WO2005015205A2 - Utilisation de sap - Google Patents

Utilisation de sap Download PDF

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Publication number
WO2005015205A2
WO2005015205A2 PCT/EP2004/008824 EP2004008824W WO2005015205A2 WO 2005015205 A2 WO2005015205 A2 WO 2005015205A2 EP 2004008824 W EP2004008824 W EP 2004008824W WO 2005015205 A2 WO2005015205 A2 WO 2005015205A2
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WO
WIPO (PCT)
Prior art keywords
sap
agonist
protein
sap protein
phosphatase activity
Prior art date
Application number
PCT/EP2004/008824
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English (en)
Other versions
WO2005015205A3 (fr
Inventor
Tamas Schweighoffer
Erwin Paul Schreiner
Original Assignee
Novartis Ag
Novartis Pharma Gmbh
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Filing date
Publication date
Application filed by Novartis Ag, Novartis Pharma Gmbh filed Critical Novartis Ag
Publication of WO2005015205A2 publication Critical patent/WO2005015205A2/fr
Publication of WO2005015205A3 publication Critical patent/WO2005015205A3/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/42—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving phosphatase
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/03—Phosphoric monoester hydrolases (3.1.3)
    • C12Y301/03001—Alkaline phosphatase (3.1.3.1)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5047—Cells of the immune system
    • G01N33/505—Cells of the immune system involving T-cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value

Definitions

  • the present invention relates to the use of SLAM (signaling lymphocytic activation molecule) associated protein (SAP) as a phosphatase.
  • SLAM signal lymphocytic activation molecule
  • SAP associated protein
  • T cells play an important role in allergic and inflammatory diseases and are instrumental in antiviral defense and transplant rejection.
  • Function of T cells such as signaling, cellular activation, cytokine release and proliferation are regulated by multiple concurrently acting signals and intermingled signaling pathways.
  • a particular pathway that was shown to induce proliferation and to regulate release of interferon- ⁇ is defined by SLAM (CD150), a transmembrane molecule, see e.g. Cocks B. G. et al (1995), Nature 376:260-263; Aversa G. et al (1997), J.Immunol. 158:4036-4044 and SAP, see e.g. Sayos J.C. et al (1998), Nature 395:462-469 and Coffey A. J. et al (1998), Nat.Genet. 20:129-135.
  • SAP also known as SH2D1A or DSHP. see e.g. GENBANK: NP_002342; OMIM: *308240, ' is primarily found in T and NK cells and is additionally expressed in some B cells, see e.g. Shlapatska L. M. et al (2001), J. Immunol. 166:5480-5487.
  • SAP performs vital functions since naturally occurring mutations of SAP are causing XLP, the X-chromosome linked lymphoproliferative syndrome, see e.g. Veillette A. et al (2003), Curr.Opin. Immunol. 15:277- 285; Latour S. et al (2003), Immunol.Rey.
  • SAP is designated as an "adaptor" and apart from that no specific function to the SAP molecule has been assigned to it yet.
  • EAT-2 A structurally closely related homologue of SAP has been discovered and designated as EAT-2, see e.g. Morra M. et al (2001), EMBO J. 20:5840-5852 and Tangye S.G. (2002), Eur.J.lmmunol. 32:1640-1649.
  • EAT-2 is expressed mainly in myeloid cells.
  • the published experimental data indicate that SAP and EAT-2 share a high degree of functional similarity.
  • SAP has phosphatase activity.
  • the present invention provides the use of an isolated SAP protein as a phosphatase.
  • Isolated means that the SAP protein is removed from its natural environment, e.g. by purification according, e.g. analogously, to a method as conventional.
  • SAP protein as used herein includes SAP and homologues thereof. Homologues include
  • SAP-like protein which shows phosphatase activity, e.g. that part of SAP or homologues thereof, wherein said phosphatase activity is located.
  • Homologues of a SAP protein e.g. include EAT-2 (protein), such as described by Morra, M. et al, above.
  • a SAP protein also includes functional mimetics thereof, e.g. according to Coligan et al., Current Protocols in
  • a SAP protein includes SAP and EAT-2.
  • Identity is a measure of the identity of amino acid sequences and may e.g. be calculated by techniques according to a method as conventional, e.g. by, e.g. commercially available, computer programs.
  • CLCV is herein designated as "SEQ ID NO:1" which indicates at least a part of the active binding site of the phosphatase enzyme in a SAP protein.
  • the present invention provides a peptide of SEQ ID NO:1.
  • the present invention provides the use of a peptide of SEQ ID NO:1 for the provision of a phosphatase.
  • Cys42 and optionally the Cys44 of the SAP protein as indicated in Figure 1 is essential for its phosphatase activity. Since these cysteins are also present in the EAT-2 protein as Cys41 and Cys43, as indicated in Figure 1 , it reasonably may be expected that also in EAT-2 said formation of cysteins may be essential for its function as a phosphatase. If one or both of these cysteins in SAP or EAT-2, respectively, are replaced by other amino acids, a protein may result wherein the phosphatase activity is missing. Detection of naturally occurring defective Cys42 - Cys44 formation in SAP protein or Cys41 - Cys43 formation in EAT-2 protein in a mammal, e.g.
  • cysteins may thus provide evidence that said mammal may suffer from diseases, e.g. Th1 and/or Th2 driven diseases, including immunological and allergic diseases, which diseases are mediated by the action of SAP-phosphatase or EAT-2-phosphatase.
  • diseases e.g. Th1 and/or Th2 driven diseases, including immunological and allergic diseases, which diseases are mediated by the action of SAP-phosphatase or EAT-2-phosphatase.
  • the present invention provides a diagnostic method for the determination whether a subject suffers from lacking SAP-protein phosphatase activity comprising the following steps i) isolating SAP, or EAT-2, respectively, from a sample, and ii) detecting in said SAP or EAT-2 whether formation of the cysteins in position Cys42 - Cys44 or in position Cys41 - Cys43, respectively, is present.
  • a disease mediated by SAP-phosphatase or EAT-2 phosphatase activity may be diagnosed. Detection may be carried out according, e.g. analogously, to methods as conventional, e.g. by use of an appropriate antibody to catch a SAP protein from a sample and determining whether the cysteine formation in position Cys42 - Cys44 in SAP or in position Cys41 - Cys43 in EAT-2, respectively, of said SAP protein are present.
  • the present invention provides the use of a SAP protein as a diagnostic reagent for the detection of diseases mediated by the phosphatase activity of a SAP protein or diseases caused by a non functional SAP protein, e.g. X-linked lymphoproliferative syndrome.
  • the phosphatase activity of a SAP protein may be responsible for many biological functions, including many pathologies, e.g. Th1 and/or Th2 driven diseases including immunological and allergic disorders or diseases based on a non-functional SAP protein. Accordingly, it is desirous to find compounds and drugs which stimulate the phosphatase activity of a SAP protein on the one hand (agonists), or which inhibit the phosphatase activity of a SAP protein on the other hand (antagonists).
  • a SAP protein may thus be used to assess the binding of agonists or antagonists to the SAP phosphatase receptor, e.g. in cells, cell-free preparations, chemical libraries and natural product mixtures, e.g. in a screening assay.
  • Such screening assay may comprise the steps of mixing a candidate compound with a SAP protein containing solution to form a mixture, determining the phosphatase activity of said SAP protein in said mixture and comparing the phosphatase activity of said mixture with the phosphatase activity of a standard.
  • the present invention provides the use of a SAP protein for the provision of (ant)agonists which mediate the SAP-phosphatase activity.
  • Examples of potential (ant)agonists according to the present invention include compounds which bind to the SAP phosphatase receptor, e.g. including oligopeptides, polypeptides, protein, antibodies, mimetics, small molecules, e.g. low molecular weight compounds (LMW's).
  • An (ant)agonist is preferably an antagonist.
  • the present invention provides a screening assay, e.g. a kit, for identifying an (ant)agonist of the phosphatase activity of a SAP protein of the present invention which assay comprises as a main component a) a SAP protein, or optionally b) a recombinant cell expressing a SAP protein, e.g. and means for a contact with a candidate compound; e.g. and means for determining the effect of the candidate compound on the phosphatase activity of any of a), or optionally b); and in another aspect A method of identifying an (ant)agonist which decreases or enhances the biological phosphatase activity of a SAP protein, which comprises
  • step B choosing an agonist or antagonist determined in step B), e.g. choosing an appropriate candidate compound from which an agonist/antagonist effect is positively determined in step B).
  • Recombinant cells expressing a SAP protein are known or may be provided according, e.g. analogously, to a method as conventional.
  • any such screening assay (kit), a) or optionally b) may comprise a substantial component including an appropriate environment of a sample to be tested and, e.g. appropriate means to determine the effect of a candidate compound in a sample to be tested.
  • a candidate compound includes compound (libraries), from which the effect on any of a) or b) is unknown.
  • Compound (libraries) includes compounds which are set out above as (ant)agonists to a SAP protein.
  • An (ant)agonist is a candidate compound from which an effect on any of a) or b) has been found in a screening assay or in a method for identifying (ant)agonists of the present invention.
  • an (ant)agonist may decrease or enhance the production and or the biological phosphatase activity of a SAP protein of the present invention.
  • the present invention provides an (ant)agonist of the phosphatase activity of a SAP protein which is characterized in that said antagonist or agonist is provided by the following method steps: A) contacting a) a SAP protein, or optionally b) a recombinant cell expressing a SAP protein, with a candidate compound, B) determining the effect of said candidate compound on the phosphatase activity of a) or optionally b), and C) choosing an agonist or antagonist determined in step B).
  • An (ant)agonist of the phosphatase activity of a SAP protein is herein designated also as " an (ant)agonist of the present invention".
  • An (ant)agonist of the present invention is preferably an antagonist.
  • An (ant)agonist of the present invention may be used in the treatment of diseases mediated by the phosphatase activity of a SAP protein, e.g. Th1 and/or Th2 driven diseases, including immunological and allergic disorders.
  • An (ant)agonist of a polypeptide according to the present invention may thus be useful as a pharmaceutical.
  • the present invention provides an (ant)agonist of the present invention for use as a pharmaceutical.
  • the present invention provides the use of an (ant)agonist of the present invention for the manufacture of a medicament for the treatment of a disease mediated by the phosphatase activity of a SAP protein, e.g. for the treatment of Th1 and/or Th2 driven diseases, e.g. immunological or allergic disorders.
  • the present invention provides a method of treatment of diseases which are mediated by the phosphatase activity of a SAP protein, e.g. Th1 and/or Th2 driven diseases, including immunological and allergic diseases, which treatment comprises administering to a subject in need of such treatment an effective amount of an (ant)agonist of the present invention; e.g. in the form of a pharmaceutical composition.
  • Treatment includes treatment and prophylaxis.
  • an indicated daily dosage is in the range from about 0.01 g to about 2.5 g (from about 0,125 mg/kg to about 32 mg/kg), e.g. 0.05 g to 1,0 g (from about 0,625 mg/kg to about 12,5 mg/kg), of an (ant)agonist of the present invention; conveniently administered, for example, in divided doses up to four times a day.
  • An (ant)agonist of the present invention may be administered by any conventional route, for example enterally, e.g. including nasal, buccal, rectal, oral, administration; parenterally, e.g. including intravenous, intramuscular, subcutanous administration; or topically; e.g. including epicutaneo ⁇ s, intranasal, intratracheal administration; e.g. in form of coated or uncoated tablets, capsules, injectable solutions or suspensions, e.g. in the form of ampoules, vials, in the form of creams, gels, pastes, inhaler powder, foams, tinctures, lip sticks, drops, sprays, or in the form of suppositories.
  • An (ant)agonist of the present invention may be administered in the form of a pharmaceutically acceptable salt, or in free form; optionally in the form of a solvate.
  • An (ant)agonist of the present invention may be used for pharmaceutical treatment according to the present invention alone, or in combination with one or more other pharmaceutically active agents.
  • Such other pharmaceutically active agents include e.g. agents which are effective in the treatment of immunological and/or allergic diseases.
  • Combinations include fixed combinations, in which two or more pharmaceutically active agents are in the same formulation; kits, in which two or more pharmaceutically active agents in separate formulations are sold in the same package, e.g. with instruction for co- administration; and free combinations in which the pharmaceutically active agents are packaged separately, but instruction for simultaneous or sequential administration are given.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an (ant)agonist of the present invention in association with at least one pharmaceutical excipient, e.g. appropriate carrier and/or diluents, e.g. including fillers, binders, disintegrators, flow conditioners, lubricants, sugars and sweeteners, fragrances, preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers.
  • pharmaceutical excipient e.g. appropriate carrier and/or diluents, e.g. including fillers, binders, disintegrators, flow conditioners, lubricants, sugars and sweeteners, fragrances, preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers.
  • the present invention provides a pharmaceutical composition according to the present invention, further comprising another pharmaceutically active agent.
  • compositions may be manufactured according, e.g. analogously to a method as conventional, e.g. by mixing, granulating, coating, dissolving or lyophilizing processes.
  • Unit dosage forms may contain, for example, from about 1 mg to about 1000 mg, such as 2 mg to about 500 mg.
  • Figure 1 shows alignment of selected SH2 domains, such alignments can be performed by commercially available alignment tools, e.g. by the Vector NTI package (InforMax Inc).
  • Figure 2 shows the activity of various concentrations of purified SAP (empty symbols), repeatedly determinated at different time points.
  • a control consisting of the substrate (subst) suspended in reaction buffer is shown by the closed symbols.
  • Figure 3 shows the activity of dilutions of the purified phosphatase domain of CD45 which are tested in parallel for comparison.
  • Figure 4 shows the mapping of interactions between SAP and SLAM.
  • SAP shows phosphatase activity
  • SAP1-104 containing the major SH2-like domain of the molecule, is recombinantly produced in E.coli and purified to homogeneity as described by Poy F. et al (1999), Mol.Cell 4:555- 561. Purity and identity of the product is confirmed by SDS-PAGE analysis, mass spectroscopy and Edman degradation. Phosphatase activity is measured using the DiFMUP substrate (RediPlate Assay kit, Molecular Probes, OR, USA). Dephosphorylation of DiFMUP yields DiFMU, the amount of which is determined by measuring its fluorescence. Concentration and time-dependent phosphatase activity of SAP is detected, see e.g. Figures 2 and 3. Phosphatase activity of SAP is lower than that of the CD45 molecule, which is a highly active hematopoietic phosphatase and which is used as a positive control in the present experiments.
  • SAP stands out by having two Cys residues at positions which are normally occupied by conserved small amino acids, see e.g. Figure 1.
  • the second Cys residue, corresponding to Cys44 in SAP has equivalents in a few other proteins, such as SHIP, the Ras Inhibitory protein, IPP5P, and in the second SH2 domain of Syk.
  • the first cysteine, Cys42 is however only found in SAP and EAT-2. Computational comparison of the putative substrate binding surfaces indicates that Cys42 is most likely the critical catalytic amino acid whose contribution is indispensable for the phosphatase activity.
  • the critical role of the cysteins is assessed using an intein-mediated bacterial expression system (IMPACT, New England BioLabs, MA USA).
  • SAP is purified to complete homogeneity and treated with MESNA according to protocols of the manufacturers.
  • Mass spectroscopy detects a minus 2 Dalton deviation compared to the calculated molecular mass in the majority of the products, indicating that Cys42/44 is oxidized by MESNA.
  • the MESNA- treated protein does not show phosphatase activity any more, not even in (compared to the native SAP) very high concentrations.
  • SLAM (CD150) is one of the principal binding partners of SAP. Interactions between these molecules have been extensively characterized. Binding between the intracellular portion of SLAM and SAP, either in the presence or absence of FynT, was e.g. successfully demonstrated in a two-hybrid system according to Chan B. et al (2003) Nat.Cell Biol. 5, 155- 160. Mutation of Cys42 to Serine is found to completely abolish the binding of SAP to SLAM in the absence of FynT. Significant binding is reconstituted when constitutively active FynT is present (see Figure 4). Phosphatase activities of different SAP preparations are shown in Figure 5.

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  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne l'utilisation d'une SLAM (molécule d'activation lymphocytaire de signalisation) associée à une protéine (SAP) agissant comme une phosphatase et dans des dosages.
PCT/EP2004/008824 2003-08-08 2004-08-06 Utilisation de sap WO2005015205A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US49383103P 2003-08-08 2003-08-08
US60/493,831 2003-08-08

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WO2005015205A2 true WO2005015205A2 (fr) 2005-02-17
WO2005015205A3 WO2005015205A3 (fr) 2005-06-23

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999026980A1 (fr) * 1997-11-21 1999-06-03 Beth Israel Deaconess Medical Center Reactifs et procedes d'utilisation de proteines de la famille sap, nouveaux regulateurs de transduction de signaux
WO2000058350A1 (fr) * 1999-03-26 2000-10-05 Human Genome Sciences, Inc. 49 proteines secretees par un etre humain

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999026980A1 (fr) * 1997-11-21 1999-06-03 Beth Israel Deaconess Medical Center Reactifs et procedes d'utilisation de proteines de la famille sap, nouveaux regulateurs de transduction de signaux
WO2000058350A1 (fr) * 1999-03-26 2000-10-05 Human Genome Sciences, Inc. 49 proteines secretees par un etre humain

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CASTRO A G ET AL: "Molecular and functional characterization of mouse signaling lymphocytic activation molecule (SLAM): differential expression and responsiveness in Th1 and Th2 cells." JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 1 DEC 1999, vol. 163, no. 11, 1 December 1999 (1999-12-01), pages 5860-5870, XP001206085 ISSN: 0022-1767 *
GILMOUR KIMBERLY C ET AL: "Diagnosis of X-linked lymphoproliferative disease by analysis of SLAM-associated protein expression" EUROPEAN JOURNAL OF IMMUNOLOGY, vol. 30, no. 6, June 2000 (2000-06), pages 1691-1697, XP001206214 ISSN: 0014-2980 *
MACGINNITIE ANDREW J ET AL: "X-linked lymphoproliferative disease: genetic lesions and clinical consequences." CURRENT ALLERGY AND ASTHMA REPORTS. SEP 2002, vol. 2, no. 5, September 2002 (2002-09), pages 361-367, XP009046726 ISSN: 1529-7322 *
MORRA MASSIMO ET AL: "Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells" EMBO (EUROPEAN MOLECULAR BIOLOGY ORGANIZATION) JOURNAL, vol. 20, no. 21, 1 November 2001 (2001-11-01), pages 5840-5852, XP002325721 ISSN: 0261-4189 cited in the application *
NICHOLS KIM E ET AL: "Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 95, no. 23, 10 November 1998 (1998-11-10), pages 13765-13770, XP002325722 ISSN: 0027-8424 *
NISTALA K ET AL: "X-linked lymphoproliferative disease: Three atypical cases" CLINICAL AND EXPERIMENTAL IMMUNOLOGY, vol. 126, no. 1, October 2001 (2001-10), pages 126-130, XP001206234 ISSN: 0009-9104 *

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