| 1. |
- Breitenbuecher, Frank, et al.
(författare)
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A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML
- 2009
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 113:17, s. 4063-4073
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Tidskriftsartikel (refereegranskat)abstract
- Currently, FLT3 tyrosine kinase inhibitors (TKIs) are emerging as the most promising drug therapy to overcome the dismal prognosis of acute myelogenous leukemia (AML) patients harboring internal tandem duplications (ITDs) of FLT3. However, up-front drug resistance occurs in approximately 30% of patients, and molecular mechanisms of resistance are poorly understood. Here, we have uncovered a novel mechanism of primary resistance to FLT3 TKIs in AML: an FLT3 receptor harboring a nonjuxtamembrane ITD atypically integrating into the beta-2 sheet of the first kinase domain (FLT3_ITD627E) induces dramatic up-regulation of the anti-apoptotic myeloid cell leukemia 1 protein (MCL-1). Using RNA interference technology, deregulated MCL-1 protein expression was shown to play a major role in conferring the resistance phenotype of 32D_ITD627E cells. Enhanced and sustained binding of the adaptor protein GRB-2 to the FLT3_ITD627E receptor is involved in MCL-1 up-regulation and is independent from TKI (PKC412)-induced inhibition of the receptor kinase. Thus, we describe a new mechanism of primary resistance to TKIs, which operates by reprogramming local and distant signal transduction events of the FLT3 tyrosine kinase. The data presented suggest that particular ITDs of FLT3 may be associated with rewired signaling and differential responsiveness to TKIs. (Blood. 2009; 113: 4063-4073)
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| 3. |
- Chapman, Henry N., et al.
(författare)
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Femtosecond diffractive imaging with a soft-X-ray free-electron laser
- 2006
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Ingår i: Nature Physics. - : Springer Science and Business Media LLC. - 1745-2473 .- 1745-2481. ; 2:12, s. 839-843
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Tidskriftsartikel (refereegranskat)abstract
- Theory predicts(1-4) that, with an ultrashort and extremely bright coherent X-ray pulse, a single diffraction pattern may be recorded from a large macromolecule, a virus or a cell before the sample explodes and turns into a plasma. Here we report the first experimental demonstration of this principle using the FLASH soft-X-ray free-electron laser. An intense 25 fs, 4 x 10(13) W cm(-2) pulse, containing 10(12) photons at 32 nm wavelength, produced a coherent diffraction pattern from a nanostructured non-periodic object, before destroying it at 60,000 K. A novel X-ray camera assured single-photon detection sensitivity by filtering out parasitic scattering and plasma radiation. The reconstructed image, obtained directly from the coherent pattern by phase retrieval through oversampling(5-9), shows no measurable damage, and is reconstructed at the diffraction-limited resolution. A three-dimensional data set may be assembled from such images when copies of a reproducible sample are exposed to the beam one by one(10).
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| 4. |
- Chapman, Henry N, et al.
(författare)
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Femtosecond time-delay X-ray holography
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 448:7154, s. 676-679
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Tidskriftsartikel (refereegranskat)abstract
- Extremely intense and ultrafast X-ray pulses from free-electron lasers offer unique opportunities to study fundamental aspects of complex transient phenomena in materials. Ultrafast time-resolved methods usually require highly synchronized pulses to initiate a transition and then probe it after a precisely defined time delay. In the X-ray regime, these methods are challenging because they require complex optical systems and diagnostics. Here we propose and apply a simple holographic measurement scheme, inspired by Newton's 'dusty mirror' experiment1, to monitor the X-ray-induced explosion of microscopic objects. The sample is placed near an X-ray mirror; after the pulse traverses the sample, triggering the reaction, it is reflected back onto the sample by the mirror to probe this reaction. The delay is encoded in the resulting diffraction pattern to an accuracy of one femtosecond, and the structural change is holographically recorded with high resolution. We apply the technique to monitor the dynamics of polystyrene spheres in intense free-electron-laser pulses, and observe an explosion occurring well after the initial pulse. Our results support the notion that X-ray flash imaging2, 3 can be used to achieve high resolution, beyond radiation damage limits for biological samples4. With upcoming ultrafast X-ray sources we will be able to explore the three-dimensional dynamics of materials at the timescale of atomic motion.
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| 5. |
- Durr, Hermann A., et al.
(författare)
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A Closer Look Into Magnetism : Opportunities With Synchrotron Radiation
- 2009
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Ingår i: IEEE transactions on magnetics. - 0018-9464 .- 1941-0069. ; 45:1, s. 15-57
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Forskningsöversikt (refereegranskat)abstract
- The unique properties of synchrotron radiation, such as broad energy spectrum, variable light polarization, and flexible time structure, have made it an enormously powerful tool in the study of magnetic phenomena and materials. The refinement of experimental techniques has led to many new research opportunities, keeping up with the challenges put up by modern magnetism research. In this contribution, we review some of the recent developments in the application of synchrotron radiation and particularly soft X-rays to current problems in magnetism, and we discuss future perspectives.
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| 6. |
- Gammelgaard, Jens, et al.
(författare)
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Subsidiary Role and Skilled Labour Effects in Small Developed Countries
- 2009
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Ingår i: Management International Review. - : Gabler Verlag/GWV Fachverlage GmbH. - 0025-181X .- 0938-8249 .- 1861-8901. ; 49, s. 27-42
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Tidskriftsartikel (refereegranskat)abstract
- This paper considers the proportion of skilled labour employed by subsidiaries in small countries in the context of the strategic role of subsidiaries. Strategic role is connected to autonomy and intra-organisational relationships and the mandates given to the subsidiary. In the paper, we draw on the literature on the strategic development of multinational corporations, and insights from inward foreign direct investments in small developed countries. This ispresented in a unifying framework in order to predict diverse categorizations of the impact of subsidiary role on the proportion of their employment of skilled labour. The paper derives two propositions that postulate interactions between three roles containing different levels of autonomy and intra-organisational relationships in small developed countries that lead to different proportions of skilled labour in subsidiaries. We predict the highest proportion of skilled labour by subsidiaries located in small developed countries in the case of world mandates when autonomous-based operations are emphasized. When there is an emphasis on intra-organizational relationships, measured by product flowsand integrated international value-chain configurations, we predict the proportion of skilled labour to be highest in the cases of specialized contributors. We propose the proportion of skilled labour to be lowest in the case of local implementers.
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| 10. |
- Herrholz, Andreas, et al.
(författare)
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The ANDRES Project : Analysis and Design of run-time Reconfigurable, heterogeneous Systems
- 2007
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Ingår i: Proceedings - 2007 International Conference on Field Programmable Logic and Applications, FPL. - : IEEE. - 9781424410606 - 1424410606 ; , s. 396-401
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Konferensbidrag (refereegranskat)abstract
- Today's heterogeneous embedded systems combine components from different domains, such as software, analogue hardware and digital hardware. The design and implementation of these systems is still a complex and error-prone task due to the different Models of Computations (MoCs), design languages and tools associated with each of the domains. Though making such systems adaptive is technologically feasible, most of the current design methodologies do not explicitely support adaptive architectures. This paper present the ANDRES project. The main objective of ANDRES is the development of a seamless design flow for adaptive heterogeneous embedded systems (AHES) based on the modelling language SystemC. Using domain-specific modelling extensions and libraries, ANDRES will provide means to efficiently use and exploit adaptivity in embedded system design. The design flow is completed by a methodology and tools for automatic hardware and software synthesis for adaptive architectures.
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