Could inhibition of metalloproteinases be used to block the process of metastasis?

Metastasis is a multisequential process that allows tumor cells to migrate to tissues distant from the primary tumor. Only a small number of cells escape from the primary tumor; however, the metastases generated are responsible for more than 90% of cancer deaths. Many metastatic processes initially require the total or partial start-up of a program for the transformation of tumor epithelial cells into mesenchymal cells (EMT). The launching of the EMT program is stimulated by cytokines and other elements produced by the diverse types of cells composing the tumor stroma. In parallel, a process of destabilization of the extracellular matrix (ECM) takes place by means of the synthesis of proteases of the matrix metalloproteinases (MMPs) family. EMC degradation allows the exportation of some tumor cells as mesenchymal cells to the circulatory system and their subsequent implantation in a tissue distant from the primary tumor. The blocking of these both processes appears as a hypothetical stop point in the metastatic mechanism. The present review deals with the different options to achieve the inhibition of MMPs, focusing on MMP7 as a target given its involvement in the metastatic processes of a wide variety of tumors.

Infrared Thermography for the Detection and Characterization of Photovoltaic Defects: Comparison between Illumination and Dark Conditions.

Newly installed renewable power capacity has been increasing incredibly in recent years. For example, in 2018, 181 GW were installed worldwide. In this scenario, in which photovoltaic (PV) energy plays a leading role, it is essential for main players involved in PV plants to be able to identify the failure modes in PV modules in order to reduce investment risk, to focus their maintenance efforts on preventing those failures and to improve longevity and performance of PV plants. Among the different systems for defects detection, conventional infrared thermography (IRT) is the fastest and least expensive technique. It can be applied in illumination and in dark conditions, both indoor and outdoor. These two methods can provide complementary results for the same kind of defects, which is analyzed and characterized in this research. Novel investigation in PV systems propose the use of a power inverter with bidirectional power flow capability for PV plants maintenance, which extremely facilitates the electroluminescence (EL) inspections, as well as the outdoor IRT in the fourth quadrant.

3DBIONOTES v2.0: a web server for the automatic annotation of macromolecular structures.

MOTIVATION: Complementing structural information with biochemical and biomedical annotations is a powerful approach to explore the biological function of macromolecular complexes. However, currently the compilation of annotations and structural data is a feature only available for those structures that have been released as entries to the Protein Data Bank. RESULTS: To help researchers in assessing the consistency between structures and biological annotations for structural models not deposited in databases, we present 3DBIONOTES v2.0, a web application designed for the automatic annotation of biochemical and biomedical information onto macromolecular structural models determined by any experimental or computational technique. AVAILABILITY AND IMPLEMENTATION: The web server is available at http://3dbionotes-ws.cnb.csic.es. CONTACT: jsegura@cnb.csic.es. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

ScipionCloud: An integrative and interactive gateway for large scale cryo electron microscopy image processing on commercial and academic clouds.

New instrumentation for cryo electron microscopy (cryoEM) has significantly increased data collection rate as well as data quality, creating bottlenecks at the image processing level. Current image processing model of moving the acquired images from the data source (electron microscope) to desktops or local clusters for processing is encountering many practical limitations. However, computing may also take place in distributed and decentralized environments. In this way, cloud is a new form of accessing computing and storage resources on demand. Here, we evaluate on how this new computational paradigm can be effectively used by extending our current integrative framework for image processing, creating ScipionCloud. This new development has resulted in a full installation of Scipion both in public and private clouds, accessible as public "images", with all the required preinstalled cryoEM software, just requiring a Web browser to access all Graphical User Interfaces. We have profiled the performance of different configurations on Amazon Web Services and the European Federated Cloud, always on architectures incorporating GPU's, and compared them with a local facility. We have also analyzed the economical convenience of different scenarios, so cryoEM scientists have a clearer picture of the setup that is best suited for their needs and budgets.

3DIANA: 3D Domain Interaction Analysis: A Toolbox for Quaternary Structure Modeling.

Electron microscopy (EM) is experiencing a revolution with the advent of a new generation of Direct Electron Detectors, enabling a broad range of large and flexible structures to be resolved well below 1 nm resolution. Although EM techniques are evolving to the point of directly obtaining structural data at near-atomic resolution, for many molecules the attainable resolution might not be enough to propose high-resolution structural models. However, accessing information on atomic coordinates is a necessary step toward a deeper understanding of the molecular mechanisms that allow proteins to perform specific tasks. For that reason, methods for the integration of EM three-dimensional maps with x-ray and NMR structural data are being developed, a modeling task that is normally referred to as fitting, resulting in the so called hybrid models. In this work, we present a novel application-3DIANA-specially targeted to those cases in which the EM map resolution is medium or low and additional experimental structural information is scarce or even lacking. In this way, 3DIANA statistically evaluates proposed/potential contacts between protein domains, presents a complete catalog of both structurally resolved and predicted interacting regions involving these domains and, finally, suggests structural templates to model the interaction between them. The evaluation of the proposed interactions is computed with DIMERO, a new method that scores physical binding sites based on the topology of protein interaction networks, which has recently shown the capability to increase by 200% the number of domain-domain interactions predicted in interactomes as compared to previous approaches. The new application displays the information at a sequence and structural level and is accessible through a web browser or as a Chimera plugin at http://3diana.cnb.csic.es.

Using neighborhood cohesiveness to infer interactions between protein domains.

MOTIVATION: In recent years, large-scale studies have been undertaken to describe, at least partially, protein-protein interaction maps, or interactomes, for a number of relevant organisms, including human. However, current interactomes provide a somehow limited picture of the molecular details involving protein interactions, mostly because essential experimental information, especially structural data, is lacking. Indeed, the gap between structural and interactomics information is enlarging and thus, for most interactions, key experimental information is missing. We elaborate on the observation that many interactions between proteins involve a pair of their constituent domains and, thus, the knowledge of how protein domains interact adds very significant information to any interactomic analysis. RESULTS: In this work, we describe a novel use of the neighborhood cohesiveness property to infer interactions between protein domains given a protein interaction network. We have shown that some clustering coefficients can be extended to measure a degree of cohesiveness between two sets of nodes within a network. Specifically, we used the meet/min coefficient to measure the proportion of interacting nodes between two sets of nodes and the fraction of common neighbors. This approach extends previous works where homolog coefficients were first defined around network nodes and later around edges. The proposed approach substantially increases both the number of predicted domain-domain interactions as well as its accuracy as compared with current methods.

Design, Manufacturing and Acoustic Assessment of Polymer Mouthpieces for Trombones.

Brass instruments mouthpieces have been historically built using metal materials, usually brass. With the auge of additive manufacturing technologies new possibilities have arisen, both for testing alternative designs and for using new materials. This work assesses the use of polymers for manufacturing trombone mouthpieces, specifically PLA and Nylon. The acoustical behavior of these two mouthpieces has been compared with the obtained from a third one, built from brass. Both additive and subtractive manufacturing techniques were used, and the whole manufacturing process is described. The mouthpieces were acoustically assessed in an anechoic chamber with the collaboration of a professional performer. The harmonic analysis confirmed that all the manufactured mouthpieces respect the harmonic behavior of the instrument. An energy analysis of the harmonics revealed slight differences between the mouthpieces, which implies differences in the timbre of the instrument. Although these subtle differences would not be acceptable when performing with the instrument in an orchestra, they could be perfectly valid for early learners, personal rehearsals or any kind of alternative performance.

Image formation in cellular X-ray microscopy.

Soft X-ray Tomographic (TomoX) microscopy has become a reality in the last years. The resolution range of this technique nicely fits between confocal and electron microscopies and will play a key role in the elucidation of the organization between the molecular and the organelle levels. In fact, it offers the possibility of imaging three-dimensional structures of hydrated biological specimens near their native state without chemical pre-treatment. Ideally, TomoX reconstructs the specimen absorption coefficients from projections of this specimen, but, unfortunately, X-ray micrographs are only an approximation to projections of the specimen, resulting in inaccuracies if a tomographic reconstruction is performed without explicitly incorporating these approximations. In an attempt to mitigate some of these inaccuracies, we develop in this work an image formation model within the approximation of assuming incoherent illumination.

Characterization of CaCO3 Filled Poly(lactic) Acid and Bio Polyethylene Materials for Building Applications.

Noise pollution has been identified as a cause of a broad spectrum of diseases, motivating researchers to identify building materials capable of attenuating this pollution. The most common solution is the use of gypsum boards, which show a good response for low frequencies but have a poorer response for high frequencies. In addition, due to environmental concerns associated with buildings, the use of materials that minimize environmental impacts must be favored. In this research, two biopolymers, a poly(lactic) acid and a bio-polyethylene, were filled with two typologies of calcium carbonate, and their soundproofing properties were tested using impedance tubes. In addition, the morphology of the fillers was characterized, and here we discuss its impact on the mechanical properties of the composites. The results showed that the incorporation of calcium carbonate into bio-based thermoplastic materials can represent a strong alternative to gypsum, because their mechanical properties and sound barrier performance are superior. In addition, the inclusion of mineral fillers in thermoplastic materials has a positive impact on production costs, in addition to preserving the advantages of thermoplastics in terms of processing and recycling. Although the use of carbonate calcium decreases the mechanical properties of the materials, it enables the production of materials with insulation that is four-fold higher than that of gypsum. This demonstrates the potential of these materials as building lightweight solutions.

Life-Cycle Assessment and Acoustic Simulation of Drywall Building Partitions with Bio-Based Materials.

The ecological transition is a process the building industry is bound to undertake. This study aimed to develop new bio-based building partition typologies and to determine if they are suitable ecological alternatives to the conventional non-renewable ones used today. This work started with the development of a bio-based epoxy composite board and a waste-based sheep wool acoustic absorbent. Six different partition typologies combining conventional and bio-based materials were analyzed. A drywall partition composed of gypsum plasterboard and mineral wool was used as the baseline. First, a cradle-to-gate life cycle assessment was performed to compare their environmental impacts. Secondly, a mathematical simulation was performed to evaluate their airborne acoustic insulation. The LCA results show a 50% decrease in the amount of CO2 equivalent emitted when replacing plasterboard with bio-composite boards. The bio-composites lower the overall environmental impact by 40%. In the case of the acoustic absorbents, replacing the mineral wool with cellulose or sheep wool decreases the carbon emissions and the overall environmental impact of the partition from 4% and 6%, respectively. However, while the bio-based acoustic absorbents used offer good acoustic results, the bio-composites have a lower airborne acoustic insulation than conventional gypsum plasterboard.

Scipion web tools: Easy to use cryo-EM image processing over the web.

Macromolecular structural determination by Electron Microscopy under cryogenic conditions is revolutionizing the field of structural biology, interesting a large community of potential users. Still, the path from raw images to density maps is complex, and sophisticated image processing suites are required in this process, often demanding the installation and understanding of different software packages. Here, we present Scipion Web Tools, a web-based set of tools/workflows derived from the Scipion image processing framework, specially tailored to nonexpert users in need of very precise answers at several key stages of the structural elucidation process.

Characterization of Sheep Wool as a Sustainable Material for Acoustic Applications.

In recent years, natural materials are becoming a valid alternative to traditional sound absorbers due to reduced production costs and environmental protection. This paper reports the acoustical characterization of sheep wool. Measurements on normal incidence and diffuse-incidence sound absorption coefficients of different samples are reported. The airflow resistance has also been measured. The results prove that sheep wool has a comparable sound absorption performance to that of mineral wool or recycled polyurethane foam. An empirical model is used to calculate the sound absorption of sheep wool samples. A reasonable agreement on the acoustic absorption of all sheep wool samples is obtained.

Effect of Sodium Hydroxide Treatments on the Tensile Strength and the Interphase Quality of Hemp Core Fiber-Reinforced Polypropylene Composites.

The formulation of greener composite materials by substituting glass fibers with natural fibers is a current field of research. If such natural fiber reinforcements come from industrial side streams, as hemp core fibers (HCFs) come from the extraction of hemp strands for the textile industry, an additional advantage can be identified. Nonetheless, such by-product fibers show some drawbacks, such as high lignin contents, which can make it difficult to obtain a good interphase between the fibers and the matrix and to obtain a good fiber individualization. A digestion treatment at different NaOH contents is proposed to eliminate soluble lignin and extractives from the surface of the fibers. At the same time, the use of a coupling agent solves incompatibilities between the fibers and the matrix. The composites were tensile tested and the impact of the proposed treatments is evaluated and discussed. Later, the Kelly-Tyson modified equation and a modified rule of mixtures-the micro-mechanic models-is used to study the impact of such treatments on the quality of the interphase between the polymer and the reinforcement. Both treatments showed a high impact on the tensile strength and the quality of the interphase, obtaining competitive composite materials reinforced with HCFs derived from a by-product.

HER2 status determination using RNA-ISH--a rapid and simple technique showing high correlation with FISH and IHC in 141 cases of breast cancer.

AIMS: the assessment of the human epidermic growth factor receptor 2 (HER2) is currently performed in most laboratories using two techniques: Fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC), and novel methodology is being investigated continuously in the assessment of HER2, such as SISH, CISH, DNA chips, ELISA or real time PCR to make assessment easier, faster or more accurate. RNA-ISH (RNA in Situ Hybridisation) is a new technique designed to detect mRNA expression levels, conducted by light microscope without the need for counting or grading systems in a total processing time of 4 hours. This study aims to determine if RNA-ISH is a viable and effective technique and a possible alternative to the currently used techniques by analysing and comparing genetic amplification (FISH) and protein levels (IHC) with mRNA over-expression (RNA-ISH) in 141 cases of breast cancer. RESULTS: This study demonstrated a 96.5% concordance between over-expression of HER2 as determined by RNA-ISH and gene amplification as determined by FISH. The relationship between RNA-ISH-evaluated and IHC-evaluated over-expression was equally well reflected with a 95.2% concordance. Importantly, a considerable reduction in processing and evaluation time was achieved of only 4 hours. CONCLUSIONS: We conclude that the probe developed for RNA-ISH represents a viable, effective possible alternative to FISH and IHC for analysing HER2 status in primary breast tumours.

CIGB-247: a VEGF-based therapeutic vaccine that reduces experimental and spontaneous lung metastasis of C57Bl/6 and BALB/c mouse tumors.

CIGB-247 is a novel cancer therapeutic vaccine that uses a mutated form of human VEGF as antigen. Being metastatic disease the most dramatic factor of tumor biology affecting patient survival and cure, preclinical evaluation of the impact of CIGB-247 vaccination on experimental metastasis mouse models is highly relevant, and constitutes the focus of this work. CIGB-247 was administered in a weekly schedule known to effectively reduce primary tumor growth. The vaccine was tested in experimental and spontaneous metastasis models of colon (CT26), lung (3LL-D122) and breast (F3II) carcinomas growing in C57Bl/6 or BALB/c mice. Primary tumor growth parameters, metastatic counts, and/or animal survival were recorded. Histology and specific humoral and cellular responses to the vaccine were evaluated. As compared to control groups, CIGB-247 vaccination significantly reduced the number and size of metastatic tumor foci in lungs after intravenous inoculation of CT26 and 3LL-D122 tumor cells. Spontaneous lung dissemination from 3LL-D122 and F3II breast tumor cells implanted in the footpad, or subcutaneously, was also reduced by immunization with CIGB-247. The vaccine elicited in both mouse strains antibodies specific for human and murine VEGF that effectively blocked the interaction of VEGF with VEGF receptor 2. Differing from other experimental reports that describe the use of VEGF for active tumor immunotherapy, CIGB-247 elicited a specific cellular response, measured both by a DTH increment and the induction of spleen cells cytotoxic to syngeneic tumor cells producing murine VEGF. In summary our results reinforce the potential of CIGB-247 vaccination to reduce both tumor growth and the number and size of tumor metastasis in lungs, the latter both after direct inoculations of cells in the blood stream, or as part of primary tumor progression in immunocompetent mice.

Immunogenicity and some safety features of a VEGF-based cancer therapeutic vaccine in rats, rabbits and non-human primates.

We have developed a cancer vaccine candidate (hereafter denominated CIGB-247), based on recombinant modified human vascular endothelial growth factor (VEGF) as antigen, and the adjuvant VSSP (very small sized proteoliposomes of Neisseria meningitidis outer membrane). In mice, previous work of our group had shown that vaccination with CIGB-247 extended tumor-take time, slowed tumor growth, and increased animal survival. Immunization elicited anti-human and murine VEGF-neutralizing antibodies, and spleen cells of vaccinated mice are cytotoxic in vitro to tumor cells that produce VEGF. We have now tested the immunogenicity of CIGB-247 in Wistar rats, New Zealand White rabbits and the non-human primate Chlorocebus aethiops sabaeus. Using weekly, biweekly and biweekly plus montanide immunization schemes, all three species develop antigen-specific IgG antibodies that can block the interaction of VEGF and VEGF receptor 2 in an ELISA assay. Antibody titers decline after vaccination stops, but can be boosted with new immunizations. In monkeys, DTH and direct cell cytotoxicity experiments suggest that specific T-cell responses are elicited by vaccination. Immunization with CIGB-247 had no effect on normal behavior, hematology, blood biochemistry and histology of critical organs, in the tested animals. Skin deep wound healing was not affected in vaccinated rats and monkeys.

Engene: the processing and exploratory analysis of gene expression data.

Engene is a versatile, and platform-independent web tool for exploratory analysis of gene expression data that aims at storing, visualizing and processing large sets of gene expression patterns.