62 results on '"Laure-Anne Teuwen"'
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2. Conflict of Interest Disclosure in Oncology: Preliminary Insights From the Global ONCOTRUST-1 Cross-Sectional Study
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Khalid El Bairi, Salma Najem, Arman Reza Chowdhury, Abeid Omar, Omar Abdihamid, Laure-Anne Teuwen, Nada Benhima, Ainhoa Madariaga, Safa Elkefi, Fernando Cristobal Diaz, Sadaqat Hussain, Kristina Jenei, Nazik Hammad, Miriam Mutebi, Fidel Rubagumya, Dario Trapani, Nadia El Kadmiri, Nasser Laouali, and Maryam Fourtassi
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
PURPOSEConflicts of interest (COIs) between oncologists and industry might considerably influence how the presentation of the research results is delivered, ultimately affecting clinical decisions and policy-making. Although there are many regulations on reporting COI in high-income countries (HICs), little is known about their reporting in low- and middle-income countries (LMICs). Oncology Transparency Under Scrutiny and Tracking (ONCOTRUST-1) is a pilot global survey to explore the knowledge and perceptions of oncologists regarding COI.MATERIALS AND METHODSWe designed an online 27-question–based survey in the English language to explore the perceptions and knowledge of oncologists regarding COI, with an emphasis on LMICs. Descriptive statistics and the Consensus-Based Checklist for Reporting of Survey Studies guidelines were used to report the findings.RESULTSONCOTRUST-1 surveyed 200 oncologists, 70.9% of them practicing in LMICs. Median age of the respondents was 36 (range, 26-84) years; 47.5% of them were women. Of the respondents, 40.5% reported weekly visits by pharmaceutical representatives to their institutions. Regarding oncologists' perceptions of COI that require disclosure, direct financial benefits, such as honoraria, ranked highest (58.5%), followed by gifts from pharmaceutical representatives (50%) and travel grants for attending conferences (44.5%). By contrast, personal or institutional research funding, sample drugs, consulting or advisory board, expert testimony, and food and beverage funded by pharmaceutical industry were less frequently considered as COI. Moreover, only 24% of surveyed oncologists could correctly categorize all situations representing a COI.CONCLUSIONThese findings underscore the importance of clear guidelines, education, and transparency in reporting COI in oncology. This hypothesis-generating pilot survey provided the rationale for ONCOTRUST-2 study, which will compare perceptions of COI among oncologists in LMICs and HICs.
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- 2024
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3. Molecular differences of angiogenic versus vessel co-opting colorectal cancer liver metastases at single-cell resolution
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Johannes Robert Fleischer, Alexandra Maria Schmitt, Gwendolyn Haas, Xingbo Xu, Elisabeth Maria Zeisberg, Hanibal Bohnenberger, Stefan Küffer, Laure-Anne Teuwen, Philipp Johannes Karras, Tim Beißbarth, Annalen Bleckmann, Mélanie Planque, Sarah-Maria Fendt, Peter Vermeulen, Michael Ghadimi, Joanna Kalucka, Tiago De Oliveira, and Lena-Christin Conradi
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Colorectal cancer liver metastases ,Histopathological growth patterns ,Vessel co-option ,Sprouting angiogenesis ,Glycolysis ,WNT signalling ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Colorectal cancer liver metastases (CRCLM) are associated with a poor prognosis, reflected by a five-year survival rate of 14%. Anti-angiogenic therapy through anti-VEGF antibody administration is one of the limited therapies available. However, only a subgroup of metastases uses sprouting angiogenesis to secure their nutrients and oxygen supply, while others rely on vessel co-option (VCO). The distinct mode of vascularization is reflected by specific histopathological growth patterns (HGPs), which have proven prognostic and predictive significance. Nevertheless, their molecular mechanisms are poorly understood. Methods We evaluated CRCLM from 225 patients regarding their HGP and clinical data. Moreover, we performed spatial (21,804 spots) and single-cell (22,419 cells) RNA sequencing analyses to explore molecular differences in detail, further validated in vitro through immunohistochemical analysis and patient-derived organoid cultures. Results We detected specific metabolic alterations and a signature of WNT signalling activation in metastatic cancer cells related to the VCO phenotype. Importantly, in the corresponding healthy liver of CRCLM displaying sprouting angiogenesis, we identified a predominantly expressed capillary subtype of endothelial cells, which could be further explored as a possible predictor for HGP relying on sprouting angiogenesis. Conclusion These findings may prove to be novel therapeutic targets to the treatment of CRCLM, in special the ones relying on VCO.
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- 2023
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4. Single cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast
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Vincent Geldhof, Laura P. M. H. de Rooij, Liliana Sokol, Jacob Amersfoort, Maxim De Schepper, Katerina Rohlenova, Griet Hoste, Adriaan Vanderstichele, Anne-Marie Delsupehe, Edoardo Isnaldi, Naima Dai, Federico Taverna, Shawez Khan, Anh-Co K. Truong, Laure-Anne Teuwen, François Richard, Lucas Treps, Ann Smeets, Ines Nevelsteen, Birgit Weynand, Stefan Vinckier, Luc Schoonjans, Joanna Kalucka, Christine Desmedt, Patrick Neven, Massimiliano Mazzone, Giuseppe Floris, Kevin Punie, Mieke Dewerchin, Guy Eelen, Hans Wildiers, Xuri Li, Yonglun Luo, and Peter Carmeliet
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Science - Abstract
Tumor blood vessels contribute to cancer growth, invasion and metastasis. Here, by using single cell transcriptomics, the authors report an inventory of endothelial cell heterogeneity in patients with breast cancer, including a subtype that expresses genes involved in lipid processing and is regulated by PPAR-γ.
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- 2022
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5. Predictive model for BNT162b2 vaccine response in cancer patients based on blood cytokines and growth factors
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Angelina Konnova, Fien H. R. De Winter, Akshita Gupta, Lise Verbruggen, An Hotterbeekx, Matilda Berkell, Laure-Anne Teuwen, Greetje Vanhoutte, Bart Peeters, Silke Raats, Isolde Van der Massen, Sven De Keersmaecker, Yana Debie, Manon Huizing, Pieter Pannus, Kristof Y. Neven, Kevin K. Ariën, Geert A. Martens, Marc Van Den Bulcke, Ella Roelant, Isabelle Desombere, Sébastien Anguille, Zwi Berneman, Maria E. Goossens, Herman Goossens, Surbhi Malhotra-Kumar, Evelina Tacconelli, Timon Vandamme, Marc Peeters, Peter van Dam, and Samir Kumar-Singh
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COVID-19 vaccine ,BNT162b2 ,SARS-CoV-2 ,solid cancers ,haematological malignancies ,cytokines ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundPatients with cancer, especially hematological cancer, are at increased risk for breakthrough COVID-19 infection. So far, a predictive biomarker that can assess compromised vaccine-induced anti-SARS-CoV-2 immunity in cancer patients has not been proposed.MethodsWe employed machine learning approaches to identify a biomarker signature based on blood cytokines, chemokines, and immune- and non-immune-related growth factors linked to vaccine immunogenicity in 199 cancer patients receiving the BNT162b2 vaccine.ResultsC-reactive protein (general marker of inflammation), interleukin (IL)-15 (a pro-inflammatory cytokine), IL-18 (interferon-gamma inducing factor), and placental growth factor (an angiogenic cytokine) correctly classified patients with a diminished vaccine response assessed at day 49 with >80% accuracy. Amongst these, CRP showed the highest predictive value for poor response to vaccine administration. Importantly, this unique signature of vaccine response was present at different studied timepoints both before and after vaccination and was not majorly affected by different anti-cancer treatments.ConclusionWe propose a blood-based signature of cytokines and growth factors that can be employed in identifying cancer patients at persistent high risk of COVID-19 despite vaccination with BNT162b2. Our data also suggest that such a signature may reflect the inherent immunological constitution of some cancer patients who are refractive to immunotherapy.
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- 2022
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6. Generation of vessel co-option lung metastases mouse models for single-cell isolation of metastases-derived cells and endothelial cells
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Anne Cuypers, Laure-Anne Teuwen, Victoria L. Bridgeman, Laura P.M.H. de Rooij, Guy Eelen, Mieke Dewerchin, Anna Rita Cantelmo, Joanna Kalucka, Ann Bouché, Stefan Vinckier, An Carton, Ann Manderveld, Peter B. Vermeulen, Andrew R. Reynolds, and Peter Carmeliet
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Antibody ,Cancer ,Cell isolation ,Model organisms ,Single cell ,Science (General) ,Q1-390 - Abstract
Summary: Tumor vessel co-option, a process in which cancer cells “hijack” pre-existing blood vessels to grow and invade healthy tissue, is poorly understood but is a proposed resistance mechanism against anti-angiogenic therapy (AAT). Here, we describe protocols for establishing murine renal (RENCA) and breast (4T1) cancer lung vessel co-option metastases models. Moreover, we outline a reproducible protocol for single-cell isolation from murine lung metastases using magnetic-activated cell sorting as well as immunohistochemical stainings to distinguish vessel co-option from angiogenesis.For complete details on the use and execution of this protocol, please refer to Teuwen et al. (2021). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
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- 2022
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7. Comprehensive Genomic Profiling and Therapeutic Implications for Patients with Advanced Cancers: The Experience of an Academic Hospital
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Laure-Anne Teuwen, Evelyne Roets, Pieter D’Hoore, Patrick Pauwels, and Hans Prenen
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advanced cancer ,genomic profiling ,next-generation sequencing ,OncoKB classification ,targeted therapy ,Medicine (General) ,R5-920 - Abstract
Next-generation sequencing (NGS) can be used to detect tumor-specific genomic alterations. This retrospective single-center study aims to assess the application of an extensive NGS panel to identify actionable alterations and initiate matched targeted treatment for patients with advanced cancer. We analyzed genomic alterations in solid tumor biopsies from 464 patients with advanced cancer with the Foundation Medicine assay (FoundationOne®CDx). Therapeutic implications were determined using the Memorial Sloan Kettering Precision Oncology Knowledge Base (OncoKB) classification. The FoundationOne®CDx was successfully applied in 464/521 patients (89%). The most common altered genes were TP53 (61%), KRAS (20%), CDKN2A (20%), TERT (16%), and APC (16%). Among the 419 patients with successfully analyzed tumor mutational burden (TMB), 43 patients presented with a high TMB (≥10 mutations/megabase). Out of the 126 patients with an actionable target, 40 patients received matched treatment (32%) of which 17 were within a clinical trial. This study shows that the application of NGS is feasible in an academic center and increases the detection of actionable alterations and identification of patients eligible for targeted treatment or immunotherapy regardless of tumor histology. Strategies such as early referral for NGS, inclusion in clinical (basket) trials, and the development of new targeted drugs are necessary to improve the matched treatment rate.
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- 2023
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8. Protocols for endothelial cell isolation from mouse tissues: kidney, spleen, and testis
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Sébastien J. Dumas, Elda Meta, Nadine V. Conchinha, Liliana Sokol, Rongyuan Chen, Mila Borri, Laure-Anne Teuwen, Koen Veys, Melissa García-Caballero, Vincent Geldhof, Lucas Treps, Pauline de Zeeuw, Kim D. Falkenberg, Charlotte Dubois, Magdalena Parys, Laura P.M.H. de Rooij, Katerina Rohlenova, Jermaine Goveia, Luc Schoonjans, Mieke Dewerchin, Guy Eelen, Xuri Li, Joanna Kalucka, and Peter Carmeliet
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Cell isolation ,Single Cell ,Flow Cytometry/Mass Cytometry ,Science (General) ,Q1-390 - Abstract
Summary: Endothelial cells (ECs) exhibit phenotypic and functional tissue specificities, critical for studies in the vascular field and beyond. Thus, tissue-specific methods for isolation of highly purified ECs are necessary. Kidney, spleen, and testis ECs are relevant players in health and diseases such as chronic kidney disease, acute kidney injury, myelofibrosis, and cancer. Here, we provide tailored protocols for rapid and reproducible EC purification established for scRNA sequencing from these adult murine tissues using the combination of magnetic- and fluorescence-activated cell sorting.For complete details on the use and execution of these protocols, please refer to Kalucka et al. (2020) and Dumas et al. (2020).
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- 2021
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9. Corrigendum to 'itraconazole for COVID-19: Preclinical studies and a proof-of-concept randomized clinical trial Laurens'
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Laurens Liesenborghs, Isabel Spriet, Dirk Jochmans, Ann Belmans, Iwein Gyselinck, Laure-Anne Teuwen, Sebastiaan ter Horst, Erwin Dreesen, Tatjana Geukens, Matthias M. Engelen, Ewout Landeloos, Vincent Geldhof, Helga Ceunen, Barbara Debaveye, Bert Vandenberk, Lorenz Van der Linden, Sofie Jacobs, Lana Langendries, Robbert Boudewijns, Thuc Nguyen Dan Do, Winston Chiu, Xinyu Wang, Xin Zhang, Birgit Weynand, Thomas Vanassche, Timothy Devos, Geert Meyfroidt, Wim Janssens, Robin Vos, Pieter Vermeersch, Joost Wauters, Geert Verbeke, Paul De Munter, Suzanne J.F. Kaptein, Joana Rocha-Pereira, Leen Delang, Eric Van Wijngaerden, Johan Neyts, and Peter Verhamme
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Medicine ,Medicine (General) ,R5-920 - Published
- 2021
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10. Tumor vessel co-option probed by single-cell analysis
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Laure-Anne Teuwen, Laura P.M.H. De Rooij, Anne Cuypers, Katerina Rohlenova, Sébastien J. Dumas, Melissa García-Caballero, Elda Meta, Jacob Amersfoort, Federico Taverna, Lisa M. Becker, Nuphar Veiga, Anna Rita Cantelmo, Vincent Geldhof, Nadine V. Conchinha, Joanna Kalucka, Lucas Treps, Lena-Christin Conradi, Shawez Khan, Tobias K. Karakach, Stefaan Soenen, Stefan Vinckier, Luc Schoonjans, Guy Eelen, Steven Van Laere, Mieke Dewerchin, Luc Dirix, Massimiliano Mazzone, Yonglun Luo, Peter Vermeulen, and Peter Carmeliet
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tumor vessel co-option ,tumor angiogenesis ,anti-angiogenic therapy ,metastasis ,resistance ,single-cell RNA sequencing ,Biology (General) ,QH301-705.5 - Abstract
Summary: Tumor vessel co-option is poorly understood, yet it is a resistance mechanism against anti-angiogenic therapy (AAT). The heterogeneity of co-opted endothelial cells (ECs) and pericytes, co-opting cancer and myeloid cells in tumors growing via vessel co-option, has not been investigated at the single-cell level. Here, we use a murine AAT-resistant lung tumor model, in which VEGF-targeting induces vessel co-option for continued growth. Single-cell RNA sequencing (scRNA-seq) of 31,964 cells reveals, unexpectedly, a largely similar transcriptome of co-opted tumor ECs (TECs) and pericytes as their healthy counterparts. Notably, we identify cell types that might contribute to vessel co-option, i.e., an invasive cancer-cell subtype, possibly assisted by a matrix-remodeling macrophage population, and another M1-like macrophage subtype, possibly involved in keeping or rendering vascular cells quiescent.
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- 2021
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11. Protocols for endothelial cell isolation from mouse tissues: small intestine, colon, heart, and liver
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Liliana Sokol, Vincent Geldhof, Melissa García-Caballero, Nadine V. Conchinha, Sébastien J. Dumas, Elda Meta, Laure-Anne Teuwen, Koen Veys, Rongyuan Chen, Lucas Treps, Mila Borri, Pauline de Zeeuw, Kim D. Falkenberg, Charlotte Dubois, Magdalena Parys, Laura P.M.H. de Rooij, Jermaine Goveia, Katerina Rohlenova, Luc Schoonjans, Mieke Dewerchin, Guy Eelen, Xuri Li, Joanna Kalucka, and Peter Carmeliet
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Cell isolation ,Single Cell ,Flow Cytometry/Mass Cytometry ,Science (General) ,Q1-390 - Abstract
Summary: Endothelial cells (ECs) from the small intestine, colon, liver, and heart have distinct phenotypes and functional adaptations that are dependent on their physiological environment. Gut ECs adapt to low oxygen, heart ECs to contractile forces, and liver ECs to low flow rates. Isolating high-purity ECs in sufficient quantities is crucial to study their functions. Here, we describe protocols combining magnetic and fluorescent activated cell sorting for rapid and reproducible EC purification from four adult murine tissues.For complete details on the use and execution of these protocols, please refer to Kalucka et al. (2020).
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- 2021
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12. Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial
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Laurens Liesenborghs, M.D., Isabel Spriet, Pharm.D., Dirk Jochmans, Ph.D., Ann Belmans, Ph.D., Iwein Gyselinck, M.D., Laure-Anne Teuwen, M.D., Sebastiaan ter Horst, Msc., Erwin Dreesen, Ph.D., Tatjana Geukens, M.D., Matthias M. Engelen, M.D., Ewout Landeloos, M.D., Vincent Geldhof, M.D., Helga Ceunen, Barbara Debaveye, Bert Vandenberk, M.D., Lorenz Van der Linden, Pharm.D., Sofie Jacobs, MSc., Lana Langendries, Msc., Robbert Boudewijns, Msc., Thuc Nguyen Dan Do, Msc., Winston Chiu, Msc., Xinyu Wang, Msc., Xin Zhang, Msc., Birgit Weynand, M.D., Thomas Vanassche, M.D., Timothy Devos, M.D., Geert Meyfroidt, M.D., Wim Janssens, M.D., Robin Vos, M.D., Pieter Vermeersch, M.D., Joost Wauters, M.D., Geert Verbeke, Ph.D., Paul De Munter, M.D., Suzanne J.F. Kaptein, Ph.D, Joana Rocha-Pereira, Ph.D., Leen Delang, Ph.D., Eric Van Wijngaerden, M.D., Johan Neyts, Ph.D., and Peter Verhamme, M.D.
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COVID-19 ,SARS-CoV-2 ,itraconazole ,drug repurposing ,antivirals ,Medicine ,Medicine (General) ,R5-920 - Abstract
Background: The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19. Methods: Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated. Findings: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and because an interim analysis showed no signal for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19) for itraconazole vs standard of care. Interpretation: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. This prompted the premature termination of the proof-of-concept clinical study.Funding: KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation
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- 2021
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13. Systemic treatment of localized colorectal cancer
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Hans, Dedecker, primary, Timon, Vandamme, additional, Laure-Anne, Teuwen, additional, Laura, Wuyts, additional, Hans, Prenen, additional, Tije, ten, additional, Jan, Albert, additional, and Marc, Peeters, additional
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- 2022
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14. List of contributors
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Akiyoshi, Takashi, primary, Beets-Tan, Regina, additional, Benson, Sean, additional, Bodalal, Zuhir, additional, Brouwer, Nelleke Pietronella Maria, additional, Burggraaf, Jacobus, additional, Cai, Lishan, additional, Ceelen, Wim P., additional, Chang, Daniel T., additional, De Clercq, Alexander, additional, Debbaut, Charlotte, additional, Delgado, Carlos Alejandro Silvera, additional, Elias, Alexandra, additional, Francke, Kai, additional, Frick, Melissa A., additional, Galema, Hidde A., additional, Hans, Dedecker, additional, Hans, Prenen, additional, Hardiman, Karin, additional, Hazen, Sanne-Marije J.A., additional, Hilling, Denise E., additional, Hoorens, Anne, additional, Hutteman, Merlijn, additional, Ikeda, Masataka, additional, Ito, Masaaki, additional, Jan, Albert, additional, Kanemitsu, Yukihide, additional, Kataoka, Kozo, additional, Keereweer, Stijn, additional, Koudehi, Ghazal Adeli, additional, Kusters, Miranda, additional, Laura, Wuyts, additional, Laure-Anne, Teuwen, additional, Lauwerends, Lorraine J., additional, Loo, Phoebe, additional, Maas, Monique, additional, Marc, Peeters, additional, Meijer, Ruben P.J., additional, Monson, John R.T., additional, Nagtegaal, Iris D., additional, Pollom, Erqi L., additional, Rey, Sergio, additional, Salavati, Hooman, additional, Schito, Luana, additional, Segers, Patrick, additional, Shiozawa, Manabu, additional, Sluckin, Tania C., additional, Smithson, Mary, additional, Struys, Mathieu J.R., additional, Tiernan, Jim P., additional, Tije, ten, additional, Timon, Vandamme, additional, Trebeschi, Stefano, additional, Tsukada, Yuichiro, additional, Vahrmeijer, Alexander L., additional, van Ramshorst, Gabrielle H., additional, Verhoef, Cornelis, additional, Vitzthum, Lucas K., additional, Waktola, Selam, additional, West, Nicholas P., additional, Westwood, Alice C., additional, Willaert, Wouter, additional, and Wright, Jesse P., additional
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- 2022
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15. Figure S3 from Humoral and Cellular Immune Responses against SARS-CoV-2 after Third Dose BNT162b2 following Double-Dose Vaccination with BNT162b2 versus ChAdOx1 in Patients with Cancer
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Peter A. van Dam, Marc Peeters, Eva Lion, Christof Vulsteke, Evelien L.J. Smits, Hans Prenen, Annelies Janssens, Sébastien Anguille, Kevin K. Ariën, Pieter Pannus, Maria E. Goossens, Bart Peeters, Debbie Le Blon, Lisa Verheggen, Elly Marcq, Greetje Vanhoutte, Lise Verbruggen, Laure-Anne Teuwen, Lieselot Croes, Timon Vandamme, Jonas R.M. Van Audenaerde, and Yana Debie
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Supplementary Figure 3: Gating strategy for a representative sample
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- 2023
16. Supplementary Tables S1-S2 from Humoral and Cellular Immune Responses against SARS-CoV-2 after Third Dose BNT162b2 following Double-Dose Vaccination with BNT162b2 versus ChAdOx1 in Patients with Cancer
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Peter A. van Dam, Marc Peeters, Eva Lion, Christof Vulsteke, Evelien L.J. Smits, Hans Prenen, Annelies Janssens, Sébastien Anguille, Kevin K. Ariën, Pieter Pannus, Maria E. Goossens, Bart Peeters, Debbie Le Blon, Lisa Verheggen, Elly Marcq, Greetje Vanhoutte, Lise Verbruggen, Laure-Anne Teuwen, Lieselot Croes, Timon Vandamme, Jonas R.M. Van Audenaerde, and Yana Debie
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Supplementary Tables S1-S2
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- 2023
17. Data from Humoral and Cellular Immune Responses against SARS-CoV-2 after Third Dose BNT162b2 following Double-Dose Vaccination with BNT162b2 versus ChAdOx1 in Patients with Cancer
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Peter A. van Dam, Marc Peeters, Eva Lion, Christof Vulsteke, Evelien L.J. Smits, Hans Prenen, Annelies Janssens, Sébastien Anguille, Kevin K. Ariën, Pieter Pannus, Maria E. Goossens, Bart Peeters, Debbie Le Blon, Lisa Verheggen, Elly Marcq, Greetje Vanhoutte, Lise Verbruggen, Laure-Anne Teuwen, Lieselot Croes, Timon Vandamme, Jonas R.M. Van Audenaerde, and Yana Debie
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Purpose:Patients with cancer display reduced humoral responses after double-dose COVID-19 vaccination, whereas their cellular response is more comparable with that in healthy individuals. Recent studies demonstrated that a third vaccination dose boosts these immune responses, both in healthy people and patients with cancer. Because of the availability of many different COVID-19 vaccines, many people have been boosted with a different vaccine from the one used for double-dose vaccination. Data on such alternative vaccination schedules are scarce. This prospective study compares a third dose of BNT162b2 after double-dose BNT162b2 (homologous) versus ChAdOx1 (heterologous) vaccination in patients with cancer.Experimental Design:A total of 442 subjects (315 patients and 127 healthy) received a third dose of BNT162b2 (230 homologous vs. 212 heterologous). Vaccine-induced adverse events (AE) were captured up to 7 days after vaccination. Humoral immunity was assessed by SARS-CoV-2 anti-S1 IgG antibody levels and SARS-CoV-2 50% neutralization titers (NT50) against Wuhan and BA.1 Omicron strains. Cellular immunity was examined by analyzing CD4+ and CD8+ T-cell responses against SARS-CoV-2–specific S1 and S2 peptides.Results:Local AEs were more common after heterologous boosting. SARS-CoV-2 anti-S1 IgG antibody levels did not differ significantly between homologous and heterologous boosted subjects [GMT 1,755.90 BAU/mL (95% CI, 1,276.95–2,414.48) vs. 1,495.82 BAU/mL (95% CI, 1,131.48–1,977.46)]. However, homologous-boosted subjects show significantly higher NT50 values against BA.1 Omicron. Subjects receiving heterologous boosting demonstrated increased spike-specific CD8+ T cells, including higher IFNγ and TNFα levels.Conclusions:In patients with cancer who received double-dose ChAdOx1, a third heterologous dose of BNT162b2 was able to close the gap in antibody response.
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- 2023
18. The role of immunotherapy in esophageal and gastric cancer
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Hans Dedecker, Laure-Anne Teuwen, Timon Vandamme, Andreas Domen, and Hans Prenen
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Oncology ,Gastroenterology ,Human medicine - Abstract
Upper gastrointestinal tract tumors historically have a poor prognosis. The decision to treat esophageal or gastric cancers by surgery, radiotherapy, systemic therapy, or a combination of these treatment modalities should always be discussed multidisciplinary. The introduction of immunotherapy has drastically transformed the treatment landscape of multiple solid malignancies. Emerging data from early and late phase clinical trials suggests that the use of immunother-apies that target immune checkpoint proteins such as PD-1/PD-L1 result in superior overall survival in advanced, metastatic, or recurrent esophageal and gastric cancer, whether or not with specific molecular characteristics such as PD-L1 expression level or microsatellite instability. This review offers an overview of the most recent advances in the field of immunotherapy treatment in esophageal and gastric cancer.
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- 2023
19. Humoral and cellular immune responses against SARS-CoV-2 after third dose BNT162b2 following double-dose vaccination with BNT162b2 versus ChAdOx1 in patients with cancer
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Yana Debie, Jonas R.M. Van Audenaerde, Timon Vandamme, Lieselot Croes, Laure-Anne Teuwen, Lise Verbruggen, Greetje Vanhoutte, Elly Marcq, Lisa Verheggen, Debbie Le Blon, Bart Peeters, Maria E. Goossens, Pieter Pannus, Kevin K. Ariën, Sébastien Anguille, Annelies Janssens, Hans Prenen, Evelien L.J. Smits, Christof Vulsteke, Eva Lion, Marc Peeters, Peter A. van Dam, Pharmaceutical and Pharmacological Sciences, Cellular and Molecular Immunology, Applied Mechanics, Teacher Education, Medical Genetics, Faculty of Economic and Social Sciences and Solvay Business School, and Faculty of Psychology and Educational Sciences
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Cancer Research ,Oncology ,Human medicine - Abstract
Purpose: Patients with cancer display reduced humoral responses after double-dose COVID-19 vaccination, whereas their cellular response is more comparable with that in healthy individuals. Recent studies demonstrated that a third vaccination dose boosts these immune responses, both in healthy people and patients with cancer. Because of the availability of many different COVID-19 vaccines, many people have been boosted with a different vaccine from the one used for double-dose vaccination. Data on such alternative vaccination schedules are scarce. This prospective study compares a third dose of BNT162b2 after double-dose BNT162b2 (homologous) versus ChAdOx1 (heterologous) vaccination in patients with cancer. Experimental Design: A total of 442 subjects (315 patients and 127 healthy) received a third dose of BNT162b2 (230 homologous vs. 212 heterologous). Vaccine-induced adverse events (AE) were captured up to 7 days after vaccination. Humoral immunity was assessed by SARS-CoV-2 anti-S1 IgG antibody levels and SARS-CoV-2 50% neutralization titers (NT50) against Wuhan and BA.1 Omicron strains. Cellular immunity was examined by analyzing CD4+ and CD8+ T-cell responses against SARS-CoV-2–specific S1 and S2 peptides. Results: Local AEs were more common after heterologous boosting. SARS-CoV-2 anti-S1 IgG antibody levels did not differ significantly between homologous and heterologous boosted subjects [GMT 1,755.90 BAU/mL (95% CI, 1,276.95–2,414.48) vs. 1,495.82 BAU/mL (95% CI, 1,131.48–1,977.46)]. However, homologous-boosted subjects show significantly higher NT50 values against BA.1 Omicron. Subjects receiving heterologous boosting demonstrated increased spike-specific CD8+ T cells, including higher IFNγ and TNFα levels. Conclusions: In patients with cancer who received double-dose ChAdOx1, a third heterologous dose of BNT162b2 was able to close the gap in antibody response.
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- 2023
20. Immediate hypersensitivity reactions to antineoplastic agents : a practical guide for the oncologist
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Sofie Seghers, Laure-Anne Teuwen, Michiel Beyens, Dennis De Blick, Vito Sabato, Didier G. Ebo, and Hans Prenen
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Oncology ,Radiology, Nuclear Medicine and imaging ,General Medicine ,Human medicine - Abstract
Immediate hypersensitivity reactions (IHRs) to antineoplastic agents occur frequently, and every oncologist will encounter these reactions in their clinical practice at some point. The clinical signature of IHRs can range from mild to life-threatening, and their occurrence can substantially impede the treatment course of patients with cancer. Yet, clear guidelines regarding the diagnosis and management are scarce, especially from an oncologic point of view. Therefore, herein, we review the definition, pathophysiology, epidemiology, diagnosis and management of IHRs to chemotherapeutic agents and monoclonal antibodies. First, we focus on defining the specific entities that comprise IHRs and discuss their underlying mechanisms. Then, we summarize the epidemiology for the antineoplastic agents that represent the most common causes of IHRs, i.e., platinum compounds, taxanes and monoclonal antibodies (mAbs). Next, we describe the possible clinical pictures and the comprehensive diagnostic work-up that should be executed to identify the culprit and safe alternatives for the future. Finally, we finish with reviewing the treatment options in both the acute phase and after recovery, with the aim to improve the oncologic care of patients with cancer.
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- 2023
21. Predictive model for BNT162b2 vaccine response in cancer patients based on cytokines and growth factors
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Angelina Konnova, Fien HR De Winter, Akshita Gupta, Lise Verbruggen, An Hotterbeekx, Matilda Berkell, Laure-Anne Teuwen, Greetje Vanhoutte, Bart Peeters, Silke Raats, Isolde Van der Massen, Sven De Keersmaecker, Yana Debie, Manon Huizing, Pieter Pannus, Kristof Y Neven, Kevin K Ariën, Geert A. Martens, Marc Van Den Bulcke, Ella Roelant, Isabelle Desombere, Sébastien Anguille, Zwi Berneman, Maria E Goossens, Herman Goossens, Surbhi Malhotra-Kumar, Evelina Taconelli, Timon Vandamme, Marc Peeters, Peter van Dam, and Samir Kumar-Singh
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BackgroundPatients with cancer, especially haematological cancer, are at increased risk for breakthrough COVID-19 infection. However, so far, a predictive biomarker that can assess compromised vaccine-induced anti-SARS-CoV-2 immunity in cancer patients has not been proposed.MethodsHere, we employed machine learning approaches to identify a biomarker signature based on blood cytokine and growth factors linked to vaccine response from 199 cancer patients receiving BNT162b2 vaccine.ResultsWe show that C-reactive protein (CRP; general marker of inflammation), interleukin (IL)-15 (a pro-inflammatory cytokine), IL-18 (interferon-gamma inducing factor), and placental growth factor (an angiogenic cytokine) can correctly classify patients with a diminished vaccine response assessed at day 49 with >80% accuracy. Amongst these, CRP showed the highest predictive value for poor response to vaccine administration. Importantly, this unique signature of vaccine response was present at different studied timepoints both before and after vaccination and was not majorly affected by different anti-cancer treatments.ConclusionWhile we propose a blood-based signature of cytokines and growth factors that can be employed in identifying cancer patients at continued risk of COVID-19, our data also importantly suggest that such a signature could reflect the inherent make-up of some cancer patients who are also refractive to immunotherapy.
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- 2022
22. Systemic treatment of localized colorectal cancer
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Hans Dedecker, Timon Vandamme, Laure-Anne Teuwen, Laura Wuyts, Hans Prenen, Albert Jan ten Tije, and Marc Peeters
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Human medicine - Abstract
In lymph-node-positive colorectal cancer, surgical resection alone might not be curative, and additional systemic chemotherapy might be indicated. Reported 5-year survival rates after surgical resection alone are 99% for stage I and 68% 83% for stage II, whereas in patients with stage III, lymph-node-positive disease a 5-year survival of 45% 65% was seen (Brierley et al., 2016). To determine who might benefit from additional systemic adjuvant therapy, an adequate assessment of the risk of relapse is essential. Next to the disease stage, this risk of relapse can be determined by clinicopathological features of the tumor, molecular markers, and DNA mismatch repair (dMMR)/microsatellite instability (MSI) status. The presence of circulating tumor cells and circulating tumor DNA (ctDNA) postresection can be a potential prognostic biomarker and is currently the subject of ongoing trials (Tie et al., 2019). Different chemotherapy regimens, mainly 5-fluorouracil(FU)-based with or without additional oxaliplatin, and treatment durations have been proposed for adjuvant treatment of stage II and stage III disease. In this chapter, we will discuss risk assessment of stage II disease, selection and duration of a chemotherapy regimen in stage II and III, nonchemotherapy-based interventions, and use of adjuvant treatment in specific populations. Finally, we will review neoadjuvant approaches and future perspectives for adjuvant therapy in colorectal cancer.
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- 2022
23. Chapter 16 - Systemic treatment of localized colorectal cancer
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Hans, Dedecker, Timon, Vandamme, Laure-Anne, Teuwen, Laura, Wuyts, Hans, Prenen, Tije, ten, Jan, Albert, and Marc, Peeters
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- 2022
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24. REDUCED HUMORAL IMMUNE RESPONSE AFTER BNT162B2 COVID-19 MRNA VACCINATION IN CANCER PATIENTS UNDER ANTI-NEOPLASTIC TREATMENT
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Kristof Y. Neven, S. Vande Kerckhove, Laure-Anne Teuwen, Manon T. Huizing, Ella Roelant, P. van Dam, Pieter Pannus, S. De Keersmaecker, I. Van der Massen, Marc Peeters, Isabelle Desombere, Bart Peeters, Timon Vandamme, Kevin K. Ariën, Y. Debie, Greetje Vanhoutte, Sébastien Anguille, Maria E Goossens, L. Verbruggen, M. Van Den Bulcke, Geert A. Martens, and S. Raats
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safety ,Cancer Research ,medicine.medical_specialty ,COVID-19 Vaccines ,medicine.medical_treatment ,Antineoplastic Agents ,Hematopoietic stem cell transplantation ,Booster dose ,Gastroenterology ,Internal medicine ,Neoplasms ,medicine ,Humans ,cancer ,Prospective Studies ,RNA, Messenger ,Adverse effect ,BNT162 Vaccine ,Original Research ,Chemotherapy ,anti-RBD IgG antibody response ,business.industry ,SARS-CoV-2 ,Vaccination ,Antibody titer ,Cancer ,COVID-19 ,medicine.disease ,Immunity, Humoral ,BNT162b2 COVID-19 vaccination ,Oncology ,Rituximab ,Human medicine ,business ,Anti-neoplastic treatment ,medicine.drug - Abstract
Background: Cancer patients are at a higher risk of developing severe coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccination in cancer patients undergoing treatment remain unclear. Patients and methods: In this interventional prospective multicohort study, priming and booster doses of the BNT162b2 COVID-19 vaccine were administered 21 days apart to solid tumor patients receiving chemotherapy, immunotherapy, targeted or hormonal therapy, and patients with a hematologic malignancy receiving rituximab or after allogeneic hematopoietic stem cell transplantation. Vaccine safety and efficacy (until 3 months post-booster) were assessed. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD) antibody levels were followed over time (until 28 days after the booster) and in vitro SARS-CoV-2 50% neutralization titers (NT50) toward the wild-type Wuhan strain were analyzed 28 days after the booster. Results: Local and systemic adverse events (AEs) were mostly mild to moderate (only 1%-3% of patients experienced severe AEs). Local, but not systemic, AEs occurred more frequently after the booster dose. Twenty-eight days after the booster vaccination of 197 cancer patients, RBD-binding antibody titers and NT50 were lower in the chemotherapy group {234.05 IU/ml [95% confidence interval (CI) 122.10-448.66] and 24.54 (95% CI 14.50-41.52), respectively} compared with healthy individuals [1844.93 IU/ml (95% CI 1383.57-2460.14) and 122.63 (95% CI 76.85-195.67), respectively], irrespective of timing of vaccination during chemotherapy cycles. Extremely low antibody responses were seen in hematology patients receiving rituximab; only two patients had RBD-binding antibody titers necessary for 50% protection against symptomatic SARS-CoV-2 infection (
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- 2021
25. Protocols for endothelial cell isolation from mouse tissues: kidney, spleen, and testis
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Mila Borri, Sébastien J. Dumas, Elda Meta, Melissa García-Caballero, Guy Eelen, Joanna Kalucka, Peter Carmeliet, Kim D. Falkenberg, Mieke Dewerchin, Katerina Rohlenova, Luc Schoonjans, Xuri Li, Liliana Sokol, Laura P.M.H. de Rooij, Rongyuan Chen, Koen Veys, Nadine V. Conchinha, Laure-Anne Teuwen, Magdalena Parys, Lucas Treps, Vincent Geldhof, Jermaine Goveia, Charlotte Dubois, and Pauline de Zeeuw
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Male ,Pathology ,medicine.medical_specialty ,Science (General) ,Single Cell ,Spleen ,Biology ,Kidney ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Mice ,Q1-390 ,Testis ,medicine ,Protocol ,Animals ,Flow Cytometry/Mass Cytometry ,030304 developmental biology ,0303 health sciences ,General Immunology and Microbiology ,General Neuroscience ,030302 biochemistry & molecular biology ,Acute kidney injury ,Cancer ,Endothelial Cells ,Cell sorting ,medicine.disease ,Flow Cytometry ,Phenotype ,3. Good health ,Endothelial stem cell ,medicine.anatomical_structure ,Cell isolation ,Kidney disease - Abstract
Summary Endothelial cells (ECs) exhibit phenotypic and functional tissue specificities, critical for studies in the vascular field and beyond. Thus, tissue-specific methods for isolation of highly purified ECs are necessary. Kidney, spleen, and testis ECs are relevant players in health and diseases such as chronic kidney disease, acute kidney injury, myelofibrosis, and cancer. Here, we provide tailored protocols for rapid and reproducible EC purification established for scRNA sequencing from these adult murine tissues using the combination of magnetic- and fluorescence-activated cell sorting. For complete details on the use and execution of these protocols, please refer to Kalucka et al. (2020) and Dumas et al. (2020)., Graphical abstract, Highlights • Protocols for isolation of murine endothelial cells applicable for scRNA-seq • Efficient isolation of ECs from the kidney, spleen, and testis • Combination of magnetic- and fluorescence-activated cell sorting • High purity and quality of isolated murine endothelial cells evident from scRNA-seq, Endothelial cells (ECs) exhibit phenotypic and functional tissue specificities, critical for studies in the vascular field and beyond. Thus, tissue-specific methods for isolation of highly purified ECs are necessary. Kidney, spleen, and testis ECs are relevant players in health and diseases such as chronic kidney disease, acute kidney injury, myelofibrosis, and cancer. Here, we provide tailored protocols for rapid and reproducible EC purification established for scRNA sequencing from these adult murine tissues using the combination of magnetic- and fluorescence-activated cell sorting.
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- 2021
26. Protocols for endothelial cell isolation from mouse tissues: brain, choroid, lung, and muscle
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Melissa García-Caballero, Magdalena Parys, Lucas Treps, Luc Schoonjans, Rongyuan Chen, Mila Borri, Guy Eelen, Vincent Geldhof, Peter Carmeliet, Mieke Dewerchin, Joanna Kalucka, Charlotte Dubois, Pauline de Zeeuw, Jermaine Goveia, Koen Veys, Laure-Anne Teuwen, Liliana Sokol, Nadine V. Conchinha, Sébastien J. Dumas, Elda Meta, Kim D. Falkenberg, Katerina Rohlenova, Xuri Li, and Laura P.M.H. de Rooij
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Male ,Pathology ,medicine.medical_specialty ,Science (General) ,Single Cell ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,Q1-390 ,0302 clinical medicine ,Protocol ,medicine ,Animals ,Flow Cytometry/Mass Cytometry ,Lung ,030304 developmental biology ,0303 health sciences ,General Immunology and Microbiology ,Choroid ,Muscles ,General Neuroscience ,Brain ,Endothelial Cells ,Cell sorting ,Flow Cytometry ,medicine.disease ,Phenotype ,Pulmonary hypertension ,3. Good health ,Mice, Inbred C57BL ,Endothelial stem cell ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Sarcopenia ,Cell isolation ,Blood vessel - Abstract
Summary Endothelial cells (ECs) harbor distinct phenotypical and functional characteristics depending on their tissue localization and contribute to brain, eye, lung, and muscle diseases such as dementia, macular degeneration, pulmonary hypertension, and sarcopenia. To study their function, isolation of pure ECs in high quantities is crucial. Here, we describe protocols for rapid and reproducible blood vessel EC purification established for scRNA sequencing from murine tissues using mechanical and enzymatic digestion followed by magnetic and fluorescence-activated cell sorting. For complete details on the use and execution of these protocol, please refer to Kalucka et al. (2020), Rohlenova et al. (2020), and Goveia et al. (2020)., Graphical Abstract, Highlights • Protocols for isolation of murine endothelial cells designed for scRNA-seq • Rapid and efficient isolation of ECs from brain, choroid, lung, and muscle • Combination of magnetic and fluorescent activated cell sorting • High purity and quality of isolated murine endothelial cells evident from scRNA-seq, Endothelial cells (ECs) harbor distinct phenotypical and functional characteristics depending on their tissue localization and contribute to brain, eye, lung, and muscle diseases such as dementia, macular degeneration, pulmonary hypertension, and sarcopenia. To study their function, isolation of pure ECs in high quantities is crucial. Here, we describe protocols for rapid and reproducible blood vessel EC purification established for scRNA sequencing from murine tissues using mechanical and enzymatic digestion followed by magnetic and fluorescence-activated cell sorting.
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- 2021
27. Corrigendum to 'itraconazole for COVID-19: Preclinical studies and a proof-of-concept randomized clinical trial Laurens'
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Geert Verbeke, Thuc Nguyen Dan Do, Geert Meyfroidt, Thomas Vanassche, Joana Rocha-Pereira, Birgit Weynand, Peter Verhamme, Timothy Devos, Ewout Landeloos, Robbert Boudewijns, Iwein Gyselinck, Matthias M. Engelen, Winston Chiu, Pieter Vermeersch, Paul De Munter, Xinyu Wang, Isabel Spriet, Johan Neyts, Wim Janssens, Xin Zhang, Eric Van Wijngaerden, Laure Anne Teuwen, Sebastiaan ter Horst, Robin Vos, Joost Wauters, Vincent Geldhof, Ann Belmans, Bert Vandenberk, Leen Delang, Suzanne J.F. Kaptein, Erwin Dreesen, Tatjana Geukens, Laurens Liesenborghs, Lana Langendries, Sofie Jacobs, Helga Ceunen, Dirk Jochmans, Lorenz Van der Linden, Barbara Debaveye, NEYTS, Johan/0000-0002-0033-7514, Dreesen, Erwin/0000-0002-0785-2930, and Vermeersch, Pieter/0000-0001-7076-061X
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Male ,medicine.medical_specialty ,2019-20 coronavirus outbreak ,Medicine (General) ,Coronavirus disease 2019 (COVID-19) ,Itraconazole ,Pneumonia, Viral ,Section (typography) ,Drug Evaluation, Preclinical ,MEDLINE ,Antiviral Agents ,Proof of Concept Study ,General Biochemistry, Genetics and Molecular Biology ,law.invention ,R5-920 ,Randomized controlled trial ,law ,Chlorocebus aethiops ,medicine ,Animals ,Humans ,Medical physics ,Vero Cells ,Mesocricetus ,SARS-CoV-2 ,business.industry ,Published Erratum ,COVID-19 ,General Medicine ,Middle Aged ,COVID-19 Drug Treatment ,Disease Models, Animal ,Treatment Outcome ,Proof of concept ,Medicine ,Female ,Corrigendum ,business ,medicine.drug - Abstract
The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19.Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated.In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and because an interim analysis showed no signal for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19) for itraconazole vs standard of care.Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. This prompted the premature termination of the proof-of-concept clinical study.KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation.
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- 2021
28. Tumor vessel co-option probed by single-cell analysis
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Steven Van Laere, Mieke Dewerchin, Lena-Christin Conradi, Peter Carmeliet, Anna Rita Cantelmo, Federico Taverna, Massimiliano Mazzone, Yonglun Luo, Stefan Vinckier, Stefaan J. Soenen, Nuphar Veiga, Tobias K. Karakach, Peter B. Vermeulen, Lucas Treps, Joanna Kalucka, Sébastien J. Dumas, Luc Dirix, Elda Meta, Shawez Khan, Vincent Geldhof, Guy Eelen, Laure-Anne Teuwen, Luc Schoonjans, Nadine V. Conchinha, Katerina Rohlenova, Lisa M. Becker, Anne Cuypers, Melissa García-Caballero, Laura P.M.H. de Rooij, Jacob Amersfoort, [Teuwen,LA, De Roji,PMH, Cuypers,A, Rohlenova,A, Dumas,SH, García-Caballero,M, Meta,E, Amersfoort,J, Taverna,F, Becker,LM, Veiga,N, Cantelmo,AR, Geldhof,V, Conchinha,NV, Kalucka,J, Treps,L, Conradi,LC, Khan,S, Karakach,TK, Vinckier,S, Schoonjans,L, Eelen,G, Dewerchin,M, Carmeliet,P] Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium. [Teuwen,LA, Van Laere,S, Dirix,L, Vermeulen,P] Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp, Belgium. [Teuwen,LA, Vermeulen,P] Center for Oncological Research, University of Antwerp, Antwerp, Belgium. [Soenen,S] NanoHealth and Optical Imaging Group, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium. [Schoonjans,L, Carmeliet,P] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China. [Mazzone,M] Laboratory of Tumor Inflammation and Angiogenesis, CCB, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium. [Luo,Y] Department of Biomedicine, Aarhus University, Aarhus, Denmark. [Luo,Y] Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, Qingdao, P.R. China. [Luo,Y] BGI-Shenzhen, Shenzhen, China. [Luo,Y] China National GeneBank, BGI-Shenzhen, Shenzhen, P.R. China. [Carmeliet,P] Laboratory of Angiogenesis and Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark. [Rohlenova,K] Institute of Biotechnology of the Czech Academy of Sciences, Praha – za´ pad, Central Bohemia, Czechia. [García-Caballero,M] Department of Molecular Biology and Biochemistry, Faculty of Sciences, and IBIMA (Biomedical Research Institute of Málaga), University of Málaga, Andalucía Tech, Málaga, Spain. [Cantelmo,AR] Laboratory of Cell Physiology, Lille University, Villeneuve d’Ascq, France. [Kalucka,J] Aarhus Institute of Advanced Studies (AIAS), Department of Biomedicine, Aarhus University, Aarhus, Denmark. [Conradi,LC] Clinic of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany. [Khan,S] National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. [Karakach,TK] Bioinformatics Core Laboratory, Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada. [Karakach,TK] Rady Faculty of Health Sciences, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba Canada., L.-A.T., L.D., S.V.L., and P.V. are supported by Fonds Oncologie Augustinus-Koning Boudewijnstichting and GZA Ziekenhuizen, A.C., K.R., N.V.C., L.P.M.H.d.R., and L.T. by the Fonds Wetenschappelijk Onderzoek (FWO), S.J.D. by a Marie Curie-IEF fellowship, V.G. by Strategisch Basisonderzoek FWO (SB-FWO), Y.L. by BGI-Research, Danish Research Council for Independent Research (DFF-1337-00128), Sapere Aude Young Research Talent Prize (DFF-1335–00763A), and Aarhus University Strategic Grant (AU-iCRISPR), and and P.C. by Methusalem funding (Flemish government), Fund for Scientific Research-Flanders (FWO-Vlaanderen), Foundation Against Cancer (2016-078), Kom op tegen Kanker (Stand up to Cancer, Flemish Cancer Society), European Research Council (ERC Proof of Concept grant ERC-713758 and Advanced ERC Research grant EU-ERC743074), and a NNF Laureate Research Grant from Novo Nordisk Foundation (NNF19OC0055802).
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Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor [Medical Subject Headings] ,0301 basic medicine ,Lung Neoplasms ,Diseases::Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Urologic Neoplasms::Kidney Neoplasms [Medical Subject Headings] ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Cytological Techniques::Single-Cell Analysis [Medical Subject Headings] ,Vascular permeability ,Metastasis ,Transcriptome ,anti-angiogenic therapy ,Mice ,0302 clinical medicine ,Single-cell analysis ,Neoplasms ,Organisms::Eukaryota::Animals [Medical Subject Headings] ,Anatomy::Cells::Epithelial Cells::Endothelial Cells [Medical Subject Headings] ,Macrophage ,Myeloid Cells ,Biology (General) ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Inbred Strains::Mice, Inbred BALB C [Medical Subject Headings] ,Inbred BALB C ,Mice, Inbred BALB C ,Tumor ,cancer cells ,endothelial cells ,macrophages ,metastasis ,pericytes ,resistance ,single-cell RNA sequencing ,tumor angiogenesis ,tumor vessel co-option ,Animals ,Cell Line, Tumor ,Endothelial Cells ,Female ,Kidney Neoplasms ,Macrophages ,Pericytes ,Single-Cell Analysis ,Diseases::Neoplasms [Medical Subject Headings] ,3. Good health ,Metástasis de la neoplasia ,Pericitos ,Anatomy::Cells::Pericytes [Medical Subject Headings] ,Cell type ,QH301-705.5 ,Anatomy::Cells::Myeloid Cells [Medical Subject Headings] ,Biology ,Diseases::Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms [Medical Subject Headings] ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,03 medical and health sciences ,medicine ,Macrófagos ,Inductores de la angiogénesis ,Células endoteliales ,Cancer ,medicine.disease ,030104 developmental biology ,Cancer cell ,Cancer research ,Human medicine ,030217 neurology & neurosurgery - Abstract
Tumor vessel co-option is poorly understood, yet it is a resistance mechanism against anti-angiogenic therapy (AAT). The heterogeneity of co-opted endothelial cells (ECs) and pericytes, co-opting cancer and myeloid cells in tumors growing via vessel co-option, has not been investigated at the single-cell level. Here, we use a murine AAT-resistant lung tumor model, in which VEGF-targeting induces vessel co-option for continued growth. Single-cell RNA sequencing (scRNA-seq) of 31,964 cells reveals, unexpectedly, a largely similar transcriptome of co-opted tumor ECs (TECs) and pericytes as their healthy counterparts. Notably, we identify cell types that might contribute to vessel co-option, i.e., an invasive cancer-cell subtype, possibly assisted by a matrix-remodeling macrophage population, and another M1-like macrophage subtype, possibly involved in keeping or rendering vascular cells quiescent. ispartof: CELL REPORTS vol:35 issue:11 ispartof: location:United States status: published
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- 2021
29. Management of small bowel adenocarcinoma: making the most of the available evidence to inform routine practice
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Marc Peeters, Laure-Anne Teuwen, and Hadi Mazlom
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Bevacizumab ,Colorectal cancer ,medicine.medical_treatment ,Disease ,Pembrolizumab ,Adenocarcinoma ,03 medical and health sciences ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Clinical Trials, Phase II as Topic ,Rare Diseases ,Antineoplastic Combined Chemotherapy Protocols ,Intestinal Neoplasms ,Intestine, Small ,medicine ,Humans ,Intensive care medicine ,Protein Kinase Inhibitors ,Chemotherapy ,Cetuximab ,business.industry ,medicine.disease ,030104 developmental biology ,Oncology ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Localized disease ,Human medicine ,business ,Rare disease ,medicine.drug - Abstract
Purpose of review Small bowel adenocarcinoma (SBA) is a rare disease, for which few studies have been conducted so far. Therefore, most treatment recommendations have been extrapolated from trials in colorectal cancer. In this review, we revise available data that could improve the management of SBA, with a particular focus on systemic therapy. Recent findings For advanced/irresectable disease, first-line doublet chemotherapy remains standard of care. It is uncertain whether extending treatment to triplet chemotherapy brings added benefit. Pembrolizumab is an accepted treatment modality for mismatch repair-deficient tumors, yet might also be active in microsatellite stable tumors. More trials with immunotherapy are underway. Although there is no place for anti-EGFR monotherapy, the addition of cetuximab to chemotherapy should be investigated further. Two trials suggest an added value of bevacizumab to chemotherapy, yet larger trials are needed to confirm these data. For localized disease, the role of (neo)adjuvant chemotherapy is under investigation. Summary For decades, patients with SBA have probably been treated suboptimal by basing treatment recommendations on data from colorectal cancer. An effort for SBA-specific trials and/or inclusion of SBA patients in basket trials is of utmost importance in order to improve outcome for these patients.
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- 2021
30. Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial
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Lana Langendries, Bert Vandenberk, Pieter Vermeersch, Iwein Gyselinck, Geert Verbeke, Vincent Geldhof, Laurens Liesenborghs, Joost Wauters, Leen Delang, Timothy Devos, Robbert Boudewijns, Ewout Landeloos, Sofie Jacobs, Robin Vos, Helga Ceunen, Eric Van Wijngaerden, Paul De Munter, Thomas Vanassche, Dirk Jochmans, Isabel Spriet, Sebastiaan ter Horst, Barbara Debaveye, Xinyu Wang, Suzanne J.F. Kaptein, Geert Meyfroidt, Lorenz Van der Linden, Peter Verhamme, Laure-Anne Teuwen, Erwin Dreesen, Johan Neyts, Wim Janssens, Winston Chiu, Joana Rocha-Pereira, Xin Zhang, Birgit Weynand, Matthias M. Engelen, Tatjana Geukens, Ann Belmans, and Thuc Nguyen Dan Do
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0301 basic medicine ,Drug ,medicine.medical_specialty ,Medicine (General) ,Research paper ,Itraconazole ,media_common.quotation_subject ,Antifungal drug ,General Biochemistry, Genetics and Molecular Biology ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,antivirals ,R5-920 ,Randomized controlled trial ,law ,Internal medicine ,medicine ,media_common ,drug repurposing ,business.industry ,SARS-CoV-2 ,COVID-19 ,General Medicine ,Interim analysis ,3. Good health ,itraconazole ,Clinical trial ,Drug repositioning ,030104 developmental biology ,030220 oncology & carcinogenesis ,Medicine ,business ,Viral load ,medicine.drug - Abstract
Background: The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19.Methods: Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated.Findings: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and because an interim analysis showed no signal for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19) for itraconazole vs standard of care.Interpretation: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. This prompted the premature termination of the proof-of-concept clinical study. (C) 2021 The Authors. Published by Elsevier B.V. This project has received funding from the Covid-19-Fund KU Leuven / University Hospitals Leuven, the COVID-19 call of the Research Foundation - Flanders (FWO) (grant G0G4820N), the European Union's Horizon 2020 research and innovation program (Grant 101003627, Swift COronavirus therapeutics REsponse project) and the Bill and Melinda Gates Foundation (Grant INV-00636). LLi is member of the Institute of Tropical Medicine's Outbreak Research Team which is financially supported by the Department of Economy, Science and Innovation (EWI) of the Flemish government. BV is supported by a research grant of the Frans Van de Werf Fund for Clinical Cardiovascular Research. P. Verhamme, TV, P. Vermeersch are senior clinical investigators of the FWO. We thank Johnson & Johnson for determining drug concentrations in hamster samples and for providing guidance on the dosing. We thank Lindsey Bervoets, Carolien De Keyzer, Elke Maas and Jasper Rymentants for the technical support with the animal experiments.
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- 2021
31. Role and therapeutic potential of dietary ketone bodies in lymph vessel growth
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Ann Bouché, Massimiliano Mazzone, Joris Souffreau, Stefan Vinckier, Mieke Dewerchin, Rosa Martín-Pérez, Bart Ghesquière, Peter Carmeliet, Anh-Co Khanh Truong, Pauline de Zeeuw, Ivo Cornelissen, Annalisa Zecchin, Wesley Vermaelen, Laure-Anne Teuwen, Melissa García-Caballero, and Guy Eelen
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medicine.medical_specialty ,Ketogenic ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,government.form_of_government ,Ketone Bodies ,Mice ,Immune system ,Physiology (medical) ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Humans ,OXCT1 ,Lymphatic Vessels ,Diet, Ketogenic ,Oxidation-Reduction ,Diet ,Chemistry ,Cell Biology ,Lymphangiogenesis ,Lymphatic Endothelium ,Endocrinology ,Lymphatic system ,Ketone bodies ,government ,sense organs ,Lymph ,Ketogenic diet - Abstract
Lymphatic vessels (LVs), lined by lymphatic endothelial cells (LECs), are indispensable for life1. However, the role of metabolism in LECs has been incompletely elucidated. In the present study, it is reported that LEC-specific loss of OXCT1, a key enzyme of ketone body oxidation2, reduces LEC proliferation, migration and vessel sprouting in vitro and impairs lymphangiogenesis in development and disease in Prox1ΔOXCT1 mice. Mechanistically, OXCT1 silencing lowers acetyl-CoA levels, tricarboxylic acid cycle metabolite pools, and nucleotide precursor and deoxynucleotide triphosphate levels required for LEC proliferation. Ketone body supplementation to LECs induces the opposite effects. Notably, elevation of lymph ketone body levels by a high-fat, low-carbohydrate ketogenic diet or by administration of the ketone body β-hydroxybutyrate increases lymphangiogenesis after corneal injury and myocardial infarction. Intriguingly, in a mouse model of microsurgical ablation of LVs in the tail, which repeats features of acquired lymphoedema in humans, the ketogenic diet improves LV function and growth, reduces infiltration of anti-lymphangiogenic immune cells and decreases oedema, suggesting a novel dietary therapeutic opportunity. ispartof: Nature Metabolism vol:1 issue:7 pages:666-675 ispartof: location:Germany status: Published online
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- 2019
32. Single cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast
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Vincent Geldhof, Laura P. M. H. de Rooij, Liliana Sokol, Jacob Amersfoort, Maxim De Schepper, Katerina Rohlenova, Griet Hoste, Adriaan Vanderstichele, Anne-Marie Delsupehe, Edoardo Isnaldi, Naima Dai, Federico Taverna, Shawez Khan, Anh-Co K. Truong, Laure-Anne Teuwen, François Richard, Lucas Treps, Ann Smeets, Ines Nevelsteen, Birgit Weynand, Stefan Vinckier, Luc Schoonjans, Joanna Kalucka, Christine Desmedt, Patrick Neven, Massimiliano Mazzone, Giuseppe Floris, Kevin Punie, Mieke Dewerchin, Guy Eelen, Hans Wildiers, Xuri Li, Yonglun Luo, and Peter Carmeliet
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Multidisciplinary ,Breast Neoplasms/pathology ,Endothelial Cells/pathology ,PPAR gamma/genetics ,Immunity ,General Physics and Astronomy ,Endothelial Cells ,Breast Neoplasms ,General Chemistry ,Ligands ,Lipids ,General Biochemistry, Genetics and Molecular Biology ,Metformin ,PPAR gamma ,Metformin/pharmacology ,Humans ,RNA ,Female ,Human medicine ,Retrospective Studies - Abstract
Since a detailed inventory of endothelial cell (EC) heterogeneity in breast cancer (BC) is lacking, here we perform single cell RNA-sequencing of 26,515 cells (including 8433 ECs) from 9 BC patients and compare them to published EC taxonomies from lung tumors. Angiogenic ECs are phenotypically similar, while other EC subtypes are different. Predictive interactome analysis reveals known but also previously unreported receptor-ligand interactions between ECs and immune cells, suggesting an involvement of breast EC subtypes in immune responses. We also identify a capillary EC subtype (LIPEC (Lipid Processing EC)), which expresses genes involved in lipid processing that are regulated by PPAR-gamma and is more abundant in peri-tumoral breast tissue. Retrospective analysis of 4648 BC patients reveals that treatment with metformin (an indirect PPAR-gamma signaling activator) provides long-lasting clinical benefit and is positively associated with LIPEC abundance. Our findings warrant further exploration of this LIPEC/PPAR-gamma link for BC treatment. Tumor blood vessels contribute to cancer growth, invasion and metastasis. Here, by using single cell transcriptomics, the authors report an inventory of endothelial cell heterogeneity in patients with breast cancer, including a subtype that expresses genes involved in lipid processing and is regulated by PPAR-gamma.
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- 2021
33. Antibody Response after BNT162B2 COVID-19 mRNA Vaccination in Cancer Patients Under Anti-Neoplastic Treatment
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Pieter Pannus, Kevin K. Ariën, Sébastien Anguille, Marc Peeters, Kristof Y. Neven, Peter van Dam, Manon T. Huizing, Isabelle Desombere, Ella Roelant, Laure-Anne Teuwen, Marc Van Den Bulcke, Isolde Van der Massen, Sara Vande Kerckhove, Geert A. Martens, Sven De Keersmaecker, Timon Vandamme, Silke Raats, Greetje Vanhoutte, Lise Verbruggen, Bart Peeters, and Maria E Goossens
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Chemotherapy ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Cancer ,Hematopoietic stem cell transplantation ,medicine.disease ,Vaccination ,Internal medicine ,Clinical endpoint ,Medicine ,Hormonal therapy ,Rituximab ,business ,Adverse effect ,medicine.drug - Abstract
Background: Cancer patients are at higher risk of developing severe COVID-19. However, safety and efficacy of COVID-19 vaccination in cancer patients undergoing treatment is unclear. Methods: In this interventional prospective multi-cohort study, priming and booster doses of the BNT162b2 COVID-19 vaccine were administered 21 days apart to solid tumor patients receiving chemotherapy, immunotherapy, targeted- or hormonal therapy, and patients with a hematologic malignancy receiving rituximab or after allogeneic hematopoietic stem cell transplantation. Primary endpoint was anti-SARS-CoV-2 receptor binding domain (RBD) antibody level at 28 days post-booster. Anti-RBD IgG titers above 200 IU/ml was used to define high-responders as it leads to a neutralization response required for 50% protection against symptomatic SARS-CoV-2 infection in 268 independent subjects. Secondary endpoints included self-reported adverse events (AEs), antibody response over time and number of breakthrough infections after vaccination. Findings: 28 days post-booster vaccination of 197 cancer patients, antibody response was lower in the hematological cohort (geometric mean titer (GMT) 17·61 IU/mL [95% CI 7·17-43·24]) and the chemotherapy cohort (GMT 234·05 IU/mL [95% 95%CI 122·10-448·66]) when compared to healthy individuals (n=40; GMT 1844·93 IU/mL [95% CI 1383·57-2460·14]), irrespective of timing of vaccination during chemotherapy cycles. Only 55% and 7% of patients receiving chemotherapy or rituximab could be categorized as high-responders at 28 days post-booster. During the study period, five subjects tested positive for SARS-CoV-2 infection, including three after full vaccination. Local and systemic AEs were mostly mild to moderate, with only 1-3% of patients experiencing severe AEs. Local, but not systemic, AEs occurred more frequently after booster than after priming dose. Interpretation: The BNT162b2 vaccine is well-tolerated in cancer patients under active treatment. However, the antibody response of immunized cancer patients was delayed and diminished, mainly in patients receiving chemotherapy or rituximab, resulting in breakthrough infections. Trial Registration: EudraCT number 2021-000300-38 Funding: The regulatory sponsor was the Antwerp University Hospital (EudraCT number 2021-000300-38). The trial was funded by the Belgian Government through Sciensano (COVID-19_SC004, COVID- 19_SC059, COVID-19_SC061). Declaration of Interest: MP declares to have an advisory role within Remedus, all other authors declare no competing interests. Ethical Approval: The study was approved by the local ethics committee and was executed in accordance with Good Clinical Practice and the Declaration of Helsinki (ICH GCP E6(R2)).
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- 2021
34. Single-cell RNA sequencing reveals renal endothelium heterogeneity and metabolic adaptation to water deprivation
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Peter Carmeliet, Laure-Anne Teuwen, Lin Lin, Luc Schoonjans, Guy Eelen, Rongyuan Chen, Carla De Legher, Tobias K. Karakach, Sébastien J. Dumas, Weisi Lu, Joanna Kalucka, Elda Meta, Lars Bolund, Nadine V. Conchinha, Mieke Dewerchin, Stefan Vinckier, Kim D. Falkenberg, Katerina Rohlenova, Federico Taverna, Yonglun Luo, Xuri Li, Jermaine Goveia, Laura P.M.H. de Rooij, Shawez Khan, Ton J. Rabelink, Magdalena Parys, and Mila Borri
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0301 basic medicine ,Male ,Kidney ,Transcriptome ,Mice ,0302 clinical medicine ,AMINO-ACIDS ,OSMOLYTES ,GENE-EXPRESSION ,Dehydration ,Chemistry ,urine concentration ,renal endothelial cells ,General Medicine ,Adaptation, Physiological ,Cell biology ,Endothelial stem cell ,scRNA-sequencing ,medicine.anatomical_structure ,Phenotype ,Nephrology ,Osmotic shock ,Endothelium ,METFORMIN ,Energy metabolism ,oxidative phosphorylation ,MECHANISMS ,03 medical and health sciences ,KIDNEY ,medicine ,Renal medulla ,Animals ,Humans ,IDENTIFICATION ,Osmotic concentration ,Water Deprivation ,business.industry ,Sequence Analysis, RNA ,Endothelial Cells ,dehydration ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,Basic Research ,VOLUME ,INFERENCE ,heterogeneity ,business ,030217 neurology & neurosurgery ,Homeostasis - Abstract
BACKGROUND: Renal endothelial cells from glomerular, cortical, and medullary kidney compartments are exposed to different microenvironmental conditions and support specific kidney processes. However, the heterogeneous phenotypes of these cells remain incompletely inventoried. Osmotic homeostasis is vitally important for regulating cell volume and function, and in mammals, osmotic equilibrium is regulated through the countercurrent system in the renal medulla, where water exchange through endothelium occurs against an osmotic pressure gradient. Dehydration exposes medullary renal endothelial cells to extreme hyperosmolarity, and how these cells adapt to and survive in this hypertonic milieu is unknown. METHODS: We inventoried renal endothelial cell heterogeneity by single-cell RNA sequencing >40,000 mouse renal endothelial cells, and studied transcriptome changes during osmotic adaptation upon water deprivation. We validated our findings by immunostaining and functionally by targeting oxidative phosphorylation in a hyperosmolarity model in vitro and in dehydrated mice in vivo. RESULTS: We identified 24 renal endothelial cell phenotypes (of which eight were novel), highlighting extensive heterogeneity of these cells between and within the cortex, glomeruli, and medulla. In response to dehydration and hypertonicity, medullary renal endothelial cells upregulated the expression of genes involved in the hypoxia response, glycolysis, and-surprisingly-oxidative phosphorylation. Endothelial cells increased oxygen consumption when exposed to hyperosmolarity, whereas blocking oxidative phosphorylation compromised endothelial cell viability during hyperosmotic stress and impaired urine concentration during dehydration. CONCLUSIONS: This study provides a high-resolution atlas of the renal endothelium and highlights extensive renal endothelial cell phenotypic heterogeneity, as well as a previously unrecognized role of oxidative phosphorylation in the metabolic adaptation of medullary renal endothelial cells to water deprivation. ispartof: JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY vol:31 issue:1 pages:118-138 ispartof: location:United States status: published
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- 2020
35. c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis
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Johannes L Zakrzewski, Ben S. Barksby, Jeremy French, Luc Schoonjans, Amy L Collins, Jelena Mann, Matthias Trost, Stuart Robinson, Ulf Klein, Morten A. Karsdal, Hannah L Paish, Amber Knox, Peter Carmeliet, Lee A. Borthwick, Andrew D Blanchard, Git Chung, Rainie Cameron, Neil S. Sheerin, Laure-Anne Teuwen, Ingmar Mederacke, Lucy M Gee, Colin D.A. Brown, Carmel B. Nanthakumar, Thomas G. Bird, Jack Leslie, Sandra Murphy, Robert F. Schwabe, Fiona Oakley, Marina García Macia, Xin Xu, Andrew J. Fisher, Derek A. Mann, Derek Manas, Rachel A. Burgoyne, William J Reilly, Steven A. White, Charlotte Bragg, Saimir Luli, Gourab Sen, Marco Y W Zaki, Colin Nixon, and Julie C. Worrell
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Liver Cirrhosis ,Cell signaling ,Phosphofructokinase-2 ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Liver fibrosis ,Mitosis ,Connective tissue ,Epithelium ,Article ,Mice ,Paracrine signalling ,Fibrosis ,Physiology (medical) ,Paracrine Communication ,Internal Medicine ,medicine ,Animals ,Macrophage ,Monocytes and macrophages ,Mice, Knockout ,Chemistry ,Macrophages ,Growth factor ,Mesenchymal stem cell ,Cell Polarity ,Cell Biology ,medicine.disease ,Proto-Oncogene Proteins c-rel ,Liver Regeneration ,Cell biology ,Mice, Inbred C57BL ,Hydroxyproline ,medicine.anatomical_structure ,Metabolism ,Gene Targeting ,Hepatocytes ,REL ,Cell signalling - Abstract
Fibrosis is a common pathological feature of chronic disease. Deletion of the NF-κB subunit c-Rel limits fibrosis in multiple organs, although the mechanistic nature of this protection is unresolved. Using cell-specific gene-targeting manipulations in mice undergoing liver damage, we elucidate a critical role for c-Rel in controlling metabolic changes required for inflammatory and fibrogenic activities of hepatocytes and macrophages and identify Pfkfb3 as the key downstream metabolic mediator of this response. Independent deletions of Rel in hepatocytes or macrophages suppressed liver fibrosis induced by carbon tetrachloride, while combined deletion had an additive anti-fibrogenic effect. In transforming growth factor-β1-induced hepatocytes, c-Rel regulates expression of a pro-fibrogenic secretome comprising inflammatory molecules and connective tissue growth factor, the latter promoting collagen secretion from HMs. Macrophages lacking c-Rel fail to polarize to M1 or M2 states, explaining reduced fibrosis in RelΔLysM mice. Pharmacological inhibition of c-Rel attenuated multi-organ fibrosis in both murine and human fibrosis. In conclusion, activation of c-Rel/Pfkfb3 in damaged tissue instigates a paracrine signalling network among epithelial, myeloid and mesenchymal cells to stimulate fibrogenesis. Targeting the c-Rel-Pfkfb3 axis has potential for therapeutic applications in fibrotic disease. ispartof: NATURE METABOLISM vol:2 issue:11 ispartof: location:Germany status: published
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- 2020
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36. Itraconazole for COVID-19: Preclinical Studies and a Proof-of-Concept Pilot Clinical Study
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Ewout Landeloos, Tatjana Geukens, Joost Wauters, Geert Meyfroidt, Linden LVd, Iwein Gyselinck, Matthias M. Engelen, Rita Vos, Lana Langendries, Spriet I, Peter Verhamme, Laure-Anne Teuwen, Birgit Weynand, Kaptein Sjf, Laurens Liesenborghs, Leen Delang, Thomas Vanassche, Sofie Jacobs, Eric Van Wijngaerden, Johan Neyts, Wim Janssens, Horst St, Helga Ceunen, Dirk Jochmans, Pieter Vermeersch, Barbara Debaveye, Geert Verbeke, Erwin Dreesen, Ann Belmans, Joana Rocha-Pereira, Paul De Munter, Geldhof, Timothy Devos, Robbert Boudewijns, and Bert Vandenberk
- Subjects
medicine.medical_specialty ,business.industry ,Itraconazole ,Antifungal drug ,Interim analysis ,Clinical trial ,Internal medicine ,Good clinical practice ,medicine ,Dosing ,business ,Viral load ,Declaration of Helsinki ,medicine.drug - Abstract
Background: Drug repurposing is an attractive strategy to rapidly develop affordable therapy against COVID-19. The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 comparable to that of hydroxychloroquine. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19. Methods: Due to the initial absence of preclinical models the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized patients with COVID-19 were randomly assigned to receive standard of care with or without itraconazole. The primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. Other outcomes included time to sustained clinical improvement, duration of supplemental oxygen and evolution of nasopharyngeal viral load. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated. Findings: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and interim analysis that showed no trends for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19), median time to clinical improvement 10 vs 9 days, hazard ratio 0.94 (95% CI 0.56 to 1.60) for itraconazole vs standard of care. Interpretation: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. A proof-of-concept clinical study was ended prematurely because of futility. Trial Registration: (EudraCT 2020-001243-15) Funding: Covid-19-Fund KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation Declaration of Interests: Initial dug screening and discovery of the antiviral effect of itraconazole was done in collaboration with Johnson & Johnson and described in a separate manuscript. Scientists from Johnson & Johnson also performed drug measurements on hamster samples and provided guidance on the dosing regimens for the preclinical studies. The company had no role in the design, execution, analysis, publication or funding of the clinical trial. Author Conflict of Interests: None to declare. Ethics Approval Statement: The institutional Ethical Committee approved all animal experiments (license P065-2020). The study was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki. The protocol was approved by the institutional Ethics Committee and by the Belgian Federal Agency for Medicines and Health Products (EudraCT 2020-001243-15). The trial was part of the DAWn clinical studies.
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- 2020
37. Author Correction: c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis
- Author
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Luc Schoonjans, Git Chung, Rainie Cameron, Hannah L Paish, Rachel A. Burgoyne, Colin Nixon, Julie C. Worrell, Steven A. White, Matthias Trost, Derek Manas, Thomas G. Bird, Xin Xu, Stuart Robinson, Andrew J. Fisher, Ingmar Mederacke, Charlotte Bragg, Saimir Luli, Lucy M Gee, Ben S. Barksby, Colin D.A. Brown, Jack Leslie, Jeremy French, Neil S. Sheerin, Amy L Collins, Morten A. Karsdal, Andrew D Blanchard, Marco Y W Zaki, Gourab Sen, Robert F. Schwabe, Fiona Oakley, Peter Carmeliet, Amber Knox, Marina García Macia, Carmel B. Nanthakumar, Ulf Klein, Laure-Anne Teuwen, Johannes L Zakrzewski, Sandra Murphy, Lee A. Borthwick, Jelena Mann, Derek A. Mann, and William J Reilly
- Subjects
Energy dependent ,Cell signaling ,business.industry ,Endocrinology, Diabetes and Metabolism ,Liver fibrosis ,Human kidney ,Cell Biology ,medicine.disease ,Fibrosis ,Physiology (medical) ,Internal Medicine ,Cancer research ,Medicine ,Macrophage ,business ,REL ,Reprogramming - Abstract
Correction to: Nature Metabolism https://doi.org/10.1038/s42255-020-00306-2, published online 9 November 2020. In the version of this article initially published, in the ×40 diseased human kidney images in Supplementary Fig. 1, the FSGS image duplicated the DN image. The error has been corrected in the HTML version of the article.
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- 2020
38. Tumor vessel disintegration by maximum tolerable PFKFB3 blockade
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Peter Carmeliet, Aleksandra Brajic, Anna Rita Cantelmo, Joanna Kalucka, Bart Ghesquière, Ann Bouché, Ulrike Bruning, Mieke Dewerchin, Laure-Anne Teuwen, Andreas Pircher, Lena-Christin Conradi, and Stefan Vinckier
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0301 basic medicine ,Cancer Research ,Phosphofructokinase-2 ,Pyridines ,Physiology ,Angiogenesis ,Clinical Biochemistry ,Melanoma, Experimental ,Pharmacology ,ANGIOGENESIS ,Metastasis ,NORMALIZATION ,0302 clinical medicine ,PFKFB3 ,Neoplasms ,VASCULATURE ,Neoplasm Metastasis ,Neovascularization, Pathologic ,CANCER ,Primary tumor ,INTEGRITY ,3. Good health ,030220 oncology & carcinogenesis ,GROWTH ,Life Sciences & Biomedicine ,GLYCOLYSIS ,INHIBITION ,Antiangiogenic therapy ,METABOLISM ,Biology ,03 medical and health sciences ,Cell Line, Tumor ,Human Umbilical Vein Endothelial Cells ,medicine ,Animals ,Humans ,Cell Proliferation ,Science & Technology ,Tumor hypoxia ,Activator (genetics) ,Intravasation ,Endothelial Cells ,medicine.disease ,Blockade ,Mice, Inbred C57BL ,Pancreatic Neoplasms ,030104 developmental biology ,Peripheral Vascular Disease ,METASTASIS ,Cancer cell ,Cardiovascular System & Cardiology ,Cancer research - Abstract
Blockade of the glycolytic activator PFKFB3 in cancer cells (using a maximum tolerable dose of 70 mg/kg of the PFKFB3 blocker 3PO) inhibits tumor growth in preclinical models and is currently being tested as a novel anticancer treatment in phase I clinical trials. However, a detailed preclinical analysis of the effects of such maximum tolerable dose of a PFKFB3 blocker on the tumor vasculature is lacking, even though tumor endothelial cells are hyper-glycolytic. We report here that a high dose of 3PO (70 mg/kg), which inhibits cancer cell proliferation and reduces primary tumor growth, causes tumor vessel disintegration, suppresses endothelial cell growth for protracted periods, (model-dependently) aggravates tumor hypoxia, and compromises vascular barrier integrity, thereby rendering tumor vessels more leaky and facilitating cancer cell intravasation and dissemination. These findings contrast to the effects of a low dose of 3PO (25 mg/kg), which induces tumor vessel normalization, characterized by vascular barrier tightening and maturation, but reduces cancer cell intravasation and metastasis. Our findings highlight the importance of adequately dosing a glycolytic inhibitor for anticancer treatment. ispartof: Angiogenesis vol:20 issue:4 pages:599-613 ispartof: location:Germany status: published
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- 2017
39. How glucose, glutamine and fatty acid metabolism shape blood and lymph vessel development
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Laure-Anne Teuwen, Peter Carmeliet, and Vincent Geldhof
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0301 basic medicine ,AEROBIC GLYCOLYSIS ,Glutamine ,Neovascularization, Physiologic ,Biology ,Endothelial cell differentiation ,Epigenesis, Genetic ,03 medical and health sciences ,chemistry.chemical_compound ,PYRUVATE-KINASE M2 ,TRANSPORTER EXPRESSION ,BINDING PROTEIN 4 ,Animals ,Humans ,Glycolysis ,Lymphangiogenesis ,Molecular Biology ,Beta oxidation ,Lymphatic Vessels ,GENE-EXPRESSION ,Lymph vessel development ,Science & Technology ,FOXO TRANSCRIPTION FACTORS ,Fatty acid metabolism ,Fatty Acids ,Gene Expression Regulation, Developmental ,Cell Biology ,Metabolism ,ASPARAGINE SYNTHETASE ,IN-VITRO ,Cell biology ,Citric acid cycle ,ENDOTHELIAL-CELL METABOLISM ,Metabolic pathway ,030104 developmental biology ,Glucose ,chemistry ,Fatty acid oxidation ,Blood Vessels ,Glutamine metabolism ,GROWTH ,Blood vessel development ,Angiogenesis ,Life Sciences & Biomedicine ,Endothelial cell metabolism ,Developmental Biology - Abstract
Recently, endothelial cell metabolism has emerged as an essential driver and regulator of both blood and lymph vessel development. Evidence rapidly builds that metabolism is not only necessary for endothelial cell function, but moreover controls several aspects of the (lymph)-angiogenic process. So far, the best-characterized metabolic pathways to have an impact on angiogenesis are glycolysis, fatty acid oxidation and glutamine metabolism. Glycolysis regulates tip cell behavior by providing ATP, fatty acid oxidation controls stalk cell proliferation by producing nucleotide biomass, and glutamine metabolism is critical for tip and stalk cell dynamics by supporting Krebs cycle anaplerosis, protein production and redox homeostasis, and links to asparagine metabolism. During lymphangiogenesis, glycolysis and fatty acid oxidation are key metabolic pathways. Glycolysis provides energy for growing lymph vessels, while fatty acid oxidation is a critical metabolic regulator of lymphangiogenesis, in part by promoting nucleotide synthesis as well as by mediating epigenetic changes of histone acetylation, which promotes transcription of key lymphatic genes, and hence venous-to-lymphatic endothelial cell differentiation. On the whole, increasing knowledge on the metabolic landscape of endothelial cells offers a fresh impetus to future treatment possibilities of vascular related diseases. ispartof: DEVELOPMENTAL BIOLOGY vol:447 issue:1 pages:90-102 ispartof: location:United States status: published
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- 2019
40. How to Cross the Lymphatic Fence
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Vincent Geldhof, Joanna Kalucka, Peter Carmeliet, and Laure-Anne Teuwen
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Physiology ,government.form_of_government ,030204 cardiovascular system & hematology ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Interstitial fluid ,medicine ,Lymphatic vessel ,Lymphangiogenesis ,Transcellular ,Lymphatic Vessels ,Endothelial Cells ,medicine.disease ,Lymphatic Endothelium ,030104 developmental biology ,Lymphatic system ,Lymphedema ,medicine.anatomical_structure ,Paracellular transport ,government ,Lymph ,Transcytosis ,Cardiology and Cardiovascular Medicine - Abstract
Mammals contain 2 vascular systems: the blood and the lymphatic system. Because the heart pumps the blood under pressure, fluid leaks out from distal capillaries into the interstitium. Lymph vessels then take up this leaked interstitial fluid and transport it back into blood vessels, thereby ensuring fluid homeostasis.1 Malfunctioning of lymph formation leads to deforming lymphedema, for which no curative therapy exists. Therefore, understanding how lymph is formed is a fundamental unresolved question in vascular biology. Because lymphatic capillaries have a mainly junction-free architecture, it was assumed that paracellular (and not transcellular) transport is the predominant mechanism of lymph formation. However, Triacca et al2 report in this issue of Circulation Research that transcellular and paracellular pathways are equally important for lymphatic solute transport and that both transports contribute to the increased lymphatic permeability on a rise in transmural flow and in case of inflammation. Triacca et al2 thus offer a long-awaited answer to the conundrum whether transcellular transport in lymphatic endothelial cells (LECs) contributes to lymph formation. These insights might pave the way for future treatments of lymphedema. Article, see p 1440 Although both vascular systems were described simultaneously by Hippocrates around 400 BC, our understanding of lymphatic vessel biology has lingered behind on that of blood vessels. Undeniably, both systems share several characteristics, that is, both form a hierarchical network of vessels lined by endothelial cells, can adapt the tightness of their interendothelial junctions, and can grow rapidly in disease conditions, contributing to cancer or inflammation.1 However, despite these similarities, they have distinct functions. The lymphatic system maintains tissue fluid homeostasis by absorbing extravasated fluid and transporting it back to the blood. Furthermore, …
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- 2017
41. Author Correction: COVID-19: the vasculature unleashed
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Peter Carmeliet, Laure Anne Teuwen, Vincent Geldhof, and Alessandra Pasut
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Cell biology ,History ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Molecular biology ,business.industry ,Published Erratum ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Comment ,MEDLINE ,Computational biology ,Computer Science Applications ,Education ,Medicine ,business - Abstract
On the basis of emerging evidence from patients with COVID-19, we postulate that endothelial cells are essential contributors to the initiation and propagation of severe COVID-19. Here, we discuss current insights into the link between endothelial cells, viral infection and inflammatory changes and propose novel therapeutic strategies., Here, Carmeliet and colleagues discuss the role of endothelial cells in inflammation and viral infection and propose novel therapeutic strategies for COVID-19.
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- 2020
42. Single-Cell RNA Sequencing Maps Endothelial Metabolic Plasticity in Pathological Angiogenesis
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Jermaine Goveia, Lin Lin, Geert Carmeliet, Dena Panovska, Andreas Pircher, Lena-Christin Conradi, Yizhi Liu, Lars Bolund, Stefan Vinckier, Liliana Sokol, Kim D. Falkenberg, Katerina Rohlenova, Guy Eelen, Tine Van Bergen, Huanming Yang, Rene J. Mclaughlin, Mieke Dewerchin, Abhishek Subramanian, Bernard Thienpont, Nadine Ectors, Tobias K. Karakach, Yonglun Luo, Lucas Treps, Jian Wang, Frank J. T. Staal, Joanna Kalucka, Shawez Khan, Xuri Li, Peter Carmeliet, Yingfeng Zheng, Luc Schoonjans, Laura P.M.H. de Rooij, Patrik De Haes, Melissa García-Caballero, Frederik De Smet, Laure-Anne Teuwen, Federico Taverna, Vincent Geldhof, and Steve Stegen
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Male ,0301 basic medicine ,Lung Neoplasms ,Physiology ,Angiogenesis ,Cell ,Biology ,Marker gene ,Transcriptome ,Macular Degeneration ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Gene expression ,Human Umbilical Vein Endothelial Cells ,medicine ,Animals ,Humans ,Molecular Biology ,Gene ,Neovascularization, Pathologic ,Sequence Analysis, RNA ,Endothelial Cells ,RNA ,Cell Biology ,Phenotype ,Cell biology ,Mice, Inbred C57BL ,HEK293 Cells ,030104 developmental biology ,medicine.anatomical_structure ,Human medicine ,Single-Cell Analysis ,030217 neurology & neurosurgery - Abstract
Endothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor angiogenesis and choroidal neovascularization (CNV), but little is known about individual EC metabolic transcriptomes. By single-cell RNA sequencing 28,337 murine choroidal ECs (CECs) and sprouting CNV-ECs, we constructed a taxonomy to characterize their heterogeneity. Comparison with murine lung tumor ECs (TECs) revealed congruent marker gene expression by distinct EC phenotypes across tissues and diseases, suggesting similar angiogenic mechanisms. Trajectory inference predicted that differentiation of venous to angiogenic ECs was accompanied by metabolic transcriptome plasticity. ECs displayed metabolic transcriptome heterogeneity during cellcycle progression and in quiescence. Hypothesizing that conserved genes are important, we used an integrated analysis, based on congruent transcriptome analysis, CEC-tailored genome-scale metabolic modeling, and gene expression meta-analysis in cross-species datasets, followed by in vitro and in vivo validation, to identify SQLE and ALDH18A1 as previously unknown metabolic angiogenic targets. ispartof: Cell Metabolism vol:31 issue:4 pages:862-877 ispartof: location:United States status: published
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- 2020
43. Single-Cell Transcriptome Atlas of Murine Endothelial Cells
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Federico Taverna, Liliana Sokol, Stefan Vinckier, Nadine V. Conchinha, Xuri Li, Yuxiang Du, Magdalena Parys, Robert A. Fenton, Jermaine Goveia, Koen Veys, Laura P.M.H. de Rooij, Melissa García-Caballero, Laure-Anne Teuwen, Joanna Kalucka, Kim D. Falkenberg, Katerina Rohlenova, Mieke Dewerchin, Bernard Thienpont, Guy Eelen, Yonglun Luo, Charlotte Dubois, Pauline de Zeeuw, Lucas Treps, Mila Borri, Rongyuan Chen, Tobias K. Karakach, Sébastien J. Dumas, Vincent Geldhof, Elda Meta, Peter Carmeliet, Shawez Khan, Luc Schoonjans, Lin Lin, Lars Bolund, and Xiangke Yin
- Subjects
Male ,Spleen ,Biology ,Cardiovascular System ,General Biochemistry, Genetics and Molecular Biology ,Transcriptome ,Mice ,endothelial metabolism ,03 medical and health sciences ,0302 clinical medicine ,Single cell transcriptome ,Testis ,medicine ,Animals ,RNA-Seq ,Gene ,030304 developmental biology ,0303 health sciences ,mouse endothelial atlas ,single-cell RNA-seq ,Muscles ,Brain ,Endothelial Cells ,Skeletal muscle ,Small intestine ,Cell biology ,Gastrointestinal Tract ,Mice, Inbred C57BL ,endothelial-cell heterogeneity ,medicine.anatomical_structure ,Lymphatic system ,Organ Specificity ,Single-Cell Analysis ,030217 neurology & neurosurgery - Abstract
The heterogeneity of endothelial cells (ECs) across tissues remains incompletely inventoried. We constructed an atlas of >32,000 single-EC transcriptomes from 11 mouse tissues and identified 78 EC subclusters, including Aqp7+ intestinal capillaries and angiogenic ECs in healthy tissues. ECs from brain/testis, liver/spleen, small intestine/colon, and skeletal muscle/heart pairwise expressed partially overlapping marker genes. Arterial, venous, and lymphatic ECs shared more markers in more tissues than did heterogeneous capillary ECs. ECs from different vascular beds (arteries, capillaries, veins, lymphatics) exhibited transcriptome similarity across tissues, but the tissue (rather than the vessel) type contributed to the EC heterogeneity. Metabolic transcriptome analysis revealed a similar tissue-grouping phenomenon of ECs and heterogeneous metabolic gene signatures in ECs between tissues and between vascular beds within a single tissue in a tissue-type-dependent pattern. The EC atlas taxonomy enabled identification of EC subclusters in public scRNA-seq datasets and provides a powerful discovery tool and resource value. ispartof: CELL vol:180 issue:4 pages:764-+ ispartof: location:United States status: published
- Published
- 2020
44. An Integrated Gene Expression Landscape Profiling Approach to Identify Lung Tumor Endothelial Cell Heterogeneity and Angiogenic Candidates
- Author
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Albert Wolthuis, Diether Lambrechts, Xavier Sagaert, Wouter Everaerts, Junbin Qian, Yingfeng Zheng, Johan Vansteenkiste, Guy Eelen, Luc Schoonjans, Lena-Christin Conradi, Herbert Decaluwé, Alexander Emmert, Stefan Vinckier, Erik Verbeken, Paul De Leyn, Lin Lin, Shawez Khan, Birgit Weynand, Mieke Dewerchin, Lucas Treps, Liliana Sokol, Baki Topal, Bernard Thienpont, Frank J. T. Staal, Rene J. Mclaughlin, Melissa García-Caballero, Jian Wang, Federico Taverna, Peter Carmeliet, Lars Bolund, Dena Panovska, Andreas Pircher, Laure-Anne Teuwen, Yonglun Luo, Huanming Yang, Els Wauters, Joanna Kalucka, Vincent Geldhof, Francis Impens, Jermaine Goveia, Hanibal Bohnenberger, Bram Boeckx, Massimiliano Mazzone, Frederik De Smet, Vincenzo Lagani, Xuri Li, Tobias K. Karakach, Laura P.M.H. de Rooij, and Katerina Rohlenova
- Subjects
Male ,Vascular Endothelial Growth Factor A ,0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Angiogenesis ,Angiogenesis Inhibitors ,BIOCONDUCTOR PACKAGE ,Basement Membrane ,anti-angiogenic therapy ,angiogenesis ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Single-cell analysis ,Cell Movement ,Carcinoma, Non-Small-Cell Lung ,Gene expression ,Profiling (information science) ,Medicine ,Cluster Analysis ,cancer ,endothelial cells ,endothelial heterogeneity ,multi-omics ,single-cell RNA sequencing ,Animals ,Cell Line, Tumor ,Collagen ,Endothelial Cells ,Endothelium, Vascular ,Female ,Humans ,Phenotype ,Single-Cell Analysis ,Gene Expression Profiling ,Gene Expression Regulation, Neoplastic ,Neovascularization, Pathologic ,Non-Small-Cell Lung ,0303 health sciences ,Tumor ,hemic and immune systems ,CANCER ,REVEAL ,Cell biology ,Vascular endothelial growth factor ,Endothelial stem cell ,Vascular endothelial growth factor A ,Oncology ,030220 oncology & carcinogenesis ,tissues ,education ,INHIBITION ,Biology ,Cell Line ,MECHANISMS ,03 medical and health sciences ,Vascular ,Endothelium ,Neovascularization ,030304 developmental biology ,Pathologic ,Neoplastic ,IDENTIFICATION ,business.industry ,VESSEL NORMALIZATION ,Carcinoma ,R-PACKAGE ,Cell Biology ,COLLAGEN ,Gene expression profiling ,030104 developmental biology ,Gene Expression Regulation ,chemistry ,METASTASIS ,Cancer research ,Lung tumor ,business - Abstract
Heterogeneity of lung tumor endothelial cell (TEC) phenotypes across patients, species (human/mouse), and models (in vivo/in vitro) remains poorly inventoried at the single-cell level. We single-cell RNA (scRNA)-sequenced 56,771 endothelial cells from human/mouse (peri)-tumoral lung and cultured human lung TECs, and detected 17 known and 16 previously unrecognized phenotypes, including TECs putatively regulating immune surveillance. We resolved the canonical tip TECs into a known migratory tip and a putative basement-membrane remodeling breach phenotype. Tip TEC signatures correlated with patient survival, and tip/breach TECs were most sensitive to vascular endothelial growth factor blockade. Only tip TECs were congruent across species/models and shared conserved markers. Integrated analysis of the scRNA-sequenced data with orthogonal multi-omics and meta-analysis data across different human tumors, validated by functional analysis, identified collagen modification as a candidate angiogenic pathway.
- Published
- 2020
45. Management of pulmonary toxicity associated with targeted anticancer therapies
- Author
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Luc Dirix, Laure-Anne Teuwen, and Tom Van den Mooter
- Subjects
Lung Diseases ,Pulmonary toxicity ,medicine.medical_treatment ,Antineoplastic Agents ,Biology ,Pharmacology ,Toxicology ,Risk Factors ,Neoplasms ,medicine ,Humans ,Anaplastic lymphoma kinase ,Molecular Targeted Therapy ,Epidermal growth factor receptor ,Adverse effect ,Growth factor ,Interstitial lung disease ,Cancer ,General Medicine ,medicine.disease ,Mechanism of action ,Cancer research ,biology.protein ,medicine.symptom ,Algorithms - Abstract
Targeted anticancer therapies act by interfering with defined molecular entities and/or biologic pathways. Because of their more specific mechanism of action, adverse events (AEs) on healthy tissues are intended to be minimal, resulting in a different toxicity profile from that observed with conventional cytotoxic chemotherapy. Pulmonary AEs are rare but potentially life-threatening and it is, therefore, critical to recognize early on and manage appropriately.In this review, we aim to offer an overview of both more frequent and rare pulmonary AEs caused by targeted anticancer therapies and discuss possible treatment algorithms. Anti-vascular endothelial growth factor, anti-human epidermal growth factor receptor and anti-CD20 therapy will be reviewed, as well as immune checkpoint inhibitors, anaplastic lymphoma kinase inhibitors and mammalian target of rapamycin inhibitors.Novel agents used in the treatment of cancer have specific side-effects, the result of allergic reactions, on-target and off-target effects. Clinical syndromes associated with pulmonary toxicity vary from bronchospasms, hypersensitivity reactions, pneumonitis, acute respiratory distress, lung bleeding, pleural effusion to pneumothorax. Knowledge of risk factors, a high index of suspicion and a complete diagnostic work-up are essential for limiting the risk of these events becoming life threatening. The development of treatment algorithms is extremely helpful in managing these events. It is probable that these toxicities will be even more frequent with the introduction of combination therapies with the obvious challenge of discerning the responsible agent.
- Published
- 2015
46. Malignancies and anti-TNF therapy in rheumatoid arthritis: a single-center observational cohort study
- Author
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Rene Westhovens, Patrick Verschueren, Laure-Anne Teuwen, and Nathalie Berghen
- Subjects
Adult ,Male ,medicine.medical_specialty ,Population ,Comorbidity ,Malignancy ,Etanercept ,Arthritis, Rheumatoid ,Young Adult ,Rheumatology ,Neoplasms ,Internal medicine ,medicine ,Humans ,Prospective Studies ,education ,Aged ,Aged, 80 and over ,education.field_of_study ,Tumor Necrosis Factor-alpha ,business.industry ,Incidence ,Incidence (epidemiology) ,Adalimumab ,General Medicine ,Middle Aged ,medicine.disease ,Infliximab ,Lymphoproliferative Disorders ,Surgery ,Treatment Outcome ,Standardized mortality ratio ,Antirheumatic Agents ,Rheumatoid arthritis ,Cohort ,Female ,business ,Cohort study - Abstract
Inhibitors of tumor necrosing factor alpha (TNF-a) have proven to be highly effective in the treatment of rheumatoid arthritis (RA). Concerns, however, are raised about the possible association between these treatments and an increased development of malignancies. The objective of this paper was to compare the risk of hematologic and solid malignancies in patients treated for RA with anti-TNF therapy, with the risk in the general population. From January 2000 until January 2012, all RA patients that started treatment with anti-TNF agents were included in this single-center cohort study. The primary outcome of this study was the incidence of malignancy after starting anti-TNF treatment. In our cohort of 365 patients, 34 malignancies were discovered in 30 patients after the start of anti-TNF treatment; 20 patients developed a solid malignancy, 6 a hematologic, 2 a solid and a hematologic malignancy, and 2 patients developed 2 solid malignancies. The overall incidence rate (IR) of malignancy was 1379.1 per 100.000 patient years. The risk or standardized incidence ratio (SIR) of solid malignancy, calculated by comparison with the age-adjusted population in Flanders, was 120.1 in female and 136.7 in male patients. The calculated SIR of hematologic malignancy was 450.8 for women and 473.9 for men. Some immune modulation-related lymphoproliferative disorders regressed spontaneously when stopping TNF blockers. Overall, the malignancy risk in our rheumatoid arthritis patients treated with anti-TNF therapy was slightly higher than in the normal population; the risk of hematologic malignancies was more important.
- Published
- 2015
47. Trastuzumab emtansine in advanced human epidermal growth factor receptor 2-positive breast cancer
- Author
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Tom Van den Mooter, Laure-Anne Teuwen, Annemie Rutten, and Luc Dirix
- Subjects
musculoskeletal diseases ,congenital, hereditary, and neonatal diseases and abnormalities ,Receptor, ErbB-2 ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Antineoplastic Agents ,Breast Neoplasms ,Pharmacology ,Ado-Trastuzumab Emtansine ,Antibodies, Monoclonal, Humanized ,Mertansine ,Lapatinib ,Disease-Free Survival ,Capecitabine ,chemistry.chemical_compound ,Trastuzumab ,Drug Discovery ,Animals ,Humans ,Medicine ,Maytansine ,skin and connective tissue diseases ,Clinical Trials as Topic ,Taxane ,business.industry ,medicine.disease ,Metastatic breast cancer ,chemistry ,Trastuzumab emtansine ,Female ,Pertuzumab ,business ,medicine.drug - Abstract
Ado- trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate composed of trastuzumab, a stable linker (MCC), and the cytotoxic agent DM1 (derivative of maytansine; mertansine). T-DM1 retains the mechanisms of action of trastuzumab, but also acts as a, selectively delivered, tubulin inhibitor. Following antigen-mediated binding to the tumor cell, T-DM1 is endocytosed and intracellularly catabolized resulting in the release of its cytotoxic moiety.T-DM1 has completed Phase III development and compared favorably with the lapatinib/capecitabine combination with a superior response rate (objective response rate [ORR]) and duration of response, longer duration of disease control (progression-free survival [PFS]), prolonged overall survival and improved tolerability and quality of life in patients with prior treatment with trastuzumab and a taxane. In a separate Phase III, T-DM1 was compared with any other chosen regimen in patients who had at least received two prior HER2-directed therapies. T-DM1 nearly doubled PFS.T-DM1 (Kadcyla) has become the treatment of choice in second-line and beyond for patients with advanced HER2-expressing breast cancer.
- Published
- 2015
48. Endothelial cell metabolism: an update anno 2017
- Author
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Peter Carmeliet, Nihed Draoui, Laure-Anne Teuwen, and Charlotte Dubois
- Subjects
0301 basic medicine ,KUL-METH-Angiogenesis ,medicine.medical_specialty ,Cell signaling ,Angiogenesis ,Neovascularization, Physiologic ,Cell Communication ,Biology ,Neovascularization ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Internal medicine ,Neoplasms ,medicine ,Animals ,Homeostasis ,Humans ,Glycolysis ,Neovascularization, Pathologic ,Endothelial Cells ,Hematology ,3. Good health ,Lymphangiogenesis ,Cell biology ,Endothelial stem cell ,Metabolic pathway ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Blood Vessels ,Human medicine ,medicine.symptom ,Energy Metabolism ,Biomarkers ,Metabolic Networks and Pathways ,Signal Transduction - Abstract
Purpose of review Endothelial cell metabolism has recently emerged as an important coregulator of angiogenesis and is therefore a promising new target in various angiogenesis-associated illnesses, like cancer. In this review, we discuss recent insights in endothelial cell metabolism in both physiological and pathological conditions and discuss possible translational implications. Recent findings Two metabolic pathways that determine the performance of endothelial cells are glycolysis and fatty acid oxidation (FAO). Glycolysis is essential as endothelial cells primarily rely on this pathway for ATP production. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) is a key regulator of glycolysis in endothelial cells. As endothelial cells increase glycolysis even further during angiogenesis, PFKFB3 also controls vessel sprouting and promotes endothelial cell migration. Moreover, in tumors, additional PFKFB3 upregulation leads to a more immature and dysfunctional vasculature. PFKFB3 blockade therefore results in tumor vessel normalization, with beneficial therapeutic effects on reduced metastasis and improved chemotherapy. Also, FAO stimulates endothelial cell proliferation through affecting DNA synthesis, and is critical for lymphangiogenesis, in part through epigenetic changes in histone acetylation. As FAO is controlled by carnitine palmitoyltransferase 1a, inhibition of this key enzyme decreases pathological angiogenesis. Summary Both PFKFB3 and carnitine palmitoyltransferase 1a are key metabolic regulators of vessel sprouting and promising new therapeutic targets in diseases associated with pathological angiogenesis.
- Published
- 2017
49. Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy
- Author
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Jermaine Goveia, Ton J. Rabelink, Lena Christin Conradi, Bram Boeckx, Bart Ghesquière, Pallavi Chaturvedi, Joanna Kalucka, Kim R. Kampen, Lucas Treps, Diether Lambrechts, Francesco Bifari, Koen Veys, Guy Eelen, Asrar B. Malik, Johanna Hol, Bert Cruys, Jalees Rehman, Joris Vriens, Tor Espen Stav-Noraas, Sandra Schoors, Luc Schoonjans, Katrien De Bock, Guttorm Haraldsen, Laure Anne Teuwen, Andreas Pircher, Anna Kuchnio, Aleksandra Brajic, Peter Carmeliet, Anna Rita Cantelmo, Peter C. Stapor, Lise Finotto, Mieke Dewerchin, Bernard Thienpont, and Ilaria Decimo
- Subjects
0301 basic medicine ,Cancer Research ,Endothelium ,Angiogenesis ,Phosphofructokinase-2 ,Biology ,chemotherapy ,Metastasis ,03 medical and health sciences ,Mice ,angiogenesis ,Downregulation and upregulation ,Drug Therapy ,Cell Movement ,Cell Line, Tumor ,Neoplasms ,medicine ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,metastasis ,tumor endothelial cell metabolism ,Neoplasm Invasiveness ,Neoplasm Metastasis ,tumor vessel normalization ,Cell adhesion molecule ,Activator (genetics) ,Intravasation ,Drug Synergism ,Epithelial Cells ,glycolysis ,Cell Biology ,medicine.disease ,Cadherins ,Gene Expression Regulation, Neoplastic ,Tamoxifen ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Cancer cell ,Cancer research ,Cisplatin ,Neoplasm Transplantation - Abstract
Abnormal tumor vessels promote metastasis and impair chemotherapy. Hence, tumor vessel normalization (TVN) is emerging as an anti-cancer treatment. Here, we show that tumor endothelial cells (ECs) have a hyperglycolytic metabolism, shunting intermediates to nucleotide synthesis. EC haplo-deficiency or blockade of the glycolytic activator PFKFB3 did not affect tumor growth, but reduced cancer cell invasion, intravasation, and metastasis by normalizing tumor vessels, which improved vessel maturation and perfusion. Mechanistically, PFKFB3 inhibition tightened the vascular barrier by reducing VE-cadherin endocytosis in ECs, and rendering pericytes more quiescent and adhesive (via upregulation of N-cadherin) through glycolysis reduction; it also lowered the expression of cancer cell adhesion molecules in ECs by decreasing NF-kB signaling. PFKFB3-blockade treatment also improved chemotherapy of primary and metastatic tumors. publisher: Elsevier articletitle: Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy journaltitle: Cancer Cell articlelink: http://dx.doi.org/10.1016/j.ccell.2016.10.006 associatedlink: http://dx.doi.org/10.1016/j.ccell.2016.11.007 content_type: article copyright: © 2016 Elsevier Inc. ispartof: Cancer Cell vol:30 issue:6 pages:968-985 ispartof: location:United States status: published
- Published
- 2016
50. Patients with metastatic hormone receptor-positive breast cancer express PIK3CA oncogene mutational heterogeneity in circulating tumor cells
- Author
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Annemie Rutten, Steven Van Laere, Laure-Anne Teuwen, Roberto Salgado, Anja Brouwer, Peter B. Vermeulen, Dieter Peeters, Carsten Denkert, Peter A. van Dam, Bram De Laere, Luc Dirix, and Gert Van den Eynden
- Subjects
Oncology ,CA15-3 ,medicine.medical_specialty ,Oncogene ,business.industry ,medicine.disease ,Circulating tumor cell ,Breast cancer ,Hormone receptor ,Internal medicine ,medicine ,Cancer research ,Human medicine ,business - Abstract
We present a single-cell application to determine PIK3CA mutations in CTCs, which uncovered the degree of intra-patient heterogeneity in patients with metastatic hormone receptor-positive breast cancer (HR+ MBC) and high CTC count (>10 CTCs/7.5mL). Using CellSearch and DEPArray we isolated circulating tumor cells (CTCs) and white blood cells (WBCs) from peripheral blood and sequenced PIK3CA exons 9 and 20 by targeted amplicon sequencing. Comparative analysis between the primary tumor (PT, n=27 patients), circulating cell-free DNA (cfDNA, n=31 patients), single (n=146 CTCs) and pools (n=70 CTC suspensions, ranging 5-120 cells/suspension) of CTCs from 26 patients and metastases/DTCs (n=11 patients) was performed. Mutations were frequent in PT (15/27 (55.5%)) and showed slight and substantial agreement with cfDNA (n=21; kappa=0.14) and CTCs (n=22; kappa=0.6733), respectively. A wild-type genotype in WBCs indicates a high specificity. Inter-compartmental concordance was observed in 13/18 (72.2%) patients and temporal heterogeneity in 4/18 patients (22.2%). CTC analysis reveals both mutational homo- and heterogeneity with cases showing the presence of different mutant and wild-type CTC subpopulations. Additionally, unique double-mutated CTCs were detected in 8/26 patients (30.7%). The developed liquid biopsy provides an insight into inter and intra-patient PIK3CA mutational heterogeneity in patients with HR+ MBC, paving the way towards the application of a more personalized medicine.
- Published
- 2016
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