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1. Pembrolizumab for the First-Line Treatment of Recurrent Locally Advanced or Metastatic Merkel Cell Carcinoma: Results from the Single-Arm, Open-Label, Phase III KEYNOTE-913 Study

Author

Mortier, Laurent, Villabona, Lisa, Lawrence, Ben, Arance, Ana, Butler, Marcus O., Beylot-Barry, Marie, Saiag, Philippe, Samimi, Mahtab, Ascierto, Paolo A., Spada, Francesca, De Pontville, Michel, Maio, Michele, Berrocal, Alfonso, Espinosa, Enrique, Capdevila, Jaume, Levin, Max, Das, Debasmita, Krepler, Clemens, Grebennik, Dmitri, and Chiarion-Sileni, Vanna

Published
2024
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3. Intussusceptive Angiogenesis in Human Metastatic Malignant Melanoma

Author

Pandita, Ankur, Ekstrand, Matias, Bjursten, Sara, Zhao, Zhiyuan, Fogelstrand, Per, Le Gal, Kristell, Ny, Lars, Bergo, Martin O, Karlsson, Joakim, Nilsson, Jonas A, Akyürek, Levent M, Levin, Malin C, Borén, Jan, Ewald, Andrew J, Mostov, Keith E, and Levin, Max

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cancer, Genetics, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Aged, Aged, 80 and over, Animals, Female, Heterografts, Humans, Male, Matrix Metalloproteinase 9, Melanoma, Mice, Middle Aged, Neovascularization, Pathologic, Skin Neoplasms, Medical and Health Sciences, Pathology, Biomedical and clinical sciences, Health sciences
Abstract

Angiogenesis supplies oxygen and nutrients to growing tumors. Inhibiting angiogenesis may stop tumor growth, but vascular endothelial growth factor inhibitors have limited effect in most tumors. This limited effect may be explained by an additional, less vascular endothelial growth factor-driven form of angiogenesis known as intussusceptive angiogenesis. The importance of intussusceptive angiogenesis in human tumors is not known. Epifluorescence and confocal microscopy was used to visualize intravascular pillars, the hallmark structure of intussusceptive angiogenesis, in tumors. Human malignant melanoma metastases, patient-derived melanoma xenografts in mice (PDX), and genetically engineered v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-induced, phosphatase and TENsin homolog deleted on chromosome 10 (PTEN)-deficient (BPT) mice (BrafCA/+Ptenf/fTyr-Cre+/0-mice) were analyzed for pillars. Gene expression in human melanoma metastases and PDXs was analyzed by RNA sequencing. Matrix metalloproteinase 9 (MMP9) protein expression and T-cell and macrophage infiltration in tumor sections were determined with multiplex immunostaining. Intravascular pillars were detected in human metastases but rarely in PDXs and not in BPT mice. The expression of MMP9 mRNA was higher in human metastases compared with PDXs. High expression of MMP9 protein as well as infiltration of macrophages and T-cells were detected in proximity to intravascular pillars. MMP inhibition blocked formation of pillars, but not tubes or tip cells, in vitro. In conclusion, intussusceptive angiogenesis may contribute to the growth of human melanoma metastases. MMP inhibition blocked pillar formation in vitro and should be further investigated as a potential anti-angiogenic drug target in metastatic melanoma.

Published
2021

5. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial

Author

Lesimple, Thierry, Maio, Michele, Linette, Gerald, Mortier, Laurent, Svane, Inge Marie, Schachter, Jacob, Brown, Michael, Hersey, Peter, Barrow, Catherine, Kudchadkar, Ragini, Dutriaux, Caroline, Song, Xinni, Quaglino, Pietro, Queirolo, Paola, Meier, Friedegund, Stroyakovskiy, Daniil, Guillot, Bernard, Romero, Pablo Luis Ortiz, Bastholt, Lars, Garbe, Claus, Grange, Florent, Mohr, Peter, Algazi, Alain, Bechter, Oliver, Hernberg, Micaela, Loquai, Carmen, Meiss, Frank, Chiarion Sileni, Vanna, Bar-Sela, Gil, Fitzharris, Bernard, Saiag, Philippe, Arnault, Jean-Philippe, Simon, Jan-Christoph, Stephens, Rosalie, Baurain, Jean-Francois, Lebbe, Célèste, Combemale, Patrick, Dummer, Reinhard, Hauschild, Axel, Parente, Phillip, Yamazaki, Naoya, Milhem, Mohammed, Leccia, Marie-Thérèse, Geoffrois, Lionel, Kretschmer, Lutz, Dunwoodie, Elaine, Walker, John, Lotem, Michal, Hendler, Daniel, Mackiewicz, Andrzej, Sekulovic, Lidija, Dzienis, Marcin, Hospers, Geke A.P., Siano, Marco, Hassel, Jessica, Corrie, Philippa, Passos, Maria-Jose, Levin, Max, Hoeller, Christoph, Machet, Laurent, Hallmeyer, Sigrun, Waterston, Ashita, Descamps, Vincent, Kiecker, Felix, Aarts, Maureen, Schmidt, Henrik, Raimundo, Ana, Nyakas, Marta, Lacour, Jean-Philippe, Berking, Carola, Ferrucci, Pier Francesco, Jameson, Michael, Kim, Kevin, Yokota, Kenji, Kerger, Joseph, Aubin, François, Groenewegen, Gerard, Kapiteijn, Helena, Boehncke, Wolf-Henning, Utikal, Jochen, Casasola, Richard, Marshall, Ernest, Ferraresi, Virginia, Richtig, Erika, Matkovic, Suzana, Inozume, Takashi, Crook, Timothy, McNeil, Catriona, Kiyohara, Yoshio, Avril, Marie-Francoise, Hein, Rüdiger, Terheyden, Patrick, Nathan, Paul, Aoi, Jun, Skytta, Tanja, Jouary, Thomas, Takenouchi, Tatsuya, Straume, Oddbjorn, Martins, César, Mukhametshina, Guzel, Bottomley, Andrew, Coens, Corneel, Mierzynska, Justyna, Blank, Christian U, Mandalà, Mario, Long, Georgina V, Atkinson, Victoria G, Dalle, Stéphane, Haydon, Andrew M, Meshcheryakov, Andrey, Khattak, Adnan, Carlino, Matteo S, Sandhu, Shahneen, Puig, Susana, Ascierto, Paolo A, Larkin, James, Lorigan, Paul C, Rutkowski, Piotr, Schadendorf, Dirk, Koornstra, Rutger, Hernandez-Aya, Leonel, Di Giacomo, Anna Maria, van den Eertwegh, Alfonsus J M, Grob, Jean-Jacques, Gutzmer, Ralf, Jamal, Rahima, van Akkooi, Alexander C J, Krepler, Clemens, Ibrahim, Nageatte, Marreaud, Sandrine, Kicinski, Michal, Suciu, Stefan, Robert, Caroline, and Eggermont, Alexander M M

Published
2021
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6. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial

Author

Menzies, Alex, Lesimple, Thierry, Maio, Michele, Linette, Gerald, Brown, Michael, Hersey, Peter, Svane, Inge Marie, Mortier, Laurent, Schachter, Jacob, Barrow, Catherine, Kudchadkar, Ragini, Song, Xinni, Dutriaux, Caroline, Quaglino, Pietro, Meier, Friedegund, Queirolo, Paola, Stroyakovskiy, Daniil, Bastholt, Lars, Guillot, Bernard, Garbe, Claus, Ortiz Romero, Pablo Luis, Grange, Florent, Mohr, Peter, Algazi, Alain, Bechter, Oliver, Hernberg, Micaela, Arnault, Jean-Philippe, Saiag, Philippe, Loquai, Carmen, Meiss, Frank, Simon, Jan-Christoph, Bar-Sela, Gil, Chiarion Sileni, Vanna, Fitzharris, Bernard, McCrystal, Mike, Parente, Phillip, Baurain, Jean-Francois, Combemale, Patrick, Lebbe, Célèste, Hauschild, Axel, Yamazaki, Naoya, Dummer, Reinhard, Milhem, Mohammed, Dzienis, Marcin, Walker, John, Geoffrois, Lionel, Leccia, Marie-Thérèse, Kretschmer, Lutz, Hendler, Daniel, Lotem, Michal, Mackiewicz, Andrzej, Sekulovic, Lidija, Dunwoodie, Elaine, Hoeller, Christoph, Machet, Laurent, Hassel, Jessica, Hospers, Geke A.P., Passos, Maria-Jose, Levin, Max, Fehr, Martin, Corrie, Philippa, Waterston, Ashita, Hallmeyer, Sigrun, Schmidt, Henrik, Descamps, Vincent, Lacour, Jean-Philippe, Berking, Carola, Kiecker, Felix, Ferrucci, Pier Francesco, Yokota, Kenji, Aarts, Maureen, Jameson, Michael, Winge-Main, Anna Katharina, Ferreira, Paula, Kim, Kevin, McNeil, Catriona, Hofmann-Wellenhof, Reiner, Kerger, Joseph, Aubin, François, Utikal, Jochen, Ferraresi, Virginia, Inozume, Takashi, Kiyohara, Yoshio, Groenewegen, Gerard, Kapiteijn, Helena, Matkovic, Suzana, Boehncke, Wolf-Henning, Casasola, Richard, Crook, Timothy, Marshall, Ernest, Skytta, Tanja, Avril, Marie-Francoise, Jouary, Thomas, Hein, Rüdiger, Terheyden, Patrick, Aoi, Jun, Takenouchi, Tatsuya, Straume, Oddbjorn, Martins, César, Mukhametshina, Guzel, Nathan, Paul, Eggermont, Alexander M M, Blank, Christian U, Mandalà, Mario, Long, Georgina V, Atkinson, Victoria G, Dalle, Stéphane, Haydon, Andrew M, Meshcheryakov, Andrey, Khattak, Adnan, Carlino, Matteo S, Sandhu, Shahneen, Larkin, James, Puig, Susana, Ascierto, Paolo A, Rutkowski, Piotr, Schadendorf, Dirk, Koornstra, Rutger, Hernandez-Aya, Leonel, Di Giacomo, Anna Maria, van den Eertwegh, Alfonsus J M, Grob, Jean-Jacques, Gutzmer, Ralf, Jamal, Rahima, Lorigan, Paul C, van Akkooi, Alexander C J, Krepler, Clemens, Ibrahim, Nageatte, Marreaud, Sandrine, Kicinski, Michal, Suciu, Stefan, and Robert, Caroline

Published
2021
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7. Immune mapping of human tuberculosis and sarcoidosis lung granulomas

Author

Carow, Berit, primary, Muliadi, Victoria, additional, Skålén, Kristina, additional, Yokota, Chika, additional, Kathamuthu, Gokul Raj, additional, Setiabudiawan, Todia Pediatama, additional, Lange, Christoph, additional, Scheu, Katrin, additional, Gaede, Karoline I., additional, Goldmann, Torsten, additional, Pandita, Ankur, additional, Masood, Kiran Iqbal, additional, Pervez, Shahid, additional, Grunewald, Johan, additional, Hasan, Zahra, additional, Levin, Max, additional, and Rottenberg, Martin E., additional

Published
2024
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9. FIGURE 1 from Chemokine Analysis in Patients with Metastatic Uveal Melanoma Suggests a Role for CCL21 Signaling in Combined Epigenetic Therapy and Checkpoint Immunotherapy

Author

Sah, Vasu R., primary, Jespersen, Henrik, primary, Karlsson, Joakim, primary, Nilsson, Lisa M., primary, Bergqvist, Mattias, primary, Johansson, Iva, primary, Carneiro, Ana, primary, Helgadottir, Hildur, primary, Levin, Max, primary, Ullenhag, Gustav, primary, Ståhlberg, Anders, primary, Olofsson Bagge, Roger, primary, Nilsson, Jonas A., primary, and Ny, Lars, primary

Published
2023
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10. Supplementary Table S3 from Chemokine Analysis in Patients with Metastatic Uveal Melanoma Suggests a Role for CCL21 Signaling in Combined Epigenetic Therapy and Checkpoint Immunotherapy

Author

Sah, Vasu R., primary, Jespersen, Henrik, primary, Karlsson, Joakim, primary, Nilsson, Lisa M., primary, Bergqvist, Mattias, primary, Johansson, Iva, primary, Carneiro, Ana, primary, Helgadottir, Hildur, primary, Levin, Max, primary, Ullenhag, Gustav, primary, Ståhlberg, Anders, primary, Olofsson Bagge, Roger, primary, Nilsson, Jonas A., primary, and Ny, Lars, primary

Published
2023
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11. Figure S1 from Chemokine Analysis in Patients with Metastatic Uveal Melanoma Suggests a Role for CCL21 Signaling in Combined Epigenetic Therapy and Checkpoint Immunotherapy

Author

Sah, Vasu R., primary, Jespersen, Henrik, primary, Karlsson, Joakim, primary, Nilsson, Lisa M., primary, Bergqvist, Mattias, primary, Johansson, Iva, primary, Carneiro, Ana, primary, Helgadottir, Hildur, primary, Levin, Max, primary, Ullenhag, Gustav, primary, Ståhlberg, Anders, primary, Olofsson Bagge, Roger, primary, Nilsson, Jonas A., primary, and Ny, Lars, primary

Published
2023
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12. FIGURE 5 from Chemokine Analysis in Patients with Metastatic Uveal Melanoma Suggests a Role for CCL21 Signaling in Combined Epigenetic Therapy and Checkpoint Immunotherapy

Author

Sah, Vasu R., primary, Jespersen, Henrik, primary, Karlsson, Joakim, primary, Nilsson, Lisa M., primary, Bergqvist, Mattias, primary, Johansson, Iva, primary, Carneiro, Ana, primary, Helgadottir, Hildur, primary, Levin, Max, primary, Ullenhag, Gustav, primary, Ståhlberg, Anders, primary, Olofsson Bagge, Roger, primary, Nilsson, Jonas A., primary, and Ny, Lars, primary

Published
2023
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13. FIGURE 4 from Chemokine Analysis in Patients with Metastatic Uveal Melanoma Suggests a Role for CCL21 Signaling in Combined Epigenetic Therapy and Checkpoint Immunotherapy

Author

Sah, Vasu R., primary, Jespersen, Henrik, primary, Karlsson, Joakim, primary, Nilsson, Lisa M., primary, Bergqvist, Mattias, primary, Johansson, Iva, primary, Carneiro, Ana, primary, Helgadottir, Hildur, primary, Levin, Max, primary, Ullenhag, Gustav, primary, Ståhlberg, Anders, primary, Olofsson Bagge, Roger, primary, Nilsson, Jonas A., primary, and Ny, Lars, primary

Published
2023
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14. Data from Chemokine Analysis in Patients with Metastatic Uveal Melanoma Suggests a Role for CCL21 Signaling in Combined Epigenetic Therapy and Checkpoint Immunotherapy

Author

Sah, Vasu R., primary, Jespersen, Henrik, primary, Karlsson, Joakim, primary, Nilsson, Lisa M., primary, Bergqvist, Mattias, primary, Johansson, Iva, primary, Carneiro, Ana, primary, Helgadottir, Hildur, primary, Levin, Max, primary, Ullenhag, Gustav, primary, Ståhlberg, Anders, primary, Olofsson Bagge, Roger, primary, Nilsson, Jonas A., primary, and Ny, Lars, primary

Published
2023
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15. FIGURE 2 from Chemokine Analysis in Patients with Metastatic Uveal Melanoma Suggests a Role for CCL21 Signaling in Combined Epigenetic Therapy and Checkpoint Immunotherapy

Author

Sah, Vasu R., primary, Jespersen, Henrik, primary, Karlsson, Joakim, primary, Nilsson, Lisa M., primary, Bergqvist, Mattias, primary, Johansson, Iva, primary, Carneiro, Ana, primary, Helgadottir, Hildur, primary, Levin, Max, primary, Ullenhag, Gustav, primary, Ståhlberg, Anders, primary, Olofsson Bagge, Roger, primary, Nilsson, Jonas A., primary, and Ny, Lars, primary

Published
2023
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16. FIGURE 3 from Chemokine Analysis in Patients with Metastatic Uveal Melanoma Suggests a Role for CCL21 Signaling in Combined Epigenetic Therapy and Checkpoint Immunotherapy

Author

Sah, Vasu R., primary, Jespersen, Henrik, primary, Karlsson, Joakim, primary, Nilsson, Lisa M., primary, Bergqvist, Mattias, primary, Johansson, Iva, primary, Carneiro, Ana, primary, Helgadottir, Hildur, primary, Levin, Max, primary, Ullenhag, Gustav, primary, Ståhlberg, Anders, primary, Olofsson Bagge, Roger, primary, Nilsson, Jonas A., primary, and Ny, Lars, primary

Published
2023
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17. FIGURE 6 from Chemokine Analysis in Patients with Metastatic Uveal Melanoma Suggests a Role for CCL21 Signaling in Combined Epigenetic Therapy and Checkpoint Immunotherapy

Author

Sah, Vasu R., primary, Jespersen, Henrik, primary, Karlsson, Joakim, primary, Nilsson, Lisa M., primary, Bergqvist, Mattias, primary, Johansson, Iva, primary, Carneiro, Ana, primary, Helgadottir, Hildur, primary, Levin, Max, primary, Ullenhag, Gustav, primary, Ståhlberg, Anders, primary, Olofsson Bagge, Roger, primary, Nilsson, Jonas A., primary, and Ny, Lars, primary

Published
2023
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18. Chemokine Analysis in Patients with Metastatic Uveal Melanoma Suggests a Role for CCL21 Signaling in Combined Epigenetic Therapy and Checkpoint Immunotherapy

Author

Sah, Vasu R., primary, Jespersen, Henrik, additional, Karlsson, Joakim, additional, Nilsson, Lisa M., additional, Bergqvist, Mattias, additional, Johansson, Iva, additional, Carneiro, Ana, additional, Helgadottir, Hildur, additional, Levin, Max, additional, Ullenhag, Gustav, additional, Ståhlberg, Anders, additional, Olofsson Bagge, Roger, additional, Nilsson, Jonas A., additional, and Ny, Lars, additional

Published
2023
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19. Figure S3 from Chemokine analysis in patients with metastatic uveal melanoma suggests a role for CCL21 signaling in combined epigenetic therapy and checkpoint immunotherapy

Author

Sah, Vasu R, primary, Jespersen, Henrik, primary, Karlsson, Joakim, primary, Nilsson, Lisa M, primary, Bergqvist, Mattias, primary, Johansson, Iva, primary, Carneiro, Ana, primary, Helgadottir, Hildur, primary, Levin, Max, primary, Ullenhag, Gustav J., primary, Ståhlberg, Anders, primary, Olofsson Bagge, Roger, primary, Nilsson, Jonas A., primary, and Ny, Lars, primary

Published
2023
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20. Supplementary Table S1 from Chemokine analysis in patients with metastatic uveal melanoma suggests a role for CCL21 signaling in combined epigenetic therapy and checkpoint immunotherapy

Author

Sah, Vasu R, primary, Jespersen, Henrik, primary, Karlsson, Joakim, primary, Nilsson, Lisa M, primary, Bergqvist, Mattias, primary, Johansson, Iva, primary, Carneiro, Ana, primary, Helgadottir, Hildur, primary, Levin, Max, primary, Ullenhag, Gustav J., primary, Ståhlberg, Anders, primary, Olofsson Bagge, Roger, primary, Nilsson, Jonas A., primary, and Ny, Lars, primary

Published
2023
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21. Data from Chemokine analysis in patients with metastatic uveal melanoma suggests a role for CCL21 signaling in combined epigenetic therapy and checkpoint immunotherapy

Author

Sah, Vasu R, primary, Jespersen, Henrik, primary, Karlsson, Joakim, primary, Nilsson, Lisa M, primary, Bergqvist, Mattias, primary, Johansson, Iva, primary, Carneiro, Ana, primary, Helgadottir, Hildur, primary, Levin, Max, primary, Ullenhag, Gustav J., primary, Ståhlberg, Anders, primary, Olofsson Bagge, Roger, primary, Nilsson, Jonas A., primary, and Ny, Lars, primary

Published
2023
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23. Early Increase of Circulating Transitional B Cells and Autoantibodies to Joint‐Related Proteins in Patients With Metastatic Melanoma Developing Checkpoint Inhibitor–Induced Inflammatory Arthritis

Author

Gatto, Mariele, primary, Bjursten, Sara, additional, Jonsson, Charlotte A., additional, Agelii, Monica Leu, additional, Jonell, Caroline, additional, McGrath, Sarah, additional, Lönnblom, Erik, additional, Sareila, Outi, additional, Holmdahl, Rikard, additional, Rudin, Anna, additional, Levin, Max, additional, and Gjertsson, Inger, additional

Published
2023
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24. Chemokine Analysis in Patients with Metastatic Uveal Melanoma Suggests a Role for CCL21 Signaling in Combined Epigenetic Therapy and Checkpoint Immunotherapy

Author

Sah, Vasu R., Jespersen, Henrik, Karlsson, Joakim, Nilsson, Lisa M., Bergqvist, Mattias, Johansson, Iva, Carneiro, Ana, Helgadottir, Hildur, Levin, Max, Ullenhag, Gustav, Stahlberg, Anders, Bagge, Roger Olofsson, Nilsson, Jonas A., Ny, Lars, Sah, Vasu R., Jespersen, Henrik, Karlsson, Joakim, Nilsson, Lisa M., Bergqvist, Mattias, Johansson, Iva, Carneiro, Ana, Helgadottir, Hildur, Levin, Max, Ullenhag, Gustav, Stahlberg, Anders, Bagge, Roger Olofsson, Nilsson, Jonas A., and Ny, Lars

Abstract

Purpose: Patients with metastatic uveal melanoma have limited therapeutic options and high mortality rate so new treatment options are needed.Patients and Methods: We previously reported that patients treated with the PD-1 inhibitor pembrolizumab and the histone deacetylase inhibitor entinostat in the PEMDAC trial, experienced clinical benefits if their tu-mor originated from iris or was wildtype for BAP1 tumor suppressor gene. Here we present the 2-year follow-up of the patients in the PEMDAC trial and identify additional factors that correlate with response or survival.Results: Durable responses were observed in 4 patients, with additional 8 patients exhibiting a stable disease. The median overall survival was 13.7 months. Grade 3 adverse events were reported in 62% of the patients, but they were all manageable. No fatal toxicity was observed. Activity of thymidine kinase 1 in plasma was higher in patients with stable disease or who progressed on treatment, compared with those with partial response. Chemokines and cytokines were analyzed in plasma. Three chemokines were significantly different when comparing patients with and without response. One of the factors, CCL21, was higher in the plasma of respond-ing patients before treatment initiation but decreased in the same patients upon treatment. In tumors, CCL21 was expressed in areas resembling ter -tiar y lymphoid structures (TLS). High plasma levels of CCL21 and presence of TLS-like regions in the tumor correlated with longer survival.Conclusions: This study provides insight into durable responses in the PEMDAC trial, and describes dynamic changes of chemokines and cytokines in the blood of these patients.Significance: The most significant finding from the 2-year follow-up study of the PEMDAC trial was that high CCL21 levels in blood was associated with response and survival. CCL21 was also expressed in TLS-like regions and presence of these regions was associated with longer survival. These analyses of soluble

Published
2023
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25. Perilipin 5 is protective in the ischemic heart

Author

Drevinge, Christina, Dalen, Knut T., Mannila, Maria Nastase, Täng, Margareta Scharin, Ståhlman, Marcus, Klevstig, Martina, Lundqvist, Annika, Mardani, Ismena, Haugen, Fred, Fogelstrand, Per, Adiels, Martin, Asin-Cayuela, Jorge, Ekestam, Charlotte, Gådin, Jesper R., Lee, Yun K., Nebb, Hilde, Svedlund, Sara, Johansson, Bengt R., Hultén, Lillemor Mattsson, Romeo, Stefano, Redfors, Björn, Omerovic, Elmir, Levin, Max, Gan, Li-Ming, Eriksson, Per, Andersson, Linda, Ehrenborg, Ewa, Kimmel, Alan R., Borén, Jan, and Levin, Malin C.

Published
2016
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29. Cardiac Plin5 interacts with SERCA2 and promotes calcium handling and cardiomyocyte contractility

Author

Cinato, Mathieu, primary, Mardani, Ismena, additional, Miljanovic, Azra, additional, Drevinge, Christina, additional, Laudette, Marion, additional, Bollano, Entela, additional, Henricsson, Marcus, additional, Tolö, Johan, additional, Bauza Thorbrügge, Marcos, additional, Levin, Max, additional, Lindbom, Malin, additional, Arif, Muhammad, additional, Pacher, Pal, additional, Andersson, Linda, additional, Olofsson, Charlotta S, additional, Borén, Jan, additional, and Levin, Malin C, additional

Published
2023
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31. Noninvasive detection of any-stage cancer using free glycosaminoglycans

Author

Bratulic, Sinisa, primary, Limeta, Angelo, additional, Dabestani, Saeed, additional, Birgisson, Helgi, additional, Enblad, Gunilla, additional, Stålberg, Karin, additional, Hesselager, Göran, additional, Häggman, Michael, additional, Höglund, Martin, additional, Simonson, Oscar E., additional, Stålberg, Peter, additional, Lindman, Henrik, additional, Bång-Rudenstam, Anna, additional, Ekstrand, Matias, additional, Kumar, Gunjan, additional, Cavarretta, Ilaria, additional, Alfano, Massimo, additional, Pellegrino, Francesco, additional, Mandel-Clausen, Thomas, additional, Salanti, Ali, additional, Maccari, Francesca, additional, Galeotti, Fabio, additional, Volpi, Nicola, additional, Daugaard, Mads, additional, Belting, Mattias, additional, Lundstam, Sven, additional, Stierner, Ulrika, additional, Nyman, Jan, additional, Bergman, Bengt, additional, Edqvist, Per-Henrik, additional, Levin, Max, additional, Salonia, Andrea, additional, Kjölhede, Henrik, additional, Jonasch, Eric, additional, Nielsen, Jens, additional, and Gatto, Francesco, additional

Published
2022
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32. Quantitative interactome proteomics reveals Plin5 as a novel partner of sarcoplasmic/endoplasmic reticulum Ca2+ATPase 2a (SERCA2a) in the regulation of calcium cycling

Author

Cinato, Mathieu, primary, Mardani, Ismena, additional, Miljanovic, Azra, additional, Drevinge, Christina, additional, Laudette, Marion, additional, Bollano, Entela, additional, Henricsson, Marcus, additional, Tolö, Johan, additional, Thorbrügge, Marcos Bauza, additional, Levin, Max, additional, Lindbom, Malin, additional, Klevstig, Martina, additional, Fogelstrand, Per, additional, Andersson, Linda, additional, Olofsson, Charlotta, additional, Borén, Jan, additional, and Levin, Malin, additional

Published
2022
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35. Noninvasive detection of any-stage cancer using free glycosaminoglycans

Author

Bratulic, Sinisa, Limeta, Angelo, Dabestani, Saeed, Birgisson, Helgi, Enblad, Gunilla, Stålberg, Karin, Hesselager, Göran, Häggman, Michael, Höglund, Martin, Simonson, Oscar, Stålberg, Peter, Lindman, Henrik, Bång-Rudenstam, Anna, Ekstrand, Matias, Kumar, Gunjan, Cavarretta, Ilaria, Alfano, Massimo, Pellegrino, Francesco, Mandel-Clausen, Thomas, Salanti, Ali, Maccari, Francesca, Galeotti, Fabio, Volpi, Nicola, Daugaard, Mads, Belting, Mattias, Lundstam, Sven, Stierner, Ulrika, Nyman, Jan, Bergman, Bengt, Edqvist, Per-Henrik D, Levin, Max, Salonia, Andrea, Kjölhede, Henrik, Jonasch, Eric, Nielsen, Jens, Gatto, Francesco, Bratulic, Sinisa, Limeta, Angelo, Dabestani, Saeed, Birgisson, Helgi, Enblad, Gunilla, Stålberg, Karin, Hesselager, Göran, Häggman, Michael, Höglund, Martin, Simonson, Oscar, Stålberg, Peter, Lindman, Henrik, Bång-Rudenstam, Anna, Ekstrand, Matias, Kumar, Gunjan, Cavarretta, Ilaria, Alfano, Massimo, Pellegrino, Francesco, Mandel-Clausen, Thomas, Salanti, Ali, Maccari, Francesca, Galeotti, Fabio, Volpi, Nicola, Daugaard, Mads, Belting, Mattias, Lundstam, Sven, Stierner, Ulrika, Nyman, Jan, Bergman, Bengt, Edqvist, Per-Henrik D, Levin, Max, Salonia, Andrea, Kjölhede, Henrik, Jonasch, Eric, Nielsen, Jens, and Gatto, Francesco

Abstract

Cancer mortality is exacerbated by late-stage diagnosis. Liquid biopsies based on genomic biomarkers can noninvasively diagnose cancers. However, validation studies have reported similar to 10% sensitivity to detect stage I cancer in a screening population and specific types, such as brain or genitourinary tumors, remain undetectable. We investigated urine and plasma free glycosaminoglycan profiles (GAGomes) as tumor metabolism biomarkers for multi-cancer early detection (MCED) of 14 cancer types using 2,064 samples from 1,260 cancer or healthy subjects. We observed widespread cancer-specific changes in biofluidic GAGomes recapitulated in an in vivo cancer progression model. We developed three machine learning models based on urine (N-urine = 220 cancer vs. 360 healthy) and plasma (N-plasma = 517 vs. 425) GAGomes that can detect any cancer with an area under the receiver operating characteristic curve of 0.83-0.93 with up to 62% sensitivity to stage I disease at 95% specificity. Undetected patients had a 39 to 50% lower risk of death. GAGomes predicted the putative cancer location with 89% accuracy. In a validation study on a screening-like population requiring >= 99% specificity, combined GAGomes predicted any cancer type with poor prognosis within 18 months with 43% sensitivity (21% in stage I; N = 121 and 49 cases). Overall, GAGomes appeared to be powerful MCED metabolic biomarkers, potentially doubling the number of stage I cancers detectable using genomic biomarkers.

Published
2022
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37. Early rise in brain damage markers and high ICOS expression in CD4+ and CD8+ T cells during checkpoint inhibitor-induced encephalomyelitis

Author

Bjursten, Sara, Pandita, Ankur, Zhao, Zhiyuan, Fröjd, Charlotta, Ny, Lars, Jensen, Christer, Ullerstam, Tobias, Jespersen, Henrik, Borén, Jan, Levin, Malin, Zetterberg, Henrik, Rudin, Anna, and Levin, Max

Subjects
CD4-Positive T-Lymphocytes, Male, autoimmunity, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Case Report, CD8-Positive T-Lymphocytes, 2518 1619, Inducible T-Cell Co-Stimulator Protein, melanoma, Humans, Brain Damage, Chronic, immunotherapy, Encephalomyelitis, Immune Checkpoint Inhibitors, RC254-282, Biomarkers, Aged
Abstract

We report a case of rapid eradication of melanoma brain metastases and simultaneous near-fatal encephalomyelitis following double immune checkpoint blockade. Brain damage marker S-100B and C reactive protein increased before symptoms or signs of encephalomyelitis and peaked when the patient fell into a coma. At that point, additional brain damage markers and peripheral T cell phenotype was analyzed. The analyses were repeated four times during the patient’s recovery. Axonal damage marker neurofilament light polypeptide (NFL) and astrocytic damage marker glial fibrillar acidic protein (GFAP) were very high in blood and cerebrospinal fluid and gradually normalized after immunosuppression and intensive care. The costimulatory receptor inducible T cell costimulatory receptor (ICOS) was expressed on a high proportion of CD4+ and CD8+T cells as encephalomyelitis symptoms peaked and then gradually decreased in parallel with clinical improvement. Both single and double immune checkpoint inhibitor-treated melanoma patients with other serious immune-related adverse events (irAE) (n=9) also expressed ICOS on a significantly higher proportion of CD4+ and CD8+T cells compared with controls without irAE (n=12). In conclusion, our results suggest a potential role for ICOS on CD4+ and CD8+T cells in mediating encephalomyelitis and other serious irAE. In addition, brain damage markers in blood could facilitate early diagnosis of encephalitis.

Published
2021

43. Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking

Author

Andersson, Linda, primary, Cinato, Mathieu, additional, Mardani, Ismena, additional, Miljanovic, Azra, additional, Arif, Muhammad, additional, Koh, Ara, additional, Lindbom, Malin, additional, Laudette, Marion, additional, Bollano, Entela, additional, Omerovic, Elmir, additional, Klevstig, Martina, additional, Henricsson, Marcus, additional, Fogelstrand, Per, additional, Swärd, Karl, additional, Ekstrand, Matias, additional, Levin, Max, additional, Wikström, Johannes, additional, Doran, Stephen, additional, Hyötyläinen, Tuulia, additional, Sinisalu, Lisanna, additional, Orešič, Matej, additional, Tivesten, Åsa, additional, Adiels, Martin, additional, Bergo, Martin O, additional, Proia, Richard, additional, Mardinoglu, Adil, additional, Jeppsson, Anders, additional, Borén, Jan, additional, and Levin, Malin C, additional

Published
2021
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44. Clinical outcomes in cancer patients with COVID-19 in Sweden

Author

Bondeson, Lisa, Thulin, Anna, Ny, Lars, Levin, Max, Svensson, Johanna, Lindh, Magnus, and Zhao, Zhiyuan

Abstract

The results of studies on the relationship between cancer and COVID-19 have been conflicting and therefore further studies are needed. We aimed to examine the incidence of COVID-19 among patients at one of the largest oncology departments in Sweden, and to evaluate and identify risk factors for poor outcomes, hospital care and death, associated with COVID-19 among cancer patients. This retrospective study included cancer patients at a single center who tested positive for SARS-CoV-2 by PCR either in hospital, primary health care center or commercial laboratory between 1 March and 14 August 2020. Clinical and demographic data were collected from the medical records. Logistic regression analysis was used to identify variables that associated the primary outcomes of need for hospital care and death within 30 days of positive test. Of 10,774 patients from the Department of Oncology at Sahlgrenska University Hospital, 135 tested positive for SARS-CoV-2 (1.3%). Twenty-eight patients were excluded from further the data collection since they did not meet the inclusion criteria. Altogether, 107 cancer patients were included and the case fatality rate (CFR) was 12% (13) within 30 days of confirmed SARS-CoV-2 infection by PCR. Increasing years of age (OR 1.10; CI 95% 1.03–1.18), palliative treatment intent (OR 15.7; CI 95% 1.8–135.8), and transition to end-of-life care (OR 52.0; CI 95% 3.7–735.6) were associated with increased odds of death within 30 days. Male sex was associated with needing hospital care (OR 3.7; CI 95% 1.50–9.1). As in the general population, male sex was found to be at greater risk of needing hospital care for COVID-19, with terminal cancer disease, and older age increasing the odds of fatality. Compared to the general population, slightly more cancer patients had COVID-19. The CFR was within the lower range of others reported in cancer patients.

Published
2021
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45. Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking

Author

Andersson, Linda, Cinato, Mathieu, Mardani, Ismena, Miljanovic, Azra, Arif, Muhammad, Koh, Ara, Lindbom, Malin, Laudette, Marion, Bollano, Entela, Omerovic, Elmir, Klevstig, Martina, Henricsson, Marcus, Fogelstrand, Per, Swärd, Karl, Ekstrand, Matias, Levin, Max, Wikström, Johannes, Doran, Stephen, Hyötyläinen, Tuulia, Sinisalu, Lisanna, Oresic, Matej, Tivesten, Åsa, Adiels, Martin, Bergo, Martin O., Proia, Richard, Mardinoglu, Adil, Jeppsson, Anders, Borén, Jan, Levin, Malin C., Andersson, Linda, Cinato, Mathieu, Mardani, Ismena, Miljanovic, Azra, Arif, Muhammad, Koh, Ara, Lindbom, Malin, Laudette, Marion, Bollano, Entela, Omerovic, Elmir, Klevstig, Martina, Henricsson, Marcus, Fogelstrand, Per, Swärd, Karl, Ekstrand, Matias, Levin, Max, Wikström, Johannes, Doran, Stephen, Hyötyläinen, Tuulia, Sinisalu, Lisanna, Oresic, Matej, Tivesten, Åsa, Adiels, Martin, Bergo, Martin O., Proia, Richard, Mardinoglu, Adil, Jeppsson, Anders, Borén, Jan, and Levin, Malin C.

Abstract

AIMS: Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function. METHODS AND RESULTS: Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg-/- mice). In 9- to 10-week-old hUgcg-/- mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg-/- mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to β-adrenergic stimulation was reduced in cardiomyocytes from hUgcg-/- mice and that Ugcg knockdown suppressed the internalization and trafficking of β1-adrenergic receptors. CONCLUSIONS: Our findings suggest that cardiac glycosphingolipids are required to maintain β-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function.

Published
2021
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46. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial

Author

Eggermont, Alexander M M, primary, Blank, Christian U, additional, Mandalà, Mario, additional, Long, Georgina V, additional, Atkinson, Victoria G, additional, Dalle, Stéphane, additional, Haydon, Andrew M, additional, Meshcheryakov, Andrey, additional, Khattak, Adnan, additional, Carlino, Matteo S, additional, Sandhu, Shahneen, additional, Larkin, James, additional, Puig, Susana, additional, Ascierto, Paolo A, additional, Rutkowski, Piotr, additional, Schadendorf, Dirk, additional, Koornstra, Rutger, additional, Hernandez-Aya, Leonel, additional, Di Giacomo, Anna Maria, additional, van den Eertwegh, Alfonsus J M, additional, Grob, Jean-Jacques, additional, Gutzmer, Ralf, additional, Jamal, Rahima, additional, Lorigan, Paul C, additional, van Akkooi, Alexander C J, additional, Krepler, Clemens, additional, Ibrahim, Nageatte, additional, Marreaud, Sandrine, additional, Kicinski, Michal, additional, Suciu, Stefan, additional, Robert, Caroline, additional, Menzies, Alex, additional, Lesimple, Thierry, additional, Maio, Michele, additional, Linette, Gerald, additional, Brown, Michael, additional, Hersey, Peter, additional, Svane, Inge Marie, additional, Mortier, Laurent, additional, Schachter, Jacob, additional, Barrow, Catherine, additional, Kudchadkar, Ragini, additional, Song, Xinni, additional, Dutriaux, Caroline, additional, Quaglino, Pietro, additional, Meier, Friedegund, additional, Queirolo, Paola, additional, Stroyakovskiy, Daniil, additional, Bastholt, Lars, additional, Guillot, Bernard, additional, Garbe, Claus, additional, Ortiz Romero, Pablo Luis, additional, Grange, Florent, additional, Mohr, Peter, additional, Algazi, Alain, additional, Bechter, Oliver, additional, Hernberg, Micaela, additional, Arnault, Jean-Philippe, additional, Saiag, Philippe, additional, Loquai, Carmen, additional, Meiss, Frank, additional, Simon, Jan-Christoph, additional, Bar-Sela, Gil, additional, Chiarion Sileni, Vanna, additional, Fitzharris, Bernard, additional, McCrystal, Mike, additional, Parente, Phillip, additional, Baurain, Jean-Francois, additional, Combemale, Patrick, additional, Lebbe, Célèste, additional, Hauschild, Axel, additional, Yamazaki, Naoya, additional, Dummer, Reinhard, additional, Milhem, Mohammed, additional, Dzienis, Marcin, additional, Walker, John, additional, Geoffrois, Lionel, additional, Leccia, Marie-Thérèse, additional, Kretschmer, Lutz, additional, Hendler, Daniel, additional, Lotem, Michal, additional, Mackiewicz, Andrzej, additional, Sekulovic, Lidija, additional, Dunwoodie, Elaine, additional, Hoeller, Christoph, additional, Machet, Laurent, additional, Hassel, Jessica, additional, Hospers, Geke A.P., additional, Passos, Maria-Jose, additional, Levin, Max, additional, Fehr, Martin, additional, Corrie, Philippa, additional, Waterston, Ashita, additional, Hallmeyer, Sigrun, additional, Schmidt, Henrik, additional, Descamps, Vincent, additional, Lacour, Jean-Philippe, additional, Berking, Carola, additional, Kiecker, Felix, additional, Ferrucci, Pier Francesco, additional, Yokota, Kenji, additional, Aarts, Maureen, additional, Jameson, Michael, additional, Winge-Main, Anna Katharina, additional, Ferreira, Paula, additional, Kim, Kevin, additional, McNeil, Catriona, additional, Hofmann-Wellenhof, Reiner, additional, Kerger, Joseph, additional, Aubin, François, additional, Utikal, Jochen, additional, Ferraresi, Virginia, additional, Inozume, Takashi, additional, Kiyohara, Yoshio, additional, Groenewegen, Gerard, additional, Kapiteijn, Helena, additional, Matkovic, Suzana, additional, Boehncke, Wolf-Henning, additional, Casasola, Richard, additional, Crook, Timothy, additional, Marshall, Ernest, additional, Skytta, Tanja, additional, Avril, Marie-Francoise, additional, Jouary, Thomas, additional, Hein, Rüdiger, additional, Terheyden, Patrick, additional, Aoi, Jun, additional, Takenouchi, Tatsuya, additional, Straume, Oddbjorn, additional, Martins, César, additional, Mukhametshina, Guzel, additional, and Nathan, Paul, additional

Published
2021
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47. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial

Author

Bottomley, Andrew, primary, Coens, Corneel, additional, Mierzynska, Justyna, additional, Blank, Christian U, additional, Mandalà, Mario, additional, Long, Georgina V, additional, Atkinson, Victoria G, additional, Dalle, Stéphane, additional, Haydon, Andrew M, additional, Meshcheryakov, Andrey, additional, Khattak, Adnan, additional, Carlino, Matteo S, additional, Sandhu, Shahneen, additional, Puig, Susana, additional, Ascierto, Paolo A, additional, Larkin, James, additional, Lorigan, Paul C, additional, Rutkowski, Piotr, additional, Schadendorf, Dirk, additional, Koornstra, Rutger, additional, Hernandez-Aya, Leonel, additional, Di Giacomo, Anna Maria, additional, van den Eertwegh, Alfonsus J M, additional, Grob, Jean-Jacques, additional, Gutzmer, Ralf, additional, Jamal, Rahima, additional, van Akkooi, Alexander C J, additional, Krepler, Clemens, additional, Ibrahim, Nageatte, additional, Marreaud, Sandrine, additional, Kicinski, Michal, additional, Suciu, Stefan, additional, Robert, Caroline, additional, Eggermont, Alexander M M, additional, Lesimple, Thierry, additional, Maio, Michele, additional, Linette, Gerald, additional, Mortier, Laurent, additional, Svane, Inge Marie, additional, Schachter, Jacob, additional, Brown, Michael, additional, Hersey, Peter, additional, Barrow, Catherine, additional, Kudchadkar, Ragini, additional, Dutriaux, Caroline, additional, Song, Xinni, additional, Quaglino, Pietro, additional, Queirolo, Paola, additional, Meier, Friedegund, additional, Stroyakovskiy, Daniil, additional, Guillot, Bernard, additional, Romero, Pablo Luis Ortiz, additional, Bastholt, Lars, additional, Garbe, Claus, additional, Grange, Florent, additional, Mohr, Peter, additional, Algazi, Alain, additional, Bechter, Oliver, additional, Hernberg, Micaela, additional, Loquai, Carmen, additional, Meiss, Frank, additional, Chiarion Sileni, Vanna, additional, Bar-Sela, Gil, additional, Fitzharris, Bernard, additional, Saiag, Philippe, additional, Arnault, Jean-Philippe, additional, Simon, Jan-Christoph, additional, Stephens, Rosalie, additional, Baurain, Jean-Francois, additional, Lebbe, Célèste, additional, Combemale, Patrick, additional, Dummer, Reinhard, additional, Hauschild, Axel, additional, Parente, Phillip, additional, Yamazaki, Naoya, additional, Milhem, Mohammed, additional, Leccia, Marie-Thérèse, additional, Geoffrois, Lionel, additional, Kretschmer, Lutz, additional, Dunwoodie, Elaine, additional, Walker, John, additional, Lotem, Michal, additional, Hendler, Daniel, additional, Mackiewicz, Andrzej, additional, Sekulovic, Lidija, additional, Dzienis, Marcin, additional, Hospers, Geke A.P., additional, Siano, Marco, additional, Hassel, Jessica, additional, Corrie, Philippa, additional, Passos, Maria-Jose, additional, Levin, Max, additional, Hoeller, Christoph, additional, Machet, Laurent, additional, Hallmeyer, Sigrun, additional, Waterston, Ashita, additional, Descamps, Vincent, additional, Kiecker, Felix, additional, Aarts, Maureen, additional, Schmidt, Henrik, additional, Raimundo, Ana, additional, Nyakas, Marta, additional, Lacour, Jean-Philippe, additional, Berking, Carola, additional, Ferrucci, Pier Francesco, additional, Jameson, Michael, additional, Kim, Kevin, additional, Yokota, Kenji, additional, Kerger, Joseph, additional, Aubin, François, additional, Groenewegen, Gerard, additional, Kapiteijn, Helena, additional, Boehncke, Wolf-Henning, additional, Utikal, Jochen, additional, Casasola, Richard, additional, Marshall, Ernest, additional, Ferraresi, Virginia, additional, Richtig, Erika, additional, Matkovic, Suzana, additional, Inozume, Takashi, additional, Crook, Timothy, additional, McNeil, Catriona, additional, Kiyohara, Yoshio, additional, Avril, Marie-Francoise, additional, Hein, Rüdiger, additional, Terheyden, Patrick, additional, Nathan, Paul, additional, Aoi, Jun, additional, Skytta, Tanja, additional, Jouary, Thomas, additional, Takenouchi, Tatsuya, additional, Straume, Oddbjorn, additional, Martins, César, additional, and Mukhametshina, Guzel, additional

Published
2021
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49. Meta-analysis of the gut microbiota in predicting response to cancer immunotherapy in metastatic melanoma

Author

Limeta, Angelo, Ji, Boyang, Levin, Max, Gatto, Francesco, Nielsen, Jens, Limeta, Angelo, Ji, Boyang, Levin, Max, Gatto, Francesco, and Nielsen, Jens

Abstract

BACKGROUND. Identifying factors conferring responses to therapy in cancer is critical to select the best treatment for patients. For immune checkpoint inhibition (ICI) therapy, mounting evidence suggests that the gut microbiome can determine patient treatment outcomes. However, the extent to which gut microbial features are applicable across different patient cohorts has not been extensively explored. METHODS. We performed a meta-analysis of 4 published shotgun metagenomic studies (Ntot = 130 patients) investigating differential microbiome composition and imputed metabolic function between responders and nonresponders to ICI. RESULTS. Our analysis identified both known microbial features enriched in responders, such as Faecalibacterium as the prevailing taxa, as well as additional features, including overrepresentation of Barnesiella intestinihominis and the components of vitamin B metabolism. A classifier designed to predict responders based on these features identified responders in an independent cohort of 27 patients with the area under the receiver operating characteristic curve of 0.625 (95% CI: 0.348-0.899) and was predictive of prognosis (HR = 0.35, P = 0.081). CONCLUSION. These results suggest the existence of a fecal microbiome signature inherent across responders that may be exploited for diagnostic or therapeutic purposes. FUNDING. This work was funded by the Knut and Alice Wallenberg Foundation, BioGaia AB, and Cancerfonden.

Published
2020

50. Postnatal constriction, ATP depletion, and cell death in the mature and immature ductus arteriosus

Author

Levin, Max, McCurnin, Don, Seidner, Steven R., Yoder, Bradley, Waleh, Nahid, Goldbarg, Seth, Roman, Christine, Liu, Bao Mei, Boren, Jan, and Clyman, Ronald I.

Subjects
Adenosine triphosphate -- Research, Cell death -- Research, Ductus arteriosus -- Research, Biological sciences
Abstract

After birth, constriction of the full-term ductus arteriosus induces oxygen, glucose and ATP depletion, cell death, and anatomic remodeling of the ductus wall. The immature ductus frequently fails to develop the same degree of constriction or anatomic remodeling after birth. In addition, the immature ductus loses its ability to respond to vasoconstrictive agents, like oxygen or indomethacin, with increasing postnatal age. We examined the effects of premature delivery and postnatal constriction on the immature baboon ductus arteriosus. By 6 days after birth, surrogate markers of hypoxia (HIF1[alpha]/VEGF mRNA) and cell death [dUTP nick-end labeling (TUNEL)-staining] increased, while glucose and ATP concentrations (bioluminescence imaging) decreased in the immature ductus. TUNEL-staining was significantly related to the degree of glucose and ATP depletion. Glucose and ATP depletion were directly related to the degree of ductus constriction; while TUNEL-staining was logarithmically related to the degree of ductus constriction. Extensive cell death (>15% TUNEL-positive cells) occurred only when there was no Doppler flow through the ductus lumen. In contrast, HIF1[alpha]/VEGF expression and ATP concentrations were significantly altered even when the immature ductus remained open after birth. Decreased ATP concentrations produced decreased oxygen-induced contractile responses in the immature ductus. We hypothesize that ATP depletion in the persistently patent immature newborn ductus is insufficient to induce cell death and remodeling but sufficient to decrease its ability to constrict after birth. This may explain its decreasing contractile response to oxygen, indomethacin, and other contractile agents with increasing postnatal age. baboon; hypoxia; glucose; glycogen; HIF1[alpha]

Published
2006

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