CN111999499A - Marker for predicting nasopharyngeal carcinoma metastasis risk and application thereof - Google Patents
Marker for predicting nasopharyngeal carcinoma metastasis risk and application thereof Download PDFInfo
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- CN111999499A CN111999499A CN202010500034.2A CN202010500034A CN111999499A CN 111999499 A CN111999499 A CN 111999499A CN 202010500034 A CN202010500034 A CN 202010500034A CN 111999499 A CN111999499 A CN 111999499A
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- 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
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
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- 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
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
- G01N33/57488—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds identifable in body fluids
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/50—Determining the risk of developing a disease
Abstract
The invention discloses a group of plasma protein markers for predicting nasopharyngeal carcinoma metastasis risk and application thereof. Markers include SLAMF5, ESM-1, MMP-8, INSR, Serpin A5. The protein label formed by the expression of 5 proteins can reflect the biological specificity of a nasopharyngeal carcinoma patient, can more accurately predict the transfer risk and prognosis of the nasopharyngeal carcinoma patient, better guide clinical medication, and has better prediction efficiency on no-distant survival than single protein, tumor N stage and EBV-DNA level.
Description
Technical Field
The invention relates to the technical field of biomarkers, in particular to a group of markers for predicting nasopharyngeal carcinoma metastasis risk and application thereof.
Background
Nasopharyngeal carcinoma (NPC) is an invasive head and neck malignancy, with about 40% of cases occurring worldwide in China, and the highest incidence in south China, in particular Guangdong province. The nasopharyngeal carcinoma is more severe than that in young and strong years, 70 percent of patients belong to middle and late stages when being treated for the first time, heavy burden is brought to families of the patients, and serious threat is brought to life health of people in China. In recent years, with the application of modern imaging technology, the progress of radiotherapy technology and the application of chemoradiotherapy comprehensive treatment strategy, the local control rate of nasopharyngeal carcinoma is obviously improved, and distant metastasis becomes a main mode of treatment failure. According to literature reports, the distant metastasis rate of patients with nasopharyngeal carcinoma after primary-diagnosis radical treatment is as high as 30-40%, and metastatic patients with nasopharyngeal carcinoma have poor responsiveness to treatment and poor prognosis, wherein the survival period is about 12 months, and the 3-year survival rate is less than 10%.
At present, the prediction of distant metastasis of nasopharyngeal carcinoma is mainly based on the clinical stage of TNM, (T is primary focus, N is lymph node, M is distant metastasis), wherein the risk of distant metastasis of nasopharyngeal carcinoma patients is mainly predicted by N stage, i.e. lymph node stage. Recently, researches show that the EB virus DNA load of peripheral blood before treatment (nasopharyngeal carcinoma in high incidence area is closely related to EB virus infection) also has a certain function of predicting the metastasis of patients with nasopharyngeal carcinoma. However, patients with similar EBV levels during the same period and before treatment also showed a large difference in the presence or absence of metastasis after receiving the same standard of treatment. Clearly, TNM clinical staging and pre-treatment EBV-DNA levels based solely on anatomical information do not provide a completely accurate prediction of the risk and prognosis of metastasis in nasopharyngeal carcinoma patients. Meanwhile, the EBV-DNA level of TNM in clinical staging and before treatment cannot be well used for guiding personalized medication, so that the chemotherapy effective rate of the existing metastatic nasopharyngeal carcinoma patients is only 40-65%, and the chemotherapy has large toxic and side effects. How to effectively guide clinical medication according to the phenotype of the patient has very important significance.
The nasopharyngeal carcinoma patients with the metastatic potential are screened, so that the prediction is carried out in advance and effective treatment is given, and the prognosis of the part of patients can be obviously improved.
Disclosure of Invention
It is an object of the first aspect of the present invention to provide a panel of markers for predicting the risk of metastasis of nasopharyngeal carcinoma.
The second aspect of the present invention is to provide the use of a reagent for quantifying the expression level of the above-mentioned marker or its product in the preparation of a detection reagent for predicting the risk of nasopharyngeal carcinoma metastasis.
The technical scheme adopted by the invention is as follows:
in a first aspect of the invention, there is provided a set of markers for predicting the risk of nasopharyngeal carcinoma metastasis, the set of markers comprising SLAMF5, ESM-1, MMP-8, INSR, Serpin A5.
The marker according to the first aspect of the present invention, which consists of SLAMF5, ESM-1, MMP-8, INSR, Serpin A5.
Preferably, the marker according to the first aspect of the present invention, the scoring formula for predicting the risk of metastasis of nasopharyngeal carcinoma is determined according to the LASSO-Cox model.
More specifically, according to the marker of the first aspect of the present invention, the scoring formula is: the score is (0.0208 × SLAMF5 expression level) + (0.1039 × ESM-1 expression level) + (0.1761 × MMP-8 expression level) + (0.0161 × INSR expression level) + (0.3738 × Serpin a5 expression level).
Still further, according to the marker of the first aspect of the present invention, the expression amount log2 is converted, and further, the unit is (pg/ml).
In a second aspect of the present invention, there is provided a use of a reagent for quantifying the expression level of a marker in the preparation of a detection reagent for predicting the risk of metastasis of nasopharyngeal carcinoma, wherein the marker is as defined in the first aspect of the present invention.
According to the use of the second aspect of the present invention, the reagent for quantifying the expression level of the marker is a reagent for quantitatively detecting a protein.
Preferably, the reagent for quantifying the expression level of the marker is a reagent for quantitatively detecting proteins in blood plasma.
More preferably, according to the use of the second aspect of the present invention, the protein quantitative determination reagent is selected from the group consisting of: ELISA reagent and protein quantitative chip.
According to the second aspect of the invention, the scoring formula for predicting nasopharyngeal carcinoma metastasis risk by using the quantitative marker or the expression amount of the product thereof is determined according to a LASSO-Cox model.
According to the second aspect of the present invention, the scoring formula of the reagent for quantifying expression level of the marker or its product for predicting nasopharyngeal carcinoma metastasis risk is as follows: the score is (0.0208 × SLAMF5 expression level) + (0.1039 × ESM-1 expression level) + (0.1761 × MMP-8 expression level) + (0.0161 × INSR expression level) + (0.3738 × Serpin a5 expression level).
Further, according to the use according to the second aspect of the present invention, the expression level is log2 transformed, further, in units of (pg/ml).
The invention has the beneficial effects that:
the protein label formed by the expression of 5 screened proteins can reflect the biological specificity of the nasopharyngeal carcinoma patient, can more accurately predict the transfer risk and prognosis of the nasopharyngeal carcinoma patient, better guide clinical medication, and has better prediction efficiency on no-distant survival than single protein, tumor N stage and EBV-DNA level.
Drawings
FIG. 1: K-M survival analysis showed that the PSDM high risk group of nasopharyngeal carcinoma patients (a) survived without distant metastasis, (B) survived without disease, and (C) survived overall.
FIG. 2: forest plots show single-factor and multifactorial Cox analyses, with PSDM being an independent prognostic factor for distant metastasis-free survival, disease-free survival, and overall survival in patients with nasopharyngeal carcinoma.
FIG. 3: time-dependent ROC and AUC analyses showed that (a) time-dependent ROC curves at 5-year time points showed that PSDM was more potent than each individual protein in predicting distant metastasis of nasopharyngeal carcinoma, (B) time-dependent AUC analyses over 7 years showed that PSDM was more potent than each individual protein in predicting distant metastasis of nasopharyngeal carcinoma, (C) time-dependent ROC curves at 5-year time points showed that PSDM was more potent than tumor stage N and pre-treatment EBV-DNA levels, and (D) time-dependent AUC analyses over 7 years showed that PSDM was more potent than tumor stage N and pre-treatment EBV-DNA levels.
FIG. 4: K-M survival analysis showed that depending on whether PSDM cohort nasopharyngeal carcinoma patients received a prognosis for TPF-induced chemotherapy (a) distant metastasis-free survival in low risk group, (B) disease-free survival in low risk group, (C) overall survival in low risk group, (D) distant metastasis-free survival in high risk group, (E) disease-free survival in high risk group, (F) overall survival in high risk group.
Detailed Description
In order to clearly understand the technical contents of the present invention, the following embodiments are described in detail with reference to the accompanying drawings. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally followed by conventional conditions, such as Sambrook et al, molecular cloning: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer's recommendations. The various chemicals used in the examples are commercially available.
Case screening:
the inventors selected 228 patients as plasma samples of non-metastatic primary treated locally advanced nasopharyngeal carcinoma patients who received radical radiation therapy. Of these, 93.4% of patients (211 cases) received concurrent cisplatin-based chemotherapy. Following the 87.5 month visit, 41 of them had metastases during the follow-up period.
The inventor adopts a Raybiotechniquody Human Kiloplex proteins Array high-throughput protein chip to detect 1000 angiogenesis, immunity, inflammation and other related proteins in a primary diagnosis plasma specimen of a nasopharyngeal carcinoma patient with 8 high transfer risks (no transfer in the primary diagnosis, but distant transfer after radical treatment) and 8 low transfer risks (no transfer in the primary diagnosis, and no transfer and relapse in follow-up visit after radical treatment), and obtains 50 differential proteins by screening.
Example 1 screening of markers
Determining proteins associated with metastasis-free survival of nasopharyngeal carcinoma:
the inventor utilizes a customized Raybiotechnology Array protein chip technology platform to detect the 50 differentially expressed genes in 226 samples, and utilizes single-factor Cox analysis to screen out 18 plasma proteins related to the non-distant metastasis survival of nasopharyngeal carcinoma.
Discovery of nasopharyngeal carcinoma metastasis protein markers:
the inventors further selected 5 proteins to constitute a set of markers using the LASSO-Cox model, including: SLAMF5, ESM-1, MMP-8, INSR, Serpin A5, and this 5 protein markers were named PSDM (protein-based signature for discrete metastasis in LA-NPC, distant metastasis protein signature for locally advanced nasopharyngeal carcinoma).
The scoring formula of the marker for predicting the nasopharyngeal carcinoma metastasis risk is as follows:
the PSDM score formula is (0.0208 × SLAMF5 expression) + (0.1039 × ESM-1 expression) + (0.1761 × MMP-8 expression) + (0.0161 × INSR expression) + (0.3738 × Serpin a5 expression). In the formula, the expression amount is measured by a Raybiotech human protein antibody chip, and is subjected to standardization and log2 conversion, and the unit is (pg/ml).
Using the value (7.6030) at which the sum of sensitivity and specificity of the time-dependent ROC curve at the 5-year time point curve is maximal as a threshold, thereby classifying 81 (35.8%) patients into a high risk group and 145 (64.2%) patients into a low risk group; the five-year survival rate for distant metastasis in both patients was 64.2% in the high risk group (95% CI confidence interval 54.5-75.5) and 94.41% in the low risk group (95% confidence interval 90.6-98.2; HR risk ratio 5.94, 95% CI 2.97-11.86; P < 0.001; FIG. 1A). Disease-free survival (HR 2.78, 95% CI 1.70-4.53; P < 0.001; FIG. 1B) and overall survival (HR 3.22, 95% CI 1.64-5.62; P < 0.001; FIG. 1C) were poor in the high risk group compared to the low risk group. The inventors further performed one-and multifactorial Cox analyses, showing that PSDM is an independent prognostic factor for the survival of locally advanced nasopharyngeal carcinoma patients without distant metastasis (P < 0.001; fig. 2).
Example 2 potency assay for protein markers
The inventors subsequently compared the efficacy of combinations of protein markers to predict distant metastasis of nasopharyngeal carcinoma to individual proteins as well as N stage, EBV-DNA levels. The time-dependent ROC curve shows that at the 5 year time point the potency of the protein marker combination is better than that of each individual protein (C-index:0.76, 95% CI 0.67-0.85; P < 0.05; FIG. 3A), while the time-dependent AUC analysis shows that over a continuous 7 year time span the potency of the protein marker combination is always better than that of each individual protein (P < 0.05; FIG. 3B). Similarly, we also found that protein markers predicted the efficacy of nasopharyngeal carcinoma metastasis better than both N-staging and pre-treatment EBV-DNA levels at both the 5-year time point and at consecutive times (P < 0.05; FIGS. 3C-D).
In addition, the inventors also analyzed whether DMGN could predict the benefit of docetaxel + cisplatin + 5-fluorouracil (TPF) induced chemotherapy in patients with nasopharyngeal carcinoma. Of the 226 patients, 42 nasopharyngeal carcinoma patients receiving TPF-induced chemotherapy and cisplatin concurrent chemoradiotherapy and 42 patients receiving cisplatin concurrent chemoradiotherapy alone matched to their sex, age, T-staging, N-staging, EBV-DNA level and technique of receiving radiotherapy were selected using a bias match. Analysis showed that patients in the low risk group received TFP-induced chemotherapy with no statistical difference in survival outcome (DMFS: HR 0.59; 95% CI 0.10-3.54; P ═ 0.59; DFS: HR 0.37; 95% CI 0.11-1.22; P ═ 0.089; OS: HR 0.35; 95% CI 0.07-1.83; P ═ 0.194; fig. 4A-C); patients in the high risk group received TPF-induced chemotherapy with no distant metastasis (HR 0.21; 95% CI 0.05-0.92; P ═ 0.023; fig. 4D), disease-free survival (HR 0.27; 95% CI 0.08-0.95; P ═ 0.029; fig. 4E) and overall survival (HR 0.13; 95% CI 0.02-0.99; P ═ 0.019; fig. 4F) were all significantly improved.
In conclusion, the protein label formed by the expression of the 5 proteins can reflect the biological specificity of the nasopharyngeal carcinoma patient, can more accurately predict the transfer risk and prognosis of the nasopharyngeal carcinoma patient, better guide clinical medication, and has better prediction efficiency on the non-distant survival than the single protein, the tumor N stage and the EBV-DNA level.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.
Claims (10)
1. A set of markers for predicting the risk of nasopharyngeal carcinoma metastasis, said set of markers comprising SLAMF5, ESM-1, MMP-8, INSR, Serpin A5.
2. The marker of claim 1, wherein the panel of markers consists of SLAMF5, ESM-1, MMP-8, INSR, and Serpin a 5.
3. The marker according to claim 1 or 2, wherein the scoring formula for predicting nasopharyngeal cancer metastasis risk is determined according to LASSO-Cox model.
4. A marker according to claim 3, wherein the scoring formula is: the score is (0.0208 × SLAMF5 expression level) + (0.1039 × ESM-1 expression level) + (0.1761 × MMP-8 expression level) + (0.0161 × INSR expression level) + (0.3738 × Serpin a5 expression level).
5. The marker according to claim 4, wherein the scoring formula is characterized in that the expression level is log2 transformed. .
6. Use of a reagent for quantifying the expression level of a marker in the preparation of a test reagent for predicting the risk of metastasis of nasopharyngeal carcinoma, wherein said marker is according to claim 1 or 2.
7. The use according to claim 6, wherein the reagent for quantifying the expression level of the marker is a reagent for quantitatively detecting a protein.
8. The use of claim 6, wherein the quantitative marker or the expression level of the product thereof is determined by a scoring formula for predicting nasopharyngeal cancer metastasis risk according to LASSO-Cox model.
9. The use of claim 6, wherein the quantitative marker or the expression level of the product thereof is used for predicting nasopharyngeal carcinoma metastasis risk by a scoring formula: the score is (0.0208 × SLAMF5 expression level) + (0.1039 × ESM-1 expression level) + (0.1761 × MMP-8 expression level) + (0.0161 × INSR expression level) + (0.3738 × Serpin a5 expression level).
10. The use of claim 9, wherein the scoring formula is characterized by a log2 transformation of the expression.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040167067A1 (en) * | 2002-07-01 | 2004-08-26 | David Griggs | ESM-1 gene differentially expressed in angiogenesis, antagonists thereof, and methods of using the same |
| US20110236314A1 (en) * | 2008-09-12 | 2011-09-29 | Cancer Research Initiatives Foundation | Method of detection and diagnosis of oral and nasopharyngeal cancers |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040167067A1 (en) * | 2002-07-01 | 2004-08-26 | David Griggs | ESM-1 gene differentially expressed in angiogenesis, antagonists thereof, and methods of using the same |
| US20110236314A1 (en) * | 2008-09-12 | 2011-09-29 | Cancer Research Initiatives Foundation | Method of detection and diagnosis of oral and nasopharyngeal cancers |
Non-Patent Citations (3)
| Title |
|---|
| DAOYUAN GONG ET AL: "Extensive serum biomarker analysis in patients with nasopharyngeal carcinoma", 《CYTOKINE》 * |
| KAI-PING CHANG ET AL: "MULTIPLEXED IMMUNOBEAD-BASED PROFILING OF CYTOKINE MARKERS FOR DETECTION OF NASOPHARYNGEAL CARCINOMA AND PROGNOSIS OF PATIENT SURVIVAL", 《HEAD & NECK》 * |
| 张文玲等: "鼻咽癌分子标志物研究", 《生物化学与生物物理进展》 * |
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