Transcriptional-profile changes in the medial geniculate body after noise-induced tinnitus.

Tinnitus is a disturbing condition defined as the occurrence of acoustic hallucinations with no actual sound. Although the mechanisms underlying tinnitus have been explored extensively, the pathophysiology of the disease is not completely understood. Moreover, genes and potential treatment targets related to auditory hallucinations remain unknown. In this study, we examined transcriptional-profile changes in the medial geniculate body after noise-induced tinnitus in rats by performing RNA sequencing and validated differentially expressed genes via quantitative polymerase chain reaction analysis. The rat model of tinnitus was established by analyzing startle behavior based on gap-pre-pulse inhibition of acoustic startles. We identified 87 differently expressed genes, of which 40 were upregulated and 47 were downregulated. Pathway-enrichment analysis revealed that the differentially enriched genes in the tinnitus group were associated with pathway terms, such as coronavirus disease COVID-19, neuroactive ligand-receptor interaction. Protein-protein-interaction networks were established, and two hub genes (Rpl7a and AC136661.1) were identified among the selected genes. Further studies focusing on targeting and modulating these genes are required for developing potential treatments for noise-induced tinnitus in patients.

Prognostic factor analysis in patients with early-stage nasopharyngeal carcinoma in the USA.

Aim: To evaluate independent risk factors specific for early-stage nasopharyngeal carcinoma (NPC). Methods: A total of 566 patients with early-stage NPC from 2004 to 2019 were identified using the Surveillance, Epidemiology and End Results database. Results: Older ages (70-79 and >80 years) were independent risk factors, with hazard ratios of 1.961 and 5.011, respectively. The hazard ratio for early-stage NPC in Asian and Pacific Islander residents (0.475) was lower than that for White residents. A tumor size <3 cm was a protective factor for overall and cancer-specific survival in the current study. Conclusion: In patients with early-stage NPC, age >70 years, race and tumor size were independent prognosticators for cancer-specific survival.

Transcriptional Profile Changes after Noise-Induced Tinnitus in Rats.

Tinnitus is an unpleasant symptom characterized by detective hearing without the actual sound input. Despite numerous studies elucidating a variety of pathomechanisms inducing tinnitus, the pathophysiology of tinnitus is not fully understood. The genes that are closely associated with this subtype of the auditory hallucination that could be utilized as potential treatment targets are still unknown. In this study, we explored the transcriptional profile changes of the auditory cortex after noise-induced tinnitus in rats using high throughput sequencing and verification of the detected genes using quantitative PCR (qPCR). Tinnitus models were established by analyzing startle behaviors through gap pre-pulse inhibition (PPI) of the acoustic startle. Two hundred and fifty-nine differential genes were identified, of which 162 genes were up-regulated and 97 genes were down-regulated. Analysis of the pathway enrichment indicated that the tinnitus group exhibited increased gene expression related to neurodegenerative disorders such as Huntington's disease and Amyotrophic lateral sclerosis. Based on the identified genes, networks of protein-protein interaction were established and five hub genes were identified through degree rank, including Fos, Nr4a1, Nr4a3, Egr2, and Egr3. Therein, the Fos gene ranked first with the highest degree after noise exposure, and may be a potential target for the modulation of noise-induced tinnitus.

The Comorbidity of Depression and Anxiety Symptoms in Tinnitus Sufferers: A Network Analysis.

OBJECTIVE: Sufferers of tinnitus, especially of the prolonged type, frequently suffer from comorbid depression and anxiety. From the perspective of the network model, this comorbidity is thought to be an interacting system of these two symptoms. In our study, we conducted a network analysis of depression and anxiety comorbidity in tinnitus sufferers, aiming to identify the central and bridge symptoms and make informed suggestions for clinical interventions and psychotherapy. METHOD: A total of 566 tinnitus sufferers were enrolled in our study. The Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder 7-Item Questionnaire (GAD-7) were selected to evaluate depression and anxiety symptoms, respectively, followed by network analysis to construct the interacting networks. RESULTS: The findings identified six edges of strongest regularized partial correlations in this network. Of these, three were depression symptoms and three were anxiety symptoms. The anxiety symptoms "Unable to control worry" and "Relaxation difficulty" and the depression symptom "Feeling depressed or hopeless" had the highest expected influence centrality. The analysis results also revealed three bridge symptoms: "Afraid something awful might happen", "Feeling of worthlessness", and "Trouble concentrating". As for "Suicidal ideation", the direct relations between this symptom and "Afraid something awful might happen" and "Feeling depressed or hopeless" were the strongest. CONCLUSIONS: The central and bridge symptoms of the interacting network of depression and anxiety symptoms in tinnitus sufferers can be considered a significant transdiagnostic intervention target for the management of this comorbidity. In particular, clinical prevention and psychotherapy should be implemented, targeting the symptoms that have the strongest associations with suicidal ideation.

Study on tinnitus-related electroencephalogram microstates in patients with vestibular schwannomas.

Tinnitus is closely associated with cognition functioning. In order to clarify the central reorganization of tinnitus in patients with vestibular schwannoma (VS), this study explored the aberrant dynamics of electroencephalogram (EEG) microstates and their correlations with tinnitus features in VS patients. Clinical and EEG data were collected from 98 VS patients, including 76 with tinnitus and 22 without tinnitus. Microstates were clustered into four categories. Our EEG microstate analysis revealed that VS patients with tinnitus exhibited an increased frequency of microstate C compared to those without tinnitus. Furthermore, correlation analysis demonstrated that the Tinnitus Handicap Inventory (THI) score was negatively associated with the duration of microstate A and positively associated with the frequency of microstate C. These findings suggest that the time series and syntax characteristics of EEG microstates differ significantly between VS patients with and without tinnitus, potentially reflecting abnormal allocation of neural resources and transition of functional brain activity. Our results provide a foundation for developing diverse treatments for tinnitus in VS patients.

Protective effect of ginsenoside Rd on military aviation noise-induced cochlear hair cell damage in guinea pigs.

Noise pollution has become one of the important social hazards that endanger the auditory system of residents, causing noise-induced hearing loss (NIHL). Oxidative stress has a significant role in the pathogenesis of NIHL, in which the silent information regulator 1(SIRT1)/proliferator-activated receptor-gamma coactivator 1α (PGC-1α) signaling pathway is closely engaged. Ginsenoside Rd (GSRd), a main monomer extract from ginseng plants, has been confirmed to suppress oxidative stress. Therefore, the hypothesis that GSRd may attenuate noise-induced cochlear hair cell loss seemed promising. Forty-eight male guinea pigs were randomly divided into four groups: control, noise exposure, GSRd treatment (30 mg/kg Rd for 10d + noise), and experimental control (30 mg/kg glycerol + noise). The experimental groups received military helicopter noise exposure at 115 dB (A) for 4 h daily for five consecutive days. Hair cell damage was evaluated by using inner ear basilar membrane preparation and scanning electron microscopy. Terminal dUTP nick end labeling (TUNEL) and immunofluorescence staining were conducted. Changes in the SIRT1/PGC-1α signaling pathway and other apoptosis-related markers in the cochleae, as well as oxidative stress parameters, were used as readouts. Loss of outer hair cells, more disordered cilia, prominent apoptosis, and elevated free radical levels were observed in the experimental groups. GSRd treatment markedly mitigated hearing threshold shifts, ameliorated outer hair cell loss and lodging or loss of cilia, and improved apoptosis through decreasing Bcl-2 associated X protein (Bax) expression and increasing Bcl-2 expression. In addition, GSRd alleviated the noise-induced cochlear redox injury by upregulating superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels, decreasing malondialdehyde (MDA) levels, and enhancing the activity of SIRT1 and PGC-1α messenger ribonucleic acid (mRNA) and protein expression. In conclusion, GSRd can improve structural and oxidative damage to the cochleae caused by noise. The underlying mechanisms may be associated with the SIRT1/PGC-1α signaling pathway.

Pan-cancer analysis identifies NT5E as a novel prognostic biomarker on cancer-associated fibroblasts associated with unique tumor microenvironment.

Background: Ecto-5'-nucleotidase (NT5E) encodes the cluster of differentiation 73 (CD73), whose overexpression contributes to the formation of immunosuppressive tumor microenvironment and is related to exacerbated prognosis, increased risk of metastasis and resistance to immunotherapy of various tumors. However, the prognostic significance of NT5E in pan-cancer is obscure so far. Methods: We explored the expression level of NT5E in cancers and adjacent tissues and revealed the relationship between the NT5E expression level and clinical outcomes in pan-cancer by utilizing the UCSC Xena database. Then, correlation analyses were performed to evaluate the relationship between NT5E expression and immune infiltration level via EPIC, MCP-counter and CIBERSORT methods, and the enrichment analysis were employed to identify NT5E-interacting molecules and functional pathways. Furthermore, we conducted single-cell analysis to explore the potential role of NT5E on single-cell level based on the CancerSEA database. Meanwhile, gene set enrichment analysis (GSEA) in single-cell level was also conducted in TISCH database and single-cell signature explorer was utilized to evaluate the epithelial-mesenchymal transition (EMT) level in each cell type. Results: The expression level of NT5E was aberrant in almost all cancer types, and was correlated with worse prognosis in several cancers. Notably, NT5E overexpression was related to worse overall survival (OS) in pancreatic adenocarcinoma (PAAD), head and neck squamous cell carcinoma (HNSC), mesothelioma (MESO), stomach adenocarcinoma (STAD), uveal melanoma (UVM) and cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) (p < 0.01). NT5E-related immune microenvironment analysis revealed that NT5E is associated positively with the degree of infiltration of cancer-associated fibroblasts (CAFs) and endothelial cells in most cancers. Enrichment analysis of cellular component (CC) demonstrated the critical part of NT5E played in cell-substrate junction, cell-substrate adherens junction, focal adhesion and external side of plasma membrane. Finally, single-cell analysis of NT5E illuminated that EMT function of CAFs was elevated in basal cell carcinoma (BCC), skin cutaneous melanoma (SKCM), HNSC and PAAD. Conclusion: NT5E could serve as a potential prognostic biomarker for cancers. The potential mechanism may be related to the upregulated EMT function of CAFs, which provides novel inspiration for immunotherapy by targeting CAFs with high NT5E expression.

NT5E upregulation in head and neck squamous cell carcinoma: A novel biomarker on cancer-associated fibroblasts for predicting immunosuppressive tumor microenvironment.

Despite tremendous progress made in the diagnosis and managements, head and neck squamous cell carcinoma (HNSC) remains a global medical dilemma with dismal clinical prognosis and high mortality. Gene NT5E encodes the ecto-5'-nucleotidase (CD73), which facilitates the formation of immunosuppressive tumor microenvironment (TME) permissive for tumor progression in various malignancies. Nevertheless, the cell subsets NT5E expressed on and the potential function of NT5E in the TME of HNSC remain virgin lands in HNSC. In this study, we comprehensively performed integrated prognostic analysis and elucidated that NT5E was an independent prognostic indicator for HNSC, for which a high NT5E level predicted poor overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI) in HNSC patients (p<0.05). Enrichment analyses revealed the close correlation between NT5E and ECM remodeling, and the latent function of NT5E may involve in epithelial-to-mesenchymal transition (EMT) and metastasis during HNSC progression. HNSC-related immune infiltration analysis and single-cell type analysis demonstrated that NT5E expression was significantly positively associated with cancer-associated fibroblasts (CAFs) in HNSC (p<0.01). NT5E-related TME analysis revealed that NT5E-high group are characterized by low neoantigen loads (NAL, p<0.001) and tumor mutation burden (TMB, p<0.01), indicating high-NT5E-expression HNSC patients may be recalcitrant to immunotherapy. In-situ multicolor immunofluorescence staining was later conducted and the results further verified our findings. Taken together, NT5E could be a novel biomarker in HNSC. Predominantly expressed on CAFs, the upregulation of NT5E might predict an immunosuppressive TME for HNSC patients who may benefit little from immunotherapy. Targeting CAFs with high NT5E expression might be a novel therapeutic strategy for HNSC patients.

Extended high-frequency audiometric analyses of tinnitus patients exhibiting normal hearing on conventional pure-tone audiometry.

BACKGROUND: While hearing loss is the greatest risk factor associated with developing tinnitus, some tinnitus patients exhibit no hearing loss on conventional pure-tone audiometry (PTA). OBJECTIVES: This study was developed to assess whether tinnitus patients with normal hearing as measured via conventional PTA would exhibit differences from normal controls upon extended high-frequency (EHF) audiometric evaluation. METHODS: In total, 102 tinnitus patients were separated into unilateral and bilateral tinnitus groups. Age- and sex-matched controls without tinnitus were enrolled. RESULTS: No significant differences were observed when comparing EHF audiometry results in the 9-14 kHz range between controls and tinnitus patients, with only left-sided tinnitus ears exhibiting higher hearing thresholds than contralateral ears at 9, 10, and 14 kHz. Relative to normal controls, the hearing thresholds in the 2-8 kHz range for tinnitus ears were significantly increased. CONCLUSIONS AND SIGNIFICANCE: Relative to controls, tinnitus patients with normal hearing did not exhibit any significant hearing loss in the EHF range. Unexpectedly, tinnitus patients with normal hearing exhibited significant hidden hearing loss in the conventional frequency range rather than in the EHF range. For patients with normal hearing, it appears to be unnecessary to conduct EHF examinations to detect hearing loss in the EHF range.

The Role of Genetic Variants in the Susceptibility of Noise-Induced Hearing Loss.

Noised-induced hearing loss (NIHL) is an acquired, progressive neurological damage caused by exposure to intense noise in various environments including industrial, military and entertaining settings. The prevalence of NIHL is much higher than other occupational injuries in industrialized countries. Recent studies have revealed that genetic factors, together with environmental conditions, also contribute to NIHL. A group of genes which are linked to the susceptibility of NIHL had been uncovered, involving the progression of oxidative stress, potassium ion cycling, cilia structure, heat shock protein 70 (HSP70), DNA damage repair, apoptosis, and some other genes. In this review, we briefly summarized the studies primary in population and some animal researches concerning the susceptible genes of NIHL, intending to give insights into the further exploration of NIHL prevention and individual treatment.

Ginsenoside Rd Ameliorates Auditory Cortex Injury Associated With Military Aviation Noise-Induced Hearing Loss by Activating SIRT1/PGC-1α Signaling Pathway.

Free radicals and oxidative stress play an important role in the pathogenesis of noise-induced hearing loss (NIHL). Some ginseng monomers showed certain therapeutic effects in NIHL by scavenging free radicals. Therefore, we hypothesized that ginsenoside Rd (GSRd) may exert neuroprotective effects after noise-induced auditory system damage through a mechanism involving the SIRT1/PGC-1α signaling pathway. Forty-eight guinea pigs were randomly divided into four equal groups (normal control group, noise group, experimental group that received GSRd dissolved in glycerin through an intraperitoneal injection at a dose of 30 mg/kg body weight from 5 days before noise exposure until the end of the noise exposure period, and experimental control group). Hearing levels were examined by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE). Hematoxylin-eosin and Nissl staining were used to examine neuron morphology. RT-qPCR and western blotting analysis were used to examine SIRT1/PGC-1α signaling and apoptosis-related genes, including Bax and Bcl-2, in the auditory cortex. Bax and Bcl-2 expression was assessed via immunohistochemistry analysis. Superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) levels were determined using a commercial testing kit. Noise exposure was found to up-regulate ABR threshold and down-regulate DPOAE amplitudes, with prominent morphologic changes and apoptosis of the auditory cortex neurons (p < 0.01). GSRd treatment restored hearing loss and remarkably alleviated morphological changes or apoptosis (p < 0.01), concomitantly increasing Bcl-2 expression and decreasing Bax expression (p < 0.05). Moreover, GSRd increased SOD and GSH-Px levels and decreased MDA levels, which alleviated oxidative stress damage and activated SIRT1/PGC-1α signaling pathway. Taken together, our findings suggest that GSRd ameliorates auditory cortex injury associated with military aviation NIHL by activating the SIRT1/PGC-1α signaling pathway, which can be an attractive pharmacological target for the development of novel drugs for NIHL treatment.