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.     

In Vitro and In Vivo Modeling of Normal and Leukemic Bone Marrow Niches: Cellular Senescence Contribution to Leukemia Induction and Progression

Cellular senescence is recognized as a dynamic process in which cells evolve and adapt in a context dependent manner; consequently, senescent cells can exert both beneficial and deleterious effects on their surroundings. Specifically, senescent mesenchymal stromal cells (MSC) in the bone marrow (BM) have been linked to the generation of a supporting microenvironment that enhances malignant cell survival. However, the study of MSC’s senescence role in leukemia development has been straitened not only by the availability of suitable models that faithfully reflect the structural complexity and biological diversity of the events triggered in the BM, but also by the lack of a universal, standardized method to measure senescence. Despite these constraints, two- and three dimensional in vitro models have been continuously improved in terms of cell culture techniques, support materials and analysis methods; in addition, research on animal models tends to focus on the development of techniques that allow tracking leukemic and senescent cells in the living organism, as well as to modify the available mice strains to generate individuals that mimic human BM characteristics. Here, we present the main advances in leukemic niche modeling, discussing advantages and limitations of the different systems, focusing on the contribution of senescent MSC to leukemia progression.     

Parametric study of an efficient renewable power-to-substitute-natural-gas process including high-temperature steam electrolysis

Power-to-Substitute Natural Gas processes are investigated to offer solutions for renewable energy storing or transportation. In the present study, an original Power-to-SNG process combining high-temperature steam electrolysis and CO₂ methanation is implemented and simulated. A reference process is firstly defined, including a specific modelling approach of the electrolysis and a methanation modelling including a kinetic law. The process also integrates a unit to clean the gas from residual CO₂, H₂ and H₂O for gas network injection. Having set all the units, simulations are performed with ProsimPlus 3™ software for a reference case where the electrolyser and the methanation reactors are designed. The reference case allows to produce 67.5 Nm³/h of SNG with an electrical energy consumption of 14.4 kW h/Nm³. The produced SNG satisfies specifications required for network injection. From this reference process, two sensitivity analyses on electrolysis and methanation working points and on external parameters and constraints are considered. As a main result, we observe that the reference case maximises both process efficiency and SNG production when compared with other studied cases.     

Designed amyloid beta peptide fibril - a tool for high-throughput screening of fibril inhibitors

Amyloid beta peptide (Abeta) fibril formation is widely believed to be the causative event of Alzheimer's disease pathogenesis. Therapeutic approaches are therefore in development that target various sites in the production and aggregation of Abeta. Herein we present a high-throughput screening tool to generate novel hit compounds that block Abeta fibril formation. This tool is an application for our fibril model (Abeta(16-37)Y(20)K(22)K(24))(4), which is a covalent assembly of four Abeta fragments. With this tool, screening studies are complete within one hour, as opposed to days with native Abeta(1-40). A Z' factor of 0.84+/-0.03 was determined for fibril formation and inhibition, followed by the reporter molecule thioflavin T. Herein we also describe the analysis of a broad range of reported inhibitors and non-inhibitors of Abeta fibril formation to test the validity of the system.     

The Interaction between Chondroitin Sulfate and Dermatan Sulfate Tetrasaccharides and Pleiotrophin

Pleiotrophin (PTN) is a neurotrophic factor that participates in the development of the embryonic central nervous system (CNS) and neural stem cell regulation by means of an interaction with sulfated glycosaminoglycans (GAGs). Chondroitin sulfate (CS) is the natural ligand in the CNS. We have previously studied the complexes between the tetrasaccharides used here and MK (Midkine) by ligand-observed NMR techniques. The present work describes the interactions between a tetrasaccharide library of synthetic models of CS-types and mimetics thereof with PTN using the same NMR transient techniques. We have concluded that: (1) global ligand structures do not change upon binding, (2) the introduction of lipophilic substituents in the structure of the ligand improves the strength of binding, (3) binding is weaker than for MK, (4) STD-NMR results are compatible with multiple binding modes, and (5) the replacement of GlcA for IdoA is not relevant for binding. Then we can conclude that the binding of CS derivatives to PTN and MK are similar and compatible with multiple binding modes of the same basic conformation.     

Influence of phosphorylated rice flour on the quality of gluten‐free bread

The chemical modification of rice flour by phosphorylation is an alternative to improve the technological quality of bakery products. The aim of this study was to investigate the effect of phosphorylation process of rice flour on technological properties (specific volume, crumb and crust colour) of gluten‐free breads and the hardening of these breads during two storage temperatures (21 °C and ?24 °C). Breads were made with native rice flour, with phosphorylated rice flour and with wheat flour, used as control. The phosphorylation causes significant reduction in the synaeresis of pastes and in retrogradation tendency of rice flours, varying from 258.7 cP (native rice flour) to 122 cP (phosphorylated rice flour). The breads prepared with phosphorylated rice flour showed reduction in the hardness in both storage temperatures studied and effect on rice bread volume, crumb appearance and colour, demonstrating the possibility of use of the phosphorylated rice flour in gluten‐free breads.     

Comfort of workers in office buildings: The European HOPE project

Previous studies have shown that building, social and personal factors can influence one’s perceived health and comfort. The aim of the underlying study was to get a better understanding of the relationships between these factors and perceived comfort. Self-administered questionnaires from 5732 respondents in 59 office buildings and building-specific data from the European Health Optimisation Protocol for Energy-efficient buildings (HOPE) study were used. Principal Component Analysis (PCA), reliability analyses, and linear regression analysis were performed. The outcome showed that perceived comfort is strongly influenced by several personal, social and building factors and that their relationships are complex. Results showed that perceived comfort is much more than the average of perceived indoor air quality, noise, lighting and thermal comfort responses. Perceived comfort is a phenomenon that deserves more research.     

Solid/Liquid Separation of Pig Manure by Biological Flotation: Pilot-Scale Study

Many problems are associated with pig manure production like high biochemical oxygen demand, chemical oxygen demand, nitrogen, and phosphorus contents. Manure produces may be used in land spreading for agricultural purposes. Over application of liquid manure or runoff caused by precipitation contribute notably to surface or overland flow of phosphorus. In this study, the LISOX process is proposed for use in medium size farms, namely a 2,000-head swine farm. The LISOX process uses biological passive flotation, without any gas addition, to enable the flocs to rise to the surface. Results show that this technology is able to considerably reduce the solids content in the final effluent to 1.1±0.3% and reached solids content of 17.9±2.6% in the combined solid manure obtained at the end of the LISOX process. Total phosphorus (Pt) concentrations have been reduced from 1,234±428?mg/L to 146±46?mg/L in the final effluent, while a value of Pt of 20.6±7.9?g/kg has been obtained in the final solid fraction of the treated manure. The initial ammonium ion/total phosphorus ratio of 2.3±1.0 has been increased to respectively 16.4±4.6 and 17.6±5.4 after the primary and the secondary flotation, which is clearly much higher than the target value (NH4/Pt>7).