Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells

Nitric oxide (NO) plays a relevant role during cell death regulation in tumor cells. The overexpression of nitric oxide synthase type III (NOS-3) induces oxidative and nitrosative stress, p53 and cell death receptor expression and apoptosis in hepatoblastoma cells. S-nitrosylation of cell death receptor modulates apoptosis. Sorafenib is the unique recommended molecular-targeted drug for the treatment of patients with advanced hepatocellular carcinoma. The present study was addressed to elucidate the potential role of NO during Sorafenib-induced cell death in HepG2 cells. We determined the intra- and extracellular NO concentration, cell death receptor expression and their S-nitrosylation modifications, and apoptotic signaling in Sorafenib-treated HepG2 cells. The effect of NO donors on above parameters has also been determined. Sorafenib induced apoptosis in HepG2 cells. However, low concentration of the drug (10nM) increased cell death receptor expression, as well as caspase-8 and -9 activation, but without activation of downstream apoptotic markers. In contrast, Sorafenib (10 µM) reduced upstream apoptotic parameters but increased caspase-3 activation and DNA fragmentation in HepG2 cells. The shift of cell death signaling pathway was associated with a reduction of S-nitrosylation of cell death receptors in Sorafenib-treated cells. The administration of NO donors increased S-nitrosylation of cell death receptors and overall induction of cell death markers in control and Sorafenib-treated cells. In conclusion, Sorafenib induced alteration of cell death receptor S-nitrosylation status which may have a relevant repercussion on cell death signaling in hepatoblastoma cells.Instituto de Salud Carlos III PI13/00021Ministerio de Economía y Competitividad BFU2012-32056Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía BIO-0216Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía CTS-6264Consejería de Salud, Junta de Andalucía PI13/ 0002

Glycemic index, glycemic load and invasive breast cancer incidence in postmenopausal women: The PREDIMED study

The objective of this study was to evaluate the prospective associations between dietary glycemic index (GI) and glycemic load (GL) and the risk for invasive breast cancer incidence in postmenopausal women at high cardiovascular disease (CVD) risk. This study was conducted within the framework of the PREvención con DIeta MEDiterránea (PREDIMED) study, a nutritional intervention trial for primary cardiovascular prevention. We included 4010 women aged between 60 and 80 years who were initially free from breast cancer but at high risk for CVD disease. Dietary information was collected using a validated 137-item food frequency questionnaire. We assigned GI values using the International Tables of GI and GL values. Cases were ascertained through yearly consultation of medical records and through consultation of the National Death Index. Only cases confirmed by results from cytology tests or histological evaluation were included. We estimated multivariable-adjusted hazard ratios for invasive breast cancer risk across tertiles of energy-adjusted dietary GI/GL using Cox regression models. We repeated our analyses using yearly repeated measures of GI/GL intakes. No associations were found between baseline dietary GI/GL and invasive breast cancer incidence. The multivariable hazard ratio and 95% confidence interval (CI) for the top tertile of dietary GI was 1.02 (95% CI: 0.42–2.46) and for dietary GL was 1.00 (95% CI: 0.44–2.30) when compared with the bottom tertile. Repeated-measures analyses yielded similar results. In sensitivity analyses, no significant associations were observed for women with obesity or diabetes. Dietary GI and GL did not appear to be associated with an increased risk for invasive breast cancer in postmenopausal women at high CVD risk

Association Between Preexisting Versus Newly Identified Atrial Fibrillation and Outcomes of Patients With Acute Pulmonary Embolism

Background Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. Methods and Results Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2 days from acute PE (incident AF), and (3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16 497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90-day all-cause (odds ratio [OR], 2.81; 95% CI, 2.33-3.38) and PE-related mortality (OR, 2.38; 95% CI, 1.37-4.14) and increased 1-year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10-9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of all-cause mortality (OR, 1.91; 95% CI, 1.57-2.32) but not PE-related mortality (OR, 1.50; 95% CI, 0.85-2.66). Among 16 497 patients with PE, 445 developed new incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR, 2.28; 95% CI, 1.75-2.97) and PE-related (OR, 3.64; 95% CI, 2.01-6.59) mortality but not stroke. Findings were similar in multivariable analyses. Conclusions In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset.info:eu-repo/semantics/publishedVersio

Estudio comparativo de los modelos de estimación de riesgo cardiovascular para la población española

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Medicina, leída el 05-07-2017Las enfermedades cardiovasculares continúan liderando las causas por mortalidad en nuestro medio y son una importante fuente de morbilidad para la población, constituyendo un importante problema de Salud Pública. En el siglo pasado, la comunidad científica aunó esfuerzos por lograr modelos estadísticos predictivos acerca del riesgo cardiovascular de la población mediante métodos de regresión logística. El primero en confeccionarse fue el modelo americano, sobre la población de Framingham y que ha constituido el paradigma de los modelos subsiguientes. Posteriormente, algunos autores descubrieron discordancias al aplicar tal modelo sobre diferentes poblaciones no americanas (entre ellas europeas), lo que llevó a la conclusión de que se necesitaría un modelo diferente para el continente europeo. Ello se fundamentó en la diferente distribución en la prevalencia de los factores de riesgo cardiovascular que constituyen la esencia de los modelos. Ese modelo fue llamado, por su acrónimo, SCORE. No obstante, años más tarde se constataron nuevas discordancias cuando se aplicaba el modelo europeo a las diferentes poblaciones europeas, por lo que se optó por dividir a los países según presentaran alto o bajo riesgo cardiovascular, realizando un modelo para cada grupo. Actualmente se dispone de una versión de esta herramienta en internet, con el fin de hacerla más accesible. A nivel de la nación española se confeccionaron dos modelos con metodología diferente: REGICOR fue realizado sobre una población mediterránea concreta (Girona) y DORICA fue realizada recolectando datos sobre la prevalencia de los factores cardiovasculares de nueve comunidades autónomas. En cuanto a las variables participantes en cada modelo de estimación del riesgo cardiovascular hay algunas diferencias, sin embargo, la edad, la presencia o ausencia de Diabetes Mellitus, la presencia o ausencia de tabaquismo, presión arterial, colesterol y el género son constantes. Algunos modelos utilizan la presión arterial incluyendo solo la presión arterial sistólica (PAS) y otros usan el mayor valor entre la presión arterial sistólica y la presión arterial diastólica (PAD). También hay modelos que permiten la estimación de riesgo cardiovascular con la cifra de colesterol unido a lipoproteínas (c-LDL), en lugar de usar la cifra del colesterol total...Cardiovascular diseases are still leading not only causes of mortality in our countries but they are also an important source of morbidity for our population, establishing as an important Public Health problem. In the last century, the scientific community joined efforts to achieve predictive statistical models about the cardiovascular risk of the population through methods of logistic regression. The first to be made was the American model, on the population of Framingham, which has constituted the paradigm of the subsequent models. Later, some authors found disagreements when applying this model to different non-American populations (including European population), which led to the conclusion that a different model for the European continent would be needed. This was based on the existence of different distribution in the prevalence of cardiovascular risk factors which constitute the essence of the models. This model was called, by its acronym, SCORE. However, new differences were found years later when the European model was applied to the different European populations, so it was decided to divide the countries according to whether they had high or low cardiovascular risk, making a model for each group. A version of this tool is currently available on the internet, in order to make it more accessible. At the level of the Spanish nation, two models were made with different methodology: REGICOR was made with a specific Mediterranean population (Girona) and DORICA was made collecting data over the prevalence of cardiovascular factors in nine autonomous communities. There are some differences between variables involved in each model for cardiovascular risk estimation, however, the age, presence or absence of Diabetes Mellitus, the presence or absence of smoking and gender are constant. Some models use the arterial pressure including only the systolic arterial pressure (PAS) and others use the highest value of systolic blood pressure or diastolic blood pressure (PAD). There are also models that allow estimation of cardiovascular risk using cholesterol linked to low-density lipoprotein (c-LDL), rather than total cholesterol...Depto. de MedicinaFac. de MedicinaTRUEunpu

Effect of a Mediterranean Diet Intervention on Dietary Glycemic Load and Dietary Glycemic Index: The PREDIMED Study

© 2014 Ana Isabel Rodríguez-Rejón et al. Objective. To compare the one year effect of two dietary interventions with MeDiet on GL and GI in the PREDIMED trial. Methods. Participants were older subjects at high risk for cardiovascular disease. This analysis included 2866 nondiabetic subjects. Diet was assessed with a validated 137-item food frequency questionnaire (FFQ). The GI of each FFQ item was assigned by a 5-step methodology using the International Tables of GI and GL Values. Generalized linear models were fitted to assess the relationship between the intervention group and dietary GL and GI at one year of follow-up, using control group as reference. Results. Multivariate-adjusted models showed an inverse association between GL and MeDiet + extra virgin olive oil (EVOO) group: β = -8.52 (95% CI: -10.83 to -6.20) and MeDiet + Nuts group: β = -10.34 (95% CI: -12.69 to -8.00), when comparing with control group. Regarding GI, β = -0.93 (95% CI: -1.38 to -0.49) for MeDiet + EVOO, β = -1.06 (95% CI: -1.51 to -0.62) for MeDiet + Nuts when comparing with control group. Conclusion. Dietary intervention with MeDiet supplemented with EVOO or nuts lowers dietary GL and GI.The authors thank the participants of the trial for their enthusiastic collaboration, the PREDIMED personnel for excellent assistance, and the personnel of all primary care centers affiliated. This work has been supported by the official funding agency for biomedical research of the Spanish government, Instituto de Salud Carlos III (ISCIII), through Grants provided to research networks specifically developed for the trial (RTIC G03/140; RTIC RD 06/0045, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn)) and by Grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional (PI04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, and P11/02505), Ministerio de Ciencia e Innovación (AGL-2009-13906-C02 and AGL2010-22319-C03), Fundación Mapfre 2010, Agencia Canaria de Investigación, Innovación y Sociedad de la Información-EU FEDER (PI 2007/050), Consejería de Salud de la Junta de Andalucía (PI0105/2007), Public Health Division of the Department of Health of the Autonomous government of Catalonia, Generalitat Valenciana (ACOMP06109, GVACOMP2010-181, GVACOMP2011-151, CS2010-AP-111, and CS2011-AP-042), Gobierno Regional de Navarra (P27/2011) and Rio Hortega postresidency fellowship of the Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spanish government. Itandehui Castro-Quezada is supported by a scholarship of the National Council on Science and Technology of México (CONACYT).Peer Reviewe

Patient-Level, Institutional, and Temporal Variations in Use of Imaging Modalities to Confirm Pulmonary Embolism

International audienceBackground: The choice of the imaging modality for diagnosis of pulmonary embolism (PE) could be influenced by provider, patient or hospital characteristics, or over time. However, little is known about the choice of the diagnostic modalities in practice. The aim of this study was to evaluate the variations in the use of imaging modalities for patients with acute PE. Methods: Using the data from Registro Informatizado Enfermedad TromboEmbolica (RIETE), a prospective international registry of patients with venous thromboembolism (March 2001–January 2019), we explored the imaging modalities used in patients with acute PE. The imaging modalities included computed tomography pulmonary angiography, ventilation/perfusion scanning, pulmonary angiography, a combination of these tests, or PE signs and symptoms plus imaging-confirmed proximal deep vein thrombosis but no chest imaging. Results: Among 38 025 patients with confirmed PE (53.1% female, age: 67.3±17 years), computed tomography pulmonary angiography was the dominant modality of diagnosis in all RIETE enrollees (78.2% [99% CI, 77.6–78.7]); including pregnant patients (58.9% [99% CI, 47.7%–69.4%]) and patients with severe renal insufficiency (62.5% [99% CI, 59.9–65.0]). A greater proportion of patients underwent ventilation/perfusion scanning in larger hospitals compared with smaller hospitals (13.1% versus 7.3%, P <0.001). The use of computed tomography pulmonary angiography varied between 13.3% and 98.3% across the countries, and its use increased over time (46.5% in 2002 to 91.7% in 2018, P <0.001). Conclusions: In a large multinational PE registry, variations were observed in the use of imaging modalities according to patient or institutional factors and over time. However, computed tomography pulmonary angiography was the dominant modality of diagnosis, even in pregnancy and severe renal insufficiency. The safety, costs, and downstream effects of these tests on PE-related and non-PE-related outcomes warrant further investigation