Dr Rachel Simmonds

Featured Stories

Research Interests

As a molecular biologist, my research interests concern the molecular detail of the pathogenesis of different disease systems. My group specialises in the uncovering of “unusual” mechanisms of gene regulation in eukaryotic cells; as exemplified by our work studying mycolactone function. In order to understand this fully, we have had to (and to an extent still are) follow a trial of breadcrumbs through the fundamental concepts of molecular biology starting from gene transcription, through protein translation and on to protein fate.

Mycolactone

The major focus of my research is understanding the mechanism of action of the mycobacterial virulence factor mycolactone. This lipid-like molecule is synthesised by a small group of so-called mycolactone-producing mycobacteria (MPM) which each make subtly different mycolactones. Species in this group include those which are pathogenic to frogs, fish and, importantly, humans. The latter, Mycobacterium ulcerans, causes a disease called Buruli ulcer which is a serious skin infection that affects some of the poorest communities in the world. It causes massive debilitating skin ulcers, often leading to disfigurement or amputation (see http://www.who.int/buruli/en/).

Mycolactone is known to be responsible for the pathogenesis of Buruli ulcer, because it is both immunosuppressive and cytotoxic to host cells. The immunosuppression includes inhibition of the production of cytokines that drive inflammation. We first showed that production of TNF, IL-6 and Cox-2 were supressed by a post-transcriptional mechanism. Detailed investigations then identified the mechanistic target of the molecule: it prevents the translocation of proteins into the endoplasmic reticulum. Most glycosylated and secreted proteins (like cytokines) undergo a process of co-translational translocation via the Sec61 translocon which acts channel separating the two cellular compartments. Because mycolactone blocks this, the proteins get stuck in the cytosol, are recognised as being mislocated, and are destroyed by the proteasome. Therefore cytokines (and most proteins that would normally pass through the ER, about 30% of total cellular protein) are made as normal in the presence of mycolactone, but are immediately destroyed again. This highly unusual pathogenic molecular mechanism currently seems unique to Buruli ulcer.  

We are now exploiting this knowledge in order to develop better treatments for Buruli ulcer, and other diseases where protein translocation plays an important role. We recently showed that endothelial cells are exquisitely sensitive to mycolactone; 7ng/ml mycolactone is sufficient to deplete thrombomodulin from the surface of the cells in under 24hours. Since thrombomodulin is an essential anticoagulant protein, and fibrin is commonly found in the necrotic skin tissue, this has opened up the whole area of disordered haemostasis in Buruli ulcer. You can hear Rachel talking about the potential impact of this work in her recent BBC Radio Surrey interview (http://usshl.cdn.tveyes.com/mediacat/temp/f72e1a611fe936a83deec58238e04049.mp4?start=49&end=663).

 

Inflammation

Inflammation is mediated by the innate immune system via proteins known as Pattern Recognition Receptors (PRRs) that recognise Pathogen Associated Molecular Patterns (PAMPs). Inflammation can also be caused by so-called DAMPs (Danger Associated Molecular Patterns) that are released by the host. While inflammation is a crucial component of the body’s defence against infection, inappropriate or uncontrolled inflammation can lead to a state of chronic low-grade inflammation. Chronic inflammation underlies the pathology of many diseases of the modern age, including type 2 diabetes and rheumatoid arthritis. Cellular Toll-like receptors (TLRs) play a crucial role in driving both acute and chronic inflammation, by inducing transcriptional and translational responses as well as changes to mRNA stability.

Research in my group has a broader interest in inflammation and novel mechanisms controlling the response to TLR activation:

  • Biogenesis and function of TLR-induced microRNAs, including miR-155
  • Transport of miRNAs in circulating microparticles in muscle wasting
  • TLR signalling and cytokine production by non-myeloid cells
  • Dietary endotoxaemia

Current group members

Joy Ogbechi (PhD Student)
Tong Wu (MSc Student)

Past group members

Belinda Hall (Post-Doc)
Sweta Jain (MSc Student)

Research Collaborations

Josefin Ahnström (Imperial College London): Calibrated Automated Thrombography

Phil Biggin (Oxford): Simulations of mycolactone interactions

Ben Creagh-Brown (Royal Surrey County Hospital): MAMAS study

Chuck Esmon (Oklahoma Medical Research Foundation): Coagulation in BU

Stephen High (University of Manchester): Protein translocation

Gerd Pluschke (Swiss Tropical and Public Health Institute): Buruli ulcer pathogenesis

Anne Willis (MRC Toxicology Unit): Translational control

Richard Zimmermann (Saarland University Faculty of Medicine): Protein Translocation

Teaching

Undergraduate

BMS2045: Introduction to Immunology (Module Coordinator)

Postgraduate

MSc in Medical Microbiology

MMIM026: Fundamental Research Methods (Deputy Module Coordinator)
MMIM027: Research Methods 2 (Module Coordinator)

MSc in Veterinary Microbiology

MMVM001: Microbiology and Veterinary Immunology

MSc in Nutritional Medicine

Module 5: Diet, the Gut, Food Allergy and Intolerance

Departmental Duties

Chair of the School of Biosciences and Medicine Athena SWAN Action Plan Implementation Team

Deputy Chair of the Board of Examiners for the MSc in Medical Microbiology (Euromasters)

Local Ambassador for the Biochemical Society

Contact Me

E-mail:
Phone: 01483 68 4714

Find me on campus
Room: 17 AX 01

Publications

Highlights

  • Ogbechi J, Ruf MT, Hall BS, Bodman-Smith K, Vogel M, Wu HL, Stainer A, Esmon CT, Ahnström J, Pluschke G, Simmonds RE. (2015) 'Mycolactone-Dependent Depletion of Endothelial Cell Thrombomodulin Is Strongly Associated with Fibrin Deposition in Buruli Ulcer Lesions'. PLoS Pathogens, 11 (7)

    Abstract

    © 2015 Ogbechi et al.A well-known histopathological feature of diseased skin in Buruli ulcer (BU) is coagulative necrosis caused by the Mycobacterium ulcerans macrolide exotoxin mycolactone. Since the underlying mechanism is not known, we have investigated the effect of mycolactone on endothelial cells, focussing on the expression of surface anticoagulant molecules involved in the protein C anticoagulant pathway. Congenital deficiencies in this natural anticoagulant pathway are known to induce thrombotic complications such as purpura fulimans and spontaneous necrosis. Mycolactone profoundly decreased thrombomodulin (TM) expression on the surface of human dermal microvascular endothelial cells (HDMVEC) at doses as low as 2ng/ml and as early as 8hrs after exposure. TM activates protein C by altering thrombin’s substrate specificity, and exposure of HDMVEC to mycolactone for 24 hours resulted in an almost complete loss of the cells’ ability to produce activated protein C. Loss of TM was shown to be due to a previously described mechanism involving mycolactone-dependent blockade of Sec61 translocation that results in proteasome-dependent degradation of newly synthesised ER-transiting proteins. Indeed, depletion from cells determined by live-cell imaging of cells stably expressing a recombinant TM-GFP fusion protein occurred at the known turnover rate. In order to determine the relevance of these findings to BU disease, immunohistochemistry of punch biopsies from 40 BU lesions (31 ulcers, nine plaques) was performed. TM abundance was profoundly reduced in the subcutis of 78% of biopsies. Furthermore, it was confirmed that fibrin deposition is a common feature of BU lesions, particularly in the necrotic areas. These findings indicate that there is decreased ability to control thrombin generation in BU skin. Mycolactone’s effects on normal endothelial cell function, including its ability to activate the protein C anticoagulant pathway are strongly associated with this. Fibrin-driven tissue ischemia could contribute to the development of the tissue necrosis seen in BU lesions.

  • Hall BS, Hill K, McKenna M, Ogbechi J, High S, Willis AE, Simmonds RE. (2014) 'The pathogenic mechanism of the Mycobacterium ulcerans virulence factor, mycolactone, depends on blockade of protein translocation into the ER.'. PLoS Pathog, United States: 10 (4)
  • Hall B, Simmonds R. (2014) 'Pleiotropic molecular effects of the Mycobacterium ulcerans virulence factor mycolactone underlying the cell death and immunosuppression seen in Buruli ulcer.'. Biochem Soc Trans, England: 42 (1), pp. 177-183.

    Abstract

    Mycolactone is a polyketide macrolide lipid-like secondary metabolite synthesized by Mycobacterium ulcerans, the causative agent of BU (Buruli ulcer), and is the only virulence factor for this pathogen identified to date. Prolonged exposure to high concentrations of mycolactone is cytotoxic to diverse mammalian cells (albeit with varying efficiency), whereas at lower doses it has a spectrum of immunosuppressive activities. Combined, these pleiotropic properties have a powerful influence on local and systemic cellular function that should explain the pathophysiology of BU disease. The last decade has seen significant advances in our understanding of the molecular mechanisms underlying these effects in a range of different cell types. The present review focuses on the current state of our knowledge of mycolactone function, and its molecular and cellular targets, and seeks to identify commonalities between the different functional and cellular systems. Since mycolactone influences fundamental cellular processes (cell division, cell death and inflammation), getting to the root of how mycolactone achieves this could have a profound impact on our understanding of eukaryotic cell biology.

  • Simmonds RE, Lali FV, Smallie T, Small PLC, Foxwell BM. (2009) 'Mycolactone Inhibits Monocyte Cytokine Production by a Posttranscriptional Mechanism'. AMER ASSOC IMMUNOLOGISTS JOURNAL OF IMMUNOLOGY, 182 (4), pp. 2194-2202.

Journal articles

  • McKenna M, Simmonds R, High S. (2017) 'Mycolactone reveals substrate-driven complexity of Sec61-dependent transmembrane protein biogenesis'. Company of Biologists Journal of Cell Science,
    [ Status: Accepted ]
  • McKenna M, Simmonds RE, High S. (2016) 'Mechanistic insights into the inhibition of Sec61-dependent co- and post-translational translocation by mycolactone.'. The Company of Biologists Journal of cell science, 129, pp. 1404-1415.

    Abstract

    The virulence factor mycolactone is responsible for the immunosuppression and tissue necrosis that characterise Buruli ulcer, a disease caused by infection with Mycobacterium ulcerans. In this study, we confirm that Sec61, the protein-conducting channel that coordinates entry of secretory proteins into the endoplasmic reticulum, is a primary target of mycolactone, and characterise the nature of its inhibitory effect. We conclude that mycolactone constrains the ribosome-nascent chain-Sec61 complex, consistent with its broad-ranging perturbation of the co-translational translocation of classical secretory proteins. In contrast, the effect of mycolactone on the post-translational, ribosome-independent translocation of short secretory proteins through the Sec61 complex is dependent on both signal sequence hydrophobicity and the translocation competence of the mature domain. Changes to protease sensitivity strongly suggest that mycolactone acts by inducing a conformational change in the pore-forming Sec61α subunit. These findings establish that mycolactone inhibits Sec61-mediated protein translocation and highlight differences between the co- and post-translational routes that the Sec61 complex mediates. We propose that mycolactone also provides a useful tool for further delineating the molecular mechanisms of Sec61-dependent protein translocation.

  • Sarfo FS, Phillips R, Wansbrough-Jones M, Simmonds RE. (2015) 'Recent advances: role of mycolactone in the pathogenesis and monitoring of Mycobacterium ulcerans infection/Buruli ulcer disease'. WILEY-BLACKWELL CELLULAR MICROBIOLOGY, 18 (1), pp. 17-29.
  • Ogbechi J, Ruf MT, Hall BS, Bodman-Smith K, Vogel M, Wu HL, Stainer A, Esmon CT, Ahnström J, Pluschke G, Simmonds RE. (2015) 'Mycolactone-Dependent Depletion of Endothelial Cell Thrombomodulin Is Strongly Associated with Fibrin Deposition in Buruli Ulcer Lesions'. PLoS Pathogens, 11 (7)

    Abstract

    © 2015 Ogbechi et al.A well-known histopathological feature of diseased skin in Buruli ulcer (BU) is coagulative necrosis caused by the Mycobacterium ulcerans macrolide exotoxin mycolactone. Since the underlying mechanism is not known, we have investigated the effect of mycolactone on endothelial cells, focussing on the expression of surface anticoagulant molecules involved in the protein C anticoagulant pathway. Congenital deficiencies in this natural anticoagulant pathway are known to induce thrombotic complications such as purpura fulimans and spontaneous necrosis. Mycolactone profoundly decreased thrombomodulin (TM) expression on the surface of human dermal microvascular endothelial cells (HDMVEC) at doses as low as 2ng/ml and as early as 8hrs after exposure. TM activates protein C by altering thrombin’s substrate specificity, and exposure of HDMVEC to mycolactone for 24 hours resulted in an almost complete loss of the cells’ ability to produce activated protein C. Loss of TM was shown to be due to a previously described mechanism involving mycolactone-dependent blockade of Sec61 translocation that results in proteasome-dependent degradation of newly synthesised ER-transiting proteins. Indeed, depletion from cells determined by live-cell imaging of cells stably expressing a recombinant TM-GFP fusion protein occurred at the known turnover rate. In order to determine the relevance of these findings to BU disease, immunohistochemistry of punch biopsies from 40 BU lesions (31 ulcers, nine plaques) was performed. TM abundance was profoundly reduced in the subcutis of 78% of biopsies. Furthermore, it was confirmed that fibrin deposition is a common feature of BU lesions, particularly in the necrotic areas. These findings indicate that there is decreased ability to control thrombin generation in BU skin. Mycolactone’s effects on normal endothelial cell function, including its ability to activate the protein C anticoagulant pathway are strongly associated with this. Fibrin-driven tissue ischemia could contribute to the development of the tissue necrosis seen in BU lesions.

  • Hall BS, Hill K, McKenna M, Ogbechi J, High S, Willis AE, Simmonds RE. (2014) 'The pathogenic mechanism of the Mycobacterium ulcerans virulence factor, mycolactone, depends on blockade of protein translocation into the ER.'. PLoS Pathog, United States: 10 (4)
  • Hall B, Simmonds R. (2014) 'Pleiotropic molecular effects of the Mycobacterium ulcerans virulence factor mycolactone underlying the cell death and immunosuppression seen in Buruli ulcer.'. Biochem Soc Trans, England: 42 (1), pp. 177-183.

    Abstract

    Mycolactone is a polyketide macrolide lipid-like secondary metabolite synthesized by Mycobacterium ulcerans, the causative agent of BU (Buruli ulcer), and is the only virulence factor for this pathogen identified to date. Prolonged exposure to high concentrations of mycolactone is cytotoxic to diverse mammalian cells (albeit with varying efficiency), whereas at lower doses it has a spectrum of immunosuppressive activities. Combined, these pleiotropic properties have a powerful influence on local and systemic cellular function that should explain the pathophysiology of BU disease. The last decade has seen significant advances in our understanding of the molecular mechanisms underlying these effects in a range of different cell types. The present review focuses on the current state of our knowledge of mycolactone function, and its molecular and cellular targets, and seeks to identify commonalities between the different functional and cellular systems. Since mycolactone influences fundamental cellular processes (cell division, cell death and inflammation), getting to the root of how mycolactone achieves this could have a profound impact on our understanding of eukaryotic cell biology.

  • Brenner C, Simmonds RE, Wood S, Rose V, Feldmann M, Turner J. (2012) 'TLR signalling and adapter utilization in primary human in vitro differentiated adipocytes.'. Scand J Immunol, England: 76 (4), pp. 359-370.
  • Simmonds RE, Lali FV, Smallie T, Small PLC, Foxwell BM. (2009) 'Mycolactone Inhibits Monocyte Cytokine Production by a Posttranscriptional Mechanism'. AMER ASSOC IMMUNOLOGISTS JOURNAL OF IMMUNOLOGY, 182 (4), pp. 2194-2202.
  • Sacre SM, Lo A, Gregory B, Simmonds RE, Williams L, Feldmann M, Brennan FM, Foxwell BM. (2008) 'Inhibitors of TLR8 Reduce TNF Production from Human Rheumatoid Synovial Membrane Cultures'. AMER ASSOC IMMUNOLOGISTS JOURNAL OF IMMUNOLOGY, 181 (11), pp. 8002-8009.
  • Simmonds RE, Foxwell BM. (2008) 'Signalling, inflammation and arthritis - NF-kappa B and its relevance to arthritis and inflammation'. OXFORD UNIV PRESS RHEUMATOLOGY, 47 (5), pp. 584-590.
  • White SJ, Simmonds RE, Lane DA, Baker AH. (2005) 'Efficient isolation of peptide ligands for the endothelial cell protein C receptor (EPCR) using candidate receptor phage display biopanning'. ELSEVIER SCIENCE INC PEPTIDES, 26 (7), pp. 1264-1269.
  • Biguzzi E, Razzari C, Lane DA, Castaman G, Cappellari A, Bucciarelli P, Fontana G, Margaglione M, D'Andrea G, Simmonds RE, Rezende SM, Preston R, Prisco D, Faioni EM. (2005) 'Molecular diversity and thrombotic risk in Protein S deficiency: The PROSIT study'. WILEY-LISS HUMAN MUTATION, 25 (3), pp. 259-269.
  • Rezende SM, Simmonds RE, Lane DA. (2004) 'Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex'. AMER SOC HEMATOLOGY BLOOD, 103 (4), pp. 1192-1201.
  • Rance JB, Follows GA, Cockerill PN, Bonifer C, Lane DA, Simmonds RE. (2003) 'Regulation of the human endothelial cell protein C receptor gene promoter by multiple Sp1 binding sites'. AMER SOC HEMATOLOGY BLOOD, 101 (11), pp. 4393-4401.
  • Mille-Baker B, Rezende SM, Simmonds RE, Mason PJ, Lane DA, Laffan MA. (2003) 'Deletion or replacement of the second EGF-hke domain of protein S results in loss of APC cofactor activity'. AMER SOC HEMATOLOGY BLOOD, 101 (4), pp. 1416-1418.
  • Rezende SM, Lane DA, Mille-Baker B, Samama MM, Conard J, Simmonds RE. (2002) 'Protein S Gla-domain mutations causing impaired Ca2+-induced phospholipid binding and severe functional protein S deficiency'. AMER SOC HEMATOLOGY BLOOD, 100 (8), pp. 2812-2819.
  • Rezende SM, Lane DA, Zoller B, Mille-Baker B, Laffan M, Dahlback B, Simmonds RE. (2002) 'Genetic and phenotypic variability between families with hereditary protein S deficiency'. SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN THROMBOSIS AND HAEMOSTASIS, 87 (2), pp. 258-265.
  • Simmonds RE, Lane DA. (2001) 'The endothelial cell protein C receptor: A candidate genetic risk factor for thrombosis'. F K SCHATTAUER VERLAG GMBH THROMBOSIS AND HAEMOSTASIS, 86 (4), pp. 939-941.
  • Gandrille S, Borgel D, Sala N, Espinosa-Parrilla Y, Simmonds R, Rezende S, Lind B, Mannhalter C, Pabinger I, Reitsma PH, Formstone C, Cooper DN, Saito H, Suzuki K, Bernardi F, Aiach M. (2000) 'Protein S deficiency: A database of mutations - Summary of the first update'. F K SCHATTAUER VERLAG GMBH THROMBOSIS AND HAEMOSTASIS, 84 (5), pp. 918-918.
  • Rezende SM, Simmonds RE, Zoller B, Dahlback B, Lane DA. (1999) 'The molecular basis of type I/III protein S deficiency'. F K SCHATTAUER VERLAG GMBH THROMBOSIS AND HAEMOSTASIS, , pp. 426-427.
  • Simmonds RE, Philippou H, Rance J, Lane DA. (1999) 'Structural and functional implications of the intron/exon organisation of the human endothelial cell protein C/activated protein C receptor (EPCR) gene. Comparison with the structure of CD1/major histocompatibility complex alpha 1 and alpha 2 domains'. F K SCHATTAUER VERLAG GMBH THROMBOSIS AND HAEMOSTASIS, , pp. 14-14.
  • Simmonds RE, Lane DA. (1999) 'Structural and functional implications of the intron exon organization of the human endothelial cell protein C activated protein C receptor (EPCR) gene: Comparison with the structure of CD1/major histocompatibility complex alpha 1 and alpha 2 domains'. AMER SOC HEMATOLOGY BLOOD, 94 (2), pp. 632-641.
  • Simmonds RE, Ireland H, Lane DA, Zoller B, de Frutos PG, Dahlback B. (1998) 'Clarification of the risk for venous thrombosis associated with hereditary protein S deficiency by investigation of a large kindred with a characterized gene defect'. AMER COLL PHYSICIANS ANNALS OF INTERNAL MEDICINE, 128 (1), pp. 8-+.
  • Gandrille S, Borgel D, Ireland H, Lane DA, Simmonds R, Reitsma PH, Mannhalter C, Pabinger I, Saito H, Suzuki K, Formstone C, Cooper DN, Espinosa Y, Sala N, Bernardi F, Alach M. (1997) 'Protein S deficiency: A database of mutations - For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis'. F K SCHATTAUER VERLAG GMBH THROMBOSIS AND HAEMOSTASIS, 77 (6), pp. 1201-1214.
  • Gandrille S, Borgel D, Ireland H, Lane DA, Simmonds R, Reitsma PH, Mannhalter C, Pabinger I, Saito H, Suzuki K, Formstone C, Cooper DN, Espinosa Y, Sala N, Bernardi F, Aiach M. (1997) 'Protein S deficiency: A database of mutations'. Thrombosis and Haemostasis, 77 (6), pp. 1201-1214.
  • Simmonds RE, Ireland H, Kunz G, Lane DA, Bhavnani M, Castaman G, Hambley H, Laffan M, OConnor N, Sas G, Tew CJ, Walker ID. (1996) 'Identification of 19 protein S gene mutations in patients with phenotypic protein S deficiency and thrombosis'. W B SAUNDERS CO BLOOD, 88 (11), pp. 4195-4204.

Conference papers

  • Moyo N, Westcott D, Simmonds R, Steinbach F. (2012) 'Equine arteritis virus replication in monocytic cells suppresses differentiation and function of dendritic cells'. WILEY-BLACKWELL IMMUNOLOGY, Glasgow, SCOTLAND: European Congress of Immunology 137, pp. 625-625.
  • Simmonds RE, Hermida J, Rezende SM, Lane DA. (2001) 'Haemostatic genetic risk factors in arterial thrombosis'. F K SCHATTAUER VERLAG GMBH THROMBOSIS AND HAEMOSTASIS, PARIS, FRANCE: XVIIIth Congress of the International-Society-on-Thrombosis-and-Haemostasis 86 (1), pp. 374-385.

Book chapters

  • Hall BS, Simmonds R, Benbow ME, Mosi L, Roberts S, Williamso Jordan H. (2015) 'Mycobacterium ulcerans and Buruli Ulcer'. in Singh SK (ed.) Human Emerging and Re-emerging Infections: Viral and Parasitic Infections, Volume I 1st Edition. Hoboken, NJ, USA : John Wiley and Sons 1 Article number 44

Additional key publications

Simmonds RE and Foxwell BM. NF-kB and its relevance to arthritis and inflammation (Review). Rheumatology (Oxford) 2008: 47; 584-90

Rance J, Follows GA, Cockerill PN, Bonifer C, Lane DA, Simmonds RE. Regulation of the human endothelial cell protein C receptor gene promoter by multiple Sp1 binding sites. Blood 2003:101; 4393-4401

Rezende SM, Lane DA, Mille-Baker B, Samama M, Conard J and Simmonds RE. Protein S Gla-domain mutations causing impaired Ca2+-induced phospholipid binding and severe functional protein S deficiency. Blood 2002: 100; 2812-9

Simmonds RE and Lane DA. The Endothelial Cell Protein C Receptor: A Candidate Genetic Risk Factor for Thrombosis (Invited Commentary). Thromb Haemost 2001: 86; 939-41

Simmonds RE and Lane DA. Structural and functional implications of the intron/exon organisation of the human endothelial cell protein C/activated protein C receptor (EPCR) gene. Comparison with the structure of CD1/Major Histocompatibility Complex alpha1 and alpha2 domains. Blood 1999: 94; 632-41

Simmonds RE, Ireland H, Lane DA, Zöller B, García de Frutos P and Dahlbäck B . Clarification of the risk of venous thrombosis associated with hereditary protein S deficiency by investigation of a large kindred with a characterised gene defect. Ann Int Med 1998; 128; 8-14

Simmonds RE, Zöller B, Ireland H, Thompson E, García de Frutos P, Dahlbäck B and Lane DA. Genetic and phenotypic analysis of a large (122 member) protein S-deficient kindred provides an explanation for the familial coexistence of type I and type III plasma phenotypes. Blood 1997; 89; 4364-70

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