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Akt is an important kinase in metabolism. Akt also phosphorylates and activates endothelial and neuronal nitric oxide (NO) synthases (eNOS and nNOS, respectively) expressed in M0 (unpolarized) macrophages. We showed that e/nNOS NO production downstream of bitter taste receptors enhances macrophage phagocytosis. In airway epithelial cells, we also showed that the activation of Akt by a small molecule (SC79) enhances NO production and increases levels of nuclear Nrf2, which reduces IL-8 transcription during concomitant stimulation with Toll-like receptor (TLR) 5 agonist flagellin. We hypothesized that SC79's production of NO in macrophages might likewise enhance phagocytosis and reduce the transcription of some pro-inflammatory cytokines. Using live cell imaging of fluorescent biosensors and indicator dyes, we found that SC79 induces Akt activation, NO production, and downstream cGMP production in primary human M0 macrophages. This was accompanied by a reduction in IL-6, IL-8, and IL-12 production during concomitant stimulation with bacterial lipopolysaccharide, an agonist of pattern recognition receptors including TLR4. Pharmacological inhibitors suggested that this effect was dependent on Akt and Nrf2. Together, these data suggest that several macrophage immune pathways are regulated by SC79 via Akt. A small-molecule Akt activator may be useful in some infection settings, warranting future in vivo studies. [ABSTRACT FROM AUTHOR]

Background: Chronic rhinosinusitis (CRS) is a common sinonasal disorder which results in significant inflammation in the nasal cavity and paranasal sinuses. Topical nasal steroids play an important role in the treatment of CRS. Exhalation delivery system with fluticasone (EDS-FLU) utilizes a patient's forced exhalation to power the delivery of topical steroids to deeper areas of the nasal cavity and paranasal sinuses most affected by CRS. This review focuses on evidence surrounding the safety and efficacy of the EDS-FLU system. Methods: Literature search was conducted of articles investigating the safety and efficacy of EDS-FLU. Relevant efficacy and safety data were examined and summarized from the studies. Results: The efficacy and safety of EDS-FLU in CRS, both with and without polyps, has been established in open-label and placebo-controlled phase 3 trials. There was significant improvement in the cardinal symptoms of CRS and subjective patient-reported outcomes scores. Additionally, there was objective improvement in sinonasal inflammation as measured by polyp grade. Recent studies have also established significant improvement in health status and general quality of life following treatment using EDS-FLU. Emerging data have also examined patients who have previously had endoscopic sinus surgery and on appropriate medical therapy and noted improvement in polyp burden and overall Lund-Kennedy scores after using EDS-FLU. Conclusion: Exhalation delivery system with fluticasone demonstrates significant results in both patient-oriented outcomes and objective measures of sinonasal inflammation in patients with CRS with and without polyps. Further research is needed to investigate the long-term outcomes of EDS-FLU and to compare the effects of EDS-FLU with ESS. Exhalation delivery system with fluticasone provides an additional effective treatment modality for patients suffering from CRS. [ABSTRACT FROM AUTHOR]

Taste receptors in the oral cavity guide our preferences for foods, preventing toxic ingestions and encouraging proper nutrient consumption. More recently, expression of taste receptors has been demonstrated in other locations throughout the body, including the airway, gastrointestinal tract, pancreas, and brain. The extent and specific roles of extraoral taste receptors are largely unknown, but a growing body of evidence suggests that taste receptors in the airway serve a critical role in sensing bacteria and regulating innate immunity. This review will focus on the function of bitter and sweet taste receptors in the human airway, with particular emphasis on T2R38, a bitter taste receptor found in sinonasal ciliated cells, and the bitter and sweet receptors found on specialized sinonasal solitary chemosensory cells. The importance of these novel taste receptor-immune circuits in the human airway and their clinical relevance in airway disease will also be reviewed. [ABSTRACT FROM AUTHOR]

Bitter taste receptors (T2Rs) are G protein-coupled receptors (GPCRs) expressed in various cell types including ciliated airway epithelial cells and macrophages. T2Rs in these two innate immune cell types are activated by bitter products, including those secreted by Pseudomonas aeruginosa, leading to Ca2+-dependent activation of endothelial nitric oxide (NO) synthase (eNOS). NO enhances mucociliary clearance and has direct antibacterial effects in ciliated epithelial cells. NO also increases phagocytosis by macrophages. Using biochemistry and live-cell imaging, we explored the role of heat shock protein 90 (HSP90) in regulating T2R-dependent NO pathways in primary sinonasal epithelial cells, primary monocyte-derived macrophages, and a human bronchiolar cell line (H441). Immunofluorescence showed that H441 cells express eNOS and T2Rs and that the bitter agonist denatonium benzoate activates NO production in a Ca2+- and HSP90-dependent manner in cells grown either as submerged cultures or at the air–liquid interface. In primary sinonasal epithelial cells, we determined that HSP90 inhibition reduces T2R-stimulated NO production and ciliary beating, which likely limits pathogen clearance. In primary monocyte-derived macrophages, we found that HSP-90 is integral to T2R-stimulated NO production and phagocytosis of FITC-labeled Escherichia coli and pHrodo-Staphylococcus aureus. Our study demonstrates that HSP90 serves as an innate immune modulator by regulating NO production downstream of T2R signaling by augmenting eNOS activation without impairing upstream Ca2+ signaling. These findings suggest that HSP90 plays an important role in airway antibacterial innate immunity and may be an important target in airway diseases such as chronic rhinosinusitis, asthma, or cystic fibrosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Inverted papillomas are benign sinonasal tumors that can recur or become cancerous. The mainstay of treatment is surgical resection. We summarize the biology of inverted papillomas and review surgical outcomes in an effort to define the current treatment strategy. Inverted papillomas (IP) are the most common sinonasal tumor with a tendency for recurrence, potential attachment to the orbit and skull base, and risk of malignant degeneration into squamous cell carcinoma (SCC). While the overall rate of recurrence has decreased with the widespread adoption of high-definition endoscopic optics and advanced surgical tools, there remain challenges in managing tumors that are multiply recurrent or involve vital neurovascular structures. Here, we review the state-of-the-art diagnostic tools for IP and IP-degenerated SCC, contemporary surgical management, and propose a surveillance protocol. [ABSTRACT FROM AUTHOR]

Background: The non-cancerous functions of Akt in the airway are understudied. In some tissues, Akt phosphorylates and activates endothelial nitric oxide synthase (eNOS) to produce nitric oxide (NO) that has anti-inflammatory effects. NO production has antibacterial and antiviral effects in the airway, and increasing NO may be a useful anti-pathogen strategy. Akt also stimulates the nuclear factor erythroid 2-related factor 2 (Nrf-2) transcription factor, which transcribes antioxidant genes. Therefore, we hypothesized that activation of the Akt/eNOS pathway, which also activates Nrf-2, may have protective effects in human airway cells against injury.Methods: To directly test the effects of Akt signaling in the airway, we treated A549 and 16HBE cells as well as primary bronchial, nasal, and type II alveolar epithelial cells with small molecule Akt activator SC79. We examined the effects of SC79 on eNOS activation, NO production, Nrf-2 target levels, and interleukin-8 (IL-8) transcription during exposure to TNF-α or Pseudomonas flagellin (TLR5 agonist). Additionally, air-liquid interface bronchial cultures were treated with cadmium, an oxidative stressor that causes airway barrier breakdown.Results: SC79 induced a ~ twofold induction of p-eNOS and Nrf-2 protein levels blocked by PI3K inhibitor LY294002. Live cell imaging revealed SC79 increased acute NO production. Quantitative RT-PCR showed a ~ twofold increase in Nrf-2 target gene transcription. TNF-α or flagellin-induced IL-8 levels were also significantly reduced with SC79 treatment. Moreover, the transepithelial electrical resistance decrease observed with cadmium was ameliorated by SC79, likely by an acute increase in tight junction protein ZO-1 levels.Conclusions: Together, the data presented here demonstrate SC79 activation of Akt induces potentially anti-pathogenic NO production, antioxidant gene transcription, reduces IL-8 transcription, and may protect against oxidative barrier dysfunction in a wide range of airway epithelial cells. [ABSTRACT FROM AUTHOR]

Objectives Although adjuvant radiotherapy may be indicated in patients with sinonasal squamous cell carcinoma (SNSCC) following primary surgery, some patients choose to forgo recommended postoperative radiation therapy (PORT). This study aimed to elucidate factors associated with patient refusal of recommended PORT in SNSCC and examine overall survival. Methods Retrospective analysis of patients with SNSCC treated with primary surgery from the National Cancer Database diagnosed between 2004 and 2016. A multivariable logistic regression model was created to determine the association between clinical or demographic covariates and likelihood of PORT refusal. Unadjusted Kaplan–Meier estimates, log-rank tests, and a multivariable Cox proportional hazard model were used to assess overall survival. Results A total of 2,231 patients were included in the final analysis, of which 1,456 (65.3%) were males and 73 (3.3%) refused recommended PORT. Patients older than 74 years old were more likely to refuse PORT than those younger than 54 (odds ratio [OR] 3.43, 95% confidence interval [CI]: 1.84–6.62). Median survival among the entire cohort, those who received recommended PORT, and those who refused PORT was 83.0 months (95% CI: 74.6–97.1), 83.0 months (95% CI: 74.9–98.2), and 63.6 months (95% CI: 37.3–101.4), respectively. Refusal of PORT was not associated with overall survival (hazard ratio: 0.99, 95% CI: 0.69–1.42). Conclusions PORT refusal in patients with SNSCC is rare and was found to be associated with several patient factors. The decision to forgo PORT is not independently associated with overall survival in this cohort. Further study is required to determine the clinical implications of these findings as the treatment decisions are complex. [ABSTRACT FROM AUTHOR]

Background An ectopic pituitary adenoma presenting as a clival or sphenoidmass is a rare clinical occurrence that may mislead the clinician and result in unnecessary interventions or potential medicolegal consequences. Here, we present one of the largest multi-institutional case series and review the literature with an emphasis on radiological findings and critical preoperative workup. Methods Retrospective chart review. Results Nine patients were identified with ectopic pituitary adenomas of the sphenoid or clivus. There were four females and five males. Median age was 60 years old (range, 36-73 years). The most common presenting symptom was headache (56%). Five (56%) patients presented with a mass arising fromthe clivus while four (44%) presented with a mass in the sphenoid. Six (67%) patients demonstrated biochemical evidence of hypersecretion on full endocrinology panel. All masses showed evidence of enhancement with gadolinium with a propensity for adjacent bone involvement. Lesions also had a predilection for growth toward the cavernous sinus, carotid artery, or sellar floor. Surgical intervention was performed in eight patients (89%). In eight patients (89%), tumors demonstrated immunoreactivity to prolactin. Conclusions Pituitary adenomas can rarely present as an isolated sphenoid or clival mass. Lesions displayed similar magnetic resonance imaging findings with an erosive growth pattern toward the sellar floor, cavernous sinus, or adjacent carotid artery. Patients with clival or parasellar lesions with comparable features should have a preoperative workup which includes prolactin level and alert the physician to consider an ectopic pituitary adenoma in the differential to prevent unnecessary surgery and potential complications. [ABSTRACT FROM AUTHOR]

Objective  This study aimed to provide information regarding the prognosis of patients presenting with metastatic anterior skull base malignancies based upon histology and site of distant metastasis (DM). Patients and Methods  The National Cancer Database was queried for patients with anterior skull base malignant neoplasms with DM. Outcomes  Prognosis was compared between site of DM and tumor histologies. A multivariable Cox proportional hazards model was used to identify prognostic factors for overall survival (OS). Results  A total of 481 patients were identified. Lung was the most common site of DM (24.9%), followed by bone (22.2%), liver (5.6%), and brain (2.5%). Lung was the most common site for squamous cell carcinoma (SCCa) (28.3%), melanoma (37.7%), and adenoid cystic carcinoma (ACC; 31.4%). The median survival for patients presenting with metastatic disease regardless of tumor histology was 9.0 months (95% confidence interval [CI]: 8.2–10.3), and patients with metastasis to the liver had the best median survival at 15.5 months (95% CI: 10.5–25.6). The median survivals for the most common histologies, SCCa, melanoma, and ACC were 8.2 months (95% CI: 5.5–10.2), 10.5 months (95% CI: 8.7–14.1), and 15.0 months (95% CI: 11.1–61.1), respectively. Multivariable analysis demonstrated worse overall survival (OS) for older patients, higher Charlson-Deyo comorbidity scores, and tumors with higher grade and T stage. Compared with metastasis to bone, lung metastasis had better OS on multivariable analysis (hazard ratio [HR]: 0.70, 95% CI: 0.51–97). Adenoid cystic carcinoma had improved OS compared with SCCa (HR: 0.62, 95% CI: 0.39–99). Conclusion  Tumor histology, metastatic sites, and several disease factors affected prognosis in anterior skull base malignancies with DM. [ABSTRACT FROM AUTHOR]

T2R bitter taste receptors in airway motile cilia increase ciliary beat frequency (CBF) and nitric oxide (NO) production. Polymorphisms in some T2Rs are linked to disease outcomes in chronic rhinosinusitis (CRS) and cystic fibrosis (CF). We examined the expression of cilia T2Rs during the differentiation of human nasal epithelial cells grown at air–liquid interface (ALI). The T2R expression increased with differentiation but did not vary between CF and non-CF cultures. Treatment with Pseudomonas aeruginosa flagellin decreased the expression of diphenhydramine-responsive T2R14 and 40, among others. Diphenhydramine increased both NO production, measured by fluorescent dye DAF-FM, and CBF, measured via high-speed imaging. Increases in CBF were disrupted after flagellin treatment. Diphenhydramine impaired the growth of lab and clinical strains of P. aeruginosa, a major pathogen in CF and CF-related CRS. Diphenhydramine impaired biofilm formation of P. aeruginosa, measured via crystal violet staining, as well as the surface attachment of P. aeruginosa to CF airway epithelial cells, measured using colony-forming unit counting. Because the T2R agonist diphenhydramine increases NO production and CBF while also decreasing bacterial growth and biofilm production, diphenhydramine-derived compounds may have potential clinical usefulness in CF-related CRS as a topical therapy. However, utilizing T2R agonists as therapeutics within the context of P. aeruginosa infection may require co-treatment with anti-inflammatories to enhance T2R expression. [ABSTRACT FROM AUTHOR]

Abstract: We originally showed that the protocadherin 15 gene (Pcdh15) is necessary for hearing and balance functions; mutations in Pcdh15 affect hair cell development in Ames waltzer (av) mice. Here we extend that study to understand better how Pcdh15 operates in a cell. The original report identified 33 exons in Pcdh15, with exon 1 being noncoding; additional exons of Pcdh15 have since been reported. The 33 exons of Pcdh15 described originally are embedded in 409 kb of mouse genomic sequence, while the corresponding exons of human PCDH15 are spread over 980 kb of genomic DNA; the exons in Pcdh15/PCDH15 range in size from 9 to ∼2000 bp. The genomic organization of Pcdh15/PCDH15 bears similarity to that of cadherin 23, but differs significantly from other protocadherin genes, such as Pcdhα, β, or γ. A CpG island is located ∼2900 bp upstream of the PCDH15 transcriptional start site. The Pcdh15/PCDH15 promoter lacks TATAA or CAAT sequences within 100 bases upstream of the transcription start site; deletion mapping showed that Pcdh15 harbors suppressor and enhancer elements. Preliminary searches for alternatively spliced transcripts of Pcdh15 identified novel splice variants not reported previously. Results from our study show that both mouse and human protocadherin 15 genes have complex genomic structures and transcription control mechanisms. [Copyright &y& Elsevier]

Airway submucosal gland serous cells are important sites of fluid secretion in conducting airways. Serous cells also express the cystic fibrosis (CF) transmembrane conductance regulator (CFTR). Protease-activated receptor 2 (PAR-2) is a G protein-coupled receptor that activates secretion from intact airway glands. We tested if and how human nasal serous cells secrete fluid in response to PAR-2 stimulation using Ca2+ imaging and simultaneous differential interference contrast imaging to track isosmotic cell shrinking and swelling reflecting activation of solute efflux and influx pathways, respectively. During stimulation of PAR-2, serous cells exhibited dose-dependent increases in intracellular Ca2+. At stimulation levels >EC50 for Ca2+, serous cells simultaneously shrank 20% over 90s due to KCl efflux reflecting Ca2+-activated Cl- channel (CaCC, likely TMEM16A)-dependent secretion. At lower levels of PAR-2 stimulation (

Objective  Radiation therapy represents an uncommon but important component of treatment plans for some pituitary adenomas (PAs). Although radiation therapy has been used to treat pituitary adenomas for over a century, general trends in the usage of radiation therapy for this purpose have not been reviewed. Additionally, there are few large studies evaluating how radiation therapy is used for the treatment of these benign tumors. Investigating these trends and identifying any variations in radiation therapy utilization would help to better inform treatment decisions and improve patient outcomes. Design  Present study is a retrospective analysis of cases using the National Cancer Database. Setting  The research was organized at a tertiary academic medical center. Participants  Patients were diagnosed with pituitary adenoma between 2004 and 2014 within the National Cancer Database (NCDB). Methods  Temporal trends in the usage of radiation therapy to treat pituitary adenoma were analyzed through a retrospective analysis of 77,142 pituitary adenoma cases from the NCDB between 2004 and 2014. Univariate and multivariate analyses were to examine the relationship between patient, tumor, and treatment factors, and the incorporation of radiation therapy into the treatment of pituitary adenomas. We adjusted for potential confounders such as age, sex, race, comorbidity score, facility type, and year of diagnosis. Results  A total of 77,142 patients met inclusion criteria. Inclusion of radiation therapy in pituitary adenoma treatment was 8.0% in 2004 and steadily declined to a low of 3.1% in 2014. Overall, patients were less likely to receive radiation for their pituitary adenoma over time (p  < 0.001). Similarly, patients were found to be less likely to receive any type of treatment for PA over time (p  < 0.001). Multivariable evaluation found patients who were female, between 54 and 64 years of age, or treated at either a Comprehensive Community Cancer Program or an Integrated Network Cancer Program were more likely to receive radiation as part of their pituitary adenoma treatment (p  < 0.001, odds ratio [OR] = 2.01, confidence interval [CI]: 1.54–2.63; p  < 0.001, OR = 1.84, CI: 1.38–2.44, respectively). Patients were less likely to receive radiation for their PA if they were African American (p  < 0.001, OR = 0.81, CI: 0.72–0.91). Logistic regression also identified a progressive increase in the likelihood of receiving radiation after a PA diagnosis with increasing tumor size starting with microscopic tumors, peaking at 4 to 5 cm (p  < 0.001; OR = 15.57; CI: 12.20–19.87). Conclusion  In this sample of pituitary adenoma patients treated at NCDB institutions between 2004 and 2014, we found a steady decline in the incorporation of radiation therapy in treatment, as well as in the use of any type of intervention for PA treatment, suggesting a rise in noninterventional observation of PA. [ABSTRACT FROM AUTHOR]

Coronaviruses are adept at evading host antiviral pathways induced by viral double-stranded RNA, including interferon (IFN) signaling, oligoadenylate synthetase-ribonuclease L (OAS-RNase L), and protein kinase R (PKR). While dysregulated or inadequate IFN responses have been associated with severe coronavirus infection, the extent to which the recently emerged SARS-CoV-2 activates or antagonizes these pathways is relatively unknown. We found that SARS-CoV-2 infects patient-derived nasal epithelial cells, present at the initial site of infection; induced pluripotent stem cell-derived alveolar type 2 cells (iAT2), the major cell type infected in the lung; and cardiomyocytes (iCM), consistent with cardiovascular consequences of COVID- 19 disease. Robust activation of IFN or OAS-RNase L is not observed in these cell types, whereas PKR activation is evident in iAT2 and iCM. In SARS-CoV-2-infected Calu-3 and A549ACE2 lung-derived cell lines, IFN induction remains relatively weak; however, activation of OAS-RNase L and PKR is observed. This is in contrast to Middle East respiratory syndrome (MERS)-CoV, which effectively inhibits IFN signaling and OAS-RNase L and PKR pathways, but is similar to mutant MERS-CoV lacking innate immune antagonists. Remarkably, OASRNase L and PKR are activated in MAVS knockout A549ACE2 cells, demonstrating that SARS-CoV-2 can induce these host antiviral pathways despite minimal IFN production. Moreover, increased replication and cytopathic effect in RNASEL knockout A549ACE2 cells implicates OASRNase L in restricting SARS-CoV-2. Finally, while SARS-CoV-2 fails to antagonize these host defense pathways, which contrasts with other coronaviruses, the IFN signaling response is generally weak. These host-virus interactions may contribute to the unique pathogenesis of SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Objective  Surgical resection is widely accepted as a critical component for definitive treatment of sinonasal mucosal melanoma. Systemic immunotherapy, including multiple newer agents, has been used to treat metastatic or unresectable disease. In this study, we examine its efficacy in locoregional control when used in conjunction with surgical resection for primary mucosal lesions. Design  Present study is a retrospective review of all patients at a tertiary academic medical center with primary sinonasal mucosal melanoma and distant metastatic disease. Results  A total of four patients were identified. In all cases, patients were treated with a combination of surgical resection of the primary tumor and systemic immunotherapy. Three patients were initially treated with surgery at the primary site followed by immunotherapy for distant metastases. Response to immunotherapy at the sites of primary and metastatic disease was seen in two patients. All four patients developed progression or recurrence at the primary site following initiation of immunotherapy for which they underwent surgical resection. One patient remains in follow-up without evidence of disease 20 months after initial treatment; three succumbed to the disease at 135, 37, and 16 months after initial treatment. Conclusion  Surgical resection for local control plays a critically important role in the treatment of sinonasal mucosal melanoma regardless of the presence of metastases and whether immunotherapy will be given. This case series suggests that, though immunotherapy may demonstrate efficacy in managing distant disease, surgery should remain the first-line treatment for the primary site. [ABSTRACT FROM AUTHOR]

Background: Epithelial solitary chemosensory cell (tuft cell) bitter taste signal transduction occurs through G protein coupled receptors and calcium-dependent signaling pathways. Type II taste cells, which utilize the same bitter taste signal transduction pathways, may also utilize cyclic adenosine monophosphate (cAMP) as an independent signaling messenger in addition to calcium.Methods: In this work we utilized specific pharmacologic inhibitors to interrogate the short circuit current (Isc) of polarized nasal epithelial cells mounted in Ussing chambers to assess the electrophysiologic changes associated with bitter agonist (denatonium) treatment. We also assessed release of human β-defensin-2 from polarized nasal epithelial cultures following treatment with denatonium benzoate and/or potassium channel inhibitors.Results: We demonstrate that the bitter taste receptor agonist, denatonium, decreases human respiratory epithelial two-pore potassium (K2P) current in polarized nasal epithelial cells mounted in Ussing chambers. Our data further suggest that this occurs via a cAMP-dependent signaling pathway. We also demonstrate that this decrease in potassium current lowers the threshold for denatonium to stimulate human β-defensin-2 release.Conclusions: These data thus demonstrate that, in addition to taste transducing calcium-dependent signaling, bitter taste receptor agonists can also activate cAMP-dependent respiratory epithelial signaling pathways to modulate K2P currents. Bitter-agonist regulation of potassium currents may therefore serve as a means of rapid regional epithelial signaling, and further study of these pathways may provide new insights into regulation of mucosal ionic composition and innate mechanisms of epithelial defense. [ABSTRACT FROM AUTHOR]

Background  Sinonasal adenocarcinoma (SNAC) is a rare malignancy arising from mucus-secreting glandular tissue. Limited large-scale studies are available due to its rarity. We evaluated SNAC in the National Cancer Database (NCDB), a source that affords multi-institutional, population studies of rare cancers and their outcomes. Methods  The NCDB was queried for adenocarcinoma in the sinonasal tract. Multivariate analyses were performed to evaluate for factors contributing to overall survival (OS). Results  A total of 553 patients were identified. The cohort was composed of 59.3% males. The nasal cavity was the most common primary site, representing 44.1% of cases. About 5.7% of patients presented with nodal disease, while 3.3% had distant metastases. About 40.6% of cases presented with stage IV disease. About 73.5% of patients underwent surgery, 54.2% received radiation therapy, and 27.7% had chemotherapy. Median OS was 71.7 months, while OS at 1, 2, and 5 years was 82, 73.0, and 52%, respectively. On multivariate analysis, advanced age (hazard ratio [HR]: 1.04; 95% confidence interval [CI]: 1.02–1.05), Charlson–Deyo score of 1 (HR: 1.99; 95% CI: 1.20–3.30), advanced tumor grade (HR: 2.73; 95% CI: 1.39–5.34), and advanced tumor stage (HR: 2.71; 95% CI: 1.33–5.50) were associated with worse OS, whereas surgery (HR: 0.34; 95% CI: 0.20–0.60) and radiation therapy (HR: 0.55; 95% CI: 0.33–0.91), but not chemotherapy (HR: 1.16; 95% CI: 0.66–2.05), predicted improved OS. Conclusions  SNAC is a rare malignancy with 5-year survival approximating 50%. Surgery and radiation therapy, but not chemotherapy, are associated with improved survival, and likely play a critical role in the interdisciplinary management of SNAC. [ABSTRACT FROM AUTHOR]

Objectives  A persistent craniopharyngeal canal (CPC) is a rare embryologic remnant that presents as a well-corticated defect of the midline sphenoid body extending from the sellar floor to the nasopharynx. Our case series aims to describe three unique presentations of this congenital anomaly and their subsequent management. Design  Retrospective review. Setting  Tertiary academic medical center. Participants  Patients who underwent endoscopic transnasal surgical repair of a CPC lesion. Main Outcome Measures  Resolution of symptoms and surgical outcomes. Results  A total of three patients were identified. The clinical presentation varied, however, all cases prompted further imaging which demonstrated a persistent CPC and associated pathologic lesion. The presentation of a persistent CPC with nasal obstruction and subsequent iatrogenic cerebrospinal fluid leak as in Case 1 demonstrates the importance of imaging in this work-up. Cases 2 and 3 in the series were representative of the larger subset of patients in the literature who present with the defect incidentally but still warrant surgical management. Nonetheless, a standard approach to diagnosis with preoperative imaging and subsequent transnasal endoscopic repair of the skull base defect was undertaken. Conclusion  The persistent CPC is a rare congenital anomaly associated with diverse pathology and careful review of preoperative radiology is critical to the management. When warranted, subsequent surgical repair and reconstruction is associated with excellent postoperative outcomes. [ABSTRACT FROM AUTHOR]

Protease-activated receptor 2 (PAR-2) is activated by secreted proteases from immune cells or fungi. PAR-2 is normally expressed basolaterally in differentiated nasal ciliated cells. We hypothesized that epithelial remodeling during diseases characterized by cilial loss and squamous metaplasia may alter PAR-2 polarization. Here, using a fluorescent arrestin assay, we confirmed that the common fungal airway pathogen Aspergillus fumigatus activates heterologously-expressed PAR-2. Endogenous PAR-2 activation in submerged airway RPMI 2650 or NCI-H520 squamous cells increased intracellular calcium levels and granulocyte macrophage-colony-stimulating factor, tumor necrosis factor α, and interleukin (IL)-6 secretion. RPMI 2650 cells cultured at an air-liquid interface (ALI) responded to apically or basolaterally applied PAR-2 agonists. However, welldifferentiated primary nasal epithelial ALIs responded only to basolateral PAR-2 stimulation, indicated by calcium elevation, increased cilia beat frequency, and increased fluid and cytokine secretion. We exposed primary cells to disease-related modifiers that alter epithelial morphology, including IL-13, cigarette smoke condensate, and retinoic acid deficiency, at concentrations and times that altered epithelial morphology without causing breakdown of the epithelial barrier to model early disease states. These altered primary cultures responded to both apical and basolateral PAR-2 stimulation. Imaging nasal polyps and control middle turbinate explants, we found that nasal polyps, but not turbinates, exhibit apical calcium responses to PAR-2 stimulation. However, isolated ciliated cells from both polyps and turbinates maintained basolateral PAR-2 polarization, suggesting that the calcium responses originated from nonciliated cells. Altered PAR-2 polarization in disease-remodeled epithelia may enhance apical responses and increase sensitivity to inhaled proteases. [ABSTRACT FROM AUTHOR]

Introduction  Olfactory groove meningiomas (OGMs) are often associated with loss of smell following resection. Loss of smell has a measurable impact on quality of life. Smell preservation has been previously described in open approaches for early stage or unilateral OGMs. Evidence of smell preservation in endoscopic approaches is lacking. Design  A multi-institutional retrospective review was performed on consecutive patients who underwent unilateral endoscopic endonasal resection of OGM. A gross total resection was achieved with preservation of the contralateral olfactory cleft and bulb. Olfactory function was assessed with a six-point olfactory symptom score and the Sniffin' Sticks 12-item smell identification test (SS-12). Contralateral olfactory bulb volume was measured on postoperative magnetic resonance imaging. Results  Four patients (age 42.0 ± 7.5, 75% female) were assessed. Olfactory function was assessed at 21.8 ± 5.6 months following surgery. All patients reported some degree of smell preservation (75% described a slight/mild impairment in smell or better). Olfactory identification was preserved with an SS-12 score of 9 ± 1.4 (anosmia defined as ≤6). The olfactory bulb volume was calculated to be 47.4 ± 15.9 mm 3 (normal >40 mm 3). Conclusion  Smell preservation is possible following unilateral endoscopic endonasal resection of carefully selected OGM. [ABSTRACT FROM AUTHOR]

Objectives  Pituitary carcinoma is a rare entity with fewer than 200 total cases reported in the English literature. Analysis of the population-level data from the National Cancer Database (NCDB) affords the opportunity to study this poorly understood tumor type. Methods  The NCDB was queried for site, histology, and metastasis codes corresponding to pituitary carcinoma. Statistical analyses were performed to determine factors associated with overall survival (OS). Results  A total of 92 patients with pituitary carcinoma met inclusion criteria. The 1 and 5 years of OS for all patients was 93.3% (95% confidence interval [CI]: 88.2–98.6%) and 80.0% (95% CI: 71.6–89.4%), respectively. Patients with invasive primary tumor behavior had 1 and 5 years of OS of 69.2% (95% CI: 48.2–99.5%) and 52.7% (95% CI: 31.2–89.2%), respectively. Multivariate analysis demonstrated that compared with benign primary behavior, invasive behavior had increased all-cause mortality (hazard ratio [HR], 1,296, 95% CI: 15.1– > 2,000). Surgery without adjuvant radiation or chemotherapy was the most common therapy (48.9%), followed by no treatment (40.2%). Compared with surgery alone, no treatment had worse OS (HR, 11.83, 95% CI: 1.41–99.56). Increasing age and female sex were both associated with increased mortality. Conclusions  The most common treatment for pituitary carcinoma is surgery alone followed by no surgery. Surgery alone has significantly better OS compared with no treatment. The efficacy of radiation, chemotherapy, and neurohormonal treatments needs to be examined with prospective studies. [ABSTRACT FROM AUTHOR]

TAS2R38 is a human bitter receptor gene with a common but inactive allele; people homozygous for the inactive form cannot perceive low concentrations of certain bitter compounds. The frequency of the inactive and active forms of this receptor is nearly equal in many human populations, and heterozygotes with 1 copy of the active form and 1 copy of the inactive form have the most common diplotype. However, even though they have the same genotype, heterozygotes differ markedly in their perception of bitterness, perhaps in part because of differences in TAS2R38 mRNA expression. Other tissues express this receptor too, including the nasal sinuses, where it contributes to pathogen defense. We, therefore, wondered whether heterozygous people had a similar wide range of TAS2R38 mRNA in sinonasal tissue and whether those with higher TAS2R38 mRNA expression in taste tissue were similarly high expressers in nasal tissue. To that end, we measured gene expression by quantitative PCR in taste and sinonasal tissue and found that expression abundance in one tissue was not related to the other. We confirmed the independence of expression in other tissue pairs expressing TAS2R38 mRNA, such as pancreas and small intestine, using autopsy data from the Genotype-Tissue Expression project (although people with high expression of TAS2R38 mRNA in colon also tended to have higher expression in the small intestine). Thus, taste tissue TAS2R38 mRNA expression among heterozygotes is unlikely to predict expression in other tissues, perhaps reflecting tissue-dependent function, and hence regulation, of this protein. [ABSTRACT FROM AUTHOR]

Bitter taste receptors (taste family 2 bitter receptor proteins; T2Rs), discovered in many tissues outside the tongue, have recently become potential therapeutic targets. We have shown previously that airway epithelial cells express several T2Rs that activate innate immune responses that may be important for treatment of airway diseases such as chronic rhinosinusitis. It is imperative to more clearly understand what compounds activate airway T2Rs as well as their full range of functions. T2R isoforms in airway motile cilia (T2R4, -14, -16, and -38) produce bactericidal levels of nitric oxide (NO) that also increase ciliary beating, promoting clearance of mucus and trapped pathogens. Bacterial quorum-sensing acyl-homoserine lactones activate T2Rs and stimulate these responses in primary airway cells. Quinolones are another type of quorum-sensing molecule used by Pseudomonas aeruginosa. To elucidate whether bacterial quinolones activate airway T2Rs, we analyzed calcium, cAMP, and NO dynamics using a combination of fluorescent indicator dyes and FRET-based protein biosensors. T2R-transfected HEK293T cells, several lung epithelial cell lines, and primary sinonasal cells grown and differentiated at the air--liquid interface were tested with 2-heptyl-3-hydroxy-4-quinolone (known as Pseudomonas quinolone signal; PQS), 2,4-dihydroxyquinolone, and 4-hydroxy-2-heptylquinolone (HHQ). In HEK293T cells, PQS activated T2R4, -16, and -38, whereas HHQ activated T2R14. 2,4-Dihydroxyquinolone had no effect. PQS and HHQ increased calcium and decreased both baseline and stimulated cAMP levels in cultured and primary airway cells. In primary cells, PQS and HHQ activated levels of NO synthesis previously shown to be bactericidal. This study suggests that airway T2R-mediated immune responses are activated by bacterial quinolones as well as acyl-homoserine lactones. [ABSTRACT FROM AUTHOR]

Flavones are a class of natural plant secondary metabolites that have anti-inflammatory and anti-bacterial effects. Some flavones also activate the T2R14 bitter taste receptor, which is expressed in motile cilia of the sinonasal epithelium and activates innate immune nitric oxide (NO) production. Flavones may thus be potential therapeutics for respiratory infections. Our objective was to examine the anti-microbial effects of flavones on the common sinonasal pathogens Candida albicans, Staphylococcus aureus, and Pseudomonas aeruginosa, evaluating both planktonic and biofilm growth. Flavones had only very low-level antibacterial activity alone. They did not reduce biofilm formation, but did reduce production of the important P. aeruginosa inflammatory mediator and ciliotoxin pyocyanin. However, flavones exhibited synergy against P. aeruginosa in the presence of antibiotics or recombinant human lysozyme. They also enhanced the efficacy of antimicrobials secreted by cultured and primary human airway cells grown at air-liquid interface. This suggests that flavones may have anti-gram-negative potential as topical therapeutics when combined with antibiotics or in the context of innate antimicrobials secreted by the respiratory or other epithelia. This may have an additive effect when combined with T2R14-activated NO production. Additional studies are necessary to understand which flavone compounds or mixtures are the most efficacious. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis has a significant impact on patient quality of life, creates billions of dollars of annual healthcare costs, and accounts for ~20% of adult antibiotic prescriptions in the United States. Because of the rise of resistant microorganisms, there is a critical need to better understand how to stimulate and/or enhance innate immune responses as a therapeutic modality to treat respiratory infections. We recently identified bitter taste receptors (taste family type 2 receptors, or T2Rs) as important regulators of sinonasal immune responses and potentially important therapeutic targets. Here, we examined the immunomodulatory potential of flavones, a class of flavonoids previously demonstrated to have antibacterial and anti-inflammatory effects. Some flavones are also T2R agonists. We found that several flavones inhibit Muc5AC and inducible NOS up-regulation as well as cytokine release in primary and cultured airway cells in response to several inflammatory stimuli. This occurs at least partly through inhibition of protein kinase C and receptor tyrosine kinase activity. We also demonstrate that sinonasal ciliated epithelial cells express T2R14, which closely co-localizes (<7 nm) with the T2R38 isoform. Heterologously expressed T2R14 responds to multiple flavones. These flavones also activate T2R14-driven calcium signals in primary cells that activate nitric oxide production to increase ciliary beating and mucociliary clearance. TAS2R38 polymorphisms encode functional (PAV: proline, alanine, and valine at positions 49, 262, and 296, respectively) or nonfunctional (AVI: alanine, valine, isoleucine at positions 49, 262, and 296, respectively) T2R38. Our data demonstrate that T2R14 in sinonasal cilia is a potential therapeutic target for upper respiratory infections and that flavones may have clinical potential as topical therapeutics, particularly in T2R38 AVI/AVI individuals. [ABSTRACT FROM AUTHOR]

Objective: Risk of nodal involvement in patients with sinonasal small-cell carcinoma and sinonasal undifferentiated carcinoma (SNUC) has not been well defined because of their rarity. We describe a population-based assessment of specific nodal level involvement in this group of rare neuroectodermal tumours. Methods: The Surveillance, Epidemiology and End Results (SEER) database from 2004 to 2011 identified patients with SNUC and sinonasal small-cell carcinoma. Overall neck involvement and individual nodal level involvement at presentation were assessed, and comparison was made with a contemporaneous cohort of patients with a borderline clinically significant risk of nodal involvement and recurrence. Results: Of 141 patients, 31 (22%) had gross nodal involvement at presentation (range 14-33% by site and histology). Non-nasal, non-ethmoid site with SNUC histology has the highest rates of initial nodal involvement, whereas higher stage and size do not predict for higher nodal involvement rates. Bilateral Levels 2-3 for all sinonasal small cell; Levels 2-3 for nasal or ethmoid SNUC; and bilateral Levels 1-3 in non-nasal/non-ethmoid SNUC have the highest rates of involvement compared with a clinical reference standard. Conclusion: We found high rates of initial nodal involvement in all SNUC and sinonasal small-cell carcinoma. We found higher initial involvement of Levels 2 and 3 and in certain cases to the Level 1 nodal levels, hypothesizing benefit for elective treatment to those levels. Advances in knowledge: With small single-institution series reporting conflicting nodal involvement rates, our data support high rates of nodal presentation at diagnosis, hypothesizing benefit for elective nodal treatment in this cohort. [ABSTRACT FROM AUTHOR]

Bitter taste receptors (T2Rs) in the human airway detect harmful compounds, including secreted bacterial products. Here, using human primary sinonasal air-liquid interface cultures and tissue explants, we deter- mined that activation of a subset of airway T2Rs expressed in nasal solitary chemosensory cells activates a calcium wave that propagates through gap junctions to the surrounding respiratory epithelial cells. The T2R-dependent calcium wave stimulated robust secretion of antimicrobial peptides into the mucus that was capable of killing a variety of respiratory pathogens. Furthermore, sweet taste receptor (T1R2/3) activation suppressed T2R-mediated antimicrobial peptide secretion, suggesting that T1R2/3-mediated inhibition of T2Rs prevents full antimicrobial peptide release during times of relative health. In contrast, during acute bacterial infection, T1R2/3 is likely deactivated in response to bacterial consumption of airway surface liquid glucose, alleviating T2R inhibition and resulting in antimicrobial peptide secretion. We found that patients with chronic rhinosinusitis have elevated glucose concentrations in their nasal secretions, and other reports have shown that patients with hyperglycemia likewise have elevated nasal glucose levels. These data suggest that increased glucose in respiratory secretions in pathologic states, such as chronic rhinosinusitis or hyperglycemia, promotes tonic activation of T1R2/3 and suppresses T2R-mediated innate defense. Furthermore, targeting T1R2/3-dependent suppression of T2Rs may have therapeutic potential for upper respiratory tract infections. [ABSTRACT FROM AUTHOR]

Innate and adaptive defense mechanisms protect the respiratory system from attack by microbes. Here, we present evidence that the bitter taste receptor T2R38 regulates the mucosal innate defense of the human upper airway. Utilizing immunofluorescent and live cell imaging techniques in polarized primary human sinona-sal cells, we demonstrate that T2R38 is expressed in human upper respiratory epithelium and is activated in response to acyl-homoserine lactone quorum-sensing molecules secreted by Pseudomonas aeruginosa and other gram-negative bacteria. Receptor activation regulates calcium-dependent NO production, resulting in stimu-lation of mucociliary clearance and direct antibacterial effects. Moreover, common polymorphisms of the TAS2R38 gene were linked to significant differences in the ability of upper respiratory cells to clear and kill bacteria. Lastly, TAS2R38 genotype correlated with human sinonasal gram-negative bacterial infection. These data suggest that T2R38 is an upper airway sentinel in innate defense and that genetic variation contributes to individual differences in susceptibility to respiratory infection. [ABSTRACT FROM AUTHOR]

Introduction: Nasopharyngeal angiofibroma (NA) characteristically affects adolescent men. Although benign, these tumors can cause local destruction and surgical resection is warranted. Objective: We present a case of a 62-year-old man with nasal congestion and epistaxis, found to be a right NA on pathology. We also present a review of the available NA staging systems. Findings: In this case of NA, imaging revealed an aggressive, hypervascular mass in the nasal cavity with involvement of the middle cranial fossa and cavernous sinus. The patient underwent complete endoscopic surgical resection following vascular embolization. Conclusions: Although it is rare, NA should not be disregarded in the elderly population. [ABSTRACT FROM AUTHOR]

Introduction: Nasopharyngeal angiofibroma (NA) characteristically affects adolescent men. Although benign, these tumors can cause local destruction and surgical resection is warranted. Objective: We present a case of a 62-year-old man with nasal congestion and epistaxis, found to be a right NA on pathology. We also present a review of the available NA staging systems. Findings: In this case of NA, imaging revealed an aggressive, hypervascular mass in the nasal cavity with involvement of the middle cranial fossa and cavernous sinus. The patient underwent complete endoscopic surgical resection following vascular embolization. Conclusions: Although it is rare, NA should not be disregarded in the elderly population. [ABSTRACT FROM AUTHOR]

Age-related decreases in olfactory sensitivity are often accompanied by a decrease in the quality of life. However, the molecular mechanisms underlying these changes are not well described. Inhaled substances including odorants are detected by sensory neurons in the olfactory cleft covered with a layer of mucus. This olfactory mucus is the first molecular machinery responsible for tissue protection and for detection of environmental odorants. Yet, little is known about the molecular identities of the actors because of the lack of information on the mucus proteome and its age-related changes. Here, we sampled human mucus from different nasal locations and from young and elderly subjects. The composition of the mucus was extensively analyzed by shotgun proteomic analysis for a vast array of proteins. We also explored correlations between the levels of each mucus proteins with the olfactory sensitivity of subjects. This analysis revealed previously unrecognized proteins with potentially important functions in olfaction. Taken together, this report describes the most comprehensive catalogue of the nasal mucus proteins to date, their positional and age-related differences, and candidate proteins associated with olfaction. This catalogue will provide fundamental information useful for future studies, such as identification of olfactory auxiliary proteins, causes of age-related declines in olfaction, and biomarkers for neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

An abstract of a study which examined patients undergoing extended endoscopic approach (EEA) for skull base tumors is presented.