Integrating differential expression, co-expression and gene network analysis for the identification of common genes associated with tumor angiogenesis deregulation.

Angiogenesis is essential for tumor growth and cancer metastasis. Identifying the molecular pathways involved in this process is the first step in the rational design of new therapeutic strategies to improve cancer treatment. In recent years, RNA-seq data analysis has helped to determine the genetic and molecular factors associated with different types of cancer. In this work we performed integrative analysis using RNA-seq data from human umbilical vein endothelial cells (HUVEC) and patients with angiogenesis-dependent diseases to find genes that serve as potential candidates to improve the prognosis of tumor angiogenesis deregulation and understand how this process is orchestrated at the genetic and molecular level. We downloaded four RNA-seq datasets (including cellular models of tumor angiogenesis and ischaemic heart disease) from the Sequence Read Archive. Our integrative analysis includes a first step to determine differentially and co-expressed genes. For this, we used the ExpHunter Suite, an R package that performs differential expression, co-expression and functional analysis of RNA-seq data. We used both differentially and co-expressed genes to explore the human gene interaction network and determine which genes were found in the different datasets that may be key for the angiogenesis deregulation. Finally, we performed drug repositioning analysis to find potential targets related to angiogenesis inhibition. We found that that among the transcriptional alterations identified, SEMA3D and IL33 genes are deregulated in all datasets. Microenvironment remodeling, cell cycle, lipid metabolism and vesicular transport are the main molecular pathways affected. In addition to this, interacting genes are involved in intracellular signaling pathways, especially in immune system and semaphorins, respiratory electron transport and fatty acid metabolism. The methodology presented here can be used for finding common transcriptional alterations in other genetically-based diseases.

A Proteomic Study of the Bioactivity of Annona muricata Leaf Extracts in HT-1080 Fibrosarcoma Cells.

Graviola (Annona muricata) is a tropical plant with many traditional ethnobotanic uses and pharmacologic applications. A metabolomic study of both aqueous and DMSO extracts from Annona muricata leaves recently allowed us to identify dozens of bioactive compounds. In the present study, we use a proteomic approach to detect altered patterns in proteins on both conditioned media and extracts of HT-1080 fibrosarcoma cells under treatment conditions, revealing new potential bioactivities of Annona muricata extracts. Our results reveal the complete sets of deregulated proteins after treatment with aqueous and DMSO extracts from Annona muricata leaves. Functional enrichment analysis of proteomic data suggests deregulation of cell cycle and iron metabolism, which are experimentally validated in vitro. Additional experimental data reveal that DMSO extracts protect HT-1080 fibrosarcoma cells and HMEC-1 endothelial cells from ferroptosis. Data from our proteomic study are available via ProteomeXchange with identifier PXD042354.

The impact of the first millennial teachers on education: views held by different generations of teachers.

The first people considered digital natives, the millennials, have already entered the teaching profession. As a result, we are faced with a remarkable generational diversity. This survey aimed to explore the generational change in teachers and the beginning of the incorporation of the first millennials (digital natives) into teaching. It was carried out through a qualitative study using focus groups and interviews with a total of 147 teachers. The main results found establish a generational clash between migrants and digital natives. This difference is present in the use and understanding of ICTs in the teaching task across the different teaching generations and in a generational diversity within the educational centres that has not been seen so far. However, this difference between teachers is also a condition that facilitates exchange between teachers of different generations. Junior teachers help veteran teachers in the use of ICTs and veteran teachers provide the expertise that new recruits lack.

Metabolic Reprogramming is a Hallmark of Metabolism Itself.

The reprogramming of metabolism has been identified as one of the hallmarks of cancer. It is becoming more and more frequent to connect other diseases with metabolic reprogramming. This article aims to argue that metabolic reprogramming is not driven by disease but instead is the main hallmark of metabolism, based on its dynamic behavior that allows it to continuously adapt to changes in the internal and external conditions.

The Sponge-Derived Brominated Compound Aeroplysinin-1 Impairs the Endothelial Inflammatory Response through Inhibition of the NF-κB Pathway.

(+)-Aeroplysinin-1 (Apl-1) is a brominated compound isolated from the marine sponge Aplysina aerophoba that exhibits pleiotropic bioactive effects, impairing cell growth in cancer cells, inhibiting angiogenesis in vitro and in vivo and modulating the redox status of different cell types, among other reported activities. In addition to the aforementioned effects, the anti-inflammatory potential of this natural compound was explored in previous work of our laboratory, but the mechanism of action underlying this effect was not described. In this work, we delve into the anti-inflammatory effect of Apl-1 in the context of vascular endothelial cells in vitro, providing new data regarding the molecular mechanism underlying this activity. The characterization of the mechanism of action points to an inhibitory effect of Apl-1 on the NF-κB pathway, one of the main axes involved in endothelial response during inflammatory events. Our results show that Apl-1 can inhibit the expression of pro-inflammatory genes in tumor necrosis factor alpha (TNF-α)- and lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), targeting the nuclear factor kappa B subunit (NF-κB) pathway through a mechanism of action involving the inhibition of I kappa B kinase (IKK) complex phosphorylation and RelA/p65 nuclear import. In addition, Apl-1 prevented the phosphorylation of Akt induced by TNF-α in HUVECs, probably supporting the inhibitory effect of this compound in the NF-κB pathway. Experimental evidence reported in this work opens the door to the potential pharmacological use of this compound as an anti-inflammatory agent in diseases that course with a pathological endothelial response to inflammation, such as atherosclerosis.

Design and Development of a Heterogeneous Active Assisted Living Solution for Monitoring and Following Up with Chronic Heart Failure Patients in Spain.

Heart failure is the most common disease among elderly people, and the risk increases with age. The use of smart Internet of Things (IoT) systems for monitoring patients with chronic heart failure (CHF) in a non-intrusive manner can result in better control of the disease, improving proactive healthcare through real-time and historical patient's data, promoting self-care in patients, reducing unneeded interaction between patients and doctors, reducing the number of hospitalizations and saving healthcare costs. This work presents an active assisted living (AAL) solution based on the IoT to provide a tele-assistance platform for CHF patients from the public health service of the region of Murcia in Spain, with formal and informal caregivers and health professionals also as key actors. In this article, we have detailed the methodology, results, and conclusions of the prevalidation phase for the set of IoT technologies to be integrated in the AAL platform, the first mandatory step before the deployment of a large-scale pilot that will lead to improving the innovation of the system from its current technology readiness level to the market. The work presented, in the framework of the H2020 Pharaon project, aims to serve as inspiration to the R&D community for the design, development, and deployment of AAL solutions based on heterogeneous IoT technologies, or similar approaches, for smart healthcare solutions in real healthcare institutions.

The Immunomodulator Dimethyl Itaconate Inhibits Several Key Steps of Angiogenesis in Cultured Endothelial Cells.

The dimethyl derivative of the immunomodulator itaconate has been previously shown to have anti-inflammatory, anti-oxidative, and immunomodulatory effects. In the present work, we evaluate the potential of dimethyl itaconate as an anti-angiogenic compound by using cultured endothelial cells and several in vitro assays that simulate key steps of the angiogenic process, including endothelial cell proliferation, migration, invasion, and tube formation. Our results show that dimethyl itaconate interferes with all the previously mentioned steps of the angiogenic process, suggesting that dimethyl itaconate behaves as an anti-angiogenic compound.

Turning around Cycles: An Approach Based on Selected Problems/Cases to Stimulate Collaborative Learning about Krebs and His Four Metabolic Cycles.

Metabolism is a challenging subject for bioscience students due to the intrinsic complexity of the metabolic network, as well as that of the overlapping mechanisms of metabolic regulation. Collaborative learning based on a problem-based learning approach can help students to successfully learn and understand metabolism. In the present article, we propose a selection of exercises, problems, and cases aimed to focus students' attention on the scientific work made by Sir Hans Krebs and his collaborators to elucidate four main metabolic cycles, as well as on the study of these cycles, their regulation, and their metabolic integration. The objectives, the tools, and the implementation of this proposal are described, and the results obtained during its first implementation with volunteer students enrolled in two courses on metabolic regulation at our university are presented and discussed. These volunteer students signed a learning contract and were randomly distributed in small groups (3-4 students each). Application of this collaborative learning activity to our classrooms has been very satisfactory, as evidenced by an improvement in the volunteers' academic performance and a very positive perception by most of them, who declared to be "very satisfied" or "satisfied" with their experience and felt that they had learned more.

Polyamines in mammalian pathophysiology.

Polyamines (PAs) are essential organic polycations for cell viability along the whole phylogenetic scale. In mammals, they are involved in the most important physiological processes: cell proliferation and viability, nutrition, fertility, as well as nervous and immune systems. Consequently, altered polyamine metabolism is involved in a series of pathologies. Due to their pathophysiological importance, PA metabolism has evolved to be a very robust metabolic module, interconnected with the other essential metabolic modules for gene expression and cell proliferation/differentiation. Two different PA sources exist for animals: PA coming from diet and endogenous synthesis. In the first section of this work, the molecular characteristics of PAs are presented as determinant of their roles in living organisms. In a second section, the metabolic specificities of mammalian PA metabolism are reviewed, as well as some obscure aspects on it. This second section includes information on mammalian cell/tissue-dependent PA-related gene expression and information on crosstalk with the other mammalian metabolic modules. The third section presents a synthesis of the physiological processes described as modulated by PAs in humans and/or experimental animal models, the molecular bases of these regulatory mechanisms known so far, as well as the most important gaps of information, which explain why knowledge around the specific roles of PAs in human physiology is still considered a "mysterious" subject. In spite of its robustness, PA metabolism can be altered under different exogenous and/or endogenous circumstances so leading to the loss of homeostasis and, therefore, to the promotion of a pathology. The available information will be summarized in the fourth section of this review. The different sections of this review also point out the lesser-known aspects of the topic. Finally, future prospects to advance on these still obscure gaps of knowledge on the roles on PAs on human physiopathology are discussed.

Metabolism within the tumor microenvironment and its implication on cancer progression: An ongoing therapeutic target.

Since reprogramming energy metabolism is considered a new hallmark of cancer, tumor metabolism is again in the spotlight of cancer research. Many studies have been carried out and many possible therapies have been developed in the last years. However, tumor cells are not alone. A series of extracellular components and stromal cells, such as endothelial cells, cancer-associated fibroblasts, tumor-associated macrophages, and tumor-infiltrating T cells, surround tumor cells in the so-called tumor microenvironment (TME). Metabolic features of these cells are being studied in deep in order to find relationships between metabolism within the TME and tumor progression. Moreover, it cannot be forgotten that tumor growth is able to modulate host metabolism and homeostasis, so that TME is not the whole story. Importantly, the metabolic switch in cancer is just a consequence of the flexibility and adaptability of metabolism and should not be surprising. Treatments of cancer patients with combined therapies including antitumor agents with those targeting stromal cell metabolism, antiangiogenic drugs, and/or immunotherapy are being developed as promising therapeutics.

Exploring the Antiangiogenic Potential of Solomonamide A Bioactive Precursors: In Vitro and in Vivo Evidences of the Inhibitory Activity of Solo F-OH During Angiogenesis.

Marine sponges are a prolific source of bioactive compounds. In this work, the putative antiangiogenic potential of a series of synthetic precursors of Solomonamide A, a cyclic peptide isolated from a marine sponge, was evaluated. By means of an in vitro screening, based on the inhibitory activity of endothelial tube formation, the compound Solo F-OH was selected for a deeper characterization of its antiangiogenic potential. Our results indicate that Solo F-OH is able to inhibit some key steps of the angiogenic process, including the proliferation, migration, and invasion of endothelial cells, as well as diminish their capability to degrade the extracellular matrix proteins. The antiangiogenic potential of Solo F-OH was confirmed by means of two different in vivo models: the chorioallantoic membrane (CAM) and the zebrafish yolk membrane (ZFYM) assays. The reduction in ERK1/2 and Akt phosphorylation in endothelial cells treated with Solo F-OH denotes that this compound could target the upstream components that are common to both pathways. Taken together, our results show a new and interesting biological activity of Solo F-OH as an inhibitor of the persistent and deregulated angiogenesis that characterizes cancer and other pathologies.

Synthesis and Antitumor Activity Evaluation of Compounds Based on Toluquinol.

Encouraged by the promising antitumoral, antiangiogenic, and antilymphangiogenic properties of toluquinol, a set of analogues of this natural product of marine origin was synthesized to explore and evaluate the effects of structural modifications on their cytotoxic activity. We decided to investigate the effects of the substitution of the methyl group by other groups, the introduction of a second substituent, the relative position of the substituents, and the oxidation state. A set of analogues of 2-substituted, 2,3-disubstituted, and 2,6-disubstituted derived from hydroquinone were synthesized. The results revealed that the cytotoxic activity of this family of compounds could rely on the hydroquinone/benzoquinone part of the molecule, whereas the substituents might modulate the interaction of the molecule with their targets, changing either its activity or its selectivity. The methyl group is relevant for the cytotoxicity of toluquinol, since its replacement by other groups resulted in a significant loss of activity, and in general the introduction of a second substituent, preferentially in the para position with respect to the methyl group, was well tolerated. These findings provide guidance for the design of new toluquinol analogues with potentially better pharmacological properties.

Activity Recognition for IoT Devices Using Fuzzy Spatio-Temporal Features as Environmental Sensor Fusion.

The IoT describes a development field where new approaches and trends are in constant change. In this scenario, new devices and sensors are offering higher precision in everyday life in an increasingly less invasive way. In this work, we propose the use of spatial-temporal features by means of fuzzy logic as a general descriptor for heterogeneous sensors. This fuzzy sensor representation is highly efficient and enables devices with low computing power to develop learning and evaluation tasks in activity recognition using light and efficient classifiers. To show the methodology's potential in real applications, we deploy an intelligent environment where new UWB location devices, inertial objects, wearable devices, and binary sensors are connected with each other and describe daily human activities. We then apply the proposed fuzzy logic-based methodology to obtain spatial-temporal features to fuse the data from the heterogeneous sensor devices. A case study developed in the UJAmISmart Lab of the University of Jaen (Jaen, Spain) shows the encouraging performance of the methodology when recognizing the activity of an inhabitant using efficient classifiers.

(+)-Aeroplysinin-1 Modulates the Redox Balance of Endothelial Cells.

The bioactive natural compound from marine origin, (+)-aeroplysinin-1, has been shown to exhibit potent anti-inflammatory and anti-angiogenic effects. The aim of the present study was to identify new targets for (+)-aeroplysinin-1 in endothelial cells. The sequential use of 2D-electrophoresis and MALDI-TOF-TOF/MS allowed us to identify several differentially expressed proteins. Four of these proteins were involved in redox processes and were validated by Western blot. The effects of (+)-aeroplysinin-1 were further studied by testing the effects of the treatment with this compound on the activity of several anti- and pro-oxidant enzymes, as well as on transcription factors involved in redox homeostasis. Finally, changes in the levels of total reactive oxygen species and mitochondrial membrane potential induced by endothelial cell treatments with (+)-aeroplysinin-1 were also determined. Taken altogether, these findings show that (+)-aeroplysinin-1 has multiple targets involved in endothelial cell redox regulation.

Pleiotropic Role of Puupehenones in Biomedical Research.

Marine sponges represent a vast source of metabolites with very interesting potential biomedical applications. Puupehenones are sesquiterpene quinones isolated from sponges of the orders Verongida and Dictyoceratida. This family of chemical compounds is composed of a high number of metabolites, including puupehenone, the most characteristic compound of the family. Chemical synthesis of puupehenone has been reached by different routes, and the special chemical reactivity of this molecule has allowed the synthesis of many puupehenone-derived compounds. The biological activities of puupehenones are very diverse, including antiangiogenic, antitumoral, antioxidant, antimicrobial, immunomodulatory and antiatherosclerotic effects. Despite the very important roles described for puupehenones concerning different pathologies, the exact mechanism of action of these compounds and the putative therapeutic effects in vivo remain to be elucidated. This review offers an updated and global view about the biology of puupehenones and their therapeutic possibilities in human diseases such as cancer.

Polyamine metabolism is sensitive to glycolysis inhibition in human neuroblastoma cells.

Polyamines are essential for cell proliferation, and their levels are elevated in many human tumors. The oncogene n-myc is known to potentiate polyamine metabolism. Neuroblastoma, the most frequent extracranial solid tumor in children, harbors the amplification of n-myc oncogene in 25% of the cases, and it is associated with treatment failure and poor prognosis. We evaluated several metabolic features of the human neuroblastoma cell lines Kelly, IMR-32, and SK-N-SH. We further investigated the effects of glycolysis impairment in polyamine metabolism in these cell lines. A previously unknown linkage between glycolysis impairment and polyamine reduction is unveiled. We show that glycolysis inhibition is able to trigger signaling events leading to the reduction of N-Myc protein levels and a subsequent decrease of both ornithine decarboxylase expression and polyamine levels, accompanied by cell cycle blockade preceding cell death. New anti-tumor strategies could take advantage of the direct relationship between glucose deprivation and polyamine metabolism impairment, leading to cell death, and its apparent dependence on n-myc. Combined therapies targeting glucose metabolism and polyamine synthesis could be effective in the treatment of n-myc-expressing tumors.

Systematic identification of phenotypically enriched loci using a patient network of genomic disorders.

BACKGROUND: Network medicine is a promising new discipline that combines systems biology approaches and network science to understand the complexity of pathological phenotypes. Given the growing availability of personalized genomic and phenotypic profiles, network models offer a robust integrative framework for the analysis of "omics" data, allowing the characterization of the molecular aetiology of pathological processes underpinning genetic diseases. METHODS: Here we make use of patient genomic data to exploit different network-based analyses to study genetic and phenotypic relationships between individuals. For this method, we analyzed a dataset of structural variants and phenotypes for 6,564 patients from the DECIPHER database, which encompasses one of the most comprehensive collections of pathogenic Copy Number Variations (CNVs) and their associated ontology-controlled phenotypes. We developed a computational strategy that identifies clusters of patients in a synthetic patient network according to their genetic overlap and phenotype enrichments. RESULTS: Many of these clusters of patients represent new genotype-phenotype associations, suggesting the identification of newly discovered phenotypically enriched loci (indicative of potential novel syndromes) that are currently absent from reference genomic disorder databases such as ClinVar, OMIM or DECIPHER itself. CONCLUSIONS: We provide a high-resolution map of pathogenic phenotypes associated with their respective significant genomic regions and a new powerful tool for diagnosis of currently uncharacterized mutations leading to deleterious phenotypes and syndromes.

[Complications and cause of death in mexican children with rocky mountain spotted fever]. / Complicaciones y causa de muerte en niños mexicanos con fiebre manchada de las Montañas Rocosas (FMMR).

BACKGROUND: Rocky Mountain spotted fever is a life threatening disease caused by Rickettsia rickettsia, characterized by multisystem involvement. METHODS: We studied 19 dead children with Rocky Mountain spotted fever. All children who were suspected of having rickettsial infections were defined as having Rocky Mountain spotted fever by serology test and clinical features. Through the analysis of each case, we identified the clinical profile and complications associated to the death of a patient. RESULTS: In nine (69.2%) of 13 cases that died in the first three days of admission, the associated condition was septic shock. Others complications included respiratory distress causes by non-cardiogenic pulmonary edema, renal impairment, and multiple organ damage. CONCLUSIONS: The main cause of death in this study was septic shock. The fatality rate from Rocky Mountain spotted fever can be related to the severity of the infection, delay in diagnosis, and delay in initiation of antibiotic therapy. Pulmonary edema and cerebral edema can be usually precipitated by administration of excess intravenous fluids.

Aeroplysinin-1, a Sponge-Derived Multi-Targeted Bioactive Marine Drug.

Organisms lacking external defense mechanisms have developed chemical defense strategies, particularly through the production of secondary metabolites with antibiotic or repellent effects. Secondary metabolites from marine organisms have proven to be an exceptionally rich source of small molecules with pharmacological activities potentially beneficial to human health. (+)-Aeroplysinin-1 is a secondary metabolite isolated from marine sponges with a wide spectrum of bio-activities. (+)-Aeroplysinin-1 has potent antibiotic effects on Gram-positive bacteria and several dinoflagellate microalgae causing toxic blooms. In preclinical studies, (+)-aeroplysinin-1 has been shown to have promising anti-inflammatory, anti-angiogenic and anti-tumor effects. Due to its versatility, (+)-aeroplysinin-1 might have a pharmaceutical interest for the treatment of different pathologies.

PhenUMA: a tool for integrating the biomedical relationships among genes and diseases.

BACKGROUND: Several types of genetic interactions in humans can be directly or indirectly associated with the causal effects of mutations. These interactions are usually based on their co-associations to biological processes, coexistence in cellular locations, coexpression in cell lines, physical interactions and so on. In addition, pathological processes can present similar phenotypes that have mutations either in the same genomic location or in different genomic regions. Therefore, integrative resources for all of these complex interactions can help us prioritize the relationships between genes and diseases that are most deserving to be studied by researchers and physicians. RESULTS: PhenUMA is a web application that displays biological networks using information from biomedical and biomolecular data repositories. One of its most innovative features is to combine the benefits of semantic similarity methods with the information taken from databases of genetic diseases and biological interactions. More specifically, this tool is useful in studying novel pathological relationships between functionally related genes, merging diseases into clusters that share specific phenotypes or finding diseases related to reported phenotypes. CONCLUSIONS: This framework builds, analyzes and visualizes networks based on both functional and phenotypic relationships. The integration of this information helps in the discovery of alternative pathological roles of genes, biological functions and diseases. PhenUMA represents an advancement toward the use of new technologies for genomics and personalized medicine.