CN101275951A - Molecule making for identifying liver fibrosis and hepatic cirrhosis and micro-array system plate thereof - Google Patents
Molecule making for identifying liver fibrosis and hepatic cirrhosis and micro-array system plate thereof Download PDFInfo
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- CN101275951A CN101275951A CNA2007101452580A CN200710145258A CN101275951A CN 101275951 A CN101275951 A CN 101275951A CN A2007101452580 A CNA2007101452580 A CN A2007101452580A CN 200710145258 A CN200710145258 A CN 200710145258A CN 101275951 A CN101275951 A CN 101275951A
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Abstract
The present invention provides a molecular mark for determining liver fibrosis and cirrhosis and a micro-array system board thereof. The invention at least comprises one in 28 proteins or at least comprises one in the genes encoding these proteins. Among these proteins or genes, 8 members are upper regulatory genes, 13 members are lower regulatory genes, and the rest 9 members are treating target. The invention is a molecular mark with filtering capacity to warn the generation of severe liver fibrosis or cirrhosis. The molecular mark of the invention is also a target which has latent capacity for the medicament design.
Description
Technical field
The invention relates to the detection of liver diseases, and particularly relevant for a kind of molecular labeling and microarray system plate thereof of identifying liver fibrosis and cirrhosis.
Background technology
Numerous disease comprises the hepatic injury that hepatites virus infections, alcohol abuse and long term exposure cause in organic solvent.The result of hepatic lesion is inflammation, the hardening of tissue and or even the formation of cancer.The lasting attack of liver inflammation has not only triggered a lot of biochemical events, the sternzellen activation of for example immune response, cytohormone and chemohormonal secretion, gangrene, liver and the pressure of oxidation, also triggered simultaneously the reorganization of cell and structure, that is liver fibrosis and cirrhosis (people such as Marcellin, the argumentation of being delivered at Hepatology the 36th interim Fibrosis and disease progression in hepatitis C the 47th～56 joint in 2002).
Liver fibrosis is described to be to repair and repair process in the wound, the process that the skin of extraordinary image on wound " scabs " liver cell.Structural reinventing also is the accumulation that comprises extracellular matrix with one of phenomenon of forming causes scar tissue.The result who repeats to repair of hepatic injury is the accumulation of causes scar tissue and the forfeiture of hepatocyte function, and for example detoxifcation, metabolic activity have caused final serious consequence-cirrhosis.Serious cirrhosis is one of dead main cause of liver disease, and all the other then are hepatocellular carcinoma (this is a liver cancer).
The infection of hepatitis C separately estimates to reach 3% of world population, and it is popular often to be accompanied by the hepar damnification that hepatitis B infects and alcoholism causes.Not having suitably, the lasting liver inflammation and the fiberization of treatment intervention lysis will cause liver hardening, swelling and finally abandon running (compensatory hypofunction), cirrhosis as everyone knows.Hepatitis will become the serious and irreversible time in 20 to 25 years of result's needs, but it is not noted by patient often.
Though current medicine agreement suggestion, for some scope, liver fibrosis and cirrhosis may be replied through the treatment of chronic hepatitis, there is no suitable treatment and can handle liver fibrosis and cirrhosis fully.In the development that solves the medicine problem that collapses like this, the medical treatment of hepatic fibrosis-renal tubular ectasia syndrome is heavy.At this moment, can detect a screening of blood test of liver fibrosis effectively on one's body from the patient who suffers from chronic hepatic lesion, this has demand to the healthcare givers.
Summary of the invention
Therefore, one of purpose of the present invention is exactly in that a kind of molecular labeling and microarray system plate thereof of identifying liver fibrosis and cirrhosis is provided, and a filler test can be provided, and with on one's body the patient who suffers from chronic hepatic lesion, judges cirrhosis.
In addition, a further object of the present invention provides a kind of microarray system plate (microarray panel) of identifying the molecular labeling of liver fibrosis and cirrhosis, it can screen the patient of shrouding under risk, generation with serious liver fibrosis of early warning or cirrhosis, and in drug design, molecular labeling of the present invention is very to have a target of potentiality.
The present invention proposes a kind of molecular labeling and microarray system plate thereof of identifying liver fibrosis and cirrhosis, comprise at least following protein one of them or these protein of encoding gene one of them:
Albumin (ALB); Alanyl (film) aminopeptidase (ANPEP); Annexin A2 (ANXA2, annexin A2); Apolipoprotein F (APOF); Amyloid-beta (A4) precursor protein (APP); α 2-glycoprotein 1, zinc is in conjunction with (AZGP1); Betaine homocysteine methyl transferase (BHMT); Complement component 8, α peptide (C8A); Chemotactic factor (CF) (C-C primitive) aglucon 19 (CCL 19); Complement factor H 4 (CFHR4) that are correlated with; Complement factor H 5 (CFHR5) that are correlated with; Collagen, I, α 2 (COL 1A2); Collagen, III, α 1 (COL3A1); Collagen, XVIII, α 1 (COL 18A1); Decorin (DCN); Skin pontin protein (DPT); Formimino transferase cyclodeaminase (FTCD); Glycogen synthetase 2 (GYS2); Gelsolin (GSN); Interferon gamma (INFG); Lactate dehydrogenase B (LDHB); Inner chamber albumen (LUM); Middle α (globulin) inhibiting factor H1 (ITIH1); Platelet derived growth factor receptor, α peptide (PDGFRA); S100 calbindin A4 (S100A4); Pth receptor associated protein 1 (THRAP1); Metallopeptidase inhibiting factor 1 (TIMP1); And TNF (TNF).
Molecular labeling and microarray system plate thereof according to described evaluation liver fibrosis of preferred embodiment and cirrhosis, because above-mentioned 28 protein/genes can be used for the detection of liver related complication, also can very have a medicine target of potentiality for treating this type of complication, the present invention can treat or slow down the carrying out of cirrhosis.
In addition, from 28 protein candidates of the present invention, comprise the formed detection of one or more candidates, can be by method based on antibody, enzymoimmunoassay (ELISA, Enzyme-Linked Immuno-Sorbent Assay) for example, institute detects.
For above and other objects of the present invention, feature and advantage can be become apparent, preferred embodiment cited below particularly, and cooperate appended accompanying drawing, be described in detail below.
Description of drawings
Fig. 1 shows for using the chart of 28 genes in the present invention.
Fig. 2 shows the chart for the molecular labeling plate of screening cirrhosis.
Fig. 3 shows the chart for the treatment target plate of the tool potentiality of being derived by path analysis.
Fig. 4 shows the chart of differentiating F0/F1 group and the patient's of F3/F4 group predictive ability for molecular marker gene.
Fig. 5 is according to a preferred embodiment of the present invention, the analysis of different expression of gene levels.
Fig. 6 is according to a preferred embodiment of the present invention, the path analysis of up-regulated gene in the serious liver vivisection of high fiberization is checked.
Embodiment
Hereinafter with reference to relevant drawings, preferred embodiment of the present invention is described, wherein identical assembly will be illustrated with identical reference marks.
Fig. 1 shows for using the chart of 28 genes in the present invention.As shown in Figure 1, a kind of molecular labeling and microarray system plate thereof of identifying liver fibrosis and cirrhosis provided by the present invention, comprise at least following protein one of them or these protein of encoding/gene one of them:
Albumin (ALB, albumin); Alanyl (film) aminopeptidase (ANPEP, alanyl[membrane] aminopeptidase); Annexin A2 (ANXA2, annexin A2); Apolipoprotein F (APOF, apolipoprotein F); Amyloid-beta (A4) precursor protein (APP, amyloid beta[A4] precursor protein); α 2-glycoprotein 1, zinc is in conjunction with (AZGP 1, and alpha-2-glycoprotein 1, zinc-binding); Betaine homocysteine methyl transferase (BHMT, betaine-homocysteinemethyltransferase); Complement component 8, and the α peptide (C8A, complement component 8, alphapolypeptide); Chemotactic factor (CF) (C-C primitive) aglucon 19 (CCL19, chemokine[C-C motif] ligand 19); Complement factor H 4 (CFHR4, the complement factor H-related 4) that are correlated with; Complement factor H 5 (CFHR5, the complement factor H-related 5) that are correlated with; Collagen, I, α 2 (COL 1A2, collagen, type I, alpha 2); Collagen, III, α 1 (COL3A 1, collagen, and typeIII, alpha 1); Collagen, XVIII, α 1 (COL18A1, collagen, type XVIII, alpha 1); Decorin (DCN, decorin); The skin pontin protein (DPT, dermatopontin); Formimino transferase cyclodeaminase (FTCD, formiminotransferase cyclodeaminase); Glycogen synthetase 2 (GYS2, glycogen synthase 2); Gelsolin (GSN, gelsolin); Interferon gamma (INFG, interferon gamma); Lactate dehydrogenase B (LDHB, lactatedehydrogenase B); Inner chamber albumen (LUM, lumican); Middle α (globulin) inhibiting factor H1 (ITIH1, inter-alpha[globulin] inhibitor H1); Platelet derived growth factor receptor, α peptide (PDGFRA, platelet-derived growth factor receptor, alpha polypeptide); S100 calbindin A4 (S100A4, S100calcium binding protein A4); Pth receptor associated protein 1 (THRAP1, thyroid hormone receptor associated protein 1); Metallopeptidase inhibiting factor 1 (TIMP1, TIMP metallopeptidase inhibitor 1); And TNF (TNF, tumor necrosis factor).
In preferred embodiment, have at least a protein to be provided as the liver fibrosis protein of differential period in the above-mentioned molecular labeling.
In preferred embodiment, have the molecular labeling of a protein provision in the above-mentioned molecular labeling at least for screening protein, to detect serious liver fibrosis or cirrhosis, for example have the liver corpse or other object for laboratory examination and chemical testing sample of Metavir score classification (a kind of software analysis of assessing fibrosis) for F3 or F4.Fig. 2 shows the chart for the molecular labeling plate of screening cirrhosis.As shown in Figure 2, it is up-regulated gene (up-regulated genes) with the screening cirrhosis that 8 protein are arranged in the molecular labeling of the present invention, as follows:
Annexin A2 (ANXA2); Collagen, I, α 2 (COL1A2); Collagen, III, α 1 (COL3A1); Gelsolin (GSN); Lactate dehydrogenase B (LDHB); Inner chamber albumen (LUM); Platelet derived growth factor receptor, α peptide (PDGFRA); And metallopeptidase inhibiting factor 1 (TIMP1).
Simultaneously, Fig. 2 has shown also that 13 protein are arranged in the molecular labeling of the present invention is down-regulated gene (down-regulated genes) with the screening cirrhosis, and is as follows:
Albumin (ALB); Alanyl (film) aminopeptidase (ANPEP); Apolipoprotein F (APOF); α 2-glycoprotein 1, zinc is in conjunction with (AZGP1); Betaine homocysteine methyl transferase (BHMT); Complement component 8, α peptide (C8A); Complement factor H 4 (CFHR4) that are correlated with; Complement factor H 5 (CFHR5) that are correlated with; Collagen, XVIII, α 1 (COL18A1); Formimino transferase cyclodeaminase (FTCD); Glycogen synthetase 2 (GYS2); Middle α (globulin) inhibiting factor H1 (ITIH1); And pth receptor associated protein 1 (THRAP1).
In preferred embodiment, have at least 1 protein to provide in the above-mentioned molecular labeling as the indicator of repairing liver fibrosis and cirrhosis.
In preferred embodiment, have at least 1 protein can be in the above-mentioned molecular labeling, with development anti-hepatic fibrosis and anti-cirrhosis medicine as target.Fig. 3 shows and is the chart by the treatment target plate of the resulting tool potentiality of path analysis.As shown in Figure 3, there are 9 protein to be the treatment target in the molecular labeling of the present invention, as follows:
Platelet derived growth factor receptor, α peptide (PDGFRA); S100 calbindin A4 (S100A4); Collagen, III, α 1 (COL3A1); Chemotactic factor (CF) (C-C primitive) aglucon 19 (CCL19); Decorin (DCN); Skin pontin protein (DPT); Amyloid-beta (A4) precursor protein (APP); TNF (TNF); And interferon gamma (INFG).
In preferred embodiment, have at least 1 protein can be in screening technique, in the above-mentioned molecular labeling as the potpourri that influences liver fibrosis or cirrhosis process.
In preferred embodiment, have at least 1 protein can be in the above-mentioned molecular labeling as the advance notice that liver is damaged.
In preferred embodiment, have at least 1 protein can be used in the immunodiagnosis external member in the above-mentioned molecular labeling, to judge liver diseases.
The present invention serves as reasons gene representation of data chart with fiberization stage hepatic tissue gradually and the result of study of coming, and it is resultant by the chronic hepatitis patient.The serve as reasons molecular labeling of screening of the plate of different manifestations gene judges and uses, with the generation of the serious liver fibrosis/cirrhosis of early warning, and as the target to drug design tool potentiality.
In up-regulated gene, the present invention has made up a biochemical path, and it is the center with an important function of gene-TNF (TNF, tumor necrosis factor).In this biochemistry path, TNF and transforming growth factor-1 (TGF β-1, transforming growth factor β-1) and interferon gamma (INFG, interferon gamma) gene is interrelated, and in the report in early days, this two gene also has very strong correlativity with liver fibrosis simultaneously.The present invention proposes something: TNF (TNF) is for grasping the key that liver fibrosis seriousness changes, and it is to treatment or what slow down liver fibrosis is a gratifying selection.
The present invention is a kind of molecular labeling and microarray system plate thereof of identifying liver fibrosis and cirrhosis, can have diversified embodiment along with different molecular labelings.Be simply clearly narration, the present invention collects one and adds up to 54 parts, inhales section (liver needle biopsy) by the liver live body pin that the chronic hepatitis C patient gets on one's body, to illustrate specific implementation method of the present invention.Fig. 4 shows the chart of differentiating F0/F1 group and the patient's of F3/F4 group predictive ability for molecular marker gene, and wherein PPV (positive predictive value) is positive predicted value, and NPV (negative predictive value) is negative predicted value.In chart subsequently, for consistance, with Metavir score classification (a kind of software analysis of assessing fibrosis) the liver sample fiber degree of classifying and evaluate two independent pathological evaluations, comprise criterion (inclusion criteria) and get rid of criterion (exclusion criteria).
Following chart is according to the microarray system analysis of Metavir score classification and patient distributed areas:
| Metavir score | F0 | F1 | F2 | F3 | F4 | Sum |
| Patient's |
10 | 11 | 13 | 10 | 10 | 54 |
The RNA (ribonucleic acid) of liver vivisection (RNA) extraction
The liver vivisection that is collected in the Physiological Experiment chamber for put into contain RNA (ribonucleic acid) sample storage liquid RNALater (Ambion, CA, in microtest tube USA) (microliter tube) and refrigeration when desire is used.With TRIZOL method (TRIzol Reagent) by extracting RNA (ribonucleic acid) in the biological tissue.Basically, with reagent (Invitrogen, CA, USA) add in the test tube to mix with hepatic tissue, and (people such as Smith is published in Hepatology 38 (6) in 2003: among the 1458-67 after with phenol extraction, Hepatitis C virus and liver disease:global transcriptional profiling andidentification ofpotential markers), homogenize with the plastics pestle.RNA (ribonucleic acid) behind the purifying is stored in 70% ethanol and is stored in the subzero 80 ℃ cryogenic freezing.The productive rate of RNA (ribonucleic acid) and concentration detect with spectrophotometer (spectrophotometer).On average, total RNA (total RNA) of 5-15 microgram (μ g) can be got by purifying in the single liver vivisection of length about 5 millimeters (mm).Required in order to detect, (USA) (Agilent, CA USA) analyze the quality of RNA (ribonucleic acid) with bioanalysis device Bioanalyzer 2100 for Aglient, CA by nano chips RNA 6000Nano chip.The ratio of its 18S/28S should exceed 1.2 as int RNA (ribonucleic acid) extract.
The microarray system experiment
The execution of microarray system experiment is according to manufacturer (Affymetrix, CA, USA) service manual that is provided.The total RNA that is got heavy 2 μ g by hepatic tissue makes to be used for synthesizing to connect along with the 1st synthetic chain complementary DNA (cDNA) (cDNA) of the 2nd chain.The complementary RNA (BiotinylatedcRNA) that contains biotin synthesizes for external, and cultivates 15 minutes with 95 ℃ in fracture damping fluid (fragmentation buffer).Afterwards, the complementary RNA fragment that 15 μ g contain biotin in microarray system chip (biochip) with 22,285 probe groups U133A (Affymetrix, CA, USA) hybridization.Hybridization is for (Affymetrix, CA USA) guide in 45 ℃ and carried out 16 hours by microarray system case Affymetrix microarray oven.After hybridization is finished, connect along with (USA) pick-up image utilizes GeneChip with chip for Affymetrix, CA with GeneArray Scanner 2500
Fluidics Station400 (Affymetrix, CA, USA) cleaning and dyeing in fluid state.Do the analysis of quality and preliminary data with software Affymetrixmicroarray suite (version 5.0).
Data analysis
On the program, by the microarray system experimental result of using chip Affymetrix human U133A chips gained, with by meeting (http://www.broad.mit.edu/cancer/software/genecluster2/gc2.html with GeneCluster 2.0, MA, USA) the BioConductor project that comes (the Summaries of Affymetrix GeneChip probe level data that people such as Irizarry delivers, Nucleic Acids Res.31:e 15,2003; Http:// www.bioconductor.org/) RobustMulti-array Average (RMA) method is done standardization (normalized) and is handled.(Silicon Genetics, CA USA) are used for the T analysis of experiments to software GeneSpring software.Software Genesis 1.5.0software then analyzes (http://genome.tugraz.at/Software/GenesisCenter.html in order to do group; Graz University of Technology, Graz, Austria).
Fig. 5 is according to a preferred embodiment of the present invention, the stratum analysis of different gene performances.As shown in Figure 5, the chronic hepatitis c patient liver vivisection sample on one's body that the data drawing list of the stratum analysis (hierarchical analysis) of different gene performance is served as reasons and had the different phase of liver fibrosis to 54 parts is with the stratum analysis of the experiment gained of chip Affymetrix GeneChip U133.
Fig. 6 is according to a preferred embodiment of the present invention, the path analysis of up-regulated gene.As shown in Figure 6, the path analysis of up-regulated gene is served as reasons the liver vivisection is checked that the seriousness gained for high fiberization comes.
In the gene performance of messenger RNA (mRNA) level, protein existing with it is closely bound up.Human protein's tissue (HUPO, Human Proteome Organization, http://www.hupo.org) has been made a project can detect the protein that obtains at human serum and blood plasma to disclose all.Always have the degree of accuracy that 3020 protein have height.The invention provides a process, 8 down-regulated genes and 12 up-regulated genes that can assay in the data of human protein's tissue along liver fibrosis.These factors can be used on further in the research, to inquire into the molecular labeling of serum proteins that may unlabeled fibronectin seriousness.
In the present invention, identify that the molecular labeling of liver fibrosis and cirrhosis and microarray system plate thereof are characteristic with the protein of 28 of sums, these protein can be used in the detection of the relevant complication of liver, and as the medicine target for the treatment of these complication tool potentiality.
In an example, TNF (TNF) is used to develop treatment or slows down the medicine of liver fibrosis process.
The patient of chronic hepatitis C infection is shrouded in the height risk of liver fibrosis.In another example, though the inspection of some normality treatment still might stop Fibrotic increasing the weight of, patients'blood gets usually to be extracted to do screening test comes detection fibersization whether to become serious.These tests comprise one or more molecular labelings that come protein by 28 candidates among the present invention, can be by methods based on antibody, and enzymoimmunoassay (ELISA, Enzyme-Linked Immuno-SorbentAssay) for example, institute detects.
In other situation, the patient who does not discover the liver situation can be screened by Fibrotic positive reaction, and provides as further diagnosing and treating.
Another example is that the hepatitis patient of going through treatment can be tested the recovery of their liver situation by protein molecular marker single or combination of the present invention again.These molecular labelings also can be as the test that liver fibrosis is reversed simultaneously.
Though the present invention discloses as above with preferred embodiment; right its is not in order to limiting the present invention, anyly has the knack of this skill person, without departing from the spirit and scope of the present invention; when can doing a little change and retouching, so protection scope of the present invention is as the criterion when looking the accompanying Claim person of defining.
Claims (12)
1. molecular labeling of identifying liver fibrosis and cirrhosis, comprise at least following protein one of them or comprise at least the following protein of encoding gene one of them:
Albumin; Alanyl (film) aminopeptidase; Annexin A2; Apolipoprotein F; Amyloid-beta (A4) precursor protein; α 2-glycoprotein 1, the zinc combination; Betaine homocysteine methyl transferase; Complement component 8, the α peptide; Chemotactic factor (CF) (C-C primitive) aglucon 19; Complement factor H relevant 4; Complement factor H relevant 5; Collagen, I, α 2; Collagen, III, α 1; Collagen, XVIII, α 1; Decorin; The skin pontin protein; The formimino transferase cyclodeaminase; Glycogen synthetase 2; Gelsolin; Interferon gamma; Lactate dehydrogenase B; Inner chamber albumen; Middle α (globulin) inhibiting factor H1; Platelet derived growth factor receptor, the α peptide; S100 calbindin A4; The pth receptor associated protein 1; Metallopeptidase inhibiting factor 1; And TNF.
2. microarray system plate of identifying the molecular labeling of liver fibrosis and cirrhosis, comprise at least following protein one of them or comprise at least the following protein of encoding gene one of them:
Albumin; Alanyl (film) aminopeptidase; Annexin A2; Apolipoprotein F; Amyloid-beta (A4) precursor protein; α 2-glycoprotein 1, the zinc combination; Betaine homocysteine methyl transferase; Complement component 8, the α peptide; Chemotactic factor (CF) (C-C primitive) aglucon 19; Complement factor H relevant 4; Complement factor H relevant 5; Collagen, I, α 2; Collagen, III, α 1; Collagen, XVIII, α 1; Decorin; The skin pontin protein; The formimino transferase cyclodeaminase; Glycogen synthetase 2; Gelsolin; Interferon gamma; Lactate dehydrogenase B; Inner chamber albumen; Middle α (globulin) inhibiting factor H1; Platelet derived growth factor receptor, the α peptide; S100 calbindin A4; The pth receptor associated protein 1; Metallopeptidase inhibiting factor 1; And TNF.
3. molecular labeling according to claim 1 and 2 or microarray system plate, have at least in the wherein said protein one in order to as the differentiation liver fibrosis stage.
4. molecular labeling according to claim 1 and 2 or microarray system plate have a molecular labeling that is supplied as the screening protein that is used for detecting serious liver fibrosis or cirrhosis at least in the wherein said protein.
5. molecular labeling according to claim 1 and 2 or microarray system plate wherein in order to screen liver fibrosis, have 8 to be the adjusted gene in the described protein:
Annexin A2; Collagen, I, α 2; Collagen, III, α 1; Gelsolin; Lactate dehydrogenase B; Inner chamber albumen; Platelet derived growth factor receptor, the α peptide; And metallopeptidase inhibiting factor 1.
6. molecular labeling according to claim 1 and 2 or microarray system plate wherein in order to screen liver fibrosis, have 13 to be following regulatory gene in the described protein:
Albumin; Alanyl (film) aminopeptidase; Apolipoprotein F; α 2-glycoprotein 1, the zinc combination; Betaine homocysteine methyl transferase; Complement component 8, the α peptide; Complement factor H relevant 4; Complement factor H relevant 5; Collagen, XVIII, α 1; The formimino transferase cyclodeaminase; Glycogen synthetase 2; Middle α (globulin) inhibiting factor H1; And pth receptor associated protein 1.
7. molecular labeling according to claim 1 and 2 or microarray system plate have an indicator that is provided as liver fibrosis and cirrhosis reparation at least in the wherein said protein.
8. molecular labeling according to claim 1 and 2 or microarray system plate have 9 to be the treatment target in the wherein said protein:
Platelet derived growth factor receptor, the α peptide; S100 calbindin A4; Collagen, III, α 1; Chemotactic factor (CF) (C-C primitive) aglucon 19; Decorin; The skin pontin protein; Amyloid-beta (A4) precursor protein; TNF; And interferon gamma.
9. molecular labeling according to claim 1 and 2 or microarray system plate have one at least as the advance notice that liver is damaged in the wherein said protein.
10. an anti-hepatic fibrosis and anti-cirrhosis medicine, comprise at least the described molecular labeling of claim 1 one of them.
11. one kind in screening technique as the potpourri that influences liver fibrosis or cirrhosis process, comprise at least the described molecular labeling of claim 1 one of them.
12. an immunodiagnosis external member that is used to judge liver diseases, comprise at least the described molecular labeling of claim 1 one of them.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101782583A (en) * | 2010-02-10 | 2010-07-21 | 中国医学科学院阜外心血管病医院 | Application of dermatopontin in preparing kit for detecting cardiac failure and detection kit |
| CN102460174A (en) * | 2009-05-14 | 2012-05-16 | 牛津大学之校长及学者 | Clinical diagnosis of hepatic fibrosis using a novel panel of low abundant human plasma protein biomarkers |
| CN102803955A (en) * | 2009-05-21 | 2012-11-28 | 系统生物学研究所 | New biomarkers for liver injury |
| CN103031359A (en) * | 2012-12-27 | 2013-04-10 | 上海交通大学 | Application of S100 group protein |
| CN103399158A (en) * | 2013-08-02 | 2013-11-20 | 上海市同济医院 | Liquid protein chip kit for detecting liver fibrosis degree |
| CN103520740A (en) * | 2013-10-21 | 2014-01-22 | 中国科学院生物物理研究所 | Liver fibrosis treatment method |
| CN109765378A (en) * | 2016-08-31 | 2019-05-17 | 鲁凤民 | A kind of new cirrhosis or hepatic fibrosis markers |
| CN112763716A (en) * | 2020-12-25 | 2021-05-07 | 杭州师范大学附属医院 | Liver disease fibrosis detection reagent, detection kit and detection method for detecting serum LUM expression |
| US11366124B2 (en) | 2016-08-24 | 2022-06-21 | ShOx Science Limited | Clinical diagnosis of non-alcoholic fatty liver disease using a panel of human blood protein biomarkers |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102460174A (en) * | 2009-05-14 | 2012-05-16 | 牛津大学之校长及学者 | Clinical diagnosis of hepatic fibrosis using a novel panel of low abundant human plasma protein biomarkers |
| EP2799876A3 (en) * | 2009-05-14 | 2015-07-29 | The Chancellor, Masters and Scholars of the University of Oxford | Clinical diagnosis of hepatic fibrosis using a novel panel of low abundant human plasma protein biomarkers |
| CN102803955A (en) * | 2009-05-21 | 2012-11-28 | 系统生物学研究所 | New biomarkers for liver injury |
| CN102803955B (en) * | 2009-05-21 | 2015-10-21 | 系统生物学研究所 | The new mark of hepatic injury |
| CN101782583A (en) * | 2010-02-10 | 2010-07-21 | 中国医学科学院阜外心血管病医院 | Application of dermatopontin in preparing kit for detecting cardiac failure and detection kit |
| CN101782583B (en) * | 2010-02-10 | 2013-05-01 | 中国医学科学院阜外心血管病医院 | Application of dermatopontin in preparing kit for detecting cardiac failure and detection kit |
| CN103031359A (en) * | 2012-12-27 | 2013-04-10 | 上海交通大学 | Application of S100 group protein |
| CN103399158A (en) * | 2013-08-02 | 2013-11-20 | 上海市同济医院 | Liquid protein chip kit for detecting liver fibrosis degree |
| CN103520740A (en) * | 2013-10-21 | 2014-01-22 | 中国科学院生物物理研究所 | Liver fibrosis treatment method |
| US11366124B2 (en) | 2016-08-24 | 2022-06-21 | ShOx Science Limited | Clinical diagnosis of non-alcoholic fatty liver disease using a panel of human blood protein biomarkers |
| CN109765378A (en) * | 2016-08-31 | 2019-05-17 | 鲁凤民 | A kind of new cirrhosis or hepatic fibrosis markers |
| CN112763716A (en) * | 2020-12-25 | 2021-05-07 | 杭州师范大学附属医院 | Liver disease fibrosis detection reagent, detection kit and detection method for detecting serum LUM expression |
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