Near universal detection of alterations in CTNNB1 and Wnt pathway regulators in desmoid-type fibromatosis by whole-exome sequencing and genomic analysis.

CTNNB1 mutations or APC abnormalities have been observed in ∼85% of desmoids examined by Sanger sequencing and are associated with Wnt/ß-catenin activation. We sought to identify molecular aberrations in "wild-type" tumors (those without CTNNB1 or APC alteration) and to determine their prognostic relevance. CTNNB1 was examined by Sanger sequencing in 117 desmoids; a mutation was observed in 101 (86%) and 16 were wild type. Wild-type status did not associate with tumor recurrence. Moreover, in unsupervised clustering based on U133A-derived gene expression profiles, wild-type and mutated tumors clustered together. Whole-exome sequencing of eight of the wild-type desmoids revealed that three had a CTNNB1 mutation that had been undetected by Sanger sequencing. The mutation was found in a mean 16% of reads (vs. 37% for mutations identified by Sanger). Of the other five wild-type tumors sequenced, two had APC loss, two had chromosome 6 loss, and one had mutation of BMI1. The finding of low-frequency CTNNB1 mutation or APC loss in wild-type desmoids was validated in the remaining eight wild-type desmoids; directed miSeq identified low-frequency CTNNB1 mutation in four and comparative genomic hybridization identified APC loss in one. These results demonstrate that mutations affecting CTNNB1 or APC occur more frequently in desmoids than previously recognized (111 of 117; 95%), and designation of wild-type genotype is largely determined by sensitivity of detection methods. Even true CTNNB1 wild-type tumors (determined by next-generation sequencing) may have genomic alterations associated with Wnt activation (chromosome 6 loss/BMI1 mutation), supporting Wnt/ß-catenin activation as the common pathway governing desmoid initiation.

The size-weight illusion induced through human echolocation.

Certain blind individuals have learned to interpret the echoes of self-generated sounds to perceive the structure of objects in their environment. The current work examined how far the influence of this unique form of sensory substitution extends by testing whether echolocation-induced representations of object size could influence weight perception. A small group of echolocation experts made tongue clicks or finger snaps toward cubes of varying sizes and weights before lifting them. These echolocators experienced a robust size-weight illusion. This experiment provides the first demonstration of a sensory substitution technique whereby the substituted sense influences the conscious perception through an intact sense.

Real-time vision, tactile cues, and visual form agnosia: removing haptic feedback from a "natural" grasping task induces pantomime-like grasps.

Investigators study the kinematics of grasping movements (prehension) under a variety of conditions to probe visuomotor function in normal and brain-damaged individuals. "Natural" prehensile acts are directed at the goal object and are executed using real-time vision. Typically, they also entail the use of tactile, proprioceptive, and kinesthetic sources of haptic feedback about the object ("haptics-based object information") once contact with the object has been made. Natural and simulated (pantomimed) forms of prehension are thought to recruit different cortical structures: patient DF, who has visual form agnosia following bilateral damage to her temporal-occipital cortex, loses her ability to scale her grasp aperture to the size of targets ("grip scaling") when her prehensile movements are based on a memory of a target previewed 2 s before the cue to respond or when her grasps are directed towards a visible virtual target but she is denied haptics-based information about the target. In the first of two experiments, we show that when DF performs real-time pantomimed grasps towards a 7.5 cm displaced imagined copy of a visible object such that her fingers make contact with the surface of the table, her grip scaling is in fact quite normal. This finding suggests that real-time vision and terminal tactile feedback are sufficient to preserve DF's grip scaling slopes. In the second experiment, we examined an "unnatural" grasping task variant in which a tangible target (along with any proxy such as the surface of the table) is denied (i.e., no terminal tactile feedback). To do this, we used a mirror-apparatus to present virtual targets with and without a spatially coincident copy for the participants to grasp. We compared the grasp kinematics from trials with and without terminal tactile feedback to a real-time-pantomimed grasping task (one without tactile feedback) in which participants visualized a copy of the visible target as instructed in our laboratory in the past. Compared to natural grasps, removing tactile feedback increased RT, slowed the velocity of the reach, reduced in-flight grip aperture, increased the slopes relating grip aperture to target width, and reduced the final grip aperture (FGA). All of these effects were also observed in the real time-pantomime grasping task. These effects seem to be independent of those that arise from using the mirror in general as we also compared grasps directed towards virtual targets to those directed at real ones viewed directly through a pane of glass. These comparisons showed that the grasps directed at virtual targets increased grip aperture, slowed the velocity of the reach, and reduced the slopes relating grip aperture to the widths of the target. Thus, using the mirror has real consequences on grasp kinematics, reflecting the importance of task-relevant sources of online visual information for the programming and updating of natural prehensile movements. Taken together, these results provide compelling support for the view that removing terminal tactile feedback, even when the grasps are target-directed, induces a switch from real-time visual control towards one that depends more on visual perception and cognitive supervision. Providing terminal tactile feedback and real-time visual information can evidently keep the dorsal visuomotor system operating normally for prehensile acts.

DF's visual brain in action: the role of tactile cues.

Patient DF, an extensively-tested woman with visual form agnosia from ventral-stream damage, is able to scale her grip aperture to match a goal object's geometry when reaching out to pick it up, despite being unable to explicitly distinguish amongst objects on the basis of their different geometries. Using evidence from a range of sources, including functional MRI, we have proposed that she does this through a functionally intact visuomotor system housed within the dorsal stream of the posterior parietal lobe. More recently, however, Schenk (2012a). The Journal of Neuroscience, 32(6), 2013-2017; Schenk (2012b). Trends in Cognitive Sciences, 16(5), 258-259. has argued that DF performs well in visually guided grasping, not through spared and functioning visuomotor networks in the dorsal stream, but because haptic feedback about the locations of the edges of the target is available to calibrate her grasps in such tasks, whereas it is not available in standard visual perceptual tasks. We have tested this 'calibration hypothesis' directly, by presenting DF with a grasping task in which the visible width of a target varied from trial to trial while its actual width remained the same. According to the calibration hypothesis, because haptic feedback was completely uninformative, DF should be unable to calibrate her grip aperture in this task. Contrary to this prediction, we found that DF continued to scale her grip aperture to the visual width of the targets and did so well within the range of healthy controls. We also found that DF's inability to distinguish shapes perceptually is not improved by providing haptic feedback. These findings strengthen the notion that DF's spared visuomotor abilities are driven largely by visual feedforward processing of the geometric properties of the target. Crucially, these findings also indicate that simple tactile contact with an object is needed for the visuomotor dorsal stream to be engaged, and accordingly enables DF to execute visually guided grasping successfully. This need for actions to have a tangible endpoint provides an important new modification of the Two Visual Systems theory.

The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.

The cBio Cancer Genomics Portal (http://cbioportal.org) is an open-access resource for interactive exploration of multidimensional cancer genomics data sets, currently providing access to data from more than 5,000 tumor samples from 20 cancer studies. The cBio Cancer Genomics Portal significantly lowers the barriers between complex genomic data and cancer researchers who want rapid, intuitive, and high-quality access to molecular profiles and clinical attributes from large-scale cancer genomics projects and empowers researchers to translate these rich data sets into biologic insights and clinical applications.