Silibinin Treatment Inhibits the Growth of Hedgehog Inhibitor‐Resistant Basal Cell Carcinoma Cells via Targeting EGFR‐MAPK‐Akt and Hedgehog Signaling

Basal cell carcinoma (BCC) is the most common skin malignancy. Deregulated hedgehog signaling plays a central role in BCC development; therefore, hedgehog inhibitors have been approved to treat locally advanced or metastatic BCC. However, the development of resistance to hedgehog inhibitors is the major challenge in effective treatment of this disease. Herein, we evaluated the efficacy of a natural agent silibinin to overcome resistance with hedgehog inhibitors (Sant‐1 and GDC‐0449) in BCC cells. Silibinin (25–100 μm ) treatment for 48 h strongly inhibited growth and induced death in ASZ001, Sant‐1‐resistant (ASZ001‐Sant‐1) and GDC‐0449‐resistant (ASZ001‐GDC‐0449) BCC cells. Furthermore, colony‐forming ability of ASZ001, ASZ001‐Sant‐1 and ASZ001‐GDC‐0449 cells was completely inhibited by silibinin treatment. Molecular analysis showed that silibinin treatment decreased the level of phosphorylated EGFR (Tyrosine 1173) and total EGFR in ASZ001‐Sant‐1 cells, key signaling molecules responsible for BCC resistance toward hedgehog inhibitors. Further, silibinin treatment decreased the phosphorylated Akt (Serine 473), phosphorylated ERK1/2 (Threonine 202/Tyrosine 204), cyclin D1 and Gli‐1 level but increased the SUFU expression in ASZ001‐Sant‐1‐resistant cells. Silibinin treatment of ASZ001‐Sant‐1‐resistant cells also decreased bcl‐2 but increased cleaved caspase 3 and PARP cleavage, suggesting induction of apoptosis. Together, these results support silibinin use to target hedgehog inhibitor‐resistant BCC cells.     

Some geometrical aspects of a maximal three-coloured triangle-free graph

A three-coloured triangle-free complete graph with 16 vertices is constructed in an ad hoc manner. The edges of one colour in the complete graph, with the 16 vertices, form a Greenwood-Gleason graph, which can be regarded as the edges and diagonals of a hypercube in four dimensions, and which also has a representation as a graph in five dimensions all of whose automorphisms are isometries. In the complete graph, the blue edges form 40 quadrilaterals; 20 of these have red diagonals, and these 20 “red quadrilaterals,” meeting along 40 edges and at 16 vertices, represent a topological surface of characteristic ?4, a Klein bottle with two handles. This surface can be represented using a tessellation of regular quadrilaterals in the hyperbolic plane. To obtain the only other three-coloured triangle-free complete graph with 16 vertices some of the blue and red edges are interchanged in a way that can be described very simply using either the surface of characteristic ?4 or the hyperbolic tessellation.     

Intramolecular trapping by epoxides of intermediates generatedby organocuprate additions to propiolate esters.

The facility with which intramolecular trapping of the intermediates generated by conjugate addition of organocopper nucleophiles to propiolate esters may be effected by internal epoxides is critically dependent on the nature of the nucleophile.     

Interfacing Mercury Porosimetry with Nitrogen Sorption

Combinations of gas sorption and mercury porosimetry experiments have been run in series on the same sample. This has been achieved by freezing entrapped mercury in place before a subsequent gas sorption experiment was carried out. Several different bidisperse materials with similarly shaped mercury intrusion curves and similar levels of mercury entrapment have been studied. The entrapment of mercury within certain pores in the porous medium can often lead to marked changes in the shape of the gas sorption hysteresis loop between the data obtained prior and subsequent to porosimetry. It was found that the degree of the change of shape of the sorption hysteresis loops differed markedly between different materials. The analysis of the gas sorption hysteresis loops using percolation theory has allowed information to be obtained on the pore length distribution, and/or the distribution of pore co‐ordination number and the spatial arrangement of pores within the sample, in addition to the pore connectivity and lattice size usually obtained. The interfaced experiments have also allowed the internal consistency of analysis methods based on percolation theory to be tested, semi‐empirical alternatives to the Washburn Equation for the analysis of raw mercury porosimetry data to be independently validated, and the mechanisms of mercury entrapment in various samples to be determined.     

Development and validation of COMPASS force field parameters for molecules with aliphatic azide chains

To establish force-field-based (molecular) modeling capability that will accurately predict condensed-phase thermophysical properties for materials containing aliphatic azide chains, potential parameters for atom types unique to such chains have been developed and added to the COMPASS force field. The development effort identified the need to define four new atom types: one for each of the three azide nitrogen atoms and one for the carbon atom bonded to the azide. Calculations performed with the expanded force field yield (gas-phase) molecular structures and vibrational frequencies for hydrazoic acid, azidomethane, and the anti and gauche forms of azidoethane in good agreement with values determined experimentally and/or through computational quantum mechanics. Liquid densities calculated via molecular dynamics (MD) simulations were also in good agreement with published values for 13 of 15 training set compounds, the exceptions being hydrazoic acid and azidomethane. Of the 13 compounds whose densities are well simulated, nine have experimentally determined heats of vaporization reported in the open literature, and in all of these cases, MD simulated values for this property are in reasonable agreement with the published values. Simulations with the force field also yielded reasonable density estimates for a series of 2-azidoethanamines that have been synthesized and tested for use as hydrazine-alternative fuels.     

Multiple intersections of diagonals of regular polygons,and related topics

Our main concern is to investigate geometrically all sets of three concurrent chords of regular polygons or, equivalently, all adventitious quadrangles (that is, all quadrangles such that the angle between every pair of the six sides is an integral multiple of /n radians). Most of our results are stated without proof. The proofs are elementary, often consisting of straightforward verification; to include them would make the paper much longer and less readable.     

A Double Tiling of Triangles and Regular Hexagons

A tiling of triangles and regular hexagons, which wraps around a focal point and covers the plane twice, is investigated using both synthetic triangle geometry and complex numbers. Received February 12, 1999, and in revised form October 25, 1999. Online publication May 16, 2000.     

4 + 1] cycloaddition of N-heterocyclic carbenes with vinyl isocyanates

[reaction: see text] N-Heterocyclic carbenes have been found to undergo [4 + 1] cycloaddition with various vinyl isocyanates to afford functionalized hydroindolone products.