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WO2007073005A1 - Régulateur de la réaction de transfert du méthyle - Google Patents

Régulateur de la réaction de transfert du méthyle Download PDF

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Publication number
WO2007073005A1
WO2007073005A1 PCT/JP2006/326306 JP2006326306W WO2007073005A1 WO 2007073005 A1 WO2007073005 A1 WO 2007073005A1 JP 2006326306 W JP2006326306 W JP 2006326306W WO 2007073005 A1 WO2007073005 A1 WO 2007073005A1
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WO
WIPO (PCT)
Prior art keywords
carbon monoxide
methylation
biopolymer
present
cell
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2006/326306
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English (en)
Japanese (ja)
Inventor
Makoto Suematsu
Takehiro Yamamoto
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Keio University
Original Assignee
Keio University
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Filing date
Publication date
Application filed by Keio University filed Critical Keio University
Priority to JP2007551177A priority Critical patent/JPWO2007073005A1/ja
Publication of WO2007073005A1 publication Critical patent/WO2007073005A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates to a substance that affects the methylation of biopolymers. Specifically, the present invention relates to a substance that regulates a methyl group transfer reaction in a biopolymer.
  • BACKGROUND ART Methylation of biopolymers plays an important role as a regulatory system for important biological control mechanisms involved in the protection of cells and organs. Such biopolymer modifications occur on proteins, enzymes, DNA, and the like. In particular, in the case of DNA, acetylation is a mechanism for inserting a switch for gene expression, whereas methylation is a mechanism for cutting an expression switch and is extremely important.
  • CO carbon monoxide
  • NO nitric oxide
  • This gas molecule is known to be involved in unknown cytoprotective effects, suppression of inflammatory responses, transplantation tolerance, induction of cell differentiation, etc., but the mechanism has not been elucidated (Reference:! ⁇ Four ) .
  • the problem to be solved by the present invention is to provide a substance capable of adjusting a methyl group transfer reaction in a biopolymer and a method for adjusting the methyl group transfer reaction. .
  • Another object of the present invention is to provide a substance that induces cell differentiation and a method for inducing cell differentiation.
  • CO carbon monoxide
  • the present invention is as follows.
  • a biopolymer methylation regulator comprising carbon monoxide.
  • a method for regulating methylation of a biopolymer which comprises contacting carbon monoxide with the biopolymer.
  • a cell differentiation inducer characterized by containing carbon monoxide.
  • a method for inducing cell differentiation comprising bringing carbon monoxide into contact with a cell and enhancing demethylation of a protein in the cell.
  • this invention relates to the following.
  • a biopolymer acetylation regulator containing carbon monoxide containing carbon monoxide.
  • a method for regulating acetylation of a biopolymer characterized by bringing carbon monoxide into contact with the biopolymer.
  • Fig. 1 is a flow diagram showing the outline of the verification method for CO gene modification by Chromatin immhoprecipitation.
  • FIG. 2 shows changes in chromatin dynamics due to CO administration of CDlla, which is the differentiation marker for U937.
  • Fig. 3 shows the analysis of global protein methylation by Western blotting using ADMA antibody and the effect of CO addition (Ru: Ru (DMSO) 4 Cl 2 , CO donor: CORM 2).
  • Figure 4 shows the same strategy for proteins that undergo methylation modification by carbon monoxide (CO) treatment.
  • FIG. 5 shows the detection of methylated protein by Western blotting using ADMA antibody. Spots 3, 5, 6, 34, 35, and 36 show spots with enhanced methylation by CO treatment.
  • FIG. 6 is a diagram showing a MALDI-TOF MS analysis result of a spot cut out from a two-dimensional electrophoresis gel.
  • FIG. 7 shows the detection of methylated protein by Western blotting using ADMA antibody.
  • Figure 8 summarizes the results of MALDI-TQF / MS analysis.
  • Gas mediators are a group of molecules that can easily pass through cell membranes and bind to biopolymers such as proteins and DNA to give specific functions. Carbon monoxide is one of these mediators, and heme is decomposed into biliary pigments such as biliverdin and pyryrubin, carbon monoxide, and reduced iron (Fe 2+ ) by heme oxygenase. Is known to occur. However, the specific function of carbon monoxide has not been fully clarified.
  • the present invention relates to a biopolymer methylation regulator containing carbon monoxide and a biopolymer methylation regulation method using carbon monoxide.
  • carbon monoxide has an action of controlling acetylation of a biopolymer, particularly an action of enhancing acetylation of a biopolymer. That is, in the present invention, it has been shown that carbon monoxide can be used to control acetylation of biopolymers. Therefore, the present invention relates to a biopolymer acetylation regulator for carbon monoxide and a method for regulating biopolymer acetylation with carbon monoxide. Since acetylation of biopolymers is known to be related to the control of gene expression, it can be said that carbon monoxide can control gene expression through regulation of acetylation of biopolymers.
  • the present invention relates to a cell differentiation-inducing agent containing carbon monoxide or a method for inducing cell differentiation by carbon monoxide.
  • the present invention also relates to a method for producing carbon monoxide in a biopolymer by carbon monoxide.
  • “regulation of methylation” or “regulation of methyl group transfer reaction” means control of methyl group modification state in biological polymer, enhancement of methyl group transfer or withdrawal, or methylation or desorption of biopolymer. Means increased methylation.
  • modulation of acetylation means enhancement of acetylation or withdrawal of a acetyl group in a biopolymer, or enhancement of acetylation or deacetylation of a biopolymer.
  • the degree of enhancement is not particularly limited, but is 5% or more of the degree of methylation or acetylation of the control biopolymer not treated with carbon monoxide, preferably 10% or more, more preferably 30% or more, More preferably, it is 40% or more.
  • the biopolymer is not particularly limited as long as it is a molecule derived from a living body having a side chain that can be methylated or acetylated.
  • protein protein, nucleic acid (DNA, RNA, etc.), lipid, carbohydrate Etc.
  • the biological high molecule is preferably a protein or DNA, more preferably a protein. 1.
  • biopolymers methylated by carbon oxide include transketolase or alpha-enolase, which are glycolytic enzymes.
  • the side chain methylated or acetylated by carbon monoxide A side chain of an amino acid, more preferably a side chain of arginine can be mentioned, but it is not particularly limited. Further, the number of methylation or acetylation per molecule is not particularly limited.
  • carbon monoxide may be used as it is, or in a ribosome containing carbon monoxide, heme and heme protein containing carbon monoxide, erythrocytes containing carbon monoxide or an aqueous solution.
  • Modified carbon monoxide such as a carbon monoxide-containing complex that can release carbon monoxide, or a compound that is metabolized in the body to release CO (such as aryl hydride carbon) may be used.
  • Preference is given to using gaseous carbon monoxide. From the viewpoint of operational safety, it is preferable to use modified carbon monoxide. You may use the pharmaceutical composition containing the carbon monoxide mentioned later.
  • Carbon monoxide-containing complexes include CORM-K CORM-2 ([Ru (CO) 3 Cl2] 2) (Ozawa N, Goda N, Makino N, Yamaguchi T, Yoshimura Y, Suematsu M (2002) Leydig cell-derived heme oxygenase-1 regulates apoptosis of premeiotic germ cells in response to stress. J Clin Invest 109: 457-467.)), and CO releasing molecules such as CORM-3, C0RM-A1, and CORM F3.
  • the central metals are manganese (CORM-1), ruthenium (C0RM-2, -3), boron (C0RM-A1) and iron (CORM-F3), respectively.
  • the carbon monoxide-containing complex is preferably C0RM-2 in that the action of the central metal on the biopolymer is relatively small.
  • the regulation of methylation or acetylation of a biopolymer by carbon monoxide can be performed by bringing carbon monoxide into contact with the biopolymer. More specifically, it can be carried out by bringing carbon monoxide into contact with a cell, tissue, body fluid or the like containing a biopolymer to be subjected to methylation regulation or acetylation regulation.
  • “contact” means exposing a biopolymer or a cell, tissue, or body fluid containing the biopolymer to an environment in which carbon monoxide exists.
  • a mode in which cells or tissues are cultured in the presence of carbon monoxide a mode in which cells or tissues are cultured in a medium containing carbon monoxide, or carbon monoxide gas is blown onto cells, tissues or body fluids
  • concentration of carbon monoxide when added to a cell or tissue culture is 0.1 to: ⁇ ⁇ mol / L, preferably l lOOO mol / L, more preferably 10 to: 100 / i mol L, more preferably 25 ⁇ mol L.
  • the concentration when carbon monoxide is exposed to cells, tissues or body fluids is 5-100 i mol / L, more preferably 10.30 ⁇ mol / L.
  • Contact is from 10 ° C to 60 ° C, preferably 20 ° C. C to 50 ° C, more preferably 30 ° C to 40 ° C, most preferably 37 ° C, 10 minutes to 72 hours, preferably 20 minutes to 60 hours, more preferably Can be performed from 30 minutes to 48 hours.
  • the ability to regulate methylation or acetylation of biopolymers in this way The degree of methylation or acetylation is determined by Western blot analysis using anti-methylated antibody or anti-acetylated antibody, ELISA (Enzyme It can be detected by immunochemical methods such as -linked immunosorbent assay) and immunoprecipitation. Further, methylation or acetylation of a target biopolymer can be detected by appropriately combining known biopolymer extraction, separation, and purification methods with an immunochemical method.
  • the anti-methylated antibody used for the detection of methylation may be an antibody that recognizes a methylated biopolymer or an antibody that recognizes a methyl group.
  • an anti-methylated cytosine antibody Frazier, ASB
  • Anti-methylated lysine antibody Anti-dimethylarginine antibody
  • ADMA anti-methylated histone H3 (K9) antibody
  • K9 antibody Upstate, Abeam, SIGMA
  • anti-dimethylhistone H3 (K9) antibody upstate # 07) -441
  • anti-methylated DNA antibody and anti-methyl dalixoxal antibody (Nippon Yushi, Japan Aging Control Research Laboratories).
  • the anti-acetylated antibody used for the detection of acetylation may be any antibody that recognizes a acetylated biological polymer or an antibody that recognizes a acetyl group, and is not limited to, for example, anti-acetylyl And histone H3 (Lys9) antibody (Upstate # 07-352).
  • histone methylation status can be detected by chromatin immunoprecipitation.
  • chromatin immunoprecipitation method cells that have been contacted with carbon monoxide are first fixed with formaldehyde, etc., and then enzymatically cleaved to fragment the DNA to an average of 250 to 500 bp.
  • the immunoprecipitation is performed using the anti-dimethyl histone H3 (Lys 9) antibody (upstate # 07-441). Next, reverse-crosslinking and elution are performed, and the target gene is amplified by PCR using the eluate. The amplified product can be electrophoresed to determine the methylation status of histone 113.
  • This chromatin immunoprecipitation method can also be used to detect cell differentiation induction by carbon monoxide, which will be described later. Proteins in which the modification state by methyl group or acetyl group is changed by carbon monoxide treatment can be identified by a known protein identification method.
  • proteins in spots with altered modification compared to controls can be identified using a mass spectrometer.
  • the protein in the spot may be digested with trypsin or the like and then analyzed with a mass spectrometer.
  • Mass spectrometers include, for example, matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF / MS), electrospray mass spectrometry (ESI / MS), liquid chromatography Matographic mass spectrometry (LC / MS), gas chromatography matrix spectrometry (GCMS), etc. can be used.
  • the present invention provides a cell differentiation-inducing agent containing carbon monoxide (hereinafter also referred to as “differentiation-inducing agent of the present invention”).
  • the present invention also provides a method for inducing cell differentiation, characterized in that carbon monoxide is brought into contact with a cell to enhance demethylation or acetylation of the protein in the cell.
  • the differentiation inducer of the present invention can be used for a cell differentiation induction method and a cell differentiation 'induction therapy.
  • carbon monoxide is related to induction of differentiation of lymphoid cells, and thus artificial control of inflammatory reaction and rejection in transplantation, and a pharmaceutical composition used for this control (hereinafter referred to as “the present invention”). Also referred to as “immunomodulator”). Moreover, in the present invention, when carbon monoxide is brought into contact with a biopolymer, the expression of HO-1 is induced, so that carbon monoxide can be used for the induction of HO-1. In addition, carbon monoxide enhances the production of carbon monoxide ⁇ in vivo via HO-1 with increased expression level, so carbon monoxide produces endogenous carbon monoxide in biopolymers. Can be used for That is, exogenous administration of CO increases endogenous CO and may additively regulate cell function control.
  • carbon monoxide is considered to be involved in various biological functions that biopolymers play, it is possible to artificially control all proteins or genes subject to methylation control or acetylation control according to the present invention. Became possible.
  • the present invention can also be applied to proteins or genes that will be elucidated in the future to undergo methylation control or acetylation control.
  • carbon monoxide, a carbon monoxide-containing complex, or the like can be used for the carbon monoxide that is the active ingredient of the differentiation-inducing agent of the present invention or the immunomodulator of the present invention. It is not something. CO binds to hemoglobin and is transported to peripheral tissues.
  • a gaseous carbon monoxide when using gaseous carbon monoxide, adults (60 kg), 0.1 to 300 ppm per day, preferably 10 to 200 ppm, more preferably lOOppm at a concentration of 1 minute to 24 hours, preferably 5 minutes Administer by inhalation for ⁇ 12 hours, more preferably from 10 minutes to 6 hours. Inhalation can be performed using a mask, nasal catheter, or nasal force neurone connected to a carbon monoxide source (eg, a carbon monoxide cylinder or concentrator). It is also possible to administer a saturated solution of CO (saline) through blood vessels.
  • a carbon monoxide source eg, a carbon monoxide cylinder or concentrator
  • modified hemoglobin compounds that release CO through metabolism, and carbon monoxide bound to phospho-encapsulated hemoglobin (modified carbon monoxide), adults (60 kg)
  • 0.1 nmol to 1000 ju mol preferably lnmol to 100 ⁇ mol, more preferably lOnmol to lO yu mol per day.
  • modified carbon monoxide When using modified carbon monoxide, it may be used as it is, or it may be formulated in combination with a pharmacologically acceptable carrier.
  • protoneme IX or fma protoporphyrin IX, or fma dopamine or dobutamine When used as it is, or it may be used as a preparation.
  • Examples of pharmacologically acceptable carriers include excipients, binders, disintegrants, lubricants, lubricants, emulsifiers, coloring agents, flavoring agents, surfactants, and the like, which are usually used in medicine.
  • examples include solubilizers, suspending agents, isotonic agents, stabilizers, buffers, and antioxidants.
  • preparations may include tablets, powders, granules, capsules, oral preparations such as syrups, suppositories, ointments, eye drops, external preparations such as eye drops, and injections.
  • the above injections can be used by methods such as infusion, intramuscular injection, subcutaneous injection, and intravenous injection.
  • An injection may be formulated as a ribosome preparation by appropriately combining the above pharmacologically acceptable carriers.
  • the present invention also provides a kit containing carbon monoxide (hereinafter also referred to as “kit of the present invention”).
  • kit of the present invention is used for regulation of methylation or acetylation of biopolymers or induction of cell differentiation.
  • the carbon monoxide contained in the kit of the present invention is not particularly limited, and is, for example, gaseous carbon monoxide, modified carbon monoxide, or formulated carbon monoxide.
  • the kit of the present invention can be used to regulate methylation or acetylation of biopolymers or to induce and detect differentiation of cells, such as methylation detection reagents (for example, antimethylation reagents).
  • methylation detection reagents for example, antimethylation reagents
  • Acetylated antibodies for example, acetylated detection reagents
  • biopolymers or cells enzyme substrates (chromogenic substrates, etc.), and enzyme reaction terminators.
  • the kit of the present invention may contain various buffers, sterilized water, culture vessels, reaction vessels, experimental operation instructions, and the like.
  • Example 1 Detection of DNA modification by Chromatin immnoprecipitation method
  • CDlla is a differentiation-inducing marker for liii sphere cells, and is expressed on the cell membrane when leukemia cell U937 differentiates into monocyte macrophage.
  • the cells were cultured for 30 minutes in the presence of Ru (DMSO) 4 Cl 2 ( ⁇ ) as a control or CORM-2 (100 ⁇ ) as a CO donor, and the cells were collected.
  • whole cell lysate (lGO g / gel) prepared from the collected cells was electrophoresed two-dimensionally (pH 6-ll), and the separated protein was treated with anti-dimethyl alcohol used in Example 2.
  • Western blot analysis was performed using ginin (ADMA) antibody.
  • the spot of the sample treated with Ru (DMSO) 4 Cl 2 was compared with the spot of the sample treated with CORM-2, and spots with different degrees of methylation were cut out.
  • the excised spot protein was digested in gel with trypsin and then subjected to mass spectrometry using MALDI-TOF / MS. From the results of mass spectrometry, proteins were identified by the PMF method. Result>
  • cytoplasmic fractions were separated from human monocyte-derived U937 cells treated with CORM-2 or control Ru (DMSO) 4 Cl 2 for 30 minutes, and two-dimensional electrophoresis was performed. Western blot analysis was performed using ADMA antibody. As a result, spots with increased methylation (arrows) and spots with demethylation (open arrows) were confirmed by CO treatment (Fig. 7).
  • carbon monoxide can be used for differentiation-inducing therapy in which undifferentiated cells such as cancer cells are differentiated into normal cells by carbon monoxide.
  • the present invention provides a biopolymer methylation regulator and a biopolymer methylation regulation method.
  • the present invention also provides a cell differentiation inducer and a cell differentiation induction method.
  • the present invention makes it possible to control the biological functions of carbon monoxide, the present invention can be applied to control of inflammatory reactions and rejection in transplantation, for example.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Transplantation (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Inorganic Chemistry (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un régulateur de la méthylation d'un polymère biologique, ce régulateur comprenant du monoxyde de carbone ; un procédé permettant de réguler la méthylation d'un polymère biologique ; un inducteur de la différenciation d'une cellule ; et un procédé permettant d'induire la différenciation d'une cellule.
PCT/JP2006/326306 2005-12-22 2006-12-22 Régulateur de la réaction de transfert du méthyle Ceased WO2007073005A1 (fr)

Priority Applications (1)

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JP2007551177A JPWO2007073005A1 (ja) 2005-12-22 2006-12-22 メチル基転移反応調節物質

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US75338805P 2005-12-22 2005-12-22
US60/753,388 2005-12-22

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5569761B1 (ja) * 2013-03-29 2014-08-13 シャープ株式会社 分析方法
JP2016500821A (ja) * 2012-10-25 2016-01-14 アソシエーション プール ラ ルシェルシュ セラピューティク アンティ−カンセルースＡｓｓｏｃｉａｔｉｏｎ Ｐｏｕｒ Ｌａ Ｒｅｃｈｅｒｃｈｅ Ｔｈｅｒａｐｅｕｔｉｑｕｅ Ａｎｔｉ−Ｃａｎｃｅｒｅｕｓｅ 癌マーカーとしてのメチルグリオキサール

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002092075A2 (fr) * 2001-05-15 2002-11-21 Northwick Park Institute For Medical Research Emission therapeutique de monoxyde de carbone
WO2003088748A1 (fr) * 2002-04-15 2003-10-30 Beth Israel Deaconess Medical Center Utilisation d'heme-oxygenase-1 et produits de degradation d'heme
WO2003094932A1 (fr) * 2002-05-09 2003-11-20 Yale University Monoxyde de carbone servant de biomarqueur et d'agent therapeutique
WO2003096977A2 (fr) * 2002-05-17 2003-11-27 Yale University Methodes de traitement de l'hepatite
WO2003103585A2 (fr) * 2002-06-05 2003-12-18 Yale University Methodes de traitement de l'angiogenese, de la croissance tumorale et de metastases
WO2004000368A1 (fr) * 2002-06-21 2003-12-31 University Of Pittsburgh Of The Commonwealth System Of Higher Education Utilisation pharmaceutique du monoxyde d'azote, de l'heme oxygenase-1 et des produits de la degradation de l'heme
WO2004043341A2 (fr) * 2002-11-07 2004-05-27 University Of Pittsburgh Of The Commonwealth System Of Higher Education Traitement pour choc hémorragique

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002092075A2 (fr) * 2001-05-15 2002-11-21 Northwick Park Institute For Medical Research Emission therapeutique de monoxyde de carbone
WO2003088748A1 (fr) * 2002-04-15 2003-10-30 Beth Israel Deaconess Medical Center Utilisation d'heme-oxygenase-1 et produits de degradation d'heme
WO2003094932A1 (fr) * 2002-05-09 2003-11-20 Yale University Monoxyde de carbone servant de biomarqueur et d'agent therapeutique
WO2003096977A2 (fr) * 2002-05-17 2003-11-27 Yale University Methodes de traitement de l'hepatite
WO2003103585A2 (fr) * 2002-06-05 2003-12-18 Yale University Methodes de traitement de l'angiogenese, de la croissance tumorale et de metastases
WO2004000368A1 (fr) * 2002-06-21 2003-12-31 University Of Pittsburgh Of The Commonwealth System Of Higher Education Utilisation pharmaceutique du monoxyde d'azote, de l'heme oxygenase-1 et des produits de la degradation de l'heme
WO2004043341A2 (fr) * 2002-11-07 2004-05-27 University Of Pittsburgh Of The Commonwealth System Of Higher Education Traitement pour choc hémorragique

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016500821A (ja) * 2012-10-25 2016-01-14 アソシエーション プール ラ ルシェルシュ セラピューティク アンティ−カンセルースＡｓｓｏｃｉａｔｉｏｎ Ｐｏｕｒ Ｌａ Ｒｅｃｈｅｒｃｈｅ Ｔｈｅｒａｐｅｕｔｉｑｕｅ Ａｎｔｉ−Ｃａｎｃｅｒｅｕｓｅ 癌マーカーとしてのメチルグリオキサール
JP5569761B1 (ja) * 2013-03-29 2014-08-13 シャープ株式会社 分析方法
WO2014156293A1 (fr) * 2013-03-29 2014-10-02 シャープ株式会社 Méthode d'analyse

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