| 1. |
- Ercan, Ayse Bahar, et al.
(författare)
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Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.
- 2024
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Ingår i: The Lancet. Oncology. - 1474-5488. ; 25:5, s. 668-682
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Tidskriftsartikel (refereegranskat)abstract
- Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD.In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions.We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions.The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD.The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.
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| 2. |
- Falk, Martin, et al.
(författare)
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Parallelized Agent-based Simulation on CPU and Graphics Hardware for Spatial and Stochastic Models in Biology
- 2011
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Ingår i: Proceedings of the 9th International Conference on Computational Methods in Systems Biology, CMSB'112011. - New York, NY, USA : ACM Press. - 9781450308175 ; , s. 73-82
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Konferensbidrag (refereegranskat)abstract
- The complexity of biological systems is enormous, even when considering a single cell where a multitude of highly parallel and intertwined processes take place on the molecular level. This paper focuses on the parallel simulation of signal transduction processes within a cell carried out solely on the graphics processing unit (GPU). Each signaling molecule is represented by an agent performing a discretetime continuous-space random walk to model its diffusion through the cell. Since the interactions and reactions between the agents can be competitive and are interdependent, we propose spatial partitioning for the reaction detection to overcome the data dependencies in the parallel execution of reactions. In addition, we present a simple way to simulate the Michaelis-Menten kinetics in our particle-based method using a per-particle delay. We apply this agent-based simulation to model signal transduction in the MAPK (Mitogen-Activated Protein Kinase) cascade both with and without cytoskeletal filaments. Finally, we compare the speed-up of our GPU simulation with a parallelized CPU version resulting in a twelvefold speedup.
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| 3. |
- Bogdan, Cristian, et al.
(författare)
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Evaluation of robot body movements supporting communication : Towards HRI on the move
- 2011
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Ingår i: New Frontiers in Human–Robot Interaction. - Philadelphia : John Benjamins Publishing Company. - 9789027204554 ; , s. 185-210
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Bokkapitel (refereegranskat)abstract
- In designing socially interactive robots we have focused on robot movement and its role in multi-modal human-robot communication. In this chapter we describe design and evaluation of robot body movements supporting communication, investigating the idea of using speed and orientation adjustments as design elements in human-robot interaction. The scenario studied includes a robotic shopping trolley that offers products via speech and GUI to the user while both are moving in a supermarket-like environment. Our results show that if the robot slows down while making such offers, users are more prone to react upon them and to take the product. However, even from our early pre-study with mock-up robots we observed that users tended not to mention the robot’s slow-down movements, even if these movements were shown several times to them during a video-based debriefing. This phenomenon, that users react implicitly on the robot’s movements without being consciously aware of them, was confirmed during an experimental study with a fully integrated robot prototype. We discuss our results by reflecting on human-robot interaction design methods, and we draw implications from the lessons learned in the study of the design of robot behaviours. In particular, we list a whole set of challenges for HRI when both the user and the robot are moving.
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| 4. |
- Das, Anirban, et al.
(författare)
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Combined immunotherapy improves outcome for replication repair deficient (RRD) high-grade glioma failing anti-PD1 monotherapy: A report from the International RRD Consortium.
- 2024
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Ingår i: Cancer discovery. - 2159-8290. ; 14:2, s. 258-273
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Tidskriftsartikel (refereegranskat)abstract
- Immune-checkpoint inhibition (ICI) is effective for replication-repair deficient, high-grade gliomas (RRD-HGG). Clinical/biologic impact of immune-directed approaches after failing ICI-monotherapy are unknown. We performed an international study on 75 patients treated with anti-PD1; 20 are progression-free (median follow-up: 3.7-years). After 2nd-progression/recurrence (n=55), continuing ICI-based salvage prolonged survival to 11.6-months (n=38; p<0.001), particularly for those with extreme mutation burden (p=0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and immune-microenvironment. Response to re-irradiation was explained by an absence of deleterious post-radiation indel signatures (ID8). Increased CTLA4-expression over time, and subsequent CTLA4-inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to reinvigoration of peripheral immune and radiological responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/ synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology.
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| 5. |
- Deubner, Nikolas, et al.
(författare)
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Cardiac beta1-adrenoceptor autoantibodies in human heart disease: rationale and design of the Etiology, Titre-Course, and Survival (ETiCS) Study.
- 2010
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Ingår i: European journal of heart failure : journal of the Working Group on Heart Failure of the European Society of Cardiology. - : Wiley. - 1879-0844. ; 12:7, s. 753-62
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Tidskriftsartikel (refereegranskat)abstract
- Evidence for a pathophysiologic relevance of autoimmunity in human heart disease has substantially increased over the past years. Conformational autoantibodies stimulating the cardiac beta1-adrenoceptor (beta1-aabs) are considered of importance in heart failure development and clinical pilot studies have shown their prognostic significance in human 'idiopathic' cardiomyopathy.
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| 6. |
- Ertl, Michael, et al.
(författare)
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Mössbauerite as Iron-Only Layered Oxyhydroxide Catalyst for WO3 Photoanodes
- 2019
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Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 58:15, s. 9655-9662
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Tidskriftsartikel (refereegranskat)abstract
- Mössbauerite, a trivalent iron-only layered oxyhydroxide, has been recently identified as an electrocatalyst for water oxidation. We investigated the material as potential cocatalyst for photoelectrochemical water oxidation on semiconductor photoanodes. The band edge positions of mössbauerite were determined for the first time with a combination of Mott-Schottky analysis and UV-vis diffuse reflectance spectroscopy. The positive value of the Mott-Schottky slope and the flatband potential of 0.34 V vs reversible hydrogen electrode (RHE) identifies the material as an n-type semiconductor, but bare mössbauerite does not produce noticeable photocurrent during water oxidation. Type-II heterojunction formation by facile drop-casting with WO3 thin films yielded photoanodes with amended charge carrier separation and photocurrents up to 1.22 mA cm(-2) at 1.23 V vs RHE. Mössbauerite is capable of increasing the charge carrier separation at lower potential and improving the photocurrent during photoelectrochemical water oxidation. The rise in photocurrent of the mössbauerite-functionalized WO3 photoanode thus originates from improved charge carrier separation and augmented hole collection efficiency. Our results highlight the potential of mössbauerite as a second-phase catalyst for semiconductor electrodes.
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| 7. |
- Falk, Martin, et al.
(författare)
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3D Visualization of Concentrations from Stochastic Agent-based Signal Transduction Simulations
- 2010
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Ingår i: Biomedical Imaging: From Nano to Macro, 2010 IEEE International Symposium on. - : IEEE. - 9781424441259 - 9781424441266 ; , s. 1301-1304
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Konferensbidrag (refereegranskat)abstract
- Cellular signal transduction involves a transport step from the plasma membrane towards the nucleus, during which the signaling molecules are partly deactivated in control loops. This leads to a gradient in the concentration of active signaling molecules. The low number of molecules introduces spatio-temporal fluctuations and the asymmetric cellular architecture further increases the complexity. We propose a technique to represent this pattern in a continuous three-dimensional concentration map. The local concentration is computed and visualized with volume rendering techniques at interactive frame rates and is therefore well-suited for time-dependent data. Our approach allows the transition from the nano-scale of single and discrete signaling proteins to a continuous signal on the cell level. In the application context of this paper, we employ an agent-based Monte Carlo simulation to calculate the actual particle positions depending on reaction and transport parameters in the cell. The applicability of the proposed technique is demonstrated by an investigation of the effects of different transport parameters in Mitogen-activated protein kinase (MAPK) signaling.
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| 8. |
- Falk, Martin, et al.
(författare)
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Atomistic Visualization of Mesoscopic Whole-Cell Simulations
- 2012
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Ingår i: VCBM 12: Eurographics Workshop on Visual Computing for Biology and Medicine. - : The Eurographics Association. - 9783905674385 ; , s. 123-130
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Konferensbidrag (refereegranskat)abstract
- Molecular visualizations are a principal tool for analyzing the results of biochemical simulations. With modern GPU ray casting approaches it is only possible to render several millions of atoms at interactive frame rates unless advanced acceleration methods are employed. But even simplified cell models of whole-cell simulations consist of at least several billion atoms. However, many instances of only a few different proteins occur in the intracellular environment, which is beneficial in order to fit the data into the graphics memory. One model is stored for each protein species and rendered once per instance. The proposed method exploits recent algorithmic advances for particle rendering and the repetitive nature of intracellular proteins to visualize dynamic results from mesoscopic simulations of cellular transport processes. We present two out-of-core optimizations for the interactive visualization of data sets composed of billions of atoms as well as details on the data preparation and the employed rendering techniques. Furthermore, we apply advanced shading methods to improve the image quality including methods to enhance depth and shape perception besides non-photorealistic rendering methods.
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| 9. |
- Falk, Martin, et al.
(författare)
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Atomistic Visualization of Mesoscopic Whole-Cell Simulations Using Ray-Casted Instancing
- 2013
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Ingår i: Computer graphics forum (Print). - : Wiley. - 0167-7055 .- 1467-8659. ; 32:8, s. 195-206
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Tidskriftsartikel (refereegranskat)abstract
- Molecular visualization is an important tool for analysing the results of biochemical simulations. With modern GPU ray casting approaches, it is only possible to render several million of atoms interactively unless advanced acceleration methods are employed. Whole-cell simulations consist of at least several billion atoms even for simplified cell models. However, many instances of only a few different proteins occur in the intracellular environment, which can be exploited to fit the data into the graphics memory. For each protein species, one model is stored and rendered once per instance. The proposed method exploits recent algorithmic advances for particle rendering and the repetitive nature of intracellular proteins to visualize dynamic results from mesoscopic simulations of cellular transport processes. We present two out-of-core optimizations for the interactive visualization of data sets composed of billions of atoms as well as details on the data preparation and the employed rendering techniques. Furthermore, we apply advanced shading methods to improve the image quality including methods to enhance depth and shape perception besides non-photorealistic rendering methods. We also show that the method can be used to render scenes that are composed of triangulated instances, not only implicit surfaces.
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| 10. |
- Falk, Martin, et al.
(författare)
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Visualization of Signal Transduction Processes in the Crowded Environment of the Cell
- 2009
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Ingår i: IEEE Pacific Visualization Symposium (PacificVis 2009). - 9781424444045 ; , s. 169-176
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Konferensbidrag (refereegranskat)abstract
- In this paper, we propose a stochastic simulation to model and analyze cellular signal transduction. The high number of objects in a simulation requires advanced visualization techniques: first to handle the large data sets, second to support the human perception in the crowded environment, and third to provide an interactive exploration tool. To adjust the state of the cell to an external signal, a specific set of signaling molecules transports the information to the nucleus deep inside the cell. There, key molecules regulate gene expression. In contrast to continuous ODE models we model all signaling molecules individually in a more realistic crowded and disordered environment. Beyond spatiotemporal concentration profiles our data describes the process on a mesoscopic, molecular level, allowing a detailed view of intracellular events. In our proposed schematic visualization individual molecules, their tracks, or reactions can be selected and brought into focus to highlight the signal transduction pathway. Segmentation, depth cues and depth of field are applied to reduce the visual complexity. We also provide a virtual microscope to display images for comparison with wet lab experiments. The method is applied to distinguish different transport modes of MAPK (mitogen-activated protein kinase) signaling molecules in a cell. In addition, we simulate the diffusion of drug molecules through the extracellular space of a solid tumor and visualize the challenges in cancer related therapeutic drug delivery.
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| 11. |
- Hüttenrauch, Helge, et al.
(författare)
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Evaluation of Robot Body Movements Supporting Communication
- 2010
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Ingår i: Proceedings of the 2nd International Symposium on New Frontiers in Human-Robot Interaction - A Symposium at the AISB 2010 Convention. - 9781902956879 - 1902956877 ; , s. 42-49
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Konferensbidrag (refereegranskat)abstract
- In designing socially interactive robotswe have focused on robot movement and its role in multi-modal human-robot communication. In this paper we describe a user-centred design and evaluation process, investigating the idea of using speed and orientation adjustments as design elements in human-robot interaction. The scenario studied includes a robotic shopping trolley that offers products to the user while both are moving in a supermarket-like environment. Our results show that if the robot slows down while making such offers, users are more prone to react upon them. However, in an early pre-study, performed only with a robot mock-up, we observed that users tended not to notice the robot's slow-down movements while offers are made, even if these movements were shown several times to them during a video-based debriefing. This phenomenon, that users react implicitly on the robot'smovements without being consciously aware of them, was confirmed during an experimental study with a fully integrated robot prototype.We discuss our results by reflecting on human-robot interaction design methods, and we propose implications from the lessons learnt in the study of the design of robot behaviours.
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| 12. |
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| 13. |
- Krone, Michael, et al.
(författare)
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Interactive Exploration of Protein Cavities
- 2011
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Ingår i: Computer graphics forum (Print). - : Blackhorse Publishing. - 0167-7055 .- 1467-8659. ; 30:3, s. 673-682
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Tidskriftsartikel (refereegranskat)abstract
- We present a novel application for the interactive exploration of cavities within proteins in dynamic data sets. Inside a protein, cavities can often be found close to the active center. Therefore, when analyzing a molecular dynamics simulation trajectory it is of great interest to find these cavities and determine if such a cavity opens up to the environment, making the binding site accessible to the surrounding substrate. Our user-driven approach enables expert users to select a certain cavity and track its evolution over time. The user is supported by different visualizations of the extracted cavity to facilitate the analysis. The boundary of the protein and its cavities is obtained by means of volume ray casting, where the volume is computed in real-time for each frame, therefore allowing the examination of time-dependent data sets. A fast, partial segmentation of the volume is applied to obtain the selected cavity and trace it over time. Domain experts found our method useful when they applied it exemplarily on two trajectories of lipases from Rhizomucor miehei and Candida antarctica. In both data sets cavities near the active center were easily identified and tracked over time until they reached the surface and formed an open substrate channel.
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| 14. |
- Nayahangan, Leizl Joy, et al.
(författare)
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Consensus on technical procedures in radiology to include in simulation-based training for residents : a European-wide needs assessment
- 2021
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Ingår i: European Radiology. - : Springer. - 0938-7994 .- 1432-1084. ; 31, s. 171-180
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To identify and prioritize technical procedures for simulation-based training that should be part of the education of residents in radiology.Methods: This European-wide needs assessment study used a modified Delphi technique to gather consensus from different key education stakeholders in the field. The first round was a brainstorming phase to identify all procedures that a newly specialized radiologist should potentially be able to do. In the second round, each procedure was explored for the need for simulation training; the participants determined frequency, number of radiologists performing the procedure, impact on patient comfort and safety, and feasibility of simulation. The result of this round was sent back to the participants for final evaluation and prioritization.Results: Seventy-one key education stakeholders from 27 European countries agreed to participate and were actively involved in the Delphi process: response rates were 72% and 82% in the second and third round, respectively. From 831 suggested procedures in the first round, these were grouped and categorized into 34 procedures that were pre-prioritized in the second round according to the need for simulation-based training. In the third round, 8 procedures were eliminated resulting in final inclusion of 26 procedures. Ultrasound procedures were highly ranked including basic skills such as probe handling; abdominal ultrasound; and ultrasound of kidneys, retroperitoneum, intestines, and scrotum.Conclusion: The prioritized list of procedures represents a consensus document decided upon by educational stakeholders in radiology across Europe. These procedures are suitable for simulation and should be an integral part of the education of radiologists.
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