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263 results on '"Koskimäki, Janne"'

1. Soluble Urokinase-Type Plasminogen Activator Receptor and Inflammatory Biomarker Response with Prognostic Significance after Acute Neuronal Injury – a Prospective Cohort Study

Author

Sajanti, Antti, Hellström, Santtu, Bennett, Carolyn, Srinath, Abhinav, Jhaveri, Aditya, Cao, Ying, Takala, Riikka, Frantzén, Janek, Koskimäki, Fredrika, Falter, Johannes, Lyne, Seán B., Rantamäki, Tomi, Posti, Jussi P., Roine, Susanna, Jänkälä, Miro, Puolitaival, Jukka, Kolehmainen, Sulo, Girard, Romuald, Rahi, Melissa, Rinne, Jaakko, Castrén, Eero, and Koskimäki, Janne

Published
2024
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2. Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations

Author

Pham, Van-Cuong, Rödel, Claudia Jasmin, Valentino, Mariaelena, Malinverno, Matteo, Paolini, Alessio, Münch, Juliane, Pasquier, Candice, Onyeogaziri, Favour C, Lazovic, Bojana, Girard, Romuald, Koskimäki, Janne, Hußmann, Melina, Keith, Benjamin, Jachimowicz, Daniel, Kohl, Franziska, Hagelkruys, Astrid, Penninger, Josef M, Schulte-Merker, Stefan, Awad, Issam A, Hicks, Ryan, Magnusson, Peetra U, Faurobert, Eva, Pagani, Massimiliano, and Abdelilah-Seyfried, Salim

Published
2024
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3. Except for Robust Outliers, Rapamycin Increases Lesion Burden in a Murine Model of Cerebral Cavernous Malformations

Author

Alcazar-Felix, Roberto J., Shenkar, Robert, Benavides, Christian R., Bindal, Akash, Srinath, Abhinav, Li, Ying, Kinkade, Serena, Terranova, Tatiana, DeBose-Scarlett, Evon, Lightle, Rhonda, DeBiasse, Dorothy, Almazroue, Hanadi, Cruz, Diana Vera, Romanos, Sharbel, Jhaveri, Aditya, Koskimäki, Janne, Hage, Stephanie, Bennett, Carolyn, Girard, Romuald, Marchuk, Douglas A., and Awad, Issam A.

Published
2024
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4. Author Correction: The European Reference Genome Atlas: piloting a decentralised approach to equitable biodiversity genomics

Author

Mc Cartney, Ann M., Formenti, Giulio, Mouton, Alice, De Panis, Diego, Marins, Luísa S., Leitão, Henrique G., Diedericks, Genevieve, Kirangwa, Joseph, Morselli, Marco, Salces-Ortiz, Judit, Escudero, Nuria, Iannucci, Alessio, Natali, Chiara, Svardal, Hannes, Fernández, Rosa, De Pooter, Tim, Joris, Geert, Strazisar, Mojca, Wood, Jonathan M. D., Herron, Katie E., Seehausen, Ole, Watts, Phillip C., Shaw, Felix, Davey, Robert P., Minotto, Alice, Fernández, José M., Böhne, Astrid, Alegria, Carla, Alioto, Tyler, Alves, Paulo C., Amorim, Isabel R., Aury, Jean-Marc, Backstrom, Niclas, Baldrian, Petr, Baltrunaite, Laima, Barta, Endre, BedHom, Bertrand, Belser, Caroline, Bergsten, Johannes, Bertrand, Laurie, Bilandija, Helena, Binzer-Panchal, Mahesh, Bista, Iliana, Blaxter, Mark, Borges, Paulo A. V., Dias, Guilherme Borges, Bosse, Mirte, Brown, Tom, Bruggmann, Rémy, Buena-Atienza, Elena, Burgin, Josephine, Buzan, Elena, Cariani, Alessia, Casadei, Nicolas, Chiara, Matteo, Chozas, Sergio, Čiampor, Jr., Fedor, Crottini, Angelica, Cruaud, Corinne, Cruz, Fernando, Dalen, Love, De Biase, Alessio, del Campo, Javier, Delic, Teo, Dennis, Alice B., Derks, Martijn F. L., Diroma, Maria Angela, Djan, Mihajla, Duprat, Simone, Eleftheriadi, Klara, Feulner, Philine G. D., Flot, Jean-François, Forni, Giobbe, Fosso, Bruno, Fournier, Pascal, Fournier-Chambrillon, Christine, Gabaldon, Toni, Garg, Shilpa, Gissi, Carmela, Giupponi, Luca, Gomez-Garrido, Jessica, González, Josefa, Grilo, Miguel L., Grüning, Björn, Guerin, Thomas, Guiglielmoni, Nadege, Gut, Marta, Haesler, Marcel P., Hahn, Christoph, Halpern, Balint, Harrison, Peter W., Heintz, Julia, Hindrikson, Maris, Höglund, Jacob, Howe, Kerstin, Hughes, Graham M., Istace, Benjamin, Cock, Mark J., Janžekovič, Franc, Jonsson, Zophonias O., Joye-Dind, Sagane, Koskimäki, Janne J., Krystufek, Boris, Kubacka, Justyna, Kuhl, Heiner, Kusza, Szilvia, Labadie, Karine, Lähteenaro, Meri, Lantz, Henrik, Lavrinienko, Anton, Leclère, Lucas, Lopes, Ricardo Jorge, Madsen, Ole, Magdelenat, Ghislaine, Magoga, Giulia, Manousaki, Tereza, Mappes, Tapio, Marques, Joao Pedro, Redondo, Gemma I. Martinez, Maumus, Florian, McCarthy, Shane A., Megens, Hendrik-Jan, Melo-Ferreira, Jose, Mendes, Sofia L., Montagna, Matteo, Moreno, Joao, Mosbech, Mai-Britt, Moura, Mónica, Musilova, Zuzana, Myers, Eugene, Nash, Will J., Nater, Alexander, Nicholson, Pamela, Niell, Manuel, Nijland, Reindert, Noel, Benjamin, Noren, Karin, Oliveira, Pedro H., Olsen, Remi-Andre, Ometto, Lino, Oomen, Rebekah A., Ossowski, Stephan, Palinauskas, Vaidas, Palsson, Snaebjorn, Panibe, Jerome P., Pauperio, Joana, Pavlek, Martina, Payen, Emilie, Pawlowska, Julia, Pellicer, Jaume, Pesole, Graziano, Pimenta, Joao, Pippel, Martin, Pirttilä, Anna Maria, Poulakakis, Nikos, Rajan, Jeena, M.C. Rego, Rúben, Resendes, Roberto, Resl, Philipp, Riesgo, Ana, Rodin-Morch, Patrik, Soares, Andre E. R., Fernandes, Carlos Rodriguez, Romeiras, Maria M., Roxo, Guilherme, Rüber, Lukas, Ruiz-Lopez, Maria Jose, Saarma, Urmas, da Silva, Luis P., Sim-Sim, Manuela, Soler, Lucile, Sousa, Vitor C., Santos, Carla Sousa, Spada, Alberto, Stefanovic, Milomir, Steger, Viktor, Stiller, Josefin, Stöck, Matthias, Struck, Torsten H., Sudasinghe, Hiranya, Tapanainen, Riikka, Tellgren-Roth, Christian, Trindade, Helena, Tukalenko, Yevhen, Urso, Ilenia, Vacherie, Benoit, Van Belleghem, Steven M., Van Oers, Kees, Vargas-Chavez, Carlos, Velickovic, Nevena, Vella, Noel, Vella, Adriana, Vernesi, Cristiano, Vicente, Sara, Villa, Sara, Pettersson, Olga Vinnere, Volckaert, Filip A. M., Voros, Judit, Wincker, Patrick, Winkler, Sylke, Ciofi, Claudio, Waterhouse, Robert M., and Mazzoni, Camila J.

Published
2024
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5. The European Reference Genome Atlas: piloting a decentralised approach to equitable biodiversity genomics

Author

Mc Cartney, Ann M., Formenti, Giulio, Mouton, Alice, De Panis, Diego, Marins, Luísa S., Leitão, Henrique G., Diedericks, Genevieve, Kirangwa, Joseph, Morselli, Marco, Salces-Ortiz, Judit, Escudero, Nuria, Iannucci, Alessio, Natali, Chiara, Svardal, Hannes, Fernández, Rosa, De Pooter, Tim, Joris, Geert, Strazisar, Mojca, Wood, Jonathan M. D., Herron, Katie E., Seehausen, Ole, Watts, Phillip C., Shaw, Felix, Davey, Robert P., Minotto, Alice, Fernández, José M., Böhne, Astrid, Alegria, Carla, Alioto, Tyler, Alves, Paulo C., Amorim, Isabel R., Aury, Jean-Marc, Backstrom, Niclas, Baldrian, Petr, Baltrunaite, Laima, Barta, Endre, BedHom, Bertrand, Belser, Caroline, Bergsten, Johannes, Bertrand, Laurie, Bilandija, Helena, Binzer-Panchal, Mahesh, Bista, Iliana, Blaxter, Mark, Borges, Paulo A. V., Dias, Guilherme Borges, Bosse, Mirte, Brown, Tom, Bruggmann, Rémy, Buena-Atienza, Elena, Burgin, Josephine, Buzan, Elena, Cariani, Alessia, Casadei, Nicolas, Chiara, Matteo, Chozas, Sergio, Čiampor, Jr., Fedor, Crottini, Angelica, Cruaud, Corinne, Cruz, Fernando, Dalen, Love, De Biase, Alessio, del Campo, Javier, Delic, Teo, Dennis, Alice B., Derks, Martijn F. L., Diroma, Maria Angela, Djan, Mihajla, Duprat, Simone, Eleftheriadi, Klara, Feulner, Philine G. D., Flot, Jean-François, Forni, Giobbe, Fosso, Bruno, Fournier, Pascal, Fournier-Chambrillon, Christine, Gabaldon, Toni, Garg, Shilpa, Gissi, Carmela, Giupponi, Luca, Gomez-Garrido, Jessica, González, Josefa, Grilo, Miguel L., Grüning, Björn, Guerin, Thomas, Guiglielmoni, Nadege, Gut, Marta, Haesler, Marcel P., Hahn, Christoph, Halpern, Balint, Harrison, Peter W., Heintz, Julia, Hindrikson, Maris, Höglund, Jacob, Howe, Kerstin, Hughes, Graham M., Istace, Benjamin, Cock, Mark J., Janžekovič, Franc, Jonsson, Zophonias O., Joye-Dind, Sagane, Koskimäki, Janne J., Krystufek, Boris, Kubacka, Justyna, Kuhl, Heiner, Kusza, Szilvia, Labadie, Karine, Lähteenaro, Meri, Lantz, Henrik, Lavrinienko, Anton, Leclère, Lucas, Lopes, Ricardo Jorge, Madsen, Ole, Magdelenat, Ghislaine, Magoga, Giulia, Manousaki, Tereza, Mappes, Tapio, Marques, Joao Pedro, Redondo, Gemma I. Martinez, Maumus, Florian, McCarthy, Shane A., Megens, Hendrik-Jan, Melo-Ferreira, Jose, Mendes, Sofia L., Montagna, Matteo, Moreno, Joao, Mosbech, Mai-Britt, Moura, Mónica, Musilova, Zuzana, Myers, Eugene, Nash, Will J., Nater, Alexander, Nicholson, Pamela, Niell, Manuel, Nijland, Reindert, Noel, Benjamin, Noren, Karin, Oliveira, Pedro H., Olsen, Remi-Andre, Ometto, Lino, Oomen, Rebekah A., Ossowski, Stephan, Palinauskas, Vaidas, Palsson, Snaebjorn, Panibe, Jerome P., Pauperio, Joana, Pavlek, Martina, Payen, Emilie, Pawlowska, Julia, Pellicer, Jaume, Pesole, Graziano, Pimenta, Joao, Pippel, Martin, Pirttilä, Anna Maria, Poulakakis, Nikos, Rajan, Jeena, M.C. Rego, Rúben, Resendes, Roberto, Resl, Philipp, Riesgo, Ana, Rodin-Morch, Patrik, Soares, Andre E. R., Fernandes, Carlos Rodriguez, Romeiras, Maria M., Roxo, Guilherme, Rüber, Lukas, Ruiz-Lopez, Maria Jose, Saarma, Urmas, da Silva, Luis P., Sim-Sim, Manuela, Soler, Lucile, Sousa, Vitor C., Santos, Carla Sousa, Spada, Alberto, Stefanovic, Milomir, Steger, Viktor, Stiller, Josefin, Stöck, Matthias, Struck, Torsten H., Sudasinghe, Hiranya, Tapanainen, Riikka, Tellgren-Roth, Christian, Trindade, Helena, Tukalenko, Yevhen, Urso, Ilenia, Vacherie, Benoit, Van Belleghem, Steven M., Van Oers, Kees, Vargas-Chavez, Carlos, Velickovic, Nevena, Vella, Noel, Vella, Adriana, Vernesi, Cristiano, Vicente, Sara, Villa, Sara, Pettersson, Olga Vinnere, Volckaert, Filip A. M., Voros, Judit, Wincker, Patrick, Winkler, Sylke, Ciofi, Claudio, Waterhouse, Robert M., and Mazzoni, Camila J.

Published
2024
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7. Transcriptomic signatures of individual cell types in cerebral cavernous malformation

Author

Li, Ying, Girard, Romuald, Srinath, Abhinav, Cruz, Diana Vera, Ciszewski, Cezary, Chen, Chang, Lightle, Rhonda, Romanos, Sharbel, Sone, Je Yeong, Moore, Thomas, DeBiasse, Dorothy, Stadnik, Agnieszka, Lee, Justine J., Shenkar, Robert, Koskimäki, Janne, Lopez-Ramirez, Miguel A., Marchuk, Douglas A., Ginsberg, Mark H., Kahn, Mark L., Shi, Changbin, and Awad, Issam A.

Published
2024
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8. Plasma metabolites with mechanistic and clinical links to the neurovascular disease cavernous angioma

Author

Srinath, Abhinav, Xie, Bingqing, Li, Ying, Sone, Je Yeong, Romanos, Sharbel, Chen, Chang, Sharma, Anukriti, Polster, Sean, Dorrestein, Pieter C, Weldon, Kelly C, DeBiasse, Dorothy, Moore, Thomas, Lightle, Rhonda, Koskimäki, Janne, Zhang, Dongdong, Stadnik, Agnieszka, Piedad, Kristina, Hagan, Matthew, Shkoukani, Abdallah, Carrión-Penagos, Julián, Bi, Dehua, Shen, Le, Shenkar, Robert, Ji, Yuan, Sidebottom, Ashley, Pamer, Eric, Gilbert, Jack A, Kahn, Mark L, D’Souza, Mark, Sulakhe, Dinanath, Awad, Issam A, and Girard, Romuald

Subjects
Brain Disorders, Genetics, Rare Diseases, Neurosciences
Abstract

BackgroundCavernous angiomas (CAs) affect 0.5% of the population, predisposing to serious neurologic sequelae from brain bleeding. A leaky gut epithelium associated with a permissive gut microbiome, was identified in patients who develop CAs, favoring lipid polysaccharide producing bacterial species. Micro-ribonucleic acids along with plasma levels of proteins reflecting angiogenesis and inflammation were also previously correlated with CA and CA with symptomatic hemorrhage.MethodsThe plasma metabolome of CA patients and CA patients with symptomatic hemorrhage was assessed using liquid-chromatography mass spectrometry. Differential metabolites were identified using partial least squares-discriminant analysis (p

Published
2023

9. Brain plasticity and neuroinflammatory protein biomarkers with circulating MicroRNAs as predictors of acute brain injury outcome – A prospective cohort study

Author

Sajanti, Antti, Li, Yan, Hellström, Santtu, Cao, Ying, Girard, Romuald, Umemori, Juzoh, Frantzén, Janek, Koskimäki, Fredrika, Lyne, Seán B., Falter, Johannes, Rantamäki, Tomi, Takala, Riikka, Posti, Jussi P., Roine, Susanna, Kolehmainen, Sulo, Srinath, Abhinav, Jänkälä, Miro, Puolitaival, Jukka, Rahi, Melissa, Rinne, Jaakko, Castrén, Eero, and Koskimäki, Janne

Published
2024
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10. Burr-hole drainage with or without irrigation for chronic subdural haematoma (FINISH): a Finnish, nationwide, parallel-group, multicentre, randomised, controlled, non-inferiority trial

Author

Ahmed, Abdirisak, Areda, Tarmo, Bartek, Jiri Jr, Czuba, Tomasz, Danner, Nils, Elomaa, Antti-Pekka, Frantzén, Janek, Haapala, Ilkka, Haapasalo, Joonas, Heikkilä, Juuso, Hellman, Minttu, Henttonen, Henna, Huuska, Nora, Järvinen, Teppo LN, Jyrkkänen, Henna-Kaisa, Kaipainen, Aku, Kämäräinen, Olli-Pekka, Kämppi, Hanna, Kelahaara, Milla, Kivisaari, Riku, Klimko, Nikolai, Knuutinen, Oula A, Koivisto, Timo, Korhonen, Tommi, Koskimäki, Janne, Kovalainen, Anselmi, Kuparinen, Xenia, Laukka, Dan, Lehecka, Martin, Lehtimäki, Kai, Leinonen, Ville, Lönnrot, Kimmo, Luikku, Antti, Luostarinen, Teemu, Luoto, Teemu, Luotonen, Janne, Lustig-Tammi, Lauriina, Maanpää, Henna-Riikka, Määttä, Jenni, Möttönen, Timo, Netti, Eliisa, Nevaharju-Sarantis, Laura, Niemelä, Mika, Niskakangas, Tero, Nissinen, Mette, Nurminen, Ville, Oinas, Minna, Ollonen, Teemu, Östberg, Anna, Oulasvirta, Elias, Pantzar, Krista, Piilonen, Katri, Pohjola, Anni, Polvivaara, Markus, Posti, Jussi P, Raj, Rahul, Rajala, Linnea, Ranstam, Jonas, Rauhala, Minna, Rezai Jahromi, Behnam, Roiha, Miika, Saarenpää, Ilkka, Sajanti, Antti, Salmi, Henrikki, Satopää, Jarno, Schwartz, Christoph, Shemeikka, Niina, Sorto, Pia, Taimela, Simo, Tetri, Sami, Thesleff, Tuomo, Tommiska, Pihla, Tuomisto, Maarit, Vartiainen, Nuutti, Vasankari, Ville, Virta, Jyri, Visuri, Mikko, Walle, Paula, Zeiler, Frederick A, Korhonen, Tommi K, and Järvinen, Teppo L N

Published
2024
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11. Circulating Plasma miRNA Homologs in Mice and Humans Reflect Familial Cerebral Cavernous Malformation Disease

Author

Romanos, Sharbel G., Srinath, Abhinav, Li, Ying, Xie, Bingqing, Chen, Chang, Li, Yan, Moore, Thomas, Bi, Dehua, Sone, Je Yeong, Lightle, Rhonda, Hobson, Nick, Zhang, Dongdong, Koskimäki, Janne, Shen, Le, McCurdy, Sara, Lai, Catherine Chinhchu, Stadnik, Agnieszka, Piedad, Kristina, Carrión-Penagos, Julián, Shkoukani, Abdallah, Snellings, Daniel, Shenkar, Robert, Sulakhe, Dinanath, Ji, Yuan, Lopez-Ramirez, Miguel A., Kahn, Mark L., Marchuk, Douglas A., Ginsberg, Mark H., Girard, Romuald, and Awad, Issam A.

Published
2023
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13. Permissive microbiome characterizes human subjects with a neurovascular disease cavernous angioma.

Author

Polster, Sean P, Sharma, Anukriti, Tanes, Ceylan, Tang, Alan T, Mericko, Patricia, Cao, Ying, Carrión-Penagos, Julián, Girard, Romuald, Koskimäki, Janne, Zhang, Dongdong, Stadnik, Agnieszka, Romanos, Sharbel G, Lyne, Seán B, Shenkar, Robert, Yan, Kimberly, Lee, Cornelia, Akers, Amy, Morrison, Leslie, Robinson, Myranda, Zafar, Atif, Bittinger, Kyle, Kim, Helen, Gilbert, Jack A, Kahn, Mark L, Shen, Le, and Awad, Issam A

Abstract

Cavernous angiomas (CA) are common vascular anomalies causing brain hemorrhage. Based on mouse studies, roles of gram-negative bacteria and altered intestinal homeostasis have been implicated in CA pathogenesis, and pilot study had suggested potential microbiome differences between non-CA and CA individuals based on 16S rRNA gene sequencing. We here assess microbiome differences in a larger cohort of human subjects with and without CA, and among subjects with different clinical features, and conduct more definitive microbial analyses using metagenomic shotgun sequencing. Relative abundance of distinct bacterial species in CA patients is shown, consistent with postulated permissive microbiome driving CA lesion genesis via lipopolysaccharide signaling, in humans as in mice. Other microbiome differences are related to CA clinical behavior. Weighted combinations of microbiome signatures and plasma inflammatory biomarkers enhance associations with disease severity and hemorrhage. This is the first demonstration of a sensitive and specific diagnostic microbiome in a human neurovascular disease.

Published
2020

15. Burr-hole drainage with or without irrigation for chronic subdural haematoma (FINISH): a Finnish, nationwide, parallel-group, multicentre, randomised, controlled, non-inferiority trial

Author

Raj, Rahul, primary, Tommiska, Pihla, additional, Koivisto, Timo, additional, Leinonen, Ville, additional, Danner, Nils, additional, Posti, Jussi P, additional, Laukka, Dan, additional, Luoto, Teemu, additional, Rauhala, Minna, additional, Tetri, Sami, additional, Korhonen, Tommi K, additional, Satopää, Jarno, additional, Kivisaari, Riku, additional, Luostarinen, Teemu, additional, Schwartz, Christoph, additional, Czuba, Tomasz, additional, Taimela, Simo, additional, Lönnrot, Kimmo, additional, Järvinen, Teppo L N, additional, Ahmed, Abdirisak, additional, Areda, Tarmo, additional, Bartek, Jiri Jr, additional, Elomaa, Antti-Pekka, additional, Frantzén, Janek, additional, Haapala, Ilkka, additional, Haapasalo, Joonas, additional, Heikkilä, Juuso, additional, Hellman, Minttu, additional, Henttonen, Henna, additional, Huuska, Nora, additional, Järvinen, Teppo LN, additional, Jyrkkänen, Henna-Kaisa, additional, Kaipainen, Aku, additional, Kämäräinen, Olli-Pekka, additional, Kämppi, Hanna, additional, Kelahaara, Milla, additional, Klimko, Nikolai, additional, Knuutinen, Oula A, additional, Korhonen, Tommi, additional, Koskimäki, Janne, additional, Kovalainen, Anselmi, additional, Kuparinen, Xenia, additional, Lehecka, Martin, additional, Lehtimäki, Kai, additional, Luikku, Antti, additional, Luotonen, Janne, additional, Lustig-Tammi, Lauriina, additional, Maanpää, Henna-Riikka, additional, Määttä, Jenni, additional, Möttönen, Timo, additional, Netti, Eliisa, additional, Nevaharju-Sarantis, Laura, additional, Niemelä, Mika, additional, Niskakangas, Tero, additional, Nissinen, Mette, additional, Nurminen, Ville, additional, Oinas, Minna, additional, Ollonen, Teemu, additional, Östberg, Anna, additional, Oulasvirta, Elias, additional, Pantzar, Krista, additional, Piilonen, Katri, additional, Pohjola, Anni, additional, Polvivaara, Markus, additional, Raj, Rahul, additional, Rajala, Linnea, additional, Ranstam, Jonas, additional, Rezai Jahromi, Behnam, additional, Roiha, Miika, additional, Saarenpää, Ilkka, additional, Sajanti, Antti, additional, Salmi, Henrikki, additional, Shemeikka, Niina, additional, Sorto, Pia, additional, Thesleff, Tuomo, additional, Tuomisto, Maarit, additional, Vartiainen, Nuutti, additional, Vasankari, Ville, additional, Virta, Jyri, additional, Visuri, Mikko, additional, Walle, Paula, additional, and Zeiler, Frederick A, additional

Published
2024
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16. Biomarkers of cavernous angioma with symptomatic hemorrhage

Author

Lyne, Seán B, Girard, Romuald, Koskimäki, Janne, Zeineddine, Hussein A, Zhang, Dongdong, Cao, Ying, Li, Yan, Stadnik, Agnieszka, Moore, Thomas, Lightle, Rhonda, Shi, Changbin, Shenkar, Robert, Carrión-Penagos, Julián, Polster, Sean P, Romanos, Sharbel, Akers, Amy, Lopez-Ramirez, Miguel, Whitehead, Kevin J, Kahn, Mark L, Ginsberg, Mark H, Marchuk, Douglas A, and Awad, Issam A

Subjects
Prevention, Clinical Research, Clinical Trials and Supportive Activities, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Good Health and Well Being, Adult, Biomarkers, Cohort Studies, Female, Hemangioma, Cavernous, Hemorrhage, Humans, Inflammation Mediators, Longitudinal Studies, Machine Learning, Male, Transcriptome, Diagnostics, Inflammation, Stroke, Vascular Biology
Abstract

BACKGROUNDCerebral cavernous angiomas (CAs) with a symptomatic hemorrhage (CASH) have a high risk of recurrent hemorrhage and serious morbidity.METHODSEighteen plasma molecules with mechanistic roles in CA pathobiology were investigated in 114 patients and 12 healthy subjects. The diagnostic biomarker of a CASH in the prior year was derived as that minimizing the Akaike information criterion and validated using machine learning, and was compared with the prognostic CASH biomarker predicting bleeding in the subsequent year. Biomarkers were longitudinally followed in a subset of cases. The biomarkers were queried in the lesional neurovascular unit (NVU) transcriptome and in plasma miRNAs from CASH and non-CASH patients.RESULTSThe diagnostic CASH biomarker included a weighted combination of soluble CD14 (sCD14), VEGF, C-reactive protein (CRP), and IL-10 distinguishing CASH patients with 76% sensitivity and 80% specificity (P = 0.0003). The prognostic CASH biomarker (sCD14, VEGF, IL-1β, and sROBO-4) was confirmed to predict a bleed in the subsequent year with 83% sensitivity and 93% specificity (P = 0.001). Genes associated with diagnostic and prognostic CASH biomarkers were differentially expressed in CASH lesional NVUs. Thirteen plasma miRNAs were differentially expressed between CASH and non-CASH patients.CONCLUSIONShared and unique biomarkers of recent symptomatic hemorrhage and of future bleeding in CA are mechanistically linked to lesional transcriptome and miRNA. The biomarkers may be applied for risk stratification in clinical trials and developed as a tool in clinical practice.FUNDINGNIH, William and Judith Davis Fund in Neurovascular Surgery Research, Be Brave for Life Foundation, Safadi Translational Fellowship, Pritzker School of Medicine, and Sigrid Jusélius Foundation.

Published
2019

17. Trial Readiness in Cavernous Angiomas With Symptomatic Hemorrhage (CASH).

Author

Polster, Sean P, Cao, Ying, Carroll, Timothy, Flemming, Kelly, Girard, Romuald, Hanley, Daniel, Hobson, Nicholas, Kim, Helen, Koenig, James, Koskimäki, Janne, Lane, Karen, Majersik, Jennifer J, McBee, Nichol, Morrison, Leslie, Shenkar, Robert, Stadnik, Agnieszka, Thompson, Richard E, Zabramski, Joseph, Zeineddine, Hussein A, and Awad, Issam A

Subjects
Humans, Hemangioma, Cavernous, Central Nervous System, Central Nervous System Neoplasms, Hemorrhage, Cohort Studies, Feasibility Studies, Biomarkers, Cavernous angioma, Cerebral cavernous malformation, Drug development, Symptomatic hemorrhage, Trial readiness, Clinical Trials and Supportive Activities, Stroke, Brain Disorders, Prevention, Neurosciences, Clinical Research, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Clinical Sciences, Neurology & Neurosurgery
Abstract

BACKGROUND:Brain cavernous angiomas with symptomatic hemorrhage (CASH) are uncommon but exact a heavy burden of neurological disability from recurrent bleeding, for which there is no proven therapy. Candidate drugs to stabilize the CASH lesion and prevent rebleeding will ultimately require testing of safety and efficacy in multisite clinical trials. Much progress has been made in understanding the epidemiology of CASH, and novel biomarkers have been linked to the biological mechanisms and clinical activity in lesions. Yet, the ability to enroll and risk-stratify CASH subjects has never been assessed prospectively at multiple sites. Biomarkers and other outcomes have not been evaluated for their sensitivity and reliability, nor have they been harmonized across sites. OBJECTIVE:To address knowledge gaps and establish a research network as infrastructure for future clinical trials, through the Trial Readiness grant mechanism, funded by National Institute of Neurological Disorders and Stroke/National Institutes of Health. METHODS:This project includes an observational cohort study to assess (1) the feasibility of screening, enrollment rates, baseline disease categorization, and follow-up of CASH using common data elements at multiple sites, (2) the reliability of imaging biomarkers including quantitative susceptibility mapping and permeability measures that have been shown to correlate with lesion activity, and (3) the rates of recurrent hemorrhage and change in functional status and biomarker measurements during prospective follow-up. EXPECTED OUTCOMES:We propose a harmonized multisite assessment of enrollment rates of CASH, baseline features relevant to stratification in clinical trials, and follow-up assessments of functional outcomes in relation to clinical bleeds. We introduce novel biomarkers of vascular leak and hemorrhage, with firm mechanistic foundations, which have been linked to clinical disease activity. We shall test their reliability and validity at multiple sites, and assess their changes over time, with and without clinical rebleeds, hence their fitness as outcome instruments in clinical trials. DISCUSSION:The timing cannot be more opportune, with therapeutic targets identified, exceptional collaboration among researchers and the patient community, along with several drugs ready to benefit from development of a path to clinical testing using this network in the next 5 years.

Published
2019

18. Phenotypic characterization of murine models of cerebral cavernous malformations

Author

Zeineddine, Hussein A, Girard, Romuald, Saadat, Laleh, Shen, Le, Lightle, Rhonda, Moore, Thomas, Cao, Ying, Hobson, Nick, Shenkar, Robert, Avner, Kenneth, Chaudager, Kiranj, Koskimäki, Janne, Polster, Sean P, Fam, Maged D, Shi, Changbin, Lopez-Ramirez, Miguel Alejandro, Tang, Alan T, Gallione, Carol, Kahn, Mark L, Ginsberg, Mark, Marchuk, Douglas A, and Awad, Issam A

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Rare Diseases, Neurosciences, Genetics, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Cardiovascular, Acute Disease, Animals, Apoptosis Regulatory Proteins, B-Lymphocytes, Brain, Cerebellum, Chronic Disease, Disease Models, Animal, Endothelial Cells, Hemangioma, Cavernous, Central Nervous System, Humans, Intracellular Signaling Peptides and Proteins, Iron, KRIT1 Protein, Mice, Mice, Knockout, Mice, Transgenic, Microfilament Proteins, Mutation, Occludin, Phenotype, T-Lymphocytes, rho-Associated Kinases, Clinical Sciences, Pathology, Clinical sciences
Abstract

Cerebral cavernous malformations (CCMs) are clusters of dilated capillaries that affect around 0.5% of the population. CCMs exist in two forms, sporadic and familial. Mutations in three documented genes, KRIT1(CCM1), CCM2, and PDCD10(CCM3), cause the autosomal dominant form of the disease, and somatic mutations in these same genes underlie lesion development in the brain. Murine models with constitutive or induced loss of respective genes have been applied to study disease pathobiology and therapeutic manipulations. We aimed to analyze the phenotypic characteristic of two main groups of models, the chronic heterozygous models with sensitizers promoting genetic instability, and the acute neonatal induced homozygous knockout model. Acute model mice harbored a higher lesion burden than chronic models, more localized in the hindbrain, and largely lacking iron deposition and inflammatory cell infiltrate. The chronic model mice showed a lower lesion burden localized throughout the brain, with significantly greater perilesional iron deposition, immune B- and T-cell infiltration, and less frequent junctional protein immunopositive endothelial cells. Lesional endothelial cells in both models expressed similar phosphorylated myosin light chain immunopositivity indicating Rho-associated protein kinase activity. These data suggest that acute models are better suited to study the initial formation of the lesion, while the chronic models better reflect lesion maturation, hemorrhage, and inflammatory response, relevant pathobiologic features of the human disease.

Published
2019

19. Comprehensive transcriptome analysis of cerebral cavernous malformation across multiple species and genotypes

Author

Koskimäki, Janne, Girard, Romuald, Li, Yan, Saadat, Laleh, Zeineddine, Hussein A, Lightle, Rhonda, Moore, Thomas, Lyne, Seán, Avner, Kenneth, Shenkar, Robert, Cao, Ying, Shi, Changbin, Polster, Sean P, Zhang, Dongdong, Carrión-Penagos, Julián, Romanos, Sharbel, Fonseca, Gregory, Lopez-Ramirez, Miguel A, Chapman, Eric M, Popiel, Evelyn, Tang, Alan T, Akers, Amy, Faber, Pieter, Andrade, Jorge, Ginsberg, Mark, Derry, W Brent, Kahn, Mark L, Marchuk, Douglas A, and Awad, Issam A

Subjects
Neurosciences, Genetics, Rare Diseases, Brain Disorders, Aetiology, Underpinning research, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Molecular genetics, Neuroscience, Transcription, Vascular Biology, endothelial cells
Abstract

The purpose of this study was to determine important genes, functions, and networks contributing to the pathobiology of cerebral cavernous malformation (CCM) from transcriptomic analyses across 3 species and 2 disease genotypes. Sequencing of RNA from laser microdissected neurovascular units of 5 human surgically resected CCM lesions, mouse brain microvascular endothelial cells, Caenorhabditis elegans with induced Ccm gene loss, and their respective controls provided differentially expressed genes (DEGs). DEGs from mouse and C. elegans were annotated into human homologous genes. Cross-comparisons of DEGs between species and genotypes, as well as network and gene ontology (GO) enrichment analyses, were performed. Among hundreds of DEGs identified in each model, common genes and 1 GO term (GO:0051656, establishment of organelle localization) were commonly identified across the different species and genotypes. In addition, 24 GO functions were present in 4 of 5 models and were related to cell-to-cell adhesion, neutrophil-mediated immunity, ion transmembrane transporter activity, and responses to oxidative stress. We have provided a comprehensive transcriptome library of CCM disease across species and for the first time to our knowledge in Ccm1/Krit1 versus Ccm3/Pdcd10 genotypes. We have provided examples of how results can be used in hypothesis generation or mechanistic confirmatory studies.

Published
2019

23. Brain Plasticity Modulator p75 Neurotrophin Receptor in Human Urine after Different Acute Brain Injuries—A Prospective Cohort Study

Author

Hellström, Santtu, primary, Sajanti, Antti, additional, Srinath, Abhinav, additional, Bennett, Carolyn, additional, Girard, Romuald, additional, Cao, Ying, additional, Frantzén, Janek, additional, Koskimäki, Fredrika, additional, Falter, Johannes, additional, Lyne, Seán B., additional, Rantamäki, Tomi, additional, Takala, Riikka, additional, Posti, Jussi P., additional, Roine, Susanna, additional, Puolitaival, Jukka, additional, Jänkälä, Miro, additional, Kolehmainen, Sulo, additional, Rahi, Melissa, additional, Rinne, Jaakko, additional, Castrén, Eero, additional, and Koskimäki, Janne, additional

Published
2024
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24. Common transcriptome, plasma molecules, and imaging signatures in the aging brain and a Mendelian neurovascular disease, cerebral cavernous malformation

Author

Koskimäki, Janne, Polster, Sean P., Li, Yan, Romanos, Sharbel, Srinath, Abhinav, Zhang, Dongdong, Carrión-Penagos, Julián, Lightle, Rhonda, Moore, Thomas, Lyne, Seán B., Stadnik, Agnieszka, Piedad, Kristina, Cao, Ying, Shenkar, Robert, Dimov, Alexey V., Hobson, Nick, Christoforidis, Gregory A., Carroll, Timothy, Girard, Romuald, and Awad, Issam A.

Published
2020
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27. CXCR2-Blocking Has Context-Sensitive Effects on Rat Glioblastoma Cell Line Outgrowth (S635) in an Organotypic Rat Brain Slice Culture Depending on Microglia-Depletion (PLX5622) and Dexamethasone Treatment

Author

Falter, Johannes, primary, Lohmeier, Annette, additional, Eberl, Petra, additional, Stoerr, Eva-Maria, additional, Koskimäki, Janne, additional, Falter, Lena, additional, Rossmann, Jakob, additional, Mederer, Tobias, additional, Schmidt, Nils Ole, additional, and Proescholdt, Martin, additional

Published
2023
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28. Corrigendum to “Antibodies in cerebral cavernous malformations react with cytoskeleton autoantigens in the lesional milieu” [J. Autoimmun. 113 (2020) 102469]

Author

Zhang, Dongdong, primary, Kinloch, Andrew J., additional, Srinath, Abhinav, additional, Shenkar, Robert, additional, Girard, Romuald, additional, Lightle, Rhonda, additional, Moore, Thomas, additional, Koskimäki, Janne, additional, Mohsin, Azam, additional, Carrión-Penagos, Julián, additional, Romanos, Sharbel, additional, Shen, Le, additional, Clark, Marcus R., additional, Shi, Changbin, additional, and Awad, Issam A., additional

Published
2023
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33. Transcriptome clarifies mechanisms of lesion genesis versus progression in models of Ccm3 cerebral cavernous malformations

Author

Koskimäki, Janne, Zhang, Dongdong, Li, Yan, Saadat, Laleh, Moore, Thomas, Lightle, Rhonda, Polster, Sean P., Carrión-Penagos, Julián, Lyne, Seán B., Zeineddine, Hussein A., Shi, Changbin, Shenkar, Robert, Romanos, Sharbel, Avner, Kenneth, Srinath, Abhinav, Shen, Le, Detter, Matthew R., Snellings, Daniel, Cao, Ying, Lopez-Ramirez, Miguel A., Fonseca, Gregory, Tang, Alan T., Faber, Pieter, Andrade, Jorge, Ginsberg, Mark, Kahn, Mark L., Marchuk, Douglas A., Girard, Romuald, and Awad, Issam A.

Published
2019
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39. Circulating Plasma miRNA Homologs in Mice and Humans Reflect Familial Cerebral Cavernous Malformation Disease

Author

Romanos, Sharbel G., primary, Srinath, Abhinav, additional, Li, Ying, additional, Xie, Bingqing, additional, Chen, Chang, additional, Li, Yan, additional, Moore, Thomas, additional, Bi, Dehua, additional, Sone, Je Yeong, additional, Lightle, Rhonda, additional, Hobson, Nick, additional, Zhang, Dongdong, additional, Koskimäki, Janne, additional, Shen, Le, additional, McCurdy, Sara, additional, Lai, Catherine Chinhchu, additional, Stadnik, Agnieszka, additional, Piedad, Kristina, additional, Carrión-Penagos, Julián, additional, Shkoukani, Abdallah, additional, Snellings, Daniel, additional, Shenkar, Robert, additional, Sulakhe, Dinanath, additional, Ji, Yuan, additional, Lopez-Ramirez, Miguel A., additional, Kahn, Mark L., additional, Marchuk, Douglas A., additional, Ginsberg, Mark H., additional, Girard, Romuald, additional, and Awad, Issam A., additional

Published
2022
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40. Towards a comprehensive understanding of p75 neurotrophin receptor functions and interactions in the brain

Author

Ritala, Joel, Lyne, Seán, Sajanti, Antti, Girard, Romuald, Koskimäki, Janne, Neuroscience Center, Helsinki Institute of Life Science HiLIFE, Tampere University, and Seinäjoen keskussairaala VA

Subjects
3112 Neurosciences, bioinformatics, data mining, brain injury, neurotrophins, neuron, 3124 Neurology and psychiatry, ISCHEMIA, P75(NTR), ACTIVATION, nervous system, plasticity, regeneration, BINDING, KINASE, 1182 Biochemistry, cell and molecular biology, 3111 Biomedicine
Abstract

The role of neurotrophins in neuronal plasticity has recently become a strong focus in neuroregeneration research field to elucidate the biological mechanisms by which these molecules modulate synapses, modify the response to injury, and alter the adaptation response. Intriguingly, the prior studies highlight the role of p75 neurotrophin receptor (p75NTR) in various injuries and diseases such as central nervous system injuries, Alzheimer's disease and amyotrophic lateral sclerosis. More comprehensive elucidation of the mechanisms, and therapies targeting these molecular signaling networks may allow for neuronal tissue regeneration following an injury. Due to a diverse role of the p75NTRin biology, the body of evidence comprising its biological role is diffusely spread out over numerous fields. This review condenses the main evidence of p75NTRfor clinical applications and presents new findings from published literature how data mining approach combined with bioinformatic analyses can be utilized to gain new hypotheses in a molecular and network level. publishedVersion

Published
2022

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