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.     

Toward automatic phenotyping of developing embryos from videos.

We describe a trainable system for analyzing videos of developing C. elegans embryos. The system automatically detects, segments, and locates cells and nuclei in microscopic images. The system was designed as the central component of a fully automated phenotyping system. The system contains three modules 1) a convolutional network trained to classify each pixel into five categories: cell wall, cytoplasm, nucleus membrane, nucleus, outside medium; 2) an energy-based model, which cleans up the output of the convolutional network by learning local consistency constraints that must be satisfied by label images; 3) a set of elastic models of the embryo at various stages of development that are matched to the label images.     

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.     

A Multidimensional Paper Recommender: Experiments and Evaluations

Paper recommender systems in the e-learning domain must consider pedagogical factors, such as a paper's overall popularity and learner background knowledge — factors that are less important in commercial book or movie recommender systems. This article reports evaluations of a 6D paper recommender. Experimental results from a human subject study of learner preferences suggest that pedagogical factors help to overcome a serious cold-start problem (not having enough papers or learners to start the recommender system) and help the system more appropriately support users as they learn.     

Study of Nano-Porous Silicon with Low Thermal Conductivity as Thermal Insulating Material

Recently discovered phenomenon of extremely low thermal conductivity of nano-porous silicon (nano-PS) is discussed in detail. A theoretical model describing specific mechanisms of heat transport in as-prepared and oxidized nano-PS layers is described. The theoretical estimations are in a good agreement with experimental data obtained earlier. The low thermal conductivity values allow to use this promising material as thermal insulator in microsensors and microsystems. To ensure an efficient thermal isolation, a nano-PS layer has to be as thick as possible and mechanically stable. We describe here the procedures to form thick (up to 200 m) and stable nano-PS layers. Distribution of Si oxidized fraction along the layer thickness after thermal oxidation in dry O₂ atmosphere at 300°C during 1 h is studied.     

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)