Search results for "I3"
showing 10 items of 278 documents
Triple negative breast cancer: shedding light onto the role of pi3k/akt/mtor pathway
2016
// Daniela Massihnia 1,* , Antonio Galvano 1,* , Daniele Fanale 1 , Alessandro Perez 1 , Marta Castiglia 1 , Lorena Incorvaia 1 , Angela Listi 1 , Sergio Rizzo 1 , Giuseppe Cicero 1 , Viviana Bazan 1 , Sergio Castorina 2,3,** and Antonio Russo 1,** 1 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy 2 Fondazione Mediterranea “G.B. Morgagni”, Catania, Italy 3 Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy * These authors have contributed equally to this work ** Both the authors are last name Correspondence to: Antonio Russo, email: // Keywords : ER, HER2, PI3K/AKT/mTOR inhib…
Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab: preclinical characterization and phase I clinical…
2014
Abstract Purpose: Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin–like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination. Experimental Design: In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10–40 mg/day every day × 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored. Results: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were p…
PI3K pathway mutations and PTEN levels in primary and metastatic breast cancer.
2011
Abstract The purpose of this work was to determine whether there are differences in PIK3CA mutation status and PTEN protein expression between primary and matched metastatic breast tumors as this could influence patient management. Paraffin sections of 50 μm were used for DNA extraction and slides of 3 μm for immunohistochemistry (IHC) and FISH. Estrogen receptor, progesterone receptor, and HER2 IHC were repeated in a central laboratory for both primary tumors and metastases. PTEN levels were assessed by IHC and phosphoinositide 3-kinase (PI3K) pathway mutations were detected by a mass spectroscopy–based approach. Median age was 48 years (range: 30–83 years). Tumor subtype included 72% horm…
A First-in-Human Phase I Study of the ATP-Competitive AKT Inhibitor Ipatasertib Demonstrates Robust and Safe Targeting of AKT in Patients with Solid …
2016
Abstract Activation of AKT signaling by PTEN loss or PIK3CA mutations occurs frequently in human cancers, but targeting AKT has been difficult due to the mechanism-based toxicities of inhibitors that target the inactive conformation of AKT. Ipatasertib (GDC-0068) is a novel selective ATP-competitive small-molecule inhibitor of AKT that preferentially targets active phosphorylated AKT (pAKT) and is potent in cell lines with evidence of AKT activation. In this phase I study, ipatasertib was well tolerated; most adverse events were gastrointestinal and grade 1–2 in severity. The exposures of ipatasertib ≥200 mg daily in patients correlated with preclinical TGI90, and pharmacodynamic studies co…
Hypoxic macrophages impair autophagy in epithelial cells through Wnt1: relevance in IBD.
2014
A defective induction of epithelial autophagy may have a role in the pathogenesis of inflammatory bowel diseases. This process is regulated mainly by extracellular factors such as nutrients and growth factors and is highly induced by diverse situations of stress. We hypothesized that epithelial autophagy is regulated by the immune response that in turn is modulated by local hypoxia and inflammatory signals present in the inflamed mucosa. Our results reveal that HIF-1 alpha and Wnt1 were co-localized with CD68 in cells of the mucosa of IBD patients. We have observed increased protein levels of beta-catenin, phosphorylated mTOR, and p62 and decreased expression of LC3II in colonic epithelial …
Temsirolimus for the treatment of mantle cell lymphoma.
2010
Although recent progress has been made in the treatment of mantle cell lymphoma (MCL) the majority of patients experience relapse and ultimately die of their disease. The translocation t(11;14) is a prerequisite for the diagnosis of MCL and results in overexpression of cyclin D1. Its protein translation is controlled by mTOR, a key element of the PI3K/Akt pathway, and mTOR constitutes an attractive therapeutic target. Temsirolimus, a specific inhibitor of mTOR, has been evaluated in two Phase II trials in patients with relapsed MCL, and promising response rates up to 40% were found. Subsequently, a randomized Phase III trial was initiated, in which superiority in remission induction and pro…
Mediterranean diet and healthy ageing: a Sicilian perspective.
2014
Traditional Mediterranean diet (MedDiet) is a common dietary pattern characterizing a lifestyle and culture proven to contribute to better health and quality of life in Mediterranean countries. By analyzing the diet of centenarians from the Sicani Mountains and eating habits of inhabitants of Palermo, it is reported that a close adherence to MedDiet is observed in the countryside, whereas in big towns this adherence is not so close. This has an effect on the rates of mortality at old age (and reciprocally longevity) that are lower in the countryside than in big towns. Concerning the health effects of the diet, the low content of animal protein and the low glycaemic index of the Sicilian Med…
PTEN Mediates the Antioxidant Effect of Resveratrol at Nutritionally Relevant Concentrations
2014
Introduction.Antioxidant properties of resveratrol have been intensively studied for the last years, bothin vivoandin vitro. Its bioavailability after an oral dose is very low and therefore it is very important to make sure that plasma concentrations of free resveratrol are sufficient enough to be active as antioxidant.Aims.In the present study, using nutritionally relevant concentrations of resveratrol, we aim to confirm its antioxidant capacity on reducing peroxide levels and look for the molecular pathway involved in this antioxidant effect.Methods.We used mammary gland tumor cells (MCF-7), which were pretreated with different concentrations of resveratrol for 48 h, and/or a PTEN inhibit…
Transcriptomic metaanalyses of autistic brains reveals shared gene expression and biological pathway abnormalities with cancer
2019
Este es el artículo que se ha publicado de forma definitiva en: https://molecularautism.biomedcentral.com/articles/10.1186/s13229-019-0262-8 En este artículo también participa Joan Climent, Vera Pancaldi, Lourdes Fañanás, Celso Arango, Mara Parellada, Anaïs Baudot, Daniel Vogt, John L. Rubenstein, Alfonso Valencia y Rafael Tabarés-Seisdedos. Background: Epidemiological and clinical evidence points to cancer as a comorbidity in people with autism spectrum disorders (ASD). A significant overlap of genes and biological processes between both diseases has also been reported. Methods: Here, for the first time, we compared the gene expression profiles of ASD frontal cortex tissues and 22 cancer t…
Biphasic Erk1/2 activation sequentially involving Gs and Gi signaling is required in beta3-adrenergic receptor-induced primary smooth muscle cell pro…
2013
Abstract The beta3 adrenergic receptor (B3-AR) reportedly induces cell proliferation, but the signaling pathways that were proposed, involving either Gs or Gi coupling, remain controversial. To further investigate the role of G protein coupling in B3-AR induced proliferation, we stimulated primary human myometrial smooth muscle cells with SAR150640 (B3-AR agonist) in the absence or presence of variable G-protein inhibitors. Specific B3-AR stimulation led to an Erk1/2 induced proliferation. We observed that the proliferative effects of B3-AR require two Erk1/2 activation peaks (the first after 3 min, the second at 8 h). Erk1/2 activation at 3 min was mimicked by forskolin (adenylyl-cyclase a…