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BioRxiv : the Preprint Server For... Sep 2023Our sense of hearing is mediated by cochlear hair cells, localized within the sensory epithelium called the organ of Corti. There are two types of hair cells in the...
Our sense of hearing is mediated by cochlear hair cells, localized within the sensory epithelium called the organ of Corti. There are two types of hair cells in the cochlea, which are organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains a few thousands of hair cells, and their survival is essential for our perception of sound because they are terminally differentiated and do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. However, the sheer number of cells along the cochlea makes manual quantification impractical. Machine learning can be used to overcome this challenge by automating the quantification process but requires a vast and diverse dataset for effective training. In this study, we present a large collection of annotated cochlear hair-cell datasets, labeled with commonly used hair-cell markers and imaged using various fluorescence microscopy techniques. The collection includes samples from mouse, human, pig and guinea pig cochlear tissue, from normal conditions and following and ototoxic drug application. The dataset includes over 90'000 hair cells, all of which have been manually identified and annotated as one of two cell types: inner hair cells and outer hair cells. This dataset is the result of a collaborative effort from multiple laboratories and has been carefully curated to represent a variety of imaging techniques. With suggested usage parameters and a well-described annotation procedure, this collection can facilitate the development of generalizable cochlear hair cell detection models or serve as a starting point for fine-tuning models for other analysis tasks. By providing this dataset, we aim to supply other groups within the hearing research community with the opportunity to develop their own tools with which to analyze cochlear imaging data more fully, accurately, and with greater ease.
PubMed: 37693382
DOI: 10.1101/2023.08.30.553559 -
Scientific Reports Nov 2023Studies have reported that cytokines and their related signaling pathways play a role in inner ear diseases. In clinical practice, approximately 50% of pediatric cancer... (Meta-Analysis)
Meta-Analysis
Studies have reported that cytokines and their related signaling pathways play a role in inner ear diseases. In clinical practice, approximately 50% of pediatric cancer patients experience irreversible hearing loss after cisplatin treatment. However, currently, there is a lack of systematic research on the causal relationship between circulating cytokines and cisplatin-induced hearing loss in children. Genetic variant data for 41 circulating cytokines were obtained from a meta-analysis of genome-wide association studies (GWAS) among 8293 individuals of Finnish descent. The GWAS data for Cisplatin-induced hearing loss in children were derived from a multicenter cohort of European pediatric cancer patients and survivors (N = 390), including both cases with hearing loss after cisplatin chemotherapy and controls without hearing loss. Multiple methods were employed for bidirectional Mendelian randomization (MR) estimation. Bonferroni correction was applied to adjust the original P-values, followed by a series of sensitivity analyses. In the directional Mendelian randomization (MR) analysis, it was found that IL-17 was significantly associated with a reduced risk of Cisplatin-induced hearing loss in children (OR: 0.18, CI: 0.06-0.48, P < 0.001, FDR = 0.041). In the reverse MR analysis, there were some nominal causal relationships of Cisplatin-induced hearing loss in children with certain cytokines [M-CSF: (OR: 1.04, CI: 1.01-1.08, P = 0.010, FDR = 0.41); IL-2RA: (OR: 1.03, CI: 1.00-1.05, P = 0.044, FDR = 0.447); MIP-1β: (OR: 1.02, CI: 1.00-1.04, P = 0.041, FDR = 0.447)]. leave-one-out analysis demonstrated that only M-CSF exhibited stability. These findings reveal a causal relationship between IL-17 and cisplatin-induced hearing loss in children. Further research is needed to determine the potential protective mechanisms of IL-17 in cisplatin-induced ototoxicity.
Topics: Humans; Child; Cisplatin; Antineoplastic Agents; Macrophage Colony-Stimulating Factor; Genome-Wide Association Study; Mendelian Randomization Analysis; Interleukin-17; Hearing Loss; Neoplasms; Deafness; Cytokines; Multicenter Studies as Topic
PubMed: 37919361
DOI: 10.1038/s41598-023-46299-2 -
Frontiers in Pharmacology 2023Etoposide is a broad-spectrum antitumor drug that has been extensively studied in clinical trials. However, limited information is available regarding its real-world...
Etoposide is a broad-spectrum antitumor drug that has been extensively studied in clinical trials. However, limited information is available regarding its real-world adverse reactions. Therefore, this study aimed to assess and evaluate etoposide-related adverse events in a real-world setting by using data mining method on the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. Through the analysis of 16,134,686 reports in the FAERS database, a total of 9,892 reports of etoposide-related adverse drug events (ADEs) were identified. To determine the significance of these ADEs, various disproportionality analysis algorithms were applied, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms. As a result, 478 significant disproportionality preferred terms (PTs) that were identified by all four algorithms were retained. These PTs included commonly reported adverse events such as thrombocytopenia, leukopenia, anemia, stomatitis, and pneumonitis, which align with those documented in the drug's instructions and previous clinical trials. However, our analysis also uncovered unexpected and significant ADEs, including thrombotic microangiopathy, ototoxicity, second primary malignancy, nephropathy toxic, and ovarian failure. Furthermore, we examined the time-to-onset (TTO) of these ADEs using the Weibull distribution test and found that the median TTO for etoposide-associated ADEs was 10 days (interquartile range [IQR] 2-32 days). The majority of cases occurred within the first month (73.8%) after etoposide administration. Additionally, our analysis revealed specific high-risk signals for males, such as pneumonia and cardiac infarction, while females showed signals for drug resistance and ototoxicity. These findings provide valuable insight into the occurrence of ADEs following etoposide initiation, which can potentially support clinical monitoring and risk identification efforts.
PubMed: 37954852
DOI: 10.3389/fphar.2023.1259908 -
Redox Report : Communications in Free... Dec 2024Gentamicin is one of the most common ototoxic drugs that can lower patients' quality of life. Oxidative stress is a key factors inducing sensory hair cell death during...
OBJECTIVES
Gentamicin is one of the most common ototoxic drugs that can lower patients' quality of life. Oxidative stress is a key factors inducing sensory hair cell death during gentamicin administration. So far, there are no effective drugs to prevent or treat gentamicin- induced hearing loss. A recent study found cystic fibrosis transmembrane conductance regulator (CFTR) as a new target to modulate cellular oxidative balance. The objective of this study was to estimate the effect of the CFTR activator ivacaftor on gentamicin-induced ototoxicity and determine its mechanism.
METHODS
The hair cell count was analyzed by Myosin 7a staining. Apoptosis was analyzed by TUNEL Apoptosis Kit. Cellular reactive oxygen species (ROS) level was detected by DCFH-DA probes. The Nrf2 related proteins expression levels were analyzed by western blot.
RESULTS
An in vitro cochlear explant model showed that gentamicin caused ROS accumulation in sensory hair cells and induced apoptosis, and this effect was alleviated by pretreatment with ivacaftor. Western blotting showed that ivacaftor administration markedly increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO1), and NAD(P)H:quinone oxidoreductase 1 (NQO1). The protective effect of ivacaftor was abolished by the Nrf2 inhibitor ML385.
DISCUSSION
Our results indicate the protective role of the CFTR-Nrf2-HO1/NQO1 pathway in gentamicin-induced ototoxicity. Ivacaftor may be repositioned or repurposed towards aminoglycosides-induced hearing loss.
Topics: Humans; Gentamicins; Reactive Oxygen Species; Ototoxicity; NF-E2-Related Factor 2; Cystic Fibrosis Transmembrane Conductance Regulator; Heme Oxygenase-1; Quality of Life; Oxidative Stress; Apoptosis; Hearing Loss; NAD(P)H Dehydrogenase (Quinone); Aminophenols; Quinolones
PubMed: 38563333
DOI: 10.1080/13510002.2024.2332038 -
Frontiers in Pharmacology 2024The inner ear is the organ responsible for hearing and balance. Inner ear dysfunction can be the result of infection, trauma, ototoxic drugs, genetic mutation or... (Review)
Review
The inner ear is the organ responsible for hearing and balance. Inner ear dysfunction can be the result of infection, trauma, ototoxic drugs, genetic mutation or predisposition. Often, like for Ménière disease, the cause is unknown. Due to the complex access to the inner ear as a fluid-filled cavity within the temporal bone of the skull, effective diagnosis of inner ear pathologies and targeted drug delivery pose significant challenges. Samples of inner ear fluids can only be collected during surgery because the available procedures damage the tiny and fragile structures of the inner ear. Concerning drug administration, the final dose, kinetics, and targets cannot be controlled. Overcoming these limitations is crucial for successful inner ear precision medicine. Recently, notable advancements in microneedle technologies offer the potential for safe sampling of inner ear fluids and local treatment. Ultrasharp microneedles can reach the inner ear fluids with minimal damage to the organ, collect μl amounts of perilymph, and deliver therapeutic agents . This review highlights the potential of ultrasharp microneedles, combined with nano vectors and gene therapy, to effectively treat inner ear diseases of different etiology on an individual basis. Though further research is necessary to translate these innovative approaches into clinical practice, these technologies may represent a true breakthrough in the clinical approach to inner ear diseases, ushering in a new era of personalized medicine.
PubMed: 38327988
DOI: 10.3389/fphar.2024.1328460 -
Nanoscale Advances Jul 2023Many cancer patients suffer permanent hearing loss due to accumulation of ototoxic cisplatin in the inner ear. In this study, two types of 100 nm magnetic micelles were...
Many cancer patients suffer permanent hearing loss due to accumulation of ototoxic cisplatin in the inner ear. In this study, two types of 100 nm magnetic micelles were developed to sequester cisplatin from aqueous solutions, with the goal of eliminating cochlear ototoxins magnetic microsurgery. The micellar surface was quantitatively functionalized with anionic S-rich ligands and the micelle core encapsulated superparamagnetic iron oxide nanoparticles. Exceptionally effective sequestration is demonstrated, with removal of greater than 95 and 50% of solution Pt, by means of centrifugal filtration and magnetic extraction. Attraction between negatively charged micellar surfaces and cationic Pt-species played a critical role and was only partially screened by physiologic salt solution. Importantly, magnetic micelles introduce negligible impact on the integrity of inner ear hair cells, demonstrating excellent biocompatibility. This study showcases successful magnetic sequestration of Pt-based ototoxins using highly applicable nano-micellar materials. More generally, these examples highlight features of the micelle-water interfacial environment that are important in developing nanomaterials for metallo-medicinal applications.
PubMed: 37496616
DOI: 10.1039/d3na00290j -
International Journal of Molecular... Apr 2024Hearing is essential for communication, and its loss can cause a serious disruption to one's social life. Hearing loss is also recognized as a major risk factor for... (Review)
Review
Hearing is essential for communication, and its loss can cause a serious disruption to one's social life. Hearing loss is also recognized as a major risk factor for dementia; therefore, addressing hearing loss is a pressing global issue. Sensorineural hearing loss, the predominant type of hearing loss, is mainly due to damage to the inner ear along with a variety of pathologies including ischemia, noise, trauma, aging, and ototoxic drugs. In addition to genetic factors, oxidative stress has been identified as a common mechanism underlying several cochlear pathologies. The cochlea, which plays a major role in auditory function, requires high-energy metabolism and is, therefore, highly susceptible to oxidative stress, particularly in the mitochondria. Based on these pathological findings, the potential of antioxidants for the treatment of hearing loss has been demonstrated in several animal studies. However, results from human studies are insufficient, and future clinical trials are required. This review discusses the relationship between sensorineural hearing loss and reactive oxidative species (ROS), with particular emphasis on age-related hearing loss, noise-induced hearing loss, and ischemia-reperfusion injury. Based on these mechanisms, the current status and future perspectives of ROS-targeted therapy for sensorineural hearing loss are described.
Topics: Humans; Oxidative Stress; Hearing Loss, Sensorineural; Animals; Reactive Oxygen Species; Antioxidants; Cochlea; Hearing Loss, Noise-Induced; Reperfusion Injury; Mitochondria
PubMed: 38673731
DOI: 10.3390/ijms25084146 -
Redox Report : Communications in Free... Dec 2024Cisplatin is widely employed in clinical oncology as an anticancer chemotherapy drug in clinical practice and is known for its severe ototoxic side effects. Prior...
Cisplatin is widely employed in clinical oncology as an anticancer chemotherapy drug in clinical practice and is known for its severe ototoxic side effects. Prior research indicates that the accumulation of reactive oxygen species (ROS) plays a pivotal role in cisplatin's inner ear toxicity. Hesperidin is a flavanone glycoside extracted from citrus fruits that has anti-inflammatory and antioxidant effects. Nonetheless, the specific pharmacological actions of hesperidin in alleviating cisplatin-induced ototoxicity remain elusive. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical mediator of the cellular oxidative stress response, is influenced by hesperidin. Activation of Nrf2 was shown to have a protective effect against cisplatin-induced ototoxicity. The potential of hesperidin to stimulate Nrf2 in attenuating cisplatin's adverse effects on the inner ear warrants further investigation. This study employs both and models of cisplatin ototoxicity to explore this possibility. Our results reveal that hesperidin mitigates cisplatin-induced ototoxicity by activating the Nrf2/NQO1 pathway in sensory hair cells, thereby reducing ROS accumulation, preventing hair cell apoptosis, and alleviating hearing loss.
Topics: Humans; Cisplatin; Hesperidin; NF-E2-Related Factor 2; Ototoxicity; Reactive Oxygen Species; Cell Line; Antineoplastic Agents; Hair Cells, Auditory; Apoptosis
PubMed: 38629504
DOI: 10.1080/13510002.2024.2341470 -
Biological Research Jan 2024Sensorineural hearing loss (SNHL) poses a major threat to both physical and mental health; however, there is still a lack of effective drugs to treat the disease....
BACKGROUND
Sensorineural hearing loss (SNHL) poses a major threat to both physical and mental health; however, there is still a lack of effective drugs to treat the disease. Recently, novel biological therapies, such as mesenchymal stem cells (MSCs) and their products, namely, exosomes, are showing promising therapeutic potential due to their low immunogenicity, few ethical concerns, and easy accessibility. Nevertheless, the precise mechanisms underlying the therapeutic effects of MSC-derived exosomes remain unclear.
RESULTS
Exosomes derived from MSCs reduced hearing and hair cell loss caused by neomycin-induced damage in models in vivo and in vitro. In addition, MSC-derived exosomes modulated autophagy in hair cells to exert a protective effect. Mechanistically, exogenously administered exosomes were internalized by hair cells and subsequently upregulated endocytic gene expression and endosome formation, ultimately leading to autophagy activation. This increased autophagic activity promoted cell survival, decreased the mitochondrial oxidative stress level and the apoptosis rate in hair cells, and ameliorated neomycin-induced ototoxicity.
CONCLUSIONS
In summary, our findings reveal the otoprotective capacity of exogenous exosome-mediated autophagy activation in hair cells in an endocytosis-dependent manner, suggesting possibilities for deafness treatment.
Topics: Neomycin; Exosomes; Hair Cells, Auditory; Autophagy
PubMed: 38217055
DOI: 10.1186/s40659-023-00475-w -
International Journal of Infectious... Nov 2023To investigate the preventive effect of intraarticularly administered vancomycin on acute postoperative periprosthetic joint infection (PJI) in total joint arthroplasty...
Intraarticular vancomycin decreased the risk of acute postoperative periprosthetic joint infection without increasing complication in primary total joint arthroplasty-a prospective study.
OBJECTIVES
To investigate the preventive effect of intraarticularly administered vancomycin on acute postoperative periprosthetic joint infection (PJI) in total joint arthroplasty (TJA).
METHODS
Consecutive patients who underwent unilateral primary TJA were prospectively enrolled. The patients were divided into vancomycin group and control group according to whether 1 g of vancomycin powder suspended in 30 ml normal saline was intraarticularly administered after arthrotomy closure. Acute postoperative PJI and aseptic wound complication were evaluated within 3 months postoperatively. Vancomycin-associated toxicity including acute renal failure, ototoxicity and anaphylaxis was also evaluated.
RESULTS
In terms of demographic parameters and comorbidities, no significant difference was found between the two groups. Intra-articular vancomycin significantly lowered the risk of acute postoperative PJI after primary TJA (P = 0.015) and primary total knee arthroplasty (P = 0.031). However, for patients who underwent total hip arthroplasty, the PJI rate was comparable between the two groups. Overall, the risk of aseptic wound complication between the two groups was also similar. Vancomycin-associated acute renal injury, ototoxicity, or anaphylaxis was not observed.
CONCLUSIONS
Intra-articular injection of 1 g of vancomycin suspension after arthrotomy closure during TJA lowered the risk of acute postoperative PJI without increasing the risk of aseptic wound complication and vancomycin-associated systemic toxicity.
Topics: Humans; Vancomycin; Prospective Studies; Prosthesis-Related Infections; Ototoxicity; Retrospective Studies; Arthroplasty, Replacement, Knee; Arthritis, Infectious; Acute Kidney Injury
PubMed: 37714404
DOI: 10.1016/j.ijid.2023.09.004