The Na؉ /H ؉ exchanger isoform 1 is an integral membrane protein that regulates intracellular pH by exchanging one intracellular H ؉ for one extracellular Na ؉ . It is composed of an N-terminal membrane domain of 12 transmembrane segments and an intracellular C-terminal regulatory domain. We characterized the structural and functional aspects of the critical transmembrane segment VII (TM VII, residues 251-273) by using alanine scanning mutagenesis and high resolution NMR. Each residue of TM VII was mutated to alanine, the full-length protein expressed, and its activity characterized. TM VII was sensitive to mutation. Mutations at 13 of 22 residues resulted in severely reduced activity, whereas other mutants exhibited varying degrees of decreases in activity. The impaired activities sometimes resulted from low expression and/or low surface targeting. Three of the alanine scanning mutant proteins displayed increased, and two displayed decreased resistance to the Na ؉ /H ؉ exchanger isoform 1 inhibitor EMD87580. The structure of a peptide of TM VII was determined by using high resolution NMR in dodecylphosphocholine micelles. TM VII is predominantly ␣-helical, with a break in the helix at the functionally critical residues Gly 261 -Glu 262 . The relative positions and orientations of the N-and C-terminal helical segments are seen to vary about this extended segment in the ensemble of NMR structures. Our results show that TM VII is a critical transmembrane segment structured as an interrupted helix, with several residues that are essential to both protein function and sensitivity to inhibition. The mammalian Naϩ /H ϩ exchanger isoform 1 (NHE1) 6 is a ubiquitous integral membrane protein mediating removal of a single intracellular proton in exchange for one extracellular sodium ion (1). NHE1 has several cellular and physiological functions, including protecting cells from intracellular acidification (2, 3), promoting cell growth and differentiation (2), and regulating sodium fluxes and cell volume after osmotic shrinkage (4). The Na ϩ /H ϩ exchanger also plays a critical role in the damage that occurs during ischemia and reperfusion and may play a key role in mediating heart hypertrophy. Inhibition of the exchanger protects the myocardium in these two forms of heart disease (5, 6). Amiloride and its derivatives are inhibitors of the NHE1 isoform of the Na ϩ /H ϩ exchanger, and a new generation of Na ϩ /H ϩ exchanger inhibitors is being developed for clinical treatment of heart disease (7,8). In addition to these many physiological roles, more recently, the Na ϩ /H ϩ exchanger has been demonstrated to be involved in modulating cell motility and invasiveness of neoplastic breast cancer cells (9) and has been shown to be critical to cell motility in some cell types (10).NHE1 is composed of two domains as follows: an N-terminal membrane domain of ϳ500 amino acids and a C-terminal regulatory domain of ϳ315 amino acids (1, 6). The N-terminal membrane domain is responsible for ion movement and has 12 transmembrane segments ...

BackgroundSinonasal undifferentiated carcinoma (SNUC) is a rare malignancy with often dismal outcomes. This study set to determine provincial and literature-wide survival outcomes based on treatment modality.MethodsRetrospective chart review of all SNUC patients in the province of Alberta from 1986–2010 was conducted. A review of the literature of SNUC patients was also performed. Patient/tumor characteristics, treatment, and follow-up/survival data were collected. Kaplan-Meier and Cox regression survival analyses were performed.Results20 patients were treated for SNUC in Alberta and 140 patients were identified in the literature. Pooled median disease-free survival was 12. 7 months and 5-year survival estimate was 6.25%. Cox-Regression analysis demonstrated an overall survival advantage with multimodality treatments (Log-Rank test: p = 0.015). However, no statistically significant differences in disease-free and overall survival were identified between patients treated with chemoradiation or surgery followed by adjuvant therapy.ConclusionsTreatment of SNUC remains challenging with poor survival outcomes. There appears to be no statistically significant difference in overall, or disease-free survival between treatment modalities.

IntroductionsThe incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCCs) is rising in developed nations. Studies have shown that these virally mediated tumours are epidemiologically, clinically, and biologically different than other head and neck squamous cell carcinomas and traditional concepts of field cancerization may not apply to HPV-related oropharyngeal cancer.ObjectiveThe purpose of this study was to evaluate the rate of second primary tumors and the diagnostic yield of field cancerization work up in the upper aerodigestive tract in patients with HPV-related and HPV-unrelated oropharyngeal squamous cell carcinoma.DesignRetrospective review.SettingTertiary cancer care centers in Alberta.MethodsRetrospective review of 406 patients diagnosed with OPSCC in Alberta between 2005 and 2009. HPV-status of tumours was determined by tissue microarray using immunohistochemistry staining for p16.Main outcome measuresPrimary outcome: incidence of upper aerodigestive tract second primary tumours in p16-positive versus p16-negative OPSCC. Secondary outcomes: diagnostic yield of traditional field cancerization work-up in p16-positive versus negative patients.ResultsThe overall rate of SPTs was 7.4% (30/406). The incidence rate of SPTs was significantly lower in p16-positive patients (0.7 per 100 patient-yrs vs. 8.5 in p16-negative, p < 0.0001). Field cancerization work-up for synchronous lesions in the upper aerodigestive tract, including panendoscopy and whole-body PET-CT, had decreased diagnostic yield in p16-positive patients (2.8% vs. 10.2% in HPV-negative patients, p=0.02).ConclusionsPatients with HPV-related OPSCC, who are non-smokers have decreased risk of developing second primary tumours in the upper aerodigestive tract and have low yield on field cancerization work-up. This study provides further evidence that virally mediated OPSCC are distinct and may benefit from alternate diagnostic pathways.

With the increased demand for evidence-based medicine, facial plastic surgery literature has seen an overall increase in the quantity of higher level evidence research published. However, articles representing level 1 and 2 evidence remain rare.