485 research outputs found
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
Effect of remobinant granulocyte-macrophage colony stimulating factor (GM-CSF) on leukopenia in AIDS
Optimal Time-Convex Hull under the Lp Metrics
We consider the problem of computing the time-convex hull of a point set
under the general metric in the presence of a straight-line highway in
the plane. The traveling speed along the highway is assumed to be faster than
that off the highway, and the shortest time-path between a distant pair may
involve traveling along the highway. The time-convex hull of a point
set is the smallest set containing both and \emph{all} shortest
time-paths between any two points in . In this paper we give an
algorithm that computes the time-convex hull under the metric in optimal
time for a given set of points and a real number with
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.
Absorption of femtosecond laser pulses in high-density plasma.
The absorption of 250-fs KrF laser pulses incident on solid targets of aluminum and gold has been measured as a function of polarization and angle of incidence for the intensity range of 1014–2.5×1015 W cm−2. Maximum absorption of over 60% occurs for p-polarized radiation at angles of incidence in the range of 48°–57°. The measured results are in agreement with absorption on a steep density gradient
Inhibition of HIV-1 replication by small interfering RNAs directed against Glioma Pathogenesis Related Protein (GliPR) expression
Background: Previously, we showed that glioma pathogenesis related protein (GliPR) is induced in CEM T cells upon HIV-1 infection in vitro. To examine whether GliPR plays a role as HIV dependency factor (HDF), we tested the effect of GliPR suppression by siRNA on HIV-1 replication. Results: Induction of GliPR expression by HIV-1 was confirmed in P4-CCR5 cells. When GliPR was suppressed by siRNA, HIV-1 replication was significantly reduced as measured by HIV-1 transcript levels, HIV-1 p24 protein levels, and HIV-1 LTR-driven reporter gene expression, suggesting that GliPR is a cellular co-factor of HIV-1. Microarray analysis of uninfected HeLa cells following knockdown of GliPR revealed, among a multitude of gene expression alterations, a down-regulation of syndecan-1, syndecan-2, protein kinase C alpha (PRKCA), the catalytic subunit beta of cAMP-dependent protein kinase (PRKACB), nuclear receptor co-activator 3 (NCOA3), and cell surface protein CD59 (protectin), all genes having relevance for HIV-1 pathology. Conclusions: The up-regulation of GliPR by HIV-1 and the early significant inhibition of HIV-1 replication mediated by knockdown of GliPR reveal GliPR as an important HIV-1 dependency factor (HDF), which may be exploited for HIV-1 inhibition
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 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 MK and a hotter component (to which only ASCA
was sensitive) at 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
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
Evidence for an X-ray Emitting Galactic Bulge: Shadows Cast by Distant Molecular Gas
A mosaic of 7 ROSAT PSPC pointed observations in the direction of (l,b ~ 10,0
deg) reveals deep X-ray shadows in the 0.5-2.0 keV band cast by dense molecular
gas. The comparison between the observed on-cloud and off-cloud X-ray fluxes
indicates that ~43% of the diffuse X-ray background in this direction in both
the 3/4 keV and 1.5 keV bands originates behind the molecular gas, which is
located at 2-4 kpc from the Sun. Given the short mean free path of X-rays in
the 3/4 keV band in the Galactic plane (~1 kpc assuming an average space
density of 1 cm^-3), this large percentage of the observed flux which
originates beyond the molecular gas most likely indicates a strong enhancement
in the distribution of X-ray emitting gas in the Galactic center region,
possibly associated with a Galactic X-ray bulge.Comment: 16 pages LaTex, 2 figures. Accepted for the publication in
Astrophysical Journal, Letter
The phosphatase UBASH3B/Sts-1 is a negative regulator of Bcr-Abl kinase activity and leukemogenesis
- …