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- Alvarez, Mariano J., et al.
(author)
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A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors
- 2018
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:7, s. 979-989
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Journal article (peer-reviewed)abstract
- We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.
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| 3. |
- Chen, Xingchen, et al.
(author)
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Potent, multi-target serine protease inhibition achieved by a simplified beta-sheet motif
- 2019
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In: PLOS ONE. - : Public Library Science. - 1932-6203. ; 14:1
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Journal article (peer-reviewed)abstract
- Engagement of an extended beta-sheet is a common substrate/inhibitor interaction at the active site of serine proteases and is an important feature of Laskowski mechanism inhibitors that present a substrate-like loop to a target protease. This loop is cleaved but subsequently relegated forming a stable inhibitor/protease complex. Laskowski inhibitors are ubiquitous in nature and are used extensively in serine protease inhibitor design. However, most studies concentrate on introducing new sidechain interactions rather than the direct contributions of the substrate-like beta-sheet to enzyme inhibition. Here we report the crystal structure of an simplified beta-sheet inhibitory motif within the Sunflower Trypsin Inhibitor (SFTI) in complex with trypsin. We show that the intramolecular hydrogen bond network of this SFTI variant (SFTI-TCTR) engages the inhibitor sidechains that would normally interact with a target protease, giving mainchain interactions a more prominent role in complex formation. Despite having reduced sidechain interactions, this SFTI variant is remarkably potent and inhibits a diverse range of serine proteases. Crystal structural analysis and molecular modelling of SFTI-TCTR complexes again indicates an interface dominated by beta-sheet interactions, highlighting the importance of this motif and the adaptability of SFTI as a scaffold for inhibitor design.
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| 4. |
- St. Louis, Kenneth O., et al.
(author)
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Public attitudes toward stuttering in Europe : Within-country and between-country comparisons
- 2016
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In: Journal of Communication Disorders. - : Elsevier BV. - 0021-9924. ; 62, s. 115-130
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Journal article (peer-reviewed)abstract
- Introduction: Epidemiological research methods have been shown to be useful in determining factors that might predict commonly reported negative public attitudes toward stuttering. Previous research has suggested that stuttering attitudes of respondents from North America and Europe (i.e., "The West"), though characterized by stereotypes and potential stigma, are more positive than those from several other regions of the world. This inference assumes that public attitudes within various regions characterized by "The West" are similar. Purpose: This study aimed to determine the extent to which public stuttering attitudes are similar or different both within regions of three different European countries and between or among five different European countries or similar geographic areas. It also aimed to compare these European attitudes to attitudes from 135 samples around the world using a standard measure. Material and methods: Using convenience sampling, 1111 adult respondents from eight different investigations completed the Public Opinion Survey of Human Attributes-Stuttering (POSHA-S) in the dominant language of each country or area. In Study I, the authors compared attitudes within three different regions of Bosnia & Herzegovina, Italy, and Norway. In Study II, the authors compared attitudes between combined samples from Bosnia & Herzegovina, Italy, and Norway (with additional respondents from Sweden), and two other samples, one from Germany and the other from Ireland and England. Results: Attitudes of adults from the three samples within Bosnia & Herzegovina, Italy, and Norway were remarkably similar. By contrast, attitudes between the five different countries or area were quite dramatically different. Demographic variables on the POSHA-S did not predict the rank order of these between-country/area differences. Compared to the POSHA-S worldwide database, European attitudes ranged from less positive than average (i.e., Italians) to more positive than average (i.e., Norwegians and Swedes). Conclusion: Factors related to national identity appear to play a significant role in differences in public attitudes in Europe and should be explored in future research.
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