CN106932587B - Kit based on protein marker PSG3 auxiliary diagnosis liver cancer or alimentary tract cancer patient - Google Patents
Kit based on protein marker PSG3 auxiliary diagnosis liver cancer or alimentary tract cancer patient 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
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
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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
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- 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
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57438—Specifically defined cancers of liver, pancreas or kidney
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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
- G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies; monoclonal antibodies per se are classified with their corresponding antigens
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- General Health & Medical Sciences (AREA)
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- Hospice & Palliative Care (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
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Abstract
The invention discloses one kind being based on protein label PSG3 auxiliary diagnosis cancers, the especially kit of liver cancer and colon cancer.Claimed application of the product in preparing for the kit of diagnosing liver cancer and colon cancer for detecting protein PSG3.In the present invention, inventor is found that the presence of protein marker PSG3 in liver cancer and peripheral blood of patients with colonic cancer for the first time, and finding that the concentration of protein marker PSG3 in liver cancer and peripheral blood of patients with colonic cancer is higher than healthy person, i.e. protein marker PSG3 has the value of auxiliary diagnosis liver cancer and colorectal cancer patients.The present invention is of great significance to the auxiliary diagnosis of liver cancer and colon cancer.
Description
Technical field
The present invention relates to a kind of applications of protein marker PSG3 in auxiliary diagnosis liver cancer or alimentary canal patient, and system
Application in standby corresponding detection kit.
Background technology
Primary carcinoma of liver is the 6th, the whole world, Chinese 3rd most common cancer.According to International Cancer Research Center (IARC)
Estimation, global onset of liver cancer number is 56.4 ten thousand people within 2000, wherein about 55% is happened at China, i.e. Chinese onset of liver cancer 30.6 ten thousand
People, PLC mortality 30.0 ten thousand account for the second of China's Tumor of Residents death.Belong to middle and advanced stage when symptom occurs in liver cancer, after excision more
Recurrence and metastasis rate is high.Therefore, the early diagnosis of liver cancer is to extending the life span of patient and reducing mortality of liver cancer with important
Meaning.
Currently, imaging diagnosis, cell and histodiagnosis and chemical diagnosis are three big main methods of diagnosing tumor.Shadow
It plays an important role, but is all had in diagnosis of small hepatic cell carcinoma and the good Malignant Nodules of differentiation certain in diagnosing cancer of liver as learning diagnosis
Limitation.Ultrasonic examination or CT positive findings, it is horizontal higher than 400ng/ in conjunction with serum alpha-fetoprotein (α-fetoprotein, AFP)
The testing result of ml can make liver cancer and make a definite diagnosis.But usually when these conditions all meet, treatment has been had already passed by most
Good opportunity.Either ultrasonic examination, CT scan or nuclear magnetic resonance have certain limitation, especially to the identification of small lesion
It is cirrhotic nodule on imageology with microhepatia cancerous node there are many similarity.Therefore, although Imaging Technology obtains
Huge progress, but the molecular marker in conjunction with liver cancer is clinically still needed to, in more complicated case by good pernicious hepatopathy
It distinguishes.In addition, the clinical stages and tumor size of tumour are the determinants of liver cancer treatment effect, and therefore, tumor-marker
Object can be additionally used in the generaI investigation of liver cancer population at risk (such as HBV chronic carriers and liver cirrhosis patient).
The most common marker of diagnosing cancer of liver is alpha-fetoprotein (AFP) at present, the number before symptom and Imageology occur
The moon may occur in which exception.AFP contents are generally less than 10ng/ml in normal human serum.When the diagnostic value of AFP is set to 20ng/ml,
Its sensibility is 50~60%, but in the smaller case of tumour, and sensibility significantly reduces, and has been reported that only 40%.Individually make
Another problem for using AFP as diagnosing cancer of liver marker is a lack of specificity, considerable chronic hepatitis patient especially
In liver cirrhosis patient, AFP contents also reach 20-200ng/ml.It is now recognized that the marker that can be diagnosed with AFP complementations has AFP heterogeneous
Body, gamma glutamyltransferase isodynamic enzyme II and abnormal prothrombin etc., but due to they on sensibility and specificity not
The very complicated of foot and detection method makes it rest on laboratory research level always, fails to be converted to routine clinical inspection
Project.Therefore, new tumor cells marker is explored, and establishes corresponding detection method easy to spread, is still current liver
One of the important topic of cancer research field.
Equally, tumor in digestive tract is also to lead to dead one of Etiological in China.Colorectal cancer onset therein is hidden
It hides, early stage, and progression of the disease was slower often without apparent clinical symptoms, mostly to middle evening when manifest symptom occurs in patient
Phase.Currently, the treatment of colon is mainly based on operation, but the chemotherapy effect after colon metastasis of cancer is poor, and postoperative there are about 40%
Patient is recurred, and patients with terminal survival rates are relatively low.Although having been done largely about colon cancer there are many scholar
The research of molecular level, but still lack the molecular marker for effectively early diagnosing colon cancer at present.Tumor markers can
To be effective as clinical diagnosis foundation, people at highest risk can be monitored, early diagnosis, guiding treatment, judge treatment curative effect, detection
Recurrence and transfer, are the important Index for examination of tumor patient, with important clinical meaning.The generation of colon cancer has one early period
The precancerous lesion of section time, such as polyp of colon, therefore in early detection and blocking or the development of delay cancer, have extremely important
Meaning.Therefore, find find valuable tumor markers for improve tumor in digestive tract, especially colorectal cancer diagnosis and
Prediction occurs, development and improvement prognosis have important Clinical significance of MG.
In human blood include abundant various cell components and molecular substance, can reflect well body different tissues and
The physiology of organ, pathological state, and its sample is easy to get, and is a kind of ideal tumour non-invasive diagnosis means therefore.Therefore,
Still there is the good marker of sensibility and specificity to be developed.
Pregnant differential protein 3 (Human pregnancy specific beta-1-glycoprotein 3, PSG3) is
One kind being secreted into extracellular glycoprotein.Include altogether 11 albumen in PSG families, including PSG1, PSG2, PSG3 etc..PSG albumen
All include generally the N-terminal structure similar with immune globulin variable region, is followed by 2-3 constant region for immunoglobulin C2 spline structure
Domain and a short hydrophobic tail are located at C-terminal.PSG can be divided into 4 classes according to its structure composition, I types (N-A1-A2-B2-C),
IIa types (N-A1-B2-C) and IIb types (N-A2-B2-C), type III (N-B2-C), IV types (A1-B2-C).PSG families at present
Mechanism of action is unclear, under normal circumstances, great expression in the syncytionboph-oblast of placenta, outside gestational period women
PSG protein contents increase in all blood, up to 200-400 μ g/ml.It is rarely reported about research of the PSG families in cancer.
428 amino acid of PSG3 length proteins, molecular weight 47,945Da, following (the SEQ ID of amino acid sequence of albumen
NO：1)：
MGPLSAPPCT QRITWKGLLL TALLLNFWNL PTTAQVTIEA
EPTKVSKGKD VLLLVHNLPQ NLAGYIWYKG QMKDLYHYIT
SYVVDGQIII YGPAYSGRET VYSNASLLIQ NVTREDAGSY
TLHIVKRGDG TRGETGHFTF TLYLETPKPS ISSSNLYPRE
DMEAVSLTCD PETPDASYLW WMNGQSLPMT HSLQLSKNKR
TLFLFGVTKY TAGPYECEIR NPVSASRSDP VTLNLLPKLP
KPYITINNLN PRENKDVLAF TCEPKSENYT YIWWLNGQSL
PVSPRVKRPI ENRILILPSV TRNETGPYQC EIQDRYGGIR
SYPVTLNVLY GPDLPRIYPS FTYYHSGENL YLSCFADSNP
PAEYSWTING KFQLSGQKLF IPQITTKHSG LYACSVRNSA
TGMESSKSMT VKVSAPSGTG HLPGLNPL
Research report in relation to PSGs in tumour is less.The application differential gene expression spectrum analysis such as Salahshor is found
It can detect abnormal raised PSG9 transcripts in colorectal cancer, metastatic liver cancer, cervix tumor tissue, it is viscous with normal Colon and rectum
Film is compared, and PSG9 raises 2 times in adenoma, and the up-regulation of colorectal cancer PSG9 abnormal expressions is mutated dependence in APC
(Salahshor et al,2005).Kamarli ZP's etc. studies have shown that PSG1 albumen in bone malignant tumour patients serum
Concentration increases (Kamarli et al, 2004).And it is had not been reported about researchs of the PSG3 in tumour.
Invention content
The molecule that first aspect present invention is related to detecting PSG3 albumen is being prepared for auxiliary diagnosis cancer, especially liver cancer
Alimentary tract cancer patient kit or the purposes in detection reagent.
The purposes of any one according to a first aspect of the present invention, wherein the molecule of the detection PSG3 albumen is to refer to specifically
Property detection PSG3 protein expressions molecule, such as can be nucleic acid, protein or compound.
The purposes of any one according to a first aspect of the present invention, wherein the protein is antibody, it can be with PSG3 albumen
Specific binding, preferably monoclonal antibody.
In embodiments of the invention, the molecule of the detection PSG3 albumen is monoclonal antibody, can be with PSG3
Protein-specific combines.
In specific embodiments of the present invention, PSG3 albumen is detected using immunochemical method.
The purposes of any one according to a first aspect of the present invention, wherein the liver cancer is hepatocellular carcinoma.
The purposes of any one according to a first aspect of the present invention, wherein the alimentary tract cancer is colorectal cancer.
The purposes of any one according to a first aspect of the present invention, the kit or detection reagent are used for the inspection of plasma sample
It surveys.
The purposes of any one according to a first aspect of the present invention, wherein the judgment method of the auxiliary diagnosis is, in blood plasma
The content of PSG3 is higher than 551.65 μ g/ml, then person to be checked is candidate hepatocellular carcinoma or colorectal cancer patients.
The purposes of any one according to a first aspect of the present invention, wherein the molecule of the detection PSG3 albumen is also carried and be can detect
Label.
The purposes of any one according to a first aspect of the present invention, wherein also containing buffer solution in the kit or detection reagent
And color developing agent.
It is related to a kind of examination for auxiliary diagnosis cancer, especially liver cancer or alimentary tract cancer according to a second aspect of the present invention
Agent box or detection reagent contain the product of detection marker PSG3 albumen.
It is related to a kind of examination for auxiliary diagnosis cancer, especially liver cancer or alimentary tract cancer according to a second aspect of the present invention
The product of agent box or detection reagent, the detection marker PSG3 albumen is point for referring to specific detection PSG3 protein expressions
Son, such as can be nucleic acid, protein or compound.
The kit or detection reagent of any one according to a second aspect of the present invention, wherein the protein is antibody, energy
It is enough combined with PSG3 protein-specifics, preferably monoclonal antibody.
In embodiments of the invention, the molecule of the detection PSG3 albumen is monoclonal antibody, can be with PSG3
Protein-specific combines.
In specific embodiments of the present invention, PSG3 albumen is detected using immunochemical method.
The kit or detection reagent of any one according to a second aspect of the present invention, wherein the liver cancer is hepatocellular carcinoma,
The alimentary tract cancer is colorectal cancer.
The kit or detection reagent of any one according to a second aspect of the present invention, the kit or detection reagent are used for blood
The detection of slurry samples, it is preferable that the detection method is immuno-chemical method.
The kit or detection reagent of any one according to a second aspect of the present invention, wherein the judgment method of the auxiliary diagnosis
For blood plasma PSG3 protein expressions are higher than 551.65 μ g/ml, then person to be checked is candidate hepatocellular carcinoma or colorectal cancer patients.
The kit or detection reagent of any one according to a second aspect of the present invention, wherein the molecule of the detection PSG3 albumen
Also carry detectable label.
The kit or detection reagent of any one according to a second aspect of the present invention, wherein in the kit or detection reagent
Also contain buffer solution and color developing agent.
In the present invention, wherein the molecule of the detection PSG3 albumen refers to whether detection PSG3 albumen is overexpressed
Molecule, such as can be nucleic acid, protein or compound.
In the present invention, method well known in the art may be used and prepare antibody.
The method of immunoassays can be used quantitative or the presence of qualitative detection protein marker.The immunoassays are usual
Binding antibody is detected including biological sample and antibody to be incubated with, and by a variety of known technologies.
In the present invention, the compound has meaning well known in the art, can be combined with PSG3 protein-specifics,
And then the expression for detecting PSG3 albumen.
In the present invention, detectable mark molecule can be connected on the molecule of the detection PSG3 albumen.
In the present invention, can also include in the kit or detection reagent can be with the molecule knot of detection PSG3 albumen
The molecule of conjunction, such as antibody, such as secondary antibody, the molecule can also be connected with detectable mark molecule.
In the present invention, the detectable mark molecule for example can be enzyme, fluorescein, metal ion or isotope
Deng.
Description of the drawings
Figure 1A is the ROC curve that PSG3 distinguishes normal person and patients with hepatocellular carcinoma (HCC).
Figure 1B is the ROC curve that PSG3 distinguishes normal person and colorectal cancer patients (CC).
Specific implementation mode
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
It can be with conventional products that are commercially available.
Embodiment 1 prepares the ELISA kit of PSG3 detections
Using escherichia coli prokaryotic expression PSG3 albumen, expression vector pET30a.5-6 week old BALB/c mouses are taken, profit
PSG3 full-length proteins are used to prepare PSG3 antibody as antigen addition Freund's adjuvant is immune.Every mouse immune 4 times, per minor tick 2
Utilize 15-30 μ g antigen proteins every time in week, Freund's complete adjuvant utilized when first time inoculation, after utilize Freund's incomplete adjuvant three times.
First three day of cell fusion selects one from three spleen cell donor mices and carries out intravenous injection PSG3 antigens and does and be further immunized.
Cell fusion, hybridoma screening are according to the method (Davis et al 1982) of J.M.Davis.Simple process is as follows：Reinforce
Mouse boosting cell after immune and SP2/0 myeloma cell's mixing, are slowly added into and promote 50% polyethylene glycol 0.7ml of fusion agent.37
DEG C culture 1min, 10ml IMDM culture mediums dilution, low-speed centrifugal.Then with 40ml containing 1.25% methylcellulose, 25% tire ox
The IMDM culture mediums resuspension of serum, 2%HAT (containing hypoxanthine, methotrexate (MTX) and thymidine).It turns upside down mixing,
It is transferred in 35mm tablets, per plate about 2ml, in 37 DEG C, 5%CO2It is cultivated in environment.7 days rear clones are transferred to 96 orifice plates, are added
IMDM culture mediums containing 15% fetal calf serum and 2%HT (containing hypoxanthine and thymidine) are cultivated again.When cell melts
It is right to reach 50%~70%, culture medium supernatant is collected, detects whether that there are antibody using ELISA and Western blot.
Establish the enzyme mark double antibody sandwich method of detection PSG3 antigens.Detect building for the enzyme mark double antibody sandwich method of PSG3 antigens
It is vertical：Monoclonal antibody is produced first with mouse peritoneal, obtained positive hybridoma cell is injected separately into mouse peritoneal, makes it
Ascites is generated, norphytane, every mouse 0.5ml are injected；Norphytane is injected after 1 week, injects hybridoma, every mouse injection
106A cell.Ascites is collected after 7-10 days respectively, purifies antibody respectively with caprylic acid-ammonium sulfate precipitation method, then use sodium periodate
Antibody is carried out horseradish peroxidase-labeled (enzyme labelled antibody) by method respectively.It is coated with enzyme mark respectively with the monoclonal antibody of purifying
Plate, and detection PSG3 antigens are matched with enzyme labelled antibody respectively, coated antibody P201 and the capture of enzyme mark for obtaining best pairing are anti-
Body P209.Wherein coated antibody P201 and enzyme target capture antibody P209 prepare production by hybridoma cell strain P201 and P209 respectively
It is raw.Hybridoma cell line P201 and P209 are common in China Committee for Culture Collection of Microorganisms on November 27th, 2015
The preservation of microorganism center, preserving number are respectively CGMCC NO.11597 and CGMCCNO.11598, and preservation address is Beijing's southern exposure
Area North Star West Road No.1 institute 3.
Steps are as follows by ELISA：PSG3 coated antibodies P201 is coated with 96 hole elisa Plates, 100 holes μ l/, 4 DEG C overnight；It gets rid of
Coated antibody, 0.5%PBST board-washings 3 times,2%BSA confining liquids are added,Room temperature 4 hours；It gets rid of
Confining liquid, 0.5%PBST board-washings 3 times,It is separately added into PSG3 standard proteins and sample to be tested per hole in ELISA Plate,
100 holes μ l/；Add PSG3 enzyme labelled antibodies P209,100 holes μ l/, 4 DEG C overnight after mixing；Get rid of dereaction liquid, 0.5%PBST
Board-washing 5 times, TMB developing solutions are added, 200 holes μ l/ are protected from light 15 minutes；2M sulfuric acid is added and terminates reaction,With detection absorbance at microplate reader OD450nm；Standard curve is drawn using the value of standard protein absorbance, and is counted
Calculate the albumen concentration of PSG3 in sample to be tested.
Embodiment 2 detects the albumen concentration of PSG3 in large-scale tumor patient and normal population plasma sample
The concentration of PSG3 albumen is detected in pregnant woman's blood plasma using the ELISA kit of preparation.The sample packet of detection
It includes：11 early pregnancy women (11-12 weeks), 17 Advanced pregnant women (28-38 weeks).The result of ELISA is as shown in Table 1,
Albumen concentration of the PSG3 in early pregnancy women's blood plasma is significantly higher than Advanced pregnant (P<0.001).
Albumen concentration (μ g/ml) of the table 1.PSG3 in pregnant woman's blood plasma
Detect PSG3's in large-scale tumor patient and normal population plasma sample using the ELISA kit of preparation
Albumen concentration.The sample of detection includes：178 hepatocellular carcinomas (Hepatocarcinoma, HCC), 121 lung cancer (Lung
Cancer, LC), 159 oophoromas (Ovarian Cancer, OC), 88 colorectal cancers (Colorectal Cancer, CC),
And 115 ages and the matched healthy normal person (Health Control) of sex ratio.ELISA's the results show that PSG3
It is significantly higher than Normal group (P in the plasma protein levels of hepatocellular carcinoma, colorectal cancer patients and patients with lung cancer<0.001,
Table 2).
Albumen concentration (μ g/ml) of the table 2.PSG3 in each group tumor patient and normal population blood plasma
Effect of the 3 PSG3 plasma protein concentrations of embodiment in auxiliary diagnosis of hepatoma or alimentary tract cancer
When PSG3 plasma protein concentration values are 551.65 μ g/ml, the sensibility for detecting hepatocellular carcinoma is 64.2%, special
The opposite sex is 74.8%, and area is 0.774,95%CI=0.719-0.828, P under ROC curve<0.001 (Figure 1A).Same group of liver
Also the level of hepatocellular carcinoma marker alpha-fetoprotein (alpha-fetal protein, AFP) is had detected in carninomatosis human plasma.
When the use of routine clinical detection limit value being 25ng/ml, the patient of hepatocellular carcinoma AFP negative is 107, accounts for total specimens
60.1% (107/178).And in the hepatocarcinoma patient of this 107 AFP negatives, positive (the PSG3 albumen concentration in blood plasma of PSG3>
551.65 μ g/ml) case load be 66, improve the recall rate of hepatocarcinoma patient, can clinically assist hepatocellular carcinoma sick
The diagnosis of people.
When PSG3 plasma protein concentration values are 551.65 μ g/ml, the sensibility of detection colorectal cancer (n=88) is
92.0%, specificity is 74.8%, and area is 0.873,95%CI=0.819-0.828, P under ROC curve<0.001 (Figure 1B).
This 88 patient's blood plasma also have detected colorectal cancer marker carcinomebryonic antigen (carcinoembryonic antigen, CEA)
Protein level.When the use of routine clinical detection limit value being 5ng/ml, the patient of CEA feminine genders is 67 in colorectal cancer patients,
Account for 76.1% (67/88) of total specimens.And in the Patients with Colorectal Cancer of this 67 CEA feminine genders, the PSG3 positives are (in blood plasma
PSG3 albumen concentration>551.65 μ g/ml) case load be 60, significantly improve the recall rate of Patients with Colorectal Cancer, it is clinical
On have preferable application prospect.
Bibliography
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2.Blois,S.M.,et al.(2013)."Pregnancy-specific glycoprotein 1(PSG1)
activates TGF-[beta]and prevents dextran sodium sulfate(DSS)-induced colitis
in mice."Mucosal Immunol.
3.Camolotto,S.,et al.(2010)."Expression and transcriptional
regulation of individual pregnancy-specific glycoprotein genes in
differentiating trophoblast cells."Placenta 31(4):312-319.
4.Fialova,L.,et al.(1991)."[Serum levels of trophoblast-specific
beta-1-globulin(SP1)and alpha-1-fetoprotein(AFP)in pregnant women with
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5.Ha,C.T.,et al.(2005)."Binding of pregnancy-specific glycoprotein
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pregnancy-specific glycoprotein(Psg)gene locus."Bmc Genomics 6:4.
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Claims (8)
1. the product for detecting protein marker PSG3 concentration in plasma sample is being prepared for auxiliary diagnosis hepatocellular carcinoma
With the application in the kit of colorectal cancer patients.
2. application described in claim 1, wherein the detection is carried out using immuno-chemical method.
3. application described in claim 1, wherein the product of detection protein marker PSG3 concentration is to refer to specific detection
The molecule of PSG3 protein expressions.
4. the application described in claim 3, wherein the product of detection protein marker PSG3 concentration is nucleic acid, protein or chemical combination
Object.
5. the application described in claim 3, wherein the molecule of the specific detection PSG3 protein expressions is antibody.
6. the application described in claim 5, wherein the antibody is monoclonal antibody.
7. the application described in claim 3 or 5, wherein the molecule of the detection PSG3 protein expressions also carries detectable mark
Note.
8. the application described in claim 7, wherein also containing buffer solution and color developing agent in the kit or detection reagent.
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