Somatic mutations and promotor methylation of the ryanodine receptor 2 is a common event in the pathogenesis of head and neck cancer

Genomic sequencing projects unraveled the mutational landscape of head and neck squamous cell carcinoma (HNSCC) and provided a comprehensive catalog of somatic mutations. However, the limited number of significant cancer-related genes obtained so far only partially explains the biological complexity of HNSCC and hampers the development of novel diagnostic biomarkers and therapeutic targets. We pursued a multiscale omics approach based on whole-exome sequencing, global DNA methylation and gene expression profiling data derived from tumor samples of the HIPO-HNC cohort (n = 87), and confirmed new findings with datasets from The Cancer Genome Atlas (TCGA). Promoter methylation was confirmed by MassARRAY analysis and protein expression was assessed by immunohistochemistry and immunofluorescence staining. We discovered a set of cancer-related genes with frequent somatic mutations and high frequency of promoter methylation. This included the ryanodine receptor 2 (RYR2), which showed variable promoter methylation and expression in both tumor samples and cell lines. Immunohistochemical staining of tissue sections unraveled a gradual loss of RYR2 expression from normal mucosa via dysplastic lesion to invasive cancer and indicated that reduced RYR2 expression in adjacent tissue and precancerous lesions might serve as risk factor for unfavorable prognosis and upcoming malignant conversion. In summary, our data indicate that impaired RYR2 function by either somatic mutation or epigenetic silencing is a common event in HNSCC pathogenesis. Detection of RYR2 expression and/or promoter methylation might enable risk assessment for malignant conversion of dysplastic lesions

Neue Loesungen mit Stahl beim Automobil-Leichtbau Abschlussbericht

The objective of the project was to investigate the weight-saving potential of steel for selected autobody components while maintaining cost levels and ensuring that there would be no lowering of current safety and comfort standards. To this end, the emphasis was placed on higher strength microalloyed, phosphorous alloyed and IF steels as well as bake hardening and dual phase steels with prescribed minimum yield points between 180 and 340 N/mm"2 used in conformity with material properties and processability. The components selected as being representative of the various requirement profiles were: the door structure of a two-door Volkswagen (VW) Polo, the front subframe of the AUDI A 4, the shock tower of the VW Polo and mounting bracket control arm of the Mercedes-Benz, C-class. The high-strength steels deemed appropriate for these components were provided in sheet thicknesses of 0.65 to 2,0 mm. The participating steel companies performed all necessary material tests on the specimen materials. Tensile tests at -40 C, room temperature and +80 C provided the characterizing mechanical property values required by the automotive industry. Notched tension and hole expansion tests, bulge tests, plotting of forming limit curves, cupping and cupping index tests afforded a good appraisal of formability. In addition, the surface chemistry and topography, roughness and friction characteristics were investigated. Fatigue strength tests as well as the determination of the dynamic characteristics (crash data) provided supplementary material data. The use of laser-welded tailored blanks for the door component proved most promising. The appropriate blanks were fabricated and the laser welding seams assessed as being very well suited to the task. (orig.)Im Rahmen des Forschungsprojektes wurde umfangreiches neues Datenmaterial ueber mechanische und technologische Eigenschaften der untersuchten Stahlsorten erarbeitet. Fuer die durchgefuehrten Konstruktionsarbeiten an den Bauteilen und Werkzeugen sowie fuer die Durchfuehrung und Planung von Abpressversuchen hat sich die Umformsimulation als sinnvolles und kostensparendes Werkzeug erwiesen. In Verbindung mit lasergeschweissten Tailored Blanks und alternativen Fuegeverfahren zum Widerstandspunktschweissen wurde fuer folgende Bauteile eine neue Konzeption und Konstruktion erarbeitet: Tuerrohbau des zweituerigen VW-Polo, Federbeinaufnahme des VW-Polo, Hilfsrahmen vorn des Audi A 4 und Konsole Querlenkerlager des Mercedes-Benz, C Klasse. Die mit entsprechend eingestellten Werkzeugen abgepressten Bauteile wurden im Praxistest auf ihre Verwendbarkeit geprueft. Es wurde gezeigt, dass eine werkstoffgerechte Bauteiloptimierung neben einer Gewichtsminderung zu einer Teilreduktion und damit zu kostenguenstigen Loesungen fuehrt. Mit dem Einsatz moderner, hoeherfester Staehle gelang unter den vorgegebenen Bedingungen der jeweils in der Serienfertigung befindlichen Fahrzeutgteile eine Gewichtsreduzierung in Hoehe 11 bis 15%. Bei voelliger Neukonstruktion ist mit Sicherheit eine weitere Gewichtsminderung umsetzbar. (orig.)SIGLEAvailable from TIB Hannover: RR 7808(244) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekEuropean Coal and Steel Community (ECSC), Brussels (Belgium)DEGerman