HSP90B1 regulates autophagy via PI3K/AKT/mTOR signaling, mediating HNSC biological behaviors.

Background: Autophagy, a crucial cellular mechanism, facilitates the degradation and removal of misfolded proteins and impaired organelles. Recent research has increasingly highlighted the intimate connection between autophagy and heat shock proteins (HSPs) in the context of tumor development. However, the specific role and underlying mechanisms of heat shock protein 90 beta family member 1 (HSP90B1) in modulating autophagy within head and neck squamous cell carcinoma (HNSCC) remain elusive. Methods: Quantitative real-time PCR (qRT-PCR), Western blot (WB), immunohistochemistry (IHC) were used to detect the expression in HNSC cell lines and tissues. The relationship between HSP90B1 and clinicopathologic features was explored based on TCGA (The Cancer Genome Atlas) data and IHC results. The biological functions of HSP90B1 were analyzed through in vitro and in vivo models to evaluate proliferation, migration, invasion, and autophagy. The mechanisms of HSP90B1 were studied using bioinformatics and WB. Results: HSP90B1 was upregulated in HNSC cells and tissues. High HSP90B1 levels were associated with T-stage, M-stage, clinical stage, and poor prognosis in HNSC patients. Functionally, HSP90B1 promotes HNSC cell proliferation, migration, invasion and inhibits apoptosis. We discovered that HSP90B1 obstructs autophagy and advances HNSC progression through the PI3K/Akt/mTOR pathway. Conclusion: Our study demonstrates that HSP90B1 is highly expressed in HNSC. Furthermore, HSP90B1 may regulate autophagy through the PI3K/Akt/mTOR pathway, mediating HNSC cell biological behaviors. These provide new insights into potential biomarkers and targets for HNSC therapy.

A nomogram for distinguishing benign and malignant parotid gland tumors using clinical data and preoperative blood markers: development and validation.

PURPOSE: This study aimed to construct and validate a nomogram that incorporated clinical data and preoperative blood markers to differentiate BPGTs from MPGTs more efficiently and at low cost. METHODS: We retrospectively analyzed patients who underwent parotidectomy and histopathological diagnosis at the First Affiliated Hospital of Guangxi Medical University from January 2013 to June 2022. Subjects were randomly divided into training and validation sets with a 7:3 ratio. In the training set, the least absolute shrinkage and selection operator (LASSO) regression analysis was performed to select the most relevant features from 19 variables and built a nomogram using logistic regression. We evaluated the model's performance using receiver-operating characteristic (ROC) curves, calibration curves, clinical decision curve analysis (DCA), and clinical impact curve analysis (CICA). RESULTS: The final sample consisted of 644 patients, of whom 108 (16.77%) had MPGTs. The nomogram included four features: current smoking status, pain/tenderness, peripheral facial paralysis, and lymphocyte-to-monocyte ratio (LMR). The optimal cut-off value for the nomogram was 0.17. The areas under the ROC curves (AUCs) of the nomogram were 0.748 (95% confidence interval [CI] = 0.689-0.807) and 0.754 (95% CI = 0.636-0.872) in the training and validation sets, respectively. The nomogram also showed good calibration, high accuracy, moderate sensitivity, and acceptable specificity in both sets. The DCA and CICA demonstrated that the nomogram had significant net benefits for a wide range of threshold probabilities (0.06-0.88 for the training set; 0.06-0.57 and 0.73-0.95 for the validation set). CONCLUSION: The nomogram based on clinical characteristics and preoperative blood markers was a reliable tool for discriminating BPGTs from MPGTs preoperatively.

Sterol regulatory element binding transcription factor 1 promotes proliferation and migration in head and neck squamous cell carcinoma.

Background: Sterol-regulatory element-binding protein 1 (SREBP1) is a transcription factor involved in lipid metabolism that is encoded by sterol regulatory element binding transcription factor 1(SREBF1). SREBP1 overexpression is associated with the progression of several human tumors; however, the role of SREBP1 in head and neck squamous cell carcinoma (HNSC) remains unclear. Methods: SREBF1 expression in pan-cancer was analyzed using the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data, and the association between SREBF1 expression and clinical characteristics of HNSC patients was examined using the UALCAN database. Enrichment analysis of SREBF1-related genes was performed using the Cluster Profiler R package. TCGA database was used to investigate the relationship between immune cell infiltration and SREBF1 expression. CCK-8, flow cytometry, and wound healing assays were performed to investigate the effect of SREBF1 knockdown on the proliferation and migration of HNSC cells. Results: SREBF1 was significantly upregulated in several tumor tissues, including HNSC, and SREBF1 overexpression was positively correlated with sample type, cancer stage, tumor grade, and lymph node stage in HNSC patients. Gene enrichment analysis revealed that SREBF1 is associated with DNA replication and homologous recombination. SREBF1 upregulation was positively correlated with the infiltration of cytotoxic cells, B cells, T cells, T helper cells, and NK CD56 bright cells in HNSC. Knockdown of SREBF1 inhibited the proliferation and migration of HNSC cells (Hep2 and TU212) and induced apoptosis by downregulating the expression of steroidogenic acute regulatory protein-related lipid transfer 4 (STARD4). Conclusions: SREBF1 may promote HNSC proliferation, migration and inhibit apoptosis by upregulating STARD4 and affecting the level of immune cell infiltration.

Melatonin Suppresses Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes Signaling and Delays the Development of Hearing Loss in the C57BL/6J Presbycusis Mouse Model.

Melatonin supplementation has been shown to delay age-related hearing loss (ARHL) progression. Previously, melatonin was found to inhibit neuronal mitochondrial DNA (mtDNA) release, as well as inhibit cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling, thereby delaying the onset of central nervous system diseases. Therefore, we hypothesized that melatonin may delay the progression of hearing loss in the C57BL/6J presbycusis mouse model by inhibiting cGAS-STING signaling in the auditory pathway. Oral melatonin at 10 mg/kg/d was administered to 3-month-old C57BL/6J mice until 12 months of age. The auditory brainstem response (ABR) threshold was used to assess their hearing ability. By real-time polymerase chain reaction and Western blot analysis, the levels of cytosolic mtDNA, cGAS/STING, and cytokines were examined in the mouse cochlea, inferior colliculus, and auditory cortex. We found that the 12-month-old control mice exhibited significant hearing loss, increased cytosolic mtDNA, increased expression of inflammatory factors TNF-α, IL-6, IFN-ß, Cxcl10, and Ifit3, up-regulated cGAS and STING expression, and enhanced interferon regulatory factor 3 (IRF3) phosphorylation in the C57BL/6J mouse cochlea, inferior colliculus, and auditory cortex. Melatonin treatment significantly improved hearing, decreased cytosolic mtDNA, suppressed the expression of inflammatory cytokines TNF-α, IL-6, IFN-ß, Ifit3, and Cxcl10, down-regulated cGAS and STING expression, and attenuated IRF3 phosphorylation in the C57BL/6J mouse cochlea, inferior colliculus, and auditory cortex. This study suggested that melatonin had a protective effect on auditory function in the C57BL/6J presbycusis mouse model, which may be mediated through reducing mtDNA release, inhibiting the cGAS-STING signaling pathway in the auditory pathway.

Fluid dynamics of the upper airway in pediatric patients with severe laryngomalacia.

Laryngomalacia is the top cause of pediatric laryngeal wheeze. We used computational fluid dynamics to study the inspiratory airflow dynamics in severe pediatric laryngomalacia. Computed tomography was performed on the upper airways of two infants, one with severe laryngomalacia and one with normal airway, and 3D models were reconstructed. ANSYS CFD-POST software was used to simulate airflow in these models to compare the volumetric flow rate, flow velocity, pressure, wall shear, and vortex. The volume flow rate in the laryngomalacia model was significantly reduced compared with the control model. Under inspiratory pressures, the peak flow velocity, pressure, and shear force in the control model appeared at the soft palate stenosis, while that in the laryngomalacia model appeared at the supraglottis stenosis. In both models, the maximum flow velocity and shear force increased with decreasing inspiratory pressure, while the minimum pressure decreased with decreasing inspiratory pressure. In the control model, the airflow vortex appeared anteriorly below the posterior section of the soft palate. In the laryngomalacia model, the vortex appeared anteriorly below the posterior section of the soft palate and anteriorly below the vocal folds. Our methodology provides a new mechanistic understanding of pediatric laryngomalacia.

Primary squamous cell carcinoma of thyroid gland: 11 case reports and a population-based study.

BACKGROUND: Primary squamous cell carcinoma of thyroid gland (PSCCT) is a highly aggressive malignant tumor associated with a poor prognosis. Due to the rare case, there is a knowledge gap on the features of PSCCT. There is limited understanding of the treatment and molecular biology of this tumor. More genomic work and relevant perspective work need to be done. METHODS: We retrospectively reviewed the medical information of patients with PSCCT diagnosed from December 2009 to December 2020 at The First Affiliated Hospital of Guangxi Medical University. In addition, we conducted an electronic search of the paper in CNKI, Wanfang, VIP, PubMed, Embase, Web of Science, and ProQuest databases by recently updated articles. Survival analysis was conducted using the Kaplan-Meier method. RESULTS: There were only 11 patients met the study's inclusion criteria in our institution. The patients ranged in age from 25 to 68 years old and female preponderance (M:F = 1:1.7). The median survival time was 6 months, and 1-year survival rate was 33.3%. Fifty-three patients' individual data from 45 articles were selected for analysis. The median age at diagnosis was 63 years and female preponderance (M:F = 1:2.5). The commonest complaint was the anterior neck mass (77.3%), followed by hoarseness (32.1%). The median survival time was 9 months, and the overall 1-, 2-, and 5-year survival rate was 39.8%, 33.7%, and 26.9%, respectively. The log-rank method shows that age, tumor size, lymph node status, M stage, surgical range, and tracheal status were the relevant factors affecting the prognosis. In contrast, gender, treatment modality, and resection margin were not prognostic factors. On multivariable analysis, age and M stage were associated with overall survival. CONCLUSION: The median overall survival was 6-9 months of PSCCT. Age and M stage are predictors of PSSCT.

lncRNA NR2F2-AS1 inhibits the methylation of miR-494 to regulate oral squamous cell carcinoma cell proliferation.

OBJECTIVE: This study aimed to investigate the role of lncRNA NR2F2-AS1 in oral squamous cell carcinoma cells (OSCC). MATERIALS AND METHODS: The TCGA datasets were used to explore the differential expression of NR2F2-AS1 in OSCC. To further explore the potential interaction between NR2F2-AS1 and miR-494, SCC090 cells were transfected with the NR2F2-AS1 expression vector, NR2F2-AS1 siRNA, and a miR-494 mimic. The effect of NR2F2-AS1 on miR-494 methylation was evaluated by performing methylation-specific PCR (MSP). Cell Counting Kit-8 (CCK-8) assay was used to assess the effects of NR2F2-AS1 silencing and miR-494 and NR2F2-AS1 overexpression on OSCC cell proliferation. RESULTS: NR2F2-AS1 expression was downregulated in OSCC and positively correlated with miR-494 expression. In OSCC cells, NR2F2-AS1 overexpression upregulated miR-494 level, while NR2F2-AS1 silencing decreased miR-494 expression. MSP results showed that NR2F2-AS1 overexpression decreased miR-494 methylation while NR2F2-AS1 silencing increased miR-494 methylation. In addition, NR2F2-AS1 silencing increased OSCC cell proliferation rate while overexpression of miR-494 and NR2F2-AS1 decreased OSCC cell proliferation. Furthermore, miR-494 overexpression attenuated the effects of NR2F2-AS1 silencing on cell proliferation. CONCLUSION: NR2F2-AS1 may inhibit miR-494 methylation to regulate cell proliferation in OSCC. AVAILABILITY OF DATA AND MATERIALS: The analyzed data sets generated during the study are available from the corresponding author upon reasonable request.

Age-related Activation of Cyclic GMP-AMP synthase-Stimulator of Interferon Genes Signaling in the Auditory System is Associated with Presbycusis in C57BL/6J Male Mice.

Presbycusis, or age-related hearing loss (ARHL), is primarily associated with sensory or transduction nerve cell degeneration in the peripheral and/or central auditory systems. During aging, the auditory system shows mitochondrial dysfunction and increased inflammatory responses. Mitochondrial dysfunction promotes leakage of mitochondrial DNA (mtDNA) into the cytosol, which activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway to induce type I interferon and inflammatory responses. However, whether this pathway is involved in the occurrence and development of ARHL is unknown. This study aimed to determine whether there are age-related changes in the levels of cytosolic mtDNA and cGAS-STING pathway activation in the auditory pathway and to explore their relationship with ARHL. The results showed that cGAS-positive immunoreactive cells were observed in the cochlea, inferior colliculus, and auditory cortex. Levels of cytosolic mtDNA, cGAS, STING, phosphorylated interferon regulatory factor 3, and cytokines were significantly increased in the cochlea, inferior colliculus, and auditory cortex of 6-, 9-, and 12-month-old mice compared with 3-month-old mice. These findings suggested that cytosolic mtDNA may play an important role in the pathogenesis of ARHL by activating cGAS-STING-mediated type I interferon and inflammatory responses.

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.

Acylglycerol kinase promotes paclitaxel resistance in nasopharyngeal carcinoma cells by regulating FOXM1 via the JAK2/STAT3 pathway.

OBJECTIVE: Drug resistance is an important factor that impedes the treatment of nasopharyngeal cancer (NPC). Acylglycerol kinase (AGK) has been found to be overexpressed in NPC and correlates with poor prognosis. Our objective was to demonstrate the effect of AGK on paclitaxel resistance in NPC and determine the underlying mechanisms. METHODS: MTT assay was employed to determine the IC50 of paclitaxel in NPC cells after different treatments. Flow cytometry assays were employed to evaluate cell apoptosis. RT-qPCR and Western blot assays were used to detect alterations in mRNA and protein expression, respectively. Luciferase assays and chromatin immunoprecipitation (ChIP) assays were used to determine the relationship between and the regulatory effect of STAT3 on the promoter of FOXM1. RESULTS: AGK was elevated in paclitaxel-resistant NPC cells, and knockdown of AGK suppressed the resistance of CNE1-TR and CNE2-TR cells to paclitaxel. Moreover, upregulation of FOXM1 rescued the effects of AGK knockdown. Furthermore, the JAK2/STAT3 signalling pathway was overactivated in CNE1-TR and CNE2-TR cells, and knockdown of AGK suppressed JAK2/STAT3 signalling. STAT3 was verified to bind to and activate the promoter region of FOXM1. An in vivo tumour xenograft assay also verified that AGK knockdown inhibited tumour growth and mitigated paclitaxel resistance by regulating the JAK2/STAT3/FOXM1 axis. CONCLUSION: AGK levels were increased in paclitaxel-resistant NPC cells. AGK activates JAK2/STAT3 signalling, thus promoting FOXM1 transcription and eventually enhancing the drug resistance of NPC cells.

Malignant meningioma with jugular vein invasion and carotid artery extension: A case report and review of the literature.

BACKGROUND: Grade II and III meningiomas [World Health Organization (WHO) classification] rarely have extracranial metastases via the blood circulation; however, we experienced a case with a metaplastic atypical meningioma and local de-differentiation that metastasized to the jugular vein, carotid artery and subclavian artery at the cervicothoracic junction. Such cases have seldom been reported before. CASE SUMMARY: The patient was a 30-year-old man who developed right neck masses with dysphagia, labored breathing, dizziness, and occasional earaches. Eight months earlier the patient was diagnosed with a right parietal lobe neoplasm and hemorrhage at a local hospital due to the sudden onset of headaches and left limb weakness, and the post-operative pathology was a metaplastic atypical meningioma (WHO grade II) with local de-differentiation (WHO III). Magnetic resonance imaging revealed a calcified mass at the root of the neck on the right and a large cystic mass in the right parapharyngeal space. Head and neck angiography showed that the right common carotid artery was compressed and completely occluded, and the jugular vein was enveloped by the tumor and occluded. A balloon occlusion test showed no perfusion in the right common carotid artery. Tumor resection, carotid artery ligation, and subclavian artery reconstruction were performed. The tumor was a malignant meningioma. Post-operatively, the patient had Horner's syndrome and hoarseness. CONCLUSION: This case highlights the importance of the link between a large cervical mass and a primary intracranial tumor. Malignant meningioma should not be considered merely as an intracranial metastasis spread through cerebrospinal fluid, it can also be transferred through the circulation to the parapharyngeal space and the cervical great vessels.

LncRNA-IUR Sponges miR-24 to Upregulate P53 in Laryngeal Squamous Cell Carcinoma.

OBJECTIVE: The functions of lncRNA-IUR in laryngeal squamous cell carcinoma (LSCC) were investigated in this study. METHODS: RT-qPCR and paired t-test were used to measure and compare expression levels of IUR, miR-24 and p53 in LSCC and non-tumor tissues. Human LSCC cell line UM-SCC-17A was used and transfected by pcDNA3.1 vector to overexpress IUR and miR-24. The transwell assay and wound healing assay illustrated the effect of overexpression of IUR or miR-24 in the cell invasion and migration of LSCC. Subcutaneous tumor model in nude mice was carried out to demonstrate the mechanism between IUR and miR-24 in regulating tumor growth. RESULTS: We found that IUR was downregulated in LSCC. Low expression levels of IUR were correlated with the poor survival of LSCC patients. Overexpression experiments showed that overexpression of IUR led to increased, while overexpression of miR-24 led to decreased expression levels of p53 in LSCC cells. And bioinformatics analysis showed that IUR may sponge miR-24. Cell proliferation assay showed that overexpression of IUR and p53 led to decreased proliferation rate of LSCC cells, while overexpression of miR-24 led to increased proliferation rate of LSCC cells. We also illustrated that overexpression of IUR promoted cell migration and invasion while miR-24 had opposite effects. In addition, subcutaneous tumor model in nude mice showed that overexpression of miR-24 attenuated the effects of overexpression of IUR on the expression of p53 and cancer cell proliferation. CONCLUSION: IUR sponges miR-24 to upregulate p53 in LSCC, thereby inhibiting cancer cell proliferation.

[Analysis of the effect of linear stapler closure pharyngeal after total laryngectomy].

Objective:To compare the effect of closure of pharyngeal cavity with linear stapler and manual suture in total laryngectomy. Method:A retrospective study was conducted on 32 patients who underwent total laryngectomy with linear stapler to close the pharyngeal from December 2014 to March 2019. Among them, 25 patients used closed technique and 7 patients used open technique. At the same time, 23 patients who underwent total laryngectomy with manual suture the pharyngeal by the same operator from January 2010 to December 2014 were collected. The clinical parameters of the two groups were compared and analyzed. Result:Compared with the control group, the closed technical group had no significant difference in terms of gender, diabetes mellitus, second surgery, T stage, and surgical method（P> 0.05）. While the age （63.60 ± 9.46） years and （54.35 ± 11.13） years , operation time （239.67 ± 88.43） min and （474.35 ± 140.16） min , oral feeding time （12.84 ± 3.65） min and （17.3 ± 9.71）min , hospitalization days after operation （ 15.48 ± 3.78） d and （20.22 ± 10.14） d, incidence of Pharygocutaneous fistula 4.0% （1/25） and 26.1% （6/23）, had significant statistical differences （P <0.05） Between two groups; Compared with the control group, the opener group had no statistically significant difference in gender, T stage, oral feeding time, hospitalization days after operation，surgical method and incidence of Pharygocutaneous fistula （P> 0.05），while there was a statistically significant difference in diabetes mellitus, second surgery, and operation time （P<0.05）. Conclusion:The linear stapler closed closure technique can reduce the incidence of Pharygocutaneous fistula, shorten the operation time and oral feeding time, and reduce the length of hospital stay.

MicroRNA-424-5p inhibits the proliferation, migration, and invasion of nasopharyngeal carcinoma cells by decreasing AKT3 expression.

This study examined the expression and potential mechanism of microRNA (miRNA)-424-5p in nasopharyngeal carcinoma (NPC). NPC tissues were collected from 40 patients who were enrolled in the study, and skin samples were collected from 26 healthy subjects during plastic surgery as controls. We performed various in vitro assays using miR-424-5p to examine its function in primary NPC-1 cells. Bioinformatics was employed to analyze potential target genes and signaling pathways of miR-424-5p. We found that miR-424-5p expression in NPC tissues is downregulated and negatively correlated with lymph node metastasis and clinical staging. Expression of miR-424-5p in NPC cells was also downregulated, and transfection with miR-424-5p mimics inhibited proliferation, migration, and invasion of NPC-1 cells. Bioinformatics identified the AKT3 gene as a potential target of miR-424-5p and dual luciferase assays confirmed this finding. Upregulation of AKT3 expression rescued the inhibitory effect of miR-424-5p on the proliferation, migration, and invasion. Our results suggest that miR-424-5p inhibited the proliferation, migration, and invasion of NPC cells by decreasing AKT3 expression.

MicroRNA-424-5p inhibits the proliferation, migration, and invasion of nasopharyngeal carcinoma cells by decreasing AKT3 expression

This study examined the expression and potential mechanism of microRNA (miRNA)-424-5p in nasopharyngeal carcinoma (NPC). NPC tissues were collected from 40 patients who were enrolled in the study, and skin samples were collected from 26 healthy subjects during plastic surgery as controls. We performed various in vitro assays using miR-424-5p to examine its function in primary NPC-1 cells. Bioinformatics was employed to analyze potential target genes and signaling pathways of miR-424-5p. We found that miR-424-5p expression in NPC tissues is downregulated and negatively correlated with lymph node metastasis and clinical staging. Expression of miR-424-5p in NPC cells was also downregulated, and transfection with miR-424-5p mimics inhibited proliferation, migration, and invasion of NPC-1 cells. Bioinformatics identified the AKT3 gene as a potential target of miR-424-5p and dual luciferase assays confirmed this finding. Upregulation of AKT3 expression rescued the inhibitory effect of miR-424-5p on the proliferation, migration, and invasion. Our results suggest that miR-424-5p inhibited the proliferation, migration, and invasion of NPC cells by decreasing AKT3 expression.

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.

Clinical outcomes of residual or recurrent nasopharyngeal carcinoma treated with endoscopic nasopharyngectomy plus chemoradiotherapy or with chemoradiotherapy alone: a retrospective study.

BACKGROUND: Local residual and recurrent nasopharyngeal carcinoma (NPC) generally shows treatment failure after standard radiotherapy with or without concurrent chemotherapy. Whether endoscopic nasopharyngectomy might provide an additional therapeutic advantage remains controversial. Therefore, we retrospectively compared the clinical prognoses of patients with residual or recurrent NPC treated with endoscopic nasopharyngectomy combined with chemoradiotherapy (CRT) with those of patients treated with CRT alone. METHODS AND MATERIALS: A total of sixty-two patients with local residual or recurrent NPC were studied retrospectively: 36 patients received endoscopic nasopharyngectomy combined with CRT, whereas 26 patients who refused the surgery or had surgical contraindications received CRT alone. Serum Epstein-Barr virus (EBV) DNA levels were measured pre- and post-treatment. The differences in prognosis between the two treatment regimens and the pre- and post-treatment changes in EBV-DNA levels were analyzed. RESULTS: The median follow-up time was 31 months, with a 3-year overall survival (OS) of 51.40% and a 3-year disease-free survival (DFS) of 46.86%. The surgery + CRT group had a better OS than the CRT alone group did (χ2 = 4.054, P = 0.044). The pretreatment EBV-DNA levels showed a positive correlation with the clinical staging of recurrent NPC (χ2 = 11.674, P = 0.009). Patients with negative pretreatment serum EBV-DNA levels showed a superior OS to those of patients who tested positive for EBV-DNA (>0 copy/mL) (χ2 = 9.833, P = 0.002). The post-treatment EBV-DNA levels, compared with the pretreatment levels, decreased significantly in the surgery + CRT group (Z =  - 3.484, P = 0.000). In contrast, the EBV-DNA levels after CRT alone did not decrease significantly (Z =  - 1.956, P = 0.051). Multivariate analysis indicated that local staging, pretreatment EBV-DNA load, and the treatment method were independent risk factors for OS. Subgroup analysis indicated that the patients who tested negative for EBV-DNA before the treatment and those who received surgery + CRT showed a better OS than those who received CRT alone. CONCLUSIONS: The pretreatment serum EBV-DNA level was associated with disease prognosis. The combination therapy preceded by surgery can effectively decrease the copy number of EBV-DNA. Patients with local intermediate- and late-stage NPC, especially those negative for EBV-DNA, may consider opting for surgery followed by post-operative adjuvant radiotherapy or chemotherapy.

[A study on toxic effects of sodium salicylate on rat cochlear spiral ganglion neurons: dopamine receptors mediate expressions of NMDA and GABAA receptors].

The aim of the present study was to observe whether dopamine receptor (DR) was involved in the effects of sodium salicylate (SS) on the expressions of N-methyl-D-aspartic acid (NMDA) and γ-aminobutyric acid (GABA) receptors in rat cochlear spiral ganglion neurons (SGNs). Forty-eight hours after primary culture of rat SGNs, immunofluorescence technique was applied to detect expressions of DR1 and DR2, the two subtypes of dopamine receptors. Western blot was performed to assess NMDA receptor NR1 subunit and GABAA receptor subunit α2 (GABRα2) protein expressions in the SGNs after the treatments of SS alone or in combination with DR antagonists. The results demonstrated that: (1) The DR1 and DR2 were expressed in the bodies and axons of the SGN; (2) After the treatment with SS, the surface protein expressions of GABRα2 and NR1 were decreased by 44.69% and 21.57%, respectively, while the total protein expressions showed no significant changes; (3) Neither SS + SCH23390 (DR1 antagonist) group nor SS + Eticlopride (DR2 antagonist) group showed significant differences in GABRα2 and NR1 surface protein expressions compared with the control group. These results suggest that SS regulates the surface GABAA and NMDA receptors trafficking on SGN, and the mechanism may involve DR mediation.

[Interactions between dopamine receptor and NMDA/type A γ-aminobutyric acid receptors].

Type A γ-aminobutyric acid receptors (GABAAR) and N-methyl-D-aspartate receptors (NMDAR) are the major inhibitory and excitatory receptors in the central nervous system, respectively. Co-expression of the receptors in the synapse may lead to functional influence between receptors, namely receptor interaction. The interactions between GABAAR and NMDAR can be either positive or negative. However, the mechanisms of interaction between the two receptors remain poorly understood, and potential mechanisms include (1) through a second messenger; (2) by receptors trafficking; (3) by direct interaction; (4) by a third receptor-mediation. Dopamine is the most abundant catecholamine neurotransmitter in the brain, and its receptors, dopamine receptors (DR) can activate multiple signaling pathways. Earlier studies on the interaction between DR and GABAAR/NMDAR have shown some underlying mechanisms, suggesting that DR could mediate the interaction between GABAAR and NMDAR. This paper summarized some recent progresses in the studies of the interaction between DR and NMDAR/GABAAR, providing a further understanding on the interaction between NMDAR and GABAAR mediated by DR.