Technology has a pivotal role in the continuous development of radiotherapy. The long road toward modern 'high-tech' radiation oncology has been studded with discoveries and technological... Show moreTechnology has a pivotal role in the continuous development of radiotherapy. The long road toward modern 'high-tech' radiation oncology has been studded with discoveries and technological innovations that resulted from the interaction of various disciplines. In the last decades, a dramatic technology-driven revolution has hugely improved the capability of accurately and safely delivering complex-shaped dose distributions. This has contributed to many clinical improvements, such as the successful management of lung cancer and oligometastatic disease through stereotactic body radiotherapy. Technology-driven research is an active and lively field with promising potential in several domains, including image guidance, adaptive radiotherapy, integration of artificial intelligence, heavy-particle therapy, and 'flash' ultra-high dose-rate radiotherapy. The evolution toward personalized Oncology will deeply influence technology-driven research, aiming to integrate predictive models and omics analyses into fast and efficient solutions to deliver the best treatment for each single patient. Personalized radiation oncology will need affordable technological solutions for middle-/low-income countries, as these are expected to experience the highest increase of cancer incidence and mortality. Moreover, technology solutions for automation of commissioning, quality assurance, safety tests, image segmentation, and plan optimization will be required. Although a large fraction of cancer patients receive radiotherapy, this is certainly not reflected in the worldwide budget for radiotherapy research. Differently from the pharmaceutical companies-driven research, resources for research in radiotherapy are highly limited to equipment vendors, who can, in turn, initiate a limited number of collaborations with academic research centers. Thus, enhancement of investments in technology-driven radiotherapy research via public funds, national governments, and the European Union would have a crucial societal impact. It would allow for radiotherapy to further strengthen its role as a highly effective and cost-efficient cancer treatment modality, and it could facilitate a rapid and equalitarian large-scale transfer of technology to clinic, with direct impact on patient care. Show less
Bruggemann, M.; Kotrova, M.; Knecht, H.; Bartram, J.; Boudjogrha, M.; Bystry, V.; ... ; EuroClonality-NGS Working Grp 2019
Amplicon-based next-generation sequencing (NGS) of immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements for clonality assessment, marker identification and quantification of minimal... Show moreAmplicon-based next-generation sequencing (NGS) of immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements for clonality assessment, marker identification and quantification of minimal residual disease (MRD) in lymphoid neoplasms has been the focus of intense research, development and application. However, standardization and validation in a scientifically controlled multicentre setting is still lacking. Therefore, IG/TR assay development and design, including bioinformatics, was performed within the EuroClonality-NGS working group and validated for MRD marker identification in acute lymphoblastic leukaemia (ALL). Five EuroMRD ALL reference laboratories performed IG/TR NGS in 50 diagnostic ALL samples, and compared results with those generated through routine IG/TR Sanger sequencing. A central polytarget quality control (cPT-QC) was used to monitor primer performance, and a central in-tube quality control (cIT-QC) was spiked into each sample as a library-specific quality control and calibrator. NGS identified 259 (average 5.2/sample, range 0-14) clonal sequences vs. Sanger-sequencing 248 (average 5.0/sample, range 0-14). NGS primers covered possible IG/TR rearrangement types more completely compared with local multiplex PCR sets and enabled sequencing of bi-allelic rearrangements and weak PCR products. The cPT-QC showed high reproducibility across all laboratories. These validated and reproducible quality-controlled EuroClonality-NGS assays can be used for standardized NGS-based identification of IG/TR markers in lymphoid malignancies. Show less
Repeated dose toxicity evaluation aims at assessing the occurrence of adverse effects following chronic or repeated exposure to chemicals. Non-animal approaches have gained importance in the last... Show moreRepeated dose toxicity evaluation aims at assessing the occurrence of adverse effects following chronic or repeated exposure to chemicals. Non-animal approaches have gained importance in the last decades because of ethical considerations as well as due to scientific reasons calling for more human-based strategies. A critical aspect of this challenge is linked to the capacity to cover a comprehensive set of interdependent mechanisms of action, link them to adverse effects and interpret their probability to be triggered in the light of the exposure at the (sub)cellular level. Inherent to its structured nature, an ontology addressing repeated dose toxicity could be a scientific and transparent way to achieve this goal. Additionally, repeated dose toxicity evaluation through the use of a harmonized ontology should be performed in a reproducible and consistent manner, while mimicking as accurately as possible human physiology and adaptivity. In this paper, the outcome of a series of workshops organized by Cosmetics Europe on this topic is reported. As such, this manuscript shows how experts set critical elements and ways of establishing a mode-of-action ontology model as a support to risk assessors aiming to perform animal-free safety evaluation of chemicals based on repeated dose toxicity data. Show less
Kuiken, T.; Breitbart, M.; Beer, M.; Grund, C.; Hoper, D.; Hoogen, B. van den; ... ; Koopmans, M. 2018
Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for... Show moreAdverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field. Show less
Bruggemann, M.; Knecht, H.; Kotrova, M.; Bartram, J.; Bystry, V.; Darzentas, N.; ... ; Langerak, A.W. 2017
Genes involved in detoxification of foreign compounds exhibit complex spatiotemporal expression patterns in liver. Cytochrome P450 1A1 (CYP1A1), for example, is restricted to the pericentral... Show moreGenes involved in detoxification of foreign compounds exhibit complex spatiotemporal expression patterns in liver. Cytochrome P450 1A1 (CYP1A1), for example, is restricted to the pericentral region of liver lobules in response to the interplay between aryl hydrocarbon receptor (AhR) and Wnt/β-catenin signaling pathways. However, the mechanisms by which the two pathways orchestrate gene expression are still poorly understood. With the help of 29 mutant constructs of the human CYP1A1 promoter and a mathematical model that combines Wnt/β-catenin and AhR signaling with the statistical mechanics of the promoter, we systematically quantified the regulatory influence of different transcription factor binding sites on gene induction within the promoter. The model unveils how different binding sites cooperate and how they establish the promoter logic; it quantitatively predicts two-dimensional stimulus-response curves. Furthermore, it shows that crosstalk between Wnt/β-catenin and AhR signaling is crucial to understand the complex zonated expression patterns found in liver lobules. This study exemplifies how statistical mechanical modeling together with combinatorial reporter assays has the capacity to disentangle the promoter logic that establishes physiological gene expression patterns. Show less
Ason, B.; Hoorn, J.W.A. van der; Chan, J.; Lee, E.; Pieterman, E.J.; Nguyen, K.K.; ... ; Jackson, S. 2014
