The influence of diet therapeutic intervention on the sarcopenic index of patients with metabolic syndrome.

INTRODUCTION: The published data showed the importance of metabolic control in preventing complications in metabolic syndrome (MS) and the role of nutritional medical therapy in glycemic control and in the control of dyslipidemia, hypertension, weight loss/normalization (in overweight or malnourished subjects). OBJECTIVES: This study follows the evolution of sarcopenic index (SI) and other clinical parameters (body mass index (BMI), homeostasis evaluation index (HOMA index)) correlated with MS after diet therapy or diet therapy combined with sports, in patients with MS. PATIENTS AND METHODS: Our research was conducted during 12 months, on 110 patients >18 years of age, with HOMA index>2, divided into three groups: control group (CG, N=20), diet therapy group (DTG, N=58), diet therapy and sports group (DTSG, N=32). HOMA index for insulin resistance was calculated as the product of resting plasma insulin (in microunits/milliliter) and plasma glucose (in millimoles/liter), divided by 22.5. SI was determined using BIA, as being the ratio between muscle mass and fat mass, measured in cm2/m2. RESULTS: A significant decrease of BMI (p<0.05) in DTG (from 31.63 to 24.50) and DTSG (from 30.18 to 24.17) vs. CG was observed (Pearson coefficient r=0.281, p<0.001). Weight status changed significantly (p<0.05) in the high-risk patients. There was a significant decrease of HOMA index (p<0.05) in DTG (from 5.93 to 2.57), DTSG (from 3.93 to 2.23), and in CG an increase was observed (from 3.15 to 3.37). CONCLUSION: The best results in the prevention/ treatment of sarcopenia in MS patients were obtained for DTSG, which benefited from both the positive effect of diet and physical activity.

Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors.

BACKGROUND: This phase I dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics (PDs), and preliminary antitumor activity of BGT226, a potent, oral dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin inhibitor. PATIENTS AND METHODS: Fifty-seven patients with advanced solid tumors received BGT226 2.5-125 mg/day three times weekly (TIW). Dose escalation was guided by an adaptive Bayesian logistic regression model with overdose control. Assessments included response per RECIST, [18F]-fluorodeoxyglucose uptake, and phosphorylated-S6 in skin and paired tumor samples. RESULTS: Three patients (125 mg cohort) had dose-limiting toxic effects (grade 3 nausea/vomiting, diarrhea). BGT226-related adverse events included nausea (68%), diarrhea (61%), vomiting (49%), and fatigue (19%). BGT226 demonstrated rapid absorption, variable systemic exposure, and a median half-life of 6-9 h. Seventeen patients (30%) had stable disease (SD) as best response. Nine patients had SD for ≥16 weeks. Thirty patients (53%) achieved stable metabolic disease as assessed by [18F]-fluorodeoxyglucose-positron emission tomography; however, no correlation between metabolic response and tumor shrinkage according to computed tomography was observed. PD changes suggested PI3K pathway inhibition but were inconsistent. CONCLUSIONS: The MTD of BGT226 was 125 mg/day TIW, and the clinically recommended dose was 100 mg/day TIW. Limited preliminary antitumor activity and inconsistent target inhibition were observed, potentially due to low systemic exposure.

The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling.

The PTEN tumour suppressor and pro-apoptotic gene is frequently mutated in human cancers. We show that PTEN transcription is upregulated by Egr-1 after irradiation in wild-type, but not egr-1-/-, mice in vivo. We found that Egr-1 specifically binds to the PTEN 5' untranslated region, which contains a functional GCGGCGGCG Egr-1-binding site. Inducing Egr-1 by exposing cells to ultraviolet light upregulates expression of PTEN messenger RNA and protein, and leads to apoptosis. egr-1-/- cells, which cannot upregulate PTEN expression after irradiation, are resistant to ultraviolet-light-induced apoptosis. Therefore, Egr-1 can directly regulate PTEN, triggering the initial step in this apoptotic pathway. Loss of Egr-1 expression, which often occurs in human cancers, could deregulate the PTEN gene and contribute to the radiation resistance of some cancer cells.

Protein tyrosine phosphatases.

The molecular mechanisms of signal transduction have been at the focus of increasingly intense scientific research. As a result, our understanding of protein tyrosine kinase-mediated signaling has advanced at an unprecedented pace during the past decade. In contrast, the study of protein tyrosine phosphatases has lagged behind, but is now gathering momentum and is predicted to become a "hot topic" in the field within the next few years. This review summarizes the current state-of-the art in our understanding of the structure, regulation and role of protein tyrosine phosphatases with emphasis on the lymphocyte system.

A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas.

Standard cytotoxic treatments for neuroendocrine tumours have been associated with limited activity and remarkable toxicity. A phase II study was designed to evaluate the efficacy, safety and pharmacodynamics of temsirolimus in patients with advanced neuroendocrine carcinoma (NEC). Thirty-seven patients with advanced progressive NEC received intravenous weekly doses of 25 mg of temsirolimus. Patients were evaluated for tumour response, time to progression (TTP), overall survival (OS) and adverse events (AE). Twenty-two archival specimens, as well as 13 paired tumour biopsies obtained pretreatment and after 2 weeks of temsirolimus were assessed for potential predictive and correlative markers. The intent-to-treat response rate was 5.6% (95% CI 0.6-18.7%), median TTP 6 months and 1-year OS rate 71.5%. The most frequent drug-related AE of all grades as percentage of patients were: fatigue (78%), hyperglycaemia (69%) and rash/desquamation (64%). Temsirolimus effectively inhibited the phosphorylation of S6 (P=0.02). Higher baseline levels of pmTOR (phosphorylated mammalian target of rapamycin) (P=0.01) predicted for a better response. Increases in pAKT (P=0.041) and decreases in pmTOR (P=0.048) after treatment were associated with an increased TTP. Temsirolimus appears to have little activity and does not warrant further single-agent evaluation in advanced NEC. Pharmacodynamic analysis revealed effective mTOR pathway downregulation.