Search

Abstract Objective This study aimed to investigate the utility of minor salivary glands in the hypopharynx as novel indicators for safe resection of superficial hypopharyngeal carcinomas with fewer complications. Study Design Cadaveric study. Setting Cadavers were stored in the pathology laboratory at Kansai Medical University. Methods Twenty‐three cadaveric specimens were examined for minor salivary glands in the pyriform sinus, posterior wall, and postcricoid regions of the hypopharynx. Their count, size, and depth were assessed. Resected specimens from 5 consecutive patients with superficial hypopharyngeal carcinomas were pathologically analyzed to determine the positional relationship between cancer and minor salivary glands. Results Minor salivary glands were present in more than 70% of patients in each region during autopsy, with the postcricoid region having a larger count and size. The glands were universally present, regardless of sex, height, or body mass index. Minor salivary glands in the pyriform sinus and postcricoid region were present at a depth of 30% from the bottom of the submucosal layer, whereas those in the posterior wall were present in the shallow muscularis. During surgery, endoscopic findings revealed minor salivary glands as small white nodules in the submucosal layer. Pathological examination of the resected specimen confirmed that the white nodule was a minor salivary gland. In addition, tumor position in relation to minor salivary glands provided an adequate margin for resection. Conclusion Minor salivary glands may serve as reliable indicators for determining adequate deep safety margins during surgery for superficial hypopharyngeal carcinoma.

BackgroundIn view of improving biomarkers predicting the efficacy of immunotherapy for head and neck squamous cell carcinoma (R/M HNSCC), this multicenter retrospective study aimed to identify clinical, tumor microenvironmental, and genomic factors that are related to therapeutic response to the anti- Programmed cell death protein 1 (PD-1) antibody, nivolumab, in patients with R/M HNSCC. MethodsThe study compared 53 responders and 47 non-responders, analyzing formalin-fixed paraffin-embedded samples using 14-marker multiplex immunohistochemistry and targeted gene sequencing.ResultsOf 100 patients included, responders had significantly lower smoking and alcohol index, higher incidence of immune related adverse events, and higher PD-1 ligand (PD-L1) expression in immune cells as well as PD-L1 combined positive score (CPS) than non-responders. The frequency of natural killer cells was associated with nivolumab response in patients with prior cetuximab use, but not in cetuximab-naïve status. Age-stratified analysis showed nivolumab response was linked to high CPS and lymphoid-inflamed profiles in patients aged ≥ 65. In contrast, lower NLR in peripheral blood counts was associated with response in patients aged < 65. Notably, TP53 mutation-positive group had lower CPS and T cell densities, suggesting an immune-excluded microenvironment. Patients with altered tumor suppressor gene pathways, including TP53, CDKN2A, and SMAD4 mutations, had lower CPS, higher smoking index, and were associated with poor responses. ConclusionNivolumab treatment efficacy in HNSCC is influenced by a combination of clinical factors, age, prior treatment, immune environmental characteristics, and gene mutation profiles.

The gas-species dependence of permeation flow in solid oxide fuel cell anodes is experimentally and numerically investigated to clarify the Knudsen effect on the gas transport phenomena in porous media. The effective permeability of porous anodes fabricated with pore former is experimentally measured using various working gases with different mean free paths, and the effect of the working gas species on the permeation phenomena is evaluated. A linear relationship is found between the effective permeability and the mean free path of the gas species. It is clarified that the representative pore size of the porous media fabricated with the pore formers considering the permeation phenomena is larger than that quantified by the microstructural analysis. A numerical model based on the dusty-gas model is developed and three-dimensionally visualizes the flow distribution in porous anodes. The 3D simulation shows that permeation gas mainly flows through the larger pores formed by the pore formers. In addition, the molar flux distribution of the permeation flow for the gases is similar, and its absolute flow rate depends on the physical properties of the permeation gas.

Solitary fibrous tumors (SFTs) are soft tumors (mesenchymal origin) that most likely develop from adult mesenchymal stem cells. SFTs are not common in the head and neck region, and the characteristics of tumors in this location are unclear. The present study describes the clinicopathological findings of 2 cases of SFTs arising in the parotid gland and buccal space, presenting as salivary gland tumors. The first case is a 76-year-old man presenting with a painless tumor on the right parotid gland who subsequently underwent partial superficial parotidectomy. According to the results of histopathological analysis, the tumor consisted of stellate and spindle-shaped cells proliferating on a mucous-like substrate. Immunohistochemical staining revealed that neoplastic cells were positive for CD34, vimentin, Bcl2, and STAT6. The second case is of a 64-year-old man presenting with a painless lump on his right cheek. Based on the findings of fine needle aspiration cytology, a tumor derived from myoepithelial cells of the minor salivary gland or a nonepithelial tumor was suspected. The patient underwent surgical resection via an intraoral approach. Histopathologically, the tumor consisted of spindle-shaped cells with rod-shaped or irregular nuclei. Immunohistochemical staining revealed that the neoplastic cells were positive for CD34, CD99, Bcl2, and STAT6. Briefly, SFT should be considered in the differential diagnosis of a well-marginalized lesion in the salivary gland and oral cavity. STAT6 immunohistochemistry is the most specific and sensitive method of diagnosing SFT. A thorough understanding of the morphological changes associated with SFT and their correlation with clinical, immunohistochemical, and molecular characteristics is important to avoid misdiagnosis.

Introduction: Eosinophils contribute to the pathogenesis of allergic diseases, including asthma, allergic rhinitis, and atopic dermatitis. We previously reported that human tissue eosinophils have high CD69 expression compared to blood eosinophils, and its expression is correlated with disease severity and the number of infiltrated eosinophils. However, biological CD69 signaling activity in eosinophils remains unclear. Methods: CD69 expression on lung tissue eosinophils obtained from mice with ovalbumin-induced asthma was measured using flow cytometry. CD69 crosslinking was performed on eosinophils purified from the spleen of IL-5 transgenic mice to investigate CD69 signaling and its function in eosinophils. Then, qPCR, Western blot, enzyme-linked immunosorbent assay, and survival assay results were analyzed. Results: Surface CD69 expression on lung tissue eosinophils in the asthma mice model was 2.91% ± 0.76%, whereas no expression was detected in the healthy group. CD69-expressed eosinophils intrinsically have an upregulation of IL-10 mRNA expression. Moreover, CD69 crosslinking induced further pronounced IL-10 production and apoptosis; these responses were mediated via the Erk1/2 and JNK pathways, respectively. Conclusions: Our results suggested that CD69+ eosinophils play an immunoregulator role in type 2 inflammation, whereas activated tissue eosinophils contribute to the pathogenesis of asthma.

Uncovering microstructure evolution mechanisms that accompany the long-term operation of solid oxide fuel cells is a fundamental challenge in designing a more durable energy system for the future. To date, the study of fuel cell stack degradation has focused mainly on electrochemical performance and, more rarely, on averaged microstructural parameters. Here we show an alternative approach in which an evolution of three-dimensional microstructural features is studied using electron tomography coupled with topological data analysis. The latter produces persistent diagrams of microstructure before and after long-term operation of electrodes. Those diagrams unveil a new insight into the degradation process of three involved phases: Nickel, pores, and yttrium-stabilized zirconium.

Abstract Background Extranodal extension (ENE) is an adverse prognostic factor for oral squamous cell carcinoma (OSCC), and patients with OSCC along with ENE require neck dissection. In this study, we developed a novel ENE histology-based pathological predictor using MMP14 expression patterns in small biopsy specimens. Methods A total of 71 surgically resected tissue, 64 dissected lymph node (LN), and 46 biopsy specimens were collected from 71 patients with OSCC. Immunohistochemical analyses of total MMP14 expression in the tumour nest and cancer-associated fibroblasts (CAFs) were performed using the MMP14 co-scoring system (high- or low-risk). The association analysis of MMP14 expression in metastatic LNs was performed with respect to the presence and absence of ENE. Clinicopathological analyses and multivariate examinations were performed to assess the risks of metastasis and ENE presence. The predictive value of ENE and the impact of ENE and MMP14 expression on 5-year overall survival were examined. Results High-risk MMP14 expression was detected in metastatic LN specimens with ENE. MMP14 expression in tumour nests and CAFs and its overexpression at the tumour–stromal interface significantly correlated with the presence of ENE. The MMP14 co-scoring system was an independent risk predictor for ENE, with sensitivity, specificity, and accuracy of over 80% in biopsy samples; patients with a high risk in the MMP14 co-scoring system had significantly worse prognoses in both resections and biopsies. Conclusion The MMP14 co-scoring system accurately predicted ENE presence and poor prognosis via immunohistochemical evaluation of small biopsies. This system is a simple, accurate, and inexpensive immunohistochemical approach that can be used in routine pathological diagnosis for effective treatment planning.

Despite the increase in age-related hearing loss (ARHL) prevalence owing to increased population aging, preventive measures against ARHL have not yet been established. The immune system becomes one of the most dysfunctional systems upon aging, and immunosenescence greatly affects homeostasis and promotes systemic aging along with chronic inflammation and oxidative stress. This study aimed to determine whether immuno-rejuvenation procedures can prevent ARHL and have clinical applications as well as to analyze the communication mechanisms between the systemic immune system and the cochlea using a murine model. Lymphocytes from young mice inhibited the progression of ARHL. The method of cryopreserving these lymphocytes and inoculating them at the onset of ARHL suggests their clinical application. Mice that were administered this treatment not only maintained auditory threshold but also avoided spinal ganglion degeneration, cellular immune aging, and nitric oxide production, which causes age-related tissue damage. These findings coincide with our previous strategies against immunosenescence and neuronal aging. Therefore, the manipulation of systemic immune function may contribute not only to the prevention of ARHL but also to the development of novel anti-aging clinical measures, paving the way to healthy longevity with preserved organ function.

Abstract Background Extranodal extension (ENE) is a poor prognostic factor for oral squamous cell carcinoma (OSCC). Identifying ENE by clinical and/or radiological examination is difficult, thereby leading to unnecessary neck dissections. Currently, no definitive predictors are available for ENE. Thus, we aimed to determine the histological predictors of ENE by routine histopathological examination using biopsy and surgically resected specimens. Methods This retrospective study included 186 surgically resected OSCC and 83 matched biopsy specimens. Clinical features associated with the tumor microenvironment, including desmoplastic reaction (DR), tumor budding (TB), and tumor-infiltrating lymphocytes (TILs), were evaluated using hematoxylin and eosin-stained primary OSCC and neck dissection specimens. These histological features were divided into two groups: DR-immature (DR-I) and DR-mature (DR-M); TB-high (TB-H) and TB-low (TB-L); and TILs-low (TILs-L) and TILs-high (TILs-H). Clinical depth of invasion (cDOI) and pathological DOI (pDOI) were adapted for biopsies and resections, respectively; DOI was evaluated as DOI > 10 mm and DOI ≤ 10 mm. The clinicopathological relationships between these histopathological features and ENE and the independent risk factors for ENE were analyzed. The histological predictors of ENE were evaluated. Results The histological status of DR, TILs, and TB present in biopsy and resection specimens showed high accuracy with that of ENE. DR-I, TILs-L, and TB-H were significantly associated with lymph node metastasis, cDOI, and pDOI. Bivariate and multivariate analyses revealed that TB-H and pDOI > 10 mm in resections were independent factors for the presence of ENE (ENE +). The combination of TB-H/pDOI > 10 mm in resection specimens showed high specificity (91%) and accuracy (83%) regarding ENE + . Although there proved to be no independent factors in biopsies, DR-I and TILs-L were significantly associated with ENE + (p 10 mm in biopsies exhibited high sensitivity and specificity with ENE + (70% and 77%, respectively, p 10 mm in biopsy specimens and TB-H/pDOI > 10 mm in resection specimens is a useful predictor of ENE.

Abstract Background Ectopic odontogenic tumours are rare and difficult to diagnose. Consequently, they are occasionally misdiagnosed as other tumours and overtreated. Dentinogenic ghost cell tumours (DGCTs) are odontogenic neoplasms characterised by a CTNNB1 mutation, ghost cell appearance, and dentinoid-like calcification. Herein, we present a case of ectopic DGCT on the floor of a patient’s mouth, providing reliable clinicopathological and genetic evidence of its odontogenicity for the first time. Case presentation A 72-year-old man presented with painless sublingual swelling. Imaging revealed a multi-lobulated, solid-cystic mass on the floor of his mouth. Cytological evaluation showed folded epithelial clusters composed of basaloid cells, keratinised material, and calcification. Histological analysis revealed a multi-cystic, cribriform to solid nest, with an odontogenic satellate reticulum-like epithelium, including ghost cells and dentinoid matrix deposition. Immunohistochemical analysis found that CK19, CK5/6, bcl-2, and p63 were diffuse positive, β-catenin was focal positive in the nuclei, and the cells in the dentinoid matrix were positive for DMP1. The CTNTTB1 mutation was detected, leading to the final diagnosis of ectopic DGCT. There was no recurrence during the 6-month follow-up. Conclusions Overall, we have presented a comprehensive clinical overview of DGCT and identified its pathological and genetic features. This report will aid in the recognition of this rare disease in the future and help to avoid misdiagnosis and overtreatment.

Background/purpose: Tongue pressure plays an important role in swallowing function. The purpose of this study is to investigate whether decreased tongue pressure is associated with dysphagia and the development of pneumonia in the elderly requiring long-term care. Materials and methods: Tongue pressure measurement and swallowing videoendoscopic (VE) examination were performed in 60 hospitalized elderly people (33 males and 27 females, with an average age of 84.3 years) to investigate the relationship with the clinical course. Factors related with dysphagia was analyzed by Fisher's exact test and one-way ANOVA, followed by multivariate logistic regression. The relationship between each variable and survival were analyzed by cox regression. Results: Twenty-one patients had dysphagia by VE examination. Multivariate analysis showed that smaller BMI and reduced tongue pressure were significantly correlated with dysphagia. Smaller number of remaining teeth and dysphagia were significantly related to pneumonia-related death. No patients with tongue pressure of larger than 20 kpa died by pneumonia within one year, while in those with tongue pressure of smaller than 20 kpa, one-year cumulative survival rate by pneumonia was 44.3%. Conclusion: Decreased tongue pressure was significantly associated with dysphagia and may increase the risk of pneumonia-related death in the elderly requiring long-term care.

Eosinophilic airway inflammation, complicated by bronchial asthma and eosinophilic chronic rhinosinusitis (ECRS), is difficult to treat. The disease may become refractory when eosinophilic mucin associated with eosinophil peroxidase (EPX) and autoantibodies fills in the paranasal sinus and small airway. This study investigated the functional role of an anti-EPX antibody in eosinophilic mucin of ECRS in eosinophilic airway inflammation. Eosinophilic mucin was obtained from patients with ECRS. The effects of the anti-EPX antibody on dsDNA release from eosinophils and eosinophilic mucin decomposition were evaluated. Immunofluorescence or enzyme-linked immunosorbent assays were performed to detect the anti-EPX antibody and its supernatant and serum levels in eosinophilic mucin, respectively. The serum levels of the anti-EPX antibody were positively correlated with sinus computed tomography score and fractionated exhaled nitrogen oxide. Patients with refractory ECRS had higher serum levels of the anti-EPX antibody than those without. However, dupilumab treatment decreased the serum levels of the anti-EPX antibody. Immunoglobulins (Igs) in the immunoprecipitate of mucin supernatants enhanced dsDNA release from eosinophils, whereas the neutralization of Igs against EPX stopped dsDNA release. Furthermore, EPX antibody neutralization accelerated mucin decomposition and restored corticosteroid sensitivity. Taken together, the anti-EPX antibody may be involved in the formulation of eosinophilic mucin and be used as a clinical marker and therapeutic target for intractable eosinophilic airway inflammation.

Primary cutaneous adenoid cystic carcinoma (PCACC) is extremely rare, and although distant metastasis has been reported, to date, there are no reports regarding metastasis to the nasal septum. We report a rare case of PCACC that metastasized to the nasal septum 17 years after the first surgery in a 59-year-old woman. She initially presented with a mass under the skin of her left mammary papilla. After a biopsy revealed the presence of an adenoid cystic carcinoma, the tumor was excised and definitively diagnosed as a PCACC. Five years after surgery, the patient presented with left lung metastasis and underwent a partial resection of the left lung. However, 8 years after this procedure, the patient had to undergo a partial resection of the right lung because of right lung metastasis. Four years thereafter, the patient presented with nasal septal metastasis. The tumor was excised successfully using a combined technique integrating intranasal and extranasal approaches. The patient is currently undergoing regular follow-up tests. Thus, in such cases, lifelong follow-up is necessary while checking for both distant metastasis and instances of local recurrence.

Abstract Background Secretory carcinoma (SC) of the salivary gland is a recently described malignant tumor harboring characteristic ETV6-NTRK3 gene fusion. SC generally has a favorable clinical course, and is currently regarded as a low-grade carcinoma. However, a small subset of SCs demonstrates aggressive clinical features with histologically high-grade transformed morphology, the molecular pathogenesis of which has not yet been elucidated. In this study, we performed a clinicopathological and molecular genetic study of patients with SC of the head and neck displaying various clinical characteristics to investigate the differences of pathological and molecular genetics between low-grade and high-grade components of SC. Case presentation Three cases with SC of the head and neck, including a conventional low-grade SC and two high-grade transformed SCs are described. High-grade transformed SCs with histological features such as nuclear polymorphism, distinctive nucleoli and increased mitotic activity developed locoregional recurrence and distant metastasis. Immunohistochemical analysis revealed that low- and high-grade components showed different expression patterns for S-100 protein and mammaglobin, whereas all examined components were positive for p-STAT5. p53-positive cell population was markedly higher in one case with high-grade transformed SC. The proliferative activity of high-grade components was markedly increased, with the Ki-67 labeling index ranging up to 30–32%. A fluorescence in situ hybridization study with an ETV6 (12p13) break apart probe revealed split signals in the nuclei in all 3 cases. A targeted next-generation sequencing-based fusion assay demonstrated that all 6 clinical samples from the 3 patients showed the presence of the ETV6-NTRK3 fusion transcripts. One patient with high-grade transformed SC showed a dramatic clinical response to the pan-TRK inhibitor, entrectinib, for the treatment of locoregional recurrence and pulmonary metastasis. Conclusions High-grade transformed SC showed aggressive clinical and pathological features with increased Ki-67 labeling index. Molecular genetic study of gene rearrangement appears to be beneficial treatment as the presence of ETV6-NTRK3 translocation may represent a therapeutic target in SC, particularly the high-grade transformed type.

Inverted papilloma is the most common benign tumor of the paranasal sinuses with the possibility of malignant transformation. On the one hand, adenoid cystic carcinoma (ACC) is a rare malignant neoplasm that arises from the secretory glands. Sinonasal ACC accounts for 10%–25% of all head and neck ACC. This neoplasm is defined by its distinctive histologic appearance. Surgical resection, whenever possible, is the mainstay therapy. An association between inverted papilloma and malignancy is controversial. A synchronous carcinoma has been established at diagnosis in 3.3%–11% of cases, and the risk of metachronous carcinoma is

Abstract Tooth extraction has been avoided since it has been considered a major risk factor for medication-related osteonecrosis of the jaw (MRONJ). However, MRONJ may also develop from tooth that is an infection source. This study aimed to clarify whether tooth extraction is a risk factor for the development of MRONJ in cancer patients receiving bone-modifying agents (BMAs). This retrospective observational study included 189 patients (361 jaws) from two hospitals. The risk factors of MRONJ were identified by comparing patient characteristics between those who did and did not develop MRONJ. Furthermore, the effect of tooth extraction during BMA therapy was analyzed after adjusting for confounding factors using the propensity score matching method. MRONJ occurred in 33 patients jaws. A longer duration of BMA administration, fewer number of teeth, presence of symptoms of local infection, and infected teeth were independent risk factors of MRONJ. However, tooth extraction during BMA therapy did not increase the risk. Propensity score matching analysis showed that tooth extraction significantly lowered the risk of MRONJ development. Teeth that can be an infection source increases the risk of MRONJ, and thus, they need to be extracted even during BMA administration.

Odontogenic maxillary sinusitis (OMS) is a disease in which inflammation from the teeth extend into the maxillary sinus, causing symptoms of unilateral sinusitis. OMS can recur, with some being resistant to antibiotics. In intractable cases, exodontia and endoscopic sinus surgery (ESS) are necessary treatments. Here we report our analysis on the indications for surgical intervention in cases diagnosed with and treated as OMS. We retrospectively examined 186 patients who were diagnosed with sinusitis on a computed tomography (CT) scan. For cases diagnosed with OMS, the site of the causative tooth and the presence or absence of oroantral fistula to the maxillary sinus was examined. In addition, we analyzed the therapeutic efficacy of the initial treatment of antibiotics, and what the indications were for ESS. Among the patients examined, OMS was diagnosed in 44 cases (23.6%). In 14 out of 20 cases that underwent a post-medical treatment CT scan, OMS found to be treatment-resistant. Of these 14 cases, 12 (88%) had oroantral fistulae to the maxillary sinus. In all cases where exodontia, fistula closure surgery, and endoscopic sinus surgery (ESS) were performed, the fistula disappeared and the shadow of inflammation in the paranasal sinus improved. In OMS with oroantral fistula, ESS, exodontia, and fistula closure should be recommended over medication such as macrolide therapy.

Eosinophils not only play a critical role in the pathogenesis of eosinophil-associated diseases, but they also have multiple important biological functions, including the maintenance of homeostasis, host defense against infections, immune regulation through canonical Th1/Th2 balance modulation, and anti-inflammatory and anti-tumorigenic activities. Recent studies have elucidated some emerging roles of eosinophils in steady-state conditions; for example, eosinophils contribute to adipose tissue metabolism and metabolic health through alternatively activated macrophages and the maintenance of plasma cells in intestinal tissue and bone marrow. Moreover, eosinophils exert tissue damage through eosinophil-derived cytotoxic mediators that are involved in eosinophilic airway inflammation, leading to diseases including asthma and chronic rhinosinusitis with nasal polyps characterized by fibrin deposition through excessive response by eosinophils-induced. Thus, eosinophils possessing these various effects reflect the heterogenous features of these cells, which suggests the existence of distinct different subpopulations of eosinophils between steady-state and pathological conditions. Indeed, a recent study demonstrated that instead of dividing eosinophils by classical morphological changes into normodense and hypodense eosinophils, murine eosinophils from lung tissue can be phenotypically divided into two distinct subtypes: resident eosinophils and inducible eosinophils gated by Siglec-Fint CD62L+ CD101low and Siglec-Fhigh CD62L– CD101high, respectively. However, it is difficult to explain every function of eosinophils by rEos and iEos, and the relationship between the functions and subpopulations of eosinophils remains controversial. Here, we overview the multiple roles of eosinophils in the tissue and their biological behavior in steady-state and pathological conditions. We also discuss eosinophil subpopulations.

Background: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis associated with asthma. CD69 is an important marker of activation for eosinophils. But, whether a correlation exist between the CD69 expression on eosinophils and clinical findings is unclear. Methods: We performed quantitative PCR and/or flow cytometry using tissue and purified eosinophils from the blood and nasal polyps of 12 patients with ECRS and from 8 patients without ECRS (controls). We assessed clinical findings including nasal polyp (NP) scores, sinus CT findings, and pulmonary function test results, and examined their possible association with the CD69 expression. We also performed CD69 cross-linking experiments in mouse eosinophils to investigate the functional role of CD69. Results: Levels of cytokine mRNAs (IL-4, -5, -10, and -13) were significantly higher in purified NP eosinophils and tissues from patients with ECRS than the levels of those in controls. The expressions of major basic protein (MBP), eosinophilic cationic protein (ECP), eosinophilic-derived neurotoxin (EDN), eosinophil peroxidase (EPX) in cytotoxic granules, and CD69 mRNA were significantly higher in purified eosinophils from NPs than in those from blood. We also found a correlation between expression of CD69 and clinical findings. Moreover, we found EPX release from mouse eosinophils following CD69 cross-linking. Conclusions: These data suggest that increased CD69 expression by eosinophils is not only a biomarker for nasal obstruction and pulmonary dysfunction, but also a potential therapeutic target for patients with ECRS and asthma. Keywords: Asthma, CD69, Chronic rhinosinusitis, Eosinophil, Nasal polyp

Abstract The presented research shows that the long-term operation of a solid oxide fuel cell can lead to substantial anisotropic changes in anode material. The morphology of microstructure in the investigated stack was observed before and after the aging test using electron nanotomography. The microstructural parameters were estimated based on the obtained digital representation of the anode microstructure. Anisotropy was discovered in two of the three phases that constitute the anode, namely nickel and pores. The third component of the anode, which is yttrium-stabilized zirconia, remains isotropic. The changes appear at the microscale and significantly affect the transport phenomena of electrons and gasses. The obtained results indicate that the reference anode material that represents the microstructure before the aging test has isotropic properties which evolve toward strong anisotropy after 3800 h of constant operation. The presented findings are crucial for a credible numerical simulation of solid oxide fuel cells. They indicate that all homogeneous models must adequately account for the microstructure parameters that define the anisotropy of transport phenomena, especially if microstructural data is taken from a post-operational anode.

Eosinophilic airway inflammatory disease is associated with bronchial asthma, with eosinophilic chronic rhinosinusitis (ECRS) typical of refractory type 2 airway inflammation. CCL4 produced at local inflammatory sites is involved in them via the accumulation and activation of type 2 inflammatory cells, including eosinophils. The detailed mechanism of CCL4 production remains unclear, and also the possibility it could function as a biomarker of type 2 airway inflammation remains unresolved. In this study, we evaluated CCL4 mRNA expression and production via the TSLP receptor (TSLPR) and toll-like receptors (TLRs) or proteinase-activated receptor-2 (PAR2) in BEAS-2B bronchial epithelial cells co-incubated with purified eosinophils or eosinophil peroxidase (EPX). We examined serum chemokine (CCL4, CCL11, CCL26, and CCL17) and total IgE serum levels, fractionated exhaled nitrogen oxide (FENO), and CCL4 expression in nasal polyps in patients with severe ECRS and asthma. CCL4 was induced by TSLP under eosinophilic inflammation. Furthermore, CCL4 was released via TLR3 signaling, which was enhanced by TSLP. CCL4 was mainly located in nasal polyp epithelial cells, while serum CCL4 levels were reduced after dupilumab treatment. Serum CCL4 levels were positively correlated with FENO, serum IgE, and CCL17 levels. Thus, CCL4 released from epithelial cells via the innate immune system during type 2 airway inflammation may function as a useful biomarker for the condition.

As CMOS devices are scaled down to a nanoscale range, characteristic variability has become a critical issue for yield and performance control of gigascale integrated circuit manufacturing. Nanoscale in size, few monolayers thick, and less thermally stable high-k interfaces all together cause more significant surface roughness-induced local electric field fluctuation and thus leads to a large device characteristic variability. This paper presents a comprehensive study and detailed discussion on the gate leakage variabilities of nanoscale devices corresponding to the surface roughness effects. By taking the W/La2O3/Si structure as an example, capacitance and leakage current variabilities were found to increase pronouncedly for samples even with a very low-temperature thermal annealing at 300 °C. These results can be explained consistently with the increase in surface roughness as a result of local oxidation at the La2O3/Si interface and the interface reactions at the W/La2O3 interface. The surface roughness effects are expected to be severe in future generations’ devices with even thinner gate dielectric film and smaller size of the devices.

Eosinophilic chronic rhinosinusitis (ECRS), which is a subgroup of chronic rhinosinusitis with nasal polyps, is characterized by eosinophilic airway inflammation extending across both the upper and lower airways. Some severe cases are refractory even after endoscopic sinus surgery, likely because of local steroid insensitivity. Although real-life studies indicate that treatment with omalizumab for severe allergic asthma improves the outcome of coexistent ECRS, the underlying mechanisms of omalizumab in eosinophilic airway inflammation have not been fully elucidated. Twenty-five patients with ECRS and severe asthma who were refractory to conventional treatments and who received omalizumab were evaluated. Nineteen of twenty-five patients were responsive to omalizumab according to physician-assessed global evaluation of treatment effectiveness. In the responders, the levels of peripheral blood eosinophils and fractionated exhaled nitric oxide (a marker of eosinophilic inflammation) and of CCL4 and soluble CD69 (markers of eosinophil activation) were reduced concomitantly with the restoration of corticosteroid sensitivity. Omalizumab restored the eosinophil-peroxidase-mediated PP2A inactivation and steroid insensitivity in BEAS-2B. In addition, the local inflammation simulant model using BEAS-2B cells incubated with diluted serum from each patient confirmed omalizumab’s effects on restoration of corticosteroid sensitivity via PP2A activation; thus, omalizumab could be a promising therapeutic option for refractory eosinophilic airway inflammation with corticosteroid resistance.

Metastatic renal cell carcinoma (RCC) involving the temporal bone is a rare entity. It is usually asymptomatic and misdiagnosis as acute otitis media, mastoiditis, and Ramsay-Hunt syndrome in early onset is not uncommon. We report a case of RCC metastasis to the postoperative temporal bone in the middle of molecular targeted therapy. A 60-year-old man presented left facial palsy with severe retro-auricular pain and he also underwent left middle ear surgery for cholesteatoma more than 30 years before and had been aware of discontinuous otorrhea; therefore, initially we speculated that facial palsy was derived from recurrent cholesteatoma or Ramsay-Hunt syndrome. Exploratory tympanotomy revealed RCC metastasis and postoperative MR indicated hematogenous metastasis. To the best of our knowledge, no report was obtained on temporal bone metastasis in the middle of chemotherapy or hematogenous metastasis in the postoperative middle ear. Metastasis in the temporal bone is still a possible pathological condition despite the development of present cancer therapy. Besides, this case indicates that hematogenous metastasis can occur in the postoperative state of the temporal bone.

Background: Mammary analogue secretory carcinoma (MASC) is a pathological entity arising in the salivary glands first described by Skalova et al. [Am J Surg Pathol 2010;34: 599–608]. Here, we report the first case of MASC presenting as a cervical lymph node metastasis of unknown primary site together with a brief review of the literature. Case Report: We present a 74-year-old male with a painless lump in his left neck. Based on the fine-needle aspiration cytological findings, a possible malignant tumor was suspected. No evidence of a primary lesion was observed using imaging modalities including positron emission tomography/computed tomography. The patient underwent an ipsilateral modified radical neck dissection. Immunohistochemical staining showed that the neoplastic cells were positive for S100 protein and GATA3. A rearrangement of the ETV6 gene was noted during fluorescence in situ hybridization, and the final histopathological diagnosis was MASC. Conclusion: We encountered a MASC presenting as a cervical lymph node metastasis of unknown primary site. No adjuvant therapy was administered, and no local recurrence or metastatic disease has been detected during a follow-up period of 9 months. This is the first case report of MASC presenting as a cervical lymph node metastasis of unknown primary site and suggests the new properties of MASC.

Background Eosinophilic cholecystitis (EC) is a rare condition that presents in a manner comparable to acute cholecystitis. The diagnosis is based on classical symptoms of cholecystitis with excessive eosinophilic infiltration within the gallbladder. EC has been reported alone or in combination with manifestations, such as eosinophilic gastrointestinal tract inflammation. However, association with airway inflammation in patients with EC is rare. Case Presentation: We report the case of a 65-year-old man who had refractory eosinophilic chronic rhinosinusitis with bronchial asthma. A second endoscopic sinus surgery (ESS) was performed as treatment for recurrent nasal polyps. EC occurred while inhaled corticosteroids were reduced after ESS. Pathologic examination of the excised gallbladder demonstrated submucosal infiltration with a number of eosinophils. Furthermore, immunohistostaining revealed many galectin-10-positive cells in both the gallbladder mucosa and the paranasal sinus mucosa. Galectin-10 is a major constituent of human eosinophils, also known as the Charcot–Leyden crystal protein, which has been linked with eosinophilic inflammation. Interestingly, nasal polyps were reduced without any additional treatments 1 month after the cholecystectomy. Conclusions We experienced a rare case wherein EC onset occurred in a patient with refractory eosinophilic airway inflammation during inhaled corticosteroid tapering. Galectin-10 might help diagnose rare cases of eosinophilic inflammation in multiple organs.

The purpose of this paper is to develop an analytical model of frost/ice formation on the heat exchanger (condenser) of high-pressure water separation used in the air conditioning system of commercial jet aircraft. The high-pressure water separation is based on the heat exchange between the upstream and downstream sides of the same air flow with pressure difference. That is, relatively high-pressure and warmer air upstream of a condenser with high humidity is cooled by relatively low-pressure and cooler air discharged from a turbine downstream of the condenser; condensed water in the high-pressure side is removed by a water separator while in the low-pressure side the super-cooled water mist is produced by adiabatic expansion process in the turbine. In the both sides, when the heat-exchange fins are below the freezing temperature of the humid air, frost/ice formation occur, although their physical mechanism are utterly different. In this study, a phase-change model taking the features of a cross-flow heat exchanger into account is newly proposed. In particular, attention is focused on the increase of the pressure drop in the lower pressure side due to frost/ice formation. The validity of the analytical model is checked by the comparison with the experiment.

The purpose of this study is to develop an analytical model of cross-flow heat exchangers with offset strip fins which are usually equipped in the aircraft air conditioning system (so called the environmental control system, ECS). The ECS mainly consists of four cross-flow heat exchanges, i.e., a primary heat exchanger, a secondary heat exchanger, a reheater and a condenser. Because of the special requirements of the design for the aircraft, the primary and secondary heat exchangers are set adjoiningly; the reheater and the condenser are also set adjoingly. Therefore, in both the pairs, the effect of the temperature profile of the upstream component (the secondary heat exchanger or the reheater) on those of the downstream component (the primary heat exchanger or the condenser) should be taken into account for precise prediction of the system. To this end, a core element model was newly proposed in this study. In addition to the effect of temperature profile, phase changes (condensation and evaporation) of water included in the humid air simultaneously occur except for the primary heat exchanger. Regarding these phenomena, the method of sensible heat fraction (SHF) to convert the latent heat into the equivalent sensible heat was introduced, and the global and local SHF models were examined by comparison with the experiments. The prediction by these models were found to agree well with the actual performance of the ECS operations.

Eosinophilic chronic rhinosinusitis (ECRS), a subgroup of chronic rhinosinusitis with nasal polyps, is recognized as a refractory eosinophilic disorder characterized by both upper and lower airway inflammation. In some severe cases, disease control is poor, likely due to local steroid insensitivity. In this study, we focused on protein phosphatase 2A (PP2A), a key factor regulating glucocorticoid receptor (GR) nuclear translocation, and examined its association with local responses to corticosteroids in eosinophilic airway inflammation. Our results indicated reduced responses to corticosteroids in nasal epithelial cells from ECRS patients with asthma, which were also associated with decreased PP2A mRNA expression. Eosinophil peroxidase stimulates elevated PP2A phosphorylation levels, reducing PP2A protein expression and activity. In addition, mRNA levels of inflammatory mediators (TSLP, IL-25, IL-33, CCL4, CCL5, CCL11, and CCL26) associated with eosinophilic airway inflammation in epithelial cells were increased in nasal polyps (eosinophil-rich areas) compared with those in uncinate process tissues (eosinophil-poor areas) from the same patients. PP2A reduction by siRNA reduced GR nuclear translocation, whereas PP2A overexpression by plasmid transfection, or PP2A activation by formoterol, enhanced GR nuclear translocation. Collectively, our findings indicate that PP2A may represent a promising therapeutic target in refractory eosinophilic airway inflammation characterized by local steroid insensitivity.

Background: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis with nasal polyps in Japanese. ECRS highly associated with asthma is a refractory eosinophilic airway inflammation and requires comprehensive care as part of the united airway concept. We recently reported a series of ECRS patients with asthma treated with fine-particle inhaled corticosteroid (ICS) exhalation through the nose (ETN).Objective: To evaluate fine-particle ICS ETN treatment as a potential therapeutic option in ECRS with asthma.Methods: Twenty-three patients with severe ECRS under refractory to intranasal corticosteroid treatment were randomized in a double-blind fashion to receive either HFA-134a-beclomethasone dipropionate (HFA-BDP) metered-dose inhaler (MDI) ETN (n = 11) or placebo MDI ETN (n = 12) for 4 weeks. Changes in nasal polyp score, computed tomographic (CT) score, smell test, and quality of life (QOL) score from baseline were assessed. Fractionated exhaled nitric oxide (FENO) was measured as a marker of eosinophilic airway inflammation. Response to corticosteroids was evaluated before and after treatment. Additionally, deposition of fine-particles was visualized using a particle deposition model. To examine the role of eosinophils on airway inflammation, BEAS-2B human bronchial epithelial cells were co-incubated with purified eosinophils to determine corticosteroid sensitivity.Results: HFA-BDP MDI ETN treatment improved all assessed clinical endpoints and corticosteroid sensitivity without any deterioration in pulmonary function. FENO and blood eosinophil number were reduced by HFA-BDP MDI ETN treatment. The visualization study suggested that ETN at expiratory flow rates of 10–30 L/min led to fine particle deposition in the middle meatus, including the sinus ostia. Co-incubation of eosinophils with BEAS-2B cells induced corticosteroid resistance.Conclusions: Additional HFA-BDP MDI ETN treatment was beneficial in patients with ECRS and should be considered as a potential therapeutic option for eosinophilic airway inflammation such as ECRS with asthma. (UMIN-CTR: R000019325) (http://www.umin.ac.jp/ctr/index.htm).

Airway hyperresponsiveness (AHR) has been proposed as a feature of pathogenesis of eosinophilic upper airway inflammation such as allergic rhinitis (AR). The measurement system for upper AHR (UAHR) in rodents is poorly developed, although measurements of nasal resistance have been reported. Here we assessed UAHR by direct measurement of swelling of the nasal mucosa induced by intranasal methacholine (MCh) using micro-computed tomography (micro-CT). Micro-CT analysis was performed in both naïve and ovalbumin-induced AR mice following intranasal administration of MCh. The nasal cavity was segmented into two-dimensional horizontal and axial planes, and the data for nasal mucosa were acquired for the region of interest threshold. Then, a ratio between the nasal mucosa area and nasal cavity area was calculated as nasal mucosa index. Using our novel method, nasal cavity structure was clearly identified on micro-CT, and dose-dependent increased swelling of the nasal mucosa was observed upon MCh treatment. Moreover, the nasal mucosa index was significantly increased in AR mice compared to controls following MCh treatment, while ovalbumin administration did not affect swelling of the nasal mucosa in either group. This UAHR following MCh treatment was completely reversed by pretreatment with glucocorticoids. This novel approach using micro-CT for investigating UAHR reflects a precise assessment system for swelling of the nasal mucosa following MCh treatment; it not only sheds light on the mechanism of AR but also contributes to the development of new therapeutic drugs in AR patients.

The concept of united airway disease comprises allergic rhinitis (AR) with asthma, and eosinophilic chronic rhinosinusitis (ECRS) with asthma. It embodies a comprehensive approach to the treatment of upper and lower airway inflammation. The treatment of upper airway inflammation reduces asthma symptoms and decreases the dose of inhaled corticosteroids (ICS) necessary to treat asthma. However, little is known about the mechanisms of interaction between upper and lower airway inflammation. Here we review these mechanisms, focusing on neural modulation and introduce a novel therapeutic approach to united airway disease using a fine-particle ICS. Our understanding of the relationship between the upper and lower airways and its contribution to T helper 2 (Th2)-skewed disease, such as AR and/or ECRS with asthma, has led us to this novel therapeutic strategy for a comprehensive approach to the treatment of upper airway inflammation with asthma.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a refractory upper airway disease, accompanied mainly by eosinophilia and/or asthma. In addition, the disease correlates with a high rate of hyposmia, following a marked infiltration of eosinophils into the inflamed site, the paranasal sinus. Although eosinophils are known to contribute to the development of hyposmia and CRSwNP pathology, the underlying mechanisms remain unclear. This study aimed to investigate whether eosinophilic upper airway inflammation induces hyposmia and CRSwNP in a murine model using an adoptive transfer system. Methods: To induce eosinophilic rhinosinusitis, splenocytes, including a high proportion (over 50%) of activated eosinophils (SPLhEos), were collected from interleukin-5 transgenic mice following double intraperitoneal injections of antigens, such as ovalbumin, house dust mite, or fungus. Activated SPLhEos with corresponding antigens were then transferred into the nasal cavity of recipient mice, which were sensitized and challenged by the corresponding antigen four times per week. Olfactory function, histopathological, and computed tomography (CT) analyses were performed 2 days after the final transfer of eosinophils. Results: Hyposmia was induced significantly in mice that received SPLhEos transfer compared with healthy and allergic mice, but it did not promote morphological alteration of the paranasal sinus. Pathological analysis revealed that epithelial layer injury and metaplasia similar to polyps, with prominent eosinophil infiltration, was induced in recipient tissue. However, there was no nasal polyp development with interstitial edema that was similar to those recognized in human chronic rhinosinusitis. Conclusions: This study supports the previously unsuspected contribution of eosinophils to CRS development in the murine model and suggests that murine-activated eosinophilic splenocytes contribute to the development of hyposmia due to more mucosal inflammation than physical airway obstruction and epithelial layer injury with convex lesions.

This study presents a method that can be employed to obtain the reaction rate and be widely applied to the simulation of steam methane reforming in a channel with a catalyst on the wall. Prior to the numerical simulation, an experiment was performed in an annular channel, in which the catalyst was deposited on the outer surface of the inner tube. In addition to varying the temperature and composition of the reactants, the velocity was also varied in order to investigate the range where the reaction-limiting condition occurs. Next, the results from the bulk concentration of the products were interpreted to determine the reaction rate of the surface catalyst. The reaction rate was properly introduced into the numerical simulation in two dimensions, although this method for obtaining the reaction rate is generally applied to a field that is supposed to be one-dimensional as a packed catalyst. On the other hand, a discrepancy between the experimental and simulation results was observed at a low velocity. The reason for this was investigated by considering the concentration and profile of the reactants. As a result, we concluded that it was necessary to pay close attention in a case where the amount of the reaction varied with the velocity, because the actual phenomena were controlled by other mechanisms that were not introduced into the numerical simulation.

Hydrogen can be used not only as a fuel, but also for the chemical processing. One of the applications is as a synthesis gas in the gas-to-liquid (GTL) process which produces liquid fuel from a gaseous one and has tremendous potential for the future energy industry. Steam methane reforming (SMR) is one of the major methods of hydrogen production. To optimize SMR, pressure dependence is important since the Fischer-Tropsch (FT) process, which is the oil production process in GTL, favors high pressure. In this study, using the rate expressions of SMR, which are obtained by experiment using a nickel-based catalyst supported on a metal plate in a rectangular channel, two-dimensional (2-D) simulation was performed at four different pressures ranging from 0.1 to 0.4 MPa in addition to one-dimensional (1-D) simulation. The reaction rates deduced from the experimental results on the basis of pseudo-bulk reaction naturally fit the 1-D simulation. The more precise 2-D simulation, however, inevitably needs some modification to reasonably predict the phenomena on the basis of the data from the pseudo-bulk reaction. As a result, the discrepancy between the results could be fixed by adjusting the reaction rate for the related pressure, and the adjusted factors show consistency between 1-D and 2-D calculations. Finally, the proper rate equations were estimated.

A physically based subthreshold current model for silicon nanowire transistors working in the ballistic regime is developed. Based on the electric potential distribution obtained from a 2D Poisson equation and by performing some perturbation approximations for subband energy levels, an analytical model for the subthreshold drain current is obtained. The model is further used for predicting the subthreshold slopes and threshold voltages of the transistors. Our results agree well with TCAD simulation with different geometries and under different biasing conditions.

Use of thin metal wire structures as a new type of extended heat transfer surface is proposed. As one of the most basic shapes of such wire structures, heat transfer performance of spring shaped fins is experimentally investigated under relatively low Reynolds number conditions. The averaged heat transfer coefficient is evaluated by a single-blow method while the pressure drop is measured at a steady state flow condition. The effects of the geometric parameters such as the wire diameter, the spring pitch and the pitch ratio were systematically examined and the obtained data were compared with that of a conventional offset fin, which is commercially available. It was found that the geometric parameters of the spring fins and the arrangement of spring fins in the test section affect their heat transfer performance. Some types of spring fins showed better heat transfer performance than a conventional offset fin, when they are evaluated in terms of the total heat transfer at a constant pumping power.

The purpose of this study is to clarify the effect of a component for high-pressure water separation, which is included in the air conditioning system of the general commercial aircrafts, on the air-cycle operation (reverse Brayton cycle); the high-pressure water separation consists of water separator and two heat exchangers called reheater and condenser, respectively. This paper briefly describes the typical system configuration of the air-cycle refrigeration progressed with evolutions in turbofan engine. Since nowadays, 4-Wheel air-cycle has been a trend on the aircraft air conditioning system, this paper theoretically shows its advantage on the basis of the thermodynamic cycle study. In the following chapters, an analysis was conducted on the interaction between a reheater and a condenser when each heat transfer performance changes from the baseline operating point. Also, the comparative study was made on the system performances by the 3-wheel and 4-wheel air-cycle. In addition, this paper describes how the heat transfer performance is designed for the reheater and the condenser under the system requirements for the entire air conditioning system.

This work presents a detailed study on the chemical composition and bond structures of CeO2/La2O3 stacked gate dielectrics based on x-ray photoelectron spectroscopy (XPS) measurements at different depths. The chemical bonding structures in the interfacial layers were revealed by Gaussian decompositions of Ce 3d, La 3d, Si 2s, and O 1s photoemission spectra at different depths. We found that La atoms can diffuse into the CeO2 layer and a cerium-lanthanum complex oxide was formed in between the CeO2 and La2O3 films. Ce3+ and Ce4+ states always coexist in the as-deposited CeO2 film. Quantitative analyses were also conducted. The amount of CeO2 phase decreases by about 8% as approaching the CeO2/La2O3 interface. In addition, as compared with the single layer La2O3 sample, the CeO2/La2O3 stack exhibits a larger extent of silicon oxidation at the La2O3/Si interface. For the CeO2/La2O3 gate stack, the out-diffused lanthanum atoms can promote the reduction of CeO2 which produce more atomic oxygen. This result confirms the significant improvement of electrical properties of CeO2/La2O3 gated devices as the excess oxygen would help to reduce the oxygen vacancies in the film and would suppress the formation of interfacial La-silicide also.

SMXA-5 mice are a high-fat diet-induced type 2 diabetes animal model established from non-diabetic SM/J and A/J mice. By using F2 intercross mice between SMXA-5 and SM/J mice under feeding with a high-fat diet, we previously mapped a major diabetogenic QTL (T2dm2sa) on chromosome 2. We then produced the congenic strain (SM.A-T2dm2sa (R0), 20.8-163.0 Mb) and demonstrated that the A/J allele of T2dm2sa impaired glucose tolerance and increased body weight and body mass index in the congenic strain compared to SM/J mice. We also showed that the combination of T2dm2sa and other diabetogenic loci was needed to develop the high-fat diet-induced type 2 diabetes. In this study, to narrow the potential genomic region containing the gene(s) responsible for T2dm2sa, we constructed R1 and R2 congenic strains. Both R1 (69.6-163.0 Mb) and R2 (20.8-128.2 Mb) congenic mice exhibited increases in body weight and abdominal fat weight and impaired glucose tolerance compared to SM/J mice. The R1 and R2 congenic analyses strongly suggested that the responsible genes existed in the overlapping genomic interval (69.6-128.2 Mb) between R1 and R2. In addition, studies using the newly established R1A congenic strain showed that the narrowed genomic region (69.6-75.4 Mb) affected not only obesity but also glucose tolerance. To search for candidate genes within the R1A genomic region, we performed exome sequencing analysis between SM/J and A/J mice and extracted 4 genes (Itga6, Zak, Gpr155, and Mtx2) with non-synonymous coding SNPs. These four genes might be candidate genes for type 2 diabetes caused by gene-gene interactions. This study indicated that one of the genes responsible for high-fat diet-induced diabetes exists in the 5.8 Mb genomic interval on mouse chromosome 2.