The cognitive map in humans: spatial navigation and beyond

The ‘cognitive map’ hypothesis proposes that brain builds a unified representation of the spatial environment to support memory and guide future action. Forty years of electrophysiological research in rodents suggests that cognitive maps are neurally instantiated by place, grid, border, and head direction cells in the hippocampal formation and related structures. Here we review recent work that suggests a similar functional organization in the human brain and reveals novel insights into how cognitive maps are used during spatial navigation. Specifically, these studies indicate that: (i) the human hippocampus and entorhinal cortex support map-like spatial codes; (ii) posterior brain regions such as parahippocampal and retrosplenial cortices provide critical inputs that allow cognitive maps to be anchored to fixed environmental landmarks; (iii) hippocampal and entorhinal spatial codes are used in conjunction with frontal lobe mechanisms to plan routes during navigation. We also discuss how these three basic elements of cognitive map based navigation—spatial coding, landmark anchoring, and route planning—might be applied to non-spatial domains to provide the building blocks for many core elements of human thought

Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond

The identification of mutationally activated BRAF in many cancers altered our conception of the role played by the RAF family of protein kinases in oncogenesis. In this review we describe the development of BRAF inhibitors and the results that have emerged from their analysis in both the laboratory and the clinic. We discuss the spectrum of RAF mutations in human cancer and the complex interplay between tissue of origin and response to RAF inhibition. Finally, we enumerate mechanisms of resistance to BRAF inhibition that have been characterized and postulate how strategies of RAF pathway inhibition may be extended in scope to benefit, not only the thousands of patients diagnosed annually with BRAF-mutated metastatic melanoma, but also the larger patient population with malignancies harboring mutationally activated RAF genes that is ineffectively treated with the current generation of BRAF kinase inhibitors