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Arteaga C.L.,Vanderbilt University | Sliwkowski M.X.,Genentech | Osborne C.K.,Baylor College of Medicine | Perez E.A.,Mayo Medical School | And 2 more authors.
Nature Reviews Clinical Oncology | Year: 2012

The advent of HER2-directed therapies has significantly improved the outlook for patients with HER2-positive early stage breast cancer. However, a significant proportion of these patients still relapse and die of breast cancer. Trials to define, refine and optimize the use of the two approved HER2-targeted agents (trastuzumab and lapatinib) in patients with HER2-positive early stage breast cancer are ongoing. In addition, promising new approaches are being developed including monoclonal antibodies and small-molecule tyrosine kinase inhibitors targeting HER2 or other HER family members, antibodies linked to cytotoxic moieties or modified to improve their immunological function, immunostimulatory peptides, and targeting the PI3K and IGF-1R pathways. Improved understanding of the HER2 signaling pathway, its relationship with other signaling pathways and mechanisms of resistance has also led to the development of rational combination therapies and to a greater insight into treatment response in patients with HER2-positive breast cancer. Based on promising results with new agents in HER2-positive advanced-stage disease, a series of large trials in the adjuvant and neoadjuvant settings are planned or ongoing. This Review focuses on current treatment for patients with HER2-positive breast cancer and aims to update practicing clinicians on likely future developments in the treatment for this disease according to ongoing clinical trials and translational research. © 2011 Macmillan Publishers Limited. All rights reserved. Source


Patent
Fondazione Centro San Raffaele Del Monte Tabor | Date: 2010-07-16

The instant invention refers to an optical method to extrapolate cell membrane conductance by indirect measurement of changes in transmembrane voltage, upon exposure of a cell sample to electric current pulses. The method is advantageously used for evaluating the activity of molecules able to alter, directly or indirectly, membrane permeability. A specific field of application is the screening of candidate compounds putatively acting on ion channel activity. In particular, it is open to the study of all ion channels with no limitations on the mechanisms of activation or to the ion species involved. The method is also advantageously used for evaluating a cell status, namely a differentiative or a pathologic status.


It is described in vitro methods for expanding, detecting or isolating rare populations of antigen specific memory T cells. It is also described an in vitro method for obtaining a genetically modified memory T cell population. Uses of cells so obtained are also disclosed.


Grant
Agency: Cordis | Branch: FP7 | Program: MC-IRG | Phase: FP7-PEOPLE-2009-RG | Award Amount: 100.00K | Year: 2011

Type 1 diabetes (T1D) is a chronic inflammatory disease, where predisposing genetic factors along with environmental influences result in loss of immunological tolerance and destruction of insulin-producing beta cells. Genetic studies have identified three main T1D susceptibility loci, the human leukocyte antigens (HLA), insulin and most recently PTPN22, which encodes for Lyp/Pep, a lymphoid tyrosine phosphatase. A single nucleotide polymorphism (SNP) in PTPN22 at codon 620 leads to one amino-acid substitution, Arg to Trp (R620W), associated with an increase in T1D risk. A perturbation in the effector (Teff) to regulatory T cell (Treg) equilibrium seems to be implicated in T1D and most cases of autoimmunity. Functional analysis in individuals carrying the R620W polymorphism indicate a gain of function mutant resulting in reduced TCR signaling. However, it is not currently known how PTPN22 is involved in mediating T1D susceptibility: effects on Treg and/or Teff thymic selection and peripheral homeostasis may be responsible. Understanding the mechanisms involved could be a key to our understanding of T1D pathogenesis. In addition, strategies that directly target Teff or Treg by inhibiting signaling from PTPN22 could be successful in halting T1D progression. The goal of this project is to analyze the role of PTPN22 on Treg and Teff equilibrium in (pre)diabetic human individuals and selected mouse models of T1D. The specific aims of this Marie-Curie RIG are: 1. Define the role of PTPN22 (R620W allele) on Treg and Teff cells in healthy versus (pre)diabetic individuals, and 2. Determine the role of PTPN22 signaling on Teff and/or Treg in two well-characterized murine models of T1D, (virally-induced [RIP-LCMV] and spontaneous [NOD]. Objectives to be achieved: 1. Functional characterization of PTPN22 mutation on Treg and Teff cells in (pre)diabetic human individuals. 2. Dissection of PTPN22 signaling in selected murine models of T1D crossed to Lyp/Pep deficient mice.


Grant
Agency: Cordis | Branch: FP7 | Program: MC-IRG | Phase: PEOPLE-2007-4-3.IRG | Award Amount: 100.00K | Year: 2010

The development of glial cells, oligodendrocytes (OL) in CNS and Schwann cells (SC) in PNS, critically depends on axonal contact. Gliogenesis and the phenotype of myelinating glia are regulated by axons. Glial cells promote neuronal survival, regulate the organization of myelinated axons and promote axonal differentiation and myelin sheath production. We recently showed that type III NRG1, a member of the Neuregulin1 (NRG1) family of proteins, is an essential instructive signal for myelination in PNS and directs the ensheathment fate of the axons. We also showed that type III NRG1 promotes CNS myelination and that myelination in CNS and PNS are differentially regulated. Previous studies indicate that membrane bound NRG1 are cleaved by secretases. Upon cleavage in the extracellular region type I and type II NRG1 are released from the neuronal membrane, while type III NRG1 remains tethered on the axonal surface and acts as a juxtacrine signal. The extracellular cleavage is likely to be mediated by the alpha-secretase TACE and by the beta-secretase BACE1. Our studies suggest that type III NRG1 intracellular cleavage is SC dependent and mediated by the gamma-secretase complex. In these studies we will determine the role of these cleavage events in myelination. We will analyze if lentiviruses expressing non-cleavable type III NRG1 can rescue in vitro myelination of type III NRG1 -/- neurons and if non-cleavable type I NRG1 proteins can substitute for type III NRG1. We will also investigate the nature of the molecules regulating NRG1 extracellular cleavage. We will focus on TACE and we will analyze in vitro and in vivo myelination in the absence of TACE. Finally, we will examine if type III NRG1 intracellular cleavage promotes neuronal survival. These studies will provide major insights into the role of type III NRG1 in myelination and will be relevant to develop new therapeutic strategies to promote axonal survival and remyelination.

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