Instituto Medicina Molecular

Lisbon, Portugal

Instituto Medicina Molecular

Lisbon, Portugal
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Caldeira D.,University of Lisbon | Caldeira D.,Instituto Medicina Molecular | Vaz-Carneiro A.,University of Lisbon | Vaz-Carneiro A.,Centro Colaborador Portugues da Rede Cochrane Iberoamericana | And 3 more authors.
Revista Portuguesa de Cardiologia | Year: 2014

Introduction and Objective Non-adherence to drug treatment is a major health problem. In Europe, it has been estimated that 9% of cardiovascular events can be attributed to non-adherence. The complexity of dosing regimens is one of the factors identified as contributing to non-adherence. In this systematic review we aimed to assess the impact of dosing frequency on adherence to drug treatment in patients with chronic cardiovascular disease.Methods MEDLINE and the Cochrane Library (November 2013) were searched for randomized controlled trials (RCTs) comparing different dosing regimens (once-daily administration vs. two or more daily administrations) and assessing adherence to therapy in patients with chronic cardiovascular disease. Only trials with at least five months of follow-up were included. The results of the studies were pooled through a random effects meta-analysis. Relative risk (RR) and 95% confidence interval (CI) were derived. Statistical heterogeneity was calculated using the I2 test.Results Four RCTs (a total of 2557 patients) were included. Dosing regimens with once-daily administration were associated with a significant 56% reduction in risk of non-adherence to drug therapy (RR: 0.44; 95% CI: 0.35-0.54, I2=25%). Conclusions Few clinical trials have assessed the long-term impact of dosing frequency on medication adherence in chronic cardiovascular disease. The best available evidence suggests that taking medication once daily decreases the risk of non-adherence to treatment by approximately 50%. The impact on clinical outcomes remains to be established. © 2014 Sociedade Portuguesa de Cardiologia. Published by Elsevier España, S.L.U. All rightsreserved.

Kehrer J.,University of Heidelberg | Singer M.,University of Heidelberg | Lemgruber L.,University of Heidelberg | Silva P.A.G.C.,Instituto Medicina Molecular | And 3 more authors.
PLoS Pathogens | Year: 2016

Regulated protein secretion is required for malaria parasite life cycle progression and transmission between the mammalian host and mosquito vector. During transmission from the host to the vector, exocytosis of highly specialised secretory vesicles, such as osmiophilic bodies, is key to the dissolution of the red blood cell and parasitophorous vacuole membranes enabling gamete egress. The positioning of adhesins from the TRAP family, from micronemes to the sporozoite surface, is essential for gliding motility of the parasite and transmission from mosquito to mammalian host. Here we identify a conserved role for the putative pantothenate transporter PAT in Plasmodium berghei in vesicle fusion of two distinct classes of vesicles in gametocytes and sporozoites. PAT is a membrane component of osmiophilic bodies in gametocytes and micronemes in sporozoites. Despite normal formation and trafficking of osmiophilic bodies to the cell surface upon activation, PAT-deficient gametes fail to discharge their contents, remain intraerythrocytic and unavailable for fertilisation and further development in the mosquito. Sporozoites lacking PAT fail to secrete TRAP, are immotile and thus unable to infect the subsequent rodent host. Thus, P. berghei PAT appears to regulate exocytosis in two distinct populations of vesicles in two different life cycle forms rather than acting as pantothenic transporter during parasite transmission. © 2016 Kehrer et al.

Rodrigues Dos Santos C.,Gulbenkian Programme for Advanced Medical Education | Rodrigues Dos Santos C.,Instituto Portugues Of Oncologia Of Lisbon | Domingues G.,Instituto Medicina Molecular | Matias I.,Instituto Medicina Molecular | And 4 more authors.
Lipids in Health and Disease | Year: 2014

Abstract. Lipids and cholesterol in particular, have long been associated with breast cancer (BC) onset and progression. However, the causative effects of elevated lipid levels and breast cancer remain largely undisclosed and were the subject of the present study.We took advantage of well-established in vitro and in vivo models of cholesterol enrichment to exploit the mechanism involved in LDL-cholesterol favouring BC growth and invasiveness. We analyzed its effects in models that mimic different BC subtypes and stages.Our data show that LDL-cholesterol (but not HDL-cholesterol) promotes BC cells proliferation, migration and loss of adhesion, hallmarks of the epithelial to mesenchymal transition. In vivo studies modeling cholesterol levels showed that breast tumors are consistently larger and more proliferative in hypercholesterolemic mice, which also have more frequently lung metastases. Microarray analysis revealed an over expression of intermediates of Akt and ERK pathways suggesting a survival response induced by LDL, confirmed by WB analyses. Gene expression analysis also evidenced an activation of ErbB2 signaling pathway and decreased expression of adhesion molecules (cadherin-related family member3, CD226, Claudin 7 and Ocludin) in the cells exposed to LDL.Together, the present work shows novel mechanistic evidence that high LDL-cholesterol levels promote BC progression. These data provide rationale for the clinical control of cholesterol levels in BC patients. © 2014 Rodrigues dos Santos et al.; licensee BioMed Central Ltd.

Monteiro J.,Josephine Nefkens Institute | Gaspar C.,Josephine Nefkens Institute | Gaspar C.,Instituto Medicina Molecular | Richer W.,University Pierre and Marie Curie | And 8 more authors.
Carcinogenesis | Year: 2014

Wnt signaling plays a central role in mammary stem cell (MaSC) homeostasis and in breast cancer. In particular, epigenetic alterations at different members of the Wnt pathway have been identified among triple-negative, basal-like breast cancers. Previously, we developed a mouse model for metaplastic breast adenocarcinoma, a subtype of triple-negative breast cancer, by targeting a hypomorphic mutations in the endogenous Apc gene (Apc1572T/+). Here, by employing the CD24 and CD29 cell surface antigens, we have identified a subpopulation of mammary cancer stem cells (MaCSCs) from Apc1572T/+ capable of self-renewal and differentiation both in vivo and in vitro. Moreover, immunohistochemical analysis of micro- and macrolung metastases and preliminary intravenous transplantation assays suggest that the MaCSCs underlie metastasis at distant organ sites. Expression profiling of the normal and tumor cell subpopulations encompassing MaSCs and CSCs revealed that the normal stem cell compartment is more similar to tumor cells than to their own differentiated progenies. Accordingly, Wnt signaling appears to be active in both the normal and cancer stem cell compartments, although at different levels. By comparing normal with cancer mouse mammary compartments, we identified a MaCSC gene signature able to predict outcome in breast cancer in man. Overall, our data indicate that constitutive Wnt signaling activation affects self-renewal and differentiation of MaSCs leading to metaplasia and basal-like adenocarcinomas. © The Author 2013. Published by Oxford University Press. All rights reserved.

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