Allosterische Kinaseinhibitoren

Background. Inhibition of the kinase activity of the BCR-ABL1 oncoprotein by an allosteric mechanism of action facilitates alternative treatment options for chronic myeloid leukemia (CML) patients who cannot be adequately treated with conventional catalytic site-directed tyrosine kinase inhibitor (TKI). Objectives. Pathophysiologic role of the BCR-ABL1 oncogene, mechanisms of action of catalytic site-directed TKI, clinical need for new therapies in BCR-ABL1 positive leukemias, mechanism of allosteric inhibition, development of the first clinically applicable allosteric ABL inhibitor ABL001 (asciminib), preclinical data, clinical development. Methods. Mechanistic and preclinical studies published to date and clinical results of the initial phase 1 dose escalation trial are summarized. Result. ABL001 is a potent, highly selective inhibitor of BCR-ABL, with a resistance profile distinct from that of ATP-competitive TKI. In murine models, combination studies demonstrate pronounced antileukemic efficacy with complete and sustained leukemia regression and confirmation of the non-overlapping mechanisms of resistance. In the first phase 1 study in humans, ABL001 exhibits rapid antileukemic activity and appears well tolerated to date in a heavily pretreated subgroup of patients with CML. Conclusions. Proof of principle of the effectiveness of allosteric inhibition of BCR-ABL kinase activity with ABL001 as the first-in-class compound holds promise as a novel therapeutic option for treatment of CML patients who respond insufficiently to or are intolerant of conventional TKI, and may contribute to further improving treatment of CML

Water and energy-based optimisation of a “MiniCity”: A system dynamics approach

Urban sprawls in Australia and several countries around the world have introduced a number of social, economic, and environmental issues for residents and urban planners, highlighting the need for new urban development concepts. In recent years, the concept of a vertical sprawl called "MiniCity" has been presented. The objective of a successful "MiniCity", compared to traditional high-rises, is to be as self-sufficient and self-contained as possible; whilst also minimising issues such as car dependency, loss of agricultural land and natural habitats, water and air pollution, and poorer health and wellbeing, which are common for residents in low-density, low-rise areas and developments. To date however, the viability of a MiniCity has yet to be properly addressed. Arguably, the predominant needs for a community are water, energy and food. In this research study, a System Dynamics model was developed to simulate supply and demand of the water and energy systems, as well as their interaction, for a hypothetical MiniCity located in South-East Queensland, Australia. The models were conceptualised based on expert knowledge, with data and equations collected from local Gold Coast sources and from the literature. Preliminary results show the complex, but expected, dynamics and interactions between the two systems, and their dependence to critical input parameters, such as climate data, roof area, number of floors, to name a few. Future work will focus on adding other critical modelling components such as food production and thus analyse the water-energy-food nexus. The final, validated model will allow the optimisation of critical MiniCity parameters and the identification of suitable locations that can maximise the socio-economic and environmental viability of the MiniCity.Full Tex

Forever Young: High Chromospheric Activity in M subdwarfs

We present spectroscopic observations of two halo M subdwarfs which have H alpha emission lines. We show that in both cases close companions are the most likely cause of the chromospheric activity in these old, metal-poor stars. We argue that Gl 781 A's unseen companion is most likely a cool helium white dwarf. Gl 455 is a near-equal-mass M subdwarf (sdM) system. Gl 781 A is rapidly rotating with v sin i = 30 km/s. The properties of the chromospheres and X-ray coronae of these systems are compared to M dwarfs with emission (dMe). The X-ray hardness ratios and optical chromospheric lines emission ratios are consistent with those seen in dMe stars. Comparison to active near-solar metallicity stars indicates that despite their low metallicity ([m/H] = -1/2), the sdMe stars are roughly as active in both X-rays and chromospheric emission. Measured by L_X/L_bol, the activity level of Gl 781 A is no more than a factor of 2.5 subluminous with respect to near-solar metallicity stars.Comment: 16 pages including 1 figure, AASTeX, to appear in May 1998 A.

Client self-assessment in community aged care: A comparative study involving older Australians and their case managers

Self-assessment of support needs is a relatively new and under-researched phenomenon in domiciliary aged care. This article outlines the results of a comparative study focusing on whether a self-assessment approach assists clients to identify support needs and the degree to which self-assessed needs differ from an assessment conducted by community care professionals. A total of 48 older people and their case managers completed a needs assessment tool. Twenty-two semi-structured interviews were used to ascertain older people’s views and preferences regarding the self-assessment process. The study suggests that while a co-assessment approach as outlined in this article has the potential to assist older people to gain a better understanding of their care needs as well as the assessment process and its ramifications, client self-assessment should be seen as part of a co-assessment process involving care professionals. Such a co-assessment process allows older people to gain a better understanding of their support needs and the wider community aged care context. The article suggests that a co-assessment process involving both clients and care professionals contains features that have the capacity to enhance domiciliary aged care

The Coronae of AR Lac

We observed the coronally active eclipsing binary, AR Lac, with the High Energy Transmission Grating on Chandra for a total of 97 ks, spaced over five orbits, at quadratures and conjunctions. Contemporaneous and simultaneous EUV spectra and photometry were also obtained with the Extreme Ultraviolet Explorer. Significant variability in both X-ray and EUV fluxes were observed, dominated by at least one X-ray flare and one EUV flare. We saw no evidence of primary or secondary eclipses. X-ray flux modulation was largest at high temperature, indicative of flare heating of coronal plasma. Line widths interpreted in terms of Doppler broadening suggest that both binary stellar components are active. From line fluxes obtained from total integrated spectra, we have modeled the emission measure and abundance distributions. A strong maximum was found in the differential emission measure, characterized by peaks at log T = 6.9 and 7.4, together with a weak but significant cooler maximum near log T=6.2, and a moderately strong hot tail from log T= 7.6-8.2. Coronal abundances have a broad distribution and show no simple correlation with first ionization potential. While the resulting model spectrum generally agrees very well with the observed spectrum, there are some significant discrepancies, especially among the many Fe L-lines. Both the emission measure and abundance distributions are qualitatively similar to prior determinations from other X-ray and ultraviolet spectra, indicating some long-term stability in the overall coronal structure.Comment: 31 pages, 8 figures, 3 tables; Accepted for publication in the Astrophysical Journal (tentatively October 1, 2003

From the Heart of The Ghoul: C and N Abundances in the Corona of Algol B

Chandra Low Energy Transmission Grating Spectrograph observations of Algol have been used to determine the abundances of C and N in the secondary star for the first time. The analysis was performed relative to similar observations of an adopted "standard" star HR 1099. It is demonstrated that HR 1099 and Algol are coronal twins in many respects and that their X-ray spectra are very similar in nearly all details, except for the observed strengths of C and N lines. The H-like transitions of C and N in the coronae of Algol and HR 1099 demonstrate that the surface abundances of Algol B have been strongly modified by CN-processing, as shown earlier by Schmitt & Ness (2002). It is found that N is enhanced in Algol B by a factor of 3 compared to HR 1099. No C lines are detected in the Algol spectrum, indicating a C depletion relative to HR 1099 by a factor of 10 or more. These C and N abundances indicate that Algol B must have lost at least half of its initial mass, and are consistent with predictions of evolutionary models that include non-conservative mass transfer and angular momentum loss through magnetic activity. Little or no dredge-up of material subjected to CN-processing has occurred on the subgiant component of HR 1099. It is concluded that Fe is very likely depleted in the coronae of both Algol and HR 1099 relative to their photospheres by 0.5 dex, and C, N and O by 0.3 dex. Instead, Ne is enhanced by up to 0.5 dex.Comment: 17 pages, 4 figures, ApJ accepte

Continuous heating of a giant X-ray flare on Algol

Giant flares can release large amounts of energy within a few days: X-ray emission alone can be up to ten percent of the star's bolometric luminosity. These flares exceed the luminosities of the largest solar flares by many orders of magnitude, which suggests that the underlying physical mechanisms supplying the energy are different from those on the Sun. Magnetic coupling between the components in a binary system or between a young star and an accretion disk has been proposed as a prerequisite for giant flares. Here we report X-ray observations of a giant flare on Algol B, a giant star in an eclipsing binary system. We observed a total X-ray eclipse of the flare, which demonstrates that the plasma was confined to Algol B, and reached a maximum height of 0.6 stellar radii above its surface. The flare occurred around the south pole of Algol B, and energy must have been released continously throughout its life. We conclude that a specific extrastellar environment is not required for the presence of a flare, and that the processes at work are therefore similar to those on the Sun.Comment: Nature, Sept. 2 199

Quiescent and flare analysis for the chromospherically active star Gl355 (LQHya)

We discuss ROSAT and ASCA observations of the young active star Gl355}. During the ROSAT observation a strong flare was detected with a peak flux more than an order of magnitude larger than the quiescent level. Spectral analysis of the data allows us to study the temperature and emission measure distribution, and the coronal metal abundance, for the quiescent phase and, in the case of ROSAT, also during the evolution of the flare. The global coronal metallicity $Z/Z_{\odot} \sim 0.1$ derived from both ROSAT and ASCA data is much lower than solar and presumably also much lower than the photospheric abundance expected for this very young star. The temperature structure of the quiescent corona was about the same during the various observations, with a cooler component at $T_1 \sim 7$ MK and a hotter component (to which only ASCA was sensitive) at $T_2 \sim 20$ MK. During the flare, the low temperature component remained approximately constant and equal to the quiescent value, while the high-temperature component was the only one that varied. We have modeled the flare with the hydrodynamic-decay sustained-heating approach of Reale at al. (1997) and we have derived a loop semi--length of the order of $\sim 1.5$ stellar radii, i.e. much larger than the dimensions of flares on the Sun, but comparable with the typical dimensions inferred for other stellar flares. We have compared the derived loop size with that estimated with a simpler (but physically inconsistent) approach, finding that for this, as well for several other stellar flares, the two methods give comparable loop sizes. Possible causes and consequences of this result are discussed.Comment: A&A, in pres

The photospheric abundances of active binaries III. Abundance peculiarities at high activity level

We report the determination from high-resolution spectra of the atmospheric parameters and abundances of 13 chemical species (among which lithium) in 8 single-lined active binaries. These data are combined with our previous results for 6 other RS CVn systems to examine a possible relationship between the photospheric abundance patterns and the stellar activity level. The stars analyzed are generally found to exhibit peculiar abundance ratios compared to inactive, galactic disk stars of similar metallicities. We argue that this behaviour is unlikely an artefact of errors in the determination of the atmospheric parameters or non-standard mixing processes along the red giant branch, but diagnoses instead the combined action of various physical processes related to activity. The most promising candidates are cool spot groups covering a very substantial fraction of the stellar photosphere or NLTE effects arising from nonthermal excitation. However, we cannot exclude the possibility that more general shortcomings in our understanding of K-type stars (e.g. inadequacies in the atmospheric models) also play a significant role. Lastly, we call attention to the unreliability of the (V-R) and (V-I) colour indices as temperature indicators in chromospherically active stars.Comment: Accepted for publication in A&A, 17 pages, 7 figures (6 in colour