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Sci Rep ; 10(1): 15284, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943714


Acute myocardial ischaemia and reperfusion (I-R) are major causes of ventricular arrhythmias in patients with a history of coronary artery disease. Ursodeoxycholic acid (UDCA) has previously been shown to be antiarrhythmic in fetal hearts. This study was performed to investigate if UDCA protects against ischaemia-induced and reperfusion-induced arrhythmias in the adult myocardium, and compares the effect of acute (perfusion only) versus prolonged (2 weeks pre-treatment plus perfusion) UDCA administration. Langendorff-perfused adult Sprague-Dawley rat hearts were subjected to acute regional ischaemia by ligation of the left anterior descending artery (10 min), followed by reperfusion (2 min), and arrhythmia incidence quantified. Prolonged UDCA administration reduced the incidence of acute ischaemia-induced arrhythmias (p = 0.028), with a reduction in number of ventricular ectopic beats during the ischaemic phase compared with acute treatment (10 ± 3 vs 58 ± 15, p = 0.036). No antiarrhythmic effect was observed in the acute UDCA administration group. Neither acute nor prolonged UDCA treatment altered the incidence of reperfusion arrhythmias. The antiarrhythmic effect of UDCA may be partially mediated by an increase in cardiac wavelength, due to the attenuation of conduction velocity slowing (p = 0.03), and the preservation of Connexin43 phosphorylation during acute ischaemia (p = 0.0027). The potential antiarrhythmic effects of prolonged UDCA administration merit further investigation.

Cancer Cell ; 34(4): 596-610.e11, 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30300581


Chimeric antigen receptor anti-CD19 (CAR19)-T cell immunotherapy-induced clinical remissions in CD19+ B cell lymphomas are often short lived. We tested whether CAR19-engineering of the CD1d-restricted invariant natural killer T (iNKT) cells would result in enhanced anti-lymphoma activity. CAR19-iNKT cells co-operatively activated by CD1d- and CAR19-CD19-dependent interactions are more effective than CAR19-T cells against CD1d-expressing lymphomas in vitro and in vivo. The swifter in vivo anti-lymphoma activity of CAR19-iNKT cells and their enhanced ability to eradicate brain lymphomas underpinned an improved tumor-free and overall survival. CD1D transcriptional de-repression by all-trans retinoic acid results in further enhanced cytotoxicity of CAR19-iNKT cells against CD19+ chronic lymphocytic leukemia cells. Thus, iNKT cells are a highly efficient platform for CAR-based immunotherapy of lymphomas and possibly other CD1d-expressing cancers.

Antígenos CD1d/genética , Terapia Baseada em Transplante de Células e Tecidos , Linfoma/tratamento farmacológico , Células T Matadoras Naturais/citologia , Animais , Antígenos CD19/genética , Antígenos CD19/imunologia , Antígenos CD1d/imunologia , Humanos , Imunoterapia/métodos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/imunologia , Linfoma/imunologia , Camundongos , Células T Matadoras Naturais/imunologia
Comput Biol Med ; 102: 315-326, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30025847


Atrial and ventricular fibrillation are complex arrhythmias, and their underlying mechanisms remain widely debated and incompletely understood. This is partly because the electrical signals recorded during myocardial fibrillation are themselves complex and difficult to interpret with simple analytical tools. There are currently a number of analytical approaches to handle fibrillation data. Some of these techniques focus on mapping putative drivers of myocardial fibrillation, such as dominant frequency, organizational index, Shannon entropy and phase mapping. Other techniques focus on mapping the underlying myocardial substrate sustaining fibrillation, such as voltage mapping and complex fractionated electrogram mapping. In this review, we discuss these techniques, their application and their limitations, with reference to our experimental and clinical data. We also describe novel tools including a new algorithm to map microreentrant circuits sustaining fibrillation.

Fibrilação Atrial/diagnóstico por imagem , Eletrocardiografia , Coração/diagnóstico por imagem , Miocárdio/patologia , Fibrilação Ventricular/diagnóstico por imagem , Algoritmos , Animais , Linhagem Celular , Técnicas Eletrofisiológicas Cardíacas/métodos , Entropia , Átrios do Coração/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Processamento de Sinais Assistido por Computador
J Mol Cell Cardiol ; 119: 155-164, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29746849


Fibrillation is the most common arrhythmia observed in clinical practice. Understanding of the mechanisms underlying its initiation and maintenance remains incomplete. Functional re-entries are potential drivers of the arrhythmia. Two main concepts are still debated, the "leading circle" and the "spiral wave or rotor" theories. The homogeneous subclone of the HL1 atrial-derived cardiomyocyte cell line, HL1-6, spontaneously exhibits re-entry on a microscopic scale due to its slow conduction velocity and the presence of triggers, making it possible to examine re-entry at the cellular level. We therefore investigated the re-entry cores in cell monolayers through the use of fluorescence optical mapping at high spatiotemporal resolution in order to obtain insights into the mechanisms of re-entry. Re-entries in HL1-6 myocytes required at least two triggers and a minimum colony area to initiate (3.5 to 6.4 mm2). After electrical activity was completely stopped and re-started by varying the extracellular K+ concentration, re-entries never returned to the same location while 35% of triggers re-appeared at the same position. A conduction delay algorithm also allows visualisation of the core of the re-entries. This work has revealed that the core of re-entries is conduction blocks constituted by lines and/or groups of cells rather than the round area assumed by the other concepts of functional re-entry. This highlights the importance of experimentation at the microscopic level in the study of re-entry mechanisms.

Fibrilação Atrial/metabolismo , Átrios do Coração/metabolismo , Miócitos Cardíacos/citologia , Animais , Fibrilação Atrial/fisiopatologia , Linhagem Celular , Átrios do Coração/citologia , Átrios do Coração/fisiopatologia , Humanos , Modelos Cardiovasculares , Miócitos Cardíacos/metabolismo , Codorniz
EBioMedicine ; 2(7): 642-8, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26288836


The proteasome inhibitor Bortezomib is used to treat multiple myeloma (MM). Bortezomib inhibits protein degradation by inactivating proteasomes' active-sites. MM cells are exquisitely sensitive to Bortezomib - exhibiting a low-nanomolar IC(50) - suggesting that minimal inhibition of degradation suffices to kill MM cells. Instead, we report, a low Bortezomib concentration, contrary to expectation, achieves severe inhibition of proteasome activity in MM cells: the degree of inhibition exceeds what one would expect from the small proportion of active-sites that Bortezomib inhibits. Our data indicate that Bortezomib achieves this severe inhibition by triggering secondary changes in proteasome structure that further inhibit proteasome activity. Comparing MM cells to other, Bortezomib-resistant, cancer cells shows that the degree of proteasome inhibition is the greatest in MM cells and only there leads to proteasome stress, providing an explanation for why Bortezomib is effective against MM but not other cancers.

Bortezomib/farmacologia , Espaço Intracelular/enzimologia , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Humanos , Mieloma Múltiplo/patologia
Biochim Biophys Acta ; 1844(12): 2222-8, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25192768


We report that subunits of human nuclear proteasomes carry a previously unrecognised, constitutive posttranslational modification. Subunits with this modification are not visualised by SDS-PAGE, which is used in almost all denaturing protein gel electrophoresis. In contrast, CTAB-PAGE readily visualises such modified subunits. Thus, under most experimental conditions, with identical samples, SDS-PAGE yielded gel electrophoresis patterns for subunits of nuclear proteasomes which were misleading and strikingly different from those obtained with CTAB-PAGE. Initial analysis indicates a novel modification of a high negative charge with some similarity to polyADP-ribose, possibly explaining compatibility with (positively-charged) CTAB-PAGE but not (negatively-charged) SDS-PAGE and providing a mechanism for how nuclear proteasomes may interact with chromatin, DNA and other nuclear components.