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Genetic testing for congenital or early-onset hearing loss patients has become a common diagnostic option in many countries. On the other hand, there are few late-onset hearing loss patients receiving genetic testing, as late-onset hearing loss is believed to be a complex disorder and the diagnostic rate for genetic testing in late-onset patients is lower than that for the congenital cases. To date, the etiology of late-onset hearing loss is largely unknown. In the present study, we recruited 48 unrelated Japanese patients with late-onset bilateral sensorineural hearing loss, and performed genetic analysis of 63 known deafness gene using massively parallel DNA sequencing. As a result, we identified 25 possibly causative variants in 29 patients (60.4%). The present results clearly indicated that various genes are involved in late-onset hearing loss and a significant portion of cases of late-onset hearing loss is due to genetic causes. In addition, we identified two interesting cases for whom we could expand the phenotypic description. One case with a novel MYO7A variant showed a milder phenotype with progressive hearing loss and late-onset retinitis pigmentosa. The other case presented with Stickler syndrome with a mild phenotype caused by a homozygous frameshift COL9A3 variant. In conclusion, comprehensive genetic testing for late-onset hearing loss patients is necessary to obtain accurate diagnosis and to provide more appropriate treatment for these patients.
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Perda Auditiva Neurossensorial , Perda Auditiva , Patrimônio Genético , Perda Auditiva/genética , Perda Auditiva Neurossensorial/genética , Humanos , Linhagem , FenótipoRESUMO
PURPOSE: Chemoradiotherapy with docetaxel (DOC), cisplatin (CDDP), and 5-FU (TPF-CRT) for locally advanced external auditory canal cancer (EACC) has favorable oncological and functional outcomes. To establish TPF-CRT as a standard of care for advanced EACC, we conducted this study to determine the maximum tolerated (MTD) and recommended dose (RD) of DOC in TPF-CRT for locally advanced EACC. METHODS: To determine the recommended (RD) and maximum tolerated dose (MTD) of DOC in TPF-CRT for EACC, a phase I trial was conducted using the standard "3 + 3" design for maximum dose finding. DOC was administered twice every 4 weeks, CDDP at 70 mg/m2 and 5-FU at 700 mg/m2; patients were also receiving radiotherapy (66 Gy). Eight patients with T3 or T4 EACC were prospectively enrolled. RESULTS: Two patients treated with DOC, 50 mg/m2, and one out of six patients treated with DOC, 40 mg/m2, had dose-limiting toxicities. Prolonged febrile neutropenia was observed in three patients. Grade 3 non-hematological toxicities were observed in only three patients. At study completion, six patients survived, five of whom were disease free. CONCLUSION: The RD and MTD of DOC in TPF-CRT for locally advanced EACC are 40 mg/m2 when doses of CDDP and 5-FU are 70 mg/m2 and 700 mg/m2, respectively.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/patologia , Quimiorradioterapia/efeitos adversos , Cisplatino , Docetaxel , Meato Acústico Externo/patologia , Fluoruracila , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , TaxoidesRESUMO
The expression of EGFR and p16 in the external auditory canal squamous cell carcinoma (EACSCC) and their impacts on oncological outcomes were not well studied. Seventeen-one consecutive patients who were treated for EACSCC at Kobe University Hospital from 1995 to 2018 were enrolled in this study. The expression of EGFR, and p16 were evaluated and their impacts on oncological outcomes were statistically analyzed. Positive expression of EGFR was observed in 62 patients (87%). Strong positive expression of p16 were observed in 18 patients (32.4%), and weakly positive expression in 30 patients (42.3%), respectively. While the number of the patients with negative EGFR expression were limited, all the surgically treated patients with negative EGFR expression have been alive without disease. In the patients with T3 & T4a EACSCC, prognosis of the patients with positive p16 expression EACSCC tended to be better than those with negative p16 expression. These results suggest the clinical significance of EGFR and p16 expressions in the patients with advanced EACSCC to predict oncological outcomes.
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Carcinoma de Células Escamosas , Meato Acústico Externo , Humanos , Meato Acústico Externo/metabolismo , Meato Acústico Externo/patologia , Receptores ErbB/metabolismo , Carcinoma de Células Escamosas/patologia , PrognósticoRESUMO
BACKGROUND: The goal of this study was to evaluate the antitumor immune effects of B7-1 gene expression in addition to immune checkpoint inhibitor against squamous cell carcinoma. METHODS: A murine SCC cell line, KLN205, was infected with adenoviral vector carrying B7-1 (AdB7). Infected cells were injected subcutaneously in the flanks of DBA/2 mice. Three weeks after implantation, anti-mouse PD-1 antibody (antiPD1) was intraperitonially administrated twice a week for a total of six times. RESULTS: CD80 was significantly overexpressed in the AdB7-infected tumors. IFN-gamma in the T cells in the spleen was significantly increased and tumor size was significantly reduced in the mice treated with both AdB7 and antiPD1. Targeted tumors treated with both AdB7 and antiPD1 exhibited significantly increased cell densities of total immune cells as well as Ki-67+ CD8+ T cells and decreased regulatory T cells. CONCLUSIONS: These results suggest that the B7-1 gene transfer may enhance the antitumor effect of anti-PD1 antibody against SCC.
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Introduction: Binaural hearing enhances speech intelligibility, source localization, and speech comprehension in noisy environments. Although bilateral cochlear implantation (CI) offers several benefits, concerns arise regarding the risk of bilateral postoperative vestibular dysfunction with simultaneous CI. This study aimed to longitudinally evaluate changes in vestibular function in adult patients who underwent simultaneous bilateral CI using minimally invasive electrodes and surgical techniques. Methods: A retrospective review was conducted on 10 patients who underwent simultaneous bilateral CI at our hospital. Vertigo symptoms and vestibular function test results were examined preoperatively, 1-6 months postoperatively, and 1 year postoperatively. Nystagmus tests, caloric reflex tests, vestibular evoked myogenic potentials (VEMP) measurements, and static stabilometry were performed as vestibular function tests. Results: Although an initial transient decline in vestibular function was observed, no significant long-term decline was observed in the caloric reflex test, ocular VEMP (oVEMP), or cervical VEMP (cVEMP). Moreover, regardless of the presence or absence of abnormalities in caloric reflex, oVEMP, or cVEMP, no significant deterioration was detected in the static stabilometer test. While two patients reported preoperative dizziness, all patients were symptom-free 1 year postoperatively. Discussion: The findings suggest that using current minimally invasive electrodes and surgical techniques in simultaneous bilateral CI leads to temporary vestibular function decline postoperatively. However, most patients experience a recovery in function over time, highlighting the potential safety and efficacy of the procedure. Simultaneous bilateral CI surgery is viable, depending on the patient's auditory needs and burden.
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Vestibular schwannoma (VS) is the most common tumor of the cerebellopontine angle. Despite the increasing diagnosis of sporadic VS over the past decade, the use of traditional microsurgeries to treat VS has decreased. This is likely a result of the adoption of serial imaging as the most common initial evaluation and treatment strategy, especially for small-sized VS. However, the pathobiology of VSs remains unclear, and elucidating the genetic information of tumor tissue may reveal novel insights. The present study performed a comprehensive genomic analysis of all exons in the key tumor suppressor and oncogenes from 10 small (<15 mm) sporadic VS samples. The evaluations identified NF2, SYNE1, IRS2, APC, CIC, SDHC, BRAF, NUMA1, EXT2, HRAS, BCL11B, MAGI1, RNF123, NLRP1, ASXL1, ADAMTS20, TAF1L, XPC, DDB2 and ETS1 as mutated genes. The current study could not draw any new conclusions about the relationship between VS-related hearing loss and gene mutations; however, it did reveal that NF2 was the most frequently mutated gene in small sporadic VS.
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OBJECTIVE: To investigate the isosorbide-induced dehydration effect on the endolymphatic space by intratympanic administration of isosorbide. BACKGROUND: Isosorbide, an osmotic diuretic, is used orally as a typical conservative therapy for Menière's disease (MD) in Japan. The dehydration effect occurs 6 hours after isosorbide ingestion. Intratympanic administration of isosorbide resolves endolymphatic hydrops faster than oral ingestion. In addition, the dehydration effect has never been shown directly. Therefore, we investigated the dehydration effect of intratympanic administration of isosorbide on endolymphatic hydrops using optical coherence tomography. METHODS: We used eight Hartley guinea pigs, divided into normal and hydrops groups. In the hydrops group, the animals underwent endolymphatic sac obliteration to create endolymphatic hydrops. We obtained midmodiolar section images of the cochleae using optical coherence tomography. Then, 50 to 70% isosorbide was sequentially administered intratympanically for 5 minutes, and the apical turn of the cochlea was observed. The relative midmodiolar cross-sectional area of the scala media was calculated for quantitative assessment of the endolymphatic space. RESULTS: In the normal group, 50% isosorbide had a slight but significant dehydration effect on the scala media; at 55 to 70%, Reissner's membrane became flat. In the hydrops group, 50% isosorbide slightly reduced endolymphatic hydrops; 65% flattened Reissner's membrane, and 70% slightly concaved it toward the basilar membrane. CONCLUSION: The results suggest that we could select the concentration of isosorbide according to the stage or severity of MD and relief from acute attack. Intratympanic administration of isosorbide may be a promising treatment for patients with MD.
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Hidropisia Endolinfática , Saco Endolinfático , Doença de Meniere , Cobaias , Animais , Isossorbida/efeitos adversos , Tomografia de Coerência Óptica , Desidratação , Cóclea/diagnóstico por imagem , Hidropisia Endolinfática/diagnóstico por imagem , Hidropisia Endolinfática/tratamento farmacológico , Hidropisia Endolinfática/induzido quimicamente , EdemaRESUMO
Objectives: Acute hemorrhagic rectal ulcer syndrome (AHRUS) causes massive bleeding and often recurrent rebleeding from rectal ulcers that form immediately above the dentate line. This study aimed to determine the clinical background and risk factors contributing to rebleeding in patients with AHRUS and the most appropriate method of hemostasis treatment. Methods: This retrospective study included 93 patients diagnosed with AHRUS at Showa University Fujigaoka Hospital, Japan, between April 2009 and November 2018. Information on clinical background factors, endoscopic findings, and hemostasis was obtained from medical records. The relationship with episodes of rebleeding was analyzed by multivariate logistic regression analysis. Results: The median age was 79 years, and 84 patients (90%) had a performance status of grade 2 or higher. The patients had multiple background factors, with a median number of 5 per patient. The background factors could be classified into two major factors: those related to arteriosclerosis and those related to delayed wound healing.In the multivariate analysis, significantly more rebleeding occurred in patients with active bleeding during the initial endoscopy (odds ratio 4.88, 95% confidence interval 1.80-14.46, p = 0.003); significantly less rebleeding occurred in patients for whom hemostasis was first performed by clipping (odds ratio 0.30, 95% confidence interval 0.09-0.88, p = 0.035). Conclusions: In bedridden older individuals with poor general health, multiple combinations of arteriosclerosis-related factors and protracted wound healing factors can induce AHRUS. We strongly recommend performing hemostasis via the clipping method on suspected bleeding points, including active bleeding sites, in AHRUS.
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BACKGROUND: Squamous cell carcinoma of the external auditory canal (EACSCC) is a rare condition. However, a standard treatment has not yet been established. We retrospectively evaluated the efficacy, adverse events, and feasibility of TPF-CCRT (concomitant chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil) in patients with advanced EACSCC. METHODS: Thirty-five consecutive patients with advanced EACSCC (T3, T4) initially treated with TPF-CCRT at Kobe University Hospital were included. T4 diseases with invasion of the brain, internal carotid artery, or internal jugular vein were classified as T4b, and those without these features were classified as T4a. RESULTS: Five-year overall survival rates for T3 and T4 were 100% and 64.2%, respectively. A significant difference was observed between T4a and T4b (82.4% vs. 30%, p = 0.007). Five-year progression-free survival rates of T3, T4a, and T4b were 100%, 68%, and 20% (p = 0.022), respectively. CONCLUSIONS: TPF-CCRT should be considered as a plausible treatment option for advanced EACSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Humanos , Docetaxel/uso terapêutico , Fluoruracila , Cisplatino , Estudos Retrospectivos , Meato Acústico Externo/patologia , Taxoides/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/patologia , QuimiorradioterapiaRESUMO
Kenny-Caffey syndrome type 2 (KCS2) is an extremely rare skeletal disorder involving hypoparathyroidism and short stature. It has an autosomal dominant pattern of inheritance and is caused by variants in the FAM111 trypsin-like peptidase A (FAM111A) gene. This disease is often difficult to diagnose due to a wide range of more common diseases manifesting hypoparathyroidism and short stature. Herein, we present the case of a 56-year-old female patient with idiopathic hypoparathyroidism and a short stature. The patient was treated for these conditions during childhood. Upon re-evaluating the etiology of KCS2, we suspected that the patient had the disorder because of clinical manifestations, such as cortical thickening and medullary stenosis of the bones, and lack of intellectual abnormalities. Genetic testing identified a heterozygous missense variant in the FAM111A gene (p.R569H). Interestingly, the patient also had bilateral sensorineural hearing loss and vestibular dysfunction, which have been rarely described in previous reports of pediatric cases. In KCS2, inner ear dysfunction due to Eustachian tube dysfunction may progress in middle age or later. However, this disease is now being reported in younger patients. Nevertheless, our case may be instructive of how such cases emerge chronically after middle age. Herein, we also provide a literature review of KCS2.
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Nanismo , Hiperostose Cortical Congênita , Hipoparatireoidismo , Feminino , Humanos , Criança , Pessoa de Meia-Idade , Seguimentos , Hiperostose Cortical Congênita/genética , Receptores Virais/genéticaRESUMO
OBJECTIVE: To present our results of the external auditory canal (EAC) reconstruction procedure using rolled-up full-thickness skin graft with tympanoplasty after lateral temporal bone resection (LTBR) for early-stage EAC carcinoma. PATIENTS AND METHODS: A retrospective review of 15 patients who had undergone LTBR with reconstruction of the EAC for T1 and T2 EAC cancer between 2016 and 2020. RESULTS: Postoperative mean air-bone gap was 30.7 decibel hearing level. Although a few patients experienced chronic granulation, persistent otorrhea, and/or laterization of the tympanic membrane, most patients showed no serious complications related to the EAC reconstruction. CONCLUSION: EAC reconstruction using a full-thickness skin graft in combination with tympanoplasty is useful for minimizing the hearing loss, maintaining the cosmetic appearance, and facilitating the observation into the ear cavity.
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Carcinoma Adenoide Cístico/cirurgia , Meato Acústico Externo/cirurgia , Neoplasias da Orelha/cirurgia , Transplante de Pele/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Osso Temporal/cirurgia , Timpanoplastia/métodos , Idoso , Idoso de 80 Anos ou mais , Audiometria de Tons Puros , Carcinoma Adenoide Cístico/patologia , Neoplasias da Orelha/patologia , Feminino , Tecido de Granulação , Perda Auditiva Condutiva/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Otológicos/métodos , Complicações Pós-Operatórias/epidemiologia , Procedimentos de Cirurgia Plástica/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologiaRESUMO
A previous case report of colitis and serine proteinase 3-antineutrophil cytoplasmic antibody positivity in pyogenic arthritis, pyoderma gangrenosum (PG), acne and hidradenitis suppurativa (PAPASH) syndrome with colitis has been published. Herein, we report a similar case of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) positivity. A 26-year-old man presented with recurrent aseptic pyogenic arthritis, acne, hidradenitis suppurativa and PG. Lower gastrointestinal endoscopy was performed, and colitis was observed. No PSTPIP1 gene mutation was found in the gene-sequencing test. Based on these findings and prior case reports, we diagnosed the patient with PAPASH syndrome, a PAPA spectrum disorder complicated by colitis. This patient had PAPASH syndrome with colitis and was MPO-ANCA and anticardiolipin antibodies-positive; it is unclear whether these antibodies play a role in this disease, but it may provide clues to further elucidate its pathogenesis.
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Acne Vulgar , Artrite Infecciosa , Colite , Hidradenite Supurativa , Pioderma Gangrenoso , Acne Vulgar/diagnóstico , Adulto , Anticorpos Anticardiolipina/isolamento & purificação , Anticorpos Anticitoplasma de Neutrófilos/isolamento & purificação , Artrite Infecciosa/diagnóstico , Colite/complicações , Hidradenite Supurativa/diagnóstico , Humanos , Masculino , Peroxidase/imunologia , Pioderma Gangrenoso/diagnóstico , SíndromeRESUMO
BACKGROUND AND AIM: Cases of colorectal endoscopic submucosal dissection (ESD) with poor maneuverability are often encountered. We aimed to evaluate the efficacy of balloon-assisted endoscopy (BAE) for such cases. METHODS: We confirmed maneuverability preoperatively in 400 consecutive cases of colorectal ESD performed at a single center from April 2011 to April 2018. A total of 83 deep colon cases judged as having poor maneuverability were retrospectively reviewed; 54 cases underwent BAE with a single balloon endoscope (group B), and 29 cases underwent conventional procedures without BAE (group C). Tumor size, procedure duration, dissection speed, en bloc resection rate, histology, and associated complications were compared between groups. RESULTS: The mean tumor size, tumor invasiveness, fibrosis, and complications did not differ between groups. Although the en bloc resection rate did not differ (both 98%), the groups significantly differed with regard to the R0 resection rate (B: 96%; C: 83%; P = 0.048). Overall, the procedure duration (B: 51 min; C: 70 min; P = 0.17) and dissection speed (B: 19.4 mm2/min; C: 17.4 mm2/min; P = 0.13) were not significantly different between groups. However, the dissection speed for lesions in the cecum/ascending colon was significantly faster in group B than in group C (B: 22.3 mm2/min; C: 11.3 mm2/min; P = 0.037). CONCLUSIONS: In cases of colorectal ESD with poor maneuverability, the use of BAE contributed to an improvement in the R0 resection rate. In addition, BAE contributed to a quicker dissection speed for lesions located in the cecum/ascending colon.
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BACKGROUND: Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous cell carcinomas (HNSCCs). Midkine expression is restricted in adult tissues but is increased in several malignant tumors, including HNSCCs. AIM: Here, we evaluated the antitumor effect of Midkine promoter-based conditionally replicative adenovirus expressing siRNA against EGFR for targeting HNSCCs expressing Midkine. METHODS AND RESULTS: A conditionally replicative adenovirus vector controlled by the Midkine promoter, Ad-MK-siEGFR, was generated by integrating gene-expressing siRNA against EGFR. Antitumor effect of Ad-MK-siEGFR was tested in vitro using established HNSCC cell line, T891 with strong Midkine expression. Expression of EGFR in T891 infected with Ad-MK-siEGFR was significantly lower than that of T891 infected with control. Cytotoxicity assays showed significant growth suppression of Ad-MK-siEGFR in T891 cells. CONCLUSIONS: This study demonstrated the possibility of oncolytic therapy using the Midkine promoter-based conditional replication-selective adenovirus containing siRNA against EGFR in HNSCC cell line T891. Further validation of the findings in more cell lines and in vivo should be performed to clarify the potential clinical application.
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Adenoviridae/genética , Neoplasias de Cabeça e Pescoço/terapia , Midkina/genética , Terapia Viral Oncolítica/métodos , Regiões Promotoras Genéticas , RNA Interferente Pequeno/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Células Tumorais CultivadasRESUMO
The symptoms of Meniere's disease (MD) are generally considered to be related to endolymphatic hydrops (EH). There are many recent reports supporting the possibility that vasopressin (VP) is closely linked to the formation of EH in Meniere's disease. Based on this, we developed a clinically relevant animal model of Meniere's disease in which a VP type 2 receptor agonist was administered after electrocauterization of the endolymphatic sac. We report live imaging of the internal structure, and functional changes of the inner ear after electrocauterization of the endolymphatic sac and administration of a VP type 2 receptor agonist. In this model, the development of EH was visualized in vivo using optical coherence tomography, there was no rupture of Reissner's membrane, and low-tone hearing loss and vertiginous attacks were observed. This study suggested that acute attacks are caused by the abrupt development of EH. This is the first report of live imaging of the development of EH induced by the administration of a VP type 2 receptor agonist.
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Doença de Meniere/diagnóstico , Doença de Meniere/fisiopatologia , Animais , Modelos Animais de Doenças , Hidropisia Endolinfática/diagnóstico por imagem , Hidropisia Endolinfática/etiologia , Hidropisia Endolinfática/fisiopatologia , Doença de Meniere/etiologia , Doença de Meniere/terapia , Tomografia de Coerência Óptica , Vasopressinas/farmacologia , Vasopressinas/uso terapêutico , Testes de Função VestibularRESUMO
MYO6 is known as a genetic cause of autosomal dominant and autosomal recessive inherited hearing loss. In this study, to clarify the frequency and clinical characteristics of hearing loss caused by MYO6 gene mutations, a large-scale genetic analysis of Japanese patients with hearing loss was performed. By means of massively parallel DNA sequencing (MPS) using next-generation sequencing for 8074 Japanese families, we found 27 MYO6 variants in 33 families, 22 of which are novel. In total, 2.40% of autosomal dominant sensorineural hearing loss (ADSNHL) in families in this study (32 out of 1336) was found to be caused by MYO6 mutations. The present study clarified that most cases showed juvenile-onset progressive hearing loss and their hearing deteriorated markedly after 40 years of age. The estimated hearing deterioration was found to be 0.57 dB per year; when restricted to change after 40 years of age, the deterioration speed was accelerated to 1.07 dB per year. To obtain supportive evidence for pathogenicity, variants identified in the patients were introduced to MYO6 cDNA by site-directed mutagenesis and overexpressed in epithelial cells. They were then assessed for their effects on espin1-induced microvilli formation. Cells with wildtype myosin 6 and espin1 co-expressed created long microvilli, while co-expression with mutant constructs resulted in severely shortened microvilli. In conclusion, the present data clearly showed that MYO6 is one of the genes to keep in mind with regard to ADSNHL, and the molecular characteristics of the identified gene variants suggest that a possible pathology seems to result from malformed stereocilia of the cochlear hair cells.
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Surdez/genética , Perda Auditiva Neurossensorial/genética , Cadeias Pesadas de Miosina/genética , Adolescente , Adulto , Idoso , Criança , Surdez/patologia , Feminino , Ligação Genética/genética , Genótipo , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patologia , Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Neurossensorial/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Fenótipo , Adulto JovemRESUMO
Variants in the EYA4 gene are known to lead to autosomal dominant non-syndromic hereditary hearing loss, DFNA10. To date, 30 variants have been shown to be responsible for hearing loss in a diverse set of nationalities. To better understand the clinical characteristics and prevalence of DFNA10, we performed genetic screening for EYA4 mutations in a large cohort of Japanese hearing loss patients. We selected 1,336 autosomal dominant hearing loss patients among 7,408 unrelated Japanese hearing loss probands and performed targeted genome enrichment and massively parallel sequencing of 68 target genes for all patients. Clinical information of cases with mutations in EYA4 was gathered and analyzed from medical charts. Eleven novel EYA4 variants (three frameshift variants, three missense variants, two nonsense variants, one splicing variant, and two single-copy number losses) and two previously reported variants were found in 12 probands (0.90%) among the 1,336 autosomal dominant hearing loss families. The audiometric configuration of truncating variants tends to deteriorate for all frequencies, whereas that of non-truncating variants tends to show high-frequency hearing loss, suggesting a new correlation between genotype and phenotype in DFNA10. The rate of hearing loss progression caused by EYA4 variants was considered to be 0.63 dB/year, as found in this study and previous reports.
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Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Neurossensorial/genética , Mutação , Transativadores/genética , Estudos de Coortes , Feminino , Humanos , Japão/epidemiologia , Masculino , PrevalênciaRESUMO
Objective The endocytosis of cationized feritin (CF) via a clathrin-mediated pathway is regulated by a signaling network. Marginal cells showed the active endocytosis of CF via a clathrin-mediated pathway. The internalization of receptors through this clathrin-mediated pathway is an important regulatory event in signal transduction. Numerous kinases are involved in endocytosis, and each endocytic route is subjected to high-order regulation by cellular signaling mechanisms. In this study, we investigated whether ROCK and MLCK signaling cascades and G-proteins regulate the endocytosis of CF in marginal cells of the stria vascularis. Methods CF was infused into the cochlear duct with pertussis toxin (PTX),Clostridium botulinum C3 toxin (BTX), guanosine(g-thio)-triphosphate (GTP-γS), ML-7, Y-27632. Endocytic activity was measured at 30 min after the start of infusion under an electron microscope. Results In marginal cells, CF was internalized via a clathrin-mediated pathway that depends on F-actin and microtubules (MT). Its processes were controlled by myosin light chain kinase (MLCK) and Rho-associated kinase (ROCK), but not affected by G-protein-coupled receptor (GPCR) or the RhoA signaling cascade. Conclusion Our previous study showed that the main endocytotic pathway of microperoxidase (MPO) did not depend on the Rho/ROCK molecular switch or actin/myosin motor system, but was mainly regulated by the RhoA signaling cascade. The present study results indicate that these signaling cascades regulating CF internalization completely differ from the cascades for MPO internalization.
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Vesículas Revestidas por Clatrina/metabolismo , Endocitose/fisiologia , Ferritinas/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Estria Vascular/metabolismo , Quinases Associadas a rho/metabolismo , ADP Ribose Transferases/farmacologia , Amidas/farmacologia , Animais , Azepinas/farmacologia , Toxinas Botulínicas/farmacologia , Ducto Coclear , Endocitose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Proteínas de Ligação ao GTP/antagonistas & inibidores , Cobaias , Microscopia Eletrônica , Quinase de Cadeia Leve de Miosina/antagonistas & inibidores , Fosfatase de Miosina-de-Cadeia-Leve/antagonistas & inibidores , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Naftalenos/farmacologia , Toxina Pertussis/farmacologia , Piridinas/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Estria Vascular/efeitos dos fármacos , Quinases Associadas a rho/antagonistas & inibidores , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
OBJECTIVE: The purpose of this study was to clarify the impact of superficial parotidectomy and postoperative radiotherapy (PORT) for the surgical treatment of early stage squamous cell carcinoma (SCC) in external auditory canal (EAC). MATERIALS AND METHODS: Thirty-seven patients with T1 (n = 14) or T2 (n = 19) SCC in EAC treated between 2000 and 2016 at Kobe University Hospital were enrolled in this study. Thirty-three patients were operated with sleeve resection or lateral temporal bone resection. RESULTS: The 5-year overall survival and disease-specific survival rates were 95% and 100%, respectively. Surgical margin was positive in 4 patients, who were treated by PORT and have been alive without disease. Prophylactic superficial parotidectomy was simultaneously performed at the time of initial surgery in 15 patients, in whom no lymph node (LN) metastasis was observed. Among the other 22 patients, regional recurrence in parotid LN was observed in one patient, who was successfully salvaged by total parotidectomy. Potential parotid lymph node metastasis rates of T1 and T2 SCC in EAC was 0% (0/14) and 5% (1/19) respectively. CONCLUSIONS: Complete resection without positive surgical margins is essential for the treatment of the patients with T1 and T2 ear cancers. Prophylactic superficial parotidectomy or neck dissection is not mandatory for T1 and T2 diseases, as long as precisely extent of disease is assessed preoperatively. PORT should be performed for the patients with positive surgical margins. LEVELS OF EVIDENCE: 4.