Here, we identify a panel of melanoma lines with non-V600E mutations in BRAF. These G469E-and D594G-mutated melanomas were found to exhibit constitutive levels of phospho-extracellular signal-regulated kinase (pERK) and low levels of phospho-mitogen-activated protein kinase/ERK kinase (pMEK) and were resistant to MEK inhibition. Upon treatment with the CRAF inhibitor sorafenib, these lines underwent apoptosis and associated with mitochondrial depolarization and relocalization of apoptosis-inducing factor, whereas the BRAF-V600E-mutated melanomas did not. Studies have shown low-activity mutants of BRAF (G469E/D594G) instead signal through CRAF. Unlike BRAF, CRAF directly regulates apoptosis through mitochondrial localization where it binds to Bcl-2 and phosphorylates BAD. The CRAF inhibitor sorafenib was found to induce a timedependent reduction in both BAD phosphorylation and Bcl-2 expression in the D594G/G469E lines only. Knockdown of CRAF using a lentiviral shRNA suppressed both Bcl-2 expression and induced apoptosis in the D594G melanoma line but not in a V600E-mutated line. Finally, we showed in a series of xenograft studies that sorafenib was more potent at reducing the growth of tumors with the D594G mutation than those with the V600E mutation. In summary, we have identified a group of melanomas with low-activity BRAF mutations that are reliant upon CRAF-mediated survival activity.

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We study the motion of a buoyant or a nearly neutrally buoyant nano-sized spheroid in a fluid filled tube without or with an imposed pressure gradient (weak Poiseuille flow). The fluctuating hydrodynamics approach and the deterministic method are both employed. We ensure that the fluctuation–dissipation relation and the principle of thermal equipartition of energy are both satisfied. The major focus is on the effect of the confining boundary. Results for the velocity and the angular velocity autocorrelations (VACF and AVACF), the diffusivities and the drag and the lift forces as functions of the shape, the aspect ratio, the inclination angle and the proximity to the wall are presented. For the parameters considered, the boundary modifies the VACF and AVACF such that three distinct regimes are discernible – an initial exponential decay followed by an algebraic decay culminating in a second exponential decay. The first is due to the thermal noise, the algebraic regime is due both to the thermal noise and the hydrodynamic correlations, while the second exponential decay shows the effect of momentum reflection from the confining wall. Our predictions display excellent comparison with published results for the algebraic regime (the only regime for which earlier results exist). We also discuss the role of the off-diagonal elements of the mobility and the diffusivity tensors that enable the quantifications of the degree of lift and margination of the nanocarrier. Our study covers a range of parameters that are of wide applicability in nanotechnology, microrheology and in targeted drug delivery.

A single-crystal X-ray determination of the [Li(CH(3)CN)(2)(+)](6-CH(3)-nido-5,6,9-C(3)B(7)H(9)(-)) salt has shown that the 6-CH(3)-nido-5,6,9-C(3)B(7)H(9)(-) tricarbadecaboranyl anion has a nido-cage geometry based on an octadecahedron missing the unique six-coordinate vertex. The resulting six-membered open face is puckered, with two of the cage carbons (C6 and C9) occupying the low-coordinate cage positions above the plane of the four remaining atoms (C5, B7, B8, and B10). The Li(+) ion is centered over the open face and is solvated by two acetonitrile molecules. The reactions of the 6-CH(3)-nido-5,6,9-C(3)B(7)H(9)(-) anion with various vanadium halide salts, including VCl(4), VCl(3), and VBr(2), each resulted in the isolation of the same five paramagnetic products (2-6) of composition V(CH(3)-C(3)B(7)H(9))(2). X-ray crystallographic determinations of 2-5 showed that the complexes consist of two octadecahedral VC(3)B(7) fragments sharing a common vanadium vertex and established their structures as commo-V-(1-V-4'-CH(3)-2',3',4'-C(3)B(7)H(9))(1-V-2-CH(3)-2,3,4-C(3)B(7)H(9)) (2), commo-V-(1-V-5'-CH(3)-2',3',5'-C(3)B(7)H(9))(1-V-4-CH(3)-2,3,4-C(3)B(7)H(9)) (3), commo-V-(1-V-5'-CH(3)-2',3',5'-C(3)B(7)H(9))(1-V-2-CH(3)-2,3,4-C(3)B(7)H(9)) (4), and commo-V-(1-V-2-CH(3)-2,3,4-C(3)B(7)H(9))(2) (5). These complexes can be considered as tricarbadecaboranyl analogues of vanadocene, (eta(5)-C(5)H(5))(2)V. However, unlike vanadocene, these complexes are air- and moisture-stable and have only one unpaired electron. The five complexes differ with respect to one another in that they either (1) contain different enantiomeric forms of the CH(3)-C(3)B(7)H(9) cages, (2) have a different twist orientation of the two cages, or (3) have the methyl group of the CH(3)-C(3)B(7)H(9) cage located in either the 2 or 4 position of the cage. Subsequent attempts to oxidize the compounds with reagents such as Br(2) and Ag(+) were unsuccessful, illustrating the ability of the tricarbadecaboranyl anion to stabilize metals in low oxidation states. Consistent with this, both the electrochemical oxidation and the reduction of 2 were much more positive than those of the same oxidation state changes in vanadocene. The one-electron reduction of 2 is a remarkable 2.9 V positive of that of Cp(2)V.