CN103149371A - Application of biomarker for preparing medicine for predicting feedback response of 5-aminosalicylic acid in treatment of ulcerative colitis - Google Patents
Application of biomarker for preparing medicine for predicting feedback response of 5-aminosalicylic acid in treatment of ulcerative colitis Download PDFInfo
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Abstract
The invention discloses application of a biomarker for preparing a medicine for predicting feedback response of 5-aminosalicylic acid in treatment of ulcerative colitis. The biomarker determined in the invention is the basis of a target biomarker associated with gender difference response when 5-aminosalicylic acid (5-ASA) is used to treat ulcerative colitis (UC). The biomarker comprises a group of protein biomarkers which can differentiate response difference for treatment by 5-ASA between different genders and determine the curative effect by using 5-ASA under different UC conditions. Meanwhile, a novel drug target for a UC novel curative method is effectively determined and verified by using the biomarker with specificity for genders and disease focus parts, novel diagnostic reagents, medicines, methods and diagnostic standards are developed, and the application is used for establishing a UC treatment policy.
Description
Technical field
The invention belongs to field of biomedicine technology, be specifically related to the application of biomarker in the feedback response medicine of preparation prediction 5-aminosalicylic acid treatment ulcerative colitis.
Background technology
Ulcerative colitis (ulcerative colitis, UC are called for short the knot of bursting) is a kind of inflammatory bowel disease (IBD) of outbreak repeatedly that appears in large intestine or colon.UC patient shows the symptom identical with IBS (IBS) patient usually, and only IBS patient's situation wants slight, and this also makes making a definite diagnosis of UC very complicated.Similarly, the uncertain colitis that patient suffers from might not be also ulcerative colitis, thinks colitis and more be similar to another kind of inflammatory bowel disease Crow.
From anatomical angle, the performance of each patient's UC illness is different, and focus can only be positioned at sigmoid colon, also may extend to whole colon.Originally, UC patient mainly adopts non-specific broad spectrum antiphlogistic disease drug 5-aminosalicylic acid (5-ASA) to treat.When this methods for the treatment of is invalid, will take further based on cytotoxicity or biological methods for the treatment of the patient.The progressively therapy of this employing 5-ASA treatment UC can run into 60% failure when treatment moderate ulcerative colitis, and the probability of failure has reached 80% when adopting placebo treatment.In addition, the 5-ASA effective dose greater than 2.5 gram/skies of using clinically also fails to obtain well proof.
With respect to oral anti-inflammatory medicaments, the biopreparate price is very expensive, therefore, how to confirm fast in early days that the patient has response just to become very important to 5-ASA or other treatment method.The UC that takes at present progressively therapy does not consider patient's gender differences and the particular location of focus in colon.Take identical pesticide application strategy to be considered to the key factor of clinical treatment failure high rate to all UC patients.
Many relevant with IBD biomarkers system is by develop, comprising utilizing ight soil calprotectin and lactoferrin to confirm the inflammatory bowel disease patient, and disease serious degree and recurrence state estimated; Utilize biomarker such as the anti-yeast antibody of serum (ASCA) and core week ANCA (pANCA) etc. to distinguish UC and disease (CD) is thought in the Crow; And diagnose IBD and distinguish the diseases such as UC and CD together with utilizing the biomarkers such as change of serum C type Outer membrane protein antibody (anti-OmpC), immunoglobulin A (IgA) and anti-flagellin antibody (anti-CBir1) and ASCA and other biological label detecting.the IBD disease biomarker that has been identified at present comprises anti-GM-CSF (anti-GM-CSF) antibody, adhesion molecule integrin CD11b, TNFa (TNF-a), c reactive protein (CRP), aldehyde-ketone reductase family 1 member B10(AKR1B10), perforin (perforin), the k gene syncaryon factor (NF-kB), Gro-beta-T, aquaporin, kinesin, be connected factor protein (AP-1), complement protein C5a, Interleukin-2 Receptor (IL-2R), integrin, macrophage inflammatory protein (HCC-4), interleukin-17 (IL-7), MCP 1 (MCP-1), human macrophage stimulatory protein(SP) (MSP protein), interleukin-11 (IL-11), granulocyte colony stimulating factor (G-CSF), adrenocepter, people's matrix properdin (ST2), E-cadherin (E-cadhein), keratinocyte (KC) in the skin graft epidermis, interleukin 12/23p40(IL-12/23p40), IL-17 (IL-17), chloro tyrosine, the anti-human pancreatitis associated protein of multi-clone rabbit (PAP/REG3), macrophage migration inhibition factor (MIF), brain cancer missing gene 1(DMBT1), people's ALPHA-2u (LCN2), interleukin 2 2(IL-22), hoptoglobin, CCL2 0(CCL20), interleukin-6 (IL-6), interleukin Ⅲ 3(IL-33), the reddish black element (CAP37) that kills, ubiquitin factor E4A(E4A (UBE4A)), Gro-beta-T ligand 1 6(CXCL16), phylaxin, apolipoproteins A-IV, beta-alexin, gram Rot tumor susceptibility gene NOD2/CARD15 and NOD1/CARD4, Toll sample acceptor (TLR) 2 and 4, leptin, adiponectin, interleukin 10 (IL-10), DPP IV (DPP-IV) and Gro-beta-T acceptor 4(CXCR4) etc.These biomarkers are used to determine response and the biology treatment of steroids.But the feedback response when up to now, there is no relevant biomarker and system and can be used for determine using 5-ASA treatment UC patient.
As implied above, one of Main Means of UC traditional treatment is exactly to use 5-ASA, but the effect of 5-ASA when treatment active stage UC is only 30-40%.UC Pathological Physiology and other factors of affecting 5-ASA treatment response are still not clear.Confirmed notable difference from different sexes patient's the proteinogram, and the different parts equal angles that on anatomy, colitis occurs considers, UC is a kind of disease of complexity.Thereby, we need a kind of method, reagent or medicine of measurable potential effect when using 5-ASA treatment UC patient, also wish and effectively to treat UC patient's strategy by this means exploitation one cover, and a kind of new type of safe is effective, may depend on the methods for the treatment of of sex and lesions position.
Summary of the invention
The present invention is intended to overcome the deficiencies in the prior art, and the application of a kind of biomarker in the feedback response medicine of preparation prediction 5-aminosalicylic acid treatment ulcerative colitis is provided.
In order to achieve the above object, technical scheme provided by the invention is:
the application of biomarker in the feedback response medicine of preparation prediction 5-aminosalicylic acid treatment ulcerative colitis, described biomarker is selected from one or more in following albumen: interleukin-17 (IL-7), interleukin 1 α (IL-1 α), t cell growth factor (IL-5), interleukin Ⅲ (IL-3), interleukin-13 (IL-13), granulocyte colony stimulating factor (G-CSF), cytomegalovirus, lime virus, mitochondrial antibody, fibrinogen, Transin-1 (MMP-3), testosterone, anti-polymyositis (PM-1) antibody, proliferating cell nuclear antigen (PCNA) antibody, human T-cell's lymphocyte virus 1.2, cancer antigen 19.9, progesterone albumen, all anti-neutrophil leucocyte endochylema (pANCA) antibody of core, ribonucleoprotein-c(RNP (c)) antibody, varicella (V.zoster) albumen, ferritin, helicobacter pylori (H.pylori) albumen, (urging) erythropoietin(EPO), epidermal growth factor (EGF), C reactive protein, interleukin 1 ra(IL-1ra), herpes simplex virus-2 gG, herpes simplex virus-2 gD, C1Q antibody, thyroglobulin antibody, α-1 antitrypsin, phylaxin, interleukin-6 (IL-6), islet cells (GAD) antibody, leptin, Transin-1 (MMP-3), sex hormone binding globulin (SHBG), collagen the 6th antibody-like, interleukin 8 (IL-8), ribonucleoprotein-a(RNP (a)) antibody, double-stranded-DNA antibody, parainfluenza virus 1 albumen, Leishmania donovani, Angiotensin-Converting (ACE(CD143)), α-1 antitrypsin, schizotrypanum cruzi albumen, Scl-70 antibody, mumps virus, matrix metalloproteinase (MMP-3), MMP-2 (MMP-2), somatomedin (IGF-1) albumen, creatine kinase-MB, Angiotensin-Converting (ACE(CD143)), interleukin 15 (IL-15), interleukin-17 (IL-7), growth hormone, epstein-Barr virus nuclear antigen, calcitonin, immunoglobulin A (IgA), von Willebrand factor, tumor necrosis factor-alpha (TNF-α), double-stranded-DNA antibody, SSA antibody, triiodothyronine (T3) antibody, tumor necrosis factor-alpha (TNF-α), pancreatic polypeptide, C reactive protein, C1Q antibody, brain derived neurotrophic factor, cancer antigen 125, interleukin 10 (IL-10), protease 3 (cANCA) antibody.
Above-mentioned biomarker is sex-dependent type biomarker.
Preferably, described biomarker is selected from one or more in following albumen: interleukin-17 (IL-7), interleukin 1 α (IL-1 α), t cell growth factor (IL-5), interleukin Ⅲ (IL-3), interleukin-13 (IL-13), granulocyte colony stimulating factor (G-CSF), cytomegalovirus, lime virus, mitochondrial antibody, fibrinogen, Transin-1 (MMP-3), testosterone, anti-polymyositis (PM-1) antibody and proliferating cell nuclear antigen (PCNA) antibody.This group biomarker can predict to treat with 2.4 gram 5-ASA/ days and 4.8 gram 5-ASA/ days dosage to suffer from pancolitis and the extensive effect of men and women's property patient in 6 courses for the treatment of in week by a definite date of colitis effectively.
Preferably, described biomarker is selected from one or more in following albumen: human T-cell's lymphocyte virus 1.2, cancer antigen 19.9 and progesterone albumen.This group biomarker can effectively be predicted with 2.4 gram 5-ASA/ days and 4.8 gram 5-ASA/ days dosage and treat the effect of female patient in 6 courses for the treatment of in week by a definite date of suffering from the left hemicolon inflammation.
Preferably, described biomarker is selected from one or more in following albumen: interleukin-17 (IL-7), all anti-neutrophil leucocyte endochylema (pANCA) antibody of core, fibrinogen, ribonucleoprotein-c(RNP (c)) antibody and varicella (V.zoster) albumen.This group biomarker can effectively be predicted with 2.4 gram 5-ASA/ days and 4.8 gram 5-ASA/ days dosage and treat the effect of male patient in 6 courses for the treatment of in week by a definite date of suffering from the left hemicolon inflammation.
Preferably, described biomarker is selected from one or more in following albumen: ferritin and helicobacter pylori (H.pylori) albumen.This group biomarker can effectively be predicted with 2.4 gram 5-ASA/ days and 4.8 gram 5-ASA/ days dosage and treat the effect of female patient in 6 courses for the treatment of in week by a definite date of suffering from proctosigmoiditis.
Preferably, described biomarker is selected from one or more in following albumen: (urging) erythropoietin(EPO), epidermal growth factor (EGF), C reactive protein, interleukin 1 ra(IL-1ra), herpes simplex virus-2 gG, interleukin 1 α (IL-1 α), herpes simplex virus-2 gD, C1Q antibody and thyroglobulin antibody.This group biomarker can effectively be predicted with 2.4 gram 5-ASA/ days and 4.8 gram 5-ASA/ days dosage and treat the effect of male patient in 6 courses for the treatment of in week by a definite date of suffering from proctosigmoiditis.
Preferably, described biomarker is selected from one or more in following albumen: granulocyte colony stimulating factor (G-CSF), α-1 antitrypsin, phylaxin, interleukin-6 (IL-6), islet cells (GAD) antibody, leptin, Transin-1 (MMP-3), sex hormone binding globulin (SHBG), collagen the 6th antibody-like, interleukin 8 (IL-8), ribonucleoprotein-a(RNP (a)) antibody, cytomegalovirus, mitochondrial antibody, double-stranded-DNA antibody and parainfluenza virus 1 albumen.This group biomarker can diagnose all to suffer from men and women's property patient of pancolitis and extensive colitis effectively.
Preferably, described biomarker is selected from one or more in following albumen: granulocyte colony stimulating factor (G-CSF), Leishmania donovani, Angiotensin-Converting (ACE(CD143)), α-1 antitrypsin, mitochondrial antibody, schizotrypanum cruzi albumen, Scl-70 antibody, mumps virus, matrix metalloproteinase (MMP-3), helicobacter pylori (H.pylori) albumen, MMP-2 (MMP-2), ribonucleoprotein-c(RNP (c)) antibody and somatomedin (IGF-1) albumen.The diagnosable female patient of suffering from the left hemicolon inflammation of the target organism label of one or more in this group.
Preferably, described biomarker is selected from one or more in following albumen: granulocyte colony stimulating factor (G-CSF), creatine kinase-MB, Angiotensin-Converting (ACE(CD143)), interleukin 15 (IL-15), core week anti-neutrophil leucocyte endochylema (pANCA) antibody, leptin, interleukin-17 (IL-7), growth hormone, epstein-Barr virus nuclear antigen and somatomedin (IGF-1) albumen.In this group, the target organism label of one or more is diagnosed the male patient who suffers from the left hemicolon inflammation.
Preferably, described biomarker is selected from one or more in following albumen: calcitonin, interleukin 8 (IL-8), helicobacter pylori (H.pylori) albumen, immunoglobulin A (IgA), von Willebrand factor, interleukin-6 (IL-6), granulocyte colony stimulating factor (G-CSF), tumor necrosis factor-alpha (TNF-α), double-stranded-DNA antibody, SSA antibody and triiodothyronine (T3) antibody.In this group, the target organism label of one or more is diagnosed the female patient of suffering from proctosigmoiditis.This group biomarker also can be used as the target spot of exploitation UC methods for the treatment of.
Preferably, described biomarker is selected from one or more in following albumen: (urging) erythropoietin(EPO), testosterone, tumor necrosis factor-alpha (TNF-α), pancreatic polypeptide, C reactive protein, C1Q antibody, brain derived neurotrophic factor, cancer antigen 125, interleukin 10 (IL-10), interleukin-6 (IL-6) and protease 3 (cANCA) antibody.In this group, the target organism label of one or more is diagnosed the male patient who suffers from proctosigmoiditis.This group biomarker also can be used as the target spot of exploitation UC methods for the treatment of.
The biomarker of determining in the present invention can be used as drug target and is used for exploitation for UC patient's newtype drug methods for the treatment of.
The biomarker of determining in the present invention also can be used for screening and determines to have certain curative effect, can be used as the therapeutic compound of potential treatment UC patient medicine.
By what determine in comparison the present invention, the change of one or more target organism labels as above also can be monitored the result for the treatment of for UC patient's medicine.
The method and system that relates in the present invention also can be used for determining other albumen in disease approach middle and upper reaches and downstream, with as extra target organism label, or is used for exploitation treatment UC patient's medicine.
The target organism label of determining in the present invention also can be used for monitoring the result for the treatment of for UC patient's medicine.
The biomarker of confirming in the present invention is used for distinguishing the different sexes patient to the difference response of 5-ASA take UC as target by a histone biomarker.Therefore, effect when the present invention is mainly used in determining to use 5-ASA to treat the patient who suffers from different UC symptoms, the strategy and the new type of safe that also can be used for simultaneously developing effective treatment UC patient are effective, may depend on the treatment side strategy of sex and colitis lesions position.
Can utilize the biomarker that relates in the present invention to determine not respondent to 5-ASA at the UC commitment, thereby develop the clinical drug therapy method of more effective use 5-ASA a kind of.Determine not respondent to 5-ASA at the UC commitment, thus can with replacement therapy come faster, more effectively control disease.Find the how potential target spot and the target spot metabolic pathway that are used for the UC drug development, understand better the pathology of UC simultaneously.
The invention will be further described below in conjunction with principle and beneficial effect:
Use 5-ASA treatment moderate UC patient Shi Hui to run into 60% clinical failure, can run into 80% clinical failure when using placebo.Due to the understanding that lacks the Pathological Physiology of disease, the 5-ASA therapy and reckon without sex and colon in the difference of lesions position.Personalized drug therapy based on the development of clinical biomarker thing will provide more efficiently, consider individual therapeutic scheme.The patient who suffers from left hemicolon inflammation and proctosigmoiditis is normally very unmanageable clinically.But the probability that proctosigmoiditis patient develops into colon cancer does not obviously increase; The risk that the patient of pancolitis and extensive colitis develops into colon cancer is very high.Therefore, UC patient is conciliate plane according to sex learn upper different colons positions and be divided into the subgroup, then use the biomarker of different batches to predict that specifically these subgroups just become very important to the response of 5-ASA treatment.
The present invention has determined not protein biology label (" target organism label ") on the same group.By these target organism labels, the not respondent of 5-ASA can earlier be determined.Simultaneously, utilize these target organism labels can develop a kind of new clinical drug therapy method, and this efficient method can be controlled disease more quickly and effectively, and for those not the respondent seek replacement therapy.
Ten groups of concrete biomarker essence of the present invention are divided into two class target biomarkers:
Sex-dependent type serum (or blood plasma) the target organism label of result when the first kind comprises measurable use 5-ASA treatment slightly to moderate UC patient (success or failure).Doctors can use these target organism labels to decide best personalized UC therapeutic strategy as the instrument of uniqueness.This method has also been created not on the same group target organism label for the patient that suffers from colitis at different colons positions.
Equations of The Second Kind serum or blood plasma target organism label (nominal is " serum target organism label " herein) have defined particular sex, and above-mentioned specific colon position slightly to moderate UC patient.UC target organism label can be used for determining and verifying new UC drug target.These target organism labels or itself be exactly new drug target perhaps determine that by the pathology that helps us understand UC other molecules and albumen etc. are as new treatment target spot.These target organism labels also can be used as the new tool of screening UC therapeutic compound, and can be used for diagnosing slight UC to moderate.
Be described as follows:
The first kind: the sex-dependent type serum target organism label of prediction 5-ASA treatment results
First kind sex-dependent type serum target organism label is used for prediction to be used the 5-ASA treatment (left hemicolon is scorching at different colons positions, proctosigmoiditis, pancolitis and extensive colitis) suffer from slight effect (success or failure) during to moderate UC patient.In the present invention, " serum " of indication comprises serum and plasma simultaneously.
the first group of sex-dependent type serum target organism label that uses in the present invention comprises following protein biology label: interleukin-17 (IL-7), interleukin 1 α (IL-1 α), granulocyte colony stimulating factor (G-CSF), t cell growth factor (IL-5), interleukin Ⅲ (IL-3), cytomegalovirus, lime virus, mitochondrial antibody, fibrinogen, Transin-1 (MMP-3), testosterone, anti-polymyositis (PM-1) antibody, interleukin-13 (IL-13) and proliferating cell nuclear antigen (PCNA) antibody protein.According to statistic data evaluation (p value and difference multiple), first group of target organism label can predict to treat with 2.4 gram 5-ASA/ days and 4.8 gram 5-ASA/ days dosage to suffer from pancolitis and the extensive effect of men and women's property patient in 6 courses for the treatment of in week by a definite date of colitis effectively.The effect that the present invention utilizes a certain independent biomarker in first group of target organism label or combination in any to predict above-mentioned 5-ASA.
Second group of sex-dependent type serum target organism label comprises following biomarker: human T-cell's lymphocyte virus 1.2, cancer antigen 19.9 and progesterone albumen.According to statistic data evaluation (p value and difference multiple), second group of target organism label can effectively be predicted with 2.4 gram 5-ASA/ days and 4.8 gram 5-ASA/ days dosage and treat the effect of female patient in 6 courses for the treatment of in week by a definite date of suffering from the left hemicolon inflammation.The effect that the present invention utilizes a certain independent biomarker in second group of target organism label or combination in any to predict above-mentioned 5-ASA.
The 3rd group of sex-dependent type serum target organism label comprises following biomarker: interleukin-17 (IL-7), all anti-neutrophil leucocyte endochylema (pANCA) antibody of core, fibrinogen, ribonucleoprotein-c(RNP (c)) antibody and varicella (V.zoster) albumen.According to statistic data evaluation (p value and difference multiple), the 3rd group of target organism label can effectively be predicted with 2.4 gram 5-ASA/ days and 4.8 gram 5-ASA/ days dosage and treat the effect of male patient in 6 courses for the treatment of in week by a definite date of suffering from the left hemicolon inflammation.The present invention utilizes the 3rd group of a certain independent biomarker or the combination in any effect of predicting above-mentioned 5-ASA in the target organism label.
The 4th group of sex-dependent type serum target organism label comprises following biomarker: ferritin and helicobacter pylori (H.pylori) albumen.According to statistic data evaluation (p value and difference multiple), the 4th group of target organism label can effectively be predicted with 2.4 gram 5-ASA/ days and 4.8 gram 5-ASA/ days dosage and treat the effect of female patient in 6 courses for the treatment of in week by a definite date of suffering from proctosigmoiditis.The present invention utilizes the 4th group of a certain independent biomarker or the combination in any effect of predicting above-mentioned 5-ASA in the target organism label.
The 5th group of sex-dependent type serum target organism label comprises following biomarker: (urging) erythropoietin(EPO), epidermal growth factor (EGF), C reactive protein, interleukin 1 ra(IL-1ra), herpes simplex virus-2 gG, interleukin 1 α (IL-1 α), herpes simplex virus-2 gD, C1Q antibody and thyroglobulin antibody albumen.According to statistic data evaluation (p value and difference multiple), the 5th group of target organism label can effectively be predicted with 2.4 gram 5-ASA/ days and 4.8 gram 5-ASA/ days dosage and treat the effect of male patient in 6 courses for the treatment of in week by a definite date of suffering from proctosigmoiditis.The present invention utilizes the 5th group of a certain independent biomarker or the combination in any effect of predicting above-mentioned 5-ASA in the target organism label.
Equations of The Second Kind: sex-dependent type serum target organism label is used for slight diagnosis and new drug development to moderate UC:
Equations of The Second Kind sex-dependent type serum target organism label in the present invention is used for slight diagnosis and new drug development to moderate UC.In the present invention, " serum " of indication comprises serum and plasma simultaneously.
the 6th group of serum target organism label comprises following biomarker: granulocyte colony stimulating factor (G-CSF), α-1 antitrypsin, phylaxin, interleukin-6 (IL-6), islet cells (GAD) antibody, leptin, Transin-1 (MMP-3), sex hormone binding globulin (SHBG), collagen the 6th antibody-like, interleukin 8 (IL-8), ribonucleoprotein-a(RNP (a)) antibody, cytomegalovirus, mitochondrial antibody, double-stranded-DNA antibody and parainfluenza virus 1 albumen.According to statistic data evaluation (p value and difference multiple), the 6th group of target organism label can be diagnosed patient's (comprising masculinity and femininity) of all pancolitises and extensive colitis effectively.The present invention utilizes the 6th group of a certain independent biomarker or the combination in any in the target organism label to diagnose pancolitis and extensive colitis, and develops new UC methods for the treatment of.
the 7th group of serum target organism label comprises following biomarker: granulocyte colony stimulating factor (G-CSF), Leishmania donovani, Angiotensin-Converting (ACE(CD143)), α-1 antitrypsin, mitochondrial antibody, schizotrypanum cruzi albumen, Scl-70 antibody, mumps virus, matrix metalloproteinase (MMP-3), helicobacter pylori (H.pylori) albumen, MMP-2 (MMP-2), ribonucleoprotein-c(RNP (c)) antibody and somatomedin (IGF-1) albumen.According to statistic data evaluation (p value and difference multiple), the 7th group of target organism label can be diagnosed the female patient of suffering from the left hemicolon inflammation effectively.The present invention utilizes the 7th group of a certain independent biomarker or the combination in any in the target organism label to diagnose the female patient of suffering from the left hemicolon inflammation, and develops new UC methods for the treatment of.
The 8th group of serum target organism label comprises following biomarker: granulocyte colony stimulating factor (G-CSF), creatine kinase-MB, Angiotensin-Converting (ACE(CD143)), interleukin 15 (IL-15), myeloperoxidase (pANCA) antibody, leptin, interleukin-17 (IL-7), growth hormone, epstein-Barr virus nuclear antigen and somatomedin (IGF-1) albumen.According to statistic data evaluation (p value and difference multiple), the 8th group of target organism label can be diagnosed the male patient who suffers from the left hemicolon inflammation effectively.The present invention utilizes the 8th group of a certain independent biomarker or the combination in any in the target organism label to diagnose the male patient who suffers from the left hemicolon inflammation, and develops new UC methods for the treatment of.
The 9th group of serum target organism label comprises following biomarker: calcitonin, interleukin 8 (IL-8), helicobacter pylori (H.pylori) albumen, immunoglobulin A (IgA), von Willebrand factor, interleukin-6 (IL-6), granulocyte colony stimulating factor (G-CSF), tumor necrosis factor-alpha (TNF-α), double-stranded-DNA antibody, SSA antibody and triiodothyronine (T3) antibody protein.According to statistic data evaluation (p value and difference multiple), the 9th group of target organism label can be diagnosed the female patient of suffering from proctosigmoiditis effectively.The present invention utilizes the 9th group of a certain independent biomarker or the combination in any in the target organism label to diagnose the female patient of suffering from proctosigmoiditis, and develops new UC methods for the treatment of.
The tenth group of serum target organism label comprises following biomarker: (urging) erythropoietin(EPO), testosterone, tumor necrosis factor-alpha (TNF-α), pancreatic polypeptide, C reactive protein, C1Q antibody, brain derived neurotrophic factor, cancer antigen 125, interleukin 10 (IL-10), interleukin-6 (IL-6) and protease 3 (cANCA) antibody protein.According to statistic data evaluation (p value and difference multiple), the tenth group of target organism label can be diagnosed the male patient who suffers from proctosigmoiditis effectively.The present invention utilizes the tenth group of a certain independent biomarker or the combination in any in the target organism label to diagnose the male patient who suffers from proctosigmoiditis, and develops new UC methods for the treatment of.
The application of the present invention to the target organism label, the possibility that invalid medicine capable of reducing using is treated reduces patient and experiences unnecessary 5-ASA spinoff and the possibility because using invalid medicine to cause clinical recovery to postpone.In addition, recover to postpone to have clinically very great meaning, because the pancolitis patient has very large risk to develop into colon cancer.Therefore, in the present invention, the personalized medicine for patient UC all can benefit patient, prescription doctor and insurance company.
Unite in specific UC condition and with other clinical factors the target organism label of determining when using, can be the single patient specific drug therapy of customization and Managed Solution, also can be used for developing methods for the treatment of and medicine.
The target organism label of confirming in the present invention also can be used as conventional drug target, is used for newtype drug and methods for the treatment of that UC patient can be effectively treated in exploitation.For example, if significant difference appears in patient's target organism label level, can determine whether prescription drug can improve patient's situation.
Can utilize the target organism label of confirming as a kind of screening mechanism in the present invention herein, confirm that result for the treatment of may be arranged and have very much prospect to become the compound of the medicine for the treatment of UC.For example, if certain compound can affect, produces, modifies or change one or more target organism labels under specific UC condition, so this compound just can be used as the medicine under this kind UC condition.
Can utilize the target organism label of confirming in the present invention, by the relatively variation of one or more biomarker levels as above, monitor the curative effect of UC patient's administration.
Also can determine under specific UC condition, other albumen of the upstream and downstream of disease approach, these albumen can be used as extra target organism label and formulate medicine under this specific UC condition.In addition, after being determined when change that these albumen cause with on the impact of other target organism labels, the information that obtains can also help us understand the pathogenic mechanism under this specific UC condition.
Can utilize the target organism label of confirming to monitor the curative effect of the medicine that gives UC patient herein.
Embodiment
Embodiment 1
The invention provides sex-dependent type serum target organism label, when patient uses one or more biomarkers to show to differ from normal level, can predict thus that (left hemicolon is scorching using the 5-ASA different colons for the treatment of positions, proctosigmoiditis, pancolitis and extensive colitis) suffer from slight curative effect during to moderate UC patient.
5-ASA does not respond the application of serum biomarker in personalized clinical practice
As mentioned above, use 5-ASA treatment moderate UC patient Shi Hui to run into 60% clinical failure, can run into 80% clinical failure when using placebo.Due to the understanding that lacks the Pathological Physiology of disease, the 5-ASA therapy and reckon without sex and colon in the difference of lesions position.Personalized drug therapy based on the development of clinical biomarker thing will provide more efficiently, consider individual therapeutic scheme.Determined not albumen target organism label on the same group in the present invention, and be used for distinguishing the 5-ASA that causes because sex is different with the colitis lesions position and treat response difference.By these target organism labels, the not respondent of 5-ASA can earlier be determined.Simultaneously, utilize these target organism labels efficient clinical drug therapy method of Development of Novel fully, and by respondent's replacement therapy is not controlled more quickly and effectively disease.
Generally, no matter the focus of colitis how, in clinical standard practices all with 5-ASA as conventional medicine open patient.By following limiting examples, the present invention has exemplified the complete procedure how prediction 5-ASA responds in the patient who suffers from pancolitis and extensive colitis.At first this process is determined one and is made a definite diagnosis the patient who suffers from UC, then determine the position of colon inflammation by the colonoscopy of routine.Before patient's colitis was treated, the clinician obtained one or more blood samples and serum from the patient, then utilized the above-mentioned suitable non-response target organism of 5-ASA label to measure its relevant level.The level of target organism label and standard value as shown in table 1 are compared, acquired results is the prediction of 5-ASA curative effect (dosage is 2.4 gram 5-ASA/ days and 4.8 gram 5-ASA/ days, and treatment suffers from the effect of men and women's property patient in 6 courses for the treatment of in week by a definite date of pancolitis and extensive colitis).For example, if not responding the water-glass of target organism label, patient's specificity 5-ASA do not reveal (for example variation of difference multiple of obvious difference, IL-7 〉-1.57, IL-1 α 〉-1.34, G-CSF 〉-1.92, IL-5 〉-1.36, IL-3 〉-1.30), the 5-ASA methods for the treatment of is probably invalid to this patient so.
except the above-mentioned target organism label that is common to the men and women's property patient who suffers from pancolitis and extensive colitis, can also use extra biomarker further to compare, such as the level of contrast women specificity target organism label (cytomegalovirus 〉-1.55, lime virus 〉-1.54, mitochondrial antibody＜1.59, fibrinogen 〉-1.57, MMP-3 〉-1.57), perhaps the level of male sex's specificity target organism label (PM-1 antibody 〉-1.26, testosterone 〉-1.42, IL-13 〉-1.36, PCNA antibody 〉-1.71) to determine that whether the patient is to the response of 5-ASA treatment nothing.Can consider again at last to use alternative medicine (for example anti-TNF molecule) to treat.
Table 1. predictability target organism label is used for pancolitis and the extensive colitis patient of the non-response of diagnosis 5-ASA
* use 5-ASA treatment pancolitis and extensively successfully organize during colitis and ineffective group between the horizontal p value of biomarker benchmark.
* use 5-ASA treatment pancolitis and extensively successfully organize during colitis and ineffective group between biomarker level difference multiple benchmark.
# is used for the non-response target organism of the specificity 5-ASA label of pancolitis and extensive colitis female patient.
## is used for pancolitis and extensive colitis male patient's the non-response target organism of specificity 5-ASA label.
Embodiment 2
Be used for suffering from the female patient prediction 5-ASA response of left hemicolon inflammation.At first determine one and make a definite diagnosis the patient who suffers from the left hemicolon inflammation, then make a definite diagnosis the left hemicolon inflammation by the colonoscopy of routine.When generally, the treatment left hemicolon is scorching clinically all with 5-ASA as conventional medicine open patient.Before patient's colitis was treated, the clinician checked and obtains sample to carrying out the one or many blood sample, and then serum, utilize the above-mentioned suitable non-response target organism of 5-ASA label to measure its relevant level at last.The target organism label level that records and standard value as shown in table 2 are compared, acquired results is the prediction of 5-ASA curative effect (dosage is 2.4 gram 5-ASA/ days and 4.8 gram 5-ASA/ days, and treatment suffers from the effect of female patient in 6 courses for the treatment of in week by a definite date of left hemicolon inflammation).For example, if not responding the water-glass of target organism label, patient's specificity 5-ASA do not reveal (for example variation of difference multiple of obvious difference, human T-cell's lymphocyte virus 1.2〉1.71, cancer antigen 19.9 〉-1.33, progesterone albumen〉2.26), the 5-ASA methods for the treatment of is probably invalid to this patient so.Can consider at last to use alternative medicine (for example anti-TNF molecule) to treat.
Table 2. predictability biomarker is used for the scorching female patient of left hemicolon of the non-response of diagnosis 5-ASA
Successfully organize when * using the scorching female patient of 5-ASA treatment left hemicolon and ineffective group between the horizontal p value of biomarker benchmark.
* successfully organize when using the scorching female patient of 5-ASA treatment left hemicolon and ineffective group between biomarker level difference multiple benchmark.
Embodiment 3
Be used for the method and system in male patient's prediction 5-ASA response of suffering from the left hemicolon inflammation.At first determine one and make a definite diagnosis the patient who suffers from the left hemicolon inflammation, then make a definite diagnosis the left hemicolon inflammation by the colonoscopy of routine.When generally, the treatment left hemicolon is scorching clinically all with 5-ASA as conventional medicine open patient.Before patient's colitis was treated, the clinician checked and obtains sample to carrying out the one or many blood sample, and then serum, utilize the above-mentioned suitable non-response target organism of 5-ASA label to measure its relevant level at last.The target organism label level that records and standard value as shown in table 3 are compared, acquired results is the prediction of 5-ASA curative effect (dosage is 2.4 gram 5-ASA/ days and 4.8 gram 5-ASA/ days, and treatment suffers from the effect of male patient in 6 courses for the treatment of in week by a definite date of left hemicolon inflammation).For example, if not responding the water-glass of target organism label, patient's specificity 5-ASA do not reveal (for example variation of difference multiple of obvious difference, IL-7〉1.59, pANCA antibody 〉-1.43, fibrinogen 〉-10.27, RNP (c) antibody 〉-1.62, varicella albumen 〉-1.34), the 5-ASA methods for the treatment of is probably invalid to this patient so.Can consider at last to use alternative medicine (for example anti-TNF molecule) to treat.
Table 3. predictability biomarker is used for the scorching male patient of left hemicolon of the non-response of diagnosis 5-ASA
Successfully organize when * using the scorching male patient of 5-ASA treatment left hemicolon and ineffective group between the horizontal p value of biomarker benchmark.
* successfully organize when using the scorching male patient of 5-ASA treatment left hemicolon and ineffective group between biomarker level difference multiple benchmark.
Embodiment 4
Be used for suffering from the female patient prediction 5-ASA response of proctosigmoiditis.At first determine one and make a definite diagnosis the patient who suffers from proctosigmoiditis, then make a definite diagnosis proctosigmoiditis by the colonoscopy of routine.Generally, treatment during proctosigmoiditis clinically all with 5-ASA as conventional medicine open patient.Before patient's proctosigmoiditis is treated, the clinician checks and obtains sample to carrying out the one or many blood sample, then serum, utilize the above-mentioned suitable non-response target organism of 5-ASA label to measure its relevant level at last.The target organism label level that records and standard value as shown in table 4 are compared, acquired results is the prediction of 5-ASA curative effect (dosage is 2.4 gram 5-ASA/ days and 4.8 gram 5-ASA/ days, and treatment suffers from the effect of female patient in 6 courses for the treatment of in week by a definite date of proctosigmoiditis).For example, if not responding the water-glass of target organism label, patient's specificity 5-ASA do not reveal (for example variation of difference multiple of obvious difference, ferritin〉1.58, helicobacter pylori albumen〉2.07), the 5-ASA methods for the treatment of is probably invalid to this patient so.Can consider at last to use alternative medicine (for example anti-TNF molecule) to treat.
Table 4. predictability biomarker is used for the proctosigmoiditis female patient of the non-response of diagnosis 5-ASA
Albumen P value * difference multiple * *
Ferritin 0.011 1.58
Helicobacter pylori albumen 0.017 2.07
Successfully organize when * using 5-ASA treatment proctosigmoiditis female patient and ineffective group between the horizontal p value of biomarker benchmark.
* successfully organize when using 5-ASA treatment proctosigmoiditis female patient and ineffective group between biomarker level difference multiple benchmark.
Embodiment 5
Be used for suffering from male patient's prediction 5-ASA response of proctosigmoiditis.At first determine one and make a definite diagnosis the patient who suffers from proctosigmoiditis, then make a definite diagnosis proctosigmoiditis by the colonoscopy of routine.Generally, treatment during proctosigmoiditis clinically all with 5-ASA as conventional medicine open patient.Before patient's proctosigmoiditis is treated, the clinician checks and obtains sample to carrying out the one or many blood sample, then serum, utilize the above-mentioned suitable non-response target organism of 5-ASA label to measure its relevant level at last.The target organism label level that records and standard value as shown in table 5 are compared, acquired results is the prediction of 5-ASA curative effect (dosage is 2.4 gram 5-ASA/ days and 4.8 gram 5-ASA/ days, and treatment suffers from the effect of male patient in 6 courses for the treatment of in week by a definite date of proctosigmoiditis).For example, if not responding the water-glass of target organism label, patient's specificity 5-ASA do not reveal (for example variation of difference multiple of obvious difference, (urging) erythropoietin(EPO) 〉-2.43, EGF〉1.74, C reactive protein 〉-1.31, IL-1ra 〉-1.39, herpes simplex virus-2 gG 〉-1.77, IL-1 α〉1.27, herpes simplex virus-2 gD 〉-1.77, C1Q antibody〉1.40, thyroglobulin antibody 〉-1.93), the 5-ASA methods for the treatment of is probably invalid to this patient so.Can consider at last to use alternative medicine (for example anti-TNF molecule) to treat.
Table 5. predictability biomarker is used for the proctosigmoiditis male patient of the non-response of diagnosis 5-ASA
Successfully organize when * using 5-ASA treatment proctosigmoiditis male patient and ineffective group between the horizontal p value of biomarker benchmark.
* successfully organize when using 5-ASA treatment proctosigmoiditis male patient and ineffective group between biomarker level difference multiple benchmark.
Embodiment 7
Serum target organism label slight to the diagnosis of moderate UC disease and the application in new drug development
The target organism label by determining in the 6th all samples that the present invention mentions is the specific UC serum target organism label of sex and colon Position-based type, can be used for the early diagnosis of disease, the personalized UC medicine of development of new, measure response or the screening therapeutic compound of therapeutic scheme, " serum " mentioned herein comprises serum and plasma simultaneously.
Following instance has been illustrated one group of target organism label (table 6) that is used for pancolitis and extensive colitis, can be used for drug development, screening compound, medical diagnosis on disease and treatment response monitoring.Usually in fact, the risk that the patient who suffers from inflammation at other positions of colon develops into colon cancer is than only having the patient of disease much higher at the rectum position, thus the early diagnosis of disease and effectively treatment just seem especially important.The target organism label of determining in table 6 is the specific UC biomarker of sex and lesions position, and the target spot that can be used as the disease early diagnosis is used for the exploitation of Novel individualized medicine, the tolerance of drug therapy response and the screening of therapeutic compound.
Table 6. can be used for the disease early diagnosis as the UC target spot of pancolitis and extensive colitis, UC new drug development, the biomarker of drug therapy response tolerance and therapeutic compound screening
* use 5-ASA treatment pancolitis and extensively during colitis, successfully the 6th horizontal p value of all biomarker things benchmark between group and ineffective group.
* uses 5-ASA treatment pancolitis and extensively during colitis, successfully the 6th all biomarker thing level difference multiple benchmark between group and ineffective group.
The pancolitis that * * only finds in female patients and extensive colitis biomarker.
The patient who the target organism label is used for suffering from the specific UC state of an illness.In this example, patient is diagnosed with pancolitis and extensive colitis, and the target organism label is used for drug target, drug screening, and diagnosis and treatment response are monitored.In this special case, determine that is at first made a definite diagnosis a female patients of suffering from pancolitis and extensive colitis, then make a definite diagnosis pancolitis and extensive colitis by the colonoscopy of routine.Before patient's active pancolitis was treated with extensive colitis, the clinician carried out the one or many blood sample to it and checks and obtain sample, and then the level of then serum, and mensuration target organism label begins the medication to patient.After medication a period of time,, the clinician again carries out the blood sample inspection and obtains sample, then serum it.With the target organism label level that records and specific pancolitis as shown in table 6 and extensively the level standard value of colitis compare, then according to the result of variations of target organism label level, can predict to the effect of medicine.If it is obvious that patient's target organism label level changes difference, we just can determine whether improved patient's situation to medicine.The present invention can be used for the exploitation of Novel individualized UC medicine obviously, monitoring and the tolerance of patient to the drug therapy response, and the screening of therapeutic compound.
Embodiment 8
Following instance has been illustrated one group of target organism label (table 7) that is used for suffering from the scorching female patient of left hemicolon, can be used for drug development, screening compound, medical diagnosis on disease and treatment response monitoring.Usually in fact, it is more much higher than the scorching patient of women left hemicolon that the patient who suffers from inflammation at other positions of colon develops into the risk of colon cancer, so the early diagnosis of disease and effective treatment just seem especially important.The target organism label of herein determining is the specific UC biomarker of sex and lesions position, and the target spot that can be used as the disease early diagnosis is used for the exploitation of Novel individualized medicine, the tolerance of drug therapy response and the screening of therapeutic compound.
Determine that one is made a definite diagnosis the female patients of suffering from the left hemicolon inflammation, then makes a definite diagnosis the left hemicolon inflammation by the colonoscopy of routine.Before patient's left hemicolon inflammation was treated, the clinician carried out the one or many blood sample to it and checks and obtain sample, and then the level of then serum, and mensuration target organism label begins the medication to patient.After medication a period of time, the clinician again carries out the blood sample inspection and obtains sample, then serum it.The level standard value of the target organism label level that records and specific left hemicolon inflammation as shown in table 7 is compared, then according to the result of variations of target organism label level, can predict to the effect of medicine.If it is obvious that patient's target organism label level changes difference, we just can determine whether improved patient's situation to medicine.
Table 7. can be used for the disease early diagnosis as the scorching patient UC of women's left hemicolon target spot, UC new drug development, the biomarker of drug therapy response tolerance and therapeutic compound screening
When * using the scorching female patient of 5-ASA treatment left hemicolon, successful the 6th horizontal p value of all biomarker things benchmark between group and ineffective group.
When * uses the scorching female patient of 5-ASA treatment left hemicolon, successful the 6th all biomarker thing level difference multiple benchmark between group and ineffective group.
Embodiment 9
Following instance has been illustrated one group of target organism label (table 8) that is used for suffering from the scorching male patient of left hemicolon, can be used for drug development, screening compound, medical diagnosis on disease and treatment response monitoring.The target organism label of herein determining is the specific UC biomarker of sex and lesions position, and the target spot that can be used as the disease early diagnosis is used for the exploitation of Novel individualized medicine, the tolerance of drug therapy response and the screening of therapeutic compound.This process comprises that determining one makes a definite diagnosis the male patient of suffering from the left hemicolon inflammation, then makes a definite diagnosis the left hemicolon inflammation by the colonoscopy of routine.Before patient's left hemicolon inflammation was treated, the clinician carried out the one or many blood sample to it and checks and obtain sample, and then the level of then serum, and mensuration target organism label begins the medication to patient.After medication a period of time,, the clinician again carries out the blood sample inspection and obtains sample, then serum it.The target organism label level that records and specified level standard value as shown in table 8 are compared, then according to the result of variations of target organism label level, can predict to the effect of medicine.If it is obvious that patient's target organism label level changes difference, we just can determine whether improved patient's situation to medicine.
Table 8. can be used for the disease early diagnosis as the scorching patient UC of male sex's left hemicolon target spot, UC new drug development, the biomarker of drug therapy response tolerance and therapeutic compound screening
When * using the scorching male patient of 5-ASA treatment left hemicolon, successful the 6th horizontal p value of all biomarker things benchmark between group and ineffective group.
When * uses the scorching male patient of 5-ASA treatment left hemicolon, successful the 6th all biomarker thing level difference multiple benchmark between group and ineffective group.
Embodiment 10
Following instance has been illustrated one group of target organism label (table 9) that is used for suffering from the proctosigmoiditis female patient, can be used for drug development, screening compound, medical diagnosis on disease and treatment response monitoring.The target organism label of herein determining is the specific UC biomarker of sex and lesions position, and the target spot that can be used as the disease early diagnosis is used for the exploitation of Novel individualized medicine, the tolerance of drug therapy response and the screening of therapeutic compound.This process comprises that determining one makes a definite diagnosis the female patients of suffering from proctosigmoiditis, then makes a definite diagnosis proctosigmoiditis by the colonoscopy of routine.Before patient's proctosigmoiditis was treated, the clinician carried out the one or many blood sample to it and checks and obtain sample, and then the level of then serum, and mensuration target organism label begins the medication to patient.After medication a period of time,, the clinician again carries out the blood sample inspection and obtains sample, then serum it).The target organism label level that records and specified level standard value as shown in table 9 are compared, then according to the result of variations of target organism label level, can predict to the effect of medicine).If it is obvious that patient's target organism label level changes difference, we just can determine whether improved patient's situation to medicine.
Table 9. can be used for the disease early diagnosis as female rectum sigmoiditis patient UC target spot, UC new drug development, the biomarker of drug therapy response tolerance and therapeutic compound screening
When * using 5-ASA treatment proctosigmoiditis female patient, successful the 6th horizontal p value of all biomarker things benchmark between group and ineffective group.
When * uses 5-ASA treatment proctosigmoiditis female patient, successful the 6th all biomarker thing level difference multiple benchmark between group and ineffective group.
Embodiment 11
Following instance has been illustrated one group of target organism label (table 10) that is used for suffering from the proctosigmoiditis male patient, can be used for drug development, screening compound, medical diagnosis on disease and treatment response monitoring.The target organism label of herein determining is the specific UC biomarker of sex and lesions position, and the target spot that can be used as the disease early diagnosis is used for the exploitation of Novel individualized medicine, the tolerance of drug therapy response and the screening of therapeutic compound.This process comprises that determining one makes a definite diagnosis the male patient of suffering from proctosigmoiditis, then makes a definite diagnosis proctosigmoiditis by the colonoscopy of routine.Before patient's proctosigmoiditis was treated, the clinician carried out the one or many blood sample to it and checks and obtain sample, and then the level of then serum, and mensuration target organism label begins the medication to patient.After medication a period of time,, the clinician again carries out the blood sample inspection and obtains sample, then serum it.The target organism label level that records and specified level standard value as shown in table 9 are compared, then according to the result of variations of target organism label level, can predict to the effect of medicine.If it is obvious that patient's target organism label level changes difference, we just can determine whether improved patient's situation to medicine.
Table 10. can be used for the disease early diagnosis as male sex's proctosigmoiditis patient UC target spot, UC new drug development, the biomarker of drug therapy response tolerance and therapeutic compound screening
When * using 5-ASA treatment proctosigmoiditis male patient, successful the 6th horizontal p value of all biomarker things benchmark between group and ineffective group.
When * uses 5-ASA treatment proctosigmoiditis male patient, successful the 6th all biomarker thing level difference multiple benchmark between group and ineffective group.
Claims (11)
1. the application of biomarker in the feedback response medicine of preparation prediction 5-aminosalicylic acid treatment ulcerative colitis, described biomarker is selected from one or more in following albumen: interleukin-17, interleukin 1 α, t cell growth factor, interleukin Ⅲ, interleukin-13, granulocyte colony stimulating factor, cytomegalovirus, lime virus, mitochondrial antibody, fibrinogen, Transin-1, testosterone, anti-polymyositis antibody, antibody to proliferating cell nuclear antigen, human T-cell's lymphocyte virus 1.2, cancer antigen 19.9, progesterone albumen, the all ANCAs of core, ribonucleoprotein-c antibody, varicella albumen, ferritin, helicobacter pylori albumen, erythropoietin(EPO), epidermal growth factor, C reactive protein, interleukin 1 ra, herpes simplex virus-2 gG, herpes simplex virus-2 gD, C1Q antibody, thyroglobulin antibody, α-1 antitrypsin, phylaxin, interleukin-6, insular cellular antibody, leptin, Transin-1, sex hormone binding globulin, collagen the 6th antibody-like, interleukin 8, ribonucleoprotein-a antibody, double-stranded-DNA antibody, parainfluenza virus 1 albumen, Leishmania donovani, Angiotensin-Converting, α-1 antitrypsin, schizotrypanum cruzi albumen, Scl-70 antibody, mumps virus, matrix metalloproteinase, MMP-2, somatomedin albumen, creatine kinase-MB, Angiotensin-Converting, interleukin 15, interleukin-17, growth hormone, epstein-Barr virus nuclear antigen, calcitonin, immunoglobulin A, von Willebrand factor, tumor necrosis factor-alpha, double-stranded-DNA antibody, SSA antibody, triiodothyronine antibody, tumor necrosis factor-alpha, pancreatic polypeptide, C reactive protein, C1Q antibody, brain derived neurotrophic factor, cancer antigen 125, interleukin 10, protease 3 antibody.
2. application as claimed in claim 1, it is characterized in that, described biomarker is selected from one or more in following albumen: interleukin-17, interleukin 1 α, t cell growth factor, interleukin Ⅲ, interleukin-13, granulocyte colony stimulating factor, cytomegalovirus, lime virus, mitochondrial antibody, fibrinogen, Transin-1, testosterone, anti-polymyositis antibody and antibody to proliferating cell nuclear antigen.
3. application as claimed in claim 1, is characterized in that, described biomarker is selected from one or more in following albumen: human T-cell's lymphocyte virus 1.2, cancer antigen 19.9 and progesterone albumen.
4. application as claimed in claim 1, is characterized in that, described biomarker is selected from one or more in following albumen: interleukin-17, all ANCAs of core, fibrinogen, ribonucleoprotein-c antibody and varicella albumen.
5. application as claimed in claim 1, is characterized in that, described biomarker is selected from one or more in following albumen: ferritin and helicobacter pylori albumen.
6. application as claimed in claim 1, it is characterized in that, described biomarker is selected from one or more in following albumen: erythropoietin(EPO), epidermal growth factor, C reactive protein, interleukin 1 ra, herpes simplex virus-2 gG, interleukin 1 α, herpes simplex virus-2 gD, C1Q antibody and thyroglobulin antibody.
7. application as claimed in claim 1, it is characterized in that, described biomarker is selected from one or more in following albumen: granulocyte colony stimulating factor, α-1 antitrypsin, phylaxin, interleukin-6, insular cellular antibody, leptin, Transin-1, sex hormone binding globulin, collagen the 6th antibody-like, interleukin 8, ribonucleoprotein-a antibody, cytomegalovirus, mitochondrial antibody, double-stranded-DNA antibody and parainfluenza virus 1 albumen.
8. application as claimed in claim 1, it is characterized in that, described biomarker is selected from one or more in following albumen: granulocyte colony stimulating factor, Leishmania donovani, Angiotensin-Converting, α-1 antitrypsin, mitochondrial antibody, schizotrypanum cruzi albumen, Scl-70 antibody, mumps virus, matrix metalloproteinase, helicobacter pylori albumen, MMP-2, ribonucleoprotein-c antibody and somatomedin albumen.
9. application as claimed in claim 1, it is characterized in that, described biomarker is selected from one or more in following albumen: granulocyte colony stimulating factor, creatine kinase-MB, Angiotensin-Converting, interleukin 15, all ANCAs of core, leptin, interleukin-17, growth hormone, epstein-Barr virus nuclear antigen and somatomedin albumen.
10. application as claimed in claim 1, it is characterized in that, described biomarker is selected from one or more in following albumen: calcitonin, interleukin 8, helicobacter pylori albumen, immunoglobulin A, von Willebrand factor, interleukin-6, granulocyte colony stimulating factor, tumor necrosis factor-alpha, double-stranded-DNA antibody, SSA antibody and triiodothyronine antibody.
11. application as claimed in claim 1, it is characterized in that, described biomarker is selected from one or more in following albumen: erythropoietin(EPO), testosterone, tumor necrosis factor-alpha, pancreatic polypeptide, C reactive protein, C1Q antibody, brain derived neurotrophic factor, cancer antigen 125, interleukin 10, interleukin-6 and protease 3 antibody.
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