During carcinogenesis of pancreatic islets in transgenic mice, an angiogenic switch activates the quiescent vasculature. Paradoxically, vascular endothelial growth factor (VEGF) and its receptors are expressed constitutively. Nevertheless, a synthetic inhibitor (SU5416) of VEGF signalling impairs angiogenic switching and tumour growth. Two metalloproteinases, MMP-2/gelatinase-A and MMP-9/gelatinase-B, are upregulated in angiogenic lesions. MMP-9 can render normal islets angiogenic, releasing VEGF. MMP inhibitors reduce angiogenic switching, and tumour number and growth, as does genetic ablation of MMP-9. Absence of MMP-2 does not impair induction of angiogenesis, but retards tumour growth, whereas lack of urokinase has no effect. Our results show that MMP-9 is a component of the angiogenic switch.

An efficient and highly stereoselective total synthesis of the natural product (±)-welwitindolinone A isonitrile (1) is described. The bicyclo[4.2.0]octane core of 1 was established by a regio- and diastereoselective [2+2] ketene cycloaddition. The C12 quaternary center and vicinal stereogenic chlorine were installed in a single operation with excellent stereocontrol via a chloronium ion mediated semipinacol rearrangement. Described strategies for construction of the spiro-oxinole include a SmI2−LiCl mediated reductive cyclization and a novel anionic cyclization that simultaneously constructs the spiro-oxindole and vinyl isonitrile moieties.

The range of scores elicited by a structured, an unstructured and a 'labelsonly' version of the 9-point hedonic scale were compared using consumersfrom USA, Japan and Korea. It was found that the unstructured scale elicited a wider range of scores for American and Japanese consumers. Afrer correction for hedonic ranges, it was found that Japanese had smaller ranges of scores on all three scales, although the effect was less pronounced for the unstructured scale. The Korean consumers were the exception. Their ranges were less than Americans but their ranges on the unstructured scale did not increase. The results were discussed in terms of the effects of inhibition of use of categories by the scale labels, effects of translation from the English, psychophysical style and order efsects.

These bulky adenosine triphosphate antagonists derived from K252a or related indolocarbazole compounds such as staurosporine would be potentially useful for the treatment of RAS/ PAK1-induced cancers, once their anti-PAK1 activity is significantly potentiated by a few additional chemical modifications at the sugar ring suggested in this paper.

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