MicroRNA expression signature of oral squamous cell carcinoma: functional role of microRNA-26a/b in the modulation of novel cancer pathways.

BACKGROUND: MicroRNAs (miRNAs) have been shown to play major roles in carcinogenesis in a variety of cancers. The aim of this study was to determine the miRNA expression signature of oral squamous cell carcinoma (OSCC) and to investigate the functional roles of miR-26a and miR-26b in OSCC cells. METHODS: An OSCC miRNA signature was constructed by PCR-based array methods. Functional studies of differentially expressed miRNAs were performed to investigate cell proliferation, migration, and invasion in OSCC cells. In silico database and genome-wide gene expression analyses were performed to identify molecular targets and pathways mediated by miR-26a/b. RESULTS: miR-26a and miR-26b were significantly downregulated in OSCC. Restoration of both miR-26a and miR-26b in cancer cell lines revealed that these miRNAs significantly inhibited cancer cell migration and invasion. Our data demonstrated that the novel transmembrane TMEM184B gene was a direct target of miR-26a/b regulation. Silencing of TMEM184B inhibited cancer cell migration and invasion, and regulated the actin cytoskeleton-pathway related genes. CONCLUSIONS: Loss of tumour-suppressive miR-26a/b enhanced cancer cell migration and invasion in OSCC through direct regulation of TMEM184B. Our data describing pathways regulated by tumour-suppressive miR-26a/b provide new insights into the potential mechanisms of OSCC oncogenesis and metastasis.

Identification of tumour suppressive microRNA-451a in hypopharyngeal squamous cell carcinoma based on microRNA expression signature.

BACKGROUND: Hypopharyngeal squamous cell carcinoma (HSCC) has a very poor prognosis because of its high rates of regional and distant metastasis. Identification of differentially expressed miRNAs and their regulated molecular targets in tumour cells might enhance our understanding of the molecular mechanisms of metastasis in human cancers. METHODS: A HSCC miRNA signature was constructed by array-based methods. Functional studies of microRNA-451a (miR-451a) and target genes were performed to investigate cell proliferation, migration and invasion by cancer cell lines. To identify miR-451a-regulated molecular targets, we adopted gene expression analysis and in silico database analysis. RESULTS: Our miRNA signature revealed that miR-451a was significantly downregulated in HSCC. Restoration of miR-451a in cancer cell lines revealed that this miRNA significantly inhibited cancer cell migration and invasion. Our data demonstrated that the gene coding for endothelial and smooth muscle cell-derived neuropilin-like molecule (ESDN/DCBLD2) was a direct target of miR-451a regulation. Silencing of ESDN inhibited cell migration and invasion by cancer cells. CONCLUSIONS: Loss of tumour suppressive miR-451a enhanced cancer cell migration and invasion in HSCC through direct regulation of ESDN. Our miRNA signature and functional analysis of targets regulated by tumour suppressive miR-451a provide new insights into the potential mechanisms of HSCC oncogenesis and metastasis.

Activation of invariant natural killer T cells in regional lymph nodes as new antigen-specific immunotherapy via induction of interleukin-21 and interferon-γ.

Invariant natural killer T (iNKT) cells play important immunoregulatory functions in allergen-induced airway hyperresponsiveness and inflammation. To clarify the role of iNKT cells in allergic rhinitis (AR), we generated bone marrow-derived dendritic cells (BMDCs), which were pulsed by ovalbumin (OVA) and α-galactosylceramide (OVA/α-GalCer-BMDCs) and administered into the oral submucosa of OVA-sensitized mice before nasal challenge. Nasal symptoms, level of OVA-specific immunoglobulin (IgE), and T helper type 2 (Th2) cytokine production in cervical lymph nodes (CLNs) were significantly ameliorated in wild-type (WT) mice treated with OVA/α-GalCer-BMDCs, but not in WT mice treated with OVA-BMDCs. These anti-allergic effects were not observed in Jα18(-/-) recipients that lack iNKT cells, even after similar treatment with OVA/α-GalCer-BMDCs in an adoptive transfer study with CD4(+) T cells and B cells from OVA-sensitized WT mice. In WT recipients of OVA/α-GalCer-BMDCs, the number of interleukin (IL)-21-producing iNKT cells increased significantly and the Th1/Th2 balance shifted towards the Th1 dominant state. Treatment with anti-IL-21 and anti-interferon (IFN)-γ antibodies abrogated these anti-allergic effects in mice treated with α-GalCer/OVA-BMDCs. These results suggest that activation of iNKT cells in regional lymph nodes induces anti-allergic effects through production of IL-21 or IFN-γ, and that these effects are enhanced by simultaneous stimulation with antigen. Thus, iNKT cells might be a useful target in development of new treatment strategies for AR.

Tumour-suppressive microRNA-874 contributes to cell proliferation through targeting of histone deacetylase 1 in head and neck squamous cell carcinoma.

BACKGROUND: Our recent studies of microRNA (miRNA) expression signature demonstrated that microRNA-874 (miR-874) was significantly downregulated in maxillary sinus squamous cell carcinoma (MSSCC), and a putative tumour-suppressive miRNA in human cancers. Our aim of this study was to investigate the functional significance of miR-874 in cancer cells and to identify novel miR-874-mediated cancer pathways and responsible genes in head and neck squamous cell carcinoma (HNSCC). METHODS: Gain-of-function studies using mature miR-874 were performed to investigate cell proliferation and cell cycle distribution in HNSCC cell lines (SAS and FaDu). To identify miR-874-mediated molecular pathways and targets, we utilised gene expression analysis and in silico database analysis. Loss-of-function assays were performed to investigate the functional significance of miR-874 target genes. RESULTS: Expression levels of miR-874 were significantly downregulated in HNSCC tissues (including oral, pharyngeal and laryngeal SCCs) compared with normal counterpart epithelia. Restoration of miR-874 in SAS and FaDu cell lines revealed significant inhibition of cell proliferation and induction of G2/M arrest and cell apoptosis. Our expression data and in silico analysis demonstrated that miR-874 modulated the cell cycle pathway. Moreover, histone deacetylase 1 (HDAC1) was a candidate target of miR-874 regulation. Luciferase reporter assays showed that miR-874 directly regulated HDAC1. Silencing of the HDAC1 gene significantly inhibited cell proliferation and induced G2/M arrest and cell apoptosis in SAS cells. CONCLUSIONS: Downregulation of miR-874 was a frequent event in HNSCC. miR-874 acted as a tumour suppressor and directly targeted HDAC1. Recognition of tumour-suppressive miRNA-mediated cancer pathways provides new insights into the potential mechanisms of HNSCC oncogenesis and suggests novel therapeutic strategies for the disease.

Tumour-suppressive microRNA-29s inhibit cancer cell migration and invasion by targeting laminin-integrin signalling in head and neck squamous cell carcinoma.

BACKGROUND: Our recent studies of microRNA (miRNA) expression signatures demonstrated that microRNA-29s (miR-29s; miR-29a/b/c) were significantly downregulated in head and neck squamous cell carcinoma (HNSCC) and were putative tumour-suppressive miRNAs in human cancers. Our aim in this study was to investigate the functional significance of miR-29s in cancer cells and to identify novel miR-29s-mediated cancer pathways and responsible genes in HNSCC oncogenesis and metastasis. METHODS: Gain-of-function studies using mature miR-29s were performed to investigate cell proliferation, migration and invasion in two HNSCC cell lines (SAS and FaDu). To identify miR-29s-mediated molecular pathways and targets, we utilised gene expression analysis and in silico database analysis. Loss-of-function assays were performed to investigate the functional significance of miR-29s target genes. RESULTS: Restoration of miR-29s in SAS and FaDu cell lines revealed significant inhibition of cancer cell migration and invasion. Gene expression data and in silico analysis demonstrated that miR-29s modulated the focal adhesion pathway. Moreover, laminin γ2 (LAMC2) and α6 integrin (ITGA6) genes were candidate targets of the regulation of miR-29s. Luciferase reporter assays showed that miR-29s directly regulated LAMC2 and ITGA6. Silencing of LAMC2 and ITGA6 genes significantly inhibited cell migration and invasion in cancer cells. CONCLUSION: Downregulation of miR-29s was a frequent event in HNSCC. The miR-29s acted as tumour suppressors and directly targeted laminin-integrin signalling. Recognition of tumour-suppressive miRNA-mediated cancer pathways provides new insights into the potential mechanisms of HNSCC oncogenesis and metastasis and suggests novel therapeutic strategies for the disease.

MR Imaging Findings of Carcinoma Ex Pleomorphic Adenoma Related to Extracapsular Invasion and Prognosis.

BACKGROUND AND PURPOSE: MR imaging can reflect the pathologic progression of carcinoma ex pleomorphic adenoma (CXPA). This study aimed to identify the imaging findings related to extracapsular invasion of CXPA. Additionally, the pathologic background of these findings was investigated. MATERIALS AND METHODS: This retrospective study included 37 patients with histologically confirmed CXPA. Three radiologists independently evaluated whether the CXPA showed the following characteristic MR imaging findings: border, capsule, the corona sign on fat-saturated T2WI and contrast-enhanced fat-saturated T1WI, and the black ring sign. The corona sign appeared larger on fat-saturated and/or contrast-enhanced fat-saturated T1WI than on T1WI. The black ring sign was defined as an intratumoral nodule with a thick low-intensity rim on T2WI. Interreader agreement of the visual assessment was performed using κ analysis, and MR imaging and histopathologic findings were also correlated. Kaplan-Meier survival and the log-rank test were used to estimate the 3-year disease-free survival. RESULTS: MR imaging findings, especially peritumoral findings, showed a significant difference between invasive and noninvasive CXPA. The reliability was poor for the border and capsule. In contrast, it was good for the corona sign on fat-saturated and contrast-enhanced fat-saturated T1WI and the black ring sign. Pathologically, the corona sign reflected the invasiveness of the tumor and inflammatory cells, while the black ring sign reflected hyalinization or fibrosis. The corona sign also showed a significant difference in the 3-year disease-free survival. CONCLUSIONS: MR imaging findings, including the corona and black ring signs, reliably differentiated invasive and noninvasive CXPA. The corona sign can be used as a prognostic factor for CXPA.

Tumour suppressive microRNA-874 regulates novel cancer networks in maxillary sinus squamous cell carcinoma.

BACKGROUND: On the basis of the microRNA (miRNA) expression signature of maxillary sinus squamous cell carcinoma (MSSCC), we found that miR-874 was significantly reduced in cancer cells. We focused on the functional significance of miR-874 in cancer cells and identification of miR-874-regulated novel cancer networks in MSSCC. METHODS: We used PCR-based methods to investigate the downregulated miRNAs in clinical specimens of MSSCC. Our signature analyses identified 23 miRNAs that were significantly reduced in cancer cells, such as miR-874, miR-133a, miR-375, miR-204, and miR-1. We focused on miR-874 as the most downregulated novel miRNA in our analysis. RESULTS: We found potential tumour suppressive functions such as inhibition of cancer cell proliferation and invasion. A molecular target search of miR-874 revealed that PPP1CA was directly regulated by miR-874. Overexpression of PPP1CA was observed in MSSCC clinical specimens. Silencing of the PPP1CA gene significantly inhibited cancer cell proliferation and invasion. CONCLUSION: The downregulation of miR-874 was a frequent event in MSSCC, which suggests that miR-874 functions as a tumour suppressive miRNA, directly regulating PPP1CA that has a potential role of an oncogene. The identification of novel miR-874-regulated cancer pathways could provide new insights into potential molecular mechanisms of MSSCC oncogenesis.

miR-489 is a tumour-suppressive miRNA target PTPN11 in hypopharyngeal squamous cell carcinoma (HSCC).

BACKGROUND: Hypopharyngeal squamous cell carcinoma (HSCC) is an aggressive malignancy with one of the worst prognoses among all head and neck cancers. Greater understanding of the pertinent molecular oncogenic pathways could help improve diagnosis, therapy, and prevention of this disease. The aim of this study was to identify tumour-suppressive microRNAs (miRNAs), based on miRNA expression signatures from clinical HSCC specimens, and to predict their biological target genes. METHODS: Expression levels of 365 human mature miRNAs from 10 HSCC clinical samples were screened using stem-loop real-time quantitative PCR. Downregulated miRNAs were used in cell proliferation assays to identify a tumour-suppressive miRNA. Genome-wide gene expression analyses were then performed to identify the target genes of the tumour-suppressive miRNA. RESULTS: Expression analysis identified 11 upregulated and 31 downregulated miRNAs. Gain-of-function analysis of the downregulated miRNAs revealed that miR-489 inhibited cell growth in all head and neck cancer cell lines examined. The gene PTPN11 coding for a cytoplasmic protein tyrosine phosphatase containing two Src Homology 2 domains was identified as a miR-489-targeted gene. Knockdown of PTPN11 resulted in the inhibition of cell proliferation in head and neck SCC cells. CONCLUSION: Identification of the tumour-suppressive miRNA miR-489 and its target, PTPN11, might provide new insights into the underlying molecular mechanisms of HSCC.

Beneficial effects of leukotriene receptor antagonists in the prevention of cedar pollinosis in a community setting.

BACKGROUND: In recent years, many countries have experienced an increase in the prevalence of allergic rhinitis. No effective approach is currently available to prevent the onset of symptoms in allergic individuals. Pranlukast, a leukotriene receptor antagonist with a good safety and efficacy record for the management of allergic inflammation, may be appropriate for early intervention in the management of pollinosis. OBJECTIVE: To investigate the efficacy of pranlukast as an early intervention in the control of cedar pollinosis. METHODS: In a double-blind comparative study, pranlukast (n = 102) or placebo (n = 91) was administered to cedar pollinosis patients immediately before the start of the dispersion season and continued for 4 weeks. Subsequently, pranlukast was administered to all patients for 2 weeks until the end of the cedar pollen dispersion season (mid-March). All patients were carefully monitored for severity of nasal symptoms, symptom scores, medication scores, symptom-medication scores, and quality of life (QOL). RESULTS: Compared with placebo, therapy with pranlukast before and during the dispersion of cedar pollen in these patients significantly improved nasal symptoms (paroxysmal sneezing, rhinorrhea, and nasal congestion), symptom scores, and symptom-medication scores. The drug also significantly reduced deterioration of QOL, and improved nasal symptoms and QOL throughout the dispersion period. CONCLUSION: Administering pranlukast immediately before the beginning of cedar pollen dispersion is effective in reducing symptoms of allergic rhinitis throughout the dispersion period.

Novel synthetic approach to 19-nor-1alpha,25-dihydroxyvitamin D(3) and its derivatives by Suzuki-Miyaura coupling in solution and on solid support.

19-nor-1alpha,25-Dihydroxyvitamin D(3) was synthesized by the Suzuki-Miyaura coupling of the A-ring intermediate 3, which was efficiently prepared from readily available 5-(tert-butyldimethylsilyl)oxycyclohex-2-enone (5), with the boronate compound of the C,D-ring portion. The method could be applied to a solid-phase synthesis to prepare the des-C,D derivatives of 19-nor-1alpha,25-dihydroxyvitamin D(3). [reaction: see text]

Efficient and practical synthesis of the A-ring precursor of 19-nor-1alpha,25-dihydroxyvitamin D(3) and its (13)C- or (2)H-labeled derivative.

[reaction: see text] The A-ring precursor of 19-nor-1alpha,25-dihydroxyvitamin D(3) (1) and its (13)C- or (2)H-labeled derivative were efficiently synthesized from readily available, optically active 5-(tert-butyldimethylsilyloxy)-2-cyclohexenone (2) through a five-step reaction in 68% overall yield.

Nitric oxide synthase-immunoreactive nerve fibers in the nasal mucosa of the rat.

An immunohistochemical study was performed to detect the localization of nitric oxide synthase (NOS) in the rat nasal mucosa by light and electron microscopy. NOS-immunoreactive nerve fibers were observed around blood vessels and seromucous glands. They were found in the subepithelial layer and even within the epithelium. But no NOS-immunoreactivity was found in the olfactory neuroepithelium. Electron microscopy showed that NOS-immunoreactive nerve profiles were in close contact with the cytolemma of respiratory epithelial cells and acinar cells of seromucous glands. NOS-immunoreactive axon varicosities were located at a considerable distance from the smooth muscle of arterioles and small veins as well as the endothelial cells of venules and capillaries. We confirmed that NOS-containing nerves innervated the epithelium, blood vessels and seromucous glands of the nasal mucosa. These findings, collectively, suggested the possibility that nitric oxide participated in the sensory function of the epithelium, the secretory activities of the nasal gland, and the regulation of vascular tone and vascular permeability in the nasal mucosa.

Distribution of NADPH-diaphorase positive nerve fibers in the rat nasal mucosa.

Nasal mucosa was investigated by NADPH-diaphorase histochemistry. Positive fibers were distributed around blood vessels, seromucous glands and in the subepithelial layer. The pterygopalatine, trigeminal and superior cervical ganglia were also studied to examine the origin of these fibers. Many neurons in the pterygopalatine ganglion were labeled, and a few neurons were stained in the trigeminal ganglion. No perikarya were labeled in the superior cervical ganglion. Therefore, most of the labeled fibers must be originating from the pterygopalatine ganglion, and the rest of them may originate from the trigeminal ganglion. These results suggest that nitric oxide may have some role in the nervous control of the nasal mucosa.

Lateral retropharyngeal node metastasis from carcinoma of the upper gingiva and maxillary sinus.

Clinically unsuspected metastases to the lateral retropharyngeal nodes from carcinomas of the upper gingiva or maxillary sinus were found in five patients on follow-up CT examinations. Such uncommon metastases may follow the afferent lymphatic channels from the palate or pharyngeal region or arrive by retrograde lymphatics from positive neck nodes. Careful examination of lateral retropharyngeal nodes may be required in cancers of these primary sites.

Local vasodilator response to mobile phones.

OBJECTIVES: The use of mobile phones with the resulting generation of potentially harmful electromagnetic fields (EMF) is the focus of public interest. Heat generation and the activation of the inducible form of nitric oxide (NO) synthase may be possible causes of the biological effects of EMF exposure. We investigated if a mobile telephone conversation can modify skin temperature, NO, and nasal resistance. METHODS: We studied the effect of an EMF (900 MHz) generated by a commercially available cellular phone during a 30-minute telephone conversation on skin temperature, nasal NO measured by chemiluminescence, and nasal minimal cross-sectional area (MCA) measured by rhinometry. Eleven normal subjects (mean age +/- standard error of mean [SEM], 32 +/- 5 y; 10 male) were studied. RESULTS: There was a similar and significant increase in skin temperature of the nostril and occipital area on the same side as the telephone (maximal increase 2.3 +/- 0.2 degrees C at 6 min) as well as a tendency for higher nasal NO levels (maximal increase 12.9 +/- 4.9% at 10 min), whereas the MCA was significantly reduced (maximal decrease -27 +/- 6% at 15 min). Such changes were not recorded when an earpiece was used to avoid the direct exposure to the electromagnetic field. There were no changes in the skin temperature and nasal NO measured on the opposite side to the mobile phone, whereas the MCA was significantly increased (38 +/- 10%). CONCLUSIONS: Exposure to EMF produced by a mobile phone produces biological effects that can be easily measured. Microwaves may increase skin temperature and therefore cause vasodilation and reduce MCA. Further studies are needed to study the long-term effects of mobile phone use and the relation among NO production, vasodilation, and temperature.

Role of vascular reflex in nasal mucosal swelling in nasal allergy.

OBJECTIVE: In patients with nasal allergy, antigen challenge on the unilateral nasal mucosa results in nasal secretion not only in the ipsilateral but also in the contralateral nasal cavities that can be inhibited almost completely by premedication with atropine sulfate. The present study was performed to elucidate if centrally mediated vascular reflex induced by antigen challenge plays a role in nasal mucosal swelling in subjects with nasal allergy. METHODS: Variations of mucosal swelling and mucosal blood flow in the ipsilateral and the contralateral nasal cavities after unilateral antigen challenge were evaluated by acoustic rhinometry and laser Doppler flowmetry in 20 patients with perennial nasal allergy. RESULTS: Unilateral antigen challenge caused ipsilateral and contralateral nasal mucosal swelling in 17 and 13 patients, respectively. Incidence of contralateral nasal mucosal swelling after unilateral antigen challenge was significantly higher compared with that after control disc challenge (P < .001). In 10 patients in whom unilateral antigen challenge caused bilateral nasal mucosal swelling, significant swelling of the nasal mucosa lasted for more than 30 minutes in the ipsilateral nasal cavity after antigen challenge compared with only 15 minutes in the contralateral nasal cavity. Peak values of contralateral mucosal swelling were 45.3% of those of ipsilateral nasal mucosa. CONCLUSIONS: Centrally mediated vascular reflex is partially involved in the onset of nasal mucosal swelling observed after antigen challenge in subjects with nasal allergy. However, nasal mucosal swelling that persists and proceeds even 20 minutes after antigen challenge is caused by the direct effects of chemical mediators on the nasal vasculature.

Contralateral external carotid-middle cerebral artery bypass for carotid artery resection.

Resection of the common carotid or internal carotid artery is occasionally unavoidable in cases of advanced head and neck carcinoma with carotid artery involvement. To prevent the consequent decrease in cerebral perfusion, we have developed a contralateral external carotid-middle cerebral artery bypass grafting technique. From 1990 through 1995, six patients with advanced head and neck cancer involving the carotid artery underwent total tumor resection combined with vascular reconstruction using the contralateral external carotid- middle cerebral artery bypass grafting. No bypass-related complications occurred in any patient postoperatively. Cerebral hemodynamics after surgery indicated that this bypass graft worked steadily over a long term and supplied sufficient volume of blood to the cerebral cortex on the opposite side in every case.

Time course of changes in absorption of macromolecule through the nasal mucosa after antigen challenge in guinea pig model of allergic rhinitis.

The time course of changes in absorption of horseradish peroxidase (HRP) through the nasal mucosa after antigen challenge was evaluated in a guinea pig model of allergic rhinitis immunized with ovalbumin. Before and at 5 minutes, 4 hours, and 24 hours after nasal antigen challenge, both nasal cavities were filled with 5% HRP solution for 30 minutes, and blood was obtained to measure serum HRP levels by enzyme-linked immunosorbent assay. In immunized animals, the serum HRP levels were 2.3 times higher than those of normal controls (p<.05) before antigen challenge, which was performed 7 days after a series of nasal antigenic sensitizations. At 5 to 35 minutes after antigen challenge, the HRP levels decreased to one sixth of the prechallenge levels (p<.05), and they did not show a difference from the control levels. However, they increased markedly at 4 and 24 hours after antigen challenge (p<.01). The present study suggests that the absorption of macromolecules through the allergic nasal mucosa is enhanced markedly, depending upon the time course after antigen challenge, although it shows no apparent difference from normal controls during the dominant exudative process.

Comparative role of peptide leukotrienes and histamine in the development of nasal mucosal swelling in nasal allergy.

To evaluate the importance of histamine and peptide leukotrienes (LTs) in the development of nasal mucosal swelling in nasal allergy, H1 receptor antagonist (mequitazine, 6 mg, in 2 divided doses, Rhône-Poulenc Rorer, France) and LT receptor antagonist (ONO-1078, pranlukast, 450 mg, in 2 divided doses, Ono Pharmaceutical Co, Ltd, Osaka) were administered orally for 7 days to 16 subjects with perennial nasal allergy to house dust mites, and the effects of receptor blockers of these chemical mediators on the effective cross-sectional area of the nasal cavity (ECA) at rest, at exercise load, at antigen challenge, and at exercise load following antigen challenge were studied. After the administration of H1 receptor antagonist, ECAs at all measurement points slightly increased, but no statistical significance was observed. On the other hand, LT receptor antagonist inhibited ECAs 10 minutes after exercise load, just after the end of antigen challenge, 10 minutes later, and at exercise load following antigen challenge with statistical significance. These results suggest that LTs are involved markedly, and histamine slightly, in the development of nasal mucosal swelling in nasal allergy.

Effect of diesel exhaust on guinea pig nasal mucosa.

In this study using guinea pigs, we investigated the effects of diesel exhaust (DE) containing diesel exhaust particulate (DEP) on 1) vascular permeability induced by histamine, 2) nasal mucosal permeability to horseradish peroxidase (HRP), and 3) eosinophilic epithelial infiltration. The vascular permeability induced by histamine was enhanced significantly and dose-dependently in DE-exposed guinea pigs. The HRP reaction products in epithelial cells and intercellular spaces were significantly and dose-dependently increased in those guinea pigs. Eosinophil infiltration into the epithelial layer was significantly increased in guinea pigs exposed to DE containing 3.2 mg/m3 DEP, and the reactivity of the nasal mucosa to histamine solution applied on the nasal mucosa was significantly enhanced in those guinea pigs. These findings suggest that DE may play an important role not only in promoting nasal hyperreactivity induced by the enhancement of absorption of antigen through the nasal epithelium, but also in inducing eosinophil infiltration in nasal mucosa and enhancing nasal mucosal reactivity.