Faculty Bibliography

Superficial spreading melanoma (SSM) and nodular melanoma (NM) are believed to represent sequential phases of linear progression from radial to vertical growth. Several lines of clinical, pathological and epidemiologic evidence suggest, however, that SSM and NM might be the result of independent pathways of tumor development. We utilized an integrative genomic approach that combines single nucleotide polymorphism array (SNP 6.0, Affymetrix) with gene expression array (U133A 2.0, Affymetrix) to examine molecular differences between SSM and NM. Pathway analysis of the most differentially expressed genes between SSM and NM (N=114) revealed significant differences related to metabolic processes. We identified 8 genes (DIS3, FGFR1OP, G3BP2, GALNT7, MTAP, SEC23IP, USO1, ZNF668) in which NM/SSM-specific copy number alterations correlated with differential gene expression (P<0.05, Spearman's rank). SSM-specific genomic deletions in G3BP2, MTAP, and SEC23IP were independently verified in two external data sets. Forced overexpression of metabolism-related gene methylthioadenosine phosphorylase (MTAP) in SSM resulted in reduced cell growth. The differential expression of another metabolic related gene, aldehyde dehydrogenase 7A1 (ALDH7A1), was validated at the protein level using tissue microarrays of human melanoma. In addition, we show that the decreased ALDH7A1 expression in SSM may be the result of epigenetic modifications. Our data reveal recurrent genomic deletions in SSM not present in NM, which challenge the linear model of melanoma progression. Furthermore, our data suggest a role for altered regulation of metabolism-related genes as a possible cause of the different clinical behavior of SSM and NM

BACKGROUND: Models of cocaine addiction emphasize the role of disrupted frontal circuitry supporting cognitive control processes. However, addiction-related alterations in functional interactions among brain regions, especially between the cerebral hemispheres, are rarely examined directly. Resting-state functional magnetic resonance imaging (fMRI) approaches, which reveal patterns of coherent spontaneous fluctuations in the fMRI signal, offer a means to quantify directly functional interactions between the hemispheres. We examined interhemispheric resting-state functional connectivity (RSFC) in cocaine dependence using a recently validated approach, voxel-mirrored homotopic connectivity. METHODS: We compared interhemispheric RSFC between 25 adults (aged 35.0 +/- 8.8) meeting DSM-IV criteria for cocaine dependence within the past 12 months but currently abstaining (>2 weeks) from cocaine and 24 healthy comparisons (35.1 +/- 7.5), group-matched on age, sex, education, and employment status. RESULTS: We observed reduced prefrontal interhemispheric RSFC in cocaine-dependent participants relative to control subjects. Further analyses demonstrated a striking cocaine-dependence-related reduction in interhemispheric RSFC among nodes of the dorsal attention network, comprising bilateral lateral frontal, medial premotor, and posterior parietal areas. Further, within the cocaine-dependent group, RSFC within the dorsal attention network was associated with self-reported attentional lapses. CONCLUSIONS: Our findings provide further evidence of an association between chronic exposure to cocaine and disruptions within large-scale brain circuitry supporting cognitive control. We did not detect group differences in diffusion tensor imaging measures, suggesting that alterations in the brain's functional architecture associated with cocaine exposure can be observed in the absence of detectable abnormalities in the white matter microstructure supporting that architecture

Estrogen alone cannot explain the differences in breast cancer (BC) recurrence and incidence rates in pre- and postmenopausal women. In this study, we have tested a hypothesis that, in addition to estrogen, both iron deficiency due to menstruation and iron accumulation as a result of menstrual stop play important roles in menopause-related BC outcomes. We first tested this hypothesis in cell culture models mimicking the high-estrogen and low-iron premenopausal condition or the low-estrogen and high-iron postmenopausal condition. Subsequently, we examined this hypothesis in mice that were fed iron-deficient and iron-overloaded diets. We show that estrogen only slightly up-regulates vascular endothelial growth factor (VEGF), an angiogenic factor known to be important in BC recurrence. It is, rather, iron deficiency that significantly promotes VEGF by stabilizing hypoxia-inducible factor-1alpha. Conversely, high iron levels increase oxidative stress and sustain mitogen-activated protein kinase activation, which are mechanisms of known significance in BC development. Taken together, our results suggest, for the first time, that an iron-deficiency-mediated proangiogenic environment could contribute to the high recurrence of BC in young patients, and iron-accumulation-associated pro-oxidant conditions could lead to the high incidence of BC in older women

Cirrhosis is an important and growing public health problem, affecting millions of Americans and many more people internationally. A pathological hallmark of the progression to cirrhosis is the development of liver fibrosis, so that monitoring the appearance and progression of liver fibrosis can be used to guide therapy. Here, we report a method to use magnetization-tagged magnetic resonance imaging to measure the cardiac-induced motion and deformation in the liver, as a means for noninvasively assessing liver stiffness, which is related to fibrosis. The initial results show statistically significant differences between healthy and cirrhotic subjects in the direct comparisons of the maximum displacement (mm), and the maximum (P1) and minimum (P2) two-dimensional strains, through the cardiac cycle (3.514 +/- 0.793, 2.184 +/- 0.611; 0.116 +/- 0.043, 0.048 +/- 0.011; -0.094 +/- 0.020, -0.041 +/- 0.015; healthy, cirrhosis, respectively; P < 0.005 for all). There are also significant differences in the displacement-normalized P1 and P2 strains (mm(-1) ) (0.030 +/- 0.008, 0.017 +/- 0.007; -0.024 +/- 0.006, -0.013 +/- 0.004; healthy, cirrhosis, respectively; P < 0.005 for all). Therefore, this noninvasive imaging-based method is a promising means to assess liver stiffness using clinically available imaging tools. Magn Reson Med, 2011. (c) 2011 Wiley-Liss, Inc

The multidimensional phoneme identification model is applied to consonant confusion matrices obtained from 28 postlingually deafened cochlear implant users. This model predicts consonant matrices based on these subjects' ability to discriminate a set of postulated spectral, temporal, and amplitude speech cues as presented to them by their device. The model produced confusion matrices that matched many aspects of individual subjects' consonant matrices, including information transfer for the voicing, manner, and place features, despite individual differences in age at implantation, implant experience, device and stimulation strategy used, as well as overall consonant identification level. The model was able to match the general pattern of errors between consonants, but not the full complexity of all consonant errors made by each individual. The present study represents an important first step in developing a model that can be used to test specific hypotheses about the mechanisms cochlear implant users employ to understand speech

The objective of this prospective observational study was to assess the association between dysrhythmia of EEG background (disturbance of cerebral connectivity) and sleep difficulties. Sixty children, aged 4 to 12 years, participated. Hospital records were reviewed, and sleep histories were obtained by interviewing the parents. EEGs of 39 subjects were normal, showed epileptiform activity, and/or mild to moderate background dysrhythmia. Severe unilateral dysrhythmia was noted in 6 and bilaterally in 15 EEGs, with all 15 children having profound neurodevelopmental disabilities and 14 of these 15 having long-standing severe chaotic sleep/wake patterns. Thus, there was a highly significant association between EEG evidence of severe bilateral dysrhythmia and chronic sleep/wake dysregulation. Unilateral dysrhythmia was not associated with sleep difficulties. This study delineates a specific sleep disorder in a group of children with marked neurodevelopmental disabilities and offers insight into how disturbed cerebral connectivity impacts the thalamocortical dynamics relating to neurodevelopmental disabilities, sleep, and melatonin production.

It is of considerable interest to determine how diverse subtypes of gamma-aminobutyric acidergic (GABAergic) interneurons integrate into the functional network of the cerebral cortex. Using inducible in vivo genetic fate mapping approaches, we found that interneuron precursors arising from the medial ganglionic eminence (MGE) and caudal ganglionic eminence (CGE) at E12.5, respectively, populate deep and superficial cortical layers in a complementary manner in the mature cortex. These age-matched populations initiate tangential migration into the cortex simultaneously, migrate above and below the cortical plate in a similar ratio, and complete their entrance into the cortical plate by P1. Surprisingly, while these 2 interneuron populations show a comparable layer distribution at P1, they subsequently segregate into distinct cortical layers. In addition, the initiation of the radial sorting within each lineage coincided well with the upregulation of the potassium/chloride cotransporter KCC2. Moreover, layer sorting of a later born (E16.5) CGE-derived population occurred with a similar time course to the earlier born E12.5 cohorts, further suggesting that this segregation step is controlled in a subtype specific manner. We conclude that radial sorting within the early postnatal cortex is a key mechanism by which the layer-specific integration of GABAergic interneurons into the emerging cortical network is achieved

Upon activation by nerve growth factor (NGF), TrkA is internalized, trafficked and sorted through different endosomal compartments. Proper TrkA trafficking and sorting are crucial events as alteration of these processes hinders NGF-mediated functions. However, it is not fully known which proteins are involved in the trafficking and sorting of TrkA. Here we report that Nedd4-2 regulates the trafficking of TrkA and NGF functions in sensory neurons. Depletion of Nedd4-2 disrupts the correct sorting of activated TrkA at the early and late endosome stages, resulting in an accumulation of TrkA in these compartments and, as a result of the reduced trafficking to the degradative pathway, TrkA is either reverted to the cell surface through the recycling pathway or retrogradely transported to the cell body. In addition, Nedd4-2 depletion enhances TrkA signaling and the survival of NGF-dependent dorsal root ganglion neurons, but not those of brain-derived neurotrophic factor-dependent neurons. Furthermore, neurons from a knock-in mouse expressing a TrkA mutant that does not bind Nedd4-2 protein exhibit increased NGF-mediated signaling and cell survival. Our data indicate that TrkA trafficking and sorting are regulated by Nedd4-2 protein

Melatonin, which is known to have sleep-promoting properties, has no morpho-physiological barriers and readily enters neurons and their subcellular compartments from both the blood and cerebrospinal fluid. It has multiple receptor-dependent and receptor-independent functions. Sleep is a neuronal function, and it can no longer be postulated that one or more anatomical structures fully control sleep. Neurons require sleep for metabolically driven restorative purposes, and as a result, the process of sleep is modulated by peripheral and central mechanisms. This is an important finding because it suggests that melatonin should have intracellular sleep-inducing properties. Based on recent evidence, it is proposed that melatonin induces sleep at the neuronal level independently of its membrane receptors. Thus, the hypnotic action of melatonin and the mechanisms involving the circadian rhythms are separate neurological functions. This is contrary to the presently accepted view.