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2. Proteomic Prediction and Renin Angiotensin Aldosterone System Inhibition Prevention Of Early Diabetic nephRopathy In TYpe 2 Diabetic Patients With Normoalbuminuria (PRIORITY)

Author

Mosaiques Diagnostics GmbH, University Medical Center Groningen, University of Glasgow, Istituto Di Ricerche Farmacologiche Mario Negri, Univerzita Karlova v Praze, Geniko Nosokomeio Athinas Ippokrateio, Institut Klinické a Experimentální Mediciny Praze, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Klinikum St. Georg Leipzig, Cyril and Methodius University in Skopje, Hannover Clinical Trial Center, European Commission, Diabetes Vascular Research Foundation Hoogeveen, Universitair Ziekenhuis Gent, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Stichting VUMC, Diabetologen Hessen, and Peter Rossing, Professor, Chief Physician, MD, DMSc

Published
2018

3. A Drug Repurposing Pipeline Based on Bladder Cancer Integrated Proteotranscriptomics Signatures

Author

Mokou, Marika [collaborator], Mosaiques Diagnostics [research center], Fonds National de la Recherche - FnR [sponsor], Eurostars - EUREKA [sponsor], Narayanasamy, Shaman, Stroggilos, Rafael, Balaur, Irina-Afrodita, Vlahou, Antonia, Mischak, Harald, Frantzi, Maria, Mokou, Marika [collaborator], Mosaiques Diagnostics [research center], Fonds National de la Recherche - FnR [sponsor], Eurostars - EUREKA [sponsor], Narayanasamy, Shaman, Stroggilos, Rafael, Balaur, Irina-Afrodita, Vlahou, Antonia, Mischak, Harald, and Frantzi, Maria

Abstract

Delivering better care for patients with bladder cancer (BC) necessitates the development of novel therapeutic strategies that address both the high disease heterogeneity and the limitations of the current therapeutic modalities, such as drug low efficacy and patient resistance acquisition. Drug repurposing is a cost-effective strategy that targets the reuse of existing drugs for new therapeutic purposes. Such a strategy could open new avenues toward more effective BC treatment. BC patients' multi-omics signatures can be used to guide the investigation of existing drugs that show an effective therapeutic potential through drug repurposing. In this book chapter, we present an integrated multilayer approach that includes cross-omics analyses from publicly available transcriptomics and proteomics data derived from BC tissues and cell lines that were investigated for the development of disease-specific signatures. These signatures are subsequently used as input for a signature-based repurposing approach using the Connectivity Map (CMap) tool. We further explain the steps that may be followed to identify and select existing drugs of increased potential for repurposing in BC patients.

Published
2023

6. A universal predictive and mechanistic urinary peptide signature in acute kidney injury

Author

Piedrafita, Alexis, Siwy, Justyna, Klein, Julie, Akkari, Amal, Amaya-Garrido, Ana, Mebazaa, Alexandre, Sanz, Anna Belen, Breuil, Benjamin, Montero Herrero, Laura, Marcheix, Bertrand, Depret, François, Fernandez, Lucie, Tardif, Elsa, Minville, Vincent, Alves, Melinda, Metzger, Jochen, Grunenwald, Etienne, Feuillet, Guylène, Buléon, Marie, Brunet, Manon, Mayeur, Nicolas, Casemayou, Audrey, Labaste, François, Grossac, Julia, Mischak, Harald, Ortiz, Alberto, Gazut, Stéphane, Schanstra, Joost, Faguer, Stanislas, Département de Néphrologie et Transplantation d'organes [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut des Maladies Métaboliques et Cardiovasculaires, INSERM, Université Paul Sabatier, UMR 1297-I2MC, Toulouse, France, Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Laboratoire Sciences des Données et de la Décision (LS2D), Département Métrologie Instrumentation & Information (DM2I), Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut des Humanités numériques (IDHN), Equipes Traitement de l'Information et Systèmes (ETIS - UMR 8051), Ecole Nationale Supérieure de l'Electronique et de ses Applications (ENSEA)-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY)-Ecole Nationale Supérieure de l'Electronique et de ses Applications (ENSEA)-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY)-Lexiques, Textes, Discours, Dictionnaire - Centre Jean Pruvost (LT2D), CY Cergy Paris Université (CY)-CY Cergy Paris Université (CY)-Laboratoire Mobilités, Réseaux, Territoires, Environnements (MRTE - EA 4112), CY Cergy Paris Université (CY)-CY Cergy Paris Université (CY)-Laboratoire AGORA (AGORA - EA 7392), CY Cergy Paris Université (CY)-CY Cergy Paris Université (CY), Hôpitaux Universitaires Saint-Louis, Lariboisière, Fernand-Widal, Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Service Anesthésie - Hôpital des enfants [CHU Toulouse], Pôle Anesthésie Réanimation [CHU de Toulouse], Mosaiques Diagnostics (GmbH), Mosaique Diagnostics, Service Chirurgie Cardio-Vasculaire [CHU Toulouse] (CCV), Pôle Cardiovasculaire et Métabolique [CHU Toulouse], French National Institute of Health and Medical Research, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), ANR‐18‐PERM‐0003, and ANR-21-CE14-0013,CALPROTECT,Rôle de la calprotectine dans la calcification vasculaire associée à l'insuffisance rénale(2021)

Subjects
kidney, classification, peptide signature, statistical analysis, [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], biomarker, acute kidney injury (AKI), signal processing, Critical Care and Intensive Care Medicine
Abstract

Background The delayed diagnosis of acute kidney injury (AKI) episodes and the lack of specificity of current single AKI biomarkers hamper its management. Urinary peptidome analysis may help to identify early molecular changes in AKI and grasp its complexity to identify potential targetable molecular pathways. Methods In derivation and validation cohorts totalizing 1170 major cardiac bypass surgery patients and in an external cohort of 1569 intensive care unit (ICU) patients, a peptide-based score predictive of AKI (7-day KDIGO classification) was developed, validated, and compared to the reference biomarker urinary NGAL and NephroCheck and clinical scores. Results A set of 204 urinary peptides derived from 48 proteins related to hemolysis, inflammation, immune cells trafficking, innate immunity, and cell growth and survival was identified and validated for the early discrimination (p p p Conclusions An overarching AKI physiopathology-driven urinary peptide signature shows significant promise for identifying, at an early stage, patients who will progress to AKI and thus to develop tailored treatments for this frequent and life-threatening condition. Performance of the urine peptide signature is as high as or higher than that of single biomarkers but adds mechanistic information that may help to discriminate sub-phenotypes of AKI offering new therapeutic avenues.

Published
2022
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7. Haploinsufficiency of the mouse Tshz3 gene leads to kidney defects

Author

Irene Sanchez-Martin, Pedro Magalhães, Parisa Ranjzad, Ahmed Fatmi, Fabrice Richard, Thien Phong Vu Manh, Andrew J Saurin, Guylène Feuillet, Colette Denis, Adrian S Woolf, Joost P Schanstra, Petra Zürbig, Xavier Caubit, Laurent Fasano, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Mosaiques Diagnostics GmbH [Hannover, Germany], Mosaiques Diagnostics and Therapeutics AG [Hannover, Germany], Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 642937, ANR-17-CE16-0030-01 'TSHZ3inASD', Medical Research Council project grant (MR/T016809/1), Kids Kidney Research/Kidney Research UK project grant (2010), ANR-17-CE16-0030,TSHZ3inASD,Rôle de TSHZ3 dans le développement et la fonction de systèmes neuronaux impliqués dans les troubles du spectre autistique(2017), Fasano, Laurent, Rôle de TSHZ3 dans le développement et la fonction de systèmes neuronaux impliqués dans les troubles du spectre autistique - - TSHZ3inASD2017 - ANR-17-CE16-0030 - AAPG2017 - VALID, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Toulouse (UT)

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, urogenital system, Autism Spectrum Disorder, Endothelial Cells, General Medicine, [SDV.GEN] Life Sciences [q-bio]/Genetics, Haploinsufficiency, Kidney, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Mice, Genetics, Animals, Kidney Diseases, Ureter, Molecular Biology, Genetics (clinical), Transcription Factors
Abstract

Renal tract defects and autism spectrum disorder (ASD) deficits represent the phenotypic core of the 19q12 deletion syndrome caused by the loss of one copy of the TSHZ3 gene. Although a proportion of Tshz3 heterozygous (Tshz3+/lacZ) mice display ureteral defects, no kidney defects have been reported in these mice. The purpose of this study was to characterize the expression of Tshz3 in adult kidney as well as the renal consequences of embryonic haploinsufficiency of Tshz3 by analyzing the morphology and function of Tshz3 heterozygous adult kidney. Here, we described Tshz3 expression in the smooth muscle and stromal cells lining the renal pelvis, the papilla and glomerular endothelial cells (GEnCs) of the adult kidney as well as in the proximal nephron tubules in neonatal mice. Histological analysis showed that Tshz3+/lacZ adult kidney had an average of 29% fewer glomeruli than wild-type kidney. Transmission electron microscopy of Tshz3+/lacZ glomeruli revealed a reduced thickness of the glomerular basement membrane and a larger foot process width. Compared to wild type, Tshz3+/lacZ mice showed lower blood urea, phosphates, magnesium and potassium at 2 months of age. At the molecular level, transcriptome analysis identified differentially expressed genes related to inflammatory processes in Tshz3+/lacZ compare to wild-type (control) adult kidneys. Lastly, analysis of the urinary peptidome revealed 33 peptides associated with Tshz3+/lacZ adult mice. These results provide the first evidence that in the mouse Tshz3 haploinsufficiency leads to cellular, molecular and functional abnormalities in the adult mouse kidney.

Published
2021
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8. Molecular Changes in Tissue Proteome during Prostate Cancer Development: Proof-of-Principle Investigation

Author

William Mullen, Manousos Makridakis, Harald Mischak, Katarina Davalieva, Maria Frantzi, Joost P. Schanstra, Antonia Vlahou, Agnieszka Latosinska, Mosaiques Diagnostics & Therapeutics (MOSAIQUES DIAGNOSTICS & THERAPEUTICS), Mosaiques Diagnostics & Therapeutics AG, Macedonian Academy of Sciences and Arts [Skopje, North Macedonia] (MASA), Biomedical Research Foundation of the Academy of Athens (BRFAA), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and Schanstra, Joost

Subjects
0301 basic medicine, In silico, [SDV]Life Sciences [q-bio], Clinical Biochemistry, drug target, Computational biology, Biology, Tandem mass spectrometry, Proteomics, urologic and male genital diseases, Interactome, Article, Transcriptome, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, proteomics, medicine, tissue, lcsh:R5-920, Endoplasmic reticulum, personalized medicine, medicine.disease, prostate cancer, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030220 oncology & carcinogenesis, Proteome, lcsh:Medicine (General)
Abstract

International audience; (1) Background: Prostate cancer (PCa) is characterized by high heterogeneity. The aim of this study was to investigate molecular alterations underlying PCa development based on proteomics data. (2) Methods: Liquid chromatography coupled to tandem mass spectrometry was conducted for 22 fresh-frozen tissue specimens from patients with benign prostatic hyperplasia (BPH, n = 5) and PCa (n = 17). Mann Whitney test was used to define significant differences between the two groups. Association of protein abundance with PCa progression was evaluated using Spearman correlation, followed by verification through investigating the Prostate Cancer Transcriptome Atlas. Functional enrichment and interactome analysis were carried out using Metascape and String. (3) Results: Proteomics analysis identified 1433 proteins, including 145 proteins as differentially abundant between patients with PCa and BPH. In silico analysis revealed alterations in several pathways and hallmarks implicated in metabolism and signalling, represented by 67 proteins. Among the latter, 21 proteins were correlated with PCa progression at both the protein and mRNA levels. Interactome analysis of these 21 proteins predicted interactions between Myc proto-oncogene (MYC) targets, protein processing in the endoplasmic reticulum, and oxidative phosphorylation, with MYC targets having a central role. (4) Conclusions: Tissue proteomics allowed for characterization of proteins and pathways consistently affected during PCa development. Further validation of these findings is required.

Published
2020
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9. Value of Urine Peptides in Assessing Kidney and Cardiovascular Disease

Author

Justyna Siwy, Joachim Beige, Joost P. Schanstra, Stanislas Faguer, Harald Mischak, Agnieszka Latosinska, Schanstra, Joost, Mosaiques Diagnostics GmbH [Hannover, Germany], Mosaiques Diagnostics and Therapeutics AG [Hannover, Germany], Département de Néphrologie et Transplantation d'organes [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Martin-Luther-University Halle-Wittenberg, Département de Néphrologie et Transplantation d'organes, Hôpital de Rangueil, and CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]

Subjects
0301 basic medicine, Urinary system, kidney disease, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Context (language use), Disease, Urine, Bioinformatics, 03 medical and health sciences, Fibrosis, cardiovascular disease, Medicine, Humans, Renal Insufficiency, Chronic, Kidney, 030102 biochemistry & molecular biology, business.industry, medicine.disease, peptide, urine, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Cardiovascular Diseases, Biomarker (medicine), biomarker, business, Peptides, Kidney disease
Abstract

International audience; Urinary peptides gained significant attention as potential biomarkers especially in the context of kidney and cardiovascular disease. In this manuscript the recent literature since 2015 on urinary peptide investigation in human kidney and cardiovascular disease is reviewed. The technology most commonly used in this context is capillary electrophoresis coupled mass spectrometry, in part owed to the large database available and the well-defined dataspace. Several studies based on over 1000 subjects were reported in the recent past, especially examining CKD273, a classifier for assessment of chronic kidney disease based on 273 urine peptides. Interestingly, the most abundant urinary peptides are generally collagen fragments, which may have gone undetected for some time as they are typically modified via proline hydroxylation. The data available suggest that urinary peptides specifically depict inflammation and fibrosis, and may serve as a non-invasive tool to assess fibrosis, which appears to be a key driver in kidney and cardiovascular disease. The recent successful completion of the first urinary peptide guided intervention trial, PRIORITY, is expected to further spur clinical application of urinary peptidomics, aiming especially at early detection of chronic diseases, prediction of progression and prognosis of drug response. This article is protected by copyright. All rights reserved.

Published
2020
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10. Blockade of the kallikrein-kinin system reduces endothelial complement activation in vascular inflammation

Author

Davalieva, Katarina, Makridakis, Manousos, Vlahou, Antonia, Frantzi, Maria, Boizard, Franck, Moussaoui, Nabila, Lescat, Ophélie, Fedou, Camille, Feuillet, Guylène, Casemayou, Audrey, Neau, Eric, Decatte, Luc, Raaijmakers, Anke, Vayssière, Christophe, Goua, Valérie, Lucas, Charlotte, Benachi, Alexandra, Delmas, Hélène Laurichesse, Allain-Launay, Emma, Boudailliez, Bernard, Simon, Elisabeth, Noel, Catherine, Floch, Corinne, Bourdat-Michel, Guylène, Weingertner, Anne-Sophie, Oury, Jean-François, Baudouin, Véronique, Bory, Jean-Paul, Pietrement, Christine, Fiorenza, Maryse, Kessler, Sylvie, Auriol, Françoise Conte, Marcorelles, Pascale, Collardeau-Frachon, Sophie, Magalhães, Pedro, Batut, Julie, Blader, Patrick, Saulnier Blache, Jean-Sebastien, Allegaert, Karel, Aubard, Yves, Basmaison, Odile, Benevent, Jean-Baptiste, Biquard, Florence, Champion, Gérard, Delbosc, Jean-Marie, Eckart, Philippe, Gaucherand, Pascal, Guigonis, Vincent, Hougas, Blandine, Martin, Alain, Martin, Sophie, Maupin-Hyvonnet, Mariannick, Merveille, Marina, Mousty, Eve, Nobili, François, Taque, Sophie, Latosinska, Agnieszka, Faguer, Stanislas, Beige, Joachim, van der Zanden, Loes, Levtchenko, Elena, Moulos, Panogiotis, Lounis, Nadia, Conte-Auriol, Françoise, Olsen, Henning, Hindryckx, An, De Catte, Luc, Vayssieres, Christophe, Sartor, Agnes, Groussolles, Marion, Plard, Christelle, Guerby, Paul, Connan, Laure, Morin, Mathieu, Simon, Elizabeth, Breaud, Jean, Saliou, Anne-Hélène, De Parscau, Loic, Jay, Nadine, Germouty, Isabelle, Le Bouar, Gwenaelle, Ryckewaert, Amelie, Manca-Pellissier, Marie-Christine, Merrot, Thierry, Laurichesse, Helene, Gallot, Denis, Bessenay, Lucie, Bidat, Laurent, Boize, Philippe, Winer, Norbert, Allain-Launey, Emma, Le Vaillant, Claudine, Prieur, Fabienne, Lavocat, Marie-Pierre, Coatleven, Frederic, Debromez, Eric, Harembat, Jérôme, Llanas, Brigitte, Favre, Romain, Moog, Raphael, Zaloszyc, Ariane, Massardier, Jérôme, DEMEDE, Delphine, Perrotin, Franck, Cloarec, Sylvie, Vequeau-Goua, Valérie, Descombes, Emmanuelle, Boulot, Pierre, Morin, Denis, Fuchs, Florent, Tenenbaum, Julie, Ville, Yves, Blanc, Thomas, Heidet, Laurence, Paris, Anne, Dobremez, Eric, Froute, Marie-Françoise, Gondry, Jean, Muszynski, Charles, Haraux, Elodie, Lobelle, Fabienne, Chevreau, Julien, Rosenblatt, Jonathan, Baudoin, Véronique, Deschenes, Georges, Guigue, Virginie, Amblard, Florence, Bourdat-Michel, Guylhène, Wühl, Elke, Schaefer, Franz, Elsässer, Michael, Persico, Nicola, Rossi, Federica, Manzoni, Gianantonio, De Marco, Erika, Montini, Giovanni, Capone, Valentina, Caforio, Leonardo, Zaccara, Antonio, Innocenzi, Michele, Bagolan, Pietro, Capozza, Nicola, Castagnetti, Marco, Mancini, Mariangela, Oepkes, Dick, van Scheltema, Phebe Adama, Feitz, Wout, Kortmann, Barbara, Schreuder, Michiel, Pawłowska, Barbara, Fortecka-Piestrzeniewicz, Katarzyna, Olejniczak, Dariusz, Ariceta, Gema, Arevalo, Silvia, RODO, Carlota, Fossum, Magdalena, Lindgren, Peter, Parvex, Paloma, Chehade, Hassib, He, Tianlin, Metzger, Jochen, Mullen, William, Mischak, Harald, Zürbig, Petra, Jankowski, Vera, Buffin-Meyer, Bénédicte, Tkaczyk, Marcin, Stańczyk, Małgorzata, Breuil, Benjamin, Siwy, Justyna, Szaflik, Krzysztof, Talar, Tomasz, Wojtera, Justyna, Krzeszowski, Waldemar, Decramer, Stéphane, Lopatko Fagerström, Ingrid, Ståhl, Anne-lie, Mossberg, Maria, Tati, Ramesh, Kristoffersson, Ann-Charlotte, Kahn, Robin, Bascands, Jean-Loup, Klein, Julie, Schanstra, Joost, Segelmark, Mårten, Karpman, Diana, Department of Pediatrics [Lund, Sweden] (Clinical Sciences), Lund University [Lund], Wallenberg Center for Molecular Medicine [Lund, Sweden], Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Nephrology [Lund, Sweden] (Clinical Sciences Lund), Department of Medical and Health Sciences [Lund, Sweden], Linköping University (LIU), The study was supported by The Swedish Research Council (K2015-99X-22877-01-6 and 2017-01920), The Knut and Alice Wallenberg Foundation (Wallenberg Clinical Scholar 2015.0320), The Torsten Söderberg Foundation, Skåne Centre of Excellence in Health, IngaBritt och Arne Lundberg's Research Foundation, Crown Princess Lovisa's Society for Child Care, Region Skåne and The Konung Gustaf V:s 80-årsfond (all to DK). Alfred Österlund Foundation (to LMFLL and RK). TheWallenberg Center forMolecular Medicine, The Swedish RheumatismAssociation, The Anna-Greta Crafoord Foundation, Greta and Johan Kock's Foundation, the Samariten Foundation, Fanny Ekdahl foundation, the Jerring foundation and the Thelma Zoegas Foundation (to RK). JPS and JK were partially funded by a grant from the 'Fondation pour la Recherche Médicale' (grant number DEQ20170336759). MS was funded by The Swedish Rheumatism Association and the Ingrid Asp Foundation., Schanstra, Joost, Macedonian Academy of Sciences and Arts [Skopje, North Macedonia] (MASA), Biomedical Research Foundation of the Academy of Athens (BRFAA), Mosaiques Diagnostics & Therapeutics (MOSAIQUES DIAGNOSTICS & THERAPEUTICS), Mosaiques Diagnostics & Therapeutics AG, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], KfH-Nierenzentrum und Klinikum St. Georg, Nephrologie, Leipzig, Radboud University Medical Center [Nijmegen], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), HybridStat Predictive Analytics [Athens, Greece], Centre d'investigation clinique de Toulouse (CIC 1436), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospitals Leuven [Leuven], Heidelberg University Hospital [Heidelberg], University of Milan, Mosaiques Diagnostics GmbH [Hanovre, Allemagne], Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), RWTH Aachen University, Polish Mother’s Memorial Hospital Research Institute [Lodz] (ICZMP), Mosaiques Diagnostics GmbH [Hannover, Germany], Mosaiques Diagnostics and Therapeutics AG [Hannover, Germany], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), and Université Fédérale Toulouse Midi-Pyrénées

Subjects
0301 basic medicine, Male, Research paper, Mouse, Kallikrein-Kinin System, [SDV]Life Sciences [q-bio], Pharmacology, Kidney, Mice, 0302 clinical medicine, Glomerular C3 deposition, Cell-Derived Microparticles, Complement Activation, Cells, Cultured, Chemistry, General Medicine, Kinin, Middle Aged, Receptor antagonist, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, medicine.symptom, Endothelial microvesicles, Complement C1 Inhibitor Protein, Protein Binding, Vasculitis, Complement, Radiology, Nuclear Medicine and Medical Imaging, Adult, Endothelium, medicine.drug_class, Inflammation, Bradykinin, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Classical complement pathway, medicine, Animals, Humans, Aged, Endothelial Cells, Biological Transport, Complement System Proteins, Microvesicles, Complement system, Disease Models, Animal, 030104 developmental biology, Immunoglobulin G, Endothelium, Vascular, Radiologi och bildbehandling
Abstract

Background: The complement and kallikrein-kinin systems (KKS) are activated during vascular inflammation. The aim of this study was to investigate if blockade of the KKS can affect complement activation on the endothelium during inflammation. Methods: Complement deposition on endothelial microvesicles was assayed in vasculitis patient plasma samples and controls. Plasma was perfused over glomerular endothelial cells and complement deposition assayed by flow cytometry. The effect of the kinin system was assessed using kinin receptor antagonists and C1-inhibitor. The in vivo effect was assessed in kidney sections from mice with nephrotoxic serum-induced glomerulonephritis treated with a kinin receptor antagonist. Findings: Vasculitis patient plasma had significantly more C3- and C9-positive endothelial microvesicles than controls. Perfusion of patient acute-phase plasma samples over glomerular endothelial cells induced the release of significantly more complement-positive microvesicles, in comparison to remission or control plasma. Complement activation on endothelial microvesicles was reduced by kinin B1- and B2-receptor antagonists or by C1-inhibitor (the main inhibitor of the classical pathway and the KKS). Likewise, perfusion of glomerular endothelial cells with C1-inhibitor-depleted plasma induced the release of complement-positive microvesicles, which was significantly reduced by kinin-receptor antagonists or C1-inhibitor. Mice with nephrotoxic serum-induced glomerulonephritis exhibited significantly reduced glomerular C3 deposition when treated with a B1-receptor antagonist. Interpretation: Excessive complement deposition on the endothelium will promote endothelial injury and the release of endothelial microvesicles. This study demonstrates that blockade of the KKS can reduce complement activation and thereby the inflammatory response on the endothelium. (C) 2019 The Authors. Published by Elsevier B.V. Funding Agencies|Swedish Research CouncilSwedish Research Council [K2015-99X-22877-01-6, 2017-01920]; Knut and Alice Wallenberg FoundationKnut & Alice Wallenberg Foundation [2015.0320]; Torsten Soderberg Foundation; Skane Centre of Excellence in Health; Crown Princess Lovisas Society for Child Care; Konung Gustaf V:s 80-arsfond; Alfred Osterlund Foundation; Wallenberg Center for Molecular Medicine; Swedish Rheumatism Association; Anna-Greta Crafoord Foundation; Greta and Johan Kocks Foundation; Samariten Foundation; Fanny Ekdahl foundation; Jerring foundation; Fondation pour la Recherche MedicaleFondation pour la Recherche Medicale [DEQ20170336759]; Ingrid Asp Foundation; IngaBritt och Arne Lundbergs Research Foundation; Region Skane; Thelma Zoegas Foundation

Published
2019
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11. Proteomic Bioprofiles and Mechanistic Pathways of Progression to Heart Failure

Author

João Pedro, Ferreira, Job, Verdonschot, Timothy, Collier, Ping, Wang, Anne, Pizard, Christian, Bär, Jens, Björkman, Alessandro, Boccanelli, Javed, Butler, Andrew, Clark, John G, Cleland, Christian, Delles, Javier, Diez, Nicolas, Girerd, Arantxa, González, Mark, Hazebroek, Anne-Cécile, Huby, Wouter, Jukema, Roberto, Latini, Joost, Leenders, Daniel, Levy, Alexandre, Mebazaa, Harald, Mischak, Florence, Pinet, Patrick, Rossignol, Naveed, Sattar, Peter, Sever, Jan A, Staessen, Thomas, Thum, Nicolas, Vodovar, Zhen-Yu, Zhang, Stephane, Heymans, Faiez, Zannad, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Universidade do Porto, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University [Maastricht], Maastricht University Medical Centre (MUMC), London School of Hygiene and Tropical Medicine (LSHTM), Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular and Translational Therapeutic Strategies - IMTTS [Hannover, Germany], TATAA Biocenter AB, Casa di Cura Quisisana, University of Mississippi Medical Center (UMMC), Hannover Medical School [Hannover] (MHH), Hull York Medical School, Institute of Health and Wellbeing, University of Glasgow-Gartnavel General Hospital, Glasgow, University of Glasgow, Institute of Cardiovascular and Medical Sciences [Glasgow], Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Institute of Health Carlos III, Instituto de Investigación Sanitaria de Navarra (IdiSNA), University Clinic of Navarra, Leiden University Medical Center (LUMC), IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri' [Milan, Italy], ACS Biomarker, Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Université Paris Diderot - Paris 7 (UPD7), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mosaiques Diagnostics GmbH [Hannover, Germany], Mosaiques Diagnostics and Therapeutics AG [Hannover, Germany], Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Imperial College London, Department of Cardiovascular Sciences [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institute of Molecular and Translational Therapeutic Strategies (IMTTS), IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Universidade do Porto = University of Porto, Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universiteit Leiden, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS)

Subjects
Heart Failure, Male, Proteomics, Proteome, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Case-Control Studies, Disease Progression, Humans, Female, Biomarkers, Article, Aged
Abstract

International audience; Background Identifying the mechanistic pathways potentially associated with incident heart failure (HF) may provide a basis for novel preventive strategies. Methods and Results To identify proteomic biomarkers and the potential underlying mechanistic pathways that may be associated with incident HF defined as the first hospitalization for HF, a nested-matched case-control design was used with cases (incident HF) and controls (without HF) selected from 3 cohorts (>20 000 individuals). Controls were matched on cohort, follow-up time, age, and sex. Two independent sample sets (a discovery set with 286 cases and 591 controls and a replication set with 276 cases and 280 controls) were used to discover and replicate the findings. Two hundred fifty-two circulating proteins in the plasma were studied. Adjusting for the matching variables age, sex, and follow-up time (and correcting for multiplicity of tests), 89 proteins were found to be associated with incident HF in the discovery phase, of which 38 were also associated with incident HF in the replication phase. These 38 proteins pointed to 4 main network clusters underlying incident HF: (1) inflammation and apoptosis, indicated by the expression of the TNF (tumor necrosis factor)-family members; (2) extracellular matrix remodeling, angiogenesis and growth, indicated by the expression of proteins associated with collagen metabolism, endothelial function, and vascular homeostasis; (3) blood pressure regulation, indicated by the expression of natriuretic peptides and proteins related to the renin-angiotensin-aldosterone system; and (4) metabolism, associated with cholesterol and atherosclerosis. Conclusions Clusters of biomarkers associated with mechanistic pathways leading to HF were identified linking inflammation, apoptosis, vascular function, matrix remodeling, blood pressure control, and metabolism. These findings provide important insight on the pathophysiological mechanisms leading to HF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02556450.

Published
2019
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12. The CKD plasma lipidome varies with disease severity and outcome

Author

Jonas Laget, Jean-Sébastien Saulnier-Blache, Joost P. Schanstra, Klaus M. Weinberger, Ulrika Lundin, Harald Mischak, Flore Duranton, Nathalie Gayrard, Marie-Françoise Servel, Àngel Argilés, Biocommunication en Cardio-Métabolique (BC2M), Université de Montpellier (UM), Equipe 7 Inserm U1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), BIOCRATES Life Sciences AG [Innsbruck, Austria], Mosaiques Diagnostics & Therapeutics (MOSAIQUES DIAGNOSTICS & THERAPEUTICS), Mosaiques Diagnostics & Therapeutics AG, Nephrologie - Dialyse St-guilhem [Sète], CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Unité de recherche sur les obésités, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR 31 Louis Bugnard (IFR 31), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Mosaiques Diagnostics and Therapeutics AG, Néphrologie Dialyse Saint Guilhem (NDSG), Service de Néphrologie, Dialyse et Transplantation (Hôpital Lapeyronie [Montpellier] CHU), Hôpital Lapeyronie [Montpellier] (CHU), Mosaiques Diagnostics & Therapeutics AG [Hannover, Germany], Private University for Health Sciences, Medical Informatics and Technology [Tirol] (UMIT), sAnalytiCo Ltd [Belfast, UK], and Saulnier-Blache, Jean Sébastien

Subjects
Male, Sphingomyelin, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Gastroenterology, Renal disease, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Renal Dialysis, Internal medicine, Lipidomics, Internal Medicine, medicine, Humans, 030212 general & internal medicine, Renal Insufficiency, Chronic, ComputingMilieux_MISCELLANEOUS, Aged, Lysophospholipid, chemistry.chemical_classification, Nutrition and Dietetics, business.industry, Fatty acid, Lipid metabolism, Lipidome, Middle Aged, medicine.disease, Lipid Metabolism, Elaidic acid, 3. Good health, [SDV] Life Sciences [q-bio], Primary Prevention, Phospholipid, chemistry, Phosphatidylcholines, Female, Hemodialysis, Cardiology and Cardiovascular Medicine, business, Kidney disease
Abstract

International audience; Background: Various alterations in lipid metabolism have been observed in patients with chronic kidney disease (CKD).Objectives: To determine the levels of lipid species in plasma from CKD and hemodialysis (HD) patients and test their association with CKD severity and patient outcome.Methods: Seventy-seven patients with CKD stage 2 to HD were grouped into classes of CKD severity at baseline and followed-up for 3.5 years for the occurrence of transition to HD or death (combined outcome). Plasma levels of phosphatidylcholines (PCs), lysophosphatidylcholines (LPCs), sphingomyelins (SMs), and fatty acids were analyzed by flow-injection analysis coupled to tandem mass spectrometry or gas chromatography coupled with mass spectrometry. Kruskal Wallis rank tests and Cox regressions were used to analyze the association of lipids with CKD severity and the risk of combined outcome, respectively.Results: The plasma level of PCs, LPCs, and SMs was decreased in HD patients compared with nondialyzed CKD patients (all P < .05), whereas esterified and/or nonesterified fatty acids level did not change. Thirty-four lipids displayed significantly lower abundance in plasma of HD patients, whereas elaidic acid (C18:1ω9t) level was increased (P < .001). The total amount of LPCs and individual LPCs were associated with better outcome (P < .05). In particular, LPC 18:2 and LPC 20:3 were statistically associated with outcome in adjusted models (P < .05).Discussion: In HD patients, a reduction in plasma lipids is observed. Some of the alterations, namely reduced LPCs, were associated with the risk of adverse outcome. These changes could be related to metabolic dysfunctions.

Published
2019
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13. Systems biology identifies cytosolic PLA2 as a target in vascular calcification treatment

Author

Stuart A. Nicklin, Ioana Alesutan, Dirk von Lewinski, Jean-Loup Bascands, Christian Delles, Beate Boehme, Guylène Feuillet, Trang T.D. Luong, Julie Klein, Nadeshda Schelski, Antonia Vlahou, Harald Mischak, William Mullen, Colette Denis, Burkert Pieske, Jakob Voelkl, Jean-Sébastien Saulnier-Blache, Agnieszka Latosinska, Florian Lang, Manousos Makridakis, Vasiliki Lygirou, Sophie Van Linthout, Joost P. Schanstra, Saulnier-Blache, Jean Sébastien, Systems Biology to Identify Molecular Targets for Vascular Disease Treatment - SYSVASC - - EC:FP7:HEALTH2014-02-01 - 2018-01-31 - 603288 - VALID, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Biomedical Research Foundation of the Academy of Athens, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Mosaiques Diagnostics GmbH, Johannes Kepler University Linz [Linz] (JKU), Karl-Franzens-Universität Graz, University of Glasgow, University of Tübingen, Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the European Union Seventh Framework Program (FP7/2007-2013–603288- SysVasc, to JPS, VL, SVL, CD, FL, BP, JLP, HM, JSSB, JV, AV, and JL), the European Union ERA CVD JTC2017 PROACT (ANR-17-ECVD-0006 to JK, GF, CD, JSSB, and JPS, 01KL1805 via the Federal Ministry of Education and Research to HM), INSERM, the 'Fondation pour la Recherche Médicale' (grant DEQ20170336759 to JK, GF, CD, JSSB and JPS), the British Heart Foundation Centre of Research Excellence Award (RE/13/5/30177), the Deutsche Forschungsgemeinschaft (AL2054/1-1, VO2259/2-1), the Berlin Institute of Health, and the Else Kröner-Fresenius-Stiftung to TTDL, JV, IA, BB, and NS. Immunopathological analysis of cPLA2 was provided by the iPATH.Berlin – Core Unit Immunopathology for Experimental Models of the Charité – Universitätsmedizin Berlin (Berlin, Germany)., European Project: 603288,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,SYSVASC(2014), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Karl-Franzens-Universität [Graz, Autriche], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Academy of Athens, University of Graz, BHF Glasgow Cardiovascular Research Centre, University of Glasgow-Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre (BHF GCRC), Department of Physiology, Eberhard Karls Universität Tübingen, Charité Campus Virchow-Klinikum (CVK), Institute of Cardiovascular and Medical Sciences [Glasgow], Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Biomedical Research Foundation of the Academy of Athens (BRFAA), Mosaiques Diagnostics GmbH [Hannover, Germany], Mosaiques Diagnostics and Therapeutics AG [Hannover, Germany], Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Johannes Kepler Universität Linz - Johannes Kepler University Linz [Autriche] (JKU)

Subjects
0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Mice, [SCCO]Cognitive science, 0302 clinical medicine, Cytosol, Medicine, media_common, Mice, Knockout, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Systems Biology, General Medicine, Middle Aged, Cardiovascular disease, 3. Good health, Up-Regulation, Cardiovascular Diseases, 030220 oncology & carcinogenesis, Proteome, Female, Research Article, Drug, Adult, Systems biology, media_common.quotation_subject, Myocytes, Smooth Muscle, Arachidonic Acids, 03 medical and health sciences, Phospholipase A2, Apolipoproteins E, Downregulation and upregulation, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, In vivo, Vascular Biology, Animals, Humans, Antigens, Human Platelet, Atherosclerosis, Cardiovascular disease, Vascular Biology, Vascular Calcification, Arachidonyl trifluoromethyl ketone, business.industry, [SCCO] Cognitive science, Atherosclerosis, In vitro, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, biology.protein, Cancer research, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Although cardiovascular disease (CVD) is the leading cause of morbimortality worldwide, promising new drug candidates are lacking. We compared the arterial high-resolution proteome of patients with advanced versus early-stage CVD to predict, from a library of small bioactive molecules, drug candidates able to reverse this disease signature. Of the approximately 4000 identified proteins, 100 proteins were upregulated and 52 were downregulated in advanced-stage CVD. Arachidonyl trifluoromethyl ketone (AACOCF3), a cytosolic phospholipase A2 (cPLA2) inhibitor was predicted as the top drug able to reverse the advanced-stage CVD signature. Vascular cPLA2 expression was increased in patients with advanced-stage CVD. Treatment with AACOCF3 significantly reduced vascular calcification in a cholecalciferol-overload mouse model and inhibited osteoinductive signaling in vivo and in vitro in human aortic smooth muscle cells. In conclusion, using a systems biology approach, we have identified a potentially new compound that prevented typical vascular calcification in CVD in vivo. Apart from the clear effect of this approach in CVD, such strategy should also be able to generate novel drug candidates in other complex diseases.

Published
2019
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14. Urinary proteome signature of Renal Cysts and Diabetes syndrome in children

Author

Pierbruno Ricci, Laura Goea, Jens Drube, Joost P. Schanstra, Petra Zürbig, Stéphane Decramer, Giuseppe Remuzzi, Magdalena Krochmal, Franz Schaefer, Martin Pejchinovski, Harald Mischak, Pedro Magalhães, Lars Pape, Muriel Umbhauer, Maria Rosa Caruso, Silvia Cereghini, Iwona Belczacka, Erica Daina, Schanstra, Joost, Development and disease of the renal tract - RENALTRACT - - H20202015-06-01 - 2019-05-31 - 642937 - VALID, Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), GIPSA - Signal Images Physique (GIPSA-SIGMAPHY), Département Images et Signal (GIPSA-DIS), Grenoble Images Parole Signal Automatique (GIPSA-lab ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Grenoble Images Parole Signal Automatique (GIPSA-lab ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Mosaiques Diagnostics GmbH [Hannover, Germany], Mosaiques Diagnostics and Therapeutics AG [Hannover, Germany], Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), ASST Papa Giovanni XXIII [Bergamo, Italy], Laboratoire de Biologie du Développement [IBPS] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mario Negri Institute for Pharmacological Research, Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Department of Paediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School [Hannover] (MHH), Department of Pediatric Kidney, Hannover Medical School [Hannover] (MHH)-Children's Hospital, Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Division of Pediatric Nephrology, Universität Heidelberg [Heidelberg], Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation et morphogenèse = Signalling and morphogenesis (LBD-E12), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), The research presented in this manuscript was supported by the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement No. 642937 (RENALTRACT, MSCA-ITN-2014-642937). Furthermore, J.D. and L.P. were supported by the NEOCYST consortium, which is funded by the German Federal Ministry of Research and Education (BMBF, grant 01GM1515)., European Project: 642937,H2020,H2020-MSCA-ITN-2014,RENALTRACT(2015), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), CHU Toulouse [Toulouse], Centre de Référence du Sud Ouest des Maladies Rénales Rares, CHU Toulouse [Toulouse]-Hôpital des Enfants, Université Fédérale Toulouse Midi-Pyrénées, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Heidelberg [Heidelberg] = Heidelberg University, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS)

Subjects
0301 basic medicine, Male, Proteomics, Pathology, Proteome, [SDV]Life Sciences [q-bio], lcsh:Medicine, Disease, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Mass Spectrometry, 0302 clinical medicine, Central Nervous System Diseases, lcsh:Science, Child, Congenital nephrotic syndrome, Multidisciplinary, Kidney Diseases, Cystic, 3. Good health, [SDV] Life Sciences [q-bio], Phenotype, Child, Preschool, Female, medicine.medical_specialty, Adolescent, Urinary system, Autosomal dominant polycystic kidney disease, Article, Diagnosis, Differential, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Diabetes mellitus, medicine, Humans, Dental Enamel, Hydronephrosis, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, PKD1, business.industry, lcsh:R, Reproducibility of Results, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 030104 developmental biology, Diabetes Mellitus, Type 2, lcsh:Q, business, Peptides, 030217 neurology & neurosurgery, Biomarkers, Kidney disease
Abstract

Renal Cysts and Diabetes Syndrome (RCAD) is an autosomal dominant disorder caused by mutations in the HNF1B gene encoding for the transcriptional factor hepatocyte nuclear factor-1B. RCAD is characterized as a multi-organ disease, with a broad spectrum of symptoms including kidney abnormalities (renal cysts, renal hypodysplasia, single kidney, horseshoe kidneys, hydronephrosis), early-onset diabetes mellitus, abnormal liver function, pancreatic hypoplasia and genital tract malformations. In the present study, using capillary electrophoresis coupled to mass spectrometry (CE-MS), we investigated the urinary proteome of a pediatric cohort of RCAD patients and different controls to identify peptide biomarkers and obtain further insights into the pathophysiology of this disorder. As a result, 146 peptides were found to be associated with RCAD in 22 pediatric patients when compared to 22 healthy age-matched controls. A classifier based on these peptides was generated and further tested on an independent cohort, clearly discriminating RCAD patients from different groups of controls. This study demonstrates that the urinary proteome of pediatric RCAD patients differs from autosomal dominant polycystic kidney disease (PKD1, PKD2), congenital nephrotic syndrome (NPHS1, NPHS2, NPHS4, NPHS9) as well as from chronic kidney disease conditions, suggesting differences between the pathophysiology behind these disorders.

Published
2019
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15. Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides

Author

Schanstra, Joost, Zürbig, Petra, Alkhalaf, Alaa, Argilés, Angel, Bakker, Stephan, Beige, Joachim, Bilo, Henk, Chatzikyrkou, Christos, Dakna, Mohammed, Dawson, Jesse, Delles, Christian, Haller, Hermann, Haubitz, Marion, Husi, Holger, Jankowski, Jan, Jerums, George, Kleefstra, Nanne, Kuznetsova, Tatiana, Maahs, David, Menne, Jan, Mullen, William, Ortiz, Alberto, Persson, Frederik, Rossing, Peter, Ruggenenti, Piero, Rychlik, Ivan, Serra, Andreas, Siwy, Justyna, Snell-Bergeon, Jan, Spasovski, Goce, Staessen, Jan, Vlahou, Antonia, Mischak, Harald, Vanholder, Raymond, Zurbig, P., Bakker, J., Staessen, A., Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Institut National de la Santé et de la Recherche Médicale (INSERM), Mosaiques Diagnostics GmbH, Néphrologie Dialyse Saint Guilhem (NDSG), RD-Néphrologie (R&D), Biocommunication en Cardio-Métabolique (BC2M), Université de Montpellier (UM), Isala Clinics, Diabetes Centre, Mosaiques Diagnostics and Therapeutics, Mosaiques diagnostics and therapeutics, BHF Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow, Division of Nephrology and Hypertension, Department of Medicine, Hanover Medical School, Department of Nephrology (MHH), Hannover Medical School [Hannover] (MHH), Department of Poultry Science, University of Warmia and Mazury, BHF Glasgow Cardiovascular Research Centre, University of Glasgow-Institute of Cardiovascular & Medical Sciences, Département Réseaux et Services Multimédia Mobiles (RS2M), Institut Mines-Télécom [Paris] (IMT)-Télécom SudParis (TSP), Steno Diabetes Center of Copenhagen [Gentofte, Denmark], Charles University [Prague] (CU), Maastricht University [Maastricht], Biomedical Research Foundation of the Academy of Athens, Institute of Cardiovascular and Medical Sciences [Glasgow], Nephrology Section [Ghent], Ghent University Hospital, Department of Intensive Care, and Erasmus Medical Centre

Subjects
Male, CHRONIC KIDNEY-DISEASE, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, urologic and male genital diseases, Diabetic nephropathy, Cohort Studies, 0302 clinical medicine, Fibrosis, POSITION STATEMENT, 10. No inequality, ALBUMIN EXCRETION, RISK, 0303 health sciences, Area under the curve, renal progression, General Medicine, Middle Aged, female genital diseases and pregnancy complications, 3. Good health, Nephrology, IMPROVING GLOBAL OUTCOMES, Cohort, Disease Progression, Biomarker (medicine), biomarker, Female, PROTEOMIC ANALYSIS, medicine.symptom, Glomerular Filtration Rate, Adult, medicine.medical_specialty, Urinary system, extracellular matrix, BIOMARKERS, Urology, Renal function, albuminuria, DIABETIC-NEPHROPATHY, 03 medical and health sciences, Clinical Research, Internal medicine, Up Front Matters, medicine, CKD, INJURY, Humans, Renal Insufficiency, Chronic, 030304 developmental biology, Aged, business.industry, fibrosis, NEED, medicine.disease, Endocrinology, Albuminuria, business, Peptides
Abstract

Progressive CKD is generally detected at a late stage by a sustained decline in eGFR and/or the presence of significant albuminuria. With the aim of early and improved risk stratification of patients with CKD, we studied urinary peptides in a large cross-sectional multicenter cohort of 1990 individuals, including 522 with follow-up data, using proteome analysis. We validated that a previously established multipeptide urinary biomarker classifier performed significantly better in detecting and predicting progression of CKD than the current clinical standard, urinary albumin. The classifier was also more sensitive for identifying patients with rapidly progressing CKD. Compared with the combination of baseline eGFR and albuminuria (area under the curve [AUC]=0.758), the addition of the multipeptide biomarker classifier significantly improved CKD risk prediction (AUC=0.831) as assessed by the net reclassification index (0.303±-0.065; P

Published
2015
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16. Proteomics and metabolomics for AKI diagnosis

Author

Ryan B. Gil, David Marx, Silke S. Heinzmann, Jochen Metzger, Jerome Zoidakis, Matthias Klingele, Iwona Belczacka, Agnieszka Latosinska, Maria Frantzi, Holger Husi, Stefan Herget-Rosenthal, Martin Pejchinovski, Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Mosaiques Diagnostics GmbH [Hannover, Germany], Mosaiques Diagnostics and Therapeutics AG [Hannover, Germany], Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München, Biotechnology Division - Biomedical Research Foundation, Academy of Athens, Medizinische Klinik, and Rotes Kreuz Krankenhaus

Subjects
Proteomics, 0301 basic medicine, Protein biomarkers, Hospitalized patients, medicine.medical_treatment, 030232 urology & nephrology, Context (language use), Bioinformatics, urologic and male genital diseases, Transforming Growth Factor beta1, 03 medical and health sciences, Adenosine Triphosphate, 0302 clinical medicine, Metabolomics, Pathway Analysis, Aki Diagnosis, medicine, Humans, [CHIM]Chemical Sciences, Renal replacement therapy, business.industry, urogenital system, Acute kidney injury, Computational Biology, Acute Kidney Injury, medicine.disease, female genital diseases and pregnancy complications, 3. Good health, Fibroblast Growth Factors, Fibroblast Growth Factor-23, 030104 developmental biology, Nephrology, business, Biomarkers, Omics technologies
Abstract

International audience; Acute kidney injury (AKI) is a severe and frequent condition in hospitalized patients. Currently, no efficient therapy of AKI is available. Therefore, efforts focus on early prevention and potentially early initiation of renal replacement therapy to improve the outcome in AKI. The detection of AKI in hospitalized patients implies the need for early, accurate, robust, and easily accessible biomarkers of AKI evolution and outcome prediction because only a narrow window exists to implement the earlier-described measures. Even more challenging is the multifactorial origin of AKI and the fact that the changes of molecular expression induced by AKI are difficult to distinguish from those of the diseases associated or causing AKI as shock or sepsis. During the past decade, a considerable number of protein biomarkers for AKI have been described and we expect from recent advances in the field of omics technologies that this number will increase further in the future and be extended to other sorts of biomolecules, such as RNAs, lipids, and metabolites. However, most of these biomarkers are poorly defined by their AKI-associated molecular context. In this review, we describe the state-of-the-art tissue and biofluid proteomic and metabolomic technologies and new bioinformatics approaches for proteomic and metabolomic pathway and molecular interaction analysis. In the second part of the review, we focus on AKI-associated proteomic and metabolomic biomarkers and briefly outline their pathophysiological context in AKI.

Published
2018
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17. Proteomics biomarkers for solid tumors: Current status and future prospects

Author

David Marx, Maria Frantzi, Agnieszka Latosinska, Iwona Belczacka, Antonia Vlahou, Jochen Metzger, Harald Mischak, Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Mosaiques Diagnostics GmbH [Hannover, Germany], Mosaiques Diagnostics and Therapeutics AG [Hannover, Germany], Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Research Foundation, Academy of Athens, and Mosaiques Diagnostics & Therapeutics AG

Subjects
0301 basic medicine, Proteomics, Early detection, Genomics, Bioinformatics, 01 natural sciences, General Biochemistry, Genetics and Molecular Biology, Mass Spectrometry, Analytical Chemistry, 03 medical and health sciences, Neoplasms, cancer, clinical proteomics, diagnosis, protein biomarkers, solid tumors, medicine, Biomarkers, Tumor, Animals, Humans, [CHIM]Chemical Sciences, Spectroscopy, Chemistry, 010401 analytical chemistry, Cancer, Proteins, Condensed Matter Physics, medicine.disease, Prognosis, 3. Good health, 0104 chemical sciences, Clinical trial, 030104 developmental biology, Tumor progression, Biomarker (medicine), Cancer biomarkers
Abstract

International audience; Cancer is a heterogeneous multifactorial disease, which continues to be one of the main causes of death worldwide. Despite the extensive efforts for establishing accurate diagnostic assays and efficient therapeutic schemes, disease prevalence is on the rise, in part, however, also due to improved early detection. For years, studies were focused on genomics and transcriptomics, aiming at the discovery of new tests with diagnostic or prognostic potential. However, cancer phenotypic characteristics seem most likely to be a direct reflection of changes in protein metabolism and function, which are also the targets of most drugs. Investigations at the protein level are therefore advantageous particularly in the case of in‐depth characterization of tumor progression and invasiveness. Innovative high‐throughput proteomic technologies are available to accurately evaluate cancer formation and progression and to investigate the functional role of key proteins in cancer. Employing these new highly sensitive proteomic technologies, cancer biomarkers may be detectable that contribute to diagnosis and guide curative treatment when still possible. In this review, the recent advances in proteomic biomarker research in cancer are outlined, with special emphasis placed on the identification of diagnostic and prognostic biomarkers for solid tumors. In view of the increasing number of screening programs and clinical trials investigating new treatment options, we discuss the molecular connections of the biomarkers as well as their potential as clinically useful tools for diagnosis, risk stratification and therapy monitoring of solid tumors.

Published
2018
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18. Pretransplant urinary proteome analysis does not predict development of chronic kidney disease after liver transplantation

Author

David Ribes, Joost P. Schanstra, Laurence Lavayssière, Christophe Bureau, Arnaud Del Bello, Laurent Alric, David Milongo, Jean-Loup Bascands, Lionel Rostaing, Adela Ramirez-Torres, Benjamin Breuil, Panagiotis Moulos, Laure Esposito, Fabrice Muscari, Antoine Huart, Nassim Kamar, Justyna Siwy, Hôpital de Rangueil, CHU Toulouse [Toulouse], Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), HybridStat Predictive Analytics [Athens, Greece], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Mosaiques Diagnostics (GmbH), Mosaique Diagnostics, Université Fédérale Toulouse Midi-Pyrénées, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), Hôpital Purpan [Toulouse], Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, Proteomics, medicine.medical_specialty, Pathology, Time Factors, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Urinary system, Renal function, Urinalysis, Liver transplantation, Kidney, urologic and male genital diseases, Risk Assessment, Gastroenterology, Liver disease, Predictive Value of Tests, Risk Factors, Internal medicine, medicine, Humans, viral hepatis, Prospective Studies, Renal Insufficiency, Chronic, Aged, liver transplantation, Hepatology, business.industry, Liver Diseases, Middle Aged, medicine.disease, proteome analysis, urine, female genital diseases and pregnancy complications, 3. Good health, Transplantation, Proteinuria, Treatment Outcome, surgical procedures, operative, medicine.anatomical_structure, Female, Viral hepatitis, business, Biomarkers, chronic kidney disease, Glomerular Filtration Rate, Kidney disease
Abstract

Background & Aims Chronic kidney disease (CKD) is a common complication after liver transplantation. Kidney biopsies cannot be easily performed before liver transplantation to predict patients at high risk for CKD. The aim of our study was to determine whether pre-, peri- and post-transplant factors, as well as peptides present in preliver transplant urine samples were associated with loss in kidney function at 6 months post-transplantation using proteome analysis. Methods Eighty patients who underwent a liver transplantation and that had pretransplant glomerular filtration rate (GFR) value of ≥60 mL/min/1.73 m² (MDRD) were included in the study. Results GFR decreased significantly after transplantation. At month 6 post-transplantation, 40 patients displayed a CKD, i.e. eGFR of

Published
2015
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19. Multicentre prospective validation of a urinary peptidome-based classifier for the diagnosis of type 2 diabetic nephropathy

Author

Olivera Stojceva-Taneva, Joachim Beige, Alberto Ortiz, P Boucek, Ralf Lichtinghagen, Brigitte M. Winklhofer-Roob, Peter Rossing, Stephan J. L. Bakker, Piero Ruggenenti, Frederik Persson, Mohammad Al Khatib, Andreas L. Serra, Janet K. Snell-Bergeon, Christian Delles, Morten Lindhardt, Ivan Rychlik, Maria Lajer, Flore Duranton, Matias Trillini, Marie-Luise Jankowski, Gerjan Navis, Marina Noutsou, Johannes M. Roob, Goce Spasovski, Heiko von der Leyen, William Mullen, Beatriz Fernandez-Fernandez, Harald Mischak, Joost P. Schanstra, Thomas Kunt, Joachim Jankowski, John R. Petrie, Àngel Argilés, Petra Zürbig, Korbinian Brand, David M. Maahs, Justyna Siwy, Mosaiques Diagnostics and Therapeutics, Mosaiques diagnostics and therapeutics, Institut National de la Santé et de la Recherche Médicale (INSERM), Néphrologie Dialyse Saint Guilhem (NDSG), RD-Néphrologie (R&D), BHF Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow, Biocommunication en Cardio-Métabolique (BC2M), Université de Montpellier (UM), Institute of Cardiovascular and Medical Sciences [Glasgow], BHF Glasgow Cardiovascular Research Centre, University of Glasgow-Institute of Cardiovascular & Medical Sciences, Department of Internal Medicine, University of Groningen and University Medical Center Groningen, Instituto de Investigación Sanitaria Fundación Jiménez Diaz [Madrid] (IIS-FJD), Universidad Autonoma de Madrid (UAM)-Fundacion Jimenez Diaz [Madrid] (FJD), Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-Institute of Cardiovascular and Medical Sciences, Steno Diabetes Center of Copenhagen [Gentofte, Denmark], Charles University [Prague] (CU), HNMRC (Human Nutrition and Metabolism Research and Training Center), Karl-Franzens-Universität [Graz, Autriche], University of Zurich, Jankowski, Joachim, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), and Vascular Ageing Programme (VAP)

Subjects
Male, Proteomics, CHRONIC KIDNEY-DISEASE, Pathology, 2747 Transplantation, diagnosis, [SDV]Life Sciences [q-bio], Type 2 diabetes, Diabetic nephropathy, 10035 Clinic for Nephrology, Diabetic Nephropathies, Prospective Studies, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, 2727 Nephrology, ALPHA-1-ANTITRYPSIN, Middle Aged, 3. Good health, PREVALENCE, Nephrology, CE-MS, Disease Progression, Female, Adult, medicine.medical_specialty, Urinary system, 610 Medicine & health, CLINICAL SCIENCE, Age and gender, Diagnosis, Differential, Internal medicine, Diabetes mellitus, PROTEOMIC BIOMARKERS, medicine, Humans, urine proteomics, Aged, Transplantation, business.industry, diabetic nephropathy, biomarkers, Ancillary Study, MASS-SPECTROMETRY, medicine.disease, Diabetes Mellitus, Type 2, DISCOVERY, Peptidomimetics, business, Classifier (UML), chronic kidney disease, Follow-Up Studies
Abstract

Background Diabetic nephropathy (DN) is one of the major late complications of diabetes. Treatment aimed at slowing down the progression of DN is available but methods for early and definitive detection of DN progression are currently lacking. The ‘Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria trial' (PRIORITY) aims to evaluate the early detection of DN in patients with type 2 diabetes (T2D) using a urinary proteome-based classifier (CKD273). Methods In this ancillary study of the recently initiated PRIORITY trial we aimed to validate for the first time the CKD273 classifier in a multicentre (9 different institutions providing samples from 165 T2D patients) prospective setting. In addition we also investigated the influence of sample containers, age and gender on the CKD273 classifier. Results We observed a high consistency of the CKD273 classification scores across the different centres with areas under the curves ranging from 0.95 to 1.00. The classifier was independent of age (range tested 16-89 years) and gender. Furthermore, the use of different urine storage containers did not affect the classification scores. Analysis of the distribution of the individual peptides of the classifier over the nine different centres showed that fragments of blood-derived and extracellular matrix proteins were the most consistently found. Conclusion We provide for the first time validation of this urinary proteome-based classifier in a multicentre prospective setting and show the suitability of the CKD273 classifier to be used in the PRIORITY trial

Published
2017
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20. The human urinary proteome reveals high similarity between kidney aging and chronic kidney disease

Author

Justyna Jantos, Mohammed Dakna, Jean-Loup Bascands, Flavio Bandin, Joshua J. Coon, Harald Mischak, Joost P. Schanstra, David M. Good, Stéphane Decramer, Petra Zürbig, Mosaiques Diagnostics & Therapeutics AG, Mosaiques Diagnostics and Therapeutics AG, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Néphrologie, médecine interne et hypertension pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Department of Chemistry, University of Wisconsin-Madison, Department of Biomolecular Chemistry, Hannover Medical School [Hannover] (MHH), and Simon, Marie Francoise

Subjects
Male, Aging, Proteome, Disease, Kidney, Biochemistry, Mass Spectrometry, Diabetic nephropathy, MESH: Child, Diabetic Nephropathies, MESH: Aging, Child, MESH: Aged, MESH: Middle Aged, MESH: Peptides, Middle Aged, MESH: Proteome, medicine.anatomical_structure, Child, Preschool, Female, Adult, medicine.medical_specialty, Adolescent, MESH: Diabetic Nephropathies, Urinary system, Renal function, Article, Internal medicine, medicine, Humans, Molecular Biology, Aged, MESH: Adolescent, MESH: Mass Spectrometry, MESH: Humans, business.industry, MESH: Child, Preschool, MESH: Biological Markers, Kidney metabolism, MESH: Adult, MESH: Kidney, medicine.disease, MESH: Male, Endocrinology, Peptides, business, MESH: Female, Biomarkers, Kidney disease
Abstract

International audience; Aging induces morphological changes of the kidney and reduces renal function. We analyzed the low molecular weight urinary proteome of 324 healthy individuals from 2-73 years of age to gain insight on human renal aging. We observed age-related modification of secretion of 325 out of over 5000 urinary peptides. The majority of these changes were associated with renal development before and during puberty, while 49 peptides were related to aging in adults. We therefore focussed the remainder of the study on these 49 peptides. The majority of these 49 peptides were also markers of chronic kidney disease, suggesting high similarity between aging and chronic kidney disease. Blinded evaluation of samples from healthy volunteers and diabetic nephropathy patients confirmed both the correlation of biomarkers with aging and with renal disease. Identification of a number of these aging-related peptides led us to hypothesize that reduced proteolytic activity is involved in human renal aging. Finally, among the 324 supposedly healthy individuals, some had urinary aging-related peptide excretion patterns typical of an individual significantly older than their actual age. In conclusion, these aging-related biomarkers may allow noninvasive detection of renal lesions in healthy persons and show high resemblance between human aging and chronic kidney disease. This similarity has to be taken into account when searching for biomarkers of renal disease.

Published
2009
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21. Comparison of different statistical approaches for urinary peptide biomarker detection in the context of coronary artery disease

Author

Joost P. Schanstra, Thomas Koeck, Esther Nkuipou-Kenfack, Eleanor Stanley, William Spooner, Harald Mischak, Walter Kolch, Eleni Ioanna Delatola, The Biodata Innovation Centre [Cambridge, U.K.], Eagle Genomics Ltd [Cambridge, U.K.], Systems Biology Ireland, University College Dublin [Dublin] (UCD), Mosaiques Diagnostics GmbH [Hannover, Germany], Mosaiques Diagnostics and Therapeutics AG [Hannover, Germany], Conway Institute of Biomolecular and Biomedical Research [Dublin, Irlande], School of Medicine and Medical Science [Dublin, Irlande], Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, and BMC, BMC

Subjects
Adult, Male, Proteomics, 0301 basic medicine, Wilcoxon signed-rank test, [SDV]Life Sciences [q-bio], Coronary Artery Disease, Computational biology, Biomarker detection, 030204 cardiovascular system & hematology, Bioinformatics, Biochemistry, Statistical power, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Structural Biology, Classifier modelling, Humans, Medicine, Biomarker discovery, Molecular Biology, Statistical proteome analysis, business.industry, Applied Mathematics, Discriminant Analysis, Middle Aged, Prognosis, Linear discriminant analysis, medicine.disease, Random forest, Computer Science Applications, Support vector machine, [SDV] Life Sciences [q-bio], 030104 developmental biology, Biomarker (medicine), Female, Peptides, business, Biomarkers, Research Article
Abstract

Background When combined with a clinical outcome variable, the size, complexity and nature of mass-spectrometry proteomics data impose great statistical challenges in the discovery of potential disease-associated biomarkers. The purpose of this study was thus to evaluate the effectiveness of different statistical methods applied for urinary proteomic biomarker discovery and different methods of classifier modelling in respect of the diagnosis of coronary artery disease in 197 study subjects and the prognostication of acute coronary syndromes in 368 study subjects. Results Computing the discovery sub-cohorts comprising \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ {\scriptscriptstyle \raisebox{1ex}{$2$}\!\left/ \!\raisebox{-1ex}{$3$}\right.} $$\end{document}23 of the study subjects based on the Wilcoxon rank sum test, t-score, cat-score, binary discriminant analysis and random forests provided largely different numbers (ranging from 2 to 398) of potential peptide biomarkers. Moreover, these biomarker patterns showed very little overlap limited to fragments of type I and III collagens as the common denominator. However, these differences in biomarker patterns did mostly not translate into significant differently performing diagnostic or prognostic classifiers modelled by support vector machine, diagonal discriminant analysis, linear discriminant analysis, binary discriminant analysis and random forest. This was even true when different biomarker patterns were combined into master-patterns. Conclusion In conclusion, our study revealed a very considerable dependence of peptide biomarker discovery on statistical computing of urinary peptide profiles while the observed diagnostic and/or prognostic reliability of classifiers was widely independent of the modelling approach. This may however be due to the limited statistical power in classifier testing. Nonetheless, our study showed that urinary proteome analysis has the potential to provide valuable biomarkers for coronary artery disease mirroring especially alterations in the extracellular matrix. It further showed that for a comprehensive discovery of biomarkers and thus of pathological information, the results of different statistical methods may best be combined into a master pattern that then can be used for classifier modelling. Electronic supplementary material The online version of this article (doi:10.1186/s12859-016-1390-1) contains supplementary material, which is available to authorized users.

Published
2016
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22. Assessment of Metabolomic and Proteomic Biomarkers in Detection and Prognosis of Progression of Renal Function in Chronic Kidney Disease

Author

Àngel Argilés, Petra Zürbig, Harald Mischak, Thomas Koeck, William Mullen, Holger Husi, Esther Nkuipou-Kenfack, Nathalie Gayrard, Flore Duranton, Julie Klein, Ulrika Lundin, Christian Delles, Klaus M. Weinberger, Mohammed Dakna, Hannover Medical School [Hannover] (MHH), RD-Néphrologie (R&D), Biocommunication en Cardio-Métabolique (BC2M), Université de Montpellier (UM), Néphrologie Dialyse Saint Guilhem (NDSG), Mosaiques Diagnostics and Therapeutics, Mosaiques diagnostics and therapeutics, University of Glasgow, and Institute of Cardiovascular and Medical Sciences [Glasgow]

Subjects
Proteomics, Male, Pathology, Metabolite, Urine, 030204 cardiovascular system & hematology, Pathology and Laboratory Medicine, Kidney, Biochemistry, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, chemistry.chemical_compound, 0302 clinical medicine, Chronic Kidney Disease, Medicine and Health Sciences, 0303 health sciences, Multidisciplinary, Prognosis, 3. Good health, medicine.anatomical_structure, Nephrology, Disease Progression, Medicine, Biomarker (medicine), Female, Research Article, Glomerular Filtration Rate, medicine.medical_specialty, Science, Urinary system, Urology, Renal function, Biology, 03 medical and health sciences, Metabolomics, Diagnostic Medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, Renal Insufficiency, Chronic, Aged, 030304 developmental biology, Biology and Life Sciences, medicine.disease, chemistry, Biomarkers, Follow-Up Studies, Kidney disease
Abstract

International audience; Chronic kidney disease (CKD) is part of a number of systemic and renal diseases and may reach epidemic proportions over the next decade. Efforts have been made to improve diagnosis and management of CKD. We hypothesised that combining metabolomic and proteomic approaches could generate a more systemic and complete view of the disease mechanisms. To test this approach, we examined samples from a cohort of 49 patients representing different stages of CKD. Urine samples were analysed for proteomic changes using capillary electrophoresis-mass spectrometry and urine and plasma samples for metabolomic changes using different mass spectrometry-based techniques. The training set included 20 CKD patients selected according to their estimated glomerular filtration rate (eGFR) at mild (59.9616.5 mL/min/1.73 m 2 ; n = 10) or advanced (8.964.5 mL/min/1.73 m 2 ; n = 10) CKD and the remaining 29 patients left for the test set. We identified a panel of 76 statistically significant metabolites and peptides that correlated with CKD in the training set. We combined these biomarkers in different classifiers and then performed correlation analyses with eGFR at baseline and follow-up after 2.860.8 years in the test set. A solely plasma metabolite biomarker-based classifier significantly correlated with the loss of kidney function in the test set at baseline and follow-up (r = 20.8031; p,0.0001 and r = 20.6009; p = 0.0019, respectively). Similarly, a urinary metabolite biomarker-based classifier did reveal significant association to kidney function (r = 20.6557; p = 0.0001 and r = 20.6574; p = 0.0005). A classifier utilising 46 identified urinary peptide biomarkers performed statistically equivalent to the urinary and plasma metabolite classifier (r = 20.7752; p,0.0001 and r = 20.8400; p,0.0001). The combination of both urinary proteomic and urinary and plasma metabolic biomarkers did not improve the correlation with eGFR. In conclusion, we found excellent association of plasma and urinary metabolites and urinary peptides with kidney function, and disease progression, but no added value in combining the different biomarkers data.

Published
2014
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23. Fetal Urinary Peptides to Predict Postnatal Outcome of Renal Disease in Fetuses with Posterior Urethral Valves (PUV)

Author

Cécile Caubet, Justyna Siwy, Bernard Monsarrat, Flavio Bandin, Benjamin Breuil, Mohammed Dakna, Chrystelle Lacroix, Julie Klein, Joost P. Schanstra, Jean-Loup Bascands, Françoise Muller, Harald Mischak, Angelique Stalmach, Petra Zürbig, Stéphane Decramer, William Mullen, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Mosaiques Diagnostics and Therapeutics, Mosaiques diagnostics and therapeutics, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Néphrologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Plateau de Protéomique des Liquides Biologiques, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse]-Institut of Cardiovascular and Metabolic Disease, BHF Glasgow Cardiovascular Research Centre, University of Glasgow-Institute of Cardiovascular & Medical Sciences, Pédiatrie - Néphrologie, Médecine interne, Hypertension, CHU Toulouse [Toulouse], Centre De Référence des Maladies Rénales Rares du Sud Ouest (SORARE), Centre De Référence des Maladies Rénales Rares du Sud Ouest, Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Service Néphrologie, médecine interne et hypertension pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
Male, Pathology, medicine.medical_specialty, Urinary system, 030232 urology & nephrology, Urology, Renal function, Urine, Mass Spectrometry, Ultrasonography, Prenatal, 03 medical and health sciences, 0302 clinical medicine, Fetus, Pregnancy, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, 0303 health sciences, Kidney, business.industry, Electrophoresis, Capillary, Infant, General Medicine, medicine.disease, 3. Good health, medicine.anatomical_structure, In utero, Female, Kidney Diseases, business, Peptides, Kidney disease
Abstract

International audience; Bilateral congenital abnormalities of the kidney and urinary tract (CAKUT), although are individually rare diseases, remain the main cause of chronic kidney disease in infants worldwide. Bilateral CAKUT display a wide spectrum of pre- and postnatal outcomes ranging from death in utero to normal postnatal renal function. Methods to predict these outcomes in utero are controversial and, in several cases, lead to unjustified termination of pregnancy. Using capillary electrophoresis coupled with mass spectrometry, we have analyzed the urinary proteome of fetuses with posterior urethral valves (PUV), the prototypic bilateral CAKUT, for the presence of biomarkers predicting postnatal renal function. Among more than 4000 fetal urinary peptide candidates, 26 peptides were identified that were specifically associated with PUV in 13 patients with early end-stage renal disease (ESRD) compared to 15 patients with absence of ESRD before the age of 2. A classifier based on these peptides correctly predicted postnatal renal function with 88% sensitivity and 95% specificity in an independent blinded validation cohort of 38 PUV patients, outperforming classical methods, including fetal urine biochemistry and fetal ultrasound. This study demonstrates that fetal urine is an important pool of peptides that can predict postnatal renal function and thus be used to make clinical decisions regarding pregnancy.

Published
2013
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24. Human Proteinpedia enables sharing of human protein data

Author

Ron Bose, Jean-Charles Sanchez, Young Jin Lee, Marcus Bantscheff, Pia Hønnerup Jensen, Yunping Zhu, Jonathan C. Trinidad, Juan Martínez-Heredia, Michael Moran, Samir K. Brahmachari, Pierre Gagné, Kripa Shankari, Jeffrey C. Smith, Jose-Manuel Vidal-Taboada, James P. DeLany, Shi Jun Sheng, Ragna Rönnholm, Xosé R. Bustelo, Helene L. Cardasis, Erik Björling, Ole N. Jensen, Pavel Gromov, Michael J. Dunn, Xiaoyue Wang, Guy G. Poirier, Greg T. Cantin, Richard J. Simpson, Kenny Helsens, Ming Zhou, Sumio Sugano, Samir M. Hanash, Prashantha Hebbar, Y. L. Ramachandra, Jennifer E. Van Eyk, Rafael Oliva, Philip C. Andrews, Lennart Martens, Julio E. Celis, B. Abdul Rahiman, Alexander Mehrle, Feixia Chu, Richard D. Smith, Philip A. Cole, Leroi V. DeSouza, Stefan Wiemann, Joseph A. Loo, Bernhard Kuster, Mauno Vihinen, Peter Jung, David C. Muddiman, Jayson A. Falkner, Osamu Ohara, Fredrik Levander, Gerald W. Hart, Mukhtar Ahmed, T. S. Keshava Prasad, Eric W. Deutsch, Riaz Mohmood, Indu Kheterpal, Jeffrey M. Gimble, John R. Yates, Catherine Fenselau, Timothy D. Veenstra, Julian Vasilescu, Brian M. Balgley, Heiko Hermeking, Johanna Salonen, Rainer Pepperkok, Michael Lefevre, William S. Hancock, Visith Thongboonkerd, Tao Xu, Beerelli Seshi, Christine A. Miller, Florian Gnad, Ravi Sirdeshmukh, Arnaud Droit, Renu Goel, Maarit Takatalo, Emanuel F. Petricoin, Mathias Uhlén, Vitor M. Faça, Billy Wu, Robert J. Cotter, Angelo M. De Marzo, Mark E. McComb, Alma S Burlingame, Oliver Hofmann, Martine Morzel, Rajasree Menon, Denis F. Hochstrasser, Peter James, Matthew J. Sullivan, Robin Wait, K. W. Michael Siu, H. C. Harsha, Hainard Alexandre, Megan S. Lim, Winston Hide, Kris Gevaert, Harald Mischak, Thierry Sayd, Matthias Mann, Blagoy Blagoev, Gerard Cagney, Xiangming Fang, Ralph H. Hruban, James D. Morgan, Joel S. Bader, Samuel O. Purvine, Fuchu He, Robert Moritz, Rob M. Ewing, Daniel Figeys, Min-Seok Kwon, Kumaran Kandasamy, Reiko F. Kikuno, Masaaki Oyama, Cecilia Gelfi, Gilbert S. Omenn, James P. McRedmond, Pierre Lescuyer, Kojo S.J. Elenitoba-Johnson, Akhilesh Pandey, Joël Vandekerckhove, Karin Hjernø, Subburaman Mohan, Jens Rick, Kyla Pennington, Raghothama Chaerkady, Henrik Molina, David M Horn, Faith A. Hays, Young Ki Paik, Balamurugan Periaswamy, Giulio Superti-Furga, Roman Körner, Gerard Drewes, Jun Zhong, E. Dransfield, Suresh Mathivanan, Robert H. Rice, David K. Crockett, Thomas A. Neubert, Minna Lehvaslaiho, K. Shivakumar, Catherine E. Costello, Hyoung Joo Lee, Christian Löbke, Keiryn L. Bennett, Nieves Ibarrola, Ramars Amanchy, Petra Zürbig, Vivekananda Shetty, Natalie G. Ahn, Ulrike Korf, J. Daniel Navarro, Anuradha Nalli, Prasanna Ramachandran, David J. States, Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Biological Systems Engineering, University of Wisconsin-Madison, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria, Royal Institute of Technology [Stockholm] (KTH ), University of California [San Francisco] (UC San Francisco), University of California (UC), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Radiothérapie moléculaire (UMR 1030), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Qualité des Produits Animaux (QuaPA), Institut National de la Recherche Agronomique (INRA), Université Laval [Québec] (ULaval), British Antarctic Survey (BAS), Natural Environment Research Council (NERC), Chemistry and Biochemistry Department (University of Maryland), University of Maryland [College Park], University of Maryland System-University of Maryland System, Ottawa Institute of Systems Biology, University of Ottawa [Ottawa], Cabinet de Médecine Générale (Cabinet PG), Ville, Flanders Institute for Biotechnology, Beijing Institute of Radiation medicine, South African National Bioinformatics Institute (SANBI), University of the Western Cape (UWC), Département de science des protéines humaines [Genève], Université de Genève = University of Geneva (UNIGE)-Faculté de médecine [Genève], Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Fraunhofer German-Sino Lab for Mobile Communications (MCI), Fraunhofer Institute for Manufacturing Engineering and Automation (Fraunhofer IPA), Fraunhofer (Fraunhofer-Gesellschaft)-Fraunhofer (Fraunhofer-Gesellschaft), Max Planck Institute for Human Cognitive and Brain Sciences [Leipzig] (IMPNSC), Max-Planck-Gesellschaft, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Hôpitaux Universitaires de Genève (HUG), Department of Pathology, University of Utah, University of California [Los Angeles] (UCLA), Universiteit Gent = Ghent University (UGENT), Protein Analysis for Clinical Diagnosis and Pharmaceutical Research, Mosaiques Diagnostics and Therapeutics AG, Proteomics Resource Center, Rockfeller University, Auteur indépendant, Section des Sciences de la Terre, Université de Genève = University of Geneva (UNIGE), RIKEN Research Center for Allergy and Immunology, Yokohama (RCAI), Research Unit for Immune Homeostasis, Yonsei Proteome Research Center and Department of Biochemistry, Yonsei University, European Molecular Biology Laboratory [Heidelberg] (EMBL), Department of Molecular Pathology and Microbiology, Center for Applied Proteomics and Molecular Medicine-George Mason University [Fairfax], Axe cancer, Université Laval [Québec] (ULaval)-CHUQ Research Center, The University of Arizona Medical Center, University of Arizona, The University of Tokyo (UTokyo), Research Center for Molecular Medicine of the Austrian Academy of Sciences [Vienna, Austria] (CeMM ), Austrian Academy of Sciences (OeAW), Faculty of Biological and Environmental Sciences [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Medical Molecular Biology Unit, Mahidol University [Bangkok], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Department of Experimental Medical Science, Lund University [Lund], Tsinghua University [Beijing] (THU), Deutsches Krebsforschungszentrum, Institut d’Électronique, de Microélectronique et de Nanotechnologie - UMR 8520 (IEMN), Centrale Lille-Institut supérieur de l'électronique et du numérique (ISEN)-Université de Valenciennes et du Hainaut-Cambrésis (UVHC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF), Institut Européen des membranes (IEM), Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Mosaiques Diagnostics & Therapeutics AG, University of California [San Francisco] (UCSF), University of California, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), University of the Western Cape, Université de Genève (UNIGE)-Faculté de médecine [Genève], Radboud university [Nijmegen], Universiteit Gent = Ghent University [Belgium] (UGENT), University of Geneva [Switzerland], University of Helsinki, Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hochstrasser, Denis, Lescuyer, Pierre, Moritz, Robert, Pepperkok, Rainer, and Sanchez, Jean-Charles

Subjects
Proteomics, Proteomics methods, Internationality, Magnetic Resonance Spectroscopy, Proteome, Information storage, [SDV]Life Sciences [q-bio], Biomedical Engineering, Information Storage and Retrieval, Proteome/*chemistry/classification/*metabolism, Bioengineering, Computational biology, Biology, Bioinformatics, Databases, Protein, Applied Microbiology and Biotechnology, Data type, Peptide Mapping, 03 medical and health sciences, User-Computer Interface, ddc:576, ComputingMilieux_MISCELLANEOUS, Database Management Systems, Magnetic Resonance Spectroscopy/methods, 030304 developmental biology, 0303 health sciences, Internet, business.industry, Peptide mapping, Gene Expression Profiling, 030302 biochemistry & molecular biology, Information Storage and Retrieval/*methods, Peptide Mapping/methods, Gene Expression Profiling/*methods, Molecular Medicine, The Internet, Proteomics/methods, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Software, Biotechnology
Abstract

Proteomic technologies, such as yeast two-hybrid, mass spectrometry (MS), protein/peptide arrays and fluorescence microscopy, yield multi-dimensional data sets, which are often quite large and either not published or published as supplementary information that is not easily searchable. Without a system in place for standardizing and sharing data, it is not fruitful for the biomedical community to contribute these types of data to centralized repositories.

Published
2008
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25. Body fluid proteomics for biomarker discovery: lessons from the past hold the key to success in the future

Author

Anna Dominiczak, David M. Good, Jean-Loup Bascands, Joost P. Schanstra, Jan Novak, Harald Mischak, Visith Thongboonkerd, Joshua J. Coon, Department of Chemistry, University of Wisconsin-Madison, Medical Molecular Biology Unit, Mahidol University [Bangkok], Department of Microbiology, University of Alabama at Birmingham [ Birmingham] (UAB), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biomolecular Chemistry, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Mosaiques Diagnostics (GmbH), Mosaique Diagnostics, Simon, Marie Francoise, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Proteomics, MESH: Forecasting, Proteome, Biology, Bioinformatics, Biochemistry, MESH: Body Fluids, 03 medical and health sciences, 0302 clinical medicine, Biological fluids, Animals, Humans, MESH: Animals, Biomarker discovery, 030304 developmental biology, 0303 health sciences, MESH: Humans, MESH: Proteomics, MESH: Biological Markers, Reproducibility of Results, General Chemistry, Data science, Body Fluids, 3. Good health, Biomarker (cell), Clinical Practice, MESH: Proteome, MESH: Reproducibility of Results, 030220 oncology & carcinogenesis, Key (cryptography), Biomarkers, Forecasting
Abstract

International audience; Sparked by the article from Lescuyer and colleagues in a recent issue, we aim here to further encourage interest in and discussion of clinically relevant biomarker research. We express our view on proteomics for biomarker discovery by addressing multiple relevant issues, including the inherent differences between biological fluids (and how these differences affect current analytical approaches) and experimental design to maximize the efficiency of moving from the bench to the bedside. Herein, we also include suggestions for definition of the term "biomarker", based on the use of a set of universal characterization/validation requirements, and illustrate several recent examples of successful transitions of benchtop proteomic studies work to clinical practice.

Published
2007
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26. Predicting the clinical outcome of congenital unilateral ureteropelvic junction obstruction in newborn by urinary proteome analysis

Author

Michael Walden, Jean-Loup Bascands, François Bouissou, Joost P. Schanstra, Stefan Wittke, Harald Mischak, Stéphane Decramer, Petra Zürbig, Pharmacologie Moleculaire et Physiopathologie Renale, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Mosaiques Diagnostics & Therapeutics (MOSAIQUES DIAGNOSTICS & THERAPEUTICS), Mosaiques Diagnostics & Therapeutics AG, Bascands, Jean-Loup, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Time Factors, Proteome, 030232 urology & nephrology, Ureteropelvic junction, MESH: Kidney Pelvis, urologic and male genital diseases, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Severity of Illness Index, Mass Spectrometry, 0302 clinical medicine, MESH: Double-Blind Method, Kidney Pelvis, Prospective Studies, Prospective cohort study, 0303 health sciences, MESH: Infant, Newborn, General Medicine, Reference Standards, Prognosis, MESH: Case-Control Studies, MESH: Infant, MESH: Proteome, MESH: Reproducibility of Results, medicine.anatomical_structure, MESH: Reference Standards, Female, Blinded study, Ureteral Obstruction, medicine.medical_specialty, Urinary system, Urology, General Biochemistry, Genetics and Molecular Biology, MESH: Prognosis, Specimen Handling, 03 medical and health sciences, Double-Blind Method, Severity of illness, medicine, Humans, 030304 developmental biology, Noninvasive biomarkers, MESH: Mass Spectrometry, MESH: Humans, business.industry, Case-control study, MESH: Biological Markers, Infant, Newborn, Infant, Reproducibility of Results, Surgical correction, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, MESH: Prospective Studies, MESH: Male, Surgery, Case-Control Studies, business, MESH: Female, MESH: Severity of Illness, Biomarkers
Abstract

We analyzed urinary polypeptides from individuals with neonatal ureteropelvic junction (UPJ) obstruction to predict which individuals with this condition will evolve toward obstruction that needs surgical correction. We identified polypeptides that enabled diagnosis of the severity of obstruction and validated these biomarkers in urine collected in a prospective blinded study. Using these noninvasive biomarkers, we were able to predict, several months in advance and with 94% precision, the clinical evolution of neonates with UPJ obstruction.

Published
2006
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27. Haploinsufficiency of the mouse Tshz3 gene leads to kidney dysfunction

Author

Laurent Fasano, Colette Denis, Guylène Feuillet, Andy Saurin, Ahmed Fatmi, Thien Phong Vu Manh, Petra Zürbig, Joost P. Schanstra, Irene Sanchez-Martin, Xavier Caubit, Fabrice Richard, Pedro Magalhães, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Hannover Medical School [Hannover] (MHH), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Mosaiques Diagnostics GmbH, Fasano, Laurent, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 642937, ANR-17-CE16-0030-01 'TSHZ3inASD', Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France., Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0303 health sciences, Kidney, Stromal cell, urogenital system, Urinary system, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Wild type, Biology, Molecular biology, Phenotype, [SHS]Humanities and Social Sciences, Transcriptome, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, medicine, Haploinsufficiency, Renal pelvis, 030304 developmental biology
Abstract

Renal tract defects and autism spectrum disorder (ASD) deficits represent the phenotypic core of the 19q12 deletion syndrome caused by the loss of one copy of the TSHZ3 gene. While a proportion of Tshz3 heterozygous (Tshz3+/lacZ) mice display ureteral defects, no kidney defects have been reported in these mice. The purpose of this study was to characterize the expression of Tshz3 in adult kidney as well as the renal physiological consequences of embryonic haploinsufficiency of Tshz3 by analyzing the morphology and function of Tshz3 heterozygous adult kidney. Here, we described Tshz3 expression in the smooth muscle and stromal cells lining the renal pelvis, the papilla and glomerular endothelial cells (GEnCs) of the adult kidney. Histological analysis showed that Tshz3+/lacZ adult kidney had an average of 29% fewer glomeruli than wild type kidney. Transmission electron microscopy (TEM) of Tshz3+/lacZ glomeruli revealed ultrastructural defects. Compared to wild type, Tshz3+/lacZ mice showed no difference in their urine parameters but lower blood urea, phosphates, magnesium and potassium at 2 months of age. At the molecular level, transcriptome analysis identified differentially expressed genes related to inflammatory processes in Tshz3+/lacZ compare to wild type (WT; control) adult kidneys. Lastly, analysis of the urinary peptidome revealed 33 peptides associated with Tshz3+/lacZ adult mice. These results provide the first evidence that in the mouse Tshz3 haploinsufficiency leads to cellular, molecular and functional abnormalities in the adult mouse kidney.

Published
2021

28. Data Sharing Under the General Data Protection Regulation: Time to Harmonize Law and Research Ethics?

Author

Vlahou, Antonia, Hallinan, Dara, Apweiler, Rolf, Argiles, Angel, Beige, Joachim, Benigni, Ariela, Bischoff, Rainer, Black, Peter C, Boehm, Franziska, Céraline, Jocelyn, Chrousos, George P, Delles, Christian, Evenepoel, Pieter, Fridolin, Ivo, Glorieux, Griet, van Gool, Alain J, Heidegger, Isabel, Ioannidis, John P A, Jankowski, Joachim, Jankowski, Vera, Jeronimo, Carmen, Kamat, Ashish M, Masereeuw, Rosalinde, Mayer, Gert, Mischak, Harald, Ortiz, Alberto, Remuzzi, Giuseppe, Rossing, Peter, Schanstra, Joost P, Schmitz-Dräger, Bernd J, Spasovski, Goce, Staessen, Jan A, Stamatialis, Dimitrios, Stenvinkel, Peter, Wanner, Christoph, Williams, Stephen B, Zannad, Faiez, Zoccali, Carmine, Vanholder, Raymond, Afd Pharmacology, Pharmacology, Afd Pharmacology, Pharmacology, Biomedical Research Foundation of the Academy of Athens (BRFAA), Leibniz-Institut für Informationsinfrastruktur (FIZ Karlsruhe), Leibniz Association, European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, European Molecular Biology Laboratory [Hinxton], Biocommunication en Cardio-Métabolique (BC2M), Université de Montpellier (UM), Hôpital Lapeyronie [Montpellier] (CHU), KfH-Nierenzentrum und Klinikum St. Georg, Nephrologie, Leipzig, IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri', Department of Analytical Biochemistry, University of Groningen, Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Institut de Cancérologie de Strasbourg Europe (ICANS), Université de Strasbourg (UNISTRA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University Research Institute of Maternal and Child Health & Precision Medicine, National and Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Department of Microbiology, Immunology and Transplantation [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Department of Health Technologies, Tallinn University of Technology, Nephrology Section, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Department of Urology, Medizinische Universität Innsbruck, Departments of Medicine and of Epidemiology and Population Health and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Institute of Cardiovascular Research, RWTH Aachen University, Cancer Biology and Epigenetics Group, Portuguese Oncology Institute of Porto and Abel Salazar Institute of Biomedical Sciences, University of Porto, Division of Surgery, Department of Urology, The University of Texas MD Anderson Cancer Centre, Div. Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Department of Internal Medicine IV (Nephrology and Hypertension), Medizinische Universität Innsbruck, Mosaiques Diagnostics and Therapeutics AG [Hannover, Germany], Department of Nephrology and Hypertension, IIS - Fundación Jiménez Díaz-UAM, Steno Diabetes Center, University of Copenhagen, Franco-czech Laboratory for clinical research on obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Urologie 24, Nuremberg, and Department of Urology, Friedrich-Alexander University of Erlangen, Department of Nephrology, University Clinical Center Skopje, North Macedonia, Research Institute Alliance for the Promotion of Preventive Medicine, Mechelen, Belgium, Biomedical Science Group, University of Leuven, Bioartificial organs, Department of Biomaterials Science and Technology, Technical Medical Centre, University of Twente, Enschede, Department of Renal Medicine M99, Karolinska University Hospital, Stockholm, Department of Medicine, Division of Nephrology, University Hospital, Würzburg, Department of Surgery, Division of Urology, The University of Texas Medical Branch, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension of Reggio Calabria, National Council of Research, Institute of Clinical Physiology, European Kidney Health Alliance (EKHA), BOZEC, Erwan, National and Kapodistrian University of Athens (NKUA), University of Copenhagen = Københavns Universitet (UCPH), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Context (language use), Legislation, Harmonization, 030204 cardiovascular system & hematology, Ethics, Research, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Political science, Medicine and Health Sciences, Internal Medicine, media_common.cataloged_instance, Data Protection Act 1998, 030212 general & internal medicine, European union, media_common, Ethics, Research ethics, Research, informed consent, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Data sharing, ddc:340, biomedical research, Law, General Data Protection Regulation, Government Regulation, data management
Abstract

The General Data Protection Regulation (GDPR) became binding law in the European Union Member States in 2018, as a step toward harmonizing personal data protection legislation in the European Union. The Regulation governs almost all types of personal data processing, hence, also, those pertaining to biomedical research. The purpose of this article is to highlight the main practical issues related to data and biological sample sharing that biomedical researchers face regularly, and to specify how these are addressed in the context of GDPR, after consulting with ethics/legal experts. We identify areas in which clarifications of the GDPR are needed, particularly those related to consent requirements by study participants. Amendments should target the following: (1) restricting exceptions based on national laws and increasing harmonization, (2) confirming the concept of broad consent, and (3) defining a roadmap for secondary use of data. These changes will be achieved by acknowledged learned societies in the field taking the lead in preparing a document giving guidance for the optimal interpretation of the GDPR, which will be finalized following a period of commenting by a broad multistakeholder audience. In parallel, promoting engagement and education of the public in the relevant issues (such as different consent types or residual risk for re-identification), on both local/national and international levels, is considered critical for advancement. We hope that this article will open this broad discussion involving all major stakeholders, toward optimizing the GDPR and allowing a harmonized transnational research approach. ispartof: HYPERTENSION vol:77 issue:4 pages:1029-1035 ispartof: location:United States status: published

Published
2021
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29. Urinary peptides in heart failure: a link to molecular pathophysiology

Author

Shona M. Kerr, Javier Díez, Alex McConnachie, Faiez Zannad, William Mullen, Antonia Vlahou, Patrick Rossignol, Harald Mischak, Rafael Stroggilos, Vera Jankowski, Gerasimos Filippatos, Colette E. Jackson, Helle Bosselmann, Joost P. Schanstra, John J.V. McMurray, Jan A. Staessen, Agnieszka Latosinska, Zhenyu Zhang, Nicolas Girerd, Michaela Mischak, Christian Delles, Jane A. Cannon, Kasper Rossing, Archie Campbell, Andrew L. Clark, Alexandre Mebazaa, Ross T. Campbell, Morten Schou, Arantxa González, Tianlin He, Julia Raad, Mosaiques Diagnostics GmbH [Hanovre, Allemagne], Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), University of Hull [United Kingdom], Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Clínica Universidad de Navarra [Pamplona], Instituto de Investigación Sanitaria de Navarra [Pamplona, Spain] (IdiSNA), National and Kapodistrian University of Athens (NKUA), Attikon University Hospital, Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Service d'Anesthésie-Réanimation [AP-HP Hôpitaux Saint-Louis Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Biomedical Research Foundation of the Academy of Athens (BRFAA), Copenhagen University Hospital, University of Edinburgh, Western General Hospital, Edinburgh, Queen Elizabeth University Hospital (Glasgow), Harefield Hospital, Harefield, Herlev and Gentofte Hospital, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospitals Leuven [Leuven], Non-Profit Research Institution Alliance for the Promotion of Preventive Medicine, AC, CD, JD, AG, AM, JR, NG, PR, FZ, HM, ZZ, JS, AL are supported by the EU Commission via the HOMAGE (HEALTH-FP7–305507 HOMAGE) project. CD, FZ, HM, JD and JS were previously supported by the EU-MASCARA (HEALTH-FP7–278249) project, and CD and JM receive support from the British Heart Foundation (RE/18/6/34217). TH is supported by the EU Commission via the CaReSyAn Project (MSCA-ITN-2017-Project ID: 764474). VJ is supported by the Deutsche Forschungsgemeinschaft' (DFG, German Research Foundation) by the Transregional Collaborative Research Centre (TRR 219, Project-ID 322900939) (subproject S-03). PR, NG, FZ are supported by the RHU Fight-HF, a public grant overseen by the French National Research Agency (ANR) as part of the second ‘Investissements d'Avenir’ program (reference: ANR-15-RHUS-0004), and by the French PIA project ‘Lorraine Université d'Excellence’(reference: ANR-15-IDEX-04-LUE). The Stanislas Cohort is sponsored by Nancy CHRU (France), its biobanking is managed by Biological Resource Center Lorrain BB-0033-00035. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767/Z/19/Z]. The non-profit Research Institute Alliance for the Promotion of Preventive Medicine received a non-binding grant from OMRON Healthcare Co., Inc., Kyoto, Japan., ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), ANR-15-IDEX-0004,LUE,Isite LUE(2015), European Project: 305507,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,HOMAGE(2013), European Project: 278249,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,EU-MASCARA(2011), European Project: 764474,CaReSyAn Project, RWTH Aachen University, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Université Sorbonne Paris Nord, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
collagen, medicine.medical_specialty, Proteome, Urinary system, proteome, Renal function, heart failure, 030204 cardiovascular system & hematology, Urine, Ventricular Function, Left, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Fibrosis, Diabetes mellitus, Internal medicine, medicine, Humans, Heart Failure, Ejection fraction, business.industry, fibrosis, Stroke Volume, Biomarker, medicine.disease, Prognosis, urine, 3. Good health, Blood pressure, Stroke Volume/physiology, Heart failure, Cardiology, Biomarker (medicine), biomarker, Collagen, Ventricular Function, Left/physiology, Cardiology and Cardiovascular Medicine, business, Peptides
Abstract

AIMS: Heart failure (HF) is a major public health concern worldwide. The diversity of HF makes it challenging to decipher the underlying complex pathological processes using single biomarkers. We examined the association between urinary peptides and HF with reduced (HFrEF), mid-range (HFmrEF) and preserved (HFpEF) ejection fraction, defined based on the European Society of Cardiology guidelines, and the links between these peptide biomarkers and molecular pathophysiology. METHODS AND RESULTS: Analysable data from 5608 participants were available in the Human Urinary Proteome database. The urinary peptide profiles from participants diagnosed with HFrEF, HFmrEF, HFpEF and controls matched for sex, age, estimated glomerular filtration rate, systolic and diastolic blood pressure, diabetes and hypertension were compared applying the Mann-Whitney test, followed by correction for multiple testing. Unsupervised learning algorithms were applied to investigate groups of similar urinary profiles. A total of 577 urinary peptides significantly associated with HF were sequenced, 447 of which (77%) were collagen fragments. In silico analysis suggested that urinary biomarker abnormalities in HF principally reflect changes in collagen turnover and immune response, both associated with fibrosis. Unsupervised clustering separated study participants into two clusters, with 83% of non-HF controls allocated to cluster 1, while 65% of patients with HF were allocated to cluster 2 (P

Published
2021
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30. Serum and urinary biomarkers of collagen type‐I turnover predict prognosis in patients with heart failure

Author

Joost P. Schanstra, Begoña López, Lutgarde Thijs, Yu-Ling Yu, Jan A. Staessen, Vera Jankowski, Andrew L. Clark, Javier Díez, Harald Mischak, Jesus D. Melgarejo, Zhenyu Zhang, Antonia Vlahou, Arantxa González, Tianlin He, Agnieszka Latosinska, John G.F. Cleland, Mosaiques Diagnostics GmbH [Hanovre, Allemagne], RWTH Aachen University, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Hull [United Kingdom], Clínica Universidad de Navarra [Pamplona], Institute of Health Carlos III, University Clinic of Navarra - CUN [Pamplona, Spain], University of Glasgow, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomedical Research Foundation of the Academy of Athens (BRFAA), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), and Schanstra, Joost

Subjects
[SDV]Life Sciences [q-bio], Medicine (miscellaneous), Context (language use), Research & Experimental Medicine, 030204 cardiovascular system & hematology, Bioinformatics, Letter to Editor, Collagen Type I, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, EXTRACELLULAR-MATRIX, medicine, Humans, Risk factor, Pathological, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Heart Failure, Collagen type, 0303 health sciences, Science & Technology, business.industry, Organ dysfunction, Reproducibility of Results, Prognosis, medicine.disease, R1, Biobank, 3. Good health, [SDV] Life Sciences [q-bio], Oncology, Medicine, Research & Experimental, Heart failure, Cohort, Molecular Medicine, medicine.symptom, business, Life Sciences & Biomedicine, Biomarkers, Follow-Up Studies
Abstract

Clinical and translational medicine 11(1), e267 (2021). doi:10.1002/ctm2.267, Published by Wiley, Hoboken, NJ

Published
2021
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31. Connectivity mapping of glomerular proteins identifies dimethylaminoparthenolide as a new inhibitor of diabetic kidney disease

Author

Julie Klein, Cécile Caubet, Mylène Camus, Manousos Makridakis, Colette Denis, Marion Gilet, Guylène Feuillet, Simon Rascalou, Eric Neau, Luc Garrigues, Olivier Thillaye du Boullay, Harald Mischak, Bernard Monsarrat, Odile Burlet-Schiltz, Antonia Vlahou, Jean Sébastien Saulnier-Blache, Jean-Loup Bascands, Joost P. Schanstra, Equipe 7 Inserm U1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Evotec (France) SAS [Toulouse], Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Biomedical Research Foundation of the Academy of Athens (BRFAA), Laboratoire Hétérochimie Fondamentale et Appliquée (LHFA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), Mosaiques Diagnostics GmbH [Hanovre, Allemagne], Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Evotec [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Saulnier-Blache, Jean Sébastien, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Proteomics, Male, [SDV]Life Sciences [q-bio], Kidney Glomerulus, lcsh:Medicine, Angiotensin-Converting Enzyme Inhibitors, Diabetic nephropathy, Article, Renin-Angiotensin System, Angiotensin Receptor Antagonists, Mice, Chronic kidney disease, Connectome, Animals, Diabetic Nephropathies, lcsh:Science, Kidney diseases, Drug discovery, lcsh:R, Diagnostic markers, Computational biology and bioinformatics, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, Diabetes Mellitus, Type 1, Gene Expression Regulation, Nephrology, lcsh:Q, Sesquiterpenes, Biomarkers, Glomerular Filtration Rate
Abstract

International audience; Abstract While blocking the renin angiotensin aldosterone system (RAAS) has been the main therapeutic strategy to control diabetic kidney disease (DKD) for many years, 25–30% of diabetic patients still develop the disease. In the present work we adopted a systems biology strategy to analyze glomerular protein signatures to identify drugs with potential therapeutic properties in DKD acting through a RAAS-independent mechanism. Glomeruli were isolated from wild type and type 1 diabetic (Ins2Akita) mice treated or not with the angiotensin-converting enzyme inhibitor (ACEi) ramipril. Ramipril efficiently reduced the urinary albumin/creatine ratio (ACR) of Ins2Akita mice without modifying DKD-associated renal-injuries. Large scale quantitative proteomics was used to identify the DKD-associated glomerular proteins (DKD-GPs) that were ramipril-insensitive (RI-DKD-GPs). The raw data are publicly available via ProteomeXchange with identifier PXD018728. We then applied an in silico drug repurposing approach using a pattern-matching algorithm (Connectivity Mapping) to compare the RI-DKD-GPs’s signature with a collection of thousands of transcriptional signatures of bioactive compounds. The sesquiterpene lactone parthenolide was identified as one of the top compounds predicted to reverse the RI-DKD-GPs’s signature. Oral treatment of 2 months old Ins2Akita mice with dimethylaminoparthenolide (DMAPT, a water-soluble analogue of parthenolide) for two months at 10 mg/kg/d by gavage significantly reduced urinary ACR. However, in contrast to ramipril, DMAPT also significantly reduced glomerulosclerosis and tubulointerstitial fibrosis. Using a system biology approach, we identified DMAPT, as a compound with a potential add-on value to standard-of-care ACEi-treatment in DKD.

Published
2020
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32. Comparison of the amniotic fluid and fetal urine peptidome for biomarker discovery in renal developmental disease

Author

Fédou, Camille, Breuil, Benjamin, Golovko, Igor, Decramer, Stéphane, Magalhães, Pedro, Muller, Françoise, Dreux, Sophie, Zürbig, Petra, Klein, Julie, Schanstra, Joost, Buffin-Meyer, Bénédicte, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Mosaiques Diagnostics GmbH [Hanovre, Allemagne], Service de biochimie-hormonologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université de Paris (UP), École de Droit de Sciences Po (EdD), Sciences Po (Sciences Po), and Université Fédérale Toulouse Midi-Pyrénées

Subjects
Kidney diseases, Science, [SDV]Life Sciences [q-bio], Paediatrics, Gestational Age, Paediatric research, Amniotic Fluid, Article, Prognostic markers, Pregnancy, Pregnancy Trimester, Second, Medicine, Humans, Female, Peptides, Biomarkers, Retrospective Studies
Abstract

International audience; Abstract Production of amniotic fluid (AF) is view as predominately driven by excretion of fetal urine (FU). However, the origin of AF peptides, often considered as potential biomarkers of developmental diseases, has never been investigated. Here, we evaluated the FU origin of AF peptides and if the AF peptide content can be used as a surrogate of FU. The abundance of endogenous peptides was analyzed by capillary electrophoresis coupled to mass spectrometry in 216 AF and 64 FU samples. A total of 2668 and 3257 peptides was found in AF and FU respectively. The AF peptidome largely overlapped with the FU peptidome, ranging from 54% in the second pregnancy trimester to 65% in the third trimester. Examination of a subset of 16 paired AF and FU samples revealed that 67 peptides displayed a significant positively correlated abundance in AF and FU, strongly suggesting that their presence in AF was directly associated to FU excretion. As proof-of-concept we showed that measuring the AF abundance of these 67 peptides of FU origin allowed prediction of postnatal renal survival in fetuses with posterior urethral valves. These results demonstrate that the AF peptidome can be considered as a good surrogate of the FU peptidome.

Published
2020
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33. Amniotic fluid peptides predict postnatal kidney survival in developmental kidney disease

Author

Romain Favre, Marie-Pierre Lavocat, Bernard Boudailliez, Charlotte Lucas, Camille Fédou, Jean-Sebastien Saulnier Blache, Anne-Sophie Weingertner, Blandine Hougas, Joost P. Schanstra, Pascal Gaucherand, Sylvie Cloarec, Julie Batut, Catherine Noel, J. Gondry, Philippe Eckart, Norbert Winer, Benjamin Breuil, Gérard Champion, Jean-Baptiste Benevent, Franck Perrotin, Christophe Vayssière, Florence Biquard, Harald Mischak, Gwenaelle Le Bouar, Jérôme Massardier, Françoise Conte Auriol, Pedro Magalhães, Sophie Martin, Jean-Paul Bory, Sophie Collardeau-Frachon, Eve Mousty, Lucie Bessenay, Corinne Floch, Julie Klein, Amelie Ryckewaert, Elisabeth Simon, Alain Martin, Guylène Bourdat-Michel, Marie-Françoise Froute, Franz Schaefer, Pascale Marcorelles, Stéphane Decramer, Nabila Moussaoui, Franck Boizard, Marie-Christine Manca-Pellissier, Mariannick Maupin-Hyvonnet, Marion Groussolles, Jean-Marie Delbosc, Guylène Feuillet, Anke Raaijmakers, François Nobili, Sophie Taque, Petra Zürbig, Vincent Guigonis, Audrey Casemayou, Patrick Blader, An Hindryckx, Luc Decatte, Karel Allegaert, Ophélie Lescat, Eric Neau, Odile Basmaison, Emma Allain-Launay, Agnes Sartor, Jean-Loup Bascands, Claudine Le Vaillant, Hélène Laurichesse Delmas, Bénédicte Buffin-Meyer, Nadia Lounis, Anne-Hélène Saliou, Véronique Baudouin, Elena Levtchenko, Maryse Fiorenza, Christine Pietrement, Valérie Goua, Marina Merveille, Laurent Bidat, Yves Aubard, Alexandra Benachi, Sylvie Kessler, Loic De Parscau, Jean-François Oury, Fabienne Prieur, Centre de biologie du développement (CBD), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Equipe 7 Inserm U1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées, University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Laboratoire de Gérontechnologie [Hôpital La Grave-CHU de Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Gérontopôle, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Gatien de Clocheville [Tours] (CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Clermont-Ferrand, Centre hospitalier universitaire de Nantes (CHU Nantes), Groupe de Recherche sur l'Analyse Multimodale de la Fonction Cérébrale - UMR INSERM_S 1105 (GRAMFC), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Amiens-Picardie, Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Centre Hospitalier René Dubos [Pontoise], Hôpital Louis Mourier - AP-HP [Colombes], Centre Hospitalier Universitaire [Grenoble] (CHU), Les Hôpitaux Universitaires de Strasbourg (HUS), AP-HP Hôpital universitaire Robert-Debré [Paris], Centre Hospitalier Universitaire de Reims (CHU Reims), Hospices Civils de Lyon (HCL), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Centre de dépistage des Carmes [Toulouse] (CDC), Hôpital des Enfants, CHU Toulouse [Toulouse], Laboratoire sur les interactions Epithéliums Neurones (LIEN), Université de Brest (UBO), Département de Pathologie [CHU Lyon-Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Mosaiques Diagnostics & Therapeutics AG [Hannover, Germany], University of Glasgow, Hannover Medical School [Hannover] (MHH), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Heidelberg University, Centre De Référence des Maladies Rénales Rares du Sud Ouest (SORARE), Centre De Référence des Maladies Rénales Rares du Sud Ouest, BIOMAN consortium: Karel Allegaert, Yves Aubard, Odile Basmaison, Jean-Baptiste Benevent, Florence Biquard, Gérard Champion, Jean-Marie Delbosc, Philippe Eckart, Marie-Françoise Froute, Pascal Gaucherand, Marion Groussolles, Vincent Guigonis, Blandine Hougas, Gwenaelle Le Bouar, Alain Martin, Sophie Martin, Mariannick Maupin-Hyvonnet, Marina Merveille, Eve Mousty, François Nobili, Amelie Ryckewaert, Agnes Sartor, Sophie Taque, Norbert Winer, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Development and Regeneration, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Gérontopôle-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse], Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clocheville, Department of Pediatric and Prenatal Radiology, Timone's Children-Hospital (APHM), Hôpital Dupuytren [CHU Limoges], CHU Toulouse, Hôpital des Enfants, Unité de Gastroentérologie, Hépatologie et Nutrition, Département de Pédiatrie, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Groupement Hospitalier Est [Bron], University Medical Center Heidelberg, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Saulnier-Blache, Jean Sébastien, Pôle Gériatrie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), and Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Amniotic fluid, Urinary system, [SDV]Life Sciences [q-bio], congenital anomalies of the kidney and the urinary tract, 030232 urology & nephrology, Kidney, Fetal Kidney, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, medicine, Animals, Humans, termination of pregnancy, Prospective Studies, Child, Urinary Tract, Zebrafish, ComputingMilieux_MISCELLANEOUS, Fetus, business.industry, infants, Area under the curve, amniotic fluid, prediction, medicine.disease, 3. Good health, Pronephros, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Nephrology, Urogenital Abnormalities, peptides, Female, Kidney Diseases, business, management, Kidney disease
Abstract

Although a rare disease, bilateral congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of end stage kidney disease in children. Ultrasound-based prenatal prediction of postnatal kidney survival in CAKUT pregnancies is far from accurate. To improve prediction, we conducted a prospective multicenter peptidome analysis of amniotic fluid spanning 140 evaluable fetuses with CAKUT. We identified a signature of 98 endogenous amniotic fluid peptides, mainly composed of fragments from extracellular matrix proteins and from the actin binding protein thymosin-β4. The peptide signature predicted postnatal kidney outcome with an area under the curve of 0.96 in the holdout validation set of patients with CAKUT with definite endpoint data. Additionally, this peptide signature was validated in a geographically independent sub-cohort of 12 patients (area under the curve 1.00) and displayed high specificity in non-CAKUT pregnancies (82 and 94% in 22 healthy fetuses and in 47 fetuses with congenital cytomegalovirus infection respectively). Change in amniotic fluid thymosin-β4 abundance was confirmed with ELISA. Knockout of thymosin-β4 in zebrafish altered proximal and distal tubule pronephros growth suggesting a possible role of thymosin β4 in fetal kidney development. Thus, recognition of the 98-peptide signature in amniotic fluid during diagnostic workup of prenatally detected fetuses with CAKUT can provide a long-sought evidence base for accurate management of the CAKUT disorder that is currently unavailable. ispartof: KIDNEY INTERNATIONAL vol:99 issue:3 pages:737-749 ispartof: location:United States status: published

Published
2020
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34. Associations of urinary polymeric immunoglobulin receptor peptides in the context of cardio-renal syndrome

Author

Vera Jankowski, Tianlin He, Justyna Siwy, Harald Mischak, Joost P. Schanstra, William Mullen, Petra Zürbig, Jochen Metzger, Mosaiques Diagnostics GmbH [Hanovre, Allemagne], Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), RWTH Aachen University, University of Glasgow, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant number 764474. Joost P. Schanstra was supported by the 'Fondation pour la Recherche Médicale' (grant number DEQ20170336759)., Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), and Bodescot, Myriam

Subjects
Proteomics, Adult, Male, Proteases, Secretory component, Urinary system, Cardiology, lcsh:Medicine, Immunoglobulins, Peptide, Context (language use), 030204 cardiovascular system & hematology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], lcsh:Science, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030304 developmental biology, Aged, chemistry.chemical_classification, 0303 health sciences, Multidisciplinary, biology, Cardio-Renal Syndrome, lcsh:R, Receptors, Polymeric Immunoglobulin, Middle Aged, Molecular biology, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Secretory Component, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, chemistry, Nephrology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Proteome, biology.protein, lcsh:Q, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Antibody, Polymeric immunoglobulin receptor, Peptides, Biomarkers, Glomerular Filtration Rate
Abstract

The polymeric immunoglobulin receptor (pIgR) transports immunoglobulins from the basolateral to the apical surface of epithelial cells. PIgR was recently shown to be associated with kidney dysfunction. The immune defense is initiated at the apical surface of epithelial cells where the N-terminal domain of pIgR, termed secretory component (SC), is proteolytically cleaved and released either unbound (free SC) or bound to immunoglobulins. The aim of our study was to evaluate the association of pIgR peptides with the cardio-renal syndrome in a large cohort and to obtain information on how the SC is released. We investigated urinary peptides of 2964 individuals available in the Human Urine Proteome Database generated using capillary electrophoresis coupled to mass spectrometry. The mean amplitude of 23 different pIgR peptides correlated negatively with the estimated glomerular filtration rate (eGFR, rho = −0.309, p

Published
2020
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35. Apelin affects the mouse aging urinary peptidome with minimal effects on kidney

Author

Claire, Vinel, Joost P, Schanstra, Franck, Boizard, Ophélie, Péreira, Johanna, Auriau, Alizée, Dortignac, Benjamin, Breuil, Guylène, Feuillet, Esther, Nkuipou-Kenfack, Petra, Zürbig, Philippe, Valet, Jean-Loup, Bascands, Cédric, Dray, Colette, Denis, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Mosaiques Diagnostics GmbH, Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Schanstra, Joost

Subjects
Aging, Apelin Receptors, Support Vector Machine, Proteome, [SDV]Life Sciences [q-bio], lcsh:R, lcsh:Medicine, Apoptosis, Kidney, Models, Biological, Article, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Mice, Ageing, Autophagy, Animals, Apelin, Intercellular Signaling Peptides and Proteins, lcsh:Q, Amino Acid Sequence, RNA, Messenger, Peptides, lcsh:Science, Glomerular Filtration Rate
Abstract

International audience; Kidney function is altered by age together with a declined filtration capacity of 5-10% per decade after 35 years. Renal aging shares many characteristics with chronic kidney disease. Plasma levels of the bioactive peptide apelin also decline with age and apelin has been shown to be protective in chronic kidney disease. Therefore we evaluated whether apelin could also improve aging-induced renal lesions and function in mice. Since urine is for the major part composed of proteins and peptides originating from the kidney, we first studied apelin-induced changes, in the aging urinary peptidome. Despite the recently published age-associated plasma decrease of apelin, expression of the peptide and its receptor was increased in the kidneys of 24 months old mice. Twenty-eight days treatment with apelin significantly modified the urinary peptidome of 3 and 24 months old mice towards a signature suggesting more advanced age at 3 months, and a younger age at 24 months. The latter was accompanied by a decreased staining of collagen (Sirius red staining) in 24 months old apelin-treated mice, without changing aging-induced glomerular hypertrophy. In addition, apelin was without effect on aging-induced renal autophagy, apoptosis, inflammation and reduced renal function. In conclusion, treatment of aged mice with apelin had a limited effect on kidney lesions although modifying the urinary peptidome towards a younger signature. This supports evidence of apelin inducing more general beneficial effects on other aging organs, muscles in particular, as recently shown for sarcopenia, markers of which end up via the glomerular filtration in urine.

Published
2019
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36. Proteomics based identification of KDM5 histone demethylases associated with cardiovascular disease

Author

William Mullen, Jean-Loup Bascands, Burkert Pieske, Jean Sébastien Saulnier-Blache, Julie Klein, Joost P. Schanstra, Maria G. Roubelakis, Vasiliki Bitsika, Antonia Vlahou, Marika Mokou, Jerome Zoidakis, Harald Mischak, Manousos Makridakis, Michael Sacherer, University of Athens Medical School [Athens], Equipe 7 Inserm U1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomedical Research Foundation of the Academy of Athens (BRFAA), Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), University of Glasgow, University of Graz, Berlin Institute of Health (BIH), Saulnier-Blache, Jean Sébastien, Biomedical Research Foundation of the Academy of Athens, Université Fédérale Toulouse Midi-Pyrénées, Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Karl-Franzens-Universität Graz, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Mosaiques Diagnostics GmbH, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Karl-Franzens-Universität [Graz, Autriche]

Subjects
0301 basic medicine, Apolipoprotein E, Male, Proteomics, Research paper, Angiogenesis, Diabetic Cardiomyopathies, [SDV]Life Sciences [q-bio], Biology, General Biochemistry, Genetics and Molecular Biology, Mass Spectrometry, H3K4, Minor Histocompatibility Antigens, 03 medical and health sciences, Histone H3, Mice, 0302 clinical medicine, Human Umbilical Vein Endothelial Cells, Animals, Humans, KDM5, Histone Demethylases, Diabetes, Proteins, General Medicine, Atherosclerosis, Cardiovascular disease, 3. Good health, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030220 oncology & carcinogenesis, Proteome, biology.protein, Cancer research, H3K4me3, Demethylase
Abstract

Background The increased prevalence of cardiovascular disease (CVD) indicates a demand for novel therapeutic approaches. Proteome analysis of vascular tissues from animal models and humans with CVD could lead to the identification of novel druggable targets. Methods LC-MS/MS analysis of thoracic aortas from three mouse models of non-diabetic and diabetic (streptozotocin (STZ)-induced) atherosclerosis followed by bioinformatics/pathway analysis was performed. Selected findings were confirmed by proteomics analysis of human vessels from patients with CVD as well as in vitro studies (migration, proliferation, angiogenesis assays) using endothelial (HUVEC) cells. Findings Comparative tissue proteomics of low density lipoprotein receptor deficient (Ldlr−/−) and diabetic Ldlr−/− (Ldlr−/−STZ) with wild type (WT) animals led to the identification of 284 differentially expressed proteins in both models. Among them, 177 proteins were also differentially expressed in diabetic apolipoprotein E deficient (ApoE−/−STZ) mice, suggesting expression changes associated with atherosclerosis independent of the model used. These proteins recapitulated the hallmarks of atherosclerosis. Comparison of these findings with differentially expressed proteins in human vessels with CVD enabled shortlisting of six commonly dysregulated proteins. Among them, lysine-specific demethylase 5D (KDM5D) exhibited pronounced overexpression accompanied by a reduction in the protein levels of its substrate, the trimethylated lysine 4 of histone H3 (H3K4me3), in patients with CVD. Functional interference studies applying a KDM5 inhibitor on HUVEC reduced cell proliferation, migration and tube-forming ability in vitro. Interpretation This high-throughput proteomics strategy identified KDM5 histone demethylases being potentially involved in CVD, possibly by affecting H3K4 methylation. Fund [SysVasc, HEALTH-2013 603288], [ERA-CVD PROACT: ANR-17-ECVD-0006, 01KL1805], [FRM, DEQ20170336759].

Published
2019
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37. Comparative proteome and peptidome analysis of the cephalic fluid secreted by Arapaima gigas (Teleostei: Osteoglossidae) during and outside parental care

Author

Willian Mullen, Mary K. Doherty, L. S. Torati, Herve Migaud, Amaya Albalat, Pedro E. C. Mesquita, Justyna Siwy, LUCAS SIMON TORATI, CNPASA, HERVE MIGAUD, UNIVERSITY OF STIRLING, UK, MARY K. DOHERTY, UNIVERSITY OF THE HIGHLANDS AND ISLANDS, UK, JUSTYNA SIWY, MOSAIQUES DIAGNOSTICS GmbH, Hannover-Germany, WILLIAN MULLEN, UNIVERSITY OF GLASGOW, UK, PEDRO E. C. MESQUITA, DNOCS, and AMAYA ALBALAT, UNIVERSITY OF STIRLING, UK.

Subjects
0301 basic medicine, Male, Proteome, Physiology, Proteomes, ved/biology.organism_classification_rank.species, lcsh:Medicine, Bioinformatics, Care provision, Biochemistry, Capillary Electrophoresis, Tetraspanin, Arapaima gigas, Serotransferrin, Tandem Mass Spectrometry, Medicine and Health Sciences, lcsh:Science, Multidisciplinary, Behavior, Animal, Gene Ontologies, Fishes, Genomics, Body Fluids, Female, Alloparental behavior, Structural Proteins, Anatomy, Research Article, Offspring, Fish Biology, Biology, Research and Analysis Methods, Andrology, 03 medical and health sciences, Electrophoretic Techniques, Pirarucu, Genetics, Fish Physiology, Animals, Animal Physiology, Parental investment, Secretion, Peptidome, ved/biology, lcsh:R, Electrophoresis, Capillary, Biology and Life Sciences, Computational Biology, Proteins, Genome Analysis, Vertebrate Physiology, Mucus, 030104 developmental biology, lcsh:Q, Peptides, Physiological Processes, Peixe, Paternal care, Zoology, Chromatography, Liquid
Abstract

Parental investment in Arapaima gigas includes nest building and guarding, followed by a care provision when a cephalic fluid is released from the parents' head to the offspring. This fluid has presumably important functions for the offspring but so far its composition has not been characterised. In this study the proteome and peptidome of the cephalic secretion was studied in parental and non-parental fish using capillary electrophoresis coupled to mass spectrometry (CE-MS) and GeLC-MS/MS analyses. Multiple comparisons revealed 28 peptides were significantly different between males and parental males (PC-males), 126 between females and parental females (PC-females), 51 between males and females and 9 between PC-males and PC-females. Identification revealed peptides were produced in the inner ear (pcdh15b), eyes (tetraspanin and ppp2r3a), central nervous system (otud4, ribeye a, tjp1b and syn1) among others. A total of 422 proteins were also identified and gene ontology analysis revealed 28 secreted extracellular proteins. From these, 2 hormones (prolactin and stanniocalcin) and 12 proteins associated to immunological processes (serotransferrin, α-1-antitrypsin homolog, apolipoprotein A-I, and others) were identified. This study provides novel biochemical data on the lateral line fluid which will enable future hypotheses-driven experiments to better understand the physiological roles of the lateral line in chemical communication. Made available in DSpace on 2017-10-28T23:13:12Z (GMT). No. of bitstreams: 1 CNPASA2017plos.pdf: 6615081 bytes, checksum: 5b4346a70e2c175296d1aac3fed12435 (MD5) Previous issue date: 2017-10-27

Published
2017

38. Urinary Proteome Analysis at 5-Year Followup of Patients With Nonoperated Ureteropelvic Junction Obstruction Suggests Ongoing Kidney Remodeling

Author

Stéphane Decramer, Justyna Siwy, Joost P. Schanstra, Harald Mischak, Benjamin Breuil, Flavio Bandin, Jean-Loup Bascands, Service de Pédiatrie - Néphrologie, Médecine interne, Hypertension, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Référence du sud-Ouest des maladies rénales rares [CHU Toulouse] (SODARE), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Protein Analysis for Clinical Diagnosis and Pharmaceutical Research, Mosaiques Diagnostics and Therapeutics AG, British Heart Foundation - Glasgow Cardiovascular Research Center, (BHF - GCRC), University of Glasgow-Institute of Cardiovascular and Medical Sciences-Faculty of Medical, Veterinary and Life Sciences, Simon, Marie Francoise, CHU Toulouse [Toulouse]-Hôpital des Enfants, CHU Toulouse [Toulouse], Centre de Référence du sud-Ouest des maladies rénales rares, and CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]

Subjects
Male, MESH: Electrophoresis, Capillary, Proteome, medicine.medical_treatment, 030232 urology & nephrology, Kidney, Kidney Function Tests, urologic and male genital diseases, Mass Spectrometry, 0302 clinical medicine, MESH: Child, Medicine, Child, MESH: Statistics, Nonparametric, 0303 health sciences, MESH: Case-Control Studies, MESH: Watchful Waiting, 3. Good health, MESH: Proteome, medicine.anatomical_structure, MESH: Kidney Function Tests, Child, Preschool, Female, Ureteral Obstruction, medicine.medical_specialty, Urology, Urinary system, Renal function, Statistics, Nonparametric, 03 medical and health sciences, Humans, Watchful Waiting, Hydronephrosis, Retrospective Studies, 030304 developmental biology, MESH: Mass Spectrometry, MESH: Humans, business.industry, MESH: Child, Preschool, MESH: Biological Markers, Case-control study, Electrophoresis, Capillary, MESH: Retrospective Studies, Retrospective cohort study, MESH: Kidney, medicine.disease, MESH: Male, Surgery, Case-Control Studies, MESH: Ureteral Obstruction, business, MESH: Female, Biomarkers, Watchful waiting
Abstract

International audience; PURPOSE: Severe ureteropelvic junction obstruction is treated surgically. However, for milder cases most clinical teams adopt a watchful waiting approach and only operate in the presence of significant decline of renal function combined with severe hydronephrosis. Little is known about the long-term consequences of ureteropelvic junction obstruction. MATERIALS AND METHODS: Using capillary electrophoresis coupled with mass spectrometry, we analyzed the urinary proteome of 42 patients with ureteropelvic junction obstruction 5 years postoperatively or 5 years following spontaneous resolution. RESULTS: At 5-year followup urinary proteomes were similar between patients with early surgical correction of ureteropelvic junction obstruction and age matched controls. In contrast, urinary proteomes differed significantly between conservatively followed patients and controls. Analyses of the proteomic differences suggested ongoing renal or ureteral remodeling in the conservatively followed patients that was not visible clinically. CONCLUSIONS: Long-term followup studies are warranted in patients with ureteropelvic junction obstruction, especially those followed conservatively, to determine whether the observed changes in the urinary proteomes become clinically relevant at a later stage.

Published
2012
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39. Urinary proteome analysis identifies infants but not older children requiring pyeloplasty

Author

Joost P. Schanstra, Lars Pape, Jochen H. H. Ehrich, Eric Schiffer, Jean-Loup Bascands, Martin Kirschstein, Benno M. Ure, Sylvia Glüer, Jens Drube, Harald Mischak, Stéphane Decramer, Esther Lau, Petra Zürbig, Simon, Marie Francoise, Department of Pediatric Kidney, Hannover Medical School [Hannover] (MHH)-Children's Hospital, Mosaiques Diagnostics GmbH, Center of Pediatric Surgery Hannover, Bult site, Hannover Medical School [Hannover] (MHH), Pediatric Department, Celle General Hospital-Teaching Hospital of Hannover Medical School, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Proteomics, Nephrology, medicine.medical_specialty, Pediatrics, Pyeloplasty, Urinary system, medicine.medical_treatment, 030232 urology & nephrology, Hydronephrosis, Urine, Sensitivity and Specificity, Severity of Illness Index, Mass Spectrometry, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Germany, Internal medicine, medicine, Humans, Prospective Studies, Stage (cooking), Child, Prospective cohort study, 030304 developmental biology, 0303 health sciences, business.industry, Patient Selection, Age Factors, Electrophoresis, Capillary, Infant, medicine.disease, 3. Good health, Surgery, Proteinuria, Urodynamics, Treatment Outcome, Child, Preschool, Pediatrics, Perinatology and Child Health, Proteome, Urologic Surgical Procedures, Female, business, Biomarkers, Ureteral Obstruction
Abstract

International audience; One out of every five children suffering from ureteropelvic junction obstruction (UPJO) requires pyeloplasty. This prevalence indicates an urgent necessity to identify high-grade UPJO as early as possible to avoid renal damage. A novel non-invasive proteomic urine test has recently been introduced that is able to detect these patients at an early stage. In the study reported here, we tested this approach to assess its use in our centre and to expand its application to older children. Twenty-seven children (median age 0.4 years, range 0.1-8.8 years) with hydronephrosis who had been scheduled a nuclear diuretic renal scan (DR) to identify urodynamically relevant UPJO were included in our prospective study. Patients with prior surgery of the urinary tract were excluded. The urinary proteome pattern was analysed using capillary electrophoresis coupled to mass spectrometry. Of the 27 children, 11 had a relevant UPJO diagnosed by the DR. In 19 children

Published
2010
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40. Identification of urinary biomarkers by proteomics in newborns: use in obstructive nephropathy

Author

Joost P. Schanstra, Stefan Wittke, Stéphane Decramer, Jean-Loup Bascands, Petra Zürbig, Harald Mischak, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Mosaiques Diagnostics and Therapeutics AG, Simon, Marie Francoise, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Proteomics, medicine.medical_specialty, 030232 urology & nephrology, Ureteropelvic junction, MESH: Infant, Newborn, Diseases, Infant, Newborn, Diseases, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Humans, Medicine, Intensive care medicine, 030304 developmental biology, 0303 health sciences, MESH: Humans, business.industry, MESH: Proteomics, MESH: Infant, Newborn, Infant, Newborn, MESH: Biological Markers, Urinary biomarkers, Obstructive Nephropathy, 3. Good health, medicine.anatomical_structure, Identification (biology), MESH: Ureteral Obstruction, business, Biomarkers, Ureteral Obstruction
Abstract

International audience; An important issue in congenital unilateral ureteropelvic junction (UPJ) obstruction, a frequent pathology in newborns, is whether infants should undergo surgery. Non-invasive biomarkers to reduce or replace the current invasive clinical exploration are not available. The objective of this study was to identify urinary markers of UPJ obstruction. We compared a number of proteome technologies to study the urinary proteome in UPJ obstruction and selected online capillary electrophoresis coupled to mass-spectrometry for the selection of non-invasive prognostic biomarkers. We selected 53 urinary biomarkers that were able to distinguish between different levels of UPJ obstruction. In a prospective study using these 53 biomarkers, we predicted with 97% accuracy, and several months in advance, the clinical outcome of 36 UPJ-obstruction patients. Some of the discriminating biomarkers were identified. A newly identified marker, proSAAS (proprotein convertase subtilisin/kexin type 1 inhibitor), generated a new hypothesis in the physiopathology of UPJ obstruction. These results show that analysis of urinary polypeptides in newborns with UPJ obstruction can predict their clinical outcome.

Published
2008
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41. Addressing the Challenge of Defining Valid Proteomic Biomarkers and Classifiers

Author

Harald Mischak, Marion Haubitz, Mohammed Dakna, Joost P. Schanstra, Keith Harris, Sebastien Carpentier, Alexandros Kalousis, Walter Kolch, Antonia Vlahou, Mark Girolami, Mosaiques diagnostics and therapeutics, Water and Environment Research Group, University of Glasgow-School of Engineering, Computer Science Department, University of Geneva [Switzerland], Laboratory of Tropical Crop Improvement, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), The Beatson Institute for Cancer Research, University of Glasgow, Systems Biology Ireland, Conway Institute, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Nephrology (MHH), Hannover Medical School [Hannover] (MHH), Research Foundation, Academy of Athens, Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-Institute of Cardiovascular and Medical Sciences, Department of Statistical Science, University College of London [London] (UCL), Université de Genève = University of Geneva (UNIGE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and BMC, Ed.

Subjects
urinary proteome, MESH: Electrophoresis, Capillary, Male, Proteomics, Wilcoxon signed-rank test, sample-size, computer.software_genre, Biochemistry, Mass Spectrometry, 0302 clinical medicine, Reference Values, Structural Biology, Resampling, verification bias, Statistical analysis, lcsh:QH301-705.5, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], dna microarray data, MESH: Proteomics, Applied Mathematics, MESH: Reference Values, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Computer Science Applications, Wilcoxon-test, MESH: Young Adult, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], lcsh:R858-859.7, Female, Data mining, proteomic biomarkers, Algorithms, Research Article, Adult, MESH: Algorithms, Biology, lcsh:Computer applications to medicine. Medical informatics, Young Adult, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], cancer, Humans, biomarker definition, Molecular Biology, MESH: Sample Size, 030304 developmental biology, Biomarker Identification, MESH: Mass Spectrometry, disease, MESH: Humans, MESH: Biological Markers, Electrophoresis, Capillary, MESH: Adult, mass-spectrometry, MESH: Male, Data set, clinical proteomics, lcsh:Biology (General), Sample size determination, Sample Size, Verification bias, Potential biomarkers, Multiple comparisons problem, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], serum, MESH: Female, computer, discovery, Biomarkers
Abstract

Background The purpose of this manuscript is to provide, based on an extensive analysis of a proteomic data set, suggestions for proper statistical analysis for the discovery of sets of clinically relevant biomarkers. As tractable example we define the measurable proteomic differences between apparently healthy adult males and females. We choose urine as body-fluid of interest and CE-MS, a thoroughly validated platform technology, allowing for routine analysis of a large number of samples. The second urine of the morning was collected from apparently healthy male and female volunteers (aged 21-40) in the course of the routine medical check-up before recruitment at the Hannover Medical School. Results We found that the Wilcoxon-test is best suited for the definition of potential biomarkers. Adjustment for multiple testing is necessary. Sample size estimation can be performed based on a small number of observations via resampling from pilot data. Machine learning algorithms appear ideally suited to generate classifiers. Assessment of any results in an independent test-set is essential. Conclusions Valid proteomic biomarkers for diagnosis and prognosis only can be defined by applying proper statistical data mining procedures. In particular, a justification of the sample size should be part of the study design.

Published
2010
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42. Racial and regional disparities in the risk of noncommunicable disease between sub-Saharan black and European white patients.

Author

Yu YL, An DW, Chori BS, Kaleta BP, Mokwatsi G, Martens DS, Abiodun OO, Anya T, Łebek-Szatańska A, Yeh JS, Mels CMC, Latosinska A, Kruger R, Isiguzo G, Narkiewicz K, Shehu MN, Salazar M, Espeche W, Mujaj B, Brgulian-Hitij J, Olszanecka A, Wojciechowska W, Reyskens P, Rajzer M, Januszewicz A, Stolarz-Skrzypek K, Asayama K, Allegaert K, Verhamme P, Mischak H, Nawrot TS, Odili AN, and Staessen JA

Subjects
Humans, Female, Male, Middle Aged, Aged, Noncommunicable Diseases epidemiology, Risk Factors, Black People, Africa South of the Sahara epidemiology, Africa South of the Sahara ethnology, Europe epidemiology, Renal Insufficiency, Chronic epidemiology, Cardiovascular Diseases epidemiology, White People
Abstract

Objectives: Greater vulnerability of Black vs. White individuals to cardiovascular disease (CVD) and chronic kidney disease (CKD) is well charted in the United States, but studies involving sub-Saharan blacks are scarce., Methods: Baseline data (2021-2024) were collected in 168 sub-Saharan Blacks and 93 European Whites in an ongoing clinical trial (NCT04299529), using standardized patient selection criteria. Data included clinical and biochemical risk factors, ECG and echocardiographic traits, Framingham CVD risk, CKD grades (KDIGO 2024), self-assessed symptoms (WHO questionnaire), and urinary proteomic profiles predictive of left ventricular dysfunction (LVD) and CKD, HF1, and CKD273, respectively. Racial comparisons rested on unadjusted and multivariable-adjusted analyses., Results: Despite being younger (60.4 vs. 68.3 years), blacks had a worse risk profile, as evidenced by higher diabetes prevalence, higher BMI, faster heart rate, unfavourable serum cholesterol fractions, lower estimated glomerular filtration rate, microalbuminuria, and sedentary lifestyle. This resulted in blacks having higher 10-year CVD risk, higher heart age (index of vascular ageing with chronological age as reference), and a worse CKD grades. In both races, CKD273 increased with CKD grade, but CKD273 and HF1 were not different by race. These observations were robust in subgroup and adjusted analyses., Conclusion: This study did not differentiate host (genetic, molecular, and pathogenic) from environmental drivers of disease. Nonetheless, the findings call for a multipronged and comprehensive implementation of innovative health policies in sub-Saharan countries. Education, research, empowerment of stakeholders, and international learned societies connecting experts from a wide array of disciplines should vigorously sustain this effort., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Published
2025
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43. Clinical Proteomics, Quo Vadis?

Author

Mischak H, Schanstra JP, Vlahou A, and Beige J

Abstract

The field of clinical proteomics has seen enormous growth in the past 20 years, with over 40,000 scientific manuscripts published to date. At the same time, actual clinical application of the reported findings is obviously scarce. In this viewpoint article, we discuss the key issues that may be responsible for this apparent lack of success. We conclude that success must not be assessed based on the number of publications, but via the impact on patient management and treatment. We proceed with specific suggestions for potential solutions, which include keeping a strict focus on potential patient benefit. We hope this article can help shape the field, so it can in fact deliver on its realistic promise to bring significant improvement in management and care to patients., (© 2025 The Author(s). PROTEOMICS published by Wiley‐VCH GmbH.)

Published
2025
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44. Effect of spironolactone wash-out on albuminuria after long-term treatment in individuals with type 2 diabetes and high risk of kidney disease-An observational follow-up of the PRIORITY study.

Author

Wasehuus V, Rotbain Curovic V, Tofte N, Lindhardt M, Currie G, Delles C, Frimodt-Møller M, Mischak H, von der Leyen H, Hansen TW, Kümler T, Persson F, and Rossing P

Subjects
Humans, Male, Female, Middle Aged, Follow-Up Studies, Aged, Blood Pressure drug effects, Creatinine urine, Creatinine blood, Potassium urine, Potassium blood, Spironolactone therapeutic use, Spironolactone adverse effects, Albuminuria, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 complications, Diabetic Nephropathies prevention & control, Glomerular Filtration Rate drug effects, Mineralocorticoid Receptor Antagonists therapeutic use, Mineralocorticoid Receptor Antagonists adverse effects
Abstract

Aims: This study aimed to explore the effect of discontinuation of long-term spironolactone treatment on markers of kidney function in individuals with type 2 diabetes (T2D) at high risk of kidney disease enrolled in the Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria (PRIORITY) study., Materials and Methods: An observational study following the nested randomised part of the PRIORITY study was conducted. A total of 115 individuals with T2D and normoalbuminuria but high risk for progression based on urinary proteomics, randomised to daily spironolactone (n = 50) or placebo (n = 65) for a median of 2.5 years, were re-examined approximately 6 weeks after the final visit in the PRIORITY study. Primary endpoint was relative change in geometric mean of urinary albumin-creatinine ratio (UACR) between the final visit in PRIORITY (baseline) and follow-up. Secondary endpoints were change in estimated glomerular filtration rate (eGFR), systolic blood pressure (SBP) and serum potassium., Results: No change in UACR was observed in neither the spironolactone (geometric mean change: 17%; 95% CI -12, 55; p = 0.28) nor the placebo (5%; 95% CI -13, 26; p = 0.63) group at follow-up. No difference in UACR between the groups was observed at follow-up (relative difference in geometric mean: 11%, 95% CI -26, 67; p = 0.60). For eGFR and SBP, an increase after discontinuation of spironolactone was observed, as well as for SBP after placebo discontinuation. Potassium levels were lower after discontinuation of spironolactone, but higher after placebo discontinuation (all p < 0.05)., Conclusions: UACR did not change after discontinuation of long-term treatment with spironolactone. However, an increase in eGFR was observed supporting a haemodynamic effect of spironolactone in the kidneys., (© 2024 John Wiley & Sons Ltd.)

Published
2025
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45. Investigation of the Urinary Peptidome to Unravel Collagen Degradation in Health and Kidney Disease.

Author

Mina IK, Iglesias-Martinez LF, Ley M, Fillinger L, Perco P, Siwy J, Mischak H, and Jankowski V

Abstract

Naturally occurring fragments of collagen type I alpha 1 chain (COL1A1) have been previously associated with chronic kidney disease (CKD), with some fragments showing positive and others negative associations. Using urinary peptidome data from healthy individuals (n = 1131) and CKD patients (n = 5585) this aspect was investigated in detail. Based on the hypothesis that many collagen peptides are derived not from the full, mature collagen molecule, but from (larger) collagen degradation products, relationships between COL1A1 peptides containing identical sequences were investigated, with the smaller (offspring) peptide being a possible degradation product of the larger (parent) one. The strongest correlations were found for relationships where the parent differed by a maximum of three amino acids from the offspring, indicating an exopeptidase-regulated stepwise degradation process. Regression analysis indicated that CKD affects this degradation process. A comparison of matched CKD patients and control individuals (n = 612 each) showed that peptides at the start of the degradation process were consistently downregulated in CKD, indicating an attenuation of COL1A1 endopeptidase-mediated degradation. However, as these peptides undergo further degradation, likely mediated by exopeptidases, this downregulation can become less significant or even reverse, leading to an upregulation of later-stage fragments and potentially explaining the inconsistencies observed in previous studies., (© 2024 The Author(s). Proteomics published by Wiley‐VCH GmbH.)

Published
2024
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46. Validation of a Urine-Based Proteomics Test to Predict Clinically Significant Prostate Cancer: Complementing mpMRI Pathway.

Author

Frantzi M, Morillo AC, Lendinez G, Blanca A, Lopez Ruiz D, Parada J, Heidegger I, Culig Z, Mavrogeorgis E, Beltran AL, Mora-Ortiz M, Carrasco-Valiente J, Mischak H, Medina RA, Campos Hernandez P, and Gómez Gómez E

Abstract

Introduction: Prostate cancer (PCa) is the most frequently diagnosed cancer among men. A major clinical need is to accurately predict clinically significant PCa (csPCa). A proteomics-based 19-biomarker model (19-BM) was previously developed using capillary electrophoresis-mass spectrometry (CE-MS) and validated in close to 1,000 patients at risk for PCa. This study aimed to validate 19-BM in a multicenter prospective cohort of 101 biopsy-naive patients using current diagnostic pathways., Methods: Urine samples from 101 patients with suspicious of PCa were analyzed using CE-MS. All patients underwent multiparametric or magnetic resonance imaging (mpMRI) using a 3-T system. The 19-BM score was estimated using support vector machine-based software (MosaCluster v1.7.0), employing the previously published cut-off criterion of -0.07. Diagnostic nomograms were investigated along with mpMRI., Results: Independent validation of 19-BM yielded a sensitivity of 77% and a specificity of 85% (AUC:0.81). This performance surpassed those of prostate-specific antigen (PSA; AUC:0.56) and PSA density (AUC:0.69). For PI-RADS≤ 3 patients, 19-BM showed a sensitivity of 86% and a specificity of 88%. Integrating 19-BM with mpMRI resulted in significantly better accuracy (AUC:0.90) compared to individual investigations alone (AUC19BM = 0.81; p = 0.004 and AUCmpMRI: 0.79; p = 0.001). Examining the decision curve analysis, 19-BM with mpMRI surpassed other approaches for the prevailing risk interval from a 30% cut-off., Conclusions: 19-BM exhibited favorable reproducibility for the prediction of csPCa. In patients with PI-RADS ≤3, 19-BM correctly classified 88% of the patients with insignificant PCa at the cost of 1 missed csPCa patient. Utilizing the 19-BM test could prove valuable in complementing mpMRI and reducing the need for unnecessary biopsies., (© 2024 S. Karger AG, Basel.)

Published
2024
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47. Statistical approaches applicable in managing OMICS data: Urinary proteomics as exemplary case.

Author

An DW, Yu YL, Martens DS, Latosinska A, Zhang ZY, Mischak H, Nawrot TS, and Staessen JA

Subjects
Humans, Machine Learning, Workflow, Mass Spectrometry methods, Data Interpretation, Statistical, Software, Proteomics methods, Biomarkers urine
Abstract

With urinary proteomics profiling (UPP) as exemplary omics technology, this review describes a workflow for the analysis of omics data in large study populations. The proposed workflow includes: (i) planning omics studies and sample size considerations; (ii) preparing the data for analysis; (iii) preprocessing the UPP data; (iv) the basic statistical steps required for data curation; (v) the selection of covariables; (vi) relating continuously distributed or categorical outcomes to a series of single markers (e.g., sequenced urinary peptide fragments identifying the parental proteins); (vii) showing the added diagnostic or prognostic value of the UPP markers over and beyond classical risk factors, and (viii) pathway analysis to identify targets for personalized intervention in disease prevention or treatment. Additionally, two short sections respectively address multiomics studies and machine learning. In conclusion, the analysis of adverse health outcomes in relation to omics biomarkers rests on the same statistical principle as any other data collected in large population or patient cohorts. The large number of biomarkers, which have to be considered simultaneously requires planning ahead how the study database will be structured and curated, imported in statistical software packages, analysis results will be triaged for clinical relevance, and presented., (© 2023 The Authors. Mass Spectrometry Reviews published by John Wiley & Sons Ltd.)

Published
2024
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48. Peptides as "better biomarkers"? Value, challenges, and potential solutions to facilitate implementation.

Author

Latosinska A, Frantzi M, and Siwy J

Subjects
Animals, Health Care Economics and Organizations, Mass Spectrometry methods, Peptides analysis, Peptides chemistry, Biomarkers analysis
Abstract

Peptides carry important functions in normal physiological and pathophysiological processes and can serve as clinically useful biomarkers. Given the ability to diffuse passively across endothelial barriers, endogenous peptides can be examined in several body fluids, including among others urine, blood, and cerebrospinal fluid. This review article provides an update on the recently published literature that reports on investigating native peptides in body fluids using mass spectrometry-based platforms, specifically those studies that focus on the application of peptides as biomarkers to improve clinical management. We emphasize on the critical evaluation of their clinical value, how close they are to implementation, and the associated challenges and potential solutions to facilitate clinical implementation. During the last 5 years, numerous studies have been published, demonstrating the increased interest in mass spectrometry for the assessment of endogenous peptides as potential biomarkers. Importantly, the presence of few successful examples of implementation in patients' management and/or in the context of clinical trials indicates that the peptide biomarker field is evolving. Nevertheless, most studies still report evidence based on small sample size, while validation phases are frequently missing. Therefore, a gap between discovery and implementation still exists., (© 2023 John Wiley & Sons Ltd.)

Published
2024
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49. Urinary proteomic signature of mineralocorticoid receptor antagonism by spironolactone: evidence from the HOMAGE trial.

Author

Yu YL, Siwy J, An DW, González A, Hansen T, Latosinska A, Pellicori P, Ravassa S, Mariottoni B, Verdonschot JA, Ahmed F, Petutschnigg J, Rossignol P, Heymans S, Cuthbert JJ, Girerd N, Clark AL, Verhamme P, Nawrot TS, Janssens S, Cleland JG, Zannad F, Diez J, Mischak H, Ferreira JP, and Staessen JA

Subjects
Humans, Male, Female, Aged, Middle Aged, Peptide Fragments blood, Peptide Fragments urine, Procollagen blood, Treatment Outcome, Fibrosis, Collagen Type I, alpha 1 Chain, Spironolactone therapeutic use, Mineralocorticoid Receptor Antagonists therapeutic use, Heart Failure drug therapy, Heart Failure metabolism, Proteomics methods, Biomarkers urine, Biomarkers blood, Collagen Type I urine, Collagen Type I blood
Abstract

Objective: Heart failure (HF) is characterised by collagen deposition. Urinary proteomic profiling (UPP) followed by peptide sequencing identifies parental proteins, for over 70% derived from collagens. This study aimed to refine understanding of the antifibrotic action of spironolactone., Methods: In this substudy (n=290) to the Heart 'Omics' in Ageing Study trial, patients were randomised to usual therapy combined or not with spironolactone 25-50 mg/day and followed for 9 months. The analysis included 1498 sequenced urinary peptides detectable in ≥30% of patients and carboxyterminal propeptide of procollagen I (PICP) and PICP/carboxyterminal telopeptide of collagen I (CITP) as serum biomarkers of COL1A1 synthesis. After rank normalisation of biomarker distributions, between-group differences in their changes were assessed by multivariable-adjusted mixed model analysis of variance. Correlations between the changes in urinary peptides and in serum PICP and PICP/CITP were compared between groups using Fisher's Z transform., Results: Multivariable-adjusted between-group differences in the urinary peptides with error 1 rate correction were limited to 27 collagen fragments, of which 16 were upregulated (7 COL1A1 fragments) on spironolactone and 11 downregulated (4 COL1A1 fragments). Over 9 months of follow-up, spironolactone decreased serum PICP from 81 (IQR 66-95) to 75 (61-90) µg/L and PICP/CITP from 22 (17-28) to 18 (13-26), whereas no changes occurred in the control group, resulting in a difference (spironolactone minus control) expressed in standardised units of -0.321 (95% CI 0.0007). Spironolactone did not affect the correlations between changes in urinary COL1A1 fragments and in PICP or the PICP/CITP ratio., Conclusions: Spironolactone decreased serum markers of collagen synthesis and predominantly downregulated urinary collagen-derived peptides, but upregulated others. The interpretation of these opposite UPP trends might be due to shrinking the body-wide pool of collagens, explaining downregulation, while some degree of collagen synthesis must be maintained to sustain vital organ functions, explaining upregulation. Combining urinary and serum fibrosis markers opens new avenues for the understanding of the action of antifibrotic drugs., Trial Registration Number: NCT02556450., Competing Interests: Competing interests: JS and AL are employees of Mosaiques-Diagnostics, Hanover, Germany. HM is the co-founder and co-owner of Mosaiques-Diagnostics. The other authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2024
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50. Mortality Risk and Urinary Proteome Changes in Acute COVID-19 Survivors in the Multinational CRIT-COV-U Study.

Author

Siwy J, Keller F, Banasik M, Peters B, Dudoignon E, Mebazaa A, Gülmez D, Spasovski G, Lazo MS, Rajzer MW, Fuławka Ł, Dzitkowska-Zabielska M, Mischak H, Hecking M, Beige J, Wendt R, and UriCoV Working Group

Abstract

Background/objectives: Survival prospects following SARS-CoV-2 infection may extend beyond the acute phase, influenced by various factors including age, health conditions, and infection severity; however, this topic has not been studied in detail. Therefore, within this study, the mortality risk post-acute COVID-19 in the CRIT-COV-U cohort was investigated., Methods: Survival data from 651 patients that survived an acute phase of COVID-19 were retrieved and the association between urinary peptides and future death was assessed. Data spanning until December 2023 were collected from six countries, comparing mortality trends with age- and sex-matched COVID-19-negative controls. A death prediction classifier was developed and validated using pre-existing urinary peptidomic datasets., Results: Notably, 13.98% of post-COVID-19 patients succumbed during the follow-up, with mortality rates significantly higher than COVID-19-negative controls, particularly evident in younger individuals (<65 years). These data for the first time demonstrate that SARS-CoV-2 infection highly significantly increases the risk of mortality not only during the acute phase of the disease but also beyond for a period of about one year. In our study, we were further able to identify 201 urinary peptides linked to mortality. These peptides are fragments of albumin, alpha-2-HS-glycoprotein, apolipoprotein A-I, beta-2-microglobulin, CD99 antigen, various collagens, fibrinogen alpha, polymeric immunoglobulin receptor, sodium/potassium-transporting ATPase, and uromodulin and were integrated these into a predictive classifier (DP201). Higher DP201 scores, alongside age and BMI, significantly predicted death., Conclusions: The peptide-based classifier demonstrated significant predictive value for mortality in post-acute COVID-19 patients, highlighting the utility of urinary peptides in prognosticating post-acute COVID-19 mortality, offering insights for targeted interventions. By utilizing these defined biomarkers in the clinic, risk stratification, monitoring, and personalized interventions can be significantly improved. Our data also suggest that mortality should be considered as one possible symptom or a consequence of post-acute sequelae of SARS-CoV-2 infection, a fact that is currently overlooked.

Published
2024
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