Simultaneous inhibition of pan-phosphatidylinositol-3-kinases and MEK as a potential therapeutic strategy in peripheral T-cell lymphomas

Obtained from Haematologica/the Hematology Journal website http://www.haematologica.orgPeripheral T-cell lymphomas are very aggressive hematologic malignancies for which there is no targeted therapy. New, rational approaches are necessary to improve the very poor outcome in these patients. Phosphatidylinositol- 3-kinase is one of the most important pathways in cell survival and proliferation. We hypothesized that phosphatidylinositol- 3-kinase inhibitors could be rationally selected drugs for treating peripheral T-cell lymphomas. Several phosphatidylinositol-3-kinase isoforms were inhibited genetically (using small interfering RNA) and pharmacologically (with CAL-101 and GDC-0941 compounds) in a panel of six peripheral and cutaneous T-cell lymphoma cell lines. Cell viability was measured by intracellular ATP content; apoptosis and cell cycle changes were checked by flow cytometry. Pharmacodynamic biomarkers were assessed by western blot. The PIK3CD gene, which encodes the δ isoform of phosphatidylinositol-3-kinase, was overexpressed in cell lines and primary samples, and correlated with survival pathways. However, neither genetic nor specific pharmacological inhibition of phosphatidylinositol-3-kinase δ affected cell survival. In contrast, the pan-phosphatidylinositol-3-kinase inhibitor GDC-0941 arrested all T-cell lymphoma cell lines in the G1 phase and induced apoptosis in a subset of them. We identified phospho-GSK3b and phospho-p70S6K as potential biomarkers of phosphatidylinositol-3-kinase inhibitors. Interestingly, an increase in ERK phosphorylation was observed in some GDC-0941-treated T-cell lymphoma cell lines, suggesting the presence of a combination of phosphatidylinositol-3-kinase and MEK inhibitors. A highly synergistic effect was found between the two inhibitors, with the combination enhancing cell cycle arrest at G0/G1 in all T-cell lymphoma cell lines, and reducing cell viability in primary tumor T cells ex vivo. These results suggest that the combined treatment of pan-phosphatidylinositol-3-kinase + MEK inhibitors could be more effective than single phosphatidylinositol-3-kinase inhibitor treatment, and therefore, that this combination could be of therapeutic value for treating peripheral and cutaneous T-cell lymphomas.This work was supported by grants from the Asociación Española Contra el Cáncer, Fondo de Investigaciones Sanitarias (PI051623, PI052800 and PI080856), RTICC (RD06/0020/0107) and Ministerio de Ciencia e Innovación (SAF2008-0387-1). EMS is supported by a grant from the Department of Education, Universities and Research of the Basque Government (BFI08.207). MSB is supported by a Contract Miguel Servet from Fondo de Investigaciones Sanitarias (CP11/00018

Destinos Turísticos II: Diseño de fichas tipo interactivas y Guía Docente para su estudio

El proyecto tiene como objetivo, el diseño de fichas de destinos turísticos tipo, acompañadas de guías docentes, que sirvan de modelo para que los alumnos puedan trabajar de forma interactiva dentro y fuera del aula en la confección de otros ejemplos similares

Clinical Predictors of Hyperperfusion Syndrome Following Carotid Stenting: Results From a National Prospective Multicenter Study

[Objectives] The aim of the HISPANIAS (HyperperfusIon Syndrome Post-carotid ANgIoplasty And Stenting) study was to define CHS rates and develop a clinical predictive model for cerebral hyperperfusion syndrome (CHS) after carotid artery stenting (CAS).[Background] CHS is a severe complication following CAS. The presence of clinical manifestations is estimated on the basis of retrospective reviews and is still uncertain.[Methods] The HISPANIAS study was a national prospective multicenter study with 14 recruiting hospitals. CHS was classified as mild (headache only) and moderate-severe (seizure, impaired level of consciousness, or development of focal neurological signs).[Results] A total of 757 CAS procedures were performed. CHS occurred in 22 (2.9%) patients, in which 16 (2.1%) had moderate-severe CHS and 6 (0.8%) had mild CHS (only headache). The rate of hemorrhages was 0.7% and was associated with high mortality (20%). Pre-operative predictors of moderate-severe CHS in multivariate analysis were female sex (odds ratio [OR]: 3.24; 95% confidence interval [CI]: 1.11 to 9.47; p = 0.03), older patients (OR: 1.09; 95% CI: 1.01 to 1.17; p = 0.02), left carotid artery treated (OR: 4.13; 95% CI: 1.11 to 15.40; p = 0.03), and chronic renal failure (OR: 6.29; 95% CI: 1.75 to 22.57; p = 0.005). The area under the curve of this clinical and radiological model was 0.86 (95% CI: 0.81 to 0.92; p = 0.001).[Conclusions] The rate of CHS in the HISPANIAS study was 2.9%, with moderate-severe CHS of 2.1%. CHS was independently associated with female sex, older age, history of chronic kidney disease, and a treated left carotid artery. Although further investigations are needed, the authors propose a model to identify high-risk patients and develop strategies to decrease CHS morbidity and mortality in the future.This study was supported by a Spanish grant from the Instituto de Salud Carlos III (ISCIII-FIS IP14/00971, 2014–2017). The ITRIBIS project has the registration number REGPOT-2013-1. Cooperative Cerebrovascular Disease Research Network (INVICTUS+) (RD16/0019/0015). Dr. Mancha is supported by a Río Hortega contract (CM16/00015). Abbott and Grifols have partial financial supported the conduction of the HISPANIAS project but had no role in the design of the study, interpretation of the data, or manuscript approval.Peer reviewe

Latin American dose survey results in mammography studies under IAEA Programme: Radiological Protection of Patients in Medical Exposures (TSA3)

Latin American countries (Argentina, Brazil, Chile, Costa Rica, Cuba, Ecuador, El Salvador, Guatemala, Mexico, Nicaragua, Paraguay, Uruguay and Venezuela) working under International Atomic Energy Agency (IAEA) Technical Cooperation Programme: TSA3 Radiological Protection of Patients in Medical Exposures have joined efforts in the optimization of radiation protection in mammography practice. Through surveys of patient doses, the region has a unique database of diagnostic reference levels for analog and digital equipment that will direct future optimization activities, towards the early detection of breast cancer among asymptomatic women. During RLA9/057 (2007-2009) 24 institutions participated with analog equipment in a dose survey. Regional training on methodology and measurement equipment was addressed in May 2007. Mean glandular dose (DG) was estimated using the incident kerma in air and relevant conversion coefficients for both projections craneo caudal and mediolateral oblique (CC and MLO). For phase two, RLA9/067 (2010-2011), it was decided to include also digital systems in order to see their impact in future dose optimization activities. Any new country that joined the project received training in the activities through IAEA expert missions. 29 new institutions participated (9 analog and 20 digital equipment). A total of 2262 patient doses were collected during this study and from them DG (mGy) for both projections were estimated for each institution and country. Regional results (75 percentile in mGy) show for CC and MLO respectively: RLA9/057 (analog) 2.63 and 3.17; RLA/067: 2.57 and 3.15 (analog) and 2.69 and 2.90 (digital). Regarding only digital equipment for CC and MLO respectively, computed radiography (CR) systems showed 2.59 and 2.78 and direct digital radiography (DDR) systems 2.78 and 3.04. Based on the IAEA Basic Safety Standard (BSS) reference dose (3mGy), it can be observed that there is enough room to start optimization processes in Latin America (LA); several countries or even particular institutions have values much higher than the 3mGy. Main issues to address are: lack of well established Quality Assurance (QA) programs for mammography, not enough medical physicists with training in mammography, an increase in patient doses with the introduction of digital equipment and to create awareness on radiation risk and optimization strategies,Fil: Mora, Patricia. Universidad de Costa Rica; Costa RicaFil: Blanco, Susana Alicia Ana. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Khoury, Helen. Universidade Federal de Pernambuco; BrasilFil: Leyton, Fernando. Universidad Diego Portales; Chile. Universidad de Tarapaca.; ChileFil: Cárdenas, Juan. Centro de Protección e Higiene de las Radiaciones; CubaFil: Defaz, María Yolanda. Hospital Oncológico Solca Núcleo de Quito; EcuadorFil: Escobar, Carolina. Unidad Reguladora de Radiaciones Ionizantes; El SalvadorFil: Flaviano Telón. Ministerio de Energía y Minas. Dirección General de Energía ; GuatemalaFil: García Aguilar, Juán. Instituto Nacional de Investigaciones Nucleares; MéxicoFil: Roas, Norma. Universidad Nacional Autónoma de Nicaragua; NicaraguaFil: Gamarra, Mirta. Ministerio de Salud Pública y Bienestar Social; ParaguayFil: Blanco, Daniel. Centro de Investigaciones Nucleares; UruguayFil: Quintero, Ana Rosa. Hospital Oncológico ‘Dr. Luis Razetti’; VenezuelaFil: Nader, Alejandro. Organización de Las Naciones Unidas; Argentina. International Atomic Energy Agency; Austri