Faculty Bibliography

Individual bacteria and shifts in the composition of the microbiome have been associated with human diseases including cancer. To investigate changes in the microbiome associated with oral cancers, we profiled cancers and anatomically matched contralateral normal tissue from the same patient by sequencing 16S rDNA hypervariable region amplicons. In cancer samples from both a discovery and a subsequent confirmation cohort, abundance of Firmicutes (especially Streptococcus) and Actinobacteria (especially Rothia) was significantly decreased relative to contralateral normal samples from the same patient. Significant decreases in abundance of these phyla were observed for pre-cancers, but not when comparing samples from contralateral sites (tongue and floor of mouth) from healthy individuals. Weighted UniFrac principal coordinates analysis based on 12 taxa separated most cancers from other samples with greatest separation of node positive cases. These studies begin to develop a framework for exploiting the oral microbiome for monitoring oral cancer development, progression and recurrence.

Cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) reduces survival. In this study we hypothesized that methylation of key genes mediates cisplatin resistance. We determined whether a demethylating drug, decitabine, could augment the anti-proliferative and apoptotic effects of cisplatin on SCC-25/CP, a cisplatin-resistant tongue SCC cell line. We showed that decitabine treatment restored cisplatin sensitivity in SCC-25/CP and significantly reduced the cisplatin dose required to induce apoptosis. We then created a xenograft model with SCC-25/CP and determined that decitabine and cisplatin combination treatment resulted in significantly reduced tumor growth and mechanical allodynia compared to control. To establish a gene classifier we quantified methylation in cancer tissue of cisplatin-sensitive and cisplatin-resistant HNSCC patients. Cisplatin-sensitive and cisplatin-resistant patient tumors had distinct methylation profiles. When we quantified methylation and expression of genes in the classifier in HNSCC cells in vitro, we showed that decitabine treatment of cisplatin-resistant HNSCC cells reversed methylation and gene expression toward a cisplatin-sensitive profile. The study provides direct evidence that decitabine restores cisplatin sensitivity in in vitro and in vivo models of HNSCC. Combination treatment of cisplatin and decitabine significantly reduces HNSCC growth and HNSCC pain. Furthermore, gene methylation could be used as a biomarker of cisplatin-resistance.

Principal neurons of the lateral superior olivary nucleus (LSO) respond selectively to interaural level differences (ILD). To perform this computation, LSO neurons integrate excitatory synaptic drive from the ipsilateral ear with inhibitory synaptic drive from the contralateral ear via the medial nucleus of the trapezoid body (MNTB). Previous research demonstrated that inhibitory terminals from the MNTB to the LSO are eliminated during development. Furthermore, MNTB synapses display an activity- and age-dependent long-term depression (iLTD) that may contribute to inhibitory synapse elimination. However, inhibitory synapses that are stabilized become stronger. Here, we asked whether MNTB synapses displayed activity-dependent strengthening. Whole-cell recordings were obtained from LSO neurons in a gerbil brain slice before and after hearing onset. The inhibitory MNTB afferents were stimulated at a low rate, similar to spontaneous discharge rates observed in vivo. The MNTB-evoked inhibitory responses were strengthened by 40-300% when synaptic activity was coupled with postsynaptic membrane depolarization, exogenous glutamate application, or activation of ipsilateral excitatory synaptic inputs. This inhibitory long-term potentiation (iLTP) was associated with increased spontaneous inhibitory postsynaptic current (IPSC) amplitude and frequency. One hour after iLTP induction, IPSCs could not be de-potentiated by the MNTB stimulation pattern that induces iLTD in control slices. iLTP could only be induced after hearing onset (>P12), and was blocked in the presence of a GABAB receptor antagonist. Together, these results suggest a developmental period during which the induction of iLTP depends on the conjoint activation of GABAB receptors and postsynaptic depolarization. We propose that iLTP may support stabilization of un-pruned MNTB connections and contribute to the emergence of ILD processing in the mature LSO.

OBJECT/OBJECTIVE:Endoscopic endonasal treatment of petrous apex cholesterol granulomas allows for a natural drainage pathway into the nasopharynx. Because of the limited number of case series in the literature, there is limited evidence of recurrence rates and outcomes following endoscopic endonasal management. The purpose of this study was to determine the surgical outcomes of endoscopic endonasal approaches in the treatment of cholesterol granulomas of the petrous apex. METHODS:A systematic literature review was performed using PubMed for articles published from January 1980 to April 2014 to identify all studies reporting outcomes for endoscopic endonasal surgical management of cholesterol granulomas of the petrous apex. Operative approach, use of a stent, symptom outcome, restenosis, cyst recurrence, reoperation, and complications were extracted from included studies. RESULTS:A total of 53 patient cases were included from 22 relevant studies. The mean age was 41 years, and 26 patients (49%) were female. Stents were used in 45.1% of cases. Symptom resolution or improvement was seen in 98.6% of cases at follow-up (mean follow-up 20 months). Complications were reported in 13.2% of cases, with the most common complication being epistaxis. Restenosis on follow-up office endoscopic examination occurred in 9 of 45 cases (20.0%). Only 4 of these restenosis cases resulted in symptomatic cyst recurrence, resulting in an overall recurrence rate of 7.5%. The mean time from surgery to cyst recurrence was 13.5 months. The rate of symptomatic cyst recurrence was 10.7% in cases without the use of a stent compared with 4.3% in cases with stent placement (p = 0.6). CONCLUSIONS:Based on current literature, endoscopic endonasal approaches result in a high rate of symptom improvement or resolution. Complication rates are lower than prior case series that have utilized open approaches. Asymptomatic restenosis can be managed conservatively, since it is associated with symptomatic cyst recurrence less than half of the time. This study revealed a nonsignificant trend toward a decrease in symptomatic cyst recurrence when a stent was used, but further work is needed to clarify its impact.

Micro-Electrocorticography (muECoG) offers a minimally invasive, high resolution interface with large areas of cortex. However, large arrays of electrodes with many contacts that are individually wired to external recording systems are cumbersome and make chronic recording in freely behaving small animals challenging. Multiplexed headstages overcome this limitation by combining the signals from many electrodes to a smaller number of connections directly on the animal's head. Commercially available multiplexed headstages provide high performance integrated amplification, multiplexing and analog to digital conversion. However, the cost of these systems can be prohibitive for small labs or for experiments that require a large number of animals to be continuously recorded at the same time. Here we have developed a multiplexed 60-channel headstage amplifier optimized to chronically record electrophysiological signals from high-density muECoG electrode arrays. A single, ultraflexible (2 mm thickness) microHDMI cable provided the data interface. Using low cost components, we have reduced the cost of the multiplexed headstage to ~$125. Paired with a custom interface printed circuit board (PCB) and a general purpose data acquisition system (M-series DAQ, National Instruments), an inexpensive and customizable electrophysiology system is assembled. Open source LabVIEW software that we have previously released controlled the system. It can also be used with other open source neural data acquisition packages. Combined, we have presented a scalable, low-cost platform for high-channel count electrophysiology.