[Effect of endoscopic surgery combined with chemotherapy and radiotherapy on prognosis of early nasopharyngeal carcinoma patients in high incidence area].

Objective:To investigate the differences in the therapeutic effects of endoscopic surgery combined with chemotherapy and endoscopic surgery combined with radiotherapy in the treatment of early nasopharyngeal carcinoma, and to select individualized treatment strategy for early nasopharyngeal carcinoma. Methods:The clinical data of 68 patients with early nasopharyngeal carcinoma（T1-2N0M0） who received surgical treatment in a high-incidence area were retrospectively analyzed. According to different treatment methods, they were divided into the surgery + chemotherapy group（n=34, treated with endoscopic surgery combined with chemotherapy） and the surgery + radiotherapy group（n=34, treated with endoscopic surgery combined with radiotherapy）. Propensity score matching was used to match the patient data between the two groups at a 1∶1 ratio. Patients were followed up, and the survival rates and hematological toxicities were compared between the two groups. Results:Twenty-four cases in the surgery + chemotherapy group and 24 cases in the surgery + radiotherapy group were successfully matched. After matching, there was no statistically significant difference in T stage, and clinical stage between the two groups（all P>0.05）. The 3-year OS and DFS in the surgery + chemotherapy group were 100.0% and 95.8%, respectively, while the 3-year OS and DFS in the surgery + radiotherapy group were 100.0% and 100.0%, respectively, with no significant difference in survival rates between the two groups（both P>0.05）. After treatment, there was no statistically significant difference in bone marrow suppression between the surgery + chemotherapy group and the surgery + radiotherapy group （all P> 0.05） Conclusion:Endoscopic surgery combined with chemotherapy and surgery combined with radiotherapy have comparable clinical efficacy in the treatment of early nasopharyngeal carcinoma, but without radiotherapy-related complications, which is worth further investigation.

E3 ubiquitin ligase NEDD4L inhibits epithelial-mesenchymal transition by suppressing the ß-catenin/HIF-1α positive feedback loop in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyp (CRSwNP) is a refractory inflammatory disease with epithelial-mesenchymal transition (EMT) as one of the key features. Since ubiquitin modification has been shown to regulate the EMT process in other diseases, targeting ubiquitin ligases may be a potential strategy for the treatment of CRSwNP. In this study we investigated whether certain E3 ubiquitin ligases could regulate the EMT process in CRSwNP, and whether these regulations could be the potential drug targets as well as the underlying mechanisms. After screening the potential drug target by bioinformatic analyses, the expression levels of three potential E3 ubiquitin ligases were compared among the control, eosinophilic nasal polyp (ENP) and non-eosinophilic nasal polyp (NENP) group in clinical samples, and the significant decrement of the expression level of NEDD4L was found. Then, IP-MS, bioinformatics and immunohistochemistry studies suggested that low NEDD4L expression may be associated with the EMT process. In human nasal epithelial cells (hNECs) and human nasal epithelial cell line RPMI 2650, knockdown of NEDD4L promoted EMT, while upregulating NEDD4L reversed this effect, suggesting that NEDD4L inhibited EMT in nasal epithelial cells. IP-MS and Co-IP studies revealed that NEDD4L mediated the degradation of DDR1. We demonstrated that NEDD4L inhibited the ß-catenin/HIF-1α positive feedback loop either directly (degrading ß-catenin and HIF-1α) or indirectly (mediating DDR1 degradation). These results were confirmed in a murine NP model in vivo. This study for the first time reveals the regulatory role of ubiquitin in the EMT process of nasal epithelial cells, and identifies a novel drug target NEDD4L, which has promising efficacy against both ENP and NENP by suppressing ß-catenin/HIF-1α positive feedback loop.

The causal relationship between multiple autoimmune diseases and nasal polyps.

Background: Although previous sporadic studies have reported the associations between a few autoimmune diseases and nasal polyps, these studies have limitations such as conflicting results, small sample sizes, and low levels of evidence. Methods: Several autoimmune diseases were selected as exposures while the nasal polyps were selected as outcomes. Bidirectional univariable Mendelian randomization and multivariable Mendelian randomization analyses were performed after rigorous screening of instrumental variables. Then mediation analyses were conducted to further investigate the underlying mechanisms. Results: For the first time, we investigated the causal relationships between nine autoimmune diseases and nasal polyps in different genders and found: (1) there was a causal association between adult-onset Still's disease and nasal polyps; (2) sarcoidosis, ulcerative colitis, type 1 diabetes, and Crohn's disease had no significant associations with nasal polyps; (3) celiac disease showed a suggestive positive association with female nasal polyps, whereas juvenile arthritis and multiple sclerosis showed suggestive positive associations with male nasal polyps. By contrast, arthropathic psoriasis showed a suggestive negative association with nasal polyps. In addition to these nine diseases, previous controversial issues were further investigated: (1) there was a causal relationship between rheumatoid arthritis and nasal polyps, which was partially mediated by "BAFF-R for IgD+ B cells"; (2) ankylosing spondylitis showed suggestive positive associations with the female but not the male nasal polyps. Besides, we validated that there was no causal effect of autoimmune hyperthyroidism on nasal polyps. Conclusion: Specific conclusions regarding the causal effects of multiple autoimmune diseases on nasal polyps are the same as above. By comparing results between different genders, we have initially observed the sex bimodality in the causal effects between autoimmune diseases and nasal polyps, with those on male nasal polyps being stronger than those on female nasal polyps. Our study lays a solid foundation for further research in the future, not only helping identify individuals susceptible to nasal polyps early but also improving our understanding of the immunopathogenesis of these heterogeneous diseases.

Diagnostic value of myeloperoxidase and eosinophil cationic protein in nasal secretions for endotypes of chronic rhinosinusitis.

OBJECTIVES: To explore associations between inflammatory endotypes and clinical presentations in CRS. To investigate the value of secretions myeloperoxidase (MPO) and eosinophilic cationic protein (ECP) detections in the diagnosis of endotypes of chronic rhinosinusitis (CRS), so as to provide guidance for the clinical application of MPO and ECP detection in secretions. METHODS: We collected clinical symptom scores from patients with CRS and examined the differences between endotypes in clinical features. Patients' nasal secretions and polyps (or middle turbinate for control) were collected and their NEU number, EOS%, MPO and ECP levels were measured. Correlation analysis was performed for these biomarkers in secretions and tissues, respectively. Receiver operating characteristic curves were used to assess the predictive potential of the biomarkers mentioned above in nasal secretions. RESULTS: Patients with Eos+Neu+ and Eos+Neu-CRS scored highest in most clinical symptom scores, while Eos-Neu+ and Eos-Neu-CRS scored lowest. Correlation analysis showed that tissues NEU number was correlated with NEU number and MPO level in nasal secretions (R = 0.4088; 0.6613); tissues EOS % was correlated with EOS% and ECP level in nasal secretions (R = 0.2344; 0.5774). To diagnose Neu+CRS, the highest area under the curve (AUC) (0.8961) was determined for MPO in secretions; the highest AUC (0.7400) was determined for NEU number in secretions. To diagnose Eos+Neu-CRS from Eos-Neu-CRS in Neu-CRS, the highest AUC (0.8801) was determined for ECP in secretions. CONCLUSIONS: Clinical presentations are directly associated with CRS endotypes. Measurement of MPO and ECP in nasal secretions is useful for the endotypes diagnosis of CRS.

Mapping the knowledge structure and emerging trends of efferocytosis research: a bibliometric analysis.

BACKGROUND: Efferocytosis refers to the physiological clearance process of apoptotic cells by specialized and non-phagocytes and it is essential in human health and disease. However, there is a lack of comprehensive and objective reports on the current status of efferocytosis research. Here, we visually analyzed the hotspots and trending issues of efferocytosis research with bibliometric analysis. METHODS: Relevant publications were obtained from the Web of Science Core Collection on February 18, 2022. We performed bibliometric and visual analysis using CiteSpace, VOSviewer, Microsoft Excel 2019, and the online Bibliometric platform. RESULTS: A total of 1007 publications on efferocytosis were retrieved. The number of efferocytosis studies increased rapidly from 2006 to 2021. The country that published the most efferocytosis related articles was the USA and the most productive institutions were Harvard University and Brigham and Women's Hospital. The most prolific and influential author was I. Tabas of Columbia University. Frontiers in Immunology published the most research papers on efferocytosis, the while Journal of Immunology had the highest co-citation frequency. The high-frequency keywords were "efferocytosis", "inflammation", "apoptotic cells", "macrophages", and "apoptosis". The analysis of keywords with the strongest citation bursts identified "cell" and "resolution" as emerging hotspots. CONCLUSION: Our results demonstrated that efferocytosis research increased steadily within the past decade. Current efferocytosis studies focus on three main aspects: mechanisms, basic biology, and potential role in disease. The research trends included the cellular players of the efferocytosis process and the role of efferocytosis in inflammation resolution. This bibliometric analysis presented a comprehensive overview of efferocytosis research and provided valuable references and ideas for scholars interested in this field.

Development, Validation and Comparison of Artificial Neural Network and Logistic Regression Models Predicting Eosinophilic Chronic Rhinosinusitis With Nasal Polyps.

PURPOSE: Chronic rhinosinusitis with nasal polyps (CRSwNP) can be classified into eosinophilic CRSwNP (eCRSwNP) and non-eosinophilic CRSwNP (non-eCRSwNP) by tissue biopsy, which is difficult to perform preoperatively. Clinical biomarkers have predictive value for the classification of CRSwNP. We aimed to evaluate the application of artificial neural network (ANN) modeling in distinguishing different endotypes of CRSwNP based on clinical biomarkers. METHODS: Clinical parameters were collected from 109 CRSwNP patients, and their predictive ability was analyzed. ANN and logistic regression (LR) models were developed in the training group (72 patients) and further tested in the test group (37 patients). The output variable was the diagnosis of eCRSwNP, defined as tissue eosinophil count > 10 per high-power field. The receiver operating characteristics curve was used to assess model performance. RESULTS: A total of 15 clinical features from 60 healthy controls, 60 eCRSwNP and 49 non-eCRSwNP were selected as candidate predictors. Nasal nitric oxide levels, peripheral eosinophil absolute count, total immunoglobulin E, and ratio of bilateral computed tomography scores for the ethmoid sinus and maxillary sinus were identified as important features for modeling. Two ANN models based on 4 and 15 clinical features were developed to predict eCRSwNP, which showed better performance, with the area under the receiver operator characteristics significantly higher than those from the respective LR models (0.976 vs. 0.902, P = 0.048; 0.970 vs. 0.845, P = 0.011). All ANN models had better fits than single variable prediction models (all P < 0.05), and ANN model 1 had the best predictive performance among all models. CONCLUSIONS: Machine learning models assist clinicians in predicting endotypes of nasal polyps before invasive detection. The ANN model has the potential to predict eCRSwNP with high sensitivity and specificity, and is superior to the LR model. ANNs are valuable for optimizing personalized patient management.

Knowledge mapping of the links between the microbiota and allergic diseases: A bibliometric analysis (2002-2021).

Background: In recent decades, dramatic changes in modern environmental exposures and lifestyles have resulted in a steep rise in the prevalence of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis and food allergies. Evidence is mounting that the microbiota plays a crucial role in allergic disorder development and evolution. Therefore, a better understanding of allergic diseases within the context of the microbiota is urgently needed. This work aimed to comprehensively outline general characteristics, research hotspots, evolution routes, and emerging trends in this area. Methods: Relevant publications from January 2002 to December 2021 were obtained from the Web of Science Core Collection on 5 August 2022. Bibliometric and visual analyses were performed using CiteSpace; VOSviewer; an online bibliometric platform; and Microsoft Excel 2019. Results: In total, 2535 documents met the requirements. The annual number of publications has shown rapid growth in the last two decades. The USA, University of California System, and Isolauri E of the University of Turku were the most productive and influential country, institution, and author, respectively. The Journal of Allergy and Clinical Immunology was the most prolific and most cocited journal. High-frequency keywords included "gut microbiota", "asthma", "atopic dermatitis", "children", and "probiotics". Recent studies have focused on "atopic dermatitis", "skin", "asthma", and "probiotics", according to the cocitation analysis of references. Burst detection analysis of keywords showed that "community", "skin microbiome", "microbiome", "Staphylococcus aureus", and "chain fatty acid" were emerging research frontiers, which currently have ongoing bursts. Conclusion: In the last 20 years, studies of the microbiota in allergic diseases have been flourishing, and the themes have been increasing in depth. These findings provide valuable references on the current research hotspots and gaps and development trends in the link between the microbiota and allergic diseases.

Downregulation of deubiquitinating enzyme USP25 promotes the development of allergic rhinitis by enhancing TSLP signaling in the nasal epithelium.

Ubiquitin­specific peptidase 25 (USP25) is a key deubiquitylase belonging to the USP superfamily that is primarily involved in inflammation and the immune response. Thymic stromal lymphopoietin (TSLP) is an epithelial­derived cytokine that is regarded as the master switch that initiates and maintains the type 2 immune response in allergic rhinitis (AR). However, the molecular mechanisms by which USP25 regulates TSLP signaling in the nasal epithelium in AR remain unclear. The present study assessed the protein expression levels of USP25 in the nasal epithelium of patients with AR. Moreover, USP25 knockout (KO) and wild­type (WT) mice were treated with ovalbumin (OVA) to establish a model of AR. The results of western blotting and immunohistochemistry in the present study demonstrated that the protein expression levels of USP25 were significantly decreased in the nasal mucosa of patients with AR and AR mice, whereas the protein expression levels of TSLP were significantly increased. Allergic inflammation was more severe in USP25 KO mice compared with WT mice exposed to OVA, as demonstrated by increased nose scratching and sneezing, increased eosinophil infiltration, goblet cell hyperplasia and enhanced T helper type 2 (Th2) cytokine production. The results of in vitro experiments demonstrated that silencing or overexpression of USP25 decreased or increased TNF receptor­associated factor 3 (TRAF3) protein expression levels, respectively, in human nasal epithelial cells, whereas TSLP protein expression levels were negatively associated with the expression of USP25 and TRAF3. In summary, USP25 downregulation enhanced TSLP signaling in the nasal mucosal epithelium via decreased TRAF3 expression, thereby exacerbating inflammation in AR. Therefore, USP25 may act as a novel therapeutic target in AR.

TIM-4 in macrophages contributes to nasal polyp formation through the TGF-ß1-mediated epithelial to mesenchymal transition in nasal epithelial cells.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is caused by prolonged inflammation of the paranasal sinus mucosa. The epithelial to mesenchymal transition (EMT) is involved in the occurrence and development of CRSwNP. The T-cell immunoglobulin domain and the mucin domain 4 (TIM-4) is closely related to chronic inflammation, but its mechanism in CRSwNP is poorly understood. In our study, we found that TIM-4 was increased in the sinonasal mucosa of CRSwNP patients and, especially, in macrophages. TIM-4 was positively correlated with α-SMA but negatively correlated with E-cadherin in CRS. Moreover, we confirmed that TIM-4 was positively correlated with the clinical parameters of the Lund-Mackay and Lund-Kennedy scores. In the NP mouse model, administration of TIM-4 neutralizing antibody significantly reduced the polypoid lesions and inhibited the EMT process. TIM-4 activation by stimulating with tissue extracts of CRSwNP led to a significant increase of TGF-ß1 expression in macrophages in vitro. Furthermore, coculture of macrophages and human nasal epithelial cells (hNECs) results suggested that the overexpression of TIM-4 in macrophages made a contribution to the EMT process in hNECs. Mechanistically, TIM-4 upregulated TGF-ß1 expression in macrophages via the ROS/p38 MAPK/Egr-1 pathway. In conclusion, TIM-4 contributes to the EMT process and aggravates the development of CRSwNP by facilitating the production of TGF-ß1 in macrophages. Inhibition of TIM-4 expression suppresses nasal polyp formation, which might provide a new therapeutic approach for CRSwNP.

Activation of NLRP3 inflammasome contributes to the inflammatory response to allergic rhinitis via macrophage pyroptosis.

OBJECTIVE: Allergic rhinitis (AR) is a heterogeneous disease and its pathogenesis is still unclear. Growing clinical evidence has thrown light on the key role of NOD-like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation of allergic disease. However, the effect of NLRP3 activation in macrophages for AR has not been elucidated. This study aims to investigate the role of NLRP3 in ovalbumin (OVA)-stimulated bone marrow-derived macrophages (BMDMs) and to confirm the impact of macrophage pyroptosis in allergic rhinitis. METHODS: Nasal inflammation levels were assessed by H&E and dual immunofluorescence staining. BMDMs were cultured and were stimulated with OVA in the presence or absence of MCC950 to further investigate the effect of NLRP3 activation in macrophages. The cell lysates and supernatants were harvested to measure NLRP3 and downstream molecules, as well as cell rupture, and IL-1ß production. Besides, an OVA-exposed AR mouse model was developed, and the histopathology in nasal mucosa, and the relationship between macrophage pyroptosis and local inflammation were detected. The inhibitory role of MCC950 was also evaluated. RESULTS: The present results uncovered that the number of macrophages and NLRP3 expression were increased in the nasal mucosa of AR subjects, and upregulation of macrophage pyroptosis contributed to local allergic inflammation. In addition, the OVA challenge induced NLRP3 inflammasome activation in BMDMs, as evidenced by enhanced expressions of NLRP3-ASC-caspase-1 inflammasome, gasdermin D, production of IL-1ß, and increased macrophage lysis. Furthermore, inhibition of NLRP3 inflammasome attenuated nasal inflammation, accompanied by a reduced number of inflammatory cells and lower levels of IL-1ß and OVA-specific IgE. CONCLUSIONS: Our results indicate that NLRP3 inflammasome played an important role in allergic airway inflammation by activating macrophage's pyroptotic cell death and releasing inflammatory mediators to local tissues. Inhibition of NLRP3 inflammasome-mediated pyroptosis could be a promising therapeutic strategy for ameliorating inflammatory responses in allergic rhinitis.

Characterization of global research hotspots and trends on ten-eleven translocation 2: visualization and bibliometric analysis.

BACKGROUND AND OBJECTIVE: Ten-eleven translocation-2 (TET2) is member of the methylcytosine dioxygenase family and plays important roles in a variety of physiological and pathological processes; however, no bibliometric analysis has been performed to methodically evaluate the scientific research on TET2. Therefore, the aim of this study was to conduct a visual and scientometric analysis of TET2 research and to explore its current landscape, future direction, and research frontiers. METHODS: Publications related to TET2 research were retrieved from the Web of Science Core Collection (WoSCC) from 2009 to 2021. Excel, CiteSpace, and VOSviewer were utilized to perform the bibliometric visualization analysis. RESULTS: A total of 2384 articles were retrieved. The number of publications on TET2 has been steadily increasing from 2009 to 2021. The USA is the top contributor to the topic, with the largest number of publications. Harvard University and the Institut National de la Santé et de la Recherche Médicale were the leading institutions, while Levine RL of Memorial Sloan-Kettering Cancer Center is the most prolific and influential author. In TET2-related publications, the high-frequency keywords were: "tet2", "DNA methylation", "5-hrdroxymethylcytosine", "5-methylcytosine", "mutations", and "acute myeloid-leukemia". Based on keyword bursts, the emerging TET2 research hotspots include "inflammation", "gene expression", "landscape", and "clonal hematopoiesis". CONCLUSION: Research on TET2 is constantly growing and evolving during the last decade. Here, we provide an objective and comprehensive analysis of the global status, research hotspots, and potential trends in the field of TET2 research by using a bibliometric approach. These results will assist researchers in mastering the knowledge structure and guiding the future research directions of TET2.

Activation of Dopamine D2 Receptor Alleviates Neuroinflammation in a Mouse Model of Allergic Rhinitis With Olfactory Dysfunction.

PURPOSE: Allergic rhinitis (AR) is a common otolaryngology disease and one of the clinical causes of olfactory dysfunction (OD). The olfactory bulb serves as a transfer station for olfactory information transmission, and alleviating its neuroinflammation may be expected to improve AR-induced OD. Recent studies have suggested that the dopamine D2 receptor acts as a key target in regulating immune functions and neuroinflammatory reaction. However, the effect of dopamine D2 receptor on AR-induced neuroinflammation is still unknown. METHODS: An AR mouse model with OD induced by ovalbumin were constructed. The buried food pellet test was to evaluate the olfactory function of the mice. Immunofluorescence staining, hematoxylin and eosin staining, enzyme-linked immunosorbent assay and western blotting were also used to investigate the molecular mechanisms underlying the anti-inflammatory effects of the dopamine D2 receptor in AR-induced OD. RESULTS: We found that AR-induced OD has a relationship with inflammatory responses in the olfactory bulb. Nasal administration of quinpirole (Quin, a dopamine D2 receptor agonist, 3 mg/kg) improved olfactory function in mice, inhibited the expression of toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signalings and the levels of tumor necrosis factor-α, interleukin (IL)-1ß and IL-6 in the olfactory bulb. In vitro, Quin (20 µmol/L) inhibited the release of TLR4/NF-κB signalings-dependent inflammatory cytokines in cultured microglia. CONCLUSIONS: Activation of the dopamine D2 receptor inhibits the release of inflammatory cytokines through TLR4/NF-κB signaling in the olfactory bulb microglia, and protects olfactory function.

Neuroprotective effects of dopamine D2 receptor agonist on neuroinflammatory injury in olfactory bulb neurons in vitro and in vivo in a mouse model of allergic rhinitis.

Available evidence indicates that dopamine D2 receptor modulates the neurotoxic effects induced by glutamate. However, neurotoxicity mediated by AMPA-subtype glutamate receptor has rarely been studied in the olfactory bulb. This study mainly explores the neuroprotective effects of dopamine D2 receptor agonist on AMPA receptor-mediated neurotoxicity in the olfactory bulb in a mouse model of allergic rhinitis (AR) with olfactory dysfunction (OD). In our study, we found that AR with OD was closely associated with increased surface expression of the AMPA receptor GluR1, reduced surface expression of GluR2, and apoptosis damage in the olfactory bulb in vivo. Quinpirole (a dopamine D2 receptor agonist) improved olfactory function in mice, ameliorated apoptosis injury in the olfactory bulb but not in the olfactory mucosa, and inhibited the internalization of GluR2-containing AMPA receptor in vitro and in vivo. In addition, phosphorylation plays a crucial role in the regulation of AMPA receptor trafficking. Our results showed that quinpirole reduced the phosphorylation of GluR1 S845 and GluR2 S880 in olfactory bulb neurons in vitro, but it had no obvious effect on GluR1 S831. Therefore, dopamine D2 receptor agonist may inhibit the phosphorylation of GluR1 S845 and GluR2 S880, thereby reducing AMPA receptor-mediated neurotoxicity and alleviating neurotoxic injury to the olfactory bulb caused by AR.

Salicylate Induced GABAAR Internalization by Dopamine D1-Like Receptors Involving Protein Kinase C (PKC) in Spiral Ganglion Neurons.

BACKGROUND Sodium salicylate (SS) induces excitotoxicity of spiral ganglion neurons (SGNs) by inhibiting the response of γ-aminobutyric acid type A receptors (GABAARs). Our previous studies have shown that SS can increase the internalization of GABAARs on SGNs, which involves dopamine D1-like receptors (D1Rs) and related signaling pathways. In this study, we aimed to explore the role of D1Rs and their downstream molecule protein kinase C (PKC) in the process of SS inhibiting GABAARs. MATERIAL AND METHODS The expression of D1Rs and GABARγ2 on rat cochlear SGNs cultured in vitro was tested by immunofluorescence. Then, the SGNs were exposed to SS, D1R agonist (SKF38393), D1R antagonist (SCH23390), clathrin/dynamin-mediated endocytosis inhibitor (dynasore), and PKC inhibitor (Bisindolylmaleimide I). Western blotting and whole-cell patch clamp technique were used to assess the changes of surface and total protein of GABARγ2 and GABA-activated currents. RESULTS Immunofluorescence showed that D1 receptors (DRD1) were expressed on SGNs. Data from western blotting showed that SS promoted the internalization of cell surface GABAARs, and activating D1Rs had the same result. Inhibiting D1Rs and PKC decreased the internalization of GABAARs. Meanwhile, the phosphorylation level of GABAARγ2 S327 affected by PKC was positively correlated with the degree of internalization of GABAARs. Moreover, whole-cell patch clamp recording showed that inhibition of D1Rs or co-inhibition of D1Rs and PKC attenuated the inhibitory effect of SS on GABA-activated currents. CONCLUSIONS D1Rs mediate the GABAAR internalization induced by SS via a PKC-dependent manner and participate in the excitotoxic process of SGNs.

Effects of Surgery Combined with Chemoradiotherapy on Short- and Long-Term Outcomes of Early-Stage Nasopharyngeal Carcinoma.

OBJECTIVE: The efficacy of surgery as the primary treatment modality for nasopharyngeal carcinoma (NPC) is yet to be clarified. Therefore, we aimed to explore the short- and long-term efficacy of surgery for early-stage NPC. METHODS: We retrospectively evaluated 341 patients diagnosed with early-stage NPC between September 2010 and December 2015. Among them, 58 patients underwent endoscopic nasopharyngectomy combined with chemoradiotherapy, whereas 283 patients underwent conventional chemoradiotherapy. The patients who underwent concurrent chemoradiotherapy or radiotherapy alone were matched to patients who underwent surgery in a 1:2 ratio using propensity score matching to analyze the clinical efficacy of each therapeutic modality. The primary endpoint was survival, and the secondary endpoints were tumor regression rate and reduction in Epstein-Barr virus (EBV)-DNA levels. RESULTS: After matching, 156 patients were enrolled (58 patients in the surgery group; 98 patients in the non-surgery group). The baseline data of the matched patients had good inter-group comparability (All P>0.05). The surgery group had significantly higher 5-year overall survival (98.30% vs. 91.70%), disease-free survival (98.30% vs. 81.40%), and recurrence-free survival (100.00% vs. 90.10%) rates than did the non-surgery group (All P<0.05). In total, 0 and 14 patients in the surgery and non-surgery groups, respectively, had residual cancer at the end of treatment (P=0.001). All patients in the surgery group tested negative for EBV-DNA, whereas two patients in the non-surgery group tested positive. The incidence of hematologic toxicity during treatment was similar between the two groups (All P>0.05). Still, the incidence of severe oral mucositis was lower in the surgery group than in the non-surgery group (37.9% vs. 54.08%, P=0.051). CONCLUSION: Surgery can improve the clearance rate of EB virus and reduce tumor residue. Surgery may be a safe and effective treatment for early NPC.

A novel SLC26A4 splicing mutation identified in two deaf Chinese twin sisters with enlarged vestibular aqueducts.

BACKGROUND: Variants in the SLC26A4 gene are correlated with nonsyndromic hearing loss with an enlarged vestibular aqueduct (EVA). This study aimed to identify the genetic causes in a Chinese family with EVA, and the pathogenicity of the detected variants. METHODS: We collected blood samples and clinical data from a pair of deaf twin sisters with EVA and their family members. As controls, a group of 500 normal-hearing people were enrolled in our study. Twenty-one exons and flanking splice sites of the SLC26A4 gene were screened for pathogenic mutations by polymerase chain reaction and bidirectional Sanger sequencing. Minigene assays were used to verify whether the novel SLC26A4 intronic mutation influenced the normal splicing of mRNA. RESULTS: Hearing loss in the twins with EVA was diagnosed using auditory tests and imaging examinations. Two pathogenic mutations, c.919-2A>G and c.1614+5G>A were detected in SLC26A4, the latter of which has not been reported in the literature. The minigene expression in vitro confirmed that c.1614+5G>A could cause aberrant splicing, resulting in skipping over exon 14. CONCLUSIONS: On the SLC26A4 gene, c.1614+5G>A is a pathogenic mutation. This finding enriches the mutational spectrum of the SLC26A4 gene and provides a basis for the genetic diagnosis of EVA.

Neurotoxicity of sodium salicylate to the spiral ganglion neurons: GABAA receptor regulates NMDA receptor by Fyn-dependent phosphorylation.

The purpose of this study was to observe the regulatory effects of GABAA (γ-aminobutyric acid A) receptor on the N-methyl-D-aspartate (NMDA) receptor during excitotoxicity in spiral ganglion neurons in the rat cochlea induced by sodium salicylate (SS). Western blot illustrated SS decreased the expression of NMDA receptor 2B subunit (NR2B) surface protein through affecting GABAA receptor, but the total protein content did not significantly change. Y1472 and S1480 are important phosphorylation sites in NR2B, SS downregulated the Fyn-dependent phosphorylation of Y1472 in a manner not related to the CK2 (Casein Kinase 2) dependent phosphorylation of S1480, thus regulating the surface distribution and internalization of NMDA receptor through GABAA receptor. These results suggest that the modified pattern of dynamic balance between excitation and inhibition by coactivation of the GABAA receptor can attenuate the excitatory NMDA receptor under the action of SS, via inhibiting the Fyn-dependent phosphorylation of Y1472.

Salicylate-Induced Ototoxicity of Spiral Ganglion Neurons: Ca2+/CaMKII-Mediated Interaction Between NMDA Receptor and GABAA Receptor.

Sodium salicylate (SS) is one of the nonsteroidal anti-inflammatory drugs and widely used in clinical practice. Therefore, we aimed to investigate the potential ototoxicity mechanism of sodium salicylate: the influence of Ca2+/calmodulin-dependent protein kinase II (Ca2+/CaMKII) in interaction between NMDA receptors (NMDAR) and GABAA receptors (GABAAR) in rat cochlear spiral ganglion neurons (SGNs). After treatment with SS, NMDA, and an NMDAR inhibitor (APV), the changes of GABAAR ß3 (GABR ß3) mRNA, surface and total protein, and GABAAR currents in SGNs were assessed by quantitative PCR, Western blot, and whole-cell patch clamp. Mechanistically, SS and/or NMDA increased the GABR ß3 mRNA expression, while decreased GABR ß3 surface protein levels and GABAAR-mediated currents. Moreover, application of SS and/or NMDA showed promotion in phosphorylation levels at S383 of GABR ß3. Collectively, Ca2+ chelator (BAPTA) or Ca2+/CaMKII inhibitor (KN-93) reversed the effects of SS and/or NMDA on GABAAR. Therefore, we hypothesize that the interaction between NMDAR and GABAAR is involved in the SGNs damage induced by SS. In addition, the underlying molecular mechanism is related to Ca2+/CaMKII-mediated signaling pathway, which suggests that the interaction between calcium signal-regulated receptors mediates SS ototoxicity.