10 research outputs found
X-Ray Spectroscopy of Stars
(abridged) Non-degenerate stars of essentially all spectral classes are soft
X-ray sources. Low-mass stars on the cooler part of the main sequence and their
pre-main sequence predecessors define the dominant stellar population in the
galaxy by number. Their X-ray spectra are reminiscent, in the broadest sense,
of X-ray spectra from the solar corona. X-ray emission from cool stars is
indeed ascribed to magnetically trapped hot gas analogous to the solar coronal
plasma. Coronal structure, its thermal stratification and geometric extent can
be interpreted based on various spectral diagnostics. New features have been
identified in pre-main sequence stars; some of these may be related to
accretion shocks on the stellar surface, fluorescence on circumstellar disks
due to X-ray irradiation, or shock heating in stellar outflows. Massive, hot
stars clearly dominate the interaction with the galactic interstellar medium:
they are the main sources of ionizing radiation, mechanical energy and chemical
enrichment in galaxies. High-energy emission permits to probe some of the most
important processes at work in these stars, and put constraints on their most
peculiar feature: the stellar wind. Here, we review recent advances in our
understanding of cool and hot stars through the study of X-ray spectra, in
particular high-resolution spectra now available from XMM-Newton and Chandra.
We address issues related to coronal structure, flares, the composition of
coronal plasma, X-ray production in accretion streams and outflows, X-rays from
single OB-type stars, massive binaries, magnetic hot objects and evolved WR
stars.Comment: accepted for Astron. Astrophys. Rev., 98 journal pages, 30 figures
(partly multiple); some corrections made after proof stag
Intracellular retention of ABL kinase inhibitors determines commitment to apoptosis in CML cells
Clinical development of imatinib in CML established continuous target inhibition as a paradigm for successful tyrosine kinase inhibitor (TKI) therapy. However, recent reports suggested that transient potent target inhibition of BCR-ABL by highdose TKI (HD-TKI) pulse-exposure is sufficient to irreversibly commit cells to apoptosis. Here, we report a novel mechanism of prolonged intracellular TKI activity upon HD-TKI pulse-exposure (imatinib, dasatinib) in BCR-ABL-positive cells. Comprehensive mechanistic exploration revealed dramatic intracellular accumulation of TKIs which closely correlated with induction of apoptosis. Cells were rescued from apoptosis upon HD-TKI pulse either by repetitive drug wash-out or by overexpression of ABC-family drug transporters. Inhibition of ABCB1 restored sensitivity to HD-TKI pulse-exposure. Thus, our data provide evidence that intracellular drug retention crucially determines biological activity of imatinib and dasatinib. These studies may refine our current thinking on critical requirements of TKI dose and duration of target inhibition for biological activity of TKIs.Daniel B. Lipka, Marie-Christine Wagner, Marek Dziadosz, Tina Schnöder, Florian Heidel, Mirle Schemionek, Junia V. Melo, Thomas Kindler, Carsten Müller-Tidow, Steffen Koschmieder and Thomas Fische