Molecular Medicine Partnership Unit

The MMPU is a joint venture between the Medical Faculty of the University of Heidelberg and the European Molecular Biology Laboratory (EMBL).

Systems Medicine of Cancer Drugs

Wolfgang Huber, Sascha Dietrich and Junyan Lu

Our research interest

We aim to understand intra- and inter-patient heterogeneity of response to anti-cancer drugs, a major clinical and scientific challenge. Our focus is to study the interaction of tumour cells with their microenvironment and consequences for drug response.

Background and overall goals

Response to anti-cancer agents is often restricted to subsets of patients and, even within patients, to subfractions of the tumour. In addition, signals provided by the tumour micro-environment modify pathway activities, including those targeted by drugs. Our knowledge of such complex interactions of different factors underlying drug response is incomplete. Our goal is to increase the understanding of drug response heterogeneity and to provide the scientific basis for biology-based individualised treatment of lymphoma and leukaemia.

We pursue a systems medicine approach that integrates systematic modelling of niche compartments and their crosstalk with tumour cells subsets with drug perturbation assays of primary cancer cells, multi-omic molecular profiling, cutting-edge statistical data analysis, mathematical modelling and a setup aiming towards clinical exploitation.

Approach and foci

Ex-vivo drug testing platform to map the biological complexity and inter- and intra-patient heterogeneity of blood tumours in the context of their interaction with the micro-environment.

Niche models. We isolate tumour cells from surgically extracted lymph-nodes and bone marrow aspirates and characterise their functional states and pathway activities using phospho-proteomics and phospho-specific antibodies. These results serve as a reference for in vitro models that aim to resemble the niche specific context.

Further dimensions of drug sensitivity and resistance: 3D space, timing, and dynamics of clonal composition.

Cancer cell phenotyping using an automated microscopy platform and computational image analysis of cellular morphology (mitochondria, nuclei, microtubules) for dynamic understanding of cell fate in time.

Statistical multivariate modelling to explain and predict the heterogeneity of drug response by integration of cancer cell phenotypes and multi-omics data types.

Clinical applications. This includes assessment of our ex vivo tumour models for clinical outcome prediction and preparation for prospective clinical studies.

Important publications

SpatialData: an open and universal data framework for spatial omics.
Luca Marconato, Giovanni Palla, Kevin A. Yamauchi, Isaac Virshup, Elyas Heidari, Tim Treis, Marcella Toth, Rahul B. Shrestha, Harald Vöhringer, Wolfgang Huber, Moritz Gerstung, Josh Moore, Fabian J. Theis, and Oliver Stegle.
Nature Methods, 2024.
DOI:10.1101/2023.05.05.539647 – PreprintEuropePMC.

Multimodal and spatially resolved profiling identifies distinct patterns of T-cell infiltration in nodal B-cell lymphoma entities.
Tobias Roider, Marc A. Baertsch, Donnacha Fitzgerald, Harald Vöhringer, Berit J. Brinkmann, Felix Czernilofsky, Mareike Knoll, Laura Llaó-Cid, Peter-Martin Bruch, Nora Liebers, Christian M. Schürch, Verena Passerini, Alexander Brobeil, Gunhild Mechtersheimer, Carsten Müller-Tidow, Oliver Weigert, Martina Seiffert, Garry P. Nolan, Wolfgang Huber, and Sascha Dietrich
Nature Cell Biology 2024, Feb 20 volume 26, pages 478–489, DOI:10.1038/s41556-024-01358-2

A single-cell multi-omic and spatial atlas of B cell lymphomas reveals differentiation drives intratumor heterogeneity.
Donnacha Fitzgerald, Tobias Roider, Marc-Andrea Baertsch, Artur Kibler, Anastasiia Horlova, Erin Chung, Harald Vöhringer, Anna Mathioudaki, Bettina Budeus, Verena Passerini, Mareike Knoll, Johannes Mammen, Linsha Li, Léandra Caillé, Felix Czernilofsky, Peter-Martin Bruch, Nora Liebers, Matthias Meyer-Bender, Oliver Weigert, Judith Zaugg, Garry Nolan, Marc Seifert, Sascha Dietrich, and Wolfgang Huber.
bioRχiv, 2023. DOI:10.1101/2023.11.06.565756 – PreprintEuropePMC.

Ex vivo drug response profiling for response and outcome prediction in hematologic malignancies: the prospective non-interventional SMARTrial.
Liebers N, Bruch PM, Terzer T, Hernandez-Hernandez M, Paramasivam N, Fitzgerald D, Altmann H, Roider T, Kolb C, Knoll M, Lenze A, Platzbecker U, Röllig C, Baldus C, Serve H, Bornhäuser M, Hübschmann D, Müller-Tidow C, Stölzel F, Huber W, Benner A, Zenz T, Lu J, Dietrich S.
Nat Cancer. 2023 Oct 2. doi: 10.1038/s43018-023-00645-5. Online ahead of print.PMID: 37783805

Comparing the value of mono- versus coculture for high-throughput compound screening in hematological malignancies
Sophie A. Herbst, Vladislav Kim, Tobias Roider, Eva C. Schitter, Peter-Martin Bruch, Nora Liebers, Carolin Kolb, Mareike Knoll, Junyan Lu, Peter Dreger, Carsten Müller-Tidow, Thorsten Zenz, Wolfgang Huber, Sascha Dietrich
Blood advances June 23, 2023  https://doi.org/10.1182/bloodadvances.2022009652.

Retrospective analysis of hematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: conditioning intensity matters.
Bruch PM, Dietrich S, Finel H, Boumendil A, Greinix H, Heinicke T, Bethge W, Beelen D, Schmid C, Martin H, Castagna L, Scheid C, Schäfer-Eckart K, Bittenbring J, Finke J, Sengeloev H, Heiblig M, Cornelissen J, Chevallier P, Mohty M, Robinson S, Montoto S, Dreger P.
Leukemia. 2023 Feb;37(2):465-472. doi: 10.1038/s41375-022-01782-z. Epub 2022 Dec 22.PMID: 36550212

Venetoclax synergizes with gilteritinib in FLT3 wild-type high-risk acute myeloid leukemia by suppressing MCL-1.
Janssen M, Schmidt C, Bruch PM, Blank MF, Rohde C, Waclawiczek A, Heid D, Renders S, Göllner S, Vierbaum L, Besenbeck B, Herbst SA, Knoll M, Kolb C, Przybylla A, Weidenauer K, Ludwig AK, Fabre M, Gu M, Schlenk RF, Stölzel F, Bornhäuser M, Röllig C, Platzbecker U, Baldus C, Serve H, Sauer T, Raffel S, Pabst C, Vassiliou G, Vick B, Jeremias I, Trumpp A, Krijgsveld J, Müller-Tidow C, Dietrich S.
Blood. 2022 Dec 15;140(24):2594-2610. doi: 10.1182/blood.2021014241.PMID: 35857899

Pre-analytical processing of plasma and serum samples for combined proteome and metabolome analysis.
Gegner HM, Naake T, Dugourd A, Müller T, Czernilofsky F, Kliewer G, Jäger E, Helm B, Kunze-Rohrbach N, Klingmüller U, Hopf C, Müller-Tidow C, Dietrich S, Saez-Rodriguez J, Huber W, Hell R, Poschet G, Krijgsveld J.
Front Mol Biosci. 2022 Dec 20;9:961448. doi: 10.3389/fmolb.2022.961448. eCollection 2022.PMID: 36605986

Single-cell multi-omic and spatial analysis of nodal B cell non-Hodgkin lymphomas reveals plasticity in B cell maturation as a driver of intratumor heterogeneity.
Donnacha Fitzgerald, Tobias Roider, Marc-A. Baertsch, Harald Vöhringer, Mareike Knoll, Bettina Budeus, Artur Kibler, Anna Mathioudaki, Léandra Caillé, Linsha Li, Johannes Mammen, Marc Seifert, Wolfgang Huber, and Sascha Dietrich.
Blood, 140:742, November 2022. DOI:10.1182/blood-2022-156210

Functional analysis of structural variants in single cells using Strand-seq.
Jeong H, Grimes K, Rauwolf KK, Bruch PM, Rausch T, Hasenfeld P, Benito E, Roider T, Sabarinathan R, Porubsky D, Herbst SA, Erarslan-Uysal B, Jann JC, Marschall T, Nowak D, Bourquin JP, Kulozik AE, Dietrich S, Bornhauser B, Sanders AD, Korbel JO.
Nat Biotechnol. 2022 Nov 24. doi: 10.1038/s41587-022-01551-4. Online ahead of print.PMID: 36424487

Multimodal and spatially resolved profiling identifies distinct patterns of T-cell infiltration in nodal B-cell lymphoma entities
Roider T, Marc A. Baertsch et al
bioRxiv Nov 8, 2022

Proteogenomics refines the molecular classification of chronic lymphocytic leukemia.
Herbst SA, Vesterlund M, Helmboldt AJ, Jafari R, Siavelis I, Stahl M, Schitter EC, Liebers N, Brinkmann BJ, Czernilofsky F, Roider T, Bruch PM, Iskar M, Kittai A, Huang Y, Lu J, Richter S, Mermelekas G, Umer HM, Knoll M, Kolb C, Lenze A, Cao X, Österholm C, Wahnschaffe L, Herling C, Scheinost S, Ganzinger M, Mansouri L, Kriegsmann K, Kriegsmann M, Anders S, Zapatka M, Del Poeta G, Zucchetto A, Bomben R, Gattei V, Dreger P, Woyach J, Herling M, Müller-Tidow C, Rosenquist R, Stilgenbauer S, Zenz T, Huber W, Tausch E, Lehtiö J, Dietrich S.
Nat Commun. 2022 Oct 20;13(1):6226. doi: 10.1038/s41467-022-33385-8.PMID: 36266272

Inferring tumor-specific cancer dependencies through integrating ex vivo drug response assays and drug-protein profiling.
Batzilla A, Lu J, Kivioja J, Putzker K, Lewis J, Zenz T, Huber W.
PLoS Comput Biol. 2022 Aug 22;18(8):e1010438. doi: 10.1371/journal.pcbi.1010438. eCollection 2022 Aug.PMID: 35994503

Drug-microenvironment perturbations reveal resistance mechanisms and prognostic subgroups in CLL.
Bruch PM, Giles HA, Kolb C, Herbst SA, Becirovic T, Roider T, Lu J, Scheinost S, Wagner L, Huellein J, Berest I, Kriegsmann M, Kriegsmann K, Zgorzelski C, Dreger P, Zaugg JB, Müller-Tidow C, Zenz T, Huber W, Dietrich S.
Mol Syst Biol. 2022 Aug;18(8):e10855. doi: 10.15252/msb.202110855. PMID: 35959629

Networks and graphs discovery in metabolomics data analysis and interpretation
A Amara, C Frainay, F Jourdan, T Naake, S Neumann et al
Frontiers in Molecular Biosciences, 08. March 2022, 223

Humoral and cellular responses after COVID-19 vaccination in anti-CD20-treated lymphoma patients.
Liebers N, Speer C, Benning L, Bruch PM, Kraemer I, Meissner J, Schnitzler P, Kräusslich HG, Dreger P, Mueller-Tidow C, Poschke I, Dietrich S.
Blood. 2022 Jan 6;139(1):142-147. doi: 10.1182/blood.2021013445.PMID: 34669919

Inferring tumor-specific cancer dependencies through integrating ex-vivo drug response assays and drug-protein profiling
Alina Batzilla, Junyan Lu, Jarno Kivioja, Kerstin Putzker, Joe Lewis, Thorsten Zenz, Wolfgang Huber
bioRxiv 2022.01.11.475864; doi: https://doi.org/10.1101/2022.01.11.475864

MatrixQCvis: shiny-based interactive data quality exploration for omics data.
Naake T, Huber W.
Bioinformatics. 2021 Nov 12;38(4):1181-2. doi: 10.1093/bioinformatics/btab748. Online ahead of print. PMID: 34788796

Pairwise effects between lipid GWAS genes modulate lipid plasma levels and cellular uptake.
Zimoń M, Huang Y, Trasta A, Halavatyi A, Liu JZ, Chen CY, Blattmann P, Klaus B, Whelan CD, Sexton D, John S, Huber W, Tsai EA, Pepperkok R, Runz H.
Nat Commun. 2021 Nov 5;12(1):6411. doi: 10.1038/s41467-021-26761-3. PMID: 34741066

Multi-omics reveals clinically relevant proliferative drive associated with mTOR-MYC-OXPHOS activity in chronic lymphocytic leukemia.
Lu J, Cannizzaro E, Meier-Abt F, Scheinost S, Bruch PM, Giles HA, Lütge A, Hüllein J, Wagner L, Giacopelli B, Nadeu F, Delgado J, Campo E, Mangolini M, Ringshausen I, Böttcher M, Mougiakakos D, Jacobs A, Bodenmiller B, Dietrich S, Oakes CC, Zenz T, Huber W.
Nat Cancer. 2021 Aug;2(8):853-864. doi: 10.1038/s43018-021-00216-6. Epub 2021 Jul 1. PMID: 34423310

Mapping drug-microenvironment-genetic interplay in CLL reveals trisomy 12 as a modulator of microenvironmental signals
Peter-Martin Bruch, Holly A. R. Giles, Carolin Kolb, Sophie A. Herbst, Tina Becirovic, Tobias Roider, Junyan Lu, Sebastian Scheinost, Lena Wagner, Jennifer Huellein, Ivan Berest, Mark Kriegsmann, Katharina Kriegsmann, Christiane Zgorzelski, Peter Dreger, Judith B. Zaugg, Carsten Müller-Tidow, Thorsten Zenz, Wolfgang Huber, Sascha Dietrich
biorxiv https://doi.org/10.1101/2021.07.23.453514

Polatuzumab vedotin as a salvage and bridging treatment in relapsed or refractory large B-cell lymphomas.
Liebers N, Duell J, Fitzgerald D, Kerkhoff A, Noerenberg D, Kaebisch E, Acker F, Fuhrmann S, Leng C, Welslau M, Chemnitz J, Middeke JM, Weber T, Holtick U, Trappe R, Pfannes R, Liersch R, Spoer C, Fuxius S, Gebauer N, Caillé L, Geer T, Koenecke C, Keller U, Claus R, Mougiakakos D, Mayer S, Huettmann A, Pott C, Trummer A, Wulf G, Brunnberg U, Bullinger L, Hess G, Mueller-Tidow C, Glass B, Lenz G, Dreger P, Dietrich S.
Blood Adv. 2021 Jul 13;5(13):2707-2716. doi: 10.1182/bloodadvances.2020004155. PMID: 34196677

The Protein Landscape of Chronic Lymphocytic Leukemia (CLL).
Meier-Abt F, Lu J, Cannizzaro E, Pohly MF, Kummer S, Pfammatter S, Kunz L, Collins BC, Nadeu F, Lee KS, Xue P, Gwerder M, Roiss M, Hüllein J, Scheinost S, Dietrich S, Campo E, Huber W, Aebersold R, Zenz T.
Blood. 2021 Jun 29:blood.2020009741. doi: 10.1182/blood.2020009741. Online ahead of print. PMID: 34189564

Transformation and Preprocessing of Single-Cell RNA-Seq Data
Constantin Ahlmann-Eltze, Wolfgang Huber
Biorxiv June 25, 2021 https://doi.org/10.1101/2021.06.24.449781

glmGamPoi: fitting Gamma-Poisson generalized linear models on single cell count data.
Ahlmann-Eltze C, Huber W.
Bioinformatics. 2021 Apr 5;36(24):5701-5702. doi: 10.1093/bioinformatics/btaa1009. PMID: 33295604

The impact of SAMHD1 expression and mutation status in mantle cell lymphoma: An analysis of the MCL Younger and Elderly trial.
Roider T, Wang X, Hüttl K, Müller-Tidow C, Klapper W, Rosenwald A, Stewart JP, de Castro DG, Dreger P, Hermine O, Kluin-Nelemans HC, Grabe N, Dreyling M, Pott C, Ott G, Hoster E, Dietrich S.
Int J Cancer. 2021 Jan 1;148(1):150-160. doi: 10.1002/ijc.33202. Epub 2020 Aug 15. PMID: 32638373

Miniaturized Drug Sensitivity and Resistance Test on Patient-Derived Cells Using Droplet-Microarray.
Popova AA, Dietrich S, Huber W, Reischl M, Peravali R, Levkin PA.
SLAS Technol. 2020 Aug 13:2472630320934432. doi: 10.1177/2472630320934432. Online ahead of print. PMID: 32791934

The impact of SAMHD1 expression and mutation status in mantle cell lymphoma: An analysis of the MCL Younger and Elderly trial.
Roider T, Wang X, Hüttl K, Müller-Tidow C, Klapper W, Rosenwald A, Stewart JP, Gonzalez de Castro D, Dreger P, Hermine O, Kluin-Nelemans HC, Grabe N, Dreyling M, Pott C, Ott G, Hoster E, Dietrich S.
Int J Cancer. 2020 Jul 7. doi: 10.1002/ijc.33202. Online ahead of print. PMID: 32638373

Dissecting intratumour heterogeneity of nodal B-cell lymphomas at the transcriptional, genetic and drug-response levels.
Roider T, Seufert J, Uvarovskii A, Frauhammer F, Bordas M, Abedpour N, Stolarczyk M, Mallm JP, Herbst SA, Bruch PM, Balke-Want H, Hundemer M, Rippe K, Goeppert B, Seiffert M, Brors B, Mechtersheimer G, Zenz T, Peifer M, Chapuy B, Schlesner M, Müller-Tidow C, Fröhling S, Huber W, Anders S, Dietrich S.
Nat Cell Biol. 2020 Jul;22(7):896-906. doi: 10.1038/s41556-020-0532-x. Epub 2020 Jun 15. PMID: 32541878

Survey of ex vivo drug combination effects in chronic lymphocytic leukemia reveals synergistic drug effects and genetic dependencies.
Lukas M, Velten B, Sellner L, Tomska K, Hüellein J, Walther T, Wagner L, Muley C, Wu B, Oleś M, Dietrich S, Jethwa A, Bohnenberger H, Lu J, Huber W, Zenz T.
Leukemia. 2020 May 13. doi: 10.1038/s41375-020-0846-5. Online ahead of print. PMID: 32404973

BRAF inhibitor treatment in classic hairy cell leukemia: a long-term follow-up study of patients treated outside clinical trials.
Liebers N, Roider T, Bohn JP, Haberbosch I, Pircher A, Ferstl B, Ebnöther M, Wendtner CM, Dearden C, Follows GA, Ho AD, Müller-Tidow C, Dreger P, Troussard X, Zenz T, Dietrich S.
Leukemia 2020 May;34(5):1454-1457. doi: 10.1038/s41375-019-0646-y. Epub 2019 Nov 18. PMID: 31740808

Quantification of Differential Transcription Factor Activity and Multiomics-Based Classification into Activators and Repressors: diffTF. Berest I, Arnold C, Reyes-Palomares A, Palla G, Rasmussen KD, Giles H, Bruch PM, Huber W, Dietrich S, Helin K, Zaugg JB.
Cell Rep. 2019 Dec 3;29(10):3147-3159.e12. doi: 10.1016/j.celrep.2019.10.106. PMID: 31801079

Multi-Omics Factor Analysis-a framework for unsupervised integration of multi-omics data sets.
Argelaguet R, Velten B, Arnol D, Dietrich S, Zenz T, Marioni JC, Buettner F, Huber W, Stegle O.
Mol Syst Biol. 2018 Jun 20;14(6):e8124. doi: 10.15252/msb.20178124. PMID:29925568

Drug-perturbation-based stratification of blood cancer.
Dietrich S, Oleś M, Lu J, Sellner L, Anders S, Velten B, Wu B, Hüllein J, da Silva Liberio M, Walther T, Wagner L, Rabe S, Ghidelli-Disse S, Bantscheff M, Oleś AK, Słabicki M, Mock A, Oakes CC, Wang S, Oppermann S, Lukas M, Kim V, Sill M, Benner A, Jauch A, Sutton LA, Young E, Rosenquist R, Liu X, Jethwa A, Lee KS, Lewis J, Putzker K, Lutz C, Rossi D, Mokhir A, Oellerich T, Zirlik K, Herling M, Nguyen-Khac F, Plass C, Andersson E, Mustjoki S, von Kalle C, Ho AD, Hensel M, Dürig J, Ringshausen I, Zapatka M, Huber W, Zenz T.
J Clin Invest. 2018 Jan 2;128(1):427-445. doi: 10.1172/JCI93801. Epub 2017 Dec 11.PMID:29227286

Data-driven hypothesis weighting increases detection power in genome-scale multiple testing.
Ignatiadis N, Klaus B, Zaugg JB, Huber W.
Nat Methods. 2016 Jul;13(7):577-80. doi: 10.1038/nmeth.3885.

BRAF inhibition in hairy cell leukemia with low-dose vemurafenib.
Dietrich S, Pircher A, Endris V, Peyrade F, Wendtner CM, Follows GA, Hüllein J, Jethwa A, Ellert E, Walther T, Liu X, Dyer MJ, Elter T, Brummer T, Zeiser R, Hermann M, Herold M, Weichert W, Dearden C, Haferlach T, Seiffert M, Hallek M, von Kalle C, Ho AD, Gaehler A, Andrulis M, Steurer M, Zenz T.
Blood. 2016 Jun 9;127(23):2847-55. doi: 10.1182/blood-2015-11-680074.
PMID: 26941398

A chemical-genetic interaction map of small molecules using high-throughput imaging in cancer cells.
Breinig M, Klein FA, Huber W, Boutros M.
Mol Syst Biol. 2015 Dec 23;11(12):846. doi: 10.15252/msb.20156400.
PMID: 26700849

Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells.
Brennecke P, Reyes A, Pinto S, Rattay K, Nguyen M, Küchler R, Huber W, Kyewski B, Steinmetz LM. Nat Immunol. 2015 Sep;16(9):933-41. doi: 10.1038/ni.3246.
PMID: 26237553

Recurrent CDKN1B (p27) mutations in hairy cell leukemia.
Dietrich S, Hüllein J, Lee SC, Hutter B, Gonzalez D, Jayne S, Dyer MJ, Oleś M, Else M, Liu X, Słabicki M, Wu B, Troussard X, Dürig J, Andrulis M, Dearden C, von Kalle C, Granzow M, Jauch A, Fröhling S, Huber W, Meggendorfer M, Haferlach T, Ho AD, Richter D, Brors B, Glimm H, Matutes E, Abdel Wahab O, Zenz T.
Blood. 2015 Aug 20;126(8):1005-8. doi: 10.1182/blood-2015-04-643361.
PMID: 26065650

Improved binding site assignment by high-resolution mapping of RNA-protein interactions using iCLIP.
Hauer C, Curk T, Anders S, Schwarzl T, Alleaume AM, Sieber J, Hollerer I, Bhuvanagiri M, Huber W, Hentze MW, Kulozik AE.
Nat Commun. 2015 Aug 11;6:7921. doi: 10.1038/ncomms8921.
PMID: 26260686

A map of directional genetic interactions in a metazoan cell.
Fischer B, Sandmann T, Horn T, Billmann M, Chaudhary V, Huber W, Boutros M.
Elife. 2015 Mar 6;4. doi: 10.7554/eLife.05464.

Orchestrating high-throughput genomic analysis with Bioconductor.
Huber W, Carey VJ, Gentleman R, Anders S, Carlson M, Carvalho BS, Bravo HC, Davis S, Gatto L, Girke T, Gottardo R, Hahne F, Hansen KD, Irizarry RA, Lawrence M, Love MI, MacDonald J, Obenchain V, Oleś AK, Pagès H, Reyes A, Shannon P, Smyth GK, Tenenbaum D, Waldron L, Morgan M.
Nat Methods. 2015 Feb;12(2):115-21. doi: 10.1038/nmeth.3252. Review.
PMID: 25633503

Continued response off treatment after BRAF inhibition in refractory hairy cell leukemia.
Dietrich S, Hüllein J, Hundemer M, Lehners N, Jethwa A, Capper D, Acker T, Garvalov BK, Andrulis M, Blume C, Schulte C, Mandel T, Meissner J, Fröhling S, von Kalle C, Glimm H, Ho AD, Zenz T.
J Clin Oncol. 2013 Jul 1;31(19):e300-3. doi: 10.1200/JCO.2012.45.9495. No abstract available.

Mapping genetic interactions in human cancer cells with RNAi and multiparametric phenotyping.
Laufer C, Fischer B, Billmann M, Huber W, Boutros M.
Nat Methods. 2013 May;10(5):427-31. doi: 10.1038/nmeth.2436.

BRAF inhibition in refractory hairy-cell leukemia.
Dietrich S, Glimm H, Andrulis M, von Kalle C, Ho AD, Zenz T.
N Engl J Med. 2012 May 24;366(21):2038-40. doi: 10.1056/NEJMc1202124.

Sascha Dietrich and Wolfgang Huber