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Clau-Terre F.,Vall dHebron Research Institute | Sharma V.,St Georges Healthcare NHS Trust | Cholley B.,Service danesthesie reanimation | Gonzalez-Alujas T.,University of Barcelona | And 3 more authors.
Anesthesiology | Year: 2014

There has been a recent explosion of education and training in echocardiography in the specialties of anesthesiology and critical care. These devices, by their impact on clinical management, are changing the way surgery is performed and critical care is delivered. A number of international bodies have made recommendations for training and developed examinations and accreditations. The challenge to medical educators in this area is to deliver the training needed to achieve competence into already overstretched curricula. The authors found an apparent increase in the use of simulators, with proven efficacy in improving technical skills and knowledge. There is still an absence of evidence on how it should be included in training programs and in the accreditation of certain levels. There is a conviction that this form of simulation can enhance and accelerate the understanding and practice of echocardiography by the anesthesiologist and intensivists, particularly at the beginning of the learning curve. © 2013, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins.

Koga H.,Yeshiva University | Martinez-Vicente M.,Yeshiva University | Martinez-Vicente M.,Vall dHebron Research Institute | MacIan F.,Yeshiva University | And 2 more authors.
Nature Communications | Year: 2011

Chaperone-mediated autophagy (CMA) is a selective mechanism for the degradation of soluble proteins in lysosomes. CMA contributes to cellular quality control and is activated as part of the cellular response to different stressors. Defective CMA has been identified in ageing and different age-related diseases. Until now, CMA activity could only be measured in vitro using isolated lysosomes. Here we report the development of a photoconvertible fluorescent reporter that allows monitoring of CMA activity in living cells. Activation of CMA increases the association of the reporter with lysosomes which can be visualized as a change in the intracellular fluorescence. The CMA reporter can be utilized in a broad variety of cells and is suitable for high-content microscopy. Using this reporter, we find that levels of basal and inducible CMA activity are cell-type dependent, and we have identified an upregulation of this pathway in response to the catalytic inhibition of the proteasome. © 2011 Macmillan Publishers Limited. All rights reserved.

Rafael D.,University of Lisbon | Doktorovova S.,University of Lisbon | Florindo H.F.,University of Lisbon | Gener P.,Vall dHebron Research Institute | And 3 more authors.
Current Gene Therapy | Year: 2015

Epithelial Mesenchymal Transition (EMT) is an event where epithelial cells acquire mesenchymal-like phenotype. EMT can occur as a physiological phenomenon during tissue development and wound healing, but most importantly, EMT can confer highly invasive properties to epithelial carcinoma cells. The impairment of E-cadherin expression, an essential cell-cell adhesion protein, together with an increase in the expression of mesenchymal markers, such as N-cadherin, vimentin, and fibronectin, characterize the EMT process and are usually correlated with tumor migration, and metastization. A wide range of micro-environmental and intracellular factors regulate tumor development and progression. The dynamic cross-talk between the adhesion-related proteins such as E-cadherin and the EMT-related transcription factors, with special focus on TWIST, will be discussed here, with the aim of finding a suitable biological pathway to be used as potential target for cancer therapy. Emerging concepts such as the role of the PI3K/AKT/TWIST pathway in the regulation of the E-cadherin expression will be highlighted, since it seems to be consistently involved in cells EMT. The wellknown efficacy of the RNA interference as a tool to silence the expression of specific proteins has come into focus as a strategy to control different tumor sub-populations. Despite the oligonucleotides enormous sensitivity and low in vivo stability, new (nano)technological solutions are expected to enable RNAi clinical application in cancer therapy. © 2015 Bentham Science Publishers.

Balbuena J.,University of Navarra | Pachon G.,Vall dHebron Research Institute | Lopez-Torrents G.,Vall dHebron Research Institute | Aran J.M.,IDIBELL | And 2 more authors.
Cytometry Part A | Year: 2011

The Sonic Hedgehog (Hh) pathway has been implicated in the maintenance of stem or progenitor cells in many adult tissues. Importantly, abnormal Hh pathway activation is also associated with initiation of neoplasia, but its role in tumor growth is still unclear. Here, we demonstrate that cyclopamine, a plant-derived alkaloid product used to inhibit the Hh signaling pathway, reduces the Side Population (SP) obtained by Hoechst 33342 (Ho342) dye measurements. In addition, cyclopamine is able to modulate, along with oxysterols and other products, the ABCG2 transporter by increasing Ho342 and mitoxantrone uptake. Therefore, if the SP is solely measured as a Ho342 dye extruding fraction, this may be significantly modulated by the inhibition of ABCG2 transport fraction, independently from the action of cyclopamine on the Hh pathway. Our results indicate that ABCG2 may act in the upstream regulation of the Hh signaling pathway to protect the stemness of the SP compartment, giving support to the cancer stem cell hypothesis and suggesting that ABCG2 is not only critical for increased resistance to anticancer agents. © 2011 International Society for Advancement of Cytometry.

Dehay B.,University of Bordeaux Segalen | Martinez-Vicente M.,Vall dHebron Research Institute | Caldwell G.A.,University of Alabama | Caldwell G.A.,University of Alabama at Birmingham | And 9 more authors.
Movement Disorders | Year: 2013

Impairment of autophagy-lysosomal pathways (ALPs) is increasingly regarded as a major pathogenic event in neurodegenerative diseases, including Parkinson's disease (PD). ALP alterations are observed in sporadic PD brains and in toxic and genetic rodent models of PD-related neurodegeneration. In addition, PD-linked mutations and post-translational modifications of α-synuclein impair its own lysosomal-mediated degradation, thereby contributing to its accumulation and aggregation. Furthermore, other PD-related genes, such as leucine-rich repeat kinase-2 (LRRK2), parkin, and phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), have been mechanistically linked to alterations in ALPs. Conversely, mutations in lysosomal-related genes, such as glucocerebrosidase (GBA) and lysosomal type 5 P-type ATPase (ATP13A2), have been linked to PD. New data offer mechanistic molecular evidence for such a connection, unraveling a causal link between lysosomal impairment, α-synuclein accumulation, and neurotoxicity. First, PD-related GBA deficiency/mutations initiate a positive feedback loop in which reduced lysosomal function leads to α-synuclein accumulation, which, in turn, further decreases lysosomal GBA activity by impairing the trafficking of GBA from the endoplasmic reticulum-Golgi to lysosomes, leading to neurodegeneration. Second, PD-related mutations/deficiency in the ATP13A2 gene lead to a general lysosomal impairment characterized by lysosomal membrane instability, impaired lysosomal acidification, decreased processing of lysosomal enzymes, reduced degradation of lysosomal substrates, and diminished clearance of autophagosomes, collectively contributing to α-synuclein accumulation and cell death. According to these new findings, primary lysosomal defects could potentially account for Lewy body formation and neurodegeneration in PD, laying the groundwork for the prospective development of new neuroprotective/disease-modifying therapeutic strategies aimed at restoring lysosomal levels and function. © 2013 Movement Disorder Society.

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