Multiple Mucosal Ulcers Induced by Ixekizumab: A Case Report.

OBJECTIVES: Ixekizumab, an interleukin (IL)-17A inhibitor, exerts its therapeutic effects in psoriasis by inhibiting the interleukin (IL)-17 signaling pathway. Common adverse reactions to ixekizumab include injection site reactions and upper respiratory tract infections (URIs), while occurrences of inflammatory bowel disease (IBD) and multiple mucosal ulcers are infrequent. We present a case of a 51-year-old man who developed multiple mucosal ulcers after ixekizumab treatment. METHODS: A 51-year-old man presented to our hospital with a 1-month history of pharyngalgia. The flexible laryngoscope displayed mild hyperemia in the pharyngeal mucosa and tonsils, redness and swelling of the epiglottis, as well as multiple ulcers in the oral cavity, uvula, and epiglottis. These ulcers did not improve with conventional treatment. RESULTS: Upon evaluation, the ulcers were an immune-related adverse event induced by ixekizumab. Consequently, a decision was made to discontinue the drug and initiate a therapeutic regimen including corticosteroids and thalidomide. Eventually, the patient's symptoms abated. CONCLUSIONS: Biologics are now becoming increasingly popular in psoriasis. It is vital for clinicians to be aware of this potential adverse event and to identify and intervene early to alleviate patients' suffering.

Challenges in Diagnosing and Treating Subperiosteal Orbital Hematoma Secondary to Sinusitis: A Case.

Subperiosteal orbital hematoma secondary to sinusitis is rare. Thus far, 19 cases of this disease have been reported, of which none involved postoperative skin anesthesia in the region innervated by the supraorbital nerve. In this article, for the first time we report a case of subperiosteal orbital hematoma secondary to sinusitis with skin anesthesia in the area innervated by the supraorbital nerve after surgery.

Associations between neutrophil-to-lymphocyte/platelet-to-lymphocyte and recovery in sudden sensorineural hearing loss.

Aims: This study investigated the nonlinear associations between neutrophil-to-lymphocyte (NLR)/platelet-to-lymphocyte (PLR) and recovery rates in sudden sensorineural hearing loss (SSNHL). Methods: Total of 244 SSNHL patients were included. The primary outcome was recovery rate. Results: A nonlinear association was detected between NLR and recovery rate using the LOWESS method, with a knot of 3. Patients with NLR ≥3 had a higher recovery rate than NLR <3. Using the linear-spline function, NLR was significantly associated with high recovery rate when NLR was <3. However, when NLR was ≥3, this association became nonsignificant. The trend test showed a similar result. PLR was not associated with recovery rate. Conclusion: The association between NLR and recovery rate is nonlinear, with a knot of around three. PLR is not associated with recovery rate.

Molecular subtype identification and prognosis stratification based on golgi apparatus-related genes in head and neck squamous cell carcinoma.

BACKGROUND: Abnormal dynamics of the Golgi apparatus reshape the tumor microenvironment and immune landscape, playing a crucial role in the prognosis and treatment response of cancer. This study aims to investigate the potential role of Golgi apparatus-related genes (GARGs) in the heterogeneity and prognosis of head and neck squamous cell carcinoma (HNSCC). METHODS: Transcriptional data and corresponding clinical information of HNSCC were obtained from public databases for differential expression analysis, consensus clustering, survival analysis, immune infiltration analysis, immune therapy response assessment, gene set enrichment analysis, and drug sensitivity analysis. Multiple machine learning algorithms were employed to construct a prognostic model based on GARGs. A nomogram was used to integrate and visualize the multi-gene model with clinical pathological features. RESULTS: A total of 321 GARGs that were differentially expressed were identified, out of which 69 were associated with the prognosis of HNSCC. Based on these prognostic genes, two molecular subtypes of HNSCC were identified, which showed significant differences in prognosis. Additionally, a risk signature consisting of 28 GARGs was constructed and demonstrated good performance for assessing the prognosis of HNSCC. This signature divided HNSCC into the high-risk and low-risk groups with significant differences in multiple clinicopathological characteristics, including survival outcome, grade, T stage, chemotherapy. Immune response-related pathways were significantly activated in the high-risk group with better prognosis. There were significant differences in chemotherapy drug sensitivity and immune therapy response between the high-risk and low-risk groups, with the low-risk group being more suitable for receiving immunotherapy. Riskscore, age, grade, and radiotherapy were independent prognostic factors for HNSCC and were used to construct a nomogram, which had good clinical applicability. CONCLUSIONS: We successfully identified molecular subtypes and prognostic signature of HNSCC that are derived from GARGs, which can be used for the assessment of HNSCC prognosis and treatment responses.

Cerebellopontine Angle Lipoma with Contralateral Sudden Deafness: A Case Report and Review of Literature.

BACKGROUND: Cerebellopontine angle lipoma is a rare tumor that composes less than 1% of all CPA tumors. There has been no recorded case of unilateral CPA/IAC lipoma with sudden contralateral deafness yet. CASE PRESENTATION: We report a 52-year-old man diagnosed with right cerebellopontine angle lipoma and combined left total deafness. Pure-tone audiometry revealed total sensorineural deafness in his left ear and moderate sensorineural deafness in the right ear. The patient was treated with glucocorticoids, batroxobin, and other symptomatic treatments. There was no substantial improvement in hearing after 14 days' treatment. DISCUSSION: We chose conservative treatment for him. It is advised to wear hearing aids in the right ear and to undergo regular imaging monitoring. CONCLUSION: Treatment options for such patients should be chosen by taking into account the degree of bilateral hearing loss, the size and location of the tumor, the possibility of preserving hearing during surgery, the functional level of the patient's facial nerve, and other factors.

Development and optimization of an effective method for evaluating habituation learning behavior in larval zebrafish.

BACKGROUND: Habituation learning is a simple and conserved behavior in all organisms which could be induced by repeated stimuli. However, no standard and universal methods for training and evaluating the habituation learning behavior in larval zebrafish were available. NEW METHOD: This study aims to establish effective training and detection protocols for habituation learning behavior in larval zebrafish by using the ViewPoint system. For this purpose, the detection threshold of velocity-a parameter for distinguishing the escape reaction and the spontaneous motion, the detection sensitivity-a parameter for determining the size of the identified object, the number of stimuli, and the age of larvae were optimized to obtain the best performance. RESULTS: In this study, the optimized parameters were as follows: the detection threshold of velocity at 13, the luminous intensity at 8 %, the detection sensitivity at 32, the number of stimuli at 150, and the age of larvae at 6 dpf. Furthermore, we validated the utility of the established protocol by showing a consistent memory impairment induced by cycloheximide (CHX). COMPARISON WITH EXISTING METHOD: A similar method was reported previously. However, the equipment used in those assays, including the hardware and software, were neither standard nor universal, which might impede the extensive application of the habituation learning assays. Here, we developed an alternative method for studying the habituation learning behavior in larval zebrafish using the ViewPoint system. CONCLUSIONS: Our study provided an alternative method for studying the habituation learning behavior in larval zebrafish.

Suppression of Long Noncoding RNA SNHG1 Inhibits the Development of Hypopharyngeal Squamous Cell Carcinoma via Increasing PARP6 Expression.

Purpose: This study aimed to explore the function and molecular mechanism of long noncoding RNA Small Nucleolar RNA Host Gene 1 (SNHG1) in the development of hypopharyngeal squamous cell carcinoma (HSCC). Methods: Human HSCC cell line FaDu was used in this study. Cell viability and apoptosis were detected using CCK-8 assay and flow cytometry, respectively. Cell migration and invasion were measured by Transwell assay. The expression of PARP6, XRCC6, ß-catenin, and EMT-related proteins (E-cadherin and N-cadherin) were determined using western blotting. Moreover, the regulatory relationship between SNHG1 and PARP6 was investigated. Furthermore, the effects of the SNHG1/PARP6 axis on tumorigenicity were explored in vivo. Results: Suppression of SNHG1 suppressed the viability, migration, and invasion but promoted apoptosis of FaDu cells in vitro (P < 0.01). PARP6 is a target of SNHG1, which was upregulated by SNHG1 knockdown in FaDu cells (P < 0.01). SNHG1 suppression and RARP6 overexpression inhibited FaDu cell proliferation, migration, and invasion (P < 0.05). SNHG1 suppression and RARP6 overexpression also inhibited tumorigenicity of HSCC in vivo. Furthermore, the protein expression of E-cadherin was significantly increased and that of N-cadherin, ß-catenin, and XRCC6 was dramatically decreased in HSCC after SNHG1 suppression or/and RARP6 overexpression both in vitro and in vivo (P < 0.01). Conclusions: SNHG1 silencing inhibits HSCC malignant progression via upregulating PARP6. XRCC6/ß-catenin/EMT axis may be a possible downstream mechanism of the SNHG1/PARP6 axis in HSCC. SNHG1/PARP6 can be used as a promising target for the treatment of HSCC.

Long Noncoding RNA MALAT1 Promotes Laryngocarcinoma Development by Targeting miR-708-5p/BRD4 Axis to Regulate YAP1-Mediated Epithelial-Mesenchymal Transition.

Objective: The objective of this study was to investigate whether long noncoding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) contributes to laryngocarcinoma development via regulating the Yes-associated protein 1- (YAP1-) mediated epithelial-mesenchymal transition (EMT) and the underlying mechanism. Methods: The effects of MALAT1 suppression and BET inhibitor JQ1 on the malignant phenotypes and cancer stem cell- (CSC-) like properties of laryngocarcinoma cells as well as the expression of bromodomain-containing protein 4 (BRD4), YAP1, and EMT markers were investigated. Moreover, the relationships between MALAT1 and miR-708-5p as well as between miR-708-5p and BRD4 were explored. Furthermore, whether MALAT1 regulated the malignant phenotypes of laryngocarcinoma cells via sponging miR-708-5p to target BRD4 was revealed by both in vitro and in vivo experiments. Results: MALAT1 suppression inhibited the malignant phenotypes of laryngocarcinoma cells, such as decreased proliferation, promoted apoptosis, suppressed migration, and inhibited the CSC properties. Suppression of MALAT1 increased miR-708-5p expression and decreased the expression of BRD4 and YAP1 and inhibited EMT. Moreover, there were target relationships between MALAT1 and miR-708-5p as well as between miR-708-5p and BRD4. miR-708-5p overexpression and MALAT1 suppression had synergistic inhibitory effects on the malignant phenotypes of laryngocarcinoma cells and the expression of BRD4, YAP1, and EMT. Furthermore, in vivo experiments confirmed that MALAT1/miR-708-5p regulated tumorigenicity by regulating BRD4 and YAP1-mediated EMT. Conclusions: Our results indicate that suppression of MALAT1 may inhibit laryngocarcinoma development by sponging miR-708-5p/BRD4 to regulate YAP1-mediated EMT. Targeting MALAT1/miR-708-5p/BRD4 axis may provide a promising therapeutic strategy for laryngocarcinoma.

Identifying the mechanisms underlying the protective effect of tetramethylpyrazine against cisplatin­induced in vitro ototoxicity in HEI­OC1 auditory cells using gene expression profiling.

Sensorineural hearing loss is prevalent in patients receiving cisplatin therapy. Tetramethylpyrazine (Tet) and tanshinone IIA (Tan IIA) have protective roles against hearing impairment or ototoxicity. The present study aimed to investigate the molecular mechanisms underlying cisplatin­induced ototoxicity and the protective effect of Tet and Tan IIA against it. House Ear Institute­Organ of Corti 1 auditory cells were treated with titrating doses of Tan IIA, Tet, and cisplatin. In a cell viability assay, cisplatin, Tan IIA and Tet had IC50 values of 42.89 µM, 151.80 and 1.04x103 mg/l, respectively. Tan IIA augmented cisplatin­induced cytotoxicity. However, Tet concentrations <75 mg/l attenuated cisplatin­induced cytotoxicity and apoptosis. Moreover, RNA sequencing analysis was carried out on auditory cells treated for 30 h with 30 µM cisplatin alone for 48 h or combined with 37.5 mg/l Tet for 30 h. Differentially expressed genes (DEGs) induced in these conditions were identified and examined using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Cisplatin increased the expression of genes related to the p53 and FoxO pathways, such as Fas, p21/CDKN1A, and Bcl­2 binding component 3, but decreased the expression of insulin­like growth factor 1 (IGF1), as well as genes in the histone (Hist)1 and Hist2 clusters. Treatment with Tet downregulated FOXO3 and Bcl­2 binding component 3, and increased the expression of IGF1. Moreover, Tet upregulated genes associated with Wnt signaling, but not p53­related genes. Thus, the otoprotective properties of Tet might be mediated by activation of Wnt and IGF1 signaling, and inhibition of FoxO signaling.

Association between body mass index and effectiveness of continuous positive airway pressure in patients with obstructive sleep apnea: a retrospective study.

PURPOSE: Ineffective use of continuous positive airway pressure (CPAP) therapy can result in inconvenience and additional costs in patients with obstructive sleep apnea (OSA). This study investigated the predictive value of body mass index (BMI) to assess the efficacy of CPAP in patients with OSA. METHODS: Data were extracted from a retrospective study performed in Silkeborg Hospital. The primary outcome was the improvement of Apnea-Hypopnea Index (AHI) after CPAP treatment. Association between BMI and improvement of AHI was assessed by multivariable linear regression. Interactions between BMI, baseline AHI severity (≥ 30 or < 30), and diabetes were also evaluated. RESULTS: Four hundred eighty-one patients were included in the study. After adjusting for confounders, high BMI (coefficient [coef], 0.80; 95% confidence interval [CI], 0.59-1.00; p < 0.001) and high AHI severity (AHI ≥ 30) (coef, 29.2; 95% CI, 26.7-31.7; p < 0.001) were associated with greater improvement of AHI after CPAP treatment, while diabetes was associated with less improvement of AHI (coef, - 4.91; 95% CI, - 9.40 to - 0.42; p = 0.032). Baseline AHI severity, diabetes, and BMI showed significant interactions (p < 0.001). On subgroup analysis, the association between BMI and improvement of AHI remained significant only in patients belonging to high AHI severity subgroup (coef, 1.18; 95% CI, 0.8-1.49; p < 0.001) and that without diabetes (coef, 1.42; 95% CI, 1.11-1.72; p < 0.001). CONCLUSIONS: Patients with OSA having high BMI, without diabetes, are more likely to benefit from CPAP therapy. Future studies should explore the predictors of the efficacy of CPAP in more depth.

Triptolide induces toxicity in inner ear stem cells via promoting DNA damage.

Emerging evidence and clinical case reports have observed a risk of cytotoxic effects of triptolide in patients. We aimed to investigate the triptolide-induced toxicity in mouse inner ear stem cells. The utricular sensory epithelium from adult BALB/C6 mice was used for the isolation of inner ear stem cells. Sphere formation assay was applied to examine the stemness of the cells. Cell count kit-8 and Bromodeoxyuridine assays were employed to detect the cell proliferation ability. Cell apoptosis was measured with Annexin V-FITC & propidium iodide Apoptosis kit. The relative expression levels of gamma H2A histone family member X (γH2AX), tumor suppressor p53-binding protein 1 (53BP1) and optic atrophy 1 (OPA-1) were measured by Western Blot. Mitochondrial function was analyzed by the MitoGreen green-fluorescent mitochondrial dye kit. Triptolide significantly inhibited the cell viability and proliferation and suppressed the capability of sphere formation. Furthermore, triptolide induced apoptosis as indicated by increased expression of DNA damage repair markers γH2AX and 53BP1. Moreover, triptolide influenced the function of mitochondria by inducing the cleavage of OPA-1. Our work clarifies the toxicity of triptolide in mouse inner ear stem cells, which provides clues of the toxicology mechanism for future studies and basis for clinical use.

Apoptosis is induced by shikonin through the mitochondrial signaling pathway.

The aim of the present study was to investigate the effects of shikonin (SHI) on the induction of apoptosis in human TT medullary thyroid carcinoma cells, and to explore the role of mitochondrial signaling in this process. MTT, Annexin V­phycoerythrin/7­aminoactinomycin D staining, electron microscopy and JC­1 probe staining were performed to analyze mitochondrial membrane potential, and western blot analysis was used to examine the activation of the mitochondrial signaling pathway, and the changes in mitochondrial apoptosis pathway­associated protein expression. Following culture for 24­72 h, treatment with various concentrations of SHI inhibited the proliferation of TT cells, in a dose­ and time­dependent manner. Transmission electron microscopy demonstrated the presence of typical apoptotic structures, as well as mitochondrial structural changes. The expression levels of apoptosis­associated proteins caspase­9, caspase­3 and poly adenosine triphosphate ribose polymerase increased in a dose­dependent manner following treatment with SHI. In addition, the mitochondrial membrane potential of the experimental group was significantly decreased, and the mitochondrial apoptosis pathway­associated proteins were altered. A possible mechanism underlying SHI­induced apoptosis through the mitochondrial signaling pathway is the regulation of B cell lymphoma 2 (Bcl­2)/Bcl­2­associated protein X expression levels, resulting in the decrease in mitochondrial membrane potential and the activation of the caspase­9/caspase­3 enzyme­associated reactions.

Constitutive secretion of Interleukin-4 dictates CD133+ side population cells to resist drug treatment and cell death.

PURPOSE: In the present study, we made an attempt to elucidate the role of oversecretion of interleukin-4 (IL-4) in cancer stem cells (CSCs) of head and neck squamous cell carcinoma (HNSCC). METHODS: HNSCC samples were analyzed for the presence of CSCs by flow cytometry. In addition, we have performed drug and apoptosis resistance assays to determine the role of IL-4 in CSCs. RESULTS: HNSCC samples contained 3.3% of CD133+ cancer stem like side population (SP) cells in HNSCC which displayed infinite cell proliferation and they had high self-renewal capacity. These CD133+ cells displayed enhanced expression of IL-4, which promoted multidrug and apoptosis resistance. After neutralizing IL-4, the CD133+ SP cells became more sensitive to drug treatment and apoptosis. CONCLUSIONS: Our data suggest that the autocrine secretion of IL-4 is a potential target for the development of novel anticancer drugs to prevent the CSCs-mediated therapy failure and tumorigenesis.