Hvivo Services Limited

Institut National De La Sante Et De La Recherche Medicale

Ludwig Institute for Cancer Research Limited

Université Paul Sabatier (Toulouse III)

University College London

Centre Hospitalier Universitaire De Toulouse

Université De Caen Normandie

Centre Hospitalier Regional Universitaire De Caen

University of London

Bart Vanhaesebroeck

Pedro Rodriguez Cutillas

Michael Derek Waterfield

Denis Vivien

Marie-Pierre Gratacap

Jean Darcourt

Vincent Larrue

Typhaine Anquetil

Aude Jaffre

Bernard Payrastre

Romain Solinhac

Luisa Marie Beltran

Gaëtan Chicanne

Ischemic conditions are a leading cause of death for both men and women. Ischemia, a condition characterized by reduced blood flow and oxygen to an organ. Re-establishment of blood flow, or reperfusion, and re-oxygenation of the affected area following an ischemic episode is critical to limit irreversible damage. However, reperfusion also associates potentially damaging consequences. For instance, increased vascular permeability is an important contributor to edema and tissue damage following ischemic events. Here the inventors shows that genetic inhibition of PI3K-C2β reduces cerebral infarction in two ischemia/reperfusion (I/R) models and improves neurological outcome. The genetic inhibition stabilizes the blood-brain barrier (BBB) after ischemic stroke and reduces inflammation. Accordingly, the present invention relates to a method for the preservation of vascular endothelial cell barrier integrity in a patient in need thereof comprising administering to the subject a therapeutically effective amount of a PI3KC2β inhibitor.

Use of PI3KC2B inhibitors for the preservation of vascular endothelial cell barrier integrity

The present invention provides a method for identifying differential activation of a bisubstrate protein modifying enzyme between samples, comprising:

Method for identifying activation of transferases

The present invention provides a method for quantifying modified peptides in a sample, the method comprising: (a) obtaining peptides from the sample; (b) adding reference modified peptides to the peptides obtained in step (a) to produce a mixture of peptides and reference modified peptides; (c) carrying out mass spectrometry (MS) on said mixture of peptides and reference modified peptides to obtain data relating to the peptides in the sample; and (d) comparing the data relating to the peptides in the sample with data in a database of modified peptides using a computer program; wherein the database of modified peptides is compiled by a method comprising: (i) obtaining peptides from a sample; (ii) enriching modified peptides from the peptides obtained in step (i); (iii) carrying out liquid chromatography-tandem mass spectrometry (LC-MS/MS) on the enriched modified peptides obtained in step (ii); (iv) comparing the modified peptides detected in step (iii) to a known reference database in order to identify the modified peptides; and (v) compiling data relating to the modified peptides identified in step (iv) into a database.

Method for quantifying modified peptides

The invention relates to a novel lipid kinase which is part of the PI3 Kinase family. PI3 Kinases catalyze the addition of phosphate to inositol generating inositol mono, di and triphosphate. Inositol phosphates have been implicated in regulating intracellular signalling cascades resulting in alternations in gene expression which, amongst other effects, can result in cytoskeletal remodelling and modulation of cellular motility. More particularly the invention relates to a novel human PI3 Kinase, p110&dgr; which interacts with p85, has a broad phosphoinositide specificity and is sensitive to the same kinase inhibitors as PI3 Kinase p110&agr;. However in contrast to previously identified PI3 Kinases which show a ubiquitous pattern of expression, p110&dgr; is selectively expressed in leucocytes. Importantly, p110&dgr; shows enchanced expression in most melanomas tested and therefore may play a crucial role in regulating the metastatic property exhibited by melanomas. The identification of agents that enhance or reduce p110&dgr; activity may therefore prevent cancer metastasis.

Lipid kinase

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London, United Kingdom

Bart Vanhaesebroeck