University of Naples Federico II

About: University of Naples Federico II is a education organization based out in Naples, Campania, Italy. It is known for research contribution in the topics: Population & Cancer. The organization has 29291 authors who have published 68803 publications receiving 1920149 citations. The organization is also known as: Università degli Studi di Napoli Federico II & Naples University.

Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study.

Abstract: Objective L-dopa is the most widely used and most effective therapy for Parkinson disease (PD), but chronic treatment is associated with motor complications in the majority of patients. It has been hypothesized that providing more continuous delivery of L-dopa to the brain would reduce the risk of motor complications, and that this might be accomplished by combining L-dopa with entacapone, an inhibitor of catechol-O-methyltransferase, to extend its elimination half-life. Methods We performed a prospective 134-week double-blind trial comparing the risk of developing dyskinesia in 747 PD patients randomized to initiate L-dopa therapy with L-dopa/carbidopa (LC) or L-dopa/carbidopa/entacapone (LCE), administered 4× daily at 3.5-hour intervals. The primary endpoint was time to onset of dyskinesia. Results In comparison to LC, patients receiving LCE had a shorter time to onset of dyskinesia (hazard ratio, 1.29; p = 0.04) and increased frequency at week 134 (42% vs 32%; p = 0.02). These effects were more pronounced in patients receiving dopamine agonists at baseline. Time to wearing off and motor scores were not significantly different, but trended in favor of LCE treatment. Patients in the LCE group received greater L-dopa dose equivalents than LC-treated patients (p < 0.001). Interpretation Initiating L-dopa therapy with LCE failed to delay the time of onset or reduce the frequency of dyskinesia compared to LC. In fact, LCE was associated with a shorter time to onset and increased frequency of dyskinesia compared to LC. These results may reflect that the treatment protocol employed did not provide continuous L-dopa availability and the higher L-dopa dose equivalents in the LCE group. ANN NEUROL 2010;68:18–27

Bivalirudin or Unfractionated Heparin in Acute Coronary Syndromes

Abstract: BACKGROUND Conflicting evidence exists on the efficacy and safety of bivalirudin administered as part of percutaneous coronary intervention (PCI) in patients with an acute coronary syndrome METHODS We randomly assigned 7213 patients with an acute coronary syndrome for whom PCI was anticipated to receive either bivalirudin or unfractionated heparin Patients in the bivalirudin group were subsequently randomly assigned to receive or not to receive a post-PCI bivalirudin infusion Primary outcomes for the comparison between bivalirudin and heparin were the occurrence of major adverse cardiovascular events (a composite of death, myocardial infarction, or stroke) and net adverse clinical events (a composite of major bleeding or a major adverse cardiovascular event) The primary outcome for the comparison of a post-PCI bivalirudin infusion with no post-PCI infusion was a composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events RESULTS The rate of major adverse cardiovascular events was not significantly lower with bivalirudin than with heparin (103% and 109%, respectively; relative risk, 094; 95% confidence interval [CI], 081 to 109; P = 044), nor was the rate of net adverse clinical events (112% and 124%, respectively; relative risk, 089; 95% CI, 078 to 103; P = 012) Post-PCI bivalirudin infusion, as compared with no infusion, did not significantly decrease the rate of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events (110% and 119%, respectively; relative risk, 091; 95% CI, 074 to 111; P = 034) CONCLUSIONS In patients with an acute coronary syndrome, the rates of major adverse cardiovascular events and net adverse clinical events were not significantly lower with bivalirudin than with unfractionated heparin The rate of the composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events was not significantly lower with a post-PCI bivalirudin infusion than with no post-PCI infusion (Funded by the Medicines Company and Terumo Medical; MATRIX ClinicalTrialsgov number, NCT01433627) abstr act

Kinetics of protein-ligand unbinding: Predicting pathways, rates, and rate-limiting steps.

Abstract: The ability to predict the mechanisms and the associated rate constants of protein–ligand unbinding is of great practical importance in drug design. In this work we demonstrate how a recently introduced metadynamics-based approach allows exploration of the unbinding pathways, estimation of the rates, and determination of the rate-limiting steps in the paradigmatic case of the trypsin–benzamidine system. Protein, ligand, and solvent are described with full atomic resolution. Using metadynamics, multiple unbinding trajectories that start with the ligand in the crystallographic binding pose and end with the ligand in the fully solvated state are generated. The unbinding rate k o f f is computed from the mean residence time of the ligand. Using our previously computed binding affinity we also obtain the binding rate k o n . Both rates are in agreement with reported experimental values. We uncover the complex pathways of unbinding trajectories and describe the critical rate-limiting steps with unprecedented detail. Our findings illuminate the role played by the coupling between subtle protein backbone fluctuations and the solvation by water molecules that enter the binding pocket and assist in the breaking of the shielded hydrogen bonds. We expect our approach to be useful in calculating rates for general protein–ligand systems and a valid support for drug design.

The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells

Abstract: In papillary thyroid carcinomas (PTCs), rearrangements of the RET receptor (RET/PTC) and activating mutations in the BRAF or RAS oncogenes are mutually exclusive. Here we show that the 3 proteins function along a linear oncogenic signaling cascade in which RET/PTC induces RAS-dependent BRAF activation and RAS- and BRAF-dependent ERK activation. Adoptive activation of the RET/PTC-RAS-BRAF axis induced cell proliferation and Matrigel invasion of thyroid follicular cells. Gene expression profiling revealed that the 3 oncogenes activate a common transcriptional program in thyroid cells that includes upregulation of the CXCL1 and CXCL10 chemokines, which in turn stimulate proliferation and invasion. Thus, motile and mitogenic properties are intrinsic to transformed thyroid cells and are governed by an epistatic oncogenic signaling cascade.