| 1. |
- Ladds, Marcus J. G. W., et al.
(author)
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A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
- 2018
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Journal article (peer-reviewed)abstract
- The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.
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| 2. |
- Ladds, Marcus J. G. W., et al.
(author)
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Autophagic flux blockage by accumulation of weakly basic tenovins leads to elimination of B-Raf mutant tumour cells that survive vemurafenib
- 2018
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:4
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Journal article (peer-reviewed)abstract
- Tenovin-6 is the most studied member of a family of small molecules with antitumour activity in vivo. Previously, it has been determined that part of the effects of tenovin-6 associate with its ability to inhibit SirT1 and activate p53. However, tenovin-6 has also been shown to modulate autophagic flux. Here we show that blockage of autophagic flux occurs in a variety of cell lines in response to certain tenovins, that autophagy blockage occurs regardless of the effect of tenovins on SirT1 or p53, and that this blockage is dependent on the aliphatic tertiary amine side chain of these molecules. Additionally, we evaluate the contribution of this tertiary amine to the elimination of proliferating melanoma cells in culture. We also demonstrate that the presence of the tertiary amine is sufficient to lead to death of tumour cells arrested in G1 phase following vemurafenib treatment. We conclude that blockage of autophagic flux by tenovins is necessary to eliminate melanoma cells that survive B-Raf inhibition and achieve total tumour cell kill and that autophagy blockage can be achieved at a lower concentration than by chloroquine. This observation is of great relevance as relapse and resistance are frequently observed in cancer patients treated with B-Raf inhibitors.
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| 3. |
- Sheehan, Katie J., et al.
(author)
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Conceptual Framework for an Episode of Rehabilitative Care After Surgical Repair of Hip Fracture
- 2019
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In: Physical Therapy. - : Oxford University Press. - 0031-9023 .- 1538-6724. ; 99:3, s. 276-285
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Journal article (peer-reviewed)abstract
- Researchers face a challenge when evaluating the effectiveness of rehabilitation after a surgical procedure for hip fracture. Reported outcomes of rehabilitation will vary depending on the end point of the episode of care. Evaluation at an inappropriate end point might suggest a lack of effectiveness leading to the underuse of rehabilitation that could improve outcomes. The purpose of this article is to describe a conceptual framework for a continuum-care episode of rehabilitation after a surgical procedure for hip fracture. Definitions are proposed for the index event, end point, and service scope of the episode. Challenges in defining the episode of care and operationalizing the episode, and next steps for researchers are discussed. The episode described is intended to apply to all patients eligible for entry to rehabilitation after hip fracture and includes most functional recovery end points. This framework will provide a guide for rehabilitation researchers when designing and interpreting evaluations of the effectiveness of rehabilitation after hip fracture. Evaluation of all potential care episodes facilitates transparency in reporting of outcomes, enabling researchers to determine the true effectiveness of rehabilitation after a surgical procedure for hip fracture.
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