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1. Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance

Author

Calvisi, D, Boulter, L, Vaquero, J, Saborowski, A, Fabris, L, Rodrigues, P, Coulouarn, C, Castro, R, Segatto, O, Raggi, C, van der Laan, L, Carpino, G, Goeppert, B, Roessler, S, Kendall, T, Evert, M, Gonzalez-Sanchez, E, Valle, J, Vogel, A, Bridgewater, J, Borad, M, Gores, G, Roberts, L, Marin, J, Andersen, J, Alvaro, D, Forner, A, Banales, J, Cardinale, V, Macias, R, Vicent, S, Chen, X, Braconi, C, Verstegen, M, Fouassier, L, Scheiter, A, Selaru, F, Evert, K, Utpatel, K, Broutier, L, Cadamuro, M, Huch, M, Goldin, R, Gradilone, S, Saito, Y, Calvisi D. F., Boulter L., Vaquero J., Saborowski A., Fabris L., Rodrigues P. M., Coulouarn C., Castro R. E., Segatto O., Raggi C., van der Laan L. J. W., Carpino G., Goeppert B., Roessler S., Kendall T. J., Evert M., Gonzalez-Sanchez E., Valle J. W., Vogel A., Bridgewater J., Borad M. J., Gores G. J., Roberts L. R., Marin J. J. G., Andersen J. B., Alvaro D., Forner A., Banales J. M., Cardinale V., Macias R. I. R., Vicent S., Chen X., Braconi C., Verstegen M. M. A., Fouassier L., Roberts L., Scheiter A., Selaru F. M., Evert K., Utpatel K., Broutier L., Cadamuro M., Huch M., Goldin R., Gradilone S. A., Saito Y., Calvisi, D, Boulter, L, Vaquero, J, Saborowski, A, Fabris, L, Rodrigues, P, Coulouarn, C, Castro, R, Segatto, O, Raggi, C, van der Laan, L, Carpino, G, Goeppert, B, Roessler, S, Kendall, T, Evert, M, Gonzalez-Sanchez, E, Valle, J, Vogel, A, Bridgewater, J, Borad, M, Gores, G, Roberts, L, Marin, J, Andersen, J, Alvaro, D, Forner, A, Banales, J, Cardinale, V, Macias, R, Vicent, S, Chen, X, Braconi, C, Verstegen, M, Fouassier, L, Scheiter, A, Selaru, F, Evert, K, Utpatel, K, Broutier, L, Cadamuro, M, Huch, M, Goldin, R, Gradilone, S, Saito, Y, Calvisi D. F., Boulter L., Vaquero J., Saborowski A., Fabris L., Rodrigues P. M., Coulouarn C., Castro R. E., Segatto O., Raggi C., van der Laan L. J. W., Carpino G., Goeppert B., Roessler S., Kendall T. J., Evert M., Gonzalez-Sanchez E., Valle J. W., Vogel A., Bridgewater J., Borad M. J., Gores G. J., Roberts L. R., Marin J. J. G., Andersen J. B., Alvaro D., Forner A., Banales J. M., Cardinale V., Macias R. I. R., Vicent S., Chen X., Braconi C., Verstegen M. M. A., Fouassier L., Roberts L., Scheiter A., Selaru F. M., Evert K., Utpatel K., Broutier L., Cadamuro M., Huch M., Goldin R., Gradilone S. A., and Saito Y.

Abstract

Cholangiocarcinoma (CCA) is a rare malignancy that develops at any point along the biliary tree. CCA has a poor prognosis, its clinical management remains challenging, and effective treatments are lacking. Therefore, preclinical research is of pivotal importance and necessary to acquire a deeper understanding of CCA and improve therapeutic outcomes. Preclinical research involves developing and managing complementary experimental models, from in vitro assays using primary cells or cell lines cultured in 2D or 3D to in vivo models with engrafted material, chemically induced CCA or genetically engineered models. All are valuable tools with well-defined advantages and limitations. The choice of a preclinical model is guided by the question(s) to be addressed; ideally, results should be recapitulated in independent approaches. In this Consensus Statement, a task force of 45 experts in CCA molecular and cellular biology and clinicians, including pathologists, from ten countries provides recommendations on the minimal criteria for preclinical models to provide a uniform approach. These recommendations are based on two rounds of questionnaires completed by 35 (first round) and 45 (second round) experts to reach a consensus with 13 statements. An agreement was defined when at least 90% of the participants voting anonymously agreed with a statement. The ultimate goal was to transfer basic laboratory research to the clinics through increased disease understanding and to develop clinical biomarkers and innovative therapies for patients with CCA.

Published
2023

5. Organoids

Author

Zhao, Z, Zhao, Z, Chen, X, Dowbaj, AM, Sljukic, A, Bratlie, K, Lin, L, Fong, ELS, Balachander, GM, Chen, Z, Soragni, A, Huch, M, Zeng, YA, Wang, Q, Yu, H, Zhao, Z, Zhao, Z, Chen, X, Dowbaj, AM, Sljukic, A, Bratlie, K, Lin, L, Fong, ELS, Balachander, GM, Chen, Z, Soragni, A, Huch, M, Zeng, YA, Wang, Q, and Yu, H

Abstract

Organoids are simple tissue-engineered cell-based in vitro models that recapitulate many aspects of the complex structure and function of the corresponding in vivo tissue. They can be dissected and interrogated for fundamental mechanistic studies on development, regeneration and repair in human tissues, and can also be used in diagnostics, disease modelling, drug discovery and personalized medicine. Organoids are derived from either pluripotent or tissue-resident stem (embryonic or adult) or progenitor or differentiated cells from healthy or diseased tissues, such as tumours. To date, numerous organoid engineering strategies that support organoid culture and growth, proliferation, differentiation and maturation have been reported. This Primer highlights the rationale underlying the selection and development of these materials and methods to control the cellular/tissue niche; and therefore, the structure and function of the engineered organoid. We also discuss key considerations for generating robust organoids, such as those related to cell isolation and seeding, matrix and soluble factor selection, physical cues and integration. The general standards for data quality, reproducibility and deposition within the organoid community are also outlined. Lastly, we conclude by elaborating on the limitations of organoids in different applications, and the key priorities in organoid engineering for the coming years.

Published
2022

6. SP2 - Test, Reliability and Functional Safety Trends for Automotive System-on-Chip

Author

Angione, F., Appello, D., Aribido, J., Athavale, J., Bellarmino, N., Bernardi, P., Cantoro, R., De Sio, C., Foscale, T., Gavarini, G., Guerrero, J., Huch, M., Iaria, G., Kilian, T., Mariani, R., Martone, R., Ruospo, A., Sanchez, E., Schlichtmann, U., Squillero, G., Sonza Reorda, M., Sterpone, L., Tancorre, V., Ugioli, R., Angione, F., Appello, D., Aribido, J., Athavale, J., Bellarmino, N., Bernardi, P., Cantoro, R., De Sio, C., Foscale, T., Gavarini, G., Guerrero, J., Huch, M., Iaria, G., Kilian, T., Mariani, R., Martone, R., Ruospo, A., Sanchez, E., Schlichtmann, U., Squillero, G., Sonza Reorda, M., Sterpone, L., Tancorre, V., and Ugioli, R.

Abstract

This paper encompasses three contributions by industry professionals and university researchers. The contributions describe different trends in automotive products, including both manufacturing test and run-time reliability strategies. The subjects considered in this session deal with critical factors, from optimizing the final test before shipment to market to in-field reliability during operative life.

Published
2022

7. Test, Reliability and Functional Safety trends for Automotive System-on-Chip

Author

Angione, F., Appello, D., Aribido, J., Bellarmino, N., Bernardi, P., Cantoro, R., de Sio, C., Foscale, T., Gavarini, G., Huch, M., Kilian, T, Mariani, R., Martone, R., Ruospo, A., Sanchez, E., Schlichtmann, U., Squillero, G., Sonza Reorda, M., Sterpone, L., Tancorre, V., and Ugioli, R.

Published
2022

9. List of contributors

Author

Alessandria, V., primary, Bianchini, A., additional, Bisson, L.F., additional, Brandt, M.J., additional, Brányik, T., additional, Buckenhueskes, H.J., additional, Chambers, P.J., additional, Cocolin, L., additional, Corsetti, A., additional, Csapó, J., additional, Curtin, C.D., additional, de Vos, W.M., additional, Derkx, P.M.F., additional, Dolci, P., additional, Ewe, J.A., additional, Flahaut, N.A.L., additional, Foerst, P., additional, Franz, C.M.A.P., additional, Holzapfel, W.H., additional, Huch, M., additional, Johansen, E., additional, Korhonen, H., additional, Kuda, T., additional, Kyselová, L., additional, López, P., additional, Lücke, F.-K., additional, Mohedano, M.L., additional, Nout, R., additional, Øregaard, G., additional, Ouwehand, A.C., additional, Perpetuini, G., additional, Pihlanto, A., additional, Pretorius, I.S., additional, Rantsiou, K., additional, Röytiö, H., additional, Russo, P., additional, Santivarangkna, C., additional, Sørensen, K.I., additional, Spano, G., additional, Todorov, S.D., additional, Tofalo, R., additional, Varga-Visi, É., additional, Walker, G.A., additional, Welman, A.D., additional, and Yeo, S.K., additional

Published
2015
Full Text
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11. LifeTime and improving European healthcare through cell-based interceptive medicine

Author

Rajewsky, N., Almouzni, G., Gorski, S., Aerts, S., Amit, I., Bertero, M., Bock, C., Bredenoord, A., Cavalli, G., Chiocca, S., Clevers, H., Strooper, B., Eggert, A., Ellenberg, J., Fernández, X., Figlerowicz, M., Gasser, S., Hubner, N., Kjems, J., Knoblich, J., Krabbe, G., Lichter, P., Linnarsson, S., Marine, J., Marioni, J., Marti-Renom, M., Netea, M., Nickel, D., Nollmann, M., Novak, H., Parkinson, H., Piccolo, S., Pinheiro, I., Pombo, A., Popp, C., Reik, W., Roman-Roman, S., Rosenstiel, P., Schultze, J., Stegle, O., Tanay, A., Testa, G., Thanos, D., Theis, F., Torres-Padilla, M., Valencia, A., Vallot, C., van Oudenaarden, A., Vidal, M., Voet, T., Alberi, L., Alexander, S., Alexandrov, T., Arenas, E., Bagni, C., Balderas, R., Bandelli, A., Becher, B., Becker, M., Beerenwinkel, N., Benkirame, M., Beyer, M., Bickmore, W., Biessen, E., Blomberg, N., Blumcke, I., Bodenmiller, B., Borroni, B., Boumpas, D., Bourgeron, T., Bowers, S., Braeken, D., Brooksbank, C., Brose, N., Bruining, H., Bury, J., Caporale, N., Cattoretti, G., Chabane, N., Chneiweiss, H., Cook, S., Curatolo, P., de Jonge, M., Deplancke, B., de Witte, P., Dimmeler, S., Draganski, B., Drews, A., Dumbrava, C., Engelhardt, S., Gasser, T., Giamarellos-Bourboulis, E., Graff, C., Grün, D., Gut, I., Hansson, O., Henshall, D., Herland, A., Heutink, P., Heymans, S., Heyn, H., Huch, M., Huitinga, I., Jackowiak, P., Jongsma, K., Journot, L., Junker, J., Katz, S., Kehren, J., Kempa, S., Kirchhof, P., Klein, C., Koralewska, N., Korbel, J., Kühnemund, M., Lamond, A., Lauwers, E., Le Ber, I., Leinonen, V., Tobon, A., Lundberg, E., Lunkes, A., Maatz, H., Mann, M., Marelli, L., Matser, V., Matthews, P., Mechta-Grigoriou, F., Menon, R., Nielsen, A., Pagani, M., Pasterkamp, R., Pitkänen, A., Popescu, V., Pottier, C., Puisieux, A., Rademakers, R., Reiling, D., Reiner, O., Remondini, D., Ritchie, C., Rohrer, J., Saliba, A., Sanchez-Valle, R., Santosuosso, A., Sauter, A., Scheltema, R., Scheltens, P., Schiller, H., Schneider, A., Seibler, P., Sheehan-Rooney, K., Shields, D., Sleegers, K., Smit, A., Smith, K., Smolders, I., Synofzik, M., Tam, W., Teichmann, S., Thom, M., Turco, M., van Beusekom, H., Vandenberghe, R., den Hoecke, S., de Poel, I., van der Ven, A., van der Zee, J., van Lunzen, J., van Minnebruggen, G., Paesschen, W., van Swieten, J., van Vught, R., Verhage, M., Verstreken, P., Villa, C., Vogel, J., von Kalle, C., Walter, J., Weckhuysen, S., Weichert, W., Wood, L., Ziegler, A., Zipp, F., HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany., Medical Research Council (MRC), UK DRI Ltd, TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany., Barcelona Supercomputing Center, LifeTime Community Working Groups, Cardiology, Neurology, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Human genetics, Rajewsky N., Almouzni G., Gorski S.A., Aerts S., Amit I., Bertero M.G., Bock C., Bredenoord A.L., Cavalli G., Chiocca S., Clevers H., De Strooper B., Eggert A., Ellenberg J., Fernandez X.M., Figlerowicz M., Gasser S.M., Hubner N., Kjems J., Knoblich J.A., Krabbe G., Lichter P., Linnarsson S., Marine J.-C., Marioni J.C., Marti-Renom M.A., Netea M.G., Nickel D., Nollmann M., Novak H.R., Parkinson H., Piccolo S., Pinheiro I., Pombo A., Popp C., Reik W., Roman-Roman S., Rosenstiel P., Schultze J.L., Stegle O., Tanay A., Testa G., Thanos D., Theis F.J., Torres-Padilla M.-E., Valencia A., Vallot C., van Oudenaarden A., Vidal M., Voet T., Alberi L., Alexander S., Alexandrov T., Arenas E., Bagni C., Balderas R., Bandelli A., Becher B., Becker M., Beerenwinkel N., Benkirame M., Beyer M., Bickmore W., Biessen E.E.A.L., Blomberg N., Blumcke I., Bodenmiller B., Borroni B., Boumpas D.T., Bourgeron T., Bowers S., Braeken D., Brooksbank C., Brose N., Bruining H., Bury J., Caporale N., Cattoretti G., Chabane N., Chneiweiss H., Cook S.A., Curatolo P., de Jonge M.I., Deplancke B., de Witte P., Dimmeler S., Draganski B., Drews A., Dumbrava C., Engelhardt S., Gasser T., Giamarellos-Bourboulis E.J., Graff C., Grun D., Gut I., Hansson O., Henshall D.C., Herland A., Heutink P., Heymans S.R.B., Heyn H., Huch M., Huitinga I., Jackowiak P., Jongsma K.R., Journot L., Junker J.P., Katz S., Kehren J., Kempa S., Kirchhof P., Klein C., Koralewska N., Korbel J.O., Kuhnemund M., Lamond A.I., Lauwers E., Le Ber I., Leinonen V., Tobon A.L., Lundberg E., Lunkes A., Maatz H., Mann M., Marelli L., Matser V., Matthews P.M., Mechta-Grigoriou F., Menon R., Nielsen A.F., Pagani M., Pasterkamp R.J., Pitkanen A., Popescu V., Pottier C., Puisieux A., Rademakers R., Reiling D., Reiner O., Remondini D., Ritchie C., Rohrer J.D., Saliba A.-E., Sanchez-Valle R., Santosuosso A., Sauter A., Scheltema R.A., Scheltens P., Schiller H.B., Schneider A., Seibler P., Sheehan-Rooney K., Shields D., Sleegers K., Smit A.B., Smith K.G.C., Smolders I., Synofzik M., Tam W.L., Teichmann S., Thom M., Turco M.Y., van Beusekom H.M.M., Vandenberghe R., Van den Hoecke S., Van de Poel I., van der Ven A., van der Zee J., van Lunzen J., van Minnebruggen G., Van Paesschen W., van Swieten J., van Vught R., Verhage M., Verstreken P., Villa C.E., Vogel J., von Kalle C., Walter J., Weckhuysen S., Weichert W., Wood L., Ziegler A.-G., Zipp F., Center for Neurogenomics and Cognitive Research, Functional Genomics, Rajewsky, N, Almouzni, G, Gorski, S, Aerts, S, Amit, I, Bertero, M, Bock, C, Bredenoord, A, Cavalli, G, Chiocca, S, Clevers, H, De Strooper, B, Eggert, A, Ellenberg, J, Fernández, X, Figlerowicz, M, Gasser, S, Hubner, N, Kjems, J, Knoblich, J, Krabbe, G, Lichter, P, Linnarsson, S, Marine, J, Marioni, J, Marti-Renom, M, Netea, M, Nickel, D, Nollmann, M, Novak, H, Parkinson, H, Piccolo, S, Pinheiro, I, Pombo, A, Popp, C, Reik, W, Roman-Roman, S, Rosenstiel, P, Schultze, J, Stegle, O, Tanay, A, Testa, G, Thanos, D, Theis, F, Torres-Padilla, M, Valencia, A, Vallot, C, van Oudenaarden, A, Vidal, M, Voet, T, Cattoretti, G, Alliance for Modulation in Epilepsy, Pharmaceutical and Pharmacological Sciences, Experimental Pharmacology, RS: Carim - H02 Cardiomyopathy, MUMC+: MA Med Staf Spec Cardiologie (9), and Cardiologie

Subjects
0301 basic medicine, Male, Artificial intelligence, Legislation, Medical, [SDV]Life Sciences [q-bio], Molecular datasets, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Cell- and Tissue-Based Therapy, Diseases, LifeTime Community Working Groups, Disease, Biomarkers, Systems biology, Health data, Pharmacology, Toxicology and Pharmaceutics(all), 0302 clinical medicine, Conjunts de dades, ethics [Delivery of Health Care], Health care, Pathology, Medicine, European healthcare, BRAIN, Single-cell multi-omics, GENE-EXPRESSION, Multidisciplinary, methods [Medicine], Education, Medical, Settore BIO/13, Intel.ligència artificial, 3. Good health, ALZHEIMERS-DISEASE, Europe, Health, Management system, Perspective, Female, ddc:500, Single-Cell Analysis, Biomarkers, Diseases, Systems biology, Complex diseases, Informàtica::Aplicacions de la informàtica::Bioinformàtica [Àrees temàtiques de la UPC], medicine.medical_specialty, General Science & Technology, Cells, MEDLINE, cell-based interceptive medicine, LifeTime Initiative, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Clinical datasets, Artificial Intelligence, REVEALS, LifeTime Community, standards [Medicine], Humans, OMICS, RECONSTRUCTION, Intensive care medicine, trends [Medicine], trends [Delivery of Health Care], business.industry, Disease progression, standards [Delivery of Health Care], methods [Delivery of Health Care], 030104 developmental biology, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], single cell, personalized therapy, machine learning, bioinformatics, systems biology, disease, cell-based interceptive medicine, Early Diagnosis, Cardiovascular and Metabolic Diseases, Human medicine, business, Delivery of Health Care, 030217 neurology & neurosurgery, Cell based
Abstract

Here we describe the LifeTime Initiative, which aims to track, understand and target human cells during the onset and progression of complex diseases, and to analyse their response to therapy at single-cell resolution. This mission will be implemented through the development, integration and application of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during the progression from health to disease. The analysis of large molecular and clinical datasets will identify molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. The timely detection and interception of disease embedded in an ethical and patient-centred vision will be achieved through interactions across academia, hospitals, patient associations, health data management systems and industry. The application of this strategy to key medical challenges in cancer, neurological and neuropsychiatric disorders, and infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade., The LifeTime initiative is an ambitious, multidisciplinary programme that aims to improve healthcare by tracking individual human cells during disease processes and responses to treatment in order to develop and implement cell-based interceptive medicine in Europe.

Published
2020
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12. Publisher Correction: LifeTime and improving European healthcare through cell-based interceptive medicine (Nature, (2020), 587, 7834, (377-386), 10.1038/s41586-020-2715-9)

Author

Rajewsky, N. Almouzni, G. Gorski, S.A. Aerts, S. Amit, I. Bertero, M.G. Bock, C. Bredenoord, A.L. Cavalli, G. Chiocca, S. Clevers, H. De Strooper, B. Eggert, A. Ellenberg, J. Fernández, X.M. Figlerowicz, M. Gasser, S.M. Hubner, N. Kjems, J. Knoblich, J.A. Krabbe, G. Lichter, P. Linnarsson, S. Marine, J.-C. Marioni, J.C. Marti-Renom, M.A. Netea, M.G. Nickel, D. Nollmann, M. Novak, H.R. Parkinson, H. Piccolo, S. Pinheiro, I. Pombo, A. Popp, C. Reik, W. Roman-Roman, S. Rosenstiel, P. Schultze, J.L. Stegle, O. Tanay, A. Testa, G. Thanos, D. Theis, F.J. Torres-Padilla, M.-E. Valencia, A. Vallot, C. van Oudenaarden, A. Vidal, M. Voet, T. Alberi, L. Alexander, S. Alexandrov, T. Arenas, E. Bagni, C. Balderas, R. Bandelli, A. Becher, B. Becker, M. Beerenwinkel, N. Benkirane, M. Beyer, M. Bickmore, W.A. Biessen, E.E.A.L. Blomberg, N. Blumcke, I. Bodenmiller, B. Borroni, B. Boumpas, D.T. Bourgeron, T. Bowers, S. Braeken, D. Brooksbank, C. Brose, N. Bruining, H. Bury, J. Caporale, N. Cattoretti, G. Chabane, N. Chneiweiss, H. Cook, S.A. Curatolo, P. de Jonge, M.I. Deplancke, B. de Witte, P. Dimmeler, S. Draganski, B. Drews, A. Dumbrava, C. Engelhardt, S. Gasser, T. Giamarellos-Bourboulis, E.J. Graff, C. Grün, D. Gut, I.G. Hansson, O. Henshall, D.C. Herland, A. Heutink, P. Heymans, S.R.B. Heyn, H. Huch, M. Huitinga, I. Jackowiak, P. Jongsma, K.R. Journot, L. Junker, J.P. Katz, S. Kehren, J. Kempa, S. Kirchhof, P. Klein, C. Koralewska, N. Korbel, J.O. Kühnemund, M. Lamond, A.I. Lauwers, E. Le Ber, I. Leinonen, V. López-Tobón, A. Lundberg, E. Lunkes, A. Maatz, H. Mann, M. Marelli, L. Matser, V. Matthews, P.M. Mechta-Grigoriou, F. Menon, R. Nielsen, A.F. Pagani, M. Pasterkamp, R.J. Pitkänen, A. Popescu, V. Pottier, C. Puisieux, A. Rademakers, R. Reiling, D. Reiner, O. Remondini, D. Ritchie, C. Rohrer, J.D. Saliba, A.-E. Sanchez-Valle, R. Santosuosso, A. Sauter, A. Scheltema, R.A. Scheltens, P. Schiller, H.B. Schneider, A. Seibler, P. Sheehan-Rooney, K. Shields, D.J. Sleegers, K. Smit, A.B. Smith, K.G.C. Smolders, I. Synofzik, M. Tam, W.L. Teichmann, S.A. Thom, M. Turco, M.Y. van Beusekom, H.M.M. Vandenberghe, R. Van den Hoecke, S. van de Poel, I. van der Ven, A. van der Zee, J. van Lunzen, J. van Minnebruggen, G. van Oudenaarden, A. Van Paesschen, W. van Swieten, J.C. van Vught, R. Verhage, M. Verstreken, P. Villa, C.E. Vogel, J. von Kalle, C. Walter, J. Weckhuysen, S. Weichert, W. Wood, L. Ziegler, A.-G. Zipp, F. LifeTime Community Working Groups

Subjects
ComputingMethodologies_DOCUMENTANDTEXTPROCESSING
Abstract

In this Perspective, owing to an error in the HTML, the surname of author Alejandro López-Tobón of the LifeTime Community Working Groups consortium was indexed as ‘Tobon’ rather than ‘López-Tobón’ and the accents were missing. The HTML version of the original Perspective has been corrected; the PDF and print versions were always correct. © 2021, The Author(s).

Published
2021

13. Voices of biotech research

Author

Annabi, N., Baker, M., Boettiger, A., Chakraborty, D., Chen, Y., Corbett, K.S., Correia, B., Dahlman, J., de Oliveira, T., Ertuerk, A., Yanik, M.F., Henaff, E., Huch, M., Iliev, I.D., Jacobs, T., Junca, H., Keung, A., Kolodkin-Gal, I., Krishnaswamy, S., Lancaster, M., Macosko, E., Martínez-Núñez, M.A., Miura, K., Molloy, J., Cruz, A.O., Platt, R.J., Posey, A.D., Shao, H., Simunovic, M., Slavov, N., Takebe, T., Vandenberghe, L.H., Varshney, R.K., Wang, J., Annabi, N., Baker, M., Boettiger, A., Chakraborty, D., Chen, Y., Corbett, K.S., Correia, B., Dahlman, J., de Oliveira, T., Ertuerk, A., Yanik, M.F., Henaff, E., Huch, M., Iliev, I.D., Jacobs, T., Junca, H., Keung, A., Kolodkin-Gal, I., Krishnaswamy, S., Lancaster, M., Macosko, E., Martínez-Núñez, M.A., Miura, K., Molloy, J., Cruz, A.O., Platt, R.J., Posey, A.D., Shao, H., Simunovic, M., Slavov, N., Takebe, T., Vandenberghe, L.H., Varshney, R.K., and Wang, J.

Abstract

What will be the most important areas of research in biotech over the coming years? Which technologies will be most important to advance knowledge and applications in these areas? Nature Biotechnology reached out to a set of faculty doing outstanding work in research areas representative of the journal’s remit and asked them to contribute their vision of where their fields are going.

Published
2021

14. Long-term live imaging and multiscale analysis identify heterogeneity and core principles of epithelial organoid morphogenesis

Author

Hof, L, Moreth, T, Koch, M, Liebisch, T, Kurtz, M, Tarnick, J, Lissek, SM, Verstegen, Monique, van der Laan, Luc, Huch, M, Matthaus, F, Stelzer, EHK, Pampaloni, F, Hof, L, Moreth, T, Koch, M, Liebisch, T, Kurtz, M, Tarnick, J, Lissek, SM, Verstegen, Monique, van der Laan, Luc, Huch, M, Matthaus, F, Stelzer, EHK, and Pampaloni, F

Abstract

Background: Organoids are morphologically heterogeneous three-dimensional cell culture systems and serve as an ideal model for understanding the principles of collective cell behaviour in mammalian organs during development, homeostasis, regeneration, and pathogenesis. To investigate the underlying cell organisation principles of organoids, we imaged hundreds of pancreas and cholangiocarcinoma organoids in parallel using light sheet and bright-field microscopy for up to 7 days. Results: We quantified organoid behaviour at single-cell (microscale), individual-organoid (mesoscale), and entire-culture (macroscale) levels. At single-cell resolution, we monitored formation, monolayer polarisation, and degeneration and identified diverse behaviours, including lumen expansion and decline (size oscillation), migration, rotation, and multi-organoid fusion. Detailed individual organoid quantifications lead to a mechanical 3D agent-based model. A derived scaling law and simulations support the hypotheses that size oscillations depend on organoid properties and cell division dynamics, which is confirmed by bright-field microscopy analysis of entire cultures. Conclusion: Our multiscale analysis provides a systematic picture of the diversity of cell organisation in organoids by identifying and quantifying the core regulatory principles of organoid morphogenesis.

Published
2021

15. LifeTime and improving European healthcare through cell-based interceptive medicine

Author

Rajewsky, N. (Nikolaus), Almouzni, G. (Geneviève), Gorski, S.A. (Stanislaw A.), Aerts, S. (Stein), Amit, I. (Ido), Bertero, M.G. (Michela G.), Bock, C. (Christoph), Bredenoord, A.L. (Annelien L.), Cavalli, G. (Giacomo), Chiocca, S. (Susanna), Clevers, H.C. (Hans), Strooper, B. (Bart) de, Eggert, A. (Angelika), Ellenberg, J. (Jan), Fernández, X.M. (Xosé M.), Figlerowicz, M. (Marek), Gasser, S.M. (Susan M.), Hübner, N. (Norbert), Kjems, J. (Jørgen), Knoblich, J.A. (Jürgen A.), Krabbe, G. (Grietje), Lichter, P. (Peter), Linnarsson, S. (Sten), Marine, J.-C. (J.), Marioni, J. (John), Marti-Renom, M.A. (Marc A.), Netea, M.G. (Mihai), Nickel, D. (Dörthe), Nollmann, M. (Marcelo), Novak, H.R. (Halina R.), Parkinson, H. (Helen), Piccolo, S. (Stefano), Pinheiro, I. (Inês), Pombo, A. (Ana), Popp, C. (Christian), Reik, W. (Wolf), Roman-Roman, S. (Sergio), Rosenstiel, P. (Philip), Schultze, J.L. (Joachim), Stegle, O. (Oliver), Tanay, A. (Amos), Testa, G. (Giuseppe), Thanos, D. (Dimitris), Theis, F. (Fabian), Torres-Padilla, M.-E. (Maria-Elena), Valencia, A. (Alfonso), Vallot, C. (Céline), van Oudenaarden, A. (Alexander), Vidal, M. (Marie), Voet, T. (Thierry), Alberi, L. (Lavinia), Alexander, S. (Stephanie), Alexandrov, T. (Theodore), Arenas, E. (Ernest), Bagni, C. (Claudia), Balderas, R. (Robert), Bandelli, A. (Andrea), Becher, B. (Burkhard), Becker, M. (Matthias), Beerenwinkel, N. (Niko), Benkirame, M. (Monsef), Beyer, M. (Marc), Bickmore, W. (Wendy), Biessen, E.E.A.L. (Erik E.A.L.), Blomberg, N. (Niklas), Blumcke, I. (Ingmar), Bodenmiller, B. (Bernd), Borroni, B. (Barbara), Boumpas, D.T. (Dimitrios T.), Bourgeron, T. (Thomas), Bowers, S. (Sarion), Braeken, D. (Dries), Brooksbank, C. (Catherine), Brose, N. (Nils), Bruining, J. (Hans), Bury, J. (Jo), Caporale, N. (Nicolo), Cattoretti, G. (Giorgio), Chabane, N. (Nadia), Chneiweiss, H. (Hervé), Cook, S.A. (Stuart A.), Curatolo, P. (Paolo), Jonge, M.I. (Marien) de, Deplancke, B. (Bart), De Strooper, B. (Bart), de Witte, P. (Peter), Dimmeler, S. (Stefanie), Draganski, B. (Bogdan), Drews, A.-D. (Anna-Dorothee), Dumbrava, C. (Costica), Engelhardt, S. (Stefan), Gasser, T. (Thomas), Giamarellos-Bourboulis, E. (Evangelos), Graff, C. (Caroline), Grün, D. (Dominic), Gut, I. (Ivo), Hansson, O. (Oskar), Henshall, D.C. (David C.), Herland, A. (Anna), Heutink, P. (Peter), Heymans, S. (Stephane), Heyn, H. (Holger), Huch, M. (Meritxell), Huitinga, I. (Inge), Jackowiak, P. (Paulina), Jongsma, K.R. (Karin), Journot, L. (Laurent), Junker, J.P. (Jan Philipp), Katz, S. (Shauna), Kehren, J. (Jeanne), Kempa, S. (Stefan), Kirchhof, P. (Paulus), Klein, C. (Christoph), Koralewska, N. (Natalia), Korbel, J.O. (Jan), Kühnemund, M. (Malte), Lamond, A.I. (Angus I.), Lauwers, E. (Elsa), Le Ber, I. (Isabelle), Leinonen, V. (Ville), Tobon, A.L. (Alejandro Lopez), Lundberg, E. (Emma), Lunkes, A. (Astrid), Maatz, H. (Henrike), Mann, M. (Mathias), Marelli, L. (Luca), Matser, V. (Vera), Matthews, P.M. (P.), Mechta-Grigoriou, F. (Fatima), Menon, R. (Radhika), Nielsen, A.F. (Anne F.), Pagani, M. (Massimiliano), Pasterkamp, R.J. (Jeroen), Pitkanen, A. (Asla), Popescu, V. (Valentin), Pottier, C. (Cyril), Puisieux, A. (Alain), Rademakers, R. (Rosa), Reiling, D. (Dory), Reiner, O. (Orly), Remondini, D. (Daniel), Ritchie, C. (Craig), Rohrer, J.D. (Jonathan D.), Saliba, A.-E. (Antione-Emmanuel), Sánchez-Valle, R. (Raquel), Santosuosso, A. (Amedeo), Sauter, A. (Arnold), Scheltema, R.A. (Richard A.), Scheltens, P. (Philip), Schiller, H.B. (Herbert B.), Schneider, A. (Anja), Seibler, P. (Philip), Sheehan-Rooney, K. (Kelly), Shields, D. (David), Sleegers, K. (Kristel), Smit, G. (Guus), Smith, K.G.C. (Kenneth G. C.), Smolders, I. (Ilse), Synofzik, M. (Matthis), Tam, W.L. (Wai Long), Teichmann, S. (Sarah), Thom, M. (Maria), Turco, M.Y. (Margherita Y.), Beusekom, H.M.M. (Heleen) van, Vandenberghe, R. (Rik), den Hoecke, S.V. (Silvie Van), Van de Poel, E. (Ellen), der Ven, A. (Andre van), van der Zee, J. (Julie), van Lunzen, J. (Jan), van Minnebruggen, G. (Geert), Van Paesschen, W. (Wim), Swieten, J.C. (John) van, van Vught, R. (Remko), Verhage, M. (Matthijs), Verstreken, P. (Patrik), Villa, C.E. (Carlo Emanuele), Vogel, J. (Jörg), Kalle, C. (Christof) von, Walter, J. (Jörn), Weckhuysen, S. (Sarah), Weichert, W. (Wilko), Wood, L. (Louisa), Ziegler, A.-G. (Anette-Gabriele), Zipp, F. (Frauke), Rajewsky, N. (Nikolaus), Almouzni, G. (Geneviève), Gorski, S.A. (Stanislaw A.), Aerts, S. (Stein), Amit, I. (Ido), Bertero, M.G. (Michela G.), Bock, C. (Christoph), Bredenoord, A.L. (Annelien L.), Cavalli, G. (Giacomo), Chiocca, S. (Susanna), Clevers, H.C. (Hans), Strooper, B. (Bart) de, Eggert, A. (Angelika), Ellenberg, J. (Jan), Fernández, X.M. (Xosé M.), Figlerowicz, M. (Marek), Gasser, S.M. (Susan M.), Hübner, N. (Norbert), Kjems, J. (Jørgen), Knoblich, J.A. (Jürgen A.), Krabbe, G. (Grietje), Lichter, P. (Peter), Linnarsson, S. (Sten), Marine, J.-C. (J.), Marioni, J. (John), Marti-Renom, M.A. (Marc A.), Netea, M.G. (Mihai), Nickel, D. (Dörthe), Nollmann, M. (Marcelo), Novak, H.R. (Halina R.), Parkinson, H. (Helen), Piccolo, S. (Stefano), Pinheiro, I. (Inês), Pombo, A. (Ana), Popp, C. (Christian), Reik, W. (Wolf), Roman-Roman, S. (Sergio), Rosenstiel, P. (Philip), Schultze, J.L. (Joachim), Stegle, O. (Oliver), Tanay, A. (Amos), Testa, G. (Giuseppe), Thanos, D. (Dimitris), Theis, F. (Fabian), Torres-Padilla, M.-E. (Maria-Elena), Valencia, A. (Alfonso), Vallot, C. (Céline), van Oudenaarden, A. (Alexander), Vidal, M. (Marie), Voet, T. (Thierry), Alberi, L. (Lavinia), Alexander, S. (Stephanie), Alexandrov, T. (Theodore), Arenas, E. (Ernest), Bagni, C. (Claudia), Balderas, R. (Robert), Bandelli, A. (Andrea), Becher, B. (Burkhard), Becker, M. (Matthias), Beerenwinkel, N. (Niko), Benkirame, M. (Monsef), Beyer, M. (Marc), Bickmore, W. (Wendy), Biessen, E.E.A.L. (Erik E.A.L.), Blomberg, N. (Niklas), Blumcke, I. (Ingmar), Bodenmiller, B. (Bernd), Borroni, B. (Barbara), Boumpas, D.T. (Dimitrios T.), Bourgeron, T. (Thomas), Bowers, S. (Sarion), Braeken, D. (Dries), Brooksbank, C. (Catherine), Brose, N. (Nils), Bruining, J. (Hans), Bury, J. (Jo), Caporale, N. (Nicolo), Cattoretti, G. (Giorgio), Chabane, N. (Nadia), Chneiweiss, H. (Hervé), Cook, S.A. (Stuart A.), Curatolo, P. (Paolo), Jonge, M.I. (Marien) de, Deplancke, B. (Bart), De Strooper, B. (Bart), de Witte, P. (Peter), Dimmeler, S. (Stefanie), Draganski, B. (Bogdan), Drews, A.-D. (Anna-Dorothee), Dumbrava, C. (Costica), Engelhardt, S. (Stefan), Gasser, T. (Thomas), Giamarellos-Bourboulis, E. (Evangelos), Graff, C. (Caroline), Grün, D. (Dominic), Gut, I. (Ivo), Hansson, O. (Oskar), Henshall, D.C. (David C.), Herland, A. (Anna), Heutink, P. (Peter), Heymans, S. (Stephane), Heyn, H. (Holger), Huch, M. (Meritxell), Huitinga, I. (Inge), Jackowiak, P. (Paulina), Jongsma, K.R. (Karin), Journot, L. (Laurent), Junker, J.P. (Jan Philipp), Katz, S. (Shauna), Kehren, J. (Jeanne), Kempa, S. (Stefan), Kirchhof, P. (Paulus), Klein, C. (Christoph), Koralewska, N. (Natalia), Korbel, J.O. (Jan), Kühnemund, M. (Malte), Lamond, A.I. (Angus I.), Lauwers, E. (Elsa), Le Ber, I. (Isabelle), Leinonen, V. (Ville), Tobon, A.L. (Alejandro Lopez), Lundberg, E. (Emma), Lunkes, A. (Astrid), Maatz, H. (Henrike), Mann, M. (Mathias), Marelli, L. (Luca), Matser, V. (Vera), Matthews, P.M. (P.), Mechta-Grigoriou, F. (Fatima), Menon, R. (Radhika), Nielsen, A.F. (Anne F.), Pagani, M. (Massimiliano), Pasterkamp, R.J. (Jeroen), Pitkanen, A. (Asla), Popescu, V. (Valentin), Pottier, C. (Cyril), Puisieux, A. (Alain), Rademakers, R. (Rosa), Reiling, D. (Dory), Reiner, O. (Orly), Remondini, D. (Daniel), Ritchie, C. (Craig), Rohrer, J.D. (Jonathan D.), Saliba, A.-E. (Antione-Emmanuel), Sánchez-Valle, R. (Raquel), Santosuosso, A. (Amedeo), Sauter, A. (Arnold), Scheltema, R.A. (Richard A.), Scheltens, P. (Philip), Schiller, H.B. (Herbert B.), Schneider, A. (Anja), Seibler, P. (Philip), Sheehan-Rooney, K. (Kelly), Shields, D. (David), Sleegers, K. (Kristel), Smit, G. (Guus), Smith, K.G.C. (Kenneth G. C.), Smolders, I. (Ilse), Synofzik, M. (Matthis), Tam, W.L. (Wai Long), Teichmann, S. (Sarah), Thom, M. (Maria), Turco, M.Y. (Margherita Y.), Beusekom, H.M.M. (Heleen) van, Vandenberghe, R. (Rik), den Hoecke, S.V. (Silvie Van), Van de Poel, E. (Ellen), der Ven, A. (Andre van), van der Zee, J. (Julie), van Lunzen, J. (Jan), van Minnebruggen, G. (Geert), Van Paesschen, W. (Wim), Swieten, J.C. (John) van, van Vught, R. (Remko), Verhage, M. (Matthijs), Verstreken, P. (Patrik), Villa, C.E. (Carlo Emanuele), Vogel, J. (Jörg), Kalle, C. (Christof) von, Walter, J. (Jörn), Weckhuysen, S. (Sarah), Weichert, W. (Wilko), Wood, L. (Louisa), Ziegler, A.-G. (Anette-Gabriele), and Zipp, F. (Frauke)

Abstract

LifeTime aims to track, understand and target human cells during the onset and progression of complex diseases and their response to therapy at single-cell resolution. This mission will be implemented through the development and integration of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during progression from health to disease. Analysis of such large molecular and clinical datasets will discover molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. Timely detection and interception of disease embedded in an ethical and patient-centered vision will be achieved through interactions across academia, hospitals, patient-associations, health data management systems and industry. Applying this strategy to key medical challenges in cancer, neurological, infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade.

Published
2020
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16. Hydrogeologische Notizen

Author

Wohnlich, S., Scheytt, Traugott, Langguth, R., Löhnert, E. P., Wohnlich, S., Knoke, H., Track, Th., Huch, M., Ließfeld, R., and Göbel, P.

Published
2002
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19. Mouse Model of Alagille Syndrome and Mechanisms of Jagged1 Missense Mutations.

Author

Andersson, ER, Chivukula, IV, Hankeova, S, Sjöqvist, M, Tsoi, YL, Ramsköld, D, Masek, J, Elmansuri, A, Hoogendoorn, A, Vazquez, E, Storvall, H, Netušilová, J, Huch, M, Fischler, B, Ellis, E, Contreras, A, Nemeth, A, Chien, KC, Clevers, H, Sandberg, R, Bryja, V, Lendahl, U, Andersson, ER, Chivukula, IV, Hankeova, S, Sjöqvist, M, Tsoi, YL, Ramsköld, D, Masek, J, Elmansuri, A, Hoogendoorn, A, Vazquez, E, Storvall, H, Netušilová, J, Huch, M, Fischler, B, Ellis, E, Contreras, A, Nemeth, A, Chien, KC, Clevers, H, Sandberg, R, Bryja, V, and Lendahl, U

Abstract

BACKGROUND & AIMS: Alagille syndrome is a genetic disorder characterized by cholestasis, ocular abnormalities, characteristic facial features, heart defects, and vertebral malformations. Most cases are associated with mutations in JAGGED1 (JAG1), which encodes a Notch ligand, although it is not clear how these contribute to disease development. We aimed to develop a mouse model of Alagille syndrome to elucidate these mechanisms. METHODS: Mice with a missense mutation (H268Q) in Jag1 (Jag1+/Ndr mice) were outbred to a C3H/C57bl6 background to generate a mouse model for Alagille syndrome (Jag1Ndr/Ndr mice). Liver tissues were collected at different timepoints during development, analyzed by histology, and liver organoids were cultured and analyzed. We performed transcriptome analysis of Jag1Ndr/Ndr livers and livers from patients with Alagille syndrome, cross-referenced to the Human Protein Atlas, to identify commonly dysregulated pathways and biliary markers. We used species-specific transcriptome separation and ligand-receptor interaction assays to measure Notch signaling and the ability of JAG1Ndr to bind or activate Notch receptors. We studied signaling of JAG1 and JAG1Ndr via NOTCH 1, NOTCH2, and NOTCH3 and resulting gene expression patterns in parental and NOTCH1-expressing C2C12 cell lines. RESULTS: Jag1Ndr/Ndr mice had many features of Alagille syndrome, including eye, heart, and liver defects. Bile duct differentiation, morphogenesis, and function were dysregulated in newborn Jag1Ndr/Ndr mice, with aberrations in cholangiocyte polarity, but these defects improved in adult mice. Jag1Ndr/Ndr liver organoids collapsed in culture, indicating structural instability. Whole-transcriptome sequence analyses of liver tissues from mice and patients with Alagille syndrome identified dysregulated genes encoding proteins enriched at the apical side of cholangiocytes, including CFTR and SLC5A1, as well as reduced expression of IGF1. Exposure of Notch-expressing cells to JAG

Published
2018

20. Multi-site Neurogenin3 Phosphorylation Controls Pancreatic Endocrine Differentiation

Author

Azzarelli, R., Hurley, C., Sznurkowska, M., Rulands, S., Hardwick, L., Gamper, I., Ali, F., McCracken, L., Hindley, C., McDuff, F., Nestorowa, S., Kemp, R., Jones, K., Goettgens, B., Huch, M., Evan, G., Simons, B., Winton, D., Philpott, A., Rulands, Steffen [0000-0001-6398-1553], Gottgens, Berthold [0000-0001-6302-5705], Huch Ortega, Meritxell [0000-0002-1545-5265], Evan, Gerard [0000-0003-0412-1216], Simons, Benjamin [0000-0002-3875-7071], Winton, Douglas [0000-0001-6067-7927], Philpott, Anna [0000-0003-3789-2463], and Apollo - University of Cambridge Repository

Subjects
Homeodomain Proteins, endocrine system, proneural bHLH transcription factors, diabetes, Cell Differentiation, Nerve Tissue Proteins, insulinoma, neurogenin3, β cells, digestive system, Cyclin-Dependent Kinases, Living matter, Islets of Langerhans, Mice, endocrine differentiation, pancreatic development, pancreatic organoids, Animals, Basic Helix-Loop-Helix Transcription Factors, Humans, Insulin-Secreting Cells, Pancreas, Phosphorylation, Signal Transduction
Abstract

The proneural transcription factor Neurogenin3 (Ngn3) plays a critical role in pancreatic endocrine cell differentiation, although regulation of Ngn3 protein is largely unexplored. Here we demonstrate that Ngn3 protein undergoes cyclin-dependent kinase (Cdk)-mediated phosphorylation on multiple serine-proline sites. Replacing wild-type protein with a phosphomutant form of Ngn3 increases a cell generation, the earliest endocrine cell type to be formed in the developing pancreas. Moreover, un(der)phosphorylated Ngn3 maintains insulin expression in adult beta cells in the presence of elevated c-Myc and enhances endocrine specification during ductal reprogramming. Mechanistically, preventing multi-site phosphorylation enhances both Ngn3 stability and DNA binding, promoting the increased expression of target genes that drive differentiation. Therefore, multi-site phosphorylation of Ngn3 controls its ability to promote pancreatic endocrine differentiation and to maintain beta cell function in the presence of pro-proliferation cues and could be manipulated to promote and maintain endocrine differentiation in vitro and in vivo.

Published
2017

21. Human primary liver cancer-derived organoid cultures for disease modeling and drug screening

Author

Broutier, L. (Laura), Mastrogiovanni, G. (Gianmarco), Verstegen, M.M.A. (Monique), Francies, H.E. (Hayley E.), Gavarró, L.M. (Lena Morrill), Bradshaw, C.R. (Charles R.), Allen, G.E. (George E.), Arnes-Benito, R. (Robert), Sidorova, O. (Olga), Gaspersz, M.P. (Marcia), Georgakopoulos, N. (Nikitas), Koo, B.-K. (Bon-Kyoung), Dietmann, S. (Sabine), Davies, S.E. (Susan E.), Praseedom, R.K. (Raaj K.), Lieshout, R. (Ruby), IJzermans, J.N.M. (Jan), Wigmore, S.J. (Stephen J.), Saeb-Parsy, K. (Kourosh), Garnett, M.J. (Mathew J.), Laan, L.J.W. (Luc) van der, Huch, M. (Meritxell), Broutier, L. (Laura), Mastrogiovanni, G. (Gianmarco), Verstegen, M.M.A. (Monique), Francies, H.E. (Hayley E.), Gavarró, L.M. (Lena Morrill), Bradshaw, C.R. (Charles R.), Allen, G.E. (George E.), Arnes-Benito, R. (Robert), Sidorova, O. (Olga), Gaspersz, M.P. (Marcia), Georgakopoulos, N. (Nikitas), Koo, B.-K. (Bon-Kyoung), Dietmann, S. (Sabine), Davies, S.E. (Susan E.), Praseedom, R.K. (Raaj K.), Lieshout, R. (Ruby), IJzermans, J.N.M. (Jan), Wigmore, S.J. (Stephen J.), Saeb-Parsy, K. (Kourosh), Garnett, M.J. (Mathew J.), Laan, L.J.W. (Luc) van der, and Huch, M. (Meritxell)

Abstract

Human liver cancer research currently lacks in vitro models that can faithfully recapitulate the pathophysiology of the original tumor. We recently described a novel, near-physiological organoid culture system, wherein primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumors. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumor, allowing for discrimination between different tumor tissues and subtypes, even after long-term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumorogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug-screening testing and led to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease.

Published
2017
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22. Long-Term Adult Feline Liver Organoid Cultures for Disease Modeling of Hepatic Steatosis

Author

Kruitwagen, H.S. (Hedwig S.), Oosterhoff, L.A. (Loes A.), Vernooij, I.G.W.H. (Ingrid G.W.H.), Schrall, I.M. (Ingrid M.), Wolferen, M.E. (Monique) van, Bannink, F. (Farah), Roesch, C. (Camille), van Uden, L. (Lisa), Molenaar, M.R. (Martijn R.), Helms, J.B. (J. Bernd), Grinwis, G.C.M. (Guy C.), Verstegen, M.M.A. (Monique), Laan, L.J.W. (Luc) van der, Huch, M. (Meritxell), Geijsen, N. (Niels), Vries, R.G.J. (Robert), Clevers, H.C. (Hans), Rothuizen, J. (J.), Schotanus, B.A. (Baukje A.), Penning, C. (Corine), Spee, B. (B.), Kruitwagen, H.S. (Hedwig S.), Oosterhoff, L.A. (Loes A.), Vernooij, I.G.W.H. (Ingrid G.W.H.), Schrall, I.M. (Ingrid M.), Wolferen, M.E. (Monique) van, Bannink, F. (Farah), Roesch, C. (Camille), van Uden, L. (Lisa), Molenaar, M.R. (Martijn R.), Helms, J.B. (J. Bernd), Grinwis, G.C.M. (Guy C.), Verstegen, M.M.A. (Monique), Laan, L.J.W. (Luc) van der, Huch, M. (Meritxell), Geijsen, N. (Niels), Vries, R.G.J. (Robert), Clevers, H.C. (Hans), Rothuizen, J. (J.), Schotanus, B.A. (Baukje A.), Penning, C. (Corine), and Spee, B. (B.)

Abstract

Hepatic steatosis is a highly prevalent liver disease, yet research is hampered by the lack of tractable cellular and animal models. Steatosis also occurs in cats, where it can cause severe hepatic failure. Previous studies demonstrate the potential of liver organoids for modeling genetic diseases. To examine the possibility of using organoids to model steatosis, we established a long-term feline liver organoid culture with adult liver stem cell characteristics and differentiation potential toward hepatocyte-like cells. Next, organoids from mouse, human, dog

Published
2017
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23. Long-Term Adult Feline Liver Organoid Cultures for Disease Modeling of Hepatic Steatosis

Author

Kruitwagen, HS, Oosterhoff, LA, Vernooij, I, Schrall, IM, van Wolferen, ME, Bannink, F, Roesch, C, van Uden, L, Molenaar, MR, Helms, JB, Grinwis, GCM, Verstegen, Monique, van der Laan, Luc, Huch, M, Geijsen, N, de Vries, RG, Clevers, H, Rothuizen, J, Schotanus, BA, Penning, LC, Spee, B, Kruitwagen, HS, Oosterhoff, LA, Vernooij, I, Schrall, IM, van Wolferen, ME, Bannink, F, Roesch, C, van Uden, L, Molenaar, MR, Helms, JB, Grinwis, GCM, Verstegen, Monique, van der Laan, Luc, Huch, M, Geijsen, N, de Vries, RG, Clevers, H, Rothuizen, J, Schotanus, BA, Penning, LC, and Spee, B

Published
2017

29. Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes

Author

Wills, E.S., Cnossen, W.R., Veltman, J.A., Woestenenk, R.M., Steehouwer, M., Salomon, J., Morsche, R.H.M. te, Huch, M., Hehir-Kwa, J.Y., Banning, M.J., Pfundt, R.P., Roepman, R., Hoischen, A., Drenth, J.P.H., Wills, E.S., Cnossen, W.R., Veltman, J.A., Woestenenk, R.M., Steehouwer, M., Salomon, J., Morsche, R.H.M. te, Huch, M., Hehir-Kwa, J.Y., Banning, M.J., Pfundt, R.P., Roepman, R., Hoischen, A., and Drenth, J.P.H.

Abstract

Contains fulltext : 167652.pdf (publisher's version ) (Closed access), Autosomal dominant polycystic liver disease (ADPLD) is caused by variants in PRKCSH, SEC63, and LRP5, whereas autosomal dominant polycystic kidney disease is caused by variants in PKD1 and PKD2. Liver cyst development in these disorders is explained by somatic loss-of-heterozygosity (LOH) of the wild-type allele in the developing cyst. We hypothesize that we can use this mechanism to identify novel disease genes that reside in LOH regions. In this study, we aim to map abnormal genomic regions using high-density SNP microarrays to find novel PLD genes. We collected 46 cysts from 23 patients with polycystic or sporadic hepatic cysts, and analyzed DNA from those cysts using high-resolution microarray (n=24) or Sanger sequencing (n=22). We here focused on regions of homozygosity on the autosomes (>3.0 Mb) and large CNVs (>1.0 Mb). We found frequent LOH in PRKCSH (22/29) and PKD1/PKD2 (2/3) cysts of patients with known heterozygous germline variants in the respective genes. In the total cohort, 12/23 patients harbored abnormalities outside of familiar areas. In individual ADPLD cases, we identified germline events: a 2q13 complex rearrangement resulting in BUB1 haploinsufficiency, a 47XXX karyotype, chromosome 9q copy-number loss, and LOH on chromosome 3p. The latter region was overlapping with an LOH region identified in two other cysts. Unique germline and somatic abnormalities occur frequently in and outside of known genes underlying cysts. Each liver cyst has a unique genetic makeup. LOH driver gene BUB1 may imply germline causes of genetic instability in PLD.

Published
2016

32. Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver

Author

Huch, M, Gehart, H, van Boxtel, R, Hamer, K, Blokzijl, F, Verstegen, Monique, Ellis, E, van Wenum, M, Fuchs, SA, de Ligt, J, van de Wetering, M, Sasaki, N, Boers, SJ, Kemperman, H, de Jonge, Jeroen, IJzermans, J.N.M., Nieuwenhuis, EES, Hoekstra, R, Strom, S, Vries, RRG, van der Laan, Luc, Cuppen, E, Clevers, H, Huch, M, Gehart, H, van Boxtel, R, Hamer, K, Blokzijl, F, Verstegen, Monique, Ellis, E, van Wenum, M, Fuchs, SA, de Ligt, J, van de Wetering, M, Sasaki, N, Boers, SJ, Kemperman, H, de Jonge, Jeroen, IJzermans, J.N.M., Nieuwenhuis, EES, Hoekstra, R, Strom, S, Vries, RRG, van der Laan, Luc, Cuppen, E, and Clevers, H

Abstract

Despite the enormous replication potential of the human liver, there are currently no culture systems available that sustain hepatocyte replication and/or function in vitro. We have shown previously that single mouse Lgr5+ liver stem cells can be expanded as epithelial organoids in vitro and can be differentiated into functional hepatocytes in vitro and in vivo. We now describe conditions allowing long-term expansion of adult bile duct-derived bipotent progenitor cells from human liver. The expanded cells are highly stable at the chromosome and structural level, while single base changes occur at very low rates. The cells can readily be converted into functional hepatocytes in vitro and upon transplantation in vivo. Organoids from alpha 1-antitrypsin deficiency and Alagille syndrome patients mirror the in vivo pathology. Clonal long-term expansion of primary adult liver stem cells opens up experimental avenues for disease modeling, toxicology studies, regenerative medicine, and gene therapy.

Published
2015

33. Book Reviews

Author

Huch, M., Von Leszczynski, H., Krause, R.A., Rack, U., and Fritzsche, D.

Subjects
Biodiversity, Taxonomy
Abstract

Huch, M., Von Leszczynski, H., Krause, R.A., Rack, U., Fritzsche, D. (2013): Book Reviews. Zoological Journal of the Linnean Society 168: 669-670, DOI: 10.2312/polarforschung.83.2.83, URL: http://dx.doi.org/10.2312/polarforschung.83.2.83

Published
2013

37. Dynamische Erde - Zukunftsaufgaben der Geowissenschaften : Strategieschrift

Author

Andruleit, H., Bach, W., Balzer, D., Bau, M., Becker, H., Bendix, J., Bens, O., Bill, R., Bismayer, U., von Blanckenburg, F., Blotevogel, H., Boetius, A., Bork, H., Bosbach, D., Bräuer, V., Brückner, H., Buchholz, P., Bunge, P., Cermak, J., Chakraborty, S., Christensen, U., Clauser, C., Claußen, M., Cubasch, U., Delisle, G., Deutsch, A., Diepenbroek, M., Dikau, R., Dingwell, D., Dott, W., Dresen, G., Dürr, S., Elsner, H., Emmermann, R., Erbacher, J., Flurly, J., Franke, W., Franz, G., Freiwald, A., Friederich, W., Friedrich, A., Frost, D., Gaupp, R., Gebhardt, H., Gerling, P., Gestermann, N., Gleixner, G., Grathwohl, P., Günther, A., Handy, M., Hartmann, J., Heinrich, W., Hemmer, I., Hennings, V., Hezel, D., Hinderer, M., Horsfield, B., Huch, M., Hüser, K., Hüttl, R., Isenbeck-Schröter, M., Keppler, H., Kiessling, W., Kind, R., Kolditz, O., Kothe, E., Kraas, F., Kudrass, H., Kuhn, D., Kühn, M., Kümpel, H., Langenhorst, F., Leiss, B., Leythäuser, D., Littke, R., Maronde, D., MacCammon, C., Megerle, H., Mezger, K., Mosbrugger, V., Mulch, A., Münker, C., Ochmann, N., Oncken, O., Otto, K., Palme, H., Peckmann, J., Pollock, K., di Primio, R., Radtke, U., Ranke, U., Reichert, C., Röhling, S., Rust, J., Samuel, H., Scheck-Wenderoth, M., Scherbaum, F., Schmidt, U., Schmidt-Thome, M., Schulz, M., Schütt, B., Schwalb, A., Schwarz-Schampera, U., Sester, M., Spohn, T., Steinbach, V., Steininger, F., Steinle-Neumann, G., Stöckhert, B., Stöffler, D., Strecker, M., Thiede, J., Tischner, T., Trumbull, R., Ulbrich, U., Vasters, J., Vereecken, H., Wagner, M., Weber, M., Wefer, G., Wellmer, F., Welte, D., Wenzel, F., Westphal, H., Wiesmüller, G., Wippermann, T., Woith, H., Wörner, G., Zschau, J., Wefer, G., and WB Scientific Drilling, Scientific Infrastructure and Plattforms, GFZ Publication Database, Deutsches GeoForschungsZentrum

Subjects
550 - Earth sciences
Published
2010

38. Wnt AND NOTCH REGULATE PROLIFERATION, MIGRATION AND DIFFERENTIATION OF HUMAN HEPATIC PROGENITOR CELLS AND CANINE LIVER ORGANOIDS: Journal of Hepatology

Author

Onderzoek, Sub Neuro/Tandheelkunde, CSCA TR1, LS Interne geneeskunde, Biochemisch laboratorium, Veterinair Pathologisch Diagnostisch Cnt, PB AVM, Dep Pathobiologie, LS Celbiologie-Algemeen, Sub Center for Cell Imaging, Sub Hepatologie, CSCA AVM, Schotanus, B.A., Nantasanti, S., Huch, M., Oosterhoff, L., Fieten, H., Kruitwagen, H.S., van Wolferen, M., Grinwis, G.C.M., Wubbolts, R., Favier, R.P., Penning, L.C., Vries, R.G.J., Clevers, H., Rothuizen, J., Spee, B., Onderzoek, Sub Neuro/Tandheelkunde, CSCA TR1, LS Interne geneeskunde, Biochemisch laboratorium, Veterinair Pathologisch Diagnostisch Cnt, PB AVM, Dep Pathobiologie, LS Celbiologie-Algemeen, Sub Center for Cell Imaging, Sub Hepatologie, CSCA AVM, Schotanus, B.A., Nantasanti, S., Huch, M., Oosterhoff, L., Fieten, H., Kruitwagen, H.S., van Wolferen, M., Grinwis, G.C.M., Wubbolts, R., Favier, R.P., Penning, L.C., Vries, R.G.J., Clevers, H., Rothuizen, J., and Spee, B.

Published
2014

40. Complexation de ligands dithiolènes fonctionnalisés sur des éléments de transition et des lanthanoides trivalents : synthèse, caractérisation et études de luminescence

Author

Ndiaye F. Guyon M. Knorr V. Huch M. Veith, A., Univers, Transport, Interfaces, Nanostructures, Atmosphère et environnement, Molécules (UMR 6213) (UTINAM), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)

Subjects
ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2009

43. Permafrost und der globale Klimawandel

Author

Boike, J., Hubberten, H.-W., Lantuit, H., Overduin, P., Schirrmeister, L., Wagner, D., Huch, M., and 0 Pre-GFZ, Departments, GFZ Publication Database, Deutsches GeoForschungsZentrum

Subjects
Science, 550 - Earth sciences
Abstract

Polarforschung

Published
2009

48. Das Internationale Polarjahr 2007/08

Author

Boike, Julia, Hubberten, Hans-Wolfgang, Lantuit, Hugues, Overduin, Pier Paul, Schirrmeister, Lutz, Wagner, Dirk, and Huch, M.

Published
2009

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