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1. Automatization of metabolite extraction for high-throughput metabolomics: case study on transgenic isoprene-emitting birch.

Author

Bertić, Marko, Zimmer, Ina, Andrés-Montaner, David, Rosenkranz, Maaria, Kangasjärvi, Jaakko, Schnitzler, Jörg-Peter, and Ghirardo, Andrea

Subjects
METABOLOMICS, METABOLITES, PLANT metabolites, BIRCH, EUROPEAN white birch, PLANT metabolism, POPLARS
Abstract

Metabolomics studies are becoming increasingly common for understanding how plant metabolism responds to changes in environmental conditions, genetic manipulations and treatments. Despite the recent advances in metabolomics workflow, the sample preparation process still limits the high-throughput analysis in large-scale studies. Here, we present a highly flexible robotic system that integrates liquid handling, sonication, centrifugation, solvent evaporation and sample transfer processed in 96-well plates to automatize the metabolite extraction from leaf samples. We transferred an established manual extraction protocol performed to a robotic system, and with this, we show the optimization steps required to improve reproducibility and obtain comparable results in terms of extraction efficiency and accuracy. We then tested the robotic system to analyze the metabolomes of wild-type and four transgenic silver birch (Betula pendula Roth) lines under unstressed conditions. Birch trees were engineered to overexpress the poplar (Populus × canescens) isoprene synthase and to emit various amounts of isoprene. By fitting the different isoprene emission capacities of the transgenic trees with their leaf metabolomes, we observed an isoprene-dependent upregulation of some flavonoids and other secondary metabolites as well as carbohydrates, amino acid and lipid metabolites. By contrast, the disaccharide sucrose was found to be strongly negatively correlated to isoprene emission. The presented study illustrates the power of integrating robotics to increase the sample throughput, reduce human errors and labor time, and to ensure a fully controlled, monitored and standardized sample preparation procedure. Due to its modular and flexible structure, the robotic system can be easily adapted to other extraction protocols for the analysis of various tissues or plant species to achieve high-throughput metabolomics in plant research. [ABSTRACT FROM AUTHOR]

Published
2023
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2. Método y Sistemas compositivos en la vivienda colectiva de RBTA 1968 1975

Author

Pons Montaner, David

Subjects
Flexibilidad, Variedad Tipológica, Collective Space, Taller Arquitectura, Density, Growth, Ricardo Bofill, Crecimiento, PROYECTOS ARQUITECTONICOS, Espacio Colectivo, Flexibility, Densidad, Typological Variety, Taller de Arquitectura, Grado en Fundamentos de la Arquitectura-Grau en Fonaments de l'Arquitectura
Abstract

[ES] El presente trabajo tiene por objeto el análisis y estudio de la obra producida por el Taller de Arquitectura Ricardo Bofill durante el período comprendido entre finales de la década de los sesenta y principios de los setenta. Esta etapa corresponde con la producción de una serie de viviendas colectivas con una identidad común en las que se va a identificar y depurar los principios arquitectónicos que rigen estos proyectos. Se pretende aportar una visión y valoración extensa y pormenorizada de la obra producida a través de la evaluación de conceptos tales como crecimiento, flexibilidad, espacio colectivo, recorrido, variedad tipológica y densidad. De esta forma, será posible generar un abanico de recursos y posibilidades extraídas de dicho análisis los cuales nos permitan aplicar esta metodología en la arquitectura contemporánea actual., [EN] The present work aims to analyse and study the work produced by the Ricardo Bofill Taller Arquitectura during the period between the late sixties and early seventies. This stage corresponds to the production of a series of collective dwellings with a common identity in which the architectural principles governing these projects are to be identified and refined. It is sought to provide an extensive and detailed vision and assessment of the work produced through the evaluation of concepts such as growth, flexibility, collective space, route, typological variety and density. In this way, it will be possible to generate a range of resources and possibilities extracted from this analysis which will allow us to apply this methodology in today's contemporary architecture.

Published
2022

3. Método y Sistemas compositivos en la vivienda colectiva de RBTA 1968 1975.

Author

Marí Beneit, Ignacio, Martí Cunquero, José Javier, Pons Montaner, David, Marí Beneit, Ignacio, Martí Cunquero, José Javier, and Pons Montaner, David

Abstract

[ES] El presente trabajo tiene por objeto el análisis y estudio de la obra producida por el Taller de Arquitectura Ricardo Bofill durante el período comprendido entre finales de la década de los sesenta y principios de los setenta. Esta etapa corresponde con la producción de una serie de viviendas colectivas con una identidad común en las que se va a identificar y depurar los principios arquitectónicos que rigen estos proyectos. Se pretende aportar una visión y valoración extensa y pormenorizada de la obra producida a través de la evaluación de conceptos tales como crecimiento, flexibilidad, espacio colectivo, recorrido, variedad tipológica y densidad. De esta forma, será posible generar un abanico de recursos y posibilidades extraídas de dicho análisis los cuales nos permitan aplicar esta metodología en la arquitectura contemporánea actual., [EN] The present work aims to analyse and study the work produced by the Ricardo Bofill Taller Arquitectura during the period between the late sixties and early seventies. This stage corresponds to the production of a series of collective dwellings with a common identity in which the architectural principles governing these projects are to be identified and refined. It is sought to provide an extensive and detailed vision and assessment of the work produced through the evaluation of concepts such as growth, flexibility, collective space, route, typological variety and density. In this way, it will be possible to generate a range of resources and possibilities extracted from this analysis which will allow us to apply this methodology in today's contemporary architecture.

Published
2022

6. Teatro Auditorio Olímpia de Oliva

Author

Pons Montaner, David

Subjects
Exposició, Arts Escèniques i Música professionals, Cultura, Auditorium, Oliva, PROYECTOS ARQUITECTONICOS, Teatre, Theatre, Máster Universitario en Arquitectura-Màster Universitari en Arquitectura, Auditori, Música
Abstract

[EN] The Oliva Teatre Olímpia is a cultural building that allow professional Performing Arts and Music activities, at the same time, offers a great service of citizen participation through the performances of the various associations and groups in the city . Therefore, it is necessary to reconstruct a quality space that serves as a cultural link between the main municipalities in the area and the city of Oliva itself from a rich and rigorous program as a dynamizer of the cultural sector., [CA] El Teatre Olímpia d’Oliva és un contenidor cultural en el que es recullen activitats d’Arts Escèniques i Música professionals, i a la vegada, ofereix un gran servei de participació ciutadana mitjançant les representacions que realitzen les diverses as-sociacions i col•lectius de la ciutat. A banda d’aquestes activitats, que ja de per si, omplen de contingut i sentit l’edifici, la Delegació de Cultura, mitjançant els Serveis Culturals Municipals, organitza actes que tenen continuïtat com ara: Poefes-ta, Amat, Rebombori Teatre, etc.Entre 2016 i maig de 2018, han assistit a espectacles d’arts escèniques, música i cinema, al voltant de 75.000 espectadors. El públic assistent al Teatre Olímpia, en les diverses activitats que s’hi desenvolupen, està format per un 65% de població d’Oliva, un 30 % de persones de pobles de la Safor i Marina Alta i un 5% procedent d’altres comarques. Per tant, és necessari reconstruir un espai de qualitat que serveixca de nexe cultural entre els principals municipis de la zona i la propia ciutat d’Oliva a partir d’una programació rica i rigurosa com a dinamitzador del sector cultural local.

Published
2021

9. Teatro Auditorio Olímpia de Oliva.

Author

Vidal Climent, Ivo Eliseo, Universitat Politècnica de València. Departamento de Proyectos Arquitectónicos - Departament de Projectes Arquitectònics, Universitat Politècnica de València. Escuela Técnica Superior de Arquitectura - Escola Tècnica Superior d'Arquitectura, Pons Montaner, David, Vidal Climent, Ivo Eliseo, Universitat Politècnica de València. Departamento de Proyectos Arquitectónicos - Departament de Projectes Arquitectònics, Universitat Politècnica de València. Escuela Técnica Superior de Arquitectura - Escola Tècnica Superior d'Arquitectura, and Pons Montaner, David

Abstract

[EN] The Oliva Teatre Olímpia is a cultural building that allow professional Performing Arts and Music activities, at the same time, offers a great service of citizen participation through the performances of the various associations and groups in the city . Therefore, it is necessary to reconstruct a quality space that serves as a cultural link between the main municipalities in the area and the city of Oliva itself from a rich and rigorous program as a dynamizer of the cultural sector., [CA] El Teatre Olímpia d’Oliva és un contenidor cultural en el que es recullen activitats d’Arts Escèniques i Música professionals, i a la vegada, ofereix un gran servei de participació ciutadana mitjançant les representacions que realitzen les diverses as-sociacions i col•lectius de la ciutat. A banda d’aquestes activitats, que ja de per si, omplen de contingut i sentit l’edifici, la Delegació de Cultura, mitjançant els Serveis Culturals Municipals, organitza actes que tenen continuïtat com ara: Poefes-ta, Amat, Rebombori Teatre, etc.Entre 2016 i maig de 2018, han assistit a espectacles d’arts escèniques, música i cinema, al voltant de 75.000 espectadors. El públic assistent al Teatre Olímpia, en les diverses activitats que s’hi desenvolupen, està format per un 65% de població d’Oliva, un 30 % de persones de pobles de la Safor i Marina Alta i un 5% procedent d’altres comarques. Per tant, és necessari reconstruir un espai de qualitat que serveixca de nexe cultural entre els principals municipis de la zona i la propia ciutat d’Oliva a partir d’una programació rica i rigurosa com a dinamitzador del sector cultural local.

Published
2021

12. Pluripotent Stem Cell‐Derived Hematopoietic Progenitors Are Unable to Downregulate Key Epithelial‐Mesenchymal Transition‐Associated miRNAs

Author

Meader, Ellie, Barta, Tomas, Melguizo‐Sanchis, Dario, Tilgner, Katarzyna, Montaner, David, El‐Harouni, Ashraf A., Armstrong, Lyle, and Lako, Majlinda

Subjects
Hematopoietic differentiation, Pluripotent Stem Cells, Epithelial-Mesenchymal Transition, Down-Regulation, Cell Differentiation, Hematopoietic Stem Cells, Embryonic Stem Cells/Induced Pluripotent Stem Cells, MicroRNAs, Hematopoietic Stem/Progenitor Cells, miRNAs, Mechanisms of Differentiation, Humans, Induced Pluripotent stem cells, Human embryonic stem cells, Epithelial‐mesenchymal transition, Hematopoietic Regeneration, Embryonic Stem Cells
Abstract

Hematopoietic stem cells derived from pluripotent stem cells could be used as an alternative to bone marrow transplants. Deriving these has been a long‐term goal for researchers. However, the success of these efforts has been limited with the cells produced able to engraft in the bone marrow of recipient animals only in very low numbers. There is evidence that defects in the migratory and homing capacity of the cells are due to mis‐regulation of miRNA expression and are responsible for their failure to engraft. We compared the miRNA expression profile of hematopoietic progenitors derived from pluripotent stem cells to those derived from bone marrow and found that numerous miRNAs are too highly expressed in hematopoietic progenitors derived from pluripotent stem cells, and that most of these are inhibitors of epithelial‐mesenchymal transition or metastasis (including miR‐200b, miR‐200c, miR‐205, miR‐148a, and miR‐424). We hypothesize that the high expression of these factors, which promote an adherent phenotype, may be causing the defect in hematopoietic differentiation. However, inhibiting these miRNAs, individually or in multiplex, was insufficient to improve hematopoietic differentiation in vitro, suggesting that other miRNAs and/or genes may be involved in this process. Stem Cells 2018;36:55–64

Published
2017

15. GEPAS, a web-based tool for microarray data analysis and interpretation

Author

Tárraga, Joaquín, Medina, Ignacio, Carbonell, José, Huerta-Cepas, Jaime, Minguez, Pablo, Alloza, Eva, Al-Shahrour, Fátima, Vegas-Azcárate, Susana, Goetz, Stefan, Escobar, Pablo, Garcia-Garcia, Francisco, Conesa, Ana, Montaner, David, and Dopazo, Joaquín

Published
2008

21. Four new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung’s disease

Author

Fernández Raquel Ma, Bleda Marta, Núñez-Torres Rocío, Medina Ignacio, Luzón-Toro Berta, García-Alonso Luz, Torroglosa Ana, Marbà Martina, Enguix-Riego Ma Valle, Montaner David, Antiñolo Guillermo, Dopazo Joaquín, and Borrego Salud

Subjects
HSCR, Pathway-based analysis, Network analysis, GWAS, Medicine
Abstract

Abstract Finding gene associations in rare diseases is frequently hampered by the reduced numbers of patients accessible. Conventional gene-based association tests rely on the availability of large cohorts, which constitutes a serious limitation for its application in this scenario. To overcome this problem we have used here a combined strategy in which a pathway-based analysis (PBA) has been initially conducted to prioritize candidate genes in a Spanish cohort of 53 trios of short-segment Hirschsprung’s disease. Candidate genes have been further validated in an independent population of 106 trios. The study revealed a strong association of 11 gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other HSCR-related processes. Among the preselected candidates, a total of 4 loci, RASGEF1A, IQGAP2, DLC1 and CHRNA7, related to signal transduction and migration processes, were found to be significantly associated to HSCR. Network analysis also confirms their involvement in the network of already known disease genes. This approach, based on the study of functionally-related gene sets, requires of lower sample sizes and opens new opportunities for the study of rare diseases.

Published
2012
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22. Parallel changes in gene expression in peripheral blood mononuclear cells and the brain after maternal separation in the mouse

Author

Russell Vivienne, Montaner David, Stein Dan J, Conesa Ana, van Heerden Johan H, and Illing Nicola

Subjects
Medicine, Biology (General), QH301-705.5, Science (General), Q1-390
Abstract

Abstract Background The functional integration of the neuro-, endocrine- and immune-systems suggests that the transcriptome of white blood cells may reflect neuropsychiatric states, and be used as a non-invasive diagnostic indicator. We used a mouse maternal separation model, a paradigm of early adversity, to test the hypothesis that transcriptional changes in peripheral blood mononuclear cells (PBMCs) are paralleled by specific gene expression changes in prefrontal cortex (PFC), hippocampus (Hic) and hypothalamus (Hyp). Furthermore, we evaluated whether gene expression profiles of PBMCs could be used to predict the separation status of individual animals. Findings Microarray gene expression profiles of all three brain regions provided substantial evidence of stress-related neural differences between maternally separated and control animals. For example, changes in expression of genes involved in the glutamatergic and GABAergic systems were identified in the PFC and Hic, supporting a stress-related hyperglutamatergic state within the separated group. The expression of 50 genes selected from the PBMC microarray data provided sufficient information to predict treatment classes with 95% accuracy. Importantly, stress-related transcriptome differences in PBMC populations were paralleled by stress-related gene expression changes in CNS target tissues. Conclusion These results confirm that the transcriptional profiles of peripheral immune tissues occur in parallel to changes in the brain and contain sufficient information for the efficient diagnostic prediction of stress-related neural states in mice. Future studies will need to evaluate the relevance of the predictor set of 50 genes within clinical settings, specifically within a context of stress-related disorders.

Published
2009
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23. Gene set internal coherence in the context of functional profiling

Author

Al-Shahrour Fátima, Minguez Pablo, Montaner David, and Dopazo Joaquín

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Functional profiling methods have been extensively used in the context of high-throughput experiments and, in particular, in microarray data analysis. Such methods use available biological information to define different types of functional gene modules (e.g. gene ontology -GO-, KEGG pathways, etc.) whose representation in a pre-defined list of genes is further studied. In the most popular type of microarray experimental designs (e.g. up- or down-regulated genes, clusters of co-expressing genes, etc.) or in other genomic experiments (e.g. Chip-on-chip, epigenomics, etc.) these lists are composed by genes with a high degree of co-expression. Therefore, an implicit assumption in the application of functional profiling methods within this context is that the genes corresponding to the modules tested are effectively defining sets of co-expressing genes. Nevertheless not all the functional modules are biologically coherent entities in terms of co-expression, which will eventually hinder its detection with conventional methods of functional enrichment. Results Using a large collection of microarray data we have carried out a detailed survey of internal correlation in GO terms and KEGG pathways, providing a coherence index to be used for measuring functional module co-regulation. An unexpected low level of internal correlation was found among the modules studied. Only around 30% of the modules defined by GO terms and 57% of the modules defined by KEGG pathways display an internal correlation higher than the expected by chance. This information on the internal correlation of the genes within the functional modules can be used in the context of a logistic regression model in a simple way to improve their detection in gene expression experiments. Conclusion For the first time, an exhaustive study on the internal co-expression of the most popular functional categories has been carried out. Interestingly, the real level of coexpression within many of them is lower than expected (or even inexistent), which will preclude its detection by means of most conventional functional profiling methods. If the gene-to-function correlation information is used in functional profiling methods, the results obtained improve the ones obtained by conventional enrichment methods.

Published
2009
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24. Evidence for systems-level molecular mechanisms of tumorigenesis

Author

Capellá Gabriel, Gómez Laia, Valls Joan, Montaner David, Al-Shahrour Fátima, Huerta-Cepas Jaime, Hernández Pilar, Dopazo Joaquín, and Pujana Miguel

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Cancer arises from the consecutive acquisition of genetic alterations. Increasing evidence suggests that as a consequence of these alterations, molecular interactions are reprogrammed in the context of highly connected and regulated cellular networks. Coordinated reprogramming would allow the cell to acquire the capabilities for malignant growth. Results Here, we determine the coordinated function of cancer gene products (i.e., proteins encoded by differentially expressed genes in tumors relative to healthy tissue counterparts, hereafter referred to as "CGPs") defined as their topological properties and organization in the interactome network. We show that CGPs are central to information exchange and propagation and that they are specifically organized to promote tumorigenesis. Centrality is identified by both local (degree) and global (betweenness and closeness) measures, and systematically appears in down-regulated CGPs. Up-regulated CGPs do not consistently exhibit centrality, but both types of cancer products determine the overall integrity of the network structure. In addition to centrality, down-regulated CGPs show topological association that correlates with common biological processes and pathways involved in tumorigenesis. Conclusion Given the current limited coverage of the human interactome, this study proposes that tumorigenesis takes place in a specific and organized way at the molecular systems-level and suggests a model that comprises the precise down-regulation of groups of topologically-associated proteins involved in particular functions, orchestrated with the up-regulation of specific proteins.

Published
2007
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25. From genes to functional classes in the study of biological systems

Author

Huerta-Cepas Jaime, Dopazo Hernán, Arbiza Leonardo, Al-Shahrour Fátima, Mínguez Pablo, Montaner David, and Dopazo Joaquín

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background With the popularisation of high-throughput techniques, the need for procedures that help in the biological interpretation of results has increased enormously. Recently, new procedures inspired in systems biology criteria have started to be developed. Results Here we present FatiScan, a web-based program which implements a threshold-independent test for the functional interpretation of large-scale experiments that does not depend on the pre-selection of genes based on the multiple application of independent tests to each gene. The test implemented aims to directly test the behaviour of blocks of functionally related genes, instead of focusing on single genes. In addition, the test does not depend on the type of the data used for obtaining significance values, and consequently different types of biologically informative terms (gene ontology, pathways, functional motifs, transcription factor binding sites or regulatory sites from CisRed) can be applied to different classes of genome-scale studies. We exemplify its application in microarray gene expression, evolution and interactomics. Conclusion Methods for gene set enrichment which, in addition, are independent from the original data and experimental design constitute a promising alternative for the functional profiling of genome-scale experiments. A web server that performs the test described and other similar ones can be found at: http://www.babelomics.org.

Published
2007
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26. MicroRNA profiling associated with non-small cell lung cancer: next generation sequencing detection, experimental validation, and prognostic value

Author

Gallach, Sandra, primary, Jantus-Lewintre, Eloisa, additional, Calabuig-Fariñas, Silvia, additional, Montaner, David, additional, Alonso, Sergio, additional, Sirera, Rafael, additional, Blasco, Ana, additional, Usó, Marta, additional, Guijarro, Ricardo, additional, Martorell, Miguel, additional, and Camps, Carlos, additional

Published
2017
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27. MicroRNA profiling associated with non-small cell lung cancer: next generation sequencing detection, experimental validation, and prognostic value

Author

Universitat Politècnica de València. Departamento de Biotecnología - Departament de Biotecnologia, Instituto de Salud Carlos III, European Regional Development Fund, Gallach-Garcia, Sandra, Jantus-Lewintre, Eloisa, Calabuig-Fariñas, Silvia, Montaner, David, Alonso, Sergio, Sirera Pérez, Rafael, Blasco, Ana, Usó-Marco, Marta, Guijarro, Ricardo, Martorell, Miguel, Camps-Herrero, Carlos, Universitat Politècnica de València. Departamento de Biotecnología - Departament de Biotecnologia, Instituto de Salud Carlos III, European Regional Development Fund, Gallach-Garcia, Sandra, Jantus-Lewintre, Eloisa, Calabuig-Fariñas, Silvia, Montaner, David, Alonso, Sergio, Sirera Pérez, Rafael, Blasco, Ana, Usó-Marco, Marta, Guijarro, Ricardo, Martorell, Miguel, and Camps-Herrero, Carlos

Abstract

[EN] Background: The average five-year survival for non-small cell lung cancer (NSCLC) patients is approximately 15%. Emerging evidence indicates that microRNAs (miRNAs) constitute a new class of gene regulators in humans that may play an important role in tumorigenesis. Hence, there is growing interest in studying their role as possible new biomarkers whose expression is aberrant in cancer. Therefore, in this study we identified dysregulated miRNAs by next generation sequencing (NGS) and analyzed their prognostic value. Methods: Sequencing by oligo ligation detection technology was used to identify dysregulated miRNAs in a training cohort comprising paired tumor/normal tissue samples (N = 32). We validated 22 randomly selected differentially-expressed miRNAs by quantitative real time PCR in tumor and adjacent normal tissue samples (N = 178). Kaplan-Meier survival analysis and Cox regression were used in multivariate analysis to identify independent prognostic biomarkers. Results: NGS analysis revealed that 39 miRNAs were dysregulated in NSCLC: 28 were upregulated and 11 were downregulated. Twenty-two miRNAs were validated in an independent cohort. Interestingly, the group of patients with high expression of both miRNAs (miR-21(high) and miR-188(high)) showed shorter relapse-free survival (RFS) and overall survival (OS) times. Multivariate analysis confirmed that this combined signature is an independent prognostic marker for RFS and OS (p = 0.001 and p < 0.0001, respectively). Conclusions: NGS technology can specifically identify dysregulated miRNA profiles in resectable NSCLC samples. MiR-21 or miR-188 overexpression correlated with a negative prognosis, and their combined signature may represent a new independent prognostic biomarker for RFS and OS.

Published
2017

31. Babelomics 5.0: functional interpretation for new generations of genomic data

Author

Alonso, Roberto, primary, Salavert, Francisco, additional, Garcia-Garcia, Francisco, additional, Carbonell-Caballero, Jose, additional, Bleda, Marta, additional, Garcia-Alonso, Luz, additional, Sanchis-Juan, Alba, additional, Perez-Gil, Daniel, additional, Marin-Garcia, Pablo, additional, Sanchez, Ruben, additional, Cubuk, Cankut, additional, Hidalgo, Marta R., additional, Amadoz, Alicia, additional, Hernansaiz-Ballesteros, Rosa D., additional, Alemán, Alejandro, additional, Tarraga, Joaquin, additional, Montaner, David, additional, Medina, Ignacio, additional, and Dopazo, Joaquin, additional

Published
2015
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32. FM19G11, a new HIF modulator, affects Stem Cell differentiation status

Author

Moreno Manzano, Victoria, Fernández Jiménez, Francisco Javier, Aceña, José L., Fustero, Santos, Erceg, Slaven, Dopazo, Joaquín, Montaner, David, Stojkovic, Miodrag, and Sánchez-Puelles, José María

Subjects
Oxygen/Hypoxia, Stem cells/Neural, Stem Cells, Histones/Acetylase, Cell differentiation, Development differentiation/Stem cell, Diseases/Neurological
Abstract

23 p.-4 fig.-+ 5 arch. mat. supl., The biology of the α subunits of hypoxia-inducible factors (HIFα) has expanded from their role in angiogenesis to their current position in the self-renewal and differentiation of stem cells. The results reported in this article show the discovery of FM19G11, a novel chemical entity that inhibits HIFα proteins that repress target genes of the two α subunits, in various tumor cell lines as well as in adult and embryonic stem cell models from rodents and humans, respectively. FM19G11 inhibits at nanomolar range the transcriptional and protein expression of Oct4, Sox2, Nanog, and Tgf-α undifferentiating factors, in adult rat and human embryonic stem cells, FM19G11 activity occurs in ependymal progenitor stem cells from rats (epSPC), a cell model reported for spinal cord regeneration, which allows the progression of oligodendrocyte cell differentiation in a hypoxic environment, has created interest in its characterization for pharmacological research. Experiments using small interfering RNA showed a significant depletion in Sox2 protein only in the case of HIF2α silencing, but not in HIF1α-mediated ablation. Moreover, chromatin immunoprecipitation data, together with the significant presence of functional hypoxia response element consensus sequences in the promoter region of Sox2, strongly validated that this factor behaves as a target gene of HIF2α in epSPCs. FM19G11 causes a reduction of overall histone acetylation with significant repression of p300, a histone acetyltransferase required as a co-factor for HIF-transcription activation. Arrays carried out in the presence and absence of the inhibitor showed the predominant involvement of epigenetic-associated events mediated by the drug, This work was supported by the Fondo de Investigaciones Sanitarias, the Instituto de Salud Carlos III (Spain), the Ministerio de Educación, Ciencia y Tecnología, and Generalitat Valenciana (Spain) Projects PI051973 RD06/0010/1006, SAF2007-63714, and GVRE/2008/254

Published
2010

33. Pluripotent Stem Cell-Derived Hematopoietic Progenitors Are Unable to Downregulate Key Epithelial-Mesenchymal Transition-Associated miRNAs.

Author

Meader, Ellie, Barta, Tomas, Melguizo-Sanchis, Dario, Tilgner, Katarzyna, Montaner, David, El-Harouni, Ashraf A., Armstrong, Lyle, and Lako, Majlinda

Abstract

Hematopoietic stem cells derived from pluripotent stem cells could be used as an alternative to bone marrow transplants. Deriving these has been a long-term goal for researchers. However, the success of these efforts has been limited with the cells produced able to engraft in the bone marrow of recipient animals only in very low numbers. There is evidence that defects in the migratory and homing capacity of the cells are due to mis-regulation of miRNA expression and are responsible for their failure to engraft. We compared the miRNA expression profile of hematopoietic progenitors derived from pluripotent stem cells to those derived from bone marrow and found that numerous miRNAs are too highly expressed in hematopoietic progenitors derived from pluripotent stem cells, and that most of these are inhibitors of epithelial-mesenchymal transition or metastasis (including miR-200b, miR-200c, miR-205, miR-148a, and miR-424). We hypothesize that the high expression of these factors, which promote an adherent phenotype, may be causing the defect in hematopoietic differentiation. However, inhibiting these miRNAs, individually or in multiplex, was insufficient to improve hematopoietic differentiation in vitro, suggesting that other miRNAs and/or genes may be involved in this process. S tem C ells 2018;36:55-64 [ABSTRACT FROM AUTHOR]

Published
2018
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34. Pathway network inference from gene expression data

Author

Universitat Politècnica de València. Departamento de Estadística e Investigación Operativa Aplicadas y Calidad - Departament d'Estadística i Investigació Operativa Aplicades i Qualitat, Universitat Politècnica de València. Departamento de Física Aplicada - Departament de Física Aplicada, European Commission, Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina, Universidad Nacional del Sur, Argentina, Ponzoni, Ignacio, Nueda, Maria José, Tarazona Campos, Sonia, GOTZ, STEFAN, Montaner, David, Dussaut, Julieta Sol, Dopazo, Joaquín, Conesa, Ana, Universitat Politècnica de València. Departamento de Estadística e Investigación Operativa Aplicadas y Calidad - Departament d'Estadística i Investigació Operativa Aplicades i Qualitat, Universitat Politècnica de València. Departamento de Física Aplicada - Departament de Física Aplicada, European Commission, Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina, Universidad Nacional del Sur, Argentina, Ponzoni, Ignacio, Nueda, Maria José, Tarazona Campos, Sonia, GOTZ, STEFAN, Montaner, David, Dussaut, Julieta Sol, Dopazo, Joaquín, and Conesa, Ana

Abstract

This article has been published as part of BMC Systems Biology Volume 8 Supplement 2, 2014: Selected articles from the High-Throughput Omics and Data Integration Workshop. The full contents of the supplement are available online at http://www.biomedcentral.com/bmcsystbiol/supplements/8/S2., [EN] Background: The development of high-throughput omics technologies enabled genome-wide measurements of the activity of cellular elements and provides the analytical resources for the progress of the Systems Biology discipline. Analysis and interpretation of gene expression data has evolved from the gene to the pathway and interaction level, i.e. from the detection of differentially expressed genes, to the establishment of gene interaction networks and the identification of enriched functional categories. Still, the understanding of biological systems requires a further level of analysis that addresses the characterization of the interaction between functional modules. Results: We present a novel computational methodology to study the functional interconnections among the molecular elements of a biological system. The PANA approach uses high-throughput genomics measurements and a functional annotation scheme to extract an activity profile from each functional block -or pathway- followed by machine-learning methods to infer the relationships between these functional profiles. The result is a global, interconnected network of pathways that represents the functional cross-talk within the molecular system. We have applied this approach to describe the functional transcriptional connections during the yeast cell cycle and to identify pathways that change their connectivity in a disease condition using an Alzheimer example. Conclusions: PANA is a useful tool to deepen in our understanding of the functional interdependences that operate within complex biological systems. We show the approach is algorithmically consistent and the inferred network is well supported by the available functional data. The method allows the dissection of the molecular basis of the functional connections and we describe the different regulatory mechanisms that explain the network’s topology obtained for the yeast cell cycle data.

Published
2014

35. Pathway network inference from gene expression data

Author

Universidad de Alicante. Departamento de Estadística e Investigación Operativa, Ponzoni, Ignacio, Nueda, María José, Tarazona, Sonia, Götz, Stefan, Montaner, David, Dussaut, Julieta Sol, Dopazo, Joaquín, Conesa, Ana, Universidad de Alicante. Departamento de Estadística e Investigación Operativa, Ponzoni, Ignacio, Nueda, María José, Tarazona, Sonia, Götz, Stefan, Montaner, David, Dussaut, Julieta Sol, Dopazo, Joaquín, and Conesa, Ana

Abstract

Background: The development of high-throughput omics technologies enabled genome-wide measurements of the activity of cellular elements and provides the analytical resources for the progress of the Systems Biology discipline. Analysis and interpretation of gene expression data has evolved from the gene to the pathway and interaction level, i.e. from the detection of differentially expressed genes, to the establishment of gene interaction networks and the identification of enriched functional categories. Still, the understanding of biological systems requires a further level of analysis that addresses the characterization of the interaction between functional modules. Results: We present a novel computational methodology to study the functional interconnections among the molecular elements of a biological system. The PANA approach uses high-throughput genomics measurements and a functional annotation scheme to extract an activity profile from each functional block -or pathway- followed by machine-learning methods to infer the relationships between these functional profiles. The result is a global, interconnected network of pathways that represents the functional cross-talk within the molecular system. We have applied this approach to describe the functional transcriptional connections during the yeast cell cycle and to identify pathways that change their connectivity in a disease condition using an Alzheimer example. Conclusions: PANA is a useful tool to deepen in our understanding of the functional interdependences that operate within complex biological systems. We show the approach is algorithmically consistent and the inferred network is well supported by the available functional data. The method allows the dissection of the molecular basis of the functional connections and we describe the different regulatory mechanisms that explain the network’s topology obtained for the yeast cell cycle data.

Published
2014

37. Pathway network inference from gene expression data

Author

Ponzoni, Ignacio, primary, Nueda, María José, additional, Tarazona, Sonia, additional, Götz, Stefan, additional, Montaner, David, additional, Dussaut, Julieta Sol, additional, Dopazo, Joaquín, additional, and Conesa, Ana, additional

Published
2014
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38. Extensive translatome remodeling during ER stress response in mammalian cells

Author

Fundación Mutua Madrileña, Ministerio de Ciencia e Innovación (España), Generalitat Valenciana, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Red Temática de Investigación Cooperativa en Cáncer (España), Instituto de Salud Carlos III, Russian Academy of Sciences, Ministry of Education and Science of the Russian Federation, Fundación Ramón Areces, Ventoso, Iván, Kochetov, Alex, Montaner, David, Dopazo, Joaquín, Santoyo, Javier, Fundación Mutua Madrileña, Ministerio de Ciencia e Innovación (España), Generalitat Valenciana, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Red Temática de Investigación Cooperativa en Cáncer (España), Instituto de Salud Carlos III, Russian Academy of Sciences, Ministry of Education and Science of the Russian Federation, Fundación Ramón Areces, Ventoso, Iván, Kochetov, Alex, Montaner, David, Dopazo, Joaquín, and Santoyo, Javier

Abstract

In this work we have described the translatome of two mammalian cell lines, NIH3T3 and Jurkat, by scoring the relative polysome association of ~10,000 mRNA under normal and ER stress conditions. We have found that translation efficiencies of mRNA correlated poorly with transcript abundance, although a general tendency was observed so that the highest translation efficiencies were found in abundant mRNA. Despite the differences found between mouse (NIH3T3) and human (Jurkat) cells, both cell types share a common translatome composed by ~800-900 mRNA that encode proteins involved in basic cellular functions. Upon stress, an extensive remodeling in translatomes was observed so that translation of ~50% of mRNA was inhibited in both cell types, this effect being more dramatic for those mRNA that accounted for most of the cell translation. Interestingly, we found two subsets comprising 1000-1500 mRNA whose translation resisted or was induced by stress. Translation arrest resistant class includes many mRNA encoding aminoacyl tRNA synthetases, ATPases and enzymes involved in DNA replication and stress response such as BiP. This class of mRNA is characterized by high translation rates in both control and stress conditions. Translation inducible class includes mRNA whose translation was relieved after stress, showing a high enrichment in early response transcription factors of bZIP and zinc finger C2H2 classes. Unlike yeast, a general coordination between changes in translation and transcription upon stress (potentiation) was not observed in mammalian cells. Among the different features of mRNA analyzed, we found a relevant association of translation efficiency with the presence of upstream ATG in the 5′UTR and with the length of coding sequence of mRNA, and a looser association with other parameters such as the length and the G+C content of 5′UTR. A model for translatome remodeling during the acute phase of stress response in mammalian cells is proposed. © 2012 Ventoso et al

Published
2012

39. Four new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung¿s disease

Author

Fernández, Raquel M., Bleda, Marta, Núñez-Torres, Rocío, Medina, Ignacio, Luzón-Toro, Berta, García-Alonso, Luz, Torroglosa, Ana, Marbá, Martina, Enguix-Riego, María del Valle, Montaner, David, Antiñolo, Guillermo, Dopazo, Joaquín, Borrego, Salud, Fernández, Raquel M., Bleda, Marta, Núñez-Torres, Rocío, Medina, Ignacio, Luzón-Toro, Berta, García-Alonso, Luz, Torroglosa, Ana, Marbá, Martina, Enguix-Riego, María del Valle, Montaner, David, Antiñolo, Guillermo, Dopazo, Joaquín, and Borrego, Salud

Abstract

Finding gene associations in rare diseases is frequently hampered by the reduced numbers of patients accessible. Conventional gene-based association tests rely on the availability of large cohorts, which constitutes a serious limitation for its application in this scenario. To overcome this problem we have used here a combined strategy in which a pathway-based analysis (PBA) has been initially conducted to prioritize candidate genes in a Spanish cohort of 53 trios of short-segment Hirschsprung’s disease. Candidate genes have been further validated in an independent population of 106 trios. The study revealed a strong association of 11 gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other HSCR-related processes. Among the preselected candidates, a total of 4 loci, RASGEF1A, IQGAP2, DLC1 and CHRNA7, related to signal transduction and migration processes, were found to be significantly associated to HSCR. Network analysis also confirms their involvement in the network of already known disease genes. This approach, based on the study of functionally-related gene sets, requires of lower sample sizes and opens new opportunities for the study of rare diseases.

Published
2012

40. The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models

Author

Shi, Leming, Campbell, Gregory, Jones, Wendell D, Campagne, Fabien, Wen, Zhining, Walker, Stephen J, Su, Zhenqiang, Chu, Tzu-Ming, Goodsaid, Federico M, Pusztai, Lajos, Shaughnessy, John D, Oberthuer, André, Thomas, Russell S, Paules, Richard S, Fielden, Mark, Barlogie, Bart, Chen, Weijie, Du, Pan, Fischer, Matthias, Furlanello, Cesare, Gallas, Brandon D, Ge, Xijin, Megherbi, Dalila B, Symmans, W Fraser, Wang, May D, Zhang, John, Bitter, Hans, Brors, Benedikt, Bushel, Pierre R, Bylesjö, Max, Chen, Minjun, Cheng, Jie, Cheng, Jing, Chou, Jeff, Davison, Timothy S, Delorenzi, Mauro, Deng, Youping, Devanarayan, Viswanath, Dix, David J, Dopazo, Joaquin, Dorff, Kevin C, Elloumi, Fathi, Fan, Jianqing, Fan, Shicai, Fan, Xiaohui, Fang, Hong, Gonzaludo, Nina, Hess, Kenneth R, Hong, Huixiao, Huan, Jun, Irizarry, Rafael A, Judson, Richard, Juraeva, Dilafruz, Lababidi, Samir, Lambert, Christophe G, Li, Li, Li, Yanen, Li, Zhen, Lin, Simon M, Liu, Guozhen, Lobenhofer, Edward K, Luo, Jun, Luo, Wen, McCall, Matthew N, Nikolsky, Yuri, Pennello, Gene A, Perkins, Roger G, Philip, Reena, Popovici, Vlad, Price, Nathan D, Qian, Feng, Scherer, Andreas, Shi, Tieliu, Shi, Weiwei, Sung, Jaeyun, Thierry-Mieg, Danielle, Thierry-Mieg, Jean, Thodima, Venkata, Trygg, Johan, Vishnuvajjala, Lakshmi, Wang, Sue Jane, Wu, Jianping, Wu, Yichao, Xie, Qian, Yousef, Waleed A, Zhang, Liang, Zhang, Xuegong, Zhong, Sheng, Zhou, Yiming, Zhu, Sheng, Arasappan, Dhivya, Bao, Wenjun, Lucas, Anne Bergstrom, Berthold, Frank, Brennan, Richard J, Buness, Andreas, Catalano, Jennifer G, Chang, Chang, Chen, Rong, Cheng, Yiyu, Cui, Jian, Czika, Wendy, Demichelis, Francesca, Deng, Xutao, Dosymbekov, Damir, Eils, Roland, Feng, Yang, Fostel, Jennifer, Fulmer-Smentek, Stephanie, Fuscoe, James C, Gatto, Laurent, Ge, Weigong, Goldstein, Darlene R, Guo, Li, Halbert, Donald N, Han, Jing, Harris, Stephen C, Hatzis, Christos, Herman, Damir, Huang, Jianping, Jensen, Roderick V, Jiang, Rui, Johnson, Charles D, Jurman, Giuseppe, Kahlert, Yvonne, Khuder, Sadik A, Kohl, Matthias, Li, Jianying, Li, Menglong, Li, Quan-Zhen, Li, Shao, Li, Zhiguang, Liu, Jie, Liu, Ying, Liu, Zhichao, Meng, Lu, Madera, Manuel, Martinez-Murillo, Francisco, Medina, Ignacio, Meehan, Joseph, Miclaus, Kelci, Moffitt, Richard A, Montaner, David, Mukherjee, Piali, Mulligan, George J, Neville, Padraic, Nikolskaya, Tatiana, Ning, Baitang, Page, Grier P, Parker, Joel, Parry, R Mitchell, Peng, Xuejun, Peterson, Ron L, Phan, John H, Quanz, Brian, Ren, Yi, Riccadonna, Samantha, Roter, Alan H, Samuelson, Frank W, Schumacher, Martin M, Shambaugh, Joseph D, Shi, Qiang, Shippy, Richard, Si, Shengzhu, Smalter, Aaron, Sotiriou, Christos, Soukup, Mat, Staedtler, Frank, Steiner, Guido, Stokes, Todd H, Sun, Qinglan, Tan, Pei-Yi, Tang, Rong, Tezak, Zivana, Thorn, Brett, Tsyganova, Marina, Turpaz, Yaron, Vega, Silvia C, Visintainer, Roberto, von Frese, Juergen, Wang, Charles, Wang, Eric, Wang, Junwei, Wang, Wei, Westermann, Frank, Willey, James C, Woods, Matthew, Wu, Shujian, Xiao, Nianqing, Xu, Joshua, Xu, Lei, Yang, Lun, Zeng, Xiao, Zhang, Jialu, Zhang, Li, Zhang, Min, Zhao, Chen, Puri, Raj K, Scherf, Uwe, Tong, Weida, Wolfinger, Russell D, Shi, Leming, Campbell, Gregory, Jones, Wendell D, Campagne, Fabien, Wen, Zhining, Walker, Stephen J, Su, Zhenqiang, Chu, Tzu-Ming, Goodsaid, Federico M, Pusztai, Lajos, Shaughnessy, John D, Oberthuer, André, Thomas, Russell S, Paules, Richard S, Fielden, Mark, Barlogie, Bart, Chen, Weijie, Du, Pan, Fischer, Matthias, Furlanello, Cesare, Gallas, Brandon D, Ge, Xijin, Megherbi, Dalila B, Symmans, W Fraser, Wang, May D, Zhang, John, Bitter, Hans, Brors, Benedikt, Bushel, Pierre R, Bylesjö, Max, Chen, Minjun, Cheng, Jie, Cheng, Jing, Chou, Jeff, Davison, Timothy S, Delorenzi, Mauro, Deng, Youping, Devanarayan, Viswanath, Dix, David J, Dopazo, Joaquin, Dorff, Kevin C, Elloumi, Fathi, Fan, Jianqing, Fan, Shicai, Fan, Xiaohui, Fang, Hong, Gonzaludo, Nina, Hess, Kenneth R, Hong, Huixiao, Huan, Jun, Irizarry, Rafael A, Judson, Richard, Juraeva, Dilafruz, Lababidi, Samir, Lambert, Christophe G, Li, Li, Li, Yanen, Li, Zhen, Lin, Simon M, Liu, Guozhen, Lobenhofer, Edward K, Luo, Jun, Luo, Wen, McCall, Matthew N, Nikolsky, Yuri, Pennello, Gene A, Perkins, Roger G, Philip, Reena, Popovici, Vlad, Price, Nathan D, Qian, Feng, Scherer, Andreas, Shi, Tieliu, Shi, Weiwei, Sung, Jaeyun, Thierry-Mieg, Danielle, Thierry-Mieg, Jean, Thodima, Venkata, Trygg, Johan, Vishnuvajjala, Lakshmi, Wang, Sue Jane, Wu, Jianping, Wu, Yichao, Xie, Qian, Yousef, Waleed A, Zhang, Liang, Zhang, Xuegong, Zhong, Sheng, Zhou, Yiming, Zhu, Sheng, Arasappan, Dhivya, Bao, Wenjun, Lucas, Anne Bergstrom, Berthold, Frank, Brennan, Richard J, Buness, Andreas, Catalano, Jennifer G, Chang, Chang, Chen, Rong, Cheng, Yiyu, Cui, Jian, Czika, Wendy, Demichelis, Francesca, Deng, Xutao, Dosymbekov, Damir, Eils, Roland, Feng, Yang, Fostel, Jennifer, Fulmer-Smentek, Stephanie, Fuscoe, James C, Gatto, Laurent, Ge, Weigong, Goldstein, Darlene R, Guo, Li, Halbert, Donald N, Han, Jing, Harris, Stephen C, Hatzis, Christos, Herman, Damir, Huang, Jianping, Jensen, Roderick V, Jiang, Rui, Johnson, Charles D, Jurman, Giuseppe, Kahlert, Yvonne, Khuder, Sadik A, Kohl, Matthias, Li, Jianying, Li, Menglong, Li, Quan-Zhen, Li, Shao, Li, Zhiguang, Liu, Jie, Liu, Ying, Liu, Zhichao, Meng, Lu, Madera, Manuel, Martinez-Murillo, Francisco, Medina, Ignacio, Meehan, Joseph, Miclaus, Kelci, Moffitt, Richard A, Montaner, David, Mukherjee, Piali, Mulligan, George J, Neville, Padraic, Nikolskaya, Tatiana, Ning, Baitang, Page, Grier P, Parker, Joel, Parry, R Mitchell, Peng, Xuejun, Peterson, Ron L, Phan, John H, Quanz, Brian, Ren, Yi, Riccadonna, Samantha, Roter, Alan H, Samuelson, Frank W, Schumacher, Martin M, Shambaugh, Joseph D, Shi, Qiang, Shippy, Richard, Si, Shengzhu, Smalter, Aaron, Sotiriou, Christos, Soukup, Mat, Staedtler, Frank, Steiner, Guido, Stokes, Todd H, Sun, Qinglan, Tan, Pei-Yi, Tang, Rong, Tezak, Zivana, Thorn, Brett, Tsyganova, Marina, Turpaz, Yaron, Vega, Silvia C, Visintainer, Roberto, von Frese, Juergen, Wang, Charles, Wang, Eric, Wang, Junwei, Wang, Wei, Westermann, Frank, Willey, James C, Woods, Matthew, Wu, Shujian, Xiao, Nianqing, Xu, Joshua, Xu, Lei, Yang, Lun, Zeng, Xiao, Zhang, Jialu, Zhang, Li, Zhang, Min, Zhao, Chen, Puri, Raj K, Scherf, Uwe, Tong, Weida, and Wolfinger, Russell D

Abstract

Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, >30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.

Published
2010
Full Text
View/download PDF

41. The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models.

Author

DNAVision SA, Shi, Leming, Campbell, Gregory, Jones, Wendell D, Campagne, Fabien, Wen, Zhining, Walker, Stephen J, Su, Zhenqiang, Chu, Tzu-Ming, Goodsaid, Federico M, Pusztai, Lajos, Shaughnessy, John D, Oberthuer, André, Thomas, Russell S, Paules, Richard S, Fielden, Mark, Barlogie, Bart, Chen, Weijie, Du, Pan, Fischer, Matthias, Furlanello, Cesare, Gallas, Brandon D, Ge, Xijin, Megherbi, Dalila B, Symmans, W Fraser, Wang, May D, Zhang, John, Bitter, Hans, Brors, Benedikt, Bushel, Pierre R, Bylesjo, Max, Chen, Minjun, Cheng, Jie, Cheng, Jing, Chou, Jeff, Davison, Timothy S, Delorenzi, Mauro, Deng, Youping, Devanarayan, Viswanath, Dix, David J, Dopazo, Joaquin, Dorff, Kevin C, Elloumi, Fathi, Fan, Jianqing, Fan, Shicai, Fan, Xiaohui, Fang, Hong, Gonzaludo, Nina, Hess, Kenneth R, Hong, Huixiao, Huan, Jun, Irizarry, Rafael A, Judson, Richard, Juraeva, Dilafruz, Lababidi, Samir, Lambert, Christophe G, Li, Li, Li, Yanen, Li, Zhen, Lin, Simon M, Liu, Guozhen, Lobenhofer, Edward K, Luo, Jun, Luo, Wen, McCall, Matthew N, Nikolsky, Yuri, Pennello, Gene A, Perkins, Roger G, Philip, Reena, Popovici, Vlad, Price, Nathan D, Qian, Feng, Scherer, Andreas, Shi, Tieliu, Shi, Weiwei, Sung, Jaeyun, Thierry-Mieg, Danielle, Thierry-Mieg, Jean, Thodima, Venkata, Trygg, Johan, Vishnuvajjala, Lakshmi, Wang, Sue Jane, Wu, Jianping, Wu, Yichao, Xie, Qian, Yousef, Waleed A, Zhang, Liang, Zhang, Xuegong, Zhong, Sheng, Zhou, Yiming, Zhu, Sheng, Arasappan, Dhivya, Bao, Wenjun, Lucas, Anne Bergstrom, Berthold, Frank, Brennan, Richard J, Buness, Andreas, Catalano, Jennifer G, Chang, Chang, Chen, Rong, Cheng, Yiyu, Cui, Jian, Czika, Wendy, Demichelis, Francesca, Deng, Xutao, Dosymbekov, Damir, Eils, Roland, Feng, Yang, Fostel, Jennifer, Fulmer-Smentek, Stephanie, Fuscoe, James C, Gatto, Laurent, Ge, Weigong, Goldstein, Darlene R, Guo, Li, Halbert, Donald N, Han, Jing, Harris, Stephen C, Hatzis, Christos, Herman, Damir, Huang, Jianping, Jensen, Roderick V, Jiang, Rui, Johnson, Charles D, Jurman, Giuseppe, Kahlert, Yvonne, Khuder, Sadik A, Kohl, Matthias, Li, Jianying, Li, Menglong, Li, Quan-Zhen, Li, Shao, Li, Zhiguang, Liu, Jie, Liu, Ying, Liu, Zhichao, Meng, Lu, Madera, Manuel, Martinez-Murillo, Francisco, Medina, Ignacio, Meehan, Joseph, Miclaus, Kelci, Moffitt, Richard A, Montaner, David, Mukherjee, Piali, Mulligan, George J, Neville, Padraic, Nikolskaya, Tatiana, Ning, Baitang, Page, Grier P, Parker, Joel, Parry, R Mitchell, Peng, Xuejun, Peterson, Ron L, Phan, John H, Quanz, Brian, Ren, Yi, Riccadonna, Samantha, Roter, Alan H, Samuelson, Frank W, Schumacher, Martin M, Shambaugh, Joseph D, Shi, Qiang, Shippy, Richard, Si, Shengzhu, Smalter, Aaron, Sotiriou, Christos, Soukup, Mat, Staedtler, Frank, Steiner, Guido, Stokes, Todd H, Sun, Qinglan, Tan, Pei-Yi, Tang, Rong, Tezak, Zivana, Thorn, Brett, Tsyganova, Marina, Turpaz, Yaron, Vega, Silvia C, Visintainer, Roberto, von Frese, Juergen, Wang, Charles, Wang, Eric, Wang, Junwei, Wang, Wei, Westermann, Frank, Willey, James C, Woods, Matthew, Wu, Shujian, Xiao, Nianqing, Xu, Joshua, Xu, Lei, Yang, Lun, Zeng, Xiao, Zhang, Jialu, Zhang, Li, Zhang, Min, Zhao, Chen, Puri, Raj K, Scherf, Uwe, Tong, Weida, Wolfinger, Russell D, MAQC Consortium, DNAVision SA, Shi, Leming, Campbell, Gregory, Jones, Wendell D, Campagne, Fabien, Wen, Zhining, Walker, Stephen J, Su, Zhenqiang, Chu, Tzu-Ming, Goodsaid, Federico M, Pusztai, Lajos, Shaughnessy, John D, Oberthuer, André, Thomas, Russell S, Paules, Richard S, Fielden, Mark, Barlogie, Bart, Chen, Weijie, Du, Pan, Fischer, Matthias, Furlanello, Cesare, Gallas, Brandon D, Ge, Xijin, Megherbi, Dalila B, Symmans, W Fraser, Wang, May D, Zhang, John, Bitter, Hans, Brors, Benedikt, Bushel, Pierre R, Bylesjo, Max, Chen, Minjun, Cheng, Jie, Cheng, Jing, Chou, Jeff, Davison, Timothy S, Delorenzi, Mauro, Deng, Youping, Devanarayan, Viswanath, Dix, David J, Dopazo, Joaquin, Dorff, Kevin C, Elloumi, Fathi, Fan, Jianqing, Fan, Shicai, Fan, Xiaohui, Fang, Hong, Gonzaludo, Nina, Hess, Kenneth R, Hong, Huixiao, Huan, Jun, Irizarry, Rafael A, Judson, Richard, Juraeva, Dilafruz, Lababidi, Samir, Lambert, Christophe G, Li, Li, Li, Yanen, Li, Zhen, Lin, Simon M, Liu, Guozhen, Lobenhofer, Edward K, Luo, Jun, Luo, Wen, McCall, Matthew N, Nikolsky, Yuri, Pennello, Gene A, Perkins, Roger G, Philip, Reena, Popovici, Vlad, Price, Nathan D, Qian, Feng, Scherer, Andreas, Shi, Tieliu, Shi, Weiwei, Sung, Jaeyun, Thierry-Mieg, Danielle, Thierry-Mieg, Jean, Thodima, Venkata, Trygg, Johan, Vishnuvajjala, Lakshmi, Wang, Sue Jane, Wu, Jianping, Wu, Yichao, Xie, Qian, Yousef, Waleed A, Zhang, Liang, Zhang, Xuegong, Zhong, Sheng, Zhou, Yiming, Zhu, Sheng, Arasappan, Dhivya, Bao, Wenjun, Lucas, Anne Bergstrom, Berthold, Frank, Brennan, Richard J, Buness, Andreas, Catalano, Jennifer G, Chang, Chang, Chen, Rong, Cheng, Yiyu, Cui, Jian, Czika, Wendy, Demichelis, Francesca, Deng, Xutao, Dosymbekov, Damir, Eils, Roland, Feng, Yang, Fostel, Jennifer, Fulmer-Smentek, Stephanie, Fuscoe, James C, Gatto, Laurent, Ge, Weigong, Goldstein, Darlene R, Guo, Li, Halbert, Donald N, Han, Jing, Harris, Stephen C, Hatzis, Christos, Herman, Damir, Huang, Jianping, Jensen, Roderick V, Jiang, Rui, Johnson, Charles D, Jurman, Giuseppe, Kahlert, Yvonne, Khuder, Sadik A, Kohl, Matthias, Li, Jianying, Li, Menglong, Li, Quan-Zhen, Li, Shao, Li, Zhiguang, Liu, Jie, Liu, Ying, Liu, Zhichao, Meng, Lu, Madera, Manuel, Martinez-Murillo, Francisco, Medina, Ignacio, Meehan, Joseph, Miclaus, Kelci, Moffitt, Richard A, Montaner, David, Mukherjee, Piali, Mulligan, George J, Neville, Padraic, Nikolskaya, Tatiana, Ning, Baitang, Page, Grier P, Parker, Joel, Parry, R Mitchell, Peng, Xuejun, Peterson, Ron L, Phan, John H, Quanz, Brian, Ren, Yi, Riccadonna, Samantha, Roter, Alan H, Samuelson, Frank W, Schumacher, Martin M, Shambaugh, Joseph D, Shi, Qiang, Shippy, Richard, Si, Shengzhu, Smalter, Aaron, Sotiriou, Christos, Soukup, Mat, Staedtler, Frank, Steiner, Guido, Stokes, Todd H, Sun, Qinglan, Tan, Pei-Yi, Tang, Rong, Tezak, Zivana, Thorn, Brett, Tsyganova, Marina, Turpaz, Yaron, Vega, Silvia C, Visintainer, Roberto, von Frese, Juergen, Wang, Charles, Wang, Eric, Wang, Junwei, Wang, Wei, Westermann, Frank, Willey, James C, Woods, Matthew, Wu, Shujian, Xiao, Nianqing, Xu, Joshua, Xu, Lei, Yang, Lun, Zeng, Xiao, Zhang, Jialu, Zhang, Li, Zhang, Min, Zhao, Chen, Puri, Raj K, Scherf, Uwe, Tong, Weida, Wolfinger, Russell D, and MAQC Consortium

Abstract

Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, >30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.

Published
2010

42. DNA methylation epigenotypes in breast cancer molecular subtypes

Author

Bioquímica y biología molecular, Zoología y biología celular animal, Estomatología I, Biokimika eta biologia molekularra, Zoologia eta animalia zelulen biologia, Estomatologia I, García Bediaga, Naiara, Acha Sagredo, Amelia, Guerra, Isabel, Viguri, Amparo, Albaina, Carmen, Ruiz Díaz, Irune, Rezola, Ricardo, Alberdi, María Jesús, Dopazo, Joaquín, Montaner, David, Renobales Scheifler, María Mercedes de, Fernández Fernández, Agustín, Field, John K., Fraga, Mario F., Liloglou, Liloglou, Martínez de Pancorbo Gómez, María de los Angeles, Bioquímica y biología molecular, Zoología y biología celular animal, Estomatología I, Biokimika eta biologia molekularra, Zoologia eta animalia zelulen biologia, Estomatologia I, García Bediaga, Naiara, Acha Sagredo, Amelia, Guerra, Isabel, Viguri, Amparo, Albaina, Carmen, Ruiz Díaz, Irune, Rezola, Ricardo, Alberdi, María Jesús, Dopazo, Joaquín, Montaner, David, Renobales Scheifler, María Mercedes de, Fernández Fernández, Agustín, Field, John K., Fraga, Mario F., Liloglou, Liloglou, and Martínez de Pancorbo Gómez, María de los Angeles

Abstract

Introduction: Identification of gene expression-based breast cancer subtypes is considered a critical means of prognostication. Genetic mutations along with epigenetic alterations contribute to gene-expression changes occurring in breast cancer. So far, these epigenetic contributions to sporadic breast cancer subtypes have not been well characterized, and only a limited understanding exists of the epigenetic mechanisms affected in those particular breast cancer subtypes. The present study was undertaken to dissect the breast cancer methylome and to deliver specific epigenotypes associated with particular breast cancer subtypes. Methods: By using a microarray approach, we analyzed DNA methylation in regulatory regions of 806 cancer-related genes in 28 breast cancer paired samples. We subsequently performed substantial technical and biologic validation by pyrosequencing, investigating the top qualifying 19 CpG regions in independent cohorts encompassing 47 basal-like, 44 ERBB2+ overexpressing, 48 luminal A, and 48 luminal B paired breast cancer/adjacent tissues. With the all-subset selection method, we identified the most subtype-predictive methylation profiles in multivariable logistic regression analysis. Results: The approach efficiently recognized 15 individual CpG loci differentially methylated in breast cancer tumor subtypes. We further identified novel subtype-specific epigenotypes that clearly demonstrate the differences in the methylation profiles of basal-like and human epidermal growth factor 2 (HER2)-overexpressing tumors. Conclusions: Our results provide evidence that well-defined DNA methylation profiles enable breast cancer subtype prediction and support the utilization of this biomarker for prognostication and therapeutic stratification of patients with breast cancer.

Published
2010

47. DNA methylation epigenotypes in breast cancer molecular subtypes

Author

Bediaga, Naiara G, primary, Acha-Sagredo, Amelia, additional, Guerra, Isabel, additional, Viguri, Amparo, additional, Albaina, Carmen, additional, Ruiz Diaz, Irune, additional, Rezola, Ricardo, additional, Alberdi, María Jesus, additional, Dopazo, Joaquín, additional, Montaner, David, additional, de Renobales, Mertxe, additional, Fernández, Agustín F, additional, Field, John K, additional, Fraga, Mario F, additional, Liloglou, Triantafillos, additional, and de Pancorbo, Marian M, additional

Published
2010
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49. Initial Genomics of the Human Nucleolus

Author

Németh, Attila, primary, Conesa, Ana, additional, Santoyo-Lopez, Javier, additional, Medina, Ignacio, additional, Montaner, David, additional, Péterfia, Bálint, additional, Solovei, Irina, additional, Cremer, Thomas, additional, Dopazo, Joaquin, additional, and Längst, Gernot, additional

Published
2010
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50. Hypoxia Promotes Efficient Differentiation of Human Embryonic Stem Cells to Functional Endothelium

Author

Prado-Lopez, Sonia, primary, Conesa, Ana, additional, Armiñán, Ana, additional, Martínez-Losa, Magdalena, additional, Escobedo-Lucea, Carmen, additional, Gandia, Carolina, additional, Tarazona, Sonia, additional, Melguizo, Dario, additional, Blesa, David, additional, Montaner, David, additional, Sanz-González, Silvia, additional, Sepúlveda, Pilar, additional, Götz, Stefan, additional, O'Connor, José Enrique, additional, Moreno, Rubén, additional, Dopazo, Joaquín, additional, Burks, Deborah J., additional, and Stojkovic, Miodrag, additional

Published
2010
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