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1. A genome-wide meta-analysis of palmoplantar pustulosis implicates TH2 responses and cigarette smoking in disease pathogenesis

Author

Abraham, Thamir, Ali, Muhmad, August, Suzannah, Baudry, David, Becher, Gabrielle, Bewley, Anthony, Brown, Victoria, Cornelius, Victoria, Ghaffar, Sharizan, Ingram, John, Kavakleiva, Svetlana, Kelly, Susan, Khorshid, Mohsen, Lachmann, Helen, Ladoyanni, Effie, McAteer, Helen, McKenna, John, Meynell, Freya, Patel, Prakash, Pink, Andrew, Powell, Kingsley, Pushparajah, Angela, Sinclair, Catriona, Wachsmuth, Rachel, Hernandez-Cordero, Ariana, Thomas, Laurent, Smail, Alice, Lim, Zhao Qin, Saklatvala, Jake R., Chung, Raymond, Curtis, Charles J., Baum, Patrick, Visvanathan, Sudha, Burden, A. David, Cooper, Hywel L., Dunnill, Giles, Griffiths, Christopher E.M., Levell, Nick J., Parslew, Richard, Reynolds, Nick J., Wahie, Shyamal, Warren, Richard B., Wright, Andrew, Simpson, Michael, Hveem, Kristian, Barker, Jonathan N., Dand, Nick, Løset, Mari, Smith, Catherine H., and Capon, Francesca

Published
2024
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2. Alveolar macrophages in early stage COPD show functional deviations with properties of impaired immune activation.

Author

Baßler, Kevin, Fujii, Wataru, Kapellos, Theodore, Dudkin, Erika, Reusch, Nico, Horne, Ari, Reiz, Benedikt, Luecken, Malte, Osei-Sarpong, Collins, Warnat-Herresthal, Stefanie, Bonaguro, Lorenzo, Schulte-Schrepping, Jonas, Wagner, Allon, Günther, Patrick, Pizarro, Carmen, Schreiber, Tina, Knoll, Rainer, Holsten, Lisa, Kröger, Charlotte, De Domenico, Elena, Becker, Matthias, Händler, Kristian, Wohnhaas, Christian, Baumgartner, Florian, Köhler, Meike, Theis, Heidi, Kraut, Michael, Wadsworth, Marc, Hughes, Travis, Ferreira, Humberto, Hinkley, Emily, Kaltheuner, Ines, Geyer, Matthias, Thiele, Christoph, Shalek, Alex, Feißt, Andreas, Thomas, Daniel, Dickten, Henning, Beyer, Marc, Baum, Patrick, Yosef, Nir, Aschenbrenner, Anna, Ulas, Thomas, Hasenauer, Jan, Theis, Fabian, Skowasch, Dirk, and Schultze, Joachim

Subjects
TGF-β1, blood, bronchoalveolar lavage, chronic obstructive pulmonary disease, impaired immune activation, macrophage, monocyte, Chemotaxis, Humans, Macrophages, Macrophages, Alveolar, Monocytes, Pulmonary Disease, Chronic Obstructive
Abstract

Despite its high prevalence, the cellular and molecular mechanisms of chronic obstructive pulmonary disease (COPD) are far from being understood. Here, we determine disease-related changes in cellular and molecular compositions within the alveolar space and peripheral blood of a cohort of COPD patients and controls. Myeloid cells were the largest cellular compartment in the alveolar space with invading monocytes and proliferating macrophages elevated in COPD. Modeling cell-to-cell communication, signaling pathway usage, and transcription factor binding predicts TGF-β1 to be a major upstream regulator of transcriptional changes in alveolar macrophages of COPD patients. Functionally, macrophages in COPD showed reduced antigen presentation capacity, accumulation of cholesteryl ester, reduced cellular chemotaxis, and mitochondrial dysfunction, reminiscent of impaired immune activation.

Published
2022

3. Single-cell analysis implicates TH17-to-TH2 cell plasticity in the pathogenesis of palmoplantar pustulosis

Author

McCluskey, Daniel, Benzian-Olsson, Natashia, Mahil, Satveer K., Hassi, Niina Karoliina, Wohnhaas, Christian T., Burden, A. David, Griffiths, Christopher E.M., Ingram, John R., Levell, Nick J., Parslew, Richard, Pink, Andrew E., Reynolds, Nick J., Warren, Richard B., Visvanathan, Sudha, Baum, Patrick, Barker, Jonathan N., Smith, Catherine H., and Capon, Francesca

Published
2022
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5. A genome-wide meta-analysis of palmoplantar pustulosis implicates Th2 responses and cigarette smoking in disease pathogenesis.

Author

Hernandez-Cordero, Ariana, primary, Thomas, Laurent, additional, Smail, Alice, additional, Lim, Zhao Qin, additional, Saklatvala, Jake R., additional, Chung, Raymond, additional, Curtis, Charles J., additional, Baum, Patrick, additional, Visvanathan, Sudha, additional, Burden, A David, additional, Cooper, Hywel L., additional, Dunnill, Giles, additional, Griffiths, Christopher EM., additional, Levell, Nick J., additional, Parslew, Richard, additional, Reynolds, Nick J., additional, Wahie, Shyamal, additional, Warren, Richard B., additional, Wright, Andrew, additional, Simpson, Michael, additional, Hveem, Kristian, additional, Barker, Jonathan N., additional, Dand, Nick, additional, Loset, Mari, additional, Smith, Catherine H., additional, and Capon, Francesca, additional

Published
2024
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9. Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

Author

Jennison, Christopher, Ehrhardt, Beate, Baum, Patrick, Schoelsch, Corinna, Freijer, Jan, Grempler, Rolf, Graefe-Mody, Ulrike, Hennige, Anita, Dings, Christiane, Lehr, Thorsten, Scherer, Nina, Sihinecich, Iryna, Pattou, Francois, Raverdi, Violeta, Caiazzo, Robert, Torres, Fanelly, Verkindt, Helene, Mari, Andrea, Tura, Andrea, Giorgino, Toni, Bizzotto, Roberto, Froguel, Philippe, Bonneford, Amelie, Canouil, Mickael, Dhennin, Veronique, Brorsson, Caroline, Brunak, Soren, De Masi, Federico, Gudmundsdóttir, Valborg, Pedersen, Helle, Banasik, Karina, Thomas, Cecilia, Sackett, Peter, Staerfeldt, Hans-Henrik, Lundgaard, Agnete, Nilsson, Birgitte, Nielsen, Agnes, Mazzoni, Gianluca, Karaderi, Tugce, Rasmussen, Simon, Johansen, Joachim, Allesøe, Rosa, Fritsche, Andreas, Thorand, Barbara, Adamski, Jurek, Grallert, Harald, Haid, Mark, Sharma, Sapna, Troll, Martina, Adam, Jonathan, Ferrer, Jorge, Eriksen, Heather, Frost, Gary, Haussler, Ragna, Hong, Mun-gwan, Schwenk, Jochen, Uhlen, Mathias, Nicolay, Claudia, Pavo, Imre, Steckel-Hamann, Birgit, Thomas, Melissa, Adragni, Kofi, Wu, Han, Hart, Leen't, Roderick, Slieker, van Leeuwen, Nienke, Dekkers, Koen, Frau, Francesca, Gassenhuber, Johann, Jablonka, Bernd, Musholt, Petra, Ruetten, Hartmut, Tillner, Joachim, Baltauss, Tania, Bernard Poenaru, Oana, de Preville, Nathalie, Rodriquez, Marianne, Arumugam, Manimozhiyan, Allin, Kristine, Engelbrechtsen, Line, Hansen, Torben, Hansen, Tue, Forman, Annemette, Jonsson, Anna, Pedersen, Oluf, Dutta, Avirup, Vogt, Josef, Vestergaard, Henrik, Laakso, Markku, Kokkola, Tarja, Kuulasmaa, Teemu, Franks, Paul, Giordano, Nick, Pomares-Millan, Hugo, Fitipaldi, Hugo, Mutie, Pascal, Klintenberg, Maria, Bergstrom, Margit, Groop, Leif, Ridderstrale, Martin, Atabaki Pasdar, Naeimeh, Deshmukh, Harshal, Heggie, Alison, Wake, Dianne, McEvoy, Donna, McVittie, Ian, Walker, Mark, Hattersley, Andrew, Hill, Anita, Jones, Angus, McDonald, Timothy, Perry, Mandy, Nice, Rachel, Hudson, Michelle, Thorne, Claire, Dermitzakis, Emmanouil, Viñuela, Ana, Cabrelli, Louise, Loftus, Heather, Dawed, Adem, Donnelly, Louise, Forgie, Ian, Pearson, Ewan, Palmer, Colin, Brown, Andrew, Koivula, Robert, Wesolowska-Andersen, Agata, Abdalla, Moustafa, McRobert, Nicky, Fernandez, Juan, Jiao, Yunlong, Robertson, Neil, Gough, Stephen, Kaye, Jane, Mourby, Miranda, Mahajan, Anubha, McCarthy, Mark, Shah, Nisha, Teare, Harriet, Holl, Reinhard, Koopman, Anitra, Rutters, Femke, Beulens, Joline, Groeneveld, Lenka, Bell, Jimmy, Thomas, Louise, Whitcher, Brandon, Wilman, Henry R., Parisinos, Constantinos A., Atabaki-Pasdar, Naeimeh, Kelly, Matt, Thomas, E. Louise, Neubauer, Stefan, Hingorani, Aroon D., Patel, Riyaz S., Hemingway, Harry, Franks, Paul W., Bell, Jimmy D., Banerjee, Rajarshi, and Yaghootkar, Hanieh

Published
2019
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11. Inhibiting Interleukin 36 Receptor Signaling Reduces Fibrosis in Mice With Chronic Intestinal Inflammation

Author

Scheibe, Kristina, Kersten, Christina, Schmied, Anabel, Vieth, Michael, Primbs, Tatjana, Carlé, Birgitta, Knieling, Ferdinand, Claussen, Jing, Klimowicz, Alexander C., Zheng, Jie, Baum, Patrick, Meyer, Sebastian, Schürmann, Sebastian, Friedrich, Oliver, Waldner, Maximilian J., Rath, Timo, Wirtz, Stefan, Kollias, George, Ekici, Arif B., Atreya, Raja, Raymond, Ernest L., Mbow, M. Lamine, Neurath, Markus F., and Neufert, Clemens

Published
2019
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13. Monocyte-derived alveolar macrophages are key drivers of smoke-induced lung inflammation and tissue remodeling.

Author

Wohnhaas, Christian T., Baßler, Kevin, Watson, Carolin K., Shen, Yang, Leparc, Germán G., Tilp, Cornelia, Heinemann, Fabian, Kind, David, Stierstorfer, Birgit, Delić, Denis, Brunner, Thomas, Gantner, Florian, Schultze, Joachim L., Viollet, Coralie, and Baum, Patrick

Subjects
TISSUE remodeling, PNEUMONIA, ALVEOLAR macrophages, CHRONIC obstructive pulmonary disease
Abstract

Smoking is a leading risk factor of chronic obstructive pulmonary disease (COPD), that is characterized by chronic lung inflammation, tissue remodeling and emphysema. Although inflammation is critical to COPD pathogenesis, the cellular and molecular basis underlying smoking-induced lung inflammation and pathology remains unclear. Using murine smokemodels and single-cell RNA-sequencing, we show that smoking establishes a selfamplifying inflammatory loop characterized by an influx of molecularly heterogeneous neutrophil subsets and excessive recruitment of monocytederived alveolar macrophages (MoAM). In contrast to tissue-resident AM, MoAM are absent in homeostasis and characterized by a pro-inflammatory gene signature. Moreover, MoAM represent 46% of AM in emphysematousmice and express markers causally linked to emphysema. We also demonstrate the presence of pro-inflammatory and tissue remodeling associated MoAM orthologs in humans that are significantly increased in emphysematous COPD patients. Inhibition of the IRAK4 kinase depletes a rare inflammatory neutrophil subset, diminishes MoAM recruitment, and alleviates inflammation in the lung of cigarette smoke-exposed mice. This study extends our understanding of the molecular signaling circuits and cellular dynamics in smoking-induced lung inflammation and pathology, highlights the functional consequence of monocyte and neutrophil recruitment, identifies MoAM as key drivers of the inflammatory process, and supports their contribution to pathological tissue remodeling. [ABSTRACT FROM AUTHOR]

Published
2024
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14. Interleukin 36 receptor-inducible matrix metalloproteinase 13 mediates intestinal fibrosis

Author

Koop, Kristina, primary, Enderle, Karin, additional, Hillmann, Miriam, additional, Ruspeckhofer, Laura, additional, Vieth, Michael, additional, Sturm, Gregor, additional, Trajanoski, Zlatko, additional, Kühl, Anja A., additional, Atreya, Raja, additional, Leppkes, Moritz, additional, Baum, Patrick, additional, Roy, Janine, additional, Martin, Andrea, additional, Neurath, Markus F., additional, and Neufert, Clemens, additional

Published
2023
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15. Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models

Author

Allesøe, Rosa Lundbye, Lundgaard, Agnete Troen, Hernández Medina, Ricardo, Aguayo-Orozco, Alejandro, Johansen, Joachim, Nissen, Jakob Nybo, Brorsson, Caroline, Mazzoni, Gianluca, Niu, Lili, Biel, Jorge Hernansanz, Brasas, Valentas, Webel, Henry, Benros, Michael Eriksen, Pedersen, Anders Gorm, Chmura, Piotr Jaroslaw, Jacobsen, Ulrik Plesner, Mari, Andrea, Koivula, Robert, Mahajan, Anubha, Vinuela, Ana, Tajes, Juan Fernandez, Sharma, Sapna, Haid, Mark, Hong, Mun-Gwan, Musholt, Petra B., De Masi, Federico, Vogt, Josef, Pedersen, Helle Krogh, Gudmundsdottir, Valborg, Jones, Angus, Kennedy, Gwen, Bell, Jimmy, Thomas, E. Louise, Frost, Gary, Thomsen, Henrik, Hansen, Elizaveta, Hansen, Tue Haldor, Vestergaard, Henrik, Muilwijk, Mirthe, Blom, Marieke T., ‘t Hart, Leen M., Pattou, Francois, Raverdy, Violeta, Brage, Soren, Kokkola, Tarja, Heggie, Alison, McEvoy, Donna, Mourby, Miranda, Kaye, Jane, Hattersley, Andrew, McDonald, Timothy, Ridderstråle, Martin, Walker, Mark, Forgie, Ian, Giordano, Giuseppe N., Pavo, Imre, Ruetten, Hartmut, Pedersen, Oluf, Hansen, Torben, Dermitzakis, Emmanouil, Franks, Paul W., Schwenk, Jochen M., Adamski, Jerzy, McCarthy, Mark I., Pearson, Ewan, Banasik, Karina, Rasmussen, Simon, Brunak, Søren, Froguel, Philippe, Thomas, Cecilia Engel, Häussler, Ragna S., Beulens, Joline, Rutters, Femke, Nijpels, Giel, van Oort, Sabine, Groeneveld, Lenka, Elders, Petra, Giorgino, Toni, Rodriquez, Marianne, Nice, Rachel, Perry, Mandy, Bianzano, Susanna, Graefe-Mody, Ulrike, Hennige, Anita, Grempler, Rolf, Baum, Patrick, Stærfeldt, Hans Henrik, Shah, Nisha, Teare, Harriet, Ehrhardt, Beate, Tillner, Joachim, Dings, Christiane, Lehr, Thorsten, Scherer, Nina, Sihinevich, Iryna, Cabrelli, Louise, Loftus, Heather, Bizzotto, Roberto, Tura, Andrea, Dekkers, Koen, Allesøe, Rosa Lundbye, Lundgaard, Agnete Troen, Hernández Medina, Ricardo, Aguayo-Orozco, Alejandro, Johansen, Joachim, Nissen, Jakob Nybo, Brorsson, Caroline, Mazzoni, Gianluca, Niu, Lili, Biel, Jorge Hernansanz, Brasas, Valentas, Webel, Henry, Benros, Michael Eriksen, Pedersen, Anders Gorm, Chmura, Piotr Jaroslaw, Jacobsen, Ulrik Plesner, Mari, Andrea, Koivula, Robert, Mahajan, Anubha, Vinuela, Ana, Tajes, Juan Fernandez, Sharma, Sapna, Haid, Mark, Hong, Mun-Gwan, Musholt, Petra B., De Masi, Federico, Vogt, Josef, Pedersen, Helle Krogh, Gudmundsdottir, Valborg, Jones, Angus, Kennedy, Gwen, Bell, Jimmy, Thomas, E. Louise, Frost, Gary, Thomsen, Henrik, Hansen, Elizaveta, Hansen, Tue Haldor, Vestergaard, Henrik, Muilwijk, Mirthe, Blom, Marieke T., ‘t Hart, Leen M., Pattou, Francois, Raverdy, Violeta, Brage, Soren, Kokkola, Tarja, Heggie, Alison, McEvoy, Donna, Mourby, Miranda, Kaye, Jane, Hattersley, Andrew, McDonald, Timothy, Ridderstråle, Martin, Walker, Mark, Forgie, Ian, Giordano, Giuseppe N., Pavo, Imre, Ruetten, Hartmut, Pedersen, Oluf, Hansen, Torben, Dermitzakis, Emmanouil, Franks, Paul W., Schwenk, Jochen M., Adamski, Jerzy, McCarthy, Mark I., Pearson, Ewan, Banasik, Karina, Rasmussen, Simon, Brunak, Søren, Froguel, Philippe, Thomas, Cecilia Engel, Häussler, Ragna S., Beulens, Joline, Rutters, Femke, Nijpels, Giel, van Oort, Sabine, Groeneveld, Lenka, Elders, Petra, Giorgino, Toni, Rodriquez, Marianne, Nice, Rachel, Perry, Mandy, Bianzano, Susanna, Graefe-Mody, Ulrike, Hennige, Anita, Grempler, Rolf, Baum, Patrick, Stærfeldt, Hans Henrik, Shah, Nisha, Teare, Harriet, Ehrhardt, Beate, Tillner, Joachim, Dings, Christiane, Lehr, Thorsten, Scherer, Nina, Sihinevich, Iryna, Cabrelli, Louise, Loftus, Heather, Bizzotto, Roberto, Tura, Andrea, and Dekkers, Koen

Abstract

The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities., Correction in DOI 10.1038/s41587-023-01805-9QC 20230626

Published
2023
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16. Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits

Author

Brown, Andrew A., Fernandez-Tajes, Juan J., Hong, Mun gwan, Brorsson, Caroline A., Koivula, Robert W., Davtian, David, Dupuis, Théo, Sartori, Ambra, Michalettou, Theodora Dafni, Forgie, Ian M., Adam, Jonathan, Allin, Kristine H., Caiazzo, Robert, Cederberg, Henna, De Masi, Federico, Elders, Petra J.M., Giordano, Giuseppe N., Haid, Mark, Hansen, Torben, Hansen, Tue H., Hattersley, Andrew T., Heggie, Alison J., Howald, Cédric, Jones, Angus G., Kokkola, Tarja, Laakso, Markku, Mahajan, Anubha, Mari, Andrea, McDonald, Timothy J., McEvoy, Donna, Mourby, Miranda, Musholt, Petra B., Nilsson, Birgitte, Pattou, Francois, Penet, Deborah, Raverdy, Violeta, Ridderstråle, Martin, Romano, Luciana, Rutters, Femke, Sharma, Sapna, Teare, Harriet, ‘t Hart, Leen, Tsirigos, Konstantinos D., Vangipurapu, Jagadish, Vestergaard, Henrik, Brunak, Søren, Franks, Paul W., Frost, Gary, Grallert, Harald, Jablonka, Bernd, McCarthy, Mark I., Pavo, Imre, Pedersen, Oluf, Ruetten, Hartmut, Walker, Mark, Adragni, Kofi, Allesøe, Rosa Lundbye L., Artati, Anna A., Arumugam, Manimozhiyan, Atabaki-Pasdar, Naeimeh, Baltauss, Tania, Banasik, Karina, Barnett, Anna L., Baum, Patrick, Bell, Jimmy D., Beulens, Joline W., Bianzano, Susanna B., Bizzotto, Roberto, Bonnefond, Amelie, Cabrelli, Louise, Dale, Matilda, Dawed, Adem Y., de Preville, Nathalie, Dekkers, Koen F., Deshmukh, Harshal A., Dings, Christiane, Donnelly, Louise, Dutta, Avirup, Ehrhardt, Beate, Engelbrechtsen, Line, Eriksen, Rebeca, Fan, Yong, Ferrer, Jorge, Fitipaldi, Hugo, Forman, Annemette, Fritsche, Andreas, Froguel, Philippe, Gassenhuber, Johann, Gough, Stephen, Graefe-Mody, Ulrike, Grempler, Rolf, Groeneveld, Lenka, Groop, Leif, Gudmundsdóttir, Valborg, Gupta, Ramneek, Hennige, Anita M.H., Hill, Anita V., Holl, Reinhard W., Hudson, Michelle, Jacobsen, Ulrik Plesner, Jennison, Christopher, Johansen, Joachim, Jonsson, Anna, Karaderi, Tugce, Kaye, Jane, Kennedy, Gwen, Klintenberg, Maria, Kuulasmaa, Teemu, Lehr, Thorsten, Loftus, Heather, Lundgaard, Agnete Troen T., Mazzoni, Gianluca, McRobert, Nicky, McVittie, Ian, Nice, Rachel, Nicolay, Claudia, Nijpels, Giel, Palmer, Colin N., Pedersen, Helle K., Perry, Mandy H., Pomares-Millan, Hugo, Prehn, Cornelia P., Ramisch, Anna, Rasmussen, Simon, Robertson, Neil, Rodriquez, Marianne, Sackett, Peter, Scherer, Nina, Shah, Nisha, Sihinevich, Iryna, Slieker, Roderick C., Sondertoft, Nadja B., Steckel-Hamann, Birgit, Thomas, Melissa K., Thomas, Cecilia Engel E., Thomas, Elizabeth Louise L., Thorand, Barbara, Thorne, Claire E., Tillner, Joachim, Tura, Andrea, Uhlen, Mathias, van Leeuwen, Nienke, van Oort, Sabine, Verkindt, Helene, Vogt, Josef, Wad Sackett, Peter W., Wesolowska-Andersen, Agata, Whitcher, Brandon, White, Margaret W., Adamski, Jerzy, Schwenk, Jochen M., Pearson, Ewan R., Dermitzakis, Emmanouil T., Viñuela, Ana, Brown, Andrew A., Fernandez-Tajes, Juan J., Hong, Mun gwan, Brorsson, Caroline A., Koivula, Robert W., Davtian, David, Dupuis, Théo, Sartori, Ambra, Michalettou, Theodora Dafni, Forgie, Ian M., Adam, Jonathan, Allin, Kristine H., Caiazzo, Robert, Cederberg, Henna, De Masi, Federico, Elders, Petra J.M., Giordano, Giuseppe N., Haid, Mark, Hansen, Torben, Hansen, Tue H., Hattersley, Andrew T., Heggie, Alison J., Howald, Cédric, Jones, Angus G., Kokkola, Tarja, Laakso, Markku, Mahajan, Anubha, Mari, Andrea, McDonald, Timothy J., McEvoy, Donna, Mourby, Miranda, Musholt, Petra B., Nilsson, Birgitte, Pattou, Francois, Penet, Deborah, Raverdy, Violeta, Ridderstråle, Martin, Romano, Luciana, Rutters, Femke, Sharma, Sapna, Teare, Harriet, ‘t Hart, Leen, Tsirigos, Konstantinos D., Vangipurapu, Jagadish, Vestergaard, Henrik, Brunak, Søren, Franks, Paul W., Frost, Gary, Grallert, Harald, Jablonka, Bernd, McCarthy, Mark I., Pavo, Imre, Pedersen, Oluf, Ruetten, Hartmut, Walker, Mark, Adragni, Kofi, Allesøe, Rosa Lundbye L., Artati, Anna A., Arumugam, Manimozhiyan, Atabaki-Pasdar, Naeimeh, Baltauss, Tania, Banasik, Karina, Barnett, Anna L., Baum, Patrick, Bell, Jimmy D., Beulens, Joline W., Bianzano, Susanna B., Bizzotto, Roberto, Bonnefond, Amelie, Cabrelli, Louise, Dale, Matilda, Dawed, Adem Y., de Preville, Nathalie, Dekkers, Koen F., Deshmukh, Harshal A., Dings, Christiane, Donnelly, Louise, Dutta, Avirup, Ehrhardt, Beate, Engelbrechtsen, Line, Eriksen, Rebeca, Fan, Yong, Ferrer, Jorge, Fitipaldi, Hugo, Forman, Annemette, Fritsche, Andreas, Froguel, Philippe, Gassenhuber, Johann, Gough, Stephen, Graefe-Mody, Ulrike, Grempler, Rolf, Groeneveld, Lenka, Groop, Leif, Gudmundsdóttir, Valborg, Gupta, Ramneek, Hennige, Anita M.H., Hill, Anita V., Holl, Reinhard W., Hudson, Michelle, Jacobsen, Ulrik Plesner, Jennison, Christopher, Johansen, Joachim, Jonsson, Anna, Karaderi, Tugce, Kaye, Jane, Kennedy, Gwen, Klintenberg, Maria, Kuulasmaa, Teemu, Lehr, Thorsten, Loftus, Heather, Lundgaard, Agnete Troen T., Mazzoni, Gianluca, McRobert, Nicky, McVittie, Ian, Nice, Rachel, Nicolay, Claudia, Nijpels, Giel, Palmer, Colin N., Pedersen, Helle K., Perry, Mandy H., Pomares-Millan, Hugo, Prehn, Cornelia P., Ramisch, Anna, Rasmussen, Simon, Robertson, Neil, Rodriquez, Marianne, Sackett, Peter, Scherer, Nina, Shah, Nisha, Sihinevich, Iryna, Slieker, Roderick C., Sondertoft, Nadja B., Steckel-Hamann, Birgit, Thomas, Melissa K., Thomas, Cecilia Engel E., Thomas, Elizabeth Louise L., Thorand, Barbara, Thorne, Claire E., Tillner, Joachim, Tura, Andrea, Uhlen, Mathias, van Leeuwen, Nienke, van Oort, Sabine, Verkindt, Helene, Vogt, Josef, Wad Sackett, Peter W., Wesolowska-Andersen, Agata, Whitcher, Brandon, White, Margaret W., Adamski, Jerzy, Schwenk, Jochen M., Pearson, Ewan R., Dermitzakis, Emmanouil T., and Viñuela, Ana

Abstract

We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.

Published
2023

18. Damaging Alleles Affecting Multiple CARD14 Domains Are Associated with Palmoplantar Pustulosis

Author

Niaouris, Athanasios, primary, Hernández-Cordero, Ariana, additional, Haddad, Salma, additional, Hassi, Niina Karoliina, additional, Benzian-Olsson, Natashia, additional, Bugarin Diz, Carmen, additional, Burden, A. David, additional, Cooper, Hywel L., additional, Griffiths, Christopher E.M., additional, Parslew, Richard, additional, Pink, Andrew E., additional, Reynolds, Nick J., additional, Wahie, Shyamal, additional, Warren, Richard B., additional, Wright, Andrew, additional, Simpson, Michael, additional, Baum, Patrick, additional, Visvanathan, Sudha, additional, Barker, Jonathan N., additional, Smith, Catherine H., additional, Capon, Francesca, additional, Abraham, Thamir, additional, Ali, Muhmad, additional, August, Suzannah, additional, Baudry, David, additional, Becher, Gabrielle, additional, Bewley, Anthony, additional, Cornelius, Victoria, additional, Dunnill, Giles, additional, Ferguson, Adam, additional, Ghaffar, Sharizan, additional, Ingram, John, additional, Kavakleiva, Svetlana, additional, Kelly, Susan, additional, Khorshid, Mohsen, additional, Lachmann, Helen, additional, Ladoyanni, Effie, additional, McAteer, Helen, additional, McKenna, John, additional, Meynell, Freya, additional, Levell, Nick, additional, Patel, Prakash, additional, Pushparajah, Angela, additional, Sinclair, Catriona, additional, Wachsmuth, Rachel, additional, and Wilson, Rosemary, additional

Published
2023
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19. Damaging Alleles Affecting Multiple CARD14 Domains Are Associated with Palmoplantar Pustulosis

Author

Abraham, Thamir, Ali, Muhmad, August, Suzannah, Baudry, David, Becher, Gabrielle, Bewley, Anthony, Cornelius, Victoria, Dunnill, Giles, Ferguson, Adam, Ghaffar, Sharizan, Ingram, John, Kavakleiva, Svetlana, Kelly, Susan, Khorshid, Mohsen, Lachmann, Helen, Ladoyanni, Effie, McAteer, Helen, McKenna, John, Meynell, Freya, Levell, Nick, Patel, Prakash, Pushparajah, Angela, Sinclair, Catriona, Wachsmuth, Rachel, Wilson, Rosemary, Niaouris, Athanasios, Hernández-Cordero, Ariana, Haddad, Salma, Hassi, Niina Karoliina, Benzian-Olsson, Natashia, Bugarin Diz, Carmen, Burden, A. David, Cooper, Hywel L., Griffiths, Christopher E.M., Parslew, Richard, Pink, Andrew E., Reynolds, Nick J., Wahie, Shyamal, Warren, Richard B., Wright, Andrew, Simpson, Michael, Baum, Patrick, Visvanathan, Sudha, Barker, Jonathan N., Smith, Catherine H., and Capon, Francesca

Published
2023
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21. Alveolar macrophages in early stage COPD show functional deviations with properties of impaired immune activation

Author

Baßler, Kevin, primary, Fujii, Wataru, additional, Kapellos, Theodore S., additional, Dudkin, Erika, additional, Reusch, Nico, additional, Horne, Ari, additional, Reiz, Benedikt, additional, Luecken, Malte D., additional, Osei-Sarpong, Collins, additional, Warnat-Herresthal, Stefanie, additional, Bonaguro, Lorenzo, additional, Schulte-Schrepping, Jonas, additional, Wagner, Allon, additional, Günther, Patrick, additional, Pizarro, Carmen, additional, Schreiber, Tina, additional, Knoll, Rainer, additional, Holsten, Lisa, additional, Kröger, Charlotte, additional, De Domenico, Elena, additional, Becker, Matthias, additional, Händler, Kristian, additional, Wohnhaas, Christian T., additional, Baumgartner, Florian, additional, Köhler, Meike, additional, Theis, Heidi, additional, Kraut, Michael, additional, Wadsworth, Marc H., additional, Hughes, Travis K., additional, Ferreira, Humberto J., additional, Hinkley, Emily, additional, Kaltheuner, Ines H., additional, Geyer, Matthias, additional, Thiele, Christoph, additional, Shalek, Alex K., additional, Feißt, Andreas, additional, Thomas, Daniel, additional, Dickten, Henning, additional, Beyer, Marc, additional, Baum, Patrick, additional, Yosef, Nir, additional, Aschenbrenner, Anna C., additional, Ulas, Thomas, additional, Hasenauer, Jan, additional, Theis, Fabian J., additional, Skowasch, Dirk, additional, and Schultze, Joachim L., additional

Published
2022
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22. Cigarette Smoke Specifically Affects Small Airway Epithelial Cell Populations and Triggers the Expansion of Inflammatory and Squamous Differentiation Associated Basal Cells

Author

Wohnhaas, Christian T., primary, Gindele, Julia A., additional, Kiechle, Tobias, additional, Shen, Yang, additional, Leparc, Germán G., additional, Stierstorfer, Birgit, additional, Stahl, Heiko, additional, Gantner, Florian, additional, Viollet, Coralie, additional, Schymeinsky, Jürgen, additional, and Baum, Patrick, additional

Published
2021
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23. Loss-of-Function Myeloperoxidase Mutations Are Associated with Increased Neutrophil Counts and Pustular Skin Disease

Author

Abraham, Thamir, Ali, Mahmud, August, Suzannah, Baudry, David, Bewley, Anthony, Cooper, Hywel, Griffiths, Christopher E.M., Ingram, John, Kelly, Susan, Korshid, Mohsen, Ladoyanni, Effie, McKenna, John, Meynell, Freya, Parslew, Richard, Patel, Prakash, Pushparajah, Angela, Reynolds, Nick, Smith, Catherine, Wahie, Shyamal, Warren, Richard, Wright, Andrew, Vergnano, Marta, Mockenhaupt, Maja, Benzian-Olsson, Natashia, Paulmann, Maren, Grys, Katarzyna, Mahil, Satveer K., Chaloner, Charlotte, Barbosa, Ines A., Burden, A. David, Choon, Siew-Eng, Navarini, Alex A., Reynolds, Nick J., Warren, Richard B., Huffmeier, Ulrike, Baum, Patrick, Visvanathan, Sudha, Barker, Jonathan N., Smith, Catherine H., and Capon, Francesca

Published
2020
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24. Pilot study of an occupational healthcare program to assess the SARS-CoV-2 infection and immune status of employees in a large pharmaceutical company

Author

Moroni-Zentgraf, Petra C., primary, Keller, Christoph, additional, Mahmoudi, Mazyar, additional, Kallsen, Kimberley, additional, Eschenfelder, Christoph C., additional, Sigmund, Ralf, additional, Müller, Hanns Walter, additional, Baum, Patrick, additional, Boos, Bertram, additional, Schneider, Michael, additional, and Mundt, Egbert, additional

Published
2021
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25. Loss-of-function myeloperoxidase mutations are associated with increased neutrophil counts and pustular skin disease

Author

Vergnano, Marta, primary, Mockenhaupt, Maja, additional, Benzian-Olsson, Natashia, additional, Paulmann, Maren, additional, Grys, Katarzyna, additional, Mahil, Satveer K., additional, Chaloner, Charlotte, additional, Barbosa, Ines A., additional, August, Suzannah, additional, Burden, A. David, additional, Choon, Siew-Eng, additional, Cooper, Hywel, additional, Navarini, Alex A., additional, Reynolds, Nick J., additional, Wahie, Shyamal, additional, Warren, Richard B., additional, Wright, Andrew, additional, Huffmeier, Ulrike, additional, Baum, Patrick, additional, Visvanathan, Sudha, additional, Barker, Jonathan N., additional, Smith, Catherine H., additional, Capon, Francesca, additional, Abraham, Thamir, additional, Ali, Mahmud, additional, Baudry, David, additional, Bewley, Anthony, additional, Griffiths, Christopher E.M., additional, Ingram, John, additional, Kelly, Susan, additional, Korshid, Mohsen, additional, Ladoyanni, Effie, additional, McKenna, John, additional, Meynell, Freya, additional, Parslew, Richard, additional, Patel, Prakash, additional, Pushparajah, Angela, additional, Reynolds, Nick, additional, Smith, Catherine, additional, and Warren, Richard, additional

Published
2021
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26. Loss-of-function myeloperoxidase mutations are associated with increased neutrophil counts and pustular skin disease

Author

Vergnano, Marta, Mockenhaupt, Maja, Benzian-Olsson, Natashia, Paulmann, Maren, Grys, Katarzyna, Mahil, Satveer K., Chaloner, Charlotte, Barbosa, Ines A., August, Suzannah, Burden, A. David, Choon, Siew-Eng, Cooper, Hywel, Navarini, Alex A., Reynolds, Nick J., Wahie, Shyamal, Warren, Richard B., Wright, Andrew, Huffmeier, Ulrike, Baum, Patrick, Visvanathan, Sudha, Barker, Jonathan N., Smith, Catherine H., Capon, Francesca, and APRICOT and PLUM study team

Abstract

The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused our attention on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole-exome sequencing of 19 unrelated affected individuals, we identified a subject harboring a homozygous splice-site mutation (c.2031−2A>C) in MPO. This encodes myeloperoxidase, an essential component of neutrophil azurophil granules. MPO screening in conditions phenotypically related to GPP uncovered further disease alleles in one subject with acral pustular psoriasis (c.2031−2A>C;c.2031−2A>C) and in two individuals with acute generalized exanthematous pustulosis (c.1705C>T;c.2031−2A>C and c.1552_1565del;c.1552_1565del). A subsequent analysis of UK Biobank data demonstrated that the c.2031−2A>C and c.1705C>T (p.Arg569Trp) disease alleles were also associated with increased neutrophil abundance in the general population (p = 5.1 × 10−6 and p = 3.6 × 10−5, respectively). The same applied to three further deleterious variants that had been genotyped in the cohort, with two alleles (c.995C>T [p.Ala332Val] and c.752T>C [p.Met251Thr]) yielding p values < 10−10. Finally, treatment of healthy neutrophils with an MPO inhibitor (4-Aminobenzoic acid hydrazide) increased cell viability and delayed apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers. These findings identify MPO as a genetic determinant of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.

Published
2020

27. Quantifying intrinsic causal contributions via structure preserving interventions

Author

Janzing, Dominik, Bl��baum, Patrick, Minorics, Lenon, Faller, Philipp, and Mastakouri, Atalanti

Subjects
FOS: Computer and information sciences, Artificial Intelligence (cs.AI), Computer Science - Artificial Intelligence, Statistics - Machine Learning, Information Theory (cs.IT), Computer Science - Information Theory, Machine Learning (stat.ML)
Abstract

We propose a new notion of causal contribution which describes the 'intrinsic' part of the contribution of a node on a target node in a DAG. We show that in some scenarios the existing causal quantification methods failed to capture this notion exactly. By recursively writing each node as a function of the upstream noise terms, we separate the intrinsic information added by each node from the one obtained from its ancestors. To interpret the intrinsic information as a causal contribution, we consider 'structure-preserving interventions' that randomize each node in a way that mimics the usual dependence on the parents and do not perturb the observed joint distribution. To get a measure that is invariant across arbitrary orderings of nodes we propose Shapley based symmetrization. We describe our contribution analysis for variance and entropy, but contributions for other target metrics can be defined analogously.

Published
2020

28. Exosomal miRNAs as Potential Biomarkers to Monitor Phosphodiesterase 5 Inhibitor Induced Anti-Fibrotic Effects on CCl4 Treated Rats

Author

Broermann, Andre, primary, Schmid, Ramona, additional, Gabrielyan, Ogsen, additional, Sakowski, Marlene, additional, Eisele, Claudia, additional, Keller, Sascha, additional, Wolff, Michael, additional, Baum, Patrick, additional, Stierstorfer, Birgit, additional, Huber, Jochen, additional, Krämer, Bernhard K., additional, Hocher, Berthold, additional, Streicher, Ruediger, additional, and Delić, Denis, additional

Published
2020
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29. Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

Author

Baßler, Kevin, primary, Fujii, Wataru, additional, Kapellos, Theodore S., additional, Horne, Arik, additional, Reiz, Benedikt, additional, Dudkin, Erika, additional, Lücken, Malte, additional, Reusch, Nico, additional, Osei-Sarpong, Collins, additional, Warnat-Herresthal, Stefanie, additional, Wagner, Allon, additional, Bonaguro, Lorenzo, additional, Günther, Patrick, additional, Pizarro, Carmen, additional, Schreiber, Tina, additional, Becker, Matthias, additional, Händler, Kristian, additional, Wohnhaas, Christian T., additional, Baumgartner, Florian, additional, Köhler, Meike, additional, Theis, Heidi, additional, Kraut, Michael, additional, Wadsworth, Marc H., additional, Hughes, Travis K., additional, Ferreira, Humberto J. G., additional, Schulte-Schrepping, Jonas, additional, Hinkley, Emily, additional, Kaltheuner, Ines H., additional, Geyer, Matthias, additional, Thiele, Christoph, additional, Shalek, Alex K., additional, Feißt, Andreas, additional, Thomas, Daniel, additional, Dickten, Henning, additional, Beyer, Marc, additional, Baum, Patrick, additional, Yosef, Nir, additional, Aschenbrenner, Anna C., additional, Ulas, Thomas, additional, Hasenauer, Jan, additional, Theis, Fabian J., additional, Skowasch, Dirk, additional, and Schultze, Joachim L., additional

Published
2020
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30. Fecal MicroRNAs Show Promise as Noninvasive Crohn’s Disease Biomarkers

Author

Wohnhaas, Christian T, primary, Schmid, Ramona, additional, Rolser, Marcel, additional, Kaaru, Eric, additional, Langgartner, Dominik, additional, Rieber, Kathrin, additional, Strobel, Benjamin, additional, Eisele, Claudia, additional, Wiech, Franziska, additional, Jakob, Ines, additional, Gantner, Florian, additional, Herichova, Ivona, additional, Vinisko, Richard, additional, Böcher, Wulf O, additional, Visvanathan, Sudha, additional, Shen, Fei, additional, Panzenbeck, Mark, additional, Raymond, Ernest, additional, Reber, Stefan O, additional, Delić, Denis, additional, and Baum, Patrick, additional

Published
2020
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32. Causal structure based root cause analysis of outliers

Author

Janzing, Dominik, Budhathoki, Kailash, Minorics, Lenon, and Bl��baum, Patrick

Subjects
FOS: Computer and information sciences, Computer Science - Machine Learning, Statistics - Machine Learning, FOS: Mathematics, Machine Learning (stat.ML), Mathematics - Statistics Theory, Statistics Theory (math.ST), Machine Learning (cs.LG)
Abstract

We describe a formal approach to identify 'root causes' of outliers observed in $n$ variables $X_1,\dots,X_n$ in a scenario where the causal relation between the variables is a known directed acyclic graph (DAG). To this end, we first introduce a systematic way to define outlier scores. Further, we introduce the concept of 'conditional outlier score' which measures whether a value of some variable is unexpected *given the value of its parents* in the DAG, if one were to assume that the causal structure and the corresponding conditional distributions are also valid for the anomaly. Finally, we quantify to what extent the high outlier score of some target variable can be attributed to outliers of its ancestors. This quantification is defined via Shapley values from cooperative game theory., 11 pages, 9 Figures

Published
2019

33. Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

Author

Wilman, Henry R., Parisinos, Constantinos A., Atabaki-Pasdar, Naeimeh, Kelly, Matt, Thomas, E. Louise, Neubauer, Stefan, Jennison, Christopher, Ehrhardt, Beate, Baum, Patrick, Schoelsch, Corinna, Freijer, Jan, Grempler, Rolf, Graefe-Mody, Ulrike, Hennige, Anita, Dings, Christiane, Lehr, Thorsten, Scherer, Nina, Sihinecich, Iryna, Pattou, Francois, Raverdi, Violeta, Caiazzo, Robert, Torres, Fanelly, Verkindt, Helene, Mari, Andrea, Tura, Andrea, Giorgino, Toni, Bizzotto, Froguel, Philippe, Bonneford, Amelie, Canouil, Mickael, Dhennin, Veronique, Brorsson, Caroline, Brunak, Soren, de Masi, Federico, Gudmundsdóttir, Valborg, Pedersen, Helle, Banasik, Karina, Thomas, Cecilia, Sackett, Peter, Staerfeldt, Hans-Henrik, Lundgaard, Agnete, Koopman, Anitra, Rutters, Femke, Beulens, Joline, Groeneveld, Lenka, Thomas, Louise, Whitcher, Brandon, Mahajan, Anubha, Hingorani, Aroon D., Patel, Riyaz S., Hemingway, Harry, Franks, Paul W., Bell, Jimmy D., Banerjee, Rajarshi, Yaghootkar, Hanieh, Epidemiology and Data Science, APH - Health Behaviors & Chronic Diseases, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, and APH - Aging & Later Life

Abstract

Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p

Published
2019
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34. Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile

Author

Skaug, Brian, primary, Khanna, Dinesh, additional, Swindell, William R, additional, Hinchcliff, Monique E, additional, Frech, Tracy M, additional, Steen, Virginia D, additional, Hant, Faye N, additional, Gordon, Jessica K, additional, Shah, Ami A, additional, Zhu, Lisha, additional, Zheng, W Jim, additional, Browning, Jeffrey L, additional, Barron, Alexander M S, additional, Wu, Minghua, additional, Visvanathan, Sudha, additional, Baum, Patrick, additional, Franks, Jennifer M, additional, Whitfield, Michael L, additional, Shanmugam, Victoria K, additional, Domsic, Robyn T, additional, Castelino, Flavia V, additional, Bernstein, Elana J, additional, Wareing, Nancy, additional, Lyons, Marka A, additional, Ying, Jun, additional, Charles, Julio, additional, Mayes, Maureen D, additional, and Assassi, Shervin, additional

Published
2019
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35. Effects of BI 655064, an antagonistic anti-CD40 antibody, on clinical and biomarker variables in patients with active rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase IIa study

Author

Visvanathan, Sudha, primary, Daniluk, Stefan, additional, Ptaszyński, Rafał, additional, Müller-Ladner, Ulf, additional, Ramanujam, Meera, additional, Rosenstock, Bernd, additional, Eleftheraki, Anastasia G, additional, Vinisko, Richard, additional, Petříková, Alena, additional, Kellner, Herbert, additional, Dokoupilova, Eva, additional, Kwiatkowska, Brygida, additional, Alten, Rieke, additional, Schwabe, Christian, additional, Baum, Patrick, additional, Joseph, David, additional, Fine, Jay S, additional, Padula, Steven J, additional, and Steffgen, Jürgen, additional

Published
2019
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36. Inhibition of the Interleukin-36 Pathway for the Treatment of Generalized Pustular Psoriasis

Author

Bachelez, Hervé, primary, Choon, Siew-Eng, additional, Marrakchi, Slaheddine, additional, Burden, A. David, additional, Tsai, Tsen-Fang, additional, Morita, Akimichi, additional, Turki, Hamida, additional, Hall, David B., additional, Shear, Michael, additional, Baum, Patrick, additional, Padula, Steven J., additional, and Thoma, Christian, additional

Published
2019
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37. Comparison of normalization methods for Illumina BeadChip HumanHT-12 v3

Author

Eils Roland, Brors Benedikt, Huber Wolfgang, Fundel-Clemens Katrin, Ittrich Carina, Baum Patrick, Schmid Ramona, Weith Andreas, Mennerich Detlev, and Quast Karsten

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Normalization of microarrays is a standard practice to account for and minimize effects which are not due to the controlled factors in an experiment. There is an overwhelming number of different methods that can be applied, none of which is ideally suited for all experimental designs. Thus, it is important to identify a normalization method appropriate for the experimental setup under consideration that is neither too negligent nor too stringent. Major aim is to derive optimal results from the underlying experiment. Comparisons of different normalization methods have already been conducted, none of which, to our knowledge, comparing more than a handful of methods. Results In the present study, 25 different ways of pre-processing Illumina Sentrix BeadChip array data are compared. Among others, methods provided by the BeadStudio software are taken into account. Looking at different statistical measures, we point out the ideal versus the actual observations. Additionally, we compare qRT-PCR measurements of transcripts from different ranges of expression intensities to the respective normalized values of the microarray data. Taking together all different kinds of measures, the ideal method for our dataset is identified. Conclusions Pre-processing of microarray gene expression experiments has been shown to influence further downstream analysis to a great extent and thus has to be carefully chosen based on the design of the experiment. This study provides a recommendation for deciding which normalization method is best suited for a particular experimental setup.

Published
2010
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38. Loss-of-function myeloperoxidase mutations are associated with increased neutrophil counts and pustular skin disease

Author

Abraham, Thamir, Ali, Mahmud, August, Suzannah, Baudry, David, Bewley, Anthony, Cooper, Hywel, Griffiths, Christopher E.M., Ingram, John, Kelly, Susan, Korshid, Mohsen, Ladoyanni, Effie, McKenna, John, Meynell, Freya, Parslew, Richard, Patel, Prakash, Pushparajah, Angela, Reynolds, Nick, Smith, Catherine, Wahie, Shyamal, Warren, Richard, Wright, Andrew, Vergnano, Marta, Mockenhaupt, Maja, Benzian-Olsson, Natashia, Paulmann, Maren, Grys, Katarzyna, Mahil, Satveer K., Chaloner, Charlotte, Barbosa, Ines A., Burden, A. David, Choon, Siew-Eng, Navarini, Alex A., Reynolds, Nick J., Warren, Richard B., Huffmeier, Ulrike, Baum, Patrick, Visvanathan, Sudha, Barker, Jonathan N., Smith, Catherine H., and Capon, Francesca

Published
2021
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39. Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile.

Author

Skaug, Brian, Khanna, Dinesh, Swindell, William R., Hinchcliff, Monique E., Frech, Tracy M., Steen, Virginia D., Hant, Faye N., Gordon, Jessica K., Shah, Ami A., Zhu, Lisha, Zheng, W. Jim, Browning, Jeffrey L., Barron, Alexander M. S., Minghua Wu, Visvanathan, Sudha, Baum, Patrick, Franks, Jennifer M., Whitfield, Michael L., Shanmugam, Victoria K., and Domsic, Robyn T.

Subjects
RESEARCH, SEQUENCE analysis, BIOPSY, SKIN, MULTIVARIATE analysis, RESEARCH methodology, SYSTEMIC scleroderma, REGRESSION analysis, ACQUISITION of data, EVALUATION research, MEDICAL cooperation, SEVERITY of illness index, COMPARATIVE studies, IMMUNITY, GENE expression profiling, RESEARCH funding, LONGITUDINAL method
Abstract

Objectives: Determine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease.Methods: Skin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated.Results: SSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression.Conclusions: Skin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design. [ABSTRACT FROM AUTHOR]

Published
2020
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40. Differences in Peripheral and Tissue Immune Cell Populations Following Haematopoietic Stem Cell Transplantation in Crohn’s Disease Patients

Author

Corraliza, Ana M, primary, Ricart, Elena, additional, López-García, Alicia, additional, Carme Masamunt, Maria, additional, Veny, Marisol, additional, Esteller, Miriam, additional, Mayorgas, Aida, additional, Le Bourhis, Lionel, additional, Allez, Matthieu, additional, Planell, Núria, additional, Visvanathan, Sudha, additional, Baum, Patrick, additional, España, Carolina, additional, Cabezón-Cabello, Raquel, additional, Benítez-Ribas, Daniel, additional, Rovira, Montserrat, additional, Panés, Julián, additional, and Salas, Azucena, additional

Published
2018
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41. Selective IL-23 Inhibition by Risankizumab Modulates the Molecular Profile in the Colon and Ileum of Patients With Active Crohn’s Disease: Results From a Randomised Phase II Biopsy Sub-study

Author

Visvanathan, Sudha, primary, Baum, Patrick, additional, Salas, Azucena, additional, Vinisko, Richard, additional, Schmid, Ramona, additional, Grebe, Kristie M, additional, Davis, Justin W, additional, Wallace, Kori, additional, Böcher, Wulf O, additional, Padula, Steven J, additional, Fine, Jay S, additional, and Panés, Julián, additional

Published
2018
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42. Differences in Peripheral and Tissue Immune Cell Populations Following Haematopoietic Stem Cell Transplantation in Crohn's Disease Patients.

Author

Corraliza, Ana M, Ricart, Elena, López-García, Alicia, Masamunt, Maria Carme, Veny, Marisol, Esteller, Miriam, Mayorgas, Aida, Bourhis, Lionel Le, Allez, Matthieu, Planell, Núria, Visvanathan, Sudha, Baum, Patrick, España, Carolina, Cabezón-Cabello, Raquel, Benítez-Ribas, Daniel, Rovira, Montserrat, Panés, Julián, and Salas, Azucena

Abstract

Background and Aims Recent studies have shown the efficacy of autologous haematopoietic stem cell transplantation [HSCT] in severely refractory Crohn's disease [CD] patients. HSCT is thought to eliminate auto-reactive cells; however, no specific studies of immune reconstitution in CD patients are available. Methods We followed a group of CD patients [ n = 18] receiving autologous HSCT, with 50% of them achieving endoscopic drug-free remission. To elucidate the mechanisms driving efficacy, we monitored changes after HSCT in blood and intestine immune-cell composition. CD patients [ n = 22] receiving anti-tumour necrosis factor [TNF]-α were included for comparison. Results Severe immune ablation followed by HSCT induced dramatic changes in both peripheral blood T and B cells in all patients regardless of the efficacy of the treatment. Endoscopic remission at week 52 following HSCT was associated with significant intestinal transcriptional changes. A comparison of the remission signature with that of anti-TNFα identified both common and unique genes in the HSCT-induced response. Based on deconvolution analysis of intestinal biopsy transcriptome data, we show that response to HSCT, but not to anti-TNFα, is associated with an expansion of naïve B-cells, as seen in blood, and a decrease in the memory resting T-cell content. As expected, endoscopic remission, in response to both HSCT and anti-TNFα, led to a significant reduction in intestinal neutrophil and M1 macrophage content. Conclusions Peripheral blood immune remodelling after HSCT does not predict efficacy. In contrast, a profound intestinal T-cell depletion that is maintained long after transplant is associated with mucosal healing following HSCT, but not anti-TNFα. [ABSTRACT FROM AUTHOR]

Published
2019
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45. ITPA genotypes predict anemia but do not affect virological response with interferon-free faldaprevir, deleobuvir, and ribavirin for HCV infection

Author

Asselah, Tarik, Zeuzem, Stefan, Soriano, Vicente, Bronowicki, Jean-Pierre, Lohse, Ansgar W., Müllhaupt, Beat, Schuchmann, Marcus, Bourlière, Marc, Buti, Maria, Roberts, Stuart K., Gane, Edward J., Stern, Jerry O., Voss, Florian, Baum, Patrick, Gallivan, John-Paul, Böcher, Wulf Otto, Mensa, Federico J., Asselah, Tarik, Zeuzem, Stefan, Soriano, Vicente, Bronowicki, Jean-Pierre, Lohse, Ansgar W., Müllhaupt, Beat, Schuchmann, Marcus, Bourlière, Marc, Buti, Maria, Roberts, Stuart K., Gane, Edward J., Stern, Jerry O., Voss, Florian, Baum, Patrick, Gallivan, John-Paul, Böcher, Wulf Otto, and Mensa, Federico J.

Abstract

Background & aim: Whether inosine triphosphatase (ITPA) gene polymorphisms predict anemia during interferon-free therapy in chronic hepatitis C virus (HCV)-infected patients is unknown. We examined the relationship between two ITPA polymorphisms, anemia, and sustained virological response 12 weeks post-treatment (SVR12) in patients receiving the NS3/4A protease inhibitor faldaprevir, the non-nucleoside polymerase inhibitor deleobuvir, and ribavirin. Methods: HCV genotype 1-infected, treatment-naïve patients (N = 362) were randomized and treated in one of five treatment arms with faldaprevir and deleobuvir with or without ribavirin. Two ITPA polymorphisms (rs1127354 and rs6051702) were genotyped and defined as ITPA-deficient (rs1127354 AA or AC; rs6051702 CC or CA) or ITPA-non-deficient (rs1127354 CC; rs6051702 AA) according to their association with ITPA deficiency. Baseline and on-treatment variables associated with anemia and SVR12 were identified using logistic regression. Results: In the pooled ribavirin-containing arms, 10.1% (32/316) of patients experienced on-treatment hemoglobin <10 g/dL, and 32.6% (103/316) experienced on-treatment hemoglobin <10 g/dL or a change from baseline ≥3.5 g/dL. Of the latter group, 99% (102/103) had the ITPA-non-deficient rs1127354 genotype. Other variables associated with on-treatment hemoglobin <10 g/dL or a decrease ≥3.5 g/dL were age, baseline hemoglobin, rs6051702 genotype, and plasma ribavirin concentration. In a multivariate analysis, high plasma ribavirin concentration, low baseline hemoglobin, HCV genotype 1b, and IL28B genotype CC were associated with higher SVR12. Conclusions: The ITPA rs1127354 CC and rs6051702 AA genotypes may predict ribavirin-induced anemia during treatment with interferon-free, ribavirin-containing regimens. With this interferon-free regimen, SVR was associated with ribavirin levels, but not with anemia or ITPA genotypes.

Published
2015

46. ITPA Genotypes Predict Anemia but Do Not Affect Virological Response with Interferon-Free Faldaprevir, Deleobuvir, and Ribavirin for HCV Infection

Author

Asselah, Tarik, primary, Zeuzem, Stefan, additional, Soriano, Vicente, additional, Bronowicki, Jean-Pierre, additional, Lohse, Ansgar W., additional, Müllhaupt, Beat, additional, Schuchmann, Marcus, additional, Bourlière, Marc, additional, Buti, Maria, additional, Roberts, Stuart K., additional, Gane, Edward J., additional, Stern, Jerry O., additional, Voss, Florian, additional, Baum, Patrick, additional, Gallivan, John-Paul, additional, Böcher, Wulf O., additional, and Mensa, Federico J., additional

Published
2015
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47. Phenocopy : a strategy to qualify chemical compounds during hit-to-lead and/or lead optimization

Author

Baum, Patrick and Kontermann, Roland (Prof. Dr.)

Subjects
Microarray, expression profiling , drug discovery , functional genomics , Transforming Growth Factor beta , kinase inhibitors
Abstract

A phenocopy is defined as an environmentally induced phenotype of one individual which is identical to the genotype determined phenotype of another individual. In the present work, the phenocopy phenomenon has been translated to the drug discovery process as phenotypes produced by the treatment of cellular systems with small interfering RNAs (siRNAs) or new chemical entities (NCE) may resemble environmentally induced phenotypic modifications. Various new chemical entities exerting inhibition of the kinase activity of Transforming Growth Factor Beta Receptor I (TGF-betaR1) were ranked by high-throughput RNA expression profiling. This chemical genomics approach was able to unravel both on-target effects (effects, caused by the inhibition of the drug target) and off-target effects (effects, caused by the interaction of the NCE with additional molecules). It resulted in a precise time-dependent insight into the TGF-beta biology (referred to as on-target signature) and allowed furthermore a comprehensive analysis of each NCE's off-target effects (re-ferred to as off-target signatures). Both signature types can support the drug discovery process. The on-target signature helps to characterize the mode of action of the drug target (TGF-betaR1) and thereby supports the target validation as well as the assay development process. Furthermore, the evaluation of off-target effects by the Phenocopy approach allows a more accurate and integrated view on the mode of action of the compounds, supplementing classical biological evaluation parameters such as potency and selectivity. The presented proof of concept study allowed the ranking of NCEs that were before indistinguishable solely based on potency and selectivity. According to the newly introduced criteria, several of the tested NCEs revealed liabilities at e.g. the induction of off-target effects and of induction of gene regulation inverse to the desired TGF-beta inhibition effect, at the induction of cell death, at acting as pro-inflammatory stimuli and as promoting cellular growth and at induction of cancer pathways. Ultimately, this approach has therefore the potential to become a novel method for ranking compounds during various drug discovery phases., Eine Phänokopie ist als ein Individuum definiert, dessen Phänotyp durch einen Umwelteinfluss mit dem eines anderen Individuums identisch ist, dessen Phänotyp durch seinen Genotyp bestimmt ist. In der vorliegenden Arbeit wurde das Phänokopiephänomen auf den Wirkstoffentwicklungsprozess übertragen. Hierbei wurden die speziellen Phänotypen in einem Zellsystem durch die Behandlung mit "new chemical entities" (NCE), potentiellen neuen Wirkstoffkandidaten, oder mittels "small interfering RNAs" (siRNAs) induziert. Somit können beide Molekülklassen als externe Umweltbedingung angesehen werden. Hierbei wurden diverse der potentiellen Wirkstoffkandidaten zur Inhibition der Kinaseaktivität von Transforming Growth Factor Beta Receptor I (TGF-betaR1) mittels Hochdurchsatz-Expressionsprofilierung klassifiziert. Dieser „chemical genomics“ Ansatz war in der Lage, sowohl die On-target Effekte (Effekte, welche durch die Inhibition des Wirkstofftargets aus-gelöst werden), als auch die Off-target Effekte (Effekte, welche durch die Interaktion des NCEs mit zusätzlichen Molekülen ausgelöst werden) zu identifizieren. Weiterhin ermöglichte er präzise, zeitlich aufgelöste Einblicke in die TGF-beta Biologie (im Folgenden als On-target Signatur bezeichnet) und erlaubte eine umfassende Analyse der jeweiligen Off-target Effekte der Wirkstoffkandidaten (im Folgenden als Off-target Signatur bezeichnet). Beide Signaturtypen können zur Unterstützung des Wirkstoffentwicklungsprozesses herangezogen werden. Die On-target Signatur charakterisiert die Wirkungsweise des Wirkstoffziels (target) und unterstützt somit sowohl den "target validation" Prozess, als auch den "assay development" Prozess. Des Weiteren erlaubt das Ermitteln der Off-target Effekte durch den Phänokopieansatz einen präzisen und ganzheitlichen Einblick in die Wirkungsweise der Wirkstoffkandidaten und ergänzt klassische, biologische Bewertungsparameter wie Wirksamkeit und Selektivität. Die hier präsentierte Machbarkeitsstudie ermöglicht die Klassifizierung von Wirkstoffkandidaten, die zuvor auf der Basis von Wirksamkeit und Selektivität nicht zu unterscheiden waren. Entsprechend der neu eingeführten Kriterien zeigen verschiedene der getesteten Wirkstoffkandidaten unterschiedliche Vorbelastungen, wie z.B. das Auslösen von Off-target Effekten und von Genregulation, welche gegenläufig zu dem gewünschten TGF-beta Inhibitionseffekt verlaufen. Des Weiteren konnte gezeigt werden, dass manche NCEs Zelltod induzieren, als proinflammatorische Stimuli fungieren, das Zellwachstum steigern könnten und Krebssignalwege induzieren. Letztendlich hat dieser Ansatz somit das Potential eine neue Methode zur Klassifizierung von neuen Wirkstoffkandidaten, während verschiedenster Phasen des Wirkstoffentwicklungsprozesses, zu werden.

Published
2010
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49. Phenocopy – A Strategy to Qualify Chemical Compounds during Hit-to-Lead and/or Lead Optimization

Author

Baum, Patrick, primary, Schmid, Ramona, additional, Ittrich, Carina, additional, Rust, Werner, additional, Fundel-Clemens, Katrin, additional, Siewert, Susanne, additional, Baur, Martin, additional, Mara, Lisa, additional, Gruenbaum, Lore, additional, Heckel, Armin, additional, Eils, Roland, additional, Kontermann, Roland E., additional, Roth, Gerald J., additional, Gantner, Florian, additional, Schnapp, Andreas, additional, Park, John E., additional, Weith, Andreas, additional, Quast, Karsten, additional, and Mennerich, Detlev, additional

Published
2010
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