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.     

Dynamical modelling of an activated sludge system of a petrochemical plant operating at high temperatures.

The Mexican petrochemical industry, Morelos S.A. de C.V., is one of the biggest and more important petroleum industries in Mexico and Latin America. It has an activated sludge system to treat its wastewater flow, which is approximately 7,000 m3/d. The wastewater contains volatile organic carbon substances classified as toxics. The old surface aeration system was changed for fine bubble diffusers; however, one major drawback of the new aeration system is that the temperature in the bioreactor has increased due to the compression of the air, which at the compressor exit reaches 85 degrees C. This effect results in the temperature in the bioreactor attaining 32 degrees C during the fall, whereas in the spring and summer, the bioreactor temperature reaches higher values than 40 degrees C. The high temperatures reduce the microorganism activity and cause a higher volatilisation rate of volatile compounds, among other effects, which affect the performance of the biological treatment. This work was performed to obtain a better modelling of the wastewater treatment from the petrochemical industry. The model describes the effect of the temperature on the performance of the biological treatment. The model was obtained from tests that were carried out in laboratory reactors with 14 L capacity, which were operated at different temperatures (from 30 to 45 degrees C), with the same wastewater and conditions as the actual system.     

Improvement of the optical properties of electrodeposited CuInSe2 thin films by thermal and chemical treatments

Cu, In and Se have been codeposited in thin films by potentiostatic one-step electrodeposition. The as-deposited material has shown direct optical transitions attributable to the CuInSe₂ semiconductor, but also additional absorption corresponding to another semimetallic phase. The secondary phases are selenium and copper selenide compounds which have been determined by composition measurements. In order to eliminate the semimetallic phases and to improve the semiconductor behaviour of the electrodeposited material, thermal and chemical treatments have been performed. After heat-treatment of the samples at 400°C in flowing argon, elemental selenium loss has been detected together with an enhancement of the allowed direct optical transition. The subsequent chemical etching of the layers in a KCN solution has showed to be successful in eliminating the copper selenide phases which were responsible of the remaining sub-bandgap absorption.     

Structural Changes in EPDM Subjected to Ageing in High Voltage Transmission Lines

This work presents a study of the structural changes in aged EPDM (ethylene-propylene-diene monomer) from outdoor high voltage transmission lines. Samples were taken from failed and non-failed insulators after up to ten years in service on a 33 kV line. Infrared absorption, hydrophobicity index, dynamical mechanical analysis (DMA) and dielectric relaxation (DR) were employed as experimental techniques. The same experimental techniques were also applied to new samples of EPDM that were subjected to high electric fields (up to 14 kV/mm) for several hours. Results from DMA and DR techniques are in good agreement and, together with previous results from neutron irradiation techniques, suggest that the experimental data obtained from outdoor-aged and laboratory tested samples may be explained by a decrease in the degree of crystallinity due to the interaction between electrical and mechanical effects in the dielectric. The proposed model is based on the disentanglement of the crystallites by forces originated in the interaction of the electric field with the polar groups located in the amorphous phase of the polymer matrix. An alternative explanation, based on a relaxation process appearing at the interfaces between the filler (ATH) and the polymer matrix conflicts with several experimental results presented in this work.     

Dispersion characterization in layered double hydroxide/Nylon 66 nanocomposites using FIB imaging

Layered double hydroxides (LDHs), a newly emerging 2D host material, consist of cationic brucite-like layers and exchangeable interlayer anions. In this work, the morphology and dispersion of LDH particles in LDH/Nylon 66 (salt) nanocomposites has been investigated using focused ion beam (FIB) techniques, transmission electron microscopy (TEM) and X-ray diffraction (XRD). The FIB images show that LDHs are present in the polymer phase dispersed to different degrees, with partial intercalation, exfoliation, and aggregation all being observed. The most even dispersion was achieved in nanocomposites with the lowest loading (0.5 wt % LDH). Residual tactoids and agglomerates were most common in the samples made with the highest concentration of LDHs studied here (5 wt %). The dispersion observed using FIB was consistent with TEM and XRD analysis, yet this technique had significant benefits in terms of time and simplicity over these “conventional” technologies. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Thermodynamic compatibility of sepiolite-filled poly(vinylidene fluoride)-polystyrene blends

Summary Inverse gas chromatography (IGC) and differential scanning calorimetry (DSC) were used to investigate the effect produced by sepiolite on the thermodynamical compatibility of poly(vinylidene fluoride)-polystyrene blends. Polymer-polymer interaction parameters were calculated from the retention data, for various polar and non-polar probes in pure and mixed stationary phases of these polymers, using sepiolite as solid support, as well as from melting point depression analysis of the sepiolite filled blends. Both techniques give us positive values of the interaction parameters, in accordance with the non-compatibility of these blends; However negative values of the interaction parameters were obtained for polystyrene-rich blends (_PS 85 wt%) and high sepiolite loadings, indicating that sepiolite acts as a compatibilizing agent for the system PVF₂/PS.     

A New Tool to Study Parkinsonism in the Context of Aging: MPTP Intoxication in a Natural Model of Multimorbidity

The diurnal rodent Octodon degus (O. degus) is considered an attractive natural model for Alzheimer’s disease and other human age-related features. However, it has not been explored so far if the O. degus could be used as a model to study Parkinson’s disease. To test this idea, 10 adult male O. degus were divided into control group and MPTP-intoxicated animals. Motor condition and cognition were examined. Dopaminergic degeneration was studied in the ventral mesencephalon and in the striatum. Neuroinflammation was also evaluated in the ventral mesencephalon, in the striatum and in the dorsal hippocampus. MPTP animals showed significant alterations in motor activity and in visuospatial memory. Postmortem analysis revealed a significant decrease in the number of dopaminergic neurons in the ventral mesencephalon of MPTP animals, although no differences were found in their striatal terminals. We observed a significant increase in neuroinflammatory responses in the mesencephalon, in the striatum and in the hippocampus of MPTP-intoxicated animals. Additionally, changes in the subcellular expression of the calcium-binding protein S100β were found in the astrocytes in the nigrostriatal pathway. These findings prove for the first time that O. degus are sensitive to MPTP intoxication and, therefore, is a suitable model for experimental Parkinsonism in the context of aging.     

Genetic Contribution of Endometriosis to the Risk of Developing Hormone-Related Cancers

Endometriosis is a common gynecological disorder that has been associated with endometrial, breast and epithelial ovarian cancers in epidemiological studies. Since complex diseases are a result of multiple environmental and genetic factors, we hypothesized that the biological mechanism underlying their comorbidity might be explained, at least in part, by shared genetics. To assess their potential genetic relationship, we performed a two-sample mendelian randomization (2SMR) analysis on results from public genome-wide association studies (GWAS). This analysis confirmed previously reported genetic pleiotropy between endometriosis and endometrial cancer. We present robust evidence supporting a causal genetic association between endometriosis and ovarian cancer, particularly with the clear cell and endometrioid subtypes. Our study also identified genetic variants that could explain those associations, opening the door to further functional experiments. Overall, this work demonstrates the value of genomic analyses to support epidemiological data, and to identify targets of relevance in multiple disorders.     

Sensitive glasslike sol–gel materials suitable for environmental light sensors

New sol–gel based sensitive materials able to detect moderate doses of UV, Vis and near IR radiations have been designed, prepared and characterised. These glasslike detectors are respectively composed by four different sols of inorganic and hybrid organic–inorganic silica matrixes. The sols were prepared from alkoxide (TEOS) and alkylalkoxide (GLYMO) precursors with molar ratios 1:0, 1:1, 1:4 and 0:1, respectively. All the sols were doped with an organic photochromic dye (spiropyran). The detectors characterisation was carried out by means of exposures to natural light under different light intensities (100–3000 lx). The highest sensitivity against the light radiation was found for sols with molar ratio TEOS:GLYMO of 1:1. The time response of detectors is found at about 10 min and their life time is roughly 4 months at least. Moreover, the detectors show good optical reversibility. These sensitive glasslike materials have been designed to be applied for preservation of historical goods. They can detect and evaluate dangerous light doses for the proper conservation conditions of historical materials, which are sensitive or moderately sensitive against light radiation (<600 lx).     

A new graphical visualization of n-dimensional Pareto front for decision-making in multiobjective optimization

New challenges in engineering design lead to multiobjective (multicriteria) problems. In this context, the Pareto front supplies a set of solutions where the designer (decision-maker) has to look for the best choice according to his preferences. Visualization techniques often play a key role in helping decision-makers, but they have important restrictions for more than two-dimensional Pareto fronts. In this work, a new graphical representation, called Level Diagrams, for n-dimensional Pareto front analysis is proposed. Level Diagrams consists of representing each objective and design parameter on separate diagrams. This new technique is based on two key points: classification of Pareto front points according to their proximity to ideal points measured with a specific norm of normalized objectives (several norms can be used); and synchronization of objective and parameter diagrams. Some of the new possibilities for analyzing Pareto fronts are shown. Additionally, in order to introduce designer preferences, Level Diagrams can be coloured, so establishing a visual representation of preferences that can help the decision-maker. Finally, an example of a robust control design is presented - a benchmark proposed at the American Control Conference. This design is set as a six-dimensional multiobjective problem.