ZUSAMMENFASSUNG Hintergrund Der extrakorporale hochintensive fokussierte Ultraschall (HIFU) ist ein vielversprechendes Verfahren zur nichtinvasiven Thermoablation gutartigen und bösartigen Gewebes. Derzeitige HIFU-Therapien nutzen Ultraschall (US-HIFU) oder MRT (MR-HIFU) zur Bildsteuerung mit der Möglichkeit zur integrierten Therapieplanung, Echtzeit-Therapiekontrolle (räumliche Orientierung und Temperatursteuerung) und Therapieevaluation. Methode Dieser Übersichtsartikel basiert auf Publikationen aus Fachzeitschriften, die die thermale Ablation mittels HIFU thematisieren, und beinhaltet zudem eigene klinische Ergebnisse. Es wird ein kurzer Überblick über die häufigsten CEzertifizierten klinischen Applikationen für MR-HIFU gegeben. Ergebnisse Im Laufe des letzten Jahrzehnts erhielten zahlreiche HIFU-basierte Applikationen die Zulassung in diversen Ländern. Im Speziellen ist MR-HIFU nun zugelassen für die Therapie von Uterusmyomen, Linderung von Knochenschmerzen, der Ablation der Prostata und die Therapie des essenziellen Tremors als erste neurologische Applikationsform. Schlussfolgerung MR-HIFU ist eine patientenfreundliche, nichtinvasive Methode zur Thermoablation, welche mittlerweile für mehrere klinische Applikationen zugelassen wurde. Insgesamt bestätigen die bisherigen klinischen Daten die Wirksamkeit und Sicherheit der Therapie sowie die Kosteneffizienz der Methode.Kernaussagen: ▪ HIFU stellt eine vielversprechende Technik zur nichtinvasiven Thermoablation von Gewebe dar. ▪ HIFU wird üblicherweise unter Bildkontrolle mittels Ultraschall (US-HIFU) oder MRT (MR-HIFU) durchgeführt. ▪ Die bevorzugte Bildkontrolle (US-HIFU vs. MR-HIFU) hängt von der geplanten Applikation ab. ▪ MRT bietet einen höheren Weichteilkontrast zur Therapieplanung, eine nahezu in Echtzeit und nichtinvasiv erfolgende Temperaturkontrolle und eine postinterventionelle Therapieevaluation. ▪ MR-HIFU ist CE-zertifiziert für die Therapie von Uterusmyomen, Linderung von Knochenschmerzen, Ablation der Prostata und Therapie des essenziellen Tremors. ABSTR AC TBackground Extracorporeal high-intensity focused ultrasound (HIFU) is a promising method for the noninvasive thermal ablation of benign and malignant tissue. Current HIFU treatments are performed under ultrasound (US-HIFU) or magnetic resonance (MR-HIFU) image guidance offering integrated therapy planning, real-time control (spatial and temperature guidance) and evaluation.Methods This review is based on publications in peer-reviewed journals addressing thermal ablation using HIFU and includes our own clinical results as well. The technical background of HIFU is explained with an emphasis on MR-HIFU applications. A brief overview of the most commonly performed CE-approved clinical applications for MR-HIFU is given.Results Over the last decade, several HIFU-based applications have received clinical approval in various countries. In particular, MR-HIFU is now approved for the clinical treatment of uterine fibroids, palliation of bone pain, ablation of the prostate and treatment of essential tre...

This study is the first to describe an effect of the NCAN risk variant on brain structure. Our data show that the NCAN risk allele influences cortical folding in the occipital and prefrontal cortex, which may establish disease susceptibility during neurodevelopment. The findings suggest that NCAN is involved in visual processing and top-down cognitive functioning. Both major cognitive processes are known to be disturbed in schizophrenia. Moreover, our study reveals new evidence for a specific genetic influence on local cortical folding in schizophrenia.

KRAS is one of the most frequently mutated oncogenes in human cancer. Despite substantial efforts, no clinically applicable strategy has yet been developed to effectively treat KRAS-mutant tumors. Here, we perform a cell-line-based screen and identify strong synergistic interactions between cell-cycle checkpoint-abrogating Chk1- and MK2 inhibitors, specifically in KRAS- and BRAF-driven cells. Mechanistically, we show that KRAS-mutant cancer displays intrinsic genotoxic stress, leading to tonic Chk1- and MK2 activity. We demonstrate that simultaneous Chk1- and MK2 inhibition leads to mitotic catastrophe in KRAS-mutant cells. This actionable synergistic interaction is validated using xenograft models, as well as distinct Kras- or Braf-driven autochthonous murine cancer models. Lastly, we show that combined checkpoint inhibition induces apoptotic cell death in KRAS- or BRAF-mutant tumor cells directly isolated from patients. These results strongly recommend simultaneous Chk1- and MK2 inhibition as a therapeutic strategy for the treatment of KRAS- or BRAF-driven cancers.

Cell 162, 146-159; July 2, 2015) Our paper presented a new algorithm, named PreCISE, designed to identify synergistic drug interactions that are effective at killing cancer cells harboring specific driver mutations. Using this platform and a cell-line-based screen, we identified a synergistic drug interaction between Chk1-and MK2 inhibitors in KRASor BRAF-driven cells, and that combination of therapy focused on these two kinase inhibitors is effective at inducing cell death of KRASand BRAF mutant tumors in vivo.While reviewing the paper after publication, we noticed that we had included two erroneous duplications of western blot loading control bands in the final version of Figure 2E. This figure shows that simultaneous inhibition of Chk1 and MK2 induces genotoxic stress and apoptosis in several KRAS-driven cancer cell lines and respective controls. The incorrect loading controls are presented for the HSP27 blot for the H1703 cell line, as well as for the CDC25B blot for the H1437 cell line. The errors occurred when we were copying each blot to construct the final figure. We recovered the original autoradiographs of these experiments and now provide a new version of the figure containing the correct loading controls. The correct data supports the original interpretation of the experiment, and the conclusions of the paper remain unchanged. In addition, we observed a typo in Figure S3A, showing the distribution of all cell lines used in the initial screen of our paper. In the pie chart, the slice of the pie in purple representing ''lung squamous'' cell lines was incorrectly labeled with n = 18. The correct value is n = 3, as depicted in the figure legend and in the main text. Both figures are now corrected online. We regret not being able to identify these errors before and sincerely apologize for any inconvenience they may have caused.