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...

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

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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).

Juvenile and mature mouse cochleae contain various low-abundant, vulnerable sensory epithelial cells embedded in the calcified temporal bone, making it challenging to profile the dynamic transcriptome changes of these cells during maturation at the single-cell level. Here we performed the 10x Genomics single-cell RNA sequencing (scRNA-seq) of mouse cochleae at postnatal days 14 (P14) and 28. We attained the transcriptomes of multiple cell types, including hair cells, supporting cells, spiral ganglia, stria fibrocytes, and immune cells. Our hair cell scRNA-seq datasets are consistent with published transcripts from bulk RNA-seq. We also mapped known deafness genes to corresponding cochlear cell types. Importantly, pseudotime trajectory analysis revealed that inner hair cell maturation peaks at P14 while outer hair cells continue development until P28. We further identified and confirmed a long non-coding RNA gene Miat to be expressed during maturation in cochlear hair cells and spiral ganglia neurons, and Pcp4 to be expressed during maturation in cochlear hair cells. Our transcriptomes of juvenile and mature mouse cochlear cells provide the sequel to those previously published at late embryonic and early postnatal ages and will be valuable resources to investigate cochlear maturation at the single-cell resolution.