Handwerkliches Lackieren mit Virtual Reality (HandLeVR)

Kompetenzentwicklung in der beruflichen Aus- und Weiterbildung beinhaltet den Erwerb von Wissen, Fertigkeiten und Einstellungen, häufig mit einem Schwerpunkt auf psychomotorischer Koordination. Der Kompetenzerwerb in der Ausbildung zum Fahrzeuglackierer bzw. zur Fahrzeuglackiererin wird durch soziale, wirtschaftliche und ökologische Faktoren behindert. Um diese Hürden zu überwinden, entwickelt das Forschungsprojekt HandLeVR (Handlungsorientiertes Lernen in der VR-Lackierwerkstatt) ein Virtual-Reality-Training auf der Grundlage des empirisch validierten 4C/ID-Modells. Der Artikel stellt das Vorgehen und die Resultate des Projekts vor und präsentiert Ergebnisse einer ersten Evaluierungsstudie (z. B. zu Akzeptanz und Präsenzerleben)

Regulation of KIF23 by miR-107 controls replicative tumor cell fitness in mouse and human hepatocellular carcinoma

Background &amp; Aims:In hepatocellular carcinoma (HCC), successful translation of experimental targets identified in mouse models to human patients has proven challenging. In this study, we used a comprehensive transcriptomic approach in mice to identify novel potential targets for therapeutic intervention in humans. Methods: We analyzed combined genome-wide miRNA and mRNA expression data in three pathogenically distinct mouse models of liver cancer. Effects of target genes on hepatoma cell fitness were evaluated by proliferation, survival and motility assays. TCGA and GEO databases, in combination with tissue microarrays, were used to validate the mouse targets and their impact on human HCC prognosis. Finally, the functional effects of the identified targets on tumorigenesis and tumor therapy were tested in hydrodynamic tail vein injection-based preclinical HCC models in vivo. Results: The expression of miR-107 was found to be significantly reduced in mouse models of liver tumors of various etiologies and in cohorts of humans with HCC. Overexpression of miR-107 or inhibition of its novel target kinesin family member 23 (Kif23) significantly reduced proliferation by interfering with cytokinesis, thereby controlling survival and motility of mouse and human hepatoma cells. In humans, KIF23 expression was found to be a prognostic marker in liver cancer, with high expression associated with poor prognosis. Hydrodynamic tail vein injection of vectors carrying either pre-miR-107 or anti-Kif23 shRNA inhibited the development of highly aggressive c-Myc-NRAS-induced liver cancers in mice. Conclusions: Disruption of the miR-107/Kif23 axis inhibited hepatoma cell proliferation in vitro and prevented oncogene-induced liver cancer development in vivo, offering a novel potential avenue for the treatment of HCC in humans. Impact and implications: Our study revealed the central role of the miR-107/KIF23 axis in controlling tumor cell fitness and hepatocellular carcinoma progression. The results demonstrate that the overexpression of miR-107 or silencing of its target, KIF23, markedly suppresses the proliferation, survival, and motility of human and mouse hepatoma cells. In this work, we demonstrate that the disruption of miR-107/Kif23 signaling effectively protects mice from an aggressive form of oncogene-induced liver cancer in vivo, implying that targeting miR-107/KIF23 might be a novel therapeutic approach for hepatocellular carcinoma in humans.</p

NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment