Faculty Bibliography

The anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab has been shown to improve survival in patients with metastatic non-CNS melanoma. The purpose of this study was to investigate the efficacy of CTLA-4 inhibitors in the treatment of metastatic melanoma with limited brain metastases treated with stereotactic radiosurgery (SRS). Between January 2008 and June 2011, 58 patients with limited brain metastases from melanoma were treated with SRS with a median dose of 20 Gy delivered to the 50% isodose line (range, 15-20 Gy). In 25 patients, ipilimumab was administered intravenously at a dose of 3 mg/kg over 90 min every 3 weeks for a median of four doses (range, 1-8). Local control (LC), freedom from new brain metastases, and overall survival (OS) were assessed from the date of the SRS procedure. The median LC, freedom from new brain metastases, and OS for the entire group were 8.7, 4.3, and 5.9 months, respectively. The cause of death was CNS progression in all but eight patients. Six-month LC, freedom from new brain metastases, and OS were 65, 35, and 56%, respectively, for those who received ipilimumab and 63, 47, and 46% for those who did not (P=NS). Intracranial hemorrhage was noted in seven patients who received ipilimumab compared with 10 patients who received SRS alone (P=NS). In this retrospective study, administration of ipilimumab neither increased toxicity nor improved intracerebral disease control in patients with limited brain metastases who received SRS.

The purposes of this study were to evaluate for differences in phenotypic and genotypic characteristics in women who did and did not develop lymphedema (LE) following breast cancer treatment. Breast cancer patients completed a number of self-report questionnaires. LE was evaluated using bioimpedance spectroscopy. Genotyping was done using a custom genotyping array. No differences were found between patients with (n = 155) and without LE (n = 387) for the majority of the demographic and clinical characteristics. Patients with LE had a significantly higher body mass index, more advanced disease and a higher number of lymph nodes removed. Genetic associations were identified for four genes (i.e., lymphocyte cytosolic protein 2 (rs315721), neuropilin-2 (rs849530), protein tyrosine kinase (rs158689), vascular cell adhesion molecule 1 (rs3176861)) and three haplotypes (i.e., Forkhead box protein C2 (haplotype A03), neuropilin-2 (haplotype F03), vascular endothelial growth factor-C (haplotype B03)) involved in lymphangiogensis and angiogenesis. These genetic associations suggest a role for a number of lymphatic and angiogenic genes in the development of LE following breast cancer treatment.

Two supplements were awarded to the New York University Health Sciences Libraries from the National Library of Medicine's informationist grant program. These supplements funded research support in a number of areas, including data management and bioinformatics, two fields that the library had recently begun to explore. As such, the supplements were of particular value to the library as a testing ground for these newer services. This paper will discuss a supplement received in support of a grant from the National Institute of Dental and Craniofacial Research (PI: Brian Schmidt) on the role of proteases and peptides in cancer pain. A number of barriers were preventing the research team from maximizing the efficiency and effectiveness of their work. A critical component of the research was to identify which proteins, from among hundreds identified in collected samples, to include in preclinical testing. This selection involved laborious and prohibitively time-consuming manual searching of the literature on protein function. Additionally, the research team encompassed ten investigators working in two different cities, which led to issues around the sharing and tracking of both data and citations. The supplement outlined three areas in which the informationists would assist the researchers in overcoming these barriers: 1) creating an automated literature searching system for protein function discovery, 2) introducing tools and associated workflows for sharing citations, and 3) introducing tools and workflows for sharing data and specimens

Informationists at NYU Health Sciences Libraries (NYUHSL) successfully applied for a NLM supplement to a translational research grant obtained by PIs in the NYU School of Medicine Department of Otolaryngology titled, "Clinical Management of Cochlear Implant Patients with Contralateral Hearing Aids". The grant involves development of evidence-based guidelines for post-implant management of patients with bimodal cochlear implants. The PIs are also seeking to acquire new data sets to merge with grant-generated data. In light of the shifting data requirements, and the potential introduction of additional datasets, informationists will evaluate and restructure the data model and data entry tool. Report queries will be refined for the new data model and options for a query tool appropriate for users unfamiliar with query languages will be assessed and implemented. The services offered through this supplement represent the deepest and most detailed data management support offered by NYUHSL to date. The components of the supplement are being analyzed as a pilot of a broader offering of these data management services

BACKGROUND: The extensive amount of medical literature available on the Internet is frequently accessed by patients. To effectively contribute to healthcare decision-making, these online resources should be worded at a level that is readable by any patient seeking information. The American Medical Association and National Institutes of Health recommend the readability of patient information material should be between a 4th to 6th grade level. In this study, we evaluate the readability of online patient education information available from the American Rhinologic Society (ARS) website using 9 different assessment tools that analyze the materials for reading ease and grade level of the target audience. METHODS: Online patient education material from the ARS was downloaded in February 2012 and assessed for level of readability using the Flesch Reading Ease, Flesch-Kincaid Grade Level, Simple Measure of Gobbledygook (SMOG) Grading, Coleman-Liau Index, Gunning-Fog Index, FORCAST formula, Raygor Readability Estimate, the Fry Graph, and the New Dale-Chall Readability Formula. Each article was pasted as plain text into a Microsoft(R) Word(R) document and each subsection was analyzed using the software package Readability Studio Professional Edition Version 2012.1. RESULTS: All healthcare education materials assessed were written between a 9th grade and graduate reading level and were considered "difficult" to read by the assessment scales. CONCLUSION: Online patient education materials on the ARS website are written above the recommended 6th grade level and may require revision to make them easily understood by a broader audience.

Rationale: Compartmentation of ion channels on the cardiomyocyte surface is important for electric propagation and electromechanical coupling. The specialized T-tubule and costameric structures facilitate spatial coupling of various ion channels and receptors. Existing methods such as immunofluorescence and patch clamp techniques are limited in their ability to localize functional ion channels. As such, a correlation between channel protein location and channel function remains incomplete. Objective: To validate a method that permits routine imaging of the topography of a live cardiomyocyte and study clustering of functional ion channels from a specific microdomain. Methods and Results: We used scanning ion conductance microscopy and conventional cell-attached patch clamp with a software modification that allows controlled increase of pipette tip diameter. The sharp nanopipette used for topography scan was modified into a larger patch pipette that could be positioned with nanoscale precision to a specific site of interest (crest, groove, or T-tubules of cardiomyocytes) and sealed to the membrane for cell-attached recording of ion channels. Using this method, we significantly increased the probability of detecting activity of L-type calcium channels in the T-tubules of ventricular cardiomyocytes. We also demonstrated that active sodium channels do not distribute homogenously on the sarcolemma instead, they segregate into clusters of various densities, most crowded in the crest region, that are surrounded by areas virtually free of functional sodium channels. Conclusions: Our new method substantially increases the throughput of recording location-specific functional ion channels on the cardiomyocyte sarcolemma, thereby allowing characterization of ion channels in relation to the microdomain where they reside.

Panobinostat (LBH589), a novel histone deacetylase inhibitor (HDACi), was evaluated in a phase I study of patients with primary myelofibrosis (PMF) and post-essential thrombocythaemia/polycythaemia vera-related myelofibrosis (Post-ET/PV MF). Eighteen patients (PMF 56%; Post-PV MF 28%; Post-ET MF 17%) were treated in three cohorts at oral doses of (i) 20, (ii) 30, and (iii) 25 mg three times weekly consecutively. Reversible thrombocytopenia was the dose-limiting toxicity. Five patients (two in Dose Cohort 1, one in Dose Cohort 2 and two in Dose Cohort 3) received six or more cycles and were evaluable for response assessment. After the sixth cycle, three of these five patients achieved clinical improvement (CI) with 100% reduction in palpable splenomegaly from baseline, and two patients experienced stable disease. Panobinostat therapy was also associated with improvement in the degree of anaemia in two of the five patients. Of the three patients who achieved CI after six cycles, one patient achieved a near complete remission after 15 cycles of treatment and another patient had resolution of marrow fibrosis after 16 cycles. We conclude that panobinostat is a well-tolerated, clinically active treatment for MF patients, regardless of JAK2 V617F status, and most effective when given at low doses over long periods of time.

Inhibitory synapse dysfunction may contribute to many developmental brain disorders, including the secondary consequences of sensory deprivation. In fact, developmental hearing loss leads to a profound reduction in the strength of inhibitory postsynaptic currents (IPSCs) in the auditory cortex, and this deficit persists into adulthood. This finding is consistent with the general theory that the emergence of mature synaptic properties requires activity during development. Therefore, we tested the prediction that inhibitory strength can be restored following developmental hearing loss by boosting GABAergic transmission in vivo. Conductive or sensorineural hearing loss was induced surgically in gerbils prior to hearing onset and GABA agonists were then administered for one week. IPSCs were subsequently recorded from pyramidal neurons in a thalamocortical brain slice preparation. Administration of either a GABA(A) receptor a1 subunit specific agonist (zolpidem), or a selective GABA reuptake inhibitor (SGRI), rescued IPSC amplitude in hearing loss animals. Furthermore, this restoration persisted in adults, long after drug treatment ended. In contrast, a GABA(B) receptor agonist baclofen did not restore inhibitory strength. IPSCs could also be restored when SGRI administration began 3 weeks after sensory deprivation. Together, these results demonstrate long-lasting restoration of cortical inhibitory strength in the absence of normal experience. This suggests that in vivo GABA(A) receptor activation is sufficient to promote maturation, and this principle may extend to other developmental disorders associated with diminished inhibitory function.

OBJECTIVES: We utilized dynamic magnetic resonance imaging to visualize the pharynx and upper esophageal segment in normal, healthy subjects. METHODS: A 3-T scanner with a 4-channel head coil and a dual-channel neck coil was used to obtain high-speed magnetic resonance images of subjects who were swallowing liquids and pudding. Ninety sequential images were acquired with a temporal resolution of 113 ms. Imaging was performed in axial planes at the levels of the oropharynx and the pharyngoesophageal segment. The images were then analyzed for variables related to alterations in the area of the pharynx and pharyngoesophageal segment during swallowing, as well as temporal measures related to these structures. RESULTS: All subjects tolerated the study protocol without complaint. Changes in the area of the pharyngeal wall lumen and temporal measurements were consistent within and between subjects. The inter-rater and intra-rater reliabilities for the measurement tool were excellent. CONCLUSIONS: Dynamic magnetic resonance imaging of the swallow sequence is both feasible and reliable and may eventually complement currently used diagnostic methods, as it adds substantive information.

The mechanisms by which natural rewards such as sugar affect synaptic transmission and behavior are largely unexplored. Here, we investigate regulation of nucleus accumbens synapses by sucrose intake. Previous studies have shown that AMPA receptor (AMPAR) trafficking is a major mechanism for regulating synaptic strength, and that in vitro, trafficking of AMPARs containing the GluA1 subunit takes place by a two-step mechanism involving extrasynaptic and then synaptic receptor transport. We report that in rat, repeated daily ingestion of a 25% sucrose solution transiently elevated spontaneous locomotion and potentiated accumbens core synapses through incorporation of Ca(2+)-permeable AMPA receptors (CPARs), which are GluA1-containing, GluA2-lacking AMPARs. Electrophysiological, biochemical, and quantitative electron microscopy studies revealed that sucrose training (7 d) induced a stable (>24 h) intraspinous GluA1 population, and that in these rats a single sucrose stimulus rapidly (5 min) but transiently (<24 h) elevated GluA1 at extrasynaptic sites. CPARs and dopamine D1 receptors were required in vivo for elevated locomotion after sucrose ingestion. Significantly, a 7 d protocol of daily ingestion of a 3% solution of saccharin, a noncaloric sweetener, induced synaptic GluA1 similarly to 25% sucrose ingestion. These findings identify multistep GluA1 trafficking, previously described in vitro, as a mechanism for acute regulation of synaptic transmission in vivo by a natural orosensory reward. Trafficking is stimulated by a chemosensory pathway that is not dependent on the caloric value of sucrose.