Imaging in pulmonary hypertension: Focus on the role of echocardiography

SummaryPatients with pulmonary hypertension must be evaluated using a multimodality approach to ensure a correct diagnosis and basal evaluation as well as a prognostic assessment. Beyond the assessment of pulmonary pressures, the echocardiographical examination allows the evaluation of right ventricular adaptation to elevated afterload. Numbers of variables are commonly used in the assessment of the pulmonary hypertension patient in order to detect changes in right heart geometry, right-to-left interaction and right ventricular dysfunction. Whereas an isolated change in one echocardiographical variable is not meaningful, multiple echocardiographical variable modifications together provide accurate information. In this review, we will link pulmonary hypertension pathophysiological changes with echocardiographical indices and describe the clinical implications of echocardiographical findings

Inactivation of class II PI3K-C2 alpha induces leptin resistance, age-dependent insulin resistance and obesity in male mice

AIMS/HYPOTHESIS: While the class I phosphoinositide 3-kinases (PI3Ks) are well-documented positive regulators of metabolism, the involvement of class II PI3K isoforms (PI3K-C2α, -C2β and -C2γ) in metabolic regulation is just emerging. Organismal inactivation of PI3K-C2β increases insulin signalling and sensitivity, whereas PI3K-C2γ inactivation has a negative metabolic impact. In contrast, the role of PI3K-C2α in organismal metabolism remains unexplored. In this study, we investigated whether kinase inactivation of PI3K-C2α affects glucose metabolism in mice. METHODS: We have generated and characterised a mouse line with a constitutive inactivating knock-in (KI) mutation in the kinase domain of the gene encoding PI3K-C2α (Pik3c2a). RESULTS: While homozygosity for kinase-dead PI3K-C2α was embryonic lethal, heterozygous PI3K-C2α KI mice were viable and fertile, with no significant histopathological findings. However, male heterozygous mice showed early onset leptin resistance, with a defect in leptin signalling in the hypothalamus, correlating with a mild, age-dependent obesity, insulin resistance and glucose intolerance. Insulin signalling was unaffected in insulin target tissues of PI3K-C2α KI mice, in contrast to previous reports in which downregulation of PI3K-C2α in cell lines was shown to dampen insulin signalling. Interestingly, no metabolic phenotypes were detected in female PI3K-C2α KI mice at any age. CONCLUSIONS/INTERPRETATION: Our data uncover a sex-dependent role for PI3K-C2α in the modulation of hypothalamic leptin action and systemic glucose homeostasis. ACCESS TO RESEARCH MATERIALS: All reagents are available upon request

Les adénomes hypophysaires familiaux isolés (étude d'une famille porteuse de la mutation du gène AIP (aryl-hydrocarbon receptor interacting protein) et revue de la littérrature)

TOURS-BU Médecine (372612103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Etude de la Myotubularine, une phosphoinositide phosphatase (fonction et implication dans l'action de l'insuline)

L'élaboration de nouvelles thérapies contre le diabète nécessite la compréhension des bases moléculaires de la résistance à l'insuline. Au cours de ma thèse, je me suis intéressée à la Myotubularine, une phosphatase mutée dans la myopathie myotubulaire liée au chromosome X. Nous avons montré que cette enzyme déphosphoryle spécifiquement la position D3 des phosphatidylinositol (3) et (3,5)-phosphate [PI(3)P et PI(3,5)P2]. De plus, nous avons observé que la surexpression de la Myotubularine dans les cellules musculaires L6 inhibe la translocation du transporteur de glucose GLUT4 à la membrane plasmique. Dans une deuxième partie, j'ai étudié l'effet d'une exposition prolongée à l'insuline sur le niveau des protéines Insulin Receptor Substrate-1/2 (IRS-1/2). Cette étude, réalisée dans des cellules musculaires et adipocytaires, a permis de mettre en évidence des différences de régulation entre IRS-1 et IRS-2 mais également une spécificité cellulaire de ces mécanismes. Notamment, dans les adipocytes 3T3L1, l'inhibition des histones déacétylases (HDACs) empêche en partie la baisse de la quantité de protéine IRS-1 (dégradation), probablement via une acétylation d'IRS-1. En revanche, dans les cellules musculaires L6, l'inhibition des HDACs empêche la baisse de la quantité d'ARNm d'IRS-1, mais pas d'IRS-2, vraisemblablement via acétylation de la chromatine au niveau de ce gène. L'ensemble de nos résultats démontre que la transduction du signal de l'insuline est régulée de façon importante au niveau des D3-phosphoinositides et des protéines IRS. Cette étude a en outre permis de mettre en évidence, pour la première fois que les HDACs participent à la régulation des composants de la voie de signalisation de l'insuline par l'hormone elle-même.NICE-BU Sciences (060882101) / SudocSudocFranceF

Phosphoinositide-3-kinase (PI3K) inhibitors: identification of new scaffolds using virtual screening

In the present work, we used virtual screening (VS) of the ZINC database of 2.5 million compounds to seek new PI3K inhibitory scaffolds. The VS flowchart implemented various filters, including a 3D-database screen, and extensive docking studies, to derive 89 derivatives that were experimentally assayed against the four PI3K isoforms. Seven compounds showed inhibitory activities between 1 and 100 microM, with four being sufficiently potent to constitute potential new scaffolds. The binding conformations of these four were analyzed to provide a rationalization of their activity profile

Syndecan-2 is a novel ligand for the protein tyrosine phosphatase receptor CD148

The proteoglycan syndecan-2 is a novel ligand for the tyrosine phosphatase receptor CD148, an interaction that stimulates a signaling pathway leading to integrin-mediated cell adhesion. The pathway involves SRC and PI3 kinases and is an example of cell surface receptor cross-talk influencing integrin-mediated cellular processes

Synthesis, biological evaluation and molecular modelling of sulfonohydrazides as selective PI3K p110α inhibitors

A series of 2-methyl-5-nitrobenzenesulfonohydrazides were prepared and evaluated as inhibitors of PI3K. An isoquinoline derivative shows good selectivity for the p110α isoform over p110β and p110δ, and also demonstrates good in vitro activity in a cell proliferation assay. Molecular modelling provides a rationalisation for the observed SAR. © 2007 Elsevier Ltd. All rights reserved

Effects of successive switches to different biosimilars infliximab on immunogenicity in chronic inflammatory diseases in daily clinical practice

International audienceObjective: To evaluatre the risk of immunogenicity in patients with chronic inflammatory diseases who experienced successive non-medical swiches to different biosimilars infliximab.Patients and methods: Observational study over a 3-year observation period assessing the risk of immunogenicity in i) patients in maintenance therapy with innovator infliximab who were successively switched to CT-P13, then to SB2 (cohort-1) and ii) biologic-naive patients initiated with CT-P13 before being switched to SB2 (cohort-2). A propotion meta-analysis was also performed, integrating our results to 16 additional studies.Results: Cohort-1 included 265 patients who switched to CT-P13, and 140 patients were subsequently switched to SB2. Among the 235 anti-drug antibody (ADA)-free patients at baseline, 20 patients (8.5%) developed ADA over the 3-year observation period (rate of 3 for 100 patient years). Cohort-2 included 44 patients, of whom 29 subsequently switched to SB2. A total of 11 patients (25%) developed ADA within 3 years (rate of 14 for 100 patients years). We found no influence of the number of biosimilars infliximab received on ADA deveopment in both cohorts. The risk of treatment discontinuation was significantly higher in patients with positive ADA in both cohorts. The meta-analysis including our data exposed an incidence of immunogenicity of 4.7% (95% CI 3.5-6.1%) after the switch from innovator infliximab to biosimilar infliximab and 21.1% (95% CI 13.1-30.3%) in patients initiating biosimilar infliximab.Conclusion: Immunogenicity was not favored by successive non-medical switches to biosimilars infliximab in our study, but was associated with treatment discontinuation