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

Author

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

Published
2024
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3. 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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4. 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

5. 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

6. 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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7. 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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9. 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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13. 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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15. 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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16. Precision cardiac monitoring: algorithmic real‐time assessment of right ventricular function in pulmonary hypertension.

Author

Kremer, Nils, Glocker, Felix, Schäfer, Simon, Rako, Zvonimir, Yogeswaran, Athiththan, Seeger, Werner, Hopf, Hans‐Bernd, and Tello, Khodr

Subjects
CARDIAC magnetic resonance imaging, INFORMED consent (Medical law), DIASTOLIC blood pressure, SYSTOLIC blood pressure, PULMONARY hypertension
Abstract

This article discusses a new algorithm for assessing right ventricular function in patients with pulmonary hypertension. The algorithm simplifies the calculation of right ventricular ejection fraction (RVEF) by using only three points on the right ventricular pressure curve. The algorithm was validated using retrospective data from 99 patients and showed good correlation with conventional methods. It was also able to accurately track changes in RVEF over time in a prospective analysis. While the algorithm may not be as precise as cardiac magnetic resonance imaging, it provides a valuable tool for clinicians to monitor right ventricular function in real-time and make informed decisions in managing patients with pulmonary hypertension. [Extracted from the article]

Published
2024
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17. 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

18. 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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21. Air travel in patients suffering from pulmonary hypertension—A prospective, multicentre study.

Author

Yogeswaran, Athiththan, Grimminger, Jan, Tello, Khodr, Becker, Lukas, Seeger, Werner, Grimminger, Friedrich, Sommer, Natascha, Ghofrani, Hossein A., Lange, Tobias J., Stadler, Stefan, Olsson, Karen, Kamp, Jan C., Rosenkranz, Stephan, Gerhardt, Felix, Milger, Katrin, Barnikel, Michaela, Ulrich, Silvia, Saxer, Stéphanie, Grünig, Ekkehard, and Harutynova, Satenik

Subjects
PULMONARY arterial hypertension, AIR travel safety, ADVERSE health care events, PULMONARY hypertension, MEDICAL consultation
Abstract

The PEGASUS study is the first multicentric and prospective assessment of the safety of air travel flying in pulmonary hypertension (PH) (NCT03051763). Data of air travel from 60 patients with PH was available. No severe adverse events occurred. Nine patients self‐reported mild adverse events during flight (13%), while after landing, 12 patients reported events (20%). Solely one patient (2%) had an adverse event leading to medical consultation. In patients with PH and World Health Organization functional classes II and III, air travel was safe. [ABSTRACT FROM AUTHOR]

Published
2024
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22. 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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23. 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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25. 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
2021
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26. Microenvironmental Th9 and Th17 lymphocytes induce metastatic spreading in lung cancer

Author

Salazar, Ylia, Zheng, Xiang, Brunn, David, Raifer, Hartmann, Picard, Felix, Zhang, Yajuan, Winter, Hauke, Guenther, Stefan, Weigert, Andreas, Weigmann, Benno, Dumoutier, Laure, Renauld, Jean-Christophe, Waisman, Ari, Schmall, Anja, Tufman, Amanda, Fink, Ludger, Brune, Bernhard, Bopp, Tobias, Grimminger, Friedrich, Seeger, Werner, Pullamsetti, Soni Savai, Huber, Magdalena, and Savai, Rajkumar

Subjects
Lung cancer -- Development and progression, B cells, Cancer research, Stem cells, Cancer metastasis -- Development and progression, Health care industry
Abstract

Immune microenvironment plays a critical role in lung cancer control versus progression and metastasis. In this investigation, we explored the effect of tumor-infiltrating lymphocyte subpopulations on lung cancer biology by studying in vitro cocultures, in vivo mouse models, and human lung cancer tissue. Lymphocyte conditioned media (CM) induced epithelial-mesenchymal transition (EMT) and migration in both primary human lung cancer cells and cell lines. Correspondingly, major accumulation of Th9 and Th17 cells was detected in human lung cancer tissue and correlated with poor survival. Coculturing lung cancer cells with Th9/Th17 cells or exposing them to the respective CM induced EMT in cancer cells and modulated the expression profile of genes implicated in EMT and metastasis. These features were reproduced by the signatory cytokines IL-9 and IL-17, with gene regulatory profiles evoked by these cytokines partly overlapping and partly complementary. Coinjection of Th9/Th17 cells with tumor cells in WT, [Rag1.sup.-/-], [Il9r.sup.-/-], and [Ilra.sup.-/-] mice altered tumor growth and metastasis. Accordingly, inhibition of IL-9 or IL-17 cytokines by neutralizing antibodies decreased EMT and slowed lung cancer progression and metastasis. In conclusion, Th9 and Th17 lymphocytes induce lung cancer cell EMT, thereby promoting migration and metastatic spreading and offering potentially novel therapeutic strategies., Introduction Lung cancer is the leading cause of cancer mortality worldwide, accounting for up to 19% of all cancer-related deaths. Numbers of deaths due to lung cancer are even greater [...]

Published
2020
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30. Case Report: Durable therapy response to Osimertinib in rare EGFR Exon 18 mutated NSCLC

Author

Cekay, Michael, primary, Arndt, Philipp F., additional, Dumitrascu, Rio, additional, Savai, Rajkumar, additional, Braeuninger, Andreas, additional, Gattenloehner, Stefan, additional, Steiner, Dagmar, additional, Roller, Fritz, additional, Tello, Khodr, additional, Hattar, Katja, additional, Seeger, Werner, additional, Sibelius, Ulf, additional, Grimminger, Friedrich, additional, and Eul, Bastian, additional

Published
2023
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31. Changes in Doppler‐Derived Kidney Venous Flow and Adverse Cardiorenal Outcomes in Patients With Heart Failure

Author

Husain‐Syed, Faeq, primary, Singam, Narayana Sarma V., additional, Viehman, Jason K., additional, Vaughan, Lisa, additional, Bauer, Pascal, additional, Gall, Henning, additional, Tello, Khodr, additional, Richter, Manuel J., additional, Yogeswaran, Athiththan, additional, Romero‐González, Gregorio, additional, Rosner, Mitchell H., additional, Ronco, Claudio, additional, Assmus, Birgit, additional, Ghofrani, Hossein Ardeschir, additional, Seeger, Werner, additional, Birk, Horst‐Walter, additional, and Kashani, Kianoush B., additional

Published
2023
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32. ADPGK‐AS1 long noncoding RNA switches macrophage metabolic and phenotypic state to promote lung cancer growth

Author

Karger, Annika, primary, Mansouri, Siavash, additional, Leisegang, Matthias S, additional, Weigert, Andreas, additional, Günther, Stefan, additional, Kuenne, Carsten, additional, Wittig, Ilka, additional, Zukunft, Sven, additional, Klatt, Stephan, additional, Aliraj, Blerina, additional, Klotz, Laura V, additional, Winter, Hauke, additional, Mahavadi, Poornima, additional, Fleming, Ingrid, additional, Ruppert, Clemens, additional, Witte, Biruta, additional, Alkoudmani, Ibrahim, additional, Gattenlöhner, Stefan, additional, Grimminger, Friedrich, additional, Seeger, Werner, additional, Pullamsetti, Soni Savai, additional, and Savai, Rajkumar, additional

Published
2023
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35. Echocardiographic evaluation of right ventricular diastolic function in pulmonary hypertension

Author

Yogeswaran, Athiththan, primary, Rako, Zvonimir A., additional, Yildiz, Selin, additional, Ghofrani, Hossein Ardeschir, additional, Seeger, Werner, additional, Brito da Rocha, Bruno, additional, Gall, Henning, additional, Kremer, Nils C., additional, Douschan, Philipp, additional, Papa, Silvia, additional, Vizza, Carmine Dario, additional, Filomena, Domenico, additional, Tedford, Ryan J., additional, Naeije, Robert, additional, Richter, Manuel J., additional, Badagliacca, Roberto, additional, and Tello, Khodr, additional

Published
2023
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36. Echocardiographic pressure–strain loop‐derived stroke work of the right ventricle: validation against the gold standard

Author

Richter, Manuel J., primary, Douschan, Philipp, additional, Fortuni, Federico, additional, Gall, Henning, additional, Ghofrani, Hossein A., additional, Keranov, Stanislav, additional, Kremer, Nils, additional, Kriechbaum, Steffen D., additional, Rako, Zvonimir A., additional, Rieth, Andreas J., additional, da Rocha, Bruno Brito, additional, Seeger, Werner, additional, Zedler, Daniel, additional, Yildiz, Selin, additional, Yogeswaran, Athiththan, additional, and Tello, Khodr, additional

Published
2023
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37. Evaluation of diagnostic accuracy of dual-energy computed tomography in patients with chronic thromboembolic pulmonary hypertension compared to V/Q-SPECT and pulmonary angiogram

Author

Schüssler, Armin, primary, Lug, Quirin, additional, Kremer, Nils, additional, Harth, Sebastian, additional, Kriechbaum, Steffen D., additional, Richter, Manuel J., additional, Guth, Stefan, additional, Wiedenroth, Christoph B., additional, Tello, Khodr, additional, Steiner, Dagmar, additional, Seeger, Werner, additional, Krombach, Gabriele Anja, additional, and Roller, Fritz Christian, additional

Published
2023
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38. The HDAC2-SP1 axis orchestrates pro-tumor macrophage polarization

Author

Zheng, Xiang, primary, Sarode, Poonam, additional, Weigert, Andreas, additional, Turkowski, Kati, additional, Chelladurai, Prakash, additional, Günther, Stefan, additional, Kuenne, Carsten, additional, Winter, Hauke, additional, Stenzinger, Albrecht, additional, Reu, Simone, additional, Grimminger, Friedrich, additional, Stiewe, Thorsten, additional, Seeger, Werner, additional, Pullamsetti, Soni Savai., additional, and Savai, Rajkumar, additional

Published
2023
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39. Estimated plasma volume status: association with congestion, cardiorenal syndrome and prognosis in precapillary pulmonary hypertension

Author

Yogeswaran, Athiththan, primary, Richter, Manuel J., additional, Husain-Syed, Faeq, additional, Rako, Zvonimir, additional, Sommer, Natascha, additional, Grimminger, Friedrich, additional, Seeger, Werner, additional, Ghofrani, Hossein Ardeschir, additional, Gall, Henning, additional, and Tello, Khodr, additional

Published
2023
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43. Classical IL-6 signaling: a promising therapeutic target for pulmonary arterial hypertension

Author

Pullamsetti, Soni Savai, Seeger, Werner, and Savai, Rajkumar

Subjects
Pulmonary hypertension -- Prognosis -- Health aspects -- Development and progression -- Care and treatment, Interleukin-6 -- Physiological aspects -- Health aspects, Health care industry
Abstract

Current therapies for pulmonary arterial hypertension (PAH) provide symptomatic relief and improve prognosis but fall short of improving long-term survival. There is emerging evidence for a role of inflammatory mediators, primarily IL-6, in the pathogenesis of PAH. However, the mechanisms by which IL-6 potentially affects PAH are unknown. In this issue of the JCI, Tamura, Phan, and colleagues identified ectopic upregulation of the membrane-bound IL-6 receptor (IL6R), indicating classical IL-6 signaling in the smooth muscle layer of remodeled vessels in human and experimental PAH. They performed a series of in vitro and in vivo experiments that provide deeper insights into the mechanisms of classical IL-6 signaling and propose interventions directed against IL6R as a potential therapeutic strategy for PAH., IL-6 signaling in pulmonary hypertension IL-6 is a pleiotropic cytokine with a wide range of biologic activities in immune regulation, hematopoiesis, and inflammation, as well as metabolic, proliferative, and regenerative [...]

Published
2018
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44. Targeting Wnt-ß-Catenin-FOSL Signaling Ameliorates Right Ventricular Remodeling

Author

Nayakanti, Sreenath Reddy, primary, Friedrich, Aleksandra, additional, Sarode, Poonam, additional, Jafari, Leili, additional, Maroli, Giovanni, additional, Boehm, Mario, additional, Bourgeois, Alice, additional, Grobs, Yann, additional, Khassafi, Fatemeh, additional, Kuenne, Carsten, additional, Guenther, Stefan, additional, Dabral, Swati, additional, Wilhelm, Jochen, additional, Weiss, Astrid, additional, Wietelmann, Astrid, additional, Kojonazarov, Baktybek, additional, Janssen, Wiebke, additional, Looso, Mario, additional, de Man, Frances, additional, Provencher, Steeve, additional, Tello, Khodr, additional, Seeger, Werner, additional, Bonnet, Sebastien, additional, Savai, Rajkumar, additional, Schermuly, Ralph T., additional, and Pullamsett, Soni Savai, additional

Published
2023
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45. Value of Right and Left Ventricular T1 and T2 Blood Pool Mapping in Patients with Chronic Thromboembolic Hypertension before and after Balloon Pulmonary Angioplasty

Author

Roller, Fritz C., primary, Schüßler, Armin, additional, Kremer, Nils, additional, Harth, Sebastian, additional, Kriechbaum, Steffen D., additional, Wiedenroth, Christoph B., additional, Guth, Stefan, additional, Breithecker, Andreas, additional, Richter, Manuel, additional, Tello, Khodr, additional, Seeger, Werner, additional, Mayer, Eckhard, additional, and Krombach, Gabriele A., additional

Published
2023
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46. Echocardiographic evaluation of right ventricular diastolic function in pulmonary hypertension

Author

Yogeswaran, Athiththan, Rako, Zvonimir, Yildiz, Selin, Ghofrani, Hossein Ardeschir, Seeger, Werner, da Rocha, Bruno Brito, Gall, H., Kremer, Nils, Douschan, Philipp, Papa, Silvia, Vizza, Carmine Dario, Filomena, Domenico, Tedford, Ryan R.J., Naeije, Robert, Richter, Manuel Jonas, Badagliacca, Roberto, Tello, Khodr, Yogeswaran, Athiththan, Rako, Zvonimir, Yildiz, Selin, Ghofrani, Hossein Ardeschir, Seeger, Werner, da Rocha, Bruno Brito, Gall, H., Kremer, Nils, Douschan, Philipp, Papa, Silvia, Vizza, Carmine Dario, Filomena, Domenico, Tedford, Ryan R.J., Naeije, Robert, Richter, Manuel Jonas, Badagliacca, Roberto, and Tello, Khodr

Abstract

Background Right ventricular (RV) diastolic dysfunction may be prognostic in pulmonary hypertension (PH). However, its assessment is complex and relies on conductance catheterisation. We aimed to evaluate echocardiography-based parameters as surrogates of RV diastolic function, provide validation against the gold standard, end-diastolic elastance (Eed), and define the prognostic impact of echocardiography-derived RV diastolic dysfunction. Methods Patients with suspected PH who underwent right heart catheterisation including conductance catheterisation were prospectively recruited. In this study population, an echocardiography-based RV diastolic function surrogate was derived. Survival analyses were performed in patients with precapillary PH in the Giessen PH Registry, with external validation in patients with pulmonary arterial hypertension at Sapienza University (Rome). Results In the derivation cohort (n=61), the early/late diastolic tricuspid inflow velocity ratio (E/A) and early tricuspid inflow velocity/early diastolic tricuspid annular velocity ratio (E/e′) did not correlate with Eed (p>0.05). Receiver operating characteristic analysis revealed a large area under the curve (AUC) for the peak lateral tricuspid annulus systolic velocity/right atrial area index ratio (S′/RAAi) to detect elevated Eed (AUC 0.913, 95% confidence interval (CI) 0.839–0.986) and elevated end-diastolic pressure (AUC 0.848, 95% CI 0.699–0.998) with an optimal threshold of 0.81 m2·s−1·cm−1. Subgroup analyses demonstrated a large AUC in patients with preserved RV systolic function (AUC 0.963, 95% CI 0.882– 1.000). Survival analyses confirmed the prognostic relevance of S′/RAAi in the Giessen PH Registry (n=225) and the external validation cohort (n=106). Conclusions Our study demonstrates the usefulness of echocardiography-derived S′/RAAi for noninvasive assessment of RV diastolic function and prognosis in PH., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2023

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