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| 2. |
- Stacchiotti, S., et al.
(author)
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Epithelioid hemangioendothelioma, an ultra-rare cancer : a consensus paper from the community of experts
- 2021
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In: ESMO Open. - : Elsevier BV. - 2059-7029. ; 6:3
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Research review (peer-reviewed)abstract
- Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.
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| 3. |
- Block, Keith I., et al.
(author)
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Designing a broad-spectrum integrative approach for cancer prevention and treatment
- 2015
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In: Seminars in Cancer Biology. - : Academic Press. - 1044-579X .- 1096-3650. ; 35, s. S276-S304
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Research review (peer-reviewed)abstract
- Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broadspectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered. (C) 2015 The Authors. Published by Elsevier Ltd.
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| 4. |
- Connor, T. M., et al.
(author)
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Mutations in mitochondrial DNA causing tubulointerstitial kidney disease
- 2017
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In: Plos Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 13:3
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Journal article (peer-reviewed)abstract
- Tubulointerstitial kidney disease is an important cause of progressive renal failure whose aetiology is incompletely understood. We analysed a large pedigree with maternally inherited tubulointerstitial kidney disease and identified a homoplasmic substitution in the control region of the mitochondrial genome (m.547A> T). While mutations in mtDNA coding sequence are a well recognised cause of disease affecting multiple organs, mutations in the control region have never been shown to cause disease. Strikingly, our patients did not have classical features of mitochondrial disease. Patient fibroblasts showed reduced levels of mitochondrial tRNA(Phe), tRNA(Leu1) and reduced mitochondrial protein translation and respiration. Mitochondrial transfer demonstrated mitochondrial transmission of the defect and in vitro assays showed reduced activity of the heavy strand promoter. We also identified further kindreds with the same phenotype carrying a homoplasmic mutation in mitochondrial tRNA Phe (m.616T> C). Thus mutations in mitochondrial DNA can cause maternally inherited renal disease, likely mediated through reduced function of mitochondrial tRNA(Phe)
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| 5. |
- Mottahedin, Amin, et al.
(author)
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Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke
- 2023
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In: Redox Biology. - : Elsevier BV. - 2213-2317. ; 59
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Journal article (peer-reviewed)abstract
- Current treatments for acute ischemic stroke aim to reinstate a normal perfusion in the ischemic territory but can also cause significant ischemia-reperfusion (IR) injury. Previous data in experimental models of stroke show that ischemia leads to the accumulation of succinate, and, upon reperfusion, the accumulated succinate is rapidly oxidized by succinate dehydrogenase (SDH) to drive superoxide production at mitochondrial complex I. Despite this process initiating IR injury and causing further tissue damage, the potential of targeting succinate metabolism to minimize IR injury remains unexplored. Using both quantitative and untargeted high -resolution metabolomics, we show a time-dependent accumulation of succinate in both human and mouse brain exposed to ischemia ex vivo. In a mouse model of ischemic stroke/mechanical thrombectomy mass spectrometry imaging (MSI) shows that succinate accumulation is confined to the ischemic region, and that the accumulated succinate is rapidly oxidized upon reperfusion. Targeting succinate oxidation by systemic infusion of the SDH inhibitor malonate upon reperfusion leads to a dose-dependent decrease in acute brain injury. Together these findings support targeting succinate metabolism upon reperfusion to decrease IR injury as a valuable adjunct to mechanical thrombectomy in ischemic stroke.
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| 6. |
- Kohlhauer, M., et al.
(author)
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Protection against cardiac ischemia-reperfusion injury by hypothermia and by inhibition of succinate accumulation and oxidation is additive
- 2019
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In: Basic Research in Cardiology. - : Springer Science and Business Media LLC. - 0300-8428 .- 1435-1803. ; 114:3
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Journal article (peer-reviewed)abstract
- Hypothermia induced at the onset of ischemia is a potent experimental cardioprotective strategy for myocardial infarction. The aim of our study was to determine whether the beneficial effects of hypothermia may be due to decreasing mitochondria-mediated mechanisms of damage that contribute to the pathophysiology of ischemia/reperfusion injury. New Zealand male rabbits were submitted to 30min of myocardial ischemia with hypothermia (32 degrees C) induced by total liquid ventilation (TLV). Hypothermia was applied during ischemia alone (TLV group), during ischemia and reperfusion (TLV-IR group) and normothermia (Control group). In all the cases, ischemia was performed by surgical ligation of the left anterior descending coronary artery and was followed by 3h of reperfusion before assessment of infarct size. In a parallel study, male C57BL6/J mice underwent 30min myocardial ischemia followed by reperfusion under either normothermia (37 degrees C) or conventionally induced hypothermia (32 degrees C). In both the models, the levels of the citric acid cycle intermediate succinate, mitochondrial complex I activity were assessed at various times. The benefit of hypothermia during ischemia on infarct size was compared to inhibition of succinate accumulation and oxidation by the complex II inhibitor malonate, applied as the pro-drug dimethyl malonate under either normothermic or hypothermic conditions. Hypothermia during ischemia was cardioprotective, even when followed by normothermic reperfusion. Hypothermia during ischemia only, or during both, ischemia and reperfusion, significantly reduced infarct size (2.8 +/- 0.6%, 24.2 +/- 3.0% and 49.6 +/- 2.6% of the area at risk, for TLV-IR, TLV and Control groups, respectively). The significant reduction of infarct size by hypothermia was neither associated with a decrease in ischemic myocardial succinate accumulation, nor with a change in its rate of oxidation at reperfusion. Similarly, dimethyl malonate infusion and hypothermia during ischemia additively reduced infarct size (4.8 +/- 2.2% of risk zone) as compared to either strategy alone. Hypothermic cardioprotection is neither dependent on the inhibition of succinate accumulation during ischemia, nor of its rapid oxidation at reperfusion. The additive effect of hypothermia and dimethyl malonate on infarct size shows that they are protective by distinct mechanisms and also suggests that combining these different therapeutic approaches could further protect against ischemia/reperfusion injury during acute myocardial infarction.
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| 7. |
- Clear, A., et al.
(author)
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Designing Computer Science Competency Statements : A Process and Curriculum Model for the 21st Century
- 2020
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In: Proceedings of the Working Group Reports on Innovation and Technology in Computer Science Education, ITiCSE 2020. - New York, NY, USA : Association for Computing Machinery (ACM). ; , s. 211-246
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Conference paper (peer-reviewed)abstract
- The broadly influential document Computing Curricula 2005 (CC2005) is in the process of being updated through a project called Computing Curricula 2020 (CC2020). CC2020 provides a vision for the future of computing education, including a comprehensive report that contrasts curricular guidelines, and contextualizing those guidelines within the broader landscape of computing education. In the process, a framework of competency-based educational principles has been developed which is closely aligned with other skills and qualifications frameworks. This working group report demonstrates one way in which the transition from current learning-outcomes-based practices to the competency-based practices can be approached. Further, the paper discusses the challenges and insights that have emerged as the learning outcomes for various Knowledge Areas in the CS2013 report were re-expressed in terms of competencies.
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| 8. |
- Frezza, S., et al.
(author)
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Modeling global competencies for computing education
- 2018
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In: ITiCSE 2018 Proceedings of the 23rd Annual ACM Conference on Innovation and Technology in Computer Science Education. - New York, NY, USA : Association for Computing Machinery (ACM). - 9781450357074 ; , s. 348-349
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Conference paper (peer-reviewed)abstract
- This working group contributes to formulating a framework for modeling competencies in the current and future disciplines that comprise computing education. We draw upon the innovative approach taken in the curricular document for information technology (IT2017), curricular competency frameworks, other related documents such as the software engineering competency model (SWECOM), the Skills Framework for the Information Age (SFIA), current research in competency models, and elicitation workshop results from other computing conferences. The outcomes contribute to the Computing Curricula 2020 (CC2020) project, and include the formulation and review of sets of disciplinary-relevant competencies for use in computing education. This work directly informs the CC2020 project sponsored by the Association for Computing Machinery (ACM) and the IEEE Computer Society.
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| 9. |
- Frezza, S., et al.
(author)
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Modelling competencies for computing education beyond 2020 : A research based approach to defining competencies in the computing disciplines
- 2018
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In: Annual Conference on Innovation and Technology in Computer Science Education, ITiCSE. - New York, NY, USA : Association for Computing Machinery. - 9781450362238 ; , s. 148-174, s. 148-174
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Conference paper (peer-reviewed)abstract
- How might the content and outcomes of tertiary education programmes be described and analysed in order to understand how they are structured and function? To address this question we develop a framework for modelling graduate competencies linked to tertiary degree programmes in the computing disciplines. While the focus of our work is computing the framework is applicable to education more broadly. The work presented here draws upon the pioneering curricular document for information technology (IT2017), curricular competency frameworks, other related documents such as the software engineering competency model (SWECOM), the Skills Framework for the Information Age (SFIA), current research in competency models, and elicitation workshop results from recent computing conferences. The aim is to inform the ongoing Computing Curricula (CC2020) project, an endeavour supported by the Association for Computing Machinery (ACM) and the IEEE Computer Society. We develop the Competency Learning Framework (CoLeaF), providing an internationally relevant tool for describing competencies. We argue that this competency based approach is well suited for constructing learning environments and assists degree programme architects in dealing with the challenge of developing, describing and including competencies relevant to computer and IT professionals. In this paper we demonstrate how the CoLeaF competency framework can be applied in practice, and though a series of case studies demonstrate its effectiveness and analytical power as a tool for describing and comparing degree programmes in the international higher education landscape.
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