CN109251241A - Detect neonatal necrotizing enterocolitis peripheral blood inflammatory biomarker Zonulin and its application - Google Patents
Detect neonatal necrotizing enterocolitis peripheral blood inflammatory biomarker Zonulin and its application Download PDFInfo
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- CN109251241A CN109251241A CN201811269273.0A CN201811269273A CN109251241A CN 109251241 A CN109251241 A CN 109251241A CN 201811269273 A CN201811269273 A CN 201811269273A CN 109251241 A CN109251241 A CN 109251241A
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- zonulin
- peripheral blood
- necrotizing enterocolitis
- inflammatory biomarker
- neonatal necrotizing
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/06—Gastro-intestinal diseases
- G01N2800/065—Bowel diseases, e.g. Crohn, ulcerative colitis, IBS
Abstract
The present invention provides a kind of detection neonatal necrotizing enterocolitis peripheral blood inflammatory biomarker Zonulin, and the inflammatory biomarker Zonulin includes having the amino acid sequence as shown in SEQ ID:1.Present invention determine that Zonulin and the index of neonatal necrotizing enterocolitis peripheral blood sample are closely related, it is positively correlated by stages with Bell, it can be detected as marker for neonatal necrotizing enterocolitis peripheral blood, provide effective evidence for the prediction, diagnosis and screening of neonatal necrotizing enterocolitis.The present invention also provides a kind of kit for detecting newborn's peripheral blood sample, the reagent comprising specific recognition inflammatory biomarker Zonulin, this method is easy to be quick and economical and practical.
Description
Technical field
The present invention relates to neonatal necrotizing enterocolitis peripheral blood inflammatory biomarkers, and in particular to inflammatory biology
Marker Zonulin and its application.
Background technique
Intestinal flora field planting, formula milk are fed and other factors collaboration causes the immature intestinal mucosa of premature to be in
Inflammatory reaction state is spent, making enterocyte damage, even necrosis is neonatal necrotizing enterocolitis (necrotizing
Enterocolitis of newborn, NEC) basic pathology physiological characteristic.Therefore, intestinal inflammation is not only in regulation
Play a significant role in epithelial cell proliferation, differentiation and transition process, in intestinal epithelial cell damage, apoptosis, necrosis progression
Play a significant role.Therefore, important link of the inflammatory reaction as NEC occurrence and development, more and more researchs go to seek at present
Inflammatory biomarker relevant to NEC early diagnosis and progression of disease.
Inflammatory biomarker and pathogenesis, disease progression and severity are closely related, can be used for evaluating the state of an illness, treat
Effect has clinical indicative function well.Inflammatory biomarker relevant to NEC can be divided into nonspecific inflammatory biology mark
Remember object and specific inflammatory biomarker.The former study it is more have c reactive protein (C-reaction protein, CRP),
Calcitonin member (procalcitonin, PCT) and serum amyloid A protein (serum amyloid A, SAA), above-mentioned biology mark
Remember in object due to clinical criteria and the difference of sample size, causes the evaluation to NEC not quite identical.But it is generally considered,
CRP is worth limited but significant to the monitoring and Index for diagnosis of the state of an illness in early diagnosis；And SAA is not only in the state of an illness
Monitoring and Index for diagnosis are significant, and are worth in early diagnosis also higher；PCT is only the mark of acute inflammatory reaction
Will, with coincident with severity degree of condition without significant correlation.
Zonulin, can be reversible, quick as the unique a kind of intestinal permeability physiological regulatory protein being currently known
Intestinal tight connection is adjusted, intestinal permeability is changed.Early stage a variety of diseases, it is found that the level in its blood is significantly raised.
But in the research of patient NEC, there is not yet the relevant report of Zonulin and NEC.
Summary of the invention
The purpose of the present invention is to provide a kind of high sensitivities, the detection neonatal necrotizing enterocolitis of high specificity
Peripheral blood inflammatory biomarker Zonulin and its application.
To achieve the above object, the present invention provides a kind of detection neonatal necrotizing enterocolitis peripheral blood inflammatory biology
Marker Zonulin, the inflammatory biomarker Zonulin include having the amino acid sequence as shown in SEQ ID:1.
It is described for detecting the present invention also provides a kind of kit for detecting neonatal necrotizing enterocolitis peripheral blood
Inflammatory biomarker Zonulin in neonatal necrotizing enterocolitis peripheral blood, the inflammatory biomarker Zonulin
Including having the amino acid sequence as shown in SEQ ID:1.
Specifically, the kit includes the reagent of inflammatory biomarker Zonulin described in specific recognition.
Preferably, the reagent of inflammatory biomarker Zonulin described in the specific recognition is selected from specific binding institute
State the antibody or ligand of inflammatory biomarker Zonulin.
The present invention also provides above-mentioned detection neonatal necrotizing enterocolitis peripheral blood inflammatory biomarker Zonulin
Application in preparation prediction, diagnosis and screening neonatal necrotizing enterocolitis reagent.
The present invention analyzes inflammatory biomarker Zonulin in neonates group (77 patients NEC) and control group
The otherness expressed in (80 non-NEC newborns) peripheral blood sample, the results showed that, inflammatory biomarker Zonulin is in disease
Expression in example group is apparently higher than control group, illustrates expression of the inflammatory biomarker Zonulin in peripheral blood
It can reflect the pathological characteristic of neonatal necrotizing enterocolitis, and then it is neonatal necrotizing to determine that Zonulin can be used as detection
The biomarker of enterocolitis peripheral blood.
Further, the present invention is using Spearman grade to Zonulin and Bell (reference " practical neonatology " by stages
The modified Bell staging scale of (fourth edition) NEC) do correlation analysis, the results showed that, Zonulin and Bell are in positive by stages
It closes, and the degree of association is medium on the upper side.Further the results show that in peripheral blood the expression of Zonulin with it is neonatal necrotizing small
The severity of intestines colitis is related, clinically can be using Zonulin as neonatal necrotizing enterocolitis Bell by stages
Marker.
Compared with prior art, the present invention has the advantage that
(1) present invention determine that Zonulin and the index of neonatal necrotizing enterocolitis peripheral blood sample are closely related,
It is positively correlated by stages with Bell, the degree of association is medium on the upper side, can be as marker for outside neonatal necrotizing enterocolitis
All blood examinations are surveyed, and provide effective evidence for the prediction, diagnosis and screening of neonatal necrotizing enterocolitis；
(2) peripheral blood sample materials are convenient in the present invention, non-invasive, and can continuous vitro detection, therefore detect periphery
Inflammatory biomarker Zonulin in blood can improve the screening of neonatal necrotizing enterocolitis and diagnosis to one
A new level, and then improve cure rate and reduce the death rate；
(3) present invention provides the kit of detection newborn's peripheral blood sample, includes specific recognition inflammatory biomarker
The reagent of object Zonulin, this method are easy to be quick and economical and practical；
(4) marker of detection peripheral blood provided by the invention, can combine with other markers, be newborn's necrosis
Property the prediction of enterocolitis, diagnosis, treatment and prognosis new comprehensive kit is provided, facilitate clinical application.
Detailed description of the invention
Fig. 1 is the working curve diagram of Zonulin standard items；
Fig. 2 is expression figure of the Zonulin in case group and control group peripheral blood sample；
Fig. 3 is Zonulin and Bell correlation analysis figure by stages.
Specific embodiment
Purpose in order to better illustrate the present invention, technical scheme and beneficial effects, below in conjunction with specific embodiment and attached
The invention will be further described for figure.It should be noted that following the methods of implementing are explained further to what the present invention was done
It is bright, it should not be taken as limitation of the present invention.If material used in the embodiment of the present invention, reagent all can be from without specified otherwise
Commercial sources obtain.
1 sample Collecting and dealing of embodiment
Case group: in March, 2016 is chosen in September, 2017 in ZhongShan University attached No.6 Hospital neonate department, Guangdong Province
Healthcare hospital for women & children's neonate department (including newborn surgery), the 5th the People's Hospital's neonate department of Dongguan City, children's health care institute of Foshan City
77 patients NEC of neonate department ward hospitalization, by stages referring to the modified Bell of " practical neonatology " (fourth edition) NEC
Standard is divided into 3 groups according to final diagnosis result: doubtful NEC (NEC I phase 28) makes a definite diagnosis NEC (NEC II phase 30), progress
NEC (NEC III phase 19), wherein feeding intolerance symptom (abdominal distension, gastric retention) occurs in doubtful NEC, all cases are equal
By imageological examination.
Control group: with the same period be hospitalized with the same gestational age of case, gender, birth weight, childbirth options, birth 5min Apgar
80 non-NEC newborns that scoring and blood sampling age in days match (it is abnormal to exclude systemic inflammatory response syndrome, pyemia, alimentary canal
Shape and Inherited Metabolic Disorders infant) it is control group.This research has passed through ZhongShan University attached No.6 Hospital Ethics Committee and has examined symbol
The ethical standard that Chinese Ethics Committee formulates is closed, while obtaining the informed consent of research object guardian.
Case group sample collection is after clinical diagnosis NEC in 4h, and application is sterile, the anticoagulant heparin pipe acquisition periphery 1ml is quiet
Arteries and veins blood 4 DEG C, is centrifuged 10min, takes upper plasma in sterile EP tube, be subsequently placed in -80 DEG C through 3000r/min after mixing well
Refrigerator saves, and concentrates with enzyme-linked immunosorbent assay kit (ELISA) to relevant acute phase reactive protein and Gut barrie r function
It can Protein Detection.Group selection blood sampling selection is compareed to take a blood sample with the consistent blood sampling time point of case group.
2 ELISA of embodiment detects blood plasma inflammatory biomarker
The concentration application enzyme-linked immunosorbent assay kit of blood plasma Zonulin acute stage and intestinal barrier function albumen is (military
The magnificent bioengineering Co., Ltd of the Chinese), operation requires to be detected to specifications, specific as follows:
1) kit basic parameter:
Zonulin ELISA detection kit (detection range: 0.625ng/ml-40ng/ml；Sensitivity: 0.156ng/
ml；Precision: batch internal difference CV% < 8%, difference between batch CV% < 10%；Specificity: this kit specific detection people Zonulin,
And with other GAP-associated protein GAP no cross reactions).
2) inflammatory biomarker testing principle: using double-antibody sandwich elisa (Sandwich ELISA), and this method is suitable
Inspection for the soluble antigen in the various liquid phases such as serum, cerebrospinal fluid, Pleural effusions.In simple terms, first by known antibodies packet
In solid phase, unadsorbed antibody is washed away；Sample to be examined is added, sufficiently after effect, in sample in corresponding antigens and solid phase
Know that antibody combines, washes away unbonded antigenic component；Known enzyme labelled antibody is added, then washes away unbonded enzyme labelled antibody；Add
After substrate, enzyme bottom exploded object generates color reaction, determines antigenic content in sample to be examined according to shade.Coated antibody and enzyme
Antibody of the labeling antibody generally be directed to different epitopes in antigen molecule.
3) preparation of sample and reagent:
A. various reagents the rewarming of reagent, sample: are moved into (18-25 DEG C) 30~40min of balance of room temperature.
B. the dilution of standard items: taking the standard items restored to room temperature, and 10000rpm is centrifuged 30s, its whole is made to be sunken to bottom of bottle.
Then it gently opens and bottle cap and 1ml Sample dilution is added, blow and beat 5~8 times repeatedly with sample loading gun, after sufficiently dissolving and mix i.e.
The dilution mother liquor S7 of standard items can be obtained.
Standard items mother liquor is diluted using gradient dilution method.Take 7 1.5mlEP pipes according to number consecutively S0~S6,
Every pipe is separately added into 250 μ l Sample dilutions.250 μ l standard items are drawn out of number S7 to S6, are mixed.Then it is drawn from S6
In 250 μ l to S5, mix.Then and so on, the doubling dilution of standard items can be completed.Sample dilution is as blank control
(S0).Obtain the standard items of Zonulin (table 1) various concentration.Standard items need to be prepared in 15min before use.
1 Zonulin standard concentration of table
C. thickening and washing buffer dilutes process: 25 times of dilution is carried out to thickening and washing buffer, it is specific as follows: to measure
The deionized water of 480ml is in beaker, then measures the dense washing buffer of 20ml, and be slowly added in deionized water, to be mixed equal
It can be used after even, generally in prepared before use.When cryo-conservation, dense washing buffer, which has, to be salted out, can be in temperature before dilution
Heating helps its dissolution in water-bath.
D. it prepares biotin labelled antibodies working solution: the biotin labelled antibodies bottle 10000rpm of rewarming being centrifuged 30s, is made
Bottle interior antibody all focuses on the dilution that pipe is low, then antibody diluent is applied to carry out 100 times to it.After being mixed gently after dilution
It can be used, generally in prepared before use.
E. Horseradish peroxidase-conjugated avidin working solution is prepared: by the Horseradish peroxidase-conjugated avidin of rewarming
Bottle 10000rpm is centrifuged 30s, so that bottle content is all focused on pipe low, then dilute using Horseradish peroxidase-conjugated avidin
Release the dilution that liquid carries out 100 times to it.It can be used after being mixed gently after dilution, generally in prepared before use.
4) ELISA operating procedure:
A. be loaded: setting standard sample wells, sample to be tested hole are respectively provided with 1 multiple holes, and every hole is loaded 100 μ l.
B. it is incubated for: after sample adds, shaking gently mixing, cover plate patch, 37 DEG C of incubation 2h.
C. board-washing: carefully going board falling to paste, and discards liquid, drying, repeated washing.
D. plus biotin labelled antibodies working solution, 100 holes μ l/.
F. new plate patch, 37 DEG C of incubation 1h are covered.
G. it carefully goes board falling to paste, discards liquid, drying, board-washing 3 times on automatic plate washer, every hole adds dilution buffer
200 μ l impregnate 2min.
H. 100 hole μ l/ of Horseradish peroxidase-conjugated avidin working solution is added.
I.37 DEG C incubation 1h.
J. it discards liquid and dries, board-washing 3 times on automatic plate washer, every hole adds 200 μ l of dilution buffer, impregnates
2min。
K. TMB, 90 holes μ l/ are added.
L.37 it DEG C is protected from light and is incubated for 15min to 30min.
M. it terminates reaction: 50 hole μ l/ of terminate liquid is added.
N. data are read: being successively read each hole optical density at 450nm wavelength with microplate reader, time control is terminating reaction
In 5min.
Using the optical density of read standard items as abscissa, the concentration value of standard items is ordinate, draws working curve.
The working curve of gained standard items is as shown in Figure 1.The OD value for recording sample aperture, according to the working curve of the standard items of drafting
Calculate the concentration value of institute's test sample sheet.
The Bell of 3 NEC of embodiment is associated with Journal of Sex Research with intestinal barrier function albumen Zonulin by stages
Intestinal barrier function GAP-associated protein GAP blood plasma level is detected, statistics is all made of Mann-Whitney U inspection, with Bell
Correlation analysis uses Spearman grade related check by stages.It was found that expression of the Zonulin in case group illustrate it is significantly high
In control group, as shown in Fig. 2, CTRL is control group；NEC is case group.
Correlation analysis discovery is done by stages (I phase, II phase, III phase) to Zonulin and Bell, Zonulin and Bell are by stages
It is positively correlated, the degree of association is medium (Fig. 3) on the upper side.
The present invention provides the kit of detection neonatal necrotizing enterocolitis peripheral blood, including specific bond
The reagent of Zonulin, the specific antibody comprising specific binding Zonulin.The periphery of patient is acquired according to mode in embodiment 1
Blood sample is reacted with the antibody contained in kit, detects the expression of Zonulin in patient peripheral's blood sample, this
It is of great significance to detection, diagnosis patient with the presence or absence of neonatal necrotizing enterocolitis.
The present invention analyzes inflammatory biomarker Zonulin in neonates group (77 patients NEC) and control group
The otherness expressed in (80 non-NEC newborns) peripheral blood sample, the results showed that, inflammatory biomarker Zonulin is in disease
Expression in example group is apparently higher than control group, illustrates expression of the inflammatory biomarker Zonulin in peripheral blood
It can reflect the pathological characteristic of neonatal necrotizing enterocolitis, and then it is neonatal necrotizing to determine that Zonulin can be used as detection
The biomarker of enterocolitis peripheral blood.
Further, the present invention does correlation analysis to Zonulin and Bell using Spearman grade by stages, as a result table
Bright, Zonulin and Bell is positively correlated by stages, and the degree of association is medium on the upper side.Further the results show that Zonulin in peripheral blood
Expression it is related with the severity of neonatal necrotizing enterocolitis, clinically can be using Zonulin as newborn
The marker of necrotizing enterocolitis Bell by stages.
In conclusion the present invention has the advantage that
(1) present invention determine that Zonulin and the index of neonatal necrotizing enterocolitis peripheral blood sample are closely related,
It is positively correlated by stages with Bell, the degree of association is medium on the upper side, can be as marker for outside neonatal necrotizing enterocolitis
All blood examinations are surveyed, and provide effective evidence for the prediction, diagnosis and screening of neonatal necrotizing enterocolitis；
(2) peripheral blood sample materials are convenient in the present invention, non-invasive, and can continuous vitro detection, therefore detect periphery
Inflammatory biomarker Zonulin in blood can improve the screening of neonatal necrotizing enterocolitis and diagnosis to one
A new level, and then improve cure rate and reduce the death rate；
(3) present invention provides the kit of detection newborn's peripheral blood sample, includes specific recognition inflammatory biomarker
The reagent of object Zonulin, this method are easy to be quick and economical and practical；
(4) marker of detection peripheral blood provided by the invention, can combine with other markers, be newborn's necrosis
Property the prediction of enterocolitis, diagnosis, treatment and prognosis new comprehensive kit is provided, facilitate clinical application.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than protects to the present invention
The limitation of range is protected, although the invention is described in detail with reference to the preferred embodiments, those skilled in the art should
Understand, it can be with modification or equivalent replacement of the technical solution of the present invention are made, without departing from the essence of technical solution of the present invention
And range.
Sequence table
<110>the 5th the People's Hospital of Dongguan City (Dongguan City peace the People's Hospital)
<120>neonatal necrotizing enterocolitis peripheral blood inflammatory biomarker Zonulin and its application are detected
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<213> Homo sapiens
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Met Ser Ala Leu Gly Ala Val Ile Ala Leu Leu Leu Trp Gly Gln Leu
1 5 10 15
Phe Ala Val Asp Ser Gly Asn Asp Val Thr Asp Ile Ala Asp Asp Gly
20 25 30
Cys Pro Lys Pro Pro Glu Ile Ala His Gly Tyr Val Glu His Ser Val
35 40 45
Arg Tyr Gln Cys Lys Asn Tyr Tyr Lys Leu Arg Thr Glu Gly Asp Gly
50 55 60
Val Tyr Thr Leu Asn Asp Lys Lys Gln Trp Ile Asn Lys Ala Val Gly
65 70 75 80
Asp Lys Leu Pro Glu Cys Glu Ala Asp Asp Gly Cys Pro Lys Pro Pro
85 90 95
Glu Ile Ala His Gly Tyr Val Glu His Ser Val Arg Tyr Gln Cys Lys
100 105 110
Asn Tyr Tyr Lys Leu Arg Thr Glu Gly Asp Gly Val Tyr Thr Leu Asn
115 120 125
Asn Glu Lys Gln Trp Ile Asn Lys Ala Val Gly Asp Lys Leu Pro Glu
130 135 140
Cys Glu Ala Val Cys Gly Lys Pro Lys Asn Pro Ala Asn Pro Val Gln
145 150 155 160
Arg Ile Leu Gly Gly His Leu Asp Ala Lys Gly Ser Phe Pro Trp Gln
165 170 175
Ala Lys Met Val Ser His His Asn Leu Thr Thr Gly Ala Thr Leu Ile
180 185 190
Asn Glu Gln Trp Leu Leu Thr Thr Ala Lys Asn Leu Phe Leu Asn His
195 200 205
Ser Glu Asn Ala Thr Ala Lys Asp Ile Ala Pro Thr Leu Thr Leu Tyr
210 215 220
Val Gly Lys Lys Gln Leu Val Glu Ile Glu Lys Val Val Leu His Pro
225 230 235 240
Asn Tyr Ser Gln Val Asp Ile Gly Leu Ile Lys Leu Lys Gln Lys Val
245 250 255
Ser Val Asn Glu Arg Val Met Pro Ile Cys Leu Pro Ser Lys Asp Tyr
260 265 270
Ala Glu Val Gly Arg Val Gly Tyr Val Ser Gly Trp Gly Arg Asn Ala
275 280 285
Asn Phe Lys Phe Thr Asp His Leu Lys Tyr Val Met Leu Pro Val Ala
290 295 300
Asp Gln Asp Gln Cys Ile Arg His Tyr Glu Gly Ser Thr Val Pro Glu
305 310 315 320
Lys Lys Thr Pro Lys Ser Pro Val Gly Val Gln Pro Ile Leu Asn Glu
325 330 335
His Thr Phe Cys Ala Gly Met Ser Lys Tyr Gln Glu Asp Thr Cys Tyr
340 345 350
Gly Asp Ala Gly Ser Ala Phe Ala Val His Asp Leu Glu Glu Asp Thr
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Trp Tyr Ala Thr Gly Ile Leu Ser Phe Asp Lys Ser Cys Ala Val Ala
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Glu Tyr Gly Val Tyr Val Lys Val Thr Ser Ile Gln Asp Trp Val Gln
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Claims (5)
1. a kind of detection neonatal necrotizing enterocolitis peripheral blood inflammatory biomarker Zonulin, it is characterised in that: institute
Stating inflammatory biomarker Zonulin includes having the amino acid sequence as shown in SEQ ID:1.
2. a kind of kit for detecting neonatal necrotizing enterocolitis peripheral blood, it is characterised in that: described new for detecting
Inflammatory biomarker Zonulin in raw youngster's necrotizing enterocolitis peripheral blood, the inflammatory biomarker Zonulin packet
Including has the amino acid sequence as shown in SEQ ID:1.
3. the kit of detection neonatal necrotizing enterocolitis peripheral blood as claimed in claim 2, it is characterised in that: institute
State the reagent that kit includes inflammatory biomarker Zonulin described in specific recognition.
4. the kit of detection neonatal necrotizing enterocolitis peripheral blood as claimed in claim 3, it is characterised in that: institute
The reagent for stating inflammatory biomarker Zonulin described in specific recognition, which is selected from, specifically binds the inflammatory biomarker
The antibody or ligand of Zonulin.
5. detection neonatal necrotizing enterocolitis peripheral blood inflammatory biomarker Zonulin as described in claim 1
Application in preparation prediction, diagnosis and screening neonatal necrotizing enterocolitis reagent.
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| CN201811269273.0A CN109251241A (en) | 2018-10-29 | 2018-10-29 | Detect neonatal necrotizing enterocolitis peripheral blood inflammatory biomarker Zonulin and its application |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016012608A1 (en) * | 2014-07-24 | 2016-01-28 | Reponex Pharmaceuticals Aps | Compositions comprising granulocyte-macrophage colony-stimulating factor for the treatment of inflammatory bowel disease |
| US20180289841A1 (en) * | 2017-04-07 | 2018-10-11 | University Of South Florida | Preclinical model of neonatal necrotizing enterocolitis |
-
2018
- 2018-10-29 CN CN201811269273.0A patent/CN109251241A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016012608A1 (en) * | 2014-07-24 | 2016-01-28 | Reponex Pharmaceuticals Aps | Compositions comprising granulocyte-macrophage colony-stimulating factor for the treatment of inflammatory bowel disease |
| US20180289841A1 (en) * | 2017-04-07 | 2018-10-11 | University Of South Florida | Preclinical model of neonatal necrotizing enterocolitis |
Non-Patent Citations (7)
| Title |
|---|
| ANNA TARKO: "Zonulin: A Potential Marker of Intestine Injury in Newborns", 《DISEASE MARKERS》 * |
| BHAWAN DEEP GARG: "Biomarkers of Necrotizing enterocolitis: A review of literature", 《THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE》 * |
| MARGARET GILFILLAN: "Biomarkers for the diagnosis of neonatal sepsis and necrotizing entercolitis: Clinical practice guidelines", 《EARLY HUMAN DEVELOPMENT》 * |
| 于学林: "《现代急诊影像诊断手册》", 30 April 2018, 科学技术文献出版社 * |
| 佚名: "GenBank 登录号：NP_005134.1", 《NCBI》 * |
| 安翠平: "《免疫系统疾病临床检验与诊断》", 30 June 2017, 科学技术文献出版社 * |
| 邹鸿燕: "《免疫学检验理论与临床》", 31 January 2018, 天津科学技术出版社 * |
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Application publication date: 20190122 |
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| RJ01 | Rejection of invention patent application after publication |