Blood global DNA methylation is decreased in non-severe chronic obstructive pulmonary disease (COPD) patients.

BACKGROUND: Alterations in global DNA methylation have been associated with oxidative stress (OS). Since chronic obstructive pulmonary disease (COPD) is characterized by increased oxidative stress we aimed to evaluate the levels of global DNA methylation in this patient group. METHODS: We assessed methylcytosine (mCyt) levels in DNA from blood collected in 43 COPD patients (29 with mild and 14 with moderate disease) and 43 age- and sex-matched healthy controls. RESULTS: DNA methylation was significantly lower in COPD patients vs. controls (4.20 ± 0.18% mCyt vs. 4.29 ± 0.18% mCyt, p = 0.02). Furthermore, DNA methylation in COPD patients with moderate disease was significantly lower than that in patients with mild disease (4.14 ± 0.15% mCyt vs. 4.23 ± 0.19% mCyt, p < 0.05). Univariate logistic regression analysis showed that lower DNA methylation levels were associated with presence of COPD (crude OR = 0.06, 95% CI 0.00 to 0.67, p = 0.023). This relationship remained significant after adjusting for several confounders (OR 0.03, 95% CI 0.00 to 0.67; p = 0.028). Receiver operating characteristics (ROC) curve analysis demonstrated the area under the curve of mCyt was 0.646, with 46.6% sensitivity and 79.1% specificity for presence of COPD. CONCLUSIONS: There were no significant correlations between methylation and OS indices. The presence and severity of COPD is associated with progressively lower DNA methylation in blood. However, this epigenetic alteration seems independent of oxidative stress.

Effect of cholesterol lowering treatment on plasma markers of endothelial dysfunction in chronic kidney disease.

The elevated cardiovascular morbidity and mortality in chronic kidney disease (CKD) is linked with endothelial dysfunction secondary to the pro-inflammatory and pro-oxidative state typical of this pathology. In consideration of the well-known pleiotropic effect of statins, we investigated the effect of cholesterol lowering treatment on endothelial dysfunction markers (MED), asymmetric dimethylarginine (ADMA), vascular cell (VCAM) and intercellular (ICAM) adhesion molecule. Plasma MED concentrations, inflammation and oxidative stress indices [Kynurenine/Tryptophan (Kyn/Trp) ratio, malondialdehyde (MDA) and allantoin/uric acid (All/UA) ratio] were measured in 30 CKD patients randomized to three cholesterol lowering regimens for 12 months (simvastatin 40mg/day, ezetimibe/simvastatin 10/20mg/day, or ezetimibe/simvastatin 10/40mg/day). Treatment significantly reduced ADMA concentrations in all patients [0.694µmol/L (0.606-0.761) at baseline vs. 0.622µmol/L (0.563-0.681) after treatment, p<0.001]. ADMA reduction was paralleled by a significant decrease of MDA, All/AU ratio and Kyn/Trp ratio, but not VCAM and ICAM plasma concentrations. Cholesterol lowering treatment was associated with a significant reduction in plasma ADMA concentrations in CKD patients. This might be mediated by reduced oxidative stress and inflammation.

Effects of Ramipril and Telmisartan on Plasma Concentrations of Low Molecular Weight and Protein Thiols and Carotid Intima Media Thickness in Patients with Chronic Kidney Disease.

Hypertension, a common feature in chronic kidney disease (CKD), is an independent risk factor for CKD progression and cardiovascular disease. Although inhibitors of the renin-angiotensin system (RAS) exert salutary effects on blood pressure control and proteinuria in CKD patients, their activity towards traditional and novel oxidative markers is largely unknown. We studied the effects of 6-month treatment with telmisartan versus a combination of telmisartan and ramipril on plasma concentrations of low molecular mass (LMW, including homocysteine and cysteine) and protein thiols (PSH) plasma concentration and their relationships with carotid intima media thickness (IMT), in 24 hypertensive CKD patients (age 60 ± 12 years, 8 females and 16 males). Pretreatment PSH concentrations were independently associated with IMT (r = -0.42, p = 0.039). Neither treatment affected plasma LMW thiols, in both reduced and total form. By contrast, both treatments increased PSH plasma concentrations and reduced IMT, although significant differences were only observed in the combined treatment group. Our results suggest that the beneficial effects of combined RAS inhibitor treatment on IMT in hypertensive CKD patients may be mediated by a reduction of oxidative stress markers, particularly PSH.

EGFR kinase-dependent and kinase-independent roles in clear cell renal cell carcinoma.

Epidermal growth factor receptor (EGFR) is associated with progression of many epithelial malignancies and represents a significant therapeutic target. Although clear cell renal cell carcinoma (CCRCC) has been widely investigated for EGFR molecular alterations, genetic evidences of EGFR gene activating mutations and/or gene amplification have been rarely confirmed in the literature. Therefore, until now EGFR-targeted therapies in clinical trials have been demonstrated unsuccessful. New evidence has been given about the interactions between EGFR and the sodium glucose co-transporter-1 (SGLT1) in maintaining the glucose basal intracellular level to favour cancer cell growth and survival; thus a new functional role may be attributed to EGFR, regardless of its kinase activity. To define the role of EGFR in CCRCC an extensive investigation of genetic changes and functional kinase activities was performed in a series of tumors by analyzing the EGFR mutational status and expression profile, together with the protein expression of downstream signaling pathways members. Furthermore, we investigated the co-expression of EGFR and SGLT1 proteins and their relationships with clinic-pathological features in CCRCC. EGFR protein expression was identified in 98.4% of CCRCC. Furthermore, it was described for the first time that SGLT1 is overexpressed in CCRCC (80.9%), and that co-expression with EGFR is appreciable in 79.4% of the tumours. Moreover, the activation of downstream EGFR pathways was found in about 79.4% of SGLT1-positive CCRCCs. The mutational status analysis of EGFR failed to demonstrate mutations on exons 18 to 24 and the presence of EGFR-variantIII (EGFRvIII) in all CCRCCs analyzed. FISH analysis revealed absence of EGFR amplification, and high polysomy of chromosome 7. Finally, the EGFR gene expression profile showed gene overexpression in 38.2% of CCRCCs. Our study contributes to define the complexity of EGFR role in CCRCC, identifying its bivalent kinase-dependent and kinase-independent functions, both potentially involved in CCRCC progression. These results might have important implications on therapeutic approaches to CCRCC, since the disruption of the interaction between EGFR/SGLT1, mediated by anti-EGFR antibodies and/or SGLT1 inhibitors, might constitute a novel therapeutic target for CCRCC treatment, and new clinical trials should be evaluated on the basis of this therapeutic proposal.

Analysis of PIK3CA Mutations and Activation Pathways in Triple Negative Breast Cancer.

BACKGROUND: Triple Negative Breast Cancer (TNBC) accounts for 12-24% of all breast carcinomas, and shows worse prognosis compared to other breast cancer subtypes. Molecular studies demonstrated that TNBCs are a heterogeneous group of tumors with different clinical and pathologic features, prognosis, genetic-molecular alterations and treatment responsivity. The PI3K/AKT is a major pathway involved in the regulation of cell survival and proliferation, and is the most frequently altered pathway in breast cancer, apparently with different biologic impact on specific cancer subtypes. The most common genetic abnormality is represented by PIK3CA gene activating mutations, with an overall frequency of 20-40%. The aims of our study were to investigate PIK3CA gene mutations on a large series of TNBC, to perform a wider analysis on genetic alterations involving PI3K/AKT and BRAF/RAS/MAPK pathways and to correlate the results with clinical-pathologic data. MATERIALS AND METHODS: PIK3CA mutation analysis was performed by using cobas® PIK3CA Mutation Test. EGFR, AKT1, BRAF, and KRAS genes were analyzed by sequencing. Immunohistochemistry was carried out to identify PTEN loss and to investigate for PI3K/AKT pathways components. RESULTS: PIK3CA mutations were detected in 23.7% of TNBC, whereas no mutations were identified in EGFR, AKT1, BRAF, and KRAS genes. Moreover, we observed PTEN loss in 11.3% of tumors. Deregulation of PI3K/AKT pathways was revealed by consistent activation of pAKT and p-p44/42 MAPK in all PIK3CA mutated TNBC. CONCLUSIONS: Our data shows that PIK3CA mutations and PI3K/AKT pathway activation are common events in TNBC. A deeper investigation on specific TNBC genomic abnormalities might be helpful in order to select patients who would benefit from current targeted therapy strategies.

Educación continua: el artículo científico de revisión / Continuing education: the scientific review article

Actualmente, la cantidad de literatura publicaca en el área de la salud sobrepasa las posibilidades de lectura de cualquier profesional o investigador, para mantener actualizados sus conocimientos. Ante esta situación, es necesario contar con piezas de información procesadas, sintetizadas y organizadas que puedan ser fácilmente asimiladas por los lectores y proporcionen una visión general de confianza de los conocimientos actuales. Los artículos de revisión (AR) son la herramienta que ayuda a los profesionales para dar respuesta en forma rápida a sus preguntas, ya sean de preparación o de acción sobre un tema determinado, o estar actualizados con la literatura médica cuando no se posee el tiempo suficiente para leer toda la información disponible. En esta tercera parte de educación continua, se describen las características principales de los AR, su clasificación y estructura y algunas consideraciones para su preparación y publicación en una revista científica.

Educación continua: el artículo científico original / Continuing education: the original scientific article

El artículo científico original proporciona un método para que los científicos puedan comunicarse con otros científicos sobre los resultados de sus investigaciones. El propósito de esta segunda parte de educación continua es dar una breve guía con consejos para ayudar al proceso de una mejor redacción científica y delinear los principios de la escritura y la edición. Escribir un artículo científico en una revista revisada por pares es un proceso exigente que requiere tiempo y habilidad. El artículo científico que informa sobre una investigación original incluye tres partes importantes: preliminares, cuerpo principal y parte final. El cuerpo principal debe seguir una estructura estándar resumido por el acrónimo IMRAD: introducción, métodos, resultados y discusión/conclusión. Cada sección tiene su propio estilo de la estructura y lenguaje de presentación. Se explica la importancia del empleo de tables y figuras y se analizan otras secciones relevantes como la autoría, afiliación, conflicto de intereses y referencias...