Struell Wells: pagan past and Christian present

The complex of buildings at Struell Wells, near Downpatrick, Co. Down, is the most extensive at a holy well in Ireland. It comprises two wells, two bath-houses and the ruins of a church. Nearby is a natural rock feature known as St Patrick’s Chair. The earliest reference to the wells is likely to be in the 8th century Fíacc’s Hymn which records the site being visited by St Patrick. The earliest reference to their healing powers can be dated to the 11th/12th century and the site continued to be a focus of pilgrimage at midsummer until its suppression in the nineteenth century. The site seems to be unique in that bathing in the wells constituted an integral part of the rituals performed by pilgrims. A recent study of the holy well phenomenon in Ireland has suggested that the rituals associated with them have their origins in the Counter-Reformation (Carroll 1999). The evidence from Struell, however, strongly suggests that it was an important sacred site in pre-Christian times.

A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent activity

Activation of the MET oncogenic pathway has been implicated in the development of aggressive cancers that are difficult to treat with current chemotherapies. This has led to an increased interest in developing novel therapies that target the MET pathway. However, most existing drug modalities are confounded by their inability to specifically target and/or antagonize this pathway. Anticalins, a novel class of monovalent small biologics, are hypothesized to be "fit for purpose" for developing highly specific and potent antagonists of cancer pathways. Here, we describe a monovalent full MET antagonist, PRS-110, displaying efficacy in both ligand-dependent and ligand-independent cancer models. PRS-110 specifically binds to MET with high affinity and blocks hepatocyte growth factor (HGF) interaction. Phosphorylation assays show that PRS-110 efficiently inhibits HGF-mediated signaling of MET receptor and has no agonistic activity. Confocal microscopy shows that PRS-110 results in the trafficking of MET to late endosomal/lysosomal compartments in the absence of HGF. In vivo administration of PRS-110 resulted in significant, dose-dependent tumor growth inhibition in ligand-dependent (U87-MG) and ligand-independent (Caki-1) xenograft models. Analysis of MET protein levels on xenograft biopsy samples show a significant reduction in total MET following therapy with PRS-110 supporting its ligand-independent mechanism of action. Taken together, these data indicate that the MET inhibitor PRS-110 has potentially broad anticancer activity that warrants evaluation in patients.