591 results on '"Langerak P"'
Search Results
2. Reliability of recovery heart rate variability measurements as part of the Lamberts Submaximal Cycle Test and the relationship with training status in trained to elite cyclists
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Lamberts, Robert P., van Erp, Teun, Javaloyes, Alejandro, Eken, Maaike M., Langerak, Nelleke G., and Tam, Nicholas
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- 2024
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3. ACVIM consensus statement guidelines on diagnosing and distinguishing low-grade neoplastic from inflammatory lymphocytic chronic enteropathies in cats.
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Marsilio, Sina, Freiche, Valerie, Johnson, Eric, Leo, Chiara, Langerak, Anton W, Peters, Iain, and Ackermann, Mark R
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Lymphocytes ,Animals ,Cats ,Humans ,Enteritis ,Inflammatory Bowel Diseases ,Cat Diseases ,Prospective Studies ,T-cell ,alimentary ,cat ,chronic diarrhea ,endoscopy ,gastrointestinal ,histology ,immunohistochemistry ,inflammatory bowel disease ,lymphoma ,lymphoplasmacytic enteritis ,lymphoproliferative disorders ,Clinical Research ,Digestive Diseases ,4.1 Discovery and preclinical testing of markers and technologies ,Detection ,screening and diagnosis ,Veterinary Sciences - Abstract
BackgroundLymphoplasmacytic enteritis (LPE) and low-grade intestinal T cell lymphoma (LGITL) are common diseases in older cats, but their diagnosis and differentiation remain challenging.ObjectivesTo summarize the current literature on etiopathogenesis and diagnosis of LPE and LGITL in cats and provide guidance on the differentiation between LPE and LGITL in cats. To provide statements established using evidence-based approaches or where such evidence is lacking, statements based on consensus of experts in the field.AnimalsNone.MethodsA panel of 6 experts in the field (2 internists, 1 radiologist, 1 anatomic pathologist, 1 clonality expert, 1 oncologist) with the support of a human medical immunologist, was formed to assess and summarize evidence in the peer-reviewed literature and complement it with consensus recommendations.ResultsDespite increasing interest on the topic for clinicians and pathologists, few prospective studies were available, and interpretation of the pertinent literature often was challenging because of the heterogeneity of the cases. Most recommendations by the panel were supported by a moderate or low level of evidence. Several understudied areas were identified, including cellular markers using immunohistochemistry, genomics, and transcriptomic studies.Conclusions and clinical importanceTo date, no single diagnostic criterion or known biomarker reliably differentiates inflammatory lesions from neoplastic lymphoproliferations in the intestinal tract of cats and a diagnosis currently is established by integrating all available clinical and diagnostic data. Histopathology remains the mainstay to better differentiate LPE from LGITL in cats with chronic enteropathy.
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- 2023
4. Utilizing Synthetic Data in Supervised Learning for Robust 5-DoF Magnetic Marker Localization
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Wu, Mengfan, Langerak, Thomas, Hilliges, Otmar, and Zarate, Juan
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Computer Science - Machine Learning - Abstract
Tracking passive magnetic markers plays a vital role in advancing healthcare and robotics, offering the potential to significantly improve the precision and efficiency of systems. This technology is key to developing smarter, more responsive tools and devices, such as enhanced surgical instruments, precise diagnostic tools, and robots with improved environmental interaction capabilities. However, traditionally, the tracking of magnetic markers is computationally expensive due to the requirement for iterative optimization procedures. Moreover, these methods depend on the magnetic dipole model for their optimization function, which can yield imprecise outcomes due to the model's significant inaccuracies when dealing with short distances between non-spherical magnet and sensor.Our paper introduces a novel approach that leverages neural networks to bypass these limitations, directly inferring the marker's position and orientation to accurately determine the magnet's 5 DoF in a single step without initial estimation. Although our method demands an extensive supervised training phase, we mitigate this by introducing a computationally more efficient method to generate synthetic, yet realistic data using Finite Element Methods simulations. The benefits of fast and accurate inference significantly outweigh the offline training preparation. In our evaluation, we use different cylindrical magnets, tracked with a square array of 16 sensors. We perform the sensors' reading and position inference on a portable, neural networks-oriented single-board computer, ensuring a compact setup. We benchmark our prototype against vision-based ground truth data, achieving a mean positional error of 4 mm and an orientation error of 8 degrees within a 0.2x0.2x0.15 m working volume. These results showcase our prototype's ability to balance accuracy and compactness effectively in tracking 5 DoF.
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- 2022
5. MARLUI: Multi-Agent Reinforcement Learning for Adaptive UIs
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Langerak, Thomas, Christen, Sammy, Albaba, Mert, Gebhardt, Christoph, and Hilliges, Otmar
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Computer Science - Human-Computer Interaction - Abstract
Adaptive user interfaces (UIs) automatically change an interface to better support users' tasks. Recently, machine learning techniques have enabled the transition to more powerful and complex adaptive UIs. However, a core challenge for adaptive user interfaces is the reliance on high-quality user data that has to be collected offline for each task. We formulate UI adaptation as a multi-agent reinforcement learning problem to overcome this challenge. In our formulation, a user agent mimics a real user and learns to interact with a UI. Simultaneously, an interface agent learns UI adaptations to maximize the user agent's performance. The interface agent learns the task structure from the user agent's behavior and, based on that, can support the user agent in completing its task. Our method produces adaptation policies that are learned in simulation only and, therefore, does not need real user data. Our experiments show that learned policies generalize to real users and achieve on par performance with data-driven supervised learning baselines.
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- 2022
6. Prognosis of IGLV3-21R110 chronic lymphocytic leukemia after chemotherapy-based treatment in a real-world analysis
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Hengeveld, Paul J., Veelken, Hendrik, van Bergen, Cornelis A. M., Quinten, Edwin, Vervoordeldonk, Mischa Y. L., Ismailzada, Wahija, Barendse, Rob S., Dubois, Julie M. N., van Oers, Marinus H. J., Geisler, Christian H., Kater, Arnon P., Westerweel, Peter E., Langerak, Anton W., and Levin, Mark-David
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- 2023
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7. Updates of the ERIC recommendations on how to report the results from immunoglobulin heavy variable gene analysis in chronic lymphocytic leukemia
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Chatzikonstantinou, Thomas, Agathangelidis, Andreas, Chatzidimitriou, Anastasia, Tresoldi, Cristina, Davis, Zadie, Giudicelli, Véronique, Kossida, Sofia, Belessi, Chrysoula, Rosenquist, Richard, Ghia, Paolo, Langerak, Anton W., Davi, Frédéric, and Stamatopoulos, Kostas
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- 2024
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8. Early-stage measurable residual disease dynamics and IGHV repertoire reconstitution during venetoclax and obinutuzumab treatment in chronic lymphocytic leukemia
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Hengeveld, P. J., Schilperoord-Vermeulen, J., van der Klift, M. Y., Dubois, J. M. N., Kolijn, P. M., Kavelaars, F. G., Rijken, M., Dobber, J. A., Nasserinejad, K., Kersting, S., Westerweel, P. E., Kater, A. P., Langerak, A. W., and Levin, M-D.
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- 2023
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9. Risk of second primary malignancies in patients with chronic lymphocytic leukemia: a population-based study in the Netherlands, 1989-2019
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van der Straten, Lina, Levin, Mark-David, Dinnessen, Manette A. W., Visser, Otto, Posthuma, Eduardus F. M., Doorduijn, Jeanette K., Langerak, Anton W., Kater, Arnon P., and Dinmohamed, Avinash G.
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- 2023
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10. Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia
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Kaufman, Matthew, Yan, Xiao-Jie, Li, Wentian, Ghia, Emanuela M, Langerak, Anton W, Rassenti, Laura Z, Belessi, Chrysoula, Kay, Neil E, Davi, Frederic, Byrd, John C, Pospisilova, Sarka, Brown, Jennifer R, Catherwood, Mark, Davis, Zadie, Oscier, David, Montillo, Marco, Trentin, Livio, Rosenquist, Richard, Ghia, Paolo, Barrientos, Jacqueline C, Kolitz, Jonathan E, Allen, Steven L, R., Kanti, Stamatopoulos, Kostas, Kipps, Thomas J, Neuberg, Donna, and Chiorazzi, Nicholas
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Lymphoma ,Cancer ,Hematology ,Lymphatic Research ,Rare Diseases ,CLL ,chronic lymphocytic leukemia ,immunoglobulin variable domain ,prognosis ,somatic mutations ,Oncology and Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
Patients with CLL with mutated IGHV genes (M-CLL) have better outcomes than patients with unmutated IGHVs (U-CLL). Since U-CLL usually express immunoglobulins (IGs) that are more autoreactive and more effectively transduce signals to leukemic B cells, B-cell receptor (BCR) signaling is likely at the heart of the worse outcomes of CLL cases without/few IGHV mutations. A corollary of this conclusion is that M-CLL follow less aggressive clinical courses because somatic IGHV mutations have altered BCR structures and no longer bind stimulatory (auto)antigens and so cannot deliver trophic signals to leukemic B cells. However, the latter assumption has not been confirmed in a large patient cohort. We tried to address the latter by measuring the relative numbers of replacement (R) mutations that lead to non-conservative amino acid changes (Rnc) to the combined numbers of conservative (Rc) and silent (S) amino acid R mutations that likely do not or cannot change amino acids, "(S+Rc) to Rnc IGHV mutation ratio". When comparing time-to-first-treatment (TTFT) of patients with (S+Rc)/Rnc ≤ 1 and >1, TTFTs were similar, even after matching groups for equal numbers of samples and identical numbers of mutations per sample. Thus, BCR structural change might not be the main reason for better outcomes for M-CLL. Since the total number of IGHV mutations associated better with longer TTFT, better clinical courses appear due to the biologic state of a B cell having undergone many stimulatory events leading to IGHV mutations. Analyses of larger patient cohorts will be needed to definitively answer this question.
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- 2022
11. Parental Experiences with Early Identification and Initial Care for Their Child with Autism: Tailored Improvement Strategies
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Snijder, Michelle I. J., Langerak, Ilse P. C., Kaijadoe, Shireen P. T., Buruma, Marrit E., Verschuur, Rianne, Dietz, Claudine, Buitelaar, Jan K., and Oosterling, Iris J.
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Whereas it is well documented how parents experience the diagnostic process of their child with autism spectrum disorder (ASD), less is known about parental experiences with the course of the early identification process and first steps in receiving care for their child with ASD symptoms. This mixed-method study investigated these experiences as well as barriers and improvement strategies regarding early detection in the Netherlands. A parental survey (N = 45) showed that, on average, initial concerns started at 22 months. A focus group (N = 10) revealed multiple barriers and proposed strategies of improvement in three domains: "Knowledge and Expertise", "Attention to Parental Needs" and "System and Organization". Strategies to improve early identification will be discussed based on parental perspectives and professional perspectives.
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- 2022
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12. Clonotype definitions for immunogenetic studies: proposals from the EuroClonality NGS Working Group
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Sofou, Electra, Vlachonikola, Elisavet, Zaragoza-Infante, Laura, Brüggemann, Monika, Darzentas, Nikos, Groenen, Patricia J. T. A., Hummel, Michael, Macintyre, Elizabeth A., Psomopoulos, Fotis, Davi, Frederic, Langerak, Anton W., and Stamatopoulos, Kostas
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- 2023
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13. Early-stage measurable residual disease dynamics and IGHV repertoire reconstitution during venetoclax and obinutuzumab treatment in chronic lymphocytic leukemia
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P. J. Hengeveld, J. Schilperoord-Vermeulen, M. Y. van der Klift, J. M. N. Dubois, P. M. Kolijn, F. G. Kavelaars, M. Rijken, J. A. Dobber, K. Nasserinejad, S. Kersting, P. E. Westerweel, A. P. Kater, A. W. Langerak, and M-D. Levin
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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14. Combined Intuition and Rationality Increases Software Feature Novelty for Female Software Designers
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Pretorius, Carianne, Razavian, Maryam, Eling, Katrin, and Langerak, Fred
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Computer Science - Software Engineering ,D.2.14 - Abstract
Overcoming society's complex problems requires novel solutions. Applying different cognitive styles can promote novelty when designing software aimed at these problems. Through an experiment with 80 software design practitioners, we found that female practitioners who had a preference for more than one cognitive style (intuition and rationality) produced the most novel software features of all participants., Comment: IEEE Software
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- 2020
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15. ACVIM consensus statement guidelines on diagnosing and distinguishing low‐grade neoplastic from inflammatory lymphocytic chronic enteropathies in cats
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Sina Marsilio, Valerie Freiche, Eric Johnson, Chiara Leo, Anton W. Langerak, Iain Peters, and Mark R. Ackermann
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alimentary ,cat ,chronic diarrhea ,endoscopy ,gastrointestinal ,histology ,Veterinary medicine ,SF600-1100 - Abstract
Abstract Background Lymphoplasmacytic enteritis (LPE) and low‐grade intestinal T cell lymphoma (LGITL) are common diseases in older cats, but their diagnosis and differentiation remain challenging. Objectives To summarize the current literature on etiopathogenesis and diagnosis of LPE and LGITL in cats and provide guidance on the differentiation between LPE and LGITL in cats. To provide statements established using evidence‐based approaches or where such evidence is lacking, statements based on consensus of experts in the field. Animals None. Methods A panel of 6 experts in the field (2 internists, 1 radiologist, 1 anatomic pathologist, 1 clonality expert, 1 oncologist) with the support of a human medical immunologist, was formed to assess and summarize evidence in the peer‐reviewed literature and complement it with consensus recommendations. Results Despite increasing interest on the topic for clinicians and pathologists, few prospective studies were available, and interpretation of the pertinent literature often was challenging because of the heterogeneity of the cases. Most recommendations by the panel were supported by a moderate or low level of evidence. Several understudied areas were identified, including cellular markers using immunohistochemistry, genomics, and transcriptomic studies. Conclusions and Clinical Importance To date, no single diagnostic criterion or known biomarker reliably differentiates inflammatory lesions from neoplastic lymphoproliferations in the intestinal tract of cats and a diagnosis currently is established by integrating all available clinical and diagnostic data. Histopathology remains the mainstay to better differentiate LPE from LGITL in cats with chronic enteropathy.
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- 2023
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16. High-throughput Proteomics Identifies THEMIS2 as Independent Biomarker of Treatment-free Survival in Untreated CLL
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Paul J. Hengeveld, P. Martijn Kolijn, Jeroen A.A. Demmers, Wouter Doff, Julie M.N. Dubois, Melissa Rijken, Jorn L.J.C. Assmann, Lina van der Straten, Henk Jan Boiten, Kirsten J. Gussinklo, Peter J.M. Valk, Laura M. Faber, Peter E. Westerweel, Arnon P. Kater, Mark-David Levin, and Anton W. Langerak
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
It remains challenging in chronic lymphocytic leukemia (CLL) to distinguish between patients with favorable and unfavorable time-to-first treatment (TTFT). Additionally, the downstream protein correlates of well-known molecular features of CLL are not always clear. To address this, we selected 40 CLL patients with TTFT ≤24 months and compared their B cell intracellular protein expression with 40 age- and sex-matched CLL patients with TTFT >24 months using mass spectrometry. In total, 3268 proteins were quantified in the cohort. Immunoglobulin heavy-chain variable (IGHV) mutational status and trisomy 12 were most impactful on the CLL proteome. Comparing cases to controls, 5 proteins were significantly upregulated, whereas 3 proteins were significantly downregulated. Of these, only THEMIS2, a signaling protein acting downstream of the B cell receptor, was significantly associated with TTFT, independently of IGHV and TP53 mutational status (hazard ratio, 2.49 [95% confidence interval, 1.62-3.84]; P < 0.001). This association was validated on the mRNA and protein level by quantitative polymerase chain reaction and ELISA, respectively. Analysis of 2 independently generated RNA sequencing and mass spectrometry datasets confirmed the association between THEMIS2 expression and clinical outcome. In conclusion, we present a comprehensive characterization of the proteome of untreated CLL and identify THEMIS2 expression as a putative biomarker of TTFT.
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- 2023
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17. DLTPy: Deep Learning Type Inference of Python Function Signatures using Natural Language Context
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Boone, Casper, de Bruin, Niels, Langerak, Arjan, and Stelmach, Fabian
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Computer Science - Software Engineering ,Computer Science - Machine Learning - Abstract
Due to the rise of machine learning, Python is an increasingly popular programming language. Python, however, is dynamically typed. Dynamic typing has shown to have drawbacks when a project grows, while at the same time it improves developer productivity. To have the benefits of static typing, combined with high developer productivity, types need to be inferred. In this paper, we present DLTPy: a deep learning type inference solution for the prediction of types in function signatures based on the natural language context (identifier names, comments and return expressions) of a function. We found that DLTPy is effective and has a top-3 F1-score of 91.6%. This means that in most of the cases the correct type is within the top-3 predictions. We conclude that natural language contained in comments and return expressions are beneficial to predicting types more accurately. DLTPy does not significantly outperform or underperform the previous work NL2Type for Javascript, but does show that similar prediction is possible for Python., Comment: 10 pages, 8 figures The source code of DLTPy is publicly available at https://github.com/casperboone/dltpy/
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- 2019
18. Microscope-Cockpit: Python-based bespoke microscopy for bio-medical science
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Phillips, Mick A, Pinto, David Miguel Susano, Hall, Nicholas, Mateos-Langerak, Julio, Parton, Richard M, Titlow, Josh, Stoychev, Danail V, Parks, Thomas, Pinto, Tiago Susano, Sedat, John W, Booth, Martin J, Davis, Ilan, and Dobbie, Ian M
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Biomedical and Clinical Sciences ,Health Sciences ,Generic health relevance ,Adaptive optics ,Artificial Intelligence ,Bespoke microscope ,Free and open source software ,Imaging ,Machine Learning ,Microscope hardware device control ,Microscope-Python ,Super resolution microscopy ,Biomedical and clinical sciences ,Health sciences - Abstract
We have developed "Microscope-Cockpit" (Cockpit), a highly adaptable open source user-friendly Python-based Graphical User Interface (GUI) environment for precision control of both simple and elaborate bespoke microscope systems. The user environment allows next-generation near instantaneous navigation of the entire slide landscape for efficient selection of specimens of interest and automated acquisition without the use of eyepieces. Cockpit uses "Python-Microscope" (Microscope) for high-performance coordinated control of a wide range of hardware devices using open source software. Microscope also controls complex hardware devices such as deformable mirrors for aberration correction and spatial light modulators for structured illumination via abstracted device models. We demonstrate the advantages of the Cockpit platform using several bespoke microscopes, including a simple widefield system and a complex system with adaptive optics and structured illumination. A key strength of Cockpit is its use of Python, which means that any microscope built with Cockpit is ready for future customisation by simply adding new libraries, for example machine learning algorithms to enable automated microscopy decision making while imaging.
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- 2021
19. Risk of second primary malignancies in patients with chronic lymphocytic leukemia: a population-based study in the Netherlands, 1989-2019
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Lina van der Straten, Mark-David Levin, Manette A. W. Dinnessen, Otto Visser, Eduardus F. M. Posthuma, Jeanette K. Doorduijn, Anton W. Langerak, Arnon P. Kater, and Avinash G. Dinmohamed
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract The longevity of patients with chronic lymphocytic leukemia (CLL) has improved progressively over the past decades, making it essential to understand long-term health outcomes, such as second primary malignancies (SPMs). Therefore, this nationwide, population-based study assessed the risk of SPM development in CLL patients diagnosed during 1989-2019 in the Netherlands compared to the expected number of malignancies in an age-, sex-, and period-matched group from the general Dutch population. In 24,815 CLL patients followed for 162,698.49 person-years, 4369 SPMs were diagnosed with a standardized incidence ratio (SIR) of 1.63 (95% confidence interval [CI] 1.59–1.68). This elevated risk was observed for solid (SIR, 1.67; 95% CI, 1.65–1.75) and hematological SPMs (SIR 1.42; 95% CI, 1.24–1.62). The highest risk for SPMs was noted beyond five years post-diagnosis (SIR, 1.70; 95% CI, 1.62–1.77), for male individuals (SIR, 1.70; 95% CI, 1.64–1.77), and patients aged 18–69 years (SIR, 1.92; 95% CI, 1.79–2.05). The risk of SPMs was higher in CLL patients who received anti-neoplastic therapy (SIR, 2.12; 95% CI, 1.96–2.28), as compared with those who did not (SIR, 1.58; 95% CI, 1.53–1.63). Routine surveillance activities and tailored interventions to counteract the increased morbidity and excess mortality associated with SPMs are essential for improving long-term outcomes in CLL patients.
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- 2023
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20. Association of Altered Plasma Lipidome with Disease Severity in COVID-19 Patients
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Zhengzheng Zhang, Naama Karu, Alida Kindt, Madhulika Singh, Lieke Lamont, Adriaan J. van Gammeren, Anton A. M. Ermens, Amy C. Harms, Lutzen Portengen, Roel C. H. Vermeulen, Willem A. Dik, Anton W. Langerak, Vincent H. J. van der Velden, and Thomas Hankemeier
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SARS-CoV-2 ,COVID-19 ,lipidomics ,lipids ,cytokine ,inflammation ,Microbiology ,QR1-502 - Abstract
The severity of COVID-19 is linked to an imbalanced immune response. The dysregulated metabolism of small molecules and bioactive lipids has also been associated with disease severity. To promote understanding of the disease biochemistry and provide targets for intervention, we applied a range of LC-MS platforms to analyze over 100 plasma samples from patients with varying COVID-19 severity and with detailed clinical information on inflammatory responses (>30 immune markers). This is the third publication in a series, and it reports the results of comprehensive lipidome profiling using targeted LC-MS/MS. We identified 1076 lipid features across 25 subclasses, including glycerophospholipids, sterols, glycerolipids, and sphingolipids, among which 531 lipid features were dramatically changed in the plasma of intensive care unit (ICU) patients compared to patients in the ward. Patients in the ICU showed 1.3–57-fold increases in ceramides, (lyso-)glycerophospholipids, diglycerides, triglycerides, and plasmagen phosphoethanolamines, and 1.3–2-fold lower levels of a cyclic lysophosphatidic acid, sphingosine-1-phosphates, sphingomyelins, arachidonic acid-containing phospholipids, lactosylceramide, and cholesterol esters compared to patients in the ward. Specifically, phosphatidylinositols (PIs) showed strong fatty acid saturation-dependent behavior, with saturated fatty acid (SFA)- and monosaturated fatty acid (MUFA)-derived PI decreasing and polystaturated (PUFA)-derived PI increasing. We also found ~4000 significant Spearman correlations between lipids and multiple clinical markers of immune response with |R| ≥ 0.35 and FDR corrected Q < 0.05. Except for lysophosphatidic acid, lysophospholipids were positively associated with the CD4 fraction of T cells, and the cytokines IL-8 and IL-18. In contrast, sphingosine-1-phosphates were negatively correlated with innate immune markers such as CRP and IL-6. Further indications of metabolic changes in moderate COVID-19 disease were demonstrated in recovering ward patients compared to those at the start of hospitalization, where 99 lipid species were altered (6 increased by 30–62%; 93 decreased by 1.3–2.8-fold). Overall, these findings support and expand on early reports that dysregulated lipid metabolism is involved in COVID-19.
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- 2024
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21. A Systematic Review of the Pulmonary Microbiome in Patients with Acute Exacerbation COPD Requiring ICU Admission
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Sjoerd van der Bie, Mark E. Haaksma, Ben Vermin, Hidde van Assema, Eric C. M. van Gorp, Thomas Langerak, Henrik Endeman, Dominic Snijders, Johannes P. C. van den Akker, Marlies A. van Houten, Steven F. L. van Lelyveld, and Marco Goeijenbier
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COPD ,bacterial microbiome ,ICU ,mechanical ventilation ,Medicine - Abstract
Background: Chronic obstructive pulmonary disease (COPD) is a major health concern. Acute exacerbations (AECOPD) may require intensive care unit (ICU) admission and mechanical ventilation. Acute infections and chronic colonization of the respiratory system are known to precipitate AECOPD. Detailed knowledge of the respiratory microbiome could lead to effective treatment and prevention of exacerbations. Objective: The aim of this review is to summarize the available evidence on the respiratory microbiome of patients with a severe AECOPD requiring mechanical ventilation and intensive care admission. Methods: A systematic literature search was conducted to identify the published papers until January 2023. The collected data were then subjected to qualitative analysis. After the first analysis, a secondary focused review of the most recent publications studying the relationship between microbiome and mortality in AECOPD was performed. Results: Out of 120 screened articles six articles were included in this review. Potentially pathogenic microorganisms (PPMs) were identified in 30% to 72% of the patients with community-acquired bacteria, gram-negative enteric bacilli, Stenotrophomonas and Pseudomonas being the most frequently isolated. During hospitalization, 21% of patients experienced colonization by PPMs. Adequate antimicrobial therapy resulted in the eradication of 77% of the identified PPMs. However, 24% of the bacteria displayed multi-drug resistance leading to prolonged or failure of eradication. Conclusion: PPMs are prevalent in a significant proportion of patients experiencing an AECOPD. The most identified PPMs include community-acquired pathogens and gram-negative enteric bacilli. Notably, no differences in mortality or duration of ventilation were observed between patients with and without isolated PPMs. However, the included studies did not investigate the virome of the patients, which may influence the microbiome and the outcome of infection. Therefore, further research is essential to comprehensively investigate the complete microbial and viral composition of the lower respiratory system in COPD patients admitted to the ICU.
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- 2024
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22. P601: GENETIC DRIVERS IN THE NATURAL HISTORY OF CHRONIC LYMPHOCYTIC LEUKEMIA DEVELOPMENT AS EARLY AS 16 YEARS BEFORE DIAGNOSIS
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Pieter Martijn Kolijn, Florentin Späth, Mouhamad Khouja, Paul Hengeveld, Lina van der Straten, Nikos Darzentas, Magnus Hultdin, James D. Mckay, Christiane Pott, Roel C.H. Vermeulen, and Anton Langerak
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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23. P634: EARLY-STAGE MEASURABLE RESIDUAL DISEASE DYNAMICS AND IGHV REPERTOIRE RECONSTITUTION DURING VENETOCLAX AND OBINUTUZUMAB TREATMENT IN CHRONIC LYMPHOCYTIC LEUKEMIA
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Paul Hengeveld, Joyce Schilperoord-Vermeulen, Michèle van der Klift, Julie Dubois, Pieter Martijn Kolijn, François Kavelaars, Melissa Rijken, Johan Dobber, Kazem Nasserinejad, Sabina Kersting, Peter Westerweel, Arnon Kater, Anton Langerak, and Mark-David Levin
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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24. Editorial: The promise of immunogenetics for precision oncology
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Elisavet Vlachonikola, Anton W. Langerak, Richard Rosenquist, and Anastasia Chatzidimitriou
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immunogenetics ,precision oncology ,immune receptors ,tumor microenvironment ,next generation (deep) sequencing (NGS) ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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25. Antibodies against angiotensin II receptor type 1 and endothelin A receptor are increased in COVID-19 patients
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Jelle R. Miedema, Matthijs L. Janssen, Jan von der Thüsen, Henrik Endeman, Anton W. Langerak, Merel E. Hellemons, Els van Nood, Bas W. A. Peeters, Sara J. Baart, and Marco W. J. Schreurs
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COVID-19 ,endothelin receptor type A antibody ,angiotensin II receptor type 1 antibody ,antinuclear antibody (ANA) ,autoimmunity ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundIncreased titers of autoantibodies targeting the G-protein-coupled receptors angiotensin II type 1 receptor (AT1R) and endotelin-1 type A receptor (ETAR) are associated with severe coronavirus disease 2019 (COVID-19) infection. The aim of this study was to determine whether 1) these antibodies are specifically related to COVID-19 disease pathogenesis or increased during any severe respiratory illness, 2) if they are formed during illness, and 3) if they correlate with inflammatory markers or long-term symptoms.MethodsAntibodies against AT1R, ETAR, and antinuclear antibodies (ANAs) were measured in n=40 prospectively enrolled COVID-19 patients and n=207 COVID-19 patients included in a biobank. Clinical and laboratory findings were prospectively and retrospectively assessed in both cohorts, and results were combined for analysis. The presence of auto-antibodies against AT1R or ETAR in peripheral blood was compared between hospitalized patients with COVID-19 and controls (n=39). Additionally, AT1R and ETAR titers were compared between patients with an unfavorable disease course, defined as intensive care admission and/or death during hospital admission (n=121), to those with a favorable disease course (n=126). A subset of intubated patients with severe COVID-19 were compared to intubated patients with acute respiratory distress syndrome (ARDS) due to any other cause.ResultsSignificantly increased AT1R and ETAR antibody titers were found in COVID-19 patients compared to controls, while titers were equal between favorable and unfavorable COVID-19 disease course groups. On ICU, intubated patients with COVID-19 had significantly increased AT1R and ETAR titers compared to patients with ARDS due to any other cause. The titers did not correlate with baseline inflammatory markers during admission or with diffusion capacity, cognitive impairment, or fatigue measured at 3 months follow-up.ConclusionsIn patients hospitalized for COVID-19, antibodies against AT1R and ETAR are increased compared to controls and patients with ARDS due to other causes than COVID-19. The baseline antibody titers do not correlate with inflammatory markers or long-term symptoms in this study.
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- 2023
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26. Context-dependent T-cell Receptor Gene Repertoire Profiles in Proliferations of T Large Granular Lymphocytes
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Jorn L.J.C. Assmann, Elisavet Vlachonikola, Pieter M. Kolijn, Andreas Agathangelidis, Nikolaos Pechlivanis, Apostolia Papalexandri, Kostas Stamatopoulos, Anastasia Chatzidimitriou, and Anton W. Langerak
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
T cell large granular lymphocyte (T-LGL) lymphoproliferations constitute a disease spectrum ranging from poly/oligo to monoclonal. Boundaries within this spectrum of proliferations are not well established. T-LGL lymphoproliferations co-occur with a wide variety of other diseases ranging from autoimmune disorders, solid tumors, hematological malignancies, post solid organ, and hematopoietic stem cell transplantation, and can therefore arise as a consequence of a wide variety of antigenic triggers. Persistence of a dominant malignant T-LGL clone is established through continuous STAT3 activation. Using next-generation sequencing, we profiled a cohort of 27 well-established patients with T-LGL lymphoproliferations, aiming to identify the subclonal architecture of the T-cell receptor beta (TRB) chain gene repertoire. Moreover, we searched for associations between TRB gene repertoire patterns and clinical manifestations, with the ultimate objective of discriminating between T-LGL lymphoproliferations developing in different clinical contexts and/or displaying distinct clinical presentation. Altogether, our data demonstrates that the TRB gene repertoire of patients with T-LGL lymphoproliferations is context-dependent, displaying distinct clonal architectures in different settings. Our results also highlight that there are monoclonal T-LGL cells with or without STAT3 mutations that cause symptoms such as neutropenia on one end of a spectrum and reactive oligoclonal T-LGL lymphoproliferations on the other. Longitudinal analysis revealed temporal clonal dynamics and showed that T-LGL cells might arise as an epiphenomenon when co-occurring with other malignancies, possibly reactive toward tumor antigens.
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- 2023
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27. Dynamic Drawing Guidance via Electromagnetic Haptic Feedback
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Langerak, Thomas, Zarate, Juan, Vechev, Velko, Panozzo, Daniele, and Hilliges, Otmar
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Computer Science - Human-Computer Interaction - Abstract
We propose a system to deliver dynamic guidance in drawing, sketching and handwriting tasks via an electromagnet moving underneath a high refresh rate pressure sensitive tablet. The system allows the user to move the pen at their own pace and style and does not take away control. The system continously and iteratively measures the pen motion and adjusts magnet position and power according to the user input in real-time via a receding horizon optimal control formulation. The optimization is based on a novel approximate electromagnet model that is fast enough for use in real-time methods, yet provides very good fit to experimental data. Using a closed-loop time-free approach allows for error-correcting behavior, gently pulling the user back to the desired trajectory rather than pushing or pulling the pen to a continuously advancing setpoint. Our experimental results show that the system can control the pen position with a very low dispersion of 2.8mm (+/-0.8mm). An initial user study indicates that it significantly increases accuracy of users drawing a variety of shapes and that this improvement increases with complexity of the shape.
- Published
- 2019
28. Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: the 2022 update of the recommendations by ERIC, the European Research Initiative on CLL
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Agathangelidis, Andreas, Chatzidimitriou, Anastasia, Chatzikonstantinou, Thomas, Tresoldi, Cristina, Davis, Zadie, Giudicelli, Véronique, Kossida, Sofia, Belessi, Chrysoula, Rosenquist, Richard, Ghia, Paolo, Langerak, Anton W., Davi, Frédéric, and Stamatopoulos, Kostas
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- 2022
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29. T and NK Cells in IL2RG-Deficient Patient 50 Years After Hematopoietic Stem Cell Transplantation
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Melsen, Janine E., van Ostaijen-ten Dam, Monique M., van den Akker, Erik B., Welters, Marij J. P., Heezen, Kim C., Pico-Knijnenburg, Ingrid, Kolijn, P. Martijn, Bredius, Robbert G. M., van Doorn, Remco, Langerak, Anton W., Schilham, Marco W., and Lankester, Arjan C.
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- 2022
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30. Parental Experiences with Early Identification and Initial Care for their Child with Autism: Tailored Improvement Strategies
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Snijder, Michelle I. J., Langerak, Ilse P. C., Kaijadoe, Shireen P. T., Buruma, Marrit E., Verschuur, Rianne, Dietz, Claudine, Buitelaar, Jan K., and Oosterling, Iris J.
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- 2022
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31. Clinicobiological characteristics and treatment efficacy of novel agents in chronic lymphocytic leukemia with IGLV3-21R110
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Hengeveld, Paul J., Ertem, Y. Emre, Dubois, Julie M. N., Mellink, Clemens H. M., van der Kevie-Kersemaekers, Anne-Marie, Evers, Ludo M., Heezen, Kim, Kolijn, P. Martijn, Mook, Olaf R. F., Motazacker, M. Mahdi, Nasserinejad, Kazem, Kersting, S., Westerweel, Peter E., Niemann, Carsten U., Kater, Arnon P., Langerak, Anton W., and Levin, Mark-David
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- 2022
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32. Single-Cell Genomics Reveals the Divergent Mitochondrial Genomes of Retaria (Foraminifera and Radiolaria)
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Jan-Niklas Macher, Nicole L. Coots, Yu-Ping Poh, Elsa B. Girard, Anouk Langerak, Sergio A. Muñoz-Gómez, Savar D. Sinha, Dagmar Jirsová, Rutger Vos, Richard Wissels, Gillian H. Gile, Willem Renema, and Jeremy G. Wideman
- Subjects
Foraminifera ,mitochondrial evolution ,mitochondrial genome ,Radiolaria ,Retaria ,Rhizaria ,Microbiology ,QR1-502 - Abstract
ABSTRACT Mitochondria originated from an ancient bacterial endosymbiont that underwent reductive evolution by gene loss and endosymbiont gene transfer to the nuclear genome. The diversity of mitochondrial genomes published to date has revealed that gene loss and transfer processes are ongoing in many lineages. Most well-studied eukaryotic lineages are represented in mitochondrial genome databases, except for the superphylum Retaria—the lineage comprising Foraminifera and Radiolaria. Using single-cell approaches, we determined two complete mitochondrial genomes of Foraminifera and two nearly complete mitochondrial genomes of radiolarians. We report the complete coding content of an additional 14 foram species. We show that foraminiferan and radiolarian mitochondrial genomes contain a nearly fully overlapping but reduced mitochondrial gene complement compared to other sequenced rhizarians. In contrast to animals and fungi, many protists encode a diverse set of proteins on their mitochondrial genomes, including several ribosomal genes; however, some aerobic eukaryotic lineages (euglenids, myzozoans, and chlamydomonas-like algae) have reduced mitochondrial gene content and lack all ribosomal genes. Similar to these reduced outliers, we show that retarian mitochondrial genomes lack ribosomal protein and tRNA genes, contain truncated and divergent small and large rRNA genes, and contain only 14 or 15 protein-coding genes, including nad1, -3, -4, -4L, -5, and -7, cob, cox1, -2, and -3, and atp1, -6, and -9, with forams and radiolarians additionally carrying nad2 and nad6, respectively. In radiolarian mitogenomes, a noncanonical genetic code was identified in which all three stop codons encode amino acids. Collectively, these results add to our understanding of mitochondrial genome evolution and fill in one of the last major gaps in mitochondrial sequence databases. IMPORTANCE We present the reduced mitochondrial genomes of Retaria, the rhizarian lineage comprising the phyla Foraminifera and Radiolaria. By applying single-cell genomic approaches, we found that foraminiferan and radiolarian mitochondrial genomes contain an overlapping but reduced mitochondrial gene complement compared to other sequenced rhizarians. An alternative genetic code was identified in radiolarian mitogenomes in which all three stop codons encode amino acids. Collectively, these results shed light on the divergent nature of the mitochondrial genomes from an ecologically important group, warranting further questions into the biological underpinnings of gene content variability and genetic code variation between mitochondrial genomes.
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- 2023
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33. Recent revelations and future directions using single-cell technologies in chronic lymphocytic leukemia
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Blaž Oder, Anastasia Chatzidimitriou, Anton W. Langerak, Richard Rosenquist, and Cecilia Österholm
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single-cell sequencing ,genomics ,epigenomics ,transcriptomics ,immunogenetics ,tumor microenvironment ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Chronic lymphocytic leukemia (CLL) is a clinically and biologically heterogeneous disease with varying outcomes. In the last decade, the application of next-generation sequencing technologies has allowed extensive mapping of disease-specific genomic, epigenomic, immunogenetic, and transcriptomic signatures linked to CLL pathogenesis. These technologies have improved our understanding of the impact of tumor heterogeneity and evolution on disease outcome, although they have mostly been performed on bulk preparations of nucleic acids. As a further development, new technologies have emerged in recent years that allow high-resolution mapping at the single-cell level. These include single-cell RNA sequencing for assessment of the transcriptome, both of leukemic and non-malignant cells in the tumor microenvironment; immunogenetic profiling of B and T cell receptor rearrangements; single-cell sequencing methods for investigation of methylation and chromatin accessibility across the genome; and targeted single-cell DNA sequencing for analysis of copy-number alterations and single nucleotide variants. In addition, concomitant profiling of cellular subpopulations, based on protein expression, can also be obtained by various antibody-based approaches. In this review, we discuss different single-cell sequencing technologies and how they have been applied so far to study CLL onset and progression, also in response to treatment. This latter aspect is particularly relevant considering that we are moving away from chemoimmunotherapy to targeted therapies, with a potentially distinct impact on clonal dynamics. We also discuss new possibilities, such as integrative multi-omics analysis, as well as inherent limitations of the different single-cell technologies, from sample preparation to data interpretation using available bioinformatic pipelines. Finally, we discuss future directions in this rapidly evolving field.
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- 2023
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34. Effects of Adaptations in an Interdisciplinary Follow-Up Clinic for People with Spinal Cord Injury in the Chronic Phase: A Prospective Cohort Study
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Julia Tijsse Klasen, Tijn van Diemen, Nelleke G. Langerak, and Ilse J. W. van Nes
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spinal cord injuries ,follow-up care ,ambulatory care ,prevention ,interdisciplinary ,secondary health conditions ,Medicine - Abstract
People with spinal cord injury (SCI) often experience secondary health conditions (SHCs), which are addressed during interdisciplinary follow-up clinics. We adapted the design of our clinic, by introducing a questionnaire concerning functioning and SHCs, additional measurements of blood pressure and saturation, and participants were seen by either a specialized nurse or rehabilitation physician. In this study, we investigated the effects of these adaptations and the experienced satisfaction of the participants. The results showed an increased number of recommendations in the adapted design, compared to the initial design. Further, the nature of the recommendations shifted from somatic issues to recommendations regarding psychosocial functioning and regarding (the use of) devices. The added measurements revealed an average high systolic blood pressure, which led to more referrals to the general practitioner. The clinical weight and pulmonary functions stayed stable over time. The current adaptations in design expanded and optimized the number and nature of recommendations regarding SHCs to participants. The questionnaire helps the participant to prepare for the clinic and the professionals to tailor their recommendations, resulting in highly satisfied participants.
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- 2023
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35. miR-181a is a novel player in the STAT3-mediated survival network of TCRαβ+ CD8+ T large granular lymphocyte leukemia
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Assmann, Jorn L. J. C., Leon, Leticia G., Stavast, Christiaan J., van den Bogaerdt, Sanne E., Schilperoord-Vermeulen, Joyce, Sandberg, Yorick, Bellido, Mar, Erkeland, Stefan J., Feith, David J., Loughran Jr, Thomas P., and Langerak, Anton W.
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- 2022
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36. Long-term trends in the loss in expectation of life after a diagnosis of chronic lymphocytic leukemia: a population-based study in the Netherlands, 1989–2018
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Lina van der Straten, Carolien C. H. M. Maas, Mark-David Levin, Otto Visser, Eduardus F. M. Posthuma, Jeanette K. Doorduijn, Anton W. Langerak, Arnon P. Kater, and Avinash G. Dinmohamed
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2022
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37. Extranodal marginal zone lymphoma clonotypes are detectable prior to eMZL diagnosis in tissue biopsies and peripheral blood of Sjögren’s syndrome patients through immunogenetics
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P. Martijn Kolijn, Erika Huijser, M. Javad Wahadat, Cornelia G. van Helden-Meeuwsen, Paul L. A. van Daele, Zana Brkic, Jos Rijntjes, Konnie M. Hebeda, Patricia J. T. A. Groenen, Marjan A. Versnel, Rogier M. Thurlings, and Anton W. Langerak
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immunogenetics ,Sjögren’s syndrome ,early detection ,lymphoma ,lymphomagenesis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
IntroductionActivated B cells play a key role in the pathogenesis of primary Sjögren’s syndrome (pSS) through the production of autoantibodies and the development of ectopic germinal centers in the salivary glands and other affected sites. Around 5-10% of pSS patients develop B-cell lymphoma, usually extranodal marginal zone lymphomas (eMZL) of the mucosa-associated lymphoid tissue (MALT). The aim of the current study is to investigate if the eMZL clonotype is detectable in prediagnostic blood and tissue biopsies of pSS patients.Methods/ResultsWe studied prediagnostic tissue biopsies of three pSS patients diagnosed with eMZL and four pSS controls through immunoglobulin (IG) gene repertoire sequencing. In all three cases, we observed the eMZL clonotype in prediagnostic tissue biopsies. Among controls, we observed transient elevation of clonotypes in two pSS patients. To evaluate if eMZL clonotypes may also be detected in the circulation, we sequenced a peripheral blood mononuclear cell (PBMC) sample drawn at eMZL diagnosis and two years prior to eMZL relapse in two pSS patients. The eMZL clonotype was detected in the peripheral blood prior to diagnosis in both cases. Next, we selected three pSS patients who developed eMZL lymphoma and five additional pSS patients who remained lymphoma-free. We sequenced the IG heavy chain (IGH) gene repertoire in PBMC samples taken a median of three years before eMZL diagnosis. In two out of three eMZL patients, the dominant clonotype in the prediagnostic PBMC samples matched the eMZL clonotype in the diagnostic biopsy. The eMZL clonotypes observed consisted of stereotypic IGHV gene combinations (IGHV1-69/IGHJ4 and IGHV4-59/IGHJ5) associated with rheumatoid factor activity, a previously reported feature of eMZL in pSS.DiscussionIn conclusion, our results indicate that eMZL clonotypes in pSS patients are detectable prior to overt eMZL diagnosis in both tissue biopsies and peripheral blood through immunogenetic sequencing, paving the way for the development of improved methods of early detection of eMZL.
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- 2023
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38. Binderless SAPO-34 beads for selective CO2 adsorption
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Dina G. Boer, Dennis Čiliak, Jort Langerak, Benny Bakker, and Paolo P. Pescarmona
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CO2 adsorption ,Silicoaluminophosphate (SAPO) ,Biogas upgrading ,hierarchical porosity ,working capacity ,Chemistry ,QD1-999 ,Environmental protection ,TD169-171.8 - Abstract
Selective adsorption of CO2 from biogas allows isolating biomethane, which can then be used as a direct substitute for natural gas. The microporous zeotype SAPO-34 is a suitable material for CO2 adsorption because it can achieve high working capacity at relatively mild regeneration conditions. In industrial applications, adsorbents need to be shaped into a macroscopic format (e.g. beads, pellets) in order to reduce the pressure drop over the adsorption column. Typically, an inert binder is added to the powder to achieve the desired format. In this work, novel hierarchically porous binderless SAPO-34 beads with a diameter in the range 0.7–1.2 mm were synthesised employing an ion-exchange resin as a hard template. The interior of the beads consisted mostly of small SAPO-34 crystals (< 0.3 μm) interconnected to each other and thus generating a network of meso‑ and macropores between them, as demonstrated by XRD and SEM. Around several of the beads, a crystal overgrowth was observed consisting mostly of larger SAPO-34 crystals (1–25 μm). The SAPO beads displayed good CO2 adsorption capacity (3.0 mmol g−1 at 1 bar), which was higher than that of binder-containing SAPO-34 extrudates (2.4 mmol g−1 at 1 bar), but slightly lower compared to SAPO-34 in powder format (3.4 mmol g−1 at 1 bar). Furthermore, the SAPO-34 beads displayed high CO2/CH4 selectivity (8, at partial pressures mimicking biogas, i.e. 0.4 bar CO2 and 0.6 bar CH4) as well as high CO2/N2 selectivity (33, at partial pressures mimicking flue gas, i.e. 0.15 bar CO2 and 0.85 bar N2). Notably, a high CO2 working capacity of 1.8 mmol g−1 was estimated based on the adsorption isotherm between 1 and 0.2 bar, and this value has the potential to be further improved by increasing the adsorption pressure to > 1 bar.
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- 2023
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39. Targeted multiomics in childhood-onset SLE reveal distinct biological phenotypes associated with disease activity: results from an explorative study
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Sylvia Kamphuis, Cornelia G van Helden-Meeuwsen, Marjan A Versnel, Anton W Langerak, Mohamed Javad Wahadat, Marleen Verkaaik, Sander J van Tilburg, Yvonne M Mueller, Harm de Wit, Marike J Gruijters, Amani Mubarak, and Peter D Katsikis
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Abstract
Objective To combine targeted transcriptomic and proteomic data in an unsupervised hierarchical clustering method to stratify patients with childhood-onset SLE (cSLE) into similar biological phenotypes, and study the immunological cellular landscape that characterises the clusters.Methods Targeted whole blood gene expression and serum cytokines were determined in patients with cSLE, preselected on disease activity state (at diagnosis, Low Lupus Disease Activity State (LLDAS), flare). Unsupervised hierarchical clustering, agnostic to disease characteristics, was used to identify clusters with distinct biological phenotypes. Disease activity was scored by clinical SELENA-SLEDAI (Safety of Estrogens in Systemic Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index). High-dimensional 40-colour flow cytometry was used to identify immune cell subsets.Results Three unique clusters were identified, each characterised by a set of differentially expressed genes and cytokines, and by disease activity state: cluster 1 contained primarily patients in LLDAS, cluster 2 contained mainly treatment-naïve patients at diagnosis and cluster 3 contained a mixed group of patients, namely in LLDAS, at diagnosis and disease flare. The biological phenotypes did not reflect previous organ system involvement and over time, patients could move from one cluster to another. Healthy controls clustered together in cluster 1. Specific immune cell subsets, including CD11c+ B cells, conventional dendritic cells, plasmablasts and early effector CD4+ T cells, differed between the clusters.Conclusion Using a targeted multiomic approach, we clustered patients into distinct biological phenotypes that are related to disease activity state but not to organ system involvement. This supports a new concept where choice of treatment and tapering strategies are not solely based on clinical phenotype but includes measuring novel biological parameters.
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- 2023
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40. Patient specific real-time PCR in precision medicine – Validation of IG/TR based MRD assessment in lymphoid leukemia
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Anke Schilhabel, Monika Szczepanowski, Ellen J. van Gastel-Mol, Janina Schillalies, Jill Ray, Doris Kim, Michaela Nováková, Isabel Dombrink, Vincent H. J. van der Velden, Sebastian Boettcher, Monika Brüggemann, Michael Kneba, Jacques J. M. van Dongen, Anton W. Langerak, and Matthias Ritgen
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MRD ,RQ-PCR ,IG rearrangement ,TR rearrangement ,personalized diagnostics ,IVDR ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Detection of patient- and tumor-specific clonally rearranged immune receptor genes using real-time quantitative (RQ)-PCR is an accepted method in the field of precision medicine for hematologic malignancies. As individual primers are needed for each patient and leukemic clone, establishing performance specifications for the method faces unique challenges. Results for series of diagnostic assays for CLL and ALL patients demonstrate that the analytic performance of the method is not dependent on patients’ disease characteristics. The calibration range is linear between 10-1 and 10-5 for 90% of all assays. The detection limit of the current standardized approach is between 1.8 and 4.8 cells among 100,000 leukocytes. RQ-PCR has about 90% overall agreement to flow cytometry and next generation sequencing as orthogonal methods. Accuracy and precision across different labs, and above and below the clinically applied cutoffs for minimal/measurable residual disease (MRD) demonstrate the robustness of the technique. The here reported comprehensive, IVD-guided analytical validation provides evidence that the personalized diagnostic methodology generates robust, reproducible and specific MRD data when standardized protocols for data generation and evaluation are used. Our approach may also serve as a guiding example of how to accomplish analytical validation of personalized in-house diagnostics under the European IVD Regulation.
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- 2023
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41. Dendritic Cell–Based Immunotherapy in Patients With Resected Pancreatic Cancer.
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van 't Land, Freek R., Willemsen, Marcella, Bezemer, Koen, van der Burg, Sjoerd H., van den Bosch, Thierry P.P., Doukas, Michail, Fellah, Amine, Kolijn, P. Martijn, Langerak, Anton W., Moskie, Miranda, van der Oost, Elise, Rozendaal, Nina E.M., Baart, Sara J., Aerts, Joachim G.J.V., and van Eijck, Casper H.J.
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- 2024
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42. First report of mitochondrial COI in foraminifera and implications for DNA barcoding
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Jan-Niklas Macher, Jeremy G. Wideman, Elsa B. Girard, Anouk Langerak, Elza Duijm, Jamaluddin Jompa, Aleksey Sadekov, Rutger Vos, Richard Wissels, and Willem Renema
- Subjects
Medicine ,Science - Abstract
Abstract Foraminifera are a species-rich phylum of rhizarian protists that are highly abundant in many marine environments and play a major role in global carbon cycling. Species recognition in Foraminifera is mainly based on morphological characters and nuclear 18S ribosomal RNA barcoding. The 18S rRNA contains variable sequence regions that allow for the identification of most foraminiferal species. Still, some species show limited variability, while others contain high levels of intragenomic polymorphisms, thereby complicating species identification. The use of additional, easily obtainable molecular markers other than 18S rRNA will enable more detailed investigation of evolutionary history, population genetics and speciation in Foraminifera. Here we present the first mitochondrial cytochrome c oxidase subunit 1 (COI) gene sequences (“barcodes”) of Foraminifera. We applied shotgun sequencing to single foraminiferal specimens, assembled COI, and developed primers that allow amplification of COI in a wide range of foraminiferal species. We obtained COI sequences of 49 specimens from 17 species from the orders Rotaliida and Miliolida. Phylogenetic analysis showed that the COI tree is largely congruent with previously published 18S rRNA phylogenies. Furthermore, species delimitation with ASAP and ABGD algorithms showed that foraminiferal species can be identified based on COI barcodes.
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- 2021
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43. A novel next-generation sequencing capture-based strategy to report somatic hypermutation status using genomic regions downstream to immunoglobulin rearrangements
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Neil McCafferty, James Peter Stewart, Nikos Darzentas, Jana Gazdova, Mark Catherwood, Kostas Stamatopoulos, Anton W. Langerak, and David Gonzalez
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The somatic hypermutation (SHM) status of the clonotypic, rearranged immunoglobulin heavy variable (IGHV) gene is an established prognostic and predictive marker in chronic lymphocytic leukemia (CLL). Analysis of SHM is generally performed by polymerase chain reaction (PCR)-amplification of clonal IGHV-IGHD-IGHJ gene rearrangements followed by sequencing to identify IGHV gene sequences and germline identity. Targeted-hybridization next-generation sequencing (NGS) can simultaneously assess clonality and other genetic aberrations. However, it has limitations for SHM analysis due to sequence similarity between different IGHV genes and mutations introduced by SHM, which can affect alignment efficiency and accuracy. We developed a novel SHM assessment strategy using a targeted-hybridization NGS approach (EuroClonality- NDC assay) and applied it to 331 samples of lymphoproliferative disorder (LPD). Our strategy focuses on analyzing the sequence downstream to the clonotypic, rearranged IGHJ gene up to the IGHM enhancer (IGHJ-E) which provides more accurate alignment. Overall, 84/95 (88.4%) CLL cases with conventional SHM data showed concordant SHM status, increasing to 91.6% when excluding borderline cases. Additionally, IGHJ-E mutation analysis in a wide range of pre- and post-germinal center LPD showed significant correlation with differentiation and lineage status, suggesting that IGHJ-E analysis is a promising surrogate marker enabling SHM to be reported using NGS-capture strategies and whole genome sequencing.
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- 2022
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44. Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia
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Matthew Kaufman, Xiao-Jie Yan, Wentian Li, Emanuela M. Ghia, Anton W. Langerak, Laura Z. Rassenti, Chrysoula Belessi, Neil E. Kay, Frederic Davi, John C. Byrd, Sarka Pospisilova, Jennifer R. Brown, Mark Catherwood, Zadie Davis, David Oscier, Marco Montillo, Livio Trentin, Richard Rosenquist, Paolo Ghia, Jacqueline C. Barrientos, Jonathan E. Kolitz, Steven L. Allen, Kanti R. Rai, Kostas Stamatopoulos, Thomas J. Kipps, Donna Neuberg, and Nicholas Chiorazzi
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chronic lymphocytic leukemia ,CLL ,somatic mutations ,immunoglobulin variable domain ,prognosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Patients with CLL with mutated IGHV genes (M-CLL) have better outcomes than patients with unmutated IGHVs (U-CLL). Since U-CLL usually express immunoglobulins (IGs) that are more autoreactive and more effectively transduce signals to leukemic B cells, B-cell receptor (BCR) signaling is likely at the heart of the worse outcomes of CLL cases without/few IGHV mutations. A corollary of this conclusion is that M-CLL follow less aggressive clinical courses because somatic IGHV mutations have altered BCR structures and no longer bind stimulatory (auto)antigens and so cannot deliver trophic signals to leukemic B cells. However, the latter assumption has not been confirmed in a large patient cohort. We tried to address the latter by measuring the relative numbers of replacement (R) mutations that lead to non-conservative amino acid changes (Rnc) to the combined numbers of conservative (Rc) and silent (S) amino acid R mutations that likely do not or cannot change amino acids, “(S+Rc) to Rnc IGHV mutation ratio”. When comparing time-to-first-treatment (TTFT) of patients with (S+Rc)/Rnc ≤ 1 and >1, TTFTs were similar, even after matching groups for equal numbers of samples and identical numbers of mutations per sample. Thus, BCR structural change might not be the main reason for better outcomes for M-CLL. Since the total number of IGHV mutations associated better with longer TTFT, better clinical courses appear due to the biologic state of a B cell having undergone many stimulatory events leading to IGHV mutations. Analyses of larger patient cohorts will be needed to definitively answer this question.
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- 2022
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45. A Sensor-Based Feedback Device Stimulating Daily Life Upper Extremity Activity in Stroke Patients: A Feasibility Study
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Anthonia J. Langerak, Gerrit Ruben Hendrik Regterschot, Marc Evers, Bert-Jan F. van Beijnum, Carel G. M. Meskers, Ruud W. Selles, Gerard M. Ribbers, and Johannes B. J. Bussmann
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stroke ,rehabilitation ,accelerometry ,upper extremity ,daily life ,arm usage ,Chemical technology ,TP1-1185 - Abstract
This study aims to evaluate the feasibility and explore the efficacy of the Arm Activity Tracker (AAT). The AAT is a device based on wrist-worn accelerometers that provides visual and tactile feedback to stimulate daily life upper extremity (UE) activity in stroke patients. Methods: A randomised, crossover within-subject study was conducted in sub-acute stroke patients admitted to a rehabilitation centre. Feasibility encompassed (1) adherence: the dropout rate and the number of participants with insufficient AAT data collection; (2) acceptance: the technology acceptance model (range: 7–112) and (3) usability: the system usability scale (range: 0–100). A two-way ANOVA was used to estimate the difference between the baseline, intervention and control conditions for (1) paretic UE activity and (2) UE activity ratio. Results: Seventeen stroke patients were included. A 29% dropout rate was observed, and two participants had insufficient data collection. Participants who adhered to the study reported good acceptance (median (IQR): 94 (77–111)) and usability (median (IQR): 77.5 (75–78.5)-). We found small to medium effect sizes favouring the intervention condition for paretic UE activity (η2G = 0.07, p = 0.04) and ratio (η2G = 0.11, p = 0.22). Conclusion: Participants who adhered to the study showed good acceptance and usability of the AAT and increased paretic UE activity. Dropouts should be further evaluated, and a sufficiently powered trial should be performed to analyse efficacy.
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- 2023
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46. Long-term trends in the loss in expectation of life after a diagnosis of chronic lymphocytic leukemia: a population-based study in the Netherlands, 1989–2018
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van der Straten, Lina, Maas, Carolien C. H. M., Levin, Mark-David, Visser, Otto, Posthuma, Eduardus F. M., Doorduijn, Jeanette K., Langerak, Anton W., Kater, Arnon P., and Dinmohamed, Avinash G.
- Published
- 2022
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47. EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia
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Young, E, Noerenberg, D, Mansouri, L, Ljungström, V, Frick, M, Sutton, L-A, Blakemore, SJ, Galan-Sousa, J, Plevova, K, Baliakas, P, Rossi, D, Clifford, R, Roos-Weil, D, Navrkalova, V, Dörken, B, Schmitt, CA, Smedby, KE, Juliusson, G, Giacopelli, B, Blachly, JS, Belessi, C, Panagiotidis, P, Chiorazzi, N, Davi, F, Langerak, AW, Oscier, D, Schuh, A, Gaidano, G, Ghia, P, Xu, W, Fan, L, Bernard, OA, Nguyen-Khac, F, Rassenti, L, Li, J, Kipps, TJ, Stamatopoulos, K, Pospisilova, S, Zenz, T, Oakes, CC, Strefford, JC, Rosenquist, R, and Damm, F
- Subjects
Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Cancer ,Hematology ,Rare Diseases ,Lymphoma ,Clinical Research ,Genetics ,4.1 Discovery and preclinical testing of markers and technologies ,Detection ,screening and diagnosis ,Adult ,Aged ,Early Growth Response Protein 2 ,Female ,Genes ,p53 ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Mutation ,Proportional Hazards Models ,Clinical Sciences ,Immunology ,Cardiovascular medicine and haematology ,Clinical sciences ,Oncology and carcinogenesis - Abstract
Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.
- Published
- 2017
48. Cross-Site and Cross-Generation Knowledge Transfer in High-Tech After-Sales Service
- Author
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Zijlstra, F. S., Alblas, A. A., and Langerak, F.
- Abstract
Learning and knowledge transfer are crucial to organizational success. Knowledge can transfer between sites and generations, yet prior research has studied both types of knowledge transfer in isolation. Understanding their combined effect is essential because many manufacturing and service organizations have multiple sites and generations. In contrast to prior research, we study both types of knowledge transfer simultaneously in a high-tech after-sales service organization. In doing so, we provide new insights into the learning processes of high-tech firms providing global after-service. We leverage 10 years of weekly observations of after-sales service experience and performance of a firm in the semiconductor industry to test learning curve models with cross-site and cross-generation knowledge transfer and temporal distance between generations. Our empirical model tests the impact of these different sources of experience on the downtime performance of five machine generations serviced by 30 globally distributed service sites. We find knowledge transfer across sites and generations, except for cross-site knowledge transfer from newer to older generations. That is, the introduction of new products disturbs the cross-site learning process of older products. Furthermore, cross-generation knowledge transfer is conditional to the temporal distance between product generations. Knowledge transfer decreases when the temporal distance increases.Funding:This research was funded by the high-tech company that facilitated this study.
- Published
- 2024
- Full Text
- View/download PDF
49. Using Synthetic Data in Supervised Learning for Robust 5-DoF Magnetic Marker Localization
- Author
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Wu, Mengfan, Langerak, Thomas, Hilliges, Otmar, and Zarate, Juan
- Abstract
Tracking passive magnetic markers plays a vital role in advancing healthcare and robotics, offering the potential to significantly improve the precision and efficiency of systems. This technology is key to developing smarter, more responsive tools and devices, such as enhanced surgical instruments, precise diagnostic tools, and robots with improved environmental interaction capabilities. However, traditionally, the tracking of magnetic markers is computationally expensive due to the requirement for iterative optimization procedures. Moreover, these methods depend on the magnetic dipole model for their optimization function, which can yield imprecise outcomes due to the model’s significant inaccuracies when dealing with short distances between non-spherical magnet and sensor. Our article introduces a novel approach that leverages neural networks (NNs) to bypass these limitations, directly inferring the marker’s position and orientation to accurately determine the magnet’s five degrees of freedom (5 DoFs) in a single step without initial estimation. Although our method demands an extensive supervised training phase, we mitigate this by introducing a computationally more efficient method to generate synthetic, yet realistic data using Finite Element Methods simulations. Our novel method uses the rotational symmetry of axis-symmetric magnetic markers to transform the 3-D simulations into 2-D. The benefits of fast and accurate inference significantly outweigh the offline training preparation. In our evaluation, we use different cylindrical magnets, tracked with a square array of 16 sensors. We perform the sensors’ reading and position inference on a portable, NN-oriented single-board computer, ensuring a compact setup. We benchmark our prototype against vision-based ground-truth data, achieving a mean positional error of 4 mm and an orientation error of 8° within a
$0.2\times 0$ $2\times 0$ - Published
- 2024
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- View/download PDF
50. Zelfmetingen bij patiënten met myasthenia gravis
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Langerak, Angela, van der Geugten, Jolien, and Eftimov, Filip
- Published
- 2021
- Full Text
- View/download PDF
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