Dr. Kurt Ballmer-Hofer

Emeritus
Telefon
+41 56 310 41 65
Paul Scherrer Institute PSI
Forschungsstrasse 111
5232 Villigen PSI
Switzerland
Digitale Visitenkarte
Transmembrane signaling by receptor tyrosine kinases in vasculogenesis

The focus of our research was transmembrane signaling by receptor tyrosine kinases. We investigated Vascular Endothelial Growth Factors (VEGFs) and their receptors, which regulate blood and lymphatic vessel formation in angiogenesis and vasculogenesis. VEGF plays an essential role in normal vascular development and in many diseases such as macular degeneration of the eye, arthritis, or in tumor growth and metastasis. We studied (i) the molecular mechanisms regulating VEGF receptor activity, (ii) the intracellular signaling pathways activated by VEGF receptors, and (iii) membrane trafficking and receptor downregulation.
Image presentation of a structural model of VEGFR-1 extracellular domain in complex with VEGF-A.
Fig. 1 Structure of the VEGFR-1 extracellular domain in complex with VEGF-A.

(Top left) Schematic overview of the domain organization of VEGFR-1. Cartoon representation of the VEGFR-1 D1-6/VEGF-A complex (left) and of the VEGFR-1 D2-7/VEGF-A complex (second from left). The chains of the VEGF-A homodimer are shown in purple and orange, the two chains of VEGFR-1 D1-6 in yellow and magenta, and the VEGFR-1 D2-7 chains in light and dark gray. N-linked glycans are depicted as spheres. The N- and C-terminal residues of VEGF-A and VEGFR-1 D1-6 and D2-7, respectively, visualized in the two structures are indicated. Two images on the right show composite model of the VEGFR-1 ECD/VEGF-A complex. The dimensions of the complex and the axis of rotation relating the two views are shown.
We determined the structural changes induced in the extracellular receptor domain upon ligand binding using single particle electron microscopy and small angle solution X-ray scattering, and solved the structures of complexes between the ligand binding domain of VEGFR-2 (Ig-domains D2 and D3) and VEGF-A, -C, and -E by X-ray crystallography. We also solved the structure of the full-length extracellular domain of VEGFR-1 in complex with VEGF-A (Fig. 1). These structures led to the discovery of an allosteric regulatory site in the receptor ECD in subdomains 4-7. Based on these findings we developed novel inhibitory molecules binding subdomains 4 or 7 that block VEGF receptor activation. The functionality of these reagents in VEGF signaling was validated in vitro in cell cultures and in vivo in angiogenesis animal models. In a second project we investigated how ligand-mediated receptor dimerization, and the resulting structural changes in the extracellular domain, instigate transmembrane signaling promoting activation of the intracellular kinase domain. We generated a series of pre-dimerized receptor constructs carrying dimerization-promoting transmembrane domains. The results showed that distinct orientation of receptor monomers in the active dimer is a pre-requisite for kinase activation. The structure of activating and inactivating transmembrane domain peptides was determined by nuclear magnetic resonance spectroscopy establishing the exact orientation of the receptors in active or inactive dimers. We also studied the function of specific intracellular kinase subdomains in receptor activation and found that both the carboxyterminal as well as the kinase insert domain play a regulatory function in receptor activation. Finally, we studied the role of co-receptors such as neuropilins in VEGF receptor activation and trafficking. Neuropilins modulate receptor activity, turnover, and signaling by targeting receptor complexes to distinct intracellular endocytic compartments.

Our structure/function analysis of VEGFRs led to the development of novel allosteric inhibitors binding the extracellular receptor domain. The functionality of these reagents in VEGF signaling were validated in vitro in cell cultures and in vivo in angiogenesis animal models.

2018

  • ScFvs as Allosteric Inhibitors of VEGFR-2: Novel Tools to Harness VEGF Signaling K Ballmer-Hofer, C Hyde, T Schleier, D. Avramovic
    Int J Mol Sci , (2018).
    DOI: 10.1016/j.str.2016.12.012
  • VEGFR2 promotes central endothelial activation and the spread of pain in inflammatory arthritis N Beazley-Long, C E Moss, W R Ashby, S M Bestall, F Almahasneh, A M Durrant, A V Benest, Z Blackley, K Ballmer-Hofer, M Hirashima, R P Hulse, D O Bates, L F Donaldson
    Brain Behav Immun , (2018).
    DOI: 10.1016/j.str.2016.12.012
  • Characterization of a drug-targetable allosteric site regulating vascular endothelial growth factor signaling K M Thieltges, D Avramovic, C L Piscitelli, S Markovic-Mueller, H K Binz, K Ballmer-Hofer
    Angiogenesis , (2018).
    DOI: 10.1016/j.str.2016.12.012

2017

  • Structure of the Full-length VEGFR-1 Extracellular Domain in Complex with VEGF-A S Markovic-Mueller, E Stuttfeld, M Asthana, T Asthana, S Bliven, KN Goldie, K Kisko, G Capitani, K Ballmer-Hofer
    Structure , (2017).
    DOI: 10.1016/j.str.2016.12.012

2016

  • Monomeric gremlin is a novel vascular endothelial growth factor receptor-2 antagonist E Grillo, C Ravelli, M Corsini, K Ballmer-Hofer, L Zammataro, P Oreste, G Zoppetti, C Tobia, R Ronca, M Presta, S Mitola
    Oncotarget 7, 35353 (2016).
    DOI: 10.18632/oncotarget.9286


  • VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread X Li, N Padhan, EO Sjostrom,FP Roche, C Testini, N Honkura, M Sainz-Jaspeado, E Gordon, K Bentley, A Philippides, V Tolmachev, E DeJana, RV Stan, D Vestweber, K Ballmer-Hofer, C Betsholtz, K Pietras, L Jansson, Claesson-Welsh, L
    Nature Communications 7, 11017 (2016).
    DOI: 10.1038/ncomms11017


  • Highly efficient baculovirus-mediated multigene delivery in primary cells M Mansouri, I Bellon-Echeverria, A Rizk, Z Ehsaei, CC Cianciolo, CS Silva, Y Xie, FM Boyce, MW Davis, SC Neuhauss, V Taylor, K Ballmer-Hofer, I Berger, P Berger
    Nature Communications 7, 11529 (2016).
    DOI: 10.1038/ncomms11529


  • VEGFR-2 conformational switch in response to ligand binding S Sarabipour, K Ballmer-Hofer, K Hristova
    Elife 5, e13876 (2016).
    DOI: 10.7554/eLife.13876

2015

  • Vascular endothelial growth factor-A165b is protective and restores endothelial glycocalyx in diabetic nephropathy S Oltean, Y Qiu, JK Ferguson, M Stevens, C Neal, A Russell, A Kaura, KP Arkill, K Harris, C Symonds, K Lacey, L Wijeyaratne, M Gammons, E Wylie, RP Hulse, C Alsop, G Cope, G Damodaran, KB Betteridge, R Ramnath, SC Satchell, RR Foster, K Ballmer-Hofer, LF Donaldson, J Barratt, HJ Baelde, SJ Harper, DO Bates and AH Salmon
    J Am Soc Nephrol 26, 1889-1904 (2015).
    DOI: 10.1681/ASN.2014040350
  • Vascular endothelial growth factor-A165b prevents diabetic neuropathic pain and sensory neuronal degeneration RP Hulse, N Beazley-Long, N Ved, SM Bestall, H Riaz, P Singhal, K Ballmer Hofer, SJ Harper, DO Bates and LF Donaldson
    Clin Sci (Lond) 129, 741-756 (2015).
    DOI: 10.1042/CS20150124

2014

  • High-level secretion of recombinant full-length streptavidin in Pichia pastoris and its application to enantioselective catalysis ES Nogueira, T Schleier, M Durrenberger, K Ballmer-Hofer, TR Ward and R Jaussi
    Protein Expr Purif 93, 54-62 (2014).
    DOI: 10.1016/j.pep.2013.10.015
  • Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia RP Hulse, N Beazley-Long, J Hua, H Kennedy, J Prager, H Bevan, Y Qiu, ES Fernandes, MV Gammons, K Ballmer-Hofer, AC Gittenberger de Groot, AJ Churchill, SJ Harper, SD Brain, DO Bates and LF Donaldson
    Neurobiol Dis 71, 245-259 (2014).
    DOI: 10.1016/j.nbd.2014.08.012
  • Cell lines expressing recombinant transmembrane domain-activated receptor kinases as tools for drug discovery H Weber, D Muller, M Muller, A Ortiz, M Birkle, S Umber, C Ketterer, O Siedentopf, D Feger, F Totzke, M Kubbutat, C Schaechtele, K Ballmer-Hofer, JE Ehlert and R Graeser
    J Biomol Screen 19, 1350-1361 (2014).
    DOI: 10.1177/1087057114552414
  • Functional and structural characterization of the kinase insert and the carboxy terminal domain in VEGF receptor 2 activation S Manni, K Kisko, T Schleier, J Missimer and K Ballmer-Hofer
    FASEB J 28, 4914-4923 (2014).
    DOI: 10.1096/fj.14-256206
  • Structural and functional characterization of alternative transmembrane domain conformations in VEGF receptor 2 activation S Manni, KS Mineev, D Usmanova, EN Lyukmanova, MA Shulepko, MP Kirpichnikov, J Winter, M Matkovic, X Deupi, AS Arseniev and K Ballmer-Hofer
    Structure 22, 1077-1089 (2014).
    DOI: 10.1016/j.str.2014.05.010

2013

  • Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation VM Leppanen, D Tvorogov, K Kisko, AE Prota, M Jeltsch, A Anisimov, S Markovic-Mueller, E Stuttfeld, KN Goldie, K Ballmer-Hofer and K Alitalo
    Proc Natl Acad Sci U S A 110, 12960-12965 (2013).
    DOI: 10.1073/pnas.1301415110

2012

  • Targeting extracellular domains D4 and D7 of vascular endothelial growth factor receptor 2 reveals allosteric receptor regulatory sites CA Hyde, A Giese, E Stuttfeld, J Abram Saliba, D Villemagne, T Schleier, HK Binz and K Ballmer-Hofer
    Mol Cell Biol 32, 3802-3813 (2012).
    DOI: 10.1128/MCB.06787-11
  • Structure-function analysis of VEGF receptor activation and the role of coreceptors in angiogenic signaling FS Grunewald, AE Prota, A Giese and K Ballmer-Hofer
    Biochim Biophys Acta 1804, 567-580 (2010).
    DOI: 10.1016/j.bbapap.2009.09.002
  • Thermodynamic and structural description of allosterically regulated VEGFR-2 dimerization MS Brozzo, S Bjelic, K Kisko, T Schleier, VM Leppanen, K Alitalo, FK Winkler and K Ballmer-Hofer
    Blood 119, 1781-1788 (2012).
    DOI: 10.1182/blood-2011-11-390922
  • Structural analysis of vascular endothelial growth factor receptor-2/ligand complexes by small-angle X-ray solution scattering K Kisko, MS Brozzo, J Missimer, T Schleier, A Menzel, VM Leppanen, K Alitalo, T Walzthoeni, R Aebersold and K Ballmer-Hofer
    FASEB J 25, 2980-2986 (2012).
    DOI: 10.1096/fj.11-185397
  • Novel functional germline variants in the VEGF receptor 2 gene and their effect on gene expression and microvessel density in lung cancer DM Glubb, E Cerri, A Giese, W Zhang, O Mirza, EE Thompson, P Chen, S Das, J Jassem, W Rzyman, MW Lingen, R Salgia, FR Hirsch, R Dziadziuszko, K Ballmer-Hofer and F Innocenti
    Clin Cancer Res 17, 5257-5267 (2011).
    DOI: 10.1158/1078-0432.CCR-11-0379
  • Thermodynamic and structural description of allosterically regulated VEGFr-2 dimerization MS Brozzo, S Bjelic, K Kisko, T Schleier, VM Leppanen, K Alitalo, FK Winkler and K Ballmer-Hofer
    Blood 119, 1781-1788 (2012).
    DOI: 10.1182/blood-2011-11-390922

2011

  • Structural determinants of vascular endothelial growth factor-d receptor binding and specificity VM Leppanen, M Jeltsch, A Anisimov, D Tvorogov, K Aho, N Kalkkinen, P Toivanen, S Yla-Herttuala, K Ballmer-Hofer and K Alitalo
    Blood 117, 1507-1515 (2011).
    DOI: 10.1182/blood-2010-08-301549
  • Multilabel: Multigenexpression in säugerzellen A Kriz, K Schmid, K Ballmer-Hofer and P Berger
    GIT Labor-Fachzeitschrift 55, 776 - 777 (2011).
  • Multilabel: Multigene expression in mammalian cells A Kriz, K Schmid, K Ballmer-Hofer and P Berger
    G.I.T. Laboratory Journal 15 (3-4), 12 - 13 (2011).
  • Integration of multiple expression cassettes into mammalian genomes in a single step A Kriz, K Schmid, K Ballmer-Hofer and P Berger
    Nature protocol exchange (2011).
    DOI: doi:10.1038/ protex.2011.249
  • Structural analysis of vascular endothelial growth factor receptor-2/ligand complexes by small-angle x-ray solution scattering K Kisko, MS Brozzo, J Missimer, T Schleier, A Menzel, VM Leppanen, K Alitalo, T Walzthoeni, R Aebersold and K Ballmer-Hofer
    FASEB J 25, 2980-2986 (2011).
    DOI: 10.1096/fj.11-185397
  • Novel functional germline variants in the VEGF receptor 2 gene and their effect on gene expression and microvessel density in lung cancer DM Glubb, E Cerri, A Giese, W Zhang, O Mirza, EE Thompson, P Chen, S Das, J Jassem, W Rzyman, MW Lingen, R Salgia, FR Hirsch, R Dziadziuszko, K Ballmer-Hofer and F Innocenti
    Clin Cancer Res 17, 5257-5267 (2011).
    DOI: 10.1158/1078-0432.ccr-11-0379
  • Thermodynamic and structural description of allosterically regulated VEGF receptor 2 dimerization MS Brozzo, S Bjelic, K Kisko, T Schleier, VM Leppanen, K Alitalo, FK Winkler and K Ballmer-Hofer
    Blood (2011).
    DOI: 10.1182/blood-2011-11-390922
  • The cmt4b disease-causing proteins mtmr2 and mtmr13/sbf2 regulate akt signalling P Berger, K Tersar, K Ballmer-Hofer and U Suter
    J Cell Mol Med 15, 307-315 (2011).
    DOI: 10.1111/j.1582-4934.2009.00967.x
  • The reception and the party after: How vascular endothelial growth factor receptor 2 explores cytoplasmic space P Berger and K Ballmer-Hofer
    Swiss Med Wkly 141, w13318 (2011).
    DOI: 10.4414/smw.2011.13318
  • Neuropilin-1 promotes VEGFr-2 trafficking through Rab11 vesicles thereby specifying signal output K Ballmer-Hofer, AE Andersson, LE Ratcliffe and P Berger
    Blood 118, 816-826 (2011).
    DOI: 10.1182/blood-2011-01-328773
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2010

  • Phage-derived fully human monoclonal antibody fragments to human vascular endothelial growth factor-c block its interaction with VEGF receptor-2 and 3 M Rinderknecht, A Villa, K Ballmer-Hofer, D Neri and M Detmar
    PLoS One 5, e11941 (2010).
    DOI: 10.1371/journal.pone.0011941
  • Gremlin is a novel agonist of the major proangiogenic receptor VEGFr2 S Mitola, C Ravelli, E Moroni, V Salvi, D Leali, K Ballmer-Hofer, L Zammataro and M Presta
    Blood 116, 3677-3680 (2010).
    DOI: 10.1182/blood-2010-06-291930
  • Structural determinants of growth factor binding and specificity by VEGF receptor 2 VM Leppanen, AE Prota, M Jeltsch, A Anisimov, N Kalkkinen, T Strandin, H Lankinen, A Goldman, K Ballmer-Hofer and K Alitalo
    Proc Natl Acad Sci U S A 107, 2425-2430 (2010).
    DOI: 10.1073/pnas.0914318107
  • A plasmid-based multigene expression system for mammalian cells A Kriz, K Schmid, N Baumgartner, U Ziegler, I Berger, K Ballmer-Hofer and P Berger
    Nat Commun 1, 120 (2010).
    DOI: 10.1038/ncomms1120
  • Structure-function analysis of VEGF receptor activation and the role of coreceptors in angiogenic signaling FS Grunewald, AE Prota, A Giese and K Ballmer-Hofer
    Biochim Biophys Acta 1804, 567-580 (2010).
    DOI: 10.1016/j.bbapap.2009.09.002
  • Transmembrane domain-mediated orientation of receptor monomers in active VEGFr-2 dimers DD Dosch and K Ballmer-Hofer
    FASEB J 24, 32-38 (2010).
    DOI: 10.1096/fj.09-132670
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2009

  • A CD44v6 peptide reveals a role of CD44 in VEGFr-2 signaling and angiogenesis M Tremmel, A Matzke, I Albrecht, AM Laib, V Olaku, K Ballmer-Hofer, G Christofori, M Heroult, HG Augustin, H Ponta and V Orian-Rousseau
    Blood 114, 5236-5244 (2009).
    DOI: 10.1182/blood-2009-04-219204
  • Structure and function of VEGF receptors E Stuttfeld and K Ballmer-Hofer
    IUBMB Life 61, 915-922 (2009).
    DOI: 10.1002/iub.234
  • The soluble form of the cancer-associated l1 cell adhesion molecule is a pro-angiogenic factor A Friedli, E Fischer, I Novak-Hofer, S Cohrs, K Ballmer-Hofer, PA Schubiger, R Schibli and J Grunberg
    Int J Biochem Cell Biol 41, 1572-1580 (2009).
    DOI: 10.1016/j.biocel.2009.01.006

2008

  • A proangiogenic peptide derived from vascular endothelial growth factor receptor-1 acts through alpha5beta1 integrin S Soro, A Orecchia, L Morbidelli, PM Lacal, V Morea, K Ballmer-Hofer, F Ruffini, M Ziche, S D'Atri, G Zambruno, A Tramontano and CM Failla
    Blood 111, 3479-3488 (2008).
    DOI: 10.1182/blood-2007-03-077537
  • Recombinant human VEGF165b protein is an effective anti-cancer agent in mice ES Rennel, MA Hamdollah-Zadeh, ER Wheatley, A Magnussen, Y Schuler, SP Kelly, C Finucane, D Ellison, S Cebe-Suarez, K Ballmer-Hofer, S Mather, L Stewart, DO Bates and SJ Harper
    Eur J Cancer 44, 1883-1894 (2008).
    DOI: 10.1016/j.ejca.2008.05.027
  • Neuropilin-1 in regulation of VEGF-induced activation of p38mapk and endothelial cell organization H Kawamura, X Li, K Goishi, LA van Meeteren, L Jakobsson, S Cebe-Suarez, A Shimizu, D Edholm, K Ballmer-Hofer, L Kjellen, M Klagsbrun and L Claesson-Welsh
    Blood 112, 3638-3649 (2008).
    DOI: 10.1182/blood-2007-12-125856
  • Orf virus VEGF-e nz2 promotes paracellular nrp-1/VEGFr-2 coreceptor assembly via the peptide rppr S Cebe-Suarez, FS Grunewald, R Jaussi, X Li, L Claesson-Welsh, D Spillmann, AA Mercer, AE Prota and K Ballmer-Hofer
    FASEB J 22, 3078-3086 (2008).
    DOI: 10.1096/fj.08-107219

2007

  • Evaluation of anti-VEGFr-3 specific scfv antibodies as potential therapeutic and diagnostic tools for tumor lymph-angiogenesis AH Zehnder-Fjallman, C Marty, C Halin, A Hohn, R Schibli, K Ballmer-Hofer and RA Schwendener
    Oncol Rep 18, 933-941 (2007).
  • Structure of a VEGF-VEGF receptor complex determined by electron microscopy C Ruch, G Skiniotis, MO Steinmetz, T Walz and K Ballmer-Hofer
    Nat Struct Mol Biol 14, 249-250 (2007).
    DOI: 10.1038/nsmb1202

2006

  • Clodronate-liposome-mediated depletion of tumour-associated macrophages: A new and highly effective antiangiogenic therapy approach SM Zeisberger, B Odermatt, C Marty, AH Zehnder-Fjallman, K Ballmer-Hofer and RA Schwendener
    Br J Cancer 95, 272-281 (2006).
    DOI: 10.1038/sj.bjc.6603240
  • Structure determination of VEGF-E by sulfur SAD A Wagner, M Pieren, C Schulze-Briese, K Ballmer-Hofer and AE Prota
    Acta Crystallogr D Biol Crystallogr 62, 1430-1434 (2006).
    DOI: 10.1107/s0907444906036742
  • Crystal structure of the orf virus NZ2 variant of vascular endothelial growth factor-E. Implications for receptor specificity M Pieren, AE Prota, C Ruch, D Kostrewa, A Wagner, K Biedermann, FK Winkler and K Ballmer-Hofer
    J Biol Chem 281, 19578-19587 (2006).
    DOI: 10.1074/jbc.M601842200
  • Isolation and characterization of a scfv antibody specific for tumor endothelial marker 1 (tem1), a new reagent for targeted tumor therapy C Marty, Z Langer-Machova, S Sigrist, H Schott, RA Schwendener and K Ballmer-Hofer
    Cancer Lett 235, 298-308 (2006).
    DOI: 10.1016/j.canlet.2005.04.029
  • The role of VEGF receptors in angiogenesis; complex partnerships S Cebe-Suarez, A Zehnder-Fjallman and K Ballmer-Hofer
    Cell Mol Life Sci 63, 601-615 (2006).
    DOI: 10.1007/s00018-005-5426-3
  • A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2 S Cebe-Suarez, M Pieren, L Cariolato, S Arn, U Hoffmann, A Bogucki, C Manlius, J Wood and K Ballmer-Hofer
    Cell Mol Life Sci 63, 2067-2077 (2006).
    DOI: 10.1007/s00018-006-6254-9
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2005

  • Reconstitution of two recombinant lsm protein complexes reveals aspects of their architecture, assembly, and function B Zaric, M Chami, H Remigy, A Engel, K Ballmer-Hofer, FK Winkler and C Kambach
    J Biol Chem 280, 16066-16075 (2005).
    DOI: 10.1074/jbc.M414481200
  • Targeting human cancer cells with VEGF receptor-2-directed liposomes A Rubio Demirovic, C Marty, S Console, SM Zeisberger, C Ruch, R Jaussi, RA Schwendener and K Ballmer-Hofer
    Oncol Rep 13, 319-324 (2005).

2004

  • Preliminary study of plasma vascular endothelial growth factor (VEGF) during low- and high-dose radiation therapy of dogs with spontaneous tumors MC Wergin, K Ballmer-Hofer, M Roos, RE Achermann, N Inteeworn, MK Akens, H Blattmann and B Kaser-Hotz
    Vet Radiol Ultrasound 45, 247-254 (2004).
  • Enhanced heparan sulfate proteoglycan-mediated uptake of cell-penetrating peptide-modified liposomes C Marty, C Meylan, H Schott, K Ballmer-Hofer and RA Schwendener
    Cell Mol Life Sci 61, 1785-1794 (2004).
    DOI: 10.1007/s00018-004-4166-0

2003

  • Antennapedia and HIV transactivator of transcription (TAT) "Protein transduction domains" Promote endocytosis of high molecular weight cargo upon binding to cell surface glycosaminoglycans S Console, C Marty, C Garcia-Echeverria, R Schwendener and K Ballmer-Hofer
    J Biol Chem 278, 35109-35114 (2003).
    DOI: 10.1074/jbc.M301726200
  • Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1 M Autiero, J Waltenberger, D Communi, A Kranz, L Moons, D Lambrechts, J Kroll, S Plaisance, M De Mol, F Bono, S Kliche, G Fellbrich, K Ballmer-Hofer, D Maglione, U Mayr-Beyrle, M Dewerchin, S Dombrowski, D Stanimirovic, P Van Hummelen, C Dehio, DJ Hicklin, G Persico, JM Herbert, M Shibuya, D Collen, EM Conway and P Carmeliet
    Nat Med 9, 936-943 (2003).
    DOI: 10.1038/nm884
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2002

  • Cytotoxic targeting of F9 teratocarcinoma tumours with anti-ED-B fibronectin scFv antibody modified liposomes C Marty, B Odermatt, H Schott, D Neri, K Ballmer-Hofer, R Klemenz and RA Schwendener
    Br J Cancer 87, 106-112 (2002).
    DOI: 10.1038/sj.bjc.6600423