Background Secretoneurin is a neuropeptide located in nerve fibers along blood vessels, is up-regulated by hypoxia and induces angiogenesis. We tested the hypothesis that secretoneurin gene therapy exerts beneficial effects in a rat model of myocardial infarction and evaluated the mechanism of action on coronary endothelial cells. Methods and Results In-vivo secretoneurin improved left ventricular function, inhibited remodeling and reduced scar formation. In the infarct border zone secretoneurin induced coronary angiogenesis as shown by increased density of capillaries and arteries. In-vitro secretoneurin induced capillary tubes, stimulated proliferation, inhibited apoptosis and activated Akt and ERK in coronary endothelial cells. Effects were abrogated by a VEGF-antibody and secretoneurin stimulated VEGF receptors in these cells. Secretoneurin furthermore increased binding of VEGF to endothelial cells and binding was blocked by heparinase indicating that secretoneurin stimulates binding of VEGF to heparan sulfate proteoglycan binding sites. Additionally, secretoneurin increased binding of VEGF to its co-receptor neuropilin 1. In endothelial cells secretoneurin also stimulated FGF receptor-3 and IGF-1 receptor and in coronary vascular smooth muscle cells we observed stimulation of VEGF receptor-1 and FGF receptor-3. Exposure of cardiac myocytes to hypoxia and ischemic heart after myocardial infarction revealed increased secretoneurin m-RNA and protein. Conclusions Our data show that secretoneurin acts as an endogenous stimulator of VEGF signaling in coronary endothelial cells by enhancing binding of VEGF to low affinity binding sites and neuropilin 1 and stimulates further growth factor receptors like FGF receptor-3. Our in-vivo findings indicate that secretoneurin might be a promising therapeutic tool in ischemic heart disease.

Purpose The sino-nasal outcomes test-22 (SNOT-22) represents the reference questionnaire to assess patients with chronic rhinosinusitis (CRS). As weak correlations between objective CRS parameters and SNOT-22 total score have been observed, factor analyses have aimed to identify underlying factorial structures. However, ambiguous factor loadings and problematic item-domain assignments have resulted. Moreover, such factor analyses have mainly been performed in non-European CRS patients, while European data remain sparse. This study thus sought to address these issues. Methods Principal component analysis and confirmatory factor analysis were performed from SNOT-22 questionnaires completed by European CRS patients. Goodness of fit, internal consistencies, and factor loadings were calculated. Item-domain assignment was based on statistical grounds and clinical meaningfulness. Additionally, this study investigated correlations between SNOT-22 domains and external reference criteria, including Lund–Mackay score, Lund–Naclerio score and the brief symptom inventory 18 (BSI-18). Results One hundred and thirty-four European CRS patients were included. Principal component analysis proposed four SNOT-22 domains (“ nasal symptoms ”, “ otologic symptoms ”, “ sleep symptoms ”, “ emotional symptoms ”), which explained 63.6% of variance. Observed item-domain-assignment differed from previously proposed item-domain assignments. All factor loadings were > 0.5, except “cough” (0.42) and “facial pain or pressure” (0.49). For confirmatory factor analysis, satisfactory goodness of fit (RMSEA = 0.66; CFI = 0.92; TLI = 0.90) and internal consistencies (Cronbach-α: total score = 0.93; domains = 0.75–0.91) were observed. Significant positive correlations were found between the “ nasal symptoms ” domain and both the Lund–Mackay score ( r = 0.48; p < 0.001) and the Lund–Naclerio score ( r = 0.27, p < 0.01). Significant positive correlations were also identified between “ emotional symptoms ” and BSI-18 total score ( r = 0.64, p < 0.001). Conclusions Principal component analysis performed for SNOT-22 questionnaires completed by European CRS patients indicated a different item-domain-assignment than previously reported. Confirmatory factor analysis suggested acceptable and clinically plausible psychometric properties for the resulting factorial structure. Significant correlations between the “ nasal symptoms ” and the “ emotional symptoms ” domains were observed with objective CRS parameters. The resulting factorial structure with different item-domain assignments may ...

BACKGROUND AND PURPOSE:Localization of the electrode after cochlear implantation seems to have an impact on auditory outcome, and conebeam CT has emerged as a reliable method for visualizing the electrode array position within the cochlea. The aim of this retrospective study was to evaluate the frequency and clinical impact of scalar dislocation of various electrodes and surgical approaches and to evaluate its influence on auditory outcome.

Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Background: Epithelial to mesenchymal transition (EMT) promotes therapy resistance in head and neck cancer (HNC) cells. In this study, EMT was quantified in HNC tumor samples by the cellular co-localization of cytokeratin/vimentin, E-cadherin/β-catenin and by Slug expression. Methods: Tissue samples from HNC patients were stained with antibody pairs against cytokeratin/vimentin and E-cadherin/β-catenin. Epithelial–mesenchymal co-localization was quantified using immunofluorescence multichannel image cytometry. Double positivity was confirmed using confocal microscopy. Slug was semi-quantified by 2 specialists and quantified by bright field image cytometry. Results: Tumor samples of 102 patients were investigated. A loss of E-cadherin positive cells (56.9 ± 2.6% vs. 97.9 ± 1.0%; p < 0.0001) and E-cadherin/β-catenin double positive cells (15.4 ± 5.7% vs. 85.4 ± 1.2%; p < 0.0001) was observed in tumor samples. The percentage of Slug positive cells was increased in tumor samples (12.1 ± 3.6% vs. 3.2 ± 2.6%; p = 0.001). Ordinal Slug scores judged by two specialists closely correlated with percentage of Slug-positive cells (Spearman’s rho = 0.81; p < 0.001). Slug score correlated negatively with the percentage of E-cadherin positive cells (r = 0.4; p = 0.006), the percentage of E-cadherin/β-catenin positive cells (r = 0.5; p = 0.001) and positively with cytokeratin/vimentin positive cells (r = 0.4, p = 0.003). Conclusion: EMT can be assessed in HNC tumor probes by cytokeratin/vimentin co-expression and loss of E-cadherin/β-catenin co-expression. Slug score provides a convenient surrogate marker for EMT.

BackgroundTumor volume may serve as a predictor of response to radiochemotherapy (RCT) in head and neck squamous cell carcinoma (HNSCC). Computer assisted tumor volumetry requires time-consuming slice-by-slice manual or semi-automated segmentation. We questioned how accurately primary tumor and suspect cervical lymph node (LN) volumes can be approximated by the maximum tumor diameters in three dimensions.MethodsIn contrast-enhanced diagnostic CT scans of 74 patients with incident advanced HNSCC, manual slice-by-slice segmentation volumetry of primary tumor, total- and largest suspect cervical LN served as the reference method. In the same scans, maximum orthogonal diameters were measured using the distance measurement tool in standard visualization software in axial and coronal sections. From these diameters, approximate volumes were calculated using the cubic and ellipsoid formula. A second segmentation volumetry was performed in contrast enhanced radiotherapy-planning CT scans obtained prior to primary concurrent RCT 24 days (+/− 13 days) following the initial diagnostic CT scans. Intraclass correlation coefficients and Bland-Altman analyses were used to compare results.ResultsSlice-by-slice manual segmentation volumetry of primary and LN volumes revealed a lognormal distribution and ranged from 0 to 86 ml and 0 to 129 ml, respectively. Volume approximations in diagnostic CT scans with the ellipsoid formula resulted in an −8 % underestimation of tumor volumes (95 % CI −14 % to −1 %; p = 0.022) and an −18 % underestimation of suspect cervical LN volumes (95 % CI −25 % to −12 %; p = 0.001). Inter rater intraclass correlation for primaries was 0.95 (95 % CI +0.92 to +0.97; p = 0.001), and intra rater intraclass correlation was 0.99 (95 % CI +0.98 to +0.99; p = 0.001). The cubic formula resulted in pronounced overestimation of primary and LN volumes. Primary tumor volumes obtained by the second segmentation volumetry in radiotherapy-planning CT scans obtained on average 24 days following the initial volumetry resulted in larger primary tumor volumes (mean bias +28 %, 95 % CI +14 % to +41 %; p = 0.001). Tumor volume increase correlated with time between the diagnostic and planning CTs (r = 0.24, p = 0.05) and was approximately 1 % per day.DiscussionEllipsoid approximations of tumor and lymph node volumes in HNSCC using maximum orthogonal diameters underestimates volumes based on segmentation in multiple slices. Due to time difference and safety margins, segmented volumes in radiotherapy-planning CT scans tend to be larger than in diagnostic CT scans.ConclusionEllipsoid approximations of tumor and lymph node volumes in HNSCC are easily available from diagnostic CT scans. Volume estimates are applicable over a wide range of tumor and LN sizes and may be useful in clinical decision-making and oncologic research.

Neurotrophins and their receptors might regulate cell survival in head and neck squamous cell carcinoma (HNSCC). mRNA expression of nerve growth factor (NGF) and protein synthesis of high (NTRK1) and low affinity neurotrophin (p75 neurotrophin receptor; NTR) receptors were investigated in normal oral mucosa and in HNSCC. HNSCC cell lines were treated with mitomycin C (MMC) and cell survival was investigated. Normal and malignant epithelial cells expressed NGF mRNA. NTRK1 was upregulated in 80% of HNSCC tissue, and 50% of HNSCC samples were p75NTR positive. Interestingly, in HNSCC tissue: NTRK1 and p75NTR immunohistochemical reactions were mutually exclusive. Detroit 562 cell line contained only p75NTR, UPCI-SCC090 cells synthesized NTRK1 but not p75NTR and SCC-25 culture had p75NTR and NTRK1 in different cells. NGF (100 ng/mL) significantly improved (1.4-fold) the survival of cultured UPCI-SCC090 cells after MMC-induced cell cycle arrest, while Detroit 562 cells with high levels of p75NTR did not even get arrested by single short MMC treatment. p75NTR in HNSCC might be related with NGF-independent therapy resistance, while NTRK1 might transduce a survival signal of NGF and contribute in this way to improved tumor cell survival after cell cycle arrest.

ObjectiveEpithelial-mesenchymal crosstalk (EMC) contributes to tumor progression, chemoresistance and acquisition of a mesenchymal phenotype (EMT) of cancer cells. This study aims to investigate the effects of EMC on radioresistance in head and neck squamous cell carcinoma (HNSCC) cells.MethodsIn tumor cell lines, the response of HNSCC cells, stimulated with EMC conditioned medium (CM), to irradiation was evaluated with viability and clonogenic assays. Dose modifying factors (DMF) were calculated from the results of clonogenic assays. Potential pathways involved in radioresistance were analyzed with quantitative Real-Time PCR and western blot.ResultsCM significantly reduced the doubling time of SCC-25 cells (from 32.8 hours to 16.8 hours, p=0.0001) and Detroit 562 cells (from 88.5 hours to 29.6 hours, p=0.014). Further it increased clonogenic survival after irradiation. The DMF of CM was 2.04 ± 0.43 (mean ± standard deviation) for SCC-25 cells (p=0.015) and 2.14 ± 0.34 for Detroit 562 cells (p=0.008). Treatment with CM more than tripled the ERCC1 and survivin gene expression in SCC-25 cells.ConclusionEMC induced pathways involved in cell survival and DNA repair and led to increased radioresistance in HNSCC cells.