[Traditional Chinese medicine and active ingredients regulate M1/M2 macrophage polarization balance to treat chronic obstructive pulmonary disease: a review].

Chronic obstructive pulmonary disease(COPD) is a progressive lung dysfunction(disease) caused by long-term inhalation of toxic particles, especially smoking. The continued exposure to harmful substances triggers an abnormal inflammatory response, which causes permanent damage to the respiratory system, ultimately leading to irreversible pathological changes. Lung macrophages(LMs) are key innate immune effectors involved in the recognition, phagocytosis, and clearance of pathogens, as well as in the processing of inhaled hazardous particulate matter(e. g., cigarette smoke and particulate matter). LMs are polarized toward the M1 or M2 phenotype in response to the activation of inflammatory mediators to exert pro-/anti-inflammatory effects, respectively, thus being involved in the pulmonary parenchymal damage(emphysema) and repair(airway remodeling) throughout the process of COPD.In addition, they are responsible for phagocytosis and clearance of apoptotic or necrotic tissue cells, which helps to maintain the stability of the microenvironment in the lungs of COPD patients. Modern studies have revealed that macrophage polarization plays a pivotal role in the pathogenesis and development of COPD and is considered a potential target for treating COPD because of its ability to reduce airway inflammation, inhibit tissue remodeling, and combat oxidative stress. In recent years, traditional Chinese medicine(TCM) and its active ingredients have become a hot area in the treatment of COPD by targeting the balance of M1/M2 macrophage polarization. TCM and its active ingredients can intervene in the inflammatory response to promote the repair of the lung tissue in the patients with COPD. This paper reviews the research achievements of TCM and its active ingredients in this field in recent years,aiming to provide a scientific basis and strong support for the precise diagnosis and treatment of COPD.

Ivacaftor attenuates gentamicin-induced ototoxicity through the CFTR-Nrf2-HO1/NQO1 pathway.

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.

Cochlear implantation in patients with Streptococcus suis meningitis: clinical characteristics and postoperative evaluation.

BACKGROUND: Hearing loss is a common sequala of Streptococcus suis (S. suis) meningitis, but few have addressed cochlear implantation (CI) candidates with S. suis meningitis. OBJECTIVES: To assess the clinical characteristics and CI postoperative outcomes in S. suis meningitis patients. MATERIAL AND METHODS: Eight S. suis meningitis patients underwent CI at Sun Yat-sen Memorial Hospital between 2020 and 2023. Control groups included (1) non-Suis meningitis patients (n = 12) and (2) non-meningitis patients (n = 35). Electrode impedances and neural response telemetry (NRT) thresholds were recorded at one month after surgery. The auditory performance-II (CAP) and speech intelligibility rating (SIR) were recorded at the last visit. RESULTS: CAP scores of S. suis meningitis patients were significantly lower than those of non-Suis meningitis and non-meningitis patients (p = .019; p<.001). And NRT thresholds of S. suis meningitis patients were higher than those of non-Suis meningitis and non-meningitis patients (p = .006; p = .027). CONCLUSIONS AND SIGNIFICANCE: It is recommended for S. suis meningitis CI candidates to undergo CI promptly after controlling infection, preferably within four to six weeks. CI users with S. suis meningitis tend to exhibit suboptimal hearing rehabilitation outcomes, possibly associated with the more severe damage on spiral ganglion cells after S. suis meningitis.

Reactive Oxygen Species-Related Disruptions to Cochlear Hair Cell and Stria Vascularis Consequently Leading to Radiation-Induced Sensorineural Hearing Loss.

Aims: Radiation-induced sensorineural hearing loss (RISNHL) is one of the major side effects of radiotherapy for head and neck cancers. At present, no effective clinical treatment or prevention is available for RISNHL. This study thus aimed to investigate the cochlear pathology so that the underlying mechanisms of RISNHL may be elucidated, consequently paving the way for potential protective strategies to be developed. Results: Functional and morphological impairment in the stria vascularis (SV) was observed after irradiation (IR), as indicated by endocochlear potential (EP) reduction, hyperpermeability, and SV atrophy. The expression of zonulae occludins-1 was found to have decreased after IR. The loss of outer hair cells (OHCs) occurred later than SV damage. The disruption to the SV and OHCs could be attributed to reactive oxygen species (ROS)-related damage. In addition, EP shifts and the loss of OHCs were reduced when ROS was reduced by N-acetylcysteine (NAC) in C57BL/6 mice, attenuating auditory threshold shifts. Innovation: The damage to the SV was found to occur before OHC loss. ROS-related damage accounted for SV damage and OHC loss. The incidences of SV damage and OHC loss were decreased through ROS modulation by NAC, subsequently preventing RISNHL, suggesting the possible role of NAC as a possible protective agent against RISNHL. Conclusion: The findings from this study suggest oxidative stress-induced early SV injury and late OHC loss to be the key factors leading to RISNHL. NAC prevents IR-induced OHC loss, and attenuates auditory brainstem response and EP shifts by regulating the level of oxidative stress. Antioxid. Redox Signal. 40, 470-491.

CFTR potentiator ivacaftor protects against noise-induced hair cell loss by increasing Nrf2 and reducing oxidative stress.

Over-production of reactive oxygen species (ROS) in the inner ear can be triggered by a variety of pathological events identified in animal models after traumatic noise exposure. Our previous research found that inhibition of the AMP-activated protein kinase alpha subunit (AMPKα) protects against noise-induced cochlear hair cell loss and hearing loss by reducing ROS accumulation. However, the molecular pathway through which AMPKα exerts its antioxidative effect is still unclear. In this study, we have investigated a potential target of AMPKα and ROS, cystic fibrosis transmembrane conductance regulator (CFTR), and the protective effect against noise-induced hair cell loss of an FDA-approved CFTR potentiator, ivacaftor, in FVB/NJ mice, mouse explant cultures, and HEI-OC1 cells. We found that noise exposure increases phosphorylation of CFTR at serine 737 (p-CFTR, S737), which reduces wildtype CFTR function, resulting in oxidative stress in cochlear sensory hair cells. Pretreatment with a single dose of ivacaftor maintains CFTR function by preventing noise-increased p-CFTR (S737). Furthermore, ivacaftor treatment increases nuclear factor E2-related factor 2 (Nrf2) expression, diminishes ROS formation, and attenuates noise-induced hair cell loss and hearing loss. Additionally, inhibition of noise-induced AMPKα activation by compound C also diminishes p-CFTR (S737) expression. In line with these in-vivo results, administration of hydrogen peroxide to cochlear explants or HEI-OC1 cells increases p-CFTR (S737) expression and induces sensory hair cell or HEI-OC1 cell damage, while application of ivacaftor halts these effects. Although ivacaftor increases Nrf2 expression and reduces ROS accumulation, cotreatment with ML385, an Nrf2 inhibitor, abolishes the protective effects of ivacaftor against hydrogen-peroxide-induced HEI-OC1 cell death. Our results indicate that noise-induced sensory hair cell damage is associated with p-CFTR. Ivacaftor has potential for treatment of noise-induced hearing loss by maintaining CFTR function and increasing Nrf2 expression for support of redox homeostasis in sensory hair cells.

[Reliability and validity of the Chinese version of URICA-Voice scale].

Objective:To translate the University of Rhode Island Change Assessment of voice scale（URICA-Voice） into Chinese and test its reliability and validity. Methods:The URICA-Voice scale was converted into Chinese by literal translation, cultural adjustment, expert consultation, pre-investigation, and back translation. Convenience sampling was used to recruit patients at four speech therapy centers from February to May 2022. Then the Chinese version of the scale was distributed to them, and the reliability and validity of the scale were tested after data collection. Cronbach ɑ was used to evaluate the reliability. The critical ratio method and Pearson correlation coefficient were used for item analysis. Item-level content validity, scale-level content validity, and confirmatory factor analysis were used to test the validity of the scale. Results:A total of 247 valid questionnaires were collected. ①Item analysis: the critical ratios between a high-score and low-score groups of 32 items were all statistically significant（P<0.01） and all the critical ratios were above 3.00. The Pearson correlation between 32 items and the total score was significant（P<0.01）. ②Validity analysis: I-CVI=1.00, S-CVI/Ave=1.00, χ²/df=2.30, RMSEA=0.07. Except for item 9 and 23, the standardized factor loading coefficients of other items were all above 0.50. AVE of the four dimensions of the scale was all above 0.50, and the combined reliability of the four dimensions was all above 0.70. The correlation coefficients between dimensions were less than the square root of the AVE of the dimension itself. ③Reliability analysis: the Cronbach ɑ of the whole scale was 0.94, and the Cronbach ɑ of the four dimensions were 0.88, 0.92, 0.94, and 0.88 respectively. Conclusion:The Chinese version of URICA-Voice has good reliability and validity, and can be used as a specific measurement tool for evaluating the compliance of voice training in China.

Skeletal standardized uptake values obtained using quantitative SPECT/CT for the detection of bone metastases in patients with lung adenocarcinoma.

Purpose: To assess the utility of skeletal standardized uptake values (SUVs) obtained using quantitative single-photon emission computed tomography/computed tomography (SPECT/CT) in differentiating bone metastases from benign lesions, particularly in patients with lung adenocarcinoma. Methods: Patients with lung adenocarcinoma who had undergone whole-body Tc-99m methyl-diphosphonate (99mTc-MDP) bone scans and received late phase SPECT/CT were retrospectively analyzed in this study. The maximum SUV (SUVmax); Hounsfield units (HUs); and volumes of osteoblastic, osteolytic, mixed, CT-negative metastatic and benign bone lesions, and normal vertebrae were compared. Receiver operating characteristic curves were used to determine the optimal cutoff SUVmax between metastatic and benign lesions as well as the cutoff SUVmax between CT-negative metastatic lesions and normal vertebrae. The linear correlation between SUVmax and HUs of metastatic lesions as well as that between SUVmax and the volume of all bone lesions were investigated. Results: A total of 252 bone metastatic lesions, 140 benign bone lesions, and 199 normal vertebrae from 115 patients with lung adenocarcinoma were studied (48 males, 67 females, median age: 59 years). Metastatic lesions had a significantly higher SUVmax (23.85 ± 14.34) than benign lesions (9.67 ± 7.47) and normal vertebrae (6.19 ± 1.46; P < 0.0001). The SPECT/CT hotspot of patients with bone metastases could be distinguished from benign lesions using a cutoff SUVmax of 11.10, with a sensitivity of 87.70% and a specificity of 80.71%. The SUVmax of osteoblastic (29.16 ± 16.63) and mixed (26.62 ± 14.97) lesions was significantly greater than that of osteolytic (15.79 ± 5.57) and CT-negative (16.51 ± 6.93) lesions (P < 0.0001, P = 0.0003, and 0.002). SUVmax at the cutoff value of 8.135 could distinguish CT-negative bone metastases from normal vertebrae, with a sensitivity of 100.00% and a specificity of 91.96%. SUVmax showed a weak positive linear correlation with HUs in all bone metastases and the volume of all bone lesions. Conclusion: SUVmax of quantitative SPECT/CT is a useful index for distinguishing benign bone lesions from bone metastases in patients with lung adenocarcinoma, particularly in the diagnosis of CT-negative bone metastases, but other factors that may affect SUVmax should be considered.

Efficacy of Tailor-Made Notched Music Training Versus Tinnitus Retraining Therapy in Adults With Chronic Subjective Tinnitus: A Randomized Controlled Clinical Trial.

OBJECTIVES: Chronic subjective tinnitus can have a serious effect on daily life, even causing serious psychological disorders. Currently there are no specific effective solutions or cures. Tailor-made notched music training (TMNMT) is a recently proposed sound therapy that has simpler processes and a higher compliance rate than tinnitus retraining therapy (TRT), a widely used treatment for chronic subjective tinnitus. This study explores the therapeutic effect of TMNMT in comparison to TRT to highlight its clinical value. DESIGN: The study was a randomized controlled, single-blinded clinical trial. One hundred twenty eligible participants were randomly assigned to receive TMNMT (n = 60) or TRT (n = 60) for 3 mo with concurrent follow-up. It should be noted that the duration of sound treatment in TRT was modified to 2 hr per day for better feasibility in practice. The primary outcome was mean change in tinnitus handicap inventory (THI) measured at baseline ( T0 ), 1 mo ( T1 ) and 3 mo ( T2 ) after intervention. Change in visual analog scale (VAS) was measured as a secondary outcome. A comparison of therapeutic effectiveness between TMNMT and TRT was evaluated by repeated measure analysis of variance. RESULTS: One hundred and twelve (93%) of participants took part in the study, of which 64 were men and 48 women. Mean (SD) age was 42.80 (12.91) years. Fifty-eight were allocated to receive TMNMT and 54 to receive TRT. The between-group difference in primary outcome was -6.90 points (95% confidence interval [CI], -13.53 to -0.27) at T1 and -6.17 points (95% CI, -13.04 to 0.71) at T2 . These results closely reached to clinical significance of tinnitus-related effective relief. For the secondary outcome, the mean value in the TMNMT group was 0.83 points (95% CI, 0.12 to 1.54), significantly lower than the mean value of the TRT group. The differences in THI and VAS between the two groups were statistically significant after intervention. Further analysis showed that age and baseline THI and VAS scores were associated with change in THI and VAS scores after interventions. CONCLUSIONS: Both TMNMT and TRT were able to alleviate chronic subjective tinnitus effectively after a 3 month intervention. When the two forms of therapy were compared TMNMT appeared to be more effective and consequently potentially superior to TRT for reducing tinnitus loudness and functional and emotional disturbance associated with chronic subjective tinnitus.

CO2 transoral laser microsurgery for early glottic carcinoma with anterior commissure involvement.

OBJECTIVE: Anterior commissure (AC) involvement is an unfavorable factor for transoral laser microsurgery (TLM) treatment of early glottic carcinoma (EGC). This study aimed to evaluate the therapeutic efficacy of TLM treatment for EGC with AC involvement. METHODS: From 2008 to 2017, 177 patients with T1-T2 EGC with AC involvement were retrospectively included and divided into the TLM group (n=115) receiving CO2 laser TLM and the control group undergoing open surgery (n=62). The survival outcomes, postoperative complications, laryngeal preservation rate, recurrence and the phonological results were compared between groups. RESULT: The TLM group had significantly reduced hospital stay, hospitalization costs, and intraoperative blood loss as compared with the control group. The tracheotomy rate was significantly higher in the control group (96.8% vs. 0%). The 5-year overall survival (OS) was 89.6% and 85.5% in the TLM group and control group, respectively. Log-rank test showed no difference in survival rate between the two groups. There was no significant difference in laryngeal preservation rate and overall recurrence rate between groups. In postoperative vocal function evaluation, there were significant differences in the overall grade (G), the roughness (R), the breathiness (B), Voice Handicap Index-10 (VHI-10), Jitter, Shimmer, noise/harmonic ratio (NHR), maximum phonation time (MPT), phonation threshold pressure (PTP) between the two groups. CONCLUSION: For EGC with AC involvement, TLM has similar survival outcomes with the open surgery, but has better postoperative voice outcomes. Meanwhile, TLM can effectively reduce intraoperative blood loss, hospitalization time, hospitalization costs and postoperative complications.

A deep learning approach to the diagnosis of atelectasis and attic retraction pocket in otitis media with effusion using otoscopic images.

BACKGROUND: This study aimed to develop and validate a deep learning (DL) model to identify atelectasis and attic retraction pocket in cases of otitis media with effusion (OME) using multi-center otoscopic images. METHOD: A total of 6393 OME otoscopic images from three centers were used to develop and validate a DL model for detecting atelectasis and attic retraction pocket. A threefold random cross-validation procedure was adopted to divide the dataset into training validation sets on a patient level. A team of otologists was assigned to diagnose and characterize atelectasis and attic retraction pocket in otoscopic images. Receiver operating characteristic (ROC) curves, including area under the ROC curve (AUC), accuracy, sensitivity, and specificity were used to assess the performance of the DL model. Class Activation Mapping (CAM) illustrated the discriminative regions in the otoscopic images. RESULTS: Among all OME otoscopic images, 3564 (55.74%) were identified with attic retraction pocket, and 2460 (38.48%) with atelectasis. The diagnostic DL model of attic retraction pocket and atelectasis achieved a threefold cross-validation accuracy of 89% and 79%, AUC of 0.89 and 0.87, a sensitivity of 0.93 and 0.71, and a specificity of 0.62 and 0.84, respectively. Larger and deeper cases of atelectasis and attic retraction pocket showed greater weight, based on the red color depicted in the heat map of CAM. CONCLUSION: The DL algorithm could be employed to identify atelectasis and attic retraction pocket in otoscopic images of OME, and as a tool to assist in the accurate diagnosis of OME.

Glucose Supply Induces PsMYB2-Mediated Anthocyanin Accumulation in Paeonia suffruticosa 'Tai Yang' Cut Flower.

Tree peony (Paeonia suffruticosa) is a well-known Chinese ornamental plant with showy flower color. However, the color fading problem during vase time seriously blocks its development in the cut flower market. In this study, we found that exogenous glucose supply improved the color quality of P. suffruticosa 'Tai Yang' cut flowers with increased total soluble sugar and anthocyanin contents of petals. Besides, the promotion effect of glucose was better than the osmotic control of 3-O-methylglucose (3OMG) treatment and the glucose analog mannose treatment. The structural genes, including PsF3H, PsF3'H, PsDFR, PsAOMT, and PsUF5GT, were remarkably upregulated under glucose treatment. Meanwhile, the regulatory genes, including PsbHLH1, PsbHLH3, PsMYB2, PsWD40-1, and PsWD40-2, also showed a strong response to glucose treatment. Among these five regulatory genes, PsMYB2 showed less response to 3OMG treatment but was highly expressed under glucose and mannose treatments, indicating that PsMYB2 may have an important role in the glucose signal pathway. Ectopic overexpression of PsMYB2 in Nicotiana tabacum resulted in a strong pigmentation in petals and stamens of tobacco flowers accompanied with multiple anthocyanin biosynthetic genes upregulated. More importantly, the overexpression of PsMYB2 enhanced the ability of glucose-induced anthocyanin accumulation in Arabidopsis thaliana seedlings since PsMYB2-overexpressing Arabidopsis showed higher expression levels of AtPAL1, AtCHS, AtF3H, AtF3'H, AtDFR, and AtLDOX than those of wild type under glucose treatment. In summary, we suggested that glucose supply promoted petal coloration of P. suffruticosa 'Tai Yang' cut flower through the signal pathway, and PsMYB2 was a key component in this process. Our research made a further understanding of the mechanism that glucose-induced anthocyanin biosynthesis of P. suffruticosa cut flowers during postharvest development, laying a foundation for color retention technology development of cut flowers.

Predictive Value of Laryngeal Mucosa Pepsin in Therapeutic Response of Laryngopharyngeal Reflux.

OBJECTIVES/HYPOTHESIS: To investigate the predictive capability of pepsin level in the laryngeal mucosa to the therapeutic effect of proton-pump inhibitors in patients with suspected laryngopharyngeal reflux (LPR), so as to verify whether it can be referred to as a biomarker of LPR. STUDY DESIGN: Prospective case study. METHODS: Sixty patients with clinical empiric LPR were enrolled, with an reflux symptom index (RSI) ≥ 13 and an reflux finding score (RFS) > 7 as screening criteria. Biopsy specimens from the interarytenoid mucosa were obtained under topical anesthesia for pepsin immunohistochemical staining. Two parameters were observed in these patients with different pepsin levels after the administration of esomeprazole for 12 weeks: the RSI and the RFS. RESULTS: Among the 60 cases, 35 cases were negative or weakly positive for pepsin (Pepsin(-) group), and 25 cases were moderately positive or strongly positive for pepsin (Pepsin(+) group). After therapy, the RSI significantly decreased from 17.00 (15.00, 19.00) to 6.00 (5.00, 11.00) in the Pepsin(+) group (Z = -4.38, P < 0.01), but no difference was found in the RFS (T = 1.48, P > 0.05). No significant difference was observed in the RSI (T = 2.01, P > 0.05) or the RFS (T = 2.01, P > 0.05) in the Pepsin(-) group either before or after therapy. An improvement in the RSI ≥ 50% was taken as the standard of effective therapy. The effective rate in the Pepsin(+) group was 72.0% (18/25), while it was 14.3% (5/35) in the Pepsin(-) group. There was a significant difference in the effective rate between the two groups (χ2 = 20.55, P < 0.01). CONCLUSIONS: Proton-pump inhibitors exhibited better effects in patients with higher pepsin levels in the laryngeal mucosa. Laryngeal mucosa pepsin may serve as an ideal indicator to screen patients suitable for proton-pump inhibitor therapy and a reliable biomarker to identify patients with LPR.

A Deep Learning Approach to Predict Conductive Hearing Loss in Patients With Otitis Media With Effusion Using Otoscopic Images.

Importance: Otitis media with effusion (OME) is one of the most common causes of acquired conductive hearing loss (CHL). Persistent hearing loss is associated with poor childhood speech and language development and other adverse consequence. However, to obtain accurate and reliable hearing thresholds largely requires a high degree of cooperation from the patients. Objective: To predict CHL from otoscopic images using deep learning (DL) techniques and a logistic regression model based on tympanic membrane features. Design, Setting, and Participants: A retrospective diagnostic/prognostic study was conducted using 2790 otoscopic images obtained from multiple centers between January 2015 and November 2020. Participants were aged between 4 and 89 years. Of 1239 participants, there were 209 ears from children and adolescents (aged 4-18 years [16.87%]), 804 ears from adults (aged 18-60 years [64.89%]), and 226 ears from older people (aged >60 years, [18.24%]). Overall, 679 ears (54.8%) were from men. The 2790 otoscopic images were randomly assigned into a training set (2232 [80%]), and validation set (558 [20%]). The DL model was developed to predict an average air-bone gap greater than 10 dB. A logistic regression model was also developed based on otoscopic features. Main Outcomes and Measures: The performance of the DL model in predicting CHL was measured using the area under the receiver operating curve (AUC), accuracy, and F1 score (a measure of the quality of a classifier, which is the harmonic mean of precision and recall; a higher F1 score means better performance). In addition, these evaluation parameters were compared to results obtained from the logistic regression model and predictions made by three otologists. Results: The performance of the DL model in predicting CHL showed the AUC of 0.74, accuracy of 81%, and F1 score of 0.89. This was better than the results from the logistic regression model (ie, AUC of 0.60, accuracy of 76%, and F1 score of 0.82), and much improved on the performance of the 3 otologists; accuracy of 16%, 30%, 39%, and F1 scores of 0.09, 0.18, and 0.25, respectively. Furthermore, the DL model took 2.5 seconds to predict from 205 otoscopic images, whereas the 3 otologists spent 633 seconds, 645 seconds, and 692 seconds, respectively. Conclusions and Relevance: The model in this diagnostic/prognostic study provided greater accuracy in prediction of CHL in ears with OME than those obtained from the logistic regression model and otologists. This indicates great potential for the use of artificial intelligence tools to facilitate CHL evaluation when CHL is unable to be measured.

[Application of combined ossicular replacement prosthesis and total ossicular replacement prosthesis of type â ¢ tympanoplasty].

Objective:This study investigated the application of combined ossicular replacement prosthesis（The Kurz Omega Connector+TORP） in type Ⅲ tympanoplasty, and compared the surgical effect with traditional TORP. Methods:Twenty patients with unilateral chronic suppurative otitis media diagnosed in the Department of Otorhinolaryngology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University from January 2019 to June 2020 were included in this study.All the patients were treated with intra-auricular incision with a microscopic approach（tympanic exploration, lesion clearance+type Ⅲ tympanoplasty）. According to the placement of different types of ossicular replacement prosthesis in the ossicular chain reconstruction of type Ⅲ tympanoplasty, the patients were divided into two groups: the traditional TORP group（n=10） and the combined ossicular replacement prosthesis（The Kurz Omega Connector+TORP） group（n=10）. All patients underwent pure tone audiometry before and 1 year after the operation, and the average hearing threshold and air-bone conduction difference（ABG） were compared between the two groups before and after the operation. Results:The reconstruction of the ossicular chain was completed successfully in all patients. Endoscopic examination showed that the epithelialization of the operative cavity was good and the repair of the tympanic membrane recovered well one month after the operation. There was no significant difference in preoperative mean airway threshold between the combined ossicular replacement prosthesis and the traditional TORP group （74.13[41.50，80.50] dB vs 74.25[44.81，82.50] dB, P>0.05）, there was no significant difference in preoperative ABG （55.63[21.50，61.25] dB vs 54.13[23.63，60.38] dB, P>0.05）. After the operation, the ABG of the combined auriculus group was significantly lower than that of the traditional operation group （12.00[5.75，24.56] dB vs 34.88[14.19，46.44] dB, P<0.05）. Conclusion: The combined ossicular replacement prosthesis（The Kurz Omega Connector+TORP） can increase the stability of hearing reconstruction and improve hearing in type Ⅲ tympanoplasty.

[Clinical analysis of 32 cases of facial nerve schwannomas].

Objective:To elucidate the clinical characteristics, surgical strategy, facial nerve repair methods and outcomes of facial nerve schwannomas（FNS）. Methods:The clinical data of patients with FNS treated between January 2010 and December 2018 at Sun Yat-sen Memorial Hospital of Sun Yat-sen University were retrospectively collected, including the sidedness of FNS, clinical manifestations, imaging data, the extent of tumor, clinical management, preoperative and postoperative facial nerve function. Results:The major clinical manifestations of the 32 patients with FNS were facial palsy（27, 84.4%）, hearing loss（27, 84.4%）, tinnitus（22, 68.8%）, ear mass（15, 46.9%）, and stuffy feeling in the ear（13, 40.6%） respectively. Thirty patients were preoperatively diagnosed with FNS and 2 patients were misdiagnosed. 31 patients underwent resection of FNS, except one patient who was selected for long-term follow-up observation. The choice of surgical approach was based on the location, extent and auditory function of the FNS involved as well as the patient's wishes. The surgical approach was decided based on the location and extent of the tumor: 9 patients were operated via the inferior temporal fossa type A（Fisch A） approach; 8 patients were operated via the mastoid approach; 7 patients were operated via the enlarged mastoid approach; 3 patients were operated via the combined mastoid-cranial middle fossa approach; 1 patient was operated via the cranial middle fossa approach; 3 patients were operated via the combined Fisch A-cranial middle fossa approach. 28 patients（87.5%） had FNS with multiple segments of facial nerve involved. The most involved segment was the vertical segment of the facial nerve（26, 81.3%）. 15 patients underwent facial nerve repair simultaneously, including 7 cases of auricular nerve-facial nerve graft and 8 cases of facial nerve-sublingual nerve anastomosis. 4 cases had improved facial nerve function after auricular nerve-facial nerve graft and 2 cases had improved function after facial nerve-sublingual nerve anastomosis. Among patients who underwent facial nerve repair,the best outcome was H-B Ⅲ. Conclusion:The patients with FNS mainly presented with facial palsy and hearing loss. Temporal bone CT and cranial MR plain & enhanced scan served well to confirm the diagnosis. The improvement rate of postoperative facial nerve function was significantly higher in patients who underwent nerve repair than in those who did not. Hence, facial nerve repair should be considered. Compared with facial nerve-sublingual nerve anastomosis, auricular major nerve-facial nerve graft might be a better choice for improving postoperative facial nerve function.

LncRNA HOXC-AS1 promotes nasopharyngeal carcinoma (NPC) progression by sponging miR-4651 and subsequently upregulating FOXO6.

The incidence rate of nasopharyngeal carcinoma (NPC) is the highest among the malignant tumors of otorhinolaryngology, posing a huge burden to public health. Long noncoding RNAs (lncRNAs) exert an important role in tumorigenesis and the progression of various cancers. The present study found that HOXC-AS1 was highly expressed in NPC and in NPC cell lines, suggesting a critical role of HOXC-AS1 in NPC progression. In addition, the abundance of HOXC-AS1 was negatively correlated with the prognosis of NPC. To molecularly dissect the mechanism of HOXC-AS1 in NPC progression, we knocked down the expression of HOXC-AS1 in HNE1 and C666-1 cells. Then, we employed CCK8, colony-formation experiment and Transwell to investigate how the cell performed when HOXC-AS1 was knocked down. It could be observed that HOXC-AS1 knockdown decreases cell proliferation, migration and invasion, but induces cell apoptosis in NPC. We found that HOXC-AS1 could sponge miR-4651 subsequently binding FOXO6 and inhibiting its expression. Therefore, HOXC-AS1/miR-4651/FOXO6 may form a competing endogenous RNA (ceRNA) network that promotes NPC progression. In conclusion, our study demonstrates that HOXC-AS1 promotes NPC progression by sponging miR-4651 and regulating FOXO6 expression, thus providing potential pharmaceutical targets for developing new NPC treatments.

MicroRNA-29a promotes the proliferation of human nasal epithelial cells and inhibits their apoptosis and promotes the development of allergic rhinitis by down-regulating FOS expression.

OBJECTIVE: To explore the regulation of microRNA-29a (miR-29a) on FOS in human nasal epithelial cells and its molecular mechanism, as well as the effects of miR-29a on the cell proliferation and apoptosis. METHODS: By cell transfection, gene silencing, quantitative real-time polymerase chain reaction (qRT-PCR), flow cytometry and TUNEL assay (for cell apoptosis), CCK-8 assay (for cell proliferation), dual-luciferase reporter gene assay and Western Blot, it was validated that miR-29a promoted the proliferation of human nasal epithelial cells and inhibited their apoptosis by down-regulating FOS expression in RPMI2650 and HNEpC cell lines. RESULTS: ①Compared with healthy controls, miR-29a expression was up-regulated and FOS mRNA expression was down-regulated in the nasal tissues from the patients with allergic rhinitis (AR). ②MiR-29a over-expression promoted the proliferation of RPMI2650 cells and HNEpC cells but inhibited their apoptosis. ③MiR-29a targeted at FOS. ④MiR-29a over-expression and FOS silencing both significantly promoted cell proliferation and inhibited cell apoptosis. After transfection with both miR-29a and FOS, there was a decrease in the proliferation but an increase in the apoptosis of cells.⑤MiR-29a promoted the proliferation of human nasal epithelial cells and inhibited their apoptosis by down-regulating FOS expression. CONCLUSION: MiR-29a-/FOS axis can be regarded as a potential marker and a new therapy for AR.

Autophagy-dependent ferroptosis contributes to cisplatin-induced hearing loss.

Cisplatin-induced hearing loss is a common side effect of cisplatin chemotherapy, for which clinical therapy remains unavailable. Apoptosis of hair cells is considered the primary cause of cisplatin-induced ototoxicity; however, inhibiting apoptosis can only partially restore cisplatin-induced hearing loss. Therefore, auditory cell death caused by cisplatin damage requires further study. Ferroptosis, a novel form of regulated cell death, has been shown to play a role in the mechanism of cisplatin toxicity. In this study, we observed proferroptotic alterations (lipid peroxidation and impaired antioxidant capacity) in the cochleae of C57BL/6 mice after cisplatin damage, verifying the induction of ferroptosis. Using the HEI-OC1 cell line, we observed that cisplatin induced proferroptotic alterations and activated ferritinophagy (specific autophagy pathway). Employing chloroquine, we confirmed that the blockage of autophagy remarkably alleviated cisplatin-induced ferroptosis in HEI-OC1 cells; therefore, the induction of ferroptosis in cisplatin-treated auditory cells was dependent on the activation of autophagy. In addition, the ferroptosis inhibitor ferrostatin-1 and iron chelator deferoxamine significantly attenuated cisplatin-induced cytotoxicity in HEI-OC1 cells and cochlear explants. Moreover, pharmacologically inhibiting ferroptosis using ferrostatin-1 significantly decreased the auditory cell loss and, notably, attenuated hearing loss in C57BL/6 mice after cisplatin damage. Collectively, these findings indicate that autophagy-dependent ferroptosis plays an integrated role in the mechanism of cisplatin-induced hearing loss.

Development and validation of a novel ferroptosis-related gene signature for predicting prognosis and immune microenvironment in head and neck squamous cell carcinoma.

Ferroptosis plays an important role across variable cancer types. However, few studies have focused on the prognostic patterns of ferroptosis-related genes in HNSCC. Cohorts with mRNA expression profiles, as well as corresponding clinical data of HNSCC patients from published studies, were collected and consolidated from public databases. We performed random survival forest analysis, Kaplan-Meier (KM) analysis of best combinations, and Cox regression analysis on 231 ferroptosis-related genes to construct a gene signature in the discovery cohort (TCGA), and later validated it in the validation cohort (GEO). The 7-gene signature was constructed to stratify patients into two groups according to their level of risk. Poorer overall survival (OS) was detected in the high risk (HRisk) group than in the low risk (LRisk) group in both the TCGA cohort (P < 0.0001, HR = 1.71, 95%CI:1.41-2.07) and the GEO cohort (P < 0.001, HR = 1.68, 95%CI:1.32-2.13). The risk score was identified as an independent predictive factor of OS in multivariate Cox regression analyses (HR > 1, P < 0.0001) in both cohorts. The signature's predictive capacity was proven by the time-dependent receiver operating characteristic (ROC) curve analysis and nomogram analysis. Functional enrichment analysis revealed that immunosuppressive pathways such as matrix extracellular space, and (transforming growth factor-ß)TGF-ß were enriched. The HRisk group was strongly associated with upregulation of both cancer-related pathways and stromal scores, while higher proportions of anti-tumor immune cells and immune signatures were enriched in the LRisk group. In conclusion, the signature based on 7 ferroptosis-related genes could be applicable for predicting the prognosis of HNSCC, indicating that ferroptosis may be a potential therapeutic target for HNSCC.

Modulation of NAD+ biosynthesis activates SIRT1 and resists cisplatin-induced ototoxicity.

Cisplatin, the most widely used platinum-based anticancer drug, often causes progressive and irreversible sensorineural hearing loss in cancer patients. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. Nicotinamide adenine dinucleotide (NAD+), a co-substrate for the sirtuin family and PARPs, has emerged as a potent therapeutic molecular target in various diseases. In our investigates, we observed that NAD+ level was changed in the cochlear explants of mice treated with cisplatin. Supplementation of a specific inhibitor (TES-1025) of α-amino-ß-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), a rate-limiting enzyme of NAD+de novo synthesis pathway, promoted SIRT1 activity, increased mtDNA contents and enhanced AMPK expression, thus significantly reducing hair cells loss and deformation. The protection was blocked by EX527, a specific SIRT1 inhibitor. Meanwhile, the use of NMN, a precursor of NAD+ salvage synthesis pathway, had shown beneficial effect on hair cell under cisplatin administration, effectively suppressing PARP1. In vivo experiments confirmed the hair cell protection of NAD+ modulators in cisplatin treated mice and zebrafish. In conclusion, we demonstrated that modulation of NAD+ biosynthesis via the de novo synthesis pathway and the salvage synthesis pathway could both prevent ototoxicity of cisplatin. These results suggested that direct modulation of cellular NAD+ levels could be a promising therapeutic approach for protection of hearing from cisplatin-induced ototoxicity.