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1,091 results on '"Schornagel A"'

1. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer

Author

Sonke, Gabe S., van Ommen-Nijhof, Annemiek, Wortelboer, Noor, van der Noort, Vincent, Swinkels, Astrid C. P., Blommestein, Hedwig M., Guerrero Paez, Cristina, Mol, Linda, Beeker, Aart, Beelen, Karin, Hamming, Lisanne C., Heijns, Joan B., Honkoop, Aafke H., de Jong, Paul C., van Rossum-Schornagel, Quirine C., van Schaik-van de Mheen, Christa, Tol, Jolien, Tromp-van Driel, Cathrien S., Vrijaldenhoven, Suzan, van Leeuwen-Stok, A. Elise, Konings, Inge R., and Jager, Agnes

Published
2024
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2. Punch biopsies in tattooed skin: Complications and patient‐reported outcomes

Author

Mila Poelhekken, Ines J. Schornagel, and Sebastiaan A. S. van derBent

Subjects
biopsy, complication, cosmetic, permanent makeup, punch biopsy, scar, Dermatology, RL1-803, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Abstract Background Despite the popularity and usage of tattoos in modern society, various complications can occur such as allergic tattoo reactions, infections, tattoo removal complications and chronic granulomatous inflammatory tattoo reactions such as sarcoidosis. Histopathology of skin biopsies in tattoos is crucial in the diagnostic process of complications. As tattoos are frequently obtained for cosmetic reasons, cosmetic consequences of a skin biopsy in a tattoo are important. Remarkably, no studies have been performed regarding the consequences and expected outcome of taking a punch biopsy of tattooed skin. Objectives The objective of this study is to report on the possible complications and patient‐reported cosmetic outcomes after punch biopsies in tattooed skin. Specifically, this study aims to assess the impact on appearance, symptoms and psychosocial burden of biopsies in tattooed skin, using the SCAR‐Q. Methods Patients who underwent a punch biopsy of tattooed skin at the Tattoo Clinic in the Alrijne Hospital between 2021 and 2023 were included. To evaluate patient satisfaction of the biopsy scar the SCAR‐Q and a questionnaire regarding the recovery of the punch biopsy was used. Results The final cohort consisted of 50 patients. Across all scales, the median scores on the SCAR‐Q questionnaire were consistent with the maximum score. Patients scored significantly better on the appearance scale when the biopsy was taken longer than 8 months ago. Two‐third of the patients reported no postbiopsy symptoms, with the remainder experiencing itch, pain or redness, which typically resolved within 10 days (88%). Remarkably, 42% of the patients reported the biopsy scar was not visible on the skin anymore. Scars on the lower extremities and trunk were significantly more frequently visible, as well as scars among patients aged 40 and above. Conclusions This study demonstrates that the cosmetic and psychological impact of punch biopsies in tattooed skin is minimal and the recovery is fast with minimal symptoms. For this reason, biopsies of tattooed skin should not be avoided in the diagnostic process.

Published
2024
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5. SKAP2 acts downstream of CD11b/CD18 and regulates neutrophil effector function

Author

Panagiota Bouti, Bart J. A. M. Klein, Paul J. H. Verkuijlen, Karin Schornagel, Floris P. J. van Alphen, Kees-Karel H. Taris, Maartje van den Biggelaar, Arie J. Hoogendijk, Robin van Bruggen, Taco W. Kuijpers, and Hanke L. Matlung

Subjects
neutrophils, antibody-dependent cellular cytotoxicity (ADCC), Src kinase associated phosphoprotein 2 (SKAP2), filamentous actin, CD11b/CD18 integrin, phagocytosis, Immunologic diseases. Allergy, RC581-607
Abstract

BackgroundThe importance of CD11b/CD18 expression in neutrophil effector functions is well known. Beyond KINDLIN3 and TALIN1, which are involved in the induction of the high-affinity binding CD11b/CD18 conformation, the signaling pathways that orchestrate this response remain incompletely understood.MethodWe performed an unbiased screening method for protein selection by biotin identification (BioID) and investigated the KINDLIN3 interactome. We used liquid chromatography with tandem mass spectrometry as a powerful analytical tool. Generation of NB4 CD18, KINDLIN3, or SKAP2 knockout neutrophils was achieved using CRISPR-Cas9 technology, and the cells were examined for their effector function using flow cytometry, live cell imaging, microscopy, adhesion, or antibody-dependent cellular cytotoxicity (ADCC).ResultsAmong the 325 proteins significantly enriched, we identified Src kinase-associated phosphoprotein 2 (SKAP2), a protein involved in actin polymerization and integrin-mediated outside-in signaling. CD18 immunoprecipitation in primary or NB4 neutrophils demonstrated the presence of SKAP2 in the CD11b/CD18 complex at a steady state. Under this condition, adhesion to plastic, ICAM-1, or fibronectin was observed in the absence of SKAP2, which could be abrogated by blocking the actin rearrangements with latrunculin B. Upon stimulation of NB4 SKAP2-deficient neutrophils, adhesion to fibronectin was enhanced whereas CD18 clustering was strongly reduced. This response corresponded with significantly impaired CD11b/CD18-dependent NADPH oxidase activity, phagocytosis, and cytotoxicity against tumor cells.ConclusionOur results suggest that SKAP2 has a dual role. It may restrict CD11b/CD18-mediated adhesion only under resting conditions, but its major contribution lies in the regulation of dynamic CD11b/CD18-mediated actin rearrangements and clustering as required for cellular effector functions of human neutrophils.

Published
2024
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7. Identification of ultra-rare genetic variants in pediatric acute onset neuropsychiatric syndrome (PANS) by exome and whole genome sequencing

Author

Rosario Trifiletti, Herbert M. Lachman, Olivia Manusama, Deyou Zheng, Alberto Spalice, Pietro Chiurazzi, Allan Schornagel, Andreea M. Serban, Rogier van Wijck, Janet L. Cunningham, Sigrid Swagemakers, and Peter J. van der Spek

Subjects
Medicine, Science
Abstract

Abstract Abrupt onset of severe neuropsychiatric symptoms including obsessive–compulsive disorder, tics, anxiety, mood swings, irritability, and restricted eating is described in children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). Symptom onset is often temporally associated with infections, suggesting an underlying autoimmune/autoinflammatory etiology, although direct evidence is often lacking. The pathological mechanisms are likely heterogeneous, but we hypothesize convergence on one or more biological pathways. Consequently, we conducted whole exome sequencing (WES) on a U.S. cohort of 386 cases, and whole genome sequencing (WGS) on ten cases from the European Union who were selected because of severe PANS. We focused on identifying potentially deleterious genetic variants that were de novo or ultra-rare (MAF)

Published
2022
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9. Therapeutic Drug Monitoring of Endoxifen for Tamoxifen Precision Dosing: Feasible in Patients with Hormone-Sensitive Breast Cancer

Author

Braal, C. Louwrens, Jager, Agnes, Hoop, Esther Oomen-de, Westenberg, Justin D., Lommen, Koen M. W. T., de Bruijn, Peter, Vastbinder, Mijntje B., van Rossum-Schornagel, Quirine C., Thijs-Visser, Martine F., van Alphen, Robbert J., Struik, Liesbeth E. M., Zuetenhorst, Hanneke J. M., Mathijssen, Ron H. J., and Koolen, Stijn L. W.

Published
2022
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11. Cancer cells resist antibody-mediated destruction by neutrophils through activation of the exocyst complex

Author

Sung-Bae Kim, Taco W Kuijpers, Christos Sotiriou, Serena Di Cosimo, Jens Huober, Rebecca Roylance, Anton T J Tool, Dieke J van Rees, Bart Klein, Panagiota Bouti, Karin Schornagel, Robin van Bruggen, Hanke L Matlung, Paul J H Verkuijlen, Michel van Houdt, David Venet, Sarra El-Abed, Miguel Izquierdo, Sébastien Guillaume, Cristina Saura, and Timo K van den Berg

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2022
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12. Influence of probenecid on endoxifen systemic exposure in breast cancer patients on adjuvant tamoxifen treatment

Author

Stefan A. J. Buck, C. Louwrens Braal, Maaike M. Hofman, Esther Oomen-de Hoop, Peter de Bruijn, Inge M. Ghobadi Moghaddam-Helmantel, Koen G. A. M. Hussaarts, Mijntje B. Vastbinder, Quirine C. van Rossum-Schornagel, Ron H. N. van Schaik, Agnes Jager, Stijn L. W. Koolen, and Ron H. J. Mathijssen

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Introduction: In breast cancer patients treated with the anti-estrogen tamoxifen, low concentrations of the active metabolite endoxifen are associated with more disease recurrence. We hypothesized that we could increase endoxifen concentrations by induction of its formation and inhibition of its metabolism by co-administration of probenecid. Methods: We conducted a crossover study and measured endoxifen concentrations in patients on steady-state tamoxifen monotherapy and after 14 days of combination treatment with probenecid. Eleven evaluable patients were included. Results: Treatment with tamoxifen and probenecid resulted in a 26% increase of endoxifen area under the plasma concentration–time curve from 0 to 24 h (AUC 0–24h ) compared to tamoxifen monotherapy (95% confidence interval [CI]: 8–46%; p

Published
2022
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14. SKAP2 acts downstream of CD11b/CD18 and regulates neutrophil effector function

Author

Bouti, Panagiota, primary, Klein, Bart J. A. M., additional, Verkuijlen, Paul J. H., additional, Schornagel, Karin, additional, van Alphen, Floris P. J., additional, Taris, Kees-Karel H., additional, van den Biggelaar, Maartje, additional, Hoogendijk, Arie J., additional, van Bruggen, Robin, additional, Kuijpers, Taco W., additional, and Matlung, Hanke L., additional

Published
2024
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15. SIGLEC-5/14 Inhibits CD11b/CD18 Integrin Activation and Neutrophil-Mediated Tumor Cell Cytotoxicity

Author

Bouti, Panagiota, primary, Blans, Colin, additional, Klein, Bart J. A. M., additional, Shome, Debarati, additional, Nadafi, Reza, additional, Van Houdt, Michel, additional, Schornagel, Karin, additional, Verkuijlen, Paul J. J. H., additional, Roos, Virginie, additional, Reijmers, Rogier M., additional, Van Bruggen, Robin, additional, Kuijpers, Taco W., additional, and Matlung, Hanke L., additional

Published
2023
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16. Acute medicatie

Author

Schornagel, J. E., Derksen-Lubsen, G., Moll, H. A., Derksen-Lubsen, G., editor, Moll, H.A., editor, Oudesluys-Murphy, A.M., editor, Sprij, A.J., editor, Bolt-Wieringa, J.W., editor, van den Elzen, A.P.M., editor, Leeuwenburgh-Pronk, W.G., editor, Ropers, F.G., editor, and Verhoeven, J.J., editor

Published
2018
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17. Neutrophils Kill Antibody-Opsonized Cancer Cells by Trogoptosis

Author

Matlung, Hanke L., Babes, Liane, Zhao, Xi Wen, van Houdt, Michel, Treffers, Louise W., van Rees, Dieke J., Franke, Katka, Schornagel, Karin, Verkuijlen, Paul, Janssen, Hans, Halonen, Pasi, Lieftink, Cor, Beijersbergen, Roderick L., Leusen, Jeanette H.W., Boelens, Jaap J., Kuhnle, Ingrid, van der Werff Ten Bosch, Jutte, Seeger, Karl, Rutella, Sergio, Pagliara, Daria, Matozaki, Takashi, Suzuki, Eiji, Menke-van der Houven van Oordt, Catharina Willemien, van Bruggen, Robin, Roos, Dirk, van Lier, Rene A.W., Kuijpers, Taco W., Kubes, Paul, and van den Berg, Timo K.

Published
2018
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18. G-CSF as a suitable alternative to GM-CSF to boost dinutuximab-mediated neutrophil cytotoxicity in neuroblastoma treatment

Author

Taco W Kuijpers, Timo K van den Berg, Paula Martinez Sanz, Dieke J van Rees, Lieke M J van Zogchel, Bart Klein, Panagiota Bouti, Hugo Olsman, Karin Schornagel, Ivana Kok, Ali Sunak, Kira Leeuwenburg, Ilse Timmerman, Miranda P Dierselhuis, Waleed M Kholosy, Jan J Molenaar, Robin van Bruggen, Hanke L Matlung, Godelieve A M Tytgat, and Katka Franke

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background Current immunotherapy for patients with high-risk neuroblastoma involves the therapeutic antibody dinutuximab that targets GD2, a ganglioside expressed on the majority of neuroblastoma tumors. Opsonized tumor cells are killed through antibody-dependent cellular cytotoxicity (ADCC), a process mediated by various immune cells, including neutrophils. The capacity of neutrophils to kill dinutuximab-opsonized tumor cells can be further enhanced by granulocyte-macrophage colony-stimulating factor (GM-CSF), which has been shown in the past to improve responses to anti-GD2 immunotherapy. However, access to GM-CSF (sargramostim) is limited outside of Northern America, creating a high clinical need for an alternative method to stimulate dinutuximab responsiveness in the treatment of neuroblastoma. In this in vitro study, we have investigated whether clinically well-established granulocyte colony-stimulating factor (G-CSF) can be a potentially suitable alternative for GM-CSF in the dinutuximab immunotherapy regimen of patients with neuroblastoma.Methods We compared the capacity of neutrophils stimulated either in vitro or in vivo with GM-CSF or G-CSF to kill dinutuximab-opsonized GD2-positive neuroblastoma cell lines and primary patient tumor material. Blocking experiments with antibodies inhibiting either respective Fc gamma receptors (FcγR) or neutrophil integrin CD11b/CD18 demonstrated the involvement of these receptors in the process of ADCC. Flow cytometry and live cell microscopy were used to quantify and visualize neutrophil-neuroblastoma interactions.Results We found that G-CSF was as potent as GM-CSF in enhancing the killing capacity of neutrophils towards neuroblastoma cells. This was observed with in vitro stimulated neutrophils, and with in vivo stimulated neutrophils from both patients with neuroblastoma and healthy donors. Enhanced killing due to GM-CSF or G-CSF stimulation was consistent regardless of dinutuximab concentration, tumor-to-neutrophil ratio and concentration of the stimulating cytokine. Both GM-CSF and G-CSF stimulated neutrophils required FcγRIIa and CD11b/CD18 integrin to perform ADCC, and this was accompanied by trogocytosis of tumor material by neutrophils and tumor cell death in both stimulation conditions.Conclusions Our preclinical data support the use of G-CSF as an alternative stimulating cytokine to GM-CSF in the treatment of high-risk neuroblastoma with dinutuximab, warranting further testing of G-CSF in a clinical setting.

Published
2021
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20. Extended adjuvant aromatase inhibition after sequential endocrine therapy (DATA): a randomised, phase 3 trial

Author

Kitzen, J.J.E.M., Strobbe, L.J.A., Kouwenhoven, E.A., van Dalen, T., van Overbeeke, A.J., Nuytinck, J.K.S., Arntz, I.E., Blaisse, R.J.B., Stockmann, H.B.A.C., Nijhuis, P.H.A., Veldhuis, G.J., Mastboom, W.J.B., van Riel, J.M.G.H., van Dam, J.H., den Boer, M.O., Agterof, M.J., de Roos, M.A.J., Roumen, R.M.H., van der Hoeven, J.J.M., Beeker, A., Koelemij, R., van Bochove, A., Madretsma, G.S., Siemerink, E.J.M., Guicherit, O.R., Vos, A.H., Nieuwenhuijzen, G.A.P., Kehrer, D.F.S., Valster, F.A.A., Tanis, B.C., van Voorthuizen, T., van der Velden, A.M.T., Hellingman, R.A., Vree, R., van Rossum-Schornagel, Q., Meerum Terwogt, J.M., van Leeuwen-Breuk, W.G., Haasjes, J.G., Davidis-van Schoonhoven, M.A., Vriens, E.J.C., Jagers, M., Muller, E.W., Schiphorst, P.P.J.B.M., van Groeningen, C.J., van Dijk, M.A., Janssens- van Vliet, E., Schepers, E.E.M., Merkus, J.W.S., van Diemen, N.G.J., van Doorn, R.C., Bosscha, K., den Toom, R., van der Velden, P.C., van Rossum, C.T.A.M., Oosterkamp, H.M., van Hillegersberg, R., Jas, B., Weernink, E.E.M., Ketel, J.M.A., Jansen, J.J., Maring, J.K., Govaert, M.J.P.M., Kamm, Y.J.L., Vleugel, M.M., Hovenga, S., de Boer, J., Potthoff, H., Sommeijer, D.W., van Dulken, E.J., Tjan-Heijnen, Vivianne C G, van Hellemond, Irene E G, Peer, Petronella G M, Swinkels, Astrid C P, Smorenburg, Carolien H, van der Sangen, Maurice J C, Kroep, Judith R, De Graaf, Hiltje, Honkoop, Aafke H, Erdkamp, Frans L G, van den Berkmortel, Franchette W P J, de Boer, Maaike, de Roos, Wilfred K, Linn, Sabine C, Imholz, Alexander L T, and Seynaeve, Caroline M

Published
2017
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21. Safety and tolerability of subcutaneous trastuzumab for the adjuvant treatment of human epidermal growth factor receptor 2-positive early breast cancer: SafeHer phase III study's primary analysis of 2573 patients

Author

Koroveshi, Dhurata, Bouzid, Kamel, Casalnuovo, Monica, Cascallar, Diana, Korbenfeld, Ernesto Pablo, Bastick, Patricia, Beith, Jane, Colosimo, Maree, Friedlander, Michael, Ganju, Vinod, Green, Michael, Patterson, Kevin, Redfern, Andrew, Richardson, Gary, Ceric, Timur, Gordana, Kecman, Beato, Carlos Augusto, Ferrari, Marcela, Hegg, Roberto, Helena, Vanessa, Ismael, Gustavo Fernando, Lessa, Alvaro Edson, Mano, Max, Morelle, Alessandra, Nogueira, Jose Alberto, Timcheva, Konstanta, Tomova, Antoaneta, Tsakova, Maya, Zlatareva-Petrova, Ani, Asselah, Jamil, Assi, Hazem, Brezden-Masley, Christine, Chia, Stephen, Freedman, Ori, Harb, Mohammed, Joy, Anil Abraham, Kulkarni, Swati, Prady, Catherine, Gaete, Alejandro Andres Acevedo, Matamala, Luis, Torres, Roberto, Yanez, Eduardo, Franco, Sandra, Urrego, Marcela, Gugić, Damir, Vrbanec, Damir, Melichar, Bohuslav, Prausová, Jana, Vyzula, Rostislav, Pilarte, Rafael Gutierrez, León, María Isabel, Muñoz, Rene, Ramos, Glenda, Azeem, Hamdy Abdel, Aziz, Amr Abdel, El Zawahry, Heba, Osegueda, Finlander Rosales, Alexandre, Jerome, Artignan, Xavier, Barletta, Hugues, Beguier, Emmanuel, Berdah, Jean-François, Marty, Chantal Bernard, Bollet, Marc, Bourgeois, Hugues, Bressac, Claude, Burki, Franck, Campone, Mario, Coeffic, David, Cojocarasu, Oana Zveltlana, Dagada, Corinne, Dalenc, Florence, Del Piano, Francesco, Desauw, Christophe, Desmoulins, Isabelle, Dohollou, Nadine, Egreteau, Joelle, Ferrero, Jean-Marc, Foa, Cyril, Garidi, Reda, Gasnault, Laurent, Gligorov, Joseph, Guardiola, Emmanuel, Hamizi, Salima, Jarcau, Rosana, Jacquin, Jean-Philippe, Jaubert, Dominique, Jolimoy, Geneviève, Mineur, Hortense Laharie, Largillier, Remy, Leduc, Bernard, Martin, Philippe, Melis, Adrien, Monge, Jeremy, Moullet, Isabelle, Mousseau, Mireille, Nguyen, Suzanne, Orfeuvre, Hubert, Petit, Thierry, Pivot, Xavier, Priou, Frank, Bach, Isabelle Sillet, Simon, Helene, Stefani, Laetitia, Uwer, Lionel, Youssef, Ali, Aktas, Bahriye, von der Assen, Albert, Augustin, Doris, Balser, Christina, Bauer, Lelia-Eveline, Bechtner, Christina, Beyer, Greta, Brucker, Cosima, Bückner, Ute, Busch, Steffi, Christensen, Bernd, Deryal, Mustafa, Farrokh, Andre, Faust, Elke, Friedrichs, Kay, Graf, Heiko, Griesshammer, Martin, Grischke, Eva-Maria, Hänle, Claudia, Heider, Andrea, Henschen, Stephan, Hesse, Tobias, Jackisch, Christian, Kisro, Jens, Köhler, Andreas, Kuemmel, Sherko, Lampe, Dieter, Lantzsch, Tilmann, Latos, Kunibert, Lex, Benno, Liedtke, Cornelia, Luedders, Doerte, Maintz, Christoph, Müller, Volkmar, Overkamp, Friedrich, Park-Simon, Tjoung-won, Paul, Marion, Prechtl, Anita, Ringsdorf, Uta, Runnebaum, Ingo, Ruth, Sylvia, Salat, Christoph, Scheffen, Iris, Schilling, Jörg, Schmatloch, Sabine, Schmidt, Marcus, Schneeweiss, Andreas, Schrader, Iris, Seipelt, Gernot, Simon, Elke, Stefek, Andrea, Stickeler, Elmar, Thill, Marc, Tio, Joke, Tuczek, Anna, Warm, Mathias, Weigel, Michael, Wischnik, Arthur, Wojcinski, Sebastian, Ziegler-Löhr, Katja, Aravantinos, Gerasimos, Ardavanis, Alexandros, Fountzilas, George, Gogas, Helen, Kakolyris, Stylianos, Mavroudis, Dimitris, Papadimitriou, Christos, Papandreou, Christos, Papazisis, Konstantinos, Castro, Hugo, Hernandez-Monroy, Cesar Estuardo, Ngan, Roger, Yeo, Winnie, Bittner, Nora, Boer, Katalin, Csejtei, Andras, Horvath, Zsolt, Kocsis, Judit, Mangel, László Csaba, Mezei, Klara, Nagy, Zsuzsanna, Szanto, Janos, Atmakusuma, Djumhana, Fadjari, Heri, Kurnianda, Djohan, Prayogo, Nugroho, Tanggo, Eddie Herman, Coate, Linda, Hennessy, Bryan, Kelly, Cathy, Martin, Michael, Nasim, Saira, O'Connor, Miriam, Aieta, Michele, Allegrini, Giacomo, Amadori, Dino, Bidoli, Paolo, Biti, Giampaolo, Bordonaro, Roberto, Bottini, Alberto, Carterni, Giacomo, Cavanna, Luigi, Cazzaniga, Marina, Cognetti, Francesco, Contu, Antonio, Cruciani, Giorgio, Donadio, Michela, Falcone, Alfredo, Farci, Daniele, Forcignanò, R. Chiara, Frassoldati, Antonio, Gaion, Fernando, Gamucci, Teresa, Giotta, Francesco, de Laurentiis, Michele, Livi, Lorenzo, Lorusso, Vito, Maiello, Evaristo, Marchetti, Paolo, Mariani, Gabriella, Mion, Marta, Moscetti, Luca, Musolino, Antonino, Pazzola, Antonio, Pedrazzoli, Paolo, Pigi, Andrea, de Placido, Sabino, Caremoli, Elena Rota, Santoro, Armando, Tienghi, Amelia, Ahn, Jin-Seok, Jung, Kyung Hae, Lee, Keun Seok, Lee, Soo Hyeon, Seo, Jae Hong, Sohn, Joo-Hyuk, Cesas, Alvydas, Juozaityte, Elona, Cheah, Nellie Lay Chin, Chong, Flora Li Tze, Devi, Beena C.R., Phua, Vincent, Teoh, Darren, Ching, Lee Wei, Yusof, Mastura, Corona, Jorge, Dominguez, Adriana, Mendoza, René Lazaro González, Hernandez, Carlos Alberto, Ramiro, Alejandro Juarez, Santos, Juan Matos, Espinosa, Paola Morales, Villarreal Garza, Cynthia Mayte, Errihani, Hassan, Bakker, Sandra, van den Berkmortel, Franchette, Blaisse, R.J.B., Huinink, Daan ten Bokkel, van den Bosch, J., Braun, J.J., Dercksen, M.W., Droogendijk, Helga, Erdkamp, Frans, Haringhuizen, Annebeth, de Jongh, F.E., Kok, T.C., Los, Maartje, Madretsma, Stanley, Terwogt, Jetske M. Meerum, van der Padt, Annemieke, van Rossum-Schornagel, Quirine Clementine, Smilde, T.J., de Valk, Bart, van der Velden, Annette, van Warmerdam, Laurence, van de Wouw, A.J., North, Richard, Kersten, Christian, Mjaaland, Ingvild, Wist, Erik, Aziz, Zeba, Masood, Nehal, Rashid, Kamran, Shah, Mazhar, Alcedo, Juan Carlos, Aleman, Diana, Neciosup, Silvia, Reategui, Rocio, Valdiviezo, Natalia, Vera, Luis, Fernando, Gracieux, Roque, Fernando, Strebel, Heinrik Martin, Krzemieniecki, Krzysztof, Litwiniuk, Maria, Mruk, Andrzej, Pienkowski, Tadeusz, Sawrycki, Piotr, Slomian, Grzegorz, Tomczak, Piotr, Afonso, Noemia, Cardoso, Fátima, Damasceno, Margarida, Nave, Monica, Badulescu, Florinel, Ciule, Larisa, Curescu, Stefan, Eniu, Alexandru, Filip, Dumitru, Grecea, Daniela, Jinga, Dan-Corneliu, Lungulescu, Dan, Oprean, Cristina Marinela, Stanculeanu, Dana Lucia, Turdean, Maria, Dvornichenko, Viktoria, Emelyanov, Sergey, Lichinitser, Mikhail, Manikhas, Alexey, Sakaeva, Dina, Shirinkin, Vadim, Stroyakovskiy, Daniil, Abulkhair, Omalkhair, Zekri, Jamal, Filipovic, Sladjana, Kovcin, Vladimir, Nedovic, Jasmina, Pesic, Jasna, Vasovic, Suzana, Ng, Raymond, Bystricky, Branislav, Leskova, Jaroslava, Mardiak, Jozef, Mišurová, Etela, Wagnerova, Maria, Takač, Iztok, Demetriou, Georgia Savva, Dreosti, Lydia, Govender, Poovandren, Jordaan, Johannes Petrus, Veersamy, Petrosian, Romero, Jose Luis Alonso, Lopez, Norberto Batista, Arias, Carmen Cañabate, Chacon, Jose, Aramburo, Antonio Fernandez, Morales, Luis Antonio Fernandez, Garcia, Mirta, Estevez, Laura Garcia, Garcia-Palomo Perez, Andres, Garcia Saenz, Jose Angel, Garcia Sanchis, Laura, Cubells, Laia Garrigos, Cortijo, Lucia Gonzalez, Santiago, Santiago Gonzalez, De Aranguiz, Blanca Hernando Fernandez, Mañas, José Juan Illarramendi, Gallego, Pedro Jimenez, Cussac, Antonio Llombart, Ferrandiz, Cristina Llorca, Garrido, Maria Lomas, Alvarez, Pilar Lopez, Vega, Jose Manuel Lopez, Del Prado, Purificacion Martinez, Jañez, Noelia Martinez, Murillo, Serafin Morales, Rosales, Adolfo Murias, Jaso, Laura Murillo, Fernandez, Ignacio Pelaez, Martorell, Antonia Perello, Carrion, Ramon Perez, Simon, Sonia Pernas, Alcibar, Arrate Plazaola, Lorenzo, Jose Ponce, Garcia, Vanesa Quiroga, Asensio, Teresa Ramon y Cajal, Maicas, Maria Dolores Torregrosa, Villanueva Silva, Maria Jose, Killander, Fredrika, Svensson, Jan Henry, Fehr, Mathias, Hauser, Nik, Müller, Andreas, Pagani, Olivia, Passmann-Kegel, Heike, Popescu, Razvan, Rabaglio, Manuela, Rauch, Daniel, Schlatter, Christina, Zaman, Khalil, Chang, Tsai-Wang, Huang, Chiun-Sheng, Wang, Hwei-Chung, Yu, Jyh-Cherng, Bandidwattanawong, Chanyoot, Maneechavakajorn, Jedzada, Seetalarom, Kasan, Dejthevaporn, Thitiya (Sirisinha), Somwangprasert, Areewan, Vongsaisuwon, Mawin, Akbulut, Hakan, Altundag, Kadri, Arican, Ali, Bozcuk, Hakan, Eralp, Yesim, Idris, Mohamed, Isikdogan, Abdurrahman, Senol, Coskun Hasan, Sevinc, Alper, Uygun, Kazim, Yucel, Eftal, Yucel, Idris, Yumuk, Fulden, Shparyk, Yaroslav, Voitko, Nataliia, Jaloudi, Mohammed, Adams, Jocelyn, Agrawal, Rajiv, Ahmed, Samreen, Alhasso, Abdulla, Allerton, Rozenn, Anwar, Suhail, Archer, Caroline, Ashford, Richard, Barraclough, Lisa, Bertelli, Gianfilippo, Bishop, Jill, Branson, Tony, Butt, Mohammed, Chakrabarti, Amit, Chakraborti, Prabir, Churn, Mark, Crowley, Clare, Davis, Ruth, Dhadda, Amandeep, Eldeeb, Hany, Fraser, Judith, Hall, Julia, Hickish, Tamas, Hogg, Martin, Howe, Theresa, Joffe, Jonathan, Kelleher, Muireann, Kelly, Stephen, Kendall, Anne, Kristeleit, Hartmut, Lumsden, Graeme, Macmillan, Craig, MacPherson, Iain, Malik, Zafar, Mithal, Natasha, Neal, Anthony, Panwar, Udaiveer, Proctor, Andrew, Proctor, Steven John, Raj, Sanjay, Rehman, Shazza, Sandri, Ines, Scatchard, Kate, Sherwin, Elizabeth, Sims, Eliot, Singer, Julian, Smith, Sarah, Tahir, Saad, Taylor, Wendy, Tsalic, Medy, Verrill, Mark, Wardley, Andrew, Waters, Simon, Wheatley, Duncan, Wright, Kathryn, Yuille, Frances, Alonso, Isabel, Artagaveytia, Nora, Rodriguez, Robinson, Arbona, Esther, Garcia, Yuraima, Lion, Lorena, Marcano, Dalila, Van Thuan, Tran, Gligorov, J., Ataseven, B., Verrill, M., De Laurentiis, M., Jung, K.H., Azim, H.A., Al-Sakaff, N., Lauer, S., Shing, M., and Pivot, X.

Published
2017
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22. Field observations of the movements of locally adapted Atlantic cod (Gadus morhua) living in zero and sub-zero centigrade temperatures for half the year.

Author

Green, John M., Schornagel, Dustin, Nguyen, Khanh Q., Pennell, Curtis, and Morris, Corey J.

Subjects
*ATLANTIC cod, *CODFISH, *BIODIVERSITY conservation, *WATER temperature, *TEMPERATURE, *WINTER
Abstract

Atlantic cod (Gadus morhua Linnaeus, 1758) can experience mortality at sub-zero (<0 °C) temperatures in ice-infested waters, and many populations migrate to deeper and warmer areas during winter. An exception is the resident population in Gilbert Bay, Labrador, which annually experiences 6 months of sub-zero temperatures. We used the VEMCO Positioning System to estimate fish locations to determine depth utilization and seasonal movements of tagged Gilbert Bay cod ranging in size from 43 to 75 cm. This is the first study to directly monitor the movements of adult Atlantic cod for extended periods (months) in sub-zero temperatures. Gilbert Bay cod remained active under an ice-covered surface during the 6 months of sub-zero temperatures. During both warm (>0 °C) and cold (≤0 °C) periods, fish spent similar amounts of time not moving, moving slowly, and moving at medium and fast rates. They tended to utilize shallow depths, <10 m, beneath surface ice during winter, while utilizing deeper depths as well during other times of the year. Surprisingly, fish that resided within our tracking array year-round had greater cumulative swimming distances during sub-zero periods compared to warmer periods. No tracked fish died during winter, further highlighting the cold adaptiveness of this population and its importance to biodiversity conservation. [ABSTRACT FROM AUTHOR]

Published
2024
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24. The impact of endoxifen-guided tamoxifen dose reductions on endocrine side-effects in patients with primary breast cancer

Author

Buijs, S. M., Hoop, E. Oomen de, Braal, C. L., van Rosmalen, M. M., Drooger, J. C., van Rossum-Schornagel, Q. C., Vastbinder, M. B., Koolen, S. L.W., Jager, A., Mathijssen, R. H.J., Buijs, S. M., Hoop, E. Oomen de, Braal, C. L., van Rosmalen, M. M., Drooger, J. C., van Rossum-Schornagel, Q. C., Vastbinder, M. B., Koolen, S. L.W., Jager, A., and Mathijssen, R. H.J.

Abstract

BACKGROUND: Tamoxifen is important in the adjuvant treatment of hormone-sensitive breast cancer and substantially reduces recurrence; however, almost 50% of patients are non-compliant mainly due to side-effects. The aim of this study was to investigate whether endoxifen-guided tamoxifen dose reduction could lead to fewer side-effects.MATERIALS AND METHODS: Effects of tamoxifen dose reduction were investigated in patients with bothersome side-effects and endoxifen levels ≥32 nM and compared to patients with side-effects who remained on tamoxifen 20 mg. Endocrine symptoms and health-related quality of life (HR-QOL) were assessed after 3 months with the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) questionnaire.RESULTS: Tamoxifen dose was reduced in 20 patients, 17 of whom were assessable for side-effect analyses. A clinically relevant improvement of >6 points was observed in endocrine symptoms and HR-QOL in 41% and 65% of the patients, respectively. In total, there was a significant and clinically relevant improvement in endocrine symptoms [5.7, 95% confidence interval (CI) -0.5-11.5] and HR-QOL (8.2, 95% CI 0.9-15.4) after dose reduction. This was not seen in patients whose doses were not reduced (n = 60). In 21% of patients, endoxifen dropped slightly below the 16-nM threshold (12.8, 15.5, 15.8, 15.9 nM).CONCLUSIONS: Endoxifen-guided dose reduction of tamoxifen significantly improved tamoxifen-related side-effects and HR-QOL. Nearly 80% of patients remained above the most conservative endoxifen threshold.

Published
2023

25. Data from IgA-Mediated Killing of Tumor Cells by Neutrophils Is Enhanced by CD47–SIRPα Checkpoint Inhibition

Author

Treffers, Louise W., primary, ten Broeke, Toine, primary, Rösner, Thies, primary, Jansen, J.H. Marco, primary, van Houdt, Michel, primary, Kahle, Steffen, primary, Schornagel, Karin, primary, Verkuijlen, Paul J.J.H., primary, Prins, Jan M., primary, Franke, Katka, primary, Kuijpers, Taco W., primary, van den Berg, Timo K., primary, Valerius, Thomas, primary, Leusen, Jeanette H.W., primary, and Matlung, Hanke L., primary

Published
2023
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26. Supplementary Data from IgA-Mediated Killing of Tumor Cells by Neutrophils Is Enhanced by CD47–SIRPα Checkpoint Inhibition

Author

Treffers, Louise W., primary, ten Broeke, Toine, primary, Rösner, Thies, primary, Jansen, J.H. Marco, primary, van Houdt, Michel, primary, Kahle, Steffen, primary, Schornagel, Karin, primary, Verkuijlen, Paul J.J.H., primary, Prins, Jan M., primary, Franke, Katka, primary, Kuijpers, Taco W., primary, van den Berg, Timo K., primary, Valerius, Thomas, primary, Leusen, Jeanette H.W., primary, and Matlung, Hanke L., primary

Published
2023
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27. Supplementary Figures from IgA-Mediated Killing of Tumor Cells by Neutrophils Is Enhanced by CD47–SIRPα Checkpoint Inhibition

Author

Treffers, Louise W., primary, ten Broeke, Toine, primary, Rösner, Thies, primary, Jansen, J.H. Marco, primary, van Houdt, Michel, primary, Kahle, Steffen, primary, Schornagel, Karin, primary, Verkuijlen, Paul J.J.H., primary, Prins, Jan M., primary, Franke, Katka, primary, Kuijpers, Taco W., primary, van den Berg, Timo K., primary, Valerius, Thomas, primary, Leusen, Jeanette H.W., primary, and Matlung, Hanke L., primary

Published
2023
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28. Abstract P1-02-08: CBD-oil: a potential solution in case of severe tamoxifen-related side effects

Author

Buijs, Sanne, primary, Braal, Louwrens, additional, Buck, Stefan, additional, van Maanen, Noud F., additional, van der Meijden-Erkelens, Lonneke, additional, van Patot, Heleen Kuijper-Tissot, additional, Oomen-de Hoop, Esther, additional, Saes, Lotte, additional, van den Boogerd, Sophia, additional, Struik, Liesbeth, additional, van Rossum-Schornagel, Quirine, additional, Mathijssen, Ron, additional, Koolen, Stijn, additional, and Jager, Agnes, additional

Published
2023
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29. Data from IgA-Mediated Killing of Tumor Cells by Neutrophils Is Enhanced by CD47–SIRPα Checkpoint Inhibition

Author

Hanke L. Matlung, Jeanette H.W. Leusen, Thomas Valerius, Timo K. van den Berg, Taco W. Kuijpers, Katka Franke, Jan M. Prins, Paul J.J.H. Verkuijlen, Karin Schornagel, Steffen Kahle, Michel van Houdt, J.H. Marco Jansen, Thies Rösner, Toine ten Broeke, and Louise W. Treffers

Abstract

Therapeutic monoclonal antibodies (mAb), directed toward either tumor antigens or inhibitory checkpoints on immune cells, are effective in cancer therapy. Increasing evidence suggests that the therapeutic efficacy of these tumor antigen–targeting mAbs is mediated—at least partially—by myeloid effector cells, which are controlled by the innate immune-checkpoint interaction between CD47 and SIRPα. We and others have previously demonstrated that inhibiting CD47–SIRPα interactions can substantially potentiate antibody-dependent cellular phagocytosis and cytotoxicity of tumor cells by IgG antibodies both in vivo and in vitro. IgA antibodies are superior in killing cancer cells by neutrophils compared with IgG antibodies with the same variable regions, but the impact of CD47–SIRPα on IgA-mediated killing has not been investigated. Here, we show that checkpoint inhibition of CD47–SIRPα interactions further enhances destruction of IgA antibody–opsonized cancer cells by human neutrophils. This was shown for multiple tumor types and IgA antibodies against different antigens, i.e., HER2/neu and EGFR. Consequently, combining IgA antibodies against HER2/neu or EGFR with SIRPα inhibition proved to be effective in eradicating cancer cells in vivo. In a syngeneic in vivo model, the eradication of cancer cells was predominantly mediated by granulocytes, which were actively recruited to the tumor site by SIRPα blockade. We conclude that IgA-mediated tumor cell destruction can be further enhanced by CD47–SIRPα checkpoint inhibition. These findings provide a basis for targeting CD47–SIRPα interactions in combination with IgA therapeutic antibodies to improve their potential clinical efficacy in tumor patients.

Published
2023
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30. Supplementary Data from IgA-Mediated Killing of Tumor Cells by Neutrophils Is Enhanced by CD47–SIRPα Checkpoint Inhibition

Author

Hanke L. Matlung, Jeanette H.W. Leusen, Thomas Valerius, Timo K. van den Berg, Taco W. Kuijpers, Katka Franke, Jan M. Prins, Paul J.J.H. Verkuijlen, Karin Schornagel, Steffen Kahle, Michel van Houdt, J.H. Marco Jansen, Thies Rösner, Toine ten Broeke, and Louise W. Treffers

Abstract

Supplementary Materials and Methods

Published
2023
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32. Cancer cells resist antibody-mediated destruction by neutrophils through activation of the exocyst complex

Author

Dieke J van Rees, Panagiota Bouti, Bart Klein, Paul J H Verkuijlen, Michel van Houdt, Karin Schornagel, Anton T J Tool, David Venet, Christos Sotiriou, Sarra El-Abed, Miguel Izquierdo, Sébastien Guillaume, Cristina Saura, Serena Di Cosimo, Jens Huober, Rebecca Roylance, Sung-Bae Kim, Taco W Kuijpers, Robin van Bruggen, Timo K van den Berg, Hanke L Matlung, Institut Català de la Salut, [van Rees DJ, Bouti P, Klein B, Verkuijlen PJH, van Houdt M, Schornagel K] Department of Molecular Hematology, Sanquin Research, Amsterdam, The Netherlands. [Saura C] SOLTI Innovative Breast Cancer Research, Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Graduate School, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, and ARD - Amsterdam Reproduction and Development

Subjects
immunity, innate, Cancer Research, Neutrophils, Immunology, Breast Neoplasms, Antibodies, neoplasias [ENFERMEDADES], innate, Immunology and Allergy, Humans, RNA, Messenger, immunologic, Otros calificadores::/terapia [Otros calificadores], cytotoxicity, immunologic, Pharmacology, Cells::Blood Cells::Leukocytes::Granulocytes::Neutrophils [ANATOMY], Immune System Phenomena::Cytotoxicity, Immunologic::Antibody-Dependent Cell Cytotoxicity [PHENOMENA AND PROCESSES], Càncer - Tractament, Antibody-Dependent Cell Cytotoxicity, tumor escape, Other subheadings::/therapy [Other subheadings], Trastuzumab, Immunoglobulines - Ús terapèutic, células::células sanguíneas::leucocitos::granulocitos::neutrófilos [ANATOMÍA], immunity, Citotoxicitat per mediació cel·lular, Neoplasms [DISEASES], Oncology, Molecular Medicine, cytotoxicity, Female, immunotherapy, fenómenos del sistema inmunitario::citotoxicidad inmunológica::citotoxicidad celular dependiente de anticuerpos [FENÓMENOS Y PROCESOS], immune evation
Abstract

BackgroundNeutrophils kill antibody-opsonized tumor cells using trogocytosis, a unique mechanism of destruction of the target plasma. This previously unknown cytotoxic process of neutrophils is dependent on antibody opsonization, Fcγ receptors and CD11b/CD18 integrins. Here, we demonstrate that tumor cells can escape neutrophil-mediated cytotoxicity by calcium (Ca2+)-dependent and exocyst complex-dependent plasma membrane repair.MethodsWe knocked down EXOC7 or EXOC4, two exocyst components, to evaluate their involvement in tumor cell membrane repair after neutrophil-induced trogocytosis. We used live cell microscopy and flow cytometry for visualization of the host and tumor cell interaction and tumor cell membrane repair. Last, we reported the mRNA levels of exocyst in breast cancer tumors in correlation to the response in trastuzumab-treated patients.ResultsWe found that tumor cells can evade neutrophil antibody-dependent cellular cytotoxicity (ADCC) by Ca2+-dependent cell membrane repair, a process induced upon neutrophil trogocytosis. Absence of exocyst components EXOC7 or EXOC4 rendered tumor cells vulnerable to neutrophil-mediated ADCC (but not natural killer cell-mediated killing), while neutrophil trogocytosis remained unaltered. Finally, mRNA levels of exocyst components in trastuzumab-treated patients were inversely correlated to complete response to therapy.ConclusionsOur results support that neutrophil attack towards antibody-opsonized cancer cells by trogocytosis induces an active repair process by the exocyst complex in vitro. Our findings provide insight to the possible contribution of neutrophils in current antibody therapies and the tolerance mechanism of tumor cells and support further studies for potential use of the exocyst components as clinical biomarkers.

Published
2022

33. The impact of endoxifen-guided tamoxifen dose reductions on endocrine side-effects in patients with primary breast cancer

Author

S.M. Buijs, E. Oomen-de Hoop, C.L. Braal, M.M. van Rosmalen, J.C. Drooger, Q.C. van Rossum-Schornagel, M.B. Vastbinder, S.L.W. Koolen, A. Jager, R.H.J. Mathijssen, Medical Oncology, and Pharmacy

Subjects
Cancer Research, Oncology, SDG 3 - Good Health and Well-being
Abstract

BACKGROUND: Tamoxifen is important in the adjuvant treatment of hormone-sensitive breast cancer and substantially reduces recurrence; however, almost 50% of patients are non-compliant mainly due to side-effects. The aim of this study was to investigate whether endoxifen-guided tamoxifen dose reduction could lead to fewer side-effects.MATERIALS AND METHODS: Effects of tamoxifen dose reduction were investigated in patients with bothersome side-effects and endoxifen levels ≥32 nM and compared to patients with side-effects who remained on tamoxifen 20 mg. Endocrine symptoms and health-related quality of life (HR-QOL) were assessed after 3 months with the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) questionnaire.RESULTS: Tamoxifen dose was reduced in 20 patients, 17 of whom were assessable for side-effect analyses. A clinically relevant improvement of >6 points was observed in endocrine symptoms and HR-QOL in 41% and 65% of the patients, respectively. In total, there was a significant and clinically relevant improvement in endocrine symptoms [5.7, 95% confidence interval (CI) -0.5-11.5] and HR-QOL (8.2, 95% CI 0.9-15.4) after dose reduction. This was not seen in patients whose doses were not reduced (n = 60). In 21% of patients, endoxifen dropped slightly below the 16-nM threshold (12.8, 15.5, 15.8, 15.9 nM).CONCLUSIONS: Endoxifen-guided dose reduction of tamoxifen significantly improved tamoxifen-related side-effects and HR-QOL. Nearly 80% of patients remained above the most conservative endoxifen threshold.

Published
2023

34. Targeted new screening for congenital cytomegalovirus infection: clinical, audiological and neuroimaging findings

Author

Pui Khi Chung, Fleurtje Schornagel, Anne Marie Oudesluys-Murphy, Linda S de Vries, Wim Soede, Erik van Zwet, and Ann Vossen

Subjects
Virology, Pediatrics, Perinatology and Child Health, Obstetrics and Gynecology, Paediatrics, General Medicine, Audiology, Magnetic Resonance Imaging, Neuropathology
Abstract

ObjectiveTo evaluate clinical, audiological and neuroimaging findings in a cohort of infants diagnosed with congenital cytomegalovirus (cCMV) infection after failure at newborn hearing screening.MethodsA prospective observational study in the Netherlands, using the existing newborn hearing screening infrastructure for well babies. Between July 2012 and November 2016, cytomegalovirus (CMV) PCR testing of neonatally obtained dried blood spots (DBS) was offered to all infants who failed newborn hearing screening. Clinical, neuroimaging and audiological data were collected.ResultsDBS of 1374 infants were successfully tested and 59 were positive for CMV (4.3%). Data of 54 infants were retrieved. Three were small for gestational age and six had microcephaly. Forty-eight (89%) had sensorineural hearing loss (SNHL), of whom half had unilateral SNHL. In both unilaterally and bilaterally affected children, the majority of the impaired ears had severe or profound hearing loss. Neuroimaging abnormalities were found in 40 of 48 (83%) children who had evaluable cranial ultrasound and/or cerebral MRI. The abnormalities were mild in 34, moderate in 3 and severe in 3 infants. The degree of SNHL and the severity of neuroimaging abnormalities were found to be correlated (p=0.002).ConclusionsThe yield of targeted cCMV screening following newborn hearing screening failure was eight times higher than the estimated national birth prevalence of cCMV. The majority of this cohort of infants with clinically unsuspected cCMV disease had confirmed SNHL, neuroimaging abnormalities and lower than average birth weights and head circumferences. Newborns who fail newborn hearing screening should be tested for CMV to ensure appropriate clinical, neurodevelopmental and audiological follow-up.

Published
2022

36. Mammacarcinoom

Author

Rutgers, E. J. Th., Schornagel, J. H., Merkus, J. M. W. M., editor, van den Bosch, W. J. H. M., editor, and Sitsen, J. M. A., editor

Published
2008
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37. Abstract P1-02-08: CBD-oil: a potential solution in case of severe tamoxifen-related side effects

Author

Sanne Buijs, Louwrens Braal, Stefan Buck, Noud F. van Maanen, Lonneke van der Meijden-Erkelens, Heleen Kuijper-Tissot van Patot, Esther Oomen-de Hoop, Lotte Saes, Sophia van den Boogerd, Liesbeth Struik, Quirine van Rossum-Schornagel, Ron Mathijssen, Stijn Koolen, and Agnes Jager

Subjects
Cancer Research, Oncology
Abstract

Background Tamoxifen is frequently used in the adjuvant treatment of hormone sensitive breast cancer. Unfortunately, tamoxifen can lead to bothersome side effects resulting in non-adherence in 40% of patients. Patients searching for relief from these side effects are increasingly turning to cannabinoids such as CBD. However, since tamoxifen is mainly metabolised by CYP2D6, and CBD is suggested to be an inhibitor of CYP2D6, the use of CBD might affect tamoxifen pharmacokinetics (PK). Since the effect of CBD on both tamoxifen PK as tamoxifen-related side effects has never been investigated, the aims of this study were to determine the pharmacokinetic interaction between CBD and tamoxifen, and to subsequently investigate whether there is a beneficial influence of CBD on tamoxifen-related side effects. Methods Patients had to be treated with tamoxifen for at least 3 months, have steady-state endoxifen levels >16 nM (conservative threshold) and experience tamoxifen-related side effects. PK sampling was done at initiation of CBD-oil and 28 days thereafter. Bio-equivalence could be concluded if the 90% confidence interval (CI) for the difference in endoxifen area under the curve (AUC) fell within the [-20%; +25%] interval (n = 15, two-sided α 0.05, β 0.20). In addition, endoxifen PK was analyzed for each CYP2D6 phenotype separately. The effect of CBD on side effects was evaluated with the FACT-ES questionnaire (n = 25, two-sided α 0.05, β 0.20). An improvement > 0.5 times standard deviation (SD) of baseline score was considered clinically relevant. Last, potential side effects of CBD were assessed. Results In this study 15 patients were included for PK analysis and 24 patients for side effect analysis. Endoxifen AUC decreased after CBD by 12.6% (90% CI -18.7%, -6,1%) but remained within bio-equivalence boundaries. The decrease seemed more pronounced in patients with intermediate (IM) CYP2D6 phenotype (-20.8%, 90% CI -26.4%, -14.8%, n = 8) compared to normal CYP2D6 phenotype (-2.2%, 90% CI -11.1%, 7.6%, n = 7). There was no difference in tamoxifen AUC (with or without CBD). On average, the endocrine sub-scale of the FACT-ES improved with a clinically relevant improvement of 8.3 points (95% CI 4.9 – 11.7) after using CBD (baseline SD = 12.8). CBD itself has a mild toxicity profile with few side effects in 10 of 24 patients. Side effects were headache (n=2), dry mouth (n=3), fatigue (n=3), gastroesophageal reflux (n=1), abdominal pain (n=1) and nausea (n=1) and all graded CTCAE 1. Conclusions As endoxifen levels with or without CBD remained within bio-equivalence boundaries and CBD-oil might have a positive effect on tamoxifen-related side effects, it could be considered in case of treatment-related side effects. However, caution is needed in patients with IM or poor metabolizer CYP2D6 phenotypes. Citation Format: Sanne Buijs, Louwrens Braal, Stefan Buck, Noud F. van Maanen, Lonneke van der Meijden-Erkelens, Heleen Kuijper-Tissot van Patot, Esther Oomen-de Hoop, Lotte Saes, Sophia van den Boogerd, Liesbeth Struik, Quirine van Rossum-Schornagel, Ron Mathijssen, Stijn Koolen, Agnes Jager. CBD-oil: a potential solution in case of severe tamoxifen-related side effects [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-02-08.

Published
2023
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43. Identification of ultra-rare genetic variants in pediatric acute onset neuropsychiatric syndrome (PANS) by exome and whole genome sequencing

Author

Trifiletti, Rosario, primary, Lachman, Herbert M., additional, Manusama, Olivia, additional, Zheng, Deyou, additional, Spalice, Alberto, additional, Chiurazzi, Pietro, additional, Schornagel, Allan, additional, Serban, Andreea M., additional, van Wijck, Rogier, additional, Cunningham, Janet L., additional, Swagemakers, Sigrid, additional, and van der Spek, Peter J., additional

Published
2022
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44. Cancer cells resist antibody-mediated destruction by neutrophils through activation of the exocyst complex

Author

van Rees, Dieke J, primary, Bouti, Panagiota, additional, Klein, Bart, additional, Verkuijlen, Paul J H, additional, van Houdt, Michel, additional, Schornagel, Karin, additional, Tool, Anton T J, additional, Venet, David, additional, Sotiriou, Christos, additional, El-Abed, Sarra, additional, Izquierdo, Miguel, additional, Guillaume, Sébastien, additional, Saura, Cristina, additional, Di Cosimo, Serena, additional, Huober, Jens, additional, Roylance, Rebecca, additional, Kim, Sung-Bae, additional, Kuijpers, Taco W, additional, van Bruggen, Robin, additional, K van den Berg, Timo, additional, and Matlung, Hanke L, additional

Published
2022
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46. Therapeutic Drug Monitoring of Endoxifen for Tamoxifen Precision Dosing: Feasible in Patients with Hormone-Sensitive Breast Cancer

Author

Martine F Thijs-Visser, Mijntje B. Vastbinder, Liesbeth E. M. Struik, Hanneke J. M. Zuetenhorst, Justin D. Westenberg, C. Louwrens Braal, Koen M. W. T. Lommen, Ron H.J. Mathijssen, Robbert J. van Alphen, Stijn L.W. Koolen, Agnes Jager, Esther Oomen-de Hoop, Peter de Bruijn, Quirine C. van Rossum-Schornagel, Medical Oncology, and Pharmacy

Subjects
Pharmacology, Oncology, medicine.medical_specialty, CYP2D6, medicine.diagnostic_test, business.industry, medicine.disease, Confidence interval, Breast cancer, SDG 3 - Good Health and Well-being, Therapeutic drug monitoring, Internal medicine, medicine, Clinical endpoint, Pharmacology (medical), Dosing, business, Adverse effect, Tamoxifen, medicine.drug
Abstract

Background: Endoxifen is the most important active metabolite of tamoxifen. Several retrospective studies have suggested a minimal or threshold endoxifen systemic concentration of 14–16 nM is required for a lower recurrence rate. The aim of this study was to investigate the feasibility of reaching a predefined endoxifen level of ≥ 16 nM (5.97 ng/mL) over time using therapeutic drug monitoring (TDM). Methods: This prospective open-label intervention study enrolled patients who started treatment with a standard dose of tamoxifen 20 mg once daily for early breast cancer. An outpatient visit was combined with a TDM sample at 3, 4.5, and 6 months after initiation of the tamoxifen treatment. The tamoxifen dose was escalated to a maximum of 40 mg if patients had an endoxifen concentration

Published
2022

47. SIRPα Controls the Activity of the Phagocyte NADPH Oxidase by Restricting the Expression of gp91phox

Author

Ellen M. van Beek, Julian Alvarez Zarate, Robin van Bruggen, Karin Schornagel, Anton T.J. Tool, Takashi Matozaki, Georg Kraal, Dirk Roos, and Timo K. van den Berg

Subjects
Biology (General), QH301-705.5
Abstract

The phagocyte NADPH oxidase mediates oxidative microbial killing in granulocytes and macrophages. However, because the reactive oxygen species produced by the NADPH oxidase can also be toxic to the host, it is essential to control its activity. Little is known about the endogenous mechanism(s) that limits NADPH oxidase activity. Here, we demonstrate that the myeloid-inhibitory receptor SIRPα acts as a negative regulator of the phagocyte NADPH oxidase. Phagocytes isolated from SIRPα mutant mice were shown to have an enhanced respiratory burst. Furthermore, overexpression of SIRPα in human myeloid cells prevented respiratory burst activation. The inhibitory effect required interactions between SIRPα and its natural ligand, CD47, as well as signaling through the SIRPα cytoplasmic immunoreceptor tyrosine-based inhibitory motifs. Suppression of the respiratory burst by SIRPα was caused by a selective repression of gp91phox expression, the catalytic component of the phagocyte NADPH oxidase complex. Thus, SIRPα can limit gp91phox expression during myeloid development, thereby controlling the magnitude of the respiratory burst in phagocytes.

Published
2012
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48. Sodium stibogluconate and CD47-SIRPa blockade overcome resistance of anti-CD20–opsonized B cells to neutrophil killing

Author

Rees, Dieke J. van, Brinkhaus, Maximilian, Klein, Bart, Verkuijlen, Paul, Tool, Anton T.J., Schornagel, Karin, Treffers, Louise W., Houdt, Michel van, Kater, Arnon P., Vidarsson, Gestur, Gennery, Andrew R., Kuijpers, Taco W., Bruggen, Robin van, Matlung, Hanke L., Berg, Timo K. van den, Rees, Dieke J. van, Brinkhaus, Maximilian, Klein, Bart, Verkuijlen, Paul, Tool, Anton T.J., Schornagel, Karin, Treffers, Louise W., Houdt, Michel van, Kater, Arnon P., Vidarsson, Gestur, Gennery, Andrew R., Kuijpers, Taco W., Bruggen, Robin van, Matlung, Hanke L., and Berg, Timo K. van den

Abstract

Anti-CD20 antibodies such as rituximab are broadly used to treat B-cell malignancies. These antibodies can induce various effector functions, including immune cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Neutrophils can induce ADCC toward solid cancer cells by trogoptosis, a cytotoxic mechanism known to be dependent on trogocytosis. However, neutrophils seem to be incapable of killing rituximab-opsonized B-cell lymphoma cells. Nevertheless, neutrophils do trogocytose rituximab-opsonized B-cell lymphoma cells, but this only reduces CD20 surface expression and is thought to render tumor cells therapeutically resistant to further rituximab-dependent destruction. Here, we demonstrate that resistance of B-cell lymphoma cells toward neutrophil killing can be overcome by a combination of CD47-SIRPa checkpoint blockade and sodium stibogluconate (SSG), an anti-leishmaniasis drug and documented inhibitor of the tyrosine phosphatase SHP-1. SSG enhanced neutrophil-mediated ADCC of solid tumor cells but enabled trogoptotic killing of B-cell lymphoma cells by turning trogocytosis from a mechanism that contributes to resistance into a cytotoxic anti-cancer mechanism. Tumor cell killing in the presence of SSG required both antibody opsonization of the target cells and disruption of CD47-SIRPa interactions. These results provide a more detailed understanding of the role of neutrophil trogocytosis in antibody-mediated destruction of B cells and clues on how to further optimize antibody therapy of B-cell malignancies.

Published
2022

49. Identification of ultra-rare genetic variants in pediatric acute onset neuropsychiatric syndrome (PANS) by exome and whole genome sequencing

Author

Trifiletti, Rosario, Lachman, Herbert M., Manusama, Olivia, Zheng, Deyou, Spalice, Alberto, Chiurazzi, Pietro, Schornagel, Allan, Serban, Andreea M., van Wijck, Rogier, Cunningham, Janet L., Swagemakers, Sigrid, van der Spek, Peter J., Trifiletti, Rosario, Lachman, Herbert M., Manusama, Olivia, Zheng, Deyou, Spalice, Alberto, Chiurazzi, Pietro, Schornagel, Allan, Serban, Andreea M., van Wijck, Rogier, Cunningham, Janet L., Swagemakers, Sigrid, and van der Spek, Peter J.

Abstract

Abrupt onset of severe neuropsychiatric symptoms including obsessive–compulsive disorder, tics, anxiety, mood swings, irritability, and restricted eating is described in children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). Symptom onset is often temporally associated with infections, suggesting an underlying autoimmune/autoinflammatory etiology, although direct evidence is often lacking. The pathological mechanisms are likely heterogeneous, but we hypothesize convergence on one or more biological pathways. Consequently, we conducted whole exome sequencing (WES) on a U.S. cohort of 386 cases, and whole genome sequencing (WGS) on ten cases from the European Union who were selected because of severe PANS. We focused on identifying potentially deleterious genetic variants that were de novo or ultra-rare (MAF) < 0.001. Candidate mutations were found in 11 genes (PPM1D, SGCE, PLCG2, NLRC4, CACNA1B, SHANK3, CHK2, GRIN2A, RAG1, GABRG2, and SYNGAP1) in 21 cases, which included two or more unrelated subjects with ultra-rare variants in four genes. These genes converge into two broad functional categories. One regulates peripheral immune responses and microglia (PPM1D, CHK2, NLRC4, RAG1, PLCG2). The other is expressed primarily at neuronal synapses (SHANK3, SYNGAP1, GRIN2A, GABRG2, CACNA1B, SGCE). Mutations in these neuronal genes are also described in autism spectrum disorder and myoclonus-dystonia. In fact, 12/21 cases developed PANS superimposed on a preexisting neurodevelopmental disorder. Genes in both categories are also highly expressed in the enteric nervous system and the choroid plexus. Thus, genetic variation in PANS candidate genes may function by disrupting peripheral and central immune functions, neurotransmission, and/or the blood-CSF/brain barriers following stressors such as infection.

Published
2022
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50. Improving climb and descent profiles in BlueSky using ATC performance models

Author

Schornagel, Folkert (author) and Schornagel, Folkert (author)

Abstract

Testing novel concepts in the allocation and use of aircraft is commonly done in air traffic simulators. Current day simulators rely on proprietary models and often propose questionable solutions. This paper uses BlueSky as simulator, in cooperation with performance models OpenAP and BADA. BlueSky aims to provide the user with full freedom to simulate any scenario. Improving BlueSky and adding functionality further aids in this goal. By expanding logic of the simulator, the user should attain more functionality without compromising the user-friendliness of BlueSky. This paper treats the implementation of thrust setting and flight path angle in BlueSky. This enables continuous descent operations to become part of the possibilities within BlueSky. The challenge was to prepare a set of ADS-B data using Fuzzy logic to validate the new model. Its robustness was then be demonstrated using a large number of flights., Aerospace Engineering | Control & Simulation

Published
2022

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