Genomic biomarkers for patient selection and stratification: the cancer paradigm.

The revolution in disease diagnosis and treatment promised on the completion of the human genome project over a decade ago has materialized in the form of unified drug and biomarker discovery and development pipelines. This strategic shift has been principally catalyzed through success stories in the field of oncology, ushering in the era of personalized medicine. Thus, a number of molecular targets have also been demonstrated to be reliable markers for selecting patients wherein treatment can be efficacious. Perhaps more importantly, however, the late adoption of biomarker strategies has also rescued drug candidates from complete late-stage failure. This review examines the historical lessons of key challenges in translating biomarker assay information into strategic and clinically actionable decisions and assesses the impact of personalized genome sequencing in the future of companion diagnostic development and commercialization

Alimentary tract innervation deficits and dysfunction in mice lacking GDNF family receptor α2

Subsets of parasympathetic and enteric neurons require neurturin signaling via glial cell line–derived neurotrophic factor family receptor α2 (GFRα2) for development and target innervation. Why GFRα2-deficient (Gfra2(–/–)) mice grow poorly has remained unclear. Here, we analyzed several factors that could contribute to the growth retardation. Neurturin mRNA was localized in the gut circular muscle. GFRα2 protein was expressed in most substance P–containing myenteric neurons, in most intrapancreatic neurons, and in surrounding glial cells. In the Gfra2(–/–) mice, density of substance P–containing myenteric ganglion cells and nerve bundles in the myenteric ganglion cell layer was significantly reduced, and transit of test material through small intestine was 25% slower compared to wild-type mice. Importantly, the knockout mice had approximately 80% fewer intrapancreatic neurons, severely impaired cholinergic innervation of the exocrine but not the endocrine pancreas, and increased fecal fat content. Vagally mediated stimulation of pancreatic secretion by 2-deoxy-glucose in vivo was virtually abolished. Retarded growth of the Gfra2(–/–) mice was accompanied by reduced fat mass and elevated basal metabolic rate. Moreover, the knockout mice drank more water than wild-type controls, and wet-mash feeding resulted in partial growth rescue. Taken together, the results suggest that the growth retardation in mice lacking GFRα2 is largely due to impaired salivary and pancreatic secretion and intestinal dysmotility