CN110208409A - A kind of biomarker of breast cancer and its application - Google Patents
A kind of biomarker of breast cancer and its application Download PDFInfo
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Abstract
The present invention provides a kind of biomarker GM3 of breast cancer and its applications.The invention belongs to field of medicaments, the present invention also provides breast cancer kit for screening, it can show the content of the gangliosides of GM3 type in serum, can not only distinguish normal person, mammary gland fiber limit tumor and breast cancer patient, can also distinguish different molecular parting breast cancer.The features such as kit provided by the invention has operating procedure easy to learn, is easy to universal, and detection is time-consuming short, and testing cost is low, and sample dosage is few.Biomarker GM3 provided by the invention can be used as the biomarker of breast cancer, have important clinical meaning.
Description
Technical field
The invention belongs to biomedicine technical fields, and in particular to a kind of biomarker of breast cancer and its application.
Background technique
Gangliosides (Gangliosides, GAs) are a kind of acidic glycosphingolipids, mainly by with N-acetyl-neuraminate
Sugar chain and ceramide link, and in vivo, gangliosides usually pass through hydrophobic ceramide, insert in cell
In membrane lipid bilayer, as a part of membrane component, hydrophilic oligonucleotide chain is stretched in the external environment of cell surface.Ganglioside
Rouge is not only the important component of cell surface antigen, and is the receptor of many extracellular physiological activators, and participates in thin
Born of the same parents' identification and information exchanging process.The biological function of gangliosides in vivo mainly has the following aspects: (1) as thin
Cellular surface label and antigen, have immunologic function；(2) being mutually distinguishable between mediated cell, and can be used as cell recognition receptor；
(3) inducing nerve cell differentiation inhibits its growth, maintains the function and form of nerve cell；(4) cell transmembrane signal is adjusted
Conduction etc.；(5) stabilizing cell membrane bilayer structure.Gangliosides can promote development and and the energy restoration and protection of nervous system
Injuring nerve, therefore people is caused greatly to pay close attention to.Research shows that single sialic acid Ganglioside GM1 treatment Parkinson's disease has well
Curative effect.
During the occurrence and development of tumour, expression and the structure of gangliosides can change, possible mechanism
Include: the gangliosides antigen of (1) cell surface or from the gangliosides antigen of cell detachment as immunosuppressor, such as
It is generally observed and inhibits cytotoxic T cell and dendritic cells；(2) gangliosides such as GD3 or GM2 promotes the relevant blood of tumour
Pipe generates；(3) gangliosides adjust cell adherence/movement strongly and thus start metastases；(4) gangliosides antigen
It is directly connect with the transduction molecule in microcell to cause adhesion；(5) gangliosides antigen and its catabolite by with life
Growth factor receptor body or the relevant tyrosine kinase interactions of other protein kinases and carry out signal transduction.Bifunctional sialyltransferase neuromere
Glycosides rouge GD2 is the highly expressed neuroderm antigen in various cancers, has preferable diagnosis for triple negative breast cancer
Effect.Important function of the GM3 in various diseases is by wide coverage.GM3 is had found in idiopathic parkinsonism human plasma
Concentration significantly increases.The significant reduction of GM3 is observed in early stage Relapsing-remitting MS disease patients serum, can be used as blood
The biomarker of brain barrier breakdown.In addition, GM3 goes out higher level in melanoma metastasis Late manifestations.GM3 synthase gene is
The new biomarkers of Non-Small Cell Lung Carcinoma histological grading.Chinese patent (publication number: 104698059 B of CN) discloses
A kind of gangliosides of double-sialylated are as glioma tumor markers and its application；Chinese patent (publication number: CN
105407916 A) it discloses by the extracellular domain of growth factor receptors HER-1 and HER-2 or its segment, derived from meningitis
The proteoliposome and Ganglioside GM3 (vSSP- of the outer membrane protein of Neisser's coccus (Neisseria meningitidis)
GM3) the bivalent vaccine composition constituted can be used for the treatment of malignant tumour；Chinese patent (publication number: 103998098 B of CN)
It discloses a kind of for treating the pharmaceutical composition of the tumour of high expression EGFR and N- hydroxyl acetyl gangliosides (NeuGcGM3)；
International monopoly (WO2002/081661) discloses a kind of for treating the immunization therapy group of the tumour of overexpression gangliosides
Close object.
Breast cancer is one of malignant tumour most commonly seen in global women, according to recent statistics data, Chinese women cream
Gland cancer incidence and mortality occupy the 1st and the 5th of female malignant respectively.According to clinical immunization group as a result,
Breast cancer can be divided into four kinds of molecule partings: Luminal A (LA) type, Luminal B (LB) type, HER-2 are overexpressed (HER)
Type and substrate sample (BS) type breast cancer.Molecule parting and the clinical pathologic characteristic of breast cancer, prognosis of disease, patient's prognosis and treatment
React closely related.There are not patent or document report gangliosides as breast cancer serum marker at present, and not yet
About the differentiation of different molecular parting cancer.
Summary of the invention
For current technology to gangliosides marker in breast cancer serum and different molecular parting markers for breast cancer
The blank of research, the present invention provides a kind of biomarker of breast cancer and its applications.
For achieving the above object, the present invention is achieved by the following scheme:
The present invention provides a kind of breast cancer kit for screening, the kit includes optional for detecting warp knuckle glycosides rouge
The reagent of GM3 expression.
Further, the reagent of the detection Ganglioside GM3 expression is LC-MS/MS-MRM analysis method use
Reagent.
Further, the mobile phase that the analysis method uses are as follows:
Mobile phase A: 10mM ammonium acetate contains 0.1% acetic acid；
Mobile phase B: 85% methanol/15% isopropanol, ammonium acetate containing 10mM, 0.1% acetic acid.
Further, the elution program of the analysis method are as follows: 0~3min keeps 30% Mobile phase B, rises in 1min
Then 100% Mobile phase B keeps 10-15min with 100% Mobile phase B.
The present invention also provides the articles of the expression for detecting biomarker to be used to indicate in object in preparation
Breast cancer reagent in application, the biomarker be Ganglioside GM3.
Further, the reagent is the reagent for detecting the expression of Ganglioside GM3.
Further, the reagent is the reagent for detecting Ganglioside GM3 expression in the ring polymer.
Further, the reagent of the detection Ganglioside GM3 expression is LC-MS/MS-MRM analysis method use
Reagent, specific steps are as follows:
Detect the concentration of Ganglioside GM3 in the object；
The concentration of Ganglioside GM3 in the object is compared with the reference concentration of Ganglioside GM3, obtains mind
The expression of warp knuckle glycosides rouge GM3.
Further, the mobile phase that the analysis method uses are as follows:
Mobile phase A: 10mM ammonium acetate contains 0.1% acetic acid；
Mobile phase B: 85% methanol/15% isopropanol, ammonium acetate containing 10mM, 0.1% acetic acid.
Further, elution program are as follows: 0~3min keeps 30% Mobile phase B, rises to 100% Mobile phase B in 1min, so
10-15min is kept with 100% Mobile phase B afterwards.
When the expression of the Ganglioside GM3 is greater than 1.5, indicate that the object is breast cancer.
When the expression of the Ganglioside GM3 is greater than 2.5, indicate that the breast cancer of the object is Luminal-B
Type breast cancer.
When the expression of the Ganglioside GM3 is between 1.3~1.5, indicate that the object is benign tumour.
Compared with prior art, the advantages and positive effects of the present invention are: kit operating procedure provided by the invention is simple
It is single easy to learn, it is easy to popularize, detects the features such as time-consuming is short, and testing cost is low.Kit sample dosage provided by the invention is few, serum
20~200 μ L of blood plasma dosage, while being suitable for tissue (5-100mg) and cell (105-107) detection.Examination provided by the invention
Agent box high sensitivity, detection limit range are 0.15~0.52pg/ μ L, and quantitative limit range is 0.50~1.72pg/ μ L, and can be real
It is separated online while existing 54 kinds of gangliosides.Kit provided by the invention can not only distinguish normal person and breast cancer disease
People, fiber limit tumor patient and cancer patient, can also distinguish different molecular parting breast cancer, be expected to find hematologic cancers with this method
Biomarker.
After a specific embodiment of the invention is read in conjunction with the figure, further advantage of the invention and feature will become more clear
It is clear.
Detailed description of the invention
Fig. 1 is the normal person of the present invention based on RP-HPLC-FTMS method and blood serum of patients with human breast carcinoma GAs difference.
Fig. 2 is normal person of the present invention, different type neuromere in Benign Breast tumor patient and Serum of Patients With Breast Cancer
The content difference column diagram of glycosides rouge.
Fig. 3 is the PCA analysis chart of GM3 series in Healthy People of the present invention and blood serum of patients with human breast carcinoma.
Fig. 4 is patient with breast cancer of the present invention compared to GAs (the AUC > for having high diagnostic value in Healthy Human Serum
0.9)。
Fig. 5 is different molecular parting Serum of Patients With Breast Cancer GM3 content difference column diagram of the present invention.
Fig. 6 is the ROC curve analysis chart of different molecular parting Serum of Patients With Breast Cancer GAs of the present invention.
Specific embodiment
Technical solution of the present invention is further described in detail with reference to the accompanying drawings and detailed description, but the present invention
Claimed range is not limited to the range of example statement.
Embodiment 1: gangliosides in detection serum
1, in serum gangliosides extracting method
After 1mL methanol, 2mL chloroform is added into 20-200uL serum, ultrasound extraction 20min, 8000rmp are centrifuged 10min,
Supernatant is extracted for glycolipid.1mL water is added into supernatant, is vortexed, is stored at room temperature 10min, make its layering, 8000rmp from
Heart 10min, upper layer are produced.Lower layer continuously adds 1mL methanol, 0.5mL water repeats to be extracted twice, and 8000rmp is centrifuged 10min, closes
And upper layer, as gangliosides.Upper layer is blown to nitrogen dry, redissolves in 80% methanol, analyzed for LC-MS.
2, serum GA type is determined by the non-targeted analysis method of LC-FTMS
Mass spectrometer: 1290 LC UPLC liquid chromatograph of Agilent, LTQ ORBITRAP XL mass spectrograph are furnished with
Electric spray ion source (ESI)；
Liquid chromatographic system: chromatographic column be 120 EC-C18 chromatographic column of Agilent Poroshell (50 x 3.0mm,
2.7 μm), chromatography eluant uses the gradient elution mode of binary pump high pressure mixing.Mobile phase A is that 10mM ammonium acetate (contains 0.1% vinegar
Acid), Mobile phase B is 85% methanol/15% isopropanol (ammonium acetate containing 10mM, 0.1% acetic acid).Flow velocity is 0.2mL/min.Gradient
Elution program: 0~3min, 30% Mobile phase B；3~3.1min, 30~100% Mobile phase Bs；3.1~14min, 100% flowing
Phase B；14~14.1min, 100~30% Mobile phase Bs；14.1~17min, 30% Mobile phase B.Detector is negative ion mode,
Spray voltage 4.2kV, 275 DEG C of capillary temperature, nitrogen flow rate 40L/min.
In the present invention, as non-targeted method, first using GA type all in LC-FTMS method identification serum.
In the negative ion mode, the blood of 20 patient with breast cancers and 10 healthy volunteers are analyzed by RP-HPLC-FTMS method
Clearly.According to accurate m/z, retention time, relative retention time and the second order ms parsing of similar GA has finally determined 49 kinds
GA type.All GA types, retention time and its m/z that FTMS is identified are listed in table 1.It is wherein the richest as content
Rich gangliosides, GM3 occupies 23 kinds altogether, and dramatically increases in cancer patient, has the value further studied.Such as figure
Shown in 1, the peak area of the GAs of extraction shows the significant difference (p < 0.05) between patient with breast cancer and normal healthy controls.But
Complicated data processing limits the application of this method.In order to simplify data processing and realize quantitative analysis, we have turned to one
The targeted LC-MS/MS-MRM method of kind.
3: the foundation of gangliosides LC-MS/MS-MRM analysis method
(1) foundation of mass spectrometry method
6 kinds of gangliosides standard items, after 80% methanol aqueous solution is diluted to 1ng/ μ L, in 50% methanol as mobile phase
In, by flow injection single standard product respectively, optimize response.Detector is negative ion mode, spray voltage 2.8-
3kV, 300-350 DEG C of ion transfer tube temperature, assist gas 2-8Arb by 250-300 DEG C of poling temperature, sheath gas 25-35Arb.It determines
Suitable daughter ion and optimal Collisional energy and Tube lens.And fatty chain length identical for sugar chain is not
Same gangliosides, Optimal Parameters are identical.According in preliminary result serum early period, there are following 49 kinds of neuromeres
Glycosides rouge.Therefore, it is as shown in table 1 that MRM optimum results are obtained.
The Mass Spectrometry Conditions Optimal Parameters of 1 glycolipid standard items of table
(2) foundation of chromatographic condition
Mass spectrometer: TSQ Quantiva mass spectrograph is furnished with electric spray ion source (ESI)；
Detect liquid phase used: liquid chromatographic system；Chromatographic column is 120 EC-C18 chromatographic column of Agilent Poroshell
(50 x 3.0mm, 2.7 μm), chromatography eluant use the gradient elution mode of binary pump high pressure mixing.Mobile phase A is 10mM acetic acid
Ammonium (contains 0.1% acetic acid), and Mobile phase B is 85% methanol/15% isopropanol (ammonium acetate containing 10mM, 0.1% acetic acid).Flow velocity is
0.1-0.2mL/min.Scanning mode is selection reaction detection (SRM).Under the Mass Spectrometry Conditions optimized, by changing mobile phase
Ratio, gradient, flow velocity etc., optimize chromatographic separation condition.Finally determine following elution program: 0~3min keeps 30%
Mobile phase B rises to 100% Mobile phase B in 1min, then keeps 10-15min with 100% Mobile phase B.When based on MRM and retaining
Between, realize the fully separating of 54 kinds of gangliosides.
(3) evaluation of methodology
6 kinds of standard items are respectively with GM1-36: 1, GM2-36: 1, GM3-41: 1, GD1-38: 1, GD3-41: 1, GT1b-38: 1
For quantitative ingredient.After 6 kinds of standard items are mixed, it is diluted to serial various concentration: 5pg/ μ L, 10pg/ μ L with 80% methanol solution,
50pg/ μ L, 100pg/ μ L, 500pg/ μ L, 1ng/ μ L, 5ng/ μ L, 10ng/ μ L, 20ng/ μ L is subsequently used for LC-MS/MS analysis,
Sample volume is 5 μ L.The peak area of sample volume and multiple-reaction monitoring MRM based on standard disaccharides draws standard curve.Signal strength
(S) and the ratio of ambient noise (N) is signal-to-noise ratio (S/N), and various concentration standard items analysis data can pass through Xcalibur2.0.7
S/N is calculated, concentration when by S/N being 3 is detection limit (LOD), and concentration when S/N is 10 is quantitative limit (LOQ).Based on standard items
Sample introduction concentration and MRM peak area draw standard curve, as shown in table 2, all gangliosides standard curves are linearly good,
R2It is all larger than 0.9994.S/N is calculated according to Xcalibur2.0.7, concentration when by S/N being 3 is LOD, concentration when S/N is 10
For LOQ.As a result as listed in table 2, this method is that 0.15~0.52pg/ μ L, LOQ range are for the LOD range of all disaccharides
0.50~1.72pg/ μ L.
Linear and the detection limit, quantitative limit of 2 analysis method of table
Embodiment 2: the diagnosis capability of the variation of GAs and GM3 for breast cancer in blood serum of patients with human breast carcinoma
The data obtained is handled by Xcalibur software, calculates ganglioside in every microlitre of serum according to standard curve
The absolute content of rouge.Compare the content difference of gangliosides in normal person and blood serum of patients with human breast carcinoma by variance analysis, with
And between different parting patient with breast cancers gangliosides content difference, to find cancer markers.Based on above-mentioned LC-MS/
MS-MRM method, to from 30 healthy women adults, 20 Benign Breast tumor patients and 70 blood serum of patients with human breast carcinoma samples
In GAs analyzed.The results show that GAs is horizontal significant higher than normal group (Fig. 2) in cancer group serum.And non-targeted
Under targeted approach, the variation tendency and relative abundance of GAs is consistent.GAs level in blood serum of patients with human breast carcinoma is health
2~3 times (tables 3) in serum.It analyzes according to ROC curve, compared with normal serum, GM1, GM2, the abundance of GM3, GD1 and GD3
Dramatically increased in cancer serum (AUC > 0.7, p value less than 0.01), this with reported through 2D-HPTLC and the side GC-MS
The result that method is measured to is consistent.In addition, as main glycosyl sphingolipid ingredient, GM3 shows high diagnosis in cancer serum
Accuracy (AUC > 0.9) has the value for being further developed as marker.ROC analysis is carried out to specific GAs type, in cancer
Find that 7 kinds of GAs have fabulous diagnostic accuracy (Fig. 3) in serum altogether, and they are all GM3 types.It is currently reported
Prove GM3 it is related to carcinogenesis, such as by integrin and CD9 dependence mechanism, cell surface express GM3 with it is pernicious
The reverse of tumour is related.
In order to further judge GM3 to the separating capacity of breast cancer and normal person, further progress principal component analysis
(principal component analysis, PCA), this is a kind of thought using dimensionality reduction, before losing little information
Put the multivariate statistical method for multiple indexs being converted into several overall targets.To 23 obtained in normal and cancer patient's serum
Kind GM3 carries out PCA analysis, as a result such as Fig. 4.Although being kept completely separate between cancer and normal serum is not implemented, observe bright
Aobvious differentiation boundary line shows that GM3 to the distinguishing ability of breast cancer, also plays effect predictive of GM3 in breast cancer progression.
In addition, the GM3 level of blood serum of patients with human breast carcinoma is also dramatically different with benign adenoma patient.ROC curve shows, and good
Gonadoma patient compares, and GM3 shows higher diagnostic value (AUC > 0.8) (Fig. 2 and table 3) in cancer patient's serum.So
And PCA analysis can not effectively distinguish optimum group and other two groups (data do not provide).In addition, GM3 is good compared with Healthy People
Significant increase (AUC > 0.7) (Fig. 2 and table 3) is shown in gonadoma serum.Finally, based on AUC value and variation multiple, GM3 makees
For a kind of new biomarkers of hypersensitivity, it can be used for distinguishing patient with breast cancer, healthy volunteer and Benign Breast cancer
Patient.
Table 3 is normal, benign with GAs content difference table in cancer patient's serum.
Embodiment 3: diagnosis marker of the increased GM3 of serum as Luminal-B breast cancer hypotype
In research of the invention, serum GM3 raising is considered as the potential source biomolecule marker of breast cancer diagnosis.With it is normal
Group compared with optimum group, total GM3, GM3-38: 1, GM3-40: 1 and GM3-40: 2 shown in breast cancer serum it is higher
Diagnostic accuracy (AUC > 0.8).Have confirmed that GM3 to the diagnosis capability of breast cancer, the following present invention according to the above results
GM3 has further been probed into the ability for distinguishing breast cancer different subtype.
As shown in figure 5, LA, HER and BS parting Patients with Various Cancers GM3 concentration significantly reduce compared with LB parting.Its
In, GM3 content is as follows in each parting patients serum: LB parting patient is between 12.58~13.83 μ g/mL, LA parting patient
Between 6.34~7.64 μ g/mL, HER parting patient is between 6.64~8.34 μ g/mL, and BS parting patient is 7.19~9.22
Between μ g/mL.ROC curve analysis also turns out that LB parting and other partings can significantly be distinguished (ROC > 0.7, Fig. 6) by GM3.
Luminal-B breast cancer is a kind of increased breast cancer hypotype of proliferation of the ER positive, compared with other high proliferation breast cancer, display
Out to the poor prognosis of the drug resistance of chemotherapy and endocrine therapy.It is of the invention research shows that GM3 is to Luminal-B mammary gland
The distinguishing ability of cancer has directive significance for individualized clinical treatment.
Based on the above research, finds that raised Ganglioside GM3 can be used as biomarker in serum for the first time, be used for
The detection of breast cancer, and Luminal Type B breast cancer and other partings are distinguished, it is expected to provide one for the clinical diagnosis of breast cancer
The more sensitive marker of kind, and promote the development of individualized treatment.
Above embodiments only illustrate technical solution of the present invention, rather than are limited；Although with reference to the foregoing embodiments
Invention is explained in detail, for those of ordinary skill in the art, still can be to previous embodiment institute
The technical solution of record is modified or equivalent replacement of some of the technical features；And these modifications or substitutions, and
The essence of corresponding technical solution is not set to be detached from the spirit and scope of claimed technical solution of the invention.
Claims (10)
1. a kind of breast cancer kit for screening, it is characterised in that: the kit includes optional for detecting warp knuckle glycosides rouge GM3
The reagent of expression.
2. breast cancer kit for screening according to claim 1, it is characterised in that: the detection Ganglioside GM3 table
It is LC-MS/MS-MRM analysis method reagent up to horizontal reagent.
3. breast cancer kit for screening according to claim 2, it is characterised in that: the mobile phase that the analysis method uses
Are as follows:
Mobile phase A: 10mM ammonium acetate contains 0.1% acetic acid；
Mobile phase B: 85% methanol/15% isopropanol, ammonium acetate containing 10mM, 0.1% acetic acid.
4. breast cancer kit for screening according to claim 3, it is characterised in that: the elution program of the analysis method
Are as follows: 0 ~ 3 min keeps 30% Mobile phase B, rises to 100% Mobile phase B in 1min, then keeps 10- with 100% Mobile phase B
15min。
5. the articles of the expression for detecting biomarker are in the reagent for the breast cancer that preparation is used to indicate in object
Application, it is characterised in that: the biomarker be Ganglioside GM3.
6. the articles of the expression according to claim 5 for detecting biomarker are used to indicate object in preparation
In breast cancer reagent in application, it is characterised in that: the reagent is the expression for detecting Ganglioside GM3
Reagent.
7. the articles of the expression according to claim 6 for detecting biomarker are used to indicate object in preparation
In breast cancer reagent in application, it is characterised in that: the reagent is for detecting ganglioside in the ring polymer
The reagent of rouge GM3 expression.
8. the articles of the expression according to claim 6 for detecting biomarker are used to indicate object in preparation
In breast cancer reagent in application, it is characterised in that: it is described detection Ganglioside GM3 expression reagent be LC-
MS/MS-MRM analysis method reagent, uses the specific steps of the reagent are as follows:
Detect the concentration of Ganglioside GM3 in the object；
The concentration of Ganglioside GM3 in the object is compared with the reference concentration of Ganglioside GM3, obtains neuromere
The expression of glycosides rouge GM3.
9. the articles of the expression according to claim 8 for detecting biomarker are used to indicate object in preparation
In breast cancer reagent in application, it is characterised in that: the mobile phase that the analysis method uses are as follows:
Mobile phase A: 10mM ammonium acetate contains 0.1% acetic acid；
Mobile phase B: 85% methanol/15% isopropanol, ammonium acetate containing 10mM, 0.1% acetic acid；
10. the articles according to claim 9 for detecting the expression of biomarker are used to indicate pair in preparation
Application in the reagent of breast cancer as in, it is characterised in that: elution program are as follows: 0 ~ 3 min keeps 30% Mobile phase B, 1min
100% Mobile phase B is inside risen to, 10-15min is then kept with 100% Mobile phase B.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1809592A (en) * | 2003-04-23 | 2006-07-26 | 分子免疫中心 | Recombinant antibodies and fragments recognising ganglioside N-glycolyl-GM3 and use thereof in the diagnosis and treatment of tumours |
| CN102925569A (en) * | 2012-10-25 | 2013-02-13 | 北京迈誉森生物科技有限公司 | MicroRNA (ribonucleic acid) marker set for detecting breast cancer and application of microRNA marker set in kit |
| CN106995837A (en) * | 2016-01-22 | 2017-08-01 | 益善生物技术股份有限公司 | Early diagnosing mammary cancer kit |
-
2019
- 2019-06-05 CN CN201910484640.7A patent/CN110208409A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1809592A (en) * | 2003-04-23 | 2006-07-26 | 分子免疫中心 | Recombinant antibodies and fragments recognising ganglioside N-glycolyl-GM3 and use thereof in the diagnosis and treatment of tumours |
| CN102925569A (en) * | 2012-10-25 | 2013-02-13 | 北京迈誉森生物科技有限公司 | MicroRNA (ribonucleic acid) marker set for detecting breast cancer and application of microRNA marker set in kit |
| CN106995837A (en) * | 2016-01-22 | 2017-08-01 | 益善生物技术股份有限公司 | Early diagnosing mammary cancer kit |
Non-Patent Citations (2)
| Title |
|---|
| GILDA MARQUINA ET AL.: "Gangliosides Expressed in Human Breast Cancer", 《CANCER RESEARCH》 * |
| HYEYOUNG LEE ET AL.: "Hydrolysis of milk gangliosides by infant-gut associated bifidobacteria determined by microfluidic chips and highresolution mass spectrometry", 《ELECTROPHORESIS》 * |
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