Faculty Bibliography

Background: Although patient age at diagnosis is not currently included in guidelines for treatment of primary melanoma, several lines of evidence suggest that patient age is an important, yet understudied, factor when considering treatment options. Here, we attempt to address the limited knowledge of the impact of age on primary melanoma treatment. Methods: In a prospectively enrolled and followed-up cohort of melanoma patients at NYU, we used logistic regression models to evaluate the association between patient age at diagnosis, tumor baseline characteristics, including BRAF and NRAS mutation status, and likelihood of receiving and responding to adjuvant therapy. We examined adjuvant therapy effectiveness using recurrence and melanoma-specific survival as endpoints. Results: 444 primary melanoma patients were included in the study (median follow-up: 6.3 years; age range: 19-95 years). Age was categorized into three groups spanning the range of age at presentation: younger (19-45 years; 24%), middle (46-70 years; 50%), and older (71-95 years; 26%). Older patients were significantly more likely to have advanced stage, nodular subtype (P < 0.01, both variables), and BRAF wildtype tumors (P = 0.04). Controlling for these factors as well as gender, older patients experienced a higher risk of recurrence (HR older vs. younger 3.34, 95% CI 1.53-7.25; P < 0.01). Of the 128/444 (29%) patients who were eligible for adjuvant treatment (clinical stage IIB), only 67/128 (52%) received treatment. Using a propensity score that accounts for stage at presentation, patients in the middle age group were more likely to receive adjuvant therapy than those in the older group (OR 2.61, 95% CI 1.12-6.08; P = 0.03). In addition, a trend suggesting benefit from adjuvant therapy (defined as longer melanoma-specific survival) was observed only in the middle age group (P = 0.07). Conclusions: Our data suggest that older melanoma patients, despite having a significantly worse prognosis, are less likely to receive and bene!

Background: PP6C binds to regulatory units toaffect a number of important pathways including cell proliferation and DNA repair. Recently two independent groups reported for the first time the presence of somatic mutations in the PPP6C gene in ~10% of short term cultures and limited number of human melanoma tissues. However, the clinical or biological relevance of PPP6C mutations in melanoma patients is unknown. Our objectives were to examine the clinical relevance of PPP6C mutations in a well characterized cohort of melanoma specimens linked to extensive, prospectively-collected clinical information and to explore the functional consequence of different categories of mutations. Methods: Sanger dideoxy sequencing was performed on PCR-amplified DNA from macro-dissected FFPE tumors. Associations between PPP6C mutations and baseline characteristics, recurrence, survival, and BRAF/ NRAS mutational status were examined. The impact of mutations on binding PP6C regulatory units was assessed as well as the effect on additional downstream pathways. Results: 308 primary melanoma patients (118 Stage I, 92 Stage II, and 98 Stage III) were examined (median follow up: 5.3 years). 50 PPP6C mutations in 33 patients (10.7%) were identified with 11 tumors harboring more than one mutation. One mutation (R301C) was identified in 6 patients. PPP6C mutations occurred with similar frequencies across stages and showed no association with BRAF or NRAS mutations.Mutations were categorized into 3 groups: Mutations resulting in premature stop codon (n=9), those occurring in the active site (n=16) and others (n=8). 8/9 (89%) patients with stop mutations recurred and developed visceral metastases. Functional studies revealed that PPP6C mutants also behaved differently; some PPP6C mutations led to decreased binding to regulatory subunits, others, including the R301C mutation did not. Conclusions: Our data suggest that PPP6C mutation is an early event in melanoma progression and independent of BRAF or NRAS mutations. Data also!

In addition to intellectual disability, individuals with Down syndrome (DS) exhibit dementia by the third or fourth decade of life, due to the early onset of neuropathological changes typical of Alzheimer's disease (AD). Deficient ontogenetic neurogenesis contributes to the brain hypoplasia and hypocellularity evident in fetuses and children with DS. A murine model of DS and AD (the Ts65Dn mouse) exhibits key features of these disorders, notably deficient ontogenetic neurogenesis, degeneration of basal forebrain cholinergic neurons (BFCNs), and cognitive deficits. Adult hippocampal (HP) neurogenesis is also deficient in Ts65Dn mice and may contribute to the observed cognitive dysfunction. Herein, we demonstrate that supplementing the maternal diet with additional choline (approximately 4.5 times the amount in normal rodent chow) dramatically improved the performance of the adult trisomic offspring in a radial arm water maze task. Ts65Dn offspring of choline-supplemented dams performed significantly better than unsupplemented Ts65Dn mice. Furthermore, adult hippocampal neurogenesis was partially normalized in the maternal choline supplemented (MCS) trisomic offspring relative to their unsupplemented counterparts. A significant correlation was observed between adult hippocampal neurogenesis and performance in the water maze, suggesting that the increased neurogenesis seen in the supplemented trisomic mice contributed functionally to their improved spatial cognition. These findings suggest that supplementing the maternal diet with additional choline has significant translational potential for DS.

Menstruation and desquamation are important routes for humans to excrete iron. Because menstruation is no longer available in postmenopausal women, in the present study, we examined whether iron accumulates more in postmenopausal skin than in premenopausal skin. Skin biopsy samples were obtained from six pre- and six postmenopausal Caucasian women. Iron levels in the form of ferritin were 42% higher, but vascular endothelial growth factor and total antioxidant capacity were 45% and 34% lower in postmenopausal skin (58.8 +/- 1.3 years old) than in premenopausal skin (41.6 +/- 1.7 years old), respectively. Moreover, in vitro cultured normal human epidermal keratinocytes had surprisingly high levels of ferritin when compared to immortalized human breast epithelial MCF-10A cells or human liver HepG2 cancer cells. Our results indicate that skin is a cellular repository of iron and that menopause increases iron in skin and, thus, may contribute to the manifestation of accelerated skin aging and photo aging after menopause.

BACKGROUND: Pain and natural rewards such as food elicit different behavioral effects. Both pain and rewards, however, have been shown to alter synaptic activities in the nucleus accumbens (NAc), a key component of the brain reward system. Mechanisms by which external stimuli regulate plasticity at NAc synapses are largely unexplored. Medium spiny neurons (MSNs) from the NAc receive excitatory glutamatergic inputs and modulatory dopaminergic and cholinergic inputs from a variety of cortical and subcortical structures. Glutamate inputs to the NAc arise primarily from prefrontal cortex, thalamus, amygdala, and hippocampus, and different glutamate projections provide distinct synaptic and ultimately behavioral functions. The family of vesicular glutamate transporters (VGLUTs 1-3) plays a key role in the uploading of glutamate into synaptic vesicles. VGLUT1-3 isoforms have distinct expression patterns in the brain, but the effects of external stimuli on their expression patterns have not been studied. RESULTS: In this study, we use a sucrose self-administration paradigm for natural rewards, and spared nerve injury (SNI) model for chronic pain. We examine the levels of VGLUTs (1-3) in synaptoneurosomes of the NAc in these two behavioral models. We find that chronic pain leads to a decrease of VGLUT1, likely reflecting decreased projections from the cortex. Pain also decreases VGLUT3 levels, likely representing a decrease in projections from GABAergic, serotonergic, and/or cholinergic interneurons. In contrast, chronic consumption of sucrose increases VGLUT3 in the NAc, possibly reflecting an increase from these interneuron projections. CONCLUSION: Our study shows that natural rewards and pain have distinct effects on the VGLUT expression pattern in the NAc, indicating that glutamate inputs to the NAc are differentially modulated by rewards and pain.

To locate visual objects, the brain combines information about retinal location and direction of gaze. Studies in monkeys have demonstrated that eye position modulates the gain of visual signals with "gain fields," so that single neurons represent both retinotopic location and eye position. We wished to know whether eye position and retinotopic stimulus location are both represented in human visual cortex. Using functional magnetic resonance imaging, we measured separately for each of several different gaze positions cortical responses to stimuli that varied periodically in retinal locus. Visually evoked responses were periodic following the periodic retinotopic stimulation. Only the response amplitudes depended on eye position; response phases were indistinguishable across eye positions. We used multivoxel pattern analysis to decode eye position from the spatial pattern of response amplitudes. The decoder reliably discriminated eye position in five of the early visual cortical areas by taking advantage of a spatially heterogeneous eye position-dependent modulation of cortical activity. We conclude that responses in retinotopically organized visual cortical areas are modulated by gain fields qualitatively similar to those previously observed neurophysiologically.

The data reported in the Technical Comments by Fitz et al., Price et al., Tesseur et al., and Veeraraghavalu et al. replicate and validate our central conclusion that bexarotene stimulates the clearance of soluble beta-amyloid peptides and results in the reversal of behavioral deficits in mouse models of Alzheimer's disease (AD). The basis of the inability to reproduce the drug-stimulated microglial-mediated reduction in plaque burden is unexplained. However, we concluded that plaque burden is functionally unrelated to improved cognition and memory elicited by bexarotene.

OBJECTIVE: Both the neuronal populations and mechanisms responsible for generalized spike-wave absence seizures are poorly understood. In mutant mice carrying loss-of-function (LOF) mutations in Cacna1a, which encodes the alpha1 pore-forming subunit of CaV 2.1 (P/Q-type) voltage-gated Ca2+ channels, generalized spike-wave seizures have been suggested to result from excessive bursting of thalamocortical cells. However, other cellular populations including cortical inhibitory interneurons may contribute to this phenotype. We investigated how different cortical interneuron subtypes are affected by the loss of CaV 2.1 channel function and how this contributes to the onset of generalized epilepsy. METHODS: We designed genetic strategies to induce a selective Cacna1a LOF mutation in different cortical gamma-aminobutyric acidergic (GABAergic) and/or glutamatergic neuronal populations in mice. We assessed the cellular and network consequences of these mutations by combining immunohistochemical assays, in vitro physiology, optogenetics, and in vivo video electroencephalographic recordings. RESULTS: We demonstrate that selective Cacna1a LOF from a subset of cortical interneurons, including parvalbumin (PV)+ and somatostatin (SST)+ interneurons, results in severe generalized epilepsy. Loss of CaV 2.1 channel function compromises GABA release from PV+ but not SST+ interneurons. Moreover, thalamocortical projection neurons do not show enhanced bursting in these mutants, suggesting that this feature is not essential for the development of generalized spike-wave seizures. Notably, the concurrent removal of CaV 2.1 channels in cortical pyramidal cells and interneurons considerably lessens seizure severity by decreasing cortical excitability. INTERPRETATION: Our findings demonstrate that conditional ablation of CaV 2.1 channel function from cortical PV+ interneurons alters GABA release from these cells, impairs their ability to constrain cortical pyramidal cell excitability, and is sufficient to cause generalized seizures. Ann Neurol 2013.

Although the mechanisms underlying mild traumatic brain injury (mTBI) are becoming well understood, treatment options are still limited. In the present study, mTBI was induced by a weight drop model to produce a closed head injury to mice and the effect of inhaled nitric oxide (INO) was evaluated by a short term memory task (object recognition task) and immunohistochemical staining of glial fibrillary acidic protein (GFAP) and CD45 for the detection of reactive astrocytes and microglia. Results showed that mTBI model did not produce brain edema, skull fracture or sensorimotor coordination dysfunctions. Mice did however exhibit a significant deficit in short term memory (STM) and strong inflammatory reaction in the ipsilateral cortex and hippocampus compared to sham-injured controls 24h after mTBI. Additional groups of untreated mice tested 3 and 7 days later, demonstrated that recognition memory had recovered to normal levels by Day 3. Mice treated with 10ppm INO for 4 or 8h, beginning immediately after TBI demonstrated significantly improved STM at 24h when compared with room air controls (p<0.05). Whereas mice treated with 10ppm INO for 24h showed no improvement in STM. Mice treated with INO 10ppm for 8h exhibited significantly reduced microglia and astrocyte activation compared with room air controls. These data demonstrate that mTBI produces a disruption of STM which is evident 24h after injury and persists for 2-3 days. Treatment with low concentration or short durations of INO prevents this memory loss and also attenuates the inflammatory response. These findings may have relevance for the treatment of patients diagnosed with concussion.

BACKGROUND: Individuals with autism spectrum disorders (ASD) often exhibit symptoms of attention-deficit/hyperactivity disorder (ADHD). Across both disorders, observations of distributed functional abnormalities suggest aberrant large-scale brain network connectivity. Yet, common and distinct network correlates of ASD and ADHD remain unidentified. Here, we aimed to examine patterns of dysconnection in school-age children with ASD and ADHD and typically developing children who completed a resting state functional magnetic resonance imaging scan. METHODS: We measured voxelwise network centrality, functional connectivity metrics indexing local (degree centrality [DC]) and global (eigenvector centrality) functional relationships across the entire brain connectome, in resting state functional magnetic resonance imaging data from 56 children with ASD, 45 children with ADHD, and 50 typically developing children. A one-way analysis of covariance, with group as fixed factor (whole-brain corrected), was followed by post hoc pairwise comparisons. RESULTS: Cortical and subcortical areas exhibited centrality abnormalities, some common to both ADHD and ASD, such as in precuneus. Others were disorder-specific and included ADHD-related increases in DC in right striatum/pallidum, in contrast with ASD-related increases in bilateral temporolimbic areas. Secondary analyses differentiating children with ASD into those with or without ADHD-like comorbidity (ASD+ and ASD-, respectively) revealed that the ASD+ group shared ADHD-specific abnormalities in basal ganglia. By contrast, centrality increases in temporolimbic areas characterized children with ASD regardless of ADHD-like comorbidity. At the cluster level, eigenvector centrality group patterns were similar to DC. CONCLUSIONS: ADHD and ASD are neurodevelopmental disorders with distinct and overlapping clinical presentations. This work provides evidence for both shared and distinct underlying mechanisms at the large-scale network level.