CN101852805B - Application of ANGPTL3 as diagnostic marker of ovarian cancer - Google Patents
Application of ANGPTL3 as diagnostic marker of ovarian cancer Download PDFInfo
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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
- G01N33/57449—Specifically defined cancers of ovaries
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Abstract
The invention provides a method for diagnosing ovarian cancer in a tested person, which comprises the following steps of: detecting the content of ANGPTL3 in a sample from the tested person, analyzing the ANGPTL3 content and determining whether the tested person suffers from the ovarian cancer or not according to an analysis result. The invention also provides a reagent kit for ovarian cancer diagnosis.
Description
Technical field
The invention belongs to field of biomedicine technology.Specifically, the present invention relates to and a kind ofly improve the method for sample classification accuracy and a kind of kit for detecting ANGPTL3 albumen in sample.
Background technology
Ovarian epithelial carcinoma (epithelial ovarian cancer, EOC) is number five position in all female cancer causes of death.The percent shared in women's common cancer at the incidence of disease of China's malignant tumor of ovary is 2.4-5.6%.Its morbidity is only second to cervical carcinoma in gynecologic malignant tumor, occupies second.Its morbidity is in rising trend in recent years.In female genital cancer knurl, oophoroma is the highest a kind of tumour of reason that causes death.ACS estimates that the U.S. will increase 21650 oophoroma cases for 2008 newly, and nearly 15520 routine sufferers will die from this disease (www.cancer.org) simultaneously.The high mortality of EOC is all occur in initial period, because most of women has been late period (stage III/IV) when diagnosing, wherein the patient of 15-20% has the survival rate (1) of 5 years.Comparatively speaking, be the fraction patient of stage I by Accurate Diagnosis, have the survival rate (2) of 5 years more than 90%.The candidate policy that current EOC detects be based upon biological chemistry tumor markers basis on, such as CA125 and the biophysics label that obtained by doppler imaging that is ultrasonic or ovary.Unfortunately, positive predictive value (PPV) consistance utilizing these strategies to carry out early stage EOC detection is less than 10% (3,4).By utilizing CA125 complicated algorithm (complex longitudinal algorithms) (5-7), series connection test (sequential testing) (8,9) and the application of brand-new biomarker (10), in ovarian epithelial carcinoma (EOC) early diagnosis, certain raising is obtained.So, be still starved of now the biomarker continued in the new blood circulation system of development and early diagnosis is carried out to oophoroma.
Summary of the invention
The present invention is based in part on following discovery: the ANGPTL3 content in serum of ovarian cancer patients is starkly lower than the ANGPTL3 content in health volunteer's serum, and has significance,statistical, can be used as the diagnosis marker of oophoroma.
Therefore, the invention provides following embodiment.
The method of [embodiment 1] a kind of oophoroma diagnosed in experimenter, comprising: detect from the ANGPTL3 content in the sample of experimenter, analyze described ANGPTL3 content, and determine whether described experimenter suffers from oophoroma according to analysis result.
A kind of [embodiment 2] method improving sample classification accuracy, comprising: detect the ANGPTL3 content in described sample, analyzes, and according to described analysis result, classify to sample to described ANGPTL3 content.
[embodiment 3] a kind of oophoroma to experimenter is diagnosed, prognosis evaluation, result for the treatment of are monitored or the method for course of disease monitoring, comprising: the expression detecting ANGPTL3 in experimenter's blood sample.
The method of any one of [embodiment 4] embodiment 1-3, wherein said sample is selected from the group be made up of urine, cerebrospinal fluid, saliva and tears.
The method of any one of [embodiment 5] embodiment 1-3, wherein said sample is blood sample.
The method of any one of [embodiment 6] embodiment 1-3, wherein said sample is serum sample.
The method of any one of [embodiment 7] embodiment 1-6, wherein said detection adopts ELISA or quantitative Western blot to carry out.
The method of any one of [embodiment 8] embodiment 1-7, wherein said detection adopts the specific binding agents of ANGPTL3 to carry out.
The method of [embodiment 9] embodiment 8, the specific binding agents of wherein said ANGPTL3 is antibody or its ANGPTL3 binding fragment of ANGPTL3.
The method of [embodiment 10] embodiment 8, the antibody of wherein said ANGPTL3 is monoclonal antibody.
The method of [embodiment 11] embodiment 8, the antibody of wherein said ANGPTL3 is polyclonal antibody.
The method of any one of [embodiment 12] embodiment 1-11, wherein said analysis comprises draws ROC curve, take wherein ANGPTL3 as variable, goes out ROC curve according to different threshold renderings, and area AUC under calculated curve, and sensitivity desirably and specificity judge.
The method of any one of [embodiment 13] embodiment 1-11, wherein said analysis comprises and being compared with from the reference value of health volunteer by described ANGPTL3 content, if be starkly lower than described reference value, determines that described experimenter suffers from oophoroma.
[embodiment 14], for implementing the kit of the method for any one of embodiment 1-13, it comprises: the specific binding agents of ANGPTL3.
The kit of [embodiment 15] embodiment 14, also comprises: can in conjunction with the labelled antibody of ANGPTL3.
The kit of any one of [embodiment 16] embodiment 14-15, the specific binding agents of wherein said ANGPTL3 is antibody or its ANGPTL3 binding fragment of ANGPTL3.
The kit of [embodiment 17] embodiment 16, the antibody of wherein said ANGPTL3 is monoclonal antibody.
The kit of [embodiment 18] embodiment 16, the antibody of wherein said ANGPTL3 is polyclonal antibody.
The kit of any one of [embodiment 19] embodiment 15-18, wherein said labelled antibody is by horseradish peroxidase or fluorescence labeling.
The kit of any one of [embodiment 20] embodiment 14-19, also comprises: the standard sample comprising known quantity ANGPTL3 solution; And the antibody labeling thing for detecting, it can be combined with antibody and form conjugate.
The kit of [embodiment 21] embodiment 20, wherein said antibody labeling thing is horseradish peroxidase or fluorescent material.
The kit of any one of [embodiment 22] embodiment 14-21, also comprises: optional antibody coupling matter (antibody conjugates); The optional auxiliary reagent being selected from the group be made up of developer, enzyme inhibitor, damping fluid, stabilizing agent, thinning agent, washing reagent; With optional instructions.
The kit of any one of [embodiment 23] embodiment 14-22, the specific binding agents of wherein said ANGPTL3 is fixed on solid phase carrier.
The specific binding agents of [embodiment 24] ANGPTL3 is for the preparation of the purposes in the reagent of diagnosis of ovarian cancer.
The purposes of [embodiment 25] embodiment 24, the specific binding agents of wherein said ANGPTL3 is antibody or its ANGPTL3 binding fragment of ANGPTL3.
The purposes of [embodiment 26] embodiment 25, the antibody of wherein said ANGPTL3 is monoclonal antibody.
The purposes of [embodiment 27] embodiment 25, the antibody of wherein said ANGPTL3 is polyclonal antibody.
[embodiment 28] ANGPTL3 is as the purposes of ovarian cancer diagnosis mark.
A kind of [embodiment 29] method improving sample classification accuracy, it comprises: the content measuring ANGPTL3 in sample, and the change in time of the content of ANGPTL3; With ANGPTL3 content in time be changed to variable, according to different threshold values, ROC curve is drawn out to the sensitivity of cancer diagnosis and specificity, and area AUC under calculated curve; According to AUC value, sensitivity and specificity, sample is classified.A kind of [embodiment 30] method improving sample classification accuracy, it comprises: the content measuring ANGPTL3 and arbitrary high expressed albumen in oophoroma in sample, and their respective content changes in time; With the ratio of ANGPTL3 and this high expressed protein content in time be changed to variable, according to different threshold values, ROC curve is drawn out to the sensitivity of cancer diagnosis and specificity, and area AUC under calculated curve; According to AUC value, sensitivity and specificity, sample is classified.
Research shows, method of the present invention and kit is adopted to carry out joint-detection to albumin A NGPTL3 in the sample of individuality, effectively can improve the sensitivity of cancer diagnosis, specificity and accuracy rate, and the diagnosis of numerous disease, prognosis evaluation, result for the treatment of assessment and course of disease monitoring can be extended to.
Accompanying drawing explanation
Fig. 1 is a width histogram, show the comparison of the expression of ANGPTL3 in healthy volunteer's serum (N1-N10) and serum of ovarian cancer patients's sample (C1-C10), T-inspection has significance,statistical (T-test, P=0.0009, tail 1, type 3).Horizontal ordinate is sample ID (C=cancer, N=is normal); Ordinate is concentration, and unit is nanograms per milliliter (column diagram adds the error bar of standard error); Title is human angiogenin-like protein 3 (oophoroma vs normal serum).
Embodiment
Term
Term used herein " ANGPTL3 " refers to PP1158 3 (angiopoietin-like protein 3 is called for short ANGPTL3), and its implication is well known in the art.ANGPTL3 is the member (11) of the angiopoietin-like family of secretory protein.It has the characteristic structural of angiogenin, comprises signal peptide, N-end random coil domain and C-distal fibers proteinogen (FBN)-spline structure territory.ANGPTL3 may play a role (11) in the adjustment of Angiogenesis.ANGPTL3 is the instrumentality (12) of lipid metabolism, but its effect in cancer is also not studied.
Term used herein " experimenter ", refers to any mammal, and such as, mouse, rat, rabbit, dog, ox, particularly primate, as people.In some of the preferred embodiment of the invention, " experimenter " is people.In this article, term " experimenter " and " individuality " are used interchangeably sometimes.
Term used herein " blood sample ", refers to the sample of the blood from experimenter, such as whole blood, blood plasma or serum sample.
Term used herein " specific binding agents of ANGPTL3 ", referring to can the reagent of specific bond ANGPTL3, the antibody, binding partner (as Aptmer) etc. of such as ANGPTL3.
Term used herein " specific bond " refers to specific binding agents of the present invention in specific manner in conjunction with ANGPTL3 antigen.Such as, under normal circumstances, ANGPTL3 antibody in conjunction with the affinity of ANGPTL3 antigen be in conjunction with ANGPTL3 antigen outside at least 2 times of affinity of non-specific antigen (such as, BSA, casein).
" the ANGPTL3 binding fragment " of ANGPTL3 antibody refers to one or more fragments of ANGPTL3 antibody, and it retains the ability in conjunction with ANGPTL3 antigen, such as Fab, F (ab ')
2, Fv or Single-Chain Fv Fragment of Murine.Show that the fragment by full length antibody can implement the antigen binding function of antibody." the ANGPTL3 binding fragment " of antibody comprises (i) Fab fragment, and it is by V
l, V
h, C
land C
h1the monovalent fragment of domain composition; (ii) F (ab ')
2fragment, it is the bivalent fragment containing two the Fab fragments connected by disulfide bond in hinge area; (iii) by V
hand C
h1the Fd fragment of domain composition; (iv) by the V of the single armed of antibody
land V
hthe F of domain composition
vfragment, (v) dAb fragment (people such as Ward, (1989) Nature 341:544-546), it is by V
hdomain forms; (vi) complementary determining region (CDR) be separated.In addition, although two of FV fragment domain VL and VH are by different gene codes, they can connect through the joint of recombination method by synthesis, described joint makes VL and VH become a protein chain, and wherein VL and VH district pairing formation monovalent molecule (is called scFv (scFv); See, such as, the people such as Bird (1988) Science242:423-426; With people (1988) Proc.Natl.Acad.Sci.USA 85:5879-5883 such as Huston).
In literary composition, term used " monoclonal antibody " refers to the prepared product of the antibody molecule of single molecular chaperones.MAb compositions demonstrates single binding specificity to defined epitope and compatibility.Therefore, term " monoclonal antibody " refers to the antibody demonstrating single binding specificity.In one embodiment, by hybridoma human monoclonal antibodies, described hybridoma comprises from transgenic nonhuman animal, such as, B cell that obtain in transgenic mice, that merge with immortalized cells, the genome of described animal comprises people's heavy chain transgene and chain transgene.The preparation of antibody is well known in the art, and those skilled in the art easily can prepare the antibody of ANGPTL3.
In literary composition, term used " labelled antibody " refers to carry out the antibody that marks, the antibody such as marked by fluorophore, chemiluminescent substance, horseradish peroxidase etc. by labeled molecule.
Term used herein " optionally " (optional, optionally) represents the implication such as " not essential " or " nonessential ".Such as, " optional carrying implement " refers to there is this carrying implement, also can not this carrying implement.This according to circumstances can be selected by those skilled in the art.
Kit
In a preferred embodiment, ELISA of the present invention uses kit to complete, and can realize prompt operation like this, thus avoid normal experiment to detect loaded down with trivial details.Preferred ELISA kit of the present invention comprises ANGPTL3 detection kit.For improving the sensitivity of medical diagnosis on disease, specificity and accuracy rate, preferably use ANGPTL3 detection kit, it can record two groups of testing results respectively or simultaneously, to reach quick effect.The particularly preferred ANGPTL3ELISA detection kit of one of the present invention is purchased from Immuno-BiologicalLaboratories Co.Ltd..
In a preferred embodiment, ANGPTL3 detection kit of the present invention at least comprises: (1) can in conjunction with the antibody of ANGPTL3; And (2) are when the antibody limited during ANGPTL3 is incorporated into (1), can be incorporated into the labelled antibody of ANGPTL3.Mentioned reagent box also can comprise: (3), by the standard sample of the solution composition containing known quantity ANGPTL3, this standard sample can derive from the body fluid of genetic engineering bacterium expression, animal or human; And (4) antibody labeling thing for detecting, such as, as the enzyme label such as horseradish peroxidase of method for reporting, or fluorescence labeling, it can be combined with antibody and form conjugate.
More preferably, kit also can comprise further in following article one of at least: (5) carrying implement, its spatial division is the restriceted envelope can accommodating one or more containers, 96 orifice plates or lath etc., this container is such as medicine bottle, test tube and analog, and every sample container all can contain an independent component for the inventive method; (6) auxiliary reagent, such as, developer, enzyme inhibitor, damping fluid, stabilizing agent, thinning agent, washing reagent and analog; (7) instructions, it can write on bottle, test tube and analog, or writes on an independent paper, or in the outside or inside of container; Also can be multimedia form, such as CD, compact disk, video recording etc.
Preferred antibody can be fixed on solid phase carrier, forms capture antibody.Capture antibody is operationally convenient especially.
It can in conjunction with the antibody fragment of ANGPTL3, and can be recombinant, chimeric antibody, humanized antibody and murine antibody that contained antibody comprises any.Described antibody can be monoclonal antibody or polyclonal antibody, preferred monoclonal antibody.
Preferred antibody conjugate can use ELISA reading machine, and such as, microplate reader carries out photometering.
Sample
The present invention's sample used can comprise various ways, such as whole blood, blood plasma, serum, urine, cerebrospinal fluid, saliva or tears.Wherein preferred serum.
Sample preparation can be carried out according to commonsense method is such as centrifugal etc., such as, see such as Publication about Document: Young, D.S. & Bermes, E.W. " Specimen collection andprocessing " in Tietz Textbook of Clinical Chemistry 2nd Edition " Eds.Burtis; C.A. & Ashwood, E.R., Saunders (1994); Methods inEnzymology, H.Van Vunakis and J.J.Langone (Eds), 1981,72 (B); Practice and Theory of Enzyme Immunoassays, P Tijssen, LaboratoryTechniques in Biochemistry and Molecular Biology, R.J.Burden and P.H.Van Knippenberg (Eds), Elsevier, 1985; Introduction toRadioimmunoassay and Related Techniques, T.Chard, ibid, 3rd Edition, 1987; Methods in Enzymology, H.Van Vunakis and J.J.Langone (Eds) 1981,74 (C).
Detection method
The present invention can use ELISA or other protein quantification technology the sample of individuality to be carried out to the detection of albumin A NGPTL3.Preferably, can adopt the specific binding agents of ANGPTL3, the antibody of such as ANGPTL3 detects.In a preferred embodiment, the antibody of ANGPTL3 is fixed on solid phase carrier, such as, use as capture antibody.
Enzyme-linked immunosorbent assay (enzyme linked immunosorbentassay, ELISA) is the protein content analyzing method that biology field is commonly used, and it can be used for measuring antigen, also can be used for measuring antibody.According to the actual conditions of the source of reagent, the proterties of sample and detection, the present invention can adopt number of different types, such as: double antibody sandwich method, dibit point single stage method, indirect method are surveyed antibody, competition law, prize law survey IgM antibody and applied the ELISA etc. of Avidin and biotin.Quantitative Western blot is also the protein content analyzing method that biology field is commonly used.
Can also adopt by the quantitative test of the level of activity of chemical gauging ANGPTL3 enzyme as gelatin original position zymogram (gelatin zymography) or Fluorometric assay.
ROC curve
After the concentration detecting ANGPTL3 in sample with ELISA, available Mathematical Method carries out statistical procedures to ANGPTL3 concentration in the sample recorded, and obtains the grade scale with sample classification meaning on this basis.Such mathematical method is preferably completed by computing machine, such as with these Plotting data ROC curve, thus classifies to the sample of individuality.Such as, individuality can be divided into cancer or health, therapeutic response is good and bad, and prediction survival period is long and short.
ROC curve full name is Receiver operating curve (receiver operatorcharacteristic curve), is also called recipient's operating characteristic curve, is mainly used in clinical biochemical diagnostic test.ROC curve is the (sensitivity of reflection True Positive Rate, also known as susceptibility, sensitivity) and the overall target of false positive rate (1-specificity, specificity) continuous variable, be disclose sensitivity and specific mutual relationship by composition method.It is by setting a series of different cut off value (threshold value or critical value, cut-off value, divide the normal and abnormal dividing value of diagnostic test result) as continuous variable, thus calculate a series of sensitivity and specificity, be ordinate again with sensitivity, 1-specificity is horizontal ordinate curve plotting, area under curve (AUC) is larger, and diagnostic accuracy is higher.On ROC curve, be the critical value that sensitivity and specificity are all higher near the upper left point of coordinate diagram.ROC curve A UC value is between 1.0 and 0.5.When AUC > 0.5, AUC, more close to 1, illustrates that diagnosis effect is better.AUC has lower accuracy 0.5 ~ 0.7 time, and AUC has certain accuracy 0.7 ~ 0.9 time, has high accuracy when AUC is more than 0.9.
The evaluation method of ROC curve is different from traditional evaluation method, according to actual conditions, has allowed intermediateness, test findings can be divided into multiple ordered categorization, such as: normally, roughly normal, suspicious, roughly abnormal and abnormal five grades.
Above-mentioned ordered categorization, for the diagnosis of disease, can be divided into: negative, uncertain, positive.Further, for cancer diagnosis, can be divided into: cancer, health.
In one embodiment, the present invention improves the method for sample classification accuracy, can comprise the steps: that (1) measures the content of albumin A NGPTL3 in sample respectively; (2) with the ratio of ANGPTL3 protein content for variable, according to different threshold values, ROC curve is drawn out to the sensitivity of cancer diagnosis and specificity, and area AUC under calculated curve; And (3) sensitivity desirably and specificity, (cancer or health) is classified to mensuration sample.
The drafting of ROC curve can use software of the prior art or system, such as: MedCalc 9.2.0.1 medical statistics software, SPSS 9.0, ROCPOWER.SAS, DESIGNROC.FOR, MULTIREADER_POWER.SAS, CREATE_ROC.SAS, GB STAT V10.0 (Dynamic Microsystems, Inc.Silver Spring, MD, USA) etc.
The diagnosis of oophoroma, prognosis evaluation, result for the treatment of are monitored or course of disease monitoring
Present invention also offers the joint test kit that a kind of diagnosis for oophoroma, prognosis evaluation, result for the treatment of monitoring or the course of disease are monitored, it at least comprises: (1) can in conjunction with the antibody of ANGPTL3; And (2) are when the antibody limited during ANGPTL3 is incorporated into (1), can be incorporated into the labelled antibody of ANGPTL3.
In a preferred embodiment, the invention provides a kind of method that oophoroma to experimenter is diagnosed, prognosis evaluation, result for the treatment of are monitored or the course of disease is monitored, comprise: detect the expression of ANGPTL3 in experimenter blood sample and ANGPTL3 content change in time (as, various cancers developing period, before treatment and after treatment etc.).Present invention also offers a kind of method improving sample classification accuracy, it comprises: the content measuring ANGPTL3 in sample, and the content of ANGPTL3 change in time (e.g., various cancers developing period, before treatment and after treatment etc.); With ANGPTL3 protein content in time be changed to variable, according to different threshold values, ROC curve is drawn out to the sensitivity of cancer diagnosis and specificity, and area AUC under calculated curve; According to AUC value, sensitivity and specificity, sample is classified.Such as, individuality can be divided into cancer or health, therapeutic response is good and bad, and prediction survival period is long and short.In a preferred embodiment, such as, ANGPTL3 content and the reference value from health volunteer can be compared, if be starkly lower than described reference value, determine that described experimenter suffers from oophoroma.In another preferred embodiment, further combined with the joint-detection of the low expression of ANGPTL3 and the albumen of arbitrary high expressed in oophoroma, calculate the difference of their ratio, and with ratio in time be changed to variable, according to different threshold values, ROC curve is drawn out to the sensitivity of cancer diagnosis and specificity, and area AUC under calculated curve, and then sample is classified.Term " in oophoroma high expressed albumen " used herein refers to that the expression of this albumen in ovarian cancer patients is significantly higher than normal subjects.The example of the albumen of high expressed " in the oophoroma " comprising: CA125, Mesothelin (Hassan R, Remaley AT, Sampson ML, Zhang J, Cox DD, Pingpank J, Alexander R, Willingham M, Pastan I, Onda M:Detection and quantitation of serum mesothelin, a tumor markerfor patients with mesothelioma and ovarian cancer.Clin Cancer Res 2006, 12 (2): 447-453.), HE4, M-CSF, osteopontin, kallikrein (s), with soluble EGF receptor (soluble EGF receptor, Bast RC, Jr., Badgwell D, Lu Z, Marquez R, Rosen D, Liu J, Baggerly KA, Atkinson EN, Skates S, ZhangZ et al:New tumor markers:CA125 and beyond.Int J Gynecol Cancer2005, 15 Suppl 3:274-281.).
Below in conjunction with specific embodiment, the invention will be further described.Should be appreciated that following examples only for illustration of the present invention not in any form for limiting scope of the present invention.
Embodiment 1
Carry out ovarian cancer diagnosis for the serum of individuality for sample below, the present invention is described in further detail.
The collection of sample
Collect the serum of the healthy women of (34-82 year scope) of the preoperative serum sample of ovarian cancer patients and age-matched with comparing.Get in 2 hours of blood in venipuncture, by collected by centrifugation serum, and aliquot sample is stored in-80 DEG C until use.
Survey ANGPTL3 content
Human angiogenin-like protein 3 (ANGPTL3) ELISA kit (cat #27409) of elisa assay-used Immuno-Biological Laboratories Co.Ltd. to develop.Elisa assay can operate according to the instructions of manufacturer.The GB STAT utilizing DynamicMicrosystems company to develop adds up bag to analyze ROC curve.
And use Bio-Rad 680 type microplate reader (U.S.) to carry out ELISA operation, comprising: the kit 1, taking out stored under refrigeration, place, recovery temperature is to room temperature (20-25 DEG C).The total specimens that calculating will detect and Quality Control number.Each sample needs an antigen coated hole.Each experiment all will do positive control, negative control and calibration object.Determine the micropore quantity needed.When lath temperature is to room temperature, open the protective bag of lath, take out antigen coated micropore lath.This experiment does not need the reagent strip used should put into the sack of this resealable, and sealing, leaves 2-8 DEG C in again.2, on microwell plate, add the titer of 20 μ L, contrast liquid and serum sample successively.This process must complete in 30 minutes.What in each micropore, 3, add 100 μ L catches liquid, repeatedly blows and beats mix with pipettor in hole.4, build plate with lid for micro plate, at room temperature (18-25 DEG C) carries out incubation 55-65 minute.5, wash plate 3 times: A by hand in the steps below, acutely shake and outwell the liquid in plate; B, in hole, fill it up with washing lotion.Ensure the remaining bubble of Kong Zhongwu.C, repeat first two steps rapid twice again.D, shake the washing lotion removed in hole.Plate is overturn, paper handkerchief is patted, all washing lotions can be patted dry.Observe microwell plate, guarantee the washing lotion of noresidue.6, in the bottle of hrp-antibody complex, add the regeneration buffer of 7mL, stand-by under depositing in room temperature.7, according to same order, the multienzyme complex diluted to be added on 100 μ L to microwell plate 8, builds plate with lid for micro plate, at room temperature (18-28 DEG C) carries out incubation 55-65 minute.9, prepare substrate, in substrate buffer solution, add a slice substrate solid, dissolve after 30-60 minute, strongly rock, solution is mixed completely.10, carry out washing plate according to the method for A to D in step 5.11, with same speed and order, substrate solution is added 100 μ L in every hole.12, microwell plate at room temperature (18-28 DEG C) carry out incubation 55-65 minute.13, in each hole, the stop buffer of 100 μ L is added with same speed and order.Microwell plate should be beaten gently after having added stop buffer, guarantee that sample all mixes.14, the determined wavelength of microplate reader is set at 405nm place.Detect the OD value in each hole.Reading is carried out within Ying Jia 15 clocks of stop buffer.15, the result of ANGPTL3 is analyzed with a linear calibration curve " Y=mx+b ".16, the concentration of ANGPTL3 in serum sample and contrast liquid is read by typical curve.
Result
Through above-mentioned steps, the testing result obtained is as shown in table 1.Expression sample concentration (ng/ml) the c1 25.06c2 111.86c3 14.21c4 75.69c5 343.33c6 412.04c7 64.84c8 93.78c9 28.68c10 129.94n1 419.28n2 260.14n3 549.48n4 307.16n5 415.66n6 278.23n7 701.38n8 90.16n9 357.79n10 451.83 of table 1.ANGPTL3 in normal population and human ovarian cancer patients's serum
*c represents cancer specimen, and N represents normal specimens
As can be seen from Table 1, concentration and the oophoroma symptom of ANGPTL3 have close correlativity, and namely in serum of ovarian cancer patients, the content of ANGPTL3 albumen is starkly lower than the content in healthy volunteer's serum.
We find, compared with described 10 normal individuals, expression lower (T-test, the P=0.0009 of described 10 ovarian cancer serum sample angiopoietins sample albumen 3 (ANGPTL3), tail 1, type 3) (Fig. 1).
Result shows that the concentration of ANGPTL3 and oophoroma symptom have close correlativity,
List of references involved herein, comprises patent document, scientific paper, publication etc., is included in herein by its full content all by reference.
Should be appreciated that when without departing from the spirit and scope of the present invention, those of ordinary skill in the art can make various changes and improvements to it in form and details, and these are all considered to fall into protection scope of the present invention.
list of references[1] Greenlee, R.T., Hill-Harmon, M.B., Murray, T., Thun, M., Cancer statistics, 2001.CA Cancer J Clin 2001, 51, 15-36. [2] Young, R.C., Walton, L.A., Ellenberg, S.S., Homesley, H.D., et al., Adjuvant therapy in stage I and stage II epithelial ovarian cancer.Results of two prospective randomized trials.N Engl J Med 1990, 322, 1021-1027. [3] van Nagell, J.R., Jr., DePriest, P.D., Reedy, M.B., Gallion, H.H., et al., The efficacy of transvaginal sonographic screening inasymptomatic women at risk for ovarian cancer.Gynecol Oncol 2000, 77, 350-356. [4] Kyrgiou, M., Tsoumpou, I., Martin-Hirsch, P., Arbyn, M., et al., Ovarian cancer screening.Anticancer Res 2006, 26, 4793-4801. [5] Skates, S.J., Xu, F.J., Yu, Y.H., Sjovall, K., et al., Toward anoptimal algorithm for ovarian cancer screening with longitudinal tumormarkers.Cancer 1995, 76, 2004-2010. [6] Zhang, Z., Barnhill, S.D., Zhang, H., Xu, F., et al., Combination of multiple serum markers using an artificial neural networkto improve specificity in discriminating malignant from benign pelvicmasses.Gynecol Oncol 1999, 73, 56-61. [7] McIntosh, M.W., Urban, N., Karlan, B., Generatinglongitudinal screening algorithms using novel biomarkers for disease.Cancer Epidemiol Biomarkers Prev 2002, 11, 159-166. [8] Berek, J.S., Bast, R.C., Jr., Ovarian cancer screening.The useof serial complementary tumor markers to improve sensitivity andspecificity for early detection.Cancer 1995, 76, 2092-2096. [9] Jacobs, I.J., Skates, S.J., MacDonald, N., Menon, U., et al., Screening for ovarian cancer:a pilot randomised controlled trial.Lancet1999, 353, 1207-1210. [10] Kim, J.H., Skates, S.J., Uede, T., Wong, K.K., et al., Osteopontin as a potential diagnostic biomarker for ovarian cancer.Jama2002, 287, 1671-1679. [11] Hato, T., Tabata, M., Oike, Y., The role of angiopoietin-likeproteins in angiogenesis and metabolism.Trends Cardiovasc Med 2008, 18, 6-14. [12] Koishi, R., Ando, Y., Ono, M., Shimamura, M., et al., Angptl3regulates lipid metabolism in mice.Nat Genet 2002, 30, 151-157.
Claims (17)
1. the purposes implementing to improve for oophoroma in the medicine of the method for sample classification accuracy prepared by the reagent detecting the ANGPTL3 content in sample, and described method comprises:
Detect the ANGPTL3 content in described sample,
Described ANGPTL3 content is analyzed, and
According to described analysis result, sample is classified.
2. comprise the purposes in the medicine that kit is diagnosed the oophoroma of experimenter in preparation, prognosis evaluation, result for the treatment of are monitored or the course of disease is monitored of the specific binding agents of ANGPTL3.
3. the purposes of claim 2, wherein said kit also comprises: can in conjunction with the labelled antibody of ANGPTL3.
4. the purposes of any one of claim 2-3, the specific binding agents of wherein said ANGPTL3 is antibody or its ANGPTL3 binding fragment of ANGPTL3.
5. the purposes of claim 4, the antibody of wherein said ANGPTL3 is monoclonal antibody.
6. the purposes of claim 4, the antibody of wherein said ANGPTL3 is polyclonal antibody.
7. the purposes of claim 3, wherein said labelled antibody is by horseradish peroxidase or fluorescence labeling.
8. the purposes of claim 2, wherein said kit also comprises:
Comprise the standard sample of known quantity ANGPTL3 solution; And
For the antibody labeling thing detected, it can be combined with antibody and form conjugate.
9. the purposes of claim 8, wherein said antibody labeling thing is horseradish peroxidase or fluorescent material.
10. the purposes of claim 2, wherein said kit also comprises:
Optional antibody coupling matter;
The optional auxiliary reagent being selected from the group be made up of developer, enzyme inhibitor, damping fluid, stabilizing agent, thinning agent, washing reagent; With
Optional instructions.
The purposes of 11. claims 2, the specific binding agents of wherein said ANGPTL3 is fixed on solid phase carrier.
The specific binding agents of 12.ANGPTL3 is for the preparation of the purposes in the reagent of diagnosis of ovarian cancer.
The purposes of 13. claims 12, the specific binding agents of wherein said ANGPTL3 is antibody or its ANGPTL3 binding fragment of ANGPTL3.
The purposes of 14. claims 13, the antibody of wherein said ANGPTL3 is monoclonal antibody.
The purposes of 15. claims 13, the antibody of wherein said ANGPTL3 is polyclonal antibody.
The purposes in the medicine implementing the method improving sample classification accuracy prepared by 16. reagent detecting the ANGPTL3 content in sample, and described method comprises:
Measure the content of ANGPTL3 in sample, and the change in time of the content of ANGPTL3;
With ANGPTL3 content in time be changed to variable, according to different threshold values, ROC curve is drawn out to the sensitivity of ovarian cancer diagnosis and specificity, and area AUC under calculated curve;
According to AUC value, sensitivity and specificity, sample is classified.
The purposes in the medicine implementing the method improving sample classification accuracy prepared by 17. reagent detecting the content of ANGPTL3 and arbitrary high expressed albumen in oophoroma in sample, and described method comprises:
Measure the content of ANGPTL3 and arbitrary high expressed albumen in oophoroma in sample, and their respective content changes in time;
With the ratio of ANGPTL3 and this high expressed protein content in time be changed to variable, according to different threshold values, ROC curve is drawn out to the sensitivity of cancer diagnosis and specificity, and area AUC under calculated curve;
According to AUC value, sensitivity and specificity, sample is classified.
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| CN200910133415.5A CN101852805B (en) | 2009-03-31 | 2009-03-31 | Application of ANGPTL3 as diagnostic marker of ovarian cancer |
| PCT/CN2010/000406 WO2010111892A1 (en) | 2009-03-31 | 2010-03-30 | Use of angptl3 as a diagnostic marker for ovarian cancer |
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| JO3412B1 (en) | 2011-06-17 | 2019-10-20 | Regeneron Pharma | Anti-angptl3 antibodies and uses thereof |
| CN106636368B (en) * | 2016-11-28 | 2020-07-21 | 山东大学 | Application of miR-130a in diagnosis, treatment and prognosis of ovarian cancer |
| CN107085112B (en) * | 2017-05-10 | 2019-03-19 | 武汉圣润生物科技有限公司 | It is a kind of for detecting the kit of leukaemia |
| CN112062845B (en) * | 2019-06-10 | 2022-09-02 | 山东博安生物技术股份有限公司 | ANGPTL3 binding fragments and uses thereof |
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Non-Patent Citations (2)
| Title |
|---|
| Combining CA125 and SMR serum markers for diagnosis and early detection of ovarian carcinoma;M.W.McIntosh;《Gynecologic Oncology》;20041001;第95卷;第9-15页 * |
| Diagnostic Markers for Early Detection of Ovarian Cancer;Irene Visintin;《Clincal Cancer Reasearch》;20080215;第14卷;第1065-1075页 * |
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