Recent evidence suggests that blocking aberrant hedgehog pathway signaling may be a promising therapeutic strategy for the treatment of several types of cancer. Cyclopamine, a plant Veratrum alkaloid, is a natural product antagonist of the hedgehog pathway. In a previous report, a seven-membered D-ring semisynthetic analogue of cyclopamine, IPI-269609 (2), was shown to have greater acid stability and better aqueous solubility compared to cyclopamine. Further modifications of the A-ring system generated three series of analogues with improved potency and/or solubility. Lead compounds from each series were characterized in vitro and evaluated in vivo for biological activity and pharmacokinetic properties. These studies led to the discovery of IPI-926 (compound 28), a novel semisynthetic cyclopamine analogue with substantially improved pharmaceutical properties and potency and a favorable pharmacokinetic profile relative to cyclopamine and compound 2. As a result, complete tumor regression was observed in a Hh-dependent medulloblastoma allograft model after daily oral administration of 40 mg/kg of compound 28.

The use of tissue oximetry has decreased the authors' flap loss rate and improved the flap salvage rate in microsurgical breast reconstruction. This device is a useful adjunct in flap monitoring during the postoperative period, as it may help decrease flap loss by detecting impending vascular compromise before it becomes clinically evident.

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Cells assemble protein networks through regions of protein recognition that are found in numerous proteins as conserved peptide motifs. This allows for the specific and efficient communication of signals derived from both extracellular and intracellular sources 1 . A subset of scaffolding proteins has emerged whose members are composed principally of these discrete protein-protein interaction motifs 2 . Paxillin is one of these molecular adaptor proteins that functions primarily at focal adhesions.Focal adhesions are multi-molecular complexes at sites of integrin-extracellular matrix ligation 3 . These assemblies are multi-potent in terms of transducing extracellular and intracellular cues 4 , and appear to be a point of convergence of growth factor and integrin signaling 5 .