CN110244057A - ADORA3 is preparing the application in high-level serous ovarian cancer diagnosis and prognosis kit - Google Patents
ADORA3 is preparing the application in high-level serous ovarian cancer diagnosis and prognosis kit Download PDFInfo
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- CN110244057A CN110244057A CN201910497333.2A CN201910497333A CN110244057A CN 110244057 A CN110244057 A CN 110244057A CN 201910497333 A CN201910497333 A CN 201910497333A CN 110244057 A CN110244057 A CN 110244057A
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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
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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
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Abstract
The invention discloses application of the reagent of detection ADORA3 albumen in the kit for preparing high-level serous ovarian cancer diagnosis, chemosensitivity and Index for diagnosis, belong to molecular biology and field of biomedicine technology.The present invention is using ADORA3 albumen as the marker of diagnosis, treatment and Index for diagnosis, negative or weak expression is expressed as in normal ovarian tissue and ovarian serous cystadenoma according to ADORA3, it but is highly expressed in high-level serous ovarian cancer, and the drug resistance and prognostic indicator of this expression intensity and clinical treatment are closely related, the high-level serous ovarian cancer of antidiastole can be assisted, and high-level serous ovarian cancer therapeutic effect and prognosis are judged.Simultaneously according to the correlation between different expression intensities and high-level serous ovarian cancer prognosis, layered shaping is carried out to patient, theoretical foundation is provided to develop more effective Individual Chemotherapy drug, there is important clinical application and drug development to be worth.
Description
Technical field
The present invention relates to molecular biology and field of biomedicine technology, and in particular to the reagent of detection ADORA3 albumen exists
Prepare the application in the kit of high-level serous ovarian cancer diagnosis, chemosensitivity and Index for diagnosis.
Background technique
There are about 240,000 women to be diagnosed with oophoroma every year in the whole world, and the death rate is almost three times of breast cancer, III phase
Or 5 years survival rates of IV phase patient make oophoroma become most fatal gynecologic malignant tumor less than 25%.It is big that oophoroma is divided into three
Class: cell carcinoma, germinocarcinoma and specific Leydig's cell tumor.Most oophoromas are ovarian epithelial carcinomas
(Epithelial ovarian cancers, EOCs), ovarian epithelial carcinoma are broadly divided into two big organization types: I type and II type
Tumour.I type tumour includes various low level serosities, mucus, endometrial-like, clear cell carcinoma, is often slow-growing, and is led to
Often from identifiable precancerous lesion.In contrast, the characteristics of II type tumour is high-level and rapid progress disease.It is high-level
Serous ovarian cancer (Highgrade serous ovarian carcinoma, HGSOC) is the most common II type tumour, is accounted for about
The 75% of all oophoromas.Unfortunately, it is also most invasive.There is presently no early stage effective and that specificity is high is pre-
Survey the index and method of high-level serous ovarian cancer.Lack intraperitoneal extensive diffusive shifts even if tumour cell special
Anisotropic symptom and can not early detection and diagnosis, therefore, most of women initial diagnosis be oophoroma when proceeded to disease
Advanced stage, prognosis are very poor.Wherein DISTANT METASTASES IN and treatment after recurrence be clinical therapeutic efficacy difference basic reasons.
Oophoroma is a kind of complex disease caused by multifactor polygenes comprehensive function, each organization type has not
There is also the differences of Molecular Origin inside same molecular level origin or even same organization type.This leads to molecule and thin
There is a world of difference for born of the same parents' behavior, clinical manifestation and prognosis, and at present clinic can only according to pathological staging as therapeutic scheme with
Index for diagnosis foundation, this foundation are to completely disengage molecular biology mechanism, can not provide effective layering personalized treatment
Cytology behavior judgment basis, causes diagnostic and therapeutic effects unsatisfactory.Being badly in need of more accurately marker in real work will
Patient is divided into high risk and low-risk type, so as to take effective personalized therapy program, improves therapeutic effect, improves
Prognosis.
The molecular marked compound of oophoroma includes the molecule of two kinds of levels, nucleic acid and protein at present.Nucleic acid marker packet
It includes gene copy number variation (CNV), microsatellite instability (MSI), base mutation (Mutation), single nucleotide polymorphism
(SNP) etc., research in recent years also includes the change of miRNA, but these major parts can only be as the early warning of susceptibility, and carefully
The correlation of born of the same parents' behavior greatly differs from each other, and clinical value is little.Protein is the final product of gene expression, can directly be played
Function changes the biological behaviour of cell and the direct reaction to ambient enviroment, such as the occurrence and development of tumour, to treatment means
Reaction, therefore the research achievement of protein level can directly and effectively provide with clinical guidance value molecular labeling,
Meet the classification diagnosis of oophoroma molecular level and the needs of Index for diagnosis, personalized treatment and improvement prognosis tool to oophoroma
There is important value.But there has been no specific effective research achievements so far, are unable to reach the specificity and essence of clinical needs
Parasexuality.
Adenosine receptor subtypes belong to g protein coupled receptor (GPCR) family, participate in signal path and physiology in various kinds of cell
Function.Adenosine A 3 receptor (ADORA3) inhibits adenyl cyclase, reduces cAMP's in conjunction with the inhibition subunit of GPCR (Gi)
It generates.Adenosine receptor can express in different tissues, have different physiological and pathological roles, participate in inhibiting tissue damage
In neutrophil leucocyte threshing, participate in protection and the neurodegeneration of nerve, it is also possible to mediated cell proliferation and dead.There is text
It offers and is reported in non-small cell lung cancer, breast cancer and leukaemia cell that there are unconventionality expressions of ADORA3 albumen, and p53 etc.
The action pathway of tumor suppressor gene is related, plays an important role in the occurrence and development of tumour.But so far there is not yet in height
Research in rank serous ovarian cancer.
Summary of the invention
It is an object of the invention to study the difference of ADORA3 albumen expression quantity in high-level serous ovarian cancer, distinguish
Out between the prognostic indicators such as ADORA3 variable expression and high-level serous ovarian cancer clinical stages, pathological grading and chemotherapy is quick
The correlation of perception illustrates ADORA3 protein expression high-level serous ovarian cancer is pathogenic, clinical diagnosis and prognosis are sentenced
Its application in the detection of clinical practice kit is finally unfolded in effect and application value in disconnected.
To achieve the above object, the present invention uses following technology path and scheme:
The present invention is had detected first in normal ovarian tissue, ovarian serous cystadenoma and high-level serous ovarian cancer
The expression of ADORA3 albumen, discovery ADORA3 expression quantity in high-level serous ovarian cancer be apparently higher than normal ovarian tissue and
Ovarian serous cystadenoma tissue has significant statistical difference.
The present invention simultaneously to the Serum tumor marker CA125 of high-level serous ovarian cancer patient, ascites volume, longest diameter of tumor,
FIGO by stages, cell differentiation grade and chemosensitivity carried out chromatographic analysis, ADORA3 protein expression is higher as the result is shown
The easier chemotherapy resistance of patient, prognosis are also poorer.
In summary analysis as a result, the present invention provides ADORA3 as high-level serous ovarian cancer clinic auxiliary examine
The application value of the protein marker of disconnected, chemosensitivity and Index for diagnosis.
By expression quantity of the detection ADORA3 albumen in cancerous tissue, can diagnosis to high-level serous ovarian cancer,
Chemosensitivity and prognosis are judged, comprising: the Clinical differential diagnosis of high-level serous ovarian cancer, high-level serosity ovum
Nest cancer chemotherapy is likely to occur drug resistance and is assessed in advance, to the better personalized chemotherapeutic regimens of patient of high expression ADORA3 albumen
Theoretical foundation is provided, preferably layering treatment, the final prognosis for improving patient are carried out to high-level serous ovarian cancer.
Therefore, the present invention provides the reagents of detection ADORA3 albumen examines prepare high-level serous ovarian cancer and identify
Application in the kit of disconnected, chemosensitivity and Index for diagnosis.
The reagent of the detection ADORA3 albumen is the antibody of anti-ADORA3 albumen.
Preferably, the reagent of the detection ADORA3 is ADORA3 rabbit anti-human polyclonal antibody.
The antidiastole includes: the antidiastole of high-level serous ovarian cancer or ovarian serous cystadenoma；It is described
Chemosensitivity and Index for diagnosis include: the assessment of high-level serous ovarian cancer chemosensitivity and disease prognosis superiority and inferiority.
As the clinical detection application of the above protein molecular marker, the present invention provides one kind to be used for high-level serosity
Oophoroma antidiastole, chemosensitivity and Index for diagnosis kit, detect high-level serous ovarian cancer ADORA3 albumen
Expression quantity, to high-level serous ovarian cancer Clinical differential diagnosis, chemotherapy resistance may and prognosis prejudge.
The kit includes: the rabbit anti-human polyclonal antibody and immunohistochemistry skill that specificity is directed to ADORA3 albumen
The general secondary antibody and colour reagent that art needs.
Immunohistochemistry reagent includes: lowlenthal serum confining liquid, 0.01M citrate antigen retrieval buffers, 3%H2O2Peroxidating
Goat-anti rabbit secondary antibody, DAB colour reagent and the TBS solution of object enzyme blocking agent, HRP label.
Based on mentioned reagent box, the present invention provides a kind of immunohistochemical method and standards of grading, including walk as follows
It is rapid:
Ovary tissue sample to be measured is fixed through formalin, is dehydrated, paraffin embedding and be sliced obtain histotomy, then
It carries out immunohistochemical staining, micro- sem observation diagosis and carries out scoring and statistical analysis.
Specifically, acquisition tissue specimen of performing the operation is fixed through formalin and specimens paraffin embedding slices, then carries out aquation, antigen
It repairs, after hydrogen peroxide deactivation endogenous peroxydase and serum closing, ADORA3 rabbit anti-human polyclonal antibody is in room temperature item
It is incubated for 60 minutes under part, after TBS is flushed three times and secondary antibody was in room temperature reaction 15 minutes, and horseradish peroxidase label is incubated for, and DAB is aobvious
Color, haematoxylin are redyed, resinene fragment after last dehydration of alcohol, dimethylbenzene are transparent.The scoring of optical microphotograph sem observation.
According to positive cell percentage and staining power (400 times of lower 10 random fields), according to following standards of grading pair
ADORA3 protein expression carries out semi-quantitative assessment.Negative staining is defined as 0 point, and faint yellow to dye 1 point to be weak, isabelline is middle dye
Color 2 divides, and buff is strong 3 points of dyeing.When scoring the percentage of positive cell, < 5% is defined as 0 point, < 25% definition
It is 1 point,<75% is defined as 2 points, and>75% is defined as 3 points.Two scorings obtain semi-quantitative analysis result after being added, as follows: yin
Property-(0 point), and weakly positive+(1-2 point), moderate positive ++ (3-4 points) and strong positive +++ (5-6 points).
Show that ADORA3 expresses essentially feminine gender in normal ovarian tissue according to experimental result, in ovarian serous capsule gland
Tumor expression majority is that negative a small number of cases are weakly positive, and are expressed as moderate positive most of in high-level serous ovarian cancer
And strong positive.
Therapeutic effect and Index for diagnosis method are as follows, and ADORA3 feminine gender and weakly positive patient's prognosis are preferable, and therapeutic effect is good,
Drug resistance possibility is low, and strong positive patient's conventional therapy effect and prognosis are worst, and it is very high a possibility that drug resistance occur.Moderate positive
The therapeutic effect and prognosis situation of patient falls between.
It is that the present invention has the utility model has the advantages that
The present invention studies expression of the ADORA3 albumen in high-level serous ovarian cancer for the first time, and discovery ADORA3 exists
Normal ovarian tissue and ovarian serous cystadenoma are expressed as negative or weak expression, but are in high-level serous ovarian cancer
It is highly expressed, and the drug resistance and prognostic indicator of this expression intensity and clinical treatment are closely related, the highly expressed trouble of ADORA3
Person's therapeutic effect is poor, is easy to appear drug resistance, and every prognostic indicator performance is poor, indicates poor prognosis.Therefore, the present invention is with ADORA3 egg
The white marker as diagnosis, treatment and Index for diagnosis provides a kind of for high-level serous ovarian cancer antidiastole, change
The kit for treating sensibility and Index for diagnosis, can assist the high-level serous ovarian cancer of antidiastole, and to high-level slurries
Property treatment of ovarian cancer effect and prognosis are judged.Simultaneously according to different expression intensities and high-level serous ovarian cancer prognosis
Between correlation, layered shaping is carried out to patient, theoretical foundation is provided to develop more effective Individual Chemotherapy drug, has
Important clinical application and drug development value.
Detailed description of the invention
Fig. 1 is ADORA3 albumen in normal ovarian tissue, ovarian serous cystadenoma and high-level serous ovarian cancer
Expression.
Specific embodiment
Below with reference to embodiment, the present invention is described in further detail, it should explanation, in embodiment below
The technology path and method of use are just for the sake of more fully understanding the present invention, but its content is not limited to the present invention.
If do not illustrated, specific experiment method involved in embodiment is conventional method, experiment examination used
Agent is the purchase of conventional reagent company.Wherein primary antibody ADORA3 rabbit anti-human polyclonal antibody is bought from Thermofisher company,
Cat.No:PA5-33326。
Embodiment 1:ADORA3 albumen is in normal ovarian tissue, ovarian serous cystadenoma and high-level serous ovarian cancer
The analysis of differential expression
One, research object:
Hospital for Gynaecology and Obstetrics Attached to Medical Hospital of Zhejiang's in January, 2004 is collected in December, 2010 normal ovarian tissue, ovum
Nest serous cystadenoma and high-level serous ovarian cancer sample tissue are 241 parts total.Sample includes 41 normal ovarian epitheliums
Tissue, 97 ovarian serous cystadenoma, 103 high-level serous ovarian cancers (including 6 I phases, 30 II phases, 62 III
Phase and 5 IV phases).Exclude the preoperative patient for receiving chemotherapy, immunization therapy or radiotherapy.All patients receive first hand
Art then receives the chemotherapy based on taxol.Following clinical indices: preoperative Serum tumor marker CA125, abdomen are collected for all patients
Water, longest diameter of tumor, FIGO by stages, cell differentiation grade, chemosensitivity.Occur during chemotherapy progressive disease or
The patient for completing to recur in 6 months after first chemotherapy treatment is confirmed as chemotherapy resistance.More than 6 months or without recurrence when recurrence
Patient is defined as chemosensitivity.
This invention is studied to obtain to be agreed to according to Ethics Committee, Hospital for Gynaecology and Obstetrics Attached to Medical Hospital of Zhejiang, and is followed
The guilding principle and regulations of approval carry out.
Two, experimental method:
2.1 tissue paraffin embedded sections:
1, it draws materials: after 10% formalin of fresh specimens tissue is fixed, tissue being taken out into purpose site tissue from fixer
Equating is whole to be put in dewatering box.
2, it is dehydrated: dewatering box successively being put into graded ethanol and is dehydrated.75% alcohol, 4 hours → 85% alcohol 2 hours
→ 90% alcohol 2 hours → 95% alcohol, 1 hour → dehydrated alcohol, I 30 minutes → dehydrated alcohol, II 30 minutes → alcohol benzene 5 minutes
I 10 minutes → dimethylbenzene of → dimethylbenzene, II 10 minutes → paraffin, I 1 hours → paraffin II 1 hours → paraffin III 1 hours.
3, it embeds: the wax of thawing being first put into embedding frame, be put into packet to take out tissue out of dewatering box before wax solidification
Frame is buried, is taken out after -20 DEG C of cooling wax solidifications, finishing wax stone.
4, be sliced: wax stone is placed on paraffin slicing machine and is sliced, and piece is 4 μm thick.Slice floats on the 40 DEG C of warm water of piece machine of booth will
Tissue flattening, is picked up tissue with glass slide, and is put into and baked piece in 60 DEG C of baking ovens, is taken out and is stored at room temperature after wax roastingization.
2.2 tissue dewaterings, antigen retrieval and endogenous peroxydase block
1, paraffin section is placed in 67 DEG C of baking ovens and dries piece 2 hours, dewaxes to water, is flushed three times with TBS (pH7.4), 3 points every time
Clock.
2,0.01M citrate buffer (pH=6.0) microwave heating puts the histotomy after above-mentioned aquation to boiling
Enter in the buffer to have boiled, microwave treatment 10 minutes, flowing water is naturally cool but, and distilled water flushing twice, finally rinses two with TBS
It is secondary.3 minutes every time.
3, every slice plus 1 drop 3%H2O2, it is incubated at room temperature 10 minutes, blocks endogenous peroxidase activity, rushed with TBS
It washes three times, 3 minutes every time.
The closing of 2.3 non-specific sites and primary antibody are incubated for
1, non-specific sites are closed: blotting the moisture on slice, add lowlenthal serum confining liquid, room temperature reaction 10 in wet box
Minute.
2, confining liquid is got rid of, primary antibody (1:1000) covering all tissues are added dropwise, are put into room temperature 60 minutes in wet box.
3, TBS is flushed three times, and three minutes every time.
2.4 DAKO EnVision System secondary antibodies label develops the color and redyes:
Used kit is the EnVision of DAKO companyTM+System,Peroxidase(DAKO EnVisionTM+
System), steps are as follows for specific experiment:
1, TBS is rinsed 10 minutes, and EnVision secondary antibody reaction solution (HRP label) is incubated for 15 minutes.
2, TBS is rinsed 10 minutes, two drop (100 microlitres or so) DAB solution is added dropwise, color development at room temperature is after five minutes under microscope
Observation, dyes suitable rear termination dyeing, and tap water rinses.
3, after distilled water rinsing, haematoxylin is redyed, and 1-2 minutes, nucleus, which became blue, to be terminated, tap water or TBS
Rinse anti-blue (can be anti-blue with 0.5%an water).
4, slice is dry through gradient alcohol dehydration, and dimethylbenzene is transparent, and neutral gum sealing is observed after drying.
Three, micro- sem observation and standards of grading:
Brown yellow granule occur on tumour cell slurry neutralization cell membrane is considered as positive mark.According to positive cell percentage
Than with staining power (400 times of lower 10 random fields), according to following standards of grading to ADORA3 protein expression carry out sxemiquantitative
Evaluation.Negative staining is defined as 0 point, and faint yellow to dye 1 point to be weak, isabelline to dye 2 points to be middle, buff dyes 3 points to be strong.
When scoring the percentage of positive cell,<5% is defined as 0 point, and<25% is defined as 1 point, and<75% is defined as 2 points,>
75% is defined as 3 points.Two scorings obtain semi-quantitative analysis result after being added, as follows: negative-(0 point), weakly positive+(1-2
Point), moderate positive ++ (3-4 points) and strong positive +++ (5-6 points).
Four, ADORA3 protein expression and normal ovarian tissue, ovarian serous cystadenoma and high-level serous ovarian cancer
Correlation analysis:
Based on experimental result, it has been found that ADORA3 albumen is mainly expressed on cell membrane and in cytoplasm, ADORA3 egg
It is weak that the white expression in normal ovarian tissue essentially feminine gender, which is negative a small number of cases in ovarian serous cystadenoma expression majority,
The positive, and moderate positive and strong positive are expressed as most of in high-level serous ovarian cancer.Data are examined through statistics card side
Find there is statistically-significant difference after testing.This result can be used for clinical serous carcinoma and serosity capsule gland to ovary origin
The antidiastole of tumor.Concrete outcome and analysis data are shown in Fig. 1 and table 1.
Table 1.ADORA3 albumen is in normal ovarian tissue, ovarian serous cystadenoma and high-level serous ovarian cancer
Expression
Note: # three comparison among groups；* two comparison among groups of normal ovarian epithelium and serous cystadenoma；* normal ovarian epithelium and
High-level two comparison among groups of serous carcinoma；Two comparison among groups of * * serous cystadenoma and high-level serous carcinoma.
The clinical prognostic factors and chemosensitivity that embodiment 2:ADORA3 albumen is expressed in high-level serous ovarian cancer
The chromatographic analysis of property
It is based on embodiment 1 as a result, clinical prognostic factors and chemosensitivity to high-level serous ovarian cancer therein
Property carry out correlation analysis, as the result is shown as the expression of the raising ENPP1 albumen of clinical stages and cell differentiation grade is more next
It is stronger, and express stronger patient and occur that a possibility that drug resistance is higher, this result prompts ADORA3 feminine gender and weakly positive to suffer from
Person's prognosis is preferable, and therapeutic effect is good, and drug resistance possibility is low, and strong positive patient's conventional therapy effect and prognosis are worst, occurs resistance to
A possibility that medicine, is very high.The therapeutic effect and prognosis situation of moderate positive patient falls between.Concrete outcome and analysis number
According to being shown in Table 2.
In the high-level serous ovarian cancer of table 2. between ADORA3 protein expression and clinical prognostic factors and chemosensitivity
Relationship
Underlined values show statistical data with significant difference.
Kendall's tau-b correlation coefficients(r)were applied by the
Bivariate
Correlation analysis.A P value less than 0.05 was considered
significant.
Applicant's statement: the above embodiment is a preferred embodiment of the present invention, read above content of the invention it
Afterwards, it is specific carry out detection when, other any changes made under theoretical essence and experimental principle of the invention or repair
It is whole, it should be equivalent replacement mode of the invention, also fall within protection scope of the present invention.
Claims (6)
1. the reagent for detecting ADORA3 albumen is sentenced preparing high-level serous ovarian cancer antidiastole, chemosensitivity and prognosis
Application in disconnected kit.
2. application as described in claim 1, which is characterized in that the reagent of the detection ADORA3 albumen is anti-ADORA3 albumen
Antibody.
3. application as claimed in claim 2, which is characterized in that the reagent of the detection ADORA3 is ADORA3 rabbit-anti people Duo Ke
Grand antibody.
4. application as described in claim 1, which is characterized in that the antidiastole include: high-level serous ovarian cancer or
The antidiastole of ovarian serous cystadenoma；The chemosensitivity and Index for diagnosis include: high-level serous ovarian cancer
Treat the assessment of sensibility and disease prognosis superiority and inferiority.
5. a kind of for high-level serous ovarian cancer antidiastole, the kit of chemosensitivity and Index for diagnosis, feature
It is, including ADORA3 rabbit anti-human polyclonal antibody.
6. as claimed in claim 5 for high-level serous ovarian cancer antidiastole, chemosensitivity and Index for diagnosis
Kit, which is characterized in that further include: lowlenthal serum confining liquid, 0.01M citrate antigen retrieval buffers, 3%H2O2Peroxidating
Goat-anti rabbit secondary antibody, DAB colour reagent and the TBS solution of object enzyme blocking agent, HRP label.
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| CN108508212A (en) * | 2018-04-19 | 2018-09-07 | 山东大学齐鲁医院 | The marker of high-level serous ovarian cancer targeted therapy and Index for diagnosis |
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2019
- 2019-06-10 CN CN201910497333.2A patent/CN110244057B/en not_active Expired - Fee Related
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| WO2004086034A2 (en) * | 2003-03-28 | 2004-10-07 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with g-protein-coupled receptor adenosine a3(adora3) |
| CN106771248A (en) * | 2016-12-30 | 2017-05-31 | 山东大学齐鲁医院 | High-level serous ovarian cancer diagnosis and/or the mark of Index for diagnosis |
| CN106771248B (en) * | 2016-12-30 | 2018-05-15 | 山东大学齐鲁医院 | High-level serous ovarian cancer diagnosis and/or the marker of Index for diagnosis |
| CN108508212A (en) * | 2018-04-19 | 2018-09-07 | 山东大学齐鲁医院 | The marker of high-level serous ovarian cancer targeted therapy and Index for diagnosis |
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