Hearing loss caused by noise, aging, antibiotics, and chemotherapy affects 10% of the world population, yet there are no Food and Drug Administration (FDA)-approved drugs to prevent it. Here, we screened 162 small-molecule kinase-specific inhibitors for reduction of cisplatin toxicity in an inner ear cell line and identified dabrafenib (TAFINLAR), a BRAF kinase inhibitor FDA-approved for cancer treatment. Dabrafenib and six additional kinase inhibitors in the BRAF/MEK/ERK cellular pathway mitigated cisplatin-induced hair cell death in the cell line and mouse cochlear explants. In adult mice, oral delivery of dabrafenib repressed ERK phosphorylation in cochlear cells, and protected from cisplatin- and noise-induced hearing loss. Full protection was achieved in mice with co-treatment with oral AZD5438, a CDK2 kinase inhibitor. Our study explores a previously unidentified cellular pathway and molecular target BRAF kinase for otoprotection and may advance dabrafenib into clinics to benefit patients with cisplatin- and noise-induced ototoxicity.

Abstract. An increasing amount of evidence demonstrates that epithelial-mesenchymal transition (EMT) is important in tumor invasion and metastases. The cell-cell adhesion molecule N-cadherin and the Wnt/β-catenin cascade protein β-catenin are two biomarkers of EMT. The present study aimed to measure the expression levels of N-cadherin and β-catenin in samples from patients with nasopharyngeal carcinoma (NPC) and evaluate their prognostic significance. N-cadherin and β-catenin mRNA was evaluated using reverse transcription-quantitative polymerase chain reaction in 26 NPC tissue samples and 8 nasopharyngeal epithelium samples. Protein expression of N-cadherin and β-catenin was also detected using immunohistochemistry in 128 archival NPC paraffin-embedded specimens. Finally, associations between clinical pathological parameters and prognostic values in NPC were evaluated. The results demonstrated that both the mRNA and protein levels of N-cadherin and β-catenin were significantly increased in NPC tissues compared with the controls. Enhanced expression of N-cadherin and β-catenin protein was strongly correlated with the status of lymph node metastasis and clinical stages in patients with NPC. Notably, high expression of N-cadherin and β-catenin proteins was significantly correlated with lower overall survival (OS) rate in patients with NPC. Finally, multivariate analysis demonstrated that expression of N-cadherin protein and clinical stages were independent prognostic factors for patients with NPC. Therefore, the present study demonstrated that N-cadherin and β-catenin expression may be used as potential prognostic biomarkers for patients with NPC.

NiFe based non-precious catalysts are promising substitute for noble metal-based catalysts due to their outstanding electrochemical performance and endurance. Herein, a NiFe based MOF supported on Ni foam was designed...

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Background: Nonsyndromic hearing loss is clinically and genetically heterogeneous. In this study, we characterized the clinical features of 12 Chinese Han deaf families in which mutations in common deafness genes GJB2, SLC26A4, and MT-RNR1 were excluded. Methods: Targeted next-generation sequencing of 147 known deafness genes was performed in probands of 10 families, while whole-exome sequencing was applied in those of the rest two. Results: Pathogenic mutations in a total of 11 rare deafness genes, OTOF, CDH23, PCDH15, PDZD7, ADGRV1, KARS, OTOG, GRXCR2, MYO6, GRHL2, and POU3F4, were identified in all 12 probands, with 16 mutations being novel.Intrafamilial cosegregation of the mutations and the deafness phenotype were confirmed by Sanger sequencing. Conclusion: Our results expanded the mutation spectrum and genotype-phenotype correlation of nonsyndromic hearing loss in Chinese Hans and also emphasized the importance of combining both next-generation sequencing and detailed auditory evaluation to achieve a more accurate diagnosis for nonsyndromic hearing loss. K E Y W O R D Sdeafness, gene mutation, next-generation sequencing (NGS), nonsyndromic, phenotype

Six studies including 119 patients (119 cases) fulfilled the study requirements. The number of patients who achieved perfect recovery of House-Brackmanm (H-B) grade 1 was 40 of 119 patients (33.6%). Good results were demonstrated in 94.4% (17/18) of patients managed with surgical decompression within 2 weeks vs 63.4% (64/101) of patients undergoing surgical intervention at >2 weeks (p = 0.009).

Hair cell loss is the leading cause of hearing and balance disorders in humans. It can be caused by many factors, including noise, aging, and therapeutic agents. Previous studies have shown the therapeutic potential of quinoxaline against drug-induced ototoxicity. Here, we screened a library of 68 quinoxaline derivatives for protection against aminoglycoside-induced damage of hair cells from the zebrafish lateral line. We identified quinoxaline-5-carboxylic acid (Qx28) as the best quinoxaline derivative that provides robust protection against both aminoglycosides and cisplatin in zebrafish and mouse cochlear explants. FM1-43 and aminoglycoside uptake, as well as antibiotic efficacy studies, revealed that Qx28 is neither blocking the mechanotransduction channels nor interfering with aminoglycoside antibacterial activity, suggesting that it may be protecting the hair cells by directly counteracting the ototoxin’s mechanism of action. Only when animals were incubated with higher doses of Qx28 did we observe a partial blockage of the mechanotransduction channels. Finally, we assessed the regulation of the NF-κB pathway in vitro in mouse embryonic fibroblasts and in vivo in zebrafish larvae. Those studies showed that Qx28 protects hair cells by blocking NF-κB canonical pathway activation. Thus, Qx28 is a promising and versatile otoprotectant that can act across different species and toxins.