Our study indicates that oral administration of levocarnitine produces a reduction of total fat mass, increases total muscular mass, and facilitates an increased capacity for physical and cognitive activity by reducing fatigue and improving cognitive functions.

Dysregulation of receptor tyrosine kinases (RTKs) contributes to several aspects of oncogenesis including drug resistance. In melanoma, distinct RTKs have been involved in BRAF inhibitors (BRAFi) resistance, yet the utility of RTKs expression pattern to identify intrinsically resistant tumors has not been assessed. Transcriptional profiling of RTKs and integration with a previous classification, reveals three robust subtypes in two independent datasets of melanoma cell lines and one cohort of melanoma samples. This classification was validated by Western blot in a panel of patient-derived melanoma cell lines. One of the subtypes identified here for the first time displayed the highest and lowest expression of EGFR and ERBB3, respectively, and included BRAF-mutant tumors all intrinsically resistant to BRAFi PLX4720, as assessed by analysis of the Cancer Cell Line Encyclopedia pharmacogenomic study and by in vitro growth inhibition assays. High levels of EGFR were detected, even before therapy, in tumor cells of one of three melanoma patients unresponsive to BRAFi. Use of different pharmacological inhibitors highlighted the relevance of PI3K/mTOR signaling for growth of this PLX4720-resistant subtype. Our results identify a specific molecular profile of melanomas intrinsically resistant to BRAFi and suggest the PI3K/mTOR pathway as a potential therapeutic target for these tumors.

Reflex neural oversignaling sensitive to muscle by-products (ergoreflex) causes exercise hyperventilation in heart failure (HF). We probed whether an improved endothelial function with sildenafil intake may prevent this effect. In 16 chronic heart failure patients and 16 normal subjects, before and after sildenafil intake (50 mg) or placebo, we measured ergoreflex, flow-mediated brachial artery dilation (FMD, an index of endothelial function), and, during maximal exercise, the slope of ventilation to carbon dioxide production (VE/VCO2, an index of ventilatory efficiency), the ratio of changes in O2 uptake (VO2) versus work rate (WR) (deltaVO2/deltaWR, an index of aerobic efficiency). After sildenafil intake, patients, unlike controls, showed a significant decrease in ergoreflex and VE/VCO2 slope and an increase in FMD and deltaVO2/deltaWR. Ergoreflex changes with sildenafil intake correlated with those in FMD and VE/VCO2. Phosphodiesterase-5 inhibition, by improving endothelial activity and muscle perfusion, modulates signaling and improves ventilatory and aerobic efficiencies, potentially indicating a novel pathway in the HF therapeutic management.

No abstract

While the mammalian target of rapamycin (mTOR) signaling pathway is a promising target for well-differentiated endocrine carcinoma therapy with the mTOR inhibitor everolimus (RAD001), poorly differentiated endocrine carcinomas (PDECs) are usually excluded from clinical trials due to their aggressiveness. So far, mTOR activity in PDECs has only been tested in cell lines. This study reviewed 36 mono-institutional PDECs to determine mTOR expression. Slides of normal kidney as positive control were used to optimize mTOR staining. To ensure antibody specificity, consecutive sections were incubated in the absence of primary antibody. Immunoreactivity was evaluated on a semi-quantitative scale scoring the extent and intensity of staining. The product of these two scores was used to obtain a total immunostaining score. The main primary site of disease was the pancreas, and 83% of patients had stage IV disease. In 80% of samples, mTOR expression was maintained at similar levels, with no relationship to tumor origin or proliferation rate determined by MIB-1. This study seems to demonstrate that mTOR is expressed in human PDECs regardless of tumor site. Its role in relation to the activity of everolimus in this subset of patients needs to be confirmed.