IMIM Hospital del Mar

La Manga del Mar Menor, Spain

IMIM Hospital del Mar

La Manga del Mar Menor, Spain
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Grosdidier S.,IMIM Hospital del Mar | Fernandez-Recio J.,Barcelona Supercomputing Center
Current Pharmaceutical Design | Year: 2012

Most processes in living organisms occur through an intricate network of protein-protein interactions, in which any malfunctioning can lead to pathological situations. Therefore, current research in biomedicine is starting to focus on protein interaction networks. A detailed structural knowledge of these interactions at molecular level will be necessary for drug discovery targeting protein-protein interactions. The challenge from a structural biology point of view is determining the structure of the specific complex formed upon interaction of two or several proteins, and/or locating the surface residues involved in the interaction and identify which of them are the most important ones for binding (hot-spots). In this line, an increasing number of computer tools are available to complement experimental efforts. Docking algorithms can achieve successful predictive rates in many complexes, as shown in the community assessment experiment CAPRI, and have already been applied to a variety of cases of biomedical interest. On the other side, many methods for interface and hotspot prediction have been reported, based on a variety of evolutionary, geometrical and physico-chemical parameters. Computer predictions are reaching a significant level of maturity, and can be very useful to guide experiments and suggest mutations, or to provide a mechanistic framework to the experimental results on a given interaction. We will review here existing computer approaches for proteinprotein docking, interface prediction and hot-spot identification, with focus to drug discovery targeting protein-protein interactions. © 2012 Bentham Science Publishers.

Fuxe J.,Karolinska Institutet | Vincent T.,Cornell University | De Herreros A.G.,IMIM Hospital del Mar
Cell Cycle | Year: 2010

Tumor cells undergoing the epithelial-mesenchymal transition (EMT) acquire the capacity to migrate, invade the stroma and metastasize. EMT cells also acquire stem cell characteristics suggesting crosstalk between EMT and pathways involved in promoting cellular stemness (stem cell pathways) and that EMT may contribute to the generation of cancer stem cells. indeed, transforming growth factor-beta (TGFβ), a major inducer of EMT, cooperates with stem cell pathways like wnt, ras, Hedgehog and Notch to induce EMT. A molecular basis for this cooperative signaling is indicated by recent data showing that many EMT associated transcription factors like Snail1, Zeb1/2, Twist, β-catenin, Lef/TCF, Foxc2 and AP-1 interact with Smads and form EMT promoting Smad complexes (ePSC) engaged in either repressing epithelial genes or activating mesenchymal genes. Thus, formation and activation of ePSC represents a point of convergence between EMT and stem cell pathways. Here, we review our current understanding of the mechanisms involved in the transcriptional crosstalk between TGFβ and stem cell pathways and discuss how a fundament for the activation of these mechanisms may lead to the induction of EMT in tumors.

Deventer K.,Ghent University | Pozo O.J.,IMIM Hospital del Mar | Verstraete A.G.,Ghent University | Van Eenoo P.,Ghent University
TrAC - Trends in Analytical Chemistry | Year: 2014

In the past 20. years, liquid chromatography-mass spectrometry (LC-MS) has become a standard analytical technique in doping control and toxicology laboratories. Research groups have successfully applied it to detect substances by direct injection, or "dilute-and-shoot"-LC-MS (DS-LC-MS).However, some urinary components can precipitate into the vial, hampering the correct injection. Dissolved urinary matrix is responsible for shifted retention times and ion suppression or ion enhancement. To compensate for the effect of the matrix, an isotope-labeled internal standard (IL-ISTD) is the best choice.Dilution can also minimize the matrix effect, but can result in reduced analyte detectability. Hence, DS-LC-MS methods are predominantly available for substances for which the required urinary detection levels are high and that show good ionization efficiency.Taking into account the progressive increase in instrument sensitivity, we expect that the application of DS-LC-MS will also come available for substances with low required detection levels or limited ionization efficiency. © 2013 Elsevier Ltd.

Chen K.,Mount Sinai School of Medicine | Cerutti A.,Mount Sinai School of Medicine | Cerutti A.,IMIM Hospital del Mar
Immunity | Year: 2010

There are great interest and demand for the development of vaccines to prevent and treat diverse microbial infections. Mucosal vaccines elicit immune protection by stimulating the production of antibodies at mucosal surfaces and systemic districts. Being positioned in close proximity to a large community of commensal microbes, the mucosal immune system deploys a heterogeneous population of cells and a complex regulatory network to maintain the balance between surveillance and tolerance. A successful mucosal vaccine relies on leveraging the functions of these immune cells and regulatory components. We review the important cellular interactions and molecular pathways underlying the induction and regulation of mucosal antibody responses and discuss their implications on mucosal vaccination. © 2010 Elsevier Inc.

Chen K.,Mount Sinai School of Medicine | Cerutti A.,Mount Sinai School of Medicine | Cerutti A.,IMIM Hospital Del Mar
Immunological Reviews | Year: 2010

Immunoglobulin D (IgD) has remained a mysterious antibody class for almost half a century. IgD was initially thought to be a recently evolved Ig isotype expressed only by some mammalian species, but recent discoveries in fishes and amphibians demonstrate that IgD was present in the ancestor of all jawed vertebrates and has important immunological functions. The structure of IgD has been very dynamic throughout evolution. Mammals can express IgD through alternative splicing and class switch recombination. Active cell-dependent and T-cell-independent IgM-to-IgD class switching takes place in a unique subset of human B cells from the upper aerodigestive mucosa, which provides a layer of mucosal protection by interacting with many pathogens and their virulence factors. Circulating IgD can bind to myeloid cells such as basophils and induce antimicrobial, inflammatory, and B-cell-stimulating factors upon cross-linking, which contributes to not only immune surveillance but also inflammation and tissue damage when this pathway is overactivated under pathological conditions. Recent research shows that IgD is an important immunomodulator that orchestrates an ancestral surveillance system at the interface between immunity and inflammation. © 2010 John Wiley & Sons AS.

Cerutti A.,Catalan Institution for Research and Advanced Studies | Cerutti A.,IMIM Hospital del Mar | Cerutti A.,Mount Sinai School of Medicine | Puga I.,IMIM Hospital del Mar | Cols M.,Mount Sinai School of Medicine
Trends in Immunology | Year: 2011

Mature B cells generate protective immunity by undergoing immunoglobulin (Ig) class switching and somatic hypermutation, two Ig gene-diversifying processes that usually require cognate interactions with T cells that express CD40 ligand. This T cell-dependent pathway provides immunological memory but is relatively slow to occur. Thus, it must be integrated with a faster, T cell-independent pathway for B cell activation through CD40 ligand-like molecules that are released by innate immune cells in response to microbial products. Here, we discuss recent advances in our understanding of the interplay between the innate immune system and B cells, particularly at the mucosal interface. We also review the role of innate signals in the regulation of Ig diversification and production. © 2011 Elsevier Ltd.

Chen K.,Mount Sinai School of Medicine | Cerutti A.,Mount Sinai School of Medicine | Cerutti A.,IMIM Hospital del Mar
Current Opinion in Immunology | Year: 2011

Recent discoveries of IgD in ancient vertebrates suggest that IgD has been preserved in evolution from fish to human for important immunological functions. A non-canonical form of class switching from IgM to IgD occurs in the human upper respiratory mucosa to generate IgD-secreting B cells that bind respiratory bacteria and their products. In addition to enhancing mucosal immunity, IgD class-switched B cells enter the circulation to 'arm' basophils and other innate immune cells with secreted IgD. Although the nature of the IgD receptor remains elusive, cross-linking of IgD on basophils stimulates release of immunoactivating, proinflammatory and antimicrobial mediators. This pathway is dysregulated in autoinflammatory disorders such as hyper-IgD syndrome, indicating that IgD orchestrates an ancestral surveillance system at the interface between immunity and inflammation. © 2011 Elsevier Ltd.

Segura J.,IMIM Hospital Del Mar
Handbook of Experimental Pharmacology | Year: 2010

The list of prohibited substances in sports includes a group of masking agents that are forbidden in both in- and out-of-competition doping tests. This group consists of a series of compounds that are misused in sports to mask the administration of other doping agents, and includes: diuretics, used to reduce the concentration in urine of other doping agents either by increasing the urine volume or by reducing the excretion of basic doping agents by increasing the urinary pH; probenecid, used to reduce the concentration in urine of acidic compounds, such as glucuronoconjugates of some doping agents; 5α-reductase inhibitors, used to reduce the formation of 5α-reduced metabolites of anabolic androgenic steroids; plasma expanders, used to maintain the plasma volume after misuse of erythropoietin or red blood cells concentrates; and epitestosterone, used to mask the detection of the administration of testosterone. Diuretics may be also misused to achieve acute weight loss before competition in sports with weight categories. In this chapter, pharmacological modes of action, intended pharmacological effects for doping purposes, main routes of biotransformation and analytical procedures used for anti-doping controls to screen and confirm these substances will be reviewed and discussed. © 2009 Springer-Verlag Berlin Heidelberg.

De Herreros A.G.,IMIM Hospital Del Mar | Peiro S.,IMIM Hospital Del Mar | Nassour M.,French Institute of Health and Medical Research | Savagner P.,French Institute of Health and Medical Research
Journal of Mammary Gland Biology and Neoplasia | Year: 2010

Since its initial description, the interconversion between epithelial and mesenchymal cells (designed as epithelial-mesenchymal or mesenchymal-epithelial transition, EMTorMET, respectively) has received special attention since it provides epithelial cells with migratory features. Different studies using cell lines have identified cytokines, intercellular signaling elements and transcriptional factors capable of regulating this process. Particularly, the identification of Snail family members as key effectors of EMT has opened new ways for the study of this cellular process. In this article we discuss the molecular pathways that control EMT, showing a very tight and interdependent regulation. We also analyze the contribution of EMT and Snail genes in the process of tumorigenesis using the mammary gland as cellular model. © 2010 Springer Science+Business Media, LLC.

Garcia de Herreros A.,IMIM Hospital del Mar | Baulida J.,IMIM Hospital del Mar
Biochimica et Biophysica Acta - Reviews on Cancer | Year: 2012

The epithelial to mesenchymal transition (EMT) consists of a rapid change of cell phenotype, characterized by the loss of epithelial traits and the acquisition of a more motile phenotype reminiscent of a fibroblast. The study of this process has received considerable attention because of its potential role in the acquisition of several cancer traits, particularly in cell invasion. In this article we describe the current knowledge of the molecular mechanisms governing this transition. In particular we discuss how initiation of EMT is dependent on the mutually exclusive levels of the transmembrane cell to cell adhesion molecule E-cadherin and its transcriptional repressor Snail1 and how Snail1 and other E-cadherin transcriptional repressors drive the EMT process. We focus on several new aspects of Snail1 regulation and propose a model for understanding the initiation and progression of this transition, based on the existence of feed-back mechanisms that limit or amplify the response to extracellular cues. © 2012 Elsevier B.V..

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