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Integration of Clinical and Molecular Studies in Understanding the Pathogenesis of Hearing Loss: From Cause to Cure

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Otolaryngology".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 49144

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Special Issue Editors

Dr. Silvia Dossena

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Guest Editor

Institute of Pharmacology and Toxicology, Paracelsus Medical University, 5020 Salzburg, Austria
Interests: hearing loss; gene analysis; SLC26A4/pendrin; Pendred syndrome; Enlarged Vestibular Aqueduct (EVA); ion transport; functional testing; ion channels; ion exchangers; oxidative stress
Special Issues, Collections and Topics in MDPI journals

Dr. Sebastian Roesch

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Guest Editor

Department of Otolaryngology, Head and Neck Surgery, University Clinics Salzburg, Paracelsus Medical University, Salzburg, Austria
Interests: hearing loss; gene analysis; SLC26A4/pendrin; Pendred syndrome; Enlarged Vestibular Aqueduct (EVA); mitochondrial disease

Special Issue Information

Dear Colleagues,

Hearing loss affects at least 1 in 1000 newborns, is a major cause of disability in children and adults, and markedly affects quality of life. Inner ear malfunction, also called sensorineural hearing loss, is caused by damage to the sensory cells and/or nerve fibers of the inner ear. Genetic alterations, exposure to drugs or noise, as well as aging are among the causes of sensorineural hearing loss. Moreover, structures of the central hearing system may also be affected, potentially contributing to hearing loss. An accurate clinical appraisal plays a fundamental role in assisting patients with hearing loss. At the same time, identification of the precise molecular mechanism of hearing loss is essential to develop novel therapies. Therefore, a close integration of clinical and molecular studies is necessary to progress from cause to cure. In research-based medical care, clinical observations stimulate research, which paves the way for novel therapeutic strategies and eventually leads back to the bedside for their implementation.

The scope of this Special Issue is to collect and contribute to the dissemination of novel insights on the causes of hearing loss. Clinical studies must be accompanied by evidence illuminating the molecular mechanism of the disease and suggesting novel options and targets for therapy. The submission of original articles is encouraged; review articles as well as commentaries will also be accepted. Please note that case studies, case series, study protocols and mini reviews will not be considered.

Dr. Silvia Dossena
Dr. Sebastian Roesch
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

sensorineural hearing loss
genetic hearing loss
age-related hearing loss
noise-induced hearing loss
drug-induced hearing loss
gene analysis
molecular mechanism
molecular diagnostic
auditory cortex
retro-cochlear hearing loss

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Published Papers (7 papers)

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Research

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14 pages, 1707 KiB

Open AccessArticle

Potential Ototoxicity of Insulin-like Growth Factor 1 Receptor Signaling Inhibitors: An In Silico Drug Repurposing Study of the Regenerating Cochlear Neuron Transcriptome

by Lino E. Bertagnoli, Richard Seist, Shelley Batts and Konstantina M. Stankovic

J. Clin. Med. 2023, 12(10), 3485; https://doi.org/10.3390/jcm12103485 - 16 May 2023

Viewed by 3032

Abstract

Spiral ganglion neurons (SGNs) connect cochlear hair cells with higher auditory pathways and their degeneration due to drug toxicity (ototoxicity) contributes to hearing loss. This study aimed to identify drug classes that are negatively correlated with the transcriptome of regenerating SGNs. Human orthologs of differentially expressed genes within the regenerating neonatal mouse SGN transcriptome were entered into CMap and the LINCS unified environment and perturbation-driven gene expression was analyzed. The CMap connectivity scores ranged from 100 (positive correlation) to −100 (negative correlation). Insulin-like growth factor 1/receptor (IGF-1/R) inhibitors were highly negatively correlated with the regenerating SGN transcriptome (connectivity score: −98.87). A systematic literature review of clinical trials and observational studies reporting otologic adverse events (AEs) with IGF-1/R inhibitors identified 108 reports (6141 treated patients). Overall, 16.9% of the treated patients experienced any otologic AE; the rate was highest for teprotumumab (42.9%). In a meta-analysis of two randomized placebo-controlled trials of teprotumumab, there was a significantly higher risk of hearing-related (pooled Peto OR [95% CI]: 7.95 [1.57, 40.17]) and of any otologic AEs (3.56 [1.35, 9.43]) with teprotumumab vs. a placebo, whether or not dizziness/vertigo AEs were included. These results call for close audiological monitoring during IGF-1-targeted treatment, with prompt referral to an otolaryngologist should otologic AEs develop. Full article

(This article belongs to the Special Issue Integration of Clinical and Molecular Studies in Understanding the Pathogenesis of Hearing Loss: From Cause to Cure)

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17 pages, 8057 KiB

Open AccessArticle

Comparative Transcriptomic Analysis of Archival Human Vestibular Schwannoma Tissue from Patients with and without Tinnitus

by Krishna Bommakanti, Richard Seist, Phanidhar Kukutla, Murat Cetinbas, Shelley Batts, Ruslan I. Sadreyev, Anat Stemmer-Rachamimov, Gary J. Brenner and Konstantina M. Stankovic

J. Clin. Med. 2023, 12(7), 2642; https://doi.org/10.3390/jcm12072642 - 1 Apr 2023

Cited by 2 | Viewed by 2921

Abstract

Vestibular schwannoma (VS) is an intracranial tumor that commonly presents with tinnitus and hearing loss. To uncover the molecular mechanisms underlying VS-associated tinnitus, we applied next-generation sequencing (Illumina HiSeq) to formalin-fixed paraffin-embedded archival VS samples from nine patients with tinnitus (VS-Tin) and seven patients without tinnitus (VS-NoTin). Bioinformatic analysis was used to detect differentially expressed genes (DEG; i.e., ≥two-fold change [FC]) while correcting for multiple comparisons. Using RNA-seq analysis, VS-Tin had significantly lower expression of GFAP (logFC = −3.04), APLNR (logFC = −2.95), PREX2 (logFC = −1.44), and PLVAP (logFC = −1.04; all p < 0.01) vs. VS-NoTin. These trends were validated by using real-time RT-qPCR. At the protein level, immunohistochemistry revealed a trend for less PREX2 and apelin expression and greater expression of NLRP3 inflammasome and CD68-positive macrophages in VS-Tin than in VS-NoTin, suggesting the activation of inflammatory processes in VS-Tin. Functional enrichment analysis revealed that the top three protein categories—glycoproteins, signal peptides, and secreted proteins—were significantly enriched in VS-Tin in comparison with VS-NoTin. In a gene set enrichment analysis, the top pathway was allograft rejection, an inflammatory pathway that includes the MMP9, CXCL9, IL16, PF4, ITK, and ACVR2A genes. Future studies are needed to examine the importance of these candidates and of inflammation in VS-associated tinnitus. Full article

(This article belongs to the Special Issue Integration of Clinical and Molecular Studies in Understanding the Pathogenesis of Hearing Loss: From Cause to Cure)

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13 pages, 1884 KiB

Open AccessArticle

Associations of Tinnitus Incidence with Use of Tumor Necrosis Factor-Alpha Inhibitors among Patients with Autoimmune Conditions

by Nirvikalpa Natarajan, Shelley Batts, Saurabh Gombar, Raj Manickam, Varun Sagi, Sharon G. Curhan and Konstantina M. Stankovic

J. Clin. Med. 2023, 12(5), 1935; https://doi.org/10.3390/jcm12051935 - 1 Mar 2023

Viewed by 3187

Abstract

Tumor necrosis factor-alpha (TNFα) may promote neuroinflammation prompting tinnitus. This retrospective cohort study evaluated whether anti-TNFα therapy influences incident tinnitus risk among adults with autoimmune disorders and no baseline tinnitus selected from a US electronic health records database (Eversana; 1 January 2010–27 January 2022). Patients with anti-TNFα had ≥90-day history pre-index (first autoimmune disorder diagnosis) and ≥180-day follow-up post-index. Random samples (n = 25,000) of autoimmune patients without anti-TNFα were selected for comparisons. Tinnitus incidence was compared among patients with or without anti-TNFα therapy, overall and among at-risk age groups or by anti-TNFα category. High-dimensionality propensity score (hdPS) matching was used to adjust for baseline confounders. Compared with patients with no anti-TNFα, anti-TNFα was not associated with tinnitus risk overall (hdPS-matched HR [95% CI]: 1.06 [0.85, 1.33]), or between groups stratified by age (30–50 years: 1 [0.68, 1.48]; 51–70 years: 1.18 [0.89, 1.56]) or anti-TNFα category (monoclonal antibody vs. fusion protein: 0.91 [0.59, 1.41]). Anti-TNFα was not associated with tinnitus risk among those treated for ≥6 months (hdPS-matched HR [95% CI]: 0.96 [0.69, 1.32]) or ≥12 (1.03 [0.71, 1.5]), or those with RA (1.16 [0.88, 1.53]). Thus, in this US cohort study, anti-TNFα therapy was not associated with tinnitus incidence among patients with autoimmune disorders. Full article

(This article belongs to the Special Issue Integration of Clinical and Molecular Studies in Understanding the Pathogenesis of Hearing Loss: From Cause to Cure)

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13 pages, 897 KiB

Open AccessArticle

Targeted Resequencing of Otosclerosis Patients from Different Populations Replicates Results from a Previous Genome-Wide Association Study

by Lisse J. M. Tavernier, Thomas Vanpoucke, Isabelle Schrauwen, Guy Van Camp and Erik Fransen

J. Clin. Med. 2022, 11(23), 6978; https://doi.org/10.3390/jcm11236978 - 26 Nov 2022

Cited by 1 | Viewed by 2476

Abstract

Otosclerosis is one of the most common causes of hearing loss in young adults. It has a prevalence of 0.3–0.4% in the European population. Clinical symptoms usually occur between the second and fifth decade of life. Different studies have been performed to unravel the genetic architecture of the disease. Recently, a genome-wide association study (GWAS) identified 15 novel risk loci and replicated the regions of three previously reported candidate genes. In this study, seven candidate genes from the GWAS were resequenced using single molecule molecular inversion probes (smMIPs). smMIPs were used to capture the exonic regions and the 3′ and 5′ untranslated regions (UTR). Discovered variants were tested for association with the disease using single variant and gene-based association analysis. The single variant results showed that 13 significant variants were associated with otosclerosis. Associated variants were found in five of the seven genes studied here, including AHSG, LINC01482, MARK3, SUPT3H and RELN. Conversely, burden testing did not show a major role of rare variants in the disease. In conclusion, this study was able to replicate five out of seven candidate genes reported in the previous GWAS. This association is likely mainly driven by common variants. Full article

(This article belongs to the Special Issue Integration of Clinical and Molecular Studies in Understanding the Pathogenesis of Hearing Loss: From Cause to Cure)

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15 pages, 2925 KiB

Open AccessArticle

Molecular Features of SLC26A4 Common Variant p.L117F

by Arnoldas Matulevičius, Emanuele Bernardinelli, Zippora Brownstein, Sebastian Roesch, Karen B. Avraham and Silvia Dossena

J. Clin. Med. 2022, 11(19), 5549; https://doi.org/10.3390/jcm11195549 - 22 Sep 2022

Cited by 2 | Viewed by 2297

Abstract

The SLC26A4 gene, which encodes the anion exchanger pendrin, is involved in determining syndromic (Pendred syndrome) and non-syndromic (DFNB4) autosomal recessive hearing loss. SLC26A4 c.349C>T, p.L117F is a relatively common allele in the Ashkenazi Jewish community, where its minor allele frequency is increased compared to other populations. Although segregation and allelic data support the pathogenicity of this variant, former functional tests showed characteristics that were indistinguishable from those of the wild-type protein. Here, we applied a triad of cell-based assays, i.e., measurement of the ion transport activity by a fluorometric method, determination of the subcellular localization by confocal microscopy, and assessment of protein expression levels, to conclusively assign or exclude the pathogenicity of SLC26A4 p.L117F. This protein variant showed a moderate, but significant, reduction in ion transport function, a partial retention in the endoplasmic reticulum, and a strong reduction in expression levels as a consequence of an accelerated degradation by the Ubiquitin Proteasome System, all supporting pathogenicity. The functional and molecular features of human pendrin p.L117F were recapitulated by the mouse ortholog, thus indicating that a mouse carrying this variant might represent a good model of Pendred syndrome/DFNB4. Full article

(This article belongs to the Special Issue Integration of Clinical and Molecular Studies in Understanding the Pathogenesis of Hearing Loss: From Cause to Cure)

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Review

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34 pages, 2649 KiB

Open AccessReview

Noise-Induced Hearing Loss

by Nirvikalpa Natarajan, Shelley Batts and Konstantina M. Stankovic

J. Clin. Med. 2023, 12(6), 2347; https://doi.org/10.3390/jcm12062347 - 17 Mar 2023

Cited by 85 | Viewed by 32782 | Correction

Abstract

Noise-induced hearing loss (NIHL) is the second most common cause of sensorineural hearing loss, after age-related hearing loss, and affects approximately 5% of the world’s population. NIHL is associated with substantial physical, mental, social, and economic impacts at the patient and societal levels. Stress and social isolation in patients’ workplace and personal lives contribute to quality-of-life decrements which may often go undetected. The pathophysiology of NIHL is multifactorial and complex, encompassing genetic and environmental factors with substantial occupational contributions. The diagnosis and screening of NIHL are conducted by reviewing a patient’s history of noise exposure, audiograms, speech-in-noise test results, and measurements of distortion product otoacoustic emissions and auditory brainstem response. Essential aspects of decreasing the burden of NIHL are prevention and early detection, such as implementation of educational and screening programs in routine primary care and specialty clinics. Additionally, current research on the pharmacological treatment of NIHL includes anti-inflammatory, antioxidant, anti-excitatory, and anti-apoptotic agents. Although there have been substantial advances in understanding the pathophysiology of NIHL, there remain low levels of evidence for effective pharmacotherapeutic interventions. Future directions should include personalized prevention and targeted treatment strategies based on a holistic view of an individual’s occupation, genetics, and pathology. Full article

(This article belongs to the Special Issue Integration of Clinical and Molecular Studies in Understanding the Pathogenesis of Hearing Loss: From Cause to Cure)

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