Phosphorylation of tyrosine 1248-ERBB2 measured by chemiluminescence-linked immunoassay is an independent predictor of poor prognosis in primary breast cancer patients

ERBB2 (HER2/Neu) gene amplification and overexpression is associated with increased risk of metastases and shorter survival in breast cancer. Tyrosine 1248 is a major phosphorylation site of ERBB2 and reflects the activation status of the receptor. The aim of this study was to investigate the relationships between quantitative levels of pY1248-ERBB2 (p-ERBB2) and the expression of epidermal growth factor receptor (EGFR)-family members, and whether p-ERBB2 could provide additional prognostic value compared with established prognostic markers. For this purpose we developed a highly sensitive chemiluminescence-linked immunoassay (CLISA) and detected p-ERBB2 levels in 70 primary breast cancer biopsies. Phosphorylated ERBB2 correlated with EGFR and ERBB2, and inversely with oestrogen receptor (ER), progesterone receptor (PgR) and ERBB4 expression levels. Additionally, p-ERBB2 was associated with poor clinical outcome in univariate and multivariate Cox regression analysis. Further studies are needed to evaluate the predictive value of p-ERBB2.     

Licofelone, an inhibitor of cyclooxygenase and 5-lipoxygenase, specifically inhibits cyclooxygenase-1-dependent platelet activation

5-Lipoxygenase/cyclooxygenase inhibitors, possessing anti-inflammatory action and gastric safety due to cyclooxygenase-2 and 5-lipoxygenase inhibition and antiplatelet activity due to cyclooxygenase-1 blockade, would be beneficial in the treatment of ischemic disease because they may reduce, at the same time, inflammation, underlying the atherosclerotic process, and platelet activation, responsible for acute thrombotic events. In this study, we characterized the antiplatelet effects of the new 5-lipoxygenase/cyclooxygenase inhibitor licofelone ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3,dihydro-1H-pyrrolizine-5-yl]-acetic acid. Licofelone completely prevented platelet aggregation induced in platelet-rich plasma by threshold aggregating concentrations of arachidonic acid (0.87+/-0.14 mM) at threshold inhibitory concentrations of 0.75+/-0.35 microM (n=5). Platelet-rich plasma aggregation induced by threshold aggregating concentrations of collagen/adrenalin (0.3+/-0.05 microg/ml and 0.4+/-0.1 microM, respectively) was reduced to 3.2+/-2% of control at licofelone 100 microM, (P<0.05, n=6). Washed platelet aggregation induced by threshold aggregating concentrations of thrombin (0.07+/-0.01 U/ml) was only partially affected by licofelone at concentrations one or two order of magnitude higher than those fully preventing arachidonic acid-induced aggregation (44+/-11% of control at 100 microM, P<0.05, n=7). Failure to prevent aggregation triggered by high concentrations of collagen/adrenalin in aspirin-treated platelets supports cyclooxygenase-1 as a specific target of licofelone. In fact, licofelone inhibited thromboxane B(2) (TxB(2)) production by all the agonists tested at concentrations between 0.5 and 50 microM. At this concentration, TxB(2) production was reduced at values similar to those of unstimulated platelets. These results indicate that, at clinically relevant concentrations, licofelone exerts a potent antiplatelet effect mediated by the inhibition of cyclooxygenase-1 activity.     

Comparison of different external beam treatment techniques to deliver high-dose irradiation to local recurrent rectal carcinoma

AIMS AND BACKGROUND: Treatment of local-regional recurrent rectal carcinoma is a challenging problem, and local control may be dose dependent; doses should probably exceed 60 Gy. Our aim was to verify the possibility to deliver 66 Gy to the target, but less than 35 Gy to the small bowel, comparing different 3D irradiation techniques, in a selected group of patients. METHODS: Five patients with local recurrent rectal carcinoma were selected as representative of different presentations of the disease. Gross tumor volume and clinical target volume were defined [by RS]. Tumors ranged between 182 and 540 cc, and small bowel volumes between 748 and 1050 cc. A three-field technique, coplanar multiple fields, noncoplanar fields and a proton beam were compared using dose volume histograms. A positive result was scored when > or = 90% of the target received the prescribed dose with no more than 5% of the small bowel receiving more than 35 Gy. Doses were escalated in steps of 2 Gy from 60 to 66 Gy. RESULTS: The number of plans fitting the constraints were 7/19, 11/19, 18/19 for doses of 66 Gy, 64 Gy and 62 Gy, respectively. The stage of the tumor did not seem to correlate with the possibility to homogeneously cover the target with the prescribed dose. CONCLUSIONS: Simple coplanar and complex coplanar techniques (up to six fields), positioning the patient in a prone position with dislocation of the bowel, seem to be the best solutions to treat almost all of the patients with doses of 64 Gy. Where higher doses are concerned, it is not possible to suggest a "standard" solution. More personalized techniques have to be tested to define the best option.     

Prevention of cardiovascular disease in type-2 diabetes: how to improve the clinical efficacy of aspirin

Atherosclerotic cardiovascular disease and its thrombotic complications are the principal causes of morbidity and mortality in patients with type-2 diabetes. Aspirin reduces the risk of thrombotic events in a broad range of patients with vascular disease and, in selected individuals, is beneficial for primary prevention. Although recommended by existing guidelines, in secondary and in primary prevention trials the clinical efficacy of low-dose aspirin in patients with diabetes appears to be substantially lower than in individuals without diabetes. In this review, we discuss possible mechanisms that may contribute to reduce the antithrombotic activity of aspirin in diabetes. We also discuss adjuvant therapies used in diabetic patients that may potentially improve the antithrombotic efficacy of aspirin.     

A meta-analysis of studies on wine and beer and cardiovascular disease

Many epidemiologic studies have evaluated whether different alcoholic beverages protect against cardiovascular disease. We performed a meta-analysis of 26 studies on relationship between wine or beer consumption and vascular risk. General variance-based method and fitting models were applied to pooled data derived from 26 studies that gave quantitative estimation of the vascular risk associated with either beverage consumption. From 13 studies involving 209,418 persons, the relative risk of vascular disease associated with wine intake was 0.68 (95% CI: 0.59-0.77) relative to nondrinkers. There was strong evidence from 10 studies involving 176,042 persons to support a J-shaped relationship between different amounts of wine intake and vascular risk. A statistically significant inverse association was found up to a daily intake of 150 ml of wine. The overall relative risk of moderate beer consumption, which was measured in 15 studies involving 208,036 persons, was 0.78 (95% CI: 0.70-0.86). However, no significant relationship between different amounts of beer intake and vascular risk was found after meta-analyzing 7 studies involving 136,382 persons. These findings show evidence of a significant inverse association between light to moderate wine consumption and vascular risk. A similar, although smaller association was also apparent in beer consumption studies. The latter finding, however, is difficult to interpret because no meaningful relationship could be found between different amounts of beer intake and vascular risk.     

Computerized processing of EEG-EOG-EMG artifacts for multi-centric studies in EEG oscillations and event-related potentials.

The aim of this study is to present a package including standard software for the electroencephalographic (EEG), electro-oculographic (EOG) and electromyographic (EMG) preliminary data analysis, which may be suitable to standardize the results of many EEG research centers studies (i.e. multi-centric studies) especially focused on event-related potentials. In particular, our software package includes (semi)automatic procedures for (i) EOG artifact detection and correction, (ii) EMG analysis, (iii) EEG artifact analysis, (iv) optimization of the ratio between artifact-free EEG channels and trials to be rejected. The performances of the software package on EOG-EEG-EMG data related to cognitive-motor tasks were evaluated with respect to the preliminary data analysis performed by two expert electroencephalographists (gold standard). Due to its extreme importance for multi-centric EEG studies, we compared the performances of two representative "regression" methods for the EOG correction in time and frequency domains. The aim was the selection of the most suitable method in the perspective of a multi-centric EEG study. The results showed an acceptable agreement of approximately 95% between the human and software behaviors, for the detection of vertical and horizontal EOG artifacts, the measurement of hand EMG responses for a cognitive-motor paradigm, the detection of involuntary mirror movements, and the detection of EEG artifacts. Furthermore, our results indicated a particular reliability of a 'regression' EOG correction method operating in time domain (i.e. ordinary least squares). These results suggest that such a software package could be used for multi-centric EEG studies.     

Influence of transdermal estradiol in the regulation of leptin levels of postmenopausal women: a double-blind, placebo-controlled study.

OBJECTIVE: To investigate whether the administration of transdermal estradiol is capable of modifying circulating levels of leptin. DESIGN: Forty postmenopausal women randomly received in a double-blind fashion, a transdermal patch containing either placebo or estradiol (50 microg/day). After 2 months of treatment, they were switched to the alternate treatment for another 2 months. Leptin levels were measured at the end of the placebo and estradiol administration. In a subset of 28 women an evaluation of body composition via bioelectrical impedance and an oral glucose tolerance test (OGTT; 75 g) were also performed at the end of the placebo and estradiol administration. Glucose, insulin, and leptin levels were measured in all OGTT samples. RESULTS: Leptin levels were related directly to body mass index (BMI), fat mass, and insulin, and inversely related to lean mass. In comparison to placebo, transdermal estradiol increased estradiol (from 77.8 +/- 8.4 pmol/l to 183.1 +/- 20.9 pmol/l; p < 0.0001) but did not significantly modify leptin (19.1 +/- 2.4 microg/l vs. 18.6 +/- 2 microg/l) or BMI. Estradiol did not modify fat mass or lean mass, significantly increased intracellular water (31.1 +/- 0.7% vs. 37.2 +/- 2.3%, p < 0.05), and decreased extracellular water (40.5 +/- 0.7% vs. 36.3 +/- 1.7%; p < 0.04). Leptin did not increase during OGTT, but a significant decrease, linearly related to BMI ( r = 0.519; p = 0.0189), was observed at the end of the test. CONCLUSIONS: Low doses of transdermal estradiol exert no influence on fasting leptin levels or BMI. The possibility that different doses of estradiol exert a more pronounced effect on circulating leptin needs to be addressed in comparative studies.