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3,236 results on '"Seeger, Werner"'

2. Analysis of acute COVID-19 including chronic morbidity: protocol for the deep phenotyping National Pandemic Cohort Network in Germany (NAPKON-HAP)

Author

Steinbeis, Fridolin, Thibeault, Charlotte, Steinbrecher, Sarah, Ahlgrimm, Yvonne, Haack, Ira an, August, Dietrich, Balzuweit, Beate, Bellinghausen, Carla, Berger, Sarah, Chaplinskaya-Sobol, Irina, Cornely, Oliver, Doeblin, Patrick, Endres, Matthias, Fink, Claudia, Finke, Carsten, Frank, Sandra, Hanß, Sabine, Hartung, Tim, Hellmuth, Johannes Christian, Herold, Susanne, Heuschmann, Peter, Heyckendorf, Jan, Heyder, Ralf, Hippenstiel, Stefan, Hoffmann, Wolfgang, Kelle, Sebastian Ulrich, Knape, Philipp, Koehler, Philipp, Kretzler, Lucie, Leistner, David Manuel, Lienau, Jasmin, Lorbeer, Roberto, Lorenz-Depiereux, Bettina, Lüttke, Constanze Dorothea, Mai, Knut, Merle, Uta, Meyer-Arndt, Lil Antonia, Miljukov, Olga, Muenchhoff, Maximilian, Müller-Plathe, Moritz, Neuhann, Julia, Neuhauser, Hannelore, Nieters, Alexandra, Otte, Christian, Pape, Daniel, Pinto, Rafaela Maria, Pley, Christina, Pudszuhn, Annett, Reuken, Philipp, Rieg, Siegberg, Ritter, Petra, Rohde, Gernot, Rönnefarth, Maria, Ruzicka, Michael, Schaller, Jens, Schmidt, Anne, Schmidt, Sein, Schwachmeyer, Verena, Schwanitz, Georg, Seeger, Werner, Stahl, Dana, Stobäus, Nicole, Stubbe, Hans Christian, Suttorp, Norbert, Temmesfeld, Bettina, Thun, Sylvia, Triller, Paul, Trinkmann, Frederik, Vadasz, Istvan, Valentin, Heike, Vehreschild, Maria, von Kalle, Christof, von Lilienfeld-Toal, Marie, Weber, Joachim, Welte, Tobias, Wildberg, Christian, Wizimirski, Robert, Zvork, Saskia, Sander, Leif Erik, Vehreschild, Janne, Zoller, Thomas, Kurth, Florian, and Witzenrath, Martin

Published
2024
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3. Transcriptional profiling unveils molecular subgroups of adaptive and maladaptive right ventricular remodeling in pulmonary hypertension

Author

Khassafi, Fatemeh, Chelladurai, Prakash, Valasarajan, Chanil, Nayakanti, Sreenath Reddy, Martineau, Sandra, Sommer, Natascha, Yokokawa, Tetsuro, Boucherat, Olivier, Kamal, Aryan, Kiely, David G., Swift, Andrew J., Alabed, Samer, Omura, Junichi, Breuils-Bonnet, Sandra, Kuenne, Carsten, Potus, Francois, Günther, Stefan, Savai, Rajkumar, Seeger, Werner, Looso, Mario, Lawrie, Allan, Zaugg, Judith B., Tello, Khodr, Provencher, Steeve, Bonnet, Sébastien, and Pullamsetti, Soni Savai

Published
2023
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5. Evaluation of a medical student-delivered smoking prevention program utilizing a face-aging mobile app for secondary schools in Germany: The Education Against Tobacco cluster-randomized controlled trial

Author

Brinker, Titus J., Krieghoff-Henning, Eva I., Suhre, Janina L., Silchmüller, Marc Phillipp, Divizieva, Evgenia, Wilhelm, Jilada, Hillebrand, Gabriel, Haney, Ailís C., Srivastava, Aayushi, Haney, Caelán M., Seeger, Werner, Penka, Dominik, Gall, Henning, Gaim, Benedikt, Glisic, Lazar, Stark, Tobias, Swoboda, Susanne M., Baumermann, Sonja, Brieske, Christian M., Jakob, Lena, Fahrner, Hannah Maria, Anhuef, Ole, Schmidt, Selina Marisa, Alfitian, Jonas, Taha, Lava, Beißwenger, Hanna, Groneberg, David A., Thomas, Roger E., Fröhling, Stefan, von Kalle, Christof, Baudson, Tanja Gabriele, Buslaff, Fabian, and Mons, Ute

Published
2024
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6. Comparison of Contemporary Risk Scores in All Groups of Pulmonary Hypertension: A Pulmonary Vascular Research Institute GoDeep Meta-Registry Analysis

Author

Antoine, Tobiah, Backofen, Achim, Cannon, John, Damonte, Victoria, Echazarreta, Diego, Eichstaedt, Christina, Elwing, Jean, Förster, Kai, Gruenig, Ekkehard, Hilgendorff, Anne, Jose, Arun, Junaeda, Ernesto, Krieb, Philipp, Marquardt, Kurt, Osborn, Karen, Pepke-Zaba, Johanna, Tilea, Ioan, Varga, Andreea, Yogeswaran, Athiththan, Gall, Henning, Fünderich, Meike, Wilkins, Martin R., Howard, Luke, Kiely, David G., Lawrie, Allan, Hassoun, Paul M., Sirenklo, Yuriy, Torbas, Olena, Sweatt, Andrew J., Zamanian, Roham T., Williams, Paul G., Frauendorf, Marlize, Arvanitaki, Alexandra, Giannakoulas, George, Saleh, Khaled, Sabbour, Hani, Cajigas, Hector R., Frantz, Robert, Al Ghouleh, Imad, Chan, Stephen Y., Brittain, Evan, Annis, Jeffrey S., Pepe, Antonella, Ghio, Stefano, Orfanos, Stylianos, Anthi, Anastasia, Majeed, Raphael W., Wilhelm, Jochen, Ghofrani, Hossein Ardeschir, Richter, Manuel J., Grimminger, Friedrich, Sahay, Sandeep, Tello, Khodr, and Seeger, Werner

Published
2024
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11. CXCL10 deficiency limits macrophage infiltration, preserves lung matrix, and enables lung growth in bronchopulmonary dysplasia

Author

Hirani, Dharmesh V., Thielen, Florian, Mansouri, Siavash, Danopoulos, Soula, Vohlen, Christina, Haznedar-Karakaya, Pinar, Mohr, Jasmine, Wilke, Rebecca, Selle, Jaco, Grosch, Thomas, Mizik, Ivana, Odenthal, Margarete, Alvira, Cristina M., Kuiper-Makris, Celien, Pryhuber, Gloria S., Pallasch, Christian, van Koningsbruggen-Rietschel, S., Al-Alam, Denise, Seeger, Werner, Savai, Rajkumar, Dötsch, Jörg, and Alejandre Alcazar, Miguel A.

Published
2023
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12. Noncanonical HIPPO/MST Signaling via BUB3 and FOXO Drives Pulmonary Vascular Cell Growth and Survival

Author

Kudryashova, Tatiana V, Dabral, Swati, Nayakanti, Sreenath, Ray, Arnab, Goncharov, Dmitry A, Avolio, Theodore, Shen, Yuanjun, Rode, Analise, Pena, Andressa, Jiang, Lifeng, Lin, Derek, Baust, Jeffrey, Bachman, Timothy N, Graumann, Johannes, Ruppert, Clemens, Guenther, Andreas, Schmoranzer, Mario, Grobs, Yann, Lemay, Sarah Eve, Tremblay, Eve, Breuils-Bonnet, Sandra, Boucherat, Olivier, Mora, Ana L, DeLisser, Horace, Zhao, Jing, Zhao, Yutong, Bonnet, Sébastien, Seeger, Werner, Pullamsetti, Soni S, and Goncharova, Elena A

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Lung, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Cardiovascular, Animals, Cell Cycle Proteins, Cell Proliferation, Cells, Cultured, Chromosomal Proteins, Non-Histone, Forkhead Transcription Factors, Hypertension, Pulmonary, Hypoxia, Mammals, Mechanistic Target of Rapamycin Complex 1, Mice, Myocytes, Smooth Muscle, Poly-ADP-Ribose Binding Proteins, Proteomics, Proto-Oncogene Proteins c-akt, Pulmonary Arterial Hypertension, Pulmonary Artery, Vascular Remodeling, animals, hypoxia, mice, proteomic, pulmonary artery, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

RationaleThe MSTs (mammalian Ste20-like kinases) 1/2 are members of the HIPPO pathway that act as growth suppressors in adult proliferative diseases. Pulmonary arterial hypertension (PAH) manifests by increased proliferation and survival of pulmonary vascular cells in small PAs, pulmonary vascular remodeling, and the rise of pulmonary arterial pressure. The role of MST1/2 in PAH is currently unknown.ObjectiveTo investigate the roles and mechanisms of the action of MST1 and MST2 in PAH.Methods and resultsUsing early-passage pulmonary vascular cells from PAH and nondiseased lungs and mice with smooth muscle-specific tamoxifen-inducible Mst1/2 knockdown, we found that, in contrast to canonical antiproliferative/proapoptotic roles, MST1/2 act as proproliferative/prosurvival molecules in human PAH pulmonary arterial vascular smooth muscle cells and pulmonary arterial adventitial fibroblasts and support established pulmonary vascular remodeling and pulmonary hypertension in mice with SU5416/hypoxia-induced pulmonary hypertension. By using unbiased proteomic analysis, gain- and loss-of function approaches, and pharmacological inhibition of MST1/2 kinase activity by XMU-MP-1, we next evaluated mechanisms of regulation and function of MST1/2 in PAH pulmonary vascular cells. We found that, in PAH pulmonary arterial adventitial fibroblasts, the proproliferative function of MST1/2 is caused by IL-6-dependent MST1/2 overexpression, which induces PSMC6-dependent downregulation of forkhead homeobox type O 3 and hyperproliferation. In PAH pulmonary arterial vascular smooth muscle cells, MST1/2 acted via forming a disease-specific interaction with BUB3 and supported ECM (extracellular matrix)- and USP10-dependent BUB3 accumulation, upregulation of Akt-mTORC1, cell proliferation, and survival. Supporting our in vitro observations, smooth muscle-specific Mst1/2 knockdown halted upregulation of Akt-mTORC1 in small muscular PAs of mice with SU5416/hypoxia-induced pulmonary hypertension.ConclusionsTogether, this study describes a novel proproliferative/prosurvival role of MST1/2 in PAH pulmonary vasculature, provides a novel mechanistic link from MST1/2 via BUB3 and forkhead homeobox type O to the abnormal proliferation and survival of pulmonary arterial vascular smooth muscle cells and pulmonary arterial adventitial fibroblasts, remodeling and pulmonary hypertension, and suggests new target pathways for therapeutic intervention.

Published
2022

14. Defining the clinical validity of genes reported to cause pulmonary arterial hypertension

Author

Callejo, Emily P., Day, Kristina M., Macaya, Daniela, Maldonado-Velez, Gabriel, Archer, Stephen L., Auckland, Kathryn, Austin, Eric D., Badagliacca, Roberto, Barberà, Joan-Albert, Belge, Catharina, Bogaard, Harm Jan, Bonnet, Sébastien, Boomars, Karin A., Boucherat, Olivier, Chakinala, Murali M., Condliffe, Robin, Damico, Rachel Lynn, Delcroix, Marion, Desai, Ankit A., Doboszynska, Anna, Elliott, C. Greg, Eyries, Melanie, Escribano Subías, Maria Pilar, Gall, Henning, Ghio, Stefano, Ghofrani, Ardeschir-Hossein, Grünig, Ekkehard, Hamid, Rizwan, Harbaum, Lars, Hassoun, Paul M., Hemnes, Anna R., Hinderhofer, Katrin, Howard, Luke S., Humbert, Marc, Kiely, David G., Langleben, David, Lawrie, Allan, Loyd, Jim E., Moledina, Shahin, Montani, David, Morrell, Nichols W., Nichols, William C., Olschewski, Andrea, Olschewski, Horst, Papa, Silvia, Pauciulo, Mike W., Provencher, Steve, Quarck, Rozenn, Rhodes, Christopher J., Scelsi, Laura, Seeger, Werner, Stewart, Duncan J., Sweatt, Andrew, Swietlik, Emilia M., Treacy, Carmen, Trembath, Richard C., Tura-Ceide, Olga, Vizza, Carmine Dario, Vonk Noordegraaf, Anton, Wilkins, Martin R., Zamanian, Roham T., Zateyshchikov, Dmitry, Welch, Carrie L., Aldred, Micheala A., Balachandar, Srimmitha, Dooijes, Dennis, Eichstaedt, Christina A., Gräf, Stefan, Houweling, Arjan C., Machado, Rajiv D., Pandya, Divya, Prapa, Matina, Shaukat, Memoona, Southgate, Laura, Tenorio-Castano, Jair, and Chung, Wendy K.

Published
2023
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21. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Author

Rhodes, Christopher J, Batai, Ken, Bleda, Marta, Haimel, Matthias, Southgate, Laura, Germain, Marine, Pauciulo, Michael W, Hadinnapola, Charaka, Aman, Jurjan, Girerd, Barbara, Arora, Amit, Knight, Jo, Hanscombe, Ken B, Karnes, Jason H, Kaakinen, Marika, Gall, Henning, Ulrich, Anna, Harbaum, Lars, Cebola, Inês, Ferrer, Jorge, Lutz, Katie, Swietlik, Emilia M, Ahmad, Ferhaan, Amouyel, Philippe, Archer, Stephen L, Argula, Rahul, Austin, Eric D, Badesch, David, Bakshi, Sahil, Barnett, Christopher, Benza, Raymond, Bhatt, Nitin, Bogaard, Harm J, Burger, Charles D, Chakinala, Murali, Church, Colin, Coghlan, John G, Condliffe, Robin, Corris, Paul A, Danesino, Cesare, Debette, Stéphanie, Elliott, C Gregory, Elwing, Jean, Eyries, Melanie, Fortin, Terry, Franke, Andre, Frantz, Robert P, Frost, Adaani, Garcia, Joe GN, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, J Simon R, Harley, John, He, Hua, Hill, Nicholas S, Hirsch, Russel, Houweling, Arjan C, Howard, Luke S, Ivy, Dunbar, Kiely, David G, Klinger, James, Kovacs, Gabor, Lahm, Tim, Laudes, Matthias, Machado, Rajiv D, Ross, Robert V MacKenzie, Marsolo, Keith, Martin, Lisa J, Moledina, Shahin, Montani, David, Nathan, Steven D, Newnham, Michael, Olschewski, Andrea, Olschewski, Horst, Oudiz, Ronald J, Ouwehand, Willem H, Peacock, Andrew J, Pepke-Zaba, Joanna, Rehman, Zia, Robbins, Ivan, Roden, Dan M, Rosenzweig, Erika B, Saydain, Ghulam, Scelsi, Laura, Schilz, Robert, Seeger, Werner, Shaffer, Christian M, Simms, Robert W, Simon, Marc, Sitbon, Olivier, Suntharalingam, Jay, Tang, Haiyang, Tchourbanov, Alexander Y, Thenappan, Thenappan, Torres, Fernando, Toshner, Mark R, Treacy, Carmen M, Noordegraaf, Anton Vonk, Waisfisz, Quinten, and Walsworth, Anna K

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Genetics, Human Genome, Lung, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotyping Techniques, HLA-DP alpha-Chains, HLA-DP beta-Chains, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Pulmonary Arterial Hypertension, Risk Assessment, SOXF Transcription Factors, Signal Transduction, Survival Analysis, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, US PAH Biobank Consortium, Public Health and Health Services, Other Medical and Health Sciences, Cardiovascular medicine and haematology, Clinical sciences
Abstract

BackgroundRare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.MethodsWe did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.FindingsA locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity.InterpretationThis is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.FundingUK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.

Published
2019

22. Kidney Biopsy Findings in Patients with SARS-CoV-2 Infection or After COVID-19 Vaccination

Author

de las Mercedes Noriega, Maria, Husain-Syed, Faeq, Wulf, Sonia, Csala, Benjamin, Krebs, Christian F., Jabs, Wolfram J., Zipfel, Peter F., Gröne, Hermann-Josef, Wiech, Thorsten, Aedtner, Frank, Bačinović, Mustafa, Bartel-Kuss, Susanne, Bauer, Alexander, Beige, Joachim, Birk, Horst-Walter, Böll, Bernhard, Brylka, Philipp, Clasen, Wolfgang, Dasdelen, Süha, Eicher, Maria-Magdalena, Elnaggar, Amr, Farid, Alexander, Francois, Johannes, Gerth, Jens, Helmke, Annette, Hepburn, Helen, Hollenbeck, Markus, Huber, Tobias B., Jennert, Birgit, Jüttner, Christoph, Khaled, Akel, Kobayashi, Kazuhiro, Koop, Monika, Kuczkowski, Kamil, Loyen, Martin, Mahmud, Maida, Marczynski, Cornelia, Meyer, Tobias N., Nitschke, Martin, Reiter, Michael A., Ronco, Claudio, Schleucher, Norbert, Schmerler, Diana, Schmidt, Elisa Alba, Schmidt, Rüdiger, Schmitz, Michael, Seeger, Werner, Selbach, Jochen, Sellin, Lorenz, Srugies, Fabian, Swiecicka, Agnieszka, von Vietinghoff, Sibylle, Weinberg, Clemens, Wenzel, Ulrich, and Werth, Stephan Christian

Published
2023
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23. Fibrocytes boost tumor-supportive phenotypic switches in the lung cancer niche via the endothelin system

Author

Weigert, Andreas, Zheng, Xiang, Nenzel, Alina, Turkowski, Kati, Günther, Stefan, Strack, Elisabeth, Sirait-Fischer, Evelyn, Elwakeel, Eiman, Kur, Ivan M., Nikam, Vandana S., Valasarajan, Chanil, Winter, Hauke, Wissgott, Alexander, Voswinkel, Robert, Grimminger, Friedrich, Brüne, Bernhard, Seeger, Werner, Pullamsetti, Soni Savai, and Savai, Rajkumar

Published
2022
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25. Maternal and perinatal obesity induce bronchial obstruction and pulmonary hypertension via IL-6-FoxO1-axis in later life

Author

Selle, Jaco, Dinger, Katharina, Jentgen, Vanessa, Zanetti, Daniela, Will, Johannes, Georgomanolis, Theodoros, Vohlen, Christina, Wilke, Rebecca, Kojonazarov, Baktybek, Klymenko, Oleksiy, Mohr, Jasmine, v. Koningsbruggen-Rietschel, Silke, Rhodes, Christopher J., Ulrich, Anna, Hirani, Dharmesh, Nestler, Tim, Odenthal, Margarete, Mahabir, Esther, Nayakanti, Sreenath, Dabral, Swati, Wunderlich, Thomas, Priest, James, Seeger, Werner, Dötsch, Jörg, Pullamsetti, Soni S., and Alejandre Alcazar, Miguel A.

Published
2022
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29. Author Correction: Deficiency of Axl aggravates pulmonary arterial hypertension via BMPR2

Author

Novoyatleva, Tatyana, Rai, Nabham, Kojonazarov, Baktybek, Veeroju, Swathi, Ben-Batalla, Isabel, Caruso, Paola, Shihan, Mazen, Presser, Nadine, Götz, Elsa, Lepper, Carina, Herpel, Sebastian, Manaud, Grégoire, Perros, Frédéric, Gall, Henning, Ghofrani, Hossein Ardeschir, Weissmann, Norbert, Grimminger, Friedrich, Wharton, John, Wilkins, Martin, Upton, Paul D., Loges, Sonja, Morrell, Nicholas W., Seeger, Werner, and Schermuly, Ralph T.

Published
2022
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31. GLI1+ cells are a source of repair-supportive mesenchymal cells (RSMCs) during airway epithelial regeneration

Author

Chu, Xuran, Lingampally, Arun, Moiseenko, Alena, Kheirollahi, Vahid, Vazquez-Armendariz, Ana Ivonne, Koepke, Janine, Khadim, Ali, Kiliaris, Georgios, Shahriari Felordi, Mahtab, Zabihi, Mahsa, Shalashova, Irina, Alexopoulos, Ioannis, Günther, Stefan, Lebrigand, Kevin, Truchi, Marin, Günther, Andreas, Braun, Thomas, Mari, Bernard, Samakovlis, Christos, Li, Xiaokun, Seeger, Werner, Herold, Susanne, Zhang, Jin-San, Bellusci, Saverio, and El Agha, Elie

Published
2022
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32. Immunogenicity and reactogenicity of homologous mRNA-based and vector-based SARS-CoV-2 vaccine regimens in patients receiving maintenance dialysis

Author

Karakizlis, Hristos, Nahrgang, Christian, Strecker, Kevin, Chen, Jiangping, Aly, Mostafa, Slanina, Heiko, Schüttler, Christian G., Esso, Isla, Wolter, Martin, Todorova, Darina, Jessen, Sönke, Adamik, Andrea, Ronco, Claudio, Seeger, Werner, Weimer, Rolf, Sester, Martina, Birk, Horst-Walter, and Husain-Syed, Faeq

Published
2022
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34. Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.

Author

Gräf, Stefan, Haimel, Matthias, Bleda, Marta, Hadinnapola, Charaka, Southgate, Laura, Li, Wei, Hodgson, Joshua, Liu, Bin, Salmon, Richard M, Southwood, Mark, Machado, Rajiv D, Martin, Jennifer M, Treacy, Carmen M, Yates, Katherine, Daugherty, Louise C, Shamardina, Olga, Whitehorn, Deborah, Holden, Simon, Aldred, Micheala, Bogaard, Harm J, Church, Colin, Coghlan, Gerry, Condliffe, Robin, Corris, Paul A, Danesino, Cesare, Eyries, Mélanie, Gall, Henning, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, J Simon R, Girerd, Barbara, Houweling, Arjan C, Howard, Luke, Humbert, Marc, Kiely, David G, Kovacs, Gabor, MacKenzie Ross, Robert V, Moledina, Shahin, Montani, David, Newnham, Michael, Olschewski, Andrea, Olschewski, Horst, Peacock, Andrew J, Pepke-Zaba, Joanna, Prokopenko, Inga, Rhodes, Christopher J, Scelsi, Laura, Seeger, Werner, Soubrier, Florent, Stein, Dan F, Suntharalingam, Jay, Swietlik, Emilia M, Toshner, Mark R, van Heel, David A, Vonk Noordegraaf, Anton, Waisfisz, Quinten, Wharton, John, Wort, Stephen J, Ouwehand, Willem H, Soranzo, Nicole, Lawrie, Allan, Upton, Paul D, Wilkins, Martin R, Trembath, Richard C, and Morrell, Nicholas W

Subjects
Humans, Genetic Predisposition to Disease, Transforming Growth Factor beta, Membrane Transport Proteins, Prognosis, Case-Control Studies, Signal Transduction, Gene Expression Regulation, Base Sequence, Mutation, Models, Molecular, Adult, Female, Male, Aquaporin 1, Bone Morphogenetic Protein Receptors, Type II, Adenosine Triphosphatases, Growth Differentiation Factors, SOXF Transcription Factors, HEK293 Cells, Familial Primary Pulmonary Hypertension, Whole Genome Sequencing, Bone Morphogenetic Protein Receptors, Type II, Models, Molecular
Abstract

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

Published
2018

35. Comparison of contemporary risk scores in all groups of pulmonary hypertension - a PVRI GoDeep meta-registry analysis

Author

Yogeswaran, Athiththan, primary, Gall, Henning, additional, Fünderich, Meike, additional, Wilkins, Martin R., additional, Howard, Luke, additional, Kiely, David G., additional, Lawrie, Allan, additional, Hassoun, Paul M., additional, Sirenklo, Yuriy, additional, Torbas, Olena, additional, Sweatt, Andrew J., additional, Zamanian, Roham T., additional, Williams, Paul G., additional, Frauendorf, Marlize, additional, Arvanitaki, Alexandra, additional, Giannakoulas, George, additional, Saleh, Khaled, additional, Sabbour, Hani, additional, Cajigas, Hector R., additional, Frantz, Robert, additional, Al Ghouleh, Imad, additional, Chan, Stephen Y., additional, Brittain, Evan, additional, Annis, Jeffrey S., additional, Pepe, Antonella, additional, Ghio, Stefano, additional, Orfanos, Stylianos, additional, Anthi, Anastasia, additional, Majeed, Raphael W., additional, Wilhelm, Jochen, additional, Ghofrani, Hossein Ardeschir, additional, Richter, Manuel J., additional, Grimminger, Friedrich, additional, Sahay, Sandeep, additional, Tello, Khodr, additional, Seeger, Werner, additional, Antoine, Tobiah, additional, Backofen, Achim, additional, Cannon, John, additional, Damonte, Victoria, additional, Echazarreta, Diego, additional, Eichstaedt, Christina, additional, Elwing, Jean, additional, Förster, Kai, additional, Gruenig, Ekkehard, additional, Hilgendorff, Anne, additional, Jose, Arun, additional, Junaeda, Ernesto, additional, Krieb, Philipp, additional, Marquardt, Kurt, additional, Osborn, Karen, additional, Pepke-Zaba, Johanna, additional, Tilea, Ioan, additional, and Varga, Andreea, additional

Published
2024
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36. Alveolar macrophage-expressed Plet1 is a driver of lung epithelial repair after viral pneumonia

Author

Pervizaj-Oruqaj, Learta, primary, Selvakumar, Balachandar, additional, Ferrero, Maximiliano Ruben, additional, Heiner, Monika, additional, Malainou, Christina, additional, Glaser, Rolf David, additional, Wilhelm, Jochen, additional, Bartkuhn, Marek, additional, Weiss, Astrid, additional, Alexopoulos, Ioannis, additional, Witte, Biruta, additional, Gattenlöhner, Stefan, additional, Vadász, István, additional, Morty, Rory Edward, additional, Seeger, Werner, additional, Schermuly, Ralph Theo, additional, Vazquez-Armendariz, Ana Ivonne, additional, and Herold, Susanne, additional

Published
2024
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37. Native Hepatic T1-Time as a Non-Invasive Predictor of Diastolic Dysfunction and a Monitoring Tool for Disease Progression and Treatment Response in Patients with Pulmonary Hypertension

Author

Kremer, Nils, primary, Roller, Fritz, additional, Kremer, Sarah, additional, Schäfer, Simon, additional, Kryvenko, Vitalii, additional, Rako, Zvonimir, additional, Brito da Rocha, Bruno, additional, Yogeswaran, Athiththan, additional, Seeger, Werner, additional, Guth, Stefan, additional, Wiedenroth, Christoph, additional, and Tello, Khodr, additional

Published
2024
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38. The Role of the Redox Enzyme p66Shc in Biological Aging of the Lung

Author

Castro, Claudia F. Garcia, primary, Nardiello, Claudio, primary, Hadzic, Stefan, primary, Kojonazarov, Baktybek, primary, Kraut, Simone, primary, Gierhardt, Mareike, primary, Schäffer, Julia, primary, Bednorz, Mariola, primary, Quanz, Karin, primary, Heger, Jacqueline, primary, Korfei, Martina, primary, Wilhelm, Jochen, primary, Hecker, Matthias, primary, Bartkuhn, Marek, primary, Arnhold, Stefan, primary, Guenther, Andreas, primary, Seeger, Werner, primary, Schulz, Rainer, primary, Weissmann, Norbert, primary, Sommer, Natascha, primary, and Pak, Oleg, primary

Published
2024
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39. Abstract 15564: Transcriptional Profiling Unveils New Molecular Subgroups of Adaptive and Maladaptive Right Ventricular Remodeling in Pulmonary Hypertension

Author

Khassafi, Fatemeh, Chelladurai, Prakash, Nayakanti, Sreenath R, Martineau, Sandra, Tello, Khodr, Sommer, Natascha, Omura, Junichi, Breuils Bonnet, Sandra, Kuenne, Carsten, Guenther, Stefan, potus, francois, Boucherat, Olivier, Provencher, Steeve, Savai, Rajkumar, Seeger, Werner, Looso, Mario, Bonnet, Sebastien, and Savai Pullamsetti, Soni

Published
2022
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44. Microscopic computed tomography with AI-CNN-powered image analysis: the path to phenotype bleomycin-induced lung injury.

Author

Henneke, Ingrid, Pilz, Christina, Wilhelm, Jochen, Alexopoulos, Ioannis, Ezaddoustdar, Aysan, Mukhametshina, Regina, Weissmann, Norbert, Ghofrani, Hossein Ardeschir, Grimminger, Friedrich, Seeger, Werner, Schermuly, Ralph T., Wygrecka, Malgorzata, and Kojonazarov, Baktybek

Subjects
LUNGS, COMPUTED tomography, PATH analysis (Statistics), IMAGE analysis, LUNG injuries, PHENOTYPES
Abstract

Bleomycin (BLM)-induced lung injury in mice is a valuable model for investigating the molecular mechanisms that drive inflammation and fibrosis and for evaluating potential therapeutic approaches to treat the disease. Given high variability in the BLM model, it is critical to accurately phenotype the animals in the course of an experiment. In the present study, we aimed to demonstrate the utility of microscopic computed tomography (µCT) imaging combined with an artificial intelligence (AI)-convolutional neural network (CNN)-powered lung segmentation for rapid phenotyping of BLM mice. µCT was performed in freely breathing C57BL/6J mice under isoflurane anesthesia on days 7 and 21 after BLM administration. Terminal invasive lung function measurement and histological assessment of the left lung collagen content were conducted as well. µCT image analysis demonstrated gradual and time-dependent development of lung injury as evident by alterations in the lung density, air-to-tissue volume ratio, and lung aeration in mice treated with BLM. The right and left lung were unequally affected. µCT-derived parameters such as lung density, air-to-tissue volume ratio, and nonaerated lung volume correlated well with the invasive lung function measurement and left lung collagen content. Our study demonstrates the utility of AI-CNN-powered µCT image analysis for rapid and accurate phenotyping of BLM mice in the course of disease development and progression. NEW & NOTEWORTHY: Microscopic computed tomography (µCT) imaging combined with an artificial intelligence (AI)-convolutional neural network (CNN)-powered lung segmentation is a rapid and powerful tool for noninvasive phenotyping of bleomycin mice over the course of the disease. This, in turn, allows earlier and more reliable identification of therapeutic effects of new drug candidates, ultimately leading to the reduction of unnecessary procedures in animals in pharmacological research. [ABSTRACT FROM AUTHOR]

Published
2024
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45. Physiological mechanisms behind respiratory variations in right atrial pressure in pulmonary hypertension.

Author

Yogeswaran, Athiththan, da Rocha, Bruno Brito, Rako, Zvonimir A., Kaufmann, Samuel J., Schäfer, Simon, Kremer, Nils, Ghofrani, Hossein Ardeschir, Seeger, Werner, and Tello, Khodr

Subjects
PULMONARY hypertension, VENTILATION, PHYSIOLOGY, RECEIVER operating characteristic curves, TRICUSPID valve insufficiency, DISEASE risk factors
Abstract

Impaired respiratory variation of right atrial pressure (RAP) in severe pulmonary hypertension (PH) suggests difficulty tolerating increased preload during inspiration. Our study explores whether this impairment links to specific factors: right ventricular (RV) diastolic function, elevated RV afterload, systolic RV function, or RV-pulmonary arterial (PA) coupling. We retrospectively evaluated respiratory RAP variation in all participants enrolled in the EXERTION study. Impaired respiratory variation was defined as end-expiratory RAP − end-inspiratory RAP ≤ 2 mm Hg. RV function and afterload were evaluated using conductance catheterization. Impaired diastolic RV function was defined as end-diastolic elastance (Eed) ≥ median (0.19 mm Hg/mL). Seventy-five patients were included; PH was diagnosed in 57 patients and invasively excluded in 18 patients. Of the 75 patients, 31 (41%) had impaired RAP variation, which was linked with impaired RV systolic function and RV-PA coupling and increased tricuspid regurgitation and Eed as compared to patients with preserved RAP variation. In backward regression, RAP variation associated only with Eed. RAP variation but not simple RAP identified impaired diastolic RV function (area under the receiver operating characteristic curve [95% confidence interval]: 0.712 [0.592, 0.832] and 0.496 [0.358, 0.634], respectively). During exercise, patients with impaired RAP variation experienced greater RV dilatation and reduced diastolic reserve and cardiac output/index compared with patients with preserved RAP variation. Preserved RAP variation was associated with a better prognosis than impaired RAP variation based on the 2022 European Society of Cardiology/European Respiratory Society risk score (chi-square P = 0.025) and survival free from clinical worsening (91% vs 71% at 1 year and 79% vs 50% at 2 years [log-rank P = 0.020]; hazard ratio: 0.397 [95% confidence interval: 0.178, 0.884]). Subgroup analyses in patients with group 1 and group 4 PH demonstrated consistent findings with those observed in the overall study cohort. Respiratory RAP variations reflect RV diastolic function, are independent of RV-PA coupling or tricuspid regurgitation, are associated with exercise-induced haemodynamic changes, and are prognostic in PH. Trial registration. NCT04663217. [ABSTRACT FROM AUTHOR]

Published
2024
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46. Data Integration for a Global Deep-Phenotyping Registry for Pulmonary Hypertension – Lessons Learned.

Author

FUENDERICH, Meike T., KRIEB, Philipp, SEEGER, Werner, and MAJEED, Raphael W.

Abstract

The integration of data from various healthcare centers into disease registries is pivotal for facilitating collaborative research and enhancing clinical insights. In this study, we investigate the integration process of existing registries into the PVRI GoDeep meta-registry, focusing on the complexities and challenges encountered. We detail the integration process, including data transformation, mapping updates, and feedback mechanisms. Our findings underscore the importance of standardized processes and proactive communication in addressing data quality issues, ultimately enhancing the reliability and trustworthiness of metaregistry data. Through careful harmonization of the data and transparent documentation of data processing, we pave the way for leveraging registry data to drive advancements in pulmonary hypertension research and patient care. [ABSTRACT FROM AUTHOR]

Published
2024
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47. Hypoxia-inducible factor signaling in pulmonary hypertension

Author

Pullamsetti, Soni Savai, Mamazhakypov, Argen, Weissmann, Norbert, Seeger, Werner, and Savai, Rajkumar

Subjects
Pulmonary hypertension -- Genetic aspects -- Development and progression, Oxygen consumption (Metabolism) -- Genetic aspects -- Health aspects, Transcription factors -- Physiological aspects -- Health aspects, Health care industry
Abstract

Pulmonary hypertension (PH) is characterized by pulmonary artery remodeling that can subsequently culminate in right heart failure and premature death. Emerging evidence suggests that hypoxia-inducible factor (HIF) signaling plays a fundamental and pivotal role in the pathogenesis of PH. This Review summarizes the regulation of HIF isoforms and their impact in various PH subtypes, as well as the elaborate conditional and cell-specific knockout mouse studies that brought the role of this pathway to light. We also discuss the current preclinical status of pan- and isoform-selective HIF inhibitors, and propose new research areas that may facilitate HIF isoform-specific inhibition as a novel therapeutic strategy for PH and right heart failure., HIF signaling and biology The transcription factor hypoxia-inducible factor (HIF) is a master regulator of oxygen homeostasis that acts as a heterodimeric complex composed of the oxygen-sensitive [alpha] subunit (HIF-[alpha]; [...]

Published
2020
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48. Data from Metastasis-Associated Protein 2 Represses NF-κB to Reduce Lung Tumor Growth and Inflammation

Author

El-Nikhely, Nefertiti, primary, Karger, Annika, primary, Sarode, Poonam, primary, Singh, Indrabahadur, primary, Weigert, Andreas, primary, Wietelmann, Astrid, primary, Stiewe, Thorsten, primary, Dammann, Reinhard, primary, Fink, Ludger, primary, Grimminger, Friedrich, primary, Barreto, Guillermo, primary, Seeger, Werner, primary, Pullamsetti, Soni S., primary, Rapp, Ulf R., primary, and Savai, Rajkumar, primary

Published
2023
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49. Supplementary Data from Metastasis-Associated Protein 2 Represses NF-κB to Reduce Lung Tumor Growth and Inflammation

Author

El-Nikhely, Nefertiti, primary, Karger, Annika, primary, Sarode, Poonam, primary, Singh, Indrabahadur, primary, Weigert, Andreas, primary, Wietelmann, Astrid, primary, Stiewe, Thorsten, primary, Dammann, Reinhard, primary, Fink, Ludger, primary, Grimminger, Friedrich, primary, Barreto, Guillermo, primary, Seeger, Werner, primary, Pullamsetti, Soni S., primary, Rapp, Ulf R., primary, and Savai, Rajkumar, primary

Published
2023
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50. Postnatal FGFR-signaling establishes gradients of secretory cell identities along the proximal-distal axis of the lung airways

Author

Sountoulidis, Alexandros, primary, Firsova, Alexandra B., additional, Liontos, Andreas, additional, Theelke, Jonas, additional, Koepke, Janine, additional, Millar-Büchner, Pamela, additional, Mannerås-Holm, Louise, additional, Björklund, Åsa, additional, Fysikopoulos, Athanasios, additional, Gaengel, Konstantin, additional, Bäckhed, Fredrik, additional, Betsholtz, Christer, additional, Seeger, Werner, additional, Bellusci, Saverio, additional, and Samakovlis, Christos, additional

Published
2023
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