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Melanocortin-1 receptor ( MC1R) plays a key role in skin pigmentation, and its variants are linked with a higher melanoma risk. The influence of MC1R variants on the outcomes of patients with metastatic melanoma ( MM) treated with BRAF inhibitors ( BRAFi) is unknown. We studied the MC1R status in a cohort of 53 consecutive BRAF-mutated patients with MM treated with BRAFi. We also evaluated the effect of vemurafenib in four V600 BRAF melanoma cell lines with/without MC1R variants. We found a significant correlation between the presence of MC1R variants and worse outcomes in terms of both overall response rate ( ORR; 59% versus 95%, P = 0.011 univariate, P = 0.028 multivariate analysis) and progression-free survival ( PFS) shorter than 6 months (72% versus 33%, P = 0.012 univariate, P = 0.027 multivariate analysis). No difference in overall survival ( OS) was reported, probably due to subsequent treatments. Data in vitro showed a significant different phosphorylation of Erk1/2 and p38 MAPK during treatment, associated with a greater increase in vemurafenib IC50 in MC1R variant cell lines. [ABSTRACT FROM AUTHOR]

Emerging requirements for learning in the enterprise are developing critical reasoning and keeping the learner engaged. Advanced didactical material that exploits gameful design should increase engagement by creating a product that has the spirit, and not just the mechanics, of a good game. This article presents game design guidelines for the development of an Educational Adventure Game and how they have been applied during the development of SIRET Security Game, a game that teaches workers the importance of following computer security policies. [ABSTRACT FROM AUTHOR]

Background BRAF G469A is a missense mutation within exon 11 of the BRAF gene resulting in a constitutively active state of the enzyme responsible also for the protein localization to the mitochondria. The BRAF G469A mutation, frequently recovers in lung cancer, is rare in melanoma and uncertain is its association with a more aggressive disease. BRAF G469A mutation is frequently associated to MAP kinase cascade signaling activation, however no evidence currently exists about its role in determining sensitivity/resistance to BRAF inhibitors vemurafenib or dabrafenib. In our Institute, a patient with metastatic melanoma (MM) was treated with fotemustine, however the disease progressed. From patient biopsy, a new metastatic melanoma cell line has been established and named Mo-1. Here, we investigated the sensitivity of Mo-1 cells to vemurafenib and abraxane, both already approved for the treatment of melanoma carrying BRAF V600 mutations, comparing it with that found in MM cells wild type for BRAF or mutated in V600. Furthermore, a biomarker for the response to abraxane is hypothesized. Materials and methods We tested the sensitivity of Mo-1 (BRAF G469A), HBL and LND-1 (BRAF wild type), MBA72 and Hmel-1 (BRAF V600) to abraxane and vemurafenib by MTT cytotoxicity assay. In addition, cellular effectors were investigated by ELISA kits, western blotting and flow cytometry. Results The exposure to vemurafenib leads to a progressive inhibition of proliferation however, the concentrations utilized are high and similar to those utilized in MM models constitutively resistant to BRAF inhibitors. Thus, the BRAF mutation G469A confers resistance to vemurafenib also confirmed by the partial response obtained when the patients was treated with the drug. The cellular effector responsible for the resistance might be the activation of Erk1/2. The binding of BRAF G469A to the outer mitochondrial membrane suggested to evaluate the mitochondria functionality in Mo-1 cells. An high production of ATP and the release of lactate were evident. Finally, abraxane, which induces mitochondria-mediated apoptosis, strongly reduced proliferation in Mo-1 cells. Possible biomarker responsible for this response is the very low expression level of PMEL17, transcriptionally regulated by MITF, which is known to be negatively involved in determining the activity of taxanes. Conclusion Thus, the mutation BRAF G469A in patients with MM should be related to a weak effectiveness of therapy with BRAF inhibitors and a promising therapeutic approach may be with abraxane. [ABSTRACT FROM AUTHOR]