Publications by authors named "Hiroshi Iwai"

102 Publications

Treg and IL-1 receptor type 2-expressing CD4 T cell-deleted CD4 T cell fraction prevents the progression of age-related hearing loss in a mouse model.

J Neuroimmunol 2021 Aug 8;357:577628. Epub 2021 Jun 8.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, Hirakata, Osaka, Japan.

We investigated the association between cellular immunity and age-related hearing loss (ARHL) development using three CD4 T cell fractions, namely, naturally occurring regulatory T cells (Treg), interleukin 1 receptor type 2-expressing T cells (I1R2), and non-Treg non-I1R2 (nTnI) cells, which comprised Treg and I1R2-deleted CD4 T cells. Inoculation of the nTnI fraction into a ARHL murine model, not only prevented the development of ARHL and the degeneration of spiral ganglion neurons, but also suppressed serum nitric oxide, a source of oxidative stress. Further investigations on CD4 T cell fractions could provide novel insights into the prevention of aging, including presbycusis.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577628DOI Listing
August 2021

Utility of an immunocytochemical analysis for pan-Trk in the cytodiagnosis of secretory carcinoma of the salivary gland.

Diagn Cytopathol 2021 Aug 22;49(8):E329-E335. Epub 2021 Apr 22.

Department of Pathology and Laboratory Medicine, Kansai Medical University, Osaka, Japan.

Secretory carcinoma (SC) of the salivary gland is a rare distinct clinicopathological entity characterized by the presence of the ETV6-NTRK3 fusion. Although the characteristic cytological features of SC have been recognized, its cytodiagnosis, especially differentiating SC from acinic cell carcinoma, is challenging. Recent studies have revealed that immunohistochemistry for pan-tyrosine receptor kinase (Trk) and nuclear receptor subfamily 4 group member 3 (NR4A3) are specific for SC and acinic cell carcinoma, respectively. However, the usefulness of immunocytochemical detection of these markers in the diagnosis of SC has not been addressed. Hence, the present study aimed to analyze the usefulness of immunocytochemical staining for pan-Trk and NR4A3 in the cytodiagnosis of SC. We enrolled eight patients with a histopathological diagnosis of SC who underwent preoperative fine-needle aspiration cytological examination. The cytological characteristics were reviewed and immunocytochemical staining for pan-Trk and NR4A3 was performed. The characteristic cytological features noted in the patient cohort included neoplastic cell clusters with a sheet-like and papillary cluster arrangement as well as single cells. Additionally, neoplastic cells with mild to moderately enlarged nuclei and small nucleoli, multi-vacuolated cytoplasm, and intracytoplasmic mucin were also observed. The immunocytochemical analyses clearly demonstrated that all eight specimens showed positive nuclear staining for pan-Trk, but were negative for NR4A3 expression. Although all cases of SC do not always show positive immunoreactivity for pan-Trk, immunocytochemical analysis for pan-Trk may be useful for the cytodiagnosis of SC along with assessment of the characteristic cytological features.
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http://dx.doi.org/10.1002/dc.24750DOI Listing
August 2021

Periosteal reaction of medication-related osteonecrosis of the jaw (MRONJ): clinical significance and changes during conservative therapy.

Support Care Cancer 2021 Apr 21. Epub 2021 Apr 21.

Department of Oral Health, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan.

Purpose: We previously reported that the periosteal reaction (PR) in medication-related osteonecrosis of the jaw (MRONJ) is a poor prognostic factor in surgical cases, but it is not clear how PR changes during conservative therapy. The purpose of this retrospective study was to compare computed tomography (CT) findings at the first visit and during follow-up visits in MRONJ patients subjected to conservative therapy and to investigate factors associated with the exacerbation of PR during conservative therapy.

Methods: Sixteen patients with MRONJ of the lower jaw who underwent conservative therapy and experienced a PR on CT images at the first visit and underwent CT examination again after 6 months or more were enrolled in the study. Clinical features and CT findings (extent of osteolytic lesion, extent of PR, type of PR, and changes during conservative treatment) were investigated.

Results: On the second CT scan, the osteolytic lesion improved in 4 patients, had not changed in 5, and deteriorated in 7, whereas the PR improved in 5 patients, had not changed in 4, and deteriorated in 7 patients. PR was significantly deteriorated in patients who continued to receive antiresorptive agents during conservative treatment and in patients with deteriorated osteolytic lesions.

Conclusion: PR in MRONJ often expands during conservative therapy and the PR type progresses from the attached type to the gap type, and the irregular type, but discontinuation of antiresorptive agent may improve PR as well as osteolytic lesions.
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http://dx.doi.org/10.1007/s00520-021-06214-9DOI Listing
April 2021

Identification of risk factors for mortality and delayed oral dietary intake in patients with open drainage due to deep neck infections: Nationwide study using a Japanese inpatient database.

Head Neck 2021 07 2;43(7):2002-2012. Epub 2021 Mar 2.

Department of Otolaryngology Head and Neck Surgery, Kansai Medical University, Hirakata, Japan.

Backgrounds: Data on risk factors for deep neck infection including descending necrotizing mediastinitis (DNM) have been limited. Using a nationwide database, the aim was identifying the factors related to patient death and delay in recovering oral intake.

Methods: Data of 4949 patients were extracted from a Japanese inpatient database between 2012 and 2017. The main outcome was survival at discharge. In a subgroup analysis of the 4949 patients with survival, the second outcome was delay in the interval between admission and full recovery of oral intake.

Results: Only a few factors (advanced-age, ventilation) were associated with both mortality and delayed oral dietary intake by logistic regression analyses. Conversely, several factors including DNM (adjusted-odds ratio [OR] 1.41) and repeated surgery (adjusted-OR 1.70) were significantly related only to delayed oral dietary intake.

Conclusions: Although DNM was not necessarily related to mortality, patients with DNM should receive careful attention to avoid delayed oral dietary intake.
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http://dx.doi.org/10.1002/hed.26660DOI Listing
July 2021

Review of the cytological features of olfactory neuroblastoma: A retrospective single-center study.

Diagn Cytopathol 2021 Aug 25;49(8):E301-E306. Epub 2021 Feb 25.

Department of Pathology and Laboratory Medicine, Kansai Medical University, Osaka, Japan.

Olfactory neuroblastoma (ONB) is a rare malignant neuroectodermal tumor. Due to the rarity, there are scarce reports describing the cytological features of ONB. Thus, we aimed to analyze these cytological features and discuss their differences depending on the histological grading of ONB. Patients with a histopathological diagnosis of ONB who underwent fine-needle aspiration cytology were enrolled in the study. The cytological features, including arrangement and shape of neoplastic cells, nuclear features, and presence of rosettes, were analyzed. Eight patients with ONB were enrolled; cytological specimens of seven patients were obtained from metastatic lesions and that of one patient were obtained from the nasal cavity tumor. The cytological specimens demonstrated variable-sized clusters of neoplastic cells and single cells. Two-cell pattern, composed of large-sized viable neoplastic cells and small-sized apoptotic cells, was noted in 3 of 4 high-grade ONBs but in none of 4 low-grade ONBs. This reflects that the presence of the two-cell pattern may represent higher proliferation in neoplastic cells. The neoplastic cells had scant cytoplasm and round to oval nuclei containing fine to granular chromatin without conspicuous nucleoli. Rosettes and paranuclear blue bodies were observed in one patient. Most cytological specimens of ONB were obtained from metastatic lesions, especially from the cervical lymph node. Thus, ONB should be differentiated from malignant lymphoma and small cell neuroendocrine carcinoma. Recognition of these cytological features of ONB while considering patient history can aid in correctly diagnosing ONBs. Moreover, the presence of two-cell pattern might reflect high-grade histology of ONB.
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http://dx.doi.org/10.1002/dc.24728DOI Listing
August 2021

Long-term sublingual immunotherapy provides better effects for patients with Japanese cedar pollinosis.

Auris Nasus Larynx 2021 Aug 29;48(4):646-652. Epub 2021 Jan 29.

Department of Otorhinolaryngology, Kansai Medical University, shinmachi 2-5-1, Hirakata, Osaka, Japan.

Objective: Japanese cedar pollinosis is an endemic disease affecting a large proportion of Japan's population. Five seasons have passed since sublingual immunotherapy (SLIT) for Japanese cedar pollinosis was included in the public insurance coverage in Japan. In this study, we evaluated the clinical effects of long-term SLIT for Japanese cedar pollinosis on upper respiratory symptoms primarily represented by nasal symptoms and inflammation of the respiratory tract in the 2019 season, in which considerable amount of cedar pollen was dispersed.

Methods: This study involved 95 patients who were undergoing SLIT for Japanese cedar pollinosis after the initiation at some point between 2014 and 2018, and this group of patients was compared with a control group comprising 21 patients receiving preseasonal prophylactic treatment (with a second-generation antihistaminic drug). We evaluated the patients' nasal/eye symptoms, total nasal symptom and medication score (TNSMS), and quality of life according to relevant guidelines. In addition, the levels of peripheral blood eosinophils, serum total IgE, Japanese cedar antigen-specific IgE, Cryj1-specific IgG4, and fractional exhaled nitric oxide (FENO) were measured as objective indices.

Results: From the fourth season (SLIT4), nasal discharge, sneezing, nasal obstruction symptoms, and TNSMS significantly decreased compared with those in the preseasonal prophylactic treatment and SLIT1 groups. In the patients suspected to have eosinophilic airway inflammation (with a baseline FENO ≥25 ppb), the interannual variability of FENO levels significantly reduced after 5 years of treatment.

Conclusion: The efficacy of SLIT was noted from the first year of treatment, even in a year when pollen profusely dispersed. Thus, long-term continuous treatment with SLIT may alleviate nasal symptoms as well as eosinophilic airway inflammation.
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http://dx.doi.org/10.1016/j.anl.2021.01.003DOI Listing
August 2021

The multiple functions and subpopulations of eosinophils in tissues under steady-state and pathological conditions.

Allergol Int 2021 Jan 24;70(1):9-18. Epub 2020 Nov 24.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, Osaka, Japan.

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-F CD62L CD101 and Siglec-F CD62L CD101, 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.
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http://dx.doi.org/10.1016/j.alit.2020.11.001DOI Listing
January 2021

Combination therapy with lenvatinib and radiation significantly inhibits thyroid cancer growth by uptake of tyrosine kinase inhibitor.

Exp Cell Res 2021 01 21;398(1):112390. Epub 2020 Nov 21.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan.

Although surgical treatment cures >90% of differentiated thyroid cancer (DTC) patients, the remaining patients, including advanced DTC cases, have poor clinical outcomes. These patients with inoperable disease have only two choices of radioactive iodine therapy and tyrosine kinase inhibitors such as lenvatinib, which have a high incidence of treatment-related adverse events and can only prolong progression free survival by approximately 5-15 months. In this study, we investigated the antitumor effects of combination therapy with lenvatinib and radiation (CTLR) for DTC. CTLR synergistically inhibited cell replication and colony formation in vitro and tumor growth in nude mice without apparent toxicities and suppressed the expression of proliferation marker (Ki-67). CTLR also induced apoptosis and G2/M phase cell cycle arrest. Moreover, quantitative analysis of the intracellular uptake of lenvatinib using liquid chromatography and mass spectrometry demonstrated that intracellular uptake of lenvatinib was significantly increased 48 h following irradiation. These data suggest that increased membrane permeability caused by irradiation increases the intracellular concentration of levatinib, contributing to the synergistic effect. This mechanism-based potential of combination therapy suggests a powerful new therapeutic strategy for advanced thyroid cancer with fewer side effects and might be a milestone for developing a regimen in clinical practice.
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http://dx.doi.org/10.1016/j.yexcr.2020.112390DOI Listing
January 2021

Effect of periosteal reaction in medication-related osteonecrosis of the jaw on treatment outcome after surgery.

J Bone Miner Metab 2021 Mar 12;39(2):302-310. Epub 2020 Oct 12.

Department of Clinical Oral Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan.

Introduction: Surgical treatment in patients with medication-related osteonecrosis of the jaw (MRONJ) is superior to conservative treatment. However, treatment outcome in patients with periosteal reaction (PR) was significantly poorer than that of those without PR. The purpose of this retrospective study was to analyze the pathophysiology and clinical significance of PR in MRONJ.

Materials And Methods: Out of 181 patients with MRONJ undergoing surgery, 38 patients with PR were enrolled in the study. CT examinations, histological examinations, and bacteriological examinations using real-time polymerase chain reaction were performed, and the relationship among the opted surgical method, CT findings, and treatment outcome was investigated.

Results: The pattern of PR was classified into three types: type 1, new bone is formed parallel to the mandible, and no gap was evident between the mandible and new bone; type 2, new bone is formed parallel to the mandible, and a gap was evident between them; type 3, an irregular shape. Histological examinations revealed inflammatory tissue in the area visualized as a gap on CT. Bacteriological examination showed the presence of bacteria in the type 2 or type 3 PR. Complete cure was observed in 21 of 38 (55.3%) patients, which was lower than the cure rate of 73.4% in 143 patients without PR. The cure rate was significantly lower in cases with type 3 PR or with persistent osteolysis.

Conclusions: It seems that complete resection of both osteolytic area and type 3 PR is necessary to obtain complete healing in patients undergoing marginal mandibulectomy.
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http://dx.doi.org/10.1007/s00774-020-01154-6DOI Listing
March 2021

Spontaneous infarction of pleomorphic adenoma of the parotid gland: A case report.

Mol Clin Oncol 2020 Dec 17;13(6):68. Epub 2020 Sep 17.

Department of Pathology and Laboratory Medicine, Kansai Medical University, Hirakata, 573-1010 Osaka, Japan.

Infarction after the fine-needle aspiration (FNA) procedure is a well-recognized phenomenon of salivary gland lesions. Though extremely rare, spontaneous infarction without previous FNA can occur in pleomorphic adenoma (PA). The present report describes a fourth cytological case of spontaneous infarction of PA of the parotid gland using immunocytochemical analysis, to the best of our knowledge, for the first time. A 57-year-old Japanese female presented with persistent swelling of the right neck region. Physical examination revealed a tumour in the right parotid gland, and FNA examination of the tumour was performed following surgical resection. The Papanicolaou smear demonstrated the presence of fully necrotic cell clusters of varying sizes in a necrotic background. Only a few viable cell clusters were observed. These cells were polygonal to spindle-shaped, and exhibited large round to oval nuclei with a conspicuous nucleoli. Although nuclear pleomorphism was noted, the nuclear chromatin was fine. No neoplastic myoepithelial cells were observed. Therefore, it was suspected that these cells were malignant. Immunocytochemical analysis indicated that these atypical cells were positive for p40. Histopathological examination of the resected parotid gland tumour revealed infarcted PA. Our study revealed that the presence of atypical squamous metaplastic cells in a necrotic background was a characteristic cytological feature of infarcted PA, and that these atypical squamous cells can have large nuclei with conspicuous nucleoli and exhibit pleomorphism. Although cytological diagnosis of infarcted PA is difficult, pathologists and cytopathologists must consider the presence of atypical metaplastic squamous cells in benign salivary gland tumours, including infarcted PA.
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http://dx.doi.org/10.3892/mco.2020.2138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520748PMC
December 2020

Early voice therapy for unilateral vocal fold paralysis improves subglottal pressure and glottal closure.

Am J Otolaryngol 2020 Nov - Dec;41(6):102727. Epub 2020 Sep 13.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, 2-5-1, Shinmachi, Hirakata, Osaka 573-1010, Japan.

Purpose: In cases of unilateral vocal fold paralysis (UVFP), voice disorders caused by glottic insufficiency can lead to a considerable reduction in the patient's quality of life. Voice therapy (VT) is an effective treatment that must be started early after the onset of vocal fold paralysis. This study examined the effect of early VT for patients with UVFP occurring after esophagectomy.

Materials And Methods: Patients who had residual UVFP at 1 month postoperatively after esophagectomy for esophageal cancer between November 2014 and March 2017 were evaluated. Seventeen patients were divided into the VT group (n = 6) and non-VT group (n = 11). We compared these two groups and retrospectively examined the effect of early VT. The study endpoints included aerodynamic tests, laryngeal endoscopy, laryngeal stroboscopy, and glottal closure. All of these evaluations were performed at preoperatively and at 1 and 3 months postoperatively.

Results: Subglottal pressure reduced notably in the VT group, and both the mean flow rate and maximum phonation time tended to improve after VT. Conversely, there were no significant differences in MFR and MPT in the non-VT group. Furthermore, although UVFP remained after VT, we achieved glottal closure for all three patients. Conversely, only two of the six patients with glottic insufficiency in the non-VT group achieved glottal closure.

Conclusion: VT may be effective for improving impaired vocal function in patients with UVFP. It is reasonable to expect that VT can be initiated 1 month after the onset of vocal fold paralysis.
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http://dx.doi.org/10.1016/j.amjoto.2020.102727DOI Listing
December 2020

Prognostic impact of CRTC1/3-MAML2 fusions in salivary gland mucoepidermoid carcinoma: A multiinstitutional retrospective study.

Cancer Sci 2020 Nov 14;111(11):4195-4204. Epub 2020 Sep 14.

Department of Pathology and Molecular Diagnostics, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.

Mucoepidermoid carcinoma (MEC) is rare, but the most common primary malignancy of the salivary gland and not infrequent in young individuals. CRTC1/3-MAML2 fusions are frequently detected in MEC and are useful as a diagnostic biomarker. However, there has been debate as to whether the fusions have prognostic significance. In this study, we retrospectively collected 153 salivary gland MEC cases from 11 tertiary hospitals in Japan. As inclusion criteria, the MEC patients in this study had curative surgery as the initial treatment, received no preoperative treatment, and had no distant metastasis at the time of the initial surgery. The MEC diagnosis was validated by a central pathology review by five expert salivary gland pathologists. The CRTC1/3-MAML2 fusions were detected using FISH and RT-PCR. In 153 MEC cases, 90 (58.8%) were positive for CRTC1/3-MAML2 fusions. During the follow-up period, 28 (18.3%) patients showed tumor recurrence and 12 (7.8%) patients died. The presence of the fusions was associated with favorable tumor features. Of note, none of the fusion-positive patients died during the follow-up period. Statistical analysis showed that the presence of the fusions was a prognostic indicator of a better overall survival in the total and advanced-stage MEC cohorts, but not in the early-stage MEC cohort. In conclusion, CRTC1/3-MAML2 fusions are an excellent biomarker for favorable overall survival of patients with salivary gland MEC.
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http://dx.doi.org/10.1111/cas.14632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648036PMC
November 2020

Prominent oncocytic metaplasia in pleomorphic adenoma: A potential diagnostic pitfall.

Diagn Cytopathol 2020 Aug 25;48(8):765-768. Epub 2020 Apr 25.

Department of Pathology and Laboratory Medicine, Kansai Medical University, Osaka, Japan.

Pleomorphic adenoma (PA) is the most common salivary gland tumor. The cytological features of PA are well recognized, and its diagnosis is straightforward in most cases. Some metaplastic changes in PA are well known; however, occurrence of oncocytic metaplasia in PA is very rare. In this report, we describe the first cytological case of prominent oncocytic metaplasia in PA identified based on immunocytochemical analysis. We report the case of a 62-year-old Japanese female who presented with swelling of the left neck region. A fine-needle aspiration cytologic examination was performed followed by surgical resection. The Papanicolaou smear revealed the presence of discohesive neoplastic cells in a myxoid background. These neoplastic cells had a relatively rich, granular cytoplasm, and round nuclei with moderate pleomorphism. Initial cytodiagnosis revealed carcinoma ex PA (CXPA). Immunocytochemical analysis showed that abundant mitochondria were present in the cytoplasm of these neoplastic cells. Histopathological examination of the resected tumor demonstrated proliferation of oncocytic neoplastic cells within a myxoid material and the presence of conventional PA components. A final diagnosis of prominent oncocytic metaplasia in PA was made. Oncocytic metaplasia showed nuclear atypia and pleomorphism; therefore, CXPA, which presents with severe nuclear atypia and necrotic background, must be differentiated from oncocytic metaplastic PA. Recognition of oncocytic metaplasia in PA is important for correct diagnosis.
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http://dx.doi.org/10.1002/dc.24443DOI Listing
August 2020

Reduced Local Response to Corticosteroids in Eosinophilic Chronic Rhinosinusitis with Asthma.

Biomolecules 2020 02 18;10(2). Epub 2020 Feb 18.

Airway Disease Section, Department of Otorhinolaryngology, Kansai Medical University, Hirakata, Osaka 573-1010, Japan.

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.
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http://dx.doi.org/10.3390/biom10020326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072408PMC
February 2020

Increased CD69 expression on activated eosinophils in eosinophilic chronic rhinosinusitis correlates with clinical findings.

Allergol Int 2020 Apr 10;69(2):232-238. Epub 2020 Jan 10.

Department of Otorhinolaryngology, Head & Neck Surgery, Kansai Medical University, Osaka, Japan.

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.
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http://dx.doi.org/10.1016/j.alit.2019.11.002DOI Listing
April 2020

Multiple Biological Aspects of Eosinophils in Host Defense, Eosinophil-Associated Diseases, Immunoregulation, and Homeostasis: Is Their Role Beneficial, Detrimental, Regulator, or Bystander?

Biol Pharm Bull 2020 ;43(1):20-30

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University.

Eosinophils are innate immune leukocytes and play important roles as terminal effector cells owing to their mediators, such as tissue-destructive cationic proteins, cytokines, chemokines, and lipid mediators. Historically, they are not only considered an important player in host defense against parasitic, viral, fungal, and bacterial infections but also implicated in the pathogenesis of eosinophil-associated diseases, such as allergic rhinitis, asthma, eosinophilic chronic rhinosinusitis, esophagitis, atopic dermatitis, myopathies, and hypereosinophilic syndrome. Moreover, recent studies have shown that eosinophils have an immune regulatory and homeostatic function. Interestingly, there is emerging evidence that eosinophils are accumulated through adoptive T-helper 2 (Th2) and innate Th2 responses, mechanisms of the classical allergen-specific immunoglobulin E (IgE)-mediated response, and group 2 innate lymphoid cell-derived interleukin-5, respectively. Furthermore, in agreement with current concepts of eosinophil subtypes, it has been shown that resident and phenotypically distinct eosinophils, i.e., resident and recruited inflammatory eosinophils, exist in inflamed sites, and each has different functions. Thus, the classical and novel studies suggest that eosinophils have multiple functions, and their roles may be altered by the environment. In this article, we review multiple biological aspects of eosinophils (novel and classical roles), including their beneficial and detrimental effects, immunoregulation, and homeostatic function.
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http://dx.doi.org/10.1248/bpb.b19-00892DOI Listing
November 2020

An Anisotropic Microstructure Evolution in a Solid Oxide Fuel Cell Anode.

Nanoscale Res Lett 2020 Jan 3;15(1). Epub 2020 Jan 3.

Department of Fundamental Research in Energy Engineering, AGH University of Science and Technology, 30 Mickiewicza Ave., Krakow, 30-059, Poland.

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.
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http://dx.doi.org/10.1186/s11671-019-3226-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942056PMC
January 2020

Real-world Treatment Outcomes of the EXTREME Regimen as First-line Therapy for Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck: A Multi-center Retrospective Cohort Study in Japan.

Anticancer Res 2019 Dec;39(12):6819-6827

Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University, School of Medicine, Yokohama, Japan.

Background/aim: This Japanese multiple-center retrospective study aimed to examine the real-world treatment outcomes of the EXTREME regimen as a first-line therapy for recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

Patients And Methods: A total of 100 R/M SCCHN patients treated with the EXTREME regimen as first-line therapy were analyzed. The treatment outcomes were evaluated to compare patient and treatment characteristics with overall survival.

Results: Patients treated with carboplatin-based EXTREME regimen showed similar overall survival with less adverse effects compared to that of patients using cisplatin. The post-progression survival was significantly longer in patients treated with second-line treatment following the EXTREME regimen than in those without second-line treatment.

Conclusion: The carboplatin-based EXTREME regimen was more feasible with similar treatment outcomes compared to cisplatin-based EXTREME regimen. In addition, subsequent lines of therapy contributed to improvement of survival for R/M SCCHN patients.
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http://dx.doi.org/10.21873/anticanres.13898DOI Listing
December 2019

Cytological features of carcinoma ex pleomorphic adenoma of the salivary glands: A diagnostic challenge.

Diagn Cytopathol 2020 Feb 1;48(2):149-153. Epub 2019 Nov 1.

Department of Pathology and Laboratory Medicine, Kansai Medical University, Osaka, Japan.

Carcinoma ex pleomorphic adenoma (CXPA) of the salivary glands is a relatively rare carcinoma. The detection rate of the carcinoma component in the cytological specimens is not high and may be challenging in cytological examination. The purpose of the present study was to analyze the cytological specimens of CXPA with emphasis on the detection of the carcinoma component. We reviewed the cytological characteristics of patients histopathologically diagnosed with CXPA who underwent preoperative cytological examination. Of the 10 patients enrolled in the study, 8 had tumors located in the parotid gland, and 2 in the submandibular gland. A review of the cytological specimens revealed the presence of the carcinoma component in all 10 cases and the pleomorphic adenoma (PA) component in 6 cases, although initial cytodiagnosis detected the carcinoma component in 8 cases. The cytological feature of this component was the presence of variable-sized clusters of polygonal cells with relatively rich cytoplasm and large round to oval nuclei in a necrotic background. Interestingly, carcinoma cells mixed with the PA component were also present. On histopathological analysis, 7 cases were intracapsular, and the remaining 3 cases were widely invasive CXPA. Further, 9 cases had salivary duct carcinoma as carcinoma component. In conclusion, these findings show that careful detection of the carcinoma cells, particularly within the PA component, is crucial for early detection of CXPA, and the presence of necrosis might help with the detection of the carcinoma component.
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http://dx.doi.org/10.1002/dc.24333DOI Listing
February 2020

Eosinophilic Cholecystitis Occurred in a Patient With Refractory Eosinophilic Airway Inflammation: A Case Report.

Allergy Rhinol (Providence) 2019 Jan-Dec;10:2152656719869607. Epub 2019 Aug 19.

Department of Otolaryngology, Kansai Medical University, Osaka, Japan.

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. 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.
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http://dx.doi.org/10.1177/2152656719869607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700860PMC
August 2019

A Novel Approach for Investigating Upper Airway Hyperresponsiveness Using Micro-CT in Eosinophilic Upper Airway Inflammation such as Allergic Rhinitis Model.

Biomolecules 2019 06 27;9(7). Epub 2019 Jun 27.

Department of Otorhinolaryngology, Head and Neck Surgery, Kansai Medical University, Hirakata 573-1010, Japan.

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 (AHR) 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.
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http://dx.doi.org/10.3390/biom9070252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681309PMC
June 2019

Cytological features of basal cell adenocarcinoma of the salivary glands.

Diagn Cytopathol 2019 Jul 22;47(7):733-737. Epub 2019 Mar 22.

Department of Pathology and Laboratory Medicine, Kansai Medical University, Hirakata, Osaka, Japan.

The cytological features of basal cell adenocarcinoma (BAC) of the salivary gland, a rare carcinoma, have not been well described. This study included patients who were histopathologically diagnosed with BAC and who underwent preoperative fine-needle aspiration cytological examination. Cytological characteristics, including background, arrangement and shape of the neoplastic cells, nuclear and cytoplasmic features, and presence of stromal spindle cells, were reviewed. Seven patients were enrolled in the study. The cytological specimens were cellular and composed of large or small clusters with occasional discohesive neoplastic cells at the periphery. The predominant cellular morphology was spindle-shaped in four cases, and small round-shaped in three cases. These neoplastic cells were tightly packed, showed high cellularity and overlapping nuclei, and had mildly to moderately enlarged round to oval nuclei with occasional small nucleoli and scant cytoplasm. Stromal spindle cells were observed around the basaloid cells in three cases (42.9%). All histology-proven stromal spindle cell-positive cases had stromal spindle cells in the cytological specimens. The study findings clearly demonstrate the relatively high frequency of stromal spindle cells in cytological specimens of BAC. This finding is characteristic of BAC, although basal cell adenoma of salivary gland frequently has stromal spindle cells in the cytological specimens. The characteristic that differentiates BAC from basal cell adenoma is the presence of tightly packed and high cellular clusters with discohesive neoplastic cells. An understanding of these cytological features can aid the cytodiagnosis of BAC.
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http://dx.doi.org/10.1002/dc.24178DOI Listing
July 2019

Critical role of CCL4 in eosinophil recruitment into the airway.

Clin Exp Allergy 2019 06 29;49(6):853-860. Epub 2019 Mar 29.

Department of General Medical Practice and Laboratory Diagnostic Medicine, Akita University Graduate School of Medicine, Akita, Japan.

Background: Excessive eosinophil airway infiltration is a clinically critical condition in some cases. Eosinophilic pneumonia (EP) is a pulmonary condition involving eosinophil infiltration of the lungs. Although several chemokines, including eotaxin-1 (CCL11), RANTES (CCL5) and macrophage inflammatory protein 1β (MIP-1β or CCL4), have been detected in bronchoalveolar lavage fluid (BALF) from patients with EP, the pathophysiological mechanisms underlying EP, including potential relationships between eosinophils and CCL4, have not been fully elucidated.

Objective: To examine the involvement of CCL4 in eosinophilic airway inflammation.

Methods: We analysed supernatants of activated eosinophils and BALF from 16 patients with eosinophilic pneumonia (EP). Further, we examined the effects of CCL4 on eosinophil functions in vitro and those of anti-CCL4 neutralizing antibody in an in vivo model.

Results: We found that purified human eosinophils stimulated with IL-5 predominantly secreted CCL4 and that patients with EP had elevated CCL11 and CCL4 levels in BALF compared with samples from individuals without EP. Because CCL4 levels were more strongly correlated with eosinophil count and expression of eosinophil granule proteins than CCL11, in vitro experiments using purified eosinophils concentrated on the former chemokine. Interestingly, CCL4 acted as a chemoattractant for eosinophils. In a mouse model, administration of a CCL4-neutralizing antibody attenuated eosinophilic airway infiltration and airway hyperresponsiveness.

Conclusions And Clinical Relevance: Overall, these findings highlight an important role of CCL4 in the mechanisms underlying eosinophil recruitment into the airway and may provide a novel insight into this potential therapeutic target.
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http://dx.doi.org/10.1111/cea.13382DOI Listing
June 2019

Quantitative immunohistochemical assay with novel digital immunostaining for comparisons of PD-L1 antibodies.

Mol Clin Oncol 2019 Mar 17;10(3):391-396. Epub 2019 Jan 17.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, Osaka 573-1010, Japan.

One obstacle in diagnostic pathology is the harmonization of one drug-one diagnostic tests for programmed death ligand-1 (PD-L1). There are many challenges in accurate comparisons of diagnostic tests, such as differences in the titer of each antibody, detection system and dynamic range of visualization. Our previously developed digital immunostaining technique is highly sensitive and quantitative with the ability to quantify particles that bind in a one-to-one fashion with antibody in each cell. Determining the differences in the titer of each antibody with digital immunostaining may be beneficial for future harmonized analysis. To demonstrate the accuracy of digital immunostaining, the present study compared the number of particles with ELISA and nCounter data from five cell lines. NCI-H460 exhib-ited the highest level of PD-L1 protein, followed by A549, PC-3, NCI-H1299, and NCI-H446 cells. In addition, the PD-L1 mRNA values determined by nCounter corresponded with the order of the protein levels determined by ELISA. The present study revealed that digital immunostaining for PD-L1 was highly associated with ELISA and nCounter data. Among the four antibodies tested, the titer of all but SP142 coincided with ELISA and nCounter data. These results indicated that our digital immunostaining technique may be beneficial for future harmonized analysis.
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http://dx.doi.org/10.3892/mco.2019.1801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388504PMC
March 2019

Clinical significance of periosteal reaction as a predictive factor for treatment outcome of medication-related osteonecrosis of the jaw.

J Bone Miner Metab 2019 Sep 4;37(5):913-919. Epub 2019 Mar 4.

Department of Otolaryngology Head and Neck Surgery, Kansai Medical University, 2-3-1 Shinmachi, Hirakata, Osaka, 573-1191, Japan.

Regarding treatment strategies for medication-related osteonecrosis of the jaw (MRONJ), surgical therapy has recently been reported to be more effective than conservative therapy. However, some patients did not achieve complete healing, even when extensive surgery was performed. Periosteal reaction in MRONJ patients is often observed by the CT examination. Tssshe purpose of this study was to investigate the relationship between periosteal reaction and treatment outcome of MRONJ. A total of 164 surgeries in 136 patients with MRONJ at two hospitals were included in the study. Correlations between various clinical and radiographic factors and treatment outcome were examined with Cox regression analysis. The results showed that the presence of periosteal reaction, as well as primary disease involving malignant tumor, were independent risk factors related to poor outcome. Furthermore, we examined factors related to the occurrence of the periosteal reaction and found that 4 variables were significantly correlated with periosteal reaction by multivariate analysis: gender (female), site (lower jaw), primary disease (malignant tumor), and osteosclerosis (severe). The present study clarified that the cure rate after surgical treatment decreased in cases with periosteal reaction, suggesting that it is necessary to review the treatment method.
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http://dx.doi.org/10.1007/s00774-019-00994-1DOI Listing
September 2019

Cytological features of basal cell adenoma of salivary glands: Analysis of 19 cases emphasizing stromal spindle cells.

Diagn Cytopathol 2019 Jul 27;47(7):665-669. Epub 2019 Feb 27.

Department of Pathology and Laboratory Medicine, Kansai Medical University, Osaka, Japan.

Background: Basal cell adenoma (BCA) of the salivary gland is a relatively rare benign tumor. Although the presence of stromal spindle cells is a characteristic histopathological feature, this finding has not been the focus of much attention in the cytodiagnosis of BCA. Thus, we analyzed the cytological features of BCA, especially the presence of stromal spindle cells.

Methods: Patients who were histopathologically diagnosed with BCA and underwent preoperative fine-needle aspiration cytological examination were enrolled in this study. The cytological characteristics including arrangement and shape of the neoplastic cells, nuclear and cytoplasmic features, and the presence of stromal spindle cells were reviewed.

Results: Nineteen patients were enrolled in the study. The cytological specimens were cellular and composed of small or large clusters or both. The neoplastic cells had scant cytoplasm and small round to oval nuclei. Basement membrane-like material was observed in 57.9%, and peripheral palisading was noted in 84.2%. Loose aggregates of stromal spindle cells were present in 63.2%, and the stromal spindle cells shown in the histological examination of 85.7% of cases were expressed in the cytological specimens.

Conclusion: This study clearly demonstrated the relatively high frequency of stromal spindle cells in cytological specimens of BCA. This finding is characteristic of BCA, and therefore, the combination of cytological features, including packed clusters of neoplastic cells with scant cytoplasm and small nuclei, peripheral palisading, and basement membrane-like material, and the presence of stromal spindle cells could increase the diagnostic success of BCA.
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http://dx.doi.org/10.1002/dc.24164DOI Listing
July 2019

Eosinophilic Upper Airway Inflammation in a Murine Model Using an Adoptive Transfer System Induces Hyposmia and Epithelial Layer Injury with Convex Lesions.

Med Sci (Basel) 2019 Feb 5;7(2). Epub 2019 Feb 5.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, Hirakata 573-1010, Japan.

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.
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http://dx.doi.org/10.3390/medsci7020022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409781PMC
February 2019

Collagenous crystalloids in pleomorphic adenoma of the parotid gland.

Diagn Cytopathol 2019 Jun 12;47(6):612-613. Epub 2019 Feb 12.

Department of Pathology and Laboratory Medicine, Kansai Medical University, Osaka, Japan.

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http://dx.doi.org/10.1002/dc.24149DOI Listing
June 2019

Regulation of Interaction between the Upper and Lower Airways in United Airway Disease.

Med Sci (Basel) 2019 Feb 11;7(2). Epub 2019 Feb 11.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, Hirakata, 573-1010, Japan.

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.
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http://dx.doi.org/10.3390/medsci7020027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410259PMC
February 2019
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