WO2002059367A2 - Jeu de microechantillons de diagnostic pour ibd, maladie de crohn et colite ulcereuse - Google Patents

Jeu de microechantillons de diagnostic pour ibd, maladie de crohn et colite ulcereuse Download PDF

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WO2002059367A2
WO2002059367A2 PCT/US2001/045096 US0145096W WO02059367A2 WO 2002059367 A2 WO2002059367 A2 WO 2002059367A2 US 0145096 W US0145096 W US 0145096W WO 02059367 A2 WO02059367 A2 WO 02059367A2
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acc
protein
beta
gene expression
sample
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WO2002059367A3 (fr
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Elizabeth E. Mannick
Zhiyun Liu
Maria-Stella Serrano
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Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College
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    • 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
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • 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
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6834—Enzymatic or biochemical coupling of nucleic acids to a solid phase
    • C12Q1/6837—Enzymatic or biochemical coupling of nucleic acids to a solid phase using probe arrays or probe chips
    • 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
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A90/00—Technologies having an indirect contribution to adaptation to climate change
    • Y02A90/10—Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Definitions

  • TECHNICAL FIELD This invention pertains to a method that uses DNA microarray hybridization to identify patients with inflammatory bowel disease, and to distinguish Crohn's disease from ulcerative colitis.
  • BACKGROUND ART Despite greater than fifty years of clinical experience with Crohn's disease and ulcerative colitis, collectively known as inflammatory bowel disease (TBD), the precise etiology of these diseases remains unknown and the morbidity they engender high. Further, between 10-15% of patients cannot be accurately diagnosed as having either Crohn's disease or ulcerative colitis and are classified as indeterminate colitis, making treatment decisions and evaluation of long-term prognosis difficult.
  • TBD inflammatory bowel disease
  • IBD susceptibility loci have recently been mapped to chromosomes 1, 3, 4, 6, 10, 12, 16, X and 22. See J.P. Hugot et al., "Genome-wide scanning in inflammatory bowel diseases," Dig. Dis., vol. 16, pp. 364-369 (1998); J. Hampe et al., "A genomewide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort," Am. J. Hum. Genet., vol. 64, pp. 808-816 (1999); and K.G. Becker et al., “Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases," Proc. Natl. Acad. Sci. USA, vol. 95, pp. 9979-9984 (1998). Due to the painstaking nature of linkage analysis and positional cloning techniques, no IBD candidate gene has as yet been identified.
  • microarray gene analysis has recently been added to the arsenal of molecular genetic techniques. See M. Schena et al., "Qualitative monitoring of gene expression patterns with a complementary DNA microarray," Science, vol. 270, pp. 467-470 (1995). Microarray analysis allows an investigator to screen for thousands of genes in a relatively small patient sample such as a single endoscopic biopsy or a small amount of blood ( ⁇ 2 cc).
  • a microarray is a glass slide, microchip, or membrane with cDNA of thousands of known sequences spotted on it.
  • microarrays then serve as sequence targets for hybridization to cDNA probes prepared from RNA samples from cells or tissues.
  • a two-color fluorescence labeling technique is generally used in the preparation of the cDNA probes such that a simultaneous hybridization, but separate detection of signals, provides a comparative analysis and a determination of the relative abundance of specific genes expressed.
  • Microarrays can be constructed from specific cDNA clones of interest, a cDNA library, or a select number of open-reading frames from a genome sequencing database to allow a large-scale functional analysis of expressed sequences. See R.A.
  • the diagnostic genes identified by microarray analysis may be different from the genes found by positional cloning, because the occurrence of RNA in the sample used for the microarray analysis may be influenced by environmental factors, including medical treatments, that induce or suppress genetic expression.
  • Microarray analysis using selected human sequences of probable significance in inflammation, as well as with sequences expressed in peripheral human blood cells, has been used to compare gene expression in tissue samples of rheumatoid arthritis (late stage rheumatoid synovial tissue) and inflammatory bowel disease (inflamed lower intestinal mucosa of patients with Crohn's disease). See Heller et al., 1997.
  • RNA samples from mononuclear blood cells gene sequences that can be used to identify patients with IBD, Crohn's disease, and ulcerative colitis. Sequences were identified whose over- or underexpression was distinct to patients with IBD, Crohn's disease, or ulcerative colitis when compared to patients with non-IBD intestinal disorders. Additionally, cluster analysis was used to identify twenty-five sequences that are IBD-related, and whose transcription pattern can be used in a microarray analysis to identify patients with IBD with a sensitivity of 84% and a specificity of 100%. Cluster analysis also identified thirty-six genes that could be used to distinguish patients with Crohn's disease from those with ulcerative colitis with a sensitivity of 80% and a specificity of 89%.
  • the microarray information on over- and under-expression of gene sequences can be used to develop diagnostic tests for Crohn's disease, ulcerative colitis and inflammatory bowel disease. It can be used to identify subcategories of patients in order to predict disease prognosis. For example, Crohn's disease is subclassifed into fibrostenosing and inflammatory subtypes, which may correspond to genotypic as well as phenotypic differences. It can also be used to monitor the results of drug therapy for inflammatory bowel disease, ulcerative colitis and Crohn's disease. Finally, it has the potential to be used to identify drug targets in order to develop new therapies for the treatment of inflammatory bowel disease.
  • underexpressed genes, such as G protein-gamma 4, ARC34, SHPS-1 or carbonic anhydrase ⁇ which, based on their biological function, could play a role in IBD pathogenesis, could be targets for replacement with gene therapy.
  • PBMC peripheral blood mononuclear cells
  • a MICROMAXTM Human cDNA Microarray System was obtained from NEN Life Sciences, Inc. (Boston, Massachusetts). The MICROMAXTM system comes with 2400 human sequences spotted on a glass slide. Except for a small number of plant control sequences, all sequences are from over 50 human cDNA libraries representing more than 10 tissue sources created by Alphagene, Incorporated (Woburn, Massachusetts).
  • PBMC Peripheral blood mononuclear cells
  • DNP dinitrophenol
  • cDNA of each sample was then purified by ethanol precipitation, analyzed by dot blot using horseradish peroxidase (HRP). HRP-conjugated, anti-DNP antibody and streptavidin-HRP conjugate, and the total amount was estimated using known cDNA standards. All of the above procedures followed the detailed protocol of and used the reagents provided with the MICROMAXTM kit available from NEN Life Sciences, Inc.
  • Equal amounts of cDNA from a patient and from an age- and sex-matched control were combined and denatured in hybridization buffer (NEN Life Sciences, Inc.) at 90°C, and then hybridized on the glass slide microarray (NEN Life Sciences, Inc.) at 65 °C overnight. After washing in a sodium citrate-sodium chloride buffer (3M sodium chloride, 0.3m sodium citrate, ph 7.0) (NEN Life Sciences, Inc.) three times, the slides were blocked with normal goat serum, incubated with anti-DNP-HRP conjugate, followed by Cyanine 3 (red fluorescent) dye conjugated to tyramide for signal amplification.
  • a sodium citrate-sodium chloride buffer 3M sodium chloride, 0.3m sodium citrate, ph 7.0
  • Table 1 is a list of the 25 sequences of the 2400 sequences assayed that were the most overexpressed and of the 25 sequences that were the most underexpressed in the fourteen Crohn's patients.
  • the sequences are sorted by the median ratio after normalization of data by median centering each array. A median ratio of greater than 2 or less than 0.50 is often used to identify sequences of potential biological significance; i.e., genes that are overexpressed or underexpressed, respectively.
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • 5 had active disease and 6 were inactive.
  • Six were untreated, and five were being treated with some combination of steroids, immunosuppressive agents, and 5-ASA compounds.
  • the procedure was as described in Example 1, using the MICROMAXTM Human cDNA Microarray System obtained from NEN Life Sciences, Inc. (Boston, Massachusetts).
  • Table 2 is a list ofthe 25 sequences ofthe 2400 sequences assayed that were the most overexpressed and of the 25 sequences that were the most underexpressed in the eleven UC patients.
  • the sequences are sorted by the median ratio after normalization of data by median centering each array. A median ratio of greater than 2 or less than 0.50 is often used to identify genes of potential biological significance.
  • This study used the same IBD patients as in Examples 1 and 2. This study was designed to identify specific genes whose expression pattern might be used to diagnose patients with inflammatory bowel disease ("IBD"), and also to distinguish patients with Crohn's disease from those with ulcerative colitis.
  • IBD inflammatory bowel disease
  • the RNA extraction and the microarray analysis were performed as described above in Example 1 using the MICROMAXTM Human cDNA Microarray System from NEN Life Sciences, Inc. (Boston, Massachusetts).
  • IBD-specific genes In order to identify IBD-specific genes, the following criteria were applied to the results obtained from scanning the microarray slides. Sequences were identified as IBD- related genes if the gene was overexpressed or underexpressed by a factor of two or more in at least 25% of the patients with either ulcerative colitis or Crohn's disease as compared to patients with chronic intestinal inflammation unrelated to IBD after normalization by median centering arrays. The genes listed in Table 3 met this criteria.
  • Table 3 also lists sequences specific for Crohn's disease and for ulcerative colitis (UC). Sequences were identified as Crohn' s-specific genes if the gene was overexpressed or underexpressed by a factor of 2 or more in at least 25% of patients with Crohn's disease as compared to patients with chronic intestinal inflammation unrelated to IBD.
  • Sequences were identified as UC-specific genes if the gene was overexpressed or underexpressed by a factor of 2 or more in at least 25% of patients with ulcerative colitis as compared to patients with other inflammatory gastrointestinal disorders.
  • Example 4 Diagnostic Array for Patients with IBD, Crohn 's Disease and Ulcerative Colitis Using the microarray data generated in Example 3, cluster analysis was performed to identify clusters of related genes that may be involved in disease processes using the Cluster Analysis software kindly provided by Michael Eisen on the internet (http://rana.stanford.edu/software) See M.B. Eisen et al., "Cluster analysis and display of genome-wise expression patterns," Proc. Natl. Acad. Sci. USA, vol. 95, pp. 14863-14868 (1998)
  • IBD Cluster analysis indicated that by using 24 genes, IBD could be identified in our patient sample with a sensitivity of 84% and a specificity of 100%. By using 25 genes (the 24 genes plus one additional gene), IBD could be identified with a sensitivity of 88% and a specificity of 90%.
  • the genes identified are the following: Acidic calponin (Acc# S80562), Beta-sarcoglycan A3b (Acc# U31116), CL100 mRNA for protein tyrosine phosphatase (Acc# X68277), ZIP-kinase (Acc# AB007144), G protein gamma-4 subunit (Acc# U31382), Fibroblast muscle-type tropomyosin (Acc# M12125), Alkali myosin light chain 1 (Acc# M20642), Achaete scute homologous protein (Acc# L08424), Sorting nexin 2 (SNX2) (Acc# AF043453), Tristetraproline (TTP) (Acc# M63625), serine/threonine protein kinase (#D86550) (Acc# U59305), KIAA0210 (Acc# D86965), Methionine aminopeptidase (Acc# U29607), (p23) (Acc# L
  • a microarray could be custom-made using cD ⁇ As ofthe above sequences, along with housekeeping sequences and plant or other control sequences.
  • Such a custom-made microarray with cD ⁇ A from fewer sequences than the original 2400 sequences would decrease the cost of using a microarray as a diagnostic tool for IBD.
  • the microarray could include all genes identified for IBD, Crohn's, and UC as listed in Table 2.
  • the better method would be a microarray that would contain the twenty-five sequences that can identify IBD, and the thirty-six sequences that could then distinguish Crohn's from ulcerative colitis.
  • Such a microarray would contain the following sixty genes (because one sequence overlaps in the two lists): Acidic calponin (Acc# S80562), Beta-sarcoglycan A3b (Acc# U31116), CL100 mR ⁇ A for protein tyrosine phosphatase (Acc# X68277), ZTP-kinase (Acc# AB007144), G protein gamma-4 subunit (Acc# U31382), Fibroblast muscle-type tropomyosin (Acc# M12125), Alkali myosin light chain 1 (Acc# M20642), Achaete scute homologous protein (Acc# L08424), Sorting nexin 2 (SNX2) (Acc# AF043453), Tristetraproline (TTP) (Acc# M63625), serine/threonine protein kinase (#D86550) (Acc# U59305), KIAA0210 (Acc# D86965), Methionine amino
  • SYBR green real-time PCR involves the introduction of a SYBR green dye that fluoresces when bound to double-stranded (ds) DNA.
  • ds double-stranded
  • C ( ) value for each sample was calculated to determine the cycle time at which the fluorescent intensity exceeded a threshold (10 times the standard deviation from baseline emissions). Threshold cycle, or sample positivity, was directly proportional to the amount of target material allowing quantization of gene expression.
  • Primers designed for the genes of interest was designed and tested for primer stability using ABI Primer Express software (Applied Biosystems, Foster City, CA) and synthesized by Integrated DNA technologies (Coral Nille, Iowa). Briefly, reverse transcription of lOOng of R ⁇ A was performed using Rnase H-deficient reverse transcriptase (Superscript TJ, Life Technologies, Rockville, Maryland) and Random Hexamer primers. The PCR reaction was performed using the Taq-Man Core PCR kit (PE Applied Biosystems) in 96-well trays with optical caps containing triplicates of each sample.
  • the reaction mixture was generally preheated for 10 minutes at 95°C, then 35 cycles of 15 seconds at 95°C and one minute at 60°C, followed by one cycle of heating from 60°C to 95°C over 20 minutes to obtain a melting curve ofthe PCR products and carried out by a 7700 Sequence Detector (PE Applied Biosystems).
  • PCR conditions for each of the overexpressed and underexpressed genes was optimized including primer concentration and magnesium concentration.
  • the relative gene expression is determined based on the normalized threshold cycle ofthe gene of interest to a pool of unaffected control samples to control for transcription efficiency.
  • the normalized C t value obtained for each gene for IBD samples was compared with the value obtained for each gene for unaffected control samples. Ratios of relative gene expression are then compared with microarray results.
  • Acidic Calponin (Accession #S80562), Arp 2/3 protein complex subunit 34-Arc (ARC34) (Accession #AF006085), Human antigen CD36 (clone 13) mRNA (Accession #M98398), Human epidermal growth factor receptor substrate (epsl5) (Accession #U07707), mRNA for Hrs (Accession #D84064), Serine threonine kinase 11 (STKll) (Accession #AF035625), and mRNA for SHPS-1 (Acc# D86043).

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Abstract

En utilisant des échantillons d'ARN provenant de cellules sanguines mononucléaires, on a identifié des séquences de gènes qui peuvent être utilisées pour identifier des patients atteints d'IBD, ce qui permet de distinguer des patients atteints de la maladie de Crohn, de patients atteints de colite ulcéreuse. On a identifié des séquence dont la surexpression était distincte de patients atteints d'IBD, de maladie de Crohn et de colite ulcéreuse, comparativement aux patients atteints d'infections intestinales non-IBD. En outre, une analyse par amas a été utilisée pour identifier vingt cinq séquences qui sont en rapport avec l'IBD, et dont les modèles de transcription peuvent être utilisés dans une analyse par microéchantillons pour identifier des patients atteints d'IBD avec une sensibilité de 84 % et une spécificité de 100 %. Une analyse par amas a également permis d'identifier trente six gènes qui peuvent être utilisés pour distinguer des patients atteints de la maladie de Crohn de ceux atteints de colite ulcéreuse avec une sensibilité de 89 % et une spécificité de 80 %.
PCT/US2001/045096 2000-11-30 2001-11-30 Jeu de microechantillons de diagnostic pour ibd, maladie de crohn et colite ulcereuse WO2002059367A2 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003027321A2 (fr) * 2001-09-24 2003-04-03 University Of Aarhus Methodes de diagnostic et de traitement de maladies associees a une expression alteree de neurogranine
EP1462527A1 (fr) * 2003-03-26 2004-09-29 CONARIS research institute AG Nouveaux marqueurs des affections intestinales inflammatoires
US6893828B2 (en) 2001-09-06 2005-05-17 Decode Genetics Ehf. Methods for producing ex vivo models for inflammatory disease and uses thereof
WO2006010516A1 (fr) * 2004-07-29 2006-02-02 Bayer Healthcare Ag Diagnostic et traitement therapeutique des maladies associees a la proteine de type methionine aminopeptidase 2 (metap2-like)
US7148008B2 (en) 2001-09-06 2006-12-12 Decode Genetics Ehf. Methods for predicting drug sensitivity in patients afflicted with an inflammatory disease
WO2006133287A2 (fr) * 2005-06-06 2006-12-14 Wyeth Profils d'expression des cellules mononucleaires du sang peripherique pour le traitement des maladies intestinales inflammatoires
EP1844158A2 (fr) * 2004-12-06 2007-10-17 The Johns-Hopkins University Biomarqueurs pour maladie intestinale inflammatoire
US7820382B2 (en) 2004-08-03 2010-10-26 Bauer A Robert Method for the early detection of breast cancer, lung cancer, pancreatic cancer and colon polyps, growths and cancers as well as other gastrointestinal disease conditions and the preoperative and postoperative monitoring of transplanted organs from the donor and in the recipient and their associated conditions related and unrelated to the organ transplantation
US8080373B2 (en) * 2004-08-03 2011-12-20 Bauer Jr A Robert Method for the early detection of pancreatic cancer and other gastrointestinal disease conditions
US8105773B2 (en) 2004-06-02 2012-01-31 Diagenic As Oligonucleotides for cancer diagnosis
US8396872B2 (en) 2010-05-14 2013-03-12 National Research Council Of Canada Order-preserving clustering data analysis system and method
EP2328105A3 (fr) * 2009-10-30 2016-05-18 Sysmex Corporation Procédé pour déterminer la présence d'une maladie
WO2016179469A1 (fr) * 2015-05-07 2016-11-10 Abbvie Inc. Méthodes et compositions de diagnostic et de traitement de la maladie intestinale inflammatoire
WO2023156714A1 (fr) 2022-02-18 2023-08-24 Åbo Akademi Procédé de détection et de sous-typage de maladies intestinales inflammatoires

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE EMBL [Online] "acidic calponin" Database accession no. S80562 XP002226217 *
GRAHAM M F ET AL: "Phenotypic differentiation of human intestinal smooth muscle cells induced by chronic inflammation: Increased expression of smooth muscle-specific proteins in vitro." MOLECULAR BIOLOGY OF THE CELL, vol. 7, no. SUPPL., 1996, page 539A XP008011952 Annual Meeting of the 6th International Congress on Cell Biology and the 36th American Society for Cell Biology;San Francisco, California, USA; December 7-11, 1996 ISSN: 1059-1524 *
HELLER R A ET AL: "Discovery and analysis of inflammatory disease-related genes using cDNA microarrays." PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. UNITED STATES 18 MAR 1997, vol. 94, no. 6, 18 March 1997 (1997-03-18), pages 2150-2155, XP002171597 ISSN: 0027-8424 *
SERRANO MARIA-STELLA ET AL: "Application of microarray analysis to Crohn's disease." JPGN, vol. 31, no. Supplement 2, 2000, page S83 XP008011953 World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition;Boston, Massachusetts, USA; August 05-09, 2000 *

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7384736B2 (en) * 2001-09-06 2008-06-10 Decode Genetics Ehf. Methods for predicting drug sensitivity in patients afflicted with an inflammatory disease
US6893828B2 (en) 2001-09-06 2005-05-17 Decode Genetics Ehf. Methods for producing ex vivo models for inflammatory disease and uses thereof
US7148008B2 (en) 2001-09-06 2006-12-12 Decode Genetics Ehf. Methods for predicting drug sensitivity in patients afflicted with an inflammatory disease
US7244571B2 (en) 2001-09-06 2007-07-17 Decode Genetics Ehf. Methods for producing Ex vivo models for inflammatory disease and uses thereof
US7435548B2 (en) 2001-09-06 2008-10-14 Decode Genetics Ehf. Methods for producing ex vivo models for inflammatory disease and uses thereof
WO2003027321A3 (fr) * 2001-09-24 2003-11-06 Univ Aarhus Methodes de diagnostic et de traitement de maladies associees a une expression alteree de neurogranine
WO2003027321A2 (fr) * 2001-09-24 2003-04-03 University Of Aarhus Methodes de diagnostic et de traitement de maladies associees a une expression alteree de neurogranine
EP1462527A1 (fr) * 2003-03-26 2004-09-29 CONARIS research institute AG Nouveaux marqueurs des affections intestinales inflammatoires
WO2004085677A2 (fr) * 2003-03-26 2004-10-07 Conaris Research Institute Ag Nouveaux marqueurs de maladie inflammatoire intestinale
WO2004085677A3 (fr) * 2003-03-26 2004-11-04 Conaris Res Inst Ag Nouveaux marqueurs de maladie inflammatoire intestinale
US8105773B2 (en) 2004-06-02 2012-01-31 Diagenic As Oligonucleotides for cancer diagnosis
WO2006010516A1 (fr) * 2004-07-29 2006-02-02 Bayer Healthcare Ag Diagnostic et traitement therapeutique des maladies associees a la proteine de type methionine aminopeptidase 2 (metap2-like)
US7820382B2 (en) 2004-08-03 2010-10-26 Bauer A Robert Method for the early detection of breast cancer, lung cancer, pancreatic cancer and colon polyps, growths and cancers as well as other gastrointestinal disease conditions and the preoperative and postoperative monitoring of transplanted organs from the donor and in the recipient and their associated conditions related and unrelated to the organ transplantation
US8080373B2 (en) * 2004-08-03 2011-12-20 Bauer Jr A Robert Method for the early detection of pancreatic cancer and other gastrointestinal disease conditions
EP1844158A2 (fr) * 2004-12-06 2007-10-17 The Johns-Hopkins University Biomarqueurs pour maladie intestinale inflammatoire
EP1844158A4 (fr) * 2004-12-06 2010-09-08 Univ Johns Hopkins Biomarqueurs pour maladie intestinale inflammatoire
WO2006133287A3 (fr) * 2005-06-06 2007-09-07 Wyeth Corp Profils d'expression des cellules mononucleaires du sang peripherique pour le traitement des maladies intestinales inflammatoires
WO2006133287A2 (fr) * 2005-06-06 2006-12-14 Wyeth Profils d'expression des cellules mononucleaires du sang peripherique pour le traitement des maladies intestinales inflammatoires
EP2328105A3 (fr) * 2009-10-30 2016-05-18 Sysmex Corporation Procédé pour déterminer la présence d'une maladie
US9898574B2 (en) 2009-10-30 2018-02-20 Sysmex Corporation Method for determining the presence of disease
US8396872B2 (en) 2010-05-14 2013-03-12 National Research Council Of Canada Order-preserving clustering data analysis system and method
WO2016179469A1 (fr) * 2015-05-07 2016-11-10 Abbvie Inc. Méthodes et compositions de diagnostic et de traitement de la maladie intestinale inflammatoire
WO2023156714A1 (fr) 2022-02-18 2023-08-24 Åbo Akademi Procédé de détection et de sous-typage de maladies intestinales inflammatoires

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