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| 16. |
- Roels, Juliette, et al.
(författare)
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Aging of preleukemic thymocytes drives CpG island hypermethylation in T-cell acute lymphoblastic leukemia
- 2020
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Ingår i: Blood cancer discovery. - : American Association for Cancer Research. - 2643-3249. ; 1:3, s. 274-289
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Tidskriftsartikel (refereegranskat)abstract
- Cancer cells display DNA hypermethylation at specific CpG islands in comparison to their normal healthy counterparts, but the mechanism that drives this so-called CpG island methylator phenotype (CIMP) remains poorly understood. Here, we show that CpG island methylation in human T-cell acute lymphoblastic leukemia (T-ALL) mainly occurs at promoters of Polycomb Repressor Complex 2 (PRC2) target genes that are not expressed in normal or malignant T-cells and which display a reciprocal association with H3K27me3 binding. In addition, we revealed that this aberrant methylation profile reflects the epigenetic history of T-ALL and is established already in pre-leukemic, self-renewing thymocytes that precede T-ALL development. Finally, we unexpectedly uncover that this age-related CpG island hypermethylation signature in T-ALL is completely resistant to the FDA-approved hypomethylating agent Decitabine. Altogether, we here provide conceptual evidence for the involvement of a pre-leukemic phase characterized by self-renewing thymocytes in the pathogenesis of human T-ALL.
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| 18. |
- Andrés-Jensen, Liv, et al.
(författare)
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Severe toxicity free survival : physician-derived definitions of unacceptable long-term toxicities following acute lymphocytic leukaemia
- 2021
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Ingår i: The Lancet Haematology. - : Elsevier. - 2352-3026. ; 8:7, s. E513-E523
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Forskningsöversikt (refereegranskat)abstract
- 5-year overall survival rates have surpassed 90% for childhood acute lymphocytic leukaemia, but survivors are at risk for permanent health sequelae. Although event-free survival appropriately represents the outcome for cancers with poor overall survival, this metric is inadequate when cure rates are high but challenged by serious, persistent complications. Accordingly, a group of experts in paediatric haematology-oncology, representative of 17 international acute lymphocytic leukaemia study groups, launched an initiative to construct a measure, designated severe toxicity-free survival (STFS), to quantify the occurrence of physician-prioritised toxicities to be integrated with standard cancer outcome reporting. Five generic inclusion criteria (not present before cancer diagnosis, symptomatic, objectifiable, of unacceptable severity, permanent, or requiring unacceptable treatments) were used to assess 855 health conditions, which resulted in inclusion of 21 severe toxicities. Consensus definitions were reached through a modified Delphi process supplemented by two additional plenary meetings. The 21 severe toxicities include severe adverse health conditions that substantially affect activities of daily living and are refractory to therapy (eg, refractory seizures), are without therapeutic options (eg, blindness), or require substantially invasive treatment (eg, cardiac transplantation). Incorporation of STFS assessment into clinical trials has the potential to improve and diversify treatment strategies, focusing not only on traditional outcome events and overall survival but also the frequencies of the most severe toxicities. The two major aims of this Review were to: prioritise and define unacceptable long-term toxicity for patients with childhood acute lymphocytic leukaemia, and define how these toxicities should be combined into a composite quantity to be integrated with other reported outcomes. Although STFS quantifies the clinically unacceptable health tradeoff for cure using childhood acute lymphocytic leukaemia as a model disease, the prioritised severe toxicities are based on generic considerations of relevance to any other cancer diagnosis and age group.
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| 19. |
- Boij, Susann, et al.
(författare)
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Reflection properties of a flow pipe with a small angle diffuser outlet
- 2010
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Ingår i: 17th International Congress on Sound and Vibration 2010, ICSV 2010. - 9781617822551 ; , s. 706-712
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Konferensbidrag (refereegranskat)abstract
- The reflection of plane acoustic waves is studied for an open pipe termination where the outlet section about 10 cm long is a diffuser with a small angle. Diffuser angles up to 6o with a sharp outlet edge are considered both without and with a mean flow. The experiments are performed for Helmholtz numbers, He, based on the pipe diameter, up to 1.0 and mean flow Mach numbers, M, up to 0.25. A multi-microphone method is used for accurate measurements of the acoustic fields inside the pipe. With no mean flow, the reflection coefficient results are compared with the theories for thin walls by Levine and Schwinger [1] and for the end correction and thick walls by Ando [2], respectively. The data for the magnitude of the reflection coefficient for different pipe end geometries show that in the low frequency regime it is the outlet radius that determines the magnitude of the energy reflection coefficient. The same collapse in the data is not obtained for the end correction which is strongly affected by the pipe end geometry. Experimental results of the reflection coefficient in the presence of a mean flow show a similar behaviour as without flow. However, it is the Strouhal number of the outlet that governs the losses, i.e., radiation and flow losses. For a region of small Strouhal numbers, the reflection is larger than one, as predicted for straight pipes, [3, 4]. An increased diffuser angle and rounded edges both increase the reflection at the pipe termination in a critical range of Strouhal numbers, which indicates that the reflection coefficient is strongly dependent on the shape, half angle, and edge curvature of the pipe end in this region.
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