Faculty Bibliography

Localizing neuronal patterns that generate pathological brain signals may assist with tissue resection and intervention strategies in patients with neurological diseases. Precise localization requires high spatiotemporal recording from populations of neurons while minimizing invasiveness and adverse events. We describe a large-scale, high-density, organic material-based, conformable neural interface device ("NeuroGrid") capable of simultaneously recording local field potentials (LFPs) and action potentials from the cortical surface. We demonstrate the feasibility and safety of intraoperative recording with NeuroGrids in anesthetized and awake subjects. Highly localized and propagating physiological and pathological LFP patterns were recorded, and correlated neural firing provided evidence about their local generation. Application of NeuroGrids to brain disorders, such as epilepsy, may improve diagnostic precision and therapeutic outcomes while reducing complications associated with invasive electrodes conventionally used to acquire high-resolution and spiking data.

Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we identified previously unidentified gene fusions involving the MET oncogene in ~10% of cases. These MET fusions activated mitogen-activated protein kinase (MAPK) signaling and, in cooperation with lesions compromising cell cycle regulation, induced aggressive glial tumors in vivo. MET inhibitors suppressed MET tumor growth in xenograft models. Finally, we treated a pediatric patient bearing a MET-fusion-expressing glioblastoma with the targeted inhibitor crizotinib. This therapy led to substantial tumor shrinkage and associated relief of symptoms, but new treatment-resistant lesions appeared, indicating that combination therapies are likely necessary to achieve a durable clinical response.

Introduction: Oral mucositis (OM) is among the most common, painful and debilitating toxicities of cancer regimen-related treatment, resulting in the formation of ulcers, which are susceptible to increased colonization of microorganisms. Objectives: The aim of this study is to explore the changes in the microbiome associated with OM onset in head and neck cancer patients (oral cavity and oropharynx squamous cell carcinoma) undergoing radiotherapy alone (RT) or chemoradiotherapy (chemoRT) using molecular techniques. Methods: We recruited patients scheduled for receiving radiotherapy alone or chemoRT. Site-specific oral biofilms samples were collected using Isohelix swabs at two time points: before initiating RT/ChemoRT (pre-OM), and at the onset of OM (post-OM ie OM > 1, WHO scale). Changes in microbial abundance were detected using the Human Oral Microbe Identification using Next Generation Sequencing (HOMINGS) and metagenomic analyses. An integrative computational model estimated average changes of microbial abundance patterns of 768 species identified from pre-and-post OM onset. Results: Relative changes in abundance of 54 microbial biomarkers in 16 subjects were discriminative between pre and post OM onset. Discriminant species such as Gemella haemolysans, Granulicatella elegans, Haemophilus spp., Prevotellaoris, and Aggregatibacter sp. HOT512 were found to be significantly overabundant in post-OM onset samples as compared to pre-OM. (Table Presented) Conclusions: Our results suggest a dynamic shift in the oral microbiome during the onset of OM. These species may act as opportunistic pathogens in this population, and further investigation is warranted to explore if they facilitate further tissue damage and subsequent pain

Raf Kinase Inhibitory Protein (RKIP) expression has been profiled for a number of unique tissue cancers. However, certain tissues have not been explored, and oral and oropharyngeal cancers stand out as high priority targets, given their relatively high incidence, high morbidity rate, and in many cases, preventable nature. The purpose of this study was to examine changes in RKIP expression and phosphorylation in tissues resected from oral cancer patients, and compare to results generated from immortalized cell lines raised from primary oral cancer tissues, including oral squamous cell carcinoma line 4 (SCC4) and human squamous cell carcinoma line 3 (HSC3). Out of 4 human samples collected from male and female patients across various ages with variable risk factors, we observed an across the board reduction in RKIP expression. Two human samples demonstrated a significant increase in phosphorylated RKIP when normalized to total RKIP, however all 4 were increased when normalized to total cellular protein. The immortalized oral cancer cell culture HSC3 revealed significant increases in phosphorylated RKIP with no change in total RKIP expression, while line SCC4 demonstrated an increase in both total and phosphorylated RKIP. Results presented here indicate that oral cancers behave similarly to other cancers in terms of changes in RKIP expression and phosphorylation, although immortalized cell line expression profiles significantly differ from human tissue biopsies.