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Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with a high mortality rate. The tumor microenvironment (TME) is composed of numerous noncancerous cells that contribute to tumorigenesis and prediction of therapeutic effects. In this study, we aimed to develop a cell component-related prognostic model based on TME. We screened cell component enrichments from samples in The Cancer Genome Atlas (TCGA) HNSCC cohort using the xCell algorithm. Univariate Cox and multivariate Cox regression analyses were performed to establish an optimal independent risk model. The prognostic value of the model was further validated using Gene Expression Omnibus datasets. We found that patients in the low-risk group had a better outcome and activated immunity and may benefit more from the immune checkpoint inhibitor therapy. We also explored microRNAs (miRNAs) that may regulate these identified cell components, and 11 miRNA expression levels influenced the overall survival time. Moreover, their target mRNAs were differentially expressed in TCGA cohort and enriched in pathways of cell cycle pathways, extracellular matrix receptor interaction, human papillomavirus infection, and cancer. In summary, our cell component-related signature was a promising prognostic biomarker that provides new insights into the predictive value of nontumor components in the TME.
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Background: Sensorineural hearing loss can be cured by cochlear implantation (CI), but complications can occur. Based on when the complications develop, they are categorized as intraoperative complications, early postoperative complications, or delayed postoperative complications (>3 months after the surgery).Aims/objectives: We aimed to investigate the occurrence of delayed complications after CI surgery, and identify appropriate management methods.Material and methods: We analyzed 624 sensorineural hearing loss patients who had been consecutively treated with CI using the conventional surgical technique in our institution and had been followed-up until September 2017.Results: A total of 43 (6.86%) patients out of the 624 CIs (627 ears) reported complications, and 9 (1.44%) were major complications and 34 (5.42%) were minor complications. Wound infection and device failure were the most common major complications, and hematoma was the most common minor complication.Conclusions and significance: CI surgery is a relatively mature technology; the incidence of complications is low, and with early diagnosis and treatment most complications have a good prognosis. Head trauma was the main reason for children's complications, and patients and guardians should be given good education preoperatively about how to manage the CI postoperatively.
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Implante Coclear/efeitos adversos , Implantes Cocleares , Complicações Pós-Operatórias/epidemiologia , Falha de Prótese , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Implantes Cocleares/efeitos adversos , Feminino , Seguimentos , Perda Auditiva Neurossensorial/cirurgia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Seroma/etiologia , Infecção da Ferida Cirúrgica/epidemiologia , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Patient prognosis in hypopharyngeal carcinoma remains difficult to predict, necessitating new, readily available biomarkers. OBJECTIVE: Platelet-lymphocyte ratio (PLR)'s effects on recurrence-free survival (RFS) and overall survival (OS) were evaluated in individuals undergoing radical resection for advanced hypopharyngeal squamous cell carcinoma (HSCC). METHODS: A total of 89 patients were retrospectively assessed. PLR, and derived neutrophil-lymphocyte (dNLR) and neutrophil-lymphocyte (NLR) ratios were determined based on complete blood count. Then, the prognostic values of PLR, dNLR and NLR were assessed by univariate and multivariate Cox regression analyses adjusted for disease-specific prognostic factors. Endpoints of interest were RFS and OS. RESULTS: The optimal cutoff of PLR was 98.815, based on which individuals were categorized into the high- (PLR ≥98.815) and low- (PLR <98.815) PLR groups. High PLR (p = .022) had a significant association with reduced RFS, which still showed significance in multivariable analysis (HR = 2.020, 95%CI: 1.076-3.794, p = .029). In univariate analysis, PLR (p = .046) and positive surgical margin (p = .021) also had significant associations with OS. CONCLUSION: Elevated PLR has associations with increased risk of recurrence and reduced survival in advanced HSCC cases undergoing radical resection. High presurgical PLR may independently predict RFS. Therefore, further multi-institutional prospective studies are needed to better characterize the role of pre-operative blood PLR as prognostic factors in HSCC.
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Neoplasias Hipofaríngeas/sangue , Contagem de Linfócitos , Esvaziamento Cervical , Contagem de Plaquetas , Carcinoma de Células Escamosas de Cabeça e Pescoço/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Neoplasias Hipofaríngeas/mortalidade , Neoplasias Hipofaríngeas/cirurgia , Laringectomia , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Cuidados Pré-Operatórios , Prognóstico , Curva ROC , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Análise de SobrevidaRESUMO
Nasopharyngeal carcinoma (NPC) is a head and neck cancer with severe local invasion and early distant metastasis. SIRT6 serves as a critical modulator of the development and metastasis of multiple types of cancer; however, the roles and underlying mechanisms of SIRT6 in regulating NPC metastasis remain largely unknown. Here, the expression of SIRT6 in high metastatic 5-8F cells and low metastatic 6-10B cells was analyzed. SIRT6 expression was found to be negatively associated with the metastatic capability of NPC cells. Moreover, we identified that SIRT6 inhibited NPC cell metastasis through suppression of SNAIL expression. Mechanistically, we demonstrated that SIRT6 interacted with transcription factor p65 (NF-kB subunit) and deacetylated histone H3 lysine 9 (H3K9) and lysine 56 (H3K56) at the promoter of SNAIL, leading to reduced transcription of SNAIL. In summary, SIRT6 functions as a metastasis suppressor in NPC cells through epigenetic regulation of SNAIL gene expression.
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Genetic hearing loss is a common health problem with no effective therapy currently available. DFNA15, caused by mutations of the transcription factor POU4F3, is one of the most common forms of autosomal dominant non-syndromic deafness. In this study, we established a novel mouse model of the human DFNA15 deafness, with a Pou4f3 gene mutation (Pou4f3Δ) identical to that found in a familial case of DFNA15. The Pou4f3(Δ/+) mice suffered progressive deafness in a similar manner to the DFNA15 patients. Hair cells in the Pou4f3(Δ/+) cochlea displayed significant stereociliary and mitochondrial pathologies, with apparent loss of outer hair cells. Progression of hearing and outer hair cell loss of the Pou4f3(Δ/+) mice was significantly modified by other genetic and environmental factors. Using Pou4f3(-/+) heterozygous knockout mice, we also showed that DFNA15 is likely caused by haploinsufficiency of the Pou4f3 gene. Importantly, inhibition of retinoic acid signaling by the aldehyde dehydrogenase (Aldh) and retinoic acid receptor inhibitors promoted Pou4f3 expression in the cochlear tissue and suppressed the progression of hearing loss in the mutant mice. These data demonstrate Pou4f3 haploinsufficiency as the main underlying cause of human DFNA15 deafness and highlight the therapeutic potential of Aldh inhibitors for treatment of progressive hearing loss.
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Aldeído Desidrogenase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Células Ciliadas Auditivas/patologia , Perda Auditiva/tratamento farmacológico , Perda Auditiva/etiologia , Proteínas de Homeodomínio/genética , Fator de Transcrição Brn-3C/genética , Animais , Benzaldeídos/farmacologia , Modelos Animais de Doenças , Haploinsuficiência/genética , Perda Auditiva/genética , Perda Auditiva/patologia , Proteínas de Homeodomínio/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Ruído/efeitos adversos , Quinolinas/farmacologia , Fator de Transcrição Brn-3C/metabolismo , Tretinoína/farmacologia , para-Aminobenzoatos/farmacologiaRESUMO
BACKGROUND/AIMS: Nasopharyngeal carcinoma remains a devastating and difficult disease to treat. This study explores the antineoplastic effect of prodigiosin on nasopharyngeal cancer cells. METHODS: Human nasopharyngeal carcinoma CNE2 cells and human normal nasopharyngeal epithelial NP69 cells were obtained and treated with prodigiosin or fluorouracil (5-FU). Colony formation assay was performed to screen for the optimal experimental concentrations of prodigiosin and 5-FU, and MTT assay was used to examine cell proliferative ability. Flow cytometry was used to examine cell cycle distribution, the scratch test was employed to examine cell migration, and Transwell migration assay (Boyden chamber) was used to study cell invasion. RESULTS: The optimal concentrations of prodigiosin and 5-FU for treatment were 4 mg/L and 0.35 mg/L, respectively. Both prodigiosin and 5-FU inhibited tumor cell proliferation. The percentage of cells in G0/G1 phase was higher and the percentage of cells in S phase was lower in the prodigiosin and 5-FU groups than in the untreated groups. Both prodigiosin and 5-FU inhibited tumor cell migration and tumor cell invasion. CONCLUSIONS: Our results suggest that prodigiosin can inhibit proliferation, migration, and invasion of nasopharyngeal carcinoma cells.
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Proliferação de Células/efeitos dos fármacos , Prodigiosina/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fluoruracila/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologiaRESUMO
An eightbase pair (bp) deletion in the Pou4f3 gene in hair cells is associated with DFNA15, a hereditary form of hearing loss. To explore the pathological mechanisms underlying the development of DFNA15, the effect of the mutation in Pou4f3 on the activity of the myosin VI (Myo6) promoter, was investigated. The upstream regulatory sequence of Myo6 (2625 bp), consisting of an 1899 bp upstream sequence and a 727 bp intron 1 sequence, was amplified using polymerase chain reaction and subcloned into the pGL3Basic vector expressing firefly luciferase. For verification of inserted fragments, plasmids were subjected to restriction analysis and then sequenced. HEK293T human embryonic kidney cells were transiently transfected with renilla luciferasethymidine kinase vectors expressing Renilla luciferase and the Myo6 promoterdriven firefly luciferase expressing vectors along with pIRES2enhanced green fluorescent protein (EGFP)Pou4f3 (expressing wildtype Pou4f3) or pIRES2EGFPPou4f3 (expressing the truncation mutant of Pou4f3). The relative luciferase activities were measured to determine the activity of the Myo6 promoter. The Myo6 promoter activity was not affected by coexpression of wildtype Pou4f3, as indicated by the comparable relative luciferase activities in the presence of the pIRES2EGFPPou4f3 and the empty control vectors. However, coexpression of mutated Pou4f3 significantly inhibited the activity of the Myo6 promoter to almost half of that of the control (P<0.001). The data suggests that mutated Pou4f3 has a negative role in the promoter activity of Myo6, and by extension, the expression of myosin VI, and this may be an underlying mechanism of DFNA15 hearing loss.
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Regulação da Expressão Gênica , Células Ciliadas Auditivas/metabolismo , Mutação/genética , Cadeias Pesadas de Miosina/genética , Fator de Transcrição Brn-3C/genética , Fator de Transcrição Brn-3C/metabolismo , Animais , Sequência de Bases , Genes Reporter , Vetores Genéticos/metabolismo , Humanos , Luciferases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Cadeias Pesadas de Miosina/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas Recombinantes/metabolismoRESUMO
Myosin light chain kinase (MLCK) phosphorylates myosin regulatory light chains to facilitate its interaction with actin filaments and produce contractile activity. The outer hair cells (OHCs) in the ear contain large amounts of actin and a variety myosins. The stereociliary and somatic motility of OHCs are closely related to hearing. It appears likely that MLCK may play an important role in acoustic trans-duction. In this study, we analyzed, both in vivo and in vitro, the OHCs of mice bearing a specific deletion of the MLCK gene and the OHCs of control mice. The phenotype was assessed by auditory function [acoustic brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs)], inner ear morphology and histology. MLCK-deficient mice aged 6-7 months showed impaired hearing, a 5- to 10-dB sound pressure level (SPL) increase in the ABR thresholds, when responding to clicks and tones of different frequencies (8 and 16 kHz) (P<0.05). The DPOAE amplitudes of 3-month-old MLCK-deficient mice decreased significantly (>10 dB SPL) at low frequencies (4, 5 and 6 kHz). The OHCs in the MLCK-deficient mice increased with abnormal stereocilia. The staining of F-actin and the phosphorylation of the regulatory light chain in MLCK-deficient OHCs was weak. Our results indicate that MLCK may regulate the structure and the motility of stereocilia through F-actin polymerization.
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Actinas/metabolismo , Citoesqueleto/metabolismo , Células Ciliadas Auditivas Externas/enzimologia , Células Ciliadas Auditivas Externas/fisiologia , Audição/fisiologia , Quinase de Cadeia Leve de Miosina/metabolismo , Animais , Limiar Auditivo/fisiologia , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Imunofluorescência , Células Ciliadas Auditivas Externas/citologia , Células Ciliadas Auditivas Externas/ultraestrutura , Camundongos , Camundongos Knockout , Cadeias Leves de Miosina/metabolismo , Quinase de Cadeia Leve de Miosina/deficiência , Emissões Otoacústicas Espontâneas/fisiologia , FosforilaçãoRESUMO
OBJECTIVE: To investigate the treatment for benign tumor of external auditory canal by carbon dioxide laser under microscope. METHOD: Ten cases of benign tumor of external auditory canal were treated by carbon dioxide laser under microscope. The curative effects and complications were observed. RESULT: Ten cases of benign tumor of external auditory canal were satisfied after operation without any complications. There were no recurrences during 3 months to 2 years of follow up. CONCLUSION: The operation for benign tumor of external auditory canal by carbon dioxide laser under microscope was easy, safe and effective.
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Meato Acústico Externo/patologia , Neoplasias da Orelha/terapia , Terapia a Laser/métodos , Humanos , Lasers de Gás , Microscopia , Recidiva Local de Neoplasia , NeoplasiasRESUMO
OBJECTIVE: To investigate the function of myosin light chain kinase (MLCK) in hearing in mouse by generating inner hair cell-specific Mlck knockout mice and analyze the effect on their hearing. METHODS: Cross Mlck floxed mice with IHC-Cre mice, the genotype and knockout efficiency were confirmed by PCR. We used auditory brain stem response (ABR) to evaluate mice hearing function at different frequencies. RESULTS: Mlck knockout mice were selected by mice tail DNA genotyping and confirmed the deletion of the target gene by isolated inner hair cell DNA genotyping. Mlck-deficient mice showed impaired hearing with a rise in ABR threshold response to click and three different pure tones (8 kHz, 16 kHz, 32 kHz), and the rise was over 20 dB at high-frequency(32 kHz). Further analyses of waveforms showed that wave-I amplitudes on 60 dB SPL, 50 dB SPL and 40 dBSPL in response to tone (16 kHz) were less than control group(P < 0.05) on average, but the ratio of wave I/II and I/III were not difference (P > 0.05). CONCLUSIONS: Mlck is successfully deleted in inner hair cell-specific Mlck knockout mice. Mlck knockout mice display a significantly higher threshold in response to click and tones, especially in high-frequencies.