| 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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| 2. |
- Trautmann, Marcel, et al.
(författare)
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Requirement for YAP1 signaling in myxoid liposarcoma.
- 2019
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Ingår i: EMBO molecular medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 11:5
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Tidskriftsartikel (refereegranskat)abstract
- Myxoid liposarcomas (MLS), malignant tumors of adipocyte origin, are driven by the FUS-DDIT3 fusion gene encoding an aberrant transcription factor. The mechanisms whereby FUS-DDIT3 mediates sarcomagenesis are incompletely understood, and strategies to selectively target MLS cells remain elusive. Here we show, using an unbiased functional genomic approach, that FUS-DDIT3-expressing mesenchymal stem cells and MLS cell lines are dependent on YAP1, a transcriptional co-activator and central effector of the Hippo pathway involved in tissue growth and tumorigenesis, and that increased YAP1 activity is a hallmark of human MLS Mechanistically, FUS-DDIT3 promotes YAP1 expression, nuclear localization, and transcriptional activity and physically associates with YAP1 in the nucleus of MLS cells. Pharmacologic inhibition of YAP1 activity impairs the growth of MLS cells invitro and invivo These findings identify overactive YAP1 signaling as unifying feature of MLS development that could represent a novel target for therapeutic intervention.
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| 3. |
- Aurand, Bastian, et al.
(författare)
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Preparation and characterization of nanometer-thin freestanding polymer foils for laser-ion acceleration
- 2013
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Ingår i: Journal of Polymer Science. Part B, Polymer Physics. - : Wiley. - 0887-6266. ; 51:18, s. 1355-1360
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Tidskriftsartikel (refereegranskat)abstract
- We report on the production and characterization of polymer-based ultra-thin (sub 10 nm) foils suited for experiments on laser-ion acceleration in the regime of radiation pressure acceleration. Beside the remarkable mechanical stability compared with commonly used diamond-like-carbon foils, a very homogeneous layer thickness and a small surface roughness have been achieved. We describe the technical issues of the production process as well as detailed studies of the mechanical stability and surface roughness tests. The capability of producing uniform targets of large area is essential for advanced laser-ion acceleration projects which are dealing with high repetition rate and extended measurement series, but might also be useful for other applications which require ultra-thin and freestanding substrates of high quality. (c) 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2013, 51, 1355-1360
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| 4. |
- Kanungo, R., et al.
(författare)
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Exploring the anomaly in the interaction cross section and matter radius of 23O
- 2011
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Ingår i: Physical Review C - Nuclear Physics. - 2469-9985 .- 2469-9993 .- 0556-2813 .- 1089-490X. ; 84:6, s. art. no. 061304(R)-
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Tidskriftsartikel (refereegranskat)abstract
- New measurements of the interaction cross sections of 22,23O at 900A MeV performed at the GSI, Darmstadt are reported that address the unsolved puzzle of the large cross section previously observed for 23O. The matter radii for these oxygen isotopes extracted through a Glauber model analysis are in good agreement with the new predictions of the ab initio coupled-cluster theory reported here. They are consistent with a 22O+neutron description of 23O as well.
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| 5. |
- Kanungo, R., et al.
(författare)
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Matter radii of 32-35Mg
- 2011
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Ingår i: Physical Review C - Nuclear Physics. - 2469-9985 .- 2469-9993 .- 0556-2813 .- 1089-490X. ; 83:2
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Tidskriftsartikel (refereegranskat)abstract
- The interaction cross sections of Mg32-35 at 900A MeV have been measurmed using the fragment separator at GSI. The deviation from the r(0)A(1/3) trend is slightly larger for Mg-35, signaling the possible formation of a longer tail in the neutron distribution for Mg-35. The radii extracted from a Glauber model analysis with Fermi densities are consistent with models predicting the development of neutron skins.
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| 6. |
- Kanungo, R., et al.
(författare)
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One-Neutron Removal Measurement Reveals O-24 as a New Doubly Magic Nucleus
- 2009
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Ingår i: Physical Review Letters. - 1079-7114 .- 0031-9007. ; 102:15
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Tidskriftsartikel (refereegranskat)abstract
- The first measurement of the momentum distribution for one-neutron removal from O-24 at 920A MeV performed at GSI, Darmstadt is reported. The observed distribution has a width (FWHM) of 99 +/- 4 MeV/c in the projectile rest frame and a one-neutron removal cross section of 63 +/- 7 mb. The results are well explained with a nearly pure 2s(1/2) neutron spectroscopic factor of 1.74 +/- 0.19 within the eikonal model. This large s-wave probability shows a spherical shell closure thereby confirming earlier suggestions that O-24 is a new doubly magic nucleus.
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| 7. |
- Kanungo, R., et al.
(författare)
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Structure of Mg-33 sheds new light on the N=20 island of inversion
- 2010
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Ingår i: Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics. - Elsevier : Elsevier BV. - 0370-2693 .- 1873-2445. ; 685:4-5, s. 253-257
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Tidskriftsartikel (refereegranskat)abstract
- The first reaction spectroscopy oil the ground state structure of Mg-33 through the measurement of the longitudinal momentum distribution from the one-neutron removal reaction Using a C target at 898A MeV is reported The experiment was performed at the FRS, GSI The distribution has a relatively narrow width (150 +/- 3 MeV/c (FWHM)) and the one-neutron removal cross-section is 74 +/- 4 mb An increased contribution from the (2)p(3/2) orbital is required to explain the observation showing its lowering compared to existing model predictions This provides new information regarding the configuration of Mg-33 and the island of inversion (C) 2010 Elsevier B V All rights reserved
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| 8. |
- Nociforo, C., et al.
(författare)
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One-neutron removal reactions on Al isotopes around the N=20 shell closure
- 2012
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Ingår i: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X .- 2469-9985 .- 2469-9993. ; 85:4, s. 044312-1-044312-10
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Tidskriftsartikel (refereegranskat)abstract
- The one-neutron removal cross sections of neutron-rich Al isotopes and longitudinal momentum distributions of the residues have been measured for A=33 to 36 at relativistic energies (≈900 MeV/u). The inclusive data have been interpreted within the eikonal approximation. The evolution of the single-particle occupancy in the ground state of 33,34,35Al has been studied and compared with shell model predictions. The inferred 2s1/2 neutron occupancy in the 33Al ground-state wave function is 20% to 40% lower than the predicted one. The inclusive data do not exclude the presence of intruder states. Some intruder l=1 occupancy is found in 34Al, similarly to 33Mg. The single-particle 1f7/2 occupancy shows a gradual increase at N=22. Correspondingly, a decrease of the 1d3/2 strength has been observed.
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| 9. |
- Nociforo, C., et al.
(författare)
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Shell Closure N=16 in O-24
- 2009
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Ingår i: AIP Conference Proceedings. - 1551-7616 .- 0094-243X. ; 1165, s. 90-93 461
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Konferensbidrag (refereegranskat)abstract
- Advanced nuclear structure models predict the presence of the shell closures N=14, 16 in neutron-rich O isotopes rather than N=20. Spectroscopic investigations performed at the neutron drip line have recently confirmed such predictions showing that the O-24 is a doubly magic nucleus (Z=8, N=16). Predictions within the shell model calculation for the O-23,O-24 ground state have been confirmed measuring their spectroscopic factors. Results obtained in one-neutron removal reactions performed by using in-flight radioactive ion beams produced at the Fragment Separator FRS of GSI are reported.
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| 10. |
- Schöpf, Julia, et al.
(författare)
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Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions
- 2024
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Ingår i: Nature Communications. - 2041-1723. ; 15, s. 1-17
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Tidskriftsartikel (refereegranskat)abstract
- Linking clinical multi-omics with mechanistic studies may improve the understanding of rare cancers. We leverage two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective therapies. All tumors exhibit outlier ALK expression, partly accompanied by intragenic deletions and aberrant splicing resulting in ALK variants that are oncogenic and sensitive to ALK inhibitors. Additionally, recurrent CKDN2A/MTAP co-deletions provide a rationale for PRMT5-targeted therapies. Functional studies show that FUS-TFCP2 blocks myogenic differentiation, induces transcription of ALK and truncated TERT, and inhibits DNA repair. Unlike other fusion-driven sarcomas, TFCP2-rearranged tumors exhibit genomic instability and signs of defective homologous recombination. DNA methylation profiling demonstrates a close relationship with undifferentiated sarcomas. In two patients, sarcoma was preceded by benign lesions carrying FUS-TFCP2, indicating stepwise sarcomagenesis. This study illustrates the potential of linking precision oncology with preclinical research to gain insight into the classification, pathogenesis, and therapeutic vulnerabilities of rare cancers.
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