage of biodegradation for the biosurfactant was calculated based on the increase in the surface tension of samples of the crude extract. Furthermore, it was also possible to predict the variation in t_1/2 for the biosurfactant (time to achieve the 50% of biodegradation) under different conditions.     

Solvent effect modelling of isocyanuric products synthesis by chemometric methods

Chemometric tools were used to generate the modelling of solvent e inverted exclamation markects on the N-alkylation of an isocyanuric acid salt. The method proceeded from a central composite design applied on the Carlson solvent classification using principal components analysis. The selectivity of the reaction was studied from the production of different substituted isocyanuric derivatives. Response graphs were obtained for each compound and used to devise a strategy for solvent selection. The prediction models were validated and used to search for the best selectivity for the reaction system. The solvent most often selected as the best for the reaction is the N,N-dimethylformamide.     

Archiving the web using page changes patterns: a case study

A pattern is a model or a template used to summarize and describe the behavior (or the trend) of data having generally some recurrent events. Patterns have received a considerable attention in recent years and were widely studied in the data mining field. Various pattern mining approaches have been proposed and used for different applications such as network monitoring, moving object tracking, financial or medical data analysis, scientific data processing, etc. In these different contexts, discovered patterns were useful to detect anomalies, to predict data behavior (or trend) or, more generally, to simplify data processing or to improve system performance. However, to the best of our knowledge, patterns have never been used in the context of Web archiving. Web archiving is the process of continuously collecting and preserving portions of the World Wide Web for future generations. In this paper, we show how patterns of page changes can be useful tools to efficiently archive Websites. We first define our pattern model that describes the importance of page changes. Then, we present the strategy used to (i) extract the temporal evolution of page changes, (ii) discover patterns, to (iii) exploit them to improve Web archives. The archive of French public TV channels France Télévisions is chosen as a case study to validate our approach. Our experimental evaluation based on real Web pages shows the utility of patterns to improve archive quality and to optimize indexing or storing.     

Using aspects for testing of embedded software: experiences from two industrial case studies

Aspect-oriented software testing is emerging as an important alternative to conventional procedural and object-oriented testing techniques. This paper reports experiences from two case studies where aspects were used for the testing of embedded software in the context of an industrial application. In the first study, we used code-level aspects for testing non-functional properties. The methodology we used for deriving test aspect code was based on translating high-level requirements into test objectives, which were then implemented using test aspects in AspectC++. In the second study, we used high-level visual scenario-based models for the test specification, test generation, and aspect-based test execution. To specify scenario-based tests, we used a UML2-compliant variant of live sequence charts. To automatically generate test code from the models, a modified version of the S2A Compiler, outputting AspectC++ code, was used. Finally, to examine the results of the tests, we used the Tracer, a prototype tool for model-based trace visualization and exploration. The results of the two case studies show that aspects offer benefits over conventional techniques in the context of testing embedded software; these benefits are discussed in detail. Finally, towards the end of the paper, we also discuss the lessons learned, including the technological and other barriers to the future successful use of aspects in the testing of embedded software in industry.     

On tracing reactive systems

We present a rich and highly dynamic technique for analyzing, visualizing, and exploring the execution traces of reactive systems. The two inputs are a designer’s inter-object scenario-based behavioral model, visually described using a UML2-compliant dialect of live sequence charts (LSC), and an execution trace of the system. Our method allows one to visualize, navigate through, and explore, the activation and progress of the scenarios as they “come to life” during execution. Thus, a concrete system’s runtime is recorded and viewed through abstractions provided by behavioral models used for its design, tying the visualization and exploration of system execution traces to model-driven engineering. We support both event-based and real-time-based tracing, and use details-on-demand mechanisms, multi-scaling grids, and gradient coloring methods. Novel model exploration techniques include semantics-based navigation, filtering, and trace comparison. The ideas are implemented and tested in a prototype tool called the Tracer.     

Application of the CALPHAD approach to Mg-alloys design

The CALPHAD method can be applied as a tool for both alloy development and process guideline determination. In this study, two Mg alloys were designed, their process parameters derived and, using the CALPHAD method, the final results simulated. These results were later confirmed using tangible experimental methods. It was found that γ$\gamma$- Mg₁₇Al₁₂ precipitates along the grain boundaries (GB), Mg₂Sn forms both along the GB and as fine precipitates in the α$\alpha$-Mg matrix and the addition of Ce mishmetal (MM) leads to the formation of elongated Al- rare earth (RE) precipitates along the GB. The microstructural stability at 200 ^°C is high, showing no decrease in microhardness for 32 days. It is shown that the CALPHAD method considerably reduces the effort of alloy design and that the reliability of the results is high.     

Conceptualizing and Measuring Personality Vulnerability to Depression: Comment on Coyne and Whiffen (1995).

J. C. Coyne and V. E. Whiffen (1995) reviewed research on personality vulnerability to depression, focusing on S. J. Blatt's (1974, 1990) concepts of dependency and self-criticism and A. T. Beck's (1983) concepts of sociotropy and autonomy. The authors discuss 6 issues raised in that review: (a) the typological or dimensional nature of vulnerability, (b) the theoretical implications of "mixed" vulnerability, (c) the relations of vulnerability to Neuroticism. (d) the potential confounding of vulnerability with concurrent depression, (e) the potential confounding of vulnerability with social context, and (f) the differentiation of dependency from relatedness. The authors conclude that Blatt's and Beck's concepts are continuous, nearly orthogonal dimensions that can be identified and measured independently from Neuroticism, depression, and social context. (PsycINFO Database Record (c) 2010 APA, all rights reserved)