| 1. |
- Jain, Neeraj, et al.
(författare)
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Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in diffuse large B cell lymphoma
- 2019
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 11:497
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Tidskriftsartikel (refereegranskat)abstract
- The activated B cell (ABC-like) subtype of diffuse large B cell lymphoma (DLBCL) is characterized by chronic activation of signaling initiated by immunoglobulin m (IgM). By analyzing the DNA copy number profiles of 1000 DLBCL tumors, we identified gains of 18q21.2 as the most frequent genetic alteration in ABC-like DLBCL. Using integrative analysis of matched gene expression profiling data, we found that the TCF4 (E2-2) transcription factor gene was the target of these alterations. Overexpression of TCF4 in ABC-like DLBCL cell lines led to its occupancy on immunoglobulin (IGHM) and MYC gene enhancers and increased expression of these genes at the transcript and protein levels. Inhibition of TCF4 activity with dominant-negative constructs was synthetically lethal to ABC-like DLBCL cell lines harboring TCF4 DNA copy gains, highlighting these gains as an attractive potential therapeutic target. Furthermore, the TCF4 gene was one of the top BRD4-regulated genes in DLBCL cell lines. BET proteolysistargeting chimera (PROTAC) ARV771 extinguished TCF4, MYC, and IgM expression and killed ABC-like DLBCL cells in vitro. In DLBCL xenograft models, ARV771 treatment reduced tumor growth and prolonged survival. This work highlights a genetic mechanism for promoting immunoglobulin signaling in ABC-like DLBCL and provides a functional rationale for the use of BET inhibitors in this disease.
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| 2. |
- Reichelt, Andreas F, et al.
(författare)
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Adaptation of lift forces in object manipulation through action observation.
- 2013
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Ingår i: Experimental Brain Research. - : Springer. - 0014-4819 .- 1432-1106. ; 228:2, s. 221-234
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Tidskriftsartikel (refereegranskat)abstract
- The ability to predict accurately the weights of objects is essential for skilled and dexterous manipulation. A potentially important source of information about object weight is through the observation of other people lifting objects. Here, we tested the hypothesis that when watching an actor lift an object, people naturally learn the object's weight and use this information to scale forces when they subsequently lift the object themselves. Participants repeatedly lifted an object in turn with an actor. Object weight unpredictably changed between 2 and 7 N every 5th to 9th of the actor's lifts, and the weight lifted by the participant always matched that previously lifted by the actor. Even though the participants were uninformed about the structure of the experiment, they appropriately adapted their lifting force in the first trial after a weight change. Thus, participants updated their internal representation about the object's weight, for use in action, when watching a single lift performed by the actor. This ability presumably involves the comparison of predicted and actual sensory information related to actor's actions, a comparison process that is also fundamental in action.
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