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The human airway is protected by a defensive mucus barrier. The most prominent components of mucus are the mucin glycoproteins MUC5AC and MUC5B. They are produced by goblet cells and submucosal gland cells in the upper and lower airways. Hyperplasia of these cells and hypersecretion of MUC5AC and MUC5B characterize chronic inflammatory diseases of the upper and lower airways. Recent studies have revealed that MUC5AC and MUC5B are expressed at specific sites in the respiratory tract through different molecular mechanisms and have distinct functions. Morphometric and histochemical studies have also examined the roles of goblet cells, submucosal gland cells, MUC5AC, and MUC5B in different chronic airway diseases individually. The individual study of goblet cells, submucosal gland cells, MUC5AC, and MUC5B in airway diseases would be helpful for precisely diagnosing chronic inflammatory diseases of the airway and establishing optimal treatments. This review focuses on the distinct secretion of MUC5AC and MUC5B and their producing cells in chronic inflammatory diseases of the upper and lower airway.

Cervical esophageal cancer (CEC) carries a poor prognosis; however, due to its low incidence, optimal treatment for CEC remains to be established. The purpose of this study was to clarify the current status of treatment of CEC in Japan and obtain evidence for establishing the appropriate treatment method.We asked specialist training facilities accredited by the Japanese Broncho-Esophageal Society to register data on CEC cases that received curative treatment from January 2009 to December 2014, and conducted a retrospective review of the clinical data of 302 cases registered from 27 facilities.In regard to the initial therapy, of the 302 patients, 33 had undergone endoscopic resection, 41 had undergone surgery, 67 had received induction chemotherapy (IC), and 143 had received chemoradiotherapy (CRT). There were no significant differences in the 5-year overall survival rates among the patient groups that had received surgery, IC or CRT as the initial treatment; advanced stage and recurrent nerve invasion were identified as independent poor prognostic factors. Among the patients who had received IC or CRT as laryngeal-preserving surgery was not indicated at the time of the initial diagnosis, the functional laryngeal preservation rate at the end of the observation period was 34.8%.Even in patients with advanced CEC, there is the possibility of preserving the larynx by adopting IC or CRT. However, if the laryngeal function cannot be preserved, there is a risk of complications from aspiration pneumonia, so that the choice of treatment should be made carefully.

ObjectiveThis study aimed to clarify whether circulating miR-21 represents a predictive biomarker in patients with head and neck squamous cell carcinoma (HNSCC) undergoing chemoradiotherapy, and to investigate the effect of miR-21 inhibitor for chemoradiation in human SCC cells.MethodsPlasma samples were obtained from 22 patients with HNSCC and 25 non-cancer volunteers. Plasma miR-21 expression was measured using real-time quantitative reverse transcription polymerase chain reaction. The effects of miR-21 inhibitor in human SCC cells were investigated by performing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, and Western blot analysis.ResultsPlasma miR-21 expression was higher in HNSCC patients than in control patients (p< 0.001). Seven patients with recurrence showed significantly higher plasma miR-21 than the 15 patients without recurrence. Moreover, miR-21 inhibition significantly enhanced cisplatin- or radiation-induced apoptosis. Western blot analysis suggested the programmed cell death 4 (PDCD4) protein as a potential target of miR-21 in relation to apoptosis. Adding miR-21 inhibition to radiation or cisplatin treatment provided clear and potent suppression of tumor cell proliferation.ConclusionThis study provides new insights into the role of miR-21 as a predictive biomarker for HNSCC treated with chemoradiotherapy, and suggests a potential target to improve the effects of chemoradiotherapy against HNSCC.

Background To assess the effects of Epstein–Barr virus (EBV) and human papillomavirus (HPV) infection on the tumor microenvironment, we examined the relationship between viral infection status, macrophage migration inhibitory factor (MIF), and tumor-associated macrophages in nasopharyngeal carcinoma (NPC). Methods A tissue microarray containing 150 cores from 90 patients with NPC and six with chronic inflammation was used. EBV and HPV status were detected using in situ hybridization with commercial EBER1 and HPV16/18 probes. Immunofluorescence double staining of MIF, pan-macrophage marker CD68, M1 macrophage marker CD11c, and M2 macrophage marker CD163 were analyzed using the same tissue microarray. The levels of these markers between NPC and inflammation cases and between tumor nests and stroma were compared. Correlations among these markers were analyzed. Results We found EBER1(+) cases in 90% of NPC patients, including 10% EBV/HPV co-infection. M1 macrophages mainly infiltrated the tumor nest, while M2 macrophages infiltrated the tumor stroma. We found a significant positive correlation between EBER1 levels and MIF levels in tumor nests and a significant positive correlation between HPV16/18 and CD11c(+) cell levels in NPC tissues. Conclusions It is suggested that MIF is associated with EBV, and M1 macrophage infiltration is affected by HPV status in NPC.

To elucidate the molecular mechanisms underlying the progression of head and neck squamous cell carcinoma (HNSCC), we investigated the function of let-7c as a tumor suppressor. Let-7c expression was significantly down-regulated in HNSCC tumor tissues and cell lines. In vitro and in vivo studies revealed that let-7c negatively regulated HNSCC proliferation, migration and epithelial-mesenchymal transition (EMT). To explore the underlying mechanisms that affect these molecular events achieved by let-7c, we predicted its target genes. We performed luciferase assay and confirmed that insulin-like growth factor 1 receptor (IGF1R) and high mobility group AT-hook 2 (HMGA2) were the direct targets of let-7c. Knocking down of IGF1R and HMGA2 inhibited HNSCC progression, including proliferation, migration and EMT in HNSCC cells. Re-expression of these genes overcame let-7c-mediated inhibition. Taken together, our finding suggests that let-7c inhibits HNSCC progression by targeting IGF1R and HMGA2 and might be a novel target for HNSCC treatment.

To determine the efficacy of endoscopic electrocauterization for pyriform sinus fistula (PSF) using a flexible Bugbee cautery electrode. From 2009 to 2016, a total of eight patients with acute suppurative thyroiditis or cervical abscess secondary to PSF were retrospectively registered in our study (three males, five females; median age 6.5 years). All patients underwent endoscopic electrocauterization as treatment for PSF. Six of eight patients had no recurrence after the initial endoscopic electrocauterization of PSF. One patient with recurrence developed symptoms 9 days after cauterization and another experienced recurrence after 2 years. Mean follow-up for the eight patients was 50 months (range 5-96 months). No post-operative complication was reported. Endoscopic electrocauterization appears to be a less-invasive, safe, and effective method for the treatment of PSF.

Clarithromycin is a 14-membered macrolide antibiotic. Low-dose, long-term macrolide therapy is effective in patients with chronic airway diseases, such as diffuse panbronchitis, chronic bronchitis, and chronic sinusitis. However, the mechanism underlying this clinical efficacy remains unclear. The dual specificity phosphatase MKP-1 (MAPK phosphatase-1), also called DUSP (dual specificity phosphatase-1), was initially identified as an in vitro ERK-specific phosphatase, but depending on the cell type, it can also dephosphorylate other members of the MAPK family, such as p38 and JNK, and thus suppress downstream signaling of these kinases. It was recently reported that MKP-1 appears to mediate the effects of several anti-inflammatory drugs, including glucocorticoids, but the role of MKP-1 on mucin gene expression in the presence of macrolides in the human airway remains unknown. Here, we demonstrate that the MKP-1 protein is induced by clarithromycin and that clarithromycin suppresses TNF-α-induced MUC5AC mucin gene expression in a p38 MAPK-dependent manner in human airway epithelial (NCI-H292) cells. Our study thus provides new insights into the role of MKP-1 in mediating the effects of macrolides and may help in the development of new therapeutic strategies against mucin overproduction.

The present study aimed to clarify the incidence and clinical outcomes of nasopharyngeal carcinoma (NPC) in the Chubu region of Japan from 2006 to 2015, compared with previous reports. A retrospective analysis was conducted based on medical records from 40 hospitals located in the Chubu region in the central Japanese main island, with a population of around 22.66 million individuals. This study was designed in line with to two previous clinical studies into NPC conducted in the same area of Japan. We recruited NPC patients diagnosed in hospitals across this area over a 10-year period (2006&ndash, 2015) using a questionnaire about sex, age, primary site, clinical symptoms, pathology, Union for International Cancer Control (UICC) staging, serological exam, treatment, and survival. A total of 620 NPC patients were identified. The age-standardized incidence of NPC from 2006 to 2015 was 0.27 per 100,000 individuals per year. There were no significant differences between this study and the previous two studies conducted in the same area of Japan. The five-year overall survival rate for all patients was 75.9%, while those for patients with stages I, II, III, and IVA were 97%, 91%, 79%, and 68%, respectively. The age-standardized annual incidence of NPC in the present study was 0.27 per 100,000 individuals per year, which was relatively low and stable. The five-year overall survival rate for all NPC patients was significantly improved in this decade compared with previous studies. The smoking rates in male and female NPC patients were 64.5% and 18.8%, respectively, thereby suggesting the involvement of smoking in the incidence of NPC.

The aim of the study is to investigate plasma miR-21 for a possible therapeutic effect determination marker in head and neck squamous cell carcinoma (HNSCC). Plasma samples are obtained from 86 HNSCC patients and 29 non-cancer volunteers who had been treated at Mie University Hospital between May 2015 and December 2016, and plasma miR-21 expression was measured using real-time quantitative reverse transcription polymerase chain reaction. In addition, plasma miR-21 level of advanced HNSCC patients including 22 non-recurrent cases and 11 recurrent cases before and after treatment was analyzed using a longitudinal design. Plasma miR-21 expression in 86 HNSCC patients was obviously higher than in 29 control patients (P < 0.0001). The area under the curve (AUC) for plasma miR-21 was 0.756 (95% confidence interval: 0.661-0.851). Furthermore, our longitudinal study of plasma miR-21 showed that the expression level of plasma miR-21 was significantly reduced at the time point of 2 months after treatment in case of no recurrence. On the other hand, plasma miR-21 was not decreased after treatment in case of 10 patients who had developed recurrences during the follow-up period. This study may provide new insights into the role of plasma miR-21 as a biomarker for HNSCC, and plasma miR-21 would be useful for early detection of tumor recurrence after operation or chemoradiotherapy.

Primary ciliary dyskinesia (PCD) is a genetic disease inherited in an autosomal recessive manner. The prevalence of PCD is estimated to be 1 in 20,000 live births. Congenital abnormality of the primary cilia results in situs inversus in 50% of patients. Decreased function of motile cilia causes chronic rhinosinusitis, otitis media with effusion, bronchiectasis and infertility. Cases with situs inversus are considered to show "Kartagener's syndrome", and diagnosis is not difficult. However, in cases without situs inversus, the diagnosis is much more troublesome. PCD without situs inversus is thus probably underdiagnosed. Prolonged chronic cough represents an important symptom that is seen in most patients. The diagnosis of PCD requires the presence of the characteristic clinical phenotypes and either: (1) specific ciliary ultrastructural defects identified by transmission electron microscopy in biopsy samples of respiratory epithelium; or (2) identification of mutation in one of the genes known to be associated with PCD. Nasal nitric oxide concentration is extremely low in PCD, and this could be useful for screening of the disease. At present, no fundamental therapies are available for PCD. Diagnosis in the early stages is important to prevent progression of bronchiectasis and deterioration of lung function by guidance for daily life, immunization, cessation of smoking and prompt therapy at the time of respiratory tract infection. Since PCD is inherited in an autosomal-recessive manner, genetic counseling is necessary after definite diagnosis.

Pyriform sinus fistula (PSF) is an anomaly that can arise due to failure of involution of the third or fourth branchial cleft during embryogenesis. It can manifest clinically as sinuses, cysts, or abscesses in the neck and is common in childhood. Herein, we describe a neonate who presented with neck swelling and respiratory distress, which was secondary to a fourth branchial pouch sinus. Physical examination revealed swollen areas in the posterolateral pharyngeal wall and on the external left side of the neck. Computed tomography imaging showed a left-sided mass that was filled with air and fluid. Eventually, the pyriform sinus cyst and the entire fistulous tract were excised. The postoperative course was uneventful. Follow-up after 18 months showed no recurrence.

Circulating microRNAs (miRNAs) are emerging as promising non-invasive biomarkers for human cancer. Head and neck squamous cell carcinoma (HNSCC) is a prevalent malignancy worldwide, but its overall survival has remained unchanged in the past 3 decades. Biomarkers for evaluating efficacy of cancer therapy are urgently needed. To explore circulating miRNAs as cancer therapy biomarkers, we initially identified that 8 miRNAs were distinctly dysregulated in cancerous tissues compared with adjacent non-cancerous counterparts from 16 patients, using microarray and real-time PCR. Based on this discovery, the comparison study was performed between pre- and 6 months post-operative paired plasma samples on 9 patients. MiR-99a, which was down-regulated in cancerous tissues, was significantly increased in plasma after operation. Meanwhile, oncomiR miR-21 and miR-223 that were up-regulated in cancerous tissues, were significantly reduced in post-operative plasma samples. We firstly report the significant changes of miR-99a in plasma of HNSCC patients after surgery. Furthermore, plasma miR-223 was inversely increased in a patient whose cancer relapsed within 6 months after operation. We conclude that these circulating miRNAs may serve as biomarkers to evaluate the efficacy of therapy and the prognosis of HNSCC.

Foreign body ingestion is a commonly encountered clinical problem. In particular, sharp foreign bodies lodged in the esophagus or hypopharynx can cause complications and require urgent removal. Removal by flexible esophagogastroduodenoscopy or rigid esophagoscopy is the treatment of choice and has high success rates, but cases in which these methods are unsuccessful must be treated with an external incision. A 62-year-old man was referred for a fish bone lodged in the hypopharynx that could not be removed by flexible esophagogastroduodenoscopy. We removed the bone transorally using a specially designed rigid curved laryngoscope. Based on our experience, this method may have clear practical value due to advantages of a wide field of view and use of multiple rigid forceps. Indications may be limited, but this novel method may reduce the limitations of noninvasive removal of foreign bodies.

To elucidate the molecular mechanisms underlying the progression of head and neck squamous cell carcinoma (HNSCC), we investigated the function of let-7c as a tumor suppressor. Let-7c expression was significantly down-regulated in HNSCC tumor tissues and cell lines. In vitro and in vivo studies revealed that let-7c negatively regulated HNSCC proliferation, migration and epithelial–mesenchymal transition (EMT). To explore the underlying mechanisms that affect these molecular events achieved by let-7c, we predicted its target genes. We performed luciferase assay and confirmed that insulin-like growth factor 1 receptor (IGF1R) and high mobility group AT-hook 2 (HMGA2) were the direct targets of let-7c. Knocking down of IGF1R and HMGA2 inhibited HNSCC progression, including proliferation, migration and EMT in HNSCC cells. Re-expression of these genes overcame let-7c–mediated inhibition. Taken together, our finding suggests that let-7c inhibits HNSCC progression by targeting IGF1R and HMGA2 and might be a novel target for HNSCC treatment.

Oxytetracycline is a broad-spectrum antibiotic, but its nonantibacterial effects in the human respiratory tract are unknown. In this study, the effects of oxytetracycline on mucus secretion and inflammation were examined by PCR and ELISA in the human airway epithelial cell line NCI-H292. Oxytetracycline (10 μg/mL) significantly inhibited TNF-α-induced MUC5AC gene expression and MUC5AC protein levels in NCI-H292 cells. It also downregulated IL-8 and IL-1β gene expression and IL-1β protein levels. Our findings demonstrated that oxytetracycline suppressed mucus production and inflammation in human respiratory epithelial cells, providing further evidence for the usefulness of oxytetracycline for human airway inflammatory diseases.

We report a case of papillary carcinoma of the thyroid gland and cervical lymph node metastases with concurrent tuberculous lymphadenitis that was diagnosed preoperatively. A 35-year-old woman presented with multiple lymph node swellings and an anterior neck mass. No findings suggesting the coexistence of pulmonary tuberculosis were present. The patient underwent a total thyroidectomy with bilateral neck dissection together with medication. Measures to prevent tuberculosis were undertaken during the perioperative period. The histopathological diagnosis was papillary carcinoma with both metastatic and tuberculous lymphadenitis of the lymph nodes in the neck. The possible coexistence of tuberculous lymphadenitis must be ruled out when lymph node swellings are observed in patients with head and neck cancer, including thyroid carcinoma.

We investigated whether IL-33 is involved in mucus overproduction and goblet cell hyperplasia in eosinophilic chronic rhinosinusitis (ECRS). IL-33 mRNA was significantly higher in the eosinophilic CRS group than in the non-eosinophilic CRS group from human nasal polyps. IL-33 induced MUC5AC mRNA and MUC5AC protein, and also goblet cell hyperplasia at air liquid interface culture in human nasal epithelial cells. In addition to that, IL-33 induced MUC5B and FOXA3, and reduces FOXJmRNA. In conclusion, our present study demonstrated that the direct evidence of IL-33 which lead to increase mucin gene and protein expression, as well as goblet cell hyperplasia. This study provides novel insights into the role of IL-33 on mucus overproduction in eosinophilic inflammation of human airways.

Cetuximab is remarkable for the relatively high rate and severity of hypersensitivity reactions (HR) being reported in the literature. Screening for cetuximab‐specific IgE in serum via immunoassay has been found to be useful in preventing HR; however, these tests are known to have a low positive predictive rate. In an attempt to remedy this, we evaluated the interaction between cetuximab and IgE on basophils for predicting severe cetuximab‐induced HR. Twelve head and neck cancer patients were enrolled in this single‐institution study: four with a history of cetuximab‐induced HR and eight with no such history. Cetuximab‐specific and galactose‐α‐1,3‐galactose (α‐gal) specific IgEs in serum were measured in vitro using an enzyme‐linked immunosorbent assay (ELISA). IgE‐cetuximab binding on basophils was also analyzed to evaluate the decrease in cetuximab molecules on basophils after dissociation of IgE from FcεRI. The positive predictive value associated with the presence of cetuximab‐ or α‐gal‐specific IgE in serum was found to be only 0.67, whereas the negative predictive value was 1.00. On the other hand, in all four patients who developed HR, the cetuximab molecules on basophils were decreased significantly due to the dissociation of IgE from basophils (P

Objectives: The purpose of this study was to develop an animal model for the study of mucus overproduction and to assess the effect of a 14-membered macrolide antibiotic and a glucocorticoid on lipopolysaccharide (LPS)-induced mucus production. Methods: Tracheas from donor rats were homografted to recipient rats for 4 weeks, and the usefulness of this tracheal homograft model in the study of mucus production was examined. Results: Oral administration of clarithromycin (CAM) to recipient rats for 4 weeks significantly reduced LPS-induced mucus production in the homografted trachea. Dexamethasone administered for 4 weeks also significantly reduced the mucus volume in LPS-treated homografted trachea compared with that in the control rats. The implanted trachea containing control medium was not histologically different from normal trachea. When the medium instilled into the implanted trachea contained 1 µg/ml LPS, the volume and spinability of mucus produced in the tracheal lumen were significantly increased compared to those in the trachea instilled with control medium. Goblet cell metaplasia was also observed in the implanted trachea containing LPS. Conclusions: The present study shows that LPS-administered homografted trachea is a good animal model of chronic hypersecretory diseases of the upper and lower airways. CAM and dexamethasone could be treatment choices in such hypersecretory diseases.

重度誤嚥で苦しむ2症例に対し，鹿野らにより修正された声門閉鎖術を行った。甲状軟骨ならびに輪状軟骨を鉗除した後に正中にて喉頭内腔に侵入し視野を展開した。その後，上下声帯粘膜弁ならびに胸骨舌骨筋弁を用いて声門閉鎖を行った。この術式はこの2症例に対し成功し，かつ術後経過も良好であった。結論として，成人の嚥下性肺炎の治療としては，本術式は効果的でリスクも少ないと思われた。

Objectives: Eosinophilic chronic rhinosinusitis (ECRS) is considered a refractory and intractable disease with thick mucus production, long-term nasal congestion, loss of sense of smell and intermittent acute exacerbations secondary to bacterial infections. In this study, we investigated which growth factor is deeply involved in the mucin overproduction in ECRS. Method: We employed fluorescence immunohistochemical analysis to evaluate whether or not TGF-α expression was upregulated in the nasal tissue of ECRS patients. We also examined MUC5AC transcription using a luciferase reporter plasmid in HM3-MUC5AC cells and A549 cells in order to assess the role of TGF-α in human epithelial cells. Results: TGF-α immunoreactivity was found markedly increased in the submucosal tissue in the ECRS patient compared with that of a normal patient and with noneosinophilic CRS. TGF-α synergized with TNF-α to upregulate MUC5AC expression in human epithelial cells through the ERK signaling pathway. Conclusion: Our results demonstrated that TGF-α was highly expressed in the upper airway tract in ECRS patients and is deeply involved in mucus hypersecretion.

2005年から2009年の間に当科で初回治療を行った下咽頭扁平上皮癌53例に対し検討を行った。そのうち40例は800mg/m2の5-FUを1日目から5日目にかけて投与し，6日目に80mg/m2のシスプラチンを投与するレジメンを用いた同時化学放射線療法にて治療を行った。局所CRに至ったのは40例中34例，85%であり，切除可能例では97%であった。全体では疾患特異的5年生存率は51%であり，切除可能例では68%であった。主な有害事象は白血球減少と粘膜炎であるが，それらは許容範囲内であり，死に至るような重篤な例はみられなかった。今回の検討でシスプラチン（80mg/m2）と5-FU（800mg/m2）を用いた同時併用化学放射線療法は下咽頭扁平上皮癌に対し効果的な治療法であり，有害事象も共用できる範囲であると思われた。しかしながら進行下咽頭癌に対する新しい治療戦略における更なる見当が必要と思われた。

Background/Aims: Long-term macrolide therapy is an effective treatment for chronic sinusitis and diffuse panbronchiolitis. However, long-term use of macrolides may promote the growth of drug-resistant bacteria; therefore, development of macrolides with no antibacterial action is desirable. A new erythromycin (EM) derivative, (8R,9S)- 8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A (EM900), does not possess antibacterial action. Methods: To determine whether EM900 induced a clinically relevant anti-inflammatory response and repressed mucin gene expression in cells derived from human airway epithelia, we assessed the effects of EM900 on IL-1β-induced inflammatory cytokines in A549 cells and MUC5AC gene expression in HM3-MUC5AC cells. We also investigated the effects of EM900 on IL-1β-induced NF-ĸB activation. We performed reporter gene assays and quantitative PCR in A549 and HM3-MUC5AC cells. Results: Both EM and EM900 suppressed IL-1β-induced IL-8 expression in A549 cells. EM900 also suppressed IL-1β-induced IL-1β and TNF-α expression in A549 cells. EM900 inhibited IL-1β-induced MUC5AC expression in HM3-MUC5AC cells. Both EM and EM900 suppressed IL-1β-induced NF-ĸB activation in A549 cells. Conclusion: This study demonstrated that EM900 suppressed the induction of inflammatory cytokines and MUC5AC gene expression in cells derived from human airway epithelia, and our findings indicate that these effects may be mediated by the suppression of NF-ĸB activation.

Head and neck cancer is frequently accompanied with other primary cancers, especially esophageal cancer. Among 337 cases with head and neck cancers treated at Mie University Hospital from January 2001 to December 2005, 31 cases (9.2%) had multiple cancers. Oropharyngeal cancer and hypopharyngeal cancer cases showed esophageal cancer significantly more frequently than other head and neck cancer cases (25.0-26.7%). Brinkman's index was significantly higher in the group with cancer of the oropharynx associated with esophageal cancer than in the group without any other primary cancer. Sake index was significantly higher in the group with cancer of the oropharynx or hypopharinx associated with esophageal cancer than in the group without any other primary cancer. Endoscopic examinations should be routinely performed after the treatment of head and neck cancer.

Gram-positive bacterium Streptococcus pneumoniae is an important human pathogen that colonizes the upper respiratory tract and is also the major cause of morbidity and mortality worldwide. S. pneumoniae causes invasive diseases such as pneumonia, meningitis, and otitis media. Despite the importance of pneumococcal diseases, little is known about the molecular mechanisms by which S. pneumoniae-induced inflammation is regulated, especially the negative regulatory mechanisms. Here we show that S. pneumoniae activates nuclear factor of activated T cells (NFAT) signaling pathway and the subsequent up-regulation of inflammatory mediators via a key pneumococcal virulence factor, pneumolysin. We also demonstrate that S. pneumoniae activates NFAT transcription factor independently of Toll-like receptors 2 and 4. Moreover, S. pneumoniae induces NFAT activation via both Ca2+-calcineurin and transforming growth factor-β-activated kinase 1 (TAK1)-mitogen-activated protein kinase kinase (MKK) 3/6-p38α/β-dependent signaling pathways. Interestingly, we found for the first time that tumor suppressor cylindromatosis (CYLD) acts as a negative regulator for S. pneumoniae-induced NFAT signaling pathway via a deubiquitination-dependent mechanism. Finally, we showed that CYLD interacts with and deubiquitinates TAK1 to negatively regulate the activation of the downstream MKK3/6-p38α/β pathway. Our studies thus bring new insights into the molecular pathogenesis of S. pneumoniae infections through the NFAT-dependent mechanism and further identify CYLD as a negative regulator for NFAT signaling, thereby opening up new therapeutic targets for these diseases.

A retrospective clinical study was conducted involving 143 patients with laryngeal cancer treated in our department between 1998 and 2006. The subjects consisted of 138 males and 5 females, with a ratio of 28:1. The mean age was 68.1 years old. The subsite of origin comprised 78 (54.5%) in the glottis, 61 (42.7%) in the supraglottis, and 4 (2.8%) in the subglottis. The clinical stage according to the 1997 UICC TMN classification system was I in 53 cases (37.1%), II in 34 (23.8%), III in 20 (14.0%), and IV in 36 (25.2%). The 5-year overall survival rate was 71.2% in the total cases, 84.4% in stage I, 89.6% in stage II, 51.2% in stage III, and 38.9% in stage IV. The disease-specific 5-year survival rate was 88.3% in the total cases, 75.5% in the supraglottic type, 98.1% in the glottic type, and 100% in the subglottic type. The preservation rate of the larynx at 5 years was 83.3% in T1, 56.5% in T2, and 0% in T3 and T4.