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PubMed | Sanford Burnham Institute for Medical Research, University of Maryland, Baltimore, Childrens Hospital of Pittsburgh of UPMC Pittsburgh and Norwegian University of Science and Technology
Type: Journal Article | Journal: Journal of medicinal chemistry | Year: 2015

The rational design of inhibitors of the bHLH-ZIP oncoprotein c-Myc is hampered by a lack of structure in its monomeric state. We describe herein the design of novel, low-molecular-weight, synthetic -helix mimetics that recognize helical c-Myc in its transcriptionally active coiled-coil structure in association with its obligate bHLH-ZIP partner Max. These compounds perturb the heterodimers binding to its canonical E-box DNA sequence without causing protein-protein dissociation, heralding a new mechanistic class of direct c-Myc inhibitors. In addition to electrophoretic mobility shift assays, this model was corroborated by further biophysical methods, including NMR spectroscopy and surface plasmon resonance. Several compounds demonstrated a 2-fold or greater selectivity for c-Myc-Max heterodimers over Max-Max homodimers with IC50 values as low as 5.6 M. Finally, these compounds inhibited the proliferation of c-Myc-expressing cell lines in a concentration-dependent manner that correlated with the loss of expression of a c-Myc-dependent reporter plasmid despite the fact that c-Myc-Max heterodimers remained intact.


PubMed | University of Cincinnati, Childrens Hospital of Pittsburgh of UPMC Pittsburgh and Cincinnati Childrens Hospital Medical Center Cincinnati
Type: Journal Article | Journal: Brain and behavior | Year: 2014

The purpose of the present study was to identify biomarkers of listening difficulties by investigating white matter microstructure in children suspected of auditory processing disorder (APD) using diffusion tensor imaging (DTI). Behavioral studies have suggested that impaired cognitive and/or attention abilities rather than a pure sensory processing deficit underlie listening difficulties and auditory processing disorder (APD) in children. However, the neural signature of listening difficulties has not been investigated.Twelve children with listening difficulties and atypical left ear advantage (LEA) in dichotic listening and twelve age- and gender-matched typically developing children with typical right ear advantage (REA) were tested. Using voxel-based analysis, fractional anisotropy (FA), and mean, axial and radial diffusivity (MD, AD, RD) maps were computed and contrasted between the groups.Listening difficulties were associated with altered white matter microstructure, reflected by decreased FA in frontal multifocal white matter regions centered in prefrontal cortex bilaterally and left anterior cingulate. Increased RD and decreased AD accounted for the decreased FA, suggesting delayed myelination in frontal white matter tracts and disrupted fiber organization in the LEA group. Furthermore, listening difficulties were associated with increased MD (with increase in both RD and AD) in the posterior limb of the internal capsule (sublenticular part) at the auditory radiations where auditory input is transmitted between the thalamus and the auditory cortex.Our results provide direct evidence that listening difficulties in children are associated with altered white matter microstructure and that both sensory and supramodal deficits underlie the differences between the groups.


PubMed | Childrens Hospital of Pittsburgh of UPMC Pittsburgh
Type: Journal Article | Journal: Current treatment options in pediatrics | Year: 2015

Acute central nervous system conditions due to hypoxic-ischemic encephalopathy, traumatic brain injury (TBI), status epilepticus, and central nervous system infection/inflammation, are a leading cause of death and disability in childhood. There is a critical need for effective neuroprotective therapies to improve outcome targeting distinct disease pathology. Fever, defined as patient temperature > 38C, has been clearly shown to exacerbate brain injury. Therapeutic hypothermia (HT) is an intervention using targeted temperature management that has multiple mechanisms of action and robust evidence of efficacy in multiple experimental models of brain injury. Prospective clinical evidence for its neuroprotective efficacy exists in narrowly-defined populations with hypoxic-ischemic injury outside of the pediatric age range while trials comparing hypothermia to normothermia after TBI have failed to demonstrate a benefit on outcome but consistently demonstrate potential use in decreasing refractory intracranial pressure. Data in children from prospective, randomized controlled trials using different strategies of targeted temperature management for various outcomes are few but a large study examining HT versus controlled normothermia to improve neurological outcome in cardiac arrest is underway.

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