Molecular Modeling Unveils the Effective Interaction of B-RAF Inhibitors with Rare B-RAF Insertion Variants.

The Food and Drug Administration (FDA) has approved MAPK inhibitors as a treatment for melanoma patients carrying a mutation in codon V600 of the BRAF gene exclusively. However, BRAF mutations outside the V600 codon may occur in a small percentage of melanomas. Although these rare variants may cause B-RAF activation, their predictive response to B-RAF inhibitor treatments is still poorly understood. We exploited an integrated approach for mutation detection, tumor evolution tracking, and assessment of response to treatment in a metastatic melanoma patient carrying the rare p.T599dup B-RAF mutation. He was addressed to Dabrafenib/Trametinib targeted therapy, showing an initial dramatic response. In parallel, in-silico ligand-based homology modeling was set up and performed on this and an additional B-RAF rare variant (p.A598_T599insV) to unveil and justify the success of the B-RAF inhibitory activity of Dabrafenib, showing that it could adeptly bind both these variants in a similar manner to how it binds and inhibits the V600E mutant. These findings open up the possibility of broadening the spectrum of BRAF inhibitor-sensitive mutations beyond mutations at codon V600, suggesting that B-RAF V600 WT melanomas should undergo more specific investigations before ruling out the possibility of targeted therapy.

Alexithymia in patients with Parkinson's disease treated with DBS of the subthalamic nucleus: a case-control study.

OBJECTIVES: To evaluate the effect of deep brain stimulation of the subthalamic nucleus (STN-DBS) on alexithymia, a deficit in affective regulation, comparing patients with Parkinson's disease (PD) submitted to STN-DBS (DBS group) to PD patients not yet treated with STN-DBS (pre-DBS group) and to healthy participants (C group). METHODS: We recruited 27 consecutive STN-DBS PD patients, 38 consecutive pre-DBS patients and 27 healthy participants. Patients were assessed for alexithymia (Toronto Alexithymia Scale), depression, [beck depression inventory (BDI)], and cognitive functions (reasoning, memory, attentional, and executive tests). RESULTS: The DBS patients performed worse than the pre-DBS patients in the corsi's block-tapping test, in the phonemic fluency task and in the Frontal Assessment Battery. Around 30% of DBS (29.6%) and pre-DBS (31.6%) patients resulted alexithymic, compared with 14.8% in the C group. The results pointed out significantly higher alexithymia scores in both the DBS and pre-DBS groups compared with the C group, while no difference emerged between the DBS and pre-DBS groups. Pre-DBS group showed a significantly higher BDI score than the C group, while DBS group did not. CONCLUSION: Although the results suggest that STN-DBS does not affect alexithymia, both the DBS and pre-DBS patients reported higher prevalence (about 30%) of alexithymia than did healthy subjects (14.8%).