We conducted a phase I trial in newly diagnosed acute myeloid leukaemia (AML) to investigate the combination of two novel targeted agents, gemtuzumab ozogamicin (GO) and midostaurin, with intensive ...chemotherapy in FLT3-mutated AML and CBF leukaemia. Three dose levels of midostaurin and one to three sequential doses of 3 mg/m
GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m
GO on Days 1 + 4 and 100 mg midostaurin on Days 8-21 can be safely combined with IC in newly diagnosed AML.
The spontaneous transformations associated with symmetry-breaking phase transitions generate domain structures and defects that may be topological in nature. The formation of these defects can be ...described according to the Kibble-Zurek mechanism, which provides a generic relation that applies from cosmological to interatomic length scales. Its verification is challenging, however, in particular at the cosmological scale where experiments are impractical. While it has been demonstrated for selected condensed-matter systems, major questions remain regarding, e.g., its degree of universality. Here, we develop a global Kibble-Zurek picture from the condensed-matter level. We show theoretically that a transition between two fluctuation regimes (Ginzburg and mean field) can lead to an intermediate region with reversed scaling, and we verify experimentally this behavior for the structural transition in the series of multiferroic hexagonal manganites. Trends across the series allow us to identify additional intrinsic features of the defect formation beyond the original Kibble-Zurek paradigm.
The purpose of this study was to investigate the antitumor activity of regorafenib and sorafenib in preclinical models of HCC and to assess their mechanism of action by associated changes in protein ...expression in a HCC-PDX mouse model. Both drugs were administered orally once daily at 10 mg/kg (regorafenib) or 30 mg/kg (sorafenib), which recapitulate the human exposure at the maximally tolerated dose in mice. In a H129 hepatoma model, survival times differed significantly between regorafenib versus vehicle (p=0.0269; median survival times 36 vs 27 days), but not between sorafenib versus vehicle (p=0.1961; 33 vs 28 days). Effects on tumor growth were assessed in 10 patient-derived HCC xenograft (HCC-PDX) models. Significant tumor growth inhibition was observed in 8/10 models with regorafenib and 7/10 with sorafenib; in four models, superior response was observed with regorafenib versus sorafenib which was deemed not to be due to lower sorafenib exposure. Bead-based multiplex western blot analysis was performed with total protein lysates from drug- and vehicle-treated HCC-PDX xenografts. Protein expression was substantially different in regorafenib- and sorafenib-treated samples compared with vehicle. The pattern of upregulated proteins was similar with both drugs and indicates an activated RAF/MEK/ERK pathway, but more proteins were downregulated with sorafenib versus regorafenib. Overall, both regorafenib and sorafenib were effective in mouse models of HCC, although several cases showed better regorafenib activity which may explain the observed efficacy of regorafenib in sorafenib-refractory patients.
This paper investigates the properties of quartz sampled at different sites in the Riss, Iller, Mindel, and Isar Valley of the northern Alpine Foreland of Germany and ties in with a previous study of ...optically stimulated luminescence (OSL) dating of glaciofluvial sediments from the type regions of the Würmian, the Rissian, and the Mindelian Glaciations. The previous investigation showed severe underestimation of quartz ages compared to the existing tentative chronology based on morphostratigraphic evidence as well as fading uncorrected feldspar Infrared Stimulated Luminescence (IRSL) ages. In this paper we present laboratory experiments and data analyses such as pulse annealing and isothermal decay measurements, De(t) and NR(t) plots as well as curve fitting analyses to demonstrate that the quartz has unfavourable luminescence characteristics. We conclude that the quartz from the study area is not suitable for OSL dating using standard single-aliquot regenerative-dose techniques.
Mutants of the FLT3 receptor tyrosine kinase (RTK) with duplications in the juxtamembrane domain (FLT3-ITD) act as drivers of acute myeloid leukemia (AML). Potent tyrosine kinase inhibitors (TKi) of ...FLT3-ITD entered clinical trials and showed a promising, but transient success due to the occurrence of secondary drug-resistant AML clones. A further caveat of drugs targeting FLT3-ITD is the co-targeting of other RTKs which are required for normal hematopoiesis. This is observed quite frequently. Therefore, novel drugs are necessary to treat AML effectively and safely. Recently bis(1H-indol-2-yl)methanones were found to inhibit FLT3 and PDGFR kinases. In order to optimize these agents we synthesized novel derivatives of these methanones with various substituents. Methanone 16 and its carbamate derivative 17b inhibit FLT3-ITD at least as potently as the TKi AC220 (quizartinib). Models indicate corresponding interactions of 16 and quizartinib with FLT3. The activity of 16 is accompanied by a high selectivity for FLT3-ITD.
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•Mutants of the FLT3 receptor tyrosine kinase act as drivers of acute myeloid leukemia.•A series of novel aryl-methanone derivatives as inhibitors of FLT3 was prepared.•Models indicate closely corresponding interactions of these inhibitors and quizartinib.•The aryl-methanone derivatives show an improved activity towards FLT3 mutants.•The activity of is accompanied by a high specificity for FLT3-ITD.
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