Therapy directed against oncogenic FLT3 has been shown to induce response in patients with acute myeloid leukemia (AML), but these responses are almost always transient. To address the mechanism of ...FLT3 inhibitor resistance, we generated two resistant AML cell lines by sustained treatment with the FLT3 inhibitor sorafenib. Parental cell lines carry the FLT3-ITD (tandem duplication) mutation and are highly responsive to FLT3 inhibitors, whereas resistant cell lines display resistance to multiple FLT3 inhibitors. Sanger sequencing and protein mass-spectrometry did not identify any acquired mutations in FLT3 in the resistant cells. Moreover, sorafenib treatment effectively blocked FLT3 activation in resistant cells, whereas it was unable to block colony formation or cell survival, suggesting that the resistant cells are no longer FLT3 dependent. Gene expression analysis of sensitive and resistant cell lines, as well as of blasts from patients with sorafenib-resistant AML, suggested an enrichment of the PI3K/mTOR pathway in the resistant phenotype, which was further supported by next-generation sequencing and phospho-specific-antibody array analysis. Furthermore, a selective PI3K/mTOR inhibitor, gedatolisib, efficiently blocked proliferation, colony and tumor formation, and induced apoptosis in resistant cell lines. Gedatolisib significantly extended survival of mice in a sorafenib-resistant AML patient-derived xenograft model. Taken together, our data suggest that aberrant activation of the PI3K/mTOR pathway in FLT3-ITD-dependent AML results in resistance to drugs targeting FLT3.
A code, epic5, has been developed which computes, in the two-dimensional case, the initially circular orbits of guiding centra in an arbitrary axisymmetric potential with an arbitrary, weak ...perturbing potential in solid body rotation. This perturbing potential is given by its Fourier expansion. The analytic solution solves the linear epicyclic approximation of the equations of motion. To simulate the motion of interstellar matter and to damp the Lindblad resonances, in these equations we have introduced a friction which is proportional to the deviation from circular velocity. The corotation resonance is also damped by a special parameter. The program produces, in just a few seconds, orbital and density maps, as well as line-of-sight velocity maps for a chosen orientation of the galaxy.
We test epic5 by comparing its results with previous simulations and observations from the literature, which gives satisfactory agreement. The aim is that this program should be a useful complement to elaborate numerical simulations. Particularly so are its abilities to quickly explore the parameter space, to construct artificial galaxies and to isolate various single agents important for developing the structure of interstellar matter in disc galaxies. The epic5 code can be obtained from npi@astro.su.se.
An interlaboratory comparison on cheese making trials was conducted to examine the differences between model cheeses manufactured in pilot plants at six European laboratories. The experimental design ...(within each laboratory) for the model cheese was an unreplicated 23full factorial design in one block of eight cheese vats. The three factors were the pasteurization of skimmed milk, microfiltration of skimmed milk and pasteurization of cream. Although the manufacture, sampling and analyses were generally standardized, the gross composition and sensorial properties of the cheeses differed greatly across the laboratories. Good statistical design and analysis of the experimental data aided in minimizing the effect caused by the technical difficulties experienced by some of the laboratories during the cheese making trials. Despite the problems encountered, all six laboratories noted similar effects between model cheeses that were produced from milk in which the initial load of indigenous flora was reduced by either pasteurization or microfiltration. The cheeses produced from milk in which the raw milk flora had been reduced had lower concentrations of D-lactate and a less intense aroma and odour. With few exceptions the individual laboratories observed similar effects, although these were less significant when compared with the overall effect.
A code, Epic5, has been developed which computes, in the two-dimensional case, the initially circular orbits of guiding centra in an arbitrary axisymmetric potential with an arbitrary, weak ...perturbing potential in solid body rotation. This perturbing potential is given by its Fourier expansion. The analytic solution solves the linear epicyclic approximation of the equations of motion. To simulate the motion of interstellar matter and to damp the Lindblad resonances, we have in these equations introduced a friction which is proportional to the deviation from circular velocity. The corotation resonance is also damped by a special parameter. The program produces, in just a few seconds, orbital and density maps, as well as line of sight velocity maps for a chosen orientation of the galaxy. We test Epic5 by comparing its results with previous simulations and observations from the literature, which gives satisfactory agreement. The aim is that this program should be a useful complement to elaborate numerical simulations. Particularly so are its abilities to quickly explore the parameter space, to construct artificial galaxies, and to isolate various single agents important for developing structure of interstellar matter in disc galaxies.
NGC 1365 Lindblad, Per Olof
The Astronomy and astrophysics review,
09/1999, Letnik:
9, Številka:
3-4
Journal Article
Recenzirano
The aim of the present review is to give a global picture of the supergiant barred galaxy NGC 1365. This galaxy with its strong bar and prominent spiral structure displays a variety of nuclear ...activity and ongoing star formation. The kinematics of the galaxy has been mapped in detail by optical long slit and Fabry-Perot observations as well as radio observations of Hi and CO interstellar lines. From these observations a combined velocity field has been derived, describing the circulation of interstellar gas in the symmetry plane of the galaxy. With a gravitational potential based on near infrared photometry of the bar and the shape of the apparent rotation curve, computer simulations of the dynamics of the interstellar gas have been made with the aim to reproduce both the morphology of the interstellar matter as well as the observed velocity field. The simulations demonstrate the role of the bar and the importance of resonances between the bar rotation and the rotation of the galaxy for the formation of the spiral structure. Polarization of radio radiation reveals magnetic fields concentrated to the dust lanes along and across the bar, where they are aligned with the flow pattern of the gas, and along the spiral arms. The kinematics of the outer region of the galaxy with a fairly unique decline of the rotation curve leads to the conclusion that NGC 1365 lacks a very massive dark matter halo, which may permit the formation of a very strong bar. The galaxy contains an active nucleus with both broad and narrow components of the permitted spectral emission lines. The nucleus is surrounded by a molecular torus, numerous star forming regions and continuum radio sources. The star forming regions are, as seen with the Hubble Space Telescope (HST), resolved into a large number of super star clusters suggested to be young globular clusters. A very compact radio source, seen at high spatial resolution with the Very Large Array (VLA), has been claimed to coincide with one of the super star clusters. This compact source has a radio brightness of the order of 100 times that of the bright galactic supernova remnant Cas A and is suggested to be a so called 'radio supernova'. Two other such compact radio sources, positioned in the prominent dark dust lane penetrating the nuclear region, are identified as strong infrared sources by observations with the Very Large Telescope (VLT). The cause of this infrared radiation may be dust heated by the objects that drive the radio sources. The X-ray radiation from the nucleus is interpreted to consist of hard continuum radiation from the active nucleus itself, Fe-K line emission from a rotating disk, and thermal emission from the surrounding star burst activity. A secondary, highly variable source has been discovered close to the nuclear region. It seems to be one of the most luminous and most highly variable off-nuclear X-ray sources known. The higher excitation optical emission lines in the nuclear region, primarily from Oiii, reveal a velocity field quite different from that described by the galactic rotation. The deviating Oiii morphology and velocity field in the nuclear region is interpreted in terms of a high excitation outflow double-cone with its apex at the nucleus and symmetry axis perpendicular to the symmetry plane of the galaxy. One of the circumnuclear radio sources seems to be a one-sided jet emerging from the nucleus aligned with the cone axis. According to the model, the outward flow within the cone is accelerated and the flow velocity highest at the cone axis.PUBLICATION ABSTRACT
The quality of cheese made from pasteurised milk depends on limitation of the heat load to cheese milk. Analysis of heat denatured whey proteins and inactivated milk enzymes were evaluated for ...routine testing of heat load using pasteurisation and microfiltration equipment currently used in the production of semi-hard cheese. Significant differences between the routinely used milk treatments were seen when heat denatured
α-lactalbumin and
β-lactoglobulin were analysed by capillary electrophoresis, or the inactivation of two milk enzymes were analysed with simple colorimetric methods. GGT,
γ-glutamyl transpeptidase (EC 2.3.2.2) retained 35–70% of its activity and NAG,
N-acetyl-
β-glucosaminidase (EC 3.2.1.30) 1–12% after the milk treatments. The results show that, similar to the alkaline phosphatase test for pasteurised milk, tests can be developed that give an NAG positive result to assure that the properties of importance to cheese ripening have not been lost.
Optical emission line velocities in NGC 1365 are presented along 35 slit positions, of which 18 have not been published earlier. Diagrams of emission line velocities as function of distance along the ...slits are presented, and separate velocity fields are derived for the disc as given by the low excitation lines, combined with H i 21 cm VLA data, and for the nuclear outflow cone as given mainly by the high excitation lines. An algorithm for creating a velocity field and contour maps based on measurements along randomly oriented spectrograph slits is given in the Appendix. Detailed discussions and interpretations of these velocity fields are given elsewhere. The combined optical and 21 cm disc velocity field is available by an anonymous ftp.
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