Sebastian Strieth

Expressional analysis of disease-relevant signalling-pathways in primary tumours and metastasis of head and neck cancers

Head and neck squamous cell carcinoma (HNSCC) often metastasize to lymph nodes resulting in poor prognosis for patients. Unfortunately, the underlying molecular mechanisms contributing to tumour aggressiveness, recurrences, and metastasis are still not fully understood. However, such knowledge is key to identify biomarkers and drug targets to improve prognosis and treatments. Consequently, we performed genome-wide expression profiling of 15 primary HNSSCs compared to corresponding lymph node metastases and non-malignant tissue of the same patient. Differentially expressed genes were bioinformatically exploited applying stringent filter criteria, allowing the discrimination between normal mucosa, primary tumours, and metastases. Signalling networks involved in invasion contain remodelling of the extracellular matrix, hypoxia-induced transcriptional modulation, and the recruitment of cancer associated fibroblasts, ultimately converging into a broad activation of PI3K/AKT-signalling pathway in lymph node metastasis. Notably, when we compared the diagnostic and prognostic value of sequencing data with our expression analysis significant differences were uncovered concerning the expression of the receptor tyrosine kinases EGFR and ERBB2, as well as other oncogenic regulators. Particularly, upregulated receptor tyrosine kinase combinations for individual patients varied, implying potential compensatory and resistance mechanisms against specific targeted therapies. Collectively, we here provide unique transcriptional profiles for disease predictions and comprehensively analyse involved signalling pathways in advanced HNSCC.

Dexamethasone prevents hearing loss by restoring glucocorticoid receptor expression in the guinea pig cochlea

Dexamethasone is widely used in the treatment of various inner ear diseases. However, knowledge about its direct impact on glucocorticoid receptor (GR) expression is still limited.

The “Comprehensive ICF Core Set for Head and Neck Cancer”: a Delphi consensus survey among German speaking speech and language therapists

The “Comprehensive ICF Core Set for Head and Neck Cancer” (ICF-HNC) is an application of the “International Classification of Functioning, Disability and Health” (ICF), representing the characteristic spectrum of issues in patients with head and neck cancer (HNC). Our primary aim was to evaluate which categories of the ICF-HNC are dealt with by speech and language therapists (SLTs) in Germany, Austria, and Switzerland. The secondary aim was to identify outcome measures used by SLTs to measure the categories of the ICF-HNC in clinical practice. SLTs experienced in the treatment of HNC patients evaluated the categories of the ICF-HNC in a three-round Delphi survey. They were asked whether the listed categories represented issues treated by SLTs in HNC patients, and what outcome measures were used to assess them. Altogether, 31 SLTs completed the survey. 47 of 108 previously selected categories of the ICF-HNC achieved the cut-off value. Out of these, 40.4% were derived from the component “Body Functions”, 36.2% from “Body Structures”, 12.8% from “Environmental Factors”, and 10.6% from “Activities and Participation”. Altogether, 82 of the mentioned outcome measures were considered as reasonable from the perspective of SLTs. Of these, only 37 achieved more than 50% approval. This study emphasises the importance of “Body Structures” and “Body Functions” for SLTs in Germany and Switzerland in treating patients with HNC. Moreover, the results highlighted the need to agree on evidence-based outcome measures in speech and language therapy.

Gentamicin alters Akt-expression and its activation in the guinea pig cochlea

Gentamicin treatment induces hair cell death or survival in the inner ear. Besides the well-known toxic effects, the phosphatidylinositol-3 kinase/Akt (PI3K/Akt) pathway was found to be involved in cell protection. After gentamicin application, the spatiotemporal expression patterns of Akt and its activated form (p-Akt) were determined in male guinea pigs. A single dose of 0.1 mL gentamicin (4 mg/ear/animal) was intratympanically injected. The auditory brainstem responses (ABRs) were recorded prior to application and 1, 2 and 7 days afterward. At these three time points the cochleae (n=10 in each case) were removed, transferred to fixative and embedded in paraffin. Seven ears were used as untreated controls. Gentamicin, Akt and p-Akt were identified immunohistochemically in various regions of the cochlea and their staining intensities were quantified on sections using digital image analysis. The application of gentamicin resulted in hearing loss with a concomitant up-regulation of Akt-expression in the organ of Corti and spiral ganglion cells and an additional activation in spiral ganglion cells. At the level of individual ears, clear intracellular correlations were found between Akt- and p-Akt-expression in the stria vascularis and interdental cells and, to a minor extent, in the spiral ligament and the organ of Corti. Furthermore, statistical evidence for the connection between gentamicin up-take and hearing loss was detected. The increase in Akt- and p-Akt-expression in the organ of Corti and spiral ganglion cells indicates a selected response of the cochlea against gentamicin toxicity.

A method for determining precise electrical hearing thresholds in cochlear implant users

Abstract Objective: A psychoacoustic procedure designed for the precise assessment of perceptional threshold (T-level) in cochlear implant (CI) users is presented. The impact of this procedure on speech perception was investigated. Design: Individual T-level measurements were obtained with the proposed procedure and three different speech processor fitting conditions were applied: (1) fitting familiar to the subject, T-levels unchanged, (2) T-level set to thresholds determined with the new procedure, (3) T-level set to thresholds determined with the new procedure, but T-level is decreased by 10 clinical units (CU). The impact of the different fitting conditions was measured by means of categorical loudness scaling (CLS) and speech perception tests in quiet and noise. Study sample: A prospective study at a tertiary referral university hospital. 18 experienced postlingually deafened cochlear implanted adult subjects. Results: Average sound-field thresholds obtained by CLS were lowest in condition using the new procedure yielding a larger dynamic range with significantly higher speech scores in quiet compared to those with a subject’s commonly used programme, and significantly improved in noise even after reducing T-levels by 10 CU. Conclusion: The precise determination of T-levels by means of the proposed procedure improved performance in several speech recognition tasks. Compared to the default behavioural setting, T-level increased on median by 9 CU. Average speech reception threshold in noise for soft speech levels (50 dB sound pressure level) decreased by 1 dB.

Components of the plasminogen activation system promote engraftment of porous polyethylene biomaterial via common and distinct effects.

Rapid fibrovascularization is a prerequisite for successful biomaterial engraftment. In addition to their well-known roles in fibrinolysis, urokinase-type plasminogen activator (uPA) and tissue plasminogen activator (tPA) or their inhibitor plasminogen activator inhibitor-1 (PAI-1) have recently been implicated as individual mediators in non-fibrinolytic processes, including cell adhesion, migration, and proliferation. Since these events are critical for fibrovascularization of biomaterial, we hypothesized that the components of the plasminogen activation system contribute to biomaterial engraftment. Employing in vivo and ex vivo microscopy techniques, vessel and collagen network formation within porous polyethylene (PPE) implants engrafted into dorsal skinfold chambers were found to be significantly impaired in uPA-, tPA-, or PAI-1-deficient mice. Consequently, the force required for mechanical disintegration of the implants out of the host tissue was significantly lower in the mutant mice than in wild-type controls. Conversely, surface coating with recombinant uPA, tPA, non-catalytic uPA, or PAI-1, but not with non-catalytic tPA, accelerated implant vascularization in wild-type mice. Thus, uPA, tPA, and PAI-1 contribute to the fibrovascularization of PPE implants through common and distinct effects. As clinical perspective, surface coating with recombinant uPA, tPA, or PAI-1 might provide a novel strategy for accelerating the vascularization of this biomaterial.