Zebrafish swimming behavior as a biomarker for ototoxicity-induced hair cell damage: a high-throughput drug development platform targeting hearing loss.

Hearing loss is one of the most common human sensory disabilities, adversely affecting communication, socialization, mood, physical functioning, and quality of life. In addition to age and noise-induced damage, ototoxicity is a common cause of sensorineural hearing loss with chemotherapeutic agents, for example, cisplatin, being a major contributor. Zebrafish (Danio rerio) are an excellent model to study hearing loss as they have neurosensory hair cells on their body surface that are structurally similar to those within the human inner ear. Anatomic assays of toxin-mediated hair cell damage in zebrafish have been established; however, using fish swimming behavior--rheotaxis--as a biomarker for this anatomic damage was only recently described. We hypothesized that, in parallel, multilane measurements of rheotaxis could be used to create a high-throughput platform for drug development assessing both ototoxic and potentially otoprotective compounds in real time. Such a device was created, and results demonstrated a clear dose response between cisplatin exposure, progressive hair cell damage, and reduced rheotaxis in zebrafish. Furthermore, pre-exposure to the otoprotective medication dexamethasone, before cisplatin exposure, partially rescued rheotaxis swimming behavior and hair cell integrity. These results provide the first evidence that rescued swimming behavior can serve as a biomarker for rescued hair cell function. Developing a drug against hearing loss represents an unmet clinical need with global implications. Because hearing loss from diverse etiologies may result from common end-effects at the hair cell level, lessons learned from the present study may be broadly used.

The Solid Component of Radiographically Non-Growing, Post-Radiated Vestibular Schwannoma Retains Proliferative Capacity: Implications for Patient Counseling.

OBJECTIVE: Nearly all radiated vestibular schwannomas (VS) have solid tissue remaining at the radiation bed. The viability and proliferation capacity of this tissue has never been objectively assessed. The goals of our study were to (1) determine whether this tissue retains the morphological and immunohistochemical features of VS and (2) evaluate whether the tissue is capable of proliferation in cell culture. METHODS: Case history, magnetic resonance imaging (MRI), cell culture, histology, and immunohistochemistry. RESULTS: We report the first case of a post-radiated, sporadic VS patient whose non-growing, residual MR-enhancing solid tissue was examined histologically and in cell culture. These cells were architecturally identical to non-radiated VS, had a Ki67 proliferative index similar to non-radiated sporadic and NF2-associated VS, were S100 positive, and grew in culture with kinetics comparable to non-radiated VS. CONCLUSION: The long-term risk for delayed tumor growth and/or secondary malignancy in radiated VS patients is unknown. Because the average life span in the United States is nearly 80 years, patients should be informed that (1) residual VS cells are viable even when tumors appear to be non-growing on MRI, (2) post-radiation surveillance imaging is required indefinitely, and (3) radiation may incur more risk in those patients with life expectancy>20-25 years.