WO2021101146A1 - Composition de biomarqueur pour prédire un pronostic ou déterminer un stade de progression d'une maladie hépatique chronique - Google Patents

Composition de biomarqueur pour prédire un pronostic ou déterminer un stade de progression d'une maladie hépatique chronique Download PDF

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WO2021101146A1
WO2021101146A1 PCT/KR2020/015618 KR2020015618W WO2021101146A1 WO 2021101146 A1 WO2021101146 A1 WO 2021101146A1 KR 2020015618 W KR2020015618 W KR 2020015618W WO 2021101146 A1 WO2021101146 A1 WO 2021101146A1
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liver disease
chronic liver
expression level
prognosis
composition
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PCT/KR2020/015618
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Korean (ko)
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유경현
박종훈
오수민
성노현
이연수
이용선
한상영
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숙명여자대학교산학협력단
서울대학교 산학협력단
국립암센터
의료법인 온그룹의료재단
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Priority claimed from KR1020190149638A external-priority patent/KR102341336B1/ko
Priority claimed from KR1020190149639A external-priority patent/KR102288299B1/ko
Application filed by 숙명여자대학교산학협력단, 서울대학교 산학협력단, 국립암센터, 의료법인 온그룹의료재단 filed Critical 숙명여자대학교산학협력단
Publication of WO2021101146A1 publication Critical patent/WO2021101146A1/fr

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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
    • 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

Definitions

  • the present invention relates to a biomarker composition for predicting the prognosis of chronic liver disease or determining the progression stage.
  • Fatty liver or steatosis refers to a condition in which fat is accumulated in hepatocytes, and the ratio of fat to normal liver is about 5%, and a condition in which more fat is accumulated is called fatty liver.
  • fatty liver deteriorates and the fat mass in the hepatocyte becomes large, the important components of the cell including the nucleus are pushed to one side and the function of the hepatocyte decreases. This causes disorders in the circulation of blood and lymphatic fluid in the liver. In this case, the liver cells cannot receive adequate supply of oxygen and nutrients, resulting in decreased liver function.
  • Non-alcoholic fatty liver disease is the most common chronic liver disease and refers to a condition in which fat is accumulated in hepatocytes without excessive alcohol consumption.
  • the prevalence of non-alcoholic fatty liver disease is rapidly increasing not only in the West but also in Korea with an increase in the prevalence of obesity, and is closely related to type 2 diabetes, obesity and metabolic syndrome. Although there are some differences in frequency by region, it has been reported that as little as 6.3%, as many as 33%, and about 20% of patients are on average worldwide. Some of these patients have non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • liver disease such as cirrhosis or liver cancer
  • end-stage liver disease such as cirrhosis or liver cancer
  • the pathogenesis of non-alcoholic steatohepatitis has not been fully elucidated, but it has been reported that various factors such as fat deposition, inflammatory response, and genetic factors are related to each other.
  • Non-alcoholic fatty liver disease includes diet and exercise therapy, and drug treatments include vitamin E, insulin sensitizer, ursodeoxycholic acid (UCDA), and statins.
  • UCDA ursodeoxycholic acid
  • statins have become.
  • the effect of the drug has not been proven medically, and until now, there is no approved drug for non-alcoholic fatty liver disease.
  • symptoms should be improved through diet and exercise therapy, there are many cases where patients cannot practice this. Therefore, there is a need for research on the development of biomarkers capable of discriminating fatty liver disease or non-alcoholic steatohepatitis.
  • An object of the present invention is to provide a biomarker composition for predicting the prognosis of chronic liver disease.
  • Another object of the present invention is to provide a composition for predicting the prognosis of chronic liver disease.
  • Another object of the present invention is to provide a kit for predicting the prognosis of chronic liver disease.
  • Another object of the present invention is to provide a method of providing useful information for predicting the prognosis of chronic liver disease.
  • Another object of the present invention is to provide a biomarker composition for determining the progression stage of chronic liver disease.
  • Another object of the present invention is to provide a composition for determining the progression stage of chronic liver disease.
  • Another object of the present invention is to provide a kit for determining the progression stage of chronic liver disease.
  • Another object of the present invention is to provide a method of providing information necessary for determining the progression stage of chronic liver disease.
  • the present invention is AEBP1, ALDH3A1, ANTXR1, BICC1, C7, CCDC80, CCL19, CCL2, COL16A1, COL1A1, COL1A2, COL4A1, COL4A2, CRISPLD2, DCDC2, DPYSLCAM3, EFE3 FBLN5, FSTL3, GEM, GPC3, ITGBL1, LOXL4, LTBP2, LUM, MMP2, MMP7, PODN, PTGDS, SORT1, SVEP1, THBS1, THBS2, THY1 and any one or more proteins selected from the group consisting of THY1 and VCAN or a gene encoding the same It provides a biomarker composition for predicting the prognosis of chronic liver disease, including as an active ingredient.
  • the present invention is AEBP1, ALDH3A1, ANTXR1, BICC1, C7, CCDC80, CCL19, CCL2, COL16A1, COL1A1, COL1A2, COL4A1, COL4A2, CRISPLD2, DCDC2, DPYSL3, EFEMP1, FBLN5, FTL3CAM, FBLN5 , GPC3, ITGBL1, LOXL4, LTBP2, LUM, MMP2, MMP7, PODN, PTGDS, SORT1, SVEP1, THBS1, THBS2, THY1 and VCAN. It provides a composition for predicting the prognosis of chronic liver disease, comprising a possible agent as an active ingredient.
  • the present invention provides a kit for predicting the prognosis of chronic liver disease, including the composition for predicting the prognosis of chronic liver disease.
  • the present invention (a) from samples isolated from chronic liver disease patients AEBP1, ALDH3A1, ANTXR1, BICC1, C7, CCDC80, CCL19, CCL2, COL16A1, COL1A1, COL1A2, COL4A1, COL4A2, CRISPLD2, DCDC2, DPYSL3 , EPCAM, EPHA3, F3, FBLN5, FSTL3, GEM, GPC3, ITGBL1, LOXL4, LTBP2, LUM, MMP2, MMP7, PODN, PTGDS, SORT1, SVEP1, THBS1, THBS2, THY1 and any one or more selected from the group consisting of VCAN Measuring the expression level of the protein or the mRNA expression level of the gene encoding the same; (b) comparing the expression level of the protein or the mRNA expression level of the gene encoding the protein with a control sample; And (c) determining that the risk of progression of chronic liver disease is high when the expression level of the protein or
  • the present invention provides a biomarker composition for determining the progression stage of chronic liver disease, including any one or more proteins selected from the group consisting of HS3ST2 and CAPG or a gene encoding the same as an active ingredient. .
  • the present invention provides a composition for determining the progression stage of chronic liver disease, comprising as an active ingredient an agent capable of measuring the expression level of any one or more proteins selected from the group consisting of HS3ST2 and CAPG or a gene encoding the same.
  • the present invention provides a kit for determining the progression stage of chronic liver disease, including the composition for determining the progression stage of the chronic liver disease.
  • the present invention comprises the steps of: (a) measuring the expression level of any one or more proteins selected from the group consisting of HS3ST2 and CAPG from a sample isolated from the patient or the mRNA expression level of a gene encoding the same; And (b) applying the expression level of the protein or the mRNA expression level of the gene encoding the same to a support vector machine (SVM) algorithm model; to provide.
  • SVM support vector machine
  • RNA-seq analysis was performed on tissues of patients with steatosis and non-alcoholic steatohepatitis to identify 38 genes that are specifically highly expressed during disease progression from steatosis to non-alcoholic steatohepatitis.
  • Genes showing an expression pattern were selected, and as a result of constructing a classification model capable of distinguishing fatty hepatosis and non-alcoholic steatohepatitis with the genes, it was verified that the classification of steatohepatic and non-alcoholic steatohepatitis was possible with high accuracy.
  • the genes may be used as biomarkers for predicting the prognosis of chronic liver disease or as biomarkers for classifying steatohepatitis and non-alcoholic steatohepatitis, and development of gene therapy or other drugs that inhibit the expression or activity thereof It can improve the therapeutic effect of chronic liver disease.
  • 1 is a diagram showing a stage in which the disease progresses from normal liver to liver cancer.
  • FIG. 2 shows a pipeline of total RAN-seq analysis using samples of steatohepatic and non-alcoholic steatohepatitis in order to select biomarkers for predicting prognosis of chronic liver disease.
  • FIG. 3 shows a pipeline of total RAN-seq analysis using samples of steatohepatic and non-alcoholic steatohepatitis in order to select a biomarker for determining the progression stage of chronic liver disease.
  • FIG. 4 is a diagram showing a classification model of steatohepatitis and non-alcoholic steatohepatitis using data obtained from the RAN-seq analysis.
  • the present invention is AEBP1, ALDH3A1, ANTXR1, BICC1, C7, CCDC80, CCL19, CCL2, COL16A1, COL1A1, COL1A2, COL4A1, COL4A2, CRISPLD2, DCDC2, DPYSL3, EFEMP1, EPCAM, GEM, EPHA3BL, GPC3BL, , ITGBL1, LOXL4, LTBP2, LUM, MMP2, MMP7, PODN, PTGDS, SORT1, SVEP1, THBS1, THBS2, THY1, and chronic liver comprising any one or more proteins selected from the group consisting of VCAN or a gene encoding the same as an active ingredient It provides a biomarker composition for predicting disease prognosis.
  • prognosis prediction means an act of predicting the course and outcome of a disease in advance. More specifically, the prognosis prediction may vary according to the patient's physiological or environmental condition, and may be interpreted to mean any act of predicting the course and outcome of a disease by comprehensively considering the patient's condition.
  • the present invention is AEBP1, ALDH3A1, ANTXR1, BICC1, C7, CCDC80, CCL19, CCL2, COL16A1, COL1A1, COL1A2, COL4A1, COL4A2, CRISPLD2, DCDC2, DPYSL3, EFEMP1, FBLN5, FTL3CAM, FBLN5 , GPC3, ITGBL1, LOXL4, LTBP2, LUM, MMP2, MMP7, PODN, PTGDS, SORT1, SVEP1, THBS1, THBS2, THY1 and VCAN. It provides a composition for predicting the prognosis of chronic liver disease, comprising a possible agent as an active ingredient.
  • the agent capable of measuring the expression level of the protein is an antibody, peptide, aptamer or compound that specifically binds to the protein, and the agent capable of measuring the expression level of the gene is a primer or probe that specifically binds to the gene. It may be, but is not limited thereto.
  • the chronic liver disease may be non-alcoholic steatohepatitis, and more specifically, it may be non-alcoholic steatohepatitis of stages F3 and F4, but is not limited thereto.
  • the non-alcoholic steatohepatitis is divided into stages F0, F1, F2, F3, and F4 depending on the stage of disease progression.
  • the prognosis prediction in the present invention is from NASH-F1 (F1 and F2) to NASH-F2 (F3 and F4) stages. It predicts the prognosis of non-alcoholic steatohepatitis that transitions to, and through this, the progression to cirrhosis or liver cancer in the future can be predicted.
  • primer is a nucleic acid sequence having a short free 3'-hydroxyl group, capable of forming a base pair with a complementary template, and as a starting point for template strand copying. It refers to a short nucleic acid sequence that acts. Primers can initiate DNA synthesis in the presence of a reagent for polymerization (ie, DNA polymerase or reverse transcriptase) and four different nucleoside triphosphates at an appropriate buffer and temperature. PCR conditions, the length of the sense and antisense primers can be appropriately selected according to techniques known in the art.
  • a reagent for polymerization ie, DNA polymerase or reverse transcriptase
  • PCR conditions, the length of the sense and antisense primers can be appropriately selected according to techniques known in the art.
  • probe refers to a nucleic acid fragment such as RNA or DNA corresponding to a few bases to hundreds of bases that can be specifically bound in addition to mRNA, and is labeled so that the presence or absence of a specific mRNA , The expression level can be confirmed.
  • the probe may be manufactured in the form of an oligonucleotide probe, a single strand DNA probe, a double strand DNA probe, an RNA probe, or the like. Selection of an appropriate probe and conditions for hybridization can be appropriately selected according to techniques known in the art.
  • antibody refers to a specific immunoglobulin directed against an antigenic site as a term known in the art.
  • the antibody in the present invention refers to an antibody that specifically binds to Gnpat of the present invention, and an antibody can be prepared according to a conventional method in the art.
  • the form of the antibody includes a polyclonal antibody or a monoclonal antibody, and all immunoglobulin antibodies are included.
  • the antibody refers to a complete form having two full-length light chains and two full-length heavy chains.
  • the antibody includes special antibodies such as humanized antibodies.
  • peptide used in the present invention has the advantage of high binding power to a target substance, and does not denature even during thermal/chemical treatment.
  • molecular size since the molecular size is small, it can be attached to other proteins and used as a fusion protein. Specifically, since it can be used by attaching it to a high molecular protein chain, it can be used as a diagnostic kit and a drug delivery material.
  • aptamer used in the present invention refers to a special kind of single-stranded nucleic acid (DNA, RNA or modified nucleic acid) that has a stable tertiary structure and can bind to a target molecule with high affinity and specificity. It means a kind of composed polynucleotide. As described above, aptamers are composed of polynucleotides that are more stable than proteins, have simple structures, and are easy to synthesize, while being able to specifically bind to antigenic substances in the same way as antibodies. I can.
  • the present invention provides a kit for predicting the prognosis of chronic liver disease, including the composition for predicting the prognosis of chronic liver disease.
  • the kit of the present invention comprises an antibody that specifically binds to a biomarker component, a secondary antibody conjugate to which a label that develops color by reaction with a substrate is conjugated, a solution of a color developing substrate to react with the label, a washing solution, and an enzyme. It may contain a reaction stop liquid, etc., and may be manufactured as a plurality of separate packaging or compartments including the reagent components used.
  • the present invention (a) from samples isolated from chronic liver disease patients AEBP1, ALDH3A1, ANTXR1, BICC1, C7, CCDC80, CCL19, CCL2, COL16A1, COL1A1, COL1A2, COL4A1, COL4A2, CRISPLD2, DCDC2, DPYSL3 , EPCAM, EPHA3, F3, FBLN5, FSTL3, GEM, GPC3, ITGBL1, LOXL4, LTBP2, LUM, MMP2, MMP7, PODN, PTGDS, SORT1, SVEP1, THBS1, THBS2, THY1 and any one or more selected from the group consisting of VCAN Measuring the expression level of the protein or the mRNA expression level of the gene encoding the same; (b) comparing the expression level of the protein or the mRNA expression level of the gene encoding the protein with a control sample; And (c) determining that the risk of progression of chronic liver disease is high when the expression level of the protein or
  • sample isolated from a patient refers to a sample such as tissue, cells, whole blood, serum, plasma, saliva, sputum, cerebrospinal fluid, or urine that differs from the control in the expression level of the protein or gene. It may be included, and more specifically, may be a liver tissue or a hepatocyte, but is not limited thereto.
  • the method of measuring the mRNA expression level is RT-PCR, competitive RT-PCR, real-time RT-PCR, RNase protection assay (RPA; RNase protection assay) ), Northern blotting and a DNA chip are used, but are not limited thereto.
  • methods for measuring the protein expression level include Western blot, radioimmunoassay (RIA), radioimmunodiffusion, Ouchterlony immune diffusion, and rocket ) Immunoelectrophoresis, tissue immunostaining, immunoprecipitation assay, Complement Fixation Assay, FACS, protein chip and ELISA analysis are used, but are not limited thereto.
  • the present invention provides a biomarker composition for determining the progression stage of chronic liver disease, including any one or more proteins selected from the group consisting of HS3ST2 and CAPG or a gene encoding the same as an active ingredient.
  • the present invention provides a composition for determining the progression stage of chronic liver disease, comprising as an active ingredient an agent capable of measuring the expression level of any one or more proteins selected from the group consisting of HS3ST2 and CAPG or a gene encoding the same.
  • the agent capable of measuring the expression level of the protein is an antibody, peptide, aptamer or compound that specifically binds to the protein, and the agent capable of measuring the expression level of the gene is a primer or probe that specifically binds to the gene. It may be, but is not limited thereto.
  • chronic liver disease may be fatty liver disease or non-alcoholic steatohepatitis, but is not limited thereto.
  • the present invention provides a kit for determining the progression stage of chronic liver disease, including the composition for determining the progression stage of the chronic liver disease.
  • the kit of the present invention comprises an antibody that specifically binds to a biomarker component, a secondary antibody conjugate to which a label that develops color by reaction with a substrate is conjugated, a solution of a color developing substrate to react with the label, a washing solution, and an enzyme. It may contain a reaction stop liquid, etc., and may be manufactured as a plurality of separate packaging or compartments including the reagent components used.
  • the present invention comprises the steps of: (a) measuring the expression level of any one or more proteins selected from the group consisting of HS3ST2 and CAPG from a sample isolated from the patient or the mRNA expression level of a gene encoding the same; And (b) applying the expression level of the protein or the mRNA expression level of the gene encoding the same to a support vector machine (SVM) algorithm model; to provide.
  • SVM support vector machine
  • Example 1 For screening biomarkers for predicting prognosis of chronic liver disease Sample preparation
  • NASH non-alcoholic fatty liver disease
  • Example 2 Analysis of total RNA-seq raw data for screening biomarkers for predicting prognosis of chronic liver disease
  • RNA-seq raw data (.fastq) and to improve it, the results were obtained using Trim Galore.
  • the quality of the read was internally checked with FastQC, and the low-quality read or the remaining adapter seq was removed with Cutadapt.
  • the STAR alignment tool was used to align the read to the reference human genome.
  • the result file (.bam) aligned with the Reference was obtained as a result file (.bam) from which duplication was removed using the Picard mark duplication tool.
  • samples are grouped into fatty liver disease, NASH-F1, and NASH-F2, and cuffdiff is performed to compare and analyze the expression levels of each group and sample at the gene level. A normalized result was obtained.
  • DEG differentially expressed genes
  • CummeRbund was performed. In CummeRbund, the gene expression levels of all genes for each group, including steatosis, NASH-F1, and NASH-F2 as groups, and the gene expression levels of a total of 28 replicates were obtained as FPKM values, respectively.
  • Conditions for selecting markers capable of predicting the prognosis at the stage of disease progression were set for a total of 26,000 genes of the human genome thus obtained.
  • genes that can give meaning to the analysis of expression levels among all genes were selected in two steps.
  • the difference in expression levels between groups is significant as 1 p-value of .05 or less, 2 select genes expressing more than FPKM, and 3
  • the average of the FPKM values of replication at each stage> Standard deviation was given, and the difference in expression levels between groups at each stage was 1.3 times or more.
  • a filtering process was performed to select genes whose liver variation did not exceed the expression level value.
  • the PODN (podocan) gene, which is known to have a low level of expression in normal liver, as a gene that has not been published in a paper related to liver disease and has not been found to be associated with other tumors.
  • the PODN is a gene expressed in adipose tissue and may be used to diagnose non-alcoholic steatohepatitis.
  • the 38 genes of the present invention can be used to predict the progression of liver cirrhosis or liver cancer in the future through prediction of the prognosis of non-alcoholic steatohepatitis that transitions from NASH-F1 to NASH-F2.
  • Example 3 Preparation of samples for screening biomarkers for determining the progression stage of chronic liver disease
  • NASH non-alcoholic fatty liver disease
  • the samples of the NASH stage were divided into stages F0, F1, F2, F3, and F4 according to the stage of liver fibrosis, and stages F3 and F4 were grouped into NASH, and the fatty liver disease group and the NASH group were divided based on histological analysis.
  • Example 4 Analysis of total RNA-seq raw data for screening biomarkers for discriminating the progression stage of chronic liver disease
  • RNA-seq raw data (.fastq) and to improve it, the results were obtained using Trim Galore.
  • the quality of the read was internally checked with FastQC, and the low-quality read or the remaining adapter seq was removed with Cutadapt.
  • the STAR alignment tool was used to align the read to the reference human genome.
  • the result file (.bam) aligned with the Reference was obtained as a result file (.bam) from which duplication was removed using the Picard mark duplication tool.
  • the samples (.bam) are grouped into fatty liver disease and NASH, and cuffdiff is performed to compare and analyze the expression levels of each group and sample at the gene level. The results were obtained.
  • the average value of expression in the fatty liver disease or NASH group of training et is 0.5 or more
  • 2 The average value of expression in each group is greater than the standard deviation
  • 3 3342 genes with a difference of at least 1.3 times or more in the average expression level between groups were first selected, sigFeature(Significant Feature Selection by Using SVM-RFE & t-statistic), genes showing characteristic expression patterns in the two groups were ranked.
  • the method calculates whether each 3342 genes in the training data set can accurately distinguish between steatosis and NASH, that is, the order of importance of genes based on the SVM-RFE algorithm.
  • the characteristic genes were applied to the linear kernel-based SVM algorithm starting from the 1st place to the nth place to establish an SVM model capable of distinguishing between steatohepatitis and non-alcoholic steatohepatitis.
  • the SVM classification technique maps all features present in a sample to each vector, obtains a linear classification axis between them, and creates a model that can classify based on this axis. It can be said that the modeling process of the SVM classifier is to vectorize using all the gene expression levels in the training data and to find the most suitable linearity that can be divided into two groups of steatosis and NASH.
  • the testing set was input to the SVM model thus created and the accuracy was confirmed, it was confirmed that the classification accuracy was highest when a classification model was created using the top two genes, HS3ST2 and CAPG.

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Abstract

La présente invention concerne une composition de biomarqueur pour prédire le pronostic ou déterminer le stade d'une maladie hépatique chronique. La présente invention réalise une analyse totale RNA-seq sur des tissus de patients atteints de stéatose et de stéatohépatite non alcoolique, et identifie 38 gènes dont l'expression est particulièrement élevée pendant la progression de la maladie, de la stéatose à la stéatohépatite non alcoolique. La présente invention sélectionne des gènes présentant un motif d'expression caractéristique, et construit un modèle de classification capable de distinguer entre la stéatose et la stéatohépatite non alcoolique à l'aide desdits gènes. Par conséquent, la présente invention confirme que la stéatose et la stéatohépatite non alcoolique peuvent être classifiées avec une grande précision. En conséquence, les gènes peuvent être utilisés en tant que biomarqueurs pour prédire le pronostic d'une maladie hépatique chronique ou en tant que biomarqueurs pour la classification de la stéatose et de la stéatohépatite non alcoolique, et le développement d'une thérapie génique ou d'autres médicaments inhibant l'expression ou l'activité des gènes peuvent améliorer l'efficacité de traitement d'une maladie hépatique chronique.
PCT/KR2020/015618 2019-11-20 2020-11-09 Composition de biomarqueur pour prédire un pronostic ou déterminer un stade de progression d'une maladie hépatique chronique WO2021101146A1 (fr)

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KR1020190149638A KR102341336B1 (ko) 2019-11-20 2019-11-20 만성간질환의 예후 예측용 바이오마커 조성물
KR1020190149639A KR102288299B1 (ko) 2019-11-20 2019-11-20 만성간질환의 진행 단계 판별용 바이오마커 조성물

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Cited By (1)

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CN110229903A (zh) * 2019-06-25 2019-09-13 台州市立医院 Podn作为诊断甲状腺癌的分子标志物

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