Faculty Bibliography

OBJECTIVES/HYPOTHESIS: Although the primary goal of medialization laryngoplasty is to improve glottic closure, implant placement is also likely to alter the biomechanical properties of the vocal fold (VF). We sought to employ novel, nanoscale technology to quantify these properties following medialization based on the hypothesis that different medialization materials will likely yield differential biomechanical effects. STUDY DESIGN: Ex vivo. METHODS: Nine pig larynges were divided into three groups: control, Silastic (Dow Corning, Midland, Michigan, U.S.A.) block medialization, or Gore-Tex (W.L. Gore & Associates, Newark, Delaware) medialization. Laryngoplasty was performed on excised, intact larynges. The larynges were then bisected in the sagittal plane and each subjected to dynamic nanomechanical analysis (nano-DMA) at nine locations using a 250-mum flat-tip punch and frequency sweep-load profile across the free edge of the VF and inferiorly along the conus elasticus. RESULTS: Silastic block and Gore-Tex implant introduced increased storage and loss moduli. Overall, storage moduli mean (maximum) increased from 38 kilopascals (kPa) (119) to 72 kPa (422) and 129 kPa (978) in control, Gore-Tex, and Silastic implants, respectively. Similarly, loss moduli increased from 13 kPa (43) to 22 kPa (201) and 31 kPa (165), respectively. Moduli values varied widely by location in the Silastic block and Gore-Tex groups. At the free VF edge, mean (maximum) storage moduli were lowest in the Gore-Tex group, 20 kPa (44); compared to control, 34.5 kPa (86); and Silastic, 157.9 kPa (978), with similar loss and complex moduli trends. CONCLUSION: Medialization laryngoplasty altered VF structure biomechanical properties; Silastic and Gore-Tex implants differentially impact these properties. LEVEL OF EVIDENCE: NA. Laryngoscope, 2017.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Our laboratory and others hypothesized that Smad3 is a principle mediator of the fibrotic phenotype in the vocal folds (VFs), and we further posited that alteration of Smad3 expression through short interfering (si)RNA holds therapeutic promise, yet delivery remains challenging. To address this issue, we employed a novel synthetic oligomer, lipitoid, complexed with siRNA to improve stability and cellular uptake with the goal of increased efficiency of RNA-based therapeutics. STUDY DESIGN/METHODS:In vitro study and in vivo animal model. METHODS:In vitro, lipitoid cytotoxicity was quantified via colorimetric and LIVE/DEAD assays in immortalized human VF fibroblasts and primary rabbit VF fibroblasts. In addition, optimal incubation interval and solution for binding siRNA to lipitoid for intracellular delivery were determined. In vivo, a rabbit model of VF injury was employed to evaluate Smad3 knockdown following locally injected lipitoid-complexed siRNA. RESULTS:In vitro, lipitoid did not confer additional toxicity compared to commercially available reagents. In addition, 20-minute incubation in 1× phosphate-buffered saline resulted in maximal Smad3 knockdown. In vivo, Smad3 expression increased following VF injury. This response was significantly reduced in injured VFs at 4 and 24 hours following injection (P = .035 and .034, respectively). CONCLUSIONS:The current study is the first to demonstrate targeted gene manipulation in the VFs as well as the potential utility of lipitoid for localized delivery of genetic material in vivo. Ideally, these data will serve as a platform for future investigation regarding the functional implications of therapeutic gene manipulation in the VFs. LEVEL OF EVIDENCE/METHODS:NA Laryngoscope, 2017.

Approved pharmacological treatments for alcohol use disorder are limited in their effectiveness, and new drugs that can easily be translated into the clinic are warranted. One of those candidates is oxytocin because of its interaction with several alcohol-induced effects. Alcohol dependent rats as well as postmortem brains of human alcoholics and controls were analyzed for the expression of the oxytocin system by qRT-PCR, in situ hybridization, receptor autoradiography ([125I]-OVTA binding) and immunohistochemistry. Alcohol self-administration and cue-induced reinstatement behavior was measured after intracerebroventricular injection of 10 nM oxytocin in dependent rats. Here we show a pronounced up-regulation of oxytocin receptors in brain tissues of alcohol dependent rats and deceased alcoholics, primarily in frontal and striatal areas. This up-regulation stems most likely from reduced oxytocin expression in hypothalamic nuclei. Pharmacological validation showed that oxytocin reduced cue-induced reinstatement response in dependent rats-an effect that was not observed in non-dependent rats. Finally, a clinical pilot study (German clinical trial number DRKS00009253) using functional magnetic resonance imaging in heavy social male drinkers showed that intranasal oxytocin (24 IU) decreased neural cue-reactivity in brain networks similar to those detected in dependent rats and humans with increased oxytocin receptor expression. These studies suggest that oxytocin might be used as an anti-craving medication and thus may positively affect treatment outcomes in alcoholics.Neuropsychopharmacology accepted article preview online, 01 November 2017. doi:10.1038/npp.2017.257.

Organized and hosted by the Children's Tumor Foundation (CTF), the Neurofibromatosis (NF) conference is the premier annual gathering for clinicians and researchers interested in neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). The 2016 edition constituted a blend of clinical and basic aspects of NF research that helped in clarifying different advances in the field. The incorporation of next generation sequencing is changing the way genetic diagnostics is performed for NF and related disorders, providing solutions to problems like genetic heterogeneity, overlapping clinical manifestations, or the presence of mosaicism. The transformation from plexiform neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) is being clarified, along with new management and treatments for benign and premalignant tumors. Promising new cellular and in vivo models for understanding the musculoskeletal abnormalities in NF1, the development of NF2 or SWN associated schwannomas, and clarifying the cells that give rise to NF1-associated optic pathway glioma were presented. The interaction of neurofibromin and SPRED1 was described comprehensively, providing functional insight that will help in the interpretation of pathogenicity of certain missense variants identified in NF1 and Legius syndrome patients. Novel promising imaging techniques are being developed, as well as new integrative and holistic management models for patients that take into account psychological, social, and biological factors. Importantly, new therapeutic approaches for schwannomas, meningiomas, ependymomas, PNF, and MPNST are being pursued. This report highlights the major advances that were presented at the 2016 CTF NF conference.

Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1) or its ligand (PD-L1) have been shown to be effective in treating patients with a variety of cancers. Biomarker studies have found positive associations between clinical response rates and PD-L1 expression on tumor cells, as well as the presence of tumor infiltrating lymphocytes (TILs). It is currently unknown whether tumors associated with neurofibromatosis types 1 and 2 (NF1 and NF2) express PD-L1. We performed immunohistochemistry for PD-L1 (clones SP142 and E1L3N), CD3, CD20, CD8, and CD68 in NF1-related tumors (ten dermal and six plexiform neurofibromas) and NF2-related tumors (ten meningiomas and ten schwannomas) using archival formalin-fixed paraffin-embedded tissues. Expression of PD-L1 was considered positive in cases with > 5% membranous staining of tumor cells, in accordance with previously published biomarker studies. PD-L1 expression in tumor cells (using the SP142 and E1L3N clones, respectively) was assessed as positive in plexiform neurofibromas (6/6 and 5/6) dermal neurofibromas (8/10 and 6/10), schwannomas (7/10 and 10/10), and meningiomas (4/10 and 2/10). Sparse to moderate presence of CD68, CD3, or CD8 positive TILs was found in 36 (100%) of tumor specimens. Our findings indicate that adaptive resistance to cell-mediated immunity may play a major role in the tumor immune microenvironment of NF1 and NF2-associated tumors. Expression of PD-L1 on tumor cells and the presence of TILs suggest that these tumors might be responsive to immunotherapy with immune checkpoint inhibitors, which should be explored in clinical trials for NF patients.

Objectives/UNASSIGNED:To explore the thesis experience of recent Master of Health Professions Education (MHPE) graduates in the University of Illinois at Chicago (UIC) program. Methods/UNASSIGNED:This is a qualitative case study exploring the experience of MHPE graduates between 2014 and 2016 (n=31). Using convenience sampling, all graduates with an email address (n=30) were invited to participate in an online survey and semi-structured interviews. Interviews were completed in-person or via telephone or video conference; interviewers collected detailed notes and audio recordings.  Two authors independently analyzed the data iteratively using thematic analysis and discrepancies were discussed and resolved. Results/UNASSIGNED:Survey results (n=20, 67%) revealed an average graduation of 5.1 years; 10 graduates (33%) were interviewed. Three themes related to the thesis experience were identified: success factors, challenges, and outcomes. Success factors, when present, promoted completion of a thesis; these included: a supportive program environment, time management, available resources, MHPE foundational coursework, aligning theses with career goals, and identifying a project with limited scope. Challenges made thesis completion more difficult for graduates; these included: institutional factors, personal or professional responsibilities, burnout, externally-imposed deadlines, and barriers in the research process. Despite these challenges, completing the thesis resulted in many professional or personal benefits (outcomes). Conclusions/UNASSIGNED:Multiple success factors and challenges were identified in the master's thesis process among MHPE graduates at UIC. These findings can help students conducting education-based scholarship through the master's thesis process. This study also informs program evaluation and improvements and outlines personal and professional outcomes of completing a master's thesis.