IntroductionCutaneous T cell lymphoma (CTCL) is a heterogeneous group of extra-nodal non-Hodgkin lymphomas arising from transformation and clonal expansion of skin-homing T cells. Epigenetics ...alterations have been described for the molecular pathogenesis of CTCL. Resminostat is a potent, orally bioavailable histone deacetylase (HDAC) inhibitor targeting class I, IIb and IV and is currently in phase II of clinical development. Resminostat showed anti-tumoral in vitro efficacy by inhibiting proliferation of CTCL cell lines. The aim of this study was to elucidate resminostat’s molecular mechanism of action in CTCL using a genome-wide approach.Material and methodsResminostat’s mechanism of action was analysed using a set of established CTCL cell lines representing different types of CTCL. Global lysine acetylation was evaluated by flow cytometry and specific histone H3 acetylation at lysine residue 27 (H3K27ac) was mapped genome-widely by chromatin immunoprecipitation followed by sequencing (ChIP-seq). Resminostat’s effect on global gene expression was analysed by RNA-seq focusing on CTCL-relevant pathways and genes.Results and discussionsResminostat increased total lysine acetylation in CTCL cell lines. The active epigenetic mark H3K27ac dose-dependently accumulated on a genome-wide level as detected by ChIP-seq analysis. Global gene expression profiling revealed both gene induction and repression by resminostat. First data showed a regulation of T helper (Th) 1 and 2 specific genes implying that resminostat normalises the Th1/Th2 imbalance in CTCL which is discussed to be associated with disease progression. Moreover, expression of skin-homing receptor genes was reduced by resminostat indicating a potential effect of resminostat on the cutaneous tropism of malignant T cells. Furthermore, the pruritus mediator IL-31 was downregulated by resminostat suggesting an attenuation of itching and thus indicating an important benefit for CTCL patients regarding their health-related quality of life.ConclusionFirst results from a genome-wide study suggest a promising impact of resminostat on different targets relevant for the pathogenesis of CTCL. These data broaden our understanding of resminostat’s molecular mechanism of action in CTCL and support our current clinical phase II trial evaluating resminostat for maintenance treatment of patients with advanced stage CTCL (RESMAIN, NCT02953301).
Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late‐stage attritions in clinical ...development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well‐established and regulatory‐acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4–5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP‐Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)‐based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well‐designed dose‐finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale.
Experimental Results from the TFTR Tokamak Hawryluk, R. J.; Arunasalam, V.; Bell, J. D. ...
Philosophical transactions of the Royal Society of London. Series A, Mathematical and physical sciences,
06/1987, Volume:
322, Issue:
1563
Journal Article
Peer reviewed
Open access
Recent experiments on TFTR have extended the operating regime of TFTR in both ohmic- and neutral-beam-heated discharges. The TFTR tokamak has reached its original machine-design specifications (Ip = ...2.5 MA and BT= 5.2 T). Initial neutralbeam-heating experiments used up to 6.3 MW of deuterium beams. With the recent installation of two additional beamlines, the power has been increased up to 11 MW. A deuterium pellet injector was used to increase the central density to 2.5 × 1020m-3in high-current discharges. At the opposite extreme, by operating at low plasma current (Ip∼ 0.8 MA) and low density (n̄e∼ 1 × 1019m-3), high ion temperatures (9 ± 2 keV) and rotation speeds (7 × 105m s-1) have been achieved during injection. In addition, plasma-compression experiments have demonstrated acceleration of beam ions from 82 to 150 keV, in accord with expectations. The wide operating range of TFTR, together with an extensive set of diagnostics and a flexible control system, has facilitated transport and scaling studies of both ohmic- and neutral-beam-heated discharges. The result of these confinement studies are presented.
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