CN115469104A - Hmgb1在胶质母细胞瘤tmz化疗预后预测中的应用 - Google Patents
Hmgb1在胶质母细胞瘤tmz化疗预后预测中的应用 Download PDFInfo
- Publication number
- CN115469104A CN115469104A CN202211286490.7A CN202211286490A CN115469104A CN 115469104 A CN115469104 A CN 115469104A CN 202211286490 A CN202211286490 A CN 202211286490A CN 115469104 A CN115469104 A CN 115469104A
- Authority
- CN
- China
- Prior art keywords
- hmgb1
- glioblastoma
- high mobility
- mobility group
- expression level
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000005017 glioblastoma Diseases 0.000 title claims abstract description 65
- 238000004393 prognosis Methods 0.000 title claims abstract description 33
- 238000002512 chemotherapy Methods 0.000 title claims abstract description 23
- 101150021904 HMGB1 gene Proteins 0.000 title claims abstract description 9
- 101100339431 Arabidopsis thaliana HMGB2 gene Proteins 0.000 title claims abstract 8
- 108700010013 HMGB1 Proteins 0.000 title claims abstract 8
- 102000055207 HMGB1 Human genes 0.000 title abstract 6
- 230000014509 gene expression Effects 0.000 claims abstract description 69
- 210000002966 serum Anatomy 0.000 claims abstract description 21
- 230000000694 effects Effects 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 4
- 102100037907 High mobility group protein B1 Human genes 0.000 claims description 118
- 101710168537 High mobility group protein B1 Proteins 0.000 claims description 116
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- 201000010915 Glioblastoma multiforme Diseases 0.000 claims description 10
- 108090000623 proteins and genes Proteins 0.000 claims description 10
- 102000004169 proteins and genes Human genes 0.000 claims description 7
- 239000003550 marker Substances 0.000 claims description 6
- 108020004999 messenger RNA Proteins 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 230000003834 intracellular effect Effects 0.000 claims description 4
- 230000001737 promoting effect Effects 0.000 claims description 3
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 abstract description 41
- 229960004964 temozolomide Drugs 0.000 abstract description 40
- 206010018338 Glioma Diseases 0.000 abstract description 17
- 208000032612 Glial tumor Diseases 0.000 abstract description 15
- 238000004458 analytical method Methods 0.000 abstract description 11
- 238000002965 ELISA Methods 0.000 abstract description 7
- 230000004791 biological behavior Effects 0.000 abstract description 6
- 230000003211 malignant effect Effects 0.000 abstract description 6
- 206010059866 Drug resistance Diseases 0.000 abstract description 3
- 230000007246 mechanism Effects 0.000 abstract description 3
- 230000000007 visual effect Effects 0.000 abstract description 3
- 230000009471 action Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000012151 immunohistochemical method Methods 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 24
- 230000004083 survival effect Effects 0.000 description 21
- 206010028980 Neoplasm Diseases 0.000 description 20
- 239000000523 sample Substances 0.000 description 15
- 210000001519 tissue Anatomy 0.000 description 13
- 239000007788 liquid Substances 0.000 description 11
- 238000011160 research Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000011148 porous material Substances 0.000 description 10
- 238000007789 sealing Methods 0.000 description 9
- 230000001965 increasing effect Effects 0.000 description 8
- 210000004881 tumor cell Anatomy 0.000 description 8
- 239000012188 paraffin wax Substances 0.000 description 6
- 230000000903 blocking effect Effects 0.000 description 5
- 238000003364 immunohistochemistry Methods 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000004043 dyeing Methods 0.000 description 4
- 230000002055 immunohistochemical effect Effects 0.000 description 4
- 238000011532 immunohistochemical staining Methods 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 230000004900 autophagic degradation Effects 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000013211 curve analysis Methods 0.000 description 3
- 210000004443 dendritic cell Anatomy 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000013115 immunohistochemical detection Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 210000000822 natural killer cell Anatomy 0.000 description 3
- 210000004940 nucleus Anatomy 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 108010077544 Chromatin Proteins 0.000 description 2
- 238000008157 ELISA kit Methods 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 210000003483 chromatin Anatomy 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 208000030173 low grade glioma Diseases 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 239000011534 wash buffer Substances 0.000 description 2
- 239000012224 working solution Substances 0.000 description 2
- 241000283707 Capra Species 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 208000031448 Genomic Instability Diseases 0.000 description 1
- 102000000849 HMGB Proteins Human genes 0.000 description 1
- 108010001860 HMGB Proteins Proteins 0.000 description 1
- 101000831567 Homo sapiens Toll-like receptor 2 Proteins 0.000 description 1
- 102000039996 IL-1 family Human genes 0.000 description 1
- 108091069196 IL-1 family Proteins 0.000 description 1
- 102000039990 IL-2 family Human genes 0.000 description 1
- 108091069192 IL-2 family Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 102100024333 Toll-like receptor 2 Human genes 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 230000005975 antitumor immune response Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000009400 cancer invasion Effects 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 230000037449 immunogenic cell death Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011127 radiochemotherapy Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 229940085606 rembrandt Drugs 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 238000013077 scoring method Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 239000013595 supernatant sample Substances 0.000 description 1
- 238000010408 sweeping Methods 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Images
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
- G01N33/57488—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds identifable in body fluids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/118—Prognosis of disease development
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Analytical Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pathology (AREA)
- Biochemistry (AREA)
- Cell Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Physics & Mathematics (AREA)
- Organic Chemistry (AREA)
- Food Science & Technology (AREA)
- Oncology (AREA)
- Hospice & Palliative Care (AREA)
- General Physics & Mathematics (AREA)
- Genetics & Genomics (AREA)
- Public Health (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biophysics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
本发明属于生物医药技术领域,具体涉及一种HMGB1在胶质母细胞瘤TMZ化疗预后预测中的应用。本专利以胶质瘤为模型,通过TCGA和CGGA数据库分析、免疫组织化学方法、酶联免疫反应等方法,深入探究HMGB1在替莫唑胺治疗中的作用及机制,以及胶质母细胞瘤中HMGB1的表达与其恶性生物学行为之间的相关性,发现高表达的HMGB1促进了胶质母细胞瘤细胞的替莫唑胺耐药能力,并且经过替莫唑胺治疗的胶质母细胞瘤患者血清中的HMGB1表达量可指示预后。本专利为进一步提高替莫唑胺治疗效果,改善GB患者预后,提供新视角与理论基础。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种HMGB1在胶质母细胞瘤TMZ化疗预后预测中的应用。
背景技术
胶质母细胞瘤(Glioblastoma,GB)是一种具有高度异质性和侵袭性的原发恶性脑肿瘤,近年来,胶质母细胞瘤的发病率呈现逐年增加的趋势,但是针对其有效治疗的手段并没有增加,依然是手术切除后进行放化疗的标准治疗方案,且加入替莫唑胺(Temozolomide,TMZ)的化疗也仅使胶质母细胞瘤患者中位生存时间从12.1个月增加至14.6个月,并没有显著延长患者的生存时间。并且TMZ长期应用易产生耐药性,从而限制其疗效。鉴于GB的高致死性及对传统疗法的相对抵抗,使得寻找更加有效且敏感的治疗靶点提高替莫唑胺的治疗效果,同时深入探究与GB治疗相关的深层机制具有重要意义。
高迁移率族蛋白B1(high mobility group protein 1,HMGB1)结构特殊,是无前导序列蛋白,其出胞依赖于分泌型自噬的激活。HMGB1是一种高度保守的核蛋白,可作为结构性的染色质结合因子弯曲DNA起到维持染色质稳定的作用,越来越多的研究表明,在细胞应激状态下其可被大量分泌至胞外间质作为损伤相关分子模式(Damage-associatedmolecular pattern,DAMP)发挥更为重要的作用,如HMGB1在肿瘤血管生成、侵袭转移以及化疗耐药中发挥关键作用,且越来越多的研究表明其特殊的分泌功能在调节细胞间的相互作用,塑造肿瘤微环境,激活抗肿瘤免疫以及肿瘤微环境与炎症反应的关系中发挥重要作用。在前期研究中发现GB中HMGB1含量丰富,结合HMGB1的特殊生物学特性,合理认为HMGB1在GB中的研究具有重要病理生理学意义。
HMGB1在肿瘤恶性生物学行为中具有两面性,一方面其对于肿瘤具有促进作用,如Zong等人的研究发现肿瘤细胞释放的HMGB1对肿瘤部位的炎症反应以及肿瘤细胞的生长速率具有一定的促进作用,Tang等人的研究发现细胞外HMGB1可结合某些细胞表面受体激活下游信号通路产生功能性的免疫反应,刺激细胞黏附和迁移并促进细胞增殖和血管生成介导恶性生物学行为。另一方面,在大量研究中认为其对于肿瘤具有明显的抑制作用,如Richard A DeMarco等人的研究发现HMGB1可以与IL-1/IL-2家族成员协同促进NK细胞与单核细胞的交互,并且增强DC细胞的成熟,进而增强免疫反应;Georg Gdynia等人发现HMGB1可以通过使胶质瘤细胞内产生巨大的泡状线粒体导致明显的肿瘤细胞杀伤;令人惊喜的是James F.Curtin等人的研究发现HMGB1可以介导内源性的TLR2激活和脑肿瘤的消退抑制其恶性生物学行为。与此同时,HMGB1可以通过激活自然杀伤细胞(NK)、树突状细胞(DC)、巨噬细胞介导免疫原性的细胞死亡,进而增强抗肿瘤免疫反应,增强化疗效果。因此,HMGB1在肿瘤中的生物学功能复杂,作用多样,靶向HMGB1的产生与释放,不仅对炎症性疾病具有重要意义,而且对肿瘤的恶性生物学行为具有直观的调节作用,通过肿瘤细胞死亡而释放的HMGB1可能对肿瘤部位的局部炎症反应和肿瘤细胞生长速率都有调节作用,这个较为新颖的观点可能对肿瘤更为有效的潜在治疗方式具有深远影响。正是因为HMGB1在生理背景与疾病背景中起到诸多作用,与各种生物学进程联系紧密,且在肿瘤中发挥着重要作用,因此揭示其对于肿瘤免疫微环境与肿瘤细胞之间的相互联系具有重要临床意义。
有鉴于此,本专利以胶质瘤为模型,通过TCGA和CGGA数据库分析、免疫组织化学方法、酶联免疫反应等方法,深入探究HMGB1在替莫唑胺治疗中的作用及机制,以及胶质母细胞瘤中HMGB1的表达与其恶性生物学行为之间的相关性,进一步提高替莫唑胺治疗效果,改善GB患者预后,提供新视角与理论基础。
发明内容
本发明的目的之一在于提供一种高迁移率族蛋白B1作为预后标记物在制备用于胶质母细胞瘤TMZ化疗的预后预测的试剂盒中的应用。
为实现上述目的,本发明采用以下技术方案:
高迁移率族蛋白B1作为预后标记物在制备用于胶质母细胞瘤TMZ化疗的预后预测的试剂盒中的应用。
本专利发现HMGB1在胶质母细胞瘤胞外中显著上调,高表达的HMGB1促进了胶质母细胞瘤细胞的替莫唑胺耐药能力。进一步研究发现经过替莫唑胺治疗的胶质母细胞瘤患者血清中的HMGB1表达量可指示预后。
进一步,所述高迁移率族蛋白B1在胶质母细胞瘤胞内低表达。
进一步,所述高迁移率族蛋白B1在胶质母细胞瘤胞外高表达。
进一步,所述胶质母细胞瘤包括原发性胶质母细胞瘤和/或继发性胶质母细胞瘤。
本发明的目的之二在于提供一种检测高迁移率族蛋白B1表达量的试剂在制备用于评估胶质母细胞瘤TMZ化疗疗效的试剂盒中的应用。
为实现上述目的,本发明采用以下技术方案:
检测高迁移率族蛋白B1表达量的试剂在制备用于评估胶质母细胞瘤TMZ化疗疗效的试剂盒中的应用。
进一步,所述检测高迁移率族蛋白B1表达量的试剂为检测高迁移率族蛋白B1mRNA或蛋白表达水平的试剂。
进一步,所述检测高迁移率族蛋白B1表达量的试剂检测胞内和/或胞外的高迁移率族蛋白B1的表达量。
本发明的目的之三在于提供一种促进高迁移率族蛋白B1由胞内释放到胞外的试剂在制备提升胶质母细胞瘤TMZ化疗疗效的药物中的应用。
在替莫唑胺的治疗中,高迁移率族蛋白B1由胞内释放到胞外,提高胶质母细胞瘤TMZ化疗效果,改善胶质母细胞瘤患者预后情况。
本发明的目的之四在于提供一种用于检测高迁移率族蛋白B1表达量的试剂盒。
为实现上述目的,本发明采用以下技术方案:
用于检测胶质母细胞瘤细胞中高迁移率族蛋白B1表达量的试剂盒,所述试剂盒含有用于检测所述高迁移率族蛋白B1的mRNA和/或蛋白表达水平的试剂。
进一步,所述试剂盒用于检测胞内/胞外高迁移率族蛋白B1的表达量。
进一步,所述胶质母细胞瘤细胞为离体细胞样本。
本发明的目的之五在于提供一种采用所述试剂盒检测胶质母细胞瘤细胞中高迁移率族蛋白B1表达量的方法。
为实现上述目的,本发明采用以下技术方案:
采用所述试剂盒检测胶质母细胞瘤细胞中高迁移率族蛋白B1表达量的方法,所述方法为:(1)提取经过TMZ化疗的胶质母细胞瘤患者的血清标本,采用权利要求7所述的试剂盒检测所述血清标本中HMGB1的表达量;或(2)提取经过TMZ化疗的胶质母细胞瘤患者的组织标本,采用权利要求7所述的试剂盒检测所述组织标本中HMGB1的表达量。
本专利采用以下方法探讨高迁移率族蛋白B1在胶质母细胞瘤样本中的高表达对于胶质母细胞瘤化疗抵抗及替莫唑胺治疗的影响:
(1)利用癌症和肿瘤基因图谱(the cancer genome atlas,TCGA)数据库以及中国脑胶质瘤基因图谱(Chinese glioma genome atlas,CGGA)中胶质瘤样本的HMGB1测序数据进行差异表达及生存分析。
(2)采用免疫组织化学(Immunohistochemistry,IHC)方法检测HMGB1在本院生物样本库中收集的4例不同WHO分级胶质瘤样本中的表达。
(3)收集替莫唑胺治疗前后的胶质母细胞瘤组织和血清样本(配对的原发胶质母细胞瘤与替莫唑胺治疗后的复发胶质母细胞瘤)。通过免疫组化染色检测替莫唑胺的治疗对于HMGB1分布的影响,同时检测胶质母细胞瘤病人血清样本中TMZ治疗前后HMGB1表达量的变化。
本发明的有益效果在于:
1.本专利证实了HMGB1在胶质母细胞瘤核内高表达,并与生存预后密切相关,并发现其通过维持基因组稳定性和增强肿瘤细胞侵袭能力发挥促癌作用,该HMGB1核内表达可以作为胶质母细胞瘤诊断治疗的关键靶点,本专利为寻找治疗胶质母细胞瘤更为有效的靶点提供新的理论基础。
2.本专利研究发现GB中的HMGB1mRNA表达量明显增加,且在不同的数据集中都体现出这一趋势,而随着GB中HMGB1的表达量的增加,患者的生存期越短,生存预后越差。本专利在包含低级别胶质瘤的TCGA-LGG/GBM数据集中,研究发现随着肿瘤级别的增加HMGB1mRNA的表达量也不断递增。进而表明,HMGB1可以用于评估胶质母细胞瘤TMZ化疗疗效以及作为预后标记物用于胶质母细胞瘤TMZ化疗的预后预测。
3.本专利研究发现胞核的HMGB1是一个危险因素,但经过替莫唑胺的治疗HMGB1会由胞内释放到胞外,而在血清中HMGB1含量越高患者预后越好,进一步表明分泌至胞外的HMGB1是有利生存的因素,本发明为提高胶质母细胞瘤TMZ化疗效果、改善GB患者预后,提供了新的视角与理论基础。
附图说明
图1为HMGB1在TCGA中表达差异,其中a:P<0.01,与正常组织比较,采用非配对t检验统计分析;
图2为基于HMGB1 TCGA胶质瘤数据的生存分析,其中a:P<0.01,与低表达组比较;设定高低表达组的cut-off值为中位数值,采用Log-rank(Mantel-Cox)检验;
图3为不同级别胶质瘤组织的HMGB1免疫组化染色,标尺:50μm;
图4为HMGB1在TCGA数据库中的表达情况,图4-A为HMGB1在TCGA-GBM数据集、Rembrandt数据集、Gravendeel数据集中的mRNA表达量;图4-B为HMGB1在TCGA-LGG/GBM数据集中不同级别胶质瘤中的表达量;图4-C为HMGB1在TCGA-LGG/GBM数据集中不同组织亚型胶质瘤中的表达量;其中,*P<0.05,**P<0.01,***P<0.001,ns=无统计学差异;
图5为HMGB1在数据库中与临床预后的关系,其中,图5-A为Kaplan Meier生存曲线分析HMGB1表达量高低在TCGA-Kamoun数据集中与临床预后的关系;图5-B为Kaplan Meier生存曲线分析HMGB1表达量高低在CGGA数据库中与临床预后的关系;图5-C为Kaplan Meier生存曲线分析HMGB1表达量高低在CGGA-IDH-MU数据集中与临床预后的关系;图5-D为Kaplan Meier生存曲线分析HMGB1表达量高低在TCGA-IDH-WT数据集中与临床预后的关系;
图6为HMGB1在GB患者临床样本中的表达情况,其中,图6-A为免疫组化检测替莫唑胺治疗前后GB配对样本中HMGB1的代表性图像;图6-B为对A图中的HMGB1表达情况进行免疫组化评分;图6-C为ELISA法检测GB患者替莫唑胺治疗前后血清中HMGB1的含量变化;图6-D为Kaplan Meier生存曲线分析血清中HMGB1表达量高低与GB患者临床预后的关系。
具体实施方式
下面将结合具体的实施例对本发明的技术方案进行更进一步地清楚、完整地描述。显然,所描述的实施例仅仅是本发明的一部分实施例,而不是全部实施例。因此,基于本发明中的实施例,本领域技术人员在没有付出创造性劳动前提下所获得的其他所有实施例都属于本发明的保护范围。
以下实施例中,3例不同级别胶质瘤样本(分别为WHOⅡ、Ⅲ和Ⅳ级)和1例瘤旁脑组织(作为对照)以及本专利中使用41例经过替莫唑胺治疗前后的GB患者的配对临床样本(肿瘤组织与血清样本)均来自于陆军军医大学第一附属医院生物样本库。入选标准:患者为原发且术前未经过放化疗、术后标本经病理组织学检查证实为胶质瘤(含WHOⅡ、Ⅲ、Ⅳ级);排除标准:其他类型的肿瘤。本研究所使用样本均得到患者及其家属同意,且经陆军军医大学第一附属医院伦理委员会批准实施,伦理委员会审批件编号(KY2020294)。
实施例1
生物信息学使用的胶质母细胞瘤基因表达数据来TCGA。使用在线分析网站(http://gliovis.bioinfo.cnio.es/)下载TCGA-Gravendeel、TCGA-Kamoun等数据集的数据进行分析基因差异表达和生存预后。
结果:
(1)HMGB1基因在胶质母细胞瘤中明显上调且与预后相关
HMGB1在TCGA数据集中的表达如图1所示,肿瘤组的表达较正常组显著上调(P<0.01);生存分析显示HMGB1的表达和预后有显著关联,详见图2,高表达组的预后明显差于低表达组(P<0.01)。
(2)TCGA数据库分析表明HMGB1 mRNA在胶质瘤组织中高表达
为明确分泌型自噬蛋白HMGB1的临床病理学意义,本专利首先在TCGA数据库中分析其在GB与正常组织中的表达量变化,结果如图4-A所示,该结果表明与正常组织相比,GB中的HMGB1 mRNA表达量明显增加,且在不同的数据集中都体现出这一趋势。此外,在包含低级别胶质瘤的TCGA-LGG/GBM数据集中,本专利发现随着肿瘤级别的增加HMGB1mRNA的表达量也不断递增,详见图4-B和图4-C。
(3)TCGA与CGGA数据库中HMGB1 mRNA表达量越高,GB患者预后越差
通过分析TCGA与CGGA数据库中HMGB1的表达量与GB患者的生存预后的关系,发现随着GB中HMGB1的表达量的增加,患者的生存期越短,生存预后越差,详见图5。并且在CGGA数据库中不管GB患者的IDH状态如何,这一趋势都不会有所改变。上述分析表明,HMGB1在GB患者的肿瘤细胞中含量越丰富,其预后越差,可以起到临床预后标记物的作用。
实施例2.免疫组织化学(IHC)检测
(1)准备石蜡切片:提前将蜡块放置于-20℃冰箱中冷藏,然后使用切片机每个样本切取15张切片并做好标记,将已经编好号的石蜡切片按照顺序依次放置于装载切片的铁架子上,迅速送入烘箱中烘烤45分钟;
(2)脱蜡:将已经烘烤结束的石蜡切片从烘箱中取出迅速放入装有二甲苯的玻璃缸中,依次进行脱蜡处理,前两个二甲苯缸各脱15分钟,然后依次进入100%酒精、100%酒精、95%酒精、85%酒精、75%酒精缸中各脱5分钟;
(3)抗原修复:将提前配制好的柠檬酸抗原修复液转移至高压锅中加热至沸腾,然后将切片连同铁架一起放进高压锅中浸泡再加热2.5分钟,随后停止加热将高压锅用冷水冲洗并开盖,取出切片放入修复盒中使其自然冷却;
(4)阻断:首先将切片放置于水平摇床上清洗三次,每次5分钟,然后使用阻断液在37℃阻断30分钟;
(5)封闭:将切片用免疫组化笔圈出切片上的组织样本,然后加入即用型山羊封闭血清,37℃封闭30分钟;
(6)孵育一抗:将已经按照稀释比例配置好的抗体工作液依次加入到切片上的圆圈区域,4℃孵育过夜;
(7)孵育二抗:将切片置于37℃孵箱复温30分钟,然后用已配置好的PBS缓冲液清洗切片三次,每次5分钟,再将DAKO二抗滴加到切片上室温1小时;
(8)DAB显色:将已经清洗完毕的切片放置于正置显微镜下,用移液枪吸取100微升的DAB显色液滴加于切片进行显色;
(9)核复染:将显色完毕的切片置于苏木素中进行复染15秒,然后再用盐酸酒精分化5左右;
(10)脱水封片:依次按照75%酒精、85%酒精、95%酒精、100%酒精、100%酒精各5分钟,两个二甲苯各15分钟的顺序脱水,后晾干封片;
(11)扫片:待切片风干以后,使用扫描仪进行切片扫描,并保存实验结果。
结果:免疫组化检测不同级别胶质瘤样本显示,随着胶质瘤级别的增加,HMGB1的表达也增加,与患者的预后显著负相关(P<0.01),具体如图3所示。临床胶质瘤样本结合实施例1中TCGA数据库表明HMGB1在胶质瘤中,尤其是胶质母细胞瘤中有深入研究的意义。
实施例3.酶联免疫反应(ELISA)
(1)收集样本:细胞上清样本收集后使用0.22μm的滤器过滤去除细胞碎片和死细胞,然后转移至新的离心管中备用,如果需要将样品保存较长时间则需要将其转移至-80℃冰箱,新鲜样本也可以直接进行检测;
(2)ELISA试剂盒从-20℃冰箱取出然后置于室温缓慢进行复温,待试剂盒内所有试剂均融化后再使用;
(3)确定好每次实验所需的酶标板的孔板数,将其拆解下来置于新的架子上,并将其余孔板放回密封袋中密封好,保存于4℃;
(4)配置标准品:按试剂盒内说明书加入双蒸水至标准品冻干粉中,用枪头充分吹打后彻底溶解,室温静置后用标准品稀释液倍比梯度稀释;
(5)按照试剂盒内的操作说明将Wash buffer进行稀释,使其充分溶解均匀;
(6)将配置好的不同浓度标准品与样品同时依次加入相应孔板中,随后用封板胶纸封住反应孔板,37℃孵箱避光静置孵育90分钟;
(7)反应完全后甩去孔内液体,洗板4次,每孔洗液体积200μL;
(8)在需要检测的孔板中按照试剂盒说明书的要求加入生物素化抗体工作液,用其自带的封板胶纸封闭相应的反应孔板,37℃孵箱静置孵育60分钟;甩去孔内液体并吸干孔内剩余残液,洗板5次;
(9)在每个装有样品反应液的孔板中加入显色剂,37℃孵箱静置避光孵育30分钟,反应过后每孔分别按相应步骤加入终止稳定液,充分混匀,终止反应;
(10)使用已校准的分光光度仪测量OD 450值,并制作标准曲线,计算样品中相应目的蛋白的浓度。
实施例4.免疫组化染色评分方法
1.IHC score法评分切片染色强度,为保证客观准确分析得到的实验结果,对进行免疫组化染色的切片评分,并计算相对强度值。
(1)评分图片准备:对每个样本扫描完成后的图像进行选取视野,在40倍镜头下随机选取10张图像并保存;
(2)评分细则:切片染色阳性比<10%计0分;切片染色阳性比占11%-50%计1分;切片染色阳性比占51%-75%计2分;切片染色阳性比占>75%计3分;
(3)染色强度分数=阳性细胞比例×相应比例对应的强度。
2.通过计算IOD值法评分切片染色强度
(1)首先用Image-Pro Plus 6.0软件打开需要进行评分的组化图片,第一步xian进行光密度的矫正;
(2)其次通过软件操作选择颜色,然后选择测量参数包括IOD和Area这两个参数;
(3)最后通过圈出待测区域点击计算得到IOD的读数并保存,分析时需要计算每张图像的相对光密度,即每张图像获得的IOD总的数值/图像面积,与此同时每张图像至少获得三个平均光密度值。
实施例5.统计学分析
使用SPSS 22.0软件分析实验中获得的数据,用GraphPad 8.3软件制作实验数据生成的图片。两组样本间比较差异使用Student’s t-test检验,多组样本间差异比较使用ANOVA test方差分析,Kaplan-Meier生存曲线用于评价HMGB1在胶质母细胞瘤中的预后价值。数据表达方式为均数±标准差,其中p<0.05被认为有统计学意义;ns=无统计学差异;*代表p<0.05;**代表p<0.01;***代表P<0.001。
本专利收集了经替莫唑胺治疗前后的41例GB患者的组织标本与血清标本。对这些样本进行免疫组化染色并用ELISA试剂盒检测了患者血清中的HMGB1含量。HMGB1在GB患者临床样本中的表达情况如图6所示。其中,图6-A为免疫组化检测替莫唑胺治疗前后GB配对样本中HMGB1的代表性图像;图6-B为对A图中的HMGB1表达情况进行免疫组化评分;图6-C为ELISA法检测GB患者替莫唑胺治疗前后血清中HMGB1的含量变化;图6-D为Kaplan Meier生存曲线分析血清中HMGB1表达量高低与GB患者临床预后的关系。
图6-A结果显示,HMGB1位于胞核。如图6-A和图6-B所示,替莫唑胺治疗后GB患者组织样本中的HMGB1免疫组化评分明显降低。与此同时,这些患者血清中的HMGB1有明显增加的趋势,详见图6-C。根据血清中的HMGB1表达量的高低进行分组,结果显示血清中HMGB1含量越高其生存期越长,详见图6-D。以上结果表明胞核的HMGB1是一个危险因素,但经过替莫唑胺的治疗HMGB1由胞内释放到了胞外,在血清中含量越高患者预后越好,提示分泌至胞外的HMGB1是有利生存的因素。
Claims (10)
1.高迁移率族蛋白B1作为预后标记物在制备用于胶质母细胞瘤TMZ化疗的预后预测的试剂盒中的应用。
2.根据权利要求1所述的应用,其特征在于,所述高迁移率族蛋白B1在胶质母细胞瘤胞内低表达。
3.根据权利要求1所述的应用,其特征在于,所述高迁移率族蛋白B1在胶质母细胞瘤胞外高表达。
4.根据权利要求1所述的应用,其特征在于,所述胶质母细胞瘤包括原发性胶质母细胞瘤和/或继发性胶质母细胞瘤。
5.检测高迁移率族蛋白B1表达量的试剂在制备用于评估胶质母细胞瘤TMZ化疗疗效的试剂盒中的应用。
6.根据权利要求4所述的应用,其特征在于,所述检测高迁移率族蛋白B1表达量的试剂为检测高迁移率族蛋白B1 mRNA或蛋白表达水平的试剂。
7.根据权利要求4所述的应用,其特征在于,所述检测高迁移率族蛋白B1表达量的试剂检测胞内和/或胞外的高迁移率族蛋白B1的表达量。
8.促进高迁移率族蛋白B1由胞内释放到胞外的试剂在制备提升胶质母细胞瘤TMZ化疗疗效的药物中的应用。
9.用于检测胶质母细胞瘤细胞中高迁移率族蛋白B1表达量的试剂盒,其特征在于,所述试剂盒含有用于检测所述预后标记物高迁移率族蛋白B1的mRNA和/或蛋白表达水平的试剂。
10.采用权利要求9所述的试剂盒检测胶质母细胞瘤细胞中高迁移率族蛋白B1表达量的方法,其特征在于,所述方法为:(1)提取经过TMZ化疗的胶质母细胞瘤患者的血清标本,采用权利要求7所述的试剂盒检测所述血清标本中HMGB1的表达量;或(2)提取经过TMZ化疗的胶质母细胞瘤患者的组织标本,采用权利要求7所述的试剂盒检测所述组织标本中HMGB1的表达量。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211286490.7A CN115469104A (zh) | 2022-10-20 | 2022-10-20 | Hmgb1在胶质母细胞瘤tmz化疗预后预测中的应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211286490.7A CN115469104A (zh) | 2022-10-20 | 2022-10-20 | Hmgb1在胶质母细胞瘤tmz化疗预后预测中的应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115469104A true CN115469104A (zh) | 2022-12-13 |
Family
ID=84337356
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211286490.7A Pending CN115469104A (zh) | 2022-10-20 | 2022-10-20 | Hmgb1在胶质母细胞瘤tmz化疗预后预测中的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115469104A (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116370607A (zh) * | 2023-03-20 | 2023-07-04 | 中国人民解放军陆军军医大学第一附属医院 | 人重组hmgb1在制备治疗胶质瘤化疗增敏剂中的应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108169490A (zh) * | 2017-11-06 | 2018-06-15 | 中国人民解放军第二军医大学第二附属医院 | 一组用于评估胶质母细胞瘤预后的联合蛋白及其应用 |
CN109576366A (zh) * | 2018-11-12 | 2019-04-05 | 哈尔滨医科大学 | lnc-TALC作为分子标志物在评估胶质母细胞瘤TMZ化疗疗效和预后中的用途 |
-
2022
- 2022-10-20 CN CN202211286490.7A patent/CN115469104A/zh active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108169490A (zh) * | 2017-11-06 | 2018-06-15 | 中国人民解放军第二军医大学第二附属医院 | 一组用于评估胶质母细胞瘤预后的联合蛋白及其应用 |
CN109576366A (zh) * | 2018-11-12 | 2019-04-05 | 哈尔滨医科大学 | lnc-TALC作为分子标志物在评估胶质母细胞瘤TMZ化疗疗效和预后中的用途 |
Non-Patent Citations (1)
Title |
---|
ZHUANG LI等: "Autophagy‑based unconventional secretion of HMGB1 in glioblastoma promotes chemosensitivity to temozolomide through macrophage M1‑like polarization", 《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》, vol. 41, no. 74, pages 1 - 20 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116370607A (zh) * | 2023-03-20 | 2023-07-04 | 中国人民解放军陆军军医大学第一附属医院 | 人重组hmgb1在制备治疗胶质瘤化疗增敏剂中的应用 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Huang et al. | Interleukin-8 induces expression of FOXC1 to promote transactivation of CXCR1 and CCL2 in hepatocellular carcinoma cell lines and formation of metastases in mice | |
Suzuki et al. | Relationship between podoplanin-expressing cancer-associated fibroblasts and the immune microenvironment of early lung squamous cell carcinoma | |
Kouri et al. | Positive correlation between high aryl hydrocarbon hydroxylase activity and primary lung cancer as analyzed in cryopreserved lymphocytes | |
CN103502470A (zh) | 嗅介蛋白-4蛋白(olfm4)在结肠直肠癌诊断中的用途 | |
CN103792364A (zh) | 用于检测外周血中循环肿瘤细胞ror1蛋白的试剂及其应用 | |
CN115469104A (zh) | Hmgb1在胶质母细胞瘤tmz化疗预后预测中的应用 | |
CN110836974A (zh) | Flt3lg蛋白在制备肺腺癌术后预后评估试剂或者试剂盒中的应用 | |
CN108273062A (zh) | Foxm1抑制剂在肝内胆管细胞癌治疗中的作用 | |
CN113584173B (zh) | lncRNA SLC25A21-AS1在作为食管鳞癌标志物中的应用 | |
CN109601471B (zh) | 一种评价卷烟烟气对小鼠免疫损伤的动物模型的构建方法及其应用 | |
CN107167604B (zh) | Flot1在作为卵巢癌生物标志物中的应用 | |
CN107144695B (zh) | Arl13b蛋白在癌症诊断中的应用 | |
CN107083428B (zh) | Pak5在癌症诊断预后治疗及药物筛选中的应用 | |
CN115851947A (zh) | Dagla在肝癌诊治中的应用 | |
CN115282282A (zh) | 靶向pdk1调控糖代谢重编程联合二甲双胍在子宫内膜癌合并糖尿病患者治疗的应用 | |
CN114622014A (zh) | Pcp4作为神经母细胞瘤的肿瘤分化标志物的应用 | |
CN112587650A (zh) | 一种短肽及其铜离子螯合物的医药用途 | |
CN109696547B (zh) | 一种判断结直肠癌预后的标志物及其应用 | |
CN101893630B (zh) | 一种检测膜联蛋白a3表达水平的方法 | |
CN113855675A (zh) | 基于胆囊癌标志物的试剂盒及药物 | |
CN107607727A (zh) | H3K23ac在胶质瘤诊断中的应用 | |
CN112946268B (zh) | Hhla2作为预后标记物在制备肝癌预后预测试剂盒中的应用 | |
CN103038362B (zh) | 检测发炎与压力状态的指标、方法及检测组件 | |
CN107022627A (zh) | KPNA2基因的应用和抑制KPNA2基因表达的siRNA的应用 | |
CN117805376B (zh) | CD44和Lgr5作为标记物在筛选胃癌肿瘤干细胞中的应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |