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.     

Frequency of molecular alterations in heterozygous beta-thalassemia in southern Spain and their relation to the hematologic phenotype

INTRODUCTION: Heterozygous beta-thalassemia manifests hematologically with microcytosis, reduced red blood cell hemoglobin concentration and high hemoglobin A2 levels. Almost all molecular alterations are due to point mutations. We attempt to determinate the frequency of that mutations in the Oriental Andalusia Area, and its relationship with the hematological phenotype. PATIENTS AND METHODS: We have studied 45 heterozygous patients. DNA samples were amplified by PCR, using the printers CD7 and HI1. A 16 Kb fragment corresponding to beta globin gene was obtained and analyzed by Dot Blot assay and hybridized with allelic specific oligonucleotide (ASO) probes to detect the 6 more frequent mutations found in the South of Spain. RESULTS: Codon 39 nonsense mutation (31.1%) was the most frequent finding followed by IVS-1 NT 110 (26.7%). The relationship between hematological parameters and molecular mutations concluded that IVS-I NT 6 mutation developed a minimal anemia. DISCUSSION: From the practical point of view, this study indicates that we were able to detect more than 90% of heterozygous beta-tal. with 5 out of 6 ASO probes used in this work. Thus, our data also provides a further implication in prenatal diagnosis.     

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.     

A flexible architecture for distributed knowledge based systems with nomadic access through handheld devices

Nowadays any Knowledge Based System (KBS) realization needs of intercommunication among distributed components and to use non-connected and distributed data sources, which poses several challenges to the classical Artificial Intelligence field of KBS.

The multiagent paradigm and the use of ontologies are considered to be suitable tools to face the problems of designing and developing today KBS. On the other hand, using such networked KBS through handheld devices makes more efficient exploitation and interaction with the system.

This paper presents an open and flexible architecture for a distributed KBS and an application of it to construct a system for Psychological Disorders consulting, the so called PDA² (Psychological Disorder Assistant through PDA). We analyze the main features of the architecture as well as the agent tools we may use to construct it. Additionally, we present a support ontology for Psychological Disorders.     

Efficient procedure for computing fields created by current modes

An efficient method for computing the fields of large scatterers is presented. The current is expanded in terms of modes defined as complex exponential functions. The modes are represented efficiently by means of spline functions. Analytical expressions have been obtained to compute efficiently the fields due to the current modes.     

Theory,design, and evaluation of the rotating polarizer interferometer

We present the results of modeling the response of a Rotating Polarizer Interferometer (RPI), an actual design and the evaluation of it. The RPI was introduced almost 10 years ago by Erickson [1] and since then it has not received too much attention from the millimeter wave community despite its very attractive characteristics, this is perhaps due to a lack of proven designs to encourage potential users. Here we show that with proper design equations a predictable result can be achieved and that a working device with a low-loss dielectric filling (Teflon) is feasible     

Improving manufacturing by cost-effective process modeling

Computer-aided engineering tools are routinely used to simulate forging and heat-treatment operations and to perform thermal and stress analyses. This review gives a few examples of the current uses of process modeling tools and outlines some developing capabilities and near-term applications.     

A Simple Experimental Technique to Measure Tortuosity in Packed Beds

In this article, a simple and inexpensive experimental technique easy to build in laboratory, for the measurement of tortuosity of a packed bed of inert particles, is described. Experimental values of the tortuosity were obtained with four different packed beds of sand. The experimental results obtained are in good agreement with the theoretical values of tortuosity in a porous media; and the data reported showed the tortuosity to increase with decrease in the void fraction of the packed bed as expected.