Exosomal circPVT1 promotes angiogenesis in laryngeal cancer by activating the Rap1b-VEGFR2 signaling pathway.

Laryngeal cancer (LC) is the second most common head and neck cancer and has a decreasing 5-year survival rate worldwide. Circular RNAs regulate cancer development in diverse ways based on their distinct biogenesis mechanisms and expansive regulatory roles. However, currently, there is little research on how exosomal circular RNAs are involved in the development of laryngeal cancer. Here, we demonstrated that circPVT1, a circular RNA derived from the well-studied long noncoding RNA PVT1, is correlated with disease progression in LC and promotes angiogenesis both in vivo and in vitro. Mechanistically, circPVT1 is loaded into LC cell-secreted exosomes and taken up by vascular epithelium cells. By sponging miR-30c-5p, exosomal circPVT1 promotes Rap1b expression, which dramatically enhances VEGFR2 and PI3K/AKT pathway activation, ultimately resulting in the induction of angiogenesis. Furthermore, our xenograft models demonstrated that the combination of shRNA-circPVT1 and cetuximab showed high efficacy in inhibiting tumor growth and angiogenesis. Collectively, these findings uncover a novel mechanism of exosomal circular RNA-mediated angiogenesis modulation and provide a preclinical rationale for testing this analogous combination in patients with LC.

Labyrinthine lesions in presumed inner ear hemorrhage-related sudden deafness.

PURPOSE: Inner ear hemorrhage (IEH) is a rare cause of sudden sensorineural hearing loss (SSNHL). This study aimed to evaluate the lesional patterns in patients with presumed IEH from morphological and functional aspects. METHODS: Seventeen patients with SSNHL and presumed IEH who completed audio-vestibular tests were included. The main outcome measures included clinical characteristics, radiology, and functional test results. RESULTS: The morphological findings and functional tests revealed differences in locations and lesional spectrums. The magnetic resonance imaging (MRI) hyperintensity was likely to involve the vestibule (88.2%), the cochlea (76.5%), and the posterior and lateral semicircular canals (76.5% and 70.6%, respectively). Furthermore, 70.6% of cases showed abnormality in the entire labyrinth, and abnormalities in the vestibule/semicircular canals were observed in 17.6% of cases. Meanwhile, dysfunction was sequentially detected in the cochlea (100%), semicircular canals (94.1%), and vestibule (70.6%); 64.7% of cases showed combined deficit in the entire labyrinth, and 29.4% of cases showed combined deficit in the cochlea/semicircular canals. Although lesions in the labyrinth were frequently detected, the results of the radiological and functional tests did not always match and significantly differed in either cochlear or superior semicircular canal damage detection (p < 0.05 each). CONCLUSIONS: In this cohort, IEH preferentially caused sudden audio-vestibular impairment, which was well demonstrated by a combination of MRI and functional tests. The specific lesional configurations revealed in this study may suggest a possible pathomechanism that could be further explored as a therapeutic target.

Validity study of a multiscaled fusion network using single-lead electrocardiogram signals for obstructive sleep apnea diagnosis.

STUDY OBJECTIVES: We evaluated the validity of a squeeze-and-excitation and multiscaled fusion network (SE-MSCNN) using single-lead electrocardiogram (ECG) signals for obstructive sleep apnea detection and classification. METHODS: Overnight polysomnographic data from 436 participants at the Sleep Center of the First Affiliated Hospital of Sun Yat-sen University were used to generate a new FAH-ECG dataset comprising 260, 88, and 88 single-lead ECG signal recordings for training, validation, and testing, respectively. The SE-MSCNN was employed for detection of apnea-hypopnea events from the acquired ECG segments. Sensitivity, specificity, accuracy, and F1 scores were assigned to assess algorithm performance. We also used the SE-MSCNN to estimate the apnea-hypopnea index, classify obstructive sleep apnea severity, and compare the agreement between 2 sleep technicians. RESULTS: The SE-MSCNN's accuracy, sensitivity, specificity, and F1 score on the FAH-ECG dataset were 86.6%, 83.3%, 89.1%, and 0.843, respectively. Although slightly inferior to previously reported results using public datasets, it is superior to state-of-the-art open-source models. Furthermore, the SE-MSCNN had good agreement with manual scoring, such that the Spearman's correlations for the apnea-hypopnea index between the SE-MSCNN and 2 technicians were 0.93 and 0.94, respectively. Cohen's kappa scores in classifying the SE-MSCNN and the 2 sleep technicians were 0.72 and 0.78, respectively. CONCLUSIONS: In this study, we validated the use of the SE-MSCNN in a clinical environment, and despite some limitations the network appeared to meet the performance standards for generalizability. Therefore, updating algorithms based on single-lead ECG signals can facilitate the development of novel wearable devices for efficient obstructive sleep apnea screening. CITATION: Yue H, Li P, Li Y, et al. Validity study of a multiscaled fusion network using single-lead electrocardiogram signals for obstructive sleep apnea diagnosis. J Clin Sleep Med. 2023;19(6):1017-1025.

Report of rare and novel mutations in candidate genes in a cohort of hearing-impaired patients.

BACKGROUND: Many hearing-impaired patients carry mutations in rare or novel genes undetected in regular genetic hot regions/genes screening. METHODS: We collected clinical and genetic data from subjects with hearing loss who visited our department for genetic counseling. Next-generation sequencing was conducted after 154 deafness-related genes were captured using a designed genes panels in 14 unrelated families (37 participants). The results were filtered and assessed with in silico tools, in combination with pedigree mapping. RESULTS: Ten mutations in regular deafness genes (GJB2, SLC26A4) and uncommon genes (OTOF, MYO7A, MYO15A, and KARS) were detected, which constituted 57.2% of yielded rate. In particular, two patients with nonsyndromic deafness carried biallelic KARS mutations. In addition, we identified an unreported digenic mutational inheritance in GRP98/USH2A genes in a proband with isolated hearing loss. Functional analyses and molecular modeling suggested the damaging consequence of these variants on encoded proteins. According to the variant pathogenicity guidelines, the 17 identified variants in total were classified as "pathogenic" or "likely pathogenic." CONCLUSION: The candidate mutations in deafness genes were suggested to be co-segregated in at least 57.2% of the studied pedigrees. This is the new report of rare/novel mutations causing inherited hearing loss in Chinese.

Cochlear Implantation Outcomes in Children With CDH23 Mutations-Associated Hearing Loss.

OBJECTIVE: Mutations in the cadherin 23 gene (CDH23) have been reported to cause cochlear damage, but few studies have investigated the auditory and speech outcome of patients after cochlear implantation. Here, we describe the genetic, auditory, and postoperative outcomes of patients with CDH23 mutations who received cochlear implants. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. METHODS: Targeted deafness-related gene panels were sequenced in Chinese families with profound sensorineural hearing loss. The clinical features of subjects carrying potentially pathogenic CDH23 mutations were analyzed. RESULTS: Between 2017 and 2019, we identified 5 children with prelinguistically profound hearing loss at our center who harbored 6 variants of CDH23 that segregated with the disease. Of these, 4 variants were novel (c.2591G>T, c.4785G>C, c.5765A>G, and c.9280_9281insTT). All affected individuals had a loss of outer hair cell function, with an average residual hearing level of 3 to 10 dB SPL. Cochlear implantations were arranged for the patients at 11 to 36 months of age. All children made gains in their hearing, language, and speech performances 14 to 120 months after surgery. Their auditory outcomes improved during follow-up intervals. CONCLUSION: This study revealed that children with congenital cochlear defects caused by CDH23 variants can acquire an acceptable auditory and speech outcome after cochlear implantation. Early genetic detection and prenatal counseling for rare deafness genes such as CDH23 remain a priority for the future.

Notched Sound Alleviates Tinnitus by Reorganization Emotional Center.

BACKGROUND: Tinnitus is a common disease, and sound therapy is an effective method to alleviate it. Previous studies have shown that notched sound not only changes levels of cortical blood oxygen, but affects blood oxygen in specific cerebral cortical areas, such as Brodmann area 46 (BA46), which is associated with emotion. Extensive evidence has confirmed that tinnitus is closely related to emotion. Whether notched sound plays a role in regulating the emotional center is still unclear. METHODS: This study included 29 patients with newly diagnosed chronic tinnitus who were treated with notched sound. Functional near-infrared spectroscopy (fNIRS) was conducted before and after treatment to observe bilateral changes in cortical blood oxygen in the cerebral hemispheres. We compared the changes in connectivity between the two regions of interest (the superior temporal gyrus and BA46), as wells as other cortical regions before and after treatment. RESULTS: The results showed (1) That global connectivity between the bilateral auditory cortex of the superior temporal sulcus and the ipsilateral cortex did not change significantly between baseline and the completion of treatment, and (2) That the connectivity between channel 14 and the right superior temporal sulcus decreased after treatment. The overall connectivity between the right BA46 region and the right cortex decreased after treatment, and decreases in connectivity after treatment were specifically found for channels 10 and 14 in the right parietal lobe and channels 16, 20, 21, and 22 in the frontal lobe, while there was no significant change on the left side. There were no significant changes in the questionnaire measures of tinnitus, anxiety, or depression before and after treatment. CONCLUSION: The results of the study indicate that cerebral cortex reorganization occurs in tinnitus patients after submitted to treatment with notched sound for 1 month, and that notched sound decreases the connectivity between the auditory cortex and specific brain regions. SIGNIFICANCE: Notched sound not only regulates the auditory center through lateral inhibition, but also alleviates tinnitus by reorganizing the emotional control center.

Cortical Activation Patterns of Different Masking Noises and Correlation With Their Masking Efficacy, Determined by Functional Near-Infrared Spectroscopy.

Acoustic therapy in tinnitus treatment is poorly characterized, and efficacy assessment depends on subjective descriptions. Narrow-band noise, notched sound, and white noise have positive therapeutic effects on monotonous tinnitus. Considering the tonotopic characteristics of the auditory system and the spectral characteristics of these three masking sounds, the activation pattern of the auditory cortex and the mechanism of inhibiting tinnitus may be different. This study aimed to compare the activation patterns of three spectrally different masking noises and study the correlation between the masking effects and variational amplitude of oxygenated hemoglobin (HbO) in the corresponding cortical regions. We also assessed near-infrared spectroscopy brain function imaging (NIRS) as an objective assessment tool in acoustic therapy. Patients with persistent non-pulsatile tinnitus and control volunteers without tinnitus were enrolled in this study. The subjects were seated in a sound-proof room, with two optode arrays covering the bilateral temporal lobe. Auditory stimuli were presented; stimulation sequences followed the block design: different noises appeared randomly and repeated in five cycles. Tinnitus match and residual inhibition were performed in the tinnitus group. The data analyses were conducted using the NIRS_SPM toolbox. The group analysis results showed that the narrow-band noise caused a marginally significant decrease in HbO signal in the Brodmann 21 region (BA21), while white noise caused a significant increase in HbO signal in BA21. Notched sound did not cause significant changes in the HbO signal in the temporal cortex. And none of the three masking noises caused significant changes in the HbR signal in the temporal cortex. The depth of residual inhibition induced by the narrow-band noise and white noise significantly correlated with ΔHbO in the region of interest (ROI). However, neither the depth nor duration of the residual inhibition induced by notched sound correlated with the ΔHbO. Thus, NIRS showed three cortical activation patterns induced by three different masking noises, and correlations between residual inhibition effects and change of HbO amplitude were found. NIRS could therefore be applied in objective assessment of acoustic therapy.

Combined application of single-energy metal artifact reduction and reconstruction techniques in patients with Cochlear implants.

BACKGROUND: The purpose of this study was to develop an effective method of reducing metal artifacts in cochlear implant (CI) electrodes. METHODS: The temporal bones of 30 patients (34 ears) after CI were examined with 320-detector row computed tomography, which was evaluated by two senior radiologists using a double-blind method. Noise, artifact index, signal-to-noise ratio, and the subjective image quality score were compared before versus after using single-energy metal artifact reduction (SEMAR). The electrode position, single electrode visibility, and electrode count were evaluated using SEMAR combined with either multi-planar reconstruction (MPR) or maximum intensity projection. RESULTS: The two radiologists' measurements had good consistency. SEMAR significantly reduced the image noise and artifacts index and significantly improved the signal-to-noise ratio and subjective image quality score (P < 0.01). The combination of SEMAR with MPR was conducive to accurate assessment of electrode position and single-electrode visibility. The combination of SEMAR with MIP facilitated accurate and intuitive matching of the assessed electrode count with the number of electrodes implanted during the operation (P = 0.062). CONCLUSION: SEMAR significantly reduces metal artifacts generated by CI electrodes and improves the quality of computed tomography images. The combination of SEMAR with MPR and maximum intensity projection is beneficial for evaluating the position and number of CI electrodes.