Exploiting Vitamin D Receptor and Its Ligands to Target Squamous Cell Carcinomas of the Head and Neck.

Vitamin D (VitD) and its receptor (VDR) have been intensively investigated in many cancers. As knowledge for head and neck cancer (HNC) is limited, we investigated the (pre)clinical and therapeutic relevance of the VDR/VitD-axis. We found that VDR was differentially expressed in HNC tumors, correlating to the patients' clinical parameters. Poorly differentiated tumors showed high VDR and Ki67 expression, whereas the VDR and Ki67 levels decreased from moderate to well-differentiated tumors. The VitD serum levels were lowest in patients with poorly differentiated cancers (4.1 ± 0.5 ng/mL), increasing from moderate (7.3 ± 4.3 ng/mL) to well-differentiated (13.2 ± 3.4 ng/mL) tumors. Notably, females showed higher VitD insufficiency compared to males, correlating with poor differentiation of the tumor. To mechanistically uncover VDR/VitD's pathophysiological relevance, we demonstrated that VitD induced VDR nuclear-translocation (VitD < 100 nM) in HNC cells. RNA sequencing and heat map analysis showed that various nuclear receptors were differentially expressed in cisplatin-resistant versus sensitive HNC cells including VDR and the VDR interaction partner retinoic acid receptor (RXR). However, RXR expression was not significantly correlated with the clinical parameters, and cotreatment with its ligand, retinoic acid, did not enhance the killing by cisplatin. Moreover, the Chou-Talalay algorithm uncovered that VitD/cisplatin combinations synergistically killed tumor cells (VitD < 100 nM) and also inhibited the PI3K/Akt/mTOR pathway. Importantly, these findings were confirmed in 3D-tumor-spheroid models mimicking the patients' tumor microarchitecture. Here, VitD already affected the 3D-tumor-spheroid formation, which was not seen in the 2D-cultures. We conclude that novel VDR/VitD-targeted drug combinations and nuclear receptors should also be intensely explored for HNC. Gender-specific VDR/VitD-effects may be correlated to socioeconomic differences and need to be considered during VitD (supplementation)-therapies.

A psychoacoustic application for the adjustment of electrical hearing thresholds in cochlear implant patients.

OBJECTIVE: Fitting cochlear implants, especially the precise determination of electrical hearing thresholds, is a time-consuming and complex task for patients as well as audiologists. Aim of the study was to develop a method that enables cochlear implant (CI) patients to determine their electrical hearing thresholds precisely and independently. Applicability and impact of this method on speech perception in noise at soft speech levels were evaluated. METHOD: An adaptive psychoacoustic procedure for precise hearing threshold determination (precT) was implemented using MatLab (MathWorks) and a graphical user interface was created. Sound signals were calibrated with a CIC4-Implant-Decoder. Study design: A prospective study including 15 experienced adult cochlear implant users was conducted. Electrical hearing thresholds were determined using the automated precT procedure (auto-precT). Speech perception in noise at 50 dB SPL presentation levels was measured for three conditions: (P1) T-levels kept at the previously established T-levels; (P2) T-levels set to the hearing thresholds determined using auto-precT application; (P3) T-levels set 10 cu below the values determined with auto-precT. RESULTS: All subjects were able to perform the auto-precT application independently. T-levels were altered on average by an absolute value of 10.5 cu using auto-precT. Median speech reception thresholds were significantly improved from 2.5 dB SNR (P1) to 1.6 dB SNR (P2, p = 0.02). Speech perception was lowest using the globally lowered T-levels, median 2.9 dB SNR (P3, not significant compared to P1 and P2). CONCLUSION: The applicability of the developed auto-precT application was confirmed in the present clinical study. Patients benefited from adjusting previously established T-levels to the threshold levels determined by the auto-precT application. The integration of the application in the clinical fitting routine as well as a remote fitting software approach is recommended. Furthermore, future possibilities of auto-precT include the implementation of the application on tablets or smart phones.

Validation of contrast-enhanced ultrasound-derived intensity-time gradients in submandibular gland sialolithotomy patients.

Contrast-enhanced ultrasound (CE-US)-derived intensity-time gradients (ITGs) can be used for noninvasive monitoring of extracorporeal shock wave sialolithotripsy effects in chronic sialolithiasis-related sialadenitis. Aim of this trial was to further validate CE-US as an independent and quantitative diagnostic tool for sialolithotomy efficacy. In this prospective clinical phase II evidence level c study perfusion in patients (n = 10) with unilateral sialolithiasis of the submandibular gland was quantitatively analyzed by CEUS before and after sialolithotomy comparing with the contralateral disease-free gland. A visual analog scale (VAS) scoring clinical complaints was correlated with CE-US-derived ITGs. Furthermore, ITG ratios reflecting values from the contralateral side and the diseased side were calculated. VAS documented significantly reduced clinical complaints after sialolithotomy indicative of a successful treatment. VAS data significantly correlated with CE-US-derived ITGs. In addition, ITG ratios were significantly increased after sialolithotomy. In conclusion, CE-US-derived ITGs and ITG ratios appear as independent and valid quantitative parameters of sialolithotomy efficacy.

Quantitative estimation of minor conductive hearing loss with distortion product otoacoustic emissions in the guinea pig.

Subclinical conductive hearing losses (CHLs) can affect otoacoustic emissions and therefore limit their potential in the assessment of the cochlear function. Theoretical considerations to estimate a minor CHL from DPOAE measurements [Kummer et al. (2006). HNO 54, 457-467] are evaluated experimentally. They are based on the fact, that the level difference of the stimulus tones L(1) and L(2) for optimal excitation of the inner ear is given by L(1)=aL(2)+b. A CHL is presumed to attenuate both L(1) and L(2) to the same extent such that excitation of the inner ear is no longer optimal. From the change of L(1) that is necessary to restore optimal excitation of the inner ear and thus to produce maximal DPOAE levels, the CHL can be estimated. In 10 guinea pig ears an experimental CHL was produced, quantified by determination of compound action potential (CAP) thresholds at 8 kHz (CHL(CAP)) and estimated from DPOAE measurements at 8 kHz (CHL(DPOAE)). CHLs up to 12 dB could be assessed. CHL(DPOAE) correlated well with CHL(CAP) (R=0.741, p=0.0142). Mean difference between CHL(DPOAE) and CHL(CAP) was 4.2±2.6 dB. Estimation of minor CHL from DPOAE measurements might help to increase the diagnostic value of DPOAEs.

Static magnetic fields impair angiogenesis and growth of solid tumors in vivo.

Exposure to static magnetic fields (SMFs) results in a reduced blood flow in tumor vessels as well as in activation and adherence of platelets. Whether this phenomenon may have a significant functional impact on tumors has not been investigated as yet. The aim of our study was to evaluate the effects of prolonged exposure to SMFs on tumor angiogenesis and growth. Experiments were performed in dorsal skinfold chamber preparations of Syrian Golden hamsters bearing syngenic A-Mel-3 melanomas. On 3 d following tumor cell implantation one group of animals was immobilized and exposed to a SMF of 586 mT for three h. Control animals were immobilized for the same duration without SMF exposure. Using in vivo-fluorescence microscopy the field effects on tumor angiogenesis and microcirculation were analyzed for seven days. Tumor growth was assessed by repeated planimetry of the tumor area during the observation period. Exposure to SMFs resulted in a significant retardation of tumor growth ( approximately 30%). Furthermore, histological analysis showed an increased peri- and intratumoral edema in tumors exposed to SMFs. Analysis of microcirculatory parameters revealed a significant reduction of functional vessel density, vessel diameters and red blood cell velocity in tumors after exposure to SMFs compared to control tumors. These changes reflect retarded vessel maturation by antiangiogenesis. The increased edema after SMF exposure indicates an increased tumor microvessel leakiness possibly enhancing drug-uptake. Hence, SMF therapy appears as a promising new anticancer strategy-as an inhibitor of tumor growth and angiogenesis and as a potential sensitizer to chemotherapy.